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RF_DIS_13_SUDHA
XVI Internationa}
Cancer Congress
Risk factors of importance *
in the 21st century.
Can they be controlled?
1994
New Delni. India
30 Oct. - 5 Nov 1994
S. TOMINAGA
Aichi Cancer Center Research Institute, Nagoya (J)
SUMMARY
Among
a number of
risk
factors
for cancer
identified
free
previous
epidemiological
and
experimental studies,
tobacco,
diet and oncogenic
viruses have been most important risk factors globally
in the past and will remain the same in the 21st
Century.
Tobacco has been controlled successfully in
some developed countries, but not yet so in some other
countries.
Methods of dietary intervention should be
tailored depending on the dietary conditions in the
country/community. Prevention of infection of oncogenic
viruses is also important. Primary prevention of cancer
is an effective end economical cancer control method.
■
I
:
•
INTRODUCTION
Marked geographical variations and time-trends of
cancer incidence, as well as results of migrant studies
suggest the importance of environmental factors in the
etiology of cancer. Close correlations between specific
cancers and some environmental factors such as dietary
components and tobacco have also provided strong
evidence of being environmental risk factors of cancer
and new opportunities for cancer prevention.
Previous
analytical epidemiological and experimental studies have
revealed several important risk factors for cancers of
specific sites(Table 1).
Attributable risks for major risk factors have been
estimated by Wynder £ Gori11, Doll & Peto!> and several
Copyright 1994 oyMoncvzzi ccttore S.p.A. - Bologna (Italy)
21
XVI International
Cancer Congress
Table 1
1994
New Delhi. India
30 Oct. - 5 Nov. 1994
Risk factors of cancer and major sites of
cancer -to be affected
Risk factors
Tobacco
Major sites of
cancer to be affected
Oro-pharynx, Larynx, Lung,
Esophagus, Stomach, Pancreas
Liver, Ureter, Bladder, Cervix
Diet
Fat/calorie
Dietary fiber
*
Salt
*
Vegetables/frults
Colon, Breast?, Prostate?
Colon
Stomach
stomach and other organs
Infection
HBV/HCV
HPV/HSV-2
EBV
HTLV-1
Parasites
Liver(HCC)
Cervix
Lymphatic system. Nasopharynx
Hematp-lymphatic system(T-cells)
Liver, Bladder
Reproductive factors
Breast
Occupation
Lung, Skin, Bladder
Alcohol
Oro-pharynx, Esophagus
Colo-rectura?, Breast?
Sunlight/Radiation
Skin
Pollution
Lung
Medicine and
medical procedures
Hematopoietic system
Sexual behavior
Cervix
CONTROLLABILITY OF MAJOR RISK FACTORS
XVI International
Cancer Congress
1994
Environmental risk factors are preventable to some
extent if adequate measures are taken and much efforts
are paid.
Controllability of major risk factors for
.cancer may be as follows:
New Delhi. India
30 Oct. - 5 Nov. 1994
Tobacco: in several developed countries such as the USA,
Canada, UK, Scandinavian countries, Denmark, Australia,
Singapore, as the result of major prevention and control
efforts, public health measures directed toward reducing
smoking are succeeding and the prevalence of smokers
have been markedly reduced especially in men, but in
some other countries including Japan tobacco control is
not yet successful and tobacco will still be a major
risk factor of cancer in the 21st Century.
Betel: In some South-East Asian countries betel-chewing
is a common habit and has been a major risk factor for
oral cancer.
Betel chewing can also be controlled by
health education. The screening of oral cancer and its
precancerous lesions is effective for early detection
and provides a good opportunity for health education.
Diet: Excess intake of some food components such as fat,
calorie, and salt and insufficient intake of some other
food components such as dietary fiber, fresh vegetables
and fruits elevate risks of some specific cancers. The
impact of dietary intervention on cancer prevention may
be large as; has been estimated by Wynder & Gori1’ and
Doll & ?eto '. Methods of dietary intervention may vary
from country to country depending on dietary habits and
food processing methods. Chemoprevention has been tried
to supply protective factors.
It is also important to
avoid excess intake of fat/calorie and salt.
However,
it is not easy to change dietary habits and food
processing methods.
Thus, diet will also remain to be
a major risk factor of cancer in the 21st Century.
Industrial products
Food additives
Obesity
Breast
*
Exercise
Colon-sigmoid
Stress
Stomach
*Low risk(=protective)factor
22
other researchers.
They unanimously indicate that
attributable
risks
for
tobacco
and
diet
are
outstandingly high accounting for about 60-70%.
An
attributable risk
for
oncogenic
viruses
may
be
relatively large in populations where liver cancer and
cervical cancer are relatively common.
Attributable
risks for other risk factors are relatively low.
Attributable risks for major risk factors of cancer
today may not change appreciably in the 21st Century and
those for tobacco and diet will still be outstandingly
high.
Infection: Some oncogenic viruses(HBV, HCV, HPVs, HSV-2,
EBV, HTLV-l,etc) are major risk factors for some
specific cancers such as liver cancer and cervical
cancer, Burkitt lymphoma, nasopharyngeal cancer and
adult T-cell leukemia/lymphomafATL)(Table 1).
Some
parasites such as schistosomiasis in the urinary bladder
and liver and clonorchiasis in the bile duct are risk
factors of bladder cancer and cholangiocarcinoma in some
African and Asian countries.
If adequate preventive
measures against those oncogenic viruses and parasites
are taken, they will eventually be controlled.
Reproductive
factors:
Early pregnancy,
full
term
delivery, and lactation are protective factors for
breast cancer.
However, it may be difficult to modify
these reproductive factors for the purpose of primary
prevention of breast cancer.
Dietary intervention
avoiding excess intake of fat/calorie may be a more
practical and effective method.
Occupation: Occupational exposures to aromatic amines,
arsenic,
asbestos,
benzene,
bischloromethyl ether,
cadmium, chromium, ionizing radiation, isopropyl oil,
mustard gas, nickel, polycyclic hydrocarbons(soot, tar.
23
XVI International
Cancer Congress
1994
New Delhi, India
30OCL- 5 Nov. 1994
oil'), ultraviolet light and vinyl chloride are risk
factors for cancers of the bladder, skin, lung, marrow,
prostate, bone, nasal sinus, larynx and liver31.
Some
of
the occupational exposures have
already
been
controlled to an acceptable level largely due to
stringent regulations ,but some other occupational
exposures remain to be controlled.
Alcohol: Excess alcohol consumption is a definite risk
factor for cancers of the oro-pharynx, larynx, esophagus
and a probable risk factor for cancers of the liver,
colo-rectum and breast.
Similar control measures as
in smoking control may be applicable to alcohol control.
However, complete avoidance of alcohol intake may be
unnecessary and moderate drinking may be acceptable as
the attributable risk to alcohol is estimated to be much
smaller than that of smoking31 and some beneficial
effects of moderate drinking on total mortality have
been implicated in a recent study”.
Sunlight: Excess exposure to sunlight is a major risk
factor of skin cancer in whites.
Global efforts are
needed to protect the ozone layer and health education
is needed to avoid unnecessary exposure to sunlight.
Radiation: Exposure to ionizing radiation due to x-ray
tests and inhalation of radon gas is regarded as a risk
■ factor some cancers; leukemia, thyroid cancer, skin
' cancer and lung cancer.
Effects of the Atomic bomb in
i Hiroshima and Nagasaki have been studied extensively for
I the last 50 years and effects of the Chernobyl nuclear
power plant accident have been monitored. As the number
of nuclear power plants has been increased all over the
World," the safety of nuclear power plants will become
more and more important in the future.
Pollution: Ambient air pollution in industrialized
cities and indoor pollution in the kitchen in some
countries such as China and Hong Kong may be associated
with an increased risk of lung cancer, but more studies
are needed to confirm the causal relation.
Medicine and medical procedures: Certain drugs such as
alkylating
agents,
arsenic,
chloromaphazine,
estrogen(unopposed),
immunosuppressive
agents,
phenacetin, etc. are proven to be carcinogenic in
humans51, but the attributable risk may be small.
Sexual behavior: Cancer of the cervix is associated with
early
sexual
activity,
especially
with
multiple
partners. The human papilloma viruses(HPV16,18,33 etc. )
and the herpes simplex virus(HSV-2) are possible cause
of cervix cancer and could be passed between partners
during intercourse.
The attributable risk of those
viruses may be large.
Health and moral education is
needed to prevent infection of those oncogenic viruses.
Industrial products: Some industrial products such as
some specific types of herbicides, hair dyes and some
other chemicals are suspected to be carcinogenic, but
the attributable risk is estimated to be small.*
24
Food additives: Some food additives are carcinogenic
but some others- such as antioxidative agents(BHT,
carotene,
vitamine C,
etc. ) may contribute to a
decreased risk of cancer.
In general, the overall
attributable risk of food additives may be small.
Obesity: Obesity is associated with an increased risk
of breast cancer, especially of postmenopausal breast
cancer and endometrial cancer.
XVI International
Cancer Congress
1994
New Delhi, India
30 Oci - 5 Nov. 1994
Exercise: The risk of colon-sigmoid cancer is reported
to be elevated in sedentary workers.
Thus, physical
activity may be contributing to a decreased risk of
colon cancer possibly through increased bowel movement.
Stress:
Stress is reported to be associated with an
increased risk of stomach cancer.
More studies are
needed to establish the causal relation and to estimate
the attributable risk.
PREVENTABILITY OF CANCER
Although the risk of cancer attributable to
environmental risk factors is estimated to be large; 7090%, it is not necessarily possible to prevent them. all.
Greenwald & Sondik estimated proportions of reduction
of cancer mortality in the USA by year 2000 by
prevention, screening and treatment61.
They estimated
that 8% of cancer could be prevented by dietary control;
fat reduction to 25% of total calories and fiber
increase to 20-30g/day) and another 8(15)% of cancer
could be prevented by smoking control; reduction in
adults
smoking
prevalence
if
achieved
in
year
2000(1990).
All together only 16(23)% of cancer could
be prevented by dietary and smoking control, while Doll
& Peto had estimated that diet and tobacco occupied 65%
of cancer mortality in the USA31.
I also estimated
preventable fraction of cancer by primary prevention in
Japan.
The
optimistic(realistic)
estimate
of
preventable fraction was 8(4)% by smoking control if
smoking rate is reduced to 30(50)% in male adults and
5(10)% in female adults, 12(6)% by improvement of
dietary habits(restriction of salt intake and avoidance
of excess intake of fat, etc.) and 6(3)% by prevention
of HBV/HCV infection.
All together, optimistically
26%(realistically 13%) of cancer may prevented if much
efforts are paid to smoking control, improvement of
dietary habits and prevention of HBV/HCV infection in
Japan.
The preventable fraction of cancer and the methods
of prevention may vary from country to country depending
on the common cancer and their major risk factors in
each county.
REFERENCES
1)
WYNDER,E .L. and GORI,G.B., Contribution of the
environment to caner incidence: An epidemiologic
exercise, J. Natl. Cancer Inst., 58,825-832, 1977.
25
XVI International
Cancer Congress
1994
New Delhi, India
50 Oct. - 5 Nov. 1994
D0LL,R.
2)
and PET0,R., The causes of cancer:
Quantitative estimates of avoidable risks of cancer
in the United States today, J. Natl. Cancer Inst.,
66,1191-1308, 1981.
3)
SHOTTENFELD,D . and HAAS, J.F., Carcinogens in the work
place, CA, 29,144-168, 1979.
4JGRONBAEK,M. et al., Influence of sex, age, body mass
index
and smoking on alcohol intake and mortaliy,
Brit.’Med. J., 308,302-206, 1994.
5)H00VER,R. and FRAUMENI,J.F. Jr, Drug-induced cancer,
Cancer, 47,1071-1080, 1980.
6)GREENWALD,P. and S0MDIK,E.J. (eds), Cancer control
objectives for the nation 1985-2000, In NCI
Monographs, Chap.l, pp3-ll,Bethesda, U.S.DHHS, 1986.
XVI International
Cancer Congress
Problems' in
environmental oncology.
Lessons learnt from the
Chernobyl experience
1994
New Delhi. Inaia
30 Oct. - 5 Nov. 1994
N. NAPALKOV
World Health Organization, Geneva (CH)
The long-tern health effects of the Chernobyl
accident are only now beginning to show.
Much of the
current evidence of health-related long-term after
effects of environmental radiation emanates from the
This work has been
survivors of atomic bomb explosions.
conducted after a delay of almost 50 years.
The
Chernobyl accident has produced a population affected by
an environmental man-made catastrophy,
and exposed to a
different variety of radio-nuclides under very special
conditions, which are not similar to those caused by the
detonation cf a nuclear weapon.
The various health consequences of the Chernobyl
nuclear accident, which happened in April 1935, are still
uncertain in spite of the very intensive study which has
been undertaken during the past eight years.
The lack of
understanding of the nature of the effects from
environmental exposure to ionizing radiation when vast
areas are contaminated,
and the difficulties which arise
in estimating the actual population exposure,
especially
to short-lived isotopes, make the analysis of the
oncological situation and any predictions for its further
development very difficult.
In Hay 1991 the World Health Assembly endorsed the
establishment of the International Programme on the Health
Effects of the Chernobyl Accident (IPHECA), under the auspices
of the World Health Organization,
to study and facilitate
mitigation of the harmful influence of the catastrophy on the
health of the affected population.
IPHECA is a cooperative
effort between the three most affected countries
26
Copyright 1994 by Monduzzi Editors S.p.A. - Bologna (Italy)
-
Belarus,
the
27
The NCIC framework for
cancer control planning
Advisory Committee on Cancer Control
(Chair: Dr. ALA. Fields)
Rational Cancer Institute of Canada
i
SUMMARY
:er Institute of Car.e~= (NCIC) has
iew conceptual framework to assist
cer control activities.
The NCIC
full range of cancer control
activities including fund-raising, public education,
patient services, cancer registries and research.
I
emphasizes partnerships, our mutual dependencies and
our unifying commitment to reducing the burden of
cancer.
The model classifies cancer control activities
into five categories:
1)
Fundamental Research
2)
Intervention Research
3)
Program Delivery
4)
Surveillance and Monitoring
5)
Knowledge Synthesis and Decision-making.
The Canadian Cancer Society (CCS) and the NCIC
have used the Framework to plan conferences and
workshops, to identify critical research gaps and
priorities and to help formulate positions cn
contentious issues.
It helps service delivery
organizations ensure that their programs are soundly
based on scientific evidence and promotes systematic
program development and evaluation. Equally, it helps
research organizations ensure that the limited funds
available for intervention and program delivery
research are directed appropriately and it emphasizes
the dissemination of important new research findings
into the community to benefit the whole population.
Copyright 1994 try Monduzai Editors S.p.A. - Bologna (Italy)
XVI International
Cancer Congress
1994
New Delhi, tncia
30 Oct. - 5 Nov. 1994
XVI International
Cancer Congress
1994
New Delhi, India
30 Oct - 5 Nov. 1994
We believe that the NCIC Framework has wide
aoolicability for any agency concerned with cancer
control and that it can be easily modified to
facilitate planning for other organizations concerned
with health" care, social services or research.
INTRODUCTION
Diminishing resources have intensified the need
for systematic approaches to making decisions and
setting priorities.
The challenge is especially
pertinent to cancer control:
an aging population,
unrelenting increases in incidence rates and a
frustrating stability cf mortality rates are
compounding the problems faced by other parts of the
health care system.
Improved cancer control planning
requires a framework within which to set priorities,
allocate resources and review progress.
' THE NCIC FRAME WORK
The National Cancer Institute of Canada (NCIC) has
idefined cancer control broadly as follows:
Cancer
icontrol is the identification, development, promotion, .
idiffusion and delivery of effective and ethical methods
: of cancer prevention, screening and care services and
i programs for individuals and groups, always with their
active participation. This definition reflects a
: vision of cancer control which encompasses all
;activities that contribute to reducing the burden of
• cancer for the individual and the population.
In developing the Framework we sought to:
(A? use
' a common language applicable to the full range of
i cancer-control activities including programs such as
I fund-raising, volunteerism and advocacy as well as
ibiomedical research and service delivery; (B)
| demonstrate the interrelationships between research,
program delivery and surveillance; (C) promote a
disciplined and systematic approach to synthesising
existing knowledge and identifying the initiatives most
likely to lead co a reduction in the burden of cancer;
and, (D) incorporate societal values such as high
ethical standards, participatory decision-making for
patients, efficiency and public accountability.
Figure 1 shows the major components of the "NCiC
Framework”.
Cancer control activities are displayed
in five broad categories:
"Fundamental Research",
"Intervention Research", "Program Delivery", and
"Surveillance and Monitoring" linked by the fifth
category - Knowledge synthesis and Decision-making.
All activities are governed by the four key principles
- accountability, empowerment, ethics and efficiency.
THE CANCER CONTROL CATEGORIES
148
Activities categorized as Fundamental Research are
designed to expand our knowledge of fundamental
mechanisms that underpin effective cancer-control
urruatejles"
fundamental Research answers the question:
•«hat do we know?" All disciplines upon whose theories
ana research findings successful interventions,
programs and policies can be based are included since
aavances in cancer control may derive from many
disciplines.
Surveillance and Monitoring includes the
collection, review and analysis of data describing the
incidence, prevalence, morbidity, or mortality
attributable to cancer and answers the question:
"Where are we?" These data not only monitor our
current performance they also generate testable
hypotheses for fundamental research, intervention
research and program delivery.
The category of
Intervention Research includes activities which assess
the efficacy and effectiveness of any specific
intervention designed to achieve specified outcomes and
address the question:
"What works?" Interventions
commonly tested are those to be aoolied in diagnostic,
therapeutic, educational, behavioural, sociological,
and policy fields, but the techniques of intervention
research can be applied even more broadly to include
activities such as fund-raising and advocacy, which are
increasingly critical to the cancer-control effort.
Within the NCIC Framework, this category is subdivided
into six stages (Figure 2) .
The first five stages are
based on the model developed by the National Cancer
Institute in the U.S. (1) .
The sixth stage dissemination/adoption studies - recognizes, the ._
importance of research into the ways in which findings
can be integrated into actual practice.
Research on
any oarticular intervention should proceed sequentially
through the six stages.
The cate ger;.' cf Program Delivery is concerned with
the design ano ae_every ot programs to systematica_iy
nrovide effective interventions to large groups or
peculations and addresses the question:
"How should
effective interventions be delivered?" Evaluation is
an intecral component of this activity.
The NCIC Framework identifies six stages for the
development and implementation of programs to assist
orogram planners to develop effective programs using a
logical and orderly sequence which closely parallels
the approach used to develop and disseminate effective
interventions (Figure 2) .
The distinction between Intervention Research and
Program'Delivery in the NCIC Framework is of practical
moortan.ee.
It" recognizes that when an effective
intervention is identified, it is not always necessary
to deliver the intervention through a rormal program.
Howeve’', once it is determined that a formal program is
required, a staged approach to program delivery ensures
its systematic development.
Ficure 2 orovides a matrix which can be used to
locate the stage of development o: any particular
intervention or orogram.
For example, a syntnesis Oi
existing knowledge may lead to a conclusion thav.
screening mammoaraohy for women aged 50-69 is at stage
6 of Intervention Research and stage 4 of Program
Deliverv while screening mammography for women aged 4049 requires further Intervention Research at Stage 3.
XVI International
Cancer Congress
1994
New Delhi. India
30 Od(. - 5 Nov. 1994
149
XVI Internationa!
Cancer Congress
1994
New Delhi, India
30 Oc:. - 5 Nov. 199-1
Knowledge Synthesis and Decision-makinc is at the
hub of the NCIC Framework and orchestrates activity in
all other categories.
The conclusions and
recommendations that result answer the question:
"What's next?" and promote evidence-based decisions to
suooort work in one or more of the other four
categories.
This "filtering" process is critical in
today's economic environment and should be used in an
iterative manner whenever significant new information
becomes available.
KEY PRINCIPLES
A dvocacy
P ublic
Education
P alliation
R ehabilitation
Treatm ent
Diagnosis
P irv e n tio n
STAGES Or
INTERVENTION
RESEARCH
J n is iu jp u n j
150
The NCIC Framework has several distinctive
features.
First, it is designed to be highly
inclusionary, linking the efforts of basic scientists,
behavioural and social researchers, health care
providers, policy makers, administrators, educators,
epidemiologists, cancer registry staff, volunteers,
fundraisers, and others engaged in the cancer control
effort.
Second, it recognizes that the identification and
dissemination of effective interventions as well as the
design and delivery of effective programs should both
------------------------ —-
THE MES
‘
DISTINCTIVE FEATURES
- to reduce the ccrcez cf cancer.
*.hnu. >.»<>;
Around the boundary of the NCIC Framework are four
key principles chat should characterise all cancer
control activities: accountability, empowerment,
ethics, and efficiency (Figure 1).
Accountability is the acceptance of responsibility
for one's own actions, including the need to report,
explain cr justify actions or conduct (2) .
Er.nowerment is the acquisition, by individuals or
groups, cf the capacity to participate fully- in
decision-making processes equitably and fairly, with
the recognition chat such oarticioatcon is, and is seer.
to be, legitimate (2).
Ethics are rules or principles that govern right I
conduct, including nreceots relevant to scienticic—
merit - on the uremise chat scientific merit is a
orerecuisite for ethical research and program delivery
f ~ ’■
Hfficisncv is zhs
co wr.ich bensritis
achieved are causally related co the costs and efforts
extended, i.e., the extent to which unnecessary effort
cr waste is reduced cr eliminated (3) .
.As applied to Fundamental Research, for example,
these principles would help to ensure that
investigators conduct their research efficiently and
ethically, and chat they are held accountable to the
funding agencies and possibly other bodies for me
conduct of their research.
As applied to Program
Deliver-.’, these orincioles would be used to ensure that
the proposed program meets stated ethical standarcs,
empowers persons directly affected by the program., is
undertaken in an efficient manner and is fully
accountable to appropriate authorities and groups.
1. Hypothesis
generation
STAGES Or
PROGRAM
DELIVERY
1. Program
Formulation
2. Methods
2. Pre-testing
development
3. Efficacy
3. Pilot testing
trials
4. Effectiveness
trials (in a
single defined
population)
4. Impiementancn/
evaluation
(tn single denned
population)
5. Implementation
studies (in
multiple defined
populations)
5. Implemenn t*cn/
evaluation (in
multiple defined
populations)
6. Full operation/
6. Dtssemin-
ins ti tutus naliralion
alion/adopiion
Figure 2
• Matrix for Increvention Research and Program Delivery
, ; s-.-= the six stages for each category and selected subject
rheors Which may be explored virhin either category.
151
XVI International
Cancer Congress
1994
New Delhi. India
30 Oct. - 5 Nov. 1994
proceed systematically through six similar but
distinctive stages. The medical research community has
recognized the need for the orderly development of
interventions but has placed little emphasis on
systematic program design and evaluation.
By contrast.
the health care delivery' system including voluntarv
agencies such as the Canadian Cancer Society, have
focused on program design and delivery with less
emphasis on assessing the evidence for the
effectiveness of the interventions delivered by the
program.
The KCIC Framework supports both parties in
strengthening and balancing their cancer control
efforts.
Third, the NCIC Framework recognizes the pivotal
role of Knowledge Synthesis and Decision-making in the
development of any cancer control initiative.
New
significant research findings or surveillance data
should generate a review of "What do we know?" and a
reconsideration of "What's next?".
Review of the
facts, and the perspectives of providers and consumers
will help ensure that our resources are appropriately
directed.
It will help decision-makers delay
widespread implementation of untested programs or
i immature technology and will stimulate research that
i defines and addresses the relevant question at the
i proper stage of the research continuum.
Fourth, the KCIC Framework identifies four
! principles that should underlie all cancer control
• activities. Those responsible for reviewing or
I approving research protocols, program plans or data
collection activities should ensure that each principle
! has been appropriately incorporated into any cancer-
3 .
5th edition,- Philadelphia: W.2. Saunders Company,
1992;9,48c,487,520)
COUCH J2, (ed): Health Care Quality Management for
the 21st Century. Tampa, Florida:
The American
College oz Physician Executives, 1991;69
XVI International
Cancer Congress
1994
New Delhi. India
30 Oct. - 5 Nov. 1994
Cne of the most important benefits of the KCIC
Framework is that it encouraces these responsible for
i priority-setting ano cecision-making incorporate
1 information derived from ail areas of cancer control
i activity into their analysis and to organize their
■ knowledge systematically.
Critical gaps in knowledge
I can be identified and service delivery for priority
: attention. Use of the KCIC Framework, will not provide
| easy solutions to controversial issues, rather, it
disciplines the process of decision-making by ensuring
that evidence from all areas is critically evaluated
prior to embarking on new research, or program
initiatives.
ACKNOWLEDGEMENTS
Funds for support for the cancer control
activities of the National Cancer Institute of Canada
are provided by the Canadian Cancer Society.
REFERENCES
1.
2.
!152
GREENWALD P, CULLEN JW, WEED D:
Cancer Prevention
and Control.
Seminars in Oncology 1990;17:383-90
O'xOOLE M, (ed) :
Miller-Keane Encyclopedia and
Dictionary oz Medicine, Nursing, and Allied Health,
153
XVI International
Cancer Congress
cancers were shown as flat lesions. The common types of mucosal
cancers detected were O-Ilb type and Q-IIc type of lesions. 0-1 type
and O-III type of lesions were mostly submucosal cancer even
‘New Delhi, India
when small.- Particularly, the; O-IIb (flat) type of lesion was more
30 Oct.-5 Nov. 1994
common in epithelial cancer and it was detected more easily by
endoscopic staining with Lugol's solution than by the gross
appearance. With Lugol's solution the normal epithelium of the
esophagus stains dark brown while mucosa with pathoHgic
changes remains unstained. Endoscopic staining with Lugol's
solution was effective not only for screening examination of
mucosal cancer, but also for confirming the exact extent of
mucosal cancer. Malignancy in the basal layer of the epithelium or
dysplasia was also.demonstrated as an unstained area.
?
As for symptoms in patients of Tt cancer of the esophagus, a
tingling sensation in the esophagus caused by food and a feeling of
stenosis were the most common -symptoms, followed by
retrosternal pain. However, no symptoms were seen in 47% of
patients. The diagnosis of esophageal cancer was occasionally
made in the periodic checking.
When a lesion suspected to be mucosal cancer was less than
2cm x 2cm in size and the absence of lymph node metastasis was
i proved, endoscopic mucosal resection was indicated. Endoscopic
r~ mucosal resection was performed in 41 cases. Histologically these
consisted of mucosal cancer in 30, submucosal cancer 4, dysplasia
5 and 2 unknown. As postoperative complications, a small fissure
- was seen in one case and stenosis-m two cases and bleeding in
. three cases. But these were cured conservatively. The longest
period of follow-up in cases of endoscopic resection was 4 years
and 9 month, and no recurrence has been observed in any case.
In summary;
Endoscopic examination and the endoscopic staining with
Lugol's solution was the most advisable method in diagnosis of
early and minute cancer of the esophagus. As for the minimally
invasive surgery of the esophageal cancer, endoscopic mucosal
.resection was common for lesions suspected to be mucosal cancer
less than 2cm x 2cm in size, with nd nodal involvement. The
procedures-and the clinical results oT endoscopic mucosal resection
of the esophagus are presented.
1994
XVI International
Cancer Congress
primary prevention
of cancer in
! developing countries
1994
30 O:
199-
. Institute of Preventive Oncoloty Tokyo . (J)
| SUMMARY
Methods for cancer orevention in develop!
be inexpensive, practical and effective. Tot nc countries should I
Tobacco
control and
nutrition improvement, in particular frequent
i
)
green-yellow vegetables (GYV), fit quite well consumption of
Tobacco use, either by chewing or smoking, is tc the criteria.
;
leading risk factor’for cancer, while risks isf~undoubtedly the'
;
consumers of GYV rich in betarcarotene and . for cancer in. daily
... __n vacc
vitamine C have been
shown to be one halt or less. Hf^otitis
vaccination
programmes
have already started in selectedHepatitis
countriesB in
A
J
____
... Africa and Asia.
Until vaccination for other cancers
become also
’ cancers
become
stated .life style modification
must be
ti also available, above
gies for cancer prevention
•
. the most effective stratein developing countries.
INTRODUCTION
, +hIt wa$
PPr°ximately 7.62 million new cancer cases
*
n the world in 198u fair y evenly shared between the developed
and developing countries. (Parkin et al, 1993){1). Therefore in
any worldwide cancer control program problems in developing
countries should never be neglected in considering priority in
cancer control programmes
Primary prevention isB0? particular
importance in case of developing countries in view of limited
resources available tor early detection and diagnosis of cancer,
not to speak of treatment. Strategies for cancer primary preven- .
tion should thererore be considered carefully selecting plans
which are effective and Still can be carri-ed out w1-th low cost.
|
138
Copyright 1994 py Monduzzi Editor® S.p.A - Bologna p, j-
139
XVI International
Cancer Congress
MATERIALSAND METHODS
1994
New Delhi. India
30 Oct-5 Nov. 1994
• Considerations were given using results of numerous epidemi
ological studies on cancer in developing countries in the litera
ture.and also following monographs.
1. Cancer Incidence in Five Continents Vol. 1-6, UICC/IARC,
1956-1982.
2. Life-styles and Mortality, T. Hirayama, Karger, 1990.
FEATURES OF CANCER LN DEVELOPING COUNTRIES
Although principles of strategies for primary prevention of
cancer should basically be same in both developed and developing
countries, cancer patterns characteristic in developing countries
must carefully be taken into consideration. Number one consider
ation should be focussed on the type of cancer particularly pre
vailing in developing countries. In sharp contrast to developed
countries where cancers closely related to affluence in diet and
other life-styles prevail, major cancers in high incidence in
developing countries are more or less closely related to poverty,
malnutrition and lower levels of cleanliness, e.g. cancers of
esophagus, stomach and cervix. Tobacco related cancers prevail
both in developed and Developing countries. In developed coun
tries, tobacco is used almost exclusively ir. the form of ciga
rette smoking. However somewhat different types of tobacco use
also exist in developing countries such as tobacco chewing and/or
bidi smoking as in India. Another feature of cancer in develop
ing countries is the high prevalence of virus-related cancers,
-e.g. liver cancer
HCV), Burkitts lymphoma, nasopharyngeal
cancer (EBV), cervical cancer, penile cancer (HPV), Kapposi
sarcoma (HIV). Therefore special measures against such virus
infection, e.g. vaccination, must seriously be considered in
cancer control plan in developing countries.
CANCER PREVENTION PLAN IN DEVELOPING COUNTRIES
As in developed countries cancer prevention plan should
carefully be made under following headings ;
■.
Researchers plan ; (prevention strategies planned by basic
.
researchers and by epidemiologists)
Communityy plan
(prevention-which is-beyond indiviouals
reach)
■
Individual plan ; (behavior change, life-style modification
■
eic-)
'
-' ■
Tobacco control 'anti hutr-it-ion improvement, in particular
frequent consumption of, Green-Yel low Vegetables (GYV), fit quite
well to the above mentioned criteria.
First, the evidence for the effectiveness and practicability
of .such combined strategy of tobacco control and nutrition im
provement has been clearly shown by numerous epidemiological
studies. Second, underlying basic .me,chanism explaining the
effectiveness of such strategy has bee.t already known, it has
been shown that tobacco chewing and smoking results in continuous
production of oxygen radicals while beta-carotene and vitamine C
rich.in GYV are believed tojsuppress such, action of oxygen
radicals as scavengers assisting SOD (superoxide dismutase) and
other anti-oxidative enzymes).
"-‘-wC?
XVI International
Cancer Congress
1994
New Delhi. India
30 Oct. - 5 Nov. 1994
TOBACCO CONTROL
Tobacco use, eitner by-chewing or smoking, is undoubtedly
the leading risk factor for cancers of mouth, pharynx, esopnagus,
.stomach, liver, pancreas, lung, urinary bladder, cervix of uteri
etc. Numerous case-control studies, and cohort studies conducted
in Asia clearly Demonstrated tobacco use is the primary risk
determinant of center cf many sites which prevail in each Asian
country. For instance, tobacco chewing was identified as the
leading-risk factor cf cancerj of mouth and pharynx by series of
.case-control studies conducted in South East Asia (2'
' 1laroe---stale census-popuiation based prospective cohort std
in which 255,11c subjects age;40 and above residing in 6 prefec
tures representing .w.-.ole country were followed up for 17 years,
clearly showed cigarette smoking-is by far the most important
risk factor of cancer cf most sites as listed above (2). Lung
cancer risk was observed to be doubled by 2 cigarettes a day in
line with other 8 ccr-rt studies in the world (4). Risks tended
to be higher the hi oner the dose and the' longer the duration ot
smoking. ^Prevent!or. cf start of habit of tobacco use must be the
best approach, "foil twee by cessation of tobacco use. Cancer risk
was observed to approach to the level of.jion users with the lapse
of-years after cessation of the habit.
The discovery or lung-canter risk elevation by passive
smoking by our,large stale cohort study (5) must be of particular
importance in develooir.g?countiies as the exposure to sidestream
smoke is considered to oe muchihigher since people live in small
congested rooms. Numerous studies confirmed our observation of
lung cancer risk.elevation by household exposure to passive
smoking'. iRisks were a4Q hjgh.for nasal cancer, brain tumor and
breast cancer (6). At any event the problem of passive smoking
appear even"more-serious in developing countries.
■;
NUTRITION IMPROVEMENT
140
Methods for cancer prevention in developing countries should
be inexpensive, practical and effective. The method, first of
all, should be not only effective in reducing cancer risk but
also must be practical and cost effectiveness should be high.
The method should be preferably effective for prevention of
cancer of multiple sites, killing many birds by one stone. One
may even doubt the possibility of the existence of such methods
for primary prevention of cancer. Thanks to series of intensive
basic and epidemiological research on cancer in man, such effec
tive prevention methods which can easily be carried out in
developing countries with surprisingly low cost are now
available.
Risks for cancer ot most s^tes were observed to be much
lower in daily consumers of GYV compared with non daily consumers
(Hirayama, 1979)(7). Compared with non daily GYV consumers,
risks for cancer ot diiterent sites were observed much lower in
GYV
tho; e smoking cigarettes daily,
rvu daily consumers even *for thype
daily.
drinking alcohol daily and consuming meat daily (Fio. 1)(3).
Such risk difference by UTV conslbmption was noted to become
larger when compared by the amoui(it of beta-carotene included in
each GYV. When compared by the iSerum level of beta-carotene,
largest risk difference was obseitved (Harris et al, 1991)(8).
141
FIG.
142
Thus risks for cancer of many sites ir. those consuming GY'.1
I frequently ano in particular with higher serum level of beta; carotene have been shown by many cohort studies to be one half
or even one fifth compared with lower serum level individuals.
A cohort study is in progress in Yakumo town in Hokkaido
in which serum level of beta-carotene was measured for 2-,356 in
habitants and these subjects are under follow-up according to
the initial serum level of beta-carotene. After 5 years, multi
factor adjusted cancer mortality ratio for individuals with low,
medium and high titer of serum beta-carotene was 1.00, 0.41 and
0.21 (Sasaki et al, 1992)(9). In other words, cancer risk is
about one fifth in subjects with high beta-carotene titer (31.9pg
/dl-) compared with low titer subjects (-14.2yg/dl).
intensive public education should therefore be focussed on
cessation of tobacco use and on daily consumption of GYV with
slogans such as ’carotene instead of nicotine1, ’prevent cancer
by one carrot a day’. Public education should be easy to under
stand, and easy to practice. Message based on convincing sci
entific evidence should be given with confidence in most persua
sive way. Above shown slogans are made for such purpose and have
been proved to be quite effective in changing public behavior
(10) e.g. GYV per capita consumption doubled since 1960 in Japan.
Increased consumption of vegetables in general and fruits
are also recommended. Out of 156 epidemiological studies con
ducted to examine effect of increased consumption of vegetables
and fruits on the risk of cancer of many sites, 128 (822) showed
significantly lowered risk in frequent consumers as shown in
rig. 2 (modified from the report of Block et al, 1992)(U).
2
RISK FACTORS AND PROGNOSTIC FACTORS
As a by-product or our large scale cohort study in Japan it
was revealed that selected risk factors which govern onset of
cancer also operate to modify prognosis of cancer as wel < (12).
Daily smokers of cigarettes showed significantly worse pro
gnosis of lung cancer thaninonsmokers, risk of eying (age, sex,
other life-style adjusted) within one year after diasnosis being
1.89 (1.37-2.60). Daily alcohol drinkers exhibited significant
ly worse prognosis of esophageal cancer than non daily drinkers,
risk of dying within one year after diagnosis being 1.82 (1.212.75). Daily meat consumers showed significantly worse prog
nosis of breast cancer than non daily consumers, risk or dying
within 6 months after diagnosis being 5.86 (2.35-14.61).
Thus if we are successfully control such life-style risk
factors we can expect rar better clinical course than otherwise
even in case the disease does occur. This particular point must
also be a blessing news to the people in developing countries.
VACCINATION
Vaccination has also potentials for primary prevention
since selected chronic virus infections have been shown to pro
mote risks for cancer of li|er (hepatitis B and C virus), cervix
(numan papilloma virus}, nasopharynx and gur^tts tumor (EB
143
XVI international
virus), Kaposi sarcoma (HIV) etc. Amc
*g
these, vaccination progrartmes against Hepatitis 8 virus infection have already been
started by the initiative of MHO (IARC) in selected countries in
Africa and Asia (1).
Until vaccination programmes for other cancers become also
available, above stated life style modification must be the most
effective strategies for cancer prevention and control in
developing countries.
CancQj; Congress
1994
New Delhi, India
30 Oct. - 5 Nov. 1994
cancer prevention- a review of the epidemiological
*
evidence. Nutrition»nd Cancer 18(l):l-29, 1992.
(12) HIRAYAMA T ■ Risk facators and prognostic -actors for
cancer of selected sites. Jpn. Prev. Nephrol. Urol. 2(2),
1994, in press.
XVI International
Cancer Congress
1994
New Delhi. India
30 Oct. • 5 Nov. 1994
CONCLUSIONS
Innovative weapons to prevent and even to eradicate cancer
might become available sometimes in the next century using
rapidly developing molecular biology. However, at least in our
generation, cancer prevention must rely heavily on conventional
weapon called life-style modification especially in developing
countries, where effectiveness of such methods is believed to be
high and, above all, practical. Put thee, into practice now.
Try to prevent millions of people in developing countries from
becoming cancer victims making full use of conventional but still
surprisingly effective weapons named life-style modification
j witr. slogan such as 'Carotene instead O’ nicotine'.
Ij
REFERENCES
IARC Biennial Report 1992-1993, pp.t-5, pp.143-144, IARC,
Lyon,_1993—----- ----------------------------------------------------------(2) HIRAYAMA T.: An epidemiological study of oral and pharyngeal
cancer in central and south-east Asia. Bulletin of WHO 34
41-49, 1956.
(3) HIRAYAMA T.: Life-Style and Mortality. Contributions to
epidemiology and Biostatistics Vol. 5 (Wahrendorf J. ed.),
Karger, Basel, 1990.
(4) HIRAYAMA T.: A high risk of lung cancer among light smokers
-a large scale cohort study-, Proc. Jon. Cancer Associ. 52:
681, 1993.
(5) HIRAYAMA T.: Non-smoking wives of heavy smokers have a
higher risk of lung cancer; a study from Japan. Brit. Med.
J. 282:183-185, 1981.
(6) HIRAYAMA T.: Lung cancer and other diseases related to
passive smoking; a large-scale cohort study, in: Control
of Tobacco-Related Cancers and Other Diseases (Gupta P.C.,
Hamner III J.E., Murti P.R., eds.), Proc. Int. Sympo. 1990
(Tata Inst. Fundamental Research), Oxford Univ. Press,
Bombay, pp.129-137, 1992.
(7) HIRAYAMA T.: Diet and cancer. Nutrition and Cancer 1(3):
67-81, 1929.
(8) HARRIS R.W.C., KEY T.J.A., SILCOCKS P.B., BULL D., WALD
N.J. : A case-control study of dietary carotene in men with
lung cancer and in men with other epithelial cancer.
Nutrition and Cancer 15(1):63-68,■ 1991.
(9) SASAKI R., ITO Y., SUZUKI $., AOKI K.: A cohort study on
serum beta-caroten and cancer death in Japan, -an interm
report-. Proc. Jpn. Cancer Associ. 51:445, 1992.
(10) HIRAYAMA T.: Life-style and cancer: from epidemiological
evidence to public behavior change to mortality reduction
of target cancers. J. Natl. Cancer Inst. Monogr. 12:65-74,
1992.
(11) BLOCK G., PATTERSON B., SUBAR A.: Fruits, vegetables, and
(1)
144
145
EPIDEMIOLOGICAL OBSERVATIONS
OF HEAD AND NECK CANCER
D. N. Rao1 and B. Ganesh3
In this chapter, the main emphasis is to bring out the salient epidemiological observations
on head and neck cancer in the Indian subcontinent. In addition, efforts are also made to bring
out the changes In site-specific incidence rates and identify high risk groups in head and neck
cancer. Associated dietary factors, occupational hazards and experimental evidences are also discussed
in detail.
Based on the International Classification of Disease (ICD 9th Revision)1 the sites in the oral
cavity (ICD:140-145), pharynx (ICD:146-148), larynx (ICD:161) and paranasal sinus (ICD:160)
together constitute the head and neck region. The oral cants' includes the upper and lower lip,
anterior two thirds of the tongue, salivary' glands, gum (upper and lower), floor of the mouth,
buccal mucosa including the trigone region and the hard palate. Paymaster (1965) reported that
cancer in the base of the tongue should be separated from that of the oral tongue and be
considered as part of the oropharynx along with the soft palate and tonsil. The current international
coding system has vet to recognise this fact and the site continues to be included in the oral
easily.
Descriptive epidemiology
1. Historical Review
Cancer as a disease is well known in India since vcdic times. Scripts written in Devanagri
dialect give a fair description of the disease entity, its surgical management and transplant
techniques/ Even in the beginning of this century, the problem of cancer in India and the need
to have data was voiced in the House of Commons in London. A survey of 15 missionary and
34 Government hospitals in Travancore indicated that oral cancer accounted for 38% of all
cancers/ From a study of autopsy data and pathology' records covering many centres all over
India, Vishwanath and Grewal reported that a high frequency of buccal cancer was seen in the
6,7
Indian population. ’
‘Head :Biostadstician, Division of Epidemiology
*
St Biostatistics, Tata Memorial Hospital, Bombay 400 012, India.
1
The cancer pattern in the Indian subcontinent until the 1960s was evaluated mainly by the
use of hospital records and pathological reports. Head and neck cancer accounted for about 50%
of all cancer at the Tata Memorial Hospital (TMH). Similar observations were also present in
the data obtained from general and cancer hospitals in the country. During the 1970s, cancer
statistics from general and teaching hospitals in India’ showed striking variations in the relative
frequency of certain anatomical sites in the head and neck (Fig.l).
HL BH AT BT P -
Hypopharynx and Larynx
Buccal Mucosa
Anterior Tongue
Base Tongue
Palate
1.
Fig. 1. Relative frequency of hear! and neck cancer in cancer and
general hospitals in India.
Data from South India (Cancer Institute, Madras and Kasturba Medical Hospital, Manipal),
showed a higher percentage of buccal cancer and anterior tongue cancer. Base tongue cancer was
common in Western India (TMH, Bombay (22%) and in Gujarat Cancer Hospital, Gujarat
(27%)), compared with other hospitals in the country. This survey also brought out certain
observations such as the high percentage of lip cancer (20%) in Bihar in Northern India, hard
palate cancer i 37% 1 from the coastal districts of Andhra Pradesh in Eastern India and
hypopharyngeal cancer (38%) in Assam in the North East of the country'.
Nasopharyngeal cancer is rare in the Indian population. Paymaster (1965)’ indicated that,
unlike other cancers in the head and neck, nasopharvngeal cancer showed a double peak in the
age pyramid < Fig.2:: one in the age group 15-24 years, and the other in the age group 45-54
years. Interestingly an analysis of 560 histologically confirmed cases showed that, in both sexes.
only the poorly differentiated type showed the younger age peak, while in well differentiated
^fcamous carcinoma the peak appeared in the older age group.'
Fhj.2. Carcinoma of the nasopharynx. Tata Memorial Hospital
(1941-1974).
Incidence-The
AGE STANDARDISED RATES — PHARYNGEAL CANCER
SCCnC
The computed age-standardised rates for three major groups in head and neck cancer; oral
cavity (ICD'140'^)’ pharVnx (ICD:146-149) and larynx (ICD:161), in metropolitan registries
in India along "ith I^1C rates *n sclected countries/populations._are shown in Figs. 3, 4 and 5
respectively The age standardised incidence rates for oral, pharyngeal and laryngeal cancers are
high in both males and females in all metropolitan registries in India. '
e ■
The onlv rural cancer registry in India is in Barshi, a town in Sholapur District of the State
of Maharashtra. The rural registry covers 134 villages with a population of 1.85.296 people. The
age-adjusted incidence rates in males and females were 57.6 and 52.2 per 100.000 for all sites
respectively and these rates were lower than the rates in urban registries. Since 80% of the Indian
population lives in rural areas, the rates in Barshi may have to be considered in assessing the true
.
is
picture of cancer in India.
Age-standardised rates according to fourth digit of ICD-9 for oral, pharyngeal and laryngeal
cancer seen in six metropolitan registries in India for males and females are shown in Table 1. In
general, the oral tongue, alveolus and mouth are the major sites affected in the oral cavity. The
■ IARC <19SZ) VOL V
• NCRP (1992)
Fig. 3. Age standardised ratesfor
pharyngeal cancer. ■
AGE STANDARDISED RATES — LARYNGEAL CANCER
AGE STANDARDISED RATES — ORAL CANCER
males
MALES
17.8
females
BRAZIL,SAO PAULO ( 1978)
7] 4.3
12.6
FRANCE. BAS-RHIN
FRANCE, CALVADOS
PHILIPPINES, RHIZAL
17.7
CANADA, NEWFOUNDLAND
6.6 fc
3.1 £
1.6 I
1.9 |
10.1
6.6
10-7
12.7
8.7^
Fig. 4. Age standardised ratesfor
oral cancer.
4
5.5g
FINLAND
1.5
0.6
FINLAND
0.3
1.5
4.2 V
U.K ENGLAND. OXFORD
0.3
2.2
3.1 |
JAPAN. MIYAGI
0.2
CHINA. SHANGHAI
0.5
1.4
INDIA. BOMBAY
7.3
INDIA, BANGLORE
15.7
S11-9
W] 11.4
INDIA, BARSHI
*
0.7
4.5 v
1.1
INDIA, NAGPUR
SINGAPORE
1.3
0.6
INDIA. PUNE
0.5
0.5
1.5
_] 6.1
JAPAN, MIYAGI
INDIA, MADRAS
1.7
FRANCE. BAS-RHIN
PHILIPPINES, RHIZAL
3.5J
6.1 E CANADA. NEWFOUNDLAND
U.K. ENGLAND, OXFORD
CHINA. SHANGHAI
1.3
US. CONNECTICUT. WHITE
12.4
6.6 fe
7.9 |gy US. CONNECTICUT, WHITE J 2.9
18 8 Igjgig
A
FEMALES
BRAZIL.SAO PAULO ( 1978)
8.8 |.; J.
INDIA. BOMBAY
1.3
4.1 £
INDIA, BANGLORE
0.7
INDIA. MADRAS
0.3
INDIA. PUNE
1.4
INDIA, NAGPUR
2.3
5.5 ty
12.9 |?.T ?
§5)9
1.3
INDIA. BARSHI’
0.6
Fig. 5-Agcstanda
rdised rates for
laryngeal canccr
• IARC (1937) VOL. V
NCRP (1932}
hypopharynx is a major site for pharyngeal cancer in both males and Females respectively.'-The
rates for males are higher compared to females at all sites in the head and neck except in the
Bangalore registry where the rates for buccal mucosa cancer in females are higher than those in
males. In particular, high rates in males are observed in Madras for mouth cancer, in Bombay,
Nagpur and Poona for cancer of the anterior two thirds of the tongue, and in Bombay and
Ahmedabad for cancer of hypopharynx and base of die tongue.
Nasopharyngeal cancer is a rare disease among Caucasians but is one of the more common
tumours occurring in individuals in the south-eastern region of China, among migrants from that
geographical area and their descendants. The highest incidence reported is from Hong Kong
where the annual incidence of nasopharyngeal cancer is 30 and 12.9 per 100,000 among males
and females respectively. In India the age-standardised rates range from 0.23 in Ahmedabad to
0.9 in Bangalore for males whereas for females the rates vary from 0.08 per 100,000 in Ahmedabad
to 0.3 per 100,000 in Bombay, Nagpur and Madras. Data from the TMH cancer registry' shows
that although this cancer forms less than 1% of all cancers, the distribution according to place of
residence indicates that the frequency of nasopharyngeal cancer is high in patients from the
North Eastern region (Table 2). As there is no population based registry' in that region, the high
incidence of this cancer is not yet confirmed.
Incidence - Worldwide
Lip cancer is uncommon in males and very rare in females. Cancer of the lip is very rare in
Asia. Incidence is high in South Australia and New Foundland (Canada). The incidence is low
among U. S blacks. Generally, the incidence of lip cancer is decreasing worldwide.
Tongue cancer incidence is high among Indians and also among males in France and
Switzerland. The sex ratio is of the order of 3 in India, 8 in Geneva (Switzerland) and 13 in BasRhin (France). The risk of cancer of the tongue among males is reported to be increasing in
several populations in the U.S.A.
The incidence rate of cancer of the mouth (gum, floor of mouth, mucosa of the cheek,
hard and soft pans of the palate and uvula) has more than doubled in a short period of 15 years
in Miyagi and Osaka prefectures in Japan.1’
The incidence rate and number of new cases of 18 different cancers have been estimated for
the year 1985 in 24 areas of the world.1 About 7.6 million (excluding non melanoma skin
cancer) persons in the world developed cancer. The majority of them, about 52%, were estimated
to be in the developing countries. Cancer of the mouth and pharynx was third in order among
males (about 1,87,000 new cases) and fourth in order among females-./about 1,14,000 new
cases) in the developing countries. Among 8,06,900 estimated total cancer cases in Southern Asia
(India, Pakistan, Iran and Bangladesh) in 1985, cancer of mouth and pharynx accounted for
1,42,900 persons (17.7%) and laryngeal cancer 31,200 (3.9%).
Table 1
Age Standardised Incidence Rates per 10s for head and neck
cancers in major metropolitan cities in India
*
Males
Nagpur Poona
(ICD-9)
Bombay
Bangalore
Madras
Ahmedabad#
1140-145 i
(140)
(141.1-91
(143)
1144)
■145.01.6
0.3
3.3
1.8
0.7
2.7
0.3
1.8
1.0
0.7
1.9
0.3
2.3
0.6
0.3
D.D
0.16
10.56+
0.87
0.61
3:98++
03
3.2
2.2
0.3
1.8
0.9
375
3.2
0.1
3./
1410
; 145.3-5 >
(146)
(147)
(148)
(149)
(161)
(140-208)
6.1
1.2
3.5
0.8
9.9
3.4
10.0
145.0
3.2
0.6
2.4
0.9
5.4
0.4
5.0
103.2
2.0
-r
2.4
0.7
4.2
0.6
5.3
92.1
3.89
0.23
8.54
1.61
7.01
110.19
5.1
0.7
4.5
0.3
6.5
1.1
11.8
122.5
1 4
0.9
2.0
0.6
4.7
1.1
12.9
134.1
(ICD-9)
Bombay
Bangalore
Madras
Ahmedabad
(140-145)
(140)
(141.1-9)
(143)
(144)
145.01.6)
0.2
2.1
1.2
0.2
2.9
0.1
0.5
2.8
0.4
10.9
0.3
1.6
1.4
0.1
7.9
0.15
2.1 +
0.71
0.03
1.65++
0.2
1.1
1.9
0.1
1.8
0.5
—
1.9
0.1
—
Pharvnx
Base Tongue
^Palate
^^Dropharvnx
Nasopharynx
Hvpopharvnx
Pharynx NOS
(1410)
: 145.3-5)
1146)
(147)
(148)
(149)
1.3
0.5
0.8
0.3
2.2
1.3
0.7
0.3
0.5
0.1
1.4
0.3
0.5
0.7
0.9
0.3
1.2
0.1
+
0.42
0.08
2.04
0.23
. 1.0
0.2
0.7
0.3
1.0
0.1
—
—
0.4
0.2
1.5
0.4
Larvnx
All Sites
(161)
(140-208)
2.0
126.0
1.5
139.7
0.7
120.6
0.51
81.79
2.3
108.7
1.4
146.2
Site
Oral Cavity
Lip
Tongue
Gum
Floor Mouth
Other Mouth
Pharvnx
Base Tongue
^folate
^Tlropharvnx
Nasopharynx
Hvpopharvnx
Pharynx NOS
Larvnx
All Sites
1.4
Females
Site
Oral Cavity
Lip
Tongue
Gum
Floor Mouth
Other Mouth
* IARC (19S7),:
# Patel et al. (1991)'6
-
Nagpur Poona
+ includes Ant. tongue
++ includes Other mouth
In Southern Asia, over 5,76,200 persons were estimated to have died due to cancer in
1985. Among all cancers 65,300 males and 40,400 females were estimated to have died due to
cancer of the mouth and pharynx. The high incidence and mortality' rate due to this cancer in this
region have been attributed to tobacco chewing and smoking.
7
EDITORIAL
CHALLENGES AND REALITIES FOR THE COMING
DECADES
Dr. P. B. Desai
Introduction — Epidemiology and prevention — Prophylaxis and early diagnosis —■
Fundamental and applied research in head and neck cancer — The concept of organ
preservation in head and neck cancer — Combined treatment modalities — Predicting
treatment responses (predictive oncology) — Rehabilitation and terminal care — Where do
we go from here?
Introduction:
Despite our current technical capabilities in research and treatment
methodologies, cancer of the head and neck continues to present major challenges to all the
major oncologic disciplines worldwide. As we approach the turn of the century, the morbidity
and mortality due to this highly preventable cancer has not shown a downward trend: this,
despite head and neck cancer being a classic module for research, prevention, prediction and
effective treatment. Collated efforts towards the control and cure of head and neck cancer
worldwide and especiair in the region where it is a common disease arc not only worthwhile but
need to be intensified in a pragmatic manner. There is now enough and more knowledge about
the disease not oniy to prevent but to predict, to ensure prophylaxis, to diagnose early and treat
effectively often ensuring organ and function preservation. This knowledge has accrued by the
combined efforts of many workers in different oncology disciplines dealing with head and neck
cancers. We now have to develop an effective methodology, within institutes and beyond to
enable us to reach out to the community for the control and cure of head and neck cancer.
Epidemiology and Prevention: Exhaustive reviews and studies appear in this volume with
special reference to South .Asia where head and neck cancer forms nearly 27% of total cancers.1
This contrasts with about 5% incidence in the western world. That tobacco usage in different
forms is a major contributing cause is a well established fact and no further debate need be
encouraged on this issue. Tobacco usage in South Asia differs greatly from the usual smoking
habit in the west. Chewing tobacco with multiple other ingredients (betel nut, betel leaf, lime,
catechu, etc.; is a major cause of buccal mucosa and gingival cancers. The quid bolus with
* Director, Tara Atcmona' Centre, Bombay-400 012. India.
LX
tobacco leaves is kept-for hours on end in the buccal mucosa or the gingivo-buccal sulcus and a
cancer developing on the exact site has a direct cause and effect relationship. The left buccal
mucosa will be spared if the bolus is kept on the right side (and vice versa), and for good reasons
it is referred to as the Indian buccal mucosa cancer where the habit of tobacco chewing is most
prevalent. The rare habit of reverse smoking in South India, with the lighted end in the
mouth produces cancer of the soft and hard palate which is the target point of inhaled tobacco
smoke.
Tobacco induced premalignant lesions like erythroplakia and certain forms of leukoplakia
are now well documented and clearly the case for primary and secondary' prevention of oral
cancers cannot be disputed. Field surveys have shown that certain forms of leukoplakia and
erythroplakia are reversible2 upon cessation of the tobacco habit; hardlv 5 to 8% of leukoplakias
have a malignant potential and these must be prophylacticalh excised to ensure cancer prevention.
Secondary prevention in high risk individuals with tobacco usage merits a yearly clinical examination
and cytology studies as needed. Excision of suspect lesions of nodular forms of leukoplakia will
contribute significantly to a reduction in oral cancer incidence, though no hard data are yet at
hand. Ajl medical expertise may not be available in rural societies and these approaches could also
be implemented by well trained health care workers particularly in developing areas of the world.
Education at all levels — the public, the youngster at school, the health worker or the paramedic
and the family doctor, is crucial and should be the central point of reference in the control of
head and neck cancer. Despite all our knowledge, prevention of cancer in general, and head and
neck cancer in particular is neither cheap nor cost effective and is not always easy to justify.
Educating the public, surveying the population, training the paramedic or the doctor, studying
premalignant lesions by cytology or excision biopsv and its interpretation, modifying habits and
life styles, may be much more costly than therapy itself. Research in preventive oncology and its
effective implementation has been successful in very few instances lowering of tobacco usage in
the USA, cervical cancer reduction or downstaging in selected western societies) at a cost which
most nations will find difficult to bear and sustain. Nonetheless, to implement prevention
wisely and pragmatically with a positive cost benefit outcome will require the skill and
enthusiasm of many different experts. That it can be done is beyond doubt, witness to which is
the downstaging data on cervical and oral cancers now available from the rural cancer registrv of
the ^Barsi” area, an effort 12 years in the making by the Tata Memorial Centre in its rural
satellite centre.3
Prophylaxis and early diagnosis: Prophylaxis has been alluded to earlier on and it would
suffice merely to state that the premalignant lesions in the head and neck region, particularly the
oral cavity (which form 33% of all cancer? of the head and neck)4 arc so well defined that efficient
cancer prophylaxis can be ensured in high risk groups at least for oral cancers. The oral cavity, the
oro and hypopharvngeai regions arc die most easily accessible sites.for visual examination. Efficient
endoscopic survev of the upper aerodigestive tract cannot possible miss an early T1 lesion in these
anatomic sites. Field surveys in high risk endemic areas, undertaken by medical personnel and
well trained health workers2 have shown conclusive evidence of not only being able to downstage
the disease but also to ensure good cancer prophylaxis either by simple excisional surgery of
premalignant lesions and/or reversal of abnormal mucosal changes to normalcy by reverting back
to more prudent habits and lifestyles.5
Combined treatment modalities — The concept of organ preservation in head and
neck cancer: The conceptual changes now being witnessed in cancer therapy in general and head
and neck cancer ir. particular are based mainly on the understanding of the strengths and
weaknesses of each of the major therapeutic disciplines viz. surgery, radiotherapy and chemotherapy.
Local failures are the main causes of morbidity and mortality in head and neck cancer though an
increasing frequency of distant metastasis in long term survivors are now well documented.'’
Increasing sophisticatior. in radiotherapy- techniques including brachytherapy and more efficient
cytotoxic drugs and their appropriate combination have produced more efficient local control in
head and neck cancers, thus helping to avoid the morbidity associated with the removal of the
larynx, pharynx and a total glossectomy . Current literature is replete with such reports of organ
preservation in head and neck cancers with chemo-radiotherapv
What will be crucial to this effort is to predict chemo-radiosensitivity or resistance of a given
cancer “ab initio" so that the appropriate initial therapy is instituted to the best advantage of the
patient. It is prudent
keep in mind that salvage surgery after failed chemo-radiotherapv has a
better chance ot success than the control of a post surgical recurrent cancer bv chemo-radiotherapv
salvage. Important studies regarding the ability to predict tumour radio-chemosensitivity/resistance
are on and an appropnate decision in this regard will increase the chances of a prolonged
control/cure and significantly decrease the morbidity and mortality associated with improper or
inadequate initial therapy. The concept of combined treatment modalities in head and neck
cancer is now well entrenched and a surgeon, radiotherapist or chemotherapist treating head and
neck cancers in isolation renders great disservice to an afflicted patient. This parallels the successes
achieved in conservation of the organ and function in breast cancer and in bone and soft tissue
malignancies.
Fundamental and applied research in head and neck cancer: As the clinical sciences of
the 1950s and 1960s move towards the increasing technologic and biologic sciences of rhe 1980s
xi
and 1990s, our conceptual understanding of the anatomico-pathologic basis of cancer and its
therapv is undergoing a gradual change. This is just as it should be, for, in-vitro studies of
tumour biology in the laboratory may not identically reflect all the nuances of in-vivo interactions
between the tumour and the host. Conventional treatment methods evolved after many years of
knowledge based on clinical experiences and anatomico-pathologic studies cannot be quickly or
suddenly modified or jettisoned at the altar of the emerging new biology; admittedly, die new
science is providing us with a deeper insight into predictive oncology — predicting treatment
responses, more effective prognostication and even in some situations helping us to identify a
very high risk individual among a group of healthy individuals predisposed to malignancy because
of their habits and lifestyles.
Head and neck cancer provides an ideal module to study a cancer site in its totality; from
fundamental research and its impact on diagnosis and treatment, its preventive potential and also
effective steps to be taken for rehabilitation and terminal care. The chapters in this volume
address all these issues including the emerging biology of head and neck cancer, viz. tumour
ploidy, oncogene and cytokcratin expression in the rumour cells, growth factors and their corelation
with the clinical.stare of.the disease and its behaviour and prognosis?'1’ Lessons have to be learnt..
slowly and carefully, so that the know ledge and understanding of tumour biologv can be dovetailed into clinical oncology.
Predicting treatment responses: Predictive oncology is an emerging science based on our
?as: know ledge and current understanding of tumour biology. The morphologic characteristics
of the rumour whether proliferative and non-innitrating or infiltrating and submucosally spreading.
often determines treatment responses. The majority of the former tumour types will respond.
often dramatically to radiotherapy and chemotherapy, whereas the infiltrating, submucosal spreading
tvpe of cancers do poorly with chemo radiotherapy. Initial surgical removal in the latter group
will save much morbidity of unnecessary chemo-radiotherapy. In contradistinction, surgical ablation
and its attendant morbidity of organ losses could be avoided in the proliferative, non-infiltrating
tvpe of tumours. This prediction still have a concordance in nearly 80% of cancers and a multivariate
analvsis of other biologic factors, “beyond morphology", those of rumour ploidy, cytokcratin and
oncogene expression, S-phase growth factors may help us to predict the tumour behaviour
vis-a-vis tumour response and prognostication in the other 20% of patients." The human system
is not a mathematical model and constant endeavours will be needed at all times to collate
all the factors before treatment decisions can be made.
It is an accepted fact that the majority of T1 & T2 lesions can be effectively treated with
either surgery or radiotherapy singly or in combination, whereas treatment response predictions
xii
.
—J
will be of greater value in the locally advanced cancers to avoid treatment related morbidity.
Overall res'ults arc similar and morbidity often lesser with chemo-radiotherapy in selected T3 - T4
lesions thus allowing us to preserve organa! function so vital in the head and neck region.
Predictive oncology goes beyond the realms of treatment response, prediction and prognosis.
In the years to come it aims to explore and decipher the very basis of genetic predisposition by
studying the chromosomal aberrations either endowed or acquired bv insults of habits, life styles
or other carcinogenic factors. The implications for prophylaxis, early diagnosis and effective
treatment appear exciting; to translate it into clinical realities and application will require an
enormous amount of intfastructure, not entirely easy to create. The present era of excitement
generated bv-increasing understanding of tumour biology needs to be tempered by cautious and
sober optimism.
Rehabilitation and terminal care — Where do we go from here? Despite our present
capabilities in research, prevention, early diagnosis and effective treatment of head and neck
cancers, at least 50'.' of patients currently undergoing treatment will require appropriate post
therapy rehabilitation care and many of them will need good terminal care and pain relict. In the
excitement and glamour of research and therapy, these areas arc often neglected and only the
most human amongst the medical and paramedical groups will be able to provide this care.
Whether it is a hospice facility or home care, nursing or availabilitv of simple pain relief-medications
'oral morphine or injectiblc analgesics!, human interactions in terminal stages of uncontrolled
cancer is crucial for a holistic care of the cancer patient. Stressing this need may appear simplistic
but without doubt this is a most glaring lacuna globally and more so in developing countries in
our overall cancer effort worldwide.
In an era of continuing resource restraints, creation of large comprehensive cancer centers is
not onlv prohibitively expensive but probably even unnecessary. There is indeed much medical
capability beyond the formal institutions and these should be harnessed to create smaller, more
functional centres where reasonable adequate facilities for field work, prevention, education,
statistical collation, early diagnosis and effective treatment by surgery', radiotherapy and
chemotherapy could be organised. Such “conininnin cancer centres”,12 within reasonable budgetarypossibilities are not difficult to envisage or create. This will lead to an equitable distribution of
cancer health care not only in the developing areas of the world but even in the advanced
countries where such lacunae still exist. If our experience at the rural satellite centre at Barsi is any
indication, the future of a patient with head and neck cancer, or for that matter any cancer will be
more secure by adopting a pragmatic approach which can encompass a holistic attitude towards a
patient afflicted with cancer.
Xlll
■ ■
__________
References
1.
Desai PB, Rao RS, Rao DN, Shroff PD. (Eds.) Hospital Cancer Registry, Tata Memorial
Hospital, Division of Epidemiology and Biostatistics, 1992.
2.
Gupta PC, Mehta FS, Pindborg JJ et al. A 10 year follow-up study for primary prevention
of oral cancer among Indian villagers. Oral Cancer, Published by the Professional Education
Division, Tata Memorial Hospital, Bombay, 1991, pp. 18-24.
3.
Jayant K. Rural cancer registry (Barsi). Report of the Indian Council of Medical Research —
Downstaging of cervical and head and neck cancer. 1993.
4.
Desai PB. Oral cancer—future vistas. In Oral Cancer, Published by the Professional
Education Division, Tata Memorial Hospital, Bombay. 1991. pp. 155-159.
5.
Mehta FS, Hamner JE. In Tobacco related oral mucosal lesions and conditions in India.
Tata Institute of Fundamental Research, Bombay, 1993.
6.
Stimson PS. Louis BH. Hong WK. Tumours of the nasal cavin', paranasal sinuses,
nasopharynx. oral cavity and oro-pharvnx. In DeVita. Hellman. Rosenberg, i Eds 1 Cancer —
Principles and Practice of Oncology. 1993, pp 574-631.
7.
Wolf G, Lippman SM. Laramore G. Hong WK. Head and neck cancer . In Holland JF, Frei
E, Bast RC !jr> et al. (Eds.i. Cancer Medicine. Philadelphia. Lea and Febiger. 1993, pp.
1211-1275.
8.
Vokes EE, Weischelbaum RR. Lippman SM et al. Head and neck cancer. New Eng J Med,
1993; 328:184.
9.
Brachman DG, Graves D. Vokes E et al. Occurrence of p53 gene deletions and human
papilloma virus infection in human head and neck cancer. Cancer Res, 1992; 52:4832.
10.
Gusterson BA, Ambazhagan R, Warren W et al. Expression of p53 in premalignant and
malignant squamous epithelium. Oncogene, 1991; 1:1785.
11.
Khoo SK, Hust T, Webb MJ, et al. Chemosensitivity testing of ovarian cancer — results of
a rapid in vitro biochemical assay. Aust N Z J Obst Gynae, 1985; 25:215.
72.
Hickey R, Desai PB. Organisation of comprehensive cancer centres and other facilities for
cancer control. UICC publication, Geneva, 1990.
*
xiv
*
*
Table 2
Regional x'ariation in the relative frequency
of nasopharyngeal cancer in India
Trends
It is well known that changes in life style in terms of the tobacco habit and alcohol usage,
Number of patients
and also withdrawal or introduction of a carcinogen in the environment are likely to affect the
trend in the incidence rate of cancer. Long periods of observation are necessary' to assess the
increase or decrease in the incidence rate.
According to a recent LARC report,1’ global trends in cancer incidence and mortality show
variations at most sites. In particular, for head and neck cancer, bp cancer is declining in most
j' All India
There has been a dramatic decrease (40%) in the frequency' of head and neck cancer over
the years at TMH. The decrease svas observed in all the major sites of head and neck cancer
except that there yvas a sight increase in the percentage of nasopharvngeal cancer.
All
Cancer
118199
785
0.66
6326
11711
5520
24178
8139
8457
42
86
38
171
44
40
0.66
0.73
0.69
0.71
0.54
0.47
2608
5195
13214
8811
10199
4231
9610
42
63
104
31
45
29
50
1.61
1.21
0.79
0.35
0.44
0.69
0.52
O'
/o
1 Cancer Hospitals
parts of the world and tongue cancer which is common in India. France and Switzerland, also
shows a declining trend.
Rel.
Frequency-
Nasopharyngeal
Cancer
Calcutta
Hyderabad
Madras
Bombay
Ahmedabad
Kanpur
General Hospitals
In order to confirm this, incidence data from Bombay Cancer Registry yvas used to analyse
the trend in head and neck cancer. The site specific age adjusted incidence rates for major sites in
head and neck cancer in males in Bombay between 1964 and 1982 are shosvn in Table 3. The
incidence rate of cancer of the tongue declined gradually from 14.0 per 100,000 in the earlier
period (1960s) to 9.7 per 100,000 in 1978-82, yvhile cancers of ‘other parts of the mouth’
remained more or less stable over the years yvith an age-adjusted rate of about 7.0 per 100,000.
The rates for oropharyngeal cancer declined from 6.1 per 100,000 to 3.5 per 100,000 over the
years; yvhereas the incidence of hypopharyngeal cancers increased from 7.3 to 10.0 per 100,000.
North-East India
Assam (1)
Bengal 8c North Bihar (2)
South-East India (5)
South-West India (8)
West India (9)
North-West India (3)
North India (5)
Figures in parentheses indicate the number ofhospitals from that region
Source: Jussawalla D J and Gar.gadharan P9
There yvas a declining trend for laryngeal cancer in Bombay.
The average percentage change in incidence rate for cancer of the tongue, oropharvnx and
larynx, shosved a statistically declining trend.’ Further analysis of cumulative incidence rates for
Table 3
Site-specific age adjusted rates for cancers
in males in Bombay 1964-82
these sites in Bombay males showed that the decline in the trend yvas due to a cohort effect. The
Age adjusted incidence rate (world) per 100,000
observed changes in incidence rates probably reflect the changes in tobacco usage over the years
i.e. a marked decrease in bidi smoking, a known high risk factorffbr these sites.
Influence of religious and endogamous groups
Epidemiological studies carried out in various parts of the yvorld have shoyvn that rhe cancer
patterns change according to life styles apart from environmental and other factors. Agestandardised incidence rates by religion and sex for sites in head and neck cancer for Greater
Bombay population are presented in Table 4. High incidence rates of tongue, mouth and
hypopharyngeal cancers yvere observed in all the religious groups. Parsis, followers of the Zorastrian
faith, mainly live in Bombay and by religious customs, tobacco chewing and smoking are strictly
Site of malignant neoplasm
Oral cavity
Tongue
Mouth (all other parts)
Pharynx
Oropharynx
Hypopharynx
Larynx
All Sites
1968-72
1973-77
1978-82
,
1964-66
12.6
7.3
10.2
6.7
9_-z
7.o
i
14.0
7.0
6.1 *
7.3
13.8
139.5
5.6
7.7
13.6
143.1
4.5
8.7
12.4
142.1
3.5
10-0
10.1
147.4
f
j
ICD 7,145: tonsils and oral nasopharynx
Source: Reference Nos. 10, 19, SI, 84
I
prohibited. This communin’ belongs generally, to a higher income group and follows a westernised
and Malaysia whereas persons from tiic western part of India, Gujarathi speaking Indians migrated
life style. The Parsi communin' also has a higher percentage of persons in the older age group
to South Africa (S.A.). The incidence rates for head and neck cancer among migrant Indians arc
Among Parsis in both sexes, high incidence of
shown in Table 5. Migrant Indians generally follow die same life stvle and continue their
laryngeal cancer is observed as compared to other communities even though tobacco habits are
chewing and smoking habits. Because of continuing habits, the incidence rates among migrant
forbidden in that community. The rates for Indian Christians are found to be higher for tongue,
Indians are comparatively higher for some of the sites in head and neck cancer than the native
oropharynx and hypopharyngeal cancers. The reason for this is not known and it may be due to
population. Migrant Indian females have high rates for cancer of die mouth and pharynx compared
a more westernised life style, with a higher percentage of cigarette smokers and alcohol addicts in
this communitv.
to die corresponding rates in native African females in Natal (S.A.).
compared to die total Bombay population.
Table 5
Age standardised rates for head and neck cancer among
migrant Indians (Natal, South Africa and Singapore)
Table 4
Age adjusted incidence rates (per 105) by religion
and sex, Greater Bombay, 1979-84
Hindus
ICD Site
140 Lip
141 Tongue
143 Gum
144 Floor Mouth
145 Other Mouth
146 Oropharynx
147 Nasopharynx
148 Hypopharynx
149 Pharynx NOS
161 Larynx
Muslims
Parsis
Christians
Male
Female
Male
Female
Male
0.2
4.3
0.7
0.3
2.4
1.7
0.5
4.6
1.1
4.1
0.1
1.5
0.7
0.1
2.0
0.4
0.2
1.3
0.4
0.8
0.2
4.9
0.7
0.3
2.7
2.2
0.5
5.6
1.3
5.0
0.1
1.6
0.6
0.1
1.8
0.3
0.3
1.1
0.5
1.2
0.2
7.0
0.9
1.2
2.5
3.2
1.0
6.3
2.1
5.6
Female
1.9
0.2
0.3
1.3
0.5
0.2
0.9
0.5
0.7
Male
Female
0.7
4.6
2.0
0.6
6.3
1.3
2.6
0.7
1.3
2.0
0.7
10.6
2.5
0.6
0.6
1.3
3.2
Site
A study on the distribution of cancer in some endogamous groups using TMH hospital
data (1946-50) showed variations in the site distribution of cancer among Hindus from Maharashtra.
The sub-castes considered were marathas (40% of Hindus;, occupational castes, brahmins and
. harijans. Oral and pharyngeal cancers accounted for 50% of all male cancer cases in brahmins,
Natal @
Africans
(1964-66)
(1964-66)
Natal @
Indians
(1964-66)
Males Females Males Females Males Females Males Females Males Females
0.3
Lip
Source: Reference Nos. /7, 78, 79. 80.
Bombav @
Singapore *
Indians
(1978-82)
Madras *
Indians
(1982)
Tongue
Sal. Gland
4.3
0.3
0.3
2.1
0.2
0.8
0.3
0.4
0.4 ’
0.4
0.3
4.6
14.0
3.7
1.8
0.7
1.5
3.0
0.1
0.2
0.8
0.8
0.7
0.4
0.5
4i
4.4
8.1
0.5
3.3
1.2
Mouth
8.1
10.0
4.4
9.6
6.5
5.9
3.7
Oropharvnx
2.4
0.7
3.7
3.1
rr
#
Nasopharynx
0.7
0.3
0.3
1.3
0.6
0.5
#
0.0
TT
TT
#
TT
0.2
TT
Hypopharynx
4.2
1.2
3.6
1.6
0.6
0.1
1.0
1.0
TT
TT
TT
TT
Pharvnx
4.5
0.5
3.5
4.0
0.5
1.0
Larvnx
Other Pharvnx
5.3
0.7
8.2
1.6
13.8'
2.8
-
-
-
-
16.0
4.4
whereas in other sub-castes the percentages were 67% in harijans, 64% in marathas and 64% in
’ IARC (1987) lCD-9th Revision« V1CC (1970) ICD-7th Revision-
occupational castes. This pattern was also seen in females. Oral cancer, in particular, was less
# included in other pharynx
TT
TT
2.1
predominant among brahmins (12%) as compared to other sub-caste groups (20-33%). The study
showed that the observed variation in the relative frequency of oral cancer in Hindu sub-castes
could be due to variation in tobacco habits.
19
Multiple Primaries
The appearance of a second cancer among head and neck cancer patients has been reported
.
in the literature. Based on the TMH data, Vyas et al 20 have reported the occurrence of multiple
Migrant Studies
primaries in an Indian population (Table 6). The study pointed out that patients with a primary
Epidemiological studies on migrant populations have shown change in the site-specific
incidence rates and the pattern of cancer compared to the host population. Indians from southern
parts of India, mainly Tamil speaking people from the state of Tamil Nadu, migrated to Singapore
..io
..
. _
:
——
cancer in head and neck region did not discontinue their tobacco habits. This resulted in the
appearance of a second cancer at susceptible sites such as the lung, other head and neck sites and
the oesophagus.
.1.1
Table 6
Multiple Primaries in Head and Neck Cancer
Tata Memorial Hospital; 19417- 85 fe'V
Site
■
Laryngeal apparatus
Anterior tongue
Base tongue
Buccal Mucosa
Oropharynx
Postcricoid
Lower alveolus
Nose
Nasopharynx
Tonsil
Soft palate
Thyroid
Upper alveolus
’ T First : ■ '
'
- Primary
Site
;■ I..
L. . .... •> .
r5
’
. A—* X . .1 ■'\ . . 12"
Second
Primary
Lung
Esophagus
Head and Neck
Others
31
9
8
8
4
2
2
2
1
1
1
1
1
Table 7
Indian case-control studies on head and neck cancer j
t -1^' /Risk factorszand?RR.:estimates
,
29
12
19
11
71
71
Source: Vyas et al (19S3)‘°
1. Sanghvi et al. (1955)
Sanghvi (1981)
Oral Cavity/ ]
Pharynx/Larynx ]
4.0
2.0 (Bidi)
4.0
2. Jussawalla 8c Deshpande
(1971)
Oral Cavity
Oropharynx
Nasopharynx
Hypopharynx
Larynx
6.0
3.3
1.8
6.2
4.6
2.8
11.8
3.3
3.6
7.7
10.1
31.7
4.8
16.9
20.1
3. Reddy (1974)
Hard Palate
85.0 (males)
Reverse
132.0 (females) Smoking
4.34
1.99
4. Notani 8c Sanghvi(1976)
Oral Cavity
3.93
5. Notani & Jayant (1987)
Oral Cavity
Pharynx
Larynx
3.9
2.3
1.8
5.2
4.2
6.8
7.6
5.0
7.7
-
6. Notani (1988)
Oral Cavity
Pharynx
Gingiva
2.8
2.1
4.1--13.2
4.7
4.5
2.0
13.1
9.3
16.0
10.0-47.1
11.6-50.2
1.9
5.0
7.0
7. Sankaranarayanan ct al
(1989-a)
Analytical studies
In the following discussion, each of the known risk factors are summarized along with the
risk estimates (Table 7). The factors considered are betel quid chewing, smoking, snuff dipping,
use of masheri and nass/naswar, alcohol consumption, diet and occupational exposure.
Tobacco
.8. Sankaranarayanan ct al
(1989-b)
Oral tongue and
Floor of Mouth
6.1
9. Nandakumar ct al (1990)
Oral Cavity
12.9
1.9
9.2
10. Rao ct al (1994-a)
Oral Cavity
3.6
1.7
2.9
2.4-3.9
11. Rao et al (1994-b)
Hypopharynx
Oropharynx
2.6
2.2
4.4
7.9
3.6
5.5
3.0-6.9
7.0-9.6
* combined with other habits
Tobacco in India, is used in various forms. Placement of quid in the buccal cavin’ is quite
common. The curious forms ofchewinu . .
•'here'
h-n-!nm.
w”b
An IARC30 monograph reporred a dose-response relnrionship of rhe chewing habit with
’• 1 '■
. ■ v.lwu n <
* ’idj cancer. i i;c
m :;
c. i •.... s. . ■ -
- •’ ■
• _• •
( in those who chewed more than 6 times a day compared to uoii-cncv.crs.
and habits play an impor
cancer in India. Since ancient times pan with b.’.cl ini: arc offered during religious fim.nons a.'.'
cclcbrator’ occasions. In the early part of this century Niblock,Fells" and Orr and td.isg
reported the association of betel quid chewing with ora! cancer. The preponderance ol cheek
iCcccntlv, a hospital-based case-control study on male oral cancer was carried out at TMII,
showed the association of tobacco chewing
Bombay.34 The studv established that tobacco .chewers had a 2.64 times excess risk for ora!
with oral cancer and the risk was reported to be 4-fold among chewers compared to non-chcwcrs
and non-smokers. A detailed casc-control study was carrie'd out by Jussawalla and Deshpande in
£ cancer. Chewing of betel quid with and without tobacco is also associated with oral and pharyngeal
I cancer28 Further each individual ingredient in the quid such as bctclnut alone, bctelnut and
197128 and the study showed a 6-fold risk among chewers for oral cancer, a 3-fold risk for
I tobacco, cither alone or with smoking are also found to be associated with oral cancer.
cancers was attributed to pan chewing. ’
Sanghvi
|
’
30
29
oropharyngeal cancer and a 5-fold risk for laryngeal cancer. Hirayama carried out a survey in
central and southeast Asia and showed strong supportive evidence for the association ol oral and
pharyngeal cancer with the chewing habit.
12
Risk estimates for chewing tobacco have been provided by many studies in the past,
however the risk due to retention of the quid during sleep has not been estimated, Nimdriuimar
et al have shown that the risk estimates for quid retention versus non-rctention during sleep were
• i 33
17.7 and 8.5 times respectively.
'
t a significant r*s^ factor. A dose-response relationship, both for duration and frequency' of bidi
R smoking-.was also noted.. .
SnioKing is xCss. populsr in Inch?. Bno.ct 2I in their st?-idv
nnt
[find any excess risk for oral cancer among cigarette smokers but studies elsewhere found a
Khaini, Nass/Naswar, Masheri
Khaini, a mixture of a powder of dried tobacco leaf and lime is very popular in Bihar, India.
As early as 1945, Khanoikar and Suryabai reported that the Khaini habit was associated with an
De Stefanni et al
f positive association with oral cancer.
studied the risk due to smoking of
| hand-rolled cigarettes and manufactured cigarettes. They found that smokers of hand-rolled
I cigarettes had an increased risk of cancer of mouth and pharynx cancers (RR=2.5) compared with
excess risk of cancer of the labial mucosa.
Nass and naswar are mixtures of tobacco, lime and other ingredients. They are used in the
| smokers of manufactured cigarettes. The risk of laryngeal cancer was greater among hand-rolled
I cigarette smokers (RR=2.7).
Soviet Republic, Pakistan and Afghanistan. A very high relative risk of 20.4 for oral cancer was
reported among nass users and a risk of 14.2 among naswar users.
I Reverse Smoking
Wahi in a study from Mainpuri district in Uttar Pradesh observed that the use of Mainpuri
The habit of smoking by keeping the burning end in the mouth is practiced in the coastal
tobacco, a pre-prepared mixture of tobacco with lime and other ingredients elevated the risks for
cancers of the buccal mucosa, gingiva and lip.
districts of Andhra Pradesh, an eastern state of India. A local type of cigar, called the ‘chutta’ is
[ used. The ‘chutta’ is a roll of dried tobacco leaf which is made into a small cigar and tied at one
Masheri (burnt tobacco) is used for cleaning the teeth in some parts of India. Mehta ct al.
carried out a prevalence survey in some parts of Maharashtra, India, and found the prevalence of
this habit in approximately 20% of the population.S No oral cancer was detected among masheri
users in this survey. The association of this habit with oral and pharyngeal cancer has to be
end with a piece of thin string. In Vishakapatnam, in the state of Andhra Pradesh, cancer of the
I
hard palate is common.
Reddy and Kameshwara Rao showed that the habit of reverse smoking
I of cigars was responsible for the high incidence of palatal cancer which was further supported by
[experimental work.' Reddy48 reported an excess risk of 132 times in reverse chutta smokers for
[hard palate cancer in females compared to non smokers and a lesser risk in males (85.0). Another
established.
I type of reverse smoking which is prevalent in Goa, western India, is ‘Dhumti’ smoking. Although
'
.
.
.
I no case of palatal cancer was observed in reverse dhumti smokers in a house to house survey,
Smoking
49
I there were marked keratotic changes in the palatal mucosa. Further studies arc needed to assess
In India, there arc different smoking habits, viz. bidi smoking, cigar smoking, pipe-smoking,
chutta smoking and the use of the hookah or chihim. The different methods of smoking arc
described bv Sanghvi c: al.
the risk of cancer due to this habit.
A studs conducted in-Swedcn ami Colombia by Pindborg
revealed the: reverie smoking
was also reported to be a causal factor for base tongue cancer, a finding yet to be reported in
<
An Indian cigar called ‘Bidi’, usually 60mm in length contains 0.2g - 0.3g of tobacco. Il is
India.
sun dried, flaked and hand-rolled in rendu or temburni leaf (Ww/nroj Melnnnxylnn). Sanghvi
et al’ were the first to confirm the association of the tobacco habit, in particular bidi smoking
with aerodigestive cancers.
Jayant er al
»
in an Indian study found that the dual habits, chewing anil bidi smoking acted
synergistically in the development of oral cancer. In fact,, with the dual habit, a higher risk
Snuff
Oral use of snuff (snuff dipping) is prevalent in India. Sankaranarayan ct al ’ did not find
any significant excess risk for oral cancer among snuff users in their study conducted in southern
India but studies undertaken elsewhere confirmed the association with oral cancer.
(31.72) was also noted for oropharyngeal cancer. In a recent case-control study conducted at
TMH, Rao ct al
confirmed the association of bidi smoking with oral cavity' cancer.
A case-control study of male pharyngeal cancers seen at I MH showed a high risk among
bidi smokers lororopharyngc.il and h)poph.iryngc.il cancer. Cigarette smoking did not cuicige as
Cessation of tobacco habit
Information on cessation of habit, in particular for tobacco chewing and bidi smoking, was
smokers arc shown in Fig. 6. Although the relative risk for ex-tobacco chewers was reduced, it | (RR=4.3), and smoking (RR=2.4). The risk increased to 8.8 times for those with all the three
continued to be higher than non chcwcr controlsiFor bidi smokers however, there was a gradual I; habits (alcohol -chewing- smoking).,.This,is.in.tionfirmation of the.earlier study on the role of
reduction in the relative risk for ex-smokers .with more than 2 years of cessation of smoking.
alcohol in oral cancer.' 7An. increase; in.cancer. risk with' increase ini-duration of the alcohol habit
§ was observed, with risk enhanced to 3.16 times for those who had the alcohol drinking habit for
~ more than 20 years compared to non-alcohol drinkers (Fig 7). A case control study on pharyngeal
| cancer conducted at TMH has also revealed a positive association of alcohol with pharyngeal and
Alcohol
The social consumption of alcohol in India is not widely accepted. ‘Country liquor’ which a laryngeal cancer. Further, the risk due to alcohol when combined with chewing and/or smoking,
is locally brewed, is the most common form of alcohol consumed. In general, persons indulging I increased significantly.
in this habit also have an added habit of chewing and/or smoking. Very few studies have been
Case-control studies earned out in other parts of the globe have confirmed the association
undertaken in India in the past to establish the role of alcohol in the etiology of oral and
of alcohol consumption with oral and pharyngeal cancers.
pharyngeal cancer.
' ’
In one of the earliest studies
Notani’4 showed that the alcohol habit when combined with chewing and/or smoking
on alcohol, Wynder et al provided the risk estimates of oral cancer due to alcohol consumption.
A recent extensive review by the International Agency for Research on Cancer’3 on the role of
increased the risk for oral cancer. In males from a specific Hindu community, the risk of oral
alcohol in oral cancer concluded that epidemiological studies clearly indicate that drinking of
cancer was 10-fold among alcohol-chewers, 17-fold among alcohol-smokers and a very high
alcoholic beverages is causally related to oral cancer and there is no indication that the effect is
relative risk of 47.1 among alcohol-chewers-smokers. In studies conducted in southern India,
dependent on the type of beverage.
alcohol did not emerge as a risk factor for oral cancer’ ' . Confirming the causal effect of
smoking and alcohol in a recent case-control study on oral cancer, Rao et al from India, showed
that alcohol drinking emerged as a significant risk factor after adjusting for tobacco chewing and js
Fig. 7. RJlfor chewing, smoking, and alcohol: by duration of habits for oral cancer.
* RR FOR CHEWING, SMOKING, & ALCOHOL
smoking (Fig. 7). The risk enhanced considerably when alcohol was also combined with chewing 8
BY DURATION OF HABITS FOR ORAL CANCER
Fig. 6. RR for cx-chcwers and ex-smokers for oral cancer.
RR FOR EX-CHEWERS AND EX-SMOKERS
FOR ORAL CANCER
TOBACCO CHEWERS
NON CHEWERS
CHEWERS
EX-CHEWER 1 Yr
EX-CHEWER > 1 Yr
BIDI SMOKERS
NON SMOKERS
SMOKERS
Relative Risk (RR)
EX-SMOKER 1 Yr
Adjusted for other related (actors
ourco: Rao et at (1994)
EX-SMOKER 2 Yrs.
• P < .001
EX-SMOKER >2 Yrs
Diet
RELATIVE RISK
Source: Rao et al (1994-a)
*P<.01
Tabic 8 gives sonic of the case-control studies undertaken to evaluate the association of
dietary items with head and neck cancers. Excess use of reel chilli powder in the diet emerged as
16
17
significant risk factor for oral, pharyngeal and laryngeal cancers and a significant dose-response
relationship in terms of frequency was also observed.
Experimental Studies
An excess risk with consumption of salt-
preserved meat and fish is reported for oral and pharyngeal cancer in a Chinese study.
57
The etiologic role of betel-tobacco quid and bidi smoking in oral cancer was established
experimentally. In animals, the implantation of a betel-tobacco quid pellet was shown to produce
Table 8
Dietary risk factors in head and neck cancer
earcinomas in the cheek pouch of hamsters.
Author and Year
Factors Studied
Protective/Risk
1.
Pulses
Vegetables
Fish
Buttermilk
Fruits
Groundnut oil
Red chilli powder
Protective
Protective
Protective
Protective
Protective
Protective
Risk
Notani and Jayyant (1987)
2.
Nandakumar et al (1990)
Ragi, a cereal diet
Risk
3.
Zheng et a! (1992)
Fruits
Yellow Vegetables
Chinese Radish
Salt preserved fish
Protective
Protective
Protective
Risk
4.
Rao et al (1994 a)
Non vegetarian
Risk
5.
Kune et al (1993)
Fruits
Vegetables
Cereals
Protective
Protective
Protective
comparative chemical analysis of the Indian bidi and the American cigarette and stated that the
way the bidi is smoked exposes the smoker in general to a higher level of noxious agents.
Chemical analysis resealed that bidi smoke contained high concentrations of toxic carbon monoxide
and other toxic agents in addition to a high concentration of particulate matter (tar) and the
carcinogenic hydrocarbons, benz(a)anthracene and benzo(a)pyrene. The high temperature (760°C)
in reverse smoking is believed to be an additional causal factor.
Animal studies have demonstrated the mutagenicity of urine collected from rats fed with
salted fish and these animals are prone to develop nasal cavity tumours?9
In a study carried out in India the presence of nitrosamines in smokeless tobacco products
j was found to be carcinogenic.
g Other risk factors
| Dental and oral hygiene
Graham et af' showed that poor dentition increased the risk of oral cancer. In a recent
The rate of nasopharyngeal cancer was twice as high among the sea faring Tanka people, a
sub ethnic group of Cantonese Chinese, than among land dwelling Cantonese and this was
mainly attributed to the difference in dietary practices. The Tanka people usually added salted
...
fish in their diet and rarclv consumed citrus fruits.
Kao ct al
Chemical analysis of bidi smoke has showed
presence of potent carcinogens like bcnzo(a)pyrene, etc. ’ Earlier, Hoffmann et al° gave a
found a 39% excess risk among non-vegetarians for oral cancer after adjusting for
other known associated factors. Hirayama’ also found that among the non-vegetarians, the
chcwcrs had a 8-fold risk whereas among the vegetarians, chcwcrs hail only a 3-fold excess risk
for oral cancer. It is also reported that non tobacco chcwcrs who consumed ragi, a staple cereal
diet {Elciisinc (.'.ornciinn, familv Grnminnc}, consumed by people in southern India, had 72 n
I
I
study, Maier et al” showed that oral hygiene was affected with alcohol and tobacco consumption.
Poor dental status and oral hygiene were observed in patients with head and neck cancer." In a
study from India'4, it was shown that illiterate people had a higher risk for oral cancer compared
to literates. The factors that arc generally associated with illiteracy like poor dental hygiene, under
nourishment and low socio economic status, apart from the robacco-habit, may be responsible for
oral cancer. The pathogenetic mechanisms associated with these suspected risk factors remain to
be investigated.
times excess risk for oral cancer and the risk level increased to 242.6 when ragi users also chewed
tobacco.
Occupational exposures
j
Male carpet installers and workers exposed to asbestos and petroleum products were found
Case-control studies on dietary items have shown that certain items play a protective
role. 2 ' ' ' Notani anil Jayant
to bi- high rjs|. groupS for oral and pharyngeal cancer.'
found that consumption of certain vegetables and fish were
An occupational study carried out in Nordic countries (Denmark, Sweden, Norway and
protective factors for oral, pharyngeal ami laryngeal cancer. In another simlv undertaken in
China, a high intake of fruit, particularly oranges and tangerines, yellow vegetables and Chinese
radish decreased the risk for oral and pharyngeal cancer.
18
I
binland) demonstrated that lor oral and pharyngeal cancer, an increased risk was found in male
painters in Norwav, Finland, anil Sweden, whereas it coilld not be proved in Denmark.
In a
19
recent study conducted to determine whether pathologists with exposure to formaldehyde had an
excess risk of cancer, particularly for cancer of the nasopharynx, failed to show any significance.74
■t has now been possible to identify the problem of cancer in the country and also common forms
°f cancer in Indian people. In 1992, an estimate of over 6,44,000 new cancer cases were
diagnosed in the country. About 30 35% of these cases were mainly caused dne to tobacco
Table 9
Summary of exposures associated with nasopharyngeal cancer
Exposure
Postulated Agent
Effect on risk
Epstein Barr Virus
Diet
Preserved foods
Fruits/Vegetables
Green Tea
Smoking
Smoke
Wood
Herbal medicines
Epstein Barr Virus
Increases
Nitrosamines
Micronutrients
Poly phenols
Nitrosamines
Increases
Decreases
Decreases
Increases
Increases
Increases
Increases
related habits. The present condition, if it continues, is likely to lead to a situation where by the
year 2000 A.D., there will be over 8,00,000 new cancer cases per year in the country (Fig. 8).
In order to combat this problem, both the central and state governments have formulated
Formaldehyde
Phorbol esters
cancer control programmes. Some of the important steps are: (a) a total ban on smoking in
public and work environments and also on domestic air travel; (b) legislation to print the
statutory warning about health hazards due to smoking on cigarette packets; (c) organization of
mass screening programmes for head and neck cancer. Long term measures like mass public
education on cancer and propagation of ill effects of tobacco among school children would also
reduce the mortality due to cancer in the years to come.
Source : Hildesheim mid Levine (1993)'-
Fig. 8. Cancer in India by the year 2000 AD.
Source: NCRP (1992).
Virus etiology
Epidemiological studies on nasopharyngeal cancer carried out in high risk populations have
brought out significant leads in the etiology of this cancer. Epstein Barr Virus has been identified
and confirmed to be an causative agent in nasopharyngeal cancer. For other sites in head and
neck cancer, a virus as a causative agent has not yet been confirmed. A list of exposures and their
postulated agents along with the effect on risk is summarised in Table 9. The drinking of green
tea and increased consumption of fruit and vegetables have been shown to be protective factors
whereas daily consumption of preserved foods, use of herbal medicines, exposures to virus and
smoking are known to increase the risk of nasopharyngeal cancer
Chemoprevention
Chemoprevention is gaining ground and various products are under trial to evaluate their
1992 (est)
2000 (est)
potential. Many studies arc currently underway to identify theyffeer of beta can ‘cue in reducing
the risk of cancer among high risk populations. A recent study showed that leukoplakia responded
Source: NCRP (1992)
to treatment with beta carotene but did not regress completely after treatment. 1 he study
concluded that beta carotene is rhe ideal candidate lor potential use in the chemotherapeutic
prevention of oral cancer.
References
International Classification of Diseases (lCD-9th): Manual of the International statistical
Cancer control
With the establishment of population based cancer registries in major metropolitan cities by
the National Cancer Registry Programme of the Indian Council of Medical Research, New Delhi,
20
classification of diseases, injuries and causes of death Wl IO, Geneva, 1977.
-•
1’aymaster JG. Oral and pharyngeal cancer in India. Presented at the International Workshop
on (.anccr of the I lead and Neck, N1. May 10 I - I, I9(>5.
21
3.
Suraiya JN. Medicine in ancient India with special reference to cancer. Indian J Cancer,
jayant K and Yeolc BB. Cancers of the upper alimentary- and respiratory tracts in Bombay,
1973; 10:391.
India: A study of incidence over two decades. Br J Cancer, 1987; 56:847.
Paymaster JC and Gangadharan P. Cancer in the Parsi community of Bombay. Int J
London letter - Indian Med Gaz, 1903; 38:132.
4.
Cancer, 1970; 5:426.
5.
Bentall WC. Indian Med Gaz,1908; 43:452.
6.
Vishwanath and Grewal KS. Cancer in India. Ind J Med Res, 1935; 23:149.
endogamous groups in western India. Br J Cancer, 1971; XXV:6U.
7.
Vishwanath and Grewal KS. Cancer in India. Ind J Med Res, 1937; 24:633.
Vyas JJ, Deshpande RK, Sharma S and Desai PB. Multiple primary cancers in Indian
8.
Vishwanath and Grewal KS. Cancer in India. Ind J Med Res, 1939; 26:/85.
9.
Jussawalla DJ, Gangadharan P. (Eds). Epidemiology of cancer in the Indian sub continent.
Jayant K, Balakrishnan \ and Sanghvi LD. A note on the distribution of cancer in some
population. Metachronous and synchronous lesions. J Surg Oncol, 1983; 23:239.
Niblock WJ. Cancer in India. Indian Med Gaz, 1902; 37:161.
Ind J Cancer. Supplement Series. No. I-XII, 1973, 1974, and 1975.
10.
11.
Fells A. Cancer of the mouth in Southern India. Br Med J, 1908; 1:1357.
Balakrishnan V. An additional younger-age peak for cancer of the nasopharynx.
Orr IM and Glasg MB. Oral cancer in betel nut chewcrs in Travancore. Lancet, 1933:
Int J Cancer, 1975; 15:651.
ii:575.
Balakrishnan V, Gangadharan P, Rao DN. Some epidemiological aspects of nasopharyngeal
Sanghvi LD, Rao KCM and Khanolkar VR. Smoking and chewing of tobacco in relation to
cancer. In Shanmugaratnam K, Nambiar R, Tan KK, Chan LKC (Eds.). Liver cancer.
cancers of the upper alimentary tract. Br Med J, 1955; 1:1111.
Cancer problems in Asian countries: Proceedings of AFOCC 2nd Asian Cancer Conference:
Singapore Cancer Society, 1976.
Shanta V and Krishnamurthy S. A study of the aetiological factors in oral squamous cell
carcinoma. Br J Cancer, Vol. XIII, No. 3.
12.
Muir C, Waterhouse J, Mack T, Powell J and Whelan S. (Eds.) [ARC (1987). Cancer
Incidence in Five Continents, Vol. V. IARC Scientific Publication No. 88, Lyon, 1987.
Wahi PN, Kellar L' and Lahiri B. Factors influencing oral and oropharvngeal‘cancers tn
India. Br J Cancer, 1965; 19:642.
13.
NCRP: National Cancer Registry' Programme - A Biennial report 1988-89, Indian Council
of Medical Research, New Delhi (1992 ■
14.
Sanghvi LD. Cancer epidemiology. The Indian scene. J Cancer Res Clin Onco, 1981; 99:1.
Coleman MP, Esteve J, Damiecki P, Arslan A and Renard H. (Eds.) IARC,(1993). Trend
Jussawalla DJ and Deshpande VA. Evaluation of' cancer risk in tobacco chewcrs and
in cancer incidence and mortality. IARC Scientific Publication No. 121, IARC, Lyon,
smokers:an epidemiologic assessment. Cancer, 1971; 28:244.
1993.
Hirayama T. Epidemiology of cancer of the mouth. In NCI monograph No. 62, US Dept.
15.
16.
22
Parkin DM, Pisani P and Ferlay J. Estimates of worldwide incidence of eighteen major
of Health, Education and Welfare. Public Health Service. National Institute of Health,
cancers in 1985. Int J Cancer, 1993; 4:594.
Bethesda, Maryland, USA, 1982; 179-183.
- ...
Pisani P, Parkin DM and Ferlay J. Estimates of the worldwide mortality from eighteen
IARC (]985j Monographs on the evaluation ol the carcinogenic risk of chemicals to
major cancers in 1985. Implication for prevention anil projections of future burden.
' hnnan. Tobacco habits other than smoking betel quid and areca-nut chewing and some
Int J Cancer, 1993; 55, 6: 891.
related nitrosomiius. International Agency for Research on Cancer, Lyon, 1985; 37:176.
31.
Sankamarayanan R, Duffy SW, Padmakumary G ct al. Tobacco chewing, alcohol and nasal
44.
snuff in cancer of the gingiva in Kerala, India. Br J Cancer, 1989-a; 60.638.
32.
Sankamarayanan R, Duffy SW, Day NE et al. A case-contol study investigation of cancer of
45.
the oral tongue and the floor mouth in Southern India. Int J Cancer, 1989-b, 44.617.
33.
Nandakumar A, Thimmasetty KT, Srceramareddy NM, Vcnugopal TC, Rajanna Vinutha,
Wynder EL, Bross IJ and Feldman RM. A study of the etiological factors in cancer of the
mouth. Cancer,1957; 10:1300.
De Steffani E, Oreggia F, Rivero S and Fierro L. Hand-rolled cigarette smoking and risk of
cancer of the mouth, pharynx and larynx. Cancer, 1992; 70:679.
46.
AT Srinivas and Bhargava NIK. A population-based case-control investigation on cancers of
Reddy DG and Rao VK. Cancer of palate in coastal Andhra due to smoking cigars with
burning end in mouth. Indian J Med Sci, 1957; 11:791.
the oral cavity in Bangalore, India. Br J Cancer, 1990; 62:847.
47.
34.
Rao DN, Ganesh B, Rao RS, and Desai PB. Risk assessment of tobacco, alcohol and diet in
Reddy DG, Reddy DS and Rao PR. Experimental production of cancer with tobacco tar
and heat. Cancer, 1960; 13:263.
oral cancer - a case control study. Int J Cancer, 1994; 58:469.
35.
Khanolkar VR and Suryabai B. Cancer in relation to usages. Three new types in India. Arch
48.
Reddy' CRRM. Carcinoma of hard palate in relation to reverse smoking of chuttas. JNCI,
1974; 53:615.
Pathol, 1945; 40:351.
36.
Jafarcy NA, Mahmood Z and Zaidi SHM. Habit and dietary patterns of cases of carcinoma
49.
of the oral cavity and oropharynx. J Pakistan Med Assoc, 1977; 27:340.
37.
Wahi PN. The epidemiology of oral and oropharyngeal cancer. A report of the study in
Bhonsle RB, Murti PR, Gupta PC, Mehta FS. Reverse smoking in Goa: an epidemiologic
study of 5,449 villagers for oral prccancerous lesions. Indian J Cancer, 1976; 13:301.
50.
Pindborg JJ. Oral cancer and pre cancer. John Wright & Sons Ltd., Bristol, 1980.
Mainpuri district Uttar Pradesh, India. Bull WHO, 1968; 38:495.
51.
38.
39.
Mehta FS, Gupta PC, Daftary DK et al. An epidemiologic study of oral cancer and
prccancerous conditions among 101761 villagers in Maharashtra, India. Int J Cancer,
human cancer. 1ARC Scientific Publication No.57, International Agency for Research on
1972; 10:134.
Cancer, Lyon, 1984; 837-849.
Sanghvi LD, Jayant K and Pakhale SS. Tobacco use and cancer in India. World Smoking
52.
Jayant K, Balakrishnan V, Sanghvi LD and Jussawalla DJ. Quantification of the role of
Fraumeni JF (Jr). Etiologic studies of cancer - prone communities and families. Proc. Annu.
Meet Am Assoc Can Res, 1993; 34:563.
and Health, 1980; 5:4.
40.
Winn DM. Tobacco chewing and snuff dipping: An association with human cancer. In O.
Neil et al. (eds.J: N-Nitro compounds: Occurrence, biological effects and relevance to
53.
IARC Monographs on the evaluation of carcinogenic risks to humans. Alcohol drinking.
International Agency for Research on Cancer, Lyon, 1988; 44:153.
smoking and chewing tobacco in oral, pharyngeal and esophageal cancer. Br J Cancer,
1977; 35:232.
54.
41.
Rao DN, Ganesh B, Rao RS, and Desai 1’B. High risk factors for pharyngeal cancer in India
Notani PN. Role of alcohol in cancers of the upper alimentary tract. Use of models in risk
assessment. J Epidemiol Community Health, 1988; 42:187.
- A case-control study, (unpublished data) 1995.
55.
42.
43.
cancer of the buccal and labial mucosa in Kerala, southern India. J Epidemiol Community
pharyngeal cancer. Cancer Res, 1988; 48:3282.
Health, 1990; 44:286.
Rothman K ami Keller AZ. 1 he effect of joint exposure to alcohol and tobacco on risk ol
cancer of mouth and pharynx. J Chron Dis, 1972; 25:71 1.
24
Sankaranaravanan R, Dully SW, Padmakumary G, Day NE and Nair MK. Risk factors for
Blot WJ, McLaughlin JK, Winn DM ct al. Smoking and drinking in relation to oral anil
56.
Kabat GC and Wvndcr EL. Type of alcoholic beverage and oral cancer. Im J Cancer, 1989;
43:190.
57.
58.
Zheng W, Blot WJ, Shu XO, Diamond EL, Gao YT, Ji Bl and Fraumeni JF (Jr). Risk
70.
Bhidc SV, Kulkarni JR, Padma PR, Amankar AJ, Maru GB, Nair VJ and Nair J. Studies on
factors for oral and pharyngeal cancer in Shanghai with emphasis on diet. Cancer Epidemiol
tobacco specific nitrosamines and other carcinogenic agents in smokeless tobacco products.
Biomarkers Prev, 1992; 1(6):44'1.
In Sanghvi l.D, Notani PN (Eds.) Tobacco and Health. TMC, 1989.
Kato 1, Nomura AM, Stemmermann GN, Chyou PH. Prospective study of the association
71,
of alcohol with cancer of the upper aerodigestive tract and other sites. Cancer Causes
Graham S, Dayal H, Rohrer T ct al. Dentition diet tobacco and alcohol in rhe epidemiology
of oral cancer. JNCI. 1977; 59:1611.
Control, 1992; 3(2):145.
72.
59.
Maier H, Zolkar J, Herrmann A, Kreiss M, Heller WD. Dental status and oral hygiene
Kune GA, Kune S, Field B, Watson LF, Cleland H. Merernstein D and Vitetta L. Oral and
in patients with head and neck cancer. Otolaryngol Head Neck Surg, 1993;
pharyngeal cancer, diet, smoking, alcohol and serum vitamin A and p-Carotene levels: A
108(6):655.
Case-control study in man Nutrition and Cancer, 1993;20.
73.
60.
Maier H, Dietz A, Gewcl Ke U, Heller WD and Weidauer H. Tobacco alcohol and the risk
of head and neck cancer. Clin Invest, 1992; 70(3-4):320.
61.
Notani PN and Jayant K. Role of diet in upper aerodigestive tract cancers. Nutrition and
1993; 48(3):176.
74.
Cancer, 1987; 10:103.
62.
Ho JHC, Huang DP, Fong YY. Salted fish and nasopharyngeal carcinoma in southern
Chinese. (Letter), Lancet, 1978; 2:626.
63.
Skov T, Weiner J, Pukkala E, Malkcr H, Anderson A, Kynge E. Risk for cancer of the
pharynx and oral cavity among male painters in the nordic countries. .Arch Environ Health,
Matonoski GM. Risks of pathologists exposed to formaldehyde. National Technical
Information Service, Springfield, VA as NTIS/PB91 - 173682, 33, 1991.
75.
Garcwal HS, Meyskens FL Jr., Killen D, Reeves D, Kiersch TA, Elletson H, Strosberg A,
King D and Steinbronn K. Response of oral leukoplakia to Beta Carotene. J Clin Oncol,
1990; 8:1715.
Ning JP, Yu MC, Wang QS et al. Consumption of salted fish and other risk factors for
nasopharyngeal carcinoma in Tianjin, a low risk region for nasopharyngeal carcinoma in the
Peoples Republic of China. J Natl Cancer Inst, 1990; 82:291.
76.
Patel NL, Patel DD and Balar DB. Biennial Report 1988-89, Gujarat Cancer Registry,
Ahmcdabad, Gujarat, 1991.
64.
Notani PN and Sanghvi l.D. Role of diet in cancers of the oral cavity. Indian J Cancer,
1976; 13:156.
77.
Jussawalla DJ, Ycolc BB, Natckar MV, Rajagopalan TR. Cancer in the Sindhi population of
Greater Bombay. Cancer, 1980; 46(9):2107.
65.
Ranadive KJ, Ranadive SN. Shivapurkar NM et al. Betel quid chewing and oral cancer:
Experimental studies on hamsters. Int J Cancer, 1979; 24:835.
78.
Jussawalla DJ, Ycolc BB and Natckar MV. Cancer in Indian Moslems. Cancer, 1985;
55(5):1149.
66.
Pakhale SS, Javant K, and Bhidc SV'. Chemical analysis of smoke of Indian cigarattes, bidis
and other indigenious forms of smoking-levels of steam volatile phenols, hydrogen cyanide
79.
51:883.
and benzol a ipyrcnc. Indian J Chest Dis & Allied Sei, 1,990; 32(2):75.
&
67.
Hoffmann D, Sanghvi l.D and Wynder EL. Comparative chemical analysis of Indian bid,
80.
( hiiglev I.F, < obb ( M and I him EE. Measurement of oral and burning .zone icmpcr.il tires
81.
during conventional and reverse cigarette smoking. Arch Oral Biol, 1965; 10:35
69.
Fong I.YY, Ho IIIC, Huang DP. Preserved foods as possible cancer hazards. WA r.us led
salted fish have mutagenic urine. Int J (..nicer, 19/9; 23:542.
26
Jussawalla DJ, Ycolc BB, Natckar MV. Cancer incidence in Greater Bombay: An
epidemiologic study 1979-84. Bombay Cancer Registry, 1988.
anil American cigarette smoke. Int J (..nicer, 19/4; 14:49.
68.
Jussawalla DJ, Yeole BB and Natckar MV. Cancer in Indian Christians. Rr J Cancer, 1985;
Doll R, Waterhouse J, and Muir C. (Eds.) DICC (1970). Cancer Incidence in Five
Continents, Vol. II, I ARC, Lyon, 1970.
82.
I lildeshcim A and Levine PH. Etiology of nasopharyngeal carcinoma: Epidemiologic review.
The John Hopkins University of Hygiene and Public Health, U.S.A. 1993; 15<2):466.
27
83.
Gangadharan P. Epidemiologic observations on cancer in Indian people. Indian J Cancer,
1979; 16(19):1.
84.
Waterhouse I, Muir C, Correa P and Powell J. (Eds.) IAR.C (1976). Cancer Incidence in
Five Continents, Vol. Ill, IARC Scientific Publications No. 15, Lyon, 1976.
28
©IS' 13-5
VOL 35 (June, 1998) 65-72
RISK ASSESSMENT OF TOBACCO, ALCOHOL AND DIET IN
CANCERS OF BASE TONGUE AND ORAL TONGUE - A CASE
CONTROL STUDY
D.
Head, Division of Epidemiology
and Biostastistics,
Tata Memorial Hospital,
Patel, Mumbai - 400 012.
India.
N. Rao, M.Sc.
P. B. Desai, m s . F.R.C.S. f.aci.. fi.C.s.
SUMMARY
This is a retrospective case-control study of male tongue cancer patients seen at Tata memorial
Hospital, Bombay, during the years 1980-84. The purpose of the study was to identify the association
of tobacco, alcohol, diet and literacy status with respect to cancers of two sub sites of tongue namely
anterior portion of the tongue (AT) (ICD 1411-1414) and base of the tongue (BT) (ICD 1410). There
were 142 male AT patients and 495 BT patients interviewed during the period. 635 interviewed male
patients who were free of any disease were considered as control. Bidi smoking was found to be a
significant risk factor for BT patients and tobacco chewing for AT patients respectively. Alcohol
drinkers showed about 455k to 79% excess risk for both sites of tongue cancer. Illiteracy and non
vegetarian diet proved to be a significant factor for AT patients only. The study brings out that
the location of cancer has got a direct bearing with the type of tobacco use and other related habits
and this inturn may provide meaningful interpretation of variations observed in the incidence of tongue
cancer around the world.
INTRODUCTION
PATIENTS AND METHOD
Tongue cancer is generally an
uncommon disease and its reported incidence
is below 5 per 100,000 in about 135 populations
/ countries around the world1. In India, among
5 metropolitan registries the incidence rate of
tongue cancer (ICD 141) in males varied
between 4.7/100,000 in Bangalore and 13.2/
100,000 in Bhopal2 Clinical description,
behaviour and management of tongue cancer
depend on the location of tthc lesion, either in
the base or in the oral tongue Tobacco chewing,
smoking and alcohol habit were established
risk factors for oral and pharyngeal cancer (ICD
140 -149) in general3-'1-3-6-7-1’'-''1. The purpose of
the study is to identify tthe risk of these
established factors with respect to two sites of
tongue, namely base of the aongue (ICD 1410)
and oral tongue (ICD 141-1-14) and its risk with
respect to type of tabacco- use.
This is a part of the retrospective
unmatched case-control study of head and neck
cancer patients who attended the hospital
during the period 1980-84. There were 713
male oral cancer patients and 1498 male
laryngo pharyngeal cancer patients who were
interviewed by two social investigators at the
time of registration in the Out Patient
Department. The patients were interviewed
before clinical examination and thus
investigators were not aware of the diagnosis
of patients. Among them, 142 patients had
cancer in anterior portion of the tongue and 495
patients had cancer in base of the tongue.
During the period, there were 635 interviwed
male patients who were diagnosed as beimg free
from cancer, infections disease and benicn
lesion and these patients were classified as
hospital control. Majority of the male controls
65
Indian Journal of Cancer, Jtunc 98
Tobacco, Alcohol, Diet and Tongue Cancers
Tabic 1
General features of patients and controls
Controls
I. Number
Avg. /lge+ S. D.
Range
2. Residence
Bombay
Maharashtra
Others
Unknown
3. Religion
Hindu Maharashtra
Hindu Gujarath
Sindhi
Hindu Others
Muslim
Christian
Other Religions
4. Habits
No
Yes
5. Type
Chewers
Smokers
Alcohol
Hase Tongue
(TiT)
(%)
495
192
99.1 ± 10.9
27 - 75
635
95.5 ± 12.9
25 ■■ 87
54.76 ± 9.7
29 -80
386
136
111
2
60.8
21.4
17.5
0.3
56
47
38
1
39.4
33 1
268
0.7
186
163
146
37.6
32.9
293
255
59
15
150
104
28
24
40.2
9.3
2.4
23.6
169
4.4
3.7
62
12
1
39
19
3
6
43.6
8.5
0.7
27.5
13.3
2.1
4.3
168
88
9
119
82
16
13
33.9
17.X
l.S
24.0
16.6
175
460
27.6
72.4
23
119
16.2
83.8
36
959
73
92.7
251
295
122
39.4
46.8
19.4
76
69
39
59.2
49.3
28.2
172
404
113
39.7
81.6
22.R
2.6
logistic regression method was used to estimate
the relative risk for factors. The relative risk
estimates were obtained after stratification of
factors by four age groups (<35yrs, 35-44 yrs,
45-54 yrs, 55 yrs+) and three areas of residence
(Bombay, Maharashtra, Others).
whom we had considered for the study attended
the hospital for complaints in head & neck
region and later diagnosed to be of no evidence
of disease or any abnormality. In general,
chewcrs take pan, betal nut, lime and tobacco
with some spices and condiments and smokers
smoke Indian cigarette called bidis (obtained
by wrapping 0.2g to 0.3g of tobacco in tendu
leaf), cigarette, chutta (a kind of cigar) hukka
and chilum (clay pipe). Bidi smoking and
cigarette smoking are the commonest smoking
habits. Factors considered for the study are
tobacco usage (chewing omd smoking) alcohol,
mostly locally brewed from palm trees, (ethanol
content 40%-60%), dietary habits (vegetarian
I nonvegetarian) and literacy status. Vegetarians,
in general do not consume poultry or fish
products and avoid animal meat, The
questionnaire included details of the habit, age
started frequency per day and duration in years,
and cessation of the habit. Unconditional
Indian Journal of Cancer, June 98
3-2
RESULTS
General features like age, place of
residence, religious distribution and habits of
patients and controls are presented in Table I.
The religious distribution of cancer patients
and control did not differ and hence is not
adjusted for in the analysis. Cancer patients and
controls were in the age range of 25 years and
87 years. Base tongue cancer patients were
found to be older about five years compared
to anterior tongue cancer patients. Twenty
three patients (16.2%) in anterior tongue (AT)
group and 36 (7.3%) patients in base tongue
(BT) group did not report any of the habits
66
Rao & Desai
Tabic JI
RR estimates' for chewers, smokers and alcohol users and tests of significance.
Factors
A.
B
C.
d.
Chewers
Non Chewers
Chewers
Ant. Tongue (AT)
RR
Case
382
251
65
76
Not recorded
Chewing Type
Non Chewers
Tobacco Chcwers
4
I
382
233
65
75
Non Tobacco
U
0
Others
5
1
Not Recorded
Smoking
Non Smokers
Smokers
4
1
336
295
72
69
1.0
1.67
(1.12-2.51)
Base Tongue (BT)
Cases
RR
323
172
1.0
0.76NS
(0.96-5.27)
-
Not Recorded
Smoking Type
Non Smokers
Bidi
d
1
337
186
73
53
Cigarette
98
10
7
2
Others
3
3
Not Recorded
Alcohol
Non User
Alcohol User
4
1
509
122
102
39
Not Recorded
d
1
. Bidi + Cigarette
e
controls
1.0
1.81
(1.21-2.73)
323
154
14
0.67 NS
(0.03-7.70)
4
!0
0.70
(0.5-0.9)
1.32 NS
(0.5-3.7)
0.60 NS
(0.1-3.3)
-
1.0
0.97 NS
(0.65-1.44)
91
404
1.0
4.34
13.2-5.9)
1.0
1.12 NS
(0.73-1.74)
0.55 NS
(0.24-1.15)
0.92 NS
(0.12-5.43)
3.02 NS
(0.44-21.3)
91
360
1.0
5.90
(4.2-8.2)
1.45 NS
(0.9-2.5)
2.05 NS
(0.5-8.4)
2.29 NS
(0.3-19.6)
35
6
3
-
1.0
1.79
(1.12-2.84)
382
113
1.0
1.45
(1.1-2.1)
-
+ - Stratified by 4 age groups and 3 ureas- rtf residence: NS • Naf Significant
The figures inf) indicate lower and upper Confidence Inimul
RR estimates for chcwers, smokers and
alchohol drinkers with confidence intervals arc
shown in Table II. Chewers had excess risk for
anterior tongue cancer with relative risk
(RR)1.81 (C.I. 1.2-2.7) whereas smokers had
4.3 times excess risk (C.I.3.2-5.9) for base
tongue cancer. When categorised further.
tobacco chewing emerged as a significant risk
considered in lhe study. Alcohol drinking was
reported in 122 controls (B9.4%), 39 (28.2%)
patients in AT group and 113 (22.8%) patients
in BT group. There was notable variation of
habits with respect to two cancer groups.
Among AT group, chewing habit was
predominant (54%) whereas among BT group
smoking habit was commonly observed (81%).
67
Indian Journal of Cancer. JIjuic 98
Tobacco, Alcohol, Diet and Tongue Cancers
Table III
RR* for bidi smoking and use of alcohol and tests of significance according to frequency per day
Factors
l.
2.
3.
controls
Ant. Tongue
Case
(AT)#
RR
Base Tongue (BT)
*
Cases
1.0
1.23 NS
(0.69-2.2)
0.84
(0.78-1.78) .
1.39 NS
(0.72-2.67)
129
141
Bidi
Non User
1-10 limes
438
79
86
25
11-20 limes
54
n
21-30 times
56
18
31 + limes
4
1
Not Recorded
Alcohol
Non User
Once
4
1
509
108
102
27
Twice
14
12
Not Recorded
Tobacco
Non User
1 - 10 limes
4
1
398
203
66
67
11-20 times
28
7
21-30 times
1
1
• 31 + times
I
Not Recorded
4
94
107
24
1.0
1.46 NS
(0.85-2.48)
3.70
(1.69-10.8)
382
99
1.0
1.88
(1.24-2.87)
1.65 NS
(0.62-4.64)
8.3
(0.12-391.3)
341
135
14
14
1
4
RR
1.0
4.32
(3.04 - 6.7)
5.15
(3.39-8.5)
4.8
13.2-7.7)
14.3
(4.1-50.7)
1.0
1.51
(!.1-2.27)
/. 14 NS
(0.44-3.1)
1.0
0.7
(0.5-9.5)
0.5 NS
(0.3-1.2)
1.1 NS
(0.03-45.1)
10.04 NS
(0.5-209.40)
!
♦ - Stratified by d age groups and 3 areas of residence
< • Trend Significant for tobacco and alcanwl
• - Trend Significant for bidi and alcohoC
NS • Not Significant; The figures in () mdhcate lower lower and upper Confidence Interval
for AT group only and btdi smoking was an
important risk factor fair BT group only.
Cigarette smoking did not emerge as a
significant risk factor for two sites. Alcohol
drinking was found to be a significant risk
factor for both subsites of tongue cancer and
the estimated relative risk ranged between 1.45
and 1.79. Further the result of trend analysis
with respect to frequency amd duration of these
habits for anterior tongue and base tongue
cancers are separately sho-wn in Table III and
IV. The trend analysis again confirmed that the
two habits namely bidi smoking and tobacco
Indian Journal of Cancer. June 98
chewing showed statistically significant trends
with the increse in the frequency and duration
of the habits among BT and AT groups
respectively. The trend analysis for duration of
chewing habit was also statistically significant
foranterior tongue cancer. Smokers who smoked
bidi 31 times or more per day had about 14.3
times excess risk of getting base tongue cancer
and the risk level for over 30 years of habit
showed about 5 fold risk compared to non
smokers. Cigarette smoking did not emerge as
a risk factor for both groups cither in terms of
frequency or duration of the habit. The trend
68
Rao <4 Desai
Table IV
RR estimates • for bidi smoking and use of alcohol and tests of significance according to duration @
Factors
1.
2.
3.
controls
Ant. Tongue
Case
(AT) if
RR
Bull
Non User
1 - 10 yrs
438
63
86
7
129
30
11 - 20 yrs
48
16
21 ■ JO yrs
39
12
31 + yrs
43
20
1.0
0.52 NS
(0.2-1.3)
1.39 NS
(0.7-2.7)
1.24 NS
(0.6-2.8)
1.61 NS
(0.8-3.4)
Not Recorded
Alcohol
Non User
1 ■ 10 yrs
4
1
509
62
102
11
382
38
Il - 20 yrs
35
12
21-30 yrs
14
12
31 + yrs
11
4
1.0
1.21 NS
10.6-2.6)
2.0
(0.9-4.4)
3.3
(1.4-8.9)
1.3 NS
(0.3-4.8)
Not Recorded
Tobacco
Non User
1 • 10 times
4
/
398
93
66
20
11- 20 times
51
25
21 - 30 times
48
19
31 + times
41
11
Not Recorded
4
J
Base Tongue (BT)
*
Cases
RR
64
123
149
35
32
8
1.0
2.2
(1.3 ■ 4.1)
4.5
(3.1-8.7)
7.7
(4.8-13.0)
5.1
(3.J-8.3)
1.0
1.5 NS
(O.9-2.5)
1.6 NS
(0.9-2.9)
2.0
(1.0-4.6)
0.5 NS
(0.2-1.4)
-
1.0
2.04
(1.04-3.86)
3.58
(1.9-7.3)
1.83
(0.92-3.6)
0.77 NS
(0.33-1.77)
341
28
31
47
48
1.0
0.5
(0.3-0.89)
0.9
(0.5-1.5)
0.9
(0.5-I.4)
0.6
(0.4-0.99)
-
♦ • Stratified by 4 age grnupj and 3 anas erf residence
0 - Trend Significant for tobacco 4 nlcaitud: •- Trend Significant for bidi A alcohol
US - fiat Stgtdficanr. The figures in () iutiiceK tourer and upper Confidence Interval
analysis for alcohol habit according to frequency
and duration showed a statistically significant
association with tongue cancer.
(RR=2.1C. 1.1.41-3.2) for AT cancer amd 1.42
times excess risk (C.I. 1.08 - 1:93) for BT
cancer. Patients who took non vegetarian diet
were found to have two fold risk (RR
=2.18C.1.1.27-3.84) for anterior tongue cancer
only and for BT cancer there was a 34%
significant reduction in risk with RR 0.66 (C.I.
0.48-0.89).
The literacy status and dietary factors
were also analysed for the risk of these two
sites after stratification by 4 age groups and
3 types of residence. The estimates were
obtained without adjusting for tobacco and
alcohol habits. Considering the risk among
literate as unity, illiterates showed two fold risk
Table IV shows the unconditional
logistic regression model for two cancer sites.
69
Indian Journal of Cancer, June 98
Tobacco, Alcohol, Diet and Tongue Cancers
Table V
Unconditional logistic regression model' using five factors for two sub sites of longue
Site / Factor
Anterior Tongue (AT)
llidi (1-Yes: 0=Na)
Alcohol (l=Ycas: 0-No)
Illiteracy (1 = Yes: 0=No)
Nonvegerarian (l=Yes: 0=No)
Tobacco Chewing (1= Yeas 0= No)
RR
Confidence Interval
P Value
1.0
1.54
1.8!
1.74
1.74
0.66 - 1.52
0.97 -2.44
1 198 - 2.73
1.014 -2.995
1.173 - 2.571
p = 0.998
P = 0 063
P =0.005
P =0.044
P = 0.006
Base Tongue (BT)
Bidi (1 = Yeas: 0=No)
Alcohol (1-Yes: 0-No)
Illiteracy (1- Yes; 0=No)
Nonvegetarian (l=Yes: 0=No)
Tobacco Chewing (1 = Yes: 0=No)
4.69
1.34
1.22
0.59
0.88
3.51 - 6.27
0.93 - 1.93
0.90 - 1.66
0.43 - 083
0.65 ■ 1.19
P <001
P =0.116
P = 0.195
P = 0.002
P = 0.402
Tongue (AT + UT)
Uidi (l=Yes 0=Nt>)
Alcohol (l=Yes; = No)
Illiteracy (I-Yes; 0=No)
Nonvegetarian (!=Yes: 0=No)
Tobacco Chewing (1-Yes: 0=No)
3.32
1.38
1.41
0.77
1.13
2.56 - 4.3
0.99 - 1.9
1.08 - 1.85
0.56 ■ 1.04
0.87 - 1.47
p <.001
p = 0.05
P=0.0!3
P = 0.089
P = 0.36
* ■ Adjusted far 4 ugr groups and 3 nreact erf residence
The model confirmed the significance of tobacco
chewing, nonvegetarian diet, and illiteracy
status for anterior tongue cancer. Bidi smoking
emerged as a significant risk factor for the base
tongue cancer with RR 4.69 (C.I. 3.51-6.27).
The risk due to alcohol habit was higher than
unity in both sites but not found to be statistically
significant in this multivariate model.
interviewed, for many reasons. Controls were
chosen from among the interviewed patients
who were diagnosed as being free from cancer,
infectious diseases and benign ncoplams. The
use of hospital controls instead of population
controls may have affected the estimates of risk
factors. Previous studies carried out in India.
have identified risk factors for oral cancer (ICD
140-145) or for cancers of two or three sites
of oral cavity6-7-’-’-10. In an earlier study from
Bombay, the risk factors for individual sites
of oral cavity. pharynx and larynx were analyzed
and estimated but the study did not evaluate
for alcohol and dietary factors4.
DISCUSSION
Epidemiological research in recent limes
has become possible to adidress issues to the
specific sites of cancer according to International
Classification of Diseases flCD 9lh). Data on
cancer incidence arc being reported with certain
accuracy upto the fourth digit rubrics of ICD.
This retrospective case control study was
carried out to cvalute the association of tobacco
and alcohol habits with respect to cancer in the
base and oral tongue. Only histologically
confirmed tongue cancer cases were included
in this study. Not all of ihc tongue cancer
patients diagnosed during ti'he period could be
Indian Journal of Cancer. June IS
Tlte composition of habit pattern between
control and cancer groups shows the
predominance of smoking habit among BT
group (81.6%) and chewing habit anwms AT
group (54.2%). The study has brought ciut that
the location of cancer in the tongue te> some
extent depends upon the type of tobacco habit.
Bidi smokers in particualr had a higher rusk for
70
Kuo & Desai
larynx. The association of dietary factors with
oral cancer in particular has been confirmed
in the studies conducted from India. Non
vegetarian diet compared to vegetarian diet
seemed to increase the risk for AT cancer.
further studies are required to assess the risk
factors among individual items of
nonvegetarian diet after controlling the known
protective factors.
Base Tongue cancer Ilian for Am. Tongue
cancer. The dose response relationship was also
established according to frequency and duration
of bidi smoking habit for BT cancer and
tobacco chewing habit for AT cancer. When
the two cancer groups were combined, the
model showed significant association of bidi
smoking, alcohol, and illiteracy with tongue
cancer. Tobacco chewing and nonvegetarian
diet did not emerge as significant.
Illiterates had a higher risk for anterior
tongue cancer in our study. This may be due
to the diflcrcnt life style, habits and customs,
poor socio economic status, dietary habits and
poor oral hygiene among illiterates compared
to literates. These factors need to be considered
in future studies. It is necessary to have a new
strategy for cancer control and prevention for
such high risk groups.
The average age of the patients with
respect to two cancer group show variation.
This is also observed from the Cancer Registry
data of the hospital for the last five years".
Patients with AT cancer were found to be about
five years younger compared to BT cancer
patients in the hospital data also, further
studies arc required to identify factors
responsible for this.
In conclusion, the study brings out that
the location of cancer has got a direct bearin'.!
with the type of tobacco use and other related
habits and this inturn may provide meaningful
interpretation of variations observed in the
incidence of tongue cancer around the world.
Alcohol as a high risk factor has been
reported for ora! cavity cancer in general.
Previous studies showed that alcohol habit is
associated with oral cancer5'. In this study also
it has been shown to be associated with AT
cancer but not with BT cancer. It is necessary
to collect more information on alcohol habit
in our population and also the type of liquor
and quantity consumed to provide a meaningful
estimate of the risk involved with oral cancer
and in general for all cancer.
ACKNOWLEDGEMENT
The authors express their thanks to the
staff of the Division for their assistance in
carrying out this study. Special thanks arc due
to MRs. P. R. Peshotan and Mrs. R. U.
Vachharajani who interviewed the eases and
controls with great care, and to the patients
who participated.
Many studies have identified the role of
dietary factors in cancer of mouth, pharynx and
REFERENCES
1.
Parkin D. M., Muir C. S. Whelan S. L.
Gao Y. T., Ferlay J. and Powell J. :
Cancer Incidence in Five Continents. Vol
VI (EDS) [ARC Scientific Publication No
120. Lyon, 1992.
2.
NCRP : National. Cancer Registry
Programme Bienraaal Report - An
epidemiologic study Indian Council of
Medical Research. New Delhi. 1992.
7 I
3.
Sanghvi L. D„ Rao K. C. M. and
Khanolkar V, R. : Smoking and chewing
of tobacco in relation to cancer of the
upper alimentary tract. British Medical
Jouranl. 1955:1:1111.
4.
Jussawalla D. J. and Deshpande
V. A. : Evaluation of cancer risk in
tobacco chewcrs and smokers : an
epidemiologic assessment Cancer.
I97L2S, 244-252.
Indian Journal of Cancer. June 98
Tobacco, Alcohol, Diet and Tongue Cancers
5.
Notani P. N. : Role of alcohol in cancers
8.
of the upper alimentary tract : use of
models in risk assessment J. Epidemiol
Community Health 1988:42; 187-192.
6.
Padmakumary G., ct al : Tobacco
chewing, alcohol and nasal snuff in cancer
of the gingiva in Kerala, India Br. J.
Cancer, 1989(a):60;638.
Nandakumar A., Thimmasctty K. T.,
Sreeramareddy N. M. Venugopal T.
C.
9.
Sankarnarayanan R., Duffy S. W., Day
N. E. et al :
A case - control study
investigation of cancer of the oral tongue
and the floor mouth in Southern India. Int.
J. Cancer, 1989(b);44;617.
, Rajanna Vinutha, A. T. Srinivas,
and Bhargava M. K. : A population -
based case-control investigation on cancers
of the oral cavity in Bangalore, India, Br.
J. Cancer, I990;62,847.
7.
Sankarnarayanan R., Duffy S. W.,
10.
Notani P. N. and Jayant K. : Role of
diet in upper acrodigestive tract cancer.
Nutr. Cancer, 1987;10,103-113
Rao D. N., Ganesh B., Rao R. S. and
Desai P. B. : Risk assesment of tobacco,
alcohol and diet in oral cancer - A case
control study. Int. J. Cancer, 1994;58;469473.
11.
Hospital Cancer Registry (1991 -93).Desai
P. B. Rao R. S. Rao., D. N. and Shroff
P. D. Annual Reports - 1989-1992, Tata
Memorial Hospital Bombay.
Indian Journal of Cancer, June 98
72
' 13. G
British Journal of Cancer
77(Q}. 1514 1518
<) 1998 Cancer Research Campaiun
Survival analysis of 5595 head and neck cancers results of conventional treatment in a high-risk
population
DN Rao’, PD Shroff’, G Chattopadhyay’ and KA Dinshaw2
’Division of Epidemiology and Biosiatistics and 7Tata Memorial Center. Tala Memorial Hospital. Pare!. Mumbai 400 012. India
Summary This is a study of 5595 head and neck cancer patients treated during 1987-89 at TMH, Mumbai. The study included 1970 oral
cancers (ICD 140-145). 1495 oropharyngeal cancers (ICD 1410, 1453, 146). 1255 hypopharyngeal cancers (ICD 148). 125 nasopharyngeal
cancers (ICD 147) and 750 laryngeal cancers (ICD 161). The clinical exlent of disease at presentation was based on TNM group staging
(UICC 1978). For the majority of sites, patients attended the hospital during stage III and stage IV of the disease; the only exception was for
cancers of the lower lip. anterior tongue and vocal cord when between 46.2% and 56.5% of patients with localized cancer (stage I and II) were
seen. Generally, surgery either alone or with radiation has been administered for oral cancer patients whereas radiation either alone or in
combination with chemotherapy was administered for other head and neck sites. The overall 5-year survival rate was in the range of 20-43%
for oral cancer. 8-25% for pharyngeal cancers and 25-62% for laryngeal cancer. The 5-year relative survival rates were more or less in
agreement with the results published by the Eurocare study for head and neck cancers. The importance of primary prevention in head and
neck cancer is stressed.
Keywords: head and neck cancer; survival; TNM. stage: treatment
Incidence data that are available from six metropolitan cities and
one rural registry in India indicate that head and neck cancer is a
common problem there (IARC. 1992). Many epidemiological
studies carried out in the sub-continent have shown the association
of tobacco, alcohol and some dietary items with head and neck
cancer. Although primary prevention may be-the ideal choice for
the control of head and neck cancer, secondary prevention through
therapeutic intervention has an equal and important role to play.
Management of head and neck cancer in a high-risk population
and its response to conventional treatment and survival have not
been reported in detail. The aim is to analyse individual sites of
head and neck cancer according to stage of the disease, primary'
treatment and other prognostic factors for 5-year survival.
Comparison is also made with survival in European countries.
PATIENTS AND METHODS
This is a retrospective analysis of 5595 eligible head and neck cancer
patients who were diagnosed and treated at Tala Memorial Hospital.
Mumbai, during the period 1987-89. The eligibility criteria for
inclusion of patients in the study were: (1) no prior cancer-directed
treatment at the time of registration: (2) histologically confirmed
epithelial cancer. (3) treatment with chemotherapy together with
surgery or radiation but not as the only treatment: amd (4) al least 50
cases in each subsite of head and neck cancer. The excluded subsites
Received 5 August 1997
Revised 23 October 1997
were upper lip (five cases), commissure of lip (six cases), longue
NOS (not otherwise specified) (one case), salivary gland <39 cases).
palate NOS (two cases) and subglottic larynx (seven cases).
Information on age, sex, date of diagnosis, method of diagnosis.
primary site (ICD 1978). secondary' site, if available, histology of
primary and/or secondary tumour. TNM staging (UICC. 1978) and
primary' treatment given within 6 months of diagnosis were obtained
from the database maintained by the hospital cancer registry; The
clinical extent of the disease for head and neck cancer cases was clas
sified into four stages, viz. stage I comprising T,N() M() stams. stage II
comprising T, No Mo. stage III comprising T, No M(). T, N M(l. T, N,
M(1 and T, Nj Mo and stage IV comprising T4 No M(1. T4 N( Mo. and
any T. N, or N Mo and any T any N M,. Periodic updating of follow
up information was carried out either by scrutiny of medical records
of attending patients or by postal enquiry responses. In some cases.
follow-up information was also obtained by scrutiny of death records
maintained by the Municipal Corporation of the City, of life insur
ance claims and of records from terminal care centres/paan clinic in
the city. The study was closed on 31 March 1996, and datra available
up to that lime were used for the survival analyses. In this study of
5595 patients. 2435 patients (43%) were known to have died and
1128 patients (20%) were known to be alive at the end of 5 years
from their dale of diagnosis. For the remaining 2032 puinents. 267
patients (4.7%) had follow-up information for between 3 aind 5 years.
1384 patients (24.7%), categorized as non-responders, had less than
3 years of follow-up information and 381 patients (6.8%) had incom
plete addresses (untraced cases). Complete follow-up imfonmation
was 68% for the laryngeal group. 65% for oral cancer. (>4% for the
oropharyngeal and nasopharyngeal group and 60% for the hypo
Accepted 27 October 1997
jjh^’n^edj^p^Llb^nddiy^ea^ihe.equiYaleiiLii^ures^erfc^^
Correspondence to DN Rao
about S4% for laryngeal cancer and 70-80% for the oiincr groups.
1514
Survival analysis of head and neck cancer
Table 1
1515
Clinical characteristics and observed survival rates (%) for oral cancers 1987-89
Ant. tongue
(1411-14)
L. alvelous
U. alvelous
Floor mouth
Buccal mucosa
Hard palate
Retromolar
(1131)
(1430)
(1449)
(1450-51)
(1452)
(1456)
522
340
Site
(ICD 9)
Lower lip
Number of cases
62
Sex ratio
3.1 1
2.3 1
23 1
Average age 1 s.d. (years)
50.7 I 13 6
49 4 _• 119
52.2 .’ 10.5
I
ll
III
22.6
20 9
1 2
32.3
14 5
25.3
IV
29.0
1.6
(1401)
71
728
88
90
69
76 1
2.2 1
33 1
28 1
52.7 ’ 13 6
51.1 • 94
50 8 1 11.7
54 1 • 12 5
53 2 • 9.2
28
19 7
57
62
1.1
6.7
18.2
20.0
31 0
9 1
47 9
21 3
15
81.2
1.8
22.5
7 1
13.6
580
195
52 1
26.6
36 6
17.9
53.6
4.5
2.2
17.8
1 5
83.9
50.4
48.8
32.4
6.5
21 1
39 4
18 9
56 7
232
39.1
Surgery + radiation
18.8
22.4
239
36 4
42 9
1.6
12.9
1.6
84
20.0
4.4
24.6
*
Others
61 (49-73)
55 (51-59)
36 (32-40)
62 (57-68)
35 (30-40)
51 (41-61)
34 (25—44)
56 (45-68)
48 (36-60)
43(31-56)
33 (29-37)
31 (26-36)
31 (21-40)
25(14-35)
33
17
19
16
17
1 7 1
Stage (%)
NOS
1 5
130
30.4
Treatment summary (%)
Surgery
Radiation
Survival with Cl
1 year
3 years
5 years
Median survival (in months)
35 3
94
28 4
19.1
28 7
7.1
11 3
9.3
46 (35-58)
47 (36-57)
61 (57-64)
21 (12-31)
23(14-31)
20 (10-29)
21 (13-30)
39 (35-42)
34 (31-37)
12
12
20
13.1
29(18-40)
•Includes chemotherapy either with surgery or with radiacion or with both. Cl. 95% confidence interval; NOS. not otherwise specified
Table 2
Clinical characteristics and observed survival rates (%) for pharyngeal and laryngeal cancers 1987-89
Site
Base
(ICD 9)
tongue
(1410)
Number of cases
818
Soft
palate
Tonsil
Oropharynx
(1453)
(1460)
NOS
(1461-69)
142
34o
189
Post
cricoid
Pyriform
Hypopharynx
fossa
NOS
(1480)
(1481)
(1482-89)
171
84
1000
Vocal cord
Supra
INasopharynx
(1610)
glottic
(1611)
(1470-79)
259
491
125
Sex ratio
11.4:1
7.4:1
8.6:1
6 3:1
0.9:1
12.3:1
3.4:1
17.5:1
Average age ± sd (years)
55.0±10.6
56.2110.5
55 9110 9
56.6110 5
49.91139
55.5110.4
53.6113.5
56.0111.2 55.2110.5
382118.2
I
0.7
II
III
IV
10.1
46.2
6.3
25.4
38.7
2.0
81
2 1
13.2
0.1
8.7
1.2
11.9
51.7
15.4
1.8
11.4
0.8
2.4
50.6
37.3
55.0
280
2.0
1.7
7.8:1
42.1
Stage distribution (%)
NOS
41.7
1.3
27.5
2.1
1.2
15.2
509
52.9
60.7
29.8
37.0
25.0
20.1
9.7
56.0
25 7
76.8
2.9
1.3
1.2
3.1
5.1
4.8
152
Treatment summary (%)
Surgery
0.7
Radiation
Surgery + radiation
86.2
2.1
81.7
O.3
87.3
0
90
3.2
9.9
6.3
9.9
2.9
2.1
9.5
7.9
*
Others
Survival with Cl
1 year
3 years
5 years
Median survival (in months)
43 (39-46) 58 (49-66) 44(39-49) 45(38-52)
19 (16-21) 33(25-41) 15(11-19) 20(14-26)
15(12-17) 25 (17-32) TG(9-16)
14(8-19)
10
18
m
11
10.5
3.4
24
11.2
2.9
74.3
11.1
4.1
79.1
84.5
4.8
8.3
74.9
85.7
0
50.4
13.1
0.8
8.6
2.8
44.8
34 (26-40)
48 (44-51)
22 (19-24)
16 (11-22)
13(8-18)
7
12.9
4.6
39(29-50)
82 (77-87) 54 (41-58)
17(15-20)
13 (6-20)
8(2-14)
65 (59-71) 28 (24-32)
62 (56-68) 25 (21-29)
12
9
*
14
4.8
50 (42-59)
27(19-35)
21 (14-28)
13
•Includes chemotherapy either with surgery or with radianion or with both. DNot reached Cl. 95% confidence interval; NOS, not otherwise specified
The number of untraced cases was around 7% tkar all sites, except
laryngeal cancer for which the figure was 3.7%; similarly. the propor
tion of non-responders was around 25% for all sites except for laryn
geal cancer (21.6%). The proportion of bcith untraced and
non-responding patients who had stage III and stuige IV cancers at
their first visit to hospital was between 70% and 92% in the different
with less than 3 years of follow-up were considered as being
deceased, and survival information available up to that dime was used
for analysis purposes. The Kaplan-Meier method was tused to esti
mate survival rates for 1.3 and 5 years and also to assess certain prog
nostic factors considered in the study. As 70% of the patients attended
hospital from Maharashtra state, the life table for Maharashtra State.
-sitegroupvand these patientswenrconsidercd-unKiii table for further
published bynhe-Govemmenrof-India-for thrperiod-1
treatment, except for pain relief or symptomatic itreatinent. Patients
1994). was used to estimate the relative survival rates.
. O Cancer Research Campaign 1998
British Journal of Cancer (1998) 77(9), 1514-1518
1516
Table 3
DN Rao el al
Five-year observed survival rales (in %) for oral cavity, pharyngeal and laryngeal cancers by treatment
Radiation
Surgery
Site
Surgery
Surgery
Radiation
Surgery
♦ radiation
+ chemotherapy
♦ chemotherapy
♦ radiation
♦ chemotherapy
Oral cavity
Lower lip
47.8
o-
25
-
-
o-
132
22.0
13.6
27.2
14 3
Upper alveolus
30.4
Floor mouth
42.9
46.4
13.3
3.1
289
17.1
33.3
45.0
—
-
11 1
Lower alveolus
47.8
34.4
Anterior tongue
Buccal mucosa
Hard palate
Retromolar
36.0
27.9
23.3
19 6
14 8
588
37.5
20.0
O'
-
O'
o-
38.9
30.7
-
25.0
41.2
O’
o-
*
O
192
*
O
6.7
26.3
Oropharynx
Base tongue
66.7
Soli palate
Tonsil
Oropharynx NOS
66.7
15 3
24 2
55 6
*0
-
6.0
-
*0
-
13.9
20.0
-
14.0
*
0
3.3
7.1
Post-cncoid
Pynform fossa
11.1
14.1
14.8
15.6
79
.32.5
Hypopharynx NOS
*
0
8.5
*
0
-
-
*
0
ZOO
-
-
12.7
44 4
-
28.5
*
0
72.4
62.1
51.7
-
500
-
28.6
25.2
48.0
O’
25 0
*
0
*0
*
O
*
100
Hypopharynx
Nasopharynx
—
0
7
O’
Larynx
Vocal cord
Supraglottic
•Estimate based on five or less cases.
Table 4
No patient.
Five-year relative survival rates (%) according to sex and TNM group staging for head and neck cancers 1987-89
Five-year relative survival (%)
Sex
Oral Cavity
Lower lip
Anterior tongue
Lower alveolus
Upper alveolus
Floor mouth
Buccal mucosa
Hard palate
Retromolar
Stage
M
F
1
II
III
IV
51.3
35 6
36.2
24.8
29.5
16.5
49.8
65.6
60.3
22.8
41.7
12.7
35.8
69.8
63.6
56.0
54.0
35.5
20.8
39.4
42.6
35.3
32.1
30.4
30.6
*
0
65.2
67.4
31.2
33.7
60.6
18.0
100
*
100
49.6
36.7
19.4
26.6
25.3
23.3
11.2
30.0
13.5
14 9
25.0
31.3
7.0
17.6
Oropharynx
Base tongue
Soft palate
16.64
16.6
89.94
35.8
26.2
38.8
39.6
Tonsil
Oropharynx NOS
14.95
15.3
12.1
15.7
50.2
64.1
15.5
19.9
21.2
27.9
4.94
8 77
14.37
8.3
10.3
8.3
2.1
10.8
*
0
30.8
50.8
12.7
*
0
36.4
13.5
17.25
*
0
21.8
10.7
Hypopharynx
Post-cricoid
Pyriform fossa
Hypopharynx NOS
Nasopharynx
8.6
11.3
*
100
44.6
0
21.6
23.7
*
100
35.5
22.7
21.7
70.45
27.2
60.36
38.0
78.9
74.0
60.5
61.7
55.6
28.7
52.0
52
Larynx
Vocal cord
Supraglottic
9.1
•Estimate based on five or less cases.
RESULTS
The clinical characteristics, TNM staging, treatment summaries
and observed survival rates for 1970 oral cancer cases are
British Journal of Cancer (1998) 77(9), 1514—15119
presented in Table I. The average age of patients ranged from 49.4
years for anterior tongue cancer to 54.1 years in hard paitate cancer.
file distribution of TNM staging among eight sites of oral cancers
showed that except for lower lip (54.9%) and anteinor tongue
© Cancer Research Campaign 1998
Survival analysis ol head and nock cancor
along with chemotherapy was administered lor about 44.X% ol the
patients and the 5-ycar observed survival rale for vocal cord cancer
was about 62%. For all other sites, the 5-ycar survival rale ranged
between 8%. for hypopharyngeal cancers, and 25%. lor both soli
palate and supra glottic cancers
The 5-ycar observed survival rales according to primary treat
ment for the eighteen sites ol head and neck cancer considered arc
presented in Table 3. Surgery, when used alone for the treatment of
oral cancer, was followed by a 30-58% 5-ycar survival ol patients
The 5-ycar survival for radiotherapy alone in oral and pharyngeal
cancers in our study was in the range of 3-24%. Vocal cord cancer.
when treated by radiotherapy alone, showed a 62% 5-ycar survival
rate. The certain combinations of treatment showed good
percentage 5-ycar survival rates for particular sites, namely
nasopharynx, lower alveolus and supra glottis.
The 5-year relative survival rates by sex and TNM stage for all
the 18 sites of head and neck cancer arc presented in Table 4.
Women showed better 5-year survival rates for cancers of the floor
mouth CM. 20.8%: F. 42.6%). soft palate (M. 26.2%: F. 38.8% j and
hypopharynx (M. 8.6%: F. 11.3%) than men. The stage of the
disease is known to be an important prognostic factor. With the
increase in (he stage of disease, there has been a corresponding
decrease in survival. Although few patients were observed with
cancer (40.2%). for most of the sites, patients with stage I and
stage II disease together accounted for between 7.9%, for lower
alveolus cancers, and 27.7%. for hard palate cancers.
Management of oral cancer depends largely on the stage of the
disease. In our senes, surgery alone or radiotherapy alone or their
combination remained as the primary treatment. The ‘other’ treat
ment category mostly included (he combination of chemotherapy
with either surgery or radiation or both in the management of oral
cancer. The 5-ycar observed survival rate varied between 20% for
the upper alveolus and 43% for lower lip cancers.
The comparable data for pharyngeal and laryngeal cancers arc
presented in Table 2. In contrast to most of the cancers, a marked
predominance of men was seen for all the sites except for post
cricoid cancers, for which a female excess was observed. The
average age of the patients varied between 382 years for cancer of
the nasopharynx and 56.6 years for oropharyngeal cancer. The base
of the tongue (818 eases) and pyriform fossa (I(XX) eases) were the
two predominant sites observed in this group. The TNM stage distri
bution of individual sites indicated that 80-90% of eases presented
with stage HI or IV malignancies, the only exception being for vocal
cord cancers for which the percentage was much lower (30%). In
view' of this, for most of the patients, radiotherapy was administered
as the only treatment. In the ease of nasophary ngeal cancer, radiation
Table 5
1517
Five-year relative survival rates (%) for the Eurocare study (A) and the Tata Memorial Hospital Study (B)
(B)_______
(A)
Eurocame study
*
Hospital stuxty
Study period 1978-85
Study period 1987-89
Country (%)
Site (ICD)
Tongue (141)
Ora) cavity (143-145)
Cases
5-year survival
3299
4382
39
46
Highest
Scotland (46)
Finland (45)
Switzerland (43)
Poland (15)
The Netherlands (62)
Estonia (33)
Poland (33)
Finland (51)
England (48)
Oropharynx (146)
2457
33
The Netherlands (45)
Hypopharynx (148)
1078
2199
38
19
France (28)
The Netherlands (28)
Italy (38)
Tongue6
Base tongue
Anterior tongue
24.02
Oral cavity5
818
16.6
522
35.8
Upper alveolus
1529
71
33.2
21.7
Lower alveolus
Floor mouth
340
88
34.3
23.4
Buccal mucosa
Hard palate
Soft palate
Retromolar
728
90
37.3
34.4
142
69
27.6
27.0
535
346
14.7
Oropharynx
Italy (23)
Scotland (23)
Estonia (16)
Italy (55)
Finland (51)
Scotland (24)
The Netherlands (36)
Poland (7)
Finland (8)
Switzerland (14)
The Netherlands (73)
France (47)
Scotland (64)
Estonia (50)
Denmark (60)
England (63)
189
14.6
15.4
Nasopharynx
125
22.2
Hypopharynx
1255
171
18.0
1000
84
19.6
757
Poland (28)
•
57
5-year survival
1341
Switzerland (84)
Estonia (23)
10612
Cases
Estonia (27)
Scotland (24)
Larynx (161)
Site (ICD)
Tonsil
Oropharynx
Poland (44)
England (36)
Nasopharynx (147)
Lowest
Post-cricoid
Pyriform fossa
Hypopharynx
Larynx”
14.3
9.2
Vocal cord
259
41.8
68.0
Supraglottis
491
28.0
■Source. IARC (1995). “Includes longue NOS (one curse). ■Includes palate NOS (one case). “Includes subglottis (seven cases)
© Cancer Research Campaign 1998
British Journal of Cancer (1998) 7%(9). 1514-1518
*
«
,iu5>~ .».’rS. ,„«S£ . -»
1518
----- *. —"
.Sst- jSW
. ..ra
*<
.. ^ssC. j»w_,
. j£ssl ,j«.
DN Rao el al
stage I cancel, the 5-yeai iclaiive survival rales were in lhe range
56
lor oral cancels (except lor lhe upper alveolus). 50-90%
lor oropharyngeal cancer. 100% lor nasopharyngeal cancer and
74-79% Ibi laryngeal cancer. This indicates the effectiveness ol
conventional treatment in the early stage of lhe disease.
DISCUSSION
This is a retrospective analysis of 5595 head and neck cancer
patients treated during the period 19X7-89. Some other sites.
namely upper lip. nasal sinus, max antrum and salivary glands.
were not included mainly because of the small number of cases
and/or because non-cpithelial cancers were prevalent among these
sites. Management of head and neck cancer depends largely on the
size of the tumour, nodal status and histological variety. For oral
cancer, surgery cither alone or in combination with radiation had
been the modality of treatment. For oropharyngeal and hypo
pharyngeal cancers, radiation therapy had been administered.
largely because of the advanced stage of the disease at presenta
tion. In the case of nasopharyngeal cancer, chemotherapy had been
administered along with radiation therapy in a large percentage of
cases. Laser surgery had been performed for a few selected sites of
head and neck cancer but was not identified separately in our
analyses. The sequence of treatments, when more than one was
administered, has not been considered. In addition, no attempt has
been made to identify the nature of surgery or level of radiation
dose or chemotherapy schedule in evaluating the efficacy of the
treatment. Furthermore, statistical comparison ha> not been made
of lhe efficacy of different treatments from lhe data presented in
Table 3. mainly because of the likehood of selection bias and of
patients’ reluctance to undergo surgery', which often would have
involved reconstruction and a long stay in hospital. In this study,
we have not looked at disease-free survival to indicate lhe efficacy
of primary treatment for head and neck cancer, and many of lhe
patients during the course of follow-up may have received treat
ment for recurrences or for metastatic disease that subsequently
prolonged their survival: in which case, primary treatment alone
cannot be considered to have cured the disease.
In general, among the patients considered for the study, 25%
came from lhe city of Mumbai, about 45% from the State of
Maharashtra and lhe rest from various states in India. Cancer is not
a notifiable disease and vital statistics records for various states in
India do not provide lhe cause of death. Patients" follow-up status
was ascertained mainly through postal inquiry
*.
Non-availability of
complete addresses for lhe paiients and failure id respond io our
postal inquiry are the factors responsible for a significant
perceniage of loss during the first year of follow-up in our study.
However, lhe assumption lhal paiients lost to follow-up by the end
of 3 years were dead is probably reasonable given ihat the majority
had stage III or IV cancers the last time that they -were seen.
The results of lhe present study are compared in Table 5 with
those from lhe Eurocare study (IARC. 1995). tn our study, the
results are available for subsites of all head amd neck cancers
(fourth digit 1CD). whereas in the Eurocare study some sites are
only available by three-digit site (e.g. 141 - tonguie) or by combi
nations of three-digit codes, as in the case of oral cavity (1CD
143-145). To facilitate comparisons, grouped results arc also
given for lhe Indian data in Table 5. including here the small
number of subsites lhal were excluded from the imain body of the
study. Although the 5-year survival rates show distinct variation
British Journal of Cancer (1998) 77(9), 1514-151If
between the sites and subsites. the results obtained in out study arc
reasonably similar to those observed in the I'urocare study, lhe
importance of reporting survival by suhsiles is clearly brought out
in the case ol longue, oral cavity and pharynx.
Other studies have been reported in the literature cither for all
sites ol head and neck cancer individually or by groups (Flores cl
al. 19X6; Rice and Spiro. 19X9. Steinhart and Lcinsassaer. 1992;
Cole cl al. 1994; Sagar cl al. 1994; Mishra cl al. 1996; Mohanli ct
al. 1996; Grau cl al. 1997). 'Hie direct comparison of our studs
results with those reported in the literature has to be done with
caution, however, especially as the majority of studies report
observed rather than relative survival rates.
Head and neck cancer constitute about one-third of all cancer seen
at Tala Memorial Hospital. Mumbai. The TNM staging distribution of
head and neck cancer in lhe hospital over the years indicates that a
high percentage of cases were seen al an advanced stage of the disease
(HCR. 1996), The present study also showed a large percentage of
patients with advanced disease al presentation. This, in turn, is
reflected in lhe low survival rates observed for some sites of head and
neck cancer in comparison with those seen in European countries.
Many epidemiological studies carried out from high-risk and
low-risk populations have indicated the association of tobacco.
alcohol, lhe chewing of betel quid and some dietary items with
head and neck cancer. Eventually, head and neck cancer control
will best be achieved through primary prevention, although earlier
diagnosis should also be an aim.
ACKNOWLEDGEMENTS
The authors wish to thank the staff of the Hospital Cancer Registry
for their help and assistance and Miss Hilda Sequeira for typing
the manuscript.
REFERENCES
Cole DA. Patel PM, Malar JR. Kenady DE and Maruyama Y (1994) Ftumr of the
mouih cancer. Arch Otolaryngol Head Neck Sttrg 120; 260-263
Flores AD. Dickson Rl. Riding K and Coy P (1986) Cancer of nasopharvnx tn
British Columbia. Ain J Clin Oncol 9 281-291
Grau JJ. Cuchi A. Trascrra J. Firvida JL Arias C. Blanch JL and Estape J (1997)
Follow-up study in head and neck cancer, cure rate according to uurnour
location and stage. Oncol Switzerland. Oncol 54. 38—42
HCR (1996) Hospital Cancer Registry. Desai PB. Rao DN. Rao RS and! Shroff PD
(eds). Annual Repons 1984-94. Tala Memorial Hospital. Mumbai.,
IARC (1992) Cancer Incidence in Five Continents. Parkin DM. Muir OS. W helan
SL. Gao YT. Ferlay J and Powell J (eds). Scientific Publication nu>. 120. Lyon
IARC (1995) Survival of Cancer Patients in Europe. Scientific Publication no, 132.
International Agency for Research on Cancer Lyon
ICD (1978) International Classification of Disease. 9th revision. WHO: Geneva
Mishra RC. Singh DN and Mishra TK (1996). Post operative radiotherapy tn
carcinoma of buccal mucosa - a prospective randomized trial. Eur J Surg
Oncol 22: 502-504
Mohanti BK. Tandon DA. Bahadur S. Rath GK. Tanwar RK. Lal P and. Biswal BM
(1996) Results of definitive radiotherapy in T1 and T2 glottic cancer - Institute
of Rotary Hospital Experience. Australia Rudiol 40 287-290
RGI (1994) The Registrar General of India. SRS-Based Abridged Life Table
1986-90. Occasional Paper no. I.
Rice DH and Spiro RH (1989) Current Concepts tn Head A Neck Canuter. American
Cancer Society: USA
Sagar SM. McKenna G and Nolan MC (1994) A clinical audit of glottic cancer in
Nova Scotia: a paradigm for effectiveness research. Clin Oncol 6. 14-23
Steinhart H and Lcinsassaer D (1992) Treatment and management of sqiuamous cell
carcinoma of the floor mouth. Laryng Rhino Otol. 71. 556-560
UICC (1978) TNM Classification of Malignant Tumours. Harmer MH tied.).
International Union Against Cancer: Geneva
& Cancer Research Campaign 1998
Vol. 33 (June 96) 55 - 75
EPIDEMIOLOGICAL OBSERVATIONS ON
CANCER OF THE OESOPHAGUS
- A REVIEW OF INDIAN STUDIES
Rao D. N., M.Sc.
Divn. of Epidemiology & Biostatislics
Desai P. B„ M.S., F.R.C.S., F.A.C.S., F.l.C.S.
Tata Memorial Hospital,
Ganesh B., M.Sc.,
Dr. Ernest Borges Marg,
-
Parel, Mumbai - 400 012.
India.
SUMMARY
This is an epidemiological review on cancer of the oesophagus. In this attempt, all aspects of
epidemiological factors based on national anti inletnational studies on oesophageal cancer have been
brought out. The problem of this cancer in Indian context has been documented. The association of tobacco
and alcohol habits with oesophageal cancer has been confirmed from the studies conducted in India. There
is an urgent need to educate the c ontnion people about the harmful effect of these two habits and governments
and voluntary organisation should lake effective steps for its prevention.
groups and associated tobacco habits and
dietary factors.
Extensive epidemiological studies
carried out on cancer of the oesophagus have
highlighted the peculiarity of the disease,
high and low incidence being reported in the
same country and in some instance in
geographical areas in the country separated
by few square kilometers.
Clinical Epidemiology
Cancer of the oesophagus has
evinced a great interest among clinicians and
epidemiologists for a long time. A rapid stride
in the diagnostic techniques and increased
rate of microscopic confirmation of the
disease, and use of adjuvant chemotheraupctic management have not made great
dent in the survival rate. Epidemiologists all
oyer the world have paid greater attention to
identify the etiology of the disease and
thereby pave way for its prevention.
The disease is known to occur, in
general, among elderly people. The average
age of oesophageal cancer is about 52 years'.
The disease is predominant among males
compared to females but in areas of high
incidence, the rates in females may exceed
those in males. With the advent of Fine Needle
Aspiration Cytology and endoscopic biopsy,
diagnostic confirmation of this-disease has
increased substantially over the decades. At
present over 90% of cases are microscopically
confirmed. Squamous carcinoma is the
commonest histological type seen in most of
the hospital scries. Adenocarcinoma has been
reported in 7% of cases.
In this review, an attempt has been
made to provide bird's eye view of
epidemiological observations on cancer of
the oesophagus in the subcontinent, its
incidence and mortality, trends, high risk
At the Tata Memorial Hospital,
Bombay, oesophageal cancer accounted for
9-11% of all cancers in 1970's whereas at
present it is about 6-7% of all cancer cases.
Generally around 700-800 cases arc
55 ‘
Indian Journal of Cancer, June 96
Epidemiological review-ca. oesophagus
This accounted for 46.3% of digestive tract
cancers and 6.3%. of total cancer. Distribution
of cases according to segment of oesophagus
as seen in six hospital cancer registries 114 ’
is shown in Table I. At TMH, Bombay,
cancer in the middle third of oesophagus
accounted for 52.8%i of cases followed by
lower third (31.1%) and upper-third of
oesophagus (11.7%). The sex ratio did not
show any variation in the different segments
of oesophagus, maintaining almost two males
diagnosed annually. Fig. I shows the relative
proportion of oesophageal cancer seen in
three cancer hospitals and three general
hospitals in the country2. High percentage of
oesophageal cancer (15%) was observed in
Dibrugarh Cancer Registry, Assam, north
eastern part of India and low percentage
(4%) in Trivandrum Cancer Registry, Kerala,
the southern lip of India. Among the cancer
hospitals, the percentage varied from 6.2%,
in Madras to 8.5% in Bangalore.
RELATIVE FREQUENCY OF OESOPHAGEAL CANCER
INDIA 1986
PERCENT
18 !
15.8 I
BBY BAN MAD
(89)
CANCER HOSPITALS
TVM
■
•
Fig.
to one female ratio. Cancer was more often
seen in middle third of the oesophagus in all
cancer registries except in Madras where
higher percentage ofcanccr was. seen in lower
third of the oesophagus.
At the Tala Memorial Hospital,
Bombay, 2898 oesophageal cancer cases
were recorded among 46,243 total cancer
seen during the three year period 1989-91
■ Indian Journal of Cancer, June 96
DIB
GEN HOSPITALS
Source : NCRP 1986
■ • ■ •Segment Distribution
CHA
56
Rao et al
Table I
Segment Distribution of Oesophageal Cancer Among
Six Hospital Cancer Registries in India
Segment
Bomhay+
%
No.
Cervical Ocs.
60
2.1
*
Trivandrum
Dibrugarh®
Bangalore
*
*
Madras
Chandigarh
*
% No.%
No.
%
%
No.
No.
No.
%
13
4.7
-
9.0
18
11.4
122
12.7
14
11.5
-
-
-
Upper 143rd Ocs.
341
11.7
18
6.5
46
Middle l/3rd Ocs.
1530
52.8
88
31.9
249
48.7
78
49.4
469
48.7
58
47.5
Lower 1 /3rd Oes.
901
31.1
110
39.8
88
17.2
44
27.8
229
23.8
39
32.0
Oesophagus NOS
66
2.3
16
5.8
126
24.7
7
4.4
-
2
0.4
11
7.0
142
Oesophagus Others
Reference:
-
31
2898
276
+ - /, 3.4;
11.3
511
- 2;
158
-
14.8
962
11
9.0
122
@ - 5
Bombay) attend the Tata Memorial Hospital,
Bombay. In order to assess the magnitude of
cancer, the State of Maharashtra has been
broadly divided into six regions, namely,
Konkan - the coastal areas of Arabian sea,
northern part of Bombay as Khandcsh, central
part as Western Ghats and Marathwada, and
the eastern part as Vidharbha and the
remaining part as South Maharashtra. The
region wise attendance of cancer patients
during the period 1989-91 at the Tata
Memorial Hospital indicate that the relative
frequency of oesophageal cancer varies from
6% of all sites in Westc.rn Ghats to 9.7% in
Vidharbha region (Table II).
Maharashtra State
In order to assess the magnitude of
problem of this cancer in the state of
Maharashtra, the two available sources,
namely hospital data and population based
registry data arc used. In the State of
Maharashtra there arc, apart from Bombay
registry, population based registries in Pune
and Nagpur and a rural registry in Barshi,
Sholapur. The age standardised rates for
oesophageal cancer in Pune during 1978-82
were 14.5 per 10’ formalesand 12.4 per 10’
for females and in Nagpur during 1980-82
the incidence rates were 14.3 per 10’and 9.1
per 10’ for males and females respectively 6.
---- Even-in Barshi, a rural registry with a
population of about 3,82.904 persons
covering 346 vilages, oesophageal cancer
incidence rate in 1989 was about 6.7 per
100,000 in males and 1.4 per 100,000 in
females ’.
Available data from metropolitan
registries and rural registry indicate that
oesophageal cancer is common in the State.
Incidence - National Scene
The earliest country-wide estimate
of incidence data was reported from the
survey of cancer cases in different railway
zones in 1967. The average annual incidence
Annually about 5000 cancer patients
from the Maharashtra state (excluding
57
Indian Journal of Cancer, June 96
Epidemiological review-ca. oesophagus
possible to obtain incidence of cancer in
selected metropolitan cities in India. The ageadjusted incidence rates per 100,000 for
cancer of the oesophagus reported from five
metropolitan cancer registries and some
selected countries published in Cancer
Incidence in Five Continents Vol V and VI
arc shown in Fig. 3 *•.
There arc variations
rates per 100.000 for major sites in
gastrointestinal tract arc shown in Fig. 2.
High incidence of oesophageal cancer was
observed in western zone which included
Bombay and Gujarat states and stomach
cancer in southern zone ’.
With the establishment of
population based registries, it has become
Table II
Digestive Cancers at Tata Memorial Hospital 1989 - 91
Areawise attendance of patients from Maharashtra State *
Konkan
Western
Ghats
Khandesh
Marath- •
wada
Vidarbha
South
M.S.
Total
70 (47.6)
998 (50.0)
(9.8)
22 (15.0)
268 (13.4)
54 (56.8) 119 (55.6)
Oesophagus
368 (52.6)
182 (48.0) 205 (45.8)
Stomach
96 (13.7)
62 (16.4)
58 (12.9)
(0.8)
6
(1.3)
-
(9.5)
21
5
(5.3)
19
(8.9)
6 (4.1)
131
2
(2.1)
I
(0.5)
1
(0.7)
16 (0.8)
29 (13.6)
28 (19.0)
299 (15.0)
9
Small Intestine
3
(0.4)
3
Colon
48
(6.9)
21
(5.5)
32
(7.1)
Rectosigmoid
5
(0.7)
6
(1.6)
1
(0.2)
Rectum
91 (13.0)
61
(16.1)
73 (16.3)
17 (17.9)
-
1
(0.7)
13 (0.6)
(6.6)
Anal Canal
17
(2.4)
9
(2.4)
25
(5.6)
2
(2.1)
5
(2.3)
6 (4.1)
64 (3.2)
Liver
24
(3.4)'
18
(4.7)
25
(5.6)
3
(3.2)
8
(3.7)
6 (4.1)
84
— 6 - (0.8)
2
(0.5)
2
(0.4)
1
(1.0)
-
2 (1.4)
13 (0.7)
-
3 (0.2)
Gall Bladder
(4.2)
Bile Duct
1
(0.1)
1
(0.3)
1
(0.2)
-
-
Ampula Vater
6
(0.8)
5
(1.3)
3
(0.7)
-
3
(1.4)
I
(0.7)
18 (0.9)
;11
(1.6)
9
(2.4)
6
(1.3)
-
2
(0.9)
3 (2.0)
31. (1.6)
(3.3)
12
(3.2)
(2.5)
2
7
(3.3) ‘ 1
Pancreas
Retroperitoneum
.23
Total
699
391
448
95
214
147
1994
All Cancer
Cases
5390
3011
3325
678
1222
938
1 4564
Percentage of
Oesophagus
6.8
6.0
6.2
8.0
9.7
7.5
11
(2.1)
* Reference : 1, 3 and 4; Figures in paranthesis show percentages
Indian Journal of Cancer, June 96
58
(0.7)
-.
56 (2.8)
6.8
Rao et al
AVERAGE ANNUAL INCIDENCE RATE
PER 1,00,000 POPULATION
E3 OESOPHAGUS
STOMACH
I
J COLON
■■ RECTUM
Source : Malhotra (1967)
Fig- 2
Iran1". There seems to be high risk areas of
the world which ranges from the Caspian
Littoral in northern Iran through the southern
republics of USSR" -(Turkmenistan,
Kazakhstan and Uzbekstan) to western and
northern China. The other high risk areas
.includes part of eastern South America and
certain areas of. western Europe namely.
France and Switzerland..
in incidence between the Indian registries.
The incidence rate in males varied from 11.4
per 100,000 in Pune to 7.6 in Madras and in
females from 5.6 in'Ahmedabad to 12.4 per
100,000 in Pune. Though rates in India are
not as high as reported in Africa and some
pockets in Iran, incidence rates are 2-3 times
-higher in-malcs and five times higher in
females than the! rates in-Connecticut
Registry, (U.S.). ;
The incidence rate and number of
new cancer cases of 18 different cancers
were estimated for the year 1985 in 24 areas
of the world l2. About 7.6 million (excluding
non melanoma skin cancer) persons in the
world developed cancer discase. pnd majority
of them about 52%, were estimated to be in
the developing countries. Oesophageal cancer
Global Incidence, mortality
Available incidence data from
various parts of the world indicate that (here
is extreme diversity of rates. Incidence rates
are estimated to be as high as 195.3 per
100,000 females and 165.5 for males in
northern Gonbad in the Caspian region of
59
Indian Journal of Cancer, June 96
Epidemiological review-ca. oesophagus
AGE STANDARDISED RATE FOR CA OESOPHAGUS
IN INDIA AND SELECTED COUNTRIES
MALES
63.8 [_
FEMALES
ZIMBABWE BULMRTO • I
25.9 LI____ J
ORAZILZORTE ALEORE
|
2.2
LJ 6-9
COMHECITICUT WHITES
5-3 L! I.OCAHAOA.MWT
4 VUKOH f
, 1
2.9 I.
i4.i rL
CHINA. TIANJIN
■ J 8
16.6 L___
FINLAND
3.3 j
FRANCE.CALADOS
26.5 I
.
ITALY.VXRE8E
I 0.8
7.6 i
RU8SIA.8T.PETEESBARG ’ I 3.7
11.1 I
■I2-*
J 36.1
USSR.TURKM ANISTAN
U.K.. BIRMINGHAM
11-4 L .
7.6 j.
8.2 r _
9.9 r _
INDIA
BOMBAY
madras
bangalore
AHMEDADAD
NAGPUR
14.5 j____ I
20
0
PUKE •
10
30
40
Trends
was ranked 7th among males and 10th'among
females. Over 1,96,000 males and 1,08,000
females were estimated to be with this cancer.
In the Southern Asia region which includes
countries like India, Pakistan, Iran and
Bangladesh, there were 32,000 males and
24,400 females with oesophageal cancer. The
age adjusted rates in Southern Asia were 9.1
in males and 7.1 in females per 10 3
respectively. The mortality rates for
eosophageal cancer in this area were
estimated to be 8.9 per 10 5 in males and 6.7
per females '3. The mortality rates, as high
as 211.2 in males and 136.5 in females per
100,000 have been reported from Linxian
county in China l4.
Indian'Joumalof Cancer, June 96
20
Available data from Bombay, India,
indicate that the age adjusted incidence rate
in males during 1964-72 was 13.7 per 10 3
and it decreased to 10.3 per 10 3 persons
over a period of 25 years ls-16- ”■ ". The
decreasing trend was almost similar in
females. Jayant and Yeole (1987)1’ analysing
the cummulative rates for various birth
cohorts bom between 1913 and 1943 did not
find significant change in the rate over the
years (Table IV). International trends based
on mortality data suggest that the rates are
declining in Nordic countries, Switzerland
and Federal Republic of.Germany and
increasing in France, in US blacks and in
Australia.
60
Rao et al
confirm. Variation in incidence among ethnic
groups has also been reported in the world.
The incidence rates for oesophageal cancer
in U.S.-blacks arc about four fold higher
than those in U.S. whites and the rates in
Singapore Chinese are higher than Singapore
Indians and Singapore Malays 20.
Religious Group
Epidemiological studies carried out
in Bombay have highlighted the variation in
incidence among major religious groups.
Hindus, Muslims, Christians and Parsis arc
the major religious groups living in Bombay.
Age adjusted incidence rates per I00,0<)0 for
Greater Bombay population by religion and
sites arc shown in Table III. Comparison of
incidence rates for oesophagus and stomach
cancer for-both sexes show higher incidence
of oesophageal cancer among Hindus (16.6),
and Muslims (15.4) but not among Christians
and Parsis where higher incidence of stomach
cancer was observed. Parsis, followers of
Zorastrian faith, generally do not indulge in
tobacco habit as it is forbidden by religious
customs. The low rates observed for
oesophageal and stomach cancer among
Parsis compared to other religious groups
could be due to religious ban on tobacco
habits. Further studies-are required to
Year 2000 A.D.
Based on the data from five
metropolitan cancer registries it has been
estimated that in 1992 there were around
6,44,600 cancer cases in India 7 of which
about 40,000 persons were affected with
oesophageal cancer. Based on 1992
estimates,' it is estimated that there would be
about 8,06,000 persons with cancer disease,
of which 57,000 oesophageal cancer cases
would be recorded in 2000 A.D. annually in
India (Fig. 4).
Multiple Primaries
The appearance of second cancer
Table III
Trend of Esophageal Cancer in Greater Bombay 1964-90
Age Adjusted Incidence Rate per 100,000
All Sites
Oesophagus
Year of
Diagnosis
Male
Female
Male
Female
1964-72
13.7
10.5
137.7
- 122.7
126.5
123.6
1973-78
12.7
10.4
1979-84
10.8
8.9
115.1
113.7
1985
11.6
8.9
129.5
. 122.9
8.3
128.5
8.8
130.4
1988
11.4
. 8.0
129.6
122.7
1989
11.5
8.2
130.4
120.4
1990
10.3
9.2
138.9
124.9"
11.4
1986
1987
- . -■
.. 11.8
-
“
’■
120.9
■
118.8
Reference : 15, 16, 17 and 18
61
Indian Journal of Cancer, June 96
Epidemiological review-ca. oesophagus
CANCER IN INDIA BY THE YEAR 2000 AD.
OESOPHAGEAL CANCER
NUMBER (in thousands)
701------------------Hi MALE
50'
FEMALE
EZ] TOTAL
57
40.2
■iuuu
1992
Source: NCRP (1992 )
Fig. 4
squamous cell carcinoma of head and neck
with cancer of oesophagus observed in the
study, has also been reported elsewhere 2:.
among oesophageal cancer patients or second
cancer in oesophagus after primary elsewhere
has been reported in the literature. In a
retrospective Indian study, Vyas et al (1983)21
analysed 177 multiple primary cancers
encountered at the Tata Memorial Hospital,
Bombay during the period 1945-1981. The
study reported that among 38 synchronus
lesions, there was only one male patient with
cancer in oesophagus and larynx diagnosed
simultaneously. Among metachronus lesions,
there were five patients with oesophageal
cancer who developed second primary in the
head and neck region and the site oesophagus
as second primary was reported in 12 cases
out of a total of 71 cases with the first lesion
in head and neck region. The association of
Indian Journal of Cancer, June 96
Analytical Studies
Some of the known associated
factors with cancer of the oesophagus such
as tobacco use, alcohol consumption, dietary
aspects based on the studies carried out in
India and elsewhere are presented and
discussed. Table V gives the summary of
case-control studies conducted in India and
the risk estimates for individual factors.
Tobacco Use
Pan, a preparation consisting of
green betel leaf containing sliced betel nut,
slaked lime and some spicy ingredients, is a
62
Rao et al
controls, Paymaster et al (1937) 25 analysed
the risk factors in particular chewing and
smokig habits. The unique feature of this
study was the assessment of risk factors in
both sexes according to major segments of
the oesophagus. The study also showed that
the risk was higher in both males and females
if tobacco was added to the chewing quid.
Further the study showed increased risk due
to bidi smoking either alone or with tobacco
chewing (Fig. 5). In evaluating the risk
according to segments of the oesophagus the
study showed that chewing and smoking both
were associated with all the segments of
oesophagus in both the sexes. The smoking
habit particularly enhanced the risk for cancer
in upper third of oesophagus in both males
and females (Fig. 6).
common form of chewing habit in India.
Pan is chewed with or without tobacco.
'Bidi', an Indian cigarette, containing
0.2-0.3 gm of tobacco rolled in a dried leaf,
usually temburni leaf (Diospyros
mclanoxylan) is commonly smoked in India.
The different types of smoking in India arc
described in Sanghvi et al (1980)2’.
There arc many other case-control
studies conducted on oesophageal cancer in
India where chewing and smoking have been
implicated as the risk factors. The risk level
varied from two-fold to 16-fold forchcwcrs.
In one of the earliest studies,
Sanghvi et al (1955) 24 found that bidi
smoking was associated with the oesophageal
cancer. The risk estimates were 2.9 for
smokers only, 3.5 for chewers only and 5.3
for chewers and smokers.
Studies by other workers confirmed
the causal role of bidi smoking in
oesophageal cancer. Jussawalla and
Deshpande (1971) 26 estimated the relative
risk for bidi smokers around 8-fold. Jayant
et al (1977) 27 showed that chewing and
In a historic case-control study of
3255 oesophageal cancer patients seen during
the period 1963-71 and 5266 hospital
Table IV
Age adjusted incidence rate per 100,000 by major religious
groups and sites for Greater Bombay 1973-78 *
Major Religious Group
Christian
Muslim
Hindu
Parsi
Male
Female
Male
Female
Male
Female
Male
female
All Sites
150.9
135.6
161.3
145.0
147.0
128.9
106.7
129.5
Oesophagus
16.6
12.6
15.4
14.2
12.3
5.3
5.1
Stomach
9.4
6.1
9.1
6.6
16.3
9.1
5.5
Colon
3.3
3.4
2.7
3.9
3.4
4.1
7.7
Rectum etc.
4.5
2.7
4.5
3.9
4.9
1.8
3.3
3.6
Digestive
41.6
29.7
38.3
33.8
44.0
23.1
30.8
19.4
1.8
■
5.5
4.0
* Reference : 16
63 ,
Indian Journal of Cancer, June 96
Epidemiological review-ca. oesophagus
dual habits (chewing and smoking). Bidi
smoking in particular was a significant risk
factor in this study. A dosc-rcsponsc
relationship for hidi smoking and tobacco
chewing by frequency and duration of habit
was observed in this study. Also swallowing
of quid juice and early age at starling of the
habits were found to be contributory factors
in the development of oesophageal cancer.
smoking acted synergistically in the
development of oesophageal cancer.
A case-control study of 503 male
oesophageal cancer cases and 634 controls
carried out at the Tata Memorial Hospital
gave estimates for chcwcrs, smokers and
alcohol drinkers by dietary practice namely
vegetarian and nonvegetarian diet
For the
vegetarian group, none of the habit categories
showed a significant association with
oesophageal cancer. The study pointed that
the dietary habit is also to be considered in
evaluating the risk (Table VI).
Studies conducted elsewhere have
also demonstrated a dosc-rcsponsc
relationship between quantity of tobacco
smoked and increased risk of oesophageal
cancer
In recent case-control study from
Bangalore, South India, Ramcsh (1993) 29
found a 2-fold excess risk for chewers and
6-fold excess risk for smokers. The risk
enhanced to a level of 13.2 for those with
Doll (1971)
in his extensive
review of both prospective and retrospective
studies on oesophageal cancer stated "tobacco
smoking to be causally associated with
RR FOR TOBACCO CHEWING AND BIDI SMOKING
IN CANCER OESOPHAGUS
CHEWING ONLY
WITH TOBACCO
WITHOUT TOBACCO
WITH TOBACCO
WITHOUT TOBACCO
SMOKING only
BIDI
CIGARETTE
BIDI
CHEWING & CHEWING
TOBACCO & BIDI
TOBACCO i CIGARETTE
TOBACCO i BIDI i CIG
WITHOUT TOBACC i BID
WITHOUT TOBACCO & Cl
Source : Paymaster et all -1973
Indian Journal of Cancer, June 96
64
Rao et al
Table V
Case-control studies on Oesophageal Cancer reported from India
Relative Risk
Author & Year
Chewing
Smoking
Chcw+Smok
1.
Sanghvi cl al (1955) (M)
3.5
2.9
5.3
2.
Paymaster cl al (1968) (M)
(F)
1.9
2.5
2.5
2.4
3.1
3.6
3.
Jussjwalla & Deshpande (1971a)
2.5
3.5 (Non-tob.)
2.1 (Tob.)
2.9 (Bidi)
1.0 (Cig.)
-
6.2
-
2.8
1.6
4.
Paymaster cl al (1973) (M)
(F)
2.1
24
1.9
2.8
5.
Jayant et al (1977)
2.54
2.17
6.15
6.
Jussawalla (1971b)
2.9 (Tob.)
8.0 (Bidi)
36.2
Alcohol
12.0 - 18.1
-
7.
Jussawalla (1981)
5.3 (Bidi)
2.8 (Tob.)
12.1 (Nun-Tob.) 2.7 (Cig.)
8.
Notani & Jayant (1987)
1.5 (NS)
3.2
3.3
9.
Notani (1988)
1.6
4.0
6.3
12.2-47.9
10. Rao el al (1989)
*(NS)
!.3
1.7
1.6
3.8 - 19.5
2.4 (Smok.+Alch.)
2.6
6.4
13.2
11.4-18.0
M - Males;
F - Females
2
II. Ramesh (1993)
NS ■ Statistically not significant
oesophageal cancer consistently in all the
studies". .
Cigarettes with varying tar yields
and use of black tobacco in smoking ” were
found to enhance the risk for oesophageal
cancer. In Caspian Littoral belt of Iran, CookMozaffari et al (1979) u showed cigarette
smoking to be a factor whereas there was no
association between nass-chcwing and
oesophageal cancer:
Alcohol
Besides, tobacco use, alcohol
consumption has been implicated as a risk
factor in the development of oesophageal
cancer. One of the earliest study by Wyndcr
and Bross (1961) M showed that the
proportion of alcohol drinkers were in excess
in the oesophageal cancer group. In Europe,
as well alcohol seems to be related to cancer
of the oesophagus. Perhaps the choice of
beverage, rather than amount of alcohol, is
more important, for tn Africa, beer brewed
from maize seems to be associated with a
higher incidence of oesophageal carcinoma
than in beer brewed from other grains
’
IARC (1988) ” in a monograph on
extensive review on evaluating the
carcinogenic risk to humans from
retrospective cohort studies of alcoholics and
Indian Journal of Cancer, June 96
Epidemiological rcvicw-ca. oesophagus
■
''
brewery workers, and case-control studies
concluded that alcohol beverages were
causally related to cancer of the oesophagus.
Fig. 6
-
alcohol and tobacco chewing habit and 30fold excess risk for those with smoking and
alcohol habit. The risk for alcohol-chewerssmokers combined in that study was as high
as 47.9 times for developing oesophageal
cancer.
Rao et al (1989) ” reported the
Notani (1988) ”, in a case-control
study, from Bombay, showed that a 12-fold
excess risk was found for men who had
Indian Journal, of Cancer, June 96
66
relative risk estimates for regular alcohol
users with the duration of habit in years.
Considering relative risk of alcohol users in
10 years as 1, relative risks for 11-20 years,
21 -30 years and 30+ years arc shown in Fig.
7. The risk increased with the increasing
duration of habit.
'Samsu', a strong liquor, a form of
spirit where alcohol content is equivalent to
that of whisky, is consumed often by Chinese
in Singapore, de Jong ct al (1974) ” in their
study have shown that those who consumed
'samsu' had a 3-fold excess risk for
oesophageal cancer. Similar excess risk for
alcohol drinkers was observed in studies
conducted elsewhere 3’-.'".41-4-4’-44.
Diet
Table VII gives some of the dietary
items that have been identified as significant
factors in the etiology of oesophageal cancer.
The role of major items of daily diet in upper
acrodigcslivc tract cancers was analysed by
Notani and Jayanl (1987) 4’. The study
brought out increased use of red chilli powder
in the diet as a significant risk factor for
oesophageal cancer. Dose-response
relationship of its usage was also shown,
Intake of pulses, vegetables and fruit showed
protective effect. Intake of flesh food (except
Tish) didn't show any positive effect on the
risk of oesophageal cancer.
Intake of very spicy food was found
ALCOHOL & OESOPHAGEAL CANCER
RELATIVE RISK FOR DURATION OF HABIT
1980 - 1984
Source:D N Rao et al Sent in S oncol.vol 5 (1989)
Indianjournal of Cancer, June 96
Epidemiological rcvicw-ca. oesophagus
IRAC (1977)47 conducted in Caspian Littoral
ol Iran and Ziegler ct al (1981) 4“ found that
low intake of pulses, fresh and citrus fruits.
green'vegetables, fish protein, low intake of
dietary Vitamin A and Vitamin C were high
risk factors for oesophageal cancer. Intake of
animal proteins, in the form of fresh meal and
fish, polyunsaturated fats, citrus fruits and oil
intake were found to be protective dietary
items for oesophageal cancer 4’-5U. Earlier,
Segi (1975) 51 reported a direct association
between mortality of oesophageal cancer and
intake of lea-cooked rice gruel. Consumption
of hot tea gruel and hot green tea5-’ and
drinking hot coffee" were found to increase
(he risk of developing oesophageal cancer.
to enhance the risk (2-fold) for oesophageal
cancer compared to nil/modcratc use of
spices in food
Recently consumption of salted lea
in Kashmir has been shown to be a possible
risk factor for oesophageal cancer
Male, a Uruguayan lea made from
the herb Ilex paraguaycnsis is drunk very
hot through a metal straw in large quantities.
Individuals who drink more than 2.5 litres of
mate daily have a 12-fold risk of developing
oesophageal cancer. For those who drink
lots of male and also smoke heavily the risk
is about 22-timcs
Correlation studies by Joint Iran-
Table VI
Relative risk (RR) estimates and confidence intervals for factors studied @
Vegetarian
Non-vegetarian
Total
Chewers
1.07 (NS)
(0.01. 88.9)
1.15 (NS)
(0.9, 1.4)
1.32 (NS)
(0.8, 2.1)
Smokers
1.2 (NS) :
(0.4, 3.7)
2.3 **
(1.3, 3.95)
1.7 ****
(1.1,2.7)
Chewers + Smokers
1.3 (NS)
(0.4,4.2)
1.8 (NS)
(0.9. 3.5)
1.6 (NS)
(0.95, 2.6)
Alcohol + Chewers
-
2.6
*
(1.14.5.9)
2.15 **
(1.03,4.5)
Acohol + Smokers
-
3.1 ****
(1.7,5.4)
2.4 **
(1.5, 3.9)
3.6 (NS)
(0.16,78.6)
4.9 ***
(2.07, 11.5)
3.8 »**
(1.9, 7.9)
Alcohol + Chewers + Smokers
•
!
■@ - Adjusted for~3 levels of age groups and 3 levels of area of residence
* -p < .05; ** - p <.0j; *** - P < -001; »
*
- p < .025 ; - - only one control with this habit and
not done; NS - not significant; RR - is one for non-chewers, non-smokers and non-drinkers
Figures in parentheses show lower and upper confidence limits
Due to small numbers alcohol alone not considered.
(Courtesy - Publishers)
Indian Journal of Cancer, ~Jiine 96
fig.
Rao et al
Table VII
Some selected studies on dietary aspects and Oesophageal Cancer
Sr.
No.
(Ref.
No.)
Author, year of publication
Dietary Items
Remarks
1.
(45)
Notani and Jayant (1987)
Vegetables
Fruits
Fish
Buttermilk
Red chilli powder
> 75 g/cu/month
Tea drinking
(> 2 cup/day)
Protective
Protective
Protective
Protective
Risk
Risk
2.
(28)
Rao et al (1989)
Vegetarian diet
Protective
3.
(47)
Joint Iran-IRAC (1977)
Fresh fruits
Green Vegetables
Fish Protein
Protective
Protective
Protective
4.
(49)
Tuyns et al (1987)
Animal Protein
Polyunsaturated fats
Citrus Fruits
Oil Intake
Protective
Protective
Protective
Protective
5.
(54)
Li et al (1989)
Wheat, com
Risk
6.
(55)
Cheng et al (1992)
Pickled vegetables
Risk
7.
'(56)
(57)
Van Rensberg et al (1985)
Segal (1988)
Maize consumption
Risk
8.
(58)
‘ Yu Yet al (1993)
Pork
Com
Surface Water use
Risk
Risk
Risk
9.
(46)
Kumar et al (1992)
Salted Tea
7 Risk
10.
(29)
Ramesh(!993)
Use of very Spicy food
Risk
}
}
A retrospective cohort-study of
12,693 individuals in Linxian, a high risk
area in China was analysed to identify the
dietary and potential risk factors
They
found that pork consumption, surface water
use, corn as a primary staple food and
The risk tended to increase with the
increased intake of wheat and corn 54 and
intake of pickled vegetable 35. There has
been reports of maize consumption in
different forms and increased risk of
oesophageal cancer 54i-37.
69
Indian Journal of Cancer, June-96
Epidemiological review-ca. oesophagus
the hands and feet
Other 'type of
oesophageal injury may also lead to a high
risk of cancer - Chaga's disease.
infrequent consumption of fresh vegetables
were high risk factors for oesophageal cancer.
Other Risk Factors
Illiteracy
” and low socio
economic groups ” were found to be high
risk groups for oesophageal cancer.
Oesophageal cancer is an important
model for epidemiologic thinking. In the U.S.
oesophageal cancer in Whites is caused
primarily by a combination of cigarette
smoking and high alcohol consumption
although neither factor alone produces much,
if any excess risk. In northern Sweden the
primary cause is the dietary deficiency
associated with the Plummer Vinson
Syndrome and no carcinogen has been
identified. Fortunately the incidence of
Plummer’Vinson Syndrome seems to be
decreasing.
The influence of geo chemical
elements on the risk of oesophageal cancer
was analysed using the data on oesophageal
mortality of 78 countries of Hubei province.
China. High correlation was observed
between some geochemical elements and
oesophageal cancer. Four factors,
metamorphic rock, zinc, copper, chromium
were suspected factors which needed further
study ”.
An excess risk of the order of ten
was found in a follow up study of
vulcanisation workers “. Workers involved
in metal work 40 were high risk groups for
oesophageal cancer.
A careful epidemiological search in
Iran where the high risk and low risk areas
arc only 300 miles apart showed no increase
in exposure to aflatoxins, nitrosamincs.
alcohol or cigarettes. The only pronounced
difference seemed to be bread consumption
in the high risk zone and rice consumption
in the low risk area “■67.
Compared to other Swedish males,
brewery workers have a significantly higher
incidence of cancer of oesophagus, rectum,
pancreas and lung 6I*.
Another association with important
clinical implication is that between carcinoma
of the oesophagus and carcinoma of the head
and neck -. Eighty nine of 850 patients with
oesophageal carcinoma were found to have
cither synchronus or mctachronus squamous
cell head and neck tumours. This was nine
times the expected rate. Both tumours were
thought to be related to the use of tobacco.
Previous exposure to ionising
radiation has also been implicated u. The
long term stasis in untreated achalasia has
also been recognised, although it is of interest
that most of the tumours in the achalasia
occur in the middle of the oesophagus instead
of at the bottom, where presumably the stasis
changes would be the most marked.
Chronic irritation of the oesophageal
----- mucosa-may btt:one of the predisposing
factors leading to carcinoma. It has been
estimated that the incidence in patients with
lye strictures ismuch higher than in age and
- sex matched controls
". Another rare
disease in which cancer of the oesophagus is
increased is tylosis, a genetically transmitted
disease characterised by thickened skin of
Indian Journal of Cancer, June 96
Based on. the reported studies, the
following factors seemed to be involved in
.oesophageal carcinogenesis (1) direct alcohol
and/or acctaldcydc mediated toxic effect on
oesophagus epithelium (2) enhanced
activation of pro-carcinogens by alcohol
70
Rao et al
Conclusion
induced enzymes dependent on cytochrome
P-450(E) (3) nutritional dcficcncics,
especially of zinc (4) Vitamin A and
Riboflavin (5) changes in oesophageal
mobility causing gastroesophageal reflex
with injury (6) and altered salivary
status
71 ”,
- Epidemiological studies conducted
in Indian and in other countries have clearly
demonstrated the association of tobacco and
alcohol habits with oesophageal cancer. It is
lime for the health planners and governments
to take immediate action to prevent this
cancer.
REFERENCES
I.
Hospital Cancer Registry Eds. Desai
P.B., Rao R.S., Rao D.N. and Shroff
7.
NCRP (1992). National Cancer Registry
Programme. Biennial Report - An
epidemiologic study. Indian Council of
Medical Research, New Delhi, 1992. .
8.
Malhotra
9.
IARC (1992): Cancer Incidence in Five
Continents Vol VI (Eds) Parkin D.M.,
P.D. : Annual Report - 1989, Tata
Memorial Hospital, Bombay, 1991.
2.
NCRP (1986). National Cancer Registry
Programme consolidated Hospital
Cancer Registry Report, Indian Council
of Medical Research, New Delhi.
3.
Hospital Cancer Registry Eds. Desai
P.B., Rao R.S., Rao D.N. and Shroff
P.D. : Annual Report - 1990, Tata
Muir C.S., Whelan S.L., Gao Y.T.,
Ferlay J. and Powell J. IARC Scienti fie
Memorial Hospital, Bombay, 1992.
4.
Publication No. 120, Lyon, 1994.
Hospital Cancer Registry Eds. Desai
10. Day N. and Munoz N. : Esophagus In :
Schottenfeld D.K. Fraumeni J.F. Jr. eds:
Cancer Epidemiology and Prevention,
Philadelphia, Saunders, 1982: 569-622.
P.B., Rao R.S., Rao D.N. and Shroff
P.D. : Annual Report - 1991. Tata
Memorial Hospital, Bombay, 1993.
5.
Hospital Cancer Registry Eds. Barua
Barua K.L., and Ali M.S. Annual
Report - 1991 & 1992, Assam Medical
College, Dibfugarh, 1994.
11. IARC (1982) : Cancer Incidence in the
USSR (Eds) Napalkov N.P., Tserkovny
P.,
H.
6.
S.L.
Geographical
distribution of gaslro intestinal cancers
in India with special reference to
causation. Gut. 1967: 8 ; 361-372.
G.F. and Merabishvili V.M. IARC
Scientific Publication No.48, Lyon,
France.
1 ARC (1987): Cancer Incidence in Five
Continents Vol. V (Eds) Muir C.,
12.
Parkin D., PisariLP. and Ferlay J. :■
Estimates of worldwide incidence of
eighteen major cancers in 1985. Int. J.
Cancer, 1993 : 4,54 ; 594-606.
Waterhouse J., Mack T., Powell J.,
Whelan S. IARC Scientific Publication
No.88, Lyon, 1987.
71
Indian Journal of Cancer, June 96
Epidemiological review-ca. oesophagus
13.
Pisani P., Parkin D.M. and Fcrlay J. :
21.
Estimates of the worldwide mortality
from eighteen major cancers in 1985.
Implications for prevention and
projections of future burden. Int. J.
Cancer, 1993: 55, 6 ; 891-903.
cancers in Indian population.
Metachronous and synchronous lesions.
Jr. Surg. Onco., 1983 : 23 ; 239-249.
22.
14.
23.
Jussawalla D.J., Jain D.K., Yeole B.B.,
Natekar M.V. and Rajagopalan T.R.:
24.
Jussawalla D.J., Yeole B.B., Natekar
M.V. : Cancer Incidence in Greater
Jussawalla D.J., Yeole B.B., Natekar
M.V.: An epidemiologic study : Cancer
25.
Jussawalla D.J., Yeole B.B., Natekar
M.V. : Cancer morbidity and mortality
in Greater Bombay. Annual Reports
1985-1990. Indian Cancer Society.
26.
20.
IARC (1990) : Cancer causes,
occurrence and controls. Chief Editor
Tomatis L. IARC Scientific Publication
1990 : No. 100, 55-56, Lyon, France.
'Indian Journal of Cancer,-June-96-
Jussawalla D.J. and Deshpande V.A. :
Evaluation of cancer risk in tobacco
chewers and smoker; An epidemio
logical assessment. Cancer, 1971a : 28;
244-252.
19. Jayant k. and Yeole B.B. : Cancers of
the upper alimentary and respiratory tract
in Bombay, India : A study of incidence
over two decades. Brit. Jr. of Cancer,
1987:56; 847-852.
Paymaster J.C., Gangadharan P. and
Nagaraj Rao D.: Some high risk groups
of the esophagus in cancer detection and
prevention : Proceedings of the Second
International Symposium of cancer
detection and prevention. Bologna, Ed.
Cesare Maltoni Excerpta Medica,
Amsterdam, 1973.
incidence in Greater Bombay (by age
and ward) 1979-84. Indian Cancer
Society, 1988.
18.
Sanghvi L.D., Rao K.C.M. and
Khanolkar V.R.: Smoking and chewing
of tobacco in relation to cancer of the
upper alimentary tract. Brit Med J, 1955:
1111-1114.
Bombay (by religion and sex) 1973-78.
An epidemiblogic study Indian Cancer
Society, 1985.
17.
Sanghvi L.D., Jayant K., Pakhale S.S.:
Tobacco use and cancer in India, World
Smoking and Health, Vol.5, No. 1,4-10;
Spring (published by Anet. Cancer
Society Inc), 1980.
Trends in Cancer Incidence in Greater
Bombay 1964-72, Indian Cancer
Society, 1980.
16.
Goldstein H.M. and Zornoza J.
Association of squamous cell carcinoma
of the head and neck with cancer of the
oesophagus. Am. J. Roentgenol, 1978 :
131 ; 791.
Lu J.B., Yang W.X., Liu J.M., Li Y.S.
and Qin Y.M. : Trends in morbidity
and mortality for oesophageal cancer in
• Linxian county 1959-83. Int. J. Ca., 36,
643-645.
15.
Vyas J.J., Deshpande R.K., Sharma
S. and Desai P.B. : Multiple primary
27.
Jayant K., Balakrishnan V., Sanghvi
L.D. and Jussawalla D.J.
Quantification of the role of smoking
and chewing tobacco in oral, pharyngeal
and oesophageal cancers. Br J. Cancer,
1977:35; 232-235.
IMmiIi iI ■
Rao et al
28.
36.
Rao D.N., Sanghvi L.D. and Desai
P.B. : Epidemiology of oesophageal
cancer. Seminars in surgical oncology,
1989:5; 351-354, 1989.
29.
30.
31.
37. IARC (1988) : Monograph on the
evaluation of (he carcinogenic risk to
humans. Alcohol drinking. Vol.44, Page
57, IARC, Lyon, France.
Ramesh C. : Oesophageal cancer : An
epidemiological study in India. Ph.D.
Thesis. Acta Univcrsitatis Tamperensis.
Ser. A, Vol.385, Univ, of Tampere,
Finland (1993).
Tuyns A.J.: Oesophageal cancer in non
smoking drinkers and in non-drinking
smoker. Int. J. Cancer, 1983 : 32 ;
443-444.
38.
Notani P.N. : Role of alcohol in cancers
of the upper alimentary tract; Use of
models in risk ascssment. Jr. of Epidcm.
and Commun. Health, 1988: 42; 187192.
39.
de Jong U.W., Breslow N., Goh Ewe
Hong J., Sridharan M. and
Shanmugaratnam K. : Aetiological
Doll R. : Oesophageal cancer : A
Preventable disease ?; In: Monograph
No.l, International seminar on
epidemiology of oesophageal cancer.
Bangalore, India, November 3-8, 1971.
factors on oesophageal cancer in
Singapore Chinese. Int. J. Cancer, 1974:
13; 291-303.
40.
32.
La Vecchia C., Liati P., Decarli A.,
Nagrello I. and Franceschi S. : Tar
41.
De Steffani E., MUnoz N., Esteve J.,
Vassalo A., Victoria C.G. and
Tcuchmann S.: Mate drinking, alcohol,
42.
Franceschi S., Bidoli E., Baron A.E.
and La Vecchia C. : Maize and risk of
cancers of the oral cavity, pharynx and
oesophagus in northern Italy. JNCI.
1990: 82; 1407-1411.
Cook-Mozafari P.J., Azordegan F.,
Day N.E., Ressicaud A., Sabai C. and
ArameshB. : Esophageal cancer studies
in the Caspian littoral of Iran; Results of
a case-control study. Br J. Cancer, 1979:
39; 293-309.
35.
Tuyns A.J., Pequignot G. and Jensen
O.M. : Oesophageal cancer in Ille-et-
vilaine in relation to alcohol and tobacco
consumption multiplicative risks (Fr.)
Bull. Cancer, 1977: 64; 63-65.
tobacco, diet and esophageal cancer in
Uruguay. Cancer Res., 1990: 50; 426431.
34.
Yu Mimi C., Garabrant D.H., Peters
J.M. and Mack T.M. : Tobacco,
alcohol, diet, occupation and carcinoma
of the oesophagus. Can. Res., 1988: 48;
3843-3848.
yields of cigarette and the risk of
oesophageal cancer. Int. J. Cancer, 1986:
38; 381-385.
33.
Cook P. : Cancer of the oesophagus in
Africa. Br. J. Cancer, 1971: 25; 853.
43.
KatoL, Nomura A.M., Stcmmermann
G.N. and Chyou P.H, : Prospective
study of the association of alcohol with
cancer of the upper aerodigestivc tract
and other sites. Cancer Causes Control,
1992: 3 (2); 145-151.
Wynder E.L. and Bross I.J. : A study
of etiological factors in cancers of the
oesophagus. Cancer, 1961: 14; 389-413.
73
Indian Journal of Cancer, June 96
lipideiniological review-ca. oesophagus
44.
53.
Kabat G.C., Ng S.K. and Wynder
E.
L.:
Tobacco, alcohol intake and diet
in relation to adenocarcinoma ol the
oesophagus and gastric cardia. Cancer
Causes Control, 1993: 4(2) ; 123-132
45.
Martinez 1. Factors associated with
cancer of the oesophagus, mouth and
pharynx in Puerto Rico. JNCI. 1969:
_42: 1069-1094.
54.
diet in upper acrodigcstivc tract cancer.
Nutr. Cancer. 1987: 10; 103-113.
46.
55.
Kumar R., Nende P., Wacker C.D.,
Spiegelhaldcr B., Preussmann R. and
Siddiqui M. : Caffeine odcsive N-
56.
Joint Iran-IRAC Study group, 1977. :
57.
Ziegler R.G., Morris L.E., Blot W.J.,
Pottern L.M. Hoover R. and Fraumeni
J.F. : Oesophageal cancer among
58.
Tuyns A.J., Riboii E., Doornbos G.
and Pequignot G.
Diet and
59.
Song J. : An epidemiological analysis
on the geographic factors of esophageal
cancer. Chung Hua Liu Hsing Ping
Hscuh Tsa Chih, 1992: 13 (6); 329-332.
60.
Norcll A., Ahlbam A., Lipping H. and
Osterblam L. : Esophageal cancer and
Tavani A., Negri E-, Franceschi S. and
La Vechchia:C- ; Risk factors for
oesophageal icamccr in women in
Northern Italy, Cancer, 1993: 72 (9);
-- 2531-2536.
51.
vulcanisation work. Lancet, 1983 : 1 ;
462-463.
Segi M.: Tea-gruel as a possible factor
for cancer of the oesophagus. Gann,
61.
1975: 66; 199-202-
Carstensen J.M., Bygren L.O. and
Hatschek T. : Cancer incidence among
Swedish brewery workers. Int. J. Cancer,
1990:45:393-396.
52. Hirayama T. : Duet and cancer. Nutr.
Cancer, 1979: 1; 637-81.
Indian Journal of Cancer, June 96
Yu Y., Taylor P.R., Li Y., Dawsey
S.M., Wang G.Q., Guo W.D., Wang
W„ Lkiu B.Q., Blot W.J., Shen Q. et
al : Retrospective cohort study of risk
factors for esophageal cancer in Linxian,
People's Republic of China : Cancer
Causes Control, 1993 : 4 (3) ; 195-202.
oesophageal cancer in Calvados
(France). Nutr. Cancer. 1987; 9; 81-92.
50.
Segal I., Reinach S.G. and DE Beer
M.: Factors associated with esophageal
cancer in Soweto. South Africa. Brit. J.
Cancer, 1988: 58 ; 681-686.
blackman in Washington DC II. Role of
Nutrition. JNCI, 1981; 67; 1199-1206.
49.
Van Rensburg S.J. Brashaw E.S.,
Bradshaw D. and Rose E.F.
Esophageal cancer in Zulu men. South
Africa : A case-control study. Bril. J.
Cancer. 1985: 51 ; 399-405.
Oesophageal cancer studies in the
Caspian Littoral of Iran. Results of
population studies. JNCI. 1977: 59;
1 127-1138.
48.
Cheng K.K., Day N.E., Duffy S.W.,
Lam T.H., Fok M., Wong J. : Pickled
vegetable in the aetiology of oesophageal
cancer in Hong Kong Chinese Lancet,
1992- 339 (8805) . 1314-1318.
Nitroso compounds - I. Nitrosatable
precursors from caffeine and their
potential relevance in the etiology ol
oesophageal and gastric cancer in
Kashmir India : Carcinogenesis, 1992:
13 (11); 2179-2182.
47.
Li G.Y., Guo W„ Li B. and Blot W.J.:
A case-control study of cancer of the
oesophagus and gastric cardia in Linxian.
Im. J. Cancer. 1989; 4.3 ; 755-761.
Notani P.N. and Jayant K. ; Role of
74
Rao et al
62.
Chudecki B. : Radiation cancer ol the
thoracic oesophagus. Br. J. Radiol..
70.
Wyndcr E.L. and Chan P.C. : The
possible role of riboflavin deficiency in
.epithelial neoplasia II Effect ol skin
tumour development. Cancer. 1970 : 26;
1221-124.
71.
Wicbeck M. and Berges VV.
Esophageal and gastric lesions in the
alcoliolic In alcohol related disease in
gastroenterology (Sietz UK. Kommerell
13. eds) Berlin : Springcr-Vcrlag, 1985:
361-375.
1972: 45 ; 303.
63.
Lansing P.B., Ferrante W.A. and
Ochsner J.L. : Carcinoma of the
oesophagus at the site of lye stricture.
Am. J. Surgery, 1969 : I IX ; 10X.
64.
Appelcquist *I, and Salmo M. : Lye
corrosion carcinoma of the oesophagus.
A review of 63 eases. Cancer. 19X0:45;
2655-2658.
65.
Howel-Evans W„ McConnell R.B.,
Clarke C.A. and Sheppard P.M.
Carcinoma of the oesophagus with
Keratosis palmaris et planlaris (tylosis).
O. J. Med., 1958: 27; 413.
66.
Hormozdiari H., Day N.E., Aramesh
B. and Mahboubi E. ; Dietary factors
and oesophageal cancer in the Caspian
Littoral of Iran. Cancer Res., 1975 : 35 ;
493.
67.
72 Maier IL, Born LA., Veith S. et al :
The effect of chronic ethanol
consumption on salivary gland
morphology and function in the rat.
Alcohol Clin. Exp. Res.. 1986 : 10 ;
425-427.
Mahboubi E., Day N.E., Ghadirian P.
and Salmasizadch S. : The negligible
role of alcohol and tobacco in the
etiology of esophageal cancer in Iran A ease - control study. IN : Nieburgs
(cd) : Prevention and Detection of
Cancer, Part II, Detection, New York :
Marcel Dekker, 1978 : 1149-1159.
68.
Gabrial G.N., Schrager T.F. and
Newberne P.M. : Zinc deficiency.
alcohol and retionoid association with
oesophageal cancer in rats. J. Natl.
Cancer Inst., 1982 : 68.; 785-789.
69.
Mak K. M., Leo M. A. and Lieber
C.S. : Effect of ethanol and Vitamin A
deficiency on epithelial cell proliferation
and structure in the rat oesophagus.
Gastroenterology, 1987: 93:362-370.
75
73.
Dutta S.K., Dukehart M., Narang A.
et al : Functional and structural changes
in parotid changes in parotid glands of
alcoholic
cirrhosic
patients.
Gastroenterology, 1989 : 96 ; 510-518.
74.
Paymaster J.C., Sanghvi L.D. and
Gangadharan P.: Cancer tn the gastno
intestinal tract in Western India. Cancer.
1968 : 21 ;279-281.
75.
Jussawalla D.J. : Epidemiological
assessments of aetiology of esophageal
cancer in Greater Bombay. IN :
Monograph No. 1 . International Seminar
on epidemiology of esophageal cancer.
Bangalore, India, 1971b : 4th Nov., 2030.
76.
Jussawalla D.J. : Esophageal cancer id
India. Jr. Can. Res. Clin. Onco. 1981 :
99 ; 29-33.
Indian Journal of Cancer, June 96
■' ■—■—■
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Seminars in Surgical Oncology 5:351-354 (1989)
Epidemiology of Esophageal Cancer
D.N. RAO, MSc, L.D. SANCHV1, PhD, and P.B. DESAI, MS, frcs, facs, fcps
From the Department of Medical Records and Statistics (D.N.R.) and Division of Surgery
(P.B.D.), Tata Memorial Hospital, and the National Cancer Registry Project (ICMR) (L.D.S.), Tata
Memorial Centre, Bombay, India
The incidence of cancer of the oesophagus is high in India but not as high
as the rates reported from the Caspian Littoral of Iran. Incidence data
available for three places in India—Bombay, Madras, and Bangalore—
show regional variations. In Bombay, the rates for males are high com
pared'to Madras and Bangalore.
A case control study of 503 oesophageal cancer cases in males and 634
controls registered at the Tata Memorial Hospital during the period 1980—
84 was carried out to determine the association of oesophageal cancer with
two types of dietary practices, viz., vegetarian and non-vegetarian, in
addition to tobacco and alcohol habits. In the presence of an alcohol habit,
the relative risk for tobacco chewing and smoking was observed to be high
in the non-vegetarian group compared to the vegetarian group. A vege
tarian diet was protective. Further studies are suggested to confirm this
finding.
Key Words: oesophagus, alcohol, tobacco, diet
INTRODUCTION
nations in the incidence of cancer of the oesophat noted not only between countries but also within
le country. The high rates reported from the Casattoral of Iran are not uniformly the same even in
nt areas [ 1 ]. Case control studies conducted in difparts of the world indicate a high association of
habits, alcohol consumption, and diet with cane oesophagus (2,3]. Very few studies from India
ntified the association of alcohol with oesophacer. This is mainly due to lack of information on
consumption. This study addresses itself to the
on of diet, alcohol, and tobacco with oesophacer.
MATERIALS AND METHODS
population-based registries in India provide in
rates for the period 19X2-85 |4-7| and the Bomcer Registry provides incidence data-for the pe>4-85.
hundred three males with oesophageal cancer
ere interviewed during the period 1980-84 and
don on habits and customs were recorded in a
>ro forma. During the same period 634 patients
tnded the hospital but did not have any type of
Ian R. Liss, Inc.
cancer or any infectious disease were also interviewed
for their social habits and customs. The pro forma did not
elucidate minor dietary practices but was restricted to the
two major categories, viz., pure vegetarian and nonvegetarian diet. Hence, the analysis is restricted to the
two categories only. Chewing, smoking, and alcohol
habits were analysed according to diet habit. The study
based on these materials is presented.
RESULTS
Hospital Data
Oesophageal cancer formed about 9% of all cases seen
al the Tata Memorial Hospital. Among 255,077 cancer
cases recorded during 1941-85, 23,742 (9%) cases were
diagnosed as oesophageal cancer. The relative frequency
was 8% among 16,154 total cancers seen in 1941-50,
and in 1981-85 it was 7.2% among 53,641 total cancer
cases seen during these years.
Among 1,612 cases, out of a total of 22,605 cases
seen during 1984-85 the middle third was affected in 781
(48%) cases, lower third in 465 cases (29%), upper third
Address reprint requests to Mr D.N. Rao. Statistician, Tata Memorial
Hospital. Medical Records & Statistics Dept . Parcl. Bombay 4()0
012. India.
------.■
TABLE I. Age-Adjusted (World Population) Incidence Rate (AAR) and Truncated Standardised Rate (TR) for Oesophaj
in Three Population-Based Registries in India
Males
India
Bangalore
Bombay
Madras
U.S.A.
Connecticut (1973-77)
France
(Bas-rhin) (1975-77)
Females
India
Bangalore
Bombay
Madras
United States
Connecticut (1973-77)
France
(Bas-rhin) (1975-77)
1984
1983
1982
---- J
AAR
TR
AAR
TR
AAR
TR
9.3
11.9
7.8
17.1
19.8
16.7
7.1
10.0
7.0
12.1
15.6
13.6
8.4
12.1
7.3
18 9
20.2
13.7
6.6
11.4
8.8
5.3
17.0
8.4
38.6
8.2
9.1
3.6
16.2
13.8
8.7
8.6
7.9
6.2
17.0
15.1
12.2
10.7
8.4
5.9
20.6
16.1
11.9
6.3
8.9
6.0
1.7
0.8
3.3
1.4
in 187 cases (12%), and more than one segment was
involved in 179 cases (11%). The sex ratio (M:F) was
8:1.
1.
Incidence
Table 1 shows the age-adjusted incidence rate of oe
sophageal cancer in three population-based registries for
the period 1982-85. In both sexes, the rates observed in
the Indian population are about thrice as high as that of
United States (Connecticut) rates. The rate for males in
Bombay is high compared to the rates for males in Ban
galore and Madras for all the years, whereas there has
been a variation amongst the females in the three popu
lation-based registries. The rates among females are not
as high as the rates among males.
Case Control Study
The distribution of cases and controls according to
habits (tobacco chewing, smoking, and alcohol con
sumption) and dietary practices are shown in Table II.
Fourteen percent of cases and 28% of controls did not
have such habits. Twenty-six percent of the cases con
sumed alcohol, whereas only 15% of the controls did.
Alcohol consumption includes locally made “desi
liquor” and/or foreign liquor. The habits of chewing
“paan” and smoking are prevalent. “Paan” is made of
betel leaf, areca nut, slaked lime, and catechew with or
without tobacco and other ingredients. No attempt has
been made to distinguish chewers of “paan" with or
without tobacco. Smoking is mainly of a locally made
cigarette, the “bidi,” which consists of tobacco placed
inside dry leaves of a tree of the ebony family. The
AAR .
“bidi.” is 0.5 cm in length and contains an avt
0.216 g of tobacco. Conventional cigarettes i
smoked. In this study, both bidi and cigarette i
are included as smokers of tobacco.
One hundred eighty-six cases (37%) and 150
(24%) belonged to the vegetarian group.
Among oesophageal cancer patients, 186 wi
dents of Bombay; 197 were from Maharashtra su
eluding Bombay; and 120 were from other parts of
Among controls 386 were from Bombay, 136 wc
Maharashtra state, and 113 were from other part
dia.
The relative risks (RR) for different habit grouj
estimated by odds ratio, by stratification over 9 st
TABLE II. Distribution of Habits Among Oesophageal
Cases and Unmatched Controls 1980-84
No. (%)'
Habits
No habits
Chewers
Smokers
Chewers + smokers
Alcohol + chewers
Alcohol + smokers
Alcohol + chewers + smokers
Alcohol alone
Food habits
Vegetarian
Non-vegetarian
Mean age (yr)
Standard deviation
Cases
70
95
119
76
23
76
31
4
(14)
-■ (19)
(24)
(15)
(5)
(15)
(6)
186
(37)
317
(63)
55.0
10.25
“Two controls and nine cases habit status not known.
C
175'
120;
30
67
1?
10
484
12
■
■■ -■..■■v+v.
Epidemiology of Esophageal Cancer
III. Relative Risk Estimates and Confidence Intervals
tors Studied*
+ smokers
+ chewers
Vegetarian
Non-vegctarian
Total
1.07 |NS)
(0.01, 88.9)
1.2 [NS]
(0.4, 3.7)
1.3 [NS]
(0.4. 4.2)
—
1.15 ]NS)
(0.9. 1.4)
**
2.3
(1.3. 3.95)
18 (NS)
(0.9, 3.5)
*
2.6
(1.14. 5.9)
****
3.1
(1-7,5 4)
***
4.9
(2.07, 11.5)
1.32 [NS]
(0.8. 2.1)
****
1.7
(1.1. 2.7)
1.6 (NS)
(0.95, 2.6)
**
2.15
(1.03. 4.5)
**
2.4
(1.5. 3.9)
***
3.8
(1.9. 7.9)
4- smokers
—
+ chewers
okers
3.6 ]NS)
(0.16. 78.6)
stcd for 3 levels of age groups and 3 levels of area of residence
.05; *’P < .01; ***/> < .001; ****/> < .025; —. only one
J with this habit and not doner [NS], not significant. RR is one
1-chewers, non-smokers, and non-drinkers. Firures in parenshows lower and upper confidence limits.
>e (40 years, 40-50, 50 + ) and 3 for area of resi: (Bombay, Maharashtra state excluding Bombay,
if India). The 95% confidence intervals for the esk of RRs were computed using a test-based interval
ation procedure. A chi-square test with 3 df for
ration for the duration of alcohol habit and a chie test with 1 df for trend were carried out [8,9],
e relative risk and confidence interval for various
s are shown in Table III. For the vegetarian group,
of the habit categories showed a significant assom with oesophageal cancer. In contrast to this, for
ion-vegetarian group only non-drinking smokers
ed a significant association, with a relative risk of
In the presence of alcohol habit both chewers and
:rs showed a significant association. The data inthe possibility of protective effect of vegetarian
1 the presence of a tobacco or alcohol habit.
ative risk estimates for regular alcohol users with
on of habit irrespective of duration of other habits
wn in Table IV. Considering relative risk of alcoers in 10 years as 1, relative risks for 21-30 years
) + years are shown. The relative risk increased
icreasing duration of the habit except for the group
353
30+ years. Alcohol with chewing habits shows an in
creasing trend in RR, but all three habits combined did
not show a significant rise in the RR with increasing
duration of alcohol habit. The reason for reductions in
relative risk with duration of habit for 30 + years may be
due to the small number of cases and controls in that
category.
DISCUSSION
Available data indicate that cancer of the oesophagus
is high in India but not as high as reported in some other
parts of the world [1,10]. Compared to Madras and Ban
galore, the rates in Bombay are high in males but not so
distinctly in famales. A variation in incidence rate among
the religious communities in Bombay has been reported.
The incidence rates among Hindus and Muslims were
high compared to the rates in Christians and Parsis [11].
In this study there are certain limitations. Only males
between ages 30 and 75 years were included. Hospital
controls were used instead of population controls. Cases
and controls were interviewed immediately after regis
tration but before any medical examinations. All eligible
cancer cases seen during the period 1980-84 could not be
interviewed for many reasons. The findings of this study
are therefore to be interpreted with caution.
Due to a government prohibition policy and the social
stigma attached to alcohol drinking, information on al
cohol habits in India is very difficult to obtain. The as
sociation of alcohol with cancer of the oesophagus has
already been reported [2,3], In our study this association
was further supported.
The information on consumption of alcohol in terms of
quantity per day was not available. Hence, duration in
years for alcohol habit has been studied for trend. Due to
the small number of cases and controls in the vegetarian
group the RR with duration for alcohol usage could not
be studied separately for vegetarian and non-vegetarian
groups.
Several case control studies showed an association of
dietary factors of possible significance in cancer of the
oesophagus. At the same time some dietary items in the
food played a protective role against cancer of the oe-
IV. Relative Risk Estimates Tor Regular Alcohol Users With Duration of Habit
Years
:getarian + vegetarian group)"
*
1 + chewers
1 + smokers
1 + smokers + chewers6
1 group1-
0-10
11-20
21-30
30 +
P-value for association
P-value for trend
1
1
1
1
1.4
I.K
I.K
1.6
10.«
6.9
7.5
58
19.5
3.K
0.83
3.8
<0.01
<0.01
>0.25
<0.001
<0.001
<0.01
>0.50
<0.001
»hol with any other habit, duration of alcohol habit is considered.
gnificant
el chewers and smokers.
354
Rao et al.
sophagus |12.13). Excessive tea drinking and use of red
chili powder in the diet were shown to be high risk fac
tors for oesophageal cancer 114]. In a prospective cohort
study carried out in Japan, it was shown that the combi
nation of daily smoking and drinking was a major risk
factor, whereas the common use of green and yellow
vegetables in the diet in the presence of the habit de
creased the risk of oesophagus cancer 113].
Our study indicates the protective role played by a
vegetarian diet in cancer of the oesophagus. More studies
are warranted to confirm this finding.
ACKNOWLEDGMENTS
The authors wish to express thanks to the staff of the
Dept, of Medical Records for their assistance in carrying
out the study, and especially to Miss Sequeira for typing
the manuscript.
REFERENCES
1. Manboubi E, Kmet J, Cook PJ, ct al.: Oesophageal cancer studies
in Caspian Littoral of Iran. The Caspian Cancer Registry. Br J
Cancer 28:197, 1973.
2. Tuyns AJ: Oesophageal cancer in non-smoking drinkers and non
drinking smokers. Int J Cancer 32:443-444, 1983.
3. Pottem LM, Morris LE, Blot WJ, et al.: Esophageal cancer
«i"i m .......... . in iikh
■••
among black men in Washington DC. I.
other risk factors. JNCI 67:777-783, 1981.
4. Sanghvi LD. Krishnamurthy S. Jain DK (cds):
Registry; Annual Report for 1983.” New Delhi:
of Medical Research, 1986.
5. Sanghvi LD, Krishnamurthy S, Jain DK (eds):
Registry; Annual Report for 1984 " New Delhi
of Medical Research, 1987.
6. Sanghvi LD, Krishnamurthy S, Jain DK (eds): *
Registry; Annual Report for 1985.” New Delhi:
of Medical Research, 1988.
7. Waterhouse J, Muir C, Shanmugaratnam K,
“Cancer Incidence in Five Continents.” Vol. IV.
tional Agency for Research on Cancer, 1982.
8. Breslow NE, Day NE: “Statistical Methods in
The Analysis of Case Control Studies, Vol. I."
Publication No. 32, Lyon, France: IARC, 1980.
9. Mantel N, Haczcl W: Statistical aspects of the
from retrospective studies of disease. JNCI
10. Napalkov NP, Tserkovny GF, Merabishvili VM,
“Cancer Incidence in the USSR.” Scientific
Lyon, France: IARC, 1982.
11. Jussawalla DJ, Yeole BB, Natekar MV; Cancer in
lems. Cancer 55(5): 1149-1158, 1985.
12. Tuyns AJ, Riboli E, Doombos G. Peguignot G: Diet
ageal cancer in Calvados (France). Nutr Cancer
13. Hirayama T: A cohort study on cancer in Japan. In:
Hirayama T, Hoel DG (eds): “Statistical Methods
Epidemiology.” 1985, 73-91.
14. Notani PN, Jayant K: Role of diet in upper
cancers. Nutr Cancer 10:103-113, 1987.
*; -wvtefe.^8,
1_
Ini. J. Cancer: 58. 469-473 (1994)
c 1994 Wiley-Liss. Inc.
kxW
Aq**w1
PutAC on o< th® Intern
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Ctoco<on
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no«r
*
RISK ASSESSMENT OF TOBACCO, ALCOHOL AND DIET IN ORAL
CANCER—A CASE-CONTROL STUDY
D.N. Rao1-4. B. Ganesh1. R.S. Rao2 and P.B Di sai'
'Divbion of Epidemiology and liiostaliMics. :Taia Memorial Hoxpilal. 'Tula Memorial Centre. I’urel. Hombuv 400 012. India
as "controls” During the period 1980-1984, 713 male patients
A retrospective case-control study of 713 male oral-cancer
patients seen at Tata Memorial Hospital, Bombay, during
with histologically confirmed oral cancer were interviewed.
1980-1984 was undertaken to assess the association between
while 635 controls (unmatched) were chosen from among
chewing, smoking and alcohol habits. Male controls were
those controls who were diagnosed as being free from cancer.
chosen among those persons who attended the hospital during
infectious diseases and benign lesions. Data on females were
the same period and were diagnosed as free from cancer,
also collected but not included in this study because they were
benign tumour and infectious disease. Statistical analysis was
incomplete with regard to habits and customs. In general.
based on unconditional logistic regression and the confidence
chcwcrs lake pan, betel nut, lime and tobacco with some spices
interval for RR was calculated using the standard error of the
and condiments and smokers smoke Indian cigarette called
estimates. Established factors such as tobacco chewing and bidi
smoking showed a significant association with oral cancer. For
bidis (obtained by wrapping 0.2g to 0.3g of tobacco in tendu
the alcohol habit, the relative risk was 1.42 and the dose
leaf), cigarette, chutta (a kind of cigar), hukka and chilum (clay
response relationship, in terms of frequency and duration of the
pipe). Bidi smoking and cigarette smoking arc the commonest
habit, was also observed. The illiterate group showed an almost
smoking habits. Alcohol is locally brewed liquour, mostly from
2-fold significant excess risk compared to the literate group.
palm trees (ethanol content 40%-60%). No distinction has
After adjusting for confounding variables such as age, residence,
been made between types of.alcohol, and it is generally
illiteracy and known factors such as tobacco chewing and bidi
classified as being of local or foreign make. Collection of data
smoking, the study has brought out the significance of a
items on diet was started in 1988 and hence, in this study, diets
non-vegetarian diet as a high-risk factor for oral cancer com
pared-to a vegetarian diet. Further studies are required to- • arc broadly classified as vegetarian or non-vegetarian. Vegetar
identify specific items in the non-vegetarian diet which may.116 - ians. in general; do not consume poultry or fish products and
associated with oral cancer.
avoid animal meat totally. Statistical analysis was based on
C 7994 Wiley-Liss, Inc.
In India, the association of tobacco chewing and’smoking
with oral cancer has been documented in earlier studies
(Sanghvi ct al., 1955; Wahi cl al., 1965; Jussawalla and
Dcshparde, 1971; Jayant ci al., 1977; Notani. 1988; Shanta and
Krishnamurlhi, 1959; Sankaranarayanan el al., 1989, 1990;
Nandakumar ct al., 1990). The dose-response relationship of
tobacco chewing and bidi smoking with oral cancer has also
been demonstrated, not only for oral cancer as a whole but also
for specific sites of oral cancer (Sankaranarayanan ct al., 1989,
1990). Many studies conducted elsewhere have reported a
significant association of cigarette smoking and alcohol drink
ing with oral cancer (Rothman and Keller, 1972) (Wyndcr el
al.. 1957). In India, there are conflicting reports concerning the
association of alcohol with oral cancer (Notani, 1988; Nanda
kumar ct al., 1990). The purpose of the present study is to
explore in detail the effect of alcohol in oral cancer and also to
confirm the earlier findings on tobacco chewing and bidi
smoking in oral cancer. In this country, with its vast ethnic and
geographical variations and a wide variety of habits and
customs, there exists a section of the population which adheres
strictly to a vegetarian diet. An attempt has been made to
evaluate the association of diet and the alcohol habit and its
role in oral cancer.
MATERIAL AND METHODS
Oral cancer includes cancers of lip, anterior two-thirds of
tongue, upper and lower alveolus, floor of mouth, buccal
mucosa and hard palate. In our study, cancers of the base of
the tongue (ICD 1410) and soft palate (ICD 1453) are not
included in the oral cancer category.
Patients attending the hospital were interviewed by 2 trained
social investigators before being clinically examined in the
out-patient department. The questionnaire contained data
items on demographic factors, family history of cancer, tobacco
habits, use of alcohol, frequency, duration, cessation of these
habits and dietary practices. Medical records were subse
unconditional logistic regression and 95% confidence limits for
the estimated odds ratio were obtained from the standard
errors of the estimate (Klcinbaum ct al., 1982) (Mantel and
Hacnszcl. 1959).
RESULTS
Table 1 shows general characteristics of oral cancer patients
and controls. The average ages for cases and controls arc 50.35
yrs and 45 years, respectively. Distribution of cases and
controls according to religion did not differ and hence was not
adjusted in the later analysis. The cancer patients reported a
high illiteracy rate compared to controls (47.9% vs. 28.8%)
Sixty-eight (9.5%) patients and 175 (27.7%) controls did not
have any of the habits considered in this study, while 645
(90.5%) oral cancer patients had at least one of the habits
compared to 460 (72.3%) controls.
Tobacco chewing was more frequent in cases (64.3%) than
in controls (39.5%). In all, 55 patients (7.7%) and 99 (15.6%)
controls were cigarette smokers whereas 297 (41.7%) cases
and 187 (29.4%) controls were bidi smokers. Alcohol alone as
a habit was reported in 6 cases and 10 controls, and alcohol
addicts also had at least one of the other habits, cither tobacco
chewing or smoking. The use of snuff, generally prevalent in
this country, was rarely reported by cither cases or controls.
despite attempts to collect this information. Snuff was, there
fore, excluded from the analysis.
Relative frequencies for cases and" controls and RR esti
mates for chewing, smoking and the alcohol habit, along with
tests of significance, are shown in Table II. For these 3 habits,
the RR was significantly higher than one and when categorized
further, bidi smoking and tobacco chewing emerged as signifi
cant risk factors for oral cancer.
4To whom correspondence and reprint requests should be sent, at
the Division of Epidemiology and Biostatistics. Tata Memorial Hospi
tal. Parel. Bombay 400 012. India. Fax: 022 4146937
quently scrutinized for diagnosis and entered in the forms.
Patients who were diagnosed as cancer-free were considered
It IJJIUH.I1HI
Received: October 5. 1993 and in revised form March 24. 1994.
470
RAO El Al-
bidi smoking and alcohol drinking according to duration of
habit arc shown in Table IV. The trend for dose-response
relationship was statistically significant for all 3 habits. The risk
level increased with the increase in duration of habits.
Food habit and educational status for eases and controls and
their estimated RR arc shown in Table V. The estimates were
obtained after adjusting for 4 age groups ( <35. 35-44. 45-54
and 55 yrs+) and 3 areas of residence (Bombay, Maharashtra
and “other"). Non-vegetarian diet and illiteracy emerged as
high risk factors for oral cancer.
Unconditional logistic regression with multiplicative risk
type was used to fit the model to the data. The factors
TABLE I - GENERAL CHARACTERISTICS OF CANCER PAI I ENTS AND
considered were non-vegetarian diet, tobacco chewing, bidi
CONTROLS. I9WI-19M
smoking, alcohol habit and educational status after adjusting
(%)
*
Case
Controls
)
*
('
for age and residence. The model was fitted with stepwise
addition of factors and the results arc presented in Table VI.
635
1 Total number
713
The non-vegetarian diet showed an 68% excess risk for oral
2 Site
cancer compared to the vegetarian diet with C.I. 1.26—2.24.
—
Lip
30
4.2
The risk level for the non-vegetarian diet remained significant
—
19.9
Ant. longue
142
even after adjusting for factors such as tobacco chewing,
—
Alveolus
123
17.3
.. — . - .
alcohol and bidi smoking. Alcohol addiction carried a 50%
Floor of mouth
6.5
46
—
significant excess risk for oral cancer after adjusting for other
Buccal mucosa
315
44.2
—
factors.
Hard palate
23
3.2
—
Tongue NOS
34
4.7
Information on cessation of the habit—in particular for
3 Age group
tobacco chewing and bidi smoking—was analysed for both
139
21.9
. <35 yrs _______
43
6.0
eases and controls. There were 168 eases and 41 controls who
35-44 yrs
21.7
175
27.5
155
reported cessation of the tobacco habit, with a mean duration
45-54 yrs
156
24.6
227
31.8
in years of 2.23 ± 4.01 and 3.22 ± 3.9, respectively, while 63
55+ yrs
----26.0
288
40.3
165
cases and 28 controls reported stopping bidi smoking, with a
45.4 t 12.9
Average age ± SD
50.35 ± 10.7
mean duration in years of 2.55 ± 4.13 and 2.39 ± 2.74,
4 Residence
respectively. RR estimates for ex-tobacco-chcwcrs and ex-bidi33.4
386
Bombay
60.8
238
136 -- 21.3..... smokers and test of significance arc shown in Tablc-VII. The
— ■' Maharashtra
..--233 • • 32.7
... - 238” ' 33.2 ' ’ 1H - ' 17.5"" *■ relative risk for tobacco chcwcrs did not show a reduction in
•
Other’"**
2
risk for cx-chcwers, whereas for bidi smoking there was a
0.4
Not recorded
4
0.7
substantial reduction in the relative risk for those smokers who
5 Religion
had stopped more than 2 years previously.
40.2
Hindu Maharashtrian
297
41.7
255
Hindu Gujarati
55
7.7
59
9.3
2.4
Sindhi
8
15
1.1
Hindu, others
23.6
197
150
27.6
DISCUSSION
16.4
104
Muslims
109
15.3
Christians
22
3.1
28 * 4.4
This is a retrospective case-control study. Cases and controls
24 .
3.7
Other religions
25
3.5
were interviewed in an out-patient department using the same
Frequency per day of tobacco chewing, bidi smoking and
alcohol drinking along with RR estimates and tests of signifi
cance arc shown in Table III. Tobacco chewing, bidi smoking
and alcohol drinking showed increasing risk with increasing
frequency and the trend was significant. The relative risk
associated with chewing tobacco 21-30 times per day was 10.67
times higher than for non-chewers. Bidi smoking showed a
significant increase in risk only for the frequency categories of
1-10 and 11-20 times per day.
RR estimates and tests of significance for tobacco chewing.
TABLE II - RELATIVE FREQUENCIES OF CASES AND CONTROLS AND RR ESTIMATES FOR CHEWING.
SMOKING AND ALCOHOL HABITS. WITH TESTS OF SIGNIFICANCE
Type of habit
Chewing
Non-chewers
Ch ewers
Chewing type
Non-chewer
Chewing with tobacco
Chewing without tobacco
Chewing betel nut alone
Smoking V:-- - • .
it-t^Non-smoker
-. Smokers Smoking type
Non-smokers
Bidi
Cigarette
Bidi + cigarette
Others (hukka, chilum)
Not recorded
Alcohol drinking
No alcohol
Alcohol
’Confidence interval.
Cases
Controls
R.R.
95% Cl.1 (lower-upper)
251
462
385
250
1.0
2.83
2.26-3.56
<0.001
251
450
5
7
1.0
2.95
0.70
2.15
- ..
. 1.0
1.26
234-3.71
021-2.20
0.60-7.88
<0.001
0307
0.186
337
376
385
234
11
5
. ■- > •'
338
297
337
297
55
7
15
2
338
187
99
7
3
1
1.0
1.59
0.56
1.0
5.01
1.25-2.03
0.38-0.81
0.31-3.21
1.35-21.99
<0.001
<0.001
0.996
0.005
531
182
511
124
1.0
1.42
1.09-1.86
0.008
1.01-136
_
p-value
’
0.037
471
DIET AND ORAI (ANGER
TABU'III - KI LATIVEFRIOUENCH.SOFC ASI.S ANDI ONTROLS AND UK FSTIMATI ,S Wini Tl.STS III
SIGNIFK ANIT FOR I HEWING SMOKING AND AI.I OIIOI BY FKI UUI NCY OF IIABI I
Frequency of habit (pci day)
Tobacco chewing
Non-tobacco-uscr
1-10 times
11-20 times
21-30 times
31 + times
Bidi smoking
No H/o bidi smoking2
1-10 times
11-20 times
21-30 times
31 + times
Not recorded
Alcohol drinking
No alcohol habit
Once
Twice
( uses
( bntrols
R R
MS';. Cl 1 (luwcr-upper)
p-valuc
I rend p vaiuc
263
373
67
7
3
401
203
29
1
1
1 0
2.X0
3.52
10.67
4.57
2.21- 3.55
2 12-5.75
1.32-232.3
0.42-114.7
< 0.001
-.0.1X11
O(XX)
0.150
<0 001
4117
163
66
10
3
440
95
41
52
6
1
1.0
1.85
1.69
1.37
1.80
1.38-2.50
1.09-2.61
0.91 -2.06
0.60-5.62
< _(K)1
0.013
0.109
0.252
531
136
46
511
109
15
1.0
1.20
2.95
M
<0.001
0.90-1.60 ■
1.58-5.60
0.21X1
< 0.001
<0.001
‘Confidence interval -2H/o, history of.
TABLE IV- RELATIVE FREQUENCIES OF CASES AND CONTROLS AND RR ESTIMATES. WITH TESTS OF
SIGNIFICANCE FOR CHEWING. SMOKING AND ALCOHOL BY DURATION OF HABIT
Duration of habit (in year.)
Tobacco chewing
Non-tobacco-user
1-10 yrs
11-20 yrs
21-30 yrs
31 + yrs
Bidi smoking
No H/o bidi smoking-'
I—10 yrs
11-20 yrs
21-30 yrs
31 + yrs
Not recorded
Alcohol drinking
No alcohol habit
1-10 yrs
11-20 yrs
21-30 yrs
31 + yrs
Not recorded
C 1 ' (lower-upper)
p-valuc
Trend p-valuc
1.0
1.28
3.92
4.35
3.83
0.90-1.82
2.70-5.70
2.38-6.37
2.54-5.79
0.149
<0.001
<0.001
<0.001
<0.001
440
64
48
39
43
1
1.0
1.03
1.37
‘ 2.38
2.41
0.70-1.53
0.90-2.09
1.57-3.64
1 62-3.61
0.876
0.120
<0.001
<0.001
*511
531
63
53 ■
67
35
14
46
11
13
1
3
1.0
0.81
1.84
3.16
1.14
Cases
Controls
R R
263
79
131
137
103
401
94
51
48
41
407
61
61
86
96
o
**
95
<0 001
0.54—1-21
1.18-2.89
1.66-6.11
0.47-2.75
0.282
0.005
<0.001
0.756
<0.001
'Confidence interval.-2H/o. history of.
questionnaire, before the medical diagnosis was known to
social investigators. This has largely eliminated interviewer
bias in the collection of data. Only histologically confirmed
oral cancer cases were included in this study. Not all of the oral
cancer patients diagnosed during the period could be inter
viewed, for many reasons. Controls were chosen from among
the interviewed patients who were diagnosed as being free
from cancer, infectious diseases and benign neoplasms. The
use of hospital controls instead of population controls may
have affected the estimates of risk factors.
An attempt has been made to study the role of alcohol and
diet in oral cancer. Diets are broadly classified as vegetarian
and non-vegetarian. The major difference in diet between the
groups is that vegetarians do not consume animal meat, fish
and poultry products. Non-vegetarian food items arc not
commonly consumed on a daily basis in our population mainly
for economic reasons. These arc some of the limitations and
hence the inferences drawn from this study need to be
interpreted with caution.
The association of dietary components with oral cancer.has
already been reported (Nandakumar er al., 1990) (Nolani and
Sanghvi, 1976; Notani and Jayant, 1987; Notani. 1988). It has
been shown that the risk level for oral cancer decreased with
the increasing use of dairy produce, fruit and vegetables but
increased with increasing use of red chillies in the diet and
cereal ragi as a main staple diet (Nandakumar er aL, 1990)
(Notani and Sanghvi, 1976; Notani and Jayant, 1987). In our
study, the non-vegetarian diet showed a 39% excess risk
compared to the vegetarian diet after adjusting for known risk
factors such as tobacco chewing, bidi smoking and alcohol, and
confounding variables such as age, residence and educational
status. In an international ecological study of nutrient predic
tors for oral and oesophageal cancer, the risk level has been
shown to increase with increasing meat and animal fat consump
tion and to decrease with fruit and cabbage consumption
(Hebert ct al., 1993).
Alcohol has been established as a factor in oral cancer in
studies conducted elsewhere (Rothman and Keller, 1972;
Wyndcr er al., 1957). In our study the dose-response relation
ship also showed an increase in risk level with the increase in
duration and frequency of the alcohol habit. Mantcl-Hacnszcl
rm>i:t aiTABIJ V
RR rSTlMATI SANDT1 SI (>t SIGNIHCANCl K>R I DUCATIONAI. STATUS AND Dll VARY HABITS
AIT l.R ADJUSTING KIR AC,!. AND Rl.SIDI N< I._____________________________
(
*
l-uchit
Dietary habits
Vegetarian
Non-vegctarian
Not recorded
Educational status
Literate
Illiterate
Not recorded
RR
9S'« Cl' (lower upper)
/•■Mlllll'
I.3X
567
X
|4X
4X4
3
1.0
1.83
135 2 «
■ O.tXH
362
340
11
450
IX.3
2
1 0
1.97
1.54-2 55
< 0.00!
'Confidence interval
TABLE VI - RR liSTIMA TLS AND TT_S1 ()!• SIGNII K ANCI. FOR NON VI GI.l ARIAN Dll.T. TOBACCO< III WING.
ALCOHOL USI. AND LDIX Al IONAI STATUS IN A STI I’WISI MODI.I.
Factor
•
1 Diet
(0—Veg., 1—Non-vcg.)
2 Diet
(0—Veg., 1—Non-veg.)
Tobacco chewing
(0—Nil. 1—Yes)
.3 Diet
(0—Veg., 1—Non-veg.)
Tobacco chewing
(0—Nil, 1—Yes)
Alcohol
(0—Nil, 1—Yes)
4 Diet
(0—Veg., 1—Non-veg.)
Tobacco chewing
(0—Nil, 1—Yes)
Alcohol
(0—Nil, 1—Yes)
Education
(0—Literate, I—Illiterate)
5 Diet
(0—‘Veg., 1—Non-veg.)
Tobacco chewing
(0—Nil, 1—Yes)
Alcohol
(0—Nil, 1—Yes)
Education
(0—Lit., 1—Illit.)
Bidi
(0—Nil, 1—Yes)
*
RR1
<1.:
/••Value
1.69
1.26-2.24
< .001
1.68
2.66
1.25-2.25
2.10-3.37
< .(XII
< .001
1.49
1.09-2.01
0.010
2.71
2.13-3.43
C.tXll
1.65
1.22-2.22
0.(X)l
1.38
1.01-1.87
0.041
2.55
2.(81-3.24
1.60
1.19-2.16
0.002
1.77
1.38-2.28
<.001
1.39
1.02-1.89
0.0.36
2.64
2.07-3.38
<.001
1.51
1.12-2.05
0.007
1.69
1.31-2.18
<.001
1.37
1.06-1.77
0.017
’
<.(K)1
'Adjusted for age and residence (Bombay-—1, Non Bombay—Oj.-^CJ.—Confidence Interval
The smoking habit, in particular bidi smoking was associated
RR estimates, after adjusting for 4 age groups and 3 areas of
with a significant excess risk of oral cancer, whereas cigarette
residence, were 3.6 for chewing only, 1.7 for smoking. 2.9 for
smoking did not emerge as a high-risk factor. Previous studies
the combined effect of chewing and smoking. 43 for chewing
in India also failed to establish the association between
and alcohol, 2.4 for smoking and alcohol and 8.8 for all 3 habits
(Table VIII). Addition of alcohol to the other habits increased
cigarette smoking and oral cancer (Jussawalla and Deshpande,
the risk for oral cancer. In a recent study in India, it -was
1971; Sankaranarayanan er al., 1990), though a slightly el
reported that estimated relative risks for male oral canccrwere
evated risk has been reported (Nandakumar er aL, 1990).
4.7 for smoking, 2.8 for chewing, 13.1 for smoking and chewing,
The comparison of risk level, as estimated in our study, with
10 for alcohol and chewing, 17.0 for alcohol and smoking, and those reported from other studies in India requires careful
47.1 for alcohol, chewing and smoking in a specific Hindu
evaluation. Account has to be taken of differences between
community (Notani, 1988).
studies in the composition of oral cancer categories and also of
Case-control studies on oral cancer carried out in different
the inclusion or exclusion of females. It is well known that the
parts of India have established unequivocally the association
habit patterns among males and females differ significantly.
with tobacco-chewing habits (Jussawalla and Deshpande, 1971:
Due to the policy of prohibition adopted by many States in
Sanghvi et al., 1955; Wahi el al., 1965). The present study has
India, people do not generally admit to the habit of drinking
and in particular females will never openly admit to this habit.
also brought out the significance of tobacco-chcwing habits in
oral cancer. The dosc-rcsponsc relationship in terms of fre
Literacy as a factor in oral cancer needs careful interpreta
quency per day and duration in years, as reported in earlier
tion. Factors such as poor socio-economic status, under
nourishment. tobacco habits and poor dental hygiene arc
studies, has also been confirmed in this study.
WWM'1!.. ■mm
473
1)11 1 AND ORA! CANCI R
TABLE VII
MANII.I IIAINS/JI RR I.STIMATI-S AND TI.S I ()l SIGNII l( AN(’I I OR I X ( III W| RS AND
I X SMOKI RS
1 actors
Tobacco chewing
Non-chcwcr
Current chewer
l.x-chcwcr 1 vi
> 1 vr
Not recorded
Bidi
Non-smoker
Current smoker
Fix-smoker 1 yr
2 yrs
> 2 yrs
Not recorded
( rfx k
Conlfols
R R'
263
279
124
42
s
339
193
26
15
2
414
231
42
10
11
5
447
159
14
3
10
2
*>'■>
•>
(' 1 • (lower-upper)
/••value
1.0
2.21
5 82
2.57
1 71 2.92
3 64-1(1.21
1 42 5 77
• ().(HI|
• 0.001
• 0.00)
1 0
1.35
2.07
2.19
0 67
1 04-1.78
1.06-4.31
11.52-11 97
0 23-1.92
0.020
0.023
0.225
<1.4112
‘Stratified by 4 age groups ( < 35. 35-44, 45-54 and 55 yrs +) and 3 areas of residence (Bombay,
Maharashtra, others).-2 Confidence interval.
TABI-EVtll
RR I.STIMATI S AND TESTS OF SIGMFK AN( I IOR HABITS Al II R SI RATIFICATION BY A(il
GROUP AND RESIDENT I
Factors
Cases
Controls
R R
W- ( 1
* (Diwcr-Uppcr)
/••value
No habit
Chewer
Smoker
Chewer + smoker
Alcohol
Chewer + alcohol
Smoker + alcohol
Alcohol + chewer + smoker
Others
Not recorded
68
215
106
138
6
44
70
57
4
5
174
12(1
128
86
10
•30
67
15
3
2
1.0
.3.64
1.69
2.93
1.32
4.32
2.44
8.88
1.98
2.51-5.67
1.10-2.68
1.88-4.82
(1.39-5.08
2.33-9.40
1.48-4.18
4.69-23.06
0.34-14.19
<•0.001
0.013
<0.(K)l
0.550
<0.001
<0.001
<0.001
0.370
’Confidence interval.
commonly associated with illiteracy. Further studies arc re
quired to substantiate this finding.
Studies conducted in both high- and low-risk areas have
clearly revealed the,association of the tobacco and alcohol
habits with oral cancer. It is necessary for government and
health planners to lake serious steps, in the lighi
of
*
these
findings, with a view to preventing oral cancer.
ACKNOWLEDGEMENT
The authors express their thanks to all the staff of the
Division for their assistance in carrying out this study. Special
thanks arc due to Mrs. P. Pcshotan and Mrs. R. Vachharajani
who interviewed the cases and controls with great care, and to
the patients who participated.
REFERENCES
Hebert. J.R.. Landon. J. and Mu i er. D.R.. Consumption of meat
Notani, P N. and Sanghvi, L.D., Role of diet in cancers of lhe oral
cavity. Ind. J Cancer. 13, 156-160(1976).
and fruit in relation to oral and oesophageal cancer. A cross-national
study. Nutr. Cancer, 19. 169-179 (1993).
Jayant, K., Balakrishnan. V.. Sanghvi. L.D. and Jvssawalla. DJ..
Quantification of the role of smoking and chewing tobacco in oral.
pharyngeal and oesophageal cancers. Bnt. J Cancer, 35,232-235 (1977).
Jussawali-a. DJ. and Deshpande. V.A.. Evaluation of cancer risk in
tobacco chewers and smokers: an epidemiologic assessment. Cancer,
28, 244-252(1971).
Kleinbaum, D.G., Kupper, L.L. and Morgenstern.
Epidemio
logic research, principles and quantitative methods. Life-time Learning
PubL, Belmont, CA (1982).
ManteuH. and Haenszee, W., Statistical aspects of analysis of data
from retrospective studies of disease. J. nat. Ccwarr InsL, 22, 719-748
(1959). r .
Nandakumar, A., Thimmasetty, K.T., Sreeramareddy. N.M., Venugopal, T.C., Rajanna, Vinutha. A.T., Srintvas and Bhargava
M.K., A population-based case-control investigation on cancers of the
oral cavity in Bangalore. India. Brit. J. Cancer. 62,847-851 (1990).
Notani, P.N., Role of alcohol in cancers of lhe upper alimentary tract:
use of models in risk assessment. J Epidemiol. Commun. tilth, 42,
187-192(1988).
Notani. P.N. and Ja^ ant. K.. Role of diet in upper aerodigestive tract
cancers. Nutr. Cancer. 10, 103-113 (1987).
. • "—.'a • ■■ jnF « wp-------- ;
•
•. ,
•
■
Rothman, K. and Keller, A.Z.. The effect of joint exposure to
alcohol and tobacco on risk of cancer of mouth and pharvnx J chron
Dis.. 25,711-716(1972).
Sanghvi. L.D.. Rao. K.C.M. and Khanolkar, V.R.. Smoking and
chewing of tobacco in relation to cancer of the upper alimentary tract
Brit. med. J., i. 1111 -1114 (1955).
Sankaranarayanan. R.. Duffy, S.W., Day. N.E.. Nair. M.K. and
Padmakumary. G„ A case control investigation of cancer of lhe oral
tongue and the floor of lhe mouth in Southern India. Int. J. Cancer 44
617-621(1989).
Sankaranarayanan. R., Duffy. S.W., Padmakumary. G.. Das .
N.E. and Nair. M.IG. Risk factors for cancer of the buccal and labial
mucosa in Kerala. Southern India. J. Epidemiol. Commun. Hlth 44
286-292(1990).
Shanta. V. and Krishnamurthi, S.. A study of aetiological factors in
oral squamous cell carcinoma. Brit. J. Cancer, 13, 381-388 (1959).
Wahi. P.N.. Kehar. U. and Lahiri, B.. Factors influencing oral and
oropharyngeal cancers in India. Brit. J. Cancer. 19,642-660 (1965).
Wynder. E.L.. Bross. 1J. and Feldman, R.M.. A stud) of the
etiological factors in cancer of the mouth. Cancer 10 1MXL|V»T
(1957).
*7
” 7........
•' ;
VF'’1 T!
W. V 1 u1 hr?'
VOL 35 (June,1998) 65-72
RISK ASSESSMENT OF TOBACCO, ALCOHOL AND DIET IN
CANCERS OF BASE TONGUE AND ORAL TONGUE - A CASE
CONTROL STUDY
D.
Head, Division of Epidemiology
and Bioslastistics,
Tala Memorial Hospital,
Parci, Mumbai - 400 012.
India.
N. Rao, m.sc
P. B, Desai, M S, F.R.C.S. F.A.C.I.. F.IC.S.
SUMMARY________________________________________
This is a retrospective case-control study of male tongue cancer patients seen at Tata memorial
Hospital, Bombay, during the years 1980-84. The purpose of the study was to identify the association
of tobacco, alcohol, diet and literacy status with respect to cancers of two sub sites of tongue namely
anterior portion of the tongue (AT) (ICD 1411-1414) and base of the tongue (BT) (ICD 1410). There
were 142 male AT patients and 495 BT patients interviewed during the period. 635 interviewed male
patients who were free of any disease were considered as control. Bidi smoking was found to be a
significant risk factor for BT patients and tobacco chewing for AT patients respectively. Alcohol
drinkers showed about 45% to 79% excess risk for both sites of tongue cancer. Illiteracy and non
vegetarian diet proved to be a significant factor for AT patients only. The study brings out that
the location of cancer has got a direct bearing with the type of tobacco use and other related habits
and this inturn may provide meaningful interpretation of variations observed in the incidence of tongue
cancer around the world.
INTRODUCTION
PATIENTS AND METHOD
Tongue cancer is generally an
uncommon disease and its reported incidence
is below 5 per 100,000 in about 135 populations
/ countries around the world'. In India, among
5 metropolitan registries the incidence rate of
tongue cancer (ICD 141) in males varied
between 4.7/100,000 in Bangalore and 13.2/
100.000 in Bhopal1 Clinical description,
behaviour and management of longue cancer
depend on the location of the lesion, either in
the base or in the oral tongue Tobacco chewing,
smoking and alcohol habit were established
risk factors for oral and pharyngeal cancer (ICD
140 -149) in general-1-4,5-6’7-8-”. The purpose of
the study is to identify the risk of these
established factors with respect to two sites of
tongue, namely base of the tongue (ICD 1410)
and oral tongue (ICD 141 -144) and its risk with
respect to type of tabacco use.
This is a part ot the retrospective
unmatched case-control study of head and neck
cancer patients who attended the hospital
during the period 1980-84. There were 713
male oral cancer patients and 1498 male
laryngo pharyngeal cancer patients who were
interviewed by two social investigators at the
time of registration in the Out Patient
Department. The patients were interviewed
before clinical examination and thus
investigators were not aware of the diagnosis
of patients. Among them, 142 patients had
cancer in anterior portion of the tongue and 495
patients had cancer in base of the tongue.
During the period, there were 635 interviwed
male patients who were diagnosed as being free
from cancer, infections disease and benien
lesion and these patients were classified as
hospital control. Majority of the male controls
65
Indian Journal of Cancer. June 98
Tobacco, Alcohol, Diet and Tongue Cancers
Table I
General features of patients anil controls
Controls
1. Number
Avg. Age+ S. D.
Range
2. Residence
Bombay
Maharashtra
Others
Unknown
3. Religion
Hindu Maharashtra
Hindu Gujaralh
Sindhi
Hindu Others
Muslim
Christian
Other Religions
4. Habits
No
Yes
5. Type
Chewers
Smokers
Alcohol
(%)
Ant. Tongue
(AT)
Rase Tongue
(RT)
142
49.1 ± 10 9
27 ■ 75
635
45.5 ±12.9
25 ■■ 87
495
54 76 ±9.7
29 •80
386
136
111
2
60.8
21.4
17.5
0.3
56
47
38
1
39.4
33.1
26.8
0.7
186
163
146
37.6
32.9
29.5
255
59
15
150
104
28
24
40.2
9.3
2.4
23.6
16.4
4.4
3.7
62
12
1
39
19
3
6
43.6
8.5
0.7
27.5
13.3
2.1
4.3
168
88
9
119
82
16
13
33.9
17.8
1.8
24.0
16.6
3.2
2.6
175
460
27.6
72.4
23
119
16.2
83.8
36
459
7.3
92.7
251
295
122
39.4
46.8
19.4
76
69
39
54.2
49.3
28.2
172
404
113
34.7
81.6
22.8
whom we had considered for the study attended
the hospital for complaints in head & neck
region and later diagnosed to be of no evidence
of disease or any abnormality. In general,
chewers take pan, betal nut, lime and tobacco
with some spices and condiments and smokers
smoke Indian cigarette called bidis (obtained
by wrapping 0.2g to 0.3g of tobacco in tendu
leaf), cigarette, chutta (a kind of cigar) hukka
and chilum (clay pipe). Bidi smoking and
cigarette smoking are the commonest smoking
habits. Factors considered for the study are
tobacco usage (chewing and smoking) alcohol,
mostly locally brewed from palm trees, (ethanol
content 40%-60%), dietary habits (vegetarian
I nonvegetarian) and literacy status. Vegetarians,
in general do not consume poultry or fish
products and avoid animal meat, The
questionnaire included details of the habit, age
started frequency per day and duration in years,
and cessation of the habit. Unconditional
Indian Journal of Cancer, June 98
logistic regression method was used to estimate
the relative risk for factors. The relative risk
estimates were obtained after stratification of
factors by four age groups (<35yrs, 35-44 yrs,
45-54 yrs. 55 yrs+) and three areas of residence
(Bombay, Maharashtra, Others).
RESULTS
General features like age, place of
residence, religious distribution and habits of
patients and controls are presented in Tabic I.
The religious distribution of cancer patients
and control did not differ and hence is not
adjusted for in the analysis. Cancer patients and
controls were in the age range of 25 years and
87 years. Base tongue cancer patients were
found to be older about five years compared
to anterior tongue cancer patients. Twenty
three patients (16.2%) in anterior tongue (AT)
group and 36 (7.3%) patients in base tongue
(BT) group did not report any of the habits
6 6
Rao <£ Desai
Table 11
KR estimates' for chexers, smokers and alcohol users and tests of significance.
contrnls
Factors
A.
B
Chewen
Nan Chewers
Chewers
382
251
65
76
Not rec orded
Chewing Type
Non Chewers
Tobacco Chewers
4
1
382
233
65
75
//
0
Others
5
I
Not Recorded
Smoking
Non Smokers
Smoke i s
4
1
Non Tvbacco
C.
d.
e
Ant. Tongue (AT)
RR
Case
!
1.0
1.67
(1.12-2.51)
Base Tongue (BT)
Cases
RR
323
172
1.0
0.76NS
(0.96-5.27)
10
1.81
(1.21-2.73)
323
15d
14
0.67 NS
(0.03-7.70)
4
1.0
0.70
(0.5-0.9)
1.32 NS
(0.5-3.7)
0.60 NS
(0.1-3.3)
•
336
72
295
69
Not Recorded
Smoking Type
Non Smokers
Bidi
4
1
337
186
73
53
Cigarette
98
10
Bidi + Cigarette
7
2
Others
3
3
Not Recorded
Alcohol
Non User
Alcohol User
4
1
509
122
102
39
Not Recorded
4
1
1.0
0.97 NS
(0.65-1.dd)
91
404
1.0
4.34
(3.2-S.9)
•
1.0
1.12 NS
(0.73-!.7d)
0.55 NS
(0.24-1.15)
0.92 NS
(O.I2-5.d3)
3.02 NS
(0.44-21.3)
91
360
35
6
3
1.0
5.90
(4.2-R.2)
1.45 NS
(0.9-2.5)
2 05 NS
(0.5-8.4)
2.29 NS
(0.3-19.6)
-
1.0
1.79
(1.12-2.84)
382
113
1.0
1.45
(1.1-2.1)
•
♦ - Stratified by 4 a/;r groups and 3 ureas of residence. NS • Not Significant
The figures in() indicate lower and upper Confidence Interval
RR estimates for chcwcrs, smokers and
alchohol drinkers with confidence intervals arc
shown in Table II. Chewcrs had excess risk for
anterior tongue cancer with relative risk
(RR)1.81 (C.l. 1.2-2.7) whereas smokers had
4.3 times excess risk (C.l.3.2-5.9) for base
tongue cancer. When categorised further.
tobacco chewing emerged as a significant risk
considered in the study. Alcohol drinking was
reported in 122 controls (19.4%), 39 (28.2%)
patients in AT group and 113 (22.8%) patients
in BT group. There was notable variation of
habits with respect to two cancer groups.
Among AT group, chewing habit was
predominant (54%) whereas among BT group
smoking habit was commonly observed (81 %).
67
Indian Journal of Cancer. June 98
Tobacco, Alcohol, Diet and Tongue Cancers
Table III
RR* for bidl smoking and use of alcohol and tests of significance ai cording to frequency per day
*
Factor
1.
2.
3.
controls
Ant. Tongue
Case
(AT)
*
RR
Base Tongue (BT)
*
Cases
1.0
1.23 A'S
(0.69-2.2)
0.84
(0.78-1.78)
1.39 NS
(0.72-2.67)
129
141
Bidi
Non User
1 - 10 times
438
79
86
25
J J - 20 times
54
11
21-30 times
56
18
31 + times
4
1
Not Recorded
Alcohol
Non User
Once
4
1
509
108
102
27
Twice
14
12
Not Recorded
Tobacco
Non User
1 - 10 times
4
1
398
203
66
67
11- 20 times
28
7
21-30 times
1
1
31 + times
1
Not Recorded
4
94
107
24
1.0
1.46 NS
(0.85-2.-48)
3.70
(1.69-10.8)
382
99
1.0
1.88
(1.24-2.87)
1.65 NS
(0.62-4.64)
8.3
(0.12-391.3)
341
135
14
14
1
4
RR
1.0
4.32
(3.04 - 6.7)
5.15
(3.39-8.5)
4.8
13.2-7.7)
14.3
(4.1-50.7)
1.0
1.51
(1.1-2.27)
1.14 NS
(0.44-3.1)
1.0
0.7
(0.5-9.5)
0.5 NS
(0.3-1.2)
1.1 NS
(0.03-45.1)
10.04 NS
(0.5-209.40)
/
+ - Stratified by 4 age groups and J areas of residence
< - Trend Significant for tobacco and alcohol
• - Trend Significant for bidi and alcohol
NS • Not Significant; The figures in () indicate lower lower and upper Confidence Interval
chewing showed statistically significant trends
with the increse in the frequency and duration
of the habits among BT and AT groups
respectively. The trend analysis for duration of
chewing habit was also statistically significant
foranlerior tongue cancer. Smokers who smoked
bidi 31 times or more per day had about 14.3
times excess risk of getting base tongue cancer
and the risk level for over 30 years of habit
showed about 5 fold risk compared to non
smokers. Cigarette smoking did not emerge as
a risk factor for both groups cither in terms of
frequency or duration of the habit. The trend
for AT group only and bidi smoking was an
important risk factor for BT group only.
Cigarette smoking did not emerge as a
significant risk factor for two sites. Alcohol
drinking was found to be a significant risk
factor for both subsites of tongue cancer and
the estimated relative risk ranged between 1.45
and 1.79. Further the result of trend analysis
with respect to frequency and duration of these
habits for anterior tongue and base tongue
cancers are separately shown in Table III and
IV. The trend analysis again confirmed that the
two habits namely bidi smoking and tobacco
Indian Journal of Cancer, June 98
6 8
Rao <t Desai
Table IV
RR estimates • for bidi smoking and use of alcohol and tests of significance according to duration @
Factors
1.
2.
3.
controls
Ant. Tongue
Case
(AT) If
RR
Bidi
Non User
1 - 10 yrs
438
63
86
7
129
30
11-20 yrs
48
16
21-30 yrs
39
12
31 + yrs
43
20
1.0
0.52 NS
(0.2- 1.3)
1.39 NS
(0.7-2.7)
1.24 NS
(0.6-2.8)
1.61 NS
(0.8-3.4)
Not Recorded
Alcohol
Non User
/ - 10 yrs
4
1
509
62
102
n
382
38
II ■ 20 yrs
35
12
21 - 30 yrs
14
12
31 + yrs
11
4
1.0
1.21 NS
(O.6-2.6)
2.0
(0.9-4.4)
3.3
(1.4-8.9)
1.3 NS
(0.3-4.8)
Not Recorded
Tobacco
Non User
1-10 times
4
1
398
93
66
20
341
28
11-20 times
51
25
21-30 times
48
19
31 + limes
41
11
1.0
2.04
(1.04-3.86)
3.58
(1.9-7.3)
1.83
(0.92-3.6)
0.77 NS
(0.33-1.77)
Not Recorded
4
1
Base Tongue (BT)
*
Cases
RR
64
123
149
35
32
8
31
47
48
1.0
2.2
(1.3 ■ 4.1)
4.5
(3.1-8.7)
7.7
(4.8-13.0)
5.1
(3.3-83)
1.0
1.5 NS
(0.9-2.5)
1.6 NS
(0.9-2.9)
2.0
(I.0-4.6)
0.5 NS
(0.2-1.4)
1.0
0.5
(0.3-0.89)
0.9
(0.5-1.5)
0.9
(0.5-1.4)
0.6
(0.4-0.99)
-
♦ - Stratified by 4 age groups and 3 areas of residence
t - Trend Significant foe tobacco A tdcohal; •- Trend Significant for bidi & alcohol
NS ■ Not Significant The figures in () indicate tenter and upper Confidence Interns!
analysis for alcohol habit according to frequency
and duration showed a statistically significant
association with tongue cancer.
(RR=2.1C. 1.1.41-3.2) for AT cancer and 1.42
times excess risk (C.I. 1.08 - 153) for BT
cancer. Patients who took non vegetarian diet
were found to have two fold risk (RR
=2.18C.1.1.27-3.84) for anterior tongue cancer
only and for BT cancer there was a 34%
significant reduction in risk with RR 0.66 (CI
0.48-0.89).
The literacy status and dietary factors
were also analysed for the risk of these two
sites after stratification by 4 age groups and
3 types of residence. The estimates were
obtained without adjusting for tobacco and
alcohol habits. Considering the risk among
literate as unity, illiterates showed two fold risk
Table IV shows the unconditional
logistic regression model for two cancer sites.
69
Indian Journal of Cancer. June 98
Tobacco, Alcohol, Diet and Tongue Cancers
Table V
Um onditional logistic regression model' using five factors for two sub sites of tongue
Site / Factor
Anterior Tongue (AT)
Bidi (l = Yes; 0=No)
Alcohol (J=Yeas; 0-No)
Illiteracy (1 = Yes; 0=No)
Nonvegerarian (l=Yes; 0=No)
Tobacco Chewing (. = Yeas 0= No)
RR
Confidence Interval
P Value
1.0
1.54
1.81
1.74
1.74
0.66 - 1.52
0.97 -2.44
1.198 ■ 2.73
1.014 -2.995
1.173 - 2.571
p = 0.998
P = 0.063
p -0.005
P =0.044
P = 0.006
Rase Tongue (BT)
Bidi (I=Yeas; 0=No)
Alcohol (l=Yes; 0--No)
Illiteracy (1= Yes; 0=No)
Nonvegetarian (I-Yes; 0=No)
Tobacco Chewing '/= Yes; 0=No)
4.69
1.34
1.22
0.59
0.88
3.51 - 6.27
0.93 - 1.93
0.90 ■ 1.66
0.43 - 0.83
0.65 ■ 1.19
P <.001
P =0.116
P = 0.195
P = 0.002
P = 0.402
Tongue (AT + BT)
Bidi (l=Yes 0=No
*
Alcohol (l=Yes; = No)
Illiteracy (1 = Yes; i)= No)
Nonvegerarian (!=Ycs; 0=No)
Tobacco Chewing *1-Yest 0=No)
3.32
J 38
1.41
0 77
1.13
2.56 - 4.3
0.99 - 1.9
1.08 - 1.85
0.56 - 1.04
0.87 - 1.47
p <.001
p = 0.05
P=O.OI3
P = 0.089
P = 0.36
♦ - Adjmlrd Jar 4 agr griups and 3 arras of midener
interviewed, for many reasons. Controls were
chosen from among the interviewed patients
who were diagnosed as being free from cancer,
infectious diseases and benign ncoplams. The
use of hospital controls instead of population
controls may have affected the estimates of risk
factors. Previous studies carried out in India,
have identified risk factors for oral cancer (ICD
140-145) or for cancers of two or three sites
of oral cavity6-7-’-’-10. In an earlier study from
Bombay, the risk factors for individual sites
of oral cavity, pharynx and larynx were analyzed
and estimated but the study did not evaluate
for alcohol and dietary factors4.
The mode] confirmed the significance of tobacco
chewing, nonvegetarian diet, and illiteracy
status for anterior tongue cancer. Bidi smoking
emerged as a significant risk factor for the base
tongue cancer with RR 4.69 (C I. 3.51-6.27).
The risk due to alcohol habit was higher than
unity in both sites but not found to be statistically
significant in this multivariate model.
DISCUSSION
Epidemiological research in recent times
has become possible to address issues to the
specific sites ofcancer according to International
Classification of Diseases (ICD 9th). Data on
cancer incidence arc being reported with certain
accuracy upto the fourth digit rubrics of ICD.
This retrospective case control study was
carried out to evalute the association of tobacco
and alcohol habits with respect to cancer in the
base and oral longue. Only histologically
confirmed tongue cancer eases were included
in this study. Not all of the tongue cancer
patients diagnosed during the period could be
Indian Journal of Cancer, June 98
The composition of habit pattern between
control and cancer groups shows the
predominance of smoking habit among BT
group (81.6%) and chewing habit among AT
group (54.2%). The study has brought out that
the location of cancer in the tongue to some
extent depends upon the type of tobacco habit.
Bidi smokers in particualr had a higher risk for
70
Rao << Desai
larynx. The association of dietary factors with
oral cancer in particular has been confirmed
in the studies conducted from India. Non
vegetarian diet compared to vegetarian diet
seemed to increase the risk for AT cancer.
Further studies are required to assess the risk
factors among individual items of
nonvegetarian diet after controlling the known
protective factors.
Base Tongue cancer than for Ant. Tongue
cancer. The dose response relationship was also
established according to frequency and duration
of hidi smoking habit for BT cancer and
tobacco chewing habit for AT cancer. When
the two cancer groups were combined, (he
model showed significant association of bidi
smoking, alcohol, and illiteracy with tongue
cancer. Tobacco chewing and nonvegetarian
diet did not emerge as significant.
Illiterates had a higher risk for anterior
tongue cancer in our study. This may he due
to the different life style, habits and customs.
poor socio economic status, dietary habits and
poor oral hygiene among illiterates compared
to literates. These factors need to be considered
in future studies. It is necessary to have a new
strategy for cancer control and prevention for
such high risk groups.
The average age of the patients with
respect to two cancer group show variation.
This is also observed from the Cancer Registry
data of the hospital for the last five years".
Patients with AT cancer were found to be about
five years younger compared to BT cancer
patients in the hospital data also, further
studies arc required to identify factors
responsible for this.
In conclusion, the study brings out that
the location of cancer has got a direct bearing
with the type of tobacco use and other related
habits and this inturn may provide meaningful
interpretation of variations observed in the
incidence of tongue cancer around the world.
Alcohol as a high risk factor has been
reported for oral cavity cancer in general.
Previous studies showed that alcohol habit is
associated with oral cancer'1. In this study also
it has been shown to be associated with AT
cancer but not with BT cancer. It is necessary
to collect more information on alcohol habit
in our population and also the type of liquor
and quantity consumed to provide a meaningful
estimate of the risk involved with oral cancer
and in general for al! cancer.
ACKNOWLEDGEMENT
The authors express their thanks to the
staff of the Division for their assistance in
carrying out this study. -Special thanks arc due
to MRs. P. R. Peshotan and Mrs. R. U.
Vachharajani who interviewed the eases and
controls with great care, and to the patients
who participated.
Many studies have identified the role of
dietary factors in cancer of mouth, pharynx and
REFERENCES
1.
Parkin D. M., Muir C. S. Whelan S. L.
3.
Cancer Incidence in Five Continents. Vol
VI (EDS) 1ARC Scientific Publication No
120. Lyon. 1992.
4.
2.
Sanghvi L. D.. Rao K. C. M. and
Khanolkar V. R.: Smoking and chewing
of tobacco in relation to cancer of the
upper alimentary tract. British Medical
Journal. 1955:1:1111.
Gao Y. T., Ferlay J. and Powell J. :
National Cancer Registry
Programme Biennial Report - An
epidemiologic study. Indian Council of
Medical Research. New Delhi. 1992.
NCRP :
Jussawalla D. J. and Deshpande
V. A. : Evaluation of cancer risk in
tobacco chcwers and smokers : an
epidemiologic assessment Cancer.
1971:28.2-44-252.
7 I
Indian Journal <>; Cancer. June 98
Tobacco, Alcohol, Diet anil Tongue Cancels
5.
Notani P. N. : Role of alcohol in cancers
8.
of the upper alimentary tract : use of
models in risk assessment J. Epidemiol
Community Health 1988:42;’87-192.
6.
chewing, alcohol and nasal snuff in cancer
of the gingiva in Kerala, India Br. j.
Cancer, 1989(a):60;638.
Nandakumar A., Thimmasetty K. T-,
9.
Sreeramareddy N. M. Venugopal T.
Sankarnarayanan R., Duffy S. W., Day
A ease - control study
investigation of cancer of the oral tongue
and the floor mouth in Southern India. Int.
J. Cancer, 1989(b);44;617.
C. , Rajanna Vinutha, A. T. Srinivas,
and Bhargava M. K. : A population -
N. E. et al :
based case-control investigation on cancers
of the oral cavity in Bangalore, India, Br.
J. Cancer, 1990;62,847.
7.
Sankarnarayanan R., Duffy S. W.,
Padmakumary G., ct al : Tobacco
10.
Rao D. N., Ganesh B., Rao R. S. and
Desai P. B. : Risk assesment of tobacco,
alcohol and diet in oral cancer - A ease
control study. Int. J. Cancer, 1994:58;469473.
11.
Notani P. N. and Jayant K. : Role of
diet in upper aerodigestive tract cancer.
Nulr. Cancer, 1987,10,103-113.
Hospital Cancer Registry (1991 -93).Desai
P. B. Rao R. S. Rao., D. N. and Shroff
P. D. Annual Repons - 1989-1992, Tata
Memorial Hospital Bombay.
Indian Journal of Cancer, June 98
72
T)rs' IXo
VOL. 35 {March, 1998) 10-18
ESTIMATE OF CANCER INCIDENCE IN INDIA IN 1991
Division of Epidemiology & B iostatistics.
Tata Memorial Hospital.
Parel, Mumbai - 400 012.
Maharashtra
India.
D. N. Rao,, m Sc
B. Ganesh, Ph d
SUMMARY_________________________________________________________
Cancer incidence and eighteen site-specific age standardised rates in India were estimated for the year
1991. With the establishment of National Cancer Registry Programme, incidence rates per 100,000 are
available from six metropolitan registries and one rural registry. Using population census data for India
in 1991, about 609,vw new cancer cases weie
iiu-e uce/>
,n ,lic country ,,t , 991
I'he estimated age stanaaraised rates per iUU.UUU were 96.4for males and 88.2forfemaies. Thefive most
common cancers were lung 110.6%) pharynx (9.1%), oesophagus (6.7%). tongue (6.6%) and stomach
(5.7%) among males and cervix (23.5%). breast (19.3%). ovary (5.5%) oesophagus (4.4%). and mouth
(3.9%) among females. A comparison of estimated ASRsfor two two largest countries in Asia I China and
India) showed differences m the pattern of cancer.
PATIENTS AND METHOD
INTRODUCTION
In India, a population census was carried
out for the year 1991 for the various states in the
country and there were 843.93.0861 (M = 437.1
mill ion. F=406.8 million, people in the countryDue to non-availability of age and sex distribution
of the population for each state, the relative
frequencies of the broad age groups for the
country were used namely. 12.8% for 0 to4 yrs.
22.9% for 5 to 14yrs. 57.7% for 15 to 59 yrs. and
6.6% for 60+- yrs-’ The sex ratio for each state in
the country has enabled us to estimate the general
population of each state according to above
specified age groups and sex distribution. The
cancer incidence rates per 100.000 according to
age. sex and sitewise were available for the year
1991 from the metropolitan cities (namely Delhi.
Bhopal, Mumbai and Bangalore) and from
Ahmedabad registry' (1988-89). Madras registry
(1982-91) and a rural registry at Barshi,
The estimates of cancer incidence
reported for the year 1985 indicated that there
were 7.6 million cancer cases in the world and
over 50% of them were diagnosed in the
developing countries. In the Southern Asia region
alone (India. Pakistan. Bangladesh. Snlanka
and Iran i there were 806.000 cancer patients
The age standardised rates per lOU.OOO in 1985
for Southern Asia were 106.6 and 111.1 for
males and females respectively With the
establishment of National Cancer Registry
Programme in India, it has been possible to
identify cancer incidence in six selected
metropolitan cities and in one rural area. This
should help to assess’ cancer burden of the
country. The purpose of this paper is to estimate
the cancer incidence for the whole country in
1991 using available data.
Indian Journal of Cancer. March 98
10 .
Rao &. Ganesh
Rao <5 Ganesh
Table -I
Estimated Incidence rates per 100,000 for five regions of letba by age group and sex in 1991
Age
(in yean)
0-4
5’14
15-59
60+
% of Indian
Population
*
ASR
Northern1
F
M
F
M
Eastern1
F
17.1
13.0
62.1
538 5
13.2
73
99 I
465 5
3.0
7.0
553
622.0
2.9
5.2
73 1
331.9
2.9
8.1
52.3
606.7
2.9
5 1
71.4
324 8
7.3
6.8
24.7
23.7
25.9
98.9
M
99.8
111 6
CentraP
101.0
803
‘Ave itandardised rale per 100.000
; Delhi. nutiuHu. Punjab. Himachal Pradesh, Jammu L fash"”
Western1
M
F
9.4
Southern1
M
F
AH Regions
M
F
61.2
517.9
62
4.7
75.9
3401
9.2
7.3
58.4
474 6
7.7
58
98 2
412.2
66
79
56.3
558.1
5.4
5.4
810
359.8
26.1
19.4
19.5
22.7
23.9
100 0
100 0
78.4
95.0
83.0
88.6
812
96 4
88.2
7.7
Chandigarh
2 Uttar Pradesh and MaJnya Praaesh
3 Bihar. West Bengal. Orissa. .Assam and North Eastern states (Tnpura. Manipur. Meghaiaya. Naguland. Arunachal Pradesh. Mtzarum and
Sihkim)
} 4 Maharashtra. Gujarat. Goa. Rajasthan. Daman de Diu and Dadra d Nagar Haveli
5 Tamil Nadu. Kerala. Karnataka. Pondicherry. Andhra Pradesh. Lakshadweep and Andaman A Nicobar Island
Maharashtra (1988-92)
*.
The Delhi incidence
data5 were used to estimate the number of new
cancer cases for northern states (Punjab, Haryana.
Jammu & Kashmir, Himachal Pradesh and
Chandigarh region). The Ahmedabad data6
were used for the western states (Gujarath and
Rajasthan) and Bhopal data’ forthe states, namely
Uttar Pradesh. Madhya Pradesh. West Bengal,
Bihar. Orissa and Assam. Similarly the Mumbai
datas were used for the states of Maharashtra
and Goa and Bangalore data' for Karnataka and
Andhra Pradesh. Madras incidence data were
used to estimate the number of cancer cases in
the states of Tamilnadu. Kerala and
Pondicherry10. Though cancer incidence of a
metropolitan city in a state may not be a
representative of the entire state or the region, it
could be the best possible alternative available
for the extrapolation. A special computer
program was prepared to estimate the number of
cancer cases for each state usingrineof the six
representative registry data (4 age'groups and
sex). The crude incidence rates per 100,000 for
each sex in seven registries were recalculated
for the age groups (namely 0 to 4,5 to 14, 15 to
59 and 60+ yrs) and then multiplied by the
corresponding age groups of state populauon to
obtain the number of cancer patients. Since
there were no representative incidence data
available in the north eastern region (mostly
rural areas - see Table I), rural registry incidence
data available from Barshi were used to estimate
the total number of cancer patients tn that region.
In order to estimate the frequency of eighteen
site-specific cancers for each State, site and sex
specific percentages published by one of the
above mentioned seven registries were used.
Forthe state of Assam. Nonh Eastern States and
Kerala, the site and sex specific percentages
published by the hospital cancer registries at
Dibrugarh in Assam11 and at Trivandrum in
Kerala12 were used for the parrition of total
cancer cases. Age-specific incidence rates were
estimated for four broad age groups: 0 to 4.5 to
14.15 to 59 and 60 +yrs. Age-standardised
incidence rates for all sites and eighteen sites
were calculated using the weights of the ‘ 'world
II
Mian Journal of Carx.-er. March 08
Cancer Incidence
Table -II
Estimated number of new cancer cases (thousands) and ASR rates by sites, sex and states in India 199!
Tongue
(141)
Uliar Pradesh
Bihar
Maharashtra
West Bengal
Andhra Pradesh
Madhva Pradesh
Tamilnadu
Karnataka
Rajasthan
Guiarat
Onssa
Kerala
Assam
Punjab
Harvana
Delhi
Jcirnmu & Kashmir
Himachal Pradesh
ClHl
Others
Total
ot Total
ASR Rates
M
4 I
26
1.4
2.0
08
1 9
09
05
15
F
07
05
04
04
02
04
0.2
0.2
0t
O.Q
C i
O.J
01
03
o:
0.2
U.2
os
01
0.1
00
01
0.0
00
00
20 »
4$
6C
0j
:o
I 4
0.9
u.c
Vr
05
0.4
1 1
0.3
0.3
03
l.l
0.4
0.2
0.1
0.1
0.1
0.0
0.0
0.0
M
5.1
3.1
1.1
2.5
1.8
24
1 7
1.2
2.0
1.8
l.l
0.6
26
0.5
0.4
0.2
0.2
0.1
0.0
0.3
F
1.3
0.8
0.9
0.1
0.6
0.1
06
0.4
0.4
04
11.6
19
39
28.7
9.1
8.7
6.7
■> ■>
M
2.0
1.2
1.6
1.0
0.6
09
13
0.4
F
1.3
0.8
l.l
0.7
17
0.6
1.4
0.9
0.8
0.4
1 1
U.J
0.3
‘ 0.2
0.1
0.1
0.1
00
0.1
’3.4
aJ
4
3.9
cr of Grand Total
Oesophagus
(ISO)
Pharynx
(146-9)
Mouth
(143-145)
00
0.1
0.8
0.1
0.1
0.0
00
00
0.0
0.0
M
3.3
2.0
2 1
16
19
1.5
l.s
F
1.6
10
15
0.8
1.5
0.8
1 1
1.3
1.0
09
0.7
0.6
14
0.4
10
0.6
0.6
04
03
0.1
0.1
o;
0.0
0.2
210
6.7
6.5
1.5
13.0
44
4 1
M
28
1.7
1.6
1.4
Colon
(153)
M
08
0.3
03
0.6
F
1.5
0.9
07
0.7
1 1
07
1.2
0.8
02
02
04
>■ <
A •»
■' *•
0.4
0.3
0.2
01
0.1
0.1
0.0
0.0
0.2
0.1
0.1
0.1
0.1
0.0
0.0
0.0
0.1
0.2
0.1
0.1
01
0.0
0.0
0.0
17.8
5.7
50
92
31
28
; c
2.0
1.3
27
1.4
F
04
0.3
06
0.2
0.5
0.2
0.2
0.3
02
0.2
01
21
0.1
0!
0.1
90
0.0
00
0.0
0.0
05
0.8
0.4
0.5
0.4
03
0.4
02
02
0.2
Rectum
(154,
V/
F
09
06
0.7
04
0.7
0.4
0.4
0.8
08
07
07
06
05
0.5
0.4
04
9.5
0.3
'i i
03
UJ
0!
0.2
'j 2
97
•1 e
0.1
01
91
01
01
0.0
00
00
'j I
■j 1
0.0
6r
0.1
:6
h1
' <
; -
! 1
18
Larynx
>161)
M
2.0
12
15
10
07
09
08
0.5
10
09
Cl j
F
0.1
01
02
0.1
9.7
91
•) I
91
■j 1
■) ,
:<n
0.5
0.3
06
05
02
0.2
01
00
U.l
J0
r
69
• •>
U.O
9.0
u.O
j.O
■ J
43
4.2
J-
07
05
0.7
04
04
04
3.3
16
31
18
1 1
1 7
1
I :
■ <
J.J
9.1
9I
13 4
2.9
- -
<162)
O..:
4 t
9.3
9 '
a
•»
03
08
0.7
9.3
6 <
01
91
■) 1
0.0
01
Ou
00
Ov
0i
90
10
;oo
> -
19 4
I '■>
56
5.8
41
0.3
1.0
0.2
0.2
0.1
0.1
0.1
00
0.1
Stomach
(151)
9.3
Estimated number of new cancer cases (thousands) and ASR rates by sites, sex and states in India 1991
SOBSS
(Z74)
F
ur.tr P'ssisn
Bent
VMnSttQ
WestSengH
Ancnri Psoesn
Utavi P'laesn
tiT.njou
Rjajnun
Ohm
Gmhi
Ktnu
Asum
Pxix
-iyini
Dm
jjrmSKxsrmr
hacnn Paoesti
Gai
Otfiarj
W
Ctrva
dU)
F
Uttajs
012)
F
?9
3.6
nc
zS
Z.D
7d
25
■j £
24
23
2.1
2.9
:*
J’
%c/T<xa/
tnD.6
1193
ASR Run
.f7J
XcfGnnjTclil
:mo
Frym n () nssaa IC3-9 coauiz
i.7
U
Blidder
(IM)
F
U
,t
C.6
■ !
0.9
7.7
0.4
0.6
03
03
0.5
02
0.0
03
03
0.1
0.1
0.1
0.0
0.0
0.9
08
0.7
02
07
3.4
06
05
64
03
02
0.1
0.4
03
0.1
0.1
0.1
30
30
02
03
02
»
0.1
0.1
0.1
rJ
0.1
c.o
0.0
0.1
0.1
■30
00
00
00
0.0
3.1
■35
3.1
23
51
32
32
0.1
3.1
30
0.1
0.0
0.1
jl
0.0
0.0
0.0
3.0
9.0
19
22
.21
27
39
. ..03
21
0.7
37
23
1.4
1.2
71
7.2
•4
: ■’
.’5
0.C
’.J
Q.B
04
0.4
07
0.7
33
0.6
0.5
02
02
0.1
3.0
0.0
59.2
22.5
'9.S
52
7J
14
163
5.5
45
112
3£
4J0
It 4
0.9-
27
1J
;x
2i
no
■>.s
1.5
3.7
J'S
OS
X7
£3
28
1.8
]4
4£
z2
as
3<
Orcjry Pmtitt
(IO) (US)
u
F
■4
•7
'•
’C
-13
22
D2
22
22
:.o
3.7
3.7
n<
2.1
a
Indian Journal iof Cancer. March 98
1.9
KjOnrf
UM)
F
.j
.z
C2
i•
w.7
j;
12
Lvtr.onama
203203)
F
:7
•X
jz
•t
•3
.'6
26
•c
~r
.6
'£
•. G
■> i
■<
3.5
25
■s
23
32
24
■i->
'•
.1 ■
.in
•I n
nn
■7
CO
’22
u.
10
27
:S!
46
18
21
2.8
4.4
C.7
■234-208)
F
28
2.5
i?
•9
0.6
AB Sus
V
‘5
•j
3.1
nr
Of
0.7
SI
26
•t
■t
■X
03
u
-
426
.-7:
■
-x -■«
•t .
'£t
•S •
-■ t
24
•t
•i
•-
•-
F
O' 4
-s •
229
X- X
,r -
:S 9
•
'27
'2 ‘
•.
-4
23
:x
22
-,
•£?
:4
39
5.1
'0
C£
25
34
£i
62
2.1
r-4x
57.7
294.4
629.0
24
S64
483
M2
Rao & Ganesh
Table -III
Ten leading siUs of cancer in India in 1991 - estimated numbers /thousands) and percentage of total
Rank
I
3
J
5
6
7.
X.
9
10
Number
Site
Lung
Pharynx
oesophagus
Tongue
Stomach
Leukaemia
Lvmphoma
Larvnx
Mouth
Prostate
33.3
28.7
21.0
20.8
17.8
16.9
15.1
13.4
13.4
11.2
Both Sexes
Females
Males
%
10.6
9/
6.7
6.6
5.7
54
4.8
4.3
43
3.6
Rank
1
2
3
4
5
6
7
8
9
10
Site
Cervix
Breust
Ovary
Oesophagus
Mouth
Stomach
Lymphoma
Pharvnx
Leukaemia
Rectum
Number
%
Rank
Site
69.2
60.6
16.3
13 0
11 6
9.2
81
6.7
6.2
6.1
23.5
19.3
55
44
39
31
28
2.8
2.1
21
1
2
3
4
5
6
7
8
9
9
Cervix
Breast
Lune
Pharynx
Oesophagus
Stomach
Tongue
Mouth
Lvmphoma
Leukaemia
Number
%
69 2
606
38 4
34 7
34.0
27.0
25.6
25 0
23.2
23.1
11 4
10.0
63
5.8
56
44
4.2
4.1
38
3.8
of uterine cervix cancer. The estimated number
of cancer cases bv State varied from 900 cases in
Goa to 97.000 cases in Uttar pradesh.
standard" population (0.12.0.19.0.58 and u.l i
for 0 to 4.5 to 14.15 to 59. 60+ yrs age groups
respectively). Thus cancer incidence for the
whole country was esumated by the use of
region specific estimates, similar to the method
used in the estimation of Worldwide Incidence
for the year 1985'.
Table II shows the estimated number of
cancer cases ( in thousands! by site, sex and
statewise in India and Age Standardised Rates
(ASR)per 100.000 adjusted to world population.
Eighteen site-specific cancer together
constitututedaround 0.216millionmales (68.7%
of total male cancer) and 0 231 million female
cancers <78.5% of total female cancer) in the
country.
RESULTS
The whole country has been broadly
divided into five regions as shown in Table 1.
The estimated incidence rates per 100,000
according to fourage groups, sex and regionwise
are presented. In India, the estimated agestandardised incidence rates per 100.000 adjusted
to world population, were 96.4 for males and
88.2 for females. The ASR's were higher in both
sexes in northern region (M-99.8. F-111.6) and
in males in central regions (M-101.0). compared
to the rates in other regions of the country.
Among the ten most common cancers.
(Table - III) lung cancer was the most common
cancer among males in India with 33.300 new
cases, or 10.6% of the total and the leading site
in males in a majority of States in India (Table
II). The ASR for lung cancer is estimated to be
10.4 per 100.000 for malesand 1.6per 100.000
for females (Table II). When both sexes are
combined, lung cancer ranks third with 38.400
cases in India.
The total number of cancer patients for
the whole country in 1991 is estimated to be
around 0.609 million (0.315 million males and
0.294 million females). The number of female
cancer patients is found to be more than the
number of male cancer patients in the state of
Maharashtra. Andhra Pradesh, Karnataka, Tamil
Nadu and Kerala, partly due to high frequency
Pharyngeal cancer was the second most
common cancer among males (9.1% of the
total). The relative frequency r»f pharyngeal
cancer among males was higher than lung cancer
in the State of Assam. Oesophageal cancer is the
13
Indian Journal of Cancer. March 9S
Cancer Incidence
ASR for the common cancers between the two
countries more prominent for males and for
cancers of lung, stomach, oesophagus and colon
and rectum among both sexes. Further, the rates
of all individual sites of cancer in males were
higher in China than in India except for mouth.
larynx and prostate cancers.
third leading site among males (21,000 new
cases, 6.7% total malecancer) and fourth leading
site among females (13,000. 4.4% of total
female). Tongue cancer (20.800 new cases, 6.6%
of total male) is the fourth leading site among
males and it is higher in rank order than mouth
cancer. When both sexes are combined together,
tongue cancer accounted for 25,600 new cases
in India. Among females, tongue cancer forms
about 1.6% of total female cancer and docs not
figure among the ten leading sites in females.
The estimated ASR for tongue cancer is 6.3 per
100.000 in males and 1.4 per 100.000 in females.
DISCUSSION
Cancer incidence and eighteen site
specific age-standardised incidence rates were
estimated for the whole country in 1991 by
using seven registries data. The methodology of
using incidence data from selected areas or
populations to the whole country has already
been described. In order to estimate the cancer
incidence in Southern Asia in 1985. weighted
average of only three metropolitan registries
(Mumbai. Madras and Bangalore) and one rural
registry iBarshi) incidence data were used for
the estimation of dancer incidence in India
compared to the present study- The reliability
and validity of these estimates, are difficult to
measure in the absence of complete data for the
entire country. Non availability of age and sex
distribution of the population for each state
might have affected the estimates. In India
Cancer incidence data are available in selected
metropolitan cities only except for one rural
registry. The use of urban incidence data for
majority of states in India could possibly over
estimate the number of cancer cases.
Stomach cancer ranks fifth among males
and sixth among females and accounts for 27.000
new cases (4.4% of total cancer) in India. The
estimated ASR's are 5.0 and 2.8 per 100,000 for
males and females respectively.
Cervix cancer is the first in frequency not
only among females but also both the sexes
together and accounts for 69.200 new cases in
India. The estimated ASR is 19.9 per 100,000
and it forms about 23.5% of total female cancer.
Breast cancer is the second most frequent cancer
in females and ranks second overall when both
sexes are considered together (10% of total
cancer). The .ASR is 17.5 per 100,000 and
accounts for 60.600 new cases in India (19.3%
of total female cancer). The estimated number
of cases according to states in India showed an
excess in frequency of breast cancer cases over
cervix cancer in seven states in India (Table II).
Assuming that the estimated crude rates
for Southern Asia in 1985 (M=71.6. F= 79.5)
remained the same in 1991 triso. the expected
number of cancer cases in Endian population
would be around 0.636 million (Males =0.313.
F= 0.323) which would be higher than our
estimate. Based on the weighted averaee of
incidence rates available from registries like
The purpose of comparing ASRs for
selected sites ofcancer in Indiaand China (Table
IV) is to highlight possible differences in the
pattern of cancer in these regions. The age
distribution of the two populations is more or
less similar, more so in the 65+ yrsjgroup (India
3.9% China 5.3%)‘. There are differences in
Indian Journal iqf Cancer. March 98
14
Rao & Ganesh
Table -ZV
Comparision of ASR of selected sites in India with China ‘and Southern Asia’
ICD-9
140-149
ISO
151
153-154
161
162
174
180
182
183
IW
188
189
200-203
204.208
140-208
China
(1985)
Males
Southern
Asia
(1985)
India
(1991)
China
(1985)
Females
Southern
Asia
(1985)
8.7
22.1
431
10.5
28
28.3
25.1
9 1
75
4.3
7.6
13.2
18.9+
6.5
5.0
42
4.2
10.4
6.0
12.1
19 4
14 9
7.1
40
10.3
1 1
12.1
14 6
178
4
' i
3.5
I 3
2_2
19 1
29 1
4 .
! ”*
35
2 9
I 2
48
7
106.6
•e.U
2.8
0.7
3.8
3.9
964
Siu
Mouth
Oesophagus
Stomach
Color. <4 Rectum
Lar\nx
Breast
Centx
Uterus
Ovan.
Pmcajt
Bimi tier
Kidner
Lvrnsthnma
Leukaemus
All Sues
6 .1
2.1
59
59
189.6
India
1991
69
*
41
28
32
04
1 6
17:
19 9
'4
a •
•> 7
*
cc
1.7
42
4.4
06
2 6
■ -
07
'4
■ -
158.6
111 ■
*
+ excludes site /CD 14G- «£
Mumbai. Bangalore.Madras. Bhopal, Delhi and
Barshi for 1989. the number of cancer cases in
India in 1992 was estimated to be around 0.(144
million1-. Instead of urban incidence data for the
estimation, if one applies only the rural registry
incidence data, the number of cancer cases in
India would be around 0.349 million, probably
an under estimate. Using the average of three
metropolitan registries incidence data, namely
Madras. Mumbai and Bangalore for the period
19S2-84. in the year 1991. there would be around
0.331 million male cancers and 0.371 million
female cancers cases in the country14. This is
much higher than our estimate, perhaps due to
differences in the method of estimation, and the
use of population projections instead of actual
data used in our saudy.
cancer for developing countries. The observed
differences gives impetus to the need to identifv
the risks and protective factors in the two
population.
Eighteen site-specific age-standardized
rates for the whole country has been estimated
for the first time in India. The use of four ag6
groups namely 0-4.5-14.15-59 and 60s- may not
be the most appropriate for estimating agestandardised rates. As it is well known, the first
two strata would account only for three percent
of total cancer. In order to assess the possible
bias due to this, published ASR for all sites in
Mumbai Registry for one vear was recalculated
using these four age strata for standardisation.
The rates were 10%-13% less than the observed
rates.
A comparison of cancer occurrence in
the two largest countries (i.e. India and China)
suggests that the cancer pattern and problems
are quite different. This in turn makes it difficult
to have uniform policy and programme to combat
. In males, the most common cancers
namely lung, pharynx, oesophagus, tongue,
larynx and mouth cancers wtuch accounted for
41.6% of the cases are known, io be associated
15
Indian Journal of Cancer. March
Cancer Incidence
effect. These estimates of cancer load could
provide guideline and scope for proper planning
ofhealth needs, necessary infrastructure required
in terms ofhealth personnel, medical technology
and allocauonof funds for primary and secondary
prevention.
with
tobacco
chewing
and
smoking4'5-"'1’-1*- ”30-1-2. Even in females,
the tobacco-related cancers (oesophagus,
mouth and pharynx cancer) accounted for 31.3%
of the cases. It is not surprising that thcsccancers
emerged as most common cancers since tobacco
habit, in varying forms, are prevalent in many
parts of the country.
With the identification of the common
cancers in the country, priorities should include
screening programmes for early detection and
secondary prevention in cancers of the cervix
and breast, the two most common cancers among
women.
Cervix cancer is the leading site of cancer
in females and in most of the registries in India.
Case-control studies indicated that early age at
marriage, early age at first pregnancy, four or
more number of pregnacies and lack of genital
hygiene were high risk factors for cancer of the
cervix2-. In a rural set up. mass education on
cancer awareness and symptoms was shown to
have greatly contributed in downstaging of
cancer of the cervix24. This should be taken as a
guideline for implementing such programmes
on a national level.
With the help of voluntary organisations
and Government legislation, many tobacco
related cancers, which account for almost twofifth of total male cancers and one-third of total
female cancers, can be prevented.
Assuming that there would be no major
change in the habits and customs in the itrnmediate
future, and based on the population projections'.
it has been estimated that cancer load in the
country would likely to reach a figure of 0.75
million in 2001 A.D and 0.87 million in the vear
Breast cancer is the second commonest
cancer among females in India. Recently,
Mumbai and Delhi registry data showed that
breast cancer has become the number one cancer.
superseding cervix cancer. Though breast cancer
incidence in India is two to three times lower
than the incidence in western countries, factors
like single women, late age at marriage and
consequently the late age at first pregnancy and
two or less number of pregnancies were found
to increase the risk in Indian women”. Though
mass screening of high risk women by annual
mammography and physical examination may
have a reduction in morality, but in a country
like India, self breast examination would be
more suitable and convenient to have the desired
Indian Journal of Cancer. March 98
2011 A.D.
There is an urgent need for Government
and health personnel to take immediaac steps in
cancer control and prevention.
ACKNOWLEDGEMENT
The authors wish to thank Miss Hilda
Sequeira fortyping the manuscript and Mrs. T.
K. Santhkumary for the assistance. The authors
wish to thank the Director Dr. K. A. Dsnshaw for
her constant encouragement and saippon in
carrying out the study.
16
Rao & Ganesh
REFERENCES
1.
10.
Parkin D. M.. Pisani P. and Ferlay J.:
Estimates of the worldwide incidence of
eighteen major cancer in 1985. Int. J.
Cancer: 1993:54:594-606.
2.
3.
Cancer incidence in Madras. India. Ten
year report 1982-91. Madras
Metropolitan Tumour Registry. 1993.
Census of India 1991 : Series 14,
Maharashtra Paper-1 of 1991. Provisional
Population total. Director of Census
Operations. Maharashtra. India:20-21.
Bhandare S. S. and Mukhopadhyay J.
11.
Barua H. P. and M. S. Ali. : Hospital
Tumor Registry. Annual Report 199091. Dilbrugarh Cancer Registry, 1993.
12.
Nair M. K., Aleykutty M.A..
Gangadharan P., Sankamarayan R.
and Verghese C. : Hospital Cancer
K. : Statistical outline of India. 1995-96.
Tata Services Limited. Department of
Economics and Statistics. Bombay, 1995.
4.
Registry. Annual Report 1991.
Trivandrum Cancer Registry 1993.
Jayant K., Rao R. S. Nene B. B. and
Dale P. S. : Population based cancer
13.
NCRP (1992). :
14.
Murthy N. S.. Juneja A.. Sehgal A..
Prabhakar A. K. and Luthra U. K. :
registry in rural areas around Barshi.
Sholapur district Maharashtra. Report
for 1988-92. Barshi Cancer Registry.
Sholapur. 1994.
5.
Verma K.. George J. and Tyagi B. B.:
Cancer Morbidity and Mortality in Delhi
Urban Agglomeration 1990-91. Delhi
Cancer Registry. 1993.
6.
Patel N. I_ _Patel D.D. andBalarD.B.
15.
Kanhere S., Surange S.. Dixit R. and
Shrivastav A.: Population based cancer
16.
17.
Jussawalla D. J., Yeole B. B. and
Natekar M. V. : Cancer Morbidity and
Notani P. N. and .Jayant K. : Role of
diet in upper aerodigesteve tract cancers.
Nutr. Cancer.1987: 10.103-113.
Notani P. N. and Sanghvi L. D. : A
retrospective study of lung cancer in
Bombay. Br J Cancer. 1974:29:477-82..
Mortality in Greater Bombay -1991.
Bombay Cancer Registry. 1993.
9.
Jusawalla D. J. and Deshpande V. A.:
Evaluation of cancer risk tn tobacco
chewers and smokers: am epidemiologic
assessment Cancerl97I;2S:244-25_
registry Annual Report 1991. Bhopal
Cancer Registry. 1993.
8.
Biennial report.
Population-based cancer registries 198889: An Epidemiological Study. Indian
Council of Medical Research.
New Delhi. 1992.
Cancer projection by the turn of
century-Indian scene. Ind. J. Cancer
1990: 2774-82.
: Population Based and Hospital cancer
registry. Biennial Report 1988-89.
Ahmedabad Cancer Registry. 1991.
7.
Krishnamurthi S., Shanta V.,
Gajalakshmi C. K., Swaminathan R.:
18.
Anantha N.. and Nandakumar A. :
Rao D. N., Ganesh BL. Rao R. S. and
Desai P. B.: Risk assessment of tobacco.
alcohol and diet in oral cancer a case control study. Int. J. Cancer.
1994:58.469-473.
Pouplation based cancer registry 199091. Bangalore Cancer Registry, 1993.
17
Indian Journal of Cancer. March 98
Cancer Incidence
19.
Rao D. N., Ganesh B., and Desai P. B.
22.
: Role of reproductive factors in breast
cancer in a low-risk area : a case control
strudy. Br. J. Cancer 70. 129-132,1994.
20.
Epidemiological observations on of
cancer the oesophagus - a review of
Indian studies. India J. Cancer.
1996:33,55-75.
Sankaranarayanan R., Dufty S. W.,
Day N. E., Nair M. K. and
Padmakumary G. : A case control
23.
investigation of cancer of the oral tongue
and the floor mouth in Southern India.
Im. J. Cancer. 1989:44.61.7-621.
21.
JusawaJIa D. J., Deshpande V. A. and
Standfast S. J. : Assessment of risk
pattern in cancer of cervix. A comparison
between Greater Bombay and western
countries. Int. J. Cancer. 1971:7.259268.
Jayant K, Baiakrishnan V., L. D. and
Jussawalla D. J.: Quantification of the
24.
. role of smoking and chewing tobacco in
oral, pharyngeal and oesophageai
cancers. Brit}Cancer. 1997:35.232-235.
Indian Journal of Cancer. March 98
Rao D. N., Desai P. B. and Ganesh B.:
Jayant K.. Rao R. S., Nene B. M. and
Dale P. S.: improved stag? maenosis
of cervical cancer with increased cancer
awareness in a rural Indian population
Int. J. Cancer, 1995:63:161-163.
18
Br. J. Cancer (1994). 70. 129-132
With best com n’i.-n«n ts
from the author
© Macmillan Press Ltd., 1994
Role of reproductive factors in breast cancer in a low-risk area: a
case-control study
D.N. Rao, B. Ganesh & P.B. Desai
Division oj Epidemiology and Biostatistics. Taia Memorial Centre. Parel. Bombay 400 012. indin
A esse-control Stacy of 639 breast cancer patients seen at Tata Memorial Hospital during the
period 1980-84 was carried :ua During the same period 711 females who attendee the hospital w-.thou: a
history of benign breast iencra cr gynaecological complaints were selected as controls. Patients were
interviewed by trained investigators to collect data on reproductive factors, menstrual history, tobacco
smoking and chewing habit dicta.-- practices I vegetarian and non-vezeranan diet i anc alcohol consumption.
Cases and controls were stratified :r.to tour age groups i <35 years. 35-44. 45-54 and 55 - years) and three
piaccs of residence . Bomcay. Maharashtra, others). The adjusted relative risk (RR) tor unmarried women
compared with married woneee was 2.3. N'uilmarous women had a 2.2-foid higher risk than parous women.
Late age at marriage '30 years —c above: and iate age at first pregnane.' <30 years and above) showed excess
risks of 2.5 and 5 4 compared with women married at the age of 14 years and age at first pregnancy of :4
years. Three or more pregnancies was associated with a 40-50% reduction in risk iPO.OI). Non-vegetanan
diet, literacy status and a histor.
*
:: stillbirth and aooruon did not emerge as significant risk factors for hr—sr
cancer in our sracy. These findings, tn a low-risk population, were consistent vuo those reponeo from
high-risk populations.
Summary
Cancer of the breast is the leading cancer among wc.tten .n
developed countries, whereas it is the second commonest
cancer among women in developing countries. There has
been a steady increase in the incidence of breast cancer ad
over the world, but the mortality from breast cancer has
remained constant. In Bombay, females have a lifetime ask
of breast cancer of around 1 m 35 compared with one in nx
in the USA (NCRP. 19921. Case-control studies on breast
cancer carried out m various parts of the world have high
lighted the association with certain female reproductive fac
tors. diet and familial history of cancer (Mac.Mahon et A..
:970a.b; Adami er ai.. 1990: Wynder er <i:_ 199’3. Parian et
al. (1993) estimated that 298.000 breast mincer rases were
recorded during the year 1985 in developing countries.
Though a large number of women are acected with breast
cancer, very few studies have been undertaken to identify the
risk factors for breast cancer in developing countries. Tais
sracy has been earned out to identify tine association of
reproductive factors with breast cancer ire a low-mctcence
population.
Materials and methods
Patients attending Tata Memorial Hospital, before being
medically examined, are interviewed by our social investi
gators. The questionnaire contains items on demograpnic
factors, family history, age at menarche. age at marriage.
number of pregnancies, history of stillbirth and abortion.
family planning practices and menstrual history. In addition.
data on tobacco smoking and chewing, dietary practices and
alcohol habit were also collected. Data on dietary pracnces
are restricted to two major groups, vegetarian and non
vegetarian. During 1980 - 84, 689 female breast cancer
patients were interviewed. Females who were referred to our
hospital for suspected malignancies, mostly m the mouth and
throat, and found to be free of cancer were considered as
controls. Among the female patients who were interviewed
during the period, 711 females were found to be eligible as
controls. Cases and controls were stratified into four age
groups (<35 years, 35-44, 45 - 54, 55 +years) and three
places of residence (Bombay, Maharashtra, others). Odds
ratios were calculated by univariate methods as well as by
Correspondmm DU. Rao, Division of Epidemiology and Biosanstia, Tara Manorial Hospital, Pxrei. Bombay «Q0 012. India."
Received 26 May 1993; and in revised form 2S January 1994.
stratified analysis. The Mantel and Haenzei .1959) summer.
chi-squared test was used for testing statistical significance
and a test-based estimation procedure was 'used for calcula
tion of continence intervals for odds ratios iKfieinoaum er al
’.982).
Results
General features of breast cancer rases and controls are
shown in Table 1. Tne average age of cancer patients was
46.2 years, whereas it was 42.3 years for controls. Tne
religious distribution between cases inc controls did not
diner and hence is not adjuster! for ;n the analysis. Repro
ductive factors m cases and controls are presented in Table
II. Factors such as age at menarche. age at marriage. age at
first pregnane.- and number of pregnancies appeared to be
similar between the cancer cases and controls.
Tne relative risks (RRs) for factors studied are presented
tn Table III. Cases and controls were stratified by tour age
groups and three places of residence. In our study, unmarried
women had a 2.3 times higher risk of developing breast
cancer than married women. Tne nuiliparcus women had 2.2
times the risk of parous women (PO.OOli. Breast feeding.
Table I General features of breast cancer cases and controls
1980-84
CJJC
Number
?oy
Controls '%/
689
711
Average age at presentation (years)
Standard deviation
:o.6
<28
110.0
Residential status
Bombay
Maharashtra (excluding Bombay)
Others
294(42.7)
22X 32.1)
174(252)
383 (53.9)
225 (31.6)
103(14.5)
Marital status
Unmarried
Married
Widowed
Divorced
22(3.2)
491(713)
174(252)
2(03)
Refigion
Hindu
Muslim
Chritfiin
Other -
’ v k •
. - 537(773)
96(1X9)
37(5.4)
v .
19(23)
•
,
*
.r..\-J.
11 (1.5)
57» (81.4)
114.(16.1)
T(1.0)
565(79.5)
977(13.6)
■ 3
(4.8)
*
13(2.1)
130
D.N. RAO « al.
non-vegetarian diet and literacy status were not statistically
significantly related to risk of developing breast cancer in our
study group.
A history of abortion and stillbirth among eligible cases
and controls was also studied for the risk of breast cancer.
Seventy-one cases and 97 controls reported one or more
abortions. The relative risk for women with a history of
abortion was 0.8 (CI 0.59-1.09) compared with those with
no histbry of abortion, and this was not statistically
significant Ten cases and 12 controls had a history of still
births. The relative risk was 0.9 (CI 0.61-137) and the
difference was not statistically significant
The relative risk estimates for factors such as age at
menarche, age at marriage, age at first pregnancy and
number of pregnancies are presented in Table IV. Owing to
the small number of cases in some of the categories, it was
not possible to adjust for age and place of residence. Hence
relative risks were calculated for an unadjusted group only.
Age at menarche after 15 years compared with 14 years and
below did not show statistically significant differences for
breast cancer nsk. Women married after 30 years of age
showed a 2.5 excess risk of breast cancer compared with
Table II
Reproducnvc factors among cases and controls
Carer
Controls
Number
539
711
Average age at menarche
*
Standard deviation
13.9
13
13.3
1.4
Average age at marriage3
Standard deviation
16.3
AS
16.7
Average age at first areznanev
Standard deviation
20.4.
19.3
3.5
women married before 15 years of age (P <0.01) For women
■with a first pregnancy after 30 years of age the relative risk
was 5.4 compared to women with a first pregnancy before 15
years of age. Three or more pregnancies was associated with
Table DI Relative risk (RR) estimate for factors and their
confidence intervals
Casa
factor!
non-factor
Controls
factor!
non-factor
Marital status
Unmarried/ever married
21667
11 700
Parity stamr
Nulliparons/ parous
61.603
32.667
Risk factors
studied
2.26#
(1.01-5.06)
(1.4-3 J)
Breast feeding3
No/yes
17'579
11.653
2.02 NS
10.3-4.9)
Stillbirth4
Yes-no
10.653
12.587
0.9 NS
(0.6-1 4)
Abortion1
Yes no
'! 593
9" "602
0.3 NS
lO.s-i.i)
484202
543 164
0.3 NS
10.b-2.1 j
295 394
326.385
1.1 NS
(0.87-1.4)
rood habits'
Non-vegcarian.
vegetarian
Literacy status
Literate.-illiieraie
‘Strauncd for four age grouos i<35. 35-44. 05-54 and >55
• cars! and three places of restoeace iBombay. Manarasbtra ano
othcri. ’Sexen cases and three controls not recorded. -Three cases
and one control was oot recorded- ‘Four cases and one control not
reeoroed. Three cases and one control not recorded. Three cases
ano four controls not known. Fgures in parentneses indicate lower
and upper confidence interval. ■"FO.OOI. NS. not sagmficacL
Non-factor - reference category - RR = 1.9. fr P C
Average number of pregnane: yr
Standard deviation
43
2.1
-i
‘In 13 controls and 15 cases, age at menarcme was not recorcca.
Tn six cases and four controls the age at mamaee was unknown.
•Eight cases and nine controls unknown. ‘In one case and one
control the numoer of pregnancies was anjcncrwn.
Table IV
JUT
( adjusted)
Rciasrve risk (RR) sumate for facers and their confidence
intervals
Risk factors
studied
Controls
RR
unadjusted
Age at menarche (years)
^14
?77
171
'.6
148
17
63
18
8
T
’.9
293
203
26
•7
9
10
1.0
0.9 NS (0.7-12)
1.2 NS (09-1.5)
1.4 NS 10.9-2.1)
0.9 NS (0.3-25)
0.7 NS (025-1.9)
P>0.05
Age at marriage (years)
14
15-19
20-24
25-29
30 r _
188
346
123
23
6
1.0
0.8 NS (0.7-1.1)
0.9 NS (0.7-12)
0.8 NS (0.4-1.4)
,25" (1.0—6.6)
R<0.05
Casa
194
310
119
16
Age at first pracnancy
eg 14
23
17
15-19
317
265
20-24
235
250
25-29
55
63
304-«'A-T.-p
9
30 w.vr
■ • -vW • .. 5.
No. ofe pregnancies
/J. Nulfiparous “ . ^^^^61 f
'32
r for
trend
1.0
12 NS (0.7-26)
1.5 NS (0.8-29)
1.4 NS (0.7-29) -.
5.4~. (22-139) - P <0.004
IXSAT,;yr£S.
[ "Three. »f
iM'
3 1 Four7 ’ <in$£^?i3S
• 03-fJ (03-0.8) N't
'
5r
S-NS.'**-
REPRODUCTIVE FACTORS AND BREAST CANCER
a significant reduction in breast cancer risk compared with
nulliparity.
Discussion
Breast cancer is the second commonest cancer among females
in developing countries, including India. Many case-control
studies have been carried out in developed countries where
breast cancer has been the most common cancer among
females. It would be interesting to note whether established
high-risk factors also play a significant role in i '.cwincidence area. .An attempt has been made to icezdfy highrisk groups and the role of reproductive factor: in breast
cancer.
Cases and controls were generally interviewed by our
social investigators before medical examination. This heip-et:
*o eliminate any interviewer bias in the collection :f data.
Hospital controls were used instead of population :ozirc:s.
In the selection of controls, care was taken to include femaies
without any history of either benign breast iesions :r any
gynaecological complaints. For a number of dinerent reasons
not all patients with breast cancer registered currng me
period could be interviewed. These are some of me .imita
tions of the study which may or may not have anected me
relative-risk estimates.
The positive aspect is that me number of cases _rm :cztrois is sumcient to detect a 2-foid increases r.sk eve:
factors with 90% power when such differences exist Sm.esseiman. 19"-).
Unmanned women and nuiiiparous women .tad - 2-frid
increased r.sK for breast cancer. Aiso. '.ate age a: marrmze
;30 years and above) and iate age at first pregnancy 37 year:
and above) were found to be r.sk factors for breast cancer.
Multiparous women with three or more
hac a
-0-50% reduction in nsk of breast cancer comparer v-:fi
nuiiiparous women. These findings are consistent '<m ear ter
reported studies from high-r.sk populations.
Pavmaster ano Gangachamn 1972) ic. a me- c-.me
matched case-control srudy on women from western imz
aiso showed that factors such as man tai status, age marri
age. parity status, age at first delivery and zumoer ?f preg
nancies are associated with the r.sk of bretzst cancer.
The association of alcohol and dietar.’ factors with creast
cancer has also been reported in a high-incidence population
.Schatzkin er
1987: Willet ei ai.. 1987). Ln Incia. women
in general do not indulge in aiconoi in the same way is men.
So. because of the negligible r.umcer of cases arm control
with this habit, the erect of aicohoi couid not be -maiec. In
our srudy we did not coiiect data on diemuy factors, rut
information on type of food ii.e. vegeranam or zcn-vegetarian diet) consumed was collected for cases ano mntrcis.
131
The risk level for non-vegetarians was lower than for vege
tarians. but the difference was not statistically significant
Vegetarians who totally avoid animal meat, fish and poultry
products generally consume less fat than non-vegetarians. In
this context, the odds ratio was expected to be higher amor.”
the non-vegetarian group than among the vegetarian group
since a diet with a high animai fat intake has been shewn to
increase the risk of breast cancer. Further studies are
required to identify the association of dietary factors in
breast cancer.
Moore et al. (1971) identified certain virus-like panicles in
the milk samples from the Parsis women in Bombay How.
ever, further studies have not been cone to confirm the viral
aetiology (Gangadharan ei al.. 1975).
Toe incidence of breast cancer is low in India compared
with developed countries, but the rates are increasing Yeoie
a ai.. 1990). Cancer of the cervix uteri is the major .ending
site among femaies in most of me metropolitan registries iz
Incia. except in Greater Bombay, where for the last 10 years
female breast cancer has been the leading site of cancer
Jussawaila er al.. 1992).
Recently Jayant <1986
*
reported that the increase in me
.zc.den.ce of breast cancer m Bombay is not cue to a ezhem
erect, uniike the decrease in .ncicence of rervix cancer.
The trends .n incidence rates for the Bombay population
ever me years 1964—85 show mat crude, age-adjusted azc
nmcatec rates are .ncreasmg a: me rate of
.5% and in
ail me age groups except mose aged 35-— years - Yeoie er
a.’.. .990). The increase in ir.cider.ee of breast cancer car. be
parky explained by changes in lifestyle, such as an increase m
me zumoer of 'unmarried women', later age at marriage and
consequent later age at first pregnancy. Further studies are
necessary to explain the roie of dietary factors ir. areas:
cancer. With me change in lifestyle, smaller families and
cetter socioeconomic advancement, the incidence of areas:
cancer is bound to increase over the years. In a developing
country .ike incia. with a large female population .zt hignr.s.< groups. .mown methods of early ceiecnon such jls mass
:creen;ng inc compuisory mammography may not re eco
nomically viabie. However, propagation of oreasz seif
examination may be important In helping to comriat tins
health problem.
The authors -visr. to thank me staff of me Division for their coopera
tion and assistance. Special ihanics for the social investigators. Mrs
?ushpa Peshotan anc Mrs Raiam Vachharaian:. who iocm great
pains io :nter.iew cases ana controls curing me penoa of sttxry. Our
sincere thanks io Dr R.S. Rao. Director. Tata Memorai Hospital.
for his constant encouragement and support.
References
ADA.MI. H.-O.. ADAMS. G.. BOYLE. ?.. EWERTT. M.. ' -- N.CLUND. E.. MILLER. A.3.. OLSSON. H.. STE^ M.. 7RICHOPOULOS. D. i TULINIUS. H. 1.1990). Critical overviews of aararai
history, etiology, molecular biology and screening by mammo
graphy. Chapter II Breast Cancer Eliology fni. 1. Cancer
tSuppl.) 5. 22-39.
GANGADHARAN. ?.. JUSSAWALLA. D J.. RAO. D.X ± PAYMASTER.
J.C. (1975). Multiple approaches (for cancer to util denned
population of Parsis. In Proceedings of the XI intemanond
Cancer Congress. F.orence. Vol. 3. Bucalossi. P_ VeronesL U. i
Cascineili, N. (eds). Excerpta Medica: Amsterdam, pp. 18-25.
JAYANT. K_ (1986). Cancers of the cervix, uteri an^i breast Changes
in incidence rates in Bombav over the last two dreads WHO
Bull.. 64, 431-435.
JUSSAWALLA. D_L YEOLE B.B. Jt NATEKAR. M.V. (1992). Cancer
Morbidiry and Mortality in Greater Bombay - /990. Bomoay
Cancer Registry: Bombay.
KLEINBAUM. D.G. K.UPPER, LL. A. MORGENSTERN. It (1982).
Epidemiologic Research. Principles and Quamiatne Methods.
Lifetime Learning publications: Belmont, CA.
LIN. T.M. LOWE. C.R.. MIR&x. AJ»..
RAVNIHAR. 3.. SALBER. EJ.. VALAORAS. V.G. i YU.ASA. s”
• 1970m. Aee at first birth and breast cancer nsk. WHO Btuil 43
209-221.
MaCMAHON. 3.. LIN. T.M.. LOWE. C.R.. MIRRA. A.P.. R.AVXIHAR.
3.. SALBER. EJ.. TRICHOPOULOS. D.. VALAORAS. V G. x
YUASA. S. (!970Z>). Lacmtion and cancer of the breast WHO
Bull.. 42. 185-194.
MANTEL N. 4 HAENZEL. W. (1959). Statistical aspects of amuvsis of
data from retrospective studies of disease. J. Natl Concur Ins:
22, 719-748.
MOORE D.H- CHARNEY. J.. KARMARSKY. B.. LASFARGL’SS. EY,
SARKAR. N.IL. BRENNAN. MJ, BURROWS. J.H.. SIRSA.T. S3U
PAYMASTER. J.C. A VAIDYA. AJi. (1971). Search for a human
breast cancer virus. Nature. 229. 611-614.
NCRP (NATIONAL CANCER REGISTRY PROGRAMME) (1992:.. Bien
nial Report 1988-1989. An Epidemiological Study. Indian ’Council
of Medical Research: New Delhi.
MaC.MAHON. 3.. COLE
132
D.N. RAO et al.
PARKIN, D.M.. PISANI. P. i FERLAY. J. (1993). Estimates of the
worldwide incidence of eighteen major cancers in 1985. Ini. J.
Cancer, 54, 59
*1-606.
PAYMASTER. J.C. & GANGADHARAN. P. (1972). Some observations
on the epidemiology of cancer of the breast in women in western
India. Int. J. Cancer. 10. 443 -450.
SCHATZKIN. A- JONES. DY.. HOOVER. R.N.. TAYLOR. P.-L. BRINTON. LA_. ZIEGLER. R.G.. HARVEY. E.B.. CARTER. CL.
UCITRA. L.M.. DUFOR. M.C. & LARSON. D.B. (1987). Alcohol
consumption and breast cancer in the epidemiologic follow-up
study of the first national health and nutrition examination
survey. ,V. Eng/. J. Med.. 316. 1169-1173.
SCHLESSELM.AN. J.J. (1974). Sample size requirements in cohort and
case-control studies of disease. Am. J. Eaidemici.. 99.
331-334.
WILLETT. W.C. STAMPFER. MJ.. COLDITZ. GA. ROSNER. BA
HENNEKENS. CH. & SPE1ZER. F.E. (1987). Moderate alcohol
consumption and the risk of breast cancer. .V. Engl. J. Med., 316.
1174-1180.
WYNDER. E.L. Y.ASfYUKL F.. RaNDaLL E.H.. TAKESHI. H. k
TOMOHIKO. H. (1991). Comparative epidemiology of cancer
between the United states and Japan. A second look. Cancer. 67,
746-749.
YEOLE. B.B.. JAYANT. K. i JUSSA WALLA. DJ. (1990). Trends in
breast cancer incidence in Greater Bombay, an epidemiological
assessment. WHO Bull.. 68. 245-249.
Cancer Detection and Prevention, 23(!):37—14 (1999)
Alcohol as an Additional Risk Factor in
Laryngopharyngeal Cancer in Mumbai—
A Case-Control Study
D. N. Rao, M.Sc.,3 P. B. Desai. M.S.,b and B. Ganesh, Ph.D.a
^Division of Epidemiology and Biostatistics, and “Tata Memorial Center, Tata Memonal Hospital,
Parel. Mumbai, India
This paper was fust presented at the XVI International Cancer Congress, New Delhi. October 30-November 5. 199-:. Address all
correspondence and repnnt requests to: D. N. RAO. M
Division of Epidemiology and Biostaustics. Tata Memonal Hospital. Parel.
Mumbai. -00 012. India.
Received March 20. 199" Revised January 29. 1998. Accectea April 6. 1998
ABSTRACT: A retrospective ease-control study of 1698 male pharyngeal and lary ngeal cancers seen at the Tara
Memorial Hospital. Mumbai from I9S0 to '.9S-1 was undertaken to assess the association between the cancers and
chewing, smoking, and alcohol habits. Male controls were chosen from persons who attended the hospital during
the same period and who were diagnosed as free from cancer, benign tumor, and infectious disease. Statistical
analysis was based on unconditional logistic regression method. Bidi smoking and alcohol drinking emerged as
significant factors for pharyngeal and laryngeal cancers. Illiterates had 50 to 60% excess nsk for pharyngeal
cancer only. Nonvegetarian diet did not emerge as significant factor in our study.
KEY WORDS: alcohol, larynx, literacy, pharynx, tobacco, vegetanan diet.
I.
INTRODUCTION
The association of tobacco chewing and smoking
with head and neck cancer, in particular pharyngeal
and laryngeal cancers, has been reported from the
studies earned out in Mumbai. India.
Previous
studies also estimated the odds ratio of tobacco chew
ing and smoking for individual sites of head and neck
cancer. Many studies carried out in developed coun
tries have shown cigarette smoking and alcohol as
major risk factors for pharyngeal and laryngeal can
cers.-0 In India, due to the paucity of data, the asso
ciation of alcohol with pharyngeal and laryngeal can
cers has not been studied in detail, and the few studies
reported did not establish the dose-respemse relation
ship.0 Alcohol drinking emerged as a significant risk
factor in Indian population for oral cancer after ad
justing for other known factors? Available data from
five metropolitan cancer registries in India indicate
that there are variations in the age-adjusaed incidence
rates of oropharyngeal (males: 2.0—1.5 per 100.000).
hypopharyngeal 14.2-9.9 per 100.0001. and lar.’ngeal
(5.0-12.9 per 100.000) cancer. The incidence rates for
laryngeal cancer are higher than the rates for orcDharyngeal and hypopharyngeal cancer in almost ill reg
istries. ,0JI The aim of the study is to indiviticallv
assess the role of alcohol, tobacco, diet, and literacy
status in cancers of the pharynx and larynx, and to
identify any excess nsk due to these factors especrallv
for laryngeal cancer in Indian population.
II.
PATIENTS AND METHOD
This is a retrospective unmatched case-control
study of patients who attended the hospital dunng the
period from 1980 to 1984. Two trained social inves
tigators interviewed the patients, at the time of regis
tration but before clinical examination, in the outtpatient department. The questionnaire contained data
items on demographic factors, family history of dan
cer. tobacco habits, use of alcohol, frequency per bay.
duration in years, cessation of these habits, and di
0361-090X/99/S 10.50
© 1999 International Society for Preventive Oncology
37
Alcohol and Laryngopharyngeal Cancer in Mumbai
etary practices. Medical records were scrutinized later
for diagnosis and entered in the proforma. Among the
cancer patients interviewed during the period were
1698 male patients with the histologic confirmation of
cancer in pharyngeal and laryngeal regions. Cancer
patients were classified into three major groups ac
cording to ICD-9 category. The oropharynx group in
cluded cancers of base tongue (ICD-1410), soft palate
(ICD-1453), and oropharynx NOS (ICD-146). The
hypopharynx group included cancers of post cricoid
(ICD-1480). pyriform fossa (ICD-1481), and hypo
pharynx NOS (ICD 1489). The larynx group included
cancers of vocal cord (ICD-1610). supra glottic larynx
(ICD-1611), and larynx NOS cases (ICD-1619). Dur
ing the study period. 635 of the male patients inter
viewed were diagnosed as being free from cancer.
infectious disease (tuberculosis of lung and lymph
nodes), and benign lesion (adenoma, fibroma, etc.),
and these patients were classified as hospital control.
The majority of the male controls whom we had con
sidered for the study attended the hospital for com
plaints in the head and neck region and were later
found to have no evidence of disease or any abnor
mality. The dietary practices were broadly classified
as vegetarian and nonvegetarian diet. Those who have
a vegetarian diet do not eat poultry products, fish, or
meat.
In general, chewers consume pan. betel nut. lime.
and tobacco with some spices and condiments, and
smokers consume bidi (made by wrapping 0.2 g to 0.3
g of tobacco in tendu leat'i. cigarette, chutta (a kind of
cigar), hukka. and chilum (clay pipe). Bidi smoking is
prevalent in all section of the population in the coun
try. Cigarette smoking, though prevalent, is not as
common as bidi smoking. Alcohol is locally brewed
liquor mostly from palm trees (ethanol content: 4060%). Statistical analysis is based on the uncondi
tional logistic regression method and 95% confidence
limits for the estimated odids ratio are obtained from
the standard error of the estimates.
III.
RESULTS
The general features o>f cancer patients and con
trol are presented in Table L. Tnere are 678 patients in
the oropharynx group. 593 patients in the hypophar
ynx group, and 427 patients in the larynx group. Re
ligious distribution of cancer patients and controls did
38
not show much variation in relative frequencies, and
hence this factor was not considered in the analysis.
.Among controls, 175 patients (27.6%) did not report
any of the habits. In the cancer group, 46 patients
(6.8%) in the oropharynx group, 56 patients in the
hypopharynx group (9.4%), and 4 T patients (9.6%) in
the larynx group were free from the habits considered
in the study. The habit of alcohol drinking was re
ported in 124 males (19.2%) in the control group. In
the cancer group, there were 174 patients (25.7%)
with the alcohol habit in the orophary nx group. 162
patients (27.3%) in the hypopharynx group, and 113
patients (26.5%) in the larynx group.
Alcohol drinking as a single habit was reported
only by 2 males in the oropharynx group. 7 males
each in the hypopharyngeal and laryngeal groups, and
10 males in the control group. In general, alcohol
addicts also reported one of the other habits, like to
bacco chewing or smoking, or both, and the indepen
dent risk due to alcohol could not be analyzed in our
study. Among smokers, bidi smokers were common
in both cases and controls, and the percentages varied
between 63% in the control and 89% in the cancer
group. Among smokers. 34% of males in the control
group and 9 to 18% of males in the cancer group were
cigarette smokers. The literacy leve: was high among
the control group (71%) compared with the cancer
group (55-64%).
Relative risk (RR) estimates for factors and tests
of significance are shown in Table □. Cases and con
trols were stratified by three types of residence i Mum
bai. Maharashtra, others) and four age groups i <35.
35—44.45-54.55+ years). Among me factors studied.
smoking and alcohol drinking were shown to be sig
nificant risk factors in the three cancer grouos. The
chewing habit—in particular, tobacco chewing—did
not emerge as a significant factor. Bidi smoking, a
known risk factor, is also confirmed as a risk factor in
our data. For bidi smokers. RR is 5.6 for ororpharynx
(confidence interval [CI]: 4.1-7.6). 2.6 for hypophar
ynx (CI: 2.0—3.5). and 2.3 for larynseal >CI: 1.7-3.2)
cancer. Cigarette smoking did not emerge as a sig
nificant risk factor for all the three groups in our
study.
RR estimates and test of significance for fre
quency and duration of the habits are shown in Table
III. The trend analysts was restricted to bidi smoking
and alcohol drinking habits only. B.idi smokers who
smoked 31 times and more per day had a 12-fold risk
Cancer Detection and Prevention
TABLE I
General Features of Patients and Controls
1
:1
,
i
■.
k
"
Controls
TOTALS
Number ICD-9 site
1410 Base tongue
1453 Soft palate
1469 Oropharynx NOS
1480 Post Cricoid
1481 Pyriform
1489 Hypopharynx NOS
1610 Vocal cord
1611 Supra glottic
1619 Larynx NOS
Age group
<35 years
35-44 years
45-54 years
55+ years
Avg. age ± SD
Residence
Mumbai
Maharashtra
Others
Unknown
Religion
Hindu Maharashtra
Hindu Gujarath
Sindhi
Hindu others
Muslim
Chnstian
Other religions
a
Oropharynx
Hypopharynx
Larynx
678
593
427
495
57
126
—
—
—
—
—
—
—
—
—
29
478
86
—
—
—
—
—
—
—
—
—
81
278
68
139 (22)a
175 (28)
156 (24)
165 (26)
45.4 ± 12.9
14 (2)a
84(12)
216(32)
364 (54)
54.3 ±9.7
25 (4)a
68 (12)
174 (29)
326 (55)
54.J ± 10.6
8 (2)a
36 (8)
140 (33)
243 (57)
54.9 ± 9.3
386 (61)
136 (21)
111 (18)
2 (—)
269 (40)
229 (34)
180 (26)
—
222 (37)
248 (42)
123 (21)
—
159 (37)
164 (38)
104 (25)
—
255 (40)
59 (9)
15(3)
150 (24)
104 (16)
28 (4)
24 (4)
251 (37)
109 (16)
10(2)
152 (22)
113 (17)
26 (4)
17(2)
290 (49)
60 (10)
6(1)
105 (18)
99 (17)
17(3)
16(2)
193 (45)
50 (12)
5(1)
86 (20)
65 (15)
13 (3)
15(4)
635
Numbers within parentheses are percentages.
for oropharyngeal cancer, an 8-fold risk for hypopha
ryngeal cancer, and about a 4-fold risk for laryngeal
cancer. Alcohol users also showed a 2-fold risk of
pharyngeal and laryngeal cancers for drinking once a
day. The trend analysis for akcohol habit was also
significant. The dose-response relationship in terms of
duration in years for bidi smokers and alcohol users
was also found to be statistioally significant in all
three cancer groups.
RR estimates for literacy stratus and diet among
three cancer groups and tests, of significance are
shown in Table IV. Illiterates had more than 50%
excess risk for oropharyngeal and hypopharyngeal
cancers only. For laryngeal cancer, literacy status did
not seem to be a factor in our study. Nonvegetarian
diet did not emerge as a significant factor in our study
compared with vegetarian diet.
Unconditional logistic regression method was
used to fit the data after adjusting for xhe four aee
groups and the three types of residence, and the re
sults are presented in Table V. Bidi smoking and al
cohol habit emerged as significant excess nsk factors
for all the three cancer groups. Illiteracy as a factor
was established for cancer of oropharynx and hypo
pharynx. Diet, particularly nonvegetariam diet, seem
to be a protective factor for cancer of orophary nx
only, not for cancer of hypopharynx anc larynx. To
bacco chewing emerged as a factor only m hvpopharyngeal cancer, with a RR of 1.32 (CI: r.01-1.73).
Data op cessation of smoking and chewing habits
were collected for patients and controls. There were
28 patients who reported cessation of bith. smokina in
the control group. Among the cancer group. 91 pa
tients in the oropharynx. 60 patients in the hvpophar-
39
L
Alcohol and Laryngopharyngeal Cancer in Mumbai
TABLE II
RR Estimates for Chewers, Smokers, and Alcohol Users, and Tests of Significance3
Hypopharynx
Oropharynx
Larynx
Controls
Cases
RR
Cases
RR
Cases
RR
382
249
434
243
1.0
0.8
(0.6-1.01 )B
330
256
1.0
1.1
(0.9-1,5)b
230
191
1.0
1.1
(0.82-1.47)°
4
1
382
233
434
219
Non-tobacco chewers
11
18
Others
5
6
4
1
337
294
132
545
Factors
Chewers
Non-chewers
Chewers
Not recorded
Chewing type
Non-chewers
Tobacco chewers
Not recorded
Smoking
Nonsmokers
Smokers
Not recorded
Smoking type
Nonsmokers
Bidi
4
1
337
186
132
485
Cigarette
98
45
Bidi + cigarette
7
10
Other
3
5
Not recroded
Alcohol
Nonuser
Alcohol user
4
1
509
122
503
174
Not recorded
4
1
a
0
7
1.0
0.7
(0.6-0.9)
1.2
(0.5-3.1)
0.7
(0.2-3.4)
1.0
4.1
(3.1-5.4)
3
194
392
1.0
5.6
(4.1-7.6)
1.3
(0.8-2.2)
2.4
(0.7-8.4)
2.4
(0.4-15.7)
194
344
41
3
4
1.0
2.0
(1.5-2.6)
424
162
7
8
4
1.0
1.1
(0.83-1.51)
0.8
(0.25-2.75)
0.8
(0.15-4.62)
139
282
1.0
2.0
(1.48-2.7)
6
1.0
2.6
(2.0-3.5)
0.8
(0.5-1.4)
0.4
(0.1-2.5)
2.7
(0.1-8.4)
7
1.0
1.64
(1.2-2.3)
230
179
6
7
139
219
53
6
4
1.0
2.3
(1.7-3.2)
1.5
(0.9-2.4)
1.5
(0.4-6.0)
2.2
(0.04-94.9)
6
1.0
1.66
{1.2-2.3)
308
113
1.0
1.68
(1.20-2.43)
6
Stratified by four age groups and three types of residence.
Figures in parentheses indicate the confidence interval.
DISCUSSION
This is a retrospective unmatched case-control
study using hospital controls. The interviewer bias
40
11
1.0
1.1
(0.8-1.5)
1.0
(0.4-2.8)
0.6
(0.1-3.8)
7
ynx. and 49 patients in the larynx group reported to
have stopped the habit. For those bidi smokers who
stopped the habit for a period of 3 years or more, there
was a significant reduction in risk of cancer in all
three sites (data not shown i.
IV.
330
242
6
was eliminated, as the patients were interviewed be
fore the clinical examination. For a number of differ
ent reasons, not all patients with pharvngeal and la
ryngeal cancer who registered during the period could
be interviewed. These are some of the limitations of
the study which may or may not have affected the
relative risk estimates. Previous studies from India did
not analyze the effect of alcohol habit with head and
neck cancer mainly due to social stigma associated
with the habit and governmental ban on alcohol drink-
Cancer Detection and Prevention
TABLE 111
RR for Bidi Smoking and Use of Alcohol and according to Frequency per Day
and Duration
Larynx
Hypopharynx
Oropharynx
Controls
No.
RR
No.
RR
No.
RR
Bidi
Frequency
Nonuser
1-10 times
445
77
193
188
242
126
52
124
21-30 times
53
141
31 + times
4
31
1.0
2.1
(1.5-3.1)
2.5
(1.6-4.0)
3.5
(2.4-5.5)
8.3
(2.3-26.0)
203
93
11-20 times
1.0
4.3
(3.1-6.5)
4.9
(3.3-7.9)
4.7
(3.2-7.2)
12.2
(3.8—42.4)
1.0
1.8
(1.22-2.8)
1.4
(0.8—2.4)
2.5
(1.7-4.1)
3.8
(0.9-14.1
Not recorded
Duration
Nonuser
1-10 years
4
1
445
62
193
44
11-20 years
46
89
21-30 years
38
159
31+ years
40
192
Not recorded
Alcohol
Frequency
Nonuser
Once
4
1
509
108
503
151
Twice
14
23
Factors
Not recorded
Duration
Nonuser
1-10 years
4
1
509
62
503
58
11-20 years
35
55
21-30 years
14
43
31+ years
11
18
Not recorded
4
1
81
112
25
7
1.0
2.4
(1.5-4.1)
4.7
(3.4—8.6)
7.0
(4.5-11.4)
5.2
(3.4-8.1)
242
44
61
95
144
424
134
28
1.0
1.8
(1.1-3.1)
2.7
(1.8-4.9)
3.3
(2.2-57)
3.0
(1 -9-4.7)
424
54
54
39
15
11
203
24
44
62
88
1.0 _
1.2
(O.7-2.3)
2.3
(1-4—4.3)
2.3
(1-4—4.1)
2.0
(1.3-3.2)
6
1.0
1.7
(1.2-2.3)
1.8
(0.8-4.2)
7
1.0
1.6
(1.04—2.7)
1.8
(1.1-3.2)
2.0
(1.1-4.3)
0.9
(0.4-2.1)
76
6
7
1.0
1.7
(1.3-2.4)
1.4
(0.6-3.4)
38
308
85
27
1.0
1.5
(1-0-2.2)
2.8
(T.4-7.5)
7
1.0
1.6
(1.0-2.5)
2.0
(1.2-3.5)
1.9
(0.9-3.9)
0.95
(0.4—2.4)
7
308
37
37
29
10
1.0
1.6
(Q. 9-2.7)
2.3
(1-4—4.5)
1.9
(Q.. 9-4.1)
0.6
(Q..2-1.7)
6
Note: Figures in parentheses show lower and upper confidence limit.
ing in all the states in India. Due to this, many of the
studies carried out did not collect data on alcohol
habit. Furthermore, women in India will not openly
admit the habit of drinking alcohoL. This is one of the
reasons for restricting our data to males only for this
study. The emergence of alcohol as an additional risk
factor in our population for pharyngeal and Haryneeal
cancers is in conformity with the studies reported
41
Alcohol and Laryngopharyngeal Cancer in Mumbai
TABLE IV
RR Estimates for Literacy and Diet with Confidence Interval and Tests of Significance
after Adjusting for Age and Residence
Factor
Site
Literacy
Oropharynx
Literate
Illiterate
Not recorded
Hypopharynx
Literate
Illiterate
Not recorded
Larynx
Literate
Illiterate
Not recorded
Diet
Oropharynx
Vegetarian
Nonvegetarian
Not recorded
Hypopharynx
Vegetarian
Nonvegetarian
Not recorded
Larynx
Vegetarian
Nonvegetarian
Not recorded
Cases
Controls
RR
Confidence
interval
p value
391
286
1
448
183
4
1.0
1.56
1.21-2.06
<0.001
319
267
7
448
183
4
1.0
1.62
1.24-2.14
<0.001
267
154
6
448
183
4
1.0
1.11
0.82-1.52
0.486
231
446
1
148
483
4
0.065
143
443
7
148
483
4
0.173
117
304
6
148
483
4
from Western countries.Compared with Western
countries, the risk levels are ven.- low in our popula
tion. Further studies are required to collect detailed
data on alcohol according to types of alcohol and
quantity consumed in our population.
Data reported in “Cancer Incidence in Five Con
tinents. Vol. V''10 for different populations and ethnic
groups show that laryngeal cancer lICD-161) inci
dence rates usually are higher than or almost equal to
the rates for cancers of oropharynx (ICD-146) and
hypopharynx (ICD-14S) in both sexes. Even in India.
where population-based registry data are available.
incidence rates show a similar pattern. The reason for
higher incidence of laryngeal cancer is not clear. To
bacco and alcohol are major risk factors for laryngeal
cancer uniformly reported from the studies conducted
in both developing and developed countries.16'13
Among tobacco chewers and smokers, our study
showed that bidi smokers are at a higher risk of about
5.6 times for oropharyngeal cancer, and the risk level
42
1.0
1.12
0.504
decreased gradually for hypopharynx and larvn.x can
cer. In our study, though alcohol has emerged as a risk
factor for pharyngeal and laryngeal cancer, the risk
level is about 2-fold only. Misclassification of pri
mary site code when lesion with two adjacent sites is
involved is also a possible explanation for the differ
ences observed in incidence rate.. It is not possible to
explain from the study the reason for the high inci
dence of laryngeal cancer in our population compared
with oropharyngeal and hypopharvneeal cancers.
In this study, nonvegetanan diet was not shown
to be a risk factor for laryngeal and hypopharynseal
cancers, whereas it was found to be a risk factor for
oral cancer.3 In a case-control stuidv of aerodisestive
tract cancers. Notani and Jayanr assessed the role of
dietary items such as fruits, vegetables. beveraaes.
dairy products, meat. fish, and pomltrv products. Thev
also did not find excess risk due to- the consumption of
meat and poultry products, which are part of a non
vegetanan diet; also, in this study consumption of fish
Cancer Detection and Prevention
TABLE V
Unconditional Logistic Regression Model Using Five Factors for Three Sites
Site
Factor
Oropharynx
Bidi (1 = yes; 0 = no)
Alcohol (1 = yes; 0 = no)
illiteracy (1 = yes; 0 = no)
Nonvegetarian (1 = yes; 0 = no)
Tobacco chewing (1 = yes; 0 = no)
Hypopharynx
Bidi (1 = yes; 0 = no)
Alcohol (1 = yes; 0 = no)
Illiteracy (1 = yes; 0 = no)
Nonvegetarian (1 = yes; 0 = no)
Tobacco chewing (1 = yes; 0 = no)
Larynx
Bidi (1 = yes; 0 = no)
Alcohol (1 = yes; 0 = no)
Illiteracy (1 = yes; 0 = no)
Nonvegetarian (1 = yes; 0 = no)
Tobacco chewing (1 = yes: 0 = no)
was shown to be a protective factor, whereas Winn
and colleagues'9 did not find it to be a significant
protective factor. Nor. however, did Winn et al. find
significant association of pharyngeal cancer with meat
and fish intake.19 Further, use of red chilli powder of
more than 75 g/cu/month has been shown to increase
the risk of cancer. Salted meat consumption (fresh)
was associated with increased nsk of laryngeal can
cer.18 whereas consumption of preserved meat re
duced the risk of laryngeal cancer.15 Daily consump
tion of vegetables, fruits, and dairy products have
been shown to be protective factors for pharyngeal
cancers including nasopharynx.-15'20 Glutathione, a
tripeptide found in a variety of foods, especially de
rived from fruit and vegetables commonly consumed
raw. was associated with reduced cancer risk.21 Un
less patients and controls are assessed for each and
every item of diet, it will be difScult to quantitate the
risk of dietary items.
Mate, a tea-like infusion o>f the herb Ilex paraguariensis. commonly consumed in South America
has been shown to be associated with laryngeal can
cer.22
Some occupational exposures have emerged as
one of the risk factor for pharyngeal and laryngeal
cancer. An excess risk of laryngeal cancer associated
with exposure to machining fluids for automobile
RR
Confidence
interval
p value
4.69
1.53
1.45
0.67
0.97
3.64-6.29
1.04-2.03
1.09-1.94
0.45-0.85
0.67-1.19
<0.001
<0.001
0.011
0.004
>0.05
2.79
1.54
1.38
1.02
1.32
2.13-3.65
1.12-2.11
1.05-1.82
0.74-1.41
1.01-1.73
<0.001
0.008
0.018
0.899
0.041
2.11
1.64
1.02
0.97
1.24
1.58-2.82
1.16-2.31
0.76-1.38
0.69-1.36
0.93-1.66
<0.001
0.005
0.911
0.852
0.143
workers23 as well as exposure to asbestos for asbestos
workers-4 has been reported. An increased risk of pha
ryngeal cancer was found for construction workers
exposed to cutting oils, iron dust, asbestos cement.
cement, and coal/tar products.25
Environmental factors such as EBV and diet, and
other genetic factors are also believed to increase the
risk of tongue, oral, and nasopharyngeal cancer
among the circumpolar Inuit population, (including
that of Alaska. Canada, and Greenland).22
The emergence of illiteracy as a higt risk factor
(38—15% excess risk) for oropharyngeal and hypopha
ryngeal cancer after adjusting for other risk factors in
our study just points to the possibility of differences in
socioeconomic conditions, poor oral hygiene, and
lifestyle. An earlier case-control study also brought
out the significance of illiteracy as a factor for oral
cancer? The preventive measures in a society with
considerable variation in literacy status need to be
focused in an appropriate manner, and different strat
egies for cancer control need to evolve.
In conclusion, alcohol has been shown as a risk
factor for pral. pharyngeal, and laryngeal cancers
in Mumbai. In order to prevent head anc neck can
cer, particularly in a country like India, ihe govern
ment should propagate the ill effect of alcohol habit
along with tobacco usage and initiate saeps to ban
43
Alcohol and Laryngopharyngeal Cancer tn Mumbai
12.
Brugere J, Guenel P, Leclerc A. Rodrigues J. Differential
effects of tobacco and alcohol in cancer of the larynx, pharynx
and mouth. Cancer 1986: 57:391-395.
13.
Francheschi S, Bidoli E. Baron AE. et al. Nutrition and cancer
of the oral cavity and pharynx in north-east Italy. Int J Cancer
1991: 47:20-25.
The authors express their thanks to staff of the
division for its assistance in carrying out this study.
Special thanks are due to Mrs. P. Peshotan and Mrs.
R. U. Vachharajani, who interviewed the cases and
controls with great care, and to the patients who par
ticipated.
14.
Franceschi S. Bidoli E, Negri E. Barbone F. LaVecchia C.
Alcohol and cancers of the upper aerodigestive tract in men
and women. Cancer Epidemiol Biomarkers Prev 1994: 3:
299-304.
15.
Esteve J. Riboli E. Pequignot G. et al. Diet and cancers of the
larynx and hypopharynx: The IARC multi-center study in
southwestern Europe. Cancer Causes Control 1996: 7:
240-251
REFERENCES
16.
Sokic SI. Adanja BJ. Marinkovic JP. Vlajinac HD. Risk fac
tors for laryngeal cancer. Ear J Epidemiol 1995: 1 1:431-433.
17.
Shapiro S. Castellana JV. Sprafka JM. Alcohol containing
mouth washes and orophary ngeal cancer: A spurious associa
tion due to underascertainment of confounders? Am J Epide
miol 1996: 144:1091-1095.
18.
De Stefam E. Oreggia F. Rivero S. Ronco A. Fierro L. Salted
meat consumption and the nsk of Laryngeal cancer. Europ J
Epidemiol 1995: 11:177-1 SO.
19.
Winn DM. Ziegler RG. Pickle LW. Gridley G. Blot WJ.
Hoover RN. Diet in the etioiogy of oval and pharyngeal cancer
among women from the <outhem United States. Cancer Res
1984:44:1216-1222.
20.
Rossmg MA. Vaughan TL. McKnight B. Diet and pharyngeal
cancer. Int J Cancer 1989: 44:593—597.
21.
Flagg EW. Coates RJ. Jones DP. d al. Dietary glutathione
intake and the risk ot oral and pharyngeal cancer. Am J Epi
demiol 1994; 139:453—465.
22.
Pintos J. Franco EL. Oliveira BV. Kowalski LP. Curado MP.
Dewar R. Mate, coffee and tea consumption and nsk of can
cers of the upper aerodigesuve tract :in Southern Brazil. Epi
demiology 1994; 5:583-590.
23.
Eisen EA. Tolben PE. Hallock MF.. Monson RR. Smith TJ.
Woskie SR. Mortality studies of machining fluid exposure in
the automobile industry. A case-concrol study of larynx can
cer. Am J Ind Med 1994; 26:185-202.
24.
Kraus T. Drexler H. Weber A. Raitbd HJ. The association of
occupational asbestos dust exposure umd laryngeal carcinoma.
Israel J Med Sci 1995: 31:540-548.
25.
Maier H. Fischer G. Sennewald E. Heller WD. Occupational
risks for pharyngeal cancer. Results of the Heidelberg case
control study. HNO 1994: 42:530-540.
26.
Lanier AP, Alberts SR. Cancers of the buccal cavity and
pharynx in Circumpolar Inuit. Acta Ojncol 1996: 35:545-552.
advertising of alcohol in the press and other visual
media.
ACKNOWLEDGMENTS
Jussawalla DJ. Deshpande VA. Evaluation of cancer risk in
tobacco chewers and smokers: An epidemiologic assessment.
Cancer 1971: 28:244-252.
2. Notani PN. Jayant K. Role of diet in upper aerodigestive tract
cancer. Null Cancer 1987: 10:103-113.
3. Rao DN. Ganesh B. Rao RS. Desai PB. Risk assessment of
tobacco, alcohol and and diet in oral cancer—A case control
study. Ini J Cancer 19
*^:
58:469—173.
4. Blot WJ. McLaughlin JK. Winn DM. et al. Smoking and
drinking in relation to era! and pharyngeal cancer. Cancer Res
1988: 48:3282-3287.
5. Tuyns AJ. Esteve J. Raymond L. el al. Cancer of the larynx/
hypopharynx, tobacco and alcohol: IARC international caseconirol study in Tuna and Varese (Italy). Zaragoga and Na
varra (Spain). Geneva a Switzerland) and Calvados (France).
Int J Cancer 1988: 41:483-491.
6. Rothman K. Keller AZ. The effect of joint exposure to alcohol
and tobacco on risk of cancer of mouth and pharynx. J Chron
Dis 1972: 25:711-716..
7. Graham S. Mettlin C. Marshall J. Pnore R. Rzepka T. Shedd
D. Dietary factors in the epidemiology of cancer of the larynx.
Am J Epidemiol 1981. 113:675-680.
8. Wynder EL. Bross LI. Feldman RM. A study of the etiological
factors in cancer of the mouth. Cancer 1957: 10:1300-1323.
9. Notani PN. Role of alcohol in cancers of the upper alimentary
tract: Use of models un nsk assessment. J Epidemiol Com
munity Health 1988: 40:187-192.
10. Muir C Waterhouse J. Mack T. Powell J. Whelan S. Cancer
incidence in five contiments. Vol. V. IARC Sci Publ 1987:
88:836-867.
11. Biennial Report (1988—89). National Cancer Registry Pro
gramme. New Delhi: tndian Council of Medical Research.
1992.
I.
44
■ 13'1
VOL 25, NO 2, SUPPL 5
APRIL 1998
Oxaliplatin: A New Option for the Treatment
of Colorectal Cancer
Esteban Cvitkovic, MD, and Stephen G. Chaney, PhD, Guest Editors
Contributors
Rene Adam • Yves Becouarn • Mohamed Bekradda • Henri Bismuth • Harry Bleiberg
Silvano Brienza • Stephen G. Chaney • Esteban Cvitkovic
Aimery de Gramont • Michel Ducreux • Jean-Marc Extra • Sandrine Faivre
Christophe Louvet • Michel Marty • Jean-Louis Misset • Eric Raymond
Philippe Rougier • Jan M. Woynarowski
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Seminars in
Oncology
Oxaliplatin: A New Option for the Treatment of Colorectal Cancer
Esteban Cvitkovic, MD, and Stephen G. Chaney, PhD, Guest Editors
APRIL 1998
VOL 25, NO 2, SUPPL 5
Contents
A Historical Perspective on Oxaliplatin: Rethinking the Role of Platinum Compounds and
Learning From Near Misses
Esteban Cvitkovic
*
1
Oxaliplatin: Mechanism of Action and Antineoplastic Activity
Enc Raymond, Sandrine Faivre, Jan M. Woynarowski,* and Stephen G. Chaney
*
4
Pharmacokinetics and Safety Profile of Oxaliplatin
Jean-Marc Extra, Michel Marty, Silvano Brienza,
*
and Jean-Louis Misset
13
Clinical Efficacy of Oxaliplatin Monotherapy: Phase II Trials in Advanced Colorectal Cancer
Yves Becouam and Philippe Rougier
23
Oxaliplatin Plus 5-Fluorouracil: Clinical Experience in Patients With Advanced
Colorectal Cancer
Harry Bleiberg and Aimery de Gramont
32
Reduction of Nonresectable Liver Metastasis From Colorectal Cancer After
Oxaliplatin Chemotherapy
Henri Bismuth and Rene Adam
40
Oxaliplatin for the Treatment of Advanced Colorectal Cancer: Future Directions
Michel Ducreux, Christophe Louvet, Mohamed Bekradda, and Esteban Cvitkovic
47
* These faculty have indicated that they have a relationship which, in the context of their prcscntation(s), could be perceived
as a potential conflict of interest (eg, ownership of stock, significant honoraria or consulting fees, or direct research support r’n 'in a
commercial organization).
Seminars in
Oncology
Oxaliplatin: A New Option for the Treatment of Colorectal Cancer
Supported by an unrestricted educational grant from Sanofi
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authors and do not necessarily reflect the opinions or recommendations of Sanofi.
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and between laboratory animal models and clinical data in humans, in vitro and animal data
may not necessarily correlate with clinical results.
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Seminars in Oncology
April 1998
Vol 25, No 2, Suppl 5
A Historical Perspective on Oxaliplatin: Rethinking the Role of
Platinum Compounds and Learning From Near Misses
Esteban Cvitkovic
F THE MANY thousands of platinum com
pounds synthesized over the last 30 years
(not to mention other metal compound hopefuls),
only a few dozen have reached preclinical or early
clinical development. Of these, until recently, only
cisplatin and carboplatin were available. Both
have similar clinical properties, and carboplatin
was approved solely on its superior safety profile.
Additionally, the diaminocyclohexane (DACH)
platinum family of compounds was shown, in the
early 1970s, to be non-cross-resistant with cis
platin and to have a different preclinical activity
profile. Most of this interest was US based and
centered around a few DACH platinum research
mavens, with Stephen Chaney, the present co
editor, being the current chef-de-file. The most
promising DACH platinum, tetraplatin (ormaplatin), had a negative phase I experience char
acterized by severe neurologic toxicity with
disabling characteristics, which considerably
dam'pened the enthusiasm for DACH platinums
in the United States.
The almost-forgotten ugly duckling in the DACH
family was oxaliplatin (oxalato[crans-l-l,2-diaminocyclohexane] platinum). In the mid-1970s, Professor
Kidani described the relationship between the stereo
isomeric specificity of DACH platinum compounds
binding to DNA and cytotoxicity,1 but it was not
until 12 years later, in the late 1980s, that Professor
Georges Mathe had the foresight to bring oxaliplatin
to the clinic.2 This first and unorthodox phase 1 trial
evidenced both the activity and the exceptionally
safe toxicity profile of oxaliplatin, which was devoid
of renal, hematologic, and/or auditory toxicity.
Whereas rapid bolus administration and accelerated
intrapatient escalation did lead to underestimation
of the recommended dose of oxaliplatin, Extra and
colleagues' gave a more accurate definition of its
triweekly short intravenous dosage, while Dr Levi4
kept the flame alive on a dnig that held no one else’s
interest.
O
Seminars in Oncology. Vol 25. No 2, Suppl 5 (April), 1998: pp 1-3
Oxaliplatin was developed mainly within the
Paul Brousse Hospital by the only group that had
both experience and belief in the positive thera
peutic possibilities of this agent. While J.L. Misset5
continued with single-agent and combination ex
periences in other disease indications, Levi and
colleagues4 treated several hundred patients with
colorectal cancer in an extensive chronotherapy
delivery clinical research experience, their main
preclinical and clinical research interest. The ex
cellent results reported in patients with advanced
colorectal cancer (ACRC) by the chronotherapy
experts were emphasized more in the context of a
specific pharmacodynamic antitumoral advantage
of the delivery modality than as a specific contribu
tion from oxaliplatin.
A standard single-agent phase II program waslaunched in a variety of solid tumors, with oxali
platin given according to the currently recom
mended dose of 130 mg/nr in a 2-hour intravenous
infusion every 3 weeks, confirming its safety.
Meanwhile, three concomitant series of events re
newed interest in the essential features of the dif
ferential pharmacodynamic specificity of oxa
liplatin and in the treatment of patients with
colorectal cancer:
1. A. de Gramont,6 whose team’s interest is the
clinical optimization of a hybnd/bolus se
quence of fortnightly 48-hour delivery of
high-dose infusional 5-fluorouracil/folinic
acid (5-FU/FA) schedules, added oxali
platin to his LV5-FU2 (leucovorin/5-fluoro-
From the Senice des MaLulies Sanguines hnmunitaires et Tu
morales, Hopital Paid Brousse. Villcjuif, France.
Dr Cvitkovic is a paid consultant of Sanofi.
Address reprint requests to Esteban Cvitkovic, MD. Senice des
Maladies Sanguines hninunitaires et Tuinorales, Hopital Paul
Brousse, 14 are P. Vaillant-Coutuner, 94800 Villcjuif, France.
Copyright © 1998 by W.B. Saunders Company
0093-7754/98/2502-0501 $08.00/0
I
2
uracil) schedule and confirmed Levi’s
observation that the oxaliplatin/5-FU combi
nation was active in strictly defined 5-FUrefractory patients/ This convinced inter
ested observers that such efficacy is indepen
dent of chronotherapy delivery- schedules.
2. Preclinical studies by Rixe et al' and Ray
mond et ar confirmed the observations of
previous generations of DACH platinum au
thorities while demonstrating that the mech
anism of action of oxaliplatin is different
from that of conventional platinum agents
and that it acts synergistically in combina
tion with 5-FU and other agents. Until then,
the US preclinical research interest in
DACH platinums had been mostly confined
to teams at M.D. Anderson Cancer Center
(Houston, TX), National Cancer Institute
(Bethesda, MD), Roswell Park Cancer Insti
tute (Buffalo, NY), and the University of
North Carolina, Chapel Hill. But even after
the development of tetraplatin was curtailed,
Chaney’s team continued to study the molec
ular properties specific to DACH platinums.
3. The single-agent phase 11 trials in 5-FU-re
fractory patients with ACRC demonstrated
the specific antitumor activity of oxaliplatin
for this disease. New single-agent data in pre
viously untreated patients have since shown
the same range of objective response rates as
with 5-FU as a single agent.
A wider clinical exposure to oxaliplatin-based
ACRC treatment led quickly, through prescriber
and patient education, to an understanding of the
pattern, rate, severity, and reversibility (not a fea
ture of cisplatin neurotoxicity) of oxaliplatin neurosensory toxicity. Consequently, oxaliplatin with
stood rigorous tests of convincing and relevant
evidence, time, and negative serendipity. Marketing
approval was granted in France in March 1996 for
patients with ACRC who had been previously
treated and in early 1998 for first-line treatment.
European, US, and worldwide filings have either
been done or are forthcoming. Data from thousands
of treated patients have been reported, including
the results of two controlled phase 111 trials in pre
viously untreated patients with ACRC comparing
oxaliplatin-5-FU/FA and 5-FU/FA. The trial by
Giacchetti and colleagues’ shows a nearly threefold
increase in response rate and a 3-month extension
in time to progression, favoring the oxaliplatin arm.
ESTEBAN CVITKOVIC
The second multicentric trial of 420 patients,
chaired by A. de Gramont, completed accrual in
mid-1997; results will be available shortly.10
1 have personally led the analysis of hundreds
of patients with ACRC treated in compassionateuse, extended-access programs. The results in such
heavily pretreated, unrestricted eligibility cohorts
seem relatively independent of the 5-FU or oxali
platin delivery modality; the biweekly delivery of
oxaliplatin/5-FU ± FA appears at least as active
and as safe as the currently recommended triweekly
schedule.
The current interest in oxaliplatin is evi
denced by the plethora of ongoing and planned
clinical studies. The recently defined differences
between cisplatin and oxaliplatin, in replicative
bypass and mismatch repair-dependent cytotox
icity, have given a molecular basis for the under
standing of their different profiles of activity.
The current definition of anticancer agent
groups proposed recently by the National Cancer
Institute from analyses of its in vitro cytotoxicity
screening program relies both on the biochemi
cal targets and on the mechanisms of resistance
operational in the different cell types. In this
classification, the DACH family has been identi
fied as a completely new group of anticanccr
agents. We are thus reasonably comforted by its
apparent clinical specificity, which will open
new indications for platinum compounds. This
may eventually lead to sharing, complementing,
or even replacing cisplatin and carboplatin in a
host of specific clinical settings.
What constitutes a major new anticancer agent?
In my opinion, the prerequisites for such a role are
based on four premises:
1. It must have antitumoral activity in the clini
cal setting in which few or no previous thera
peutic options existed.
2. It is the backbone of combination schedules
in which clinical efficacy/additivity/synergy
are proven within a safe and reliable prescrip
tion possibility.
3. Its incorporation in the therapeutic arma
mentarium does improve time-related param
eters of treatment outcome.
4. Most importantly, it changes, merely through
clinical experience, the physician's therapeu
tic options algorithms, helping to individual
ize and optimize patient treatment.
All these points are characteristic of the clin-
HISTORICAL PERSPECTIVE ON OXALIPLATIN
icnl experience with oxaliplatin for colorectal
cancer treatment. The most telling piece of in
formation is probably the rate of secondary he
patic resections (approximately one third of pa
tients) performed by those teams of surgeons
most experienced in its use. The fact that the
possibility of long-term survival is acknowl
edged by experienced physicians and that the
results obtained by the Bismuth team" have
generated many followers reflects the change in
physicians’ thinking.
Until very recently, second-line treatment of
patients with colorectal cancer was a limited thera
peutic option, confined mostly to locoregional (in
tra-arterial) or infusional 5-FU treatment of 5-FU
failures. The availability of both oxaliplatin and
CPT-11, and the incoming wave of new thymidy
late synthase inhibitors (oral administration now
appears both feasible and reliably active), multi
plies the associative possibilities of these three dif
ferent agents and will expand the palliative treat
ment of colorectal cancer.
Oxaliplatin, both a new and a major anticancer
agent lor the treatment of colorectal cancer, has
arrived. It is now up to us, the medical oncologists,
to do the best. In that sense I cannot help being
optimistic, but with a warning note.
In the 1970s, anthracyclines and tamoxifen be
came available for breast cancer treatment, simul
taneously with the availability of reliable biochem
ical determinants of treatment outcome: the
tumoral hormone receptors. Such coincidental cir
cumstances, coupled with the proof of adjuvant
treatment efficacy, led to a revolution in therapeu
tic practice. In the breast cancer arena, the trick
ling down to positive changes in clinical benefit
took over two decades.
The treatment of colorectal cancer by phar
macologic means is at the same crossroads as was
breast cancer 25 years ago. New and putative
treatment-dependent prognostic/predictive bio
logical parameters of therapeutic outcome are
rapidly being identified, including p53 function
ality, thymidylate expression, and mismatch re
pair defects. Learning from rhe past means not
3
repeating mistakes. We should not spend two
decades trying to improve the treatment of colo
rectal cancer when an opportunity such as oxali
platin exists.
REFERENCES
1 Kidanr Y, Inagaki K, Saito R. Synthesis and anti-tumor
activities of platinum (II) complexes of 1,2-diaminocyclohexane isomers and their related derivatives J Clin Hematol Oncol
7 197-209, 1977
2. Mathe G, Kidani Y, Triana K, et al: A phase I trial of
trans-l-diaminocyclohexane oxalato-platinum (L-OHP) Bio
med Pharmacother 40:372-376, 1986
3. Extra |M. Espie M, Calvo F, et al; Phase I study of
oxaliplatin in patients with advanced cancer. Cancer Chemother Pharmacol 25:299-303, 1990
4 Levi F, Misset J-L, Brienza S, er al: A chronopharmacologic phase 11 clinical trial with 5-fluorouracil, tohnic acid, and
oxaliplatin using an ambulatory multichannel programmable
pump. High antitumor effectiveness against metastatic colo
rectal cancer Cancer 69.893-900, 1992
5. Misset J-L. Kidani J. Gastiaburu J, et al: Oxalatoplatinum
(L-OHP) Experimental and clinical studies, in Howell SB (ed):
Platinum and Other Metal Coordination Compounds in Can
cer Chemotherapy New York. NY, Plenum Press, 1991. pp
369-375
6 de Gramont A, Vignoud J. Toumigand C, et al;
Oxaliplatin with high-dose leucovorin and 5-fluorouracil 48hour continuous infusion in pretreated metastatic colorectal
cancer. Eur J Cancer 33:214-219, 1997
7 Rixe O, Ortuzar W, Alvarez M. et al. Oxaliplatin, tetraplatin, cisplatin, and carboplatin: Spectrum of activity in dnigresistant cell lines and in the cell lines of the National Cancer
Institute's Anticancer Drug Screen panel. Biochem Pharmacol
52:1855-1865, 1996
8. Raymond E, Djelloul C. Buquet-Fagot F, et al: Oxaliplatin
(LOHP) and cisplatin (CDDP) in combination with 5FU, spe
cific thymidase synthase (TS) inhibitors (AG337, ZDI694),
and topoisomerase 1 (Topo-1) inhibitors (SN38, CPT-11), in
human colonic, ovarian and breast cancers. Proc Am Assoc
Cancer Res 37:291, 1996 (abstr 1981)
9. Giacchetti S, Zidani R. Perpoint B, et al: Phase Ill trial
of 5-fluorouracil (5-FU), folonic acid (FA), with or without
oxaliplatin (OXA) in previously untreated patients (pts) with
metastatic colorectal cancer (MCC). Proc Am Soc Clin Oncol
16:229a, 1997 (abstr)
10. de Gramont A, Figer A. Seymour M, et al: A randomized
trial of leucovorin (LV) and 5-fluorouracil (5-FU) with or with
out oxaliplatin in advanced colorectal cancer. Proc Am Soc
Clin Oncol 17:A985, 1998 (abstr)
I I Bismuth H. Adam R. Levi F. et al: Resection of nonre*cc table liver metastases from colorectal cancer after neoadju
vant chemotherapy. Ann Surg 224:509-522, 1996
Oxaliplatin: Mechanism of Action and Antineoplastic Activity
Eric Raymond, Sandrine Faivre, Jan M. Woynarowski. and Stepnen G Chaney
Oxaliplatin, a platinum-based chemotherapeutic agent
with a 1,2-diaminocyclohexane (DACH) carrier ligand,
has shown in vitro and in vivo efficacy against many
tumor cell lines, including some that are resistant to
cisplatin and carboplatin. The retention of the bulky
DACH ring by activated oxaliplatin is thought to result
in the formation of platinum-DNA adducts, which ap
pear to be more effective at blocking DNA replication
and are more cytotoxic than adducts formed from cis
platin. Studies by the National Cancer Institute (NCI)
have suggested that oxaliplatin has a spectrum of activ
ity different from that of either cisplatin or carboplatin,
suggesting that it has different molecular targets and/
or mechanisms of resistance. Oxaliplatin has been dem
onstrated to differ in some mechanisms associated with
the development of cisplatin resistance. Compared
with cisplatin-conditioned cells, deficiencies in mis
match repair (MMR) and increases in replicative bypass,
which appear to contribute to cisplatin resistance, have
not been shown to induce a similar resistance to oxali
platin. A decreased likelihood of resistance develop
ment makes oxaliplatin a good candidate for first-line
therapy. Studies also demonstrate additive and/or syn
ergistic activity with a number of other compounds,
however, suggesting the possible use of oxaliplatin in
combination therapies.
Semin Oncol 25(suppl 5):4—l2. Copyright © 1998 by W.B.
Saunders Company.
VEN before cisplatin (cis-diamminedichloroplatinum [CDDP]) was successfully intro
duced as an antitumor agent1" in the 1970s, a
search for analogues with a better toxicity profile
and an improved spectrum of activity was actively
pursued. Over 25 years, a large number of platinum
derivatives (several thousand) were synthesized
and investigated. Among these, compounds con
taining a 1,2-diaminocyclohexane (DACH) car
rier ligand demonstrated antitumor activity in cell
lines with acquired cisplatin resistance.’4 This as-
E
From the Department of Medicine, /nriiiut Gusiaiv Roussy,
Villejuif, France; the Cancer Therapy and Research Center. Institute for Drug Development, San Anttmio, TX; and the Department
of Biochemistry and Biophysics, School of Medicine, University of
North Carolina, Chapel Hill, NC
Drs Woynarowski and Chaney are Sanofi research grant recipi
ents.
Address reprint requests to Stephen G. Chaney, PhD, Depart
ment of Biochemistry and Biophysics. School of Medicine, University
of North Carolina, 502 Mary Ellen Jones Blifo Chapel Hill, NC
27599-7260.
Copyright © 1998 by W B. Saunders Company
0093-7754l98/2502-0502$08.00l0
4
pect was important because the occurrence or de
velopment of intrinsic or acquired resistance is a
major clinical problem associated with platinum
based chemotherapy, with cisplatin and car
boplatin sharing cross-resistance in most tumor
types. Among the platinum derivatives, com
pounds bearing the DACH carrier ligand are par
ticularly promising because this class lacks the
nephrotoxicity of cisplatin and the myelosuppression of carboplatin. is effective in cell lines with
acquired cisplatin resistance, and appears to be
clinically active in tumor types that are intrinsi
cally resistant to cisplatin. Lack of cross-resistance
with cisplatin implies a different mechanism of
antitumor activity or resistance, as demonstrated
in a National Cancer Institute cytotoxicity screen
ing study?'6
Among the platinum derivatives bearing the
DACH carrier ligand, compounds such as malonatoplatinum and tetraplatin reached the early clini
cal trial stage; however, therapeutic index, toxic
ity, and galenic issues compromised their further
development. Only oxaliplatin ((SP-4-2-( 1Rtrans)] - (1,2 - cyclohexanediamine-N,N')[ethanedioato(2-)-O,O'l platinum), one of the most ac
tive DACH-platinum derivatives against cisplatin
resistant murine LI210 leukemia cells' and various
human cancer cell lines? has been successfully de
veloped, and it has already been registered for the
treatment of patients with advanced colorectal
cancer in France, Argentina, and some other coun
tries.
The DACH-platinum complex of oxaliplatin
can exist as three isomeric conformations: transf(R,R), rrans-d(S.S), and cis(R.S). Kidani and col
leagues1’'' first suggested that the stereochemical
conformation of the DACH carrier ligand may af
fect its interaction with DNA and influence cyto
toxicity. The trans-l(R,R) isomer of oxaliplatin ap
pears to be the most effective of the three
conformers against cisplatin-sensitive and cis
platin-resistant cell lines in vitro.10 Consequently,
this conformer was selected for further preclinical
development on the basis of the physicochemical
data currently available.
BIOTRANSFORMATION AND MECHANISM
OF ACTION
Preclinical studies with the malonate derivative
of 1,2-DACH-platinum, a compound expected to
Seminars in Oncology. Vol 25. No 2. Suppl 5 (April). 1998: pp 4-12
5
OXALIPLATIN: MECHANISM OF ACTION
■ Oxaliplatin Biotransformation:
Oxaliplatin —► DACH-Pt-CI2 —► DACH-Pt-CI2H2C -+■ DACH-Pt-Diaqua
■ Carboplatin / Cisplatin Biotransformation:
Carboplatin—► Cisplatin-----► cis-Diammine-Pt-H2O -► cis-Diammine-Pt-Diaqua
carboplatin
[Pt(H2O)(CI)(NH3)2]+
cisplatin
Fig I.
[Pt(H2O)2(NH3)2]2+
Biotransformations of oxaliplatin and cisplatin.
display chemical properties similar to those of oxali
platin, have suggested that weak nucleophiles such
as blood bicarbonate or intracellular dihydrogen
phosphate can displace the oxalate group in the
complex.11 The resulting intermediates are unsta
ble and readily hydrolyzed to diaquated 1,2DACH-platinum. Depending on the immediate
environment, this species can be rapidly intercon
verted to monoaqua-1,2-DACH-monochloroplatinum or 1,2-DACH-platinum dichloride. In a highchloride environment such as blood, the latter
prevails. Within the cell, where the chloride con
centration is lower, the aquated species predomi
nates. These compounds are analogous to the reac
tive aquated platinum species that result from
cisplatin and carboplatin activation.12 However,
whereas carboplatin and cisplatin have a common
cis-diammine intermediate, the biotransformation
products of oxaliplatin retain the DACH carrier
ligand in their reactive entities (Fig 1). This sug
gests the possibility that the 1,2-DACH ligand
could have major effects on the rate of reaction
of the active complex with DNA, the types of
platinum-DNA adducts formed, or the biologic
properties of the resulting adducts. Previous studies
have shown that the 1,2-DACH carrier ligand
does not affect the rate of reaction of the active
platinum complex with DNA or with the types of
platinum-DNA adducts formed.1’ However, it does
affect the rate of monoadduct to diadduct conver
sion1 ’ and the ability of cells to tolerate unrepaired
platinum-DNA adducts.14,1’ The effect of the 1,2DACH ligand on the ability of cells to tolerate
platinum-DNA adducts appears to be primarily re
sponsible for differentiating the antitumor effects
of oxaliplatin from those of carboplatin or cis
platin.
Although the precise mechanism of oxaliplatin
remains unclear, platinum compounds in general
are thought to exert their cytotoxic effects through
the formation of various types of DNA lesions.
While oxaliplatin appears to form the same type
of lesions as cisplatin11’17 at the same sites on the
DNA,1' DACH-platinum adducts formed by oxali
platin are more effective at inhibiting DNA syn
thesis17,18 and generally are more cytotoxic than
cis-diammine-platinum adducts formed from cis
platin and carboplatin.51,1'
Computer modeling of oxaliplatin-(GpG)DNA adducts in a DNA dodecamer has predicted
that the bulkier DACH group of oxaliplatin pro
jects into the major groove. Damage recognition
proteins such as the mismatch repair (MMR) en
zyme complex may be prevented from binding to
RAYMOND ET AL
oxaliplatin adducts because oi the steric hindrance
of the DACH ring.1'1 Additionally, DNA replica
tion may be adversely affected by the bulky oxali
platin adducts.
resistance to cisplatin was prompted by the realiza
tion that such resistance was probably due to en
tirely different molecular mechanisms.
Mechanisms of Resistance to Platinum Compounds
RESISTANCE TO THERAPY
Because intrinsic resistance and acquired resis
tance are critical issues of platinum therapy, preclinical studies with human cancer cell lines have
tended to evaluate the antineoplastic activity of
oxaliplatin in the context of prior resistance to
cisplatin or carboplatin, or both. In the course of
these studies, however, it was demonstrated that
in some instances, oxaliplatin was active in tumors
thar were not considered sensitive to cisplatin.520
Among the many cell lines and tumor systems
that have been screened to assess oxaliplatin activ
ity, some, including a number of colon carcinoma
cell lines, were spontaneously resistant to both cis
platin and carboplatin. Others were subclones of
cell lines sensitive to cisplatin, such as the ovarian
cancer cell line A278O, but had developed resis
tance by progressive selection after extensive expo
sure to platinum. The determination of the efficacy
of oxaliplatin in cells with intrinsic or acquired
Fig 2.
The effectiveness of cisplatin and carboplatin
therapies has been curtailed by the presence or de
velopment of resistance to these agents. Resistance
to cisplatin and carboplatin can result from one or
several biomolecular conditions in the target cells.'1
Resistance to platinum agents has been attributed
to decreased drug accumulation, drug inactivation,
enhanced tolerance to platinum-DNA adducts, or
enhanced DNA repair'2 (Fig 2). However, the only
resistance mechanisms that have reproducibly been
shown to discriminate between cisplatin and
DACH-platinum compounds, such as oxaliplatin,
are defects in mismatch repair and enhanced repli
cative bypass (postreplicative repair).
Mismatch Repair and Resistance
Recent studies suggest that alterations in MMR
activity may confer intrinsic resistance to cisplatin
or carboplatin. To date, six genes (hMLHl,
hMLH2, KPMS2, hMSH2, hMSH3, and hMSH6)
Platinum cytotoxicity and mechanisms of resistance.
OXALIPLATIN: MECHANISM OF ACTION
have been identified as related to the MMR mech
anism. When conventional mismatch occurs, the
mismatch recognition complex hMutSor (a hetero
dimer of hMSH2 and AMSH6) binds to the mis
match and primes the MMR system for recruit
ment of the hMutLor complex (a heterodimer of
hMLHl and hPMS2) and initiation of the MMR
system. Both hMSH2 and hMurSa have been
shown to bind to cisplatin but not to oxaliplatin
DNA adducts. Furthermore, defects in hMLHl,
hMSH2, and PMS2 have been shown to result in
cisplatin resistance but do not alter the sensitivity
to oxaliplatin.1418"’ 2
Recent data have shown that the MMR-binding
protein hMLH 1 may be absent from cisplatin-resis
tant ovarian cancer cells."8 Mismatch repair defi
ciency evaluated in vitro is usually associated with
resistance to cisplatin. This resistance is generally
minimal (1.5- to 2.5-fold), but low levels of resis
tance may nevertheless lead to clinical treatment
failure. One current hypothesis concerning the sig
nificance of this finding proposes that in cisplatin
sensitive cells. hMutScr may act as a lesion marker
and that binding of the MMR complex to a DNA
adduct leads to continuous “futile” cycles of exci
sion and resynthesis of the strand opposite the le
sion, presumably to correct the mismatch. Instead,
the recurring nature ot such cycles may generate
many gaps and strand breaks, leading to apoptotic
cell death."6 In resistant cells, the absence of com
ponents of either the hMutSa or hMutLo complex
allows the cancer cell to replicate the damaged
DNA with no attempt to repair the mismatch.
The development of resistance attributable to a
deficiency in an MMR protein also leads to micro
satellite DNA instability, loss of p53-dependent
cell cycle arrest function, and a reduced ability to
engage in apoptosis."'
Several studies have demonstrated the effective
ness ot oxaliplatin using models of MMR defi
ciency. Athymic nude mice with MMR-proficicnt
grafts responded significantly better to cisplatin
therapy than did mice with MMR-deficient grafts.
However, both groups responded equally well to
oxaliplatin."' Studies have also shown that colon
carcinoma cell lines defective in either liMLHI or
hMSH2 display significant resistance to cisplatin
but little or no resistance to oxaliplatin.2'1 Further
more, both HMSH2 and the hMutSa complex have
been shown to recognite cisplatin, but not oxali
platin, diadducts with DNA.2'' ''-'
7
The current data indicate that loss of MMR is
a contributor to intrinsic resistance to cisplatin,
but not oxaliplatin. The relationship of M.MR to
intrinsic platinum resistance and to oxaliplatin
toxicity may be especially relevant for patients
with nonpolyposis familial colon cancer who are
MMR-deficient and intrinsically resistant to con
ventional platinum therapies.” In addition, de
fects in MMR have also been reported in 5% to
20% of a wide variety of sporadic human tumors,
including colorectal, ovarian, and breast, among
others.’2 ’1 Further evidence suggests that cisplatin
treatment may produce selective pressure for the
survival of MMR-deficient cells, implying a role
for oxaliplatin m cisplatin-acquired resistance.2812’’6
Thus, the currently available evidence suggests
that oxaliplatin may offer a therapeutic advantage
for a variety of tumors with either intrinsic or ac
quired cisplatin resistance.
Replicative Bypass and Resistance
Additional factors may facilitate resistance to
therapy and enhance the survival of cancer cells.
For instance, enhanced replicative bypass (the
ability of the replication complex to synthesize
DNA past the site of DNA damage) of cisplatin(GpG)-DNA adducts has been demonstrated in
cisplatin-resistant murine LI 210 cells14 and human
ovarian carcinoma cell lines.18'1' In cisplatin-resis
tant human ovarian carcinoma cell lines, a twofold
to sixfold enhanced replicative bypass of cisplatin
adducts was observed; however, no difference in
replicative bypass of oxaliplatin adducts was ob
served between the cisplatin-sensitive and cis
platin-resistant cell lines.” In addition, oxaliplatin
adducts caused greater inhibition of DNA chain
elongation than did cisplatin adducts in both cis
platin-sensitive and cisplatin-resistant cell lines.
This suggests a DACH carrier ligand effect on the
ability of the replication complex to bypass the
platinum adduct. The precise molecular interac
tions involved in such a mechanism are not fully
understood, but recent studies suggest that MMR
complexes can have an important role in pre
venting the bypass process in some cell lines. Mis
match repair-deficient cell lines displayed a three
fold to sevenfold higher incidence ot replicative
bypass of cisplatin adducts than MMR-proficient
cell lines, while MMR status had no effect on the
bypass of oxaliplatin adducts.' However, en
hanced replicative bypass has also been seen tn
8
RAYMOND ET AL
PRECLINICAL EFFICACY
Table 1. Median Concentration Inhibiting
In Vitro Studies
Proliferation by 50% (ICt0) in Various Murine and
Human Tumor Cell Lines
Oxaliplatin has shown antiproliferative activity
equivalent to or higher than that of cisplatin
against both murine (L1210; P388) and human
cancer cell lines, including, among others, HT29
colon carcinoma,HEC59 colon carcinoma,29
ovarian carcinoma cell line A278O, epidermal KB
cells, breast MCF-7 cells, germ cell cancer cell
lines,1'’ and neuroblastoma cell lines25 (Table 1).
A key study investigating the sensitivity of two
cisplatin-resistant cell lines from the National
Cancer Institute human cancer cell line panel—
a clone of ovarian cancer A278O and the epithelial
KB 3-1 cell line (an HeLa subclone)—demon
strated that both clones were approximately 10fold more resistant to cisplatin or carboplatin than
to oxaliplatin’ (Table 2). These data highlighted
the activity of DACH-platinum compounds such
as oxaliplatin against cisplatin-resistant cell lines
and suggested that their mechanism of action dif
fers from that of cisplatin or carboplatin. In the
cisplatin-resistant non-small cell lung cancer sub
clones PC-9-CDDP and PC-14-CDDP, whereas
oxaliplatin was somewhat less effective than cis
platin in the parental clone, the cisplatin-resistant
clones were less resistant to oxaliplatin than to
cisplatin” (Table 2). In the nonseminomatous
germ cell cancer cell lines with either acquired
(H12DDP clone) or intrinsic (1777Nrp Cl-A
clone) intermediate levels of resistance to cis
platin, oxaliplatin was significantly more cytotoxic
than cisplatin.
Oxaliplatin also exerts potent in vitro cytotoxic
activity against a large variety of human tumor
colony-forming units isolated from patients. In
ICM (pmol/L)
Tumor Type
Cisplatin
Oxaliplatin
Murine leukemia (LI210)
*
0.80
0.41
Murine leukemia (P388)
*
067
0.97
Human colon carcinoma (HT-29)f
20.4
0.97
Human ovarian carcinoma (A2780)f
0.76
0.17
Human breast carcinoma (MCF-7)|
4.20
0.30
* Kraker and Moore.4*
f Pendyala and Creaven.w
t Silvestro et al20
MMR-proficient cell lines with acquired cisplatin
resistance,18 suggesting that alterations in either
the replication complex or the MMR complex can
lead to enhanced replicative bypass, which is selec
tive for cisplatin adducts and is associated with
acquired cisplatin resistance.
The current data demonstrate that both the al
teration of the MMR process and replicative bypass
of DNA adducts contribute to cisplatin resistance
in ovarian cancer cell lines, but that such resis
tance can be overcome by a platinum agent with
a bulky carrier group, such as oxaliplatin, that can
make bypass more difficult and can prevent the
binding of the MMR complex. While further in
vestigation of other mechanisms is warranted, of
all the known putative mechanisms of resistance
to cisplatin, only defective MMR and enhanced
replicative bypass of DNA adducts have been
shown to adequately explain the non-cross-resistance with oxaliplatin at present.
Table 2. Cytotoxicity to Platinum-Sensitive Cells and Magnitude of Resistance in Platinum-Resistant Cells Obtained With
Three Drugs in Various Human Cancer Cell Lines
Epithelial HeLa Subclone
Ovarian Cancer
KB CP(20)
Non-Small Cell Lung Cancer
A2780(IA9)
A2780-E80
KB 3-1
PC-14
PC-I4-CDDP
Antineoplasuc
CDDP-Sensitive.
CDDP-Resistant
CDDP-Sensitive.
CDDP-Resistant
CDDP-Sensitive.
CDDP-Resistant
Agent
ICi0 (pmol/L)
(Fold Resistance)
ICM (pmol/L)
(Fold Resistance)
ICW (pmol/L)
(Fold Resistance)
Cisplatin
0.21 ± 0.0$
92
0.75 r 0.38
78
2.7 * l .l
77
Carboplatin
0.35 *
0.13
64
1.65 * 0.88
57
21.1 • 3.4
3.5
Oxaliplatin
0.12 ± 0.07
4.7
0.39^ - 0.22
2.7
6.1 : 1.6
2.3
Data from Rixe et als and Fukuda et al.18
OXALIPLATIN MECHANISM OF ACTION
9
Table 3. Oxaliplatin Concentration Dependence and Response Rates of Colony-Forming Units
From Patients With Various Tumors in a Clonogenic Assay
Clonogenic Response (%)
Oxaliplatin (mg/mL)
0.5
5.0
10.0
50.0
l-hr exposure
9/1 16 (8)
18/115 (16)
38/103 (37)
7/13 (54)
14-d exposure
10/121 (8)
37/121 (31)
57/106 (54)
15/15 (100)
vitro responses have been observed in colon can
cer; non-small cell lung, gastric, and ovarian can
cers; and in a limited number of melanoma, renal
cell carcinoma, and sarcoma specimens commonly
considered highly resistant to conventional anti
cancer agents. Responses were dependent on
length of exposure and oxaliplatin concentration
(Table 3); additionally, significant responses were
observed in clones resistant to a variety of conven
tional chemotherapeutic agents.”
It is important to keep in mind, however, that
DACH-platinum complexes arc clearly not effec
tive in all cisplatin-resistant cell lines. For in
stance, oxaliplatin was less effective than cisplatin
in the human ovarian cancer cell line OVCAR3,
which is intrinsically resistant to cisplatin.40 Addi
tionally, moderate resistance to cisplatin and carboplatin, together with high resistance to DACHplatinum compounds, has been reported in some
clones, especially those selected for resistance to
DACH-platinum compounds (P6).41’42
In Vivo Models
The potent antitumor activity of oxaliplatin was
first demonstrated in mice with LI210 or P388
leukemia (Table 4). In these initial studies, mice
treated with oxaliplatin survived two to three
times longer than control mice.4'44 In addition,
mice with L1210 leukemia treated with oxaliplatin
had a higher number of cures than did mice treated
with cisplatin. Subsequently, Mathe et al44 also
demonstrated potent oxaliplatin activity against
L1210 (Table 4). Additionally, they showed that
oxaliplatin treatment prolonged survival in mice
with AkR leukemia and provided cure rates of over
50% in rodents infected with LGC lymphoma. In
this series of experiments, Mathe et al44 failed to
demonstrate any effect of either cisplatin or oxali
platin against grafts of glioma 26, B16 melanoma,
or Lewis lung carcinoma. However, Tashiro et al,'
using higher levels of oxaliplatin, were able to
demonstrate a significant prolongation of survival
in rodents grafted subcutaneously with a variety
Table 4. Antineoplastic Properties of Oxaliplatin Versus Cisplatin in Rodents
Survival Treated/
Survival Treated/
Control (%)
Control (%)
Murine Cell Type
Study
Cisplatin Dose
(Other
Oxaliplatin Dose
(Other
(mg/kg)
Observations)
(mg/kg)
Observations)
Hematologic tumors
L1210 leukemia
Tashiro et al7
6.25
249
12.5
>308
L1210/CDDP-rcsistant
Tashiro et al7
6.25
107
6.25
>726
Noji et al51
3.12
230
12.5
231
Tashiro et al7
6.25
237
12.5
221
L40 AkR leukemia
Mathe et aP
*
5
194
7.5
LGC lymphoma
Mathe et aP
*
5
Not active
5
P388 leukemia
177
>50% Cured
Solid tumors
Fibrosarcoma M 5076
Tashiro et al7
5
211
10
358
Colon 26
Tashiro et al7
6.25
322
125
143
Colon 38
Tashiro et al7
10
153
10
153
MAI6-C mammary
Mathe et aPs
5
Not active
7.5
206
RAYMOND ET AL
10
lung cancer MV-522 xenograft, m which pacli
taxel is active as a single agent, was highly sensitive
in combination studies, as exemplified by several
cases of significant tumor shrinkage with a combi
nation of paclitaxel, oxaliplatin, and tirapazamine.
Although oxaliplatin demonstrates additive/synergistic activity in combination with many standard
anticancer agents in preclinical models, some
oxaliplatin combinations do not demonstrate in
creased activity and are sometimes associated with
increased toxicity. Consequently, the clinical util
ity of these oxaliplatin combinations requires the
demonstration of clinical efficacy with acceptable
safety.
of solid tumors, including Lewis lung, colon, and
fibrosarcoma (Table 4). In these experiments, the,
antineoplastic efficacy of oxaliplatin was compara
ble to that of cisplatin against P388 leukemia, B16
melanoma, and coion 38. Oxaliplatin was superior
to cisplatin against 1.1210 leukemia, and fibrosar
coma M5O67, and was significant against a clone
of cisplatin-resistant LI 210, prolonging rodent sur
vival over sevenfold compared with the cisplatintreated control.' In addition, a subsequent study
by Mathe et al45 was able to show good activity in
MA 16-C mammary carcinoma, while cisplatin was
inactive.
Combination With Other Agents
CONCLUSION
Although the range of its preclinical interaction
or sequence specificity in combination with other
antineoplastic drugs has not been fully identified,
oxaliplatin has demonstrated in vitro or in vivo
additive or synergistic cytotoxic properties with
most agents tested to date (Table 5), including
fluoropyrimidines (5-fluorouracil [5-FU]), thymi
dylate synthase inhibitors (AG337), topoisomer
ase 1 inhibitors (CPT-11; SN-38), a microtubule
inhibitor (paclitaxel), and DNA modifying/alkylating agents (cisplatin, cyclophosphamide).46'4'
The synergistic properties of the oxaliplatin/5-FU
combination were maintained in 5-FU-resistant
cell lines and in A2780-DDP (cisplatin-resistant)
ovarian cells. Additionally, synergy with gemcita
bine was recently observed in MMR-deficient
HCT116 and c-myc-amplified Colo 320 DM co
lon cancer cell lines.46 Interestingly, the human
Years of experience with cisplatin, one of the
most useful antitumor agents available, have
shown that many tumors are intrinsically resistant
and that many more will acquire resistance during
the course of therapy. That many tumors resistant
to cisplatin are also resistant to carboplatin results
from their sharing a common intermediate capable
of reacting with DNA after intracellular transfor
mation. Therefore, out of necessity, novel plati
num agents that are converted to different reactive
species have been introduced. Oxaliplatin is one
such agent, distinct from cisplatin and carboplatin
in that the reactive intermediate includes a bulky
and rigid 1,2-DACH nonleaving carrier group that
restricts the freedom of motion about the platinum
atom and produces bulkier DNA conjugates.
Early preclinical studies demonstrated that
Table 5. Oxaliplatin-Based Combinations That Have Demonstrated Additive and/or Synergistic Activity Against
Tumor Cell Lines In Vitro and In Vivo
In Vitro
Combinations
Oxaliplatin r 5-fluorouracil (5-FU)
Oxaliplatin • gemcitabine
In Vivo
HT29. HT29-5-FU. CaCo2 (colon)”
HT29 (colon) xenograft52
2008. A2780. A2780 DDP (ovary)”
GRI (mouse mammary) tumor52
MDA-MB-231 (breast)”
LI2I0 leukemia
*
5
HCTI16. Colo 320 DM (colon)
Not evaluated
CEM (leukemia)'
*
8
Oxaliplatin • SN38orCPT-ll
HT29 (colon)"
GRI (mouse mammary) tumor '
Oxaliplatin » AG337
HT29 (colon)52
GRI (mouse mammary) tumor ‘
2008 (breast)"
Oxaliplatin - paclitaxel • tirapazamine
Not evaluated
MV-522 xenograft
Oxaliplatin - cisplatin
KB (cervix squamous cell)5
LI2I0 (leukemia)55
A2780 (ovary)'
Oxaliplatin • CBDCA
Not evaluated
LI210 (leukemia)5’
OXALIPLATIN MECHANISM OF ACTION
many tumors with cither intrinsic or acquired resis
tance to cisplatin responded to oxaliplatin. How
ever, the degrees of cross-resistance are variable.
The reason for this variability seems to result from
multiple modes of resistance and their simultane
ous presence in any given cancer cell. Resistance
mechanisms that have been identified include glutathione-based scavenging, increased efflux, re
duced accumulation, and genomic-based effects
such as MMR deficiency and enhanced replicative
bypass. The absence of cross-resistance between
oxaliplatin and cisplatin has been specifically cor
related with MMR deficiency; it is also associated
with effectiveness of the replicative bypass process
responsible for cisplatin resistance.
Observations relating to certain specific molecu
lar events at the origin of human carcinogenesis
or to the time of progression of the disease indicate
that oxaliplatin may be a DNA interacting agent
of choice, either alone or in combination. Whereas
cisplatin is as effective as oxaliplatin in sensitive
cancer cells, rhe choice of cisplatin may be ulti
mately determined by issues of clinical tolerance
and patient profile compatibility. The observed
synergism of oxaliplatin with cisplatin suggests
that this association should be further explored.
As with other potential combination therapies, de
termination of the most appropriate sequence of
oxaliplatin and cisplatin administration should be
actively pursued to provide a rational basis for their
use in clinical chemotherapy. Additionally, be
cause of the reduced opportunities for resistance
to develop with oxaliplatin, first-line therapy with
this agent may curtail the development of signifi
cant therapy-dependent resistance and leave more
second-line therapy options open at the time of
failure. The full clinical potential of oxaliplatin
resides in the successful development of oxali
platin-based combination therapies.
REFERENCES
I. Connors TA: Anti-tumour effects of platinum complexes
in experimental animals, in Connors TA. Roberts JJ (eels):
Platinum Coordination Complexes in Cancer Chemotherapy
New York. NY. Springer-Verlag, 1974, pp 112-123
2. Loehrer PJ, Einhorn LH: Drugs five years later. Cisplatin.
Ann Intern Med 100:704-71 3, 1984
3. Connors TA, Jones M, Ross WC, et al: New platinum
complexes with anti-tumour activity. Chem Biol Interact
5:415-424, 1972
4. Burchenal JH, Kalaher K, Lokys L, et al; Studies of cross
resistance, synergistic combinations and blocking of activity of
platinum derivatives. Biochimie 60:961-965, 1978
11
5. Rixe O, Ortuzar W, Alvarez M, et al: Oxaliplatin, tetraplatin, cisplatin, and carboplatin: Spectrum of activity in drugresistant cell lines and in the cell lines of the National Cancer
Institute’s Anticancer Drug Screen panel. Biochem Pharmacol
52:1855-1865, 1996
6. Weinstein JN, Myers TG, O’Connor PM, et al: An infor
mation-intensive approach to the molecular pharmacology of
cancer. Science 275.343-349, 1997
7. Tashiro T, Kawada Y, Sakurai Y, et al Antitumor activity
of a new platinum complex, oxalato (rrans-1-1,2-diaminocydohexane)platinum (11): New experimental data. Biomed Pharmacother 43:251-260, 1989
8. Kidani Y, Inagaki K, Saito R: Synthesis and anti-tumor
activities of platinum (II) complexes of 1,2-diaminocycIohexane isomers and their related derivatives. J Clin Hematol Oncol
7:197-209, 1977
9. Kidani Y, Inagaki K, ligo M, et al: Antitumor activity of
1-,2-diaminocycIohexane-platinum complexes against sar
coma-180 ascites form. J Med Chem 21:1315-1318, 1978
10. Pendyala L, Bernacki R, Glavy JS, et al: Cytotoxicity of
cycloplatam (cyclopentylamine malatoammine Ptll) in human
tumor cell lines. Proc Am Assoc Cancer Res 34:A2384, 1993
(abstr)
11. Mauldin SK, Plescia M, Richard FA, et al- Displacement
of the bidentate malonate ligand from (d,l-trans-l,2-diaminocyclohexane) malonatoplatinum(II) by physiologically im
portant compounds in vitro. Biochem Pharmacol 37:33213333, 1988
12. Daley-Yates PT, McBrien DC: Cisplatin metabolites in
plasma, a study of their pharmacokinetics and importance in
the nephrotoxic and antitumour activity of cisplatin. Biochem
Pharmacol 33:3063-3070, 1984
13. Page JD, Husain I, Sancar A, et al: Effect of the diaminocyclohexane carrier ligand on platinum adduct formation, re
pair, and lethality Biochemistry 29:1016-1024, 1990
14. Gibbons GR, Page JD, Mauldin SK, et al: Role of carrier
ligand in platinum resistance in LI210 cells. Cancer Res
50:6497-6501, 1990
15. Schmidt W, Chaney SG: Role of carrier ligand in plati
num resistance of human carcinoma cell lines. Cancer Res
5.3:799-805, 1993
16. Saris CP, van de Vaart PJ, Rictbroek RC, et al; In vitro
formation of DNA adducts by cisplatin, lobaplatin and oxali
platin in calf thymus DNA in solution and in cultured human
cells. Carcinogenesis 17:2763-2769, 1996
17. Woynarowski JM, Chapman WG, Napier C, et al: Oxali
platin (OxPt) effects on naked and intracellular DNA. Proc
Am Assoc Cancer Res 38:311, 1997 (abstr A2O83)
IS. Mamcnta EL, Poma EE, Kaufmann WK, et al: Enhanced
replicative bypass of platinum-DNA adducts in cisplatin-resis
tant human ovarian carcinoma cell lines. Cancer Res 54:35003505, 1994
19. Schecff ED, Howell SB: Computer modeling of the pri
mary cisplatin and oxaliplatin DNA adducts and relevance to
mismatch repair recognition. Proc Am Assoc Cancer Res (in
press)
20. Silvestro L, Anal H, Sommer F, et al: Comparative ef
fects of a new platinum analog (trans-1-diamine-cyclohexane
oxalato-platinum; L’OHP) with CDDP on various cells- (. Corre
lation with intracellular accumulation. Anticancer Re>
10:1376, 1990 (abstr 115)
12
21. Richon VM, Schulte N, Eastman A: Multiple mecha
nisms of resistance to ciS'diamininedichloroplatinum(ll) in mu
rine leukemia LI210 cells. Cancer Res 47:2056-2061. 19S7
22. Johnson NP, Hoeschcle JD, Rahn RO: Kinetic analysis
of the in vitro binding of radioactive cis- and trans-dichlorodiammineplatinum(II) to DNA. Chem Biol Interact 30:151169, 1980
23. Ortuzar W, Pauli K, Rixe O, et al: Comparison of the
activity of cisplatin (CP) and oxaliplatin (OXALI) alone or in
combination in parental and drug resistant sublines. Proc Am
Assoc Cancer Res 35:A1974, 1994 (abstr)
24. Dunn TA, Schmoll HJ, Grunwald V, et al: Comparative
cytotoxicity of oxaliplatin and cisplatin in non-seminomatous
germ cell cancer cell lines. Invest New Drugs 15:109-114, 1997
25. Riccardi A, Meco D, Lasorella A, et al: Comparison of
cytotoxicity of oxaliplatin, cisplatin and carboplatin in human
neuroblastoma (NB) cell lines. Proc Am Soc Clin Oncol
16:249a, 1997 (abstr)
26 Drummond JT, Anthoney A, Brown R, et al: Cisplatin
and adnamycin resistance arc associated with MutLar and mis
match repair deficiency in an ovarian tumor cell line. J Biol
Chem 271:19645-19648, 1996
27. Anthoney DA, Me II wrath AJ, Gallagher WM, et al:
Microsatellite instability, apoptosis, and loss of p53 function
in drug-resistant tumor cells. Cancer Res 56:1374-1381, 1996
28. Fink D, Zheng H, Nebel S, et al: In vitro and in vivo
resistance to cisplatin in cells that have lost DNA mismatch
repair. Cancer Res 57:1841-1845, 1997
29. Fink D, Nebel S, Aebi S, et al: The role of DNA mis
match repair in platinum drug resistance. Cancer Res 56:4881 4886, 1996
30. Aebi S, Kurdi-Haidar B, Gordon R, et al: Loss of DNA
mismatch repair in acquired resistance to cisplatin. Cancer Res
56:3087-3090, 1996
31. Brassett C, Joyce J A, Froggatt NJ, et al: Microsatellite
instability in early onset and familial colorectal cancer. J Med
Genet 33:981-985, 1996
3-2. King BL, Carcangiu ML, Carter D, et al: Microsatellite
instability in ovarian neoplasms. Br J Cancer 72:376-382, 1995
33. Kolodner RD: Mismatch repair; Mechanisms and rela
tionship to cancer susceptibility. Trends Biochem Sci 20:397401, 1995
34 Paulson TG, Wright FA, Parker BA, et al: Microsatellite
instability correlates with reduced survival and poor disease
prognosis tn breast cancer. Cancer Res 56:4021-4026, 1996
35. Herfarth KK, Kodner IJ, Whelan AJ, et al: Mutations in
MLH1 are more frequent than in MSH2 in sporadic colorectal
cancers with microsatellite instability. Genes Chromosomes
Cancer 18:42-49, 1997
36. Brown R. Hirst GL, Gallagher WM, et al: hMLHl ex
pression and cellular responses of ovarian tumour cells to treat
ment with cytotoxic anticancer agents. Oncogene 15:45-52,
1997
37. Vaisman A, Varchenko M, Chaney SG: Correlation be
tween mismatch repair defects and increased replicative bypass
in cisplatin resistant cell lines. Proc Am Assoc Cancer Res
38:A2O91, 1997 (abstr)
38. Fukuda M, Ohe Y, Kanzawa F, et al: Evaluation of novel
RAYMOND ET AL
platinum complexes, inhibitors of topoisomerase 1 and II in
non-small cell lung cancer (NSCLC) sublines resistant to cis
platin. Anticancer Res 15:393-398, 1995
39. Raymond E, Lawrence R. Izbicka E, et al: Effects of
oxaliplatin (OxPt) in human tumor cloning assay. Proc Am
Assoc Cancer Res (in press)
40. Pendyala L, Creaven PJ, Perez R, et al; Intracellular
glutathione and cytotoxicity of platinum complexes. Cancer
Chemother Pharmacol 36:271-278, 1995
41. Hills CA, Kelland LR, Abel G, et al: Biological proper
ties of ten human ovarian carcinoma cell lines; Calibration in
vitro against four platinum complexes. Br J Cancer 59:527-534,
1989
42 Perez RP, O’Dwyer PJ, Handel LM, et al: Comparative
cytotoxicity of Cl-973, cisplatin, carboplatin and tetraplarin in
human ovarian carcinoma cell lines. Int J Cancer 48:265-269,
1291
43. Kidani Y. Nojt M, Tashiro T-. Antitumor activity of
platinum(Il) complexes of 1,2-diamino-cyclohexane isomers.
Gann 71 -637-643, 1980
44- Mathe G, Kidani Y, Noji M: Antitumor activity of
1-OHP in mice. Cancer Lett 27:135-143, 1985
45. Mathe G, Kidani Y, Segiguchi M, et al; Oxalato-platinum or 1-OHP, a third-generation platinum complex: An ex
perimental and clinical appraisal and preliminary comparison
with cis-platinum and carboplatinum. Biomcd Pharmacother
43:237-250, 1989
46. Zeghari-Squalli N, Misset JL, Cvitkovic E, et al: Mecha
nism of the m vitro synergism between SN38 and oxaliplatin.
Proc Am Assoc Cancer Res 38:A2O, 1997 (abstr)
47. Goldwasser F, Chouaki N, Buthaud X, et al: CPT-11/
Oxaliplatin (L-OHP) every two weeks: A phase I study in
patients (PTS) with advanced digestive tumors. Proc Am Soc
Clin Oncol (in press)
48. Faivre S, Raymond E, Rixe O, et al; Preclinical synergy
of oxaliplatin in combination with other antitumor agents. Proc
Am Soc Clin Oncol (in press)
49. Kraker AJ, Moore CW: Accumulation of cis-diamminedichloroplatinum(Il) and platinum analogues by platinum-re
sistant murine leukemia cells in vitro. Cancer Res 48.9-13,
1988
50. Pendyala L, Creaven PJ; In vitro cytotoxicity, protein
binding, red blood cell partitioning, and biotransformation of
oxaliplatin Cancer Res 53:5970-5976, 1993
51. Noji M, Okamoto K, Kidani Y, et al; Relation of confor
mation to antitumor activity of platinum(II) complexes of 1,2cyclohexanediamine and 2-(aminomethyl)cyclohexylamine
isomers against leukemia P388. J Med Chem 24:508-515, 1981
52. Raymond E, Djelloul C, Buquet-Fagot F, et al: Oxali
platin (LOHP) and cisplatin (CDDP) in combination with
5FU, specific thymidase synthase (TS) inhibitors (AG337,
ZD1694), and topoisomerase I (Topo-I) inhibitors (SN38,
CPT-11), in human colonic, ovarian and breast cancers. Proc
Am Assoc Cancer Res 37.291, 1996 (abstr 1981)
53. Mathe G, Chenu E, Bourut C: Experimental study of
three platinum complexes: CDDP, CBDCA and l-OHP on
LI210 leukemia. Alternate or simultaneous association of two
platinum complexes. Invest New Drugs 7:404, 1989 (abstr 224)
Pharmacokinetics and Safety Profile of Oxaliplatin
Jean-Marc Extra, Michel Marty, Silvano Brienza, and Jean-Louis Misset
In early clinical trials, oxaliplatin has demonstrated sig
nificant activity against colorectal cancer, both as a sin
gle agent and in combination with 5-fluorouracil (5-FU)
and folinic acid (FA). Oxaliplatin differs from cisplatin
assessment of the pharmacodynamics of oxaliplatin
in phase I and II trials has confirmed its favorable
toxicity and safety profile.
in its lack of nephrotoxicity and from carboplatin in
its hematologic toxicity being mild. The most constant
acute side effect of oxaliplatin observed in clinical trials
was a transient peripheral neuropathy manifesting as
paresthesia and dysesthesia in the extremities, trig
gered or enhanced by exposure to cold. The neurosen-
sory phenomena, dependent on the cumulative dose of
oxaliplatin, affect all patients who receive doses 2:540
mg/m2 over four cycles or more of therapy. This neuro
logic toxicity is also highly reversible, with 82% of pa
tients having their neuropathy regress within 4 to 6
months
and
41%
experiencing
complete
recovery
within 6 to 8 months. With these considerations in
mind, the currently recommended dosing schedules for
oxaliplatin are 130 mg/m2/d as a 2- to 6-hour infusion
or 175 mg/m2/d as a chronomodulated infusion over 5
days, both of which are administered every 3 weeks.
Oxaliplatin rapidly disappears from the plasma and is
rapidly transformed into putative active species. 5-Flu-
orouracil and folinic acid, often used in combination
with oxaliplatin, do not affect its pharmacokinetics. The
favorable pharmacokinetics and safety profile of oxa
liplatin contribute to its tolerability, particularly in pre
treated cancer patients with reduced renal function.
The reversible nature of its dose-limiting neurotoxicity
and its synergistic action with 5-FU/FA make oxaliplatin
an interesting agent for the treatment of colorectal
cancer and for other potential indications.
Semin Oncol 25 (suppl 5): 13-22. Copyright © 1998 by W.B.
Saunders Company.
XALIPLATIN, a third-generation antineoplastic platinum coordination complex of
the 1,2-diaminocyclohexane family, has shown sig
nificant activity in preclinical studies against mu
rine leukemia,1 4 lymphoma,' melanoma,4 lung’'4
and colon carcinoma,4 and fibrosarcoma,4 and in
human cancer cell lines from ovarian cancer,5
non-small cell lung cancer,6 neuroblastoma,7 nonseminomatous germ cells,8 erythroleukemia,9 and
breast9 and colon cancer.9 Oxaliplatin was intro
duced into clinical trials by Mathe et al in 1986.10
Additional phase I studies were subsequently con
ducted to establish the pharmacokinetic proper
ties, tolerability, and maximal tolerated dose
(MTD) of oxaliplatin. Cumulative neurotoxicity
as well as other oxaliplatin-associated effects re
lated to dose per cycle and multiple-dose treat
ments have been assessed in large patient cohorts,
both prospectively and retrospectively. The formal
O
Seminars in Oncology, Vol 25. No 2, Suppl 5 (April). 1998: pp 13-22
PHASE I STUDIES AND SAFETY PROFILE
Shore-Term Administration
In the original phase 1 study, 23 patients re
ceived oxaliplatin as a short infusion (s30 min
utes) every 3 to 4 weeks. The study design specifi
cally allowed for accelerated intrapatient dose
escalation in the overall dose per cycle range from
0.45 mg/m2 to 67 mg/m2. Dose-limiting toxicity
was not observed and an MTD could not be deter
mined.10 Despite the low dose of oxaliplatin, one
partial response and one complete response were
recorded. Additionally, the lack of nephrotoxicity
and moderate emesis suggested that the toxicity
profile of oxaliplatin differs from that of cisplatin.
The investigators therefore recommended a high
starting dose for further investigation.
A larger phase I study of 44. patients with ad
vanced cancer was reported in 1990 by Extra et
al." In this trial, patients received 116 courses
of oxaliplatin escalated intrapatient through seven
levels, from a starting dose of 45 mg/m2, as recom
mended by Mathe et al,10 to 200 mg/m2. The dura
tion of administration varied from 30 minutes to
2 hours. Most patients had received prior chemo
therapy, some of which included cisplatin. Since
nephrotoxicity had not been observed in the ear
lier dose-escalation study, oxaliplatin was adminis
tered without prehydration or posthydration.
World Health Organization (WHO) grade 2 tran
sient creatinine elevation seen in five of 116 treat
ment cycles was not causally related to oxaliplatin
use. All patients experienced nausea and vomiting,
but the severity of emesis did not appear to be
From the Institut Curie. Pans, France; the Policlnuque d’Oncolngie Medicale, Hopital St Louis, Pans. France. the Senice des
Maladies Sanguines Immunitaires et Tumoraks. Hopital Paul
Brousse, Villejuif, France; and the Senice des Maladies Sanguines
hnmunitancs et Tumorales, Hopital Paul Brousse. Wlkjuif, France
E)r Bnen;a is an employee of De Biopharm.
Address repnnt requests to Jean-Marc Extra, MD, Institut Curie.
Rue d'Ulrn, 75005 Pans, France
Copynght © 1998 by W.B. Saunders Company
0093-7754/98/2502-0503508.00/0
13
EXTRA ET AL
*
Observed in Phase 1 Trials as a Function
Table 1. Grade 3 and 4 Toxicities
of Oxaliplatin Dose Administered as a 2-Hour Infusion
Dose, mg/m’ (%)
Toxicity
->90 (n = 40)
130-135 (n = 18)
150-180 (n = 27)
200 (n = 12)
Neutropenia
1 (2.5)
1 (5)
5(18)
4 (33)
Thrombocytopenia
0
0
1 (4)
0
Anemia
0
0
0
0
Nausea/vomiting
7 (17)
13 (72)
13 (48)
8(67)
Acute neurotoxicity
1 (2.5)
3(17)
’ (33)
3(25)
Diarrhea
0
0
3 (II)
4 (33)
* Based on WHO scale.
dose related, except at the highest dose (Table 1).
Extending the length- of infusion did not reduce
the symptoms, hut systematic pretreatment with
antiemetics reduced grade 3 or 4 nausea and vom
iting to 11%.10,11 Gastrointestinal toxicity was also
recorded as mostly grade 1 or 2 diarrhea in 24%
of therapy courses (Table 1)."
Hematologic toxicity was moderate. Thrombo
cytopenia was dose related and did not occur at
doses less than 90 mg/m" of oxaliplatin, but 13%
of patients receiving 135 to 150 mg/m2 and 28.5%
of those receiving 175 to 200 mg/m" exhibited a
decreased platelet count that never exceeded grade
2.11 Similarly, only grade 1 or 2 neutropenia was
observed, and hemoglobin levels remained mostly
unchanged (Table I).'1 The incidence of rnyelosuppression resulting from oxaliplatin therapy was
significantly lower than would be expected from a
regimen that included therapeutic doses of carboplatin.1"
The most constant acute side effect of oxali
platin administration was a transient peripheral
neuropathy manifesting as paresthesia and dyses
thesia in rhe extremities and perioral area, trig
gered or enhanced by exposure to cold. These
symptoms, often developing during oxaliplatin in
fusion, lasted between a few minutes and a few
days. This toxicity usually appeared at doses a 90
mg/m" and affected up to 75% of patients treated
with 200 mg/m2 oxaliplatin (Table 1). The dura
tion and intensity of the symptoms increased with
the number of courses administered. Thus, the
neurologic toxicity observed in this trial was cumu
lative. Grade 3 neurologic toxicity occurred in 6%
ol cycles and 14% of patients, and an MTD of 200
mg/m- was defined. These data were confirmed by
Chevallier and Armand with high-dose (>175
mg/m") oxaliplatin in two subsequent small con
firmatory phase 1 experiences involving 10 patients
(personal communication, November 1997). At
such high doses, oxaliplatin also induced severe
nausea and vomiting in up to 20% of patients, but
minimal hematologic toxicity. Grade 3 neurotox
icity has been observed at cumulative doses greater
than 540 mg/m2. A transient laryngospasm-like
syndrome and mild ataxia have occurred in pa
tients receiving the highest doses and in those pre
treated with cisplatin." The neurosensory phe
nomena affect all patients treated with over four
cycles of therapy and, although not formally de
fined, 200 mg/m" is usually considered the MTD;
the recommended dose (RD) is 130 mg/m" per
cycle repeated every 3 weeks as a 2- to 6-hour
infusion.
The morphologic changes associated with the
sensory neuropathy of oxaliplatin therapy have
been characterized with both light and electron
microscopy. Biopsy specimens taken from four pa
tients receiving single doses of 175 to 200 mg/m"
oxaliplatin revealed minimal axonal lesions and
limited wallerian degeneration under light micros
copy. Electron microscopy also revealed an in
creased density of collagen pockets in all four pa
tients. The investigators suggested that dysesthetic
symptoms may be associated with the development
of collagen pockets, resulting from a slight decrease
in the density of small myelinated fibers.
Neurotoxicity Issues
Phase 1 and II studies indicate that peripheral
neuropathy, the most severe toxicity resulting from
oxaliplatin therapy, can be maintained at isgrade
PHARMACOKINETICS/SAFETY OF OXALIPLATIN
Fig I. Risk of developing severe neurotoxicity (grade z 3
specific scale) depending on the cumulative dose (mg/m1) of
oxaliplatin.
2 at the RD of 130 mg/m2. The neurotoxic profile
of oxaliplatin is particular in its reversibility, as
well as in its rapid onset, location, and intensity
of sensory disturbance with the absence of a motor
component.
In a recent overall evaluation of safety in 682
patients who had received oxaliplatin either as a
single dose or in combination with 5-fluorouracil
(5-FU), grade 3 neurotoxicity (specific scale) pre
senting as fine movement disturbance (such as but
toning) or moderate sensitive ataxia was observed
in 12% of patients at a median cumulative dose of
900 mg/m2 oxaliplatin (Brienza et al11 and Brienza,
unpublished data). The risk of developing severe
disturbance of neurologic function with respect to
the cumulative dose administered was assessed ac
cording to a Kaplan-Meier model (Fig 1). This
evaluation demonstrated that the total cumulative
dose of oxaliplatin is the most significant prognos
tic factor used for assessing neurotoxic risk. For
instance, total cumulative doses of 780 mg/m2,
1,170 mg/m2, and 1,560 mg/m2 have been corre
lated with an incidence of 10%, 50%, and 75%
neurotoxic risks, respectively. Additionally, a sig
nificant correlation (P = 10-5) between regression
of neurologic symptoms and total cumulative dose
administered has been demonstrated (Brienza, un
published data). Symptoms resulting from a grade
2 neuropathy have also been shown to regress in
82% of patients within 4 to 6 months and have
disappeared entirely in 41% of patients within 6
to 8 months.13
Two consecutive phase 11 studies have con
firmed that the severity of neurotoxicity depends
on the cumulative dose administered (Table 2)
and that it is mostly or completely reversible.1'*
During long-term follow-up of seven patients with
IS
grade 3 neuropathy, five had complete disappear
ance of symptoms and two had major attenuation
of symptoms within 5 months of discontinuing oxali
platin. Of three patients with grade 4 neuropathy,
one had complete disappearance of symptoms
within 2 months and two had partial regression at
3 months and 5 months, respectively. 4
The assessment of oxaliplatin neurotoxicity
showed that the neurologic toxicity scales cur
rently available (National Cancer Institute-Can
cer Treatment Center, WHO) are generally insuf
ficient for grading the characteristics of dysesthesia
associated with oxaliplatin treatment and for as
sessing the gravity of the symptoms. None of the
scales allow for an evaluation of neurotoxic symp
toms that includes both intensity and duration. A
specific neurotoxicity scale for the assessment of
oxaliplatin-induced paresthesia/dysesthesia was
therefore developed by Levi’s group.1’ The pro
posed scale provides a grading system that takes
into account both intensity and duration of symp
toms. A comparative evaluation of the proposed
scale and the WHO scale was provided by Ma
chover et al.14 In the oxaliplatin specific scale,
grade 3 refers to a gradual increase in both the
severity and duration of the neurosensory symp
toms that become permanent during successive 3week cycles of oxaliplatin. Moderate functional
impairment, including buttoning difficulty and
rapid writing, are considered grade 4, as are mild
signs of ataxia from proprioception deficit. Grade
4 of the oxaliplatin specific scale is equivalent to
grade 3 of the WHO scale.
In all studies reported to date, the neurotoxicity
resulting from oxaliplatin treatment was shown to
be specific, cumulative, and, unlike cisplatin-in
duced neuropathy, reversible. In a recent study bv
Misset et al16 of 176 stage III or IV ovarian cancer
patients treated with cyclophosphamide (1,000
mg/m2) and either cisplatin (100 mg/m2) or oxali
platin (130 mg/nr), the incidence of neuropathy
was higher in the oxaliplatin arm but was rarely
severe, decreasing or disappearing after treatment,
whereas cisplatin-induced neuropathy tended to
increase posttreatment without showing signs of
reversibility (Table 3).
Because ototoxicity leading to permanent hear
ing impairment is also a concern with cisplatin
therapy, patients with head and neck cancer
treated either with oxaliplatin (130 mg/m2) or con
ventional cisplatin (100 mg/m2) plus 5-FU (1,000
EXTRA ET AL
16
Table 2. Proportion of Patients With Advanced Colorectal Carcinoma Experiencing Adverse Events
in Phase II Trials as a Function of the Cumulative Doses of Oxaliplatin
WHO Grade (Except Neurotoxicity) (%)
Cumulative Dose
Adverse Events
Nausea/vomiting
Diarrhea
Granulocytopenia
Anemia
Thrombocytopenia
Neurotoxicity (specific scale)
Nephrotoxicity
(mg/m2)
0
1
2
3
4
390
40
22
30
6
2
650
26
34
23
17
0
390
70
II
19
0
0
650
55
21
14
10
0
390
94
6
0
0
0
650
89
5
4
2
0
390
74
19
5
2
0
650
65
27
6
2
0
390
88
8
4
0
0
650
77
9
14
0
0
390
4
37
41
14
4
650
2
28
39
23
8
390
100
0
0
0
0
650
95
5
0
0
0
Adapted and reprinted with kind permission from Kluwer Academic Publishers.14
mg/m2/d) were evaluated audiometrically.1' Cis
platin was found to be significantly more ototoxic
than oxaliplatin. In the cisplatin-treated group,
nine of 16 patients (56%) developed significant
hearing loss, whereas only two of 15 (13%) in the
oxaliplatin-treated group developed mild hearing
loss confined to the high-frequency range,17 which
is characteristic of presbycusis rather than of oto
toxicity.
Table 3. Neurotoxicity Comparison Between
Cisplatin and Oxaliplatin
Cisplatin,
Oxaliplatin.
100 mg/m2
130 mg/m2
)
(*
(%)
91
85
481.9 * 162.5
643.4 ± 180
Grade 1/2
24/91 (27)
55/85 (65)
Grade 3/4
2/91 (2)
0/85 (0)
Neurotoxicity at
17/91 (19)
41/85 (48)
1/17 (6)
14/41 (34)
4/17 (24)
1/41 (2.4)
12/74 (16)
4/44 (9)
No. of patients
Cumulative dose
administered
Neurologic WHO toxicity
completion
Complete resolution within
6 months
Worsening after
completion
Occurrence after
completion
Continuous Infusion
The efficacy of antmeoplastic therapy is inti
mately related to the dose of anticancer agent that
can be administered without causing undue toxic
ity to the patient.1'' Extended infusions of chemo
therapeutic drugs have long been known to modify
the toxicity profile. In phase I trials, continuous
infusion of cisplatin was demonstrated to be safe,
and in some instances toxicity was reduced.19 Ad
ditionally, because rodent studies have shown that
cisplatin toxicity can be significantly decreased by
timing drug delivery according to the circadian
rhythm,20 chronomodulated delivery has been
applied to oxaliplatin therapy and extensively
studied.
In an open, randomized phase 1 study comparing
extended, constant-dose infusion and chronomod
ulated infusion, oxaliplatin dosage was escalated
for each course, from 125 mg/m2 to 200 mg/m’ in
25 mg/m2 increments.11 The incidence of neutro
penia was lower (sgrade 2) with the circadianmodulated schedule than with the constant-rate
infusion schedule (2% v 19% of administered
courses; P = .05). The incidence of peripheral par
esthesia (a grade 2) was also reduced (2% v 28%
of the administered courses; P = .001). Four of the
11 patients on the circadian-modulated schedule
received the targeted final dose; in contrast, none
of the 12 patients enrolled completed the con
PHARMACOKINETICS/SAFETY OF OXALIPLATIN
stant-rate schedule. Consequently, the mean dose
of oxaliplatin delivered was significantly higher
with the circadian modulated schedule (180 mg/m2)
than with the constant-rate schedule (135 mg/m2),
prompting the investigators to propose a median
MTD per y'ourse of 175 mg/m2 oxaliplatin for the
circadian-modulated schedule compared with 150
mg/m2 for the constant-rate schedule.1’ Of note,
the definitions of MTD and RD were derived from
a low median number of cycles per patient. The
insight gained from the cumulative nature of the
neurotoxic phenomena from several hundred pa
tients treated with combination oxaliplatin/5-FU
therapy led to a downward reappraisal of these
values. Accordingly, circadian-modulated delivery
schedules have been developed to deliver higher
levels of drug and reduce dose-limiting toxicity in
an attempt to enhance activity.21 28
Reduced toxicity was demonstrated in a recently
published phase III trial22 comparing a triweekly
schedule of either constant infusion or chronomod
ulated administration of oxaliplatin (125 mg/m2)
in combination with 5-FU/folinic acid (FA). In
this study, functional impairment occurred twice
as often in patients receiving the constant-rate
schedule (31% v 15%). Accordingly, the satisfac
tory safety profile has allowed the administration
of such chronomodulated schedules as a biweekly
regimen, permitting the delivery of a more intense
dose at a rate of 100 mg/m2 per cycle oxaliplatin
for up to seven cycles (cumulative dose, 700 mg/
m"), followed by continued administration for up
to 12 weeks at a rate of 30 to 40 mg/m2/wk.24
Safety Issues arid Recommended Dose
Overall, the safety data on oxaliplatin confirm
a toxicity profile that is clearly differentiated from
those of other platinum agents. Oxaliplatin dem
onstrates a lack of nephrotoxicity, even in the ab
sence of patient hydration, minimal ototoxicity,
and minimal hematologic toxicity. The gastroin
testinal side effects inherent to platinum chemo
therapy have been effectively controlled with
standard antiemctics and antidiarrheal agents.
Neurotoxicity usually regresses on cessation of oxali
platin treatment and in many cases is completely
reversible. Regression of neurotoxicity is particular
to oxaliplatin; it has not been observed with either
cisplatin or ormaplatin, another trans-l-diaminocyclohexane platinum derivative.2910
Although a correlation between neuropathy and
17
single-dose administration of oxaliplatin is evi
dent, a clearly defined MTD has not been estab
lished, but it is estimated to be approximately 200
mg/m2. In general, the total cumulative dose is
considered to be more predictive of toxic risk than
is the MTD. Consequently, current RD schedules,
based on estimated median cumulative levels, are
as follows: 130 mg/m2/d as a 2-hour intravenous
infusion in normal saline every 3 weeks or 125150 mg/m2/d as a chronomodulated intravenous
infusion over 5 days per week every 3 weeks.
BIOTRANSFORMATION OF OXALIPLATIN
The hydrolytic breakdown of 1,2-diaminocyclohexane platinum malonate, a compound expected
to have chemical properties similar to those of
oxaliplatin, has been studied in detail.” From
these studies it can be inferred that once oxali
platin enters the bloodstream, the oxalate moiety
is rapidly displaced by bicarbonate ions and the
resulting unstable species is converted first to a
monoaquate and ultimately to a diaquate. The
aquated species predominate intracellularly and ul
timately react with cellular DNA to form adducts
that hamper DNA replication.’2
Human studies have shown that approximately
85% of plasma oxaliplatin rapidly becomes protein
bound”; a significant proportion (37%) of the in
fused drug becomes sequestered in erythrocytes
within 2 to 5 hours of exposure.’4 Simultaneously,
within 2 hours after infusion, oxaliplatin disap
pears from the plasma ultrafiltrate and is undetect
able in the urine. Major biotransformation prod
ucts of oxaliplatin have been identified in the
plasma ultrafiltrate and include (trans-1,2-diaminocyclohexane) dichloroplatinum, (trans-1,2diaminocyclohexane) monochloromonoaquoplatinum, methionine (trans-l,2-diaminocyclohexane)
platinum, and glutathione (trans-1,2-diaminocyclohexane) platinum (ref 34 and D. Greenslade,
personal communication, March 1998). These
compounds, together with (trans-1,2-diaminocyclohexane) diaquoplatinum and free diaminocyclohexane, also have been identified in the urine
of patients.
Recent studies of patients with colorectal cancer
confirmed that oxaliplatin platinum is partitioned
rapidly into three compartments of unequal impor
tance: protein-bound plasma platinum, free plasma
platinum, and erythrocyte-sequestered platinum.
The proportion of protein-bound platinum in
18
EXTRA ET AL
creased over time, from 70% 2 hours after infusion
to 95% after 5 days. Approximately half of the
platinum dose was recovered in the urine within
3 days of administration, whereas fecal excretion
was minimal. Mass balance is significantly shorter
than that of cisplatin (20 days) and somewhat
longer than that of carboplatin (6 hours). By day
11, 57% ot the infused platinum had been recov
ered in the urine and 5% in the feces.’’
PHARMACOKINETICS
Clinical Studies
Until recently, clinical pharmacology studies of
oxaliplatin used the classic method of flame atomic
absorption to determine scrum platinum levels. In
these early pharmacokinetic studies, it was shown
that the route of oxaliplatin administration,
whether intravenously or intraperitoneally, had
little effect on distribution and clearance, but sig
Table 4. Comparison of Oxaliplatin Pharmacokinetic
Parameters in Patients With Normal and Impaired
Renal Function
Nephronormal
Impaired
(n = H)
(n = 10)
T Pt
5.1 ± 0.2
4 9 ± 0.3
NS
UF Pt
2.1 ± 0.2
2.3 ± 0 4
NS
T Pt
102.8 ± 6.6
119.7 ± 18.9
NS
UF Pt
9 8 x 0.9
15.2 ± 1.4
.004
P Value
Peak plasma levels
(pg/mL)
AUC (pg/mL/hr)
Clearance (L/hr)
T Pt
2 4 x 0.2
1.9 ± 0.2
NS
UF Pt
26.5 ± 2.1
15 1 ± 1.7
0009
T Pt
0.43 ± 0.1
0.69 • 0.3
NS
UF Pt
0.35 1 0.1
0 49 - 0.2
NS
Tlr2<r (hr)
Tp2/? (hr)
T Pt
38 7 r 2.4
54.9 ± 8.9
NS
UF Pt
24 2 • 6.9
27.7 * 4.1
NS
V.(L)
T Pt
70.5
44
58 1 ± 2.8
NS
UF Pt
330.1 •: 40.9
240.8 ± 311
.02
>50%
<30%
% Urinary excretion
(at 48 hr)
Abbreviations T Pt. total platinum. UF Pt. ultrafiltrable platinum. AUC. area under the curve. T(fI half-life; Va. volume of
distribution.
Adapted and reprinted with kind permission from Kluwer
Academic Publishers >•
nificantly influenced the time to maximum plasma
levels and the maximum concentration reached.’6
The pharmacokinetic behavior of oxaliplatin has
also been evaluated in patients with normal or
impaired kidney function (creatinine clearance
value, < 60 mL/nnn).' ” Administered as a short
2-hour infusion, both oxaliplatin and cisplatin ex
hibited a very high volume of distribut ion and dual
compartmentalization for total and ultrafiltrable
platinum.There were no differences in CnMS of
platinum in either plasma or ultrafiltrate; however,
the AUC of ultrafiltrable platinum in renally im
paired patients was significantly increased (Table
4). ' This suggested that at the MTD, oxaliplatin
could be administered equally safely both to nephronormal patients and to those with moderate re
nal impairment without requiring dose adjustment
or hydration.
Patients who receive chronomodulated therapy
are exposed to changing levels of oxaliplatin over
time. A recent study assessed the relationship be
tween peak time drug delivery, platinum levels,
and toxicity. Free and total plasma platinum levels
were determined in 36 patients treated with chro
nomodulated oxaliplatin (25 mg/m’/d), 5-FU (800
mg/m’/d), and FA (1 50 mg/m’/d) over a 4-day pe
riod. Results showed plasma platinum and free
platinum levels, as well as overall toxicity, to be
dependent on the time of oxaliplatin infusion (Ta
ble 5).40
Currently, the more powerful technique of in
ductively coupled plasma-mass spectrometry has
been applied to determine the pharmacokinetic
behavior of oxaliplatin. ” The sensitivity of this
procedure allows for the determination of plati
num levels in red blood cells and plasma (differ
entiated as ultrafiltrable, plasma protein-bound,
and soluble platinum). The red blood cells,
plasma, and ultrafiltrable platinum are measured
by mass spectrometry, with a sensitivity that
allows for the determination of platinum levels
3 weeks after administration.
Inductively Coupled Plasma-Mass
Spectrometry Studies
The pharmacokinetics of oxaliplatin platinum
have been evaluated in the plasma, plasma ultrafil
trate, and red blood cells of 26 patients with ad
vanced cancer treated with 130 mg/rn’ via 2-hour
intravenous infusions every 3 weeks. Platinum levels
were determined by inductively coupled plasma-
PHARMACOKINETICS/SAFETY OF OXALIPLATIN
19
Table 5. Pharmacokinetic Characteristics of Oxaliplatin Infused at Various Times
of the Circadian Rhythm and Subsequent Toxicides
Schedule
-9 (7:00 am)
0 (4:00 pm)
-9 (100 AM)
P Value (ANOVA)
Total Pt. C^,. (ng/mL)
1171 x 249
1004 ± 217
701 z 177
.001
Free Pt. CW1B (ng/mL)
236 - 24
185 z 24
123 X 20
003
Toxicity (oxaliplatin-specific grade 3 4)
Diarrhea
4/15 (27%)
1/6 (17%)
4/15 (27%)
Peripheral neuropathy
0/15 (0%)
0/6 (0%)
3/15 (20%)
NOTE. Three delivery schedules were compared: a standard infusion time at 4:00 pm (0). and infusion times 9 hours before (-9) or 9 hours
after ( — 9)
Abbreviations- Pt platinum. Cnil.. maximum concentration of drug.
Adapted and reprinted with permission.40
mass spectrometry with a limit of detection of 1 ng/
mL in ultrafiltrate and 100 ng/mL in plasma and red
blood cells. Oxaliplatin was distributed extensively
in plasma and in ultrafiltrate. Plasma protein binding
was high and did not change throughout five cycles
of therapy. The elimination of oxaliplatin was slow,
with 33% eliminated within 48 hours, but residual
levels were still detectable 63 days posttreatment
(Table 6).
The long-term administration of cisplatin leads
Table 6. Pharmacokinetics of Oxaliplatin
Administered as a 2-Hour Infusion of 130 mg/m2
Every 3 Weeks: Determination by Inductively
Coupled Plasma-Mass Spectrometry
Red Blood
Plasma
Ultrafiltrate
C„d
3 61 - 0.43
1 21 z 0 10
3 00 ± 0.33
c_.
3 61 x 0.43
1 21 z 0.10
3.25 X 0 49
79 9 ± 14 7
82 X 2.4
151.0 x 41
Cells
AUCo «8
(pg/mL • hr)
AUCow
(pg/mL • hr)
207.0 i- 60.9
11.9 X 4.6
1.326.0 • 570
T. }<• (hr)
7.3 x 4.9
0 28 x 0 06
589 0 • 89 9
T, }6 (hr)
239 0 •_ 54 4
163 • 29
NA
T _>y (hr)
NA
273.0 - 19
NA
v„ (I)
93 4 •
16 8
582.0 x 261
NA
056
0.10
10.10 • 3.07
0 09 ± 003
Clearance
(L/hr)
Abbreviations C,.,. concentration of drug at end of infusion;
C..maximum concentration of drug; AUC, area under the
curve: T| j. half-life; V$s. apparent volume of distribution. NA,
not applicable
From M Graham (personal communication. March 1998).
to neuropathy and ototoxicity, both of which de
pend on the cumulative dose of platinum achieved
in neuronal tissue. Cisplatin also accumulates in
the plasma*';
this is attributed to rapid uptake into
red blood cells, followed by a long (29.8-day) ter
minal half-life."’ Whether this effect is related to
cisplatin toxicity or reflects normal red blood cell
turnover remains an open question. The cumula
tive pharmacokinetics of oxaliplatin have recently
been evaluated to determine platinum distribu
tion, infer potential toxicities, and assess the risks
of permanent tissue damage.15 Patients with meta
static colorectal cancer received conventional
short-term (2-hour) oxaliplatin infusions every 3
weeks. 5-Fluorouracil and FA were administered
concomitantly on a weekly basis. The maximum
oxaliplatin concentration was reached within 2
hours of administration, and platinum levels de
cayed rapidly within 8 days (Table 7). Total plasma
platinum did not accumulate to any meaningful
extent after seven courses of therapy, as does cis
platin-derived platinum.41 However, platinum of
oxaliplatin origin accumulated in red blood cells,
with a mean terminal half-life of 48 ± 10 days
consistent with that of erythrocytes.14 Red blood
cell platinum from oxaliplatin administration does
not appear to be exchangeable into plasma. Conse
quently, the intraerythrocyte platinum does not,
in the short term, contribute to the maintenance
of platinum plasma levels.14 These observations
may explain in part the rapid clearance of oxa
liplatin compared with cisplatin, the lack of oxa
liplatin nephrotoxicity, and the reversible, rather
than permanent, neurotoxicity observed in phase
I trials.
20
EXTRA ET AL
Table 7. Total Platinum Concentration at Peak (2 Hours After Infusion, CmM) and Immediately Preceding the Next
in Patients With Colorectal Cancer Receiving Six or More Cycles of Therapy
Oxaliplatin Infusion (Day 22;
Cycle
Platinum (mg/L)
1
2
3
4
5
6
7
C„.
3,201 ± 60
3,349 r 796
3.095 z 542
2,619 z 805
2.914 z 571
3,526 ± 1,307
4.475 ± 933
C™
161 ± 45
187 T 31
189 ’ 31
200 ± 13
225 ± 22
244 ±43
250 ± 80
Total
Abbreviations: Cm,,, maximum concentration of drug; C^^. minimum concentration of drug.
Pharmacokinetic Interactions tn Combination
Therapy
Current pharmacokinetic data indicate that the
5-FU/FA combination does not influence the
pharmacokinetics of oxaliplatin." Preclinical stud
ies have shown that combining oxaliplatin with
either cisplatin or carboplatin results in synergistic
and supra-additive antineoplastic activity.4- How
ever, it is worth noting that the pharmacokinetic
profile of oxaliplatin is more akin to that of cis
platin than to carboplatin. An ongoing phase 1
study is evaluating the pharmacokinetics and
safety profile of the oxahplatin/carboplatin combi
nation in patients with advanced malignancies.
Preliminary data, obtained at a carboplatin ultrafiltrable area under the curve of 4.1 resulting from
carboplatin administration 1 hour before oxali
platin administration, show a high incidence of
grade 3/4 hematologic toxicity. However, periph
eral neuropathy did not exceed grade I.4'
A recent study of the irinotecan/oxaliplatin
combination for colorectal cancer has shown that
the area under the curves of irinotecan and metab
olites administered at a dose of 150 to 200 mg/min the presence of 85 to 110 mg/m- oxaliplatin are
identical to the irinotecan area under the curve
obtained when this drug is used alone at a dose of
350 mg/m2.44
CONCLUSION
Pharmacokinetic and preliminary studies in hu
mans have shown that oxaliplatin can be adminis
tered safely at a dose of 130 mg/m2 over a 2-hour
infusion. Under these conditions, nephrotoxicity,
a major dose-limiting toxicity of cisplatin, is non
existent, and hematologic toxicity, a major dose
limiting toxicity of carboplatin, is moderate and
usually confined to sgrade 2. Gastrointestinal tox
icity, apparent as nausea and vomiting, can be con
trolled with systematic antiemetic treatment. Diar
rhea occurs at s grade 2 in approximately one
quarter of patients. Sensory neuropathy is a dose
limiting toxicity of oxaliplatin; however, at the
RD, less than 8% of patients experience severe
neurotoxicity after six cycles of therapy at a cumu
lative dose of 780 mg/m2.
The pharmacokinetic profile of oxaliplatin, with
high clearance rates, high volume of distribution,
and faster elimination than cisplatin, results in no
nephrotoxicity. This allows for the use of
oxaliplatin in patients with renal impairment
without modification of schedule or pretreatment
or posttreatment hydration. This is a significant
advantage, particularly in relapsed patients whose
therapy options are often limited by reduced kid
ney function attributable to previous therapies, in
cluding nephrotoxic antibiotics used to control in
fections during neutropenic episodes. Patients
receiving chronomodulated oxaliplatin infusions
were able to tolerate a higher mean dose per cycle
of 180 mg/m- with comparatively lower toxicity
than with a constant-rate schedule over short
treatment periods.
Oxaliplatin is currently being tested in the colo
rectal cancer therapy setting. It has provided sig
nificant response rates alone and enhanced the
response to the 5-FU/FA regimen. Other cancer
types susceptible to oxaliplatin therapy are cur
rently being identified or challenged in phase 1
studies. Additional phase 1 studies are needed to
explore alternative schedules of administration
and potential combination therapies.
REFERENCES
1. Kidani Y, Inagaki K, Saito R- Synthesis and anti turn
activities of platinum (11) complexes of l,2
diaminocyc
*
PHARMACOKINETICS/SAFETY OF OXALIPLATIN
ane isomers and their related derivatives. J Clin Hematol Oncol
7:197-209, 1977
2. Kidani Y, Inagaki K, Tsukagoshi S: Examination of antitu
mor activities of platinum complexes of 1,2-diaminocyclohexane
isomers and their related complexes. Gann 67:921-922, 1976
3. Mathe G, Kidani Y, Noji M: Antitumor activity of LOHP in mice. Cancer Lett 27:135-143, 1985
4 Tashiro T, Kawada Y, Sakurai Y, et al: Antitumor activity
of a new platinum complex, oxalato (trans-l-1,2-diaminocyclohexane)platinum (II): New experimental data. Biomed Pharmacother 43:251-260, 1989
5. Rixe O, Ortuzar W, Alvarez M, et al: Oxaliplatin, tetraplatin, cisplatin, and carboplatin: Spectrum of activity in drug
resistant cell lines and in the cell lines of the National Cancer
Institute's Anticancer Drug Screen panel. Biochcm Pharmacol
52:1855-1865, 1996
6. Fukuda M, Ohe Y, Kanzawa F, et al: Evaluation of novel
platinum complexes, inhibitors of topoisomerase I and II in
non-small cell lung cancer (NSCLC) sublines resistant to cis
platin Anticancer Res 15:393-398, 1995
7. Riccardi A, Meco D, Lasorella A, et al: Comparison of
cytotoxicity of oxaliplatin, cisplatin and carboplatin in human
neuroblastoma (NB) cell lines. Proc Am Soc Clin Oncol
16:249a, 1997 (abstr)
8. Dunn TA, Schmoll HJ, Grunwald V, et al; Comparative
cytotoxicity of oxaliplatin and cisplatin m non-scminorr.atous
germ cell cancer cell lines. Invest New Drugs 15:109-114, 1997
9. Silvestro L, Anal H, Sommer F, et al: Comparative effects
of a new platinum analog (trans-1-diamine-cyclohexane oxalato-platinum; L’OHP) with CDDP on various cells: Correla
tion with intracellular accumulation. Anticancer Res 10:1376,
1990 (abstr 115)
10. Mathd G, Kidani Y, Triana K, et al: A phase I trial of
trans-1-diaminocyclohexane oxalato-platinum (L-OHP). Biomed Pharmacothcr 40:372-376, 1986
11. Extra JM, Espie M, Calvo F, et al: Phase I study of
oxaliplatin in patients with advanced cancer. Cancer Chemother Pharmacol 25:299-303, 1990
12. Jodrell DI, Egorin MJ, Canctta RM, et al: Relationships
between carboplatin exposure and tumor response and toxicity
in patients with ovarian cancer. J Clin Oncol 10:520-528, 1992
13. Brienza S, Vignoud J, Itzhaki M, et al: Oxaliplatin (LOHP): Global safety in 682 patients (pts). Proc Am Soc Clin
Oncol 14:A513, 1995 (abstr)
14- Machover D, Diaz-Rubio E, de Gramont A, et al; Two
consecutive phase II studies of oxaliplatin (L-OHP) for treat
ment of patients with advanced colorectal carcinoma who were
resistant to previous treatment with fluoropyrimidines. Ann
Oncol 7:95-98, 1996
15. Caussanel J-P, Levi F, Brienza S, et al: Phase 1 trial of
5-day continuous venous infusion of oxaliplatin at circadian
rhythm-modulated rate compared with constant rate. J Natl
Cancer Inst 82:1046-1050, 1990
16. Misset JL, Chollet PH, Vennin PH, er al; Multicentric
phase 11-111 trial of oxaliplatin (L-OHP) versus cisplatin (P)
both in association with cyclophosphamide (C) in the treat
ment of advanced ovarian cancer (AOC): Toxicity efficacy
results. Proc Am Soc Clin Oncol 16:354a, 1997 (abstr 1266)
17. Degardin M, Nguyen K, Carlier D, et al Comparative
audiometric evaluation in patients (pts) with advanced squa
mous cell carcinoma of head and neck (SCCHN) treated with
21
oxaliplatin (L-OHP, transplatin) or cisplatin (CDDP). Proc
Am Soc Clin Oncol 13:291, 1994 (abstr 945)
18. Levin L, Hryniuk W The application of dose-intensity
to problems in chemotherapy of ovarian and endometrial can
cer. Semin Oncol 14:12-19, 1987
19. Salem P, Khalyl M, Jabboury K, et al- Cis-diammine
dichloroplatinum (II) by 5-day continuous infusion. A new
dose schedule with minimal toxicity. Cancer 53:837-840, 1984
20. Levi FA, Hrushesky WJ, Blomquist CH, et al: Reduction
of cis-diamminedichloroplatinum nephrotoxicity in rats by op
timal circadian drug timing. Cancer Res 42 950-955, 1982
21. Levi F, Dogliotti L, Perpoint B, et al; A multicenter
phase II trial of intensified chronotherapy with oxaliplatin (LOHP), 5-fluorouracil (5-FU) and folinic acid (FA) in patients
(Pts) with previously untreated metastatic colorectal cancer
(MCC). Proc Am Soc Clin Oncol 16:266a, 1997 (abstr 945)
22. Levi F, Zidani R, Misset J-L, for the International Orga
nization for Cancer Chronotherapy: Randomised multicentre
trial of chronotherapy with oxaliplatin, fluorouracil, and folinic
acid in metastatic colorectal cancer Lancet 350:681-686. 1997
23. Brienza S, Levi F, Valori VM, et al: Intensified (every
2 weeks) chronotherapy with 5-fluorouracil (5-FU), folinic acid
(FA) and oxaliplatin (L-OHP) tn previously treated patients
(pts) with metastatic colorectal cancer. Proc Am Soc Clin
Oncol 12:197, 1993 (abstr 577)
24. Bertheault-Cvitkovic F, Jami A, Ithzakt M, et al Bi
weekly intensified ambulatory chronomodulated chemotherapy
with oxaliplatin, fluorouracil, and leucovorin in patients with
metastatic colorectal cancer. J Clin Oncol 14:2950-2958, 1996
25. Levi FA, Zidani R, Vannetzel J-M, et al: Chronomodu
lated versus fixed-infusion-rate delivery of ambulatory chemo
therapy with oxaliplatin, fluorouracil, and folinic acid (leuco
vorin) m patients with colorectal cancer metastases: A
randomized multi-institutional trial. J Natl Cancer Inst
86:1608-1617, 1994
26. Levi F, Zidani R, Di Palma M, et al: Circadian rhythmmodulated (CRM) vs flat delivery of combined oxaliplatin (LOHP), 5-fluorouracil (5-FU) and folinic acid (FA), against met
astatic colorectal cancer. A multicenter randomized Phase III
trial. Proc Am Assoc Cancer Res 35:230, 1994 (abstr 1376)
27. Misset JL, Levi F. Chronomodulated chemotherapy
combining 5-fluorouracil, folinic acid, and oxaliplatin in ad
vanced colorectal cancer: An overview of seven years of experi
ence. Cancer Invest 13:49-50, 1995 (suppl 1) (<ibstr)
28. Sandor V: Chronotherapy with 5-fluorouracil, oxali
platin, and folinic acid in colorectal cancer. Lancet 350:13251326, 1997
29. O’Rourke TJ, Weiss GR, New P, et al. Phase 1 clinical
trial of ormaplatin (tetraplatin, NSC 363812) Anticancer
Drugs 5:520-526, 1994
30. Schilder RJ, LaCreta FP, Perez RP, et al: Phase I and
pharmacokinetic study of ormaplatin (tetraplatin. NSC
363812) administered on a day 1 and day 8 schedule. Cancer
Res 54.709-717, 1994
31. Mauldin SK, Gibbons G, Wyrick SD, et al: Intracellular
biotransformation of platinum compounds with the 1,2-diamino
cyclohexane carrier ligand in the LI210 cell line. Cancer Res
48:5136-5144. 1988
32. Saris CP, van de Vaart PJ, Rietbroek RC, et al- In vitro
formation of DNA adducts by cisplatin, lobaplatin and oxali
platin in calf thymus DNA in solution and in cultured human
cells Carcinogenesis 17:2763-2769, 1996
22
33. Gamelin E, Le Bouil A, Boisdron-Cclle M, ct al: Cumu
lative pharmacokinetic study of oxaliplatin, administered every
three weeks, combined with 5-fluorouracil in colorectal cancer
patients Clin Cancer Res 3:891-899, 1997
34- Pendyala L, Creavcn PJ. In vitro cytotoxicity, protein
binding, red blood cell partitioning, and biotransformation of
oxaliplatin. Cancer Res 53:5970-5976, 1993
35. Mtsset JL, Brienza S, Taamma A, el al. Pharmacokinet
ics. urinary and fecal excretion of oxaliplatin in cancer patients
(pts). Proc Am Assoc Cancer Res 37:A1252, 1996 (abstr)
36. Grumblat A, Peytavin G, Vayrc P, et al: Comparative
pharmacokinetics of oxaliplatin after intraperitoneal and intra
venous administration. Bull Cancer 76:887-888, 1989
37. Massari C, Brienza S, Rotarski M, ct al: Oxaliplatin (LOHP, Transplatin®) comparative pharmacokinetics (Pk) and
tolerance in normal (NRF) and impaired renal function (1RF)
patients Ann Oncol 5:126, 1994 (suppl 5) (abstr 217)
38. Raymond E, Taamma A, Cvitkovic E, et al: Prechmcal
and clinical studies of oxaliplatin Ann Oncol (in press)
39. Vermorkcn JB, van der Vijgh WJ, Klein I, et al: Pharma
cokinetics of free and total platinum species after rapid and
prolonged infusions of cisplatin Clin Pharmacol Ther 39:136144, 1986
EXTRA ET AL
40. Metzger G, Massari C, Renee N, et al: Variations in
platinum (Pt) plasma levels depending on chronomodulared
oxaliplatin (l-OHP) peak time. Proc Am Soc Clin Oncol
16:244a, 1997 (abstr 863)
41. Gamelin E. Attain P, Maillart P, et al: Long-term
pharmacokinetic behavior of platinum after cisplatin ad
ministration. Cancer Chemorher Pharmacol 37:97-102,
1995
42. Mathc G, Chenu E, Bourut C- Experimental study of
three platinum complexes: CDDP, CBDCA and l-OHP on
LI210 leukemia. Alternate or simultaneous association of
two platinum complexes. Invest New Drugs 7 404, 1989
(abstr 224)
43. Bekradda M, Chatelut E, Cvitkovic E, ct al: Pharma
cokinetics (PK) and pharmacodynamics of the carboplattn
(CBDCA)/oxaliplatin (L-OHP) combination in patients
with advanced malignancies: Preliminary results of ongoing
phase I trial. Proc Am Assoc Cancer Res 39:A3553, 1998
(abstr)
44. Lokiec F, Wasserman E, Santoni J, et al: Pharmacokinet
ics (Pk) of the irinotecan (CPT-11 )/oxaliplatin (LOHP) com
bination. Preliminary data of an ongoing phase 1 trial. Proc
Am Assoc Cancer Res 38:76, 1997 (abstr 514)
Clinical Efficacy of Oxaliplatin Monotherapy: Phase II Trials in
Advanced Colorectal Cancer
Yves Becouarn and Philippe Rougier
For the past 40 years, the mainstay of chemotherapy
against colorectal cancer has been 5-fluorouracil (5FU), often administered in recent years with folinic acid
modulation. Traditional platinum derivatives have gen
erally been ineffective in colorectal cancer therapy;
however, the third-generation
1,2-diaminocyclohex-
ane-platinum derivative oxaliplatin has shown good an
titumor activity and a lack of cross-reactivity with cis
platin. Oddly, oxaliplatin was first developed as a
combination therapy with 5-FU plus folinic acid admin
istered as a chronomodulated infusion over 5 days.
In subsequent phase II clinical trials, the activity of
single-agent oxaliplatin was assessed in 63 previously
untreated patients and 139 patients with metastatic
disease refractory to 5-FU. In first-line therapy, the
median overall survival was approximately 13 to 14
months, whereas in previously treated patients no
longer responding to 5-FU, it was 8 to I 0 months. The
18% objective response rate obtained with first-line
therapy confirms that the activity of single-agent oxali
platin is comparable to other anticancer therapies con
sidered active against colorectal cancer. The 10% re
sponse rate obtained in second-line therapy in patients
refractory to 5-FU provides a means for palliative care
and suggests the possibility for a potentially active com
bination regimen with 5-FU.
Semin Oncol 25 (suppl S):23-31. Copyright © 1998 by W.B.
Saunders Company.
HE INCIDENCE of colorectal cancer varies
by geographic location worldwide, with the
highest rates reported from Australia, New
Zealand, North America, and certain countries in
northern and western Europe.1’' More than
300,000 new cases are diagnosed in the United
States and Europe each year.4 Despite a decline
in the incidence and mortality rates of colorectal
cancer in recent years, this malignancy ranked
fourth in estimated new cancer cases in 1997 in
the United States, exceeded only by prostate,
breast, and lung cancer, and ranked second in esti
mated cancer deaths, accounting for 10% of all
cancer deaths.5'6
T
TREATMENT OPTIONS FOR ADVANCED
COLORECTAL CANCER
The main potentially curative treatment option
for patients with colorectal cancer is surgical resec
tion, but more than 50% of patients eventually
die of metastatic disease progression.4,7 Since its
introduction into clinical practice 40 years ago, the
Seminars in Oncology. Vol 25. No 2. Suppl 5 (April). 1998. pp 23-31
mainstay of chemotherapy for advanced colorectal
cancer has been 5-fluorouracil (5-FU).1,8 The out
come with 5-FU administered as a single agent
by intravenous bolus to patients with metastatic
colonic cancer, however, has been far from ideal,
with response rates usually sl5% and median sur
vival times of 6 to 9 months.1,8,9
Attempts to increase the efficacy of 5-FU in
chemotherapy-naive patients have included (1)
modification of the route and schedule of adminis
tration of 5-FU; (2) combination of 5-FU with
other cytotoxic agents, such as semustine (methylCCNU [lomustine]), mitomycin C, or cisplatin;
(3) biochemical modulation of the cytotoxicity of
5-FU by combination with folinic acid (FA),
methotrexate, alpha interferon, PALA, or other
modulators; and (4) local/regional administration,
such as direct hepatic arterial infusion for patients
with liver metastases.1,2’'’ ' 11 Some of these firstline systemic approaches have improved response
rates up to 30%. In particular, the modulation of
5-FU by FA is routinely used, having yielded re
sponse rates that were twofold or greater than
those of 5-FU alone.1’ Unfortunately, there has
been little survival benefit, with the median sur
vival reported in multicenter trials of patients with
advanced colorectal cancer seldom exceeding 12
months111'’; moreover, many of the combination
regimens are associated with increased toxicity and
cannot be routinely recommended, and hepatic
arterial infusion does not preclude progression of
systemic disease and is reserved for specific patient
subsets.1,2,4,7,8,11,14
The need for alternative or second-line chemo
therapy also may be urgent for patients with ad
vanced colorectal cancer after failure of 5-FUbased regimens.1,4,10,16 Since the discovery of the
antitumor activity of cisplatin in the late 1960s,
this agent has been found to be effective in the
From the Centre Regional de Lutte Centre le Cancer. Institut
Bergonie, Bordeaux, France, and the Service d’Hepato Gastroenterologique, Hupital Ainbroise Pare, Boulogne, France.
Address reprint requests to Yves Becouarn. MD, Centre Regional
de Lutte Centre le Cancer, Institut Bergonie, ISO rue de StuntGenes, 33076 Bordeaux, France
Copyright © 1998 by W.B. Saunders Company
0093-7754/98/2502-0504308.00/0
23
24
BECOUARN AND ROUGIER
Table 1. Antitumor Activity of Single-Agent Cisplatin and Carboplatin in Phase II Trials
of Patients With Metastatic Colorectal Cancer
No. of Patients
in he Study
Study
Pretreated/
Dosage and
Overall
Duration of
Enrolled/
Previously
Schedule
Response Rate
Response
Progression-Free
Overall
Evaluated
Untreated
(mg/m’/d)
(%)
(mo)
Survival (mo)
Survival (mo)
__
Median
Cisplatin
Kovach et al14
32/32
18/14
50 every 5 wk
0
__
__
DeSimone et al11
54/53
23/31
120 every 3 wk
9
__
—
5 Cl. 2-35 d
0
__
__
0-9
—
—
—
Lokich et al2’
Total
25/16
25/0
1 1 1/101
66/45
Carboplatin
Nole et al’2
21/21
21/0
400 every 3 wk
0
—
__
__
Perry et al”
30/30
15/15
320-480
0
—
—
6
Asbury et al’4
56/56
0/56
400 every 4 wk
5 (1 CR. 2 PR)
__
__
10
Pazdur et al”
25/24
1/24
400-450
4 (1 PR)
6
3
4.5
3
4.5-10
every 4 wk
every 4 wk
Schmoll et al’*
Total
30/30
25/5
162/161
62/100
360-400
3 (1 PR)
6
0-5
6
Abbreviations. CR. complete response. PR. partial response; Cl. continuous infusion.
treatment of a wide range of malignancies.17'20 Al
though therapy with this platinum drug is associ
ated with dose-limiting neurotoxicity, ototoxicity,
and nephrotoxicity, cisplatin is currently the rec
ommended agent of choice for the treatment of
several types of solid tumors.17'20,21 However, nei
ther low-dose nor high-dose cisplatin administered
as a single agent appears to be of benefit in patients
with advanced colorectal cancer refractory to
5-FU (Table I).22’24
Several new agents are being developed for use
in the treatment of advanced colorectal cancer.
Most of these agents are thymidylate synthase in
hibitors, which were chosen because of their pur
ported biochemical and galenical advantages; raltitrexed, UFT (uracil and tegafur), and capecitabine
are the furthest advanced in clinical develop
ment.25'28 An agent with a different mechanism
of action is irinotecan (CPT-11), a semisynthetic
derivative of camptothecin that acts as a topoisom
erase I inhibitor.2’ Overall response rates of 10%
to 30% have been achieved with CPT-11 in both
chemotherapy-naive patients and refractory pre
treated patients with advanced colorectal cancer;
tumor growth control for a median duration of
4 months was demonstrated in 58% of patients
resistant to 5-FU.2’ ’1 The major toxicities of CPT11 are neutropenia and diarrhea, severe (World
Health Organization [WHO] grade 3 or 4) in up to
20% and 30% of patients, respectively.29 ” Further
research efforts for newer agents, including cis
platin analogues, have focused on the development
of more active and less toxic forms of treatment
for this disease.
DEVELOPMENT OF CISPLATIN
ANALOGUES
The first commercially available cisplatin deriv
ative was carboplatin, a second-generation plati
num analogue with an improved therapeutic in
dex. At effective doses, carboplatin produces
significantly less renal toxicity, neurotoxicity, and
side effects, such as nausea, emesis, anemia, and
alopecia.I7,2I,!2 Like cisplatin, however, single
agent carboplatin has been shown to he inactive
in patients with advanced colorectal cancer that
had progressed during therapy with 5-FU and is
not recommended for such patients. Anoverview
of several representative phase 11 trials that demon
strate the weak antitumor efficacy of cisplatin and
carboplatin administered as single-agent therapy
OXALIPLATIN MONOTHERAPY
to patients with advanced colorectal cancer is pre
sented in Table I.’2'36
Among the numerous second- and third-genera
tion cisplatin analogues evaluated in recent years,
the 1,2-diaminocyclohexane-platinum compounds
have been of most interest because of their stabil
ity, good antitumor activity, and lack of cross-resis
tance with cisplatin.18 ’7 One 1,2-diaminocyclohexane compound successfully developed in
France in the past decade is oxaliplatin.38'’9 Ani
mal studies have shown that in vivo, this agent is
at least as effective if not more effective than
cisplatin against solid tumors.38 ’9 Studies of the
antitumor activity of oxaliplatin have shown this
platinum complex to be active in a range of cis
platin-resistant murine leukemia cell lines in vitro
and more effective than cisplatin against both cis
platin-sensitive and -resistant murine leukemia
cell lines in vivo.38'40 Moreover, a recent study in
human cell lines that are highly resistant to cis
platin and cross-resistant to carboplatin also
showed oxaliplatin to have a different spectrum of
activity than cisplatin and low cross-resistance.18
Specifically, oxaliplatin was active against six of
eight colon cancer cell lines in the National Can
cer Institute’s Anticancer Drug Screen Panel that
were resistant to cisplatin and carboplatin.18
These preclinical observations of the antitumor
activity of oxaliplatin have been confirmed in
phase 1 studies in more than 90 patients with a
variety of histologically confirmed, advanced ma
lignancies irresponsive to conventional chemo
therapy or for which no beneficial therapy is avail
able.41"” These studies also established that the
dose-limiting toxicity of oxaliplatin is sensitive pe
ripheral neuropathy and that effective doses of oxali
platin, unlike those of cisplatin or carboplatin, are
associated with minimal hematologic toxicity,
minimal grade 3 to 4 gastrointestinal toxicity, and
the absence of renal and auditory toxicity.39'41'43
These encouraging results, which clearly differenti
ated oxaliplatin from cisplatin and carboplatin, led
to the design of phase II trials to evaluate the safety
and efficacy of oxaliplatin in patients with a variety
of advanced cancers.
It should be stressed that the clinical evaluation
of oxaliplatin in patients with advanced colorectal
cancer has been unorthodox in terms of its methodologic sequence. Several hundred patients re
ceived oxaliplatin in combination with 5-FU plus
FA administered as a 5-day chronomodulated infu
25
sion, as developed and recommended by Levi et
al.10 This combination was chosen following the
demonstration of its synergistic activity in vitro
and in vivo against murine leukemia cell lines.10'39
Subsequently, oxaliplatin given at the currently
recommended dose and schedule as a 2-hour infu
sion was also combined with 5-FU/FA in a contin
uous, nonchronomodulated, 48-hour infusional de
livery schedule, as published by de Gramont et
al.9'44'45 After several hundred patients with ad
vanced colorectal cancer had been treated with
one of these oxaliplatin-5-FU/FA combinations,
it became necessary to determine the real single
agent activity of oxaliplatin in patients with
advanced colorectal cancer. Moreover, the single
agent phase II trials in patients with advanced colo
rectal cancer who had received prior 5-FU-based
treatment preceded the trials in previously un
treated patients with advanced colorectal cancer.
For the sake of clarity and ease of understanding,
this report and those by Extra et al and Bleiberg
and de Gramont elsewhere (see pp 13-22 and 3239, respectively) in this supplement present the
clinical data for oxaliplatin in an orthodox methodologic sequence. The rest of this report is de
voted to a presentation of the phase II trials of
oxaliplatin administered as a single agent to pa
tients with advanced colorectal cancer.
PHASE II CLINICAL TRIALS OF
OXALIPLATIN AS A SINGLE AGENT
The safety and efficacy of oxaliplatin monother
apy in patients with advanced colorectal cancer
has been evaluated in five phase II trials, two in
cluding 63 previously untreated patients and three
including 139 patients with metastatic disease pre
viously treated with and mostly refractory' to
5-FU.46'49
Previously Untreated Patients
A multicenter phase II trial of the French Federa
tion Nationale des Centres de Lutte Centre le
Cancer conducted by Becouam et al46 evaluated
the single-agent activity of oxaliplatin in pre
viously untreated patients with metastatic colo
rectal cancer. Oxaliplatin was administered at a
dosage of 130 mg/m’/d, infused over 2 hours every
3 weeks. In this study, all clinical and radiologic
data were reviewed by an external expert panel,
and their assessment was considered to be defini
tive. Of 39 patients entered in the noncomparative
26
BECOUARN AND ROUGIER
trial when enrollment closed in October 1996, one
patient was excluded for having a second cancer
and did not receive oxaliplatin therapy. The re
maining 38 patients were evaluable for toxicity,
and .37 of these patients were evaluable for efficacy
at the final analysis, completed in September 1997.
An interim analysis of 27 patients has been pre
sented elsewhere.41' The median age of the total
cohort was 67 years (range, 45 to 74 years), slightly
more than half the patients were male, and all but
one patient had a WHO performance status of 0
or 1 Colon primary tumors outnumbered rectal
cancers by a ratio of 30:8. These patient and dis
ease characteristics are summarized in Table 2.
One hundred seventy-five cycles (85% of the total
207 administered; median, 5.5 cycles per patient;
range, one to nine cycles) with a median cumula
tive oxaliplatin dose of 670 mg/nf (range, 130
to 1,110 mg/m") evaluated for toxicity were well
tolerated, with peripheral neurotoxicity grade 3, as
measured by the Oxaliplatin Neurotoxicity Spe
Table 2. Characteristics of Previously Untreated
Patients Receiving Single-Agent Oxaliplatin
as First-Line Therapy
Becouarn
Diaz-Rubio
Characteristic
et al46
et al47
No of patients enrolled
39
25
For toxicity
38
25
For efficacy
37
25
No. of patients evaluable
Age (yr)
Median
67
60
Range
45-74
38-70
Male
21
17
Female
17
8
0
22
12
1
IS
13
2
1
Gender
WHO performance status
Site of primary tumor
Colon
30
14
Rectum
8
II
No of metastatic sites
1
21
11
2
12
6
u3
5
8
Liver
30
18
Lung
13
2
Other
17
5
Metastatic sues
________________ 1
cific Scale, observed in 13% of patients during
6.3% of cycles. Among the 37 patients evaluated
for response (WHO criteria), there were nine ob
jective responses (Table 3); all nine were partial
responses confirmed by third-party radiologic re
view, for an overall response rate of 24.3% (95%
confidence interval [CI], 11.8% to 41.2%). Fifteen
patients (40.5%) had disease stabilization, and 13
patients (35.2%) had disease progression. The me
dian duration of response was 7 months, the me
dian progression-free survival was 4 months (95%
Cl, 2 to 6 months), and the median overall sur
vival time was 13 months (95% Cl, 10 to 18
months). Thus, this trial shows that oxaliplatin is
an active and well-tolerated single agent in pre
viously untreated patients with advanced colo
rectal cancer.
Similar results had been obtained in an earlier
multicenter phase II trial conducted by Diaz-Rubio
et al4, at several treatment centers in Italy and
Spain. In that study, 25 patients with metastatic
colorectal carcinoma were enrolled from July 1994
to November 1995. An intermediate analysis of
14 patients has been described.47 Oxaliplatin was
administered as a 2-hour infusion of 1 30 mg/m2/d
every 3 weeks. The patient characteristics of this
trial are summarized in Table 2; there were minor
differences in patient profiles between this and the
previous trial (eg, more male patients, lower me
dian age). One hundred twenty-three treatment
cycles were administered (median, five cycles per
patient; range, one to nine cycles), with a median
cumulative oxaliplatin dose of 650 mg/m2 (range,
130 to 1,170 mg/m')- Although mild peripheral
neuiologic symptoms were frequent, occurring in
92% of patients during 82% of cycles, no patient
developed WHO grades 3 to 4 peripheral neuro
toxicity. The efficacy results are summarized in Ta
ble 3. There were three confirmed partial responses
after external radiologic review, for an overall re
sponse rate of 12%. The median duration of re
sponse was 6 months, the median progression-free
survival was 4 months (95% Cl, 2 to 7 months),
and the median overall survival time was 14.5
months (95% CI, 10 to 20 months). As in the
previous trial, this study confirmed the safety and
efficacy of single-agent oxaliplatin as first-line che
motherapy for previously untreated patients with
advanced colorectal cancer. Twelve objective re
sponses in 62 evaluable patients, for an overa
response rate of 18% (95% Cl, 9% to 30/o), con
OXALIPLATIN MONOTHERAPY
27
Table 3. Antitumor Activity of Single-Agent Oxaliplatin in Patients With Advanced Colorectal Cancer
No. of
Oxaliplatin Therapy
Patients in
Median No.
Median
Study
of Cycles
Cumulative
Median
Stable
Duration
Median
Overall
Disease
of
Progression-
(Enrolled/
per Patient
Dose, mg/m2
Response Rate.
Rate
Response
Free Survival
Median Overall
Evaluated)
(Range)
(Range)
% (95% Cl)
)
*
(
(mo)
(mo)
Survival (mo)
Becouarn et al44
39/37
5 5 (1-9)
670 (130-1.110)
24.3 (11.8-41 2)
40.5
7
4 (2-6)
13 (10-18)
Diaz-Rubio et al47
25/25
5 (1-9)
650 (130-1.170)
12 (NA)
NA
6 (4-9)
4 (2-7)
14.5 (10-20)
18 (9-30)
—
6-7
4
13-14.5
42
NA (5-13)
NA
8.2 (9-18.5)
NA (4 --I2)
First-line therapy
Total
64/62
Second-line therapy
Machover et al4’
58/55
5 (1-16)
650 (130-1.990)
II (0 03-0.19)
51/51
3 (2-8)
390 (260-1.010)
10 (0.017-0.18)
30/29
3 (2-9)
500 (275-1.550)
139/135
3-5
Diaz-Rubio (reported by
Machover et al48)
Levi et al4*
Total
31
NA (4-9)
NA
10
24
5
5
10
10.4
34
—
—
8.2-10
Abbreviation NA. not available.
firm that the single-agent activity of oxaliplatin
is comparable to that of other anticancer agents
considered active.
Previously Treated Patients
The safety and efficacy of monotherapy with
oxaliplatin were also evaluated in patients with
advanced colorectal carcinoma refractory to previ
ous treatment with 5-FU. One multicenter phase
11 study conducted by Machover et al4S enrolled
58 patients (36 men and 22 women aged 39 to 75
years) with previously diagnosed metastatic colo
rectal carcinoma and confirmed tumor progression
during prior treatment with a 5-FU-containing
regimen. The colon was the site of the primary
tumor in two thirds of the patients, 83% had liver
metastases, and the Eastern Cooperative Oncology
Group performance status was 0 to 1 in 86%. These
and other relevant patient and disease characteris
tics are summarized in Table 4- Oxaliplatin therapy
consisted of 130 mg/m2/d administered as a 2-hour
infusion every 3 weeks. Three hundred fourteen
cycles (median, five cycles per patient; range, one
to 16 cycles) were evaluated for toxicity; the me
dian cumulative dose of oxaliplatin given during
the study was 650 mg/m2 (range, 130 to 1,990 mg/
m2). Sensory peripheral neuropathy was observed
in 98% of the patients; as measured by the Neuro
toxicity Specific Scale, 23% had grade 3 and 8%
had grade 4- A correlation was found between in
creasing incidence and severity of the neuropathy
and increasing cumulative doses of oxaliplatin. De
spite the high rate of protracted dysesthesia and
minor functional impairment (grades 3 and 4 on
the Neurotoxicity Specific Scale), all patients who
had long-term neurologic follow-up had disappear
ance or partial regression of neurotoxic symptoms
during follow-up. During a median follow-up of 7
months (range, 1 to 18.5 months), 55 patients
were evaluated for efficacy. Of these, six patients
attained a partial response, for an overall response
rate of 11% (95% Cl, 0.03% to 0.19%); 23 patients
(42%) had disease stabilization; and 26 (47%) had
disease progression (Table 3). Time required to
achieve a response was 6 weeks, and times to dis
ease progression in the responders were 5, 5, 6, 6,
6+, and 13 months. Median survival time for the
58 patients was 8.2 months, and survival times of
the responders were 9, 9 + , 12, 14.5, 15, and 18.5
months.
Between May 1993 and June 1994, a second
European multicenter phase II trial conducted by
Diaz-Rubio enrolled 51 patients, 32 men and 19
women, ages 39 to 75. The results of this trial were
published in a single report with the results of a
trial conducted by Machover et al.48 As shown in
Table 4, these patients had similar characteristics
to those in the prior study, with the colon the
primary tumor site in more than half of the pa
tients, liver metastases in 78%, a WHO perfor-
BECOUARN AND ROUGIER
28
Table 4. Characteristics of Previously Treated Patients Receiving Single-Agent Oxaliplatin as Second-Line Therapy
Diaz-Rubio (Reported by
Characteristic
No. of patients enrolled
Machover et al4’
58
Machover et al43)
Levi et al4’
51
30
No of patients evaluable
For toxicity
58
51
29
For efficacy
55
51
29
Age (yr)
Median
62
61
60
Range
39-75
39-75
33-75
Male
36
32
24
Female
22
19
5
ECOG criteria
WHO criteria
WHO criteria
0-1:
Gender
Performance status
50 (86%)
0:
21 (41%)
0-1-
2.
7
1:
24 (47%)
2:
3:
1
2:
6
27 (93%)
2
Site of primary tumor
Colon
38 (66%)
28 (55%)
19 (66%)
Rectum
20 (34%)
23 (45%)
10 (34%)
No. of metastatic sites
1
40 (69%)
31 (61%)
16 (55%)
2
17
17
10
•3
1
3
3
27 (93%)
Metastatic sites
Liver
48 (83%)
40 (78%)
Lung
NA
NA
7
Other
10
11
9
Abbreviations: NA. not available; ECOG. Eastern Cooperative Oncology Group
mance status of 0 to 1 in 88% of patients, and
all 51 patients evaluable. Oxaliplatin therapy was
again 130 mg/m'/d, administered as a 2-hour infu
sion every 3 weeks. Two hundred three cycles (me
dian, three cycles per patient; range, two to eight
cycles) were delivered and evaluated; the median
cumulative dose of oxaliplatin was 390 mg/m"
(range, 260 to 1,010 mg/m'). Sensory peripheral
neuropathy was observed in 96% of the patients,
with grade 3 in 14% and grade 4 in 4% (specific
scale). As in the preceding trial, the incidence and
severity of peripheral neuropathy were correlated
with increasing cumulative dose, and neurotoxic
symptoms disappeared or were attenuated after dis
continuation of oxaliplatin; follow-up was too
short, however, for precise evaluation of neuro
toxic regression. With a median follow-up of 4-5
months (range. 1 to 13 months), all 51 patients
were evaluated for efficacy. A partial response was
attained in five patients, for an overall response
rate of 10% (95% Cl, 0.017% to 0.18%); 16 pa
tients (31%) had no change and 30 (59%) had
disease progression (Table 3). In the responders,
the times to disease progression were 4, 4, 4 5 t,
6, and 9 months, and the survival times were 4 + ,
5.5, 6+, 7+, and 12 months.
A third multicenter phase II trial conducted •'
Levi et al49 also evaluated oxaliplatin monotherapy
in patients with metastatic colorectal cancer.
Thirty patients entered the trial between May
1990 and May 1991. As shown in Table 4, 29
patients were evaluable (24 men and live women
with a median age of 60 years [range, 31 to 75
years]). The colon was the primary tumor site in
two thirds of the patients, 93% had liver metasta
ses, and 93% had a WHO performance status ot 0
to 1. Of the 29 evaluable patients, 25 (S('%1 had
failed previous chemotherapy. Oxaliplatin was ad
ministered by chronomodul.ilcd. xomuiuou' I
hour infusion (peak at 4:00 rxil of '0 iiu:im 3 i>>i
5 days (total dose, 150 mg/m ). repeated >" i'
weeks (16-day interval); in the abscnci "I ,,,v' *
"
OXALIPLATIN MONOTHERAPY
grade a3 after the first cycle, daily doses were
escalated to 35 mg/m2 for the second cycle (175
mg/m2) and 40 mg/m2 for the third cycle (200
mg/tn2). One hundred eight cycles (median, three
cycles per patient; range, two to nine cycles) were
administered, with a median total dose of 500 mg/
m2 (range, 275 to 1,550 mg/m2). Four patients
withdrew because of toxicity, one because of grades
3 and 4 diarrhea after the first and second cycles,
respectively, and three because of sensitive periph
eral neuropathy after four or six cycles. As in the
first two studies, the incidence and severity of pe
ripheral-sensitive neuropathy correlated with the
cumulative dose of oxaliplatin; moreover, neuro
toxic symptoms frequently regressed during treat
ment intervals or responded to course interruption
with reintroduction at a lower dosage. All 29 pa
tients were evaluated for efficacy (Table 3). Objec
tive responses were documented after three cycles
in three patients (response rate, 10%); all three
patients had liver metastases of colon cancer and
had prior disease progression while receiving 5-FU
plus FA. The disease was stabilized in seven pa
tients (24%) for 3.2 to 4.2 months and progressed
in the remaining 19 patients (66%). The median
progression-free survival was 20 weeks, and the
estimated median overall survival was 40 weeks.
Although modest, the consistent overall re
sponse rate of at least 10% obtained with single
agent oxaliplatin in 5-FU-refractory patients in
these trials (Table 3) contrasts sharply with the
0% and 3% overall response rates obtained, re
spectively, with single-agent cisplatin and carboplatin (Table 1). Moreover, the median num
ber of oxaliplatin cycles administered confirms
the high stabilization rates (24% to 42%) ob
served with single-agent oxaliplatin, establishing
the antitumor activity and therapeutic advantage
of this agent for patients with advanced colorectal
cancer refractory to 5-FU.
CONCLUSION
These five phase 11 clinical trials have shown
that oxaliplatin administered as a single agent has
clinical antitumor effects against metastatic colo
rectal cancer, both in previously untreated patients
and in heavily pretreated patients refractory to 5-FU.
The objective response rate achieved with firstline therapy (18%) was highly reproducible, as was
that yielded by second-line therapy (10%). More
over, these rates were achieved within acceptable
29
limits of tolerability and only moderate toxicity.
These response rates, while modest, are similar to
those obtained with single agents such as 5-FU
in previously untreated patients and in patients
resistant to 5-FU.48 ’0
Despite the antitumor activity of oxaliplatin in
patients with advanced colorectal cancer, single
agent use of oxaliplatin is not recommended as
standard therapy except in patients with dihydro
pyrimidine dehydrogenase deficiency, which is as
sociated with increased risk of very severe or lethal
5-FU toxicity, or in those with cardiotoxicity from
5-FU.51
Many in vitro and in vivo experimental data
have suggested that the action of oxaliplatin com
bined with 5-FU is not merely additive but syner
gistic.,9'52 For clinical confirmation of this effect,
the majority of patients who received oxaliplatin
in clinical trials were treated with oxaliplatin in
combination with 5-FU, as discussed in the report
by Bleiberg and de Gramont elsewhere in this sup
plement (see pp 32-39).
REFERENCES
I. Bleiberg H: Role of chemotherapy for advanced colorectal
cancer: New opportunities. Semin Oncol 23:42-50, 1996
2. Bleiberg H: Colorectal cancer: The challenge. Eur J Can
cer 32A:S2-S6, 1996 (suppl 5)
3. Cohen AM, Minsky BD, Schdsky RL: Cancer of the co
lon, in DeVita VT Jr, Hellman S, Rosenberg SA (eds): Cancer:
Principles 6t Practice of Oncology (ed 5). Philadelphia, PA,
Lippincott-Raven, 1997, pp 1144-1197
4. Cunningham D, Findlay M: The chemotherapy of colon
cancer can no longer be ignored. Eur J Cancer 29A:2077-2079,
1993
5. Cancer Facts &. Figures-1997. Atlanta, GA, American
Cancer Society, 1997
6. Parker SL, Tong T, Bolden S, et al: Cancer statistics,
1996. CA Cancer J Clin 65:5-27, 1996
7. Moertel CG: Chemotherapy for colorectal cancer. N Engl
J Med 330:1136-1142, 1994
8. Schmoll H-J: Development of treatment for advanced
colorectal cancer: Infusional 5-FU and the role of new agents.
Eur J Cancer 32A.S18-S22, 1996 (suppl 5)
9. de Gramont A, Vignoud J, Toumigand C, et al: Oxali
platin with high-dose leucovorin and 5-fluorouracil 48-hour
continuous infusion in prerreated metastatic colorectal cancer.
Eur J Cancer 33:214-219, 1997
10. Levi F, Misset J-L, Brienta S, et al: A chronopharmacologic phase 11 clinical trial with 5-(luorouracil, folinic acid, and
oxaliplatin using an ambulatory multichannel programmable
pump: High antitumor effectiveness against metastatic colo
rectal cancer. Cancer 69:893-900, 1992
11 Kemcny N: Current approaches to metastatic colorectal
cancer. Semin Oncol 21:67-75, 1994 (suppl 7)
12. Advanced Colorectal Cancer Meta-Analysis Project.
30
Modulation of fluorouracil by leucovorin in patients with ad
vanced colorectal cancer: Evidence in terms of response rate.
J Clin Oncol 10:896-903. 1992
13. Expectancy or primary chemotherapy in patients with
advanced asymptomatic colorectal cancer A randomized trial.
Nordic Gastrointestinal Tumor Adjuvant Therapy Group. J
Clin Oncol 10:904-911, 1992
14 Rougier P, Laplanchc A, Huguier M, et al; Hepatic arte
rial infusion ot tloxuridine in patients with liver metastases
from colorectal carcinoma; Long-term results of a prospective
randomized trial. J Clin Oncol 10:1112-1118, 1992
15. Schcithauer W, Rosen H. Kornek G, et al- Randomised
comparison of combination chemotherapy plus supportive care
with supportive care alone in patients with metastatic colo
rectal cancer. BMJ 306:752-755, 1993
16. Misset JL: Chemotherapy of advanced colorectal cancers
after failure of a treatment with fluoropyrimidine. Revue Praticien 47:S29-S35, 1997 (suppl)
17. Comis RL: Cisplatin: The future. Semin Oncol 21:109113, 1994 (suppl 12)
18. Rixe O, Ortuzar W, Alvarez M, et al: Oxaliplatin, tetraplatin, cisplatin, and carboplatin: Spectrum of activity in drug
resistant cell lines and in the cell lines of the National Cancer
Institute’s Anticancer Drug Screen Panel Biochem Pharmacol
52:1855-1865. 1996
19. Rosenberg B, VanCamp L, Trosko JE. et al: Platinum
compounds. A new class of potent antitumor agents. Nature
222:385-386, 1969
20. Rosenberg B: Fundamental studies with cisplatin. Can
cer 55:2303-2316, 1985
21. Alberts DS, Green S, Hannigan EV, et al: Improved
therapeutic index of carboplatin plus cyclophosphamide versus
cisplatin plus cyclophosphamide: Final report by the Southwest
Oncology Group of a phase III randomized trial in stages 111
and IV ovarian cancer. J Clin Oncol 10:706-717, 1992
22. DeSimone PA, Davila E, Jochimsen PR, et al- Highdose cisplatin in the treatment of advanced adenocarcinoma
of the colon and rectum: A Southeastern Cancer Study Group
trial. Cancer Treat Rep 70:1229-1232, 1986
23. Lokich J, Zipoli T, Greene R, et al; Protracted low-dose
cisplatin infusion in advanced colorectal cancer. Cancer Treat
Rep 70:523-524, 1986
24. Kovach JS, Moertel CG, Schutt AJ, et al: Phase 11 study
of cis-diamminedichloroplatmum (NSC-119875) in advanced
carcinoma of the large bowel. Cancer Chemother Rep 57:357359, 1973
25. Harper P: Advanced colorectal cancer (ACC): Results
from the latest raltitrexed Tomudex® (raltitrexed) comparative
study. Proc Am Soc Clin Oncol 16:228a, 1997 (abstr 802)
26. Pazdur R, Vincent M: Raltitrexed (Tomudex35) versus
5-fluorouracil and leucovorin (5-FU + LV) in patients with
advanced colorectal cancer (ACC): Results of a randomized,
multicenter, North American trial. Proc Am Soc Clin Oncol
16:228a, 1997 (abstr 801)
27. Findlay M, Van Cutsem E, Kocha W, et al: A random
ised phase II study of Xeloda™ (capecitabine) in patients with
advanced colorectal cancer. Proc Am Soc Clin Oncol 16:227a,
1997 (abstr 798)
28. Sadahiro S, Mukai M, Tokunaga N, et al: Preliminary
study on the new optimal dosage schedule for oral UFT. Proc
Am Soc Clin Oncol 16:207a, 1997 (abstr 726)
BECOUARN AND ROUGIER
29. Rougier P, Bugat R, Douillard JY, et al: Phase 11 study
of irinotecan m the treatment of advanced colorectal cancer in
chemotherapy-naive patients and patients pretreated with fluoro
uracil-based chemotherapy. J Clin Oncol 15.251-260, 1997
30. Conti JA, Kemeny NE, Saltz LB, et al: Irinotecan is an
active agent in untreated patients with metastatic colorectal
cancer. J Clin Oncol 14:709-715, 1996
31. Von Hoff DD, Rothenberg ML, Pitot HC, et al: Irino
tecan (CPT-11) therapy for patients with previously treated
metastatic colorectal cancer (CRC); Overall results of FDAreviewed pivotal US clinical trials. Proc Am Soc Clin Oncol
16:228a, 1997 (abstr 803)
32 Nole F, Biganzoli L, Buzzoni R, et al: Carboplatin in
patients with advanced colorectal cancer pretreated with flu
oropyrimidines. Eur J Cancer 29A 1330-1331, 1993
33. Pern- DJ, Weiss RB. Creekmore SP, et al: Carboplatin
for advanced colorectal carcinoma: A phase II study. Cancer
Treat Rep 70:301-302, 1986
34- Asbury RF, Kramer A, Green M, et al: A phase II study
of carboplatin and CHIP in patients with metastatic colon
carcinoma. Am J Clin Oncol 12:416-419, 1989
35. Pazdur R, Samson MK, Baker LH: CBDCA: Phase II
evaluation in advanced colorectal carcinoma. Am J Clin Oncol
10:136-138, 1987
36. Schmoll HJ, Gundersen S, Arnold A, et al; Phase 11
study of carboplatin in colorectal cancer. Ann Oncol 1:48,
1990 (abstr) (suppl)
37. O'Dwyer PJ, Johnson SW, Hamilton TC: Cisplatin and
its analogues, in DeVita VT Jr, Hellman S, Rosenberg SA
(eds); Cancer: Principles &. Practice of Oncology (ed 5). Phila
delphia, PA, Lippincott-Raven, 1997, pp 418-432
38. Tashiro T, Kawada Y, Sakurai Y, et al: Antitumor
activity of a new platinum complex, oxalato (trans-l-l,2diammocyclohexane)platinum (II); New experimental data.
Biomed Pharmacothcr 43:251-260, 1989
39. Mathe G, Kidani Y, Segiguchi M, et al: Oxalato-platinum or I-OHP, a third-generation platinum complex; An ex
perimental and clinical appraisal and preliminary comparison
with cis-platinum and carboplatinum. Biomed Pharmacother
43:237-250, 1989
40. Kraker AJ, Moore C\V: Accumulation of cis-diamminedichloroplatinum(ll) and platinum analogues by platinum-re
sistant murine leukemia cells m vitro. Cancer Res 48:9-13, 1988
41. Mathe G, Kidani Y, Triana K, et al: A phase 1 trial of
trans-l-diaminocyclohexane oxalato-platinum (1-OHP). Bio
med Pharmacother 40:372-376, 1986
42. Extra JM, Espie M, Calvo F, et al: Phase I study of
oxaliplatin in patients with advanced cancer. Cancer Chemo
ther Pharmacol 25:299-303, 1990
43. Caussanel J-P, Levi F, Bnenza S, et al: Phase I trial of
5-day continuous venous infusion of oxaliplatin at circadian
rhythm-modulated rate compared with constant rate. J Natl
Cancer Inst 82:1046-1050, 1990
44. de Gramont A, Gastiaburu J, Toumigand C, et al: Oxali
platin with high-dose folmic acid and 5-fluorouracil 48h infu
sion in pretreated metastatic colorectal cancer. Proc Am Soc
Clin Oncol 13:220, 1994 (abstr 666)
45. de Gramont A, Bosset J, Milan C: Randomized trial
comparing monthly low-dose leucovorin and fluorouracil bolus
with bimonthly high-dose leucovorin and fluorouracil o us
plus continuous infusion for advanced colorectal cancers.
French Intergroup Study. J Clin Oncol 15:808-81 ,
OXALIPLATIN MONOTHERAPY
46. Becouarn Y, Ychou M, Ducreux M, et al: Oxaliplatin
(L-OHP) as first-line chemotherapy in metastatic colorectal
cancer (MCRC) patients: Preliminary activity/toxicity report.
Proc Am Soc Clin Oncol 16 229a, 1997 (abstr 804)
47. Diaz-Rubio E, Sastre J, Zaniboni A: Oxaliplatin as single
agent in previously untreated colorectal carcinoma patients: A
phase 11 multicentric study. Ann Oncol 9:105-108, 1998
48. Machover D, Diaz-Rubio E, de Gramont A, et al: Two
consecutive phase II studies of oxaliplatin (L-OHP) for treat
ment of patients with advanced colorectal carcinoma who were
resistant to previous treatment with fluoropyrimidines. Ann
Oncol 7:95-98, 1996
49. Levi F, Perpoint B, Garun C, er al- Oxaliplatin activity
against metastatic colorectal cancer. A phase II study of 5-
31
day continuous venous infusion at circadian rhythm modulated
rate. Eur J Cancer 29A: 1280-1284, 1993
50. Raymond E, Taamma A, Cvitkovic E, et al. Prechnical
and clinical studies of oxaliplatin. Ann Oncol (in press)
51. Milano G, Etienne MC: Individualizing therapy with 5fluorouracil related to dihydropyrimidine dehydrogenase: The
ory and limits. Ther Drug Monit 18:335-340, 1996
52. Raymond E, Djelloul S, Buquct-Fagot C, et al: Oxali
platin (L-OHP) and cisplatin (CDDP) in combination with
5FU, specific thymidase synthase (TS) inhibitors (AG337,
ZD1694), and topoisomerase I (Topo-I) inhibitors (SN38,
CPT-11), in human colonic, ovarian and breast cancers.
Proc Am Assoc Cancer Res 37:291, 1996 (abstr
1981)
Oxaliplatin Plus 5-Fluorouracil: Clinical Experience in Patients
With Advanced Colorectal Cancer
Harry Bleiberg and Aimery de Gramont
Oxaliplatin was first introduced to the clinical setting
as a combination therapy with 5-fluorouracil/folinic acid
(5-FU/FA) in an attempt to improve the response rate
obtained with 5-FU/FA against colorectal cancer. To
dispel the impression that the improvements observed
in objective response were somehow due to the chro
nomodulated regimen used, oxaliplatin was also tested
in constant-rate infusion schedules and in regimens us
ing bolus administration followed by 5-FU/FA infusion.
The most current data comparing chronomodulated
infusion and constant-rate infusion in untreated pa
tients show a lower objective response rate for the lat
ter (51% v 29%), but comparable median progressionfree survival and median survival (9.8 months and 15.9
months v 7.9 months and 16.9 months, respectively).
The first trials using constant-rate therapy included
pretreated patients with metastatic colorectal cancer,
most of whom were refractory to 5-FU. In these stud
ies, conducted using two different regimens or varia
tions of them, objective response rates <46% were ob
tained.
The addition
of oxaliplatin
to
5-FU/FA
in
controlled, randomized phase III trials has resulted in
a twofold or greater increase in objective response rate
and a 3-month gain in time to progression, with survival
differences blurred by crossover effect. Compassionate-
use programs that included many heavily pretreated
relapsing patients reported response rates of 15% to
25%, confirming the value of the oxaliplatin-5-FU/FA
regimen and suggesting that oxaliplatin may act syner
gistically with 5-FU.
Semin Oncol 25 (suppl 5):32-39. Copyright © 1998 by W.B.
Sounders Company.
INCE its introduction into clinical practice 40
years ago. 5-fluorouracil (5-FU) has been the
standard chemotherapeutic agent for the treat
ment ot patients with metastatic colorectal carci
noma.1"' However, response rates with single-agent
administration of 5-FU bolus rarely exceed 15%.
There have been numerous attempts to increase
the antiproliferative activity of this cytotoxic
agent.1 h The various approaches have included
modifications of the dosage and administration
S
From the Unite de Chnniotherapic, Institut Jules Bordet, Bru
xelles, Belgium; and Service de Medecme Interne, Hopital SaintAntoine, Paris, France.
Address reprint requests to Harry Bleiberg, MD, PhD. Unite de
Chimiotherapic. Institut Jules Bordet. 125 Boulevard de Waterloo,
1000 Bruxelles, Belgium.
Copyright © 1998 by W.B Saunders Company
0095-7754/98/2502-0505808.00/0
32
schedules of 5-FU, biochemical modulation of
5-FU with folinic acid (FA) or other modulators,
and combination of 5-FU with other cytotoxic
agents such as cisplatin.1"8 Some of these strategies
have increased the toxicity of this therapy, how
ever, and the best response rates are above 30%.
Consequently, new chemotherapeutic agents with
potential clinical significance are being actively
researched.
Oxaliplatin, a new third-generation cisplatin
analogue in the 1,2-diaminocydohexane family of
platinum compounds, has recently been developed
for clinical use in France.'1,10 Preclinical studies
have shown that the antitumor activity of this
agent is superior to that of cisplatin in vitro and
in vivo against murine leukemia, in vivo against
several murine solid tumors, and in vitro against
human colon carcinoma cell lines.10"14 Other pre
clinical observations suggest that oxaliplatin has
synergistic antitumor activity with 5-FU in vitro
and in vivo in murine leukemia cell cultures trans
planted into mice and in human colonic xenografts
either sensitive or resistant to 5-FU.15"’
More than 2,000 patients have received oxali
platin in clinical trials, over 1,400 of them as treat
ment of metastatic colorectal cancer. In some tri
als, oxaliplatin was administered as a single agent
(see the report by Becouarn and Rougier elsewhere
in this supplement [pp 23-31]). In other trials,
oxaliplatin was administered in combination with
5-FU modulated by FA and was delivered either
by constant-rate infusion or via chronomodulated
therapy. This report presents the results acnieved
with constant-rate infusion of oxaliplatin. Chro
nomodulated infusion results are presented in Ta
bles 1 to 3 as a point of comparison, but are more
extensively discussed in the article by Bismuth and
Adam elsewhere in this supplement (see pp 4046).
ANTITUMOR ACTIVITY IN PREVIOUSLY
UNTREATED PATIENTS
Oxaliplatin combined with 5-FU/FA has been
evaluated in 614 previously untreated patients
with metastatic colorectal cancer: I 56 patients in
two phase II trials and 478 patients in three phase
111 trials.6"17"20
Seminars <n Oncology. Vol 25. No 2. Suppl 5 (April). 1998 PP 32-39
OXALIPLATIN/COMBINATION THERAPY
33
Phase 11 Trials
Two phase II studies evaluated oxaliplatin com
bined with 5-FU/FA in chemotherapy-naive pa
tients. In both trials, oxaliplatin was delivered
as a chronomodulated infusion (see Bismuth and
Adam, pp 40-46).
Pliase III Trials
The first phase III trial to evaluate the clinical
antitumor activity of oxaliplatin combined with
5-FU/FA compared chronomodulated and con
stant-rate delivery schedules in 92 consecutive
patients with metastatic colorectal cancer en
rolled at seven European cancer centers from May
1990 to May 1991.18 Treatment consisted of con
tinuous intravenous (IV) infusion of oxaliplatin
20 mg/m2/d, 5-FU 600 mg/m:/d, and FA 300 mg/
m2/d for 5 days, repeated every 21 days; drug deliv
ery was kept constant in 47 patients (51%) and
chronomodulated in 45 (49%). The patient char
acteristics for each treatment arm are summarized
in Table 1. Overall, 47 patients (51%) were men,
the median age was 60 years (range, 31 to 73
years), and 83 (90%) had a World Health Organi
zation performance status si. The colon was the
primary tumor site in 64 patients (70%), 43 pa
tients (47%) had two or more metastatic sites,
and 80 patients (87%) had liver metastases.
Of the 707 cycles administered, 675 to 686 (95%
to 97%) were evaluated for various toxicities. The
most frequent dose-limiting toxicity was stomati
tis, with severe toxicities (grade 3 or 4) occurring
8.7 times more frequently in patients receiving
nonchronomodulated treatment. In general, severe
(grade 3 or 4) diarrhea, nausea or vomiting, and
skin toxicity occurred in fewer than 5% of cycles.
There was no hematologic toxicity or peripheral
sensitive neuropathy above grade 2. As summa
rized in Table 2, 15 of 47 patients (32%) receiving
Table 1. Characteristics of Previously Untreated Patients in Oxaliplatin Plus 5-FU/FA Phase III Trials
With Chronomodulated Delivery
Levi et al” (%)
Constant
Characteristic
Rate
Levi et al51 (%)
Constant
Chronomodulated
Rate
Chronomodulated
Giacchecti et al” (%)
Without
With
Oxaliplatin
Oxaliplatin
47
45
93
93
Median
60
60
61
61
-
-
Range
34-73
31-73
29-75
22-75
-
-
Male
27 (57)
20 (44)
60 (65)
52 (56)
-
-
Female
20 (43)
25 (56)
33 (35)
41 (44)
—
-
No. of patients enrolled
100
100
Age (yr)
Gender
WHO performance status
0
14 (30)
19 (42)
50 (54)
49 (53)
66 (66)
69 (69)
1
27 (57)
23 (SI)
34 (37)
30 (32)
27 (27)
20 (20)
2
6(13)
3(7)
7(7)
II (II)
2-3
9(10)
14 (15)
Site of primary tumor
Colon
30 (64)
34 (76)
66 (71)
63 (68)
77 (77)
66 (66)
Rectum
17 (36)
11 (24)
27 (29)
30 (32)
23 (23)
34 (34)
No of metastatic sites
1
27 (57)
22 (49)
55 (59)
56 (60)
46 (46)
50 (50)
a2
20 (43)
23 (51)
38 (41)
37 (40)
52 (52)
50 (50)
Liver
40 (85)
40 (89)
75 (81)
76 (82)
49 (49)
50 (50)
Lung
11 (23)
20 (44)
38 (41)
29(31)
-
-
7(8)
II (12)
-
-
-
-
Metastatic sites
Lymph nodes
Peritoneum
15(32)
11 (24)
13 (14)
II (12)
Other
5(H)
3(7)
2(2)
10(11)
Abbreviation: WHO. World Health Organization.
34
BLE1BERG AND DE GRAMONT
flat-rate, continuous infusion had an objective re
sponse, which was complete in two patients (4%)
and partial in 13 (28%); 21 patients (45%) had
stable disease and 10 patients (21%) had disease
progression. The median progression-free survival
was 8 months, and the median survival was 14.9
months; overall, 18 patients (20%) were alive at
a median follow-up of 30 months. This trial was
prematurely terminated, however, because of po
tential neutralization of oxaliplatin by the basic
5-FU solution in the flat-rate infusion arm.
A second multicenter phase III trial used the
same protocol but higher doses to compare chro
nomodulated and constant-rate delivery sched
ules of oxaliplatin combined with 5-FU/FA in
186 previously untreated patients with metastatic
colorectal cancer enrolled from July 1991 to Feb
ruary 1993.
*
1 Treatment consisted of a 5-day con
tinuous IV infusion of oxaliplatin 25 mg/m2/d,
5-FU 600 mg/m'/d, and FA 300 mg/m2/d, with
patients randomized to receive, on an outpatient
basis, either flat-rate delivery (n = 93) or chrono
modulated delivery (n = 93). The patient charac
teristics of rhe two treatment arms are summarized
in Table 1.
Of 1,301 cycles, 1,259 (97%) were evaluated for
toxicity. In the constant-rate arm, 51% of patients
required withdrawal for toxic effects and 31% re
quired hospitalization for grade 4 gastrointestinal
toxicity or peripheral sensitive neuropathy. An ob
jective response was achieved in 27 patients re
ceiving flat-rate delivery’, for a response rate of 29%
(95% confidence interval [CI], 19.6 to 38.4); there
were three complete responses (Table 2). The me
dian progression-free survival was 7.9 months, and
the median survival was 16.9 months.
A third and most important recently reported
phase III study investigated the addition of a con
stant-rate infusion of oxaliplatin to the chrono
modulated delivery’ of 5-FU/FA in 200 patients
with previously untreated metastatic colorectal
cancer.20 Patients were enrolled at 15 cancer cen
ters from June 1994 to March 1996 and were ran
domized to receive chronomodulated delivery of
5-FU 700 mg/m2/d plus FA 300 mg/m2/d, each for
5 days, with or without a 6-hour flat-rate infusion
of oxaliplatin 125 mg/m2 on day 1, and repeated
every’ 3 weeks. There were 100 patients assigned
to each treatment arm. The main patient charac
teristics are listed in Table 1.
The incidence of grades 3 and 4 toxicity during
OXAUPLATIN/COMBINATION THERAPY
728 cycles without oxaliplatin was 5% for diarrhea,
4% for mucositis, and 2% for nausea and vomiting;
during 774 cycles with oxaliplatin, the incidence
was 43% for diarrhea, 10% for mucositis, 25% for
nausea and vomiting, and 13% for specific scale
grade 4 peripheral sensitive neuropathy. As shown
in Table 2, the objective response rate at 9 weeks
was 12% (95% Cl, 6 to 20) without oxaliplatin
and 34% (95% CI, 24 to 44) with oxaliplatin (P
< .001). Patients in the oxaliplatin arm achieved
better median progression-free survival (8.9
months v 5.2 months) and comparable median sur
vival (17.6 months v 19.4 months).'” Subse
quently, 57 of 70 patients in the 5-FU/FA arm
without oxaliplatin received second-line chemo
therapy with oxaliplatin plus 5-FU/FA. Oxali
platin was delivered by short infusion in 27 pa
tients and was chronomodulated in 30.22 A partial
response was achieved in 10 patients; 32 patients
had stable disease. Disease was controlled in 42 of
57 patients (74%), including 16 of 21 patients
(76%) who were refractory to 5-FU.22
A recently completed, randomized, multicenter
European trial of LV5-FU2 ± oxaliplatin enrolled
210 patients in each arm. The results will be pre
sented at the 1998 American Society of Clinical
Oncology meeting, and are expected to confirm
the efficacy of oxaliplatin in optimizing the re
sponse to 5-FU/FA in previously untreated pa
tients.
ANTITUMOR ACTIVITY IN PREVIOUSLY
TREATED PATIENTS
Oxaliplatin in combination with 5-FU/FA also
has been evaluated in 1,106 previously treated pa
tients with refractory metastatic colorectal cancer.
Eight prospective phase 1! trials included 385 of
these patients. The remaining 721 patients were
evaluated in extended-access, compassionate-use
programs, which have been thoroughly and com
pletely assessed by retrospective analyses.2'6'23'29
Constant-Rate Infusion Studies
The feasibility of high-dose, constant-rate, con
tinuous infusion of oxaliplatin plus 5-FU/FA in 2week cycles was evaluated over 137 cycles in a
study of 1 3 patients with progression of pretreated
colorectal cancer.'' Treatment consisted of
oxaliplatin 1 30 mg/m2/d over 2 hours on day 1 of
every other cycle, plus 5-FU 2,000 mg/m'/d over
24 hours after FA 500 mg/m2/d over 2 hours on
35
days 1 and 2 of every cycle (FOLFOX-1). With this
regimen, 31% of patients experienced an objective
response; seven patients (54%) experienced grade
3 or 4 toxicity (Table 3). To reduce toxicity and
to take full advantage of synergistic effects with
5-FU, oxaliplatin was administered at 100 mg/m2/
d on day 1 of every cycle and the dose of 5-FU
was reduced to 1,500 mg/m2/d for two cycles, then
increased to 2,000 mg/m2/d if there was no toxicity
higher than grade 2 (FOLFOX-2).
Use of the FOLFOX-2 regimen was expanded
into a full phase II study in 46 patients enrolled
from February 1993 to January' 1995.2 Patient char
acteristics were similar to those of the earlier study:
63% of patients were men, the median age was
59.4 years, the colon was the primary tumor site
in 52% of patients, liver and lung metastases were
present in 85% and 28% of patients, respectively,
67% of patients had only one metastatic site, and
89% of patients had a World Health Organization
performance status s 1.
During a median of 10 cycles per patient, the
dose-limiting toxicities were grade 3 or 4 neutro
penia in 18 patients (39%) and grade 2 or 3 periph
eral neuropathy in 20 patients (33%). The objec
tive response rate was 46% (95% CI, 31 to 60),
with one complete response that lasted 8 months
and 20 partial responses that had a median dura
tion of 8.5 months. Twenty-one patients (46%)
had stable disease and three (7%) had disease pro
gression (Table 3). In a subgroup of 22 patients
who had been refractory to the same 5-FU/FA
schedule without oxaliplatin, 10 patients (45%)
achieved a partial response (95% Cl, 24 to 67)
and 10 (45%) had stable disease. Moreover, rhe
response rate was 44% in patients with liver metas
tases and 46% in those with lung metastases.
The FOLFOX-3 regimen was introduced to fur
ther decrease the toxicity of the combination (Ta
ble 3).30 With this regimen, the oxaliplatin dose
was reduced to 85 mg/m2 with FA at 500 mg/m’
on days 1 and 2 and 5-FU administered as a 3,000
mg/m" 48-hour infusion starting on day 2. Patients
with ;£ grade 2 toxicity after two cycles received
4,000 mg/m" 5-FU. Thirty patients refractory to
5-FU were treated biweekly with FOLFOX-3 until
progression. Six (20%) achieved a partial response
and 15 (50%) had stable disease. Grade 3-4 toxic
ity was limited to eight patients (27%).
Two additional 2-week regimens of oxaliplatin
plus 5-FU/FA were evaluated after disease progres-
Table 3. Antitumor Activity of Oxaliplatin Plus 5-Fluorouracil and Folinic Acid in Previously Treated Patients With Metastatic Colorectal Cancer
No. of
Dosage and Schedule (mg/m2)
Patients
Objective
Complete
Suble
Median
Median
Response
Response
Disease Rate
Progression-Free
Survival Time
Evaluated
Oxaliplatin
5-Fluorouracil
Folinic Acid
Rate (%)
Rate (%)
(%)
Survival (mo)
(mo)
13
130 >' Id every 4 wk
I.5OO-2.OOO x 2 d every 2 wk
500 X 2 d every 2 wk
31
0
38
—
—
46
1
46
7
17
20
0
50
6
10
25
0
—
—
25
0
—
—
—
24
0
18
—
7
0
36
5.5
76
13
Flat-rate delivery
FOLFOX-1.
de Gramont et al2J
FOLFOX-2.
(over 2 hr)
46
de Gramont et al2
FOLFOX-3.
(over 2 hr)
30
de Gramont et al’°
FOLFOX-3?
48
85 X 1 d every 2 wk
(over 2 hr)
36
Andre et al2*
Gerard et al3'
85 x 1 d every 2 wk
(over 2 hr)
Andre et al2*
*
FOLFOX-4.
100 X 1 d every 2 wk
85 X 1 d every 2 wk
(over 2 hr)
34
1 30 X Id every 3 wk
(over 24 hr)
1.500-2,000 X 2 d every 2 wk
(over 24 hr)
1.500-2.000 x 2 d every 2 wk
(over 48 hr)
1.500 x 2 d every 2 wk
(over 48 hr)
1.000 x 2 d every 2 wk
(over 24 hr)
2.600 X 2 d (over 24 hr)
every 3 wk (d 1 & 8)
Meyer et al”
38
130 X Id every 3 wk
(over 2 hr)
500 X 2 d every 2 wk
(over 2 hr)
500 X 2 d every 2 wk
(over 2 hr)
500 x 2 d every 2 wk
—
(over 2 hr)
200 X 2 d every 2 wk
(over 2 hr)
500 X 2 d every 3 wk
(d 1 & 8)
1,300 every 3 wk
400 every 3 wk
36
(over 2 hr)
Chronotherapy
Levi et al4
42
25 X 5 d every 3 wk
700 X 5 d every 3 wk
300 x 5 d every 3 wk
55
2
40
10
Brienza et al2‘
57
25 X 4 d every 2 wk
700 X 4 d every 2 wk
300 X 4 d every 2 wk
38
4
—
10
13
Bcrtheault-Cvitkovic
37
20-25 x 4 d every 2 wk
700+ x 4 d every 2 wk
300 X 4 d every 2 wk
40
3
51
10.3
169
25
20-25 x 4 d every 2 wk
700-1,000 x 4 d every 2 wk
300 x 4 d every 2 wk
29
0
50
5.8
12
or
or
or
et al27
Garufi et al2’
X 5 d every 3 wk
X 5 d every 3 wk
Dau updated for presenution at the European Cancer Conference. Hamburg 1997 (ECCO 9, abstr 738).
Adapted and reprinted with kind permission from Kluwer Academic Publishers?2
BLEIBERG A N D DE
X 5 d every 3 wk
OXAIIPLATIN/COMBINATION THERAPY
sion on 5-FU/FA in 99 patients with metastatic
colorectal cancer enrolled in an ongoing multicen
ter study from October 1995 to November 1996.2,1
Oxaliplatin 85 mg/m2/d over 2 hours on day 1 of
each cycle was added either to 5-FU 1,500 mg/m2/
d plus FA 500 mg/m2/d on days 1 and 2 (FOLFOX3) or to 5'FU 400 mg/m2/d bolus and 600 mg/m2/
d continuous IV infusion over 22 hours plus FA
200 mg/m2/d over 2 hours on days 1 and 2 of every
cycle (FOLFOX-4), and repeated every 2 weeks.
Eighty-four patients were evaluated in an updated
interim analysis from September 1997 (Table 3).
Overall, an objective response rate of 25% was
achieved. Toxicity was assessed in 899 cycles (me
dian, six cycles per patient; some received 16 +
cycles), with the median dose of oxaliplatin at 510
mg/m2 (range, 255 to 1,360+ mg/m2). The results
confirm previous reports of clinical synergy be
tween oxaliplatin and 5-FU.
The highest-dose, flat-rate regimen reported to
date was evaluated in 34 patients with advanced
colorectal cancer progressing after previous che
motherapy.21 Every 3 weeks, oxaliplatin 130 mg/
m2 (day 1) plus FA 500 mg/m2 followed by 5-FU
2,600 mg/m2 (days 1 and 8) was administered to
16 men and 18 women. The median age was 60
years (range, 34 to 76 years), and the median per
formance status was 1 (range, 0 to 3). The primary
tumor sites were the rectum in 12 patients and the
colon in 22; the metastatic sites were the liver in
26 patients, the lung in 12, and the abdoininoperitoneal cavity in 11.
The major adverse effect was neurotoxicity,
which was mild in 19 patients, moderate in five,
severe in two, and required discontinuation in one.
Severe diarrhea occurred in four patients, and
moderate or severe nausea and vomiting occurred
in six and four patients, respectively. The objective
response rate was 24%, with eight patients achiev
ing a partial response and six having stable disease
(Table 3). The median time to progression was
7+ months (range, 4 to 12 months); the median
survival time from diagnosis was 22 months (range,
3 to 63 months) and from initiation of oxaliplatin
therapy, 7 months (range, 2 to 47 months).
The synergism observed with the oxaliplatin/5FU combination was confirmed in a recent trial of
38 patients with advanced colorectal cancer refrac
tory to 5-FU (Table 3).51 In this study, oxaliplatin
(130 mg/m2) was added as a 2-hour infusion every
3 weeks to an ongoing weekly 5-FU (1,300 mg/
37
m2)/FA (400 mg/m2) regimen. After three cycles
of oxaliplatin therapy, 14 patients (36%) had a
partial response and 14 (36%) had stable disease.
The median progression-free survival and median
overall survival were 5.5 months and 7.6 months,
respectively. In addition, nine patients survived
longer than 1 year. The response rates observed in
this study appeared higher than would be expected
with oxaliplatin alone, suggesting synergism.
New combination regimens (FOLFOX-6, FOLFOX-7) arc currently under investigation. These
studies take into account factors crucial to improv
ing oxaliplatin-based therapy. Major concerns in
clude immediate hematologic toxicity and cumula
tive neurotoxicity, which govern the dose of 5-FU
used and the duration of treatment, respectively.
FOLFOX-6 addresses these issues with an in
creased chemotherapeutic dose (oxaliplatin 100
mg/m2 plus FA 400 mg/m2 with 5-FU 2,400 to
3,000 mg/m2) given over a shorter period of time.
Compassionate-Use Programs
The results obtained in phase II trials have been
confirmed in a review of data from 206 patients
with advanced colorectal cancer treated with oxa
liplatin in a compassionate-use program at 44 Eu
ropean cancer centers from January 1994 to June
1995.211 Progression on 5-FU/FA schedules was ver
ified mill patients; oxaliplatin was then added
to the 5-FU/FA schedules, either every 2 weeks at
80 to 100 mg/m2 per cycle to 49 patients or every
3 weeks at 100 to 135 mg/m- per cycle to 62 pa
tients. The objective response rate in 98 evaluable
patients was 26% (95% CI, 17.2 to.35.5).
These results also have been confirmed by a ret
rospective analysis of a French extended-access
program in which 490 patients received oxaliplatin
for advanced colorectal cancer. In this program,
472 patients received oxaliplatin in combination
with 5-FU/FA; of these, 370 proved to be resistant
to 5-FU/FA (E. Cvitkovic, personal communica
tion, July 1996). The median dose of oxaliplatin
was 126 mg/m2 per 3-week cycle for 2,702 cycles,
and the total cumulative dose was 600 mg/m’
(range, 70 to 2,300 mg/m’). The median time to
progression was 4.3 months (95% Cl, 3.9 to 4.7).
and the median survival was 9.7 months (95% Cl,
8.5 to 10.8).
In administering 5-FU/FA. both compassionateuse programs incorporated many different regimens
with a variety of dosages, schedules, and dnig deliv
BLEIBERG AND DE GRAMONT
38
ery modalities. Delivery modalities included con
tinuous IV infusion for 5 days, protracted continu
ous IV infusion, weekly bolus, and bolus for 4 to 5
days; schedules varied from 24 to 48 hours. Despite
these differences, however, similar objective re
sponse rates were usually observed.
Finally, similar results were also obtained in a
small compassionate-use program in which 25 pa
tients received chronomodulated infusions of oxa
liplatin plus 5-FU/FA.28
CONCLUSION
The clinical trials of oxaliplatin combined with
5-FU/FA in both chemotherapy-naive and pre
viously treated patients with advanced colorectal
cancer confirm the observations of in vitro and
animal studies that the antitumor activity of oxali
platin is not merely additive but also synergistic
with that of 5-FU. These studies have shown both
the effectiveness and the tolerability of the combi
nation of oxaliplatin and 5-FU/FA. Although
these results have been substantiated by “real-life
scenario” data obtained from large compassionateuse programs, additional trials are needed to deter
mine the most adequate treatment regimens.
There are currently two ongoing, large multicenter
studies of oxaliplatin in combination with 5-FU/
FA as second-line treatment for advanced colo
rectal cancer. One large phase Ill trial of oxaliplatin-5-FU/FA as first-line therapy for colorectal
cancer completed accrual m mid-1997. Results
from this trial are expected to confirm the role of
oxaliplatin in treating colorectal cancer.
REFERENCES
1. Bleiberg H: Role of chemotherapy for advanced colorectal
cancer: New opportunities. Semin Oncol 23:42-50, 1996
2. de Gramont A, Vignoud J, Toumigand C, et al: Oxali
platin with high-dose leucovorin and 5-fluorouracil 48-hour
continuous infusion in pretreated metastatic colorectal cancer.
Eur J Cancer 33:214-219, 1997
3. Schmoll H-J: Development of treatment for advanced
colorectal cancer- Infusional 5-FU and the role of new agents.
Eur J Cancer 32A:S18-S22, 1996 (suppl 5)
4. Bleiberg H-Colorectal cancer: The challenge Eur J Can
cer 32A:S2-S6, 1996 (suppl 5)
5. Moertel CO: Chemotherapy for colorectal cancer. N Engl
J Med 330:1136-1142. 1994
6. Levi F, Misset J-L, Bnenza S, et al- A chronopharmacologic phase II clinical trial with 5-fluorouracil, folinic acid, and
oxaliplatin using an ambulatory multichannel programmable
pump: High antitumor effectiveness against metastatic colo
rectal cancer. Cancer 69:893-900, 1992
7. Kemeny N: Current approaches to metastatic colorectal
cancer. Semin Oncol 21:67-75, 1994 (suppl 7)
8. Cunningham D, Findlay M: The chemotherapy of colon
cancer can no longer be ignored. Eur J Cancer 29 A:2O7 7-2079,
1993
9. Mathc- G, Chenu E, Bourut C: Experimental study of
three platinum complexes: CDDP, CBDCA and L-OHP on
LI 210 leukemia. Alternate or simultaneous association of two
platinum complexes. Invest New Drugs 7:404, 1989
10 Tashiro T, Kawada Y, Sakurai Y, et al- Antitumor activ
ity of a new platinum complex, oxalato (trmis-I-l,2-diaminocyclohexanejplatinum (II): New experimental data. Biomed
Pharmacother 43:251-260, 1989
11. Kidani Y, Noji M, Tashiro T: Antitumor activity of
platinum (II) complexes of 1,2-diaminocyclohexane isomers
Gann 71:637-643, 1980
12. Kraker AJ, Moore C\V. Accumulation of cis-diammmedichloroplatinum (II) and platinum analogues by platinumresistant murine leukemia cells in vitro. Cancer Res 48:9-13,
1988
13- Pendyala L, Kidani Y, Perez R, et al: Cytotoxicity, cellu
lar accumulation and DNA binding of oxaliplatin isomers.
Cancer Lett 97:177-184, 1995
14- Rixe O, Ortuzar W, Alvarez M, et al. Oxaliplatin, tetraplatin, cisplatin, and carboplatin: Spectrum of activity in drug
resistant cell lines and in the cell lines of the National Cancer
Institute’s Anticancer Drug Screen Panel. Biochem Pharmacol
52 1855-1865, 1996
15. Mathe G, Kidani Y, Segiguchi M, et al: Oxalato-platinum or L-OHP, a third-generation platinum complex: An ex
perimental and clinical appraisal and preliminary comparison
with cis-platinum and carboplatinum Biomed Pharmacother
43:237-250, 1989
16. Raymond E, Djelloul S, Buquet-Fagot C, et al: Oxali
platin (L-OHP) and cisplatin (CDDP) in combination with
5FU, specific thymidylate synthase (TS) inhibitors (AG337,
ZD1694), and topoisomerase I (Topo-I) inhibitors (SN38,
CPT-11), in human colonic, ovarian and breast cancers Proc
Am Assoc Cancer Res 37:291, 1996 (abstr)
17 Levi F, Dogliotti L, Perpoint B, et al: A multiccnter
phase II trial of intensified chronotherapy with oxaliplatin (LOHP), 5-fluorouracil (5-FU) and folinic acid (FA) in patients
(pts) with previously untreated metastatic colorectal cancer
(MCC). Proc Am Soc Clin Oncol 16:266a, 1997 (abstr)
18. Levi FA, Zidani R, Vannetzel J-M, et al: Chronomodu
lated versus fixed-infusion-rate delivery of ambulatory chemo
therapy with oxaliplatin, fluorouracil, and folinic acid (leuco
vorin) in patients with colorectal cancer metastases: A
randomized multi-institutional trial. J Natl Cancer Inst
86:1608-1617, 1994
19 Levi F. Zidani R, Di Palma M, et al: Improved therapeu
tic index through ambulatory circadian rhythmic delivery
(CRD) of high dose 3-dmg chemotherapy in a randomized
phase 111 multicenter trial. Proc Am Soc Clin Oncol 1 3:197,
1994 (abstr)
20. Giacchetti S. Zidani R, Perpoint B, et al: Phase III trial
of 5-fluorouracil (5-FU), folinic acid (FA), with or without
oxaliplatin (OXA) in previously untreated patients (pts) with
metastatic colorectal-cancer (MCC). Proc Am Soc in (16:229a, 1997 (abstr)
Randomised multicentre
21. Levi F, Zidani R, Misset J-L:
OXAUPLATIN/COMBINATION THERAPY
trial of chronorherapy with oxaliplatin, fluorouracil, and fo
linic acid in metastatic colorectal cancer. For the Interna
tional Organization for Cancer Chronotherapy. Lancet
350:681-686, 1997
22. Giacchetti S, Brienza S, Focan C, et al: Contribution of
second line oxaliplatin (Oxa)-chronomodulated 5-fluorouracilfolinic acid (CM-5-FU-FA) and surgery to survival in meta
static colorectal cancer patients (MCC pts). Proc Am Soc Clin
Oncol (in press)
23. de Gramont A, Gastiaburu J, Toumigand C, et al: Oxa
liplatin with high-dose folinic acid and 5-fluorouracil 48h infu
sion in pretreated metastatic colorectal cancer. Proc Am Soc
Clin Oncol 13:220, 1994 (abstr)
24. Andr6 T, Bensmaine MA, Louvet C, et al: Addition of
oxaliplatin (Eloxatine®) to the same leucovorin (LV) and 5fluorouracil (5-FU) bimonthly regimens after progression in
patients (pts) with metastatic colorectal cancer (MCRC): Pre
liminary report. Eur J Cancer 33:S165-166, 1997
25. Gerard B, Bleiberg H, Michel J, et al: Oxaliplatin com
bined to 5-FU and folinic acid (5-FU/FA) as second- or thirdline treatment in patients with advanced colorectal cancer
(CRC). Proc Am Soc Clin Oncol 16:288a, 1997 (suppl)
26. Brienza S, Levi F, Valori VM, et al: Intensified (every
2 weeks) chronotherapy with 5-fluorouracil (5-FU), folinic acid
(FA) and oxaliplatin (L-OHP) in previously treated patients
(pts) with metastatic colorectal cancer. Proc Am Soc Clin
Oncol 12:197, 1993 (abstr)
39
27. Bertheault-Cvitkovic F, Jami A, I thzakt M, et al: Bi
weekly intensified ambulatory chronomodulared chemother
apy with oxaliplatin, fluorouracil, and leucovorin in patients
with metastatic colorectal cancer. J Clin Oncol 14:29502958, 1996
28. Garufi C, Brienza S, Bensmaine MA, et al: Addition of
oxaliplatin (L-OHP) to chronomodulated (CM), 5-fluorouracil
(5-FU), and folinic acid (FA) for reversal of acquired chemore
sistance in patients with advanced colorectal cancer (ACC).
Proc Am Soc Clin Oncol 14:192, 1995 (abstr)
29. Louvet C, Bleiberg H, Gamelin E, et al: Oxaliplatin (LOHP) synergistic clinical activity with 5-fluorouracil (FU) in
FU resistant colorectal cancer (CRC) patients (pts) is indepen
dent of FU ± folinic acid (FA) schedule. Proc Am Soc Clin
Oncol 15:206, 1996 (abstr)
30. de Gramont A, Louvet C, Raymond E, et al: Bimonthly
high-dose leucovorin (LV), 5-fluorouracil (5-FU) 48-h infusion
with oxaliplatin in metastatic colorectal cancer (MCRC) resis
tant to the same LV-5FU regimen. Ann Oncol 7:38, 1996
(abstr 175) (suppl 5)
31. Meyer V, Delva R, Gamelin E, et al. Oxaliplatin (LOHP) and 5-fluorouracil (5-FU) synergism in advanced colo
rectal cancer patients (ACRC). Eur J Cancer 33-.S167, 1997
(abstr)
32. Raymond E, Taamma A, Cvitkovic E, et al: Prechnical
and clinical studies of oxaliplatin. Ann Oncol (in press)
Reduction of Nonresectable Liver Metastasis From Colorectal
Cancer After Oxaliplatin Chemotherapy
Henri Bismuth and Rene Adam
Until recently, approximately 30% of patients with re
sectable hepatic metastases from colorectal cancer
survived 5 years after surgery. Additionally, many pa
tients present with unresectable metastases and can
look forward only to palliative care. Whereas therapeu
tic approaches such as cryosurgery appear to improve
resectability, a key to resecting hepatic metastases is
the ability to shrink the metastatic sites to make them
more amenable to surgery. The administration of tradi
tional chemotherapeutic modalities by conventional
means or via intra-arterial or portal vein infusion has
not provided significant improvements. The recent in
troduction of the combination oxaliplatin-5-fluorouracil/folinic acid administered as a chronomodulated
regimen, however, has provided better response rates
with minimal toxicity. Recent results show that the re
section of previously unresectable metastases became
possible in up to 16% of patients after chemotherapy
with a ch-onomodulated regimen of oxaliplatin plus 5-
fluorouracil/folinic acid. Of the patients who had suc
cessful resections, 54% and 40% were alive at 3 years
and 5 years after surgery, respectively. The results of
these studies demonstrate that this new approach can
significantly prolong survival for patients with a pre
viously bleak outlook. As a result, new treatment algo
rithms are evolving, integrating chemotherapeutic and
surgical strategies for the treatment of patients with
metastatic colorectal cancer.
Semin Oncol 25 (suppl 5):40-46. Copyright © 1998 by W.B.
Saunders Company.
URGERY is considered first-line therapy for
colorectal cancer; however, approximately
50% of patients die from recurrence, even though
the primary tumor had apparently been resected
successfully.1 Liver metastasis is the most prevalent
complication from colorectal cancer and a major
contributor to patient mortality due to recurrence.’
The ability of a colorectal tumor to metastasize
appears to be correlated with the expression of
various oncoproteins related to the regulation of
apoptosis and the cell cycle. The presence of p53
protein in the primary tumor is always indicative of
S
From the Groupe de Recherche en Chirurpe HepatO'Bdtaire'Ct
Transplantation Hepatique. Hopital Paul Brousse. Ville/uif.
France
Address reprint requests to Henn Bismuth. MD, FACS (Hon).
Centre He'pato-Biliaire. Hopitul Paul Brousse, 94800 Ville/uif,
France.
Copyright © 1998 by W.B, Saunders Company
0093-7754I98I2502-0506$08.00/0
40
p53 expression in lymph node and liver metastases,
and is highly correlated with patient outcome. A
recent study demonstrated that the median sur
vival time of patients with tumors positive for p53
overexpression is 21 months, compared with 53.2
months tor patients with p53-negative tumors.’
Overexpression of c-erbB-2 mRNA and/or c-neu
oncoprotein is also indicative of the metastatic
potential of colorectal tumors, since the presence
of overexpressed c-erbB-2 is highly correlated with
future development of liver metastases from tumors
that have not yet metastasized to lymph nodes.4
For patients with these genetic alterations, it is
essential to apply procedures that have the capabil
ity to eradicate not only the primary lesion, but
also, when they have occurred, metastases to the
lymph nodes and liver.
SURGICAL APPROACH TO LIVER
METASTASES
Although surgical resection of hepatic metastases
can produce long-term survival with the potential
of cure,’ 6 only approximately 30% of patients with
resectable disease survive 5 years after surgery.’ ' In
addition, a large number of patients present with
hepatic metastases that are considered unresectable
because of their size, location, and/or number. Ex
trahepatic progression is also a major impediment to
patients achieving a lasting recovery. Cryosurgery,
recently introduced to eliminate colorectal metasta
ses to the liver previously classified as unresectable,
has the potential to increase rhe number of patients
who become disease free after surgery .' A recent
trial of 123 patients demonstrated that 5-year sur
vival rates were higher for patients treated with
cryosurgical techniques (44%) than for patients un
dergoing conventional surgical resection (16%).
Additionally, twice as many patients survived 10
years after ciyosurgery (19%) than after conven
tional surgery (8%).° Some investigators, however,
feel that while promising, the current data do not
support the use of cryosurgery other than to tackle
unresectable metastases.'
CHEMOTHERAPEUTIC APPROACH TO
LIVER METASTASES
The management of unresectable disease invari
ably involves palliative chemotherapy. Howes er,
Seminars in Oncology. Vol 25. No 2. Suppl 5 (April). '
PF
MANAGEMENT OF LIVER METASTASES WITH OXALIPLATIN
a legitimate goal of chemotherapeutic treatment
is to favor shrinking of liver metastases to make
them more surgically manageable.
Since the early 1990s, the combination of 5fluorouracil (5-FU) with levamisole has been con
sidered the standard of care in adjuvant chemo
therapy. This combination was shown to provide
a survival advantage over surgical resection alone
for patients with stage 111 colon cancer.10'" This
effect, however, did not include patients with stage
11 disease who demonstrated a decreased rate of
relapse but no significant improvement in sur
vival.12 Folinic acid (FA) is often substituted for
levamisole in current combinations on the basis
that its association with 5-FU is at least as effica
cious as 5-FU plus levamisole and that stage II
patients also exhibit improved survival.1114 As
demonstrated by a mcta-analysis of nine random
ized trials involving 1,381 patients, however, the
response rate to systemic 5-FU plus FA does not
exceed 23%, and partial responses are prevalent
(20%).”
For patients with metastatic disease (stages III
or IV), a variety of approaches has been tried in
an attempt to reduce the occurrence of liver metas
tases and to attack those metastases up front. In
an effort to increase the amount of cytotoxic drug
reaching the liver, infusions have been adminis
tered directly into the portal vein or the hepatic
artery (a method currently preferred). The benefits
derived from these techniques appear, at present,
to be minimal.16,17 A meta-analysis of nine hypoth
esis-testing trials involving over 3,000 patients
treated with porta! vein chemotherapy or no fur
ther treatment after surgery demonstrated a small
improvement of a few percentage points (3.6%; P
= .04) in absolute survival for patients treated with
portal vein chemotherapy versus patients assigned
to no further treatment. However, reduction in
the incidence of liver metastases in the treatment
group (14%) was not significantly different from
that of the control group (P = .2).16 The investiga
tors concluded that the small improvement re
corded was not statistically secure and that addi
tional trials with many more patients would be
required to validate the procedure. In addition, a
survival advantage could not be demonstrated
when hepatic arterial infusion with 5-fluoro-2'deoxyuridine was compared with intravenous
chemotherapy with either 5-fluoro-2'-deoxyuridine or 5-FU (P = .14).17
41
The invasive nature of the catheter and reser
voir required to implement arterial infusions is also
a source of significant concern, since complications
that may involve infections, artery occlusion, gas
troduodenal ulcers, and upper gastrointestinal tract
symptoms have been recorded.” In addition, al
though this kind of locoregional therapy may have
demonstrated some benefit in the reduction of me
tastases confined to the liver, the possibility of
extrahepatic progression, particularly in the lungs,
limits the value of this approach and requires that
patients selected for this procedure do not have
more than one site of metastasis.19
Chemotherapeutic regimens have been en
hanced with various forms of radiation therapy,
including fractionated whole-liver irradiation, fol
lowed by a boost dose at the area of dominant
disease,20 and conformal planar radiation therapy
focused at the major site of hepatic disease.’1 Al
though survival rates may improve when such
techniques are used, significant concerns remain
with respect to the ability to deliver a high enough
dose of radiation to obtain a sustainable response
without causing severe radiation hepatitis.22 An
other approach to managing patients with unresectable disease has involved cryosurgery with in
traoperative chemotherapy, however, the toxicity
of 5-FU/FA administered under these conditions
is significant.’’ Because of the lackluster progress
made using these approaches, some investigators
are now seeking to improve the delivery regimen
and use combination therapies that offer a prospect
for synergistic effectiveness.
Continuous-fn/nsion Therapy
The concept of using a continuous infusion of
5-FU to treat patients with advanced colorectal
cancer was introduced by Seifert et al.’4 This mode
of drug delivery provided reported response rates
significantly higher than those observed with bolus
administration.25”6 The combination of FA and
5-FU intravenous bolus followed by continuous
5-FU intravenous infusion also provided signifi
cantly enhanced response rates of over 50%.’' At
tempts to chronomodulate 5-FU/FA delivery have
not been more effective, yielding response rates of
up to 40% in chemotherapy-naive patients but
only 8% in previously treated patients,’' emphasiz
ing the problem of resistance building in patients
continuously treated with 5-FU.
The development of resistance to 5-FU therapy
12
BISMUTH AND ADAM
is a major impediment to treatment success that
has been attributed to high thymidylate synthase
levels'" and impaired transport mechanisms. ? The
addition of FA to the 5-FU regimen has not im
proved response rates in patients who have devel
oped resistance to 5-FU or in those who are intrin
sically resistant.2''' 1
Combination Therapy for Liver Metastases
Most strategies that attempt to increase response
rates in patients with unrcsectable liver metastases
from colorectal cancer involve the addition of an
adjuvant to the first-line combination of 5-FU/FA.
The modulators that have been tested to effect
this goal include interferon-a and various chemo
therapeutic agents. The addition of interferon-tt
has resulted in modest responses’’ or no benefit."
The addition of chemotherapeutic agents has met
with mixed success. Biochemical modulation of
5-FU with methotrexate has not provided signifi
cant improvement after failure of 5-FU/FA
alone.''''’5 These regimens have shown only mini
mal effectiveness for the management of patients
with unrcsectable liver metastases beyond that of
palliative care.
Oxaliplatin, a 1,2-diaminocyclohexane plati
num derivative that is well tolerated, has shown
significant response rates in patients with meta
static colorectal cancer resistant to 5-FU.’6” With
a FOLFOX-2 biweekly regimen (oxaliplatin 100
mg/nr on day 1 plus FA 500 mg/m2 as a 2-hour
infusion followed by 5-FU, 1.5 to 2 g/m' as a 24hour infusion on days 1 and 2), the response rate
of liver metastases (44% objective response) was
similar to that of the primary tumor (46%).,0
Chronomodulated Therapy
Because various preclinical and clinical studies
with cisplatin have shown that the effectiveness
of the administered dose and its toxicity vary with
the rime of day at which the drug is adminis
tered, 4?42 chronomodulated schemes of delivery
have been devised. In a randomized multicenter
trial of 92 patients with metastatic colorectal can
cer,’’ a sequentially chronomodulated scheme (Fig
1) of oxaliplatin (25 mg/m'/d), delivered from
10:00 AM to 10:00 PM and peaking at 4:00 PM
and FA (300 mg/m2/d) plus 5-FU (600 mg/nr/d)
delivered from 10:00 PM to 10:00 AM and peaking
at 4:00 AM was compared with a continuous-infu
sion scheme using the same drug levels. The 5-day
Fig I. Sequential chronomodulated scheme of oxaliplatin
and 5-FU/FA delivery. (Adapted and reprinted with permis
sion/1)
treatments were repeated every 21 days. Response
rates were superior in patients in the chronomodu
lated group. In addition, after a median number
of nine courses of therapy, more patients in the
chronomodulated group became eligible for surgery
to have metastases removed and more patients
achieved a complete response after surgery than
those in the continuous-infusion group (Table 1).
These results were confirmed nva recent, larger
trial of 186 patients'" that also investigated the
resectability of previously unresectable metastatic
colorectal cancer, irrespective of the site of meta
static involvement, but including liver, lung, and
lymph node metastases. It was clearly demon
strated that a chronomodulated oxaliplatin-5-FU/
FA regimen not only provides postchemotherapy
response rates superior to those obtained with a
continuous-infusion regimen, but also causes suf
ficient metastasis reduction to allow surgery and
to increase the complete response rate after the
procedure. Compared with continuous infusion,
the chronomodulated regimen also reduced the in
cidence of 5-FU-induced grade 3/4 mucositis from
76% to 14% (P = .0001) and oxaliplatin-related
grade 2 peripheral sensitive neuropathy from 31%
to 16% (P = .01 ).44
In a subsequent phase II study of patients treated
with a similar chronomodulated regimen in which
5-FU was infused at a rate of 700 mg/m'/d (instead
of 600 mg/m2/d), a relationship between objective
response and the cumulative dose of 5-FU adminis
tered was noted. This suggested that the chrono
modulated delivery scheme, permitting the deliv
ery of higher doses of 5-FU with less toxicity,
MANAGEMENT OF LIVER METASTASES WITH OXALIPLATIN
43
Table I. Comparison of Response Rates, Ability to Resect Previously Unresectable Tumors, and Postsurgery Response
Rates in Patients Treated With a Chronomodulated Versus a Continuous Infusion of an
Oxaliplatin/5-Fluorouracil/Folinic Acid Regimen in Two Consecutive, Randomized, Multicenter Trials
Chronomodulated Regimen (%)
Levi et al
* 1
Levi et al
* 4
Continuous Infusion Regimen (%)
Levi et al41
47
Levi et al4
93
No of patients
45
93
Complete response
3(7)
5(5)
2(1)
3(3)
Partial response
21 (17)
12 (15)
13(28)
21 (26)
Eligible for surgery after chemotherapy
17 (38)
23 (25)
11 (23)
I7 (I8)
Complete response after surgery
12 (27)
20 (22)
5(H)
I3 (11)
would produce higher response rates. The effect of
chemotherapy on the resectability of previously
unresectable liver metastases was also assessed.45
The treatment allowed the complete resection of
liver metastases in 38% of chemotherapy-naive pa
tients and in 22% of those who had undergone
previous 5-FU chemotherapy in a bolus or continu
ous mode of administration without oxaliplatin
(Table 2). This trial showed that previously unre
sectable liver metastases from colorectal cancer
could be resected following chemotherapy with a
chronomodulated oxaliplatin-5-FU/FA regimen,
even in patients who have become resistant to 5FU or who are refractory to this agent. However,
achieving postchemotherapy resectability was
somewhat more likely in chemotherapy-naive pa
tients.
The ability to achieve resectability in patients
with previously unresectable liver metastases from
colorectal cancer was examined in detail in a re
cent study reflecting a cumulative single-institu
tion experience and using chronomodulated ther
apy with oxaliplatin and 5-FU/FA.46 Of 434
Table 2. Response Rates and Postchemotherapy
Resectability of Previously Unresectable Liver
Metastases in Previously Treated and Chemotherapy-
Naive Patients Treated With a Chronomodulated
Regimen of Oxaliplatin/5-Fluorouracil/Folinic Acid
Previously Treated
Chemotherapy-
Patients.
Naive Patients.
n = 37 (%)
n = I3 (%)
Complete response
I (3)
2 (IS)
Partial response
H (38)
7(51)
Complete resection
8(22)
5(38)
patients with metastatic colorectal cancer seen at
Paul Brousse Hospital, 330 had unresectable liver
metastases at the time of admission. This inopera
ble group was treated with a chronomodulated reg
imen of oxaliplatin (25 mg/m2/d), 5-FU (700 to
1,200 mg/m2/d), and FA (300 mg/m2/d) according
to the scheme shown in Fig 1. Each course "of
chemotherapy lasted 4 to 5 days and was repeated
every 3 to 4 weeks. The patients were periodically
reassessed with abdominal computed tomography
scans. Resection of previously unresectable liver
metastases became possible in 53 patients (16%)
following chemotherapy. Resections were per
formed when the tumor size (after repeated com
puted tomography scans) and the serum carcinoembryonic antigen levels (after repeated
measurements) had reached a plateau. The average
time required for chemotherapy to reduce the size
of the tumor to allow resection was approximately
8 to 9 months. Surgery was curative in 75% of the
cases in which it was felt that resection had a good
chance of success. The tumor characteristics, cause
of unresectability before chemotherapy, duration
of chemotherapy, and response rates are shown in
Table 3. Initially, hepatic recurrence was observed
in 34 patients (64%) during a mean follow-up of 42
months. Hepatic recurrence necessitated a second
resection in 15 of these 34 patients (44%), and a
third hepatectomy was required in three patients
with multinodular metastases. In addition, extra
hepatic recurrences that included intra-abdominal
and pulmonary metastases developed in 25 pa
tients (47%). Pulmonary metastases occurred
mainly in the group of patients who had prior unre
sectable multinodular liver metastases. Six of the
14 patients with, pulmonary metastases were suc
cessfully resected.
BISMUTH AND ADAM
44
Table 3. Prechemotherapy Tumor Characteristics, Chemotherapy Regimen, and Response to Postchemotherapy
Surgical Resection in Patients With Previously Unresectable Liver Metastases
Cause of Unresectability
Large
Ill-Located
Multinodular
Total
Extrahepatic
No. of patients’
8
8
24
13
Largest tumor diameter (mm)’
83 (40-135)
55 (35-80)
37 (14-70)
42 (15-74)
No. of metastases
*'
2.5 (1-5)
1.6 (1-3)
6.2 (3-11)
3.2 (1-8)
Bilateral disease (%)
3(37)
1 (12)
18 (75)
7 (51)
Segments involved’
3 8 (2-6)
2 3 (1-3)
15 (2-8)
7 8(1-5)
CEA levels (ng/mL)’
376 (7-1720)
213 (3-1560)
50 (1-212)
116 (4-350)
Chemotherapy courses
*
7.5 (4-11)
10 (3-19)
9 9 (4-29)
II (7-18)
Duration of chemotherapy’
6.5 (2-10)
7.7 (2-17)
7.9 (3-29)
9.5 (6-14)
Curative resections (%)
7(88)
8 (100)
19 (79)
12 (92)
16 (75)
Mean follow-up (mo)"
51 (30-84)
35.9 (26-53)
44 (25-85)
38 4 (25-69)
42.1 (25-85)
Hepatic recurrence (outcome)
4
4
13
6
27
Disease free (%)
1 (50)
3(37)
9(37)
3 (23)
I9 (36)
53
Abbreviation CEA. carcinoembryonic antigen.
’ Mean value (range).
Adapted and reprinted with permission 44
After 42 months of follow-up, 26 patients were
alive (49%), 19 of whom were disease free (36%)
(Table 3). Overall patient survival was 54% and
40% at 3 and 5 years, respectively (Fig 2). The 5year survival rate according to cause of unresect
ability of tumor before treatment was 75% for illlocated tumors, 62% for large tumors, 37% for
multinodular tumors, and 14% for associated extra
hepatic tumors. As expected, focused liver metas
tases (ill-located or large) were more likely to be
amenable to treatment than multiple-site tumors.
These studies demonstrated that a chronomodu
lated regimen of chemotherapy consisting of oxali-
Survival (months)
Fig 2. Cumulative survival after liver resection following
systemic chronomodulated chemotherapy for all unresectable
liver metastases. (Adapted and reprinted with permission.")
platin and 5-FU plus FA can be aggressively com
bined with surgery to ameliorate the prognosis of
patients with metastatic colorectal cancer and can
significantly prolong survival for some who were
originally classified as palliative care candidates.
CONCLUSION
Colorectal cancer preferentially metastasizes to
the liver, the lung, or both. Hepatic metastases are
the most frequent, and the proportion of patients
who can achieve a cure from hepatic resection is
estimated to be s 10%.4''”’ This outcome results
from the high proportion of patients with meta
static disease who present with unresectable liver
metastases. For these patients, the combination
chemotherapy of 5-FU and FA has long been the
main palliative option available. However, the
outcome is uniformly poor, with tumor response
rates rarely exceeding 20% and survival rates rang
ing from 3 to 6 months in patients with bilobal
involvement. A major reason for the mediocre out
come is that patients often become resistant to
5-FU or are intrinsically nonresponsive. Although
various combinations of 5-FU/FA with oihn
agents have been tested to try to achieve a betui
response, these attempts have met with little sue
cess because of either minimal improvement ot
enhancer! toxicity.
MANAGEMENT OF LIVER METASTASES WITH OXALIPLATIN
Recently, the combination of 5-FU/FA with
oxaliplatin has provided improved response rates
with conventional-administration drug schemes.
These rates have been further enhanced with con
comitant decreased toxicity by using a chrono
modulated regimen. These studies have shown that
previously unresectable liver metastases from colo
rectal carcinoma can be reduced to the point of
resectability, resulting in significant response rates
and prolonged survival. Among previously noncurable patients, 16% can eventually become resect
able, with approximately 40% of these surviving
at least 5 years.
These results suggest that for patients with no
extrahepatic involvement, improved resection
technique (including cryotherapy and emboliza
tion for difficult-to-manage liver metastases) and
an effective chemotherapeutic regimen rigorously
administered to make unmanageable metastases
amenable to resection will help change previously
bleak prognoses. Even patients with metastatic dis
ease can look forward to prolonged survival.
REFERENCES
1 Hugh TJ. Kinselln AR, Poston GJ: Management strategies
for colorectal liver metastases—Part I Surg Oncol 6:19-30,
1997
2. Burke D, Allen-Mcrsh TG: Colorectal liver metastases.
Postgrad Med J 72:464-469. 1996
3. Belluco C, Guillem JG, Kcmeny N, et al: p53 Nuclear
protein overexpression in colorectal cancer: A dominant pre
dictor of survival in patients with advanced hepatic metastases.
J Clin Oncol 14:2696-2701, 1996
4. Yang J-L. Yu Y, Markovic B, et al: Overexpression of
c-erbB-2 mRNA and/or c-neu oncoprotein is a predictor for
metastases from colorectal cancer. Anticancer Res 17'10231026, 1997
5. VanderMeer TJ, Callcry MP, Meyers WC: The approach
to the patient with single and multiple liver metastases, pulmo
nary metastases, and mrra-abdominal metastases from colo
rectal carcinoma Hematol Oncol Clin North Am 11:759-777,
1997
6. Bluingart 1., Fong Y: Surgical options in the treatment
of hepatic metastasis from colorectal cancer. Curr Probl Surg
.32:333-421, 1995
7. Weaver M, Atkinson D, Zemel R- Hepatic cryosurgery
in treating colorectal metastases Cancer 76:210-214, 1995
8. Korpan N: Hepatic cryosurgery for liver metastases. Long
term follow-up. Ann Surg 225:193-201, 1997
9. Tandan V, Harmantas A, Gallinger S: Long-term survival
after hepatic cryosurgery versus surgical resection for metastatic
colorectal carcinoma: A critical rei iew of the literature, (.an
J Surg 40:175-181. 1997
10. Moertel C. Fleming T. MacDonald J. ei ,.| I evamisole
and fluorouracil for adjuvant therapy ol re-cued colon saninoma.N Engl J Med 322.352-358, |090
45
11 Moertel C, Fleming T, Macdonald J, et al' Fluorouracil
plus levamisole as effective adjuvant therapy after resection of
stage III colon carcinoma; A final report. Ann Intern Med
122:321-326, 1995
12. Moertel C, Fleming T, Macdonald J, et al: Intergroup
study of fluorouracil plus levamisole as adjuvant therapy for
stage H/Dukes
*
B2 colon cancer. J Clin Oncol 13:2936-2943.
1995
1 3. O’Connell M, Laurie J, Shepherd L, et al: A prospective
evaluation of chemotherapy duration and regimen as surgical
adjuvant treatment for high-risk colon cancer: A collaborative
trial of the North Central Cancer Treatment Group and the
National Cancer Institute of Canada Clinical Trials Group.
Proc Am Soc Clin Oncol 15:209, 1996 (ahstr)
14. Wolmark N, Rockette H. Mamounas E, et al: The rela
tive efficacy of 5-FU + leucovorin (FU-LV), 5-FU +• levamisole
(FU-LEV), and 5-FU + leucovorin + levamisole (FU-LVLEV) in patients with Dukes’ B and C carcinoma of the colon:
First report of NSABP C-04- Proc Am Soc Clin Oncol 15:205,
1996 (abstr)
15. Advanced Colorectal Cancer Meta-Analysis Project:
Modulation of fluorouracil b\ leucovorin in patients with ad
vanced colorectal cancer: Evidence in terms of response rate.
J Clin Oncol 10:896-903, 1992
16. Liver Infusion Meta-Analysts Group- Portal vein chemo
therapy for colorectal cancer: A meta-analysis of 4000 patients
in 10 studies. J Natl Cancer Inst 89:497-505, 1997
17. Meta-Analysis Group In Cancer Reappraisal of hepatic
arterial infusion in the treatment of nonresectable liver metas
tases from colorectal cancer. J Natl Cancer Inst 88:252-258,
1996
18. Ogata Y, Shirou:u K, Akagi Y, et al. Hepatic arterial
chemotherapy for liver metastases from colorectal cancer.
Kurume Med J 43:41-47, 1996
19. Rougier P, Laplanche A, Huguier M, et al: Hepatic arte
rial infusion of floxuridine in patients with liver metastases
from colorectal carcinomas: Long term results of a prospective
randomized trial. J Clin Oncol 10.1112-1118, 1992
20. Mohiuddin M, Chen E, Ahmad N: Combined liver radi
ation and chemotherapy for palliation of hepatic metastases
from colorectal cancer. J Clin Oncol 14:722-728, 1996
21. Robertson J, Lawrence T. Walker S, et al: The treatment
of colorectal liver metastases with conformal radiation therapy
and regional chemotherapy. Int J Radiat Oncol Biol Phys
32:445-450, 1995
22. Russell A, Clyde C, Wasserman T, et al- Accelerated
hyperfractionated hepatic irradiation in the management of
patients with liver metastases: Results of the RTOG dose esca
lating protocol. Int J Radiat Oncol Biol Phys 27:117-123, 1993
23 Rodrigue:-Bigas M, Klippenstein D, Meropol N, et al.
A pilot study of cryochemotherapy for hepatic metastases from
colorectal cancer. Cryobiology 33-600-606, 1996
24. Seifert P, Baker L, Reed M, et al: Comparison of contin
uously infused 5-fluorouracil with bolus injection tn treatment
of patients with colorectal adenocarcinoma. Cancer 36:123128, 1975
25. CaballeroG, Ausman R, Qucbbeman E. Long-term am
bulatory. continuous IV infusion of 5-FU for the treatment of
advanced adenocarcinomas. Cancer Treat Rep 69:1 3-15. 1985
26. Hansen R. Quebbeman E, Ausman R. et al: Continuous
5 fluorouracil (5-FU) infusion in colorectal cancer: Update of
46
the MCW experience. Proc Am Soc Clin Oncol 6:80, 1987
(abstr)
27. de Gramont A, Krulik M, Cady J, et al: High-dose folinic
acid and 5-fluorouracil bolus and continuous infusion in ad
vanced colorectal cancer. Eur J Cancer Clin Oncol 24:14991503, 1988
28. Garufi C, L6vi F, Aschelter A, et al: A phase I trial of
5-day chronomodulated infusion of 5-fluorouracil and 1-folinic
acid in patients with metastatic colorectal cancer. Eur J Cancer
33:1566-1571. 1997
29. Spears C, Gustavsson B, Berne M, et al: Mechanisms of
innate resistance to thymidylate synthase inhibition after 5fluorouracil. Cancer Res 48:5894-5900, 1988
30. Sobrero A, Aschele C, Guglielmi A, et al: Resistance
to 5-fluorouracii and 5-fluoro-2'-deoxyuridine mechanisms and
clinical implications. J Chemother 2:12-16, 1990 (suppl 1)
31. van Groeningen C, Peters G, Pinedo H: Lack of effec
tiveness of combined 5-fluorouracil and leucovorin in patients
with 5-fluorouracil-resistant advanced colorectal cancer. Eur
J Cancer Clin Oncol 25:45-49, 1989
32. Patt Y, Hoque A, Lozano R, et al: Phase II trial of
hepatic arterial infusion of fluorouracil and recombinant human
interferon alfa-2b for liver metastases of colorectal cancer re
fractory to systemic fluorouracil and leucovorin. J Clin Oncol
15.1432-1483, 1997
33. Recchia F, Nuzzo A, Lalli A, et al: Randomized trial of
5-fluorouracil and high-dose folinic acid with or without alpha2B interferon in advanced colorectal cancer. Am J Clin Oncol
19:301-304, 1996
34. Pronzato P, Vaira F, Vigani A, et al: Biochemical modu
lation of 5-fluorouracil with methotrexate in advanced colo
rectal cancer patients pretreated with adjuvant 5-fluorouracil
and leucovorin. Anticancer Res 15:2679-2682, 1995
35. Zaniboni A, Labianca R, Martignoni G, et al: Sequential
methotrexate and 5-fluorouracil as second-line chemotherapy
for advanced colorectal cancer patients pretreated with 5-fluo
rouracil and leucovorin: A GISCAD study. J Chemother 8:8284. 1996
36. de Gramont A, Vignoud J, Toumigand C, et al: Oxali
platin with high-dose leucovorin and 5-fluorouracil 48-hour
continuous infusion in pretreated metastatic colorectal cancer.
Eur J Cancer 33:214-219, 1997
37. Andre T, Benmaine MA, Louvet C, et al: Addition of
oxaliplatin (Eloxatine®) to the same leucovorin (LV) and 5fluorouracil (5FU) bimonthly regimens after progression in pa
BISMUTH AND ADAM
tients (pts) with metastatic colorectal cancer (MCRC): Prelim
inary report. Proc Am Soc Clin Oncol 16:270a, 1997 (abstr)
38. Louvet C, Bleiberg H, Gamelin E, et al Oxaliplatin (LOHP) synergistic clinical activity with 5-fluorouracil (FU) in
FU resistant colorectal cancer (CRC) patients is independent
of FU +/- folinic acid (FA) schedule. Proc Am Soc Clin
Oncol 15:206, 1996 (abstr 467)
39. Garufi C, Brienza S, Bensmaine MA, et al: Addition of
oxaliplatin (L-OHP) to chronomodulated (CM) 5-fluorouracil
(5-FU) and folinic acid (FA) for reversal of acquired chemore
sistance in patients with advanced colorectal cancer (ACC).
Proc Am Soc Clin Oncol 14:192, 1995 (abstr)
40. Boughattas NA, Levi F, Fournier C, et al: Circadian
rhythm in toxicities and tissue uptake of 1,2-diaminocyclohcxane(trans-l)oxalatoplatinum(II) in mice. Cancer Res 49:33623368, 1989
41. Levi F, Benavides M, Chevelle C, et al: Chemotherapy
of advanced ovarian cancer with 4,-O-tetrahydropyranyl doxo
rubicin and cisplatin: A randomized phase II trial with an evalu
ation of circadian timing and dose intensity. J Clin Oncol
8:705-714, 1990
42. Hrushesky W: Circadian timing of cancer chemother
apy. Science 228:73-75, 1985
43. Levi FA, Zidani R, Vannetzel J-M, et al: Chronomodu
lated versus fixed-infusion-rate delivery of ambulatory chemo
therapy with oxaliplatin, fluorouracil, and folinic acid (leuco
vorin) in patients with colorectal cancer metastases: A
randomized multi-institutional trial. J Natl Cancer Inst
86:1608-1617, 1994
44. Levi F, Zidani R, Misset J-L: Randomised multicentre
trial of chronotherapy with oxaliplatin, fluorouracil, and folinic
acid in metastatic colorectal cancer. For the International Or
ganization for Cancer Chronotherapy. Lancet 350:681-686,
1997
45. Bertheault-Cvitkovic F, Jami A, Ithzaki M, et al: Bi
weekly intensified ambulatory chronomodulated chemotherapy
with oxaliplatin, fluorouracil, and leucovorin in patients with
metastatic colorectal cancer. J Clin Oncol 14:2950-2958, 1996
46. Bismuth H, Adam R, L6vi F, et al: Resection of nonresectable liver metastases from colorectal cancer after neoadju
vant chemotherapy. Ann Surg 224:509-522, 1996
47. Steele GJ, Ravikumar T: Resection of hepatic metastases
from colorectal cancer: Biological perspective. Ann Surg
210:127-138, 1989
48. Scheele J: Hepatectomy for liver metastases. Br J Surg
80:274-276, 1993
Oxaliplatin for the Treatment of Advanced Colorectal Cancer:
Future Directions
Michel Ducreux, Christophe Louvet, Mohamed Bekradda, and Esteban Cvitkovic
The introduction of oxaliplatin into the colorectal can
cer setting represents a significant advancement in the
treatment of the disease. Synergistic effects with tradi
tional therapy 5-fluorouracil/folinic acid have increased
response rates significantly, improved time-sensitive
response parameters, and facilitated the removal of
previously
unresectable
hepatic
metastases,
thus
changing the natural history of the disease. Ongoing
and planned trials are identifying various issues that
need to be addressed to fully realize the potential of
oxaliplatin. These include optimization of dosing and
schedule of administration, determination of the most
effective oxaliplatin-5-fluorouracil/folinic acid combi
nation, definition of the role of new thymidylate syn
thase inhibitors with respect to oxaliplatin therapy, and
identification of the most effective combinations of
oxaliplatin with the new anticancer agents that have
been recently introduced. Providing the answers to
these questions will contribute to changing the attitude
of the clinical oncologist regarding what strategy to
adopt in treating colorectal cancer in the coming years.
Semin Oncol 25 (suppl 5):47-53. Copyright © /998 by W.B.
Saunders Company.
OR OVER 40 YEARS, the mainstay of adju
vant chemotherapy for the treatment of ad
vanced colorectal cancer has been 5-fluorouracd
(5-FU), which, when administered as a single
agent, rarely achieves response rates higher than
1In addition, there is still no consensus as
to the most effective dosage, schedule, or route of
administration of 5-FU. Because the biochemical
modulator folinic acid (FA) enhances the antitu
mor activity of 5-FU rhese agents are often com
bined to improve objective response rates.4,5 An
increase in response rates, however, does not usu
ally translate into an improvement in patient sur
vival.5,6 Whereas continuous protracted infusion
results in statistically significant improvement in
time to progression and patient survival over bolus
administration,7 the statistically significant sur
vival advantage of approximately 1 month has
limited clinical relevance, and therefore bolus ad
ministration remains the preferred modality. Con
sequently, clinical research efforts have concen
trated on the development of other antitumor
agents for use alone or in combination with 5-FU.
Our current understanding of colorectal carci
nogenesis and tumor progression at the molecular
level, including the role oi p5 > in cell cycle pro
F
Seminars in Oncologf. Vol 25. No 2. Suppl 5 (April), 1998 pp 47-53
gression and apoptosis,8,9 the role of deficient mis
match repair in nonpolyposis familial colorectal
cancer,10'" and the role of thymidylate synthase
activity in resistance to 5-FU therapy," has sug
gested new therapeutic strategies and provided in
sight into the treatment-dependent natural history
and prospective therapeutic outcome of this dis
ease. New agents currently under development for
the treatment of colorectal cancer include the
third-generation platinum derivative oxaliplatin;
the thymidylate synthase inhibitors raltitrexed,
UFT (uracil and regafur), and capecitabine; the
antimetabolite gemcitabine; and the topoisomer
ase I inhibitor irinotecan (CPT-1 1).2,13 20 This re
cently acquired knowledge will require us to rede
fine the management of colorectal cancer and
carefully determine optimal combinations, sched
ules, and sequence of administration of the newly
available agents. Raltitrexed, CPT-11, and oxali
platin have been the object of the most intensive
and advanced development, with the oxaliplatin5-FU/FA combination yielding the highest effi
cacy levels against advanced colorectal cancer in
both pretreated and chemotherapy-naive patients.
The recent introduction of oxaliplatin in combi
nation with 5-FU/FA has consistently increased
objective response rates to over 40%, even in 5FU - refractory patients.2,21 The administration of
these agents in a chronomodulated schedule ap
pears to be less toxic than continuous infusion and
provides even higher response rates.22 The effec
tiveness of this combination has facilitated the sur
gical removal of distant metastases (particularly
hepatic metastases) in patients whose tumors were
previously unresectable.2’ The favorable safety pro
file of oxaliplatin (see Extra et al elsewhere in this
From the Service de Gastroenterologie et d'Oncologie Digestive,
Institut Gustave Roussy, Villejuif, France; the Service de Medicine
Inteme-Oncologie, Hopital de Saint-Antoine, Pans. France; the
Department of Medicine, Institut Gustave Roussy, Villejuif, France;
and the Service des Maladies Sanguines Immunitaires et Tumorales,
Hdpital Paul Brousse, Villejuif, France.
Address reprint requests to Esteban Cvitkovic. MD. Service des
Maladies Sanguines Immunitaires et Tumorales, Hopital Paul
Brousse, 14 ave P. Vaillant-Coutuner. 94800 Villejuif, France.
Copyright © 1998 by W.B. Saunders Company
0093-7754/98/2502-0507508 .00/0
47
DUCREUX ET AL
48
supplement [pp 13-22]) has allowed the treatment
of thousands of patients, with limited gastrointesti
nal and hematologic toxicities and no life-threat
ening toxicity or morbidity other than sporadic,
acute pharyngolaryngeal dysesthesia or cumula
tive, self-limiting, and mostly reversible neurosensory toxicity.24
The physicians most experienced in using oxali
platin have grasped the therapeutic possibilities of
this new agent. The uniqueness of its mechanism
of action and its additivity and/or synergy with
many other agents, together with the simultaneous
availability of CPT-11J418'25 26 the ongoing devel
opment of new thymidylate synthase inhibitors,
and the increasing prevalence of adjuvant treat
ment in patients with colorectal cancer, provide a
major opportunity to redefine and optimize the
currently available therapeutic decision algorithms
for this disease.
Since the spectacular results obtained in 5-FUrefractory disease with the oxaliplatin-5-FU/FA
combination have become known, a large number
of trials have been planned and carried out to opti
mize the parameters of oxaliplatin administration
and to define its place in the colorectal cancer
setting. However, there is still much to be learned
regarding the most effective method of administra
tion of this antitumor agent, both as a single agent
and in combination therapy. Currently, more than
a dozen planned and ongoing clinical trials with
oxaliplatin in patients with advanced colorectal
cancer are attempting to answer the outstanding
questions, some of which are addressed below.
WHAT IS THE OPTIMAL DOSE AND
SCHEDULE OF OXALIPLATIN?
The currently recommended dose of oxaliplatin
is 130 mg/m2 administered intravenously (IV) over
2 to 6 hours every 3 weeks. However, other sched
ules have not been attempted for single-agent ad
ministration of oxaliplatin. Both de Gramont and
Levi have used oxaliplatin in combination with 5FU/FA at biweekly doses of 85 to 100 mg/m2 either
as a 2-hour infusion or over 4 to 5 days as a chrono
modulated infusion (see these reports elsewhere in
this supplement [pp 32-39]). The dose intensity
(35 to 40 mg/m2/wk) of such schedules is similar
to that of the 130 mg/m2 every 3 weeks schedule,
and to date, there appear to be no apparent differ
ences in overt toxicity or in the rate, severity, and
reversibility of cumulative dose-dependent neuro
toxicity. Chronomodulated administration, how
ever, appears to be less toxic.21 As in most phase 1
studies, pharmacokinetics considerations were not
addressed, particularly with respect to the ability
of such schedules to maintain the initial dose of
oxaliplatin over five or six cycles of therapy. The
formal comparison of the incidence and severity
of toxicity resulting from a biweekly oxaliplatin
schedule, designed to increase the overall thera
peutic index, versus a triweekly schedule has not
yet been published. Three ongoing, multicenter,
randomized phase 11 trials do have both biweekly
and triweekly regimens in their design (Table 1).
The dose-limiting neurotoxicity of oxaliplatin
appears as the crucial end point in the determina
tion of optimal dosing schedules. The specific neu
rotoxicity scale devised by Caussanel et al2' was
based on an open randomized phase I design that
allowed for observer bias in the assessment of the
subjective acute neurosensory toxicity. Since then,
it has undergone several minor changes in consec
utive studies, making impossible a forma! compari
son of the different doses and schedules of adminis
tration. Additional variables affecting the severity
of acute dysesthesia include length of infusion
(probably the length of time it takes free plasma
platinum to achieve s75% protein binding), ex
posure to cold, and the education of both pre
scriber and patient.
The length of infusion may also be responsible
for the differential emesis and antiemetic needs
observed with the short infusion (2 to 6 hours IV)
versus 4- to 5-day chronomodulated administra
tion, which clearly lead to different maximum plat
inum concentrations, although severe oxaliplatininduced emesis is well controlled with standard
doses of modern anti-5-HTj antiemetics.
Because of these factors, the maximal tolerated
dose and the recommended dose of oxaliplatin need
to be redefined in terms of appropriate cycle fre
quency and various lengths for short infusions, partic
ularly when the total number of courses planned is
fewer than six, as in the adjuvant and neoadjuvant
settings. Disease-specific phase 1/11 trials in head and
neck cancer and malignant melanoma have been
proposed to redefine the maximal tolerated dose and
recommended dose of the triweekly schedule, with
an infusion time of 4 to 6 hours. A pharmacokinetics
assessment of free platinum and protein-binding cor
relates is necessary to clarify these issues in the appro
priate clinical trials.
OXALIPLATIN: FUTURE DIRECTIONS
49
Table I. Protocol of Four-arm Randomized Multicenter Phase II Trials of Oxaliplatin Currently in Progress
in the United States and Europe
Modalities
Trial
Fluoropyrimidine
Administration
Oxaliplatin
Administration
Biweekly
Advanced colorectal cancer first line
US trial. 160 patients
LV5-FU2
CIV 48 hr
85 mg/m2
5-FU/FA
Weekly bolus
85 mg/m2
Brweekly
5-FU/FA
Chronomodulated
130 mg/m2
T riweekly
5-FU
CIV
130 mg/m2
T riweekly
5-FU
CIV
130 mg/m2
T riweekly
5-FU (high-dose)ZFA
CIV 24 hr. weekly
85 mg/m2
Biweekly
5-FU/FA
IV bolus (5 d/mo)
130 mg/m2
T riweekly
Advanced colorectal cancer second line
US trial. 200 patients
European trial. 200 patients
5-FU/FA
IV bolus weekly
85 mg/m2
Biweekly
5-FU
CIV
130 mg/m2
Triweekly
Biweekly
5-FU (high-dose)/FA
CIV 24 hr. weekly
85 mg/m2
5-FU/FA
CIV
85 mg/m2
Biweekly
5-FU/FA
IV bolus (5 d/mo)
130 mg/m2
Triweekly
Abbreviations; LV5-FU2, leucovorin 200 mg/m2/d. 2-hr infusion, then 5-FU bolus 400 mg/mJ/d and 5-FU 600 mg/m2/d, continuous intravenous
(CIV) 22-hr, all repeated for 2 consecutive days.
The issues of tolerance, toxicity, and cumulative
toxicities with the every 2 weeks versus every 3
weeks schedule are being formally addressed in
three randomized, multicenter, four-arm phase 11
trials in the United States (as first-line therapy)
and in Europe (as second-line therapy). Two of
these trials are being conducted in pretreated pa
tients (one in the United States, one m Europe),
and one trial is being conducted in previously un
treated patients (in the United States) (Table 1).
Since the planned dose intensity is the same in all
arms, the results should settle the issue of cycle
frequency. The weekly administration of oxali
platin in combination with 8-hour weekly 5-FU/
FA IV will be explored in a trial by Gamelin and
coworkers (personal communication, February
1998).
WHAT IS THE MOST EFFECTIVE
5-FLUOROURACIUFOLINIC ACID
COMBINATION WITH OXALIPLATIN?
Over 40 years of clinical research on 5-FU sched
ules has shown that FA or methotrexate modulation
increases response with an adequate safety profile,
but has little effect on time-related efficacy parame
ters, and that infusional 5-FU delivery has pharmaco
dynamic effects and a toxicity profile unlike those
observed with bolus administration.
Infusional
delivery appears to be active in 5-FU bolus failures
and prolongs survival with statistical significance, but
with borderline clinical relevance when the quality
of life of the patient and infrastructural logistic con
straints are considered.7
It is unlikely that oxaliplatin will help clarify
the controversy regarding 5-FU delivery. However,
it should be noted that most, if not all, available
data on oxaliplatin and 5-FU have been obtained
with infusional high-dose 5-FU/FA schedules, with
little dependence on the dose or stereospecificity
of the FA administered.30 To date, however, highdose infusional 5-FU/FA schedules have given the
best response rates or time-related parameters in
advanced colorectal cancer.28
The three randomized, multicenter, four-arm
phase 11 trials are addressing this issue head on,
since the contribution of the 5-FU dosing schedule
and administration modality should be analyzed in
terms of progression-free and overall survival rates
rather than response rate, an admittedly poor effi
cacy surrogate in advanced colorectal cancer."
The efficacy of biweekly administration of chro
nomodulated 5-FU/FA for 4 days will be compared
with the 48-hour FOLFOX delivery schedule de
veloped by de Gramont (see Bleiberg and de
Gramont in this supplement, pp 32-39) with oxa
liplatin given over a 2-hour period, in a random
so
ized phase 111 trial conducted by the recently cre
ated Chronotherapy Group of the European
Organization for Research on the Treatment of
Cancer. Smaller studies with chronomodulated oxaliplatin-5-FU/FA delivered every 2 weeks have
shown a higher response rate and a shorter time
to response than the previous 5-day schedule everv
3 weeks.21'12 The resolution of these issues is im
portant, because it has been suggested that this
biweekly mode of administration has improved the
chances of removing previously unresectable he
patic metastases
Another trial conducted by Bertheault-Cvitkovic will attempt to improve on the 5-FU/FA
48-hour delivery schedule of de Gramont, using
chronomodulated delivery of 5-FU/FA, with oxali
platin given over 6 hours (personal communica
tion, July 1997).
In a trial aimed at further intensifying the fre
quency of delivery, Gamelin and coworkers will
formally study a weekly 8-hour 5-FU/FA delivery
schedule in a phase 1/11 study, with the simultane
ous weekly administration of oxaliplatin.
The FOLFOX-2 schedule, previously reported
by de Gramont et al (see Bleiberg and de Gramont
in this supplement, pp 32-39) as a biweekly treat
ment, is being administered every 3 weeks by Rougier et al, and the results of this study will be
reported shortly (Rougier, personal communica
tion, January 1998). Interesting variations in 5-FU
delivery are currently undergoing evaluation m
China and South America. Additionally, a 70patient phase II trial in Argentina is comparing
biweekly administration of oxaliplatin (85 mg/m2)
with oxaliplatin (biweekly, same dose) plus 5-FU/
FA, day 1 to 5 every 4 weeks.
Currently, there are no published data on the
use of oxaliplatin with protracted 5-FU continuous
IV infusion. However, one of the ongoing fourarm phase IL trials includes 5-FU continuous IV
administration (Table 1). An ongoing French
multicenter, randomized trial of patients with ad
vanced colorectal cancer refractory to 5-FU is also
addressing this issue. In this trial, patients in one
arm are treated with irinotecan, and patients in
the other two arms are treated with protracted 5FU continuous IV infusion; patients in one of the
latter arms also receive oxaliplatin (Table 2; Adenis, personal communication, July 1997). Phar
macokinetics issues concerning the long-term ad
ministration of 5-FU continuous IV infusion with
DUCREUX ET AL
Table 2. Multicenter Randomized Phase III Trial of
212 Patients With Advanced Colorectal Cancer
Refractory to 5-FU
z Arm 1.
R
/
A
106 patients
5-FU 250 mg/m3
CIV + oxaliplatin
N
130 mg/m3
D
triweekly
O
-------------Arm 2:
M
X.
53 patients
1
CIV d 1-49,
rest 2 wk
Z
E
5-FU 300 mg/m3
x Arm 3’
53 patients
Irinotecan
350 mg/m3
triweekly
NOTE. This three-arm trial compares 5-FU alone and 5-FU
plus oxaliplatin modalities with triweekly irinotecan. Response
rates, toxicity of each regimen, and quality of life according to
the QLQC-38 protocol will be assessed
Abbreviation; CIV, continuous intravenous.
oxaliplatin are being addressed in another phase
I/II trial by Cunningham and coworkers (personal
communication, July 1997).
WHAT IS THE ROLE OF THE NEW
THYMIDYLATE SYNTHASE INHIBITORS?
The new thymidylate synthase inhibitors (raltitrexed, capecitabine, UFT) differ from 5-FU in
their ease of administration, metabolism, and in
creased tissue selectivity; however, their efficacy
and toxicity profiles are essentially the same as
those of 5-FU. Not surprisingly, these agents are
being or will be tested in combination with oxali
platin. Both capecitabine and UFT are being or
will be orally administered agents with superior
selectivity and metabolic profiles. Although they
have shown convincing efficacy and safety profiles
in hundreds of patients, their therapeutic advan
tage as single agents in patients with advanced
colorectal cancer will be limited by the same barri
ers that 5-FU modulators have confronted.
A recent phase I trial of raltitrexed and oxali
platin has been completed by J. P. Armand (per
sonal communication, November 1997) using the
full recommended doses for both agents (3 mg/m
and 130 mg/nr, respectively) administered every
3 weeks. A phase II trial of this combination will
be conducted in previously untreated patients wi th
advanced colorectal cancer by investigators from
the French Federation of Anticancer Centers.
OXALIPLATIN
FUTURE DIRECTIONS
WHAT COMBINATIONS OF OXALIPLATIN
WITH OTHER AGENTS ARE ACTIVE IN
COLORECTAL CANCER?
The topoisomerase I inhibitor irinotecan, al
ready registered in most countries, has shown ac
tivity both in chemotherapy-naive patients and
in 5-FU-pretreated patients. On the basis of the
synergistic activity observed in vitro with oxali
platin and SN-38, the active metabolite of irino
tecan, ” a phase 1 study using oxaliplatin and CPT1 1 was conducted and reported recommended
doses of 200 mg/nr for irinotecan and 85 mg/m
*
lor oxaliplatin.''1 In this trial of 17 patients with
advanced colorectal cancer, 13 of whom were resis
tant to 5-FU, seven had an objective response.
A similar phase I study conducted by Marty and
coworkers is near completion, and a comparable
study with biweekly administration is ongoing.’5
Another biweekly study will be initiated in the
United States by Rothenberg (personal communi
cation, November 1997), and a weekly administra
tion schedule will be explored by N. Kemeny at
Memorial Sloan-Kettering Cancer Center (per
sonal communication).
Oxaliplatin synergy with gemcitabine in vitro
has been recently described.’6 A phase I/Il study
is planned for patients with advanced colorectal
cancer, as well as for other indications. Tirapazamine is a new bioreductive agent with clear activ
ity with a variety of cytotoxic agents. Because the
combination of 5-FU, cisplatin, and mitomycin
(another bioreductive agent) has shown activity
in colon cancer xenografts, ' it would be logical
to test the combination of 5-FU, oxaliplatin, and
tirapazamine.
Alternative treatment strategies with oxali
platin are being addressed in specific trials of radio
chemotherapy for rectal cancer and intra-arterial
infusion in patients with hepatic metastases.
OXALIPLATIN IN THE THERAPEUTIC
STRATEGY AGAINST COLORECTAL
CANCER: CURRENT ASSESSMENT AND
FUTURE PROSPECTS
After a very long period in which the only thera
peutic approach to colorectal cancer was the opti
mization of fluoropyrimidine-based therapy, new
therapeutic possibilities make the next decade in
gastrointestinal oncology an exciting arena. It is
obvious that the introduction of oxaliplatin in the
51
treatment of colorectal cancer has changed the
natural history of the disease, not only because the
addition of oxaliplatin to the traditional 5-FU/FA
regimen has increased response rates consistently
to the 35% to 55% range, with longer time to
progression and survival than previously reported,
but also because patients who ceased to respond
to traditional fluoropyrimidine-based therapy show
renewed response when oxaliplatin is added. At
present, first-line treatment of advanced disease is
an indication that has recently been accepted by
French regulatory authorities. It is expected that
the last completed phase III study will confirm the
excellent activity noted in previous phase 11 and
phase 111 trials. The adjuvant setting is the obvious
next step to consider, since beneficial effects can
be expected in a clinical setting in which there is
less tumor burden. Consequently, studies in both
Dukes’ stage C patients and very high-risk patients
(==4 nodes, perforation, focal peritoneal seeding)
are being planned and initiated in 1998.
The experience with postchemotherapy resec
tion of previously unresectable hepatic metastases
has been particularly rewarding. Because of this
development in patients with metastatic colorectal
cancer, the attitude of the physician has changed
concerning cases previously deemed untreatable,
and patients with hepatic metastases can look for
ward to prolonged survival and a decreased inci
dence of relapse after hepatic resection. It is evi
dent that familiarity with the combination
regimen and the availability of experienced and
motivated surgical teams working closely with the
medical oncologists are the main determinants of
the growth of such a therapeutic strategy. In this
respect, a major change in therapeutic strategy,
taking into account the possibility of eventual re
section before starting chemotherapy, is already
being considered for patients in many French and
other European centers. Aggressive therapy with
new combinations presently under development
may also provide the means to treat patients with
extrahepatic metastases.
That such initiatives are welcome and need to
be encouraged is clear Clinical trials may allow us
to define the most beneficial modalities for the
greatest proportion of patients. Of importance in
this regard is the exciting and rapidly evolving
growth of clinicobiochemical studies correlating
insights gained from molecular biology with prog
nostic and natural history parameters, some of
52
DUCREUX ET AL
Table 3. Potential Anticancer Agent Combinations for Future Colorectal Cancer Therapy
Indication
Phase
Drugs
Ongoing studies
Colon cancer, pretreated
III
LV5-FU2 alone or with oxaliplatin 85 mg/m2
Colon cancer, pretreated
II
Oxaliplatin 85 mg/m2 + CPT-I 1 200 mg/m2 every 3 wk v oxaliplatin 85 mg/m2
Gl malignancies, pretreated
II
Oxaliplatin/CPT-11 every 2 wk
Gl tumors
I
Oxaliplatin/raltitrexed
Planned studies
III
- CPT-I 1 200 mg/m2 every 3 wk alternated with CPT-I I/LV5-FU2
Colon cancer, adjuvant
Oxaliplatin-5-FU/FA v 5-FU/FA
Colon cancer, pretreated
III
Oxaliplatm-5-FU/FA chronomodulated v oxaliplatin-5-FU/FA (LV5-FU2)
Colon cancer, untreated
II
Oxaliplatin/CPT-11 every 2 wk
Gastric cancer, untreated
II
Oxaliplatm-5-FU/FA (LV5-FU2) every 3 wk
Abbreviations: LV5-FU2, leucovonn 200 mg/m2/d, 2-hr infusion, then 5-FU bolus 400 mg/m2/d and 5-FU 600 mg/m2/d. continuous intravenous
(CIV) 22-hr. all repeated for 2 consecutive days, Gl, gastrointestinal.
Adapted and reprinted with kind permission from Kluwer Academic Publishers.3’
which are treatment dependent (for example,
thymidylate synthase). Mismatch repair deficiency
has not been studied as a treatment-dependent
prognostic parameter in colorectal cancer, but
studies are planned.
Tactical issues are of more immediate concern
vis-a-vis the positioning of oxaliplatin, CPT-11,
and the combination of these with 5-FU/FA. Many
such studies are being planned or are ongoing. The
triple combination of the simultaneous administra
tion of a thymidylate synthase inhibitor (5-FU/FA
or raltitrexed), oxaliplatin, and CPT-11 is in an
early exploratory phase. The administration of all
three drugs is being studied in a variety of large
multicenter trials, some of which are randomized
phase II or III studies, comparing different combi
nations and sequences of administration (Table 3).
The exciting and innovative trials that are al
ready accruing patients or are close to startup are
only a small indication of the renewed interest in
the clinical research focused on colorectal cancer.
The past decade has seen trends for clinical studies
that seek to establish the benefit to risk ratio of
various treatments, with a baseline judgment that
not much improvement in time-related therapeu
tic outcome was to be expected. The results re
ported with oxaliplatin have changed this attitude
and, it is hoped, will also change therapeutic out
comes.
REFERENCES
1. Bleiberg H: Role of chemotherapy for advanced colorectal
cancer: New opportunities. Semin Oncol 23:42-50, 1996
2. de Gramont A, Vignoud J, Tournigand C, et al: Oxali
platin with high-dose leucovorin and 5-fluorouracil 48-hour
continuous infusion in pretreated metastatic colorectal cancer.
Eur J Cancer 33:214-219, 1997
3 Schmoll H-J: Development of treatment for advanced
colorectal cancer: Infusional 5-FU and the role of new agents
Eur J Cancer 32A.S18-S22, 1996 (suppl 5)
4 Kemeny N: Current approaches to metastatic colorect.il
cancer. Semin Oncol 21:67-75, 1994 (suppl 7)
5. Piedbois P, Buyse M, Rustum Y, et al: Meta-analysis of 5FU and leucovorin in patients with advanced colorectal cancer
Ann Oncol 3:205, 1992 (abstr) (suppl 5)
6. Advanced Colorectal Cancer Meta-Analysis Project.
Modulation of fluorouracil by leucovorin in patients with ad
vanced colorectal cancer: Evidence in terms of response rate
J Clin Oncol 10:896-903, 1992
7. The Meta-analysis Group In Cancer: Efficacy of intrave
nous continuous infusion of fluorouracil compared with bolus
administration in advanced colorectal cancer. J Clin Oncol
16:301-308, 1998
8. Gottlieb TM, Oren M: p53 in growth control and neopla
sia. Biochim Biophys Acta 1287.77-102, 1996
9. Velculescu VE, El-Deiry WS: Biological and clinical im
portance of the p53 tumor suppressor gene. Clin Chem 42:858868, 1996
10. Lynch HT, Smyrk T, Lynch JF: Overview of natural
*,
history
pathology, molecular genetics and management of
HNPCC (Lynch syndrome). Int J Cancer 69:38-43, 1996
11. Marra G, Boland. CR: Hereditary nonpolyposis colo
rectal cancer. The syndrome, the genes, and historical perspec
tives. J Natl Cancer Inst 87:1114-1125, 1995
12. Johnston PG, Lenz HJ, Leichman CG, et al- Thymidy
late svnrha.se gene and protein expression correlate and arc
associated with response to 5-fluorouracil in human colorectal
and gastric tumors. Cancer Res 55:1407-1412, 1995
1 3. Loftier TM, Freund W. Koch M. et al: Low-dose weekly
24-hour infusion gemcitabine (G) in metastatic and relapsed
solid tumors. Proc Am Six: Clin Oncol 16:243a, 1997 (abstr
856)
OXALIPLATIN: FUTURE DIRECTIONS
14. Conn J A, Kemeny NE, Saltz LB, et al: Irinotecan is an
active agent in untreated patients with metastatic colorectal
cancer. J Clin Oncol 14:709-715, 1996
15. Findlay M, Van Cutsem E, Kocha W, et al: A random
ised phase II study of Xeloda® (capecitabine) in patients with
advanced colorectal cancer. Proc Am Soc Clin Oncol 16:227a,
1997 (abstr 798)
16. Harper P: Advanced colorectal cancer (ACC): Results
from the latest raltitrexed Tomudex® (raltitrexed) comparative
study. Proc Am Soc Clin Oncol 16:228a, 1997 (abstr 802)
17. Pazdur R, Vincent M: Raltitrexed (Tomudex®) versus
5-fluorouracil and leucovorin (5-FU ■+■ LV) in patients with
advanced colorectal cancer (ACC): Results of a randomized,
multicenter, North American trial Proc Am Soc Clin Oncol
16:228a, 1997 (abstr 801)
18. Rougier P, Bugat R, Douillard JY, et al: Phase II study
of irinotecan in the treatment of advanced colorectal cancer
in chemotherapy-naive patients and patients pretreated with
fluorouracil-based chemotherapy. J Clin Oncol 15:251-260,
1997
19. Sadahiro S, Mukai M, Tokunaga N, et al: Preliminary
study on the new optimal dosage schedule for oral UFT. Proc
Am Soc Clin Oncol 16:207a, 1997 (abstr 726)
20. Von Hoff DD, Rothenberg ML, Pitot HC, et al: Irino
tecan (CPT-11) therapy for patients with previously treated
metastatic colorectal cancer (CRC): Overall results of FDAreviewed pivotal US clinical trials. Proc Am Soc Clin Oncol
16:228a, 1997 (abstr 803)
21. Bcrtheault-Cvitkovic F, Jami A, Ithzaki M, et al: Bi
weekly intensified ambulatory chronomodulated chemotherapy
with oxaliplatin, fluorouracil, and leucovorin in patients with
metastatic colorectal cancer. J Clin Oncol 14:2950-2958, 1996
22. Levi F, Zidani R, Misset J-L: For the International Orga
nization for Cancer Chronotherapy: Randomised multicentre
trial of chronotherapy with oxaliplatin, fluorouracil, and folinic
acid in metastatic colorectal cancer. Lancet 350:681-686, 1997
23. Bismuth H, Adam R, Levi F, et al: Resection of nonresectable liver metastases from colorectal cancer after neoadju
vant chemotherapy. Ann Surg 224:509-522, 1996
24. Brienza S, Vignoud J, Itzhaki M, et al: Oxaliplatin (LOHP): Global safety in 682 patients (pts). Proc Am Soc Clin
Oncol 14:A513, 1995 (abstr)
25. Rothenberg ML, Eckardt JR, Kuhn JG, et al: Phase II
trial of irinotecan in patients with progressive or rapidly recur
rent colorectal cancer. J Clin Oncol 14:1128-1135, 1996
26. Pitot HC, Wender DB, O’Connell MJ, et al: Phase II
trial of irinotecan in patients with metastatic colorectal carci
noma. J Clin Oncol 15:2910-2919, 1997
S3
27 Caussanel J-P, Levi F, Brienza S, et al: Phase I trial of
5-day continuous venous infusion of oxaliplatin at circadian
rhythm-modulated rate compared with constant rate. J Natl
Cancer Inst 82:1046-1050, 1990
28. Sobrero AF, Aschele C, Guglielmi AP, et al: Synergism
and lack of cross-resistance between short-term and continuous
exposure to fluorouracil in human colon adenocarcinoma cells.
J Natl Cancer Inst 85:1937-1944, 1993
29. Lokich JJ, Ahlgren JD, Cantrell J, et al: A prospective
randomized comparison of protracted infusional 5-fluorouracil
with or without weekly bolus cisplatin in metastatic colorectal
carcinoma: A Mid-Atlantic Oncology Program Study. Cancer
67:14-19, 1991
30. Goldberg RM, Hatfield AK, Kahn M, et al: Prospectively
randomized North Central Cancer Treatment Group trial of
intensive-course fluorouracil combined with the Lisomer of in
travenous leucovorin, oral leucovorin, or intravenous leuco
vorin for the treatment of advanced colorectal cancer. J Clin
Oncol 15:3320-3329, 1997
31. Graf W, Pahlman L, Bergstrom R, et al: The relationship
between an objective response to chemotherapy and survival
in advanced colorectal cancer. Br J Cancer 70:559-563, 1994
32. L6vi F, Dogliotti L, Perpoint B, et al: A multicenter
phase II trial of intensified chronotherapy with oxaliplatin (LOHP), 5-fluorouracil (5-FU) and folinic acid (FA) in patients
(pts) with previously untreated metastatic colorectal cancer
(MCC). Proc Am Soc Clin Oncol 16:266a, 1997 (abstr 945)
33. Zeghari-Squalli N, Misset JL, Cvitkovic E, et al: Mecha
nism of the in vitro synergism between SN38 and oxaliplatin.
Proc Am Assoc Cancer Res 38:A20, 1997 (abstr)
34. Cvitkovic E, Wasserman E, Goldwasser F, et al: Prelimi
nary report on an oxaliplatin (LOHP)/CPT-11 phase I trial
in gastrointestinal (GI) malignancies- An active combination.
Proc Am Soc Clin Oncol 16:229a, 1997 (abstr 806)
35. Goldwasser F, Chouaki N, Buthaud X, et al: CPT-11/
oxaliplatin (L-OHP) every two weeks: A phase I study in pa
tients (pts) with advanced digestive tumors. Proc Am Soc Clin
Oncol 17-.927A, 1998 (abstr)
36. Faivre S, Raymond E, Cvitkovic E, et al: Gemcitabine
(dFdC) and oxaliplatin (L-OHP) combinations: Supraadditive
effect in human colon cancer cells. Proc Am Assoc Cancer
Res 39:A3186, 1998 (abstr)
37. Kawabata K, Nio Y, Imamura M: 5-Fluorouracil + cis
platin + mitomycin C is a relatively most effective combination
against xenograft lines of human colorectal cancer. Anticancer
Drugs 8:790-796, 1997
38. Raymond E, Taamma A, Cvitkovic E, et al: Preclinical
and clinical studies of oxaliplatin. Ann Oncol (tn press)
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U.S.A.
New Treatment Strategies for Malignant Gliomas
Nicholas G. Avgeropoulos, Tracy T. Batchelor
Brain Tumor Center, Massachusetts General Hospital. Boston, Massachusetts, USA
Key Words, Glianm • Chemotherapy - Gene therapy • Angiogenesis Clinical Inals Antisense ■ Cytokine ■ Immunotherapy
Abstract
Although survival in patients with malignant gliomas
angiogenesis inhibitors, arc also being evaluated in clinical
remains limited, there is renewed optimism with the emer
trials. Delivery strategies have been developed to overcome
gence of novel treatment strategics. Cytotoxic agents such
challenges presented by the blood-brain barrier. These
as temozolomide and CPT-11 have shown promising
noteworthy treatments, alone or in combination, may ulti
clinical activity. Biological treatments for brain tumors,
mately prolong survival and enhance quality of life in this
including antisense oligonucleotides, gene therapy, and
group of patients. The Oncologist 1999;4:209-224
Introduction
While primary malignant brain tumors account for only 2%
of all adult cancers, these neoplasms cause a disproportionate
burden of cancer-related disability and death. The five-year sur
vival rates for brain tumors arc the third lowest among all types
of cancer (pancreas and lung arc first and second, respectively).
Malignant gliomas (glioblastoma multi forme [GBM] and
anaplastic astrocytoma [AA]) comprise the most common
types of primary central nervous system (CNS) tumors and
have a combined incidence of 5-8/100,000 population. The
median survival of patients with malignant gliomas treated con
servatively is 14 weeks; by surgical resection alone, 20 weeks;
by surgery and radiation, 36 weeks; and by the addition of
chemotherapy, 40-50 weeks [1-4], Although survival for GBM
has not changed significantly over the past three decades, the
emergence of novel treatment strategics for these tumors has
led to heightened interest and optimism among oncologists.
The decision to proceed with larger, more expensive and
time-consuming randomized studies should be based on
carefully designed and conducted phase 1 trials to define the
maximum tolerated dose and toxicity, and on phase II trials
to define efficacy. Because enzyme-inducing (CYP450)
antiepileptic drugs (AED) enhance the metabolism and inac
tivation of certain chemotherapies, phase I trials of new
agents that undergo hepatic metabolism should be conducted
in patients with brain tumors stratified into those on CYP450
inducers and those not on such agents with independent dose
escalations in each arm [7, 8], This will avoid the possibility
of underdosing patients Despite careful phase II study
design and execution, the possibility of selection bias
remains, especially if the outcome is progression-free or
overall survival Objective responses on ncuroimaging are
more likely to indicate activity of a drug, whereas progres
sion-free survival and overall survival may simply reflect
patient selection.
To address these challenges, one major brain tumor col
laborative group has adopted a paradigm that includes a
Clinical Trial Design
'flic history of clinical trials for brain tumors is replete
with examples of poor study design and ambiguous results
(Table 1) [5,6]. One of the challenges for testing new agents
in this disease is the fact that brain tumors arc uncommon,
one-tenth as frequent as breast or lung cancer. Therefore, an
unlimited number of large, prospective, randomized, con
trolled studies is not possible. As a result, there is reliance on
nonrandomized studies as the principal design for the identi
fication of potentially active therapies that should be studied
in more definitive, randomized trials
Tabic 1. Histoneal limitations of brain tumor clinical trials
Divergent study entry criteria
Inadequate statistical power
Use of different outcome measures (tumor response, tumor control, clinical
parameters)
A inadequate control for known prognostic factors (age, Kamofsky Performance
Score, histology)
A Inadequate control for co-interventions (steroids, treatment at recurrence)
A
A
A
Correspondence: Tracy T. Batchelor. M.D.. M.P.H., Massachusetts General Hospital. Brain Tumor Center. Cox 03-15. 100
Blossom Street. Boston. Massachusetts 02114. US?L Telephone- 617-724-8770; Fax: 617-724-8769; e-mail:
lnitchclor@helix.mgh.harvard.edu Accepted for publication March 19. 1999. ©AlphaMed Press 1083-7159/99/S5.00/0
The Oncologist 1999,4:209-224
Avgeropoulos, Batchelor
2 10
Tabic 2. Response criteria for phase II studies of supratentorial malignant glioma
Response
Enhancing tumor area
Neurological status
Steroids
Complete response
2 95% decrease
Improved or stable
Off
Partial response
50%-94% decrease
Improved or stable
Stable or decreased dose
Progressive disease
> 25% increase
Worsened
Stable or increased dose
Stable disease
/Ml other situations
All other situations
All other situations
combined phase l/ll design with dose escalation in two
independent amis (CYP450 inducers and non-CYP450
inducers); chemotherapy prior to radiation and primary out
come defined as objective radiographic responses. All
patients must have residual, enhancing tumor on postopera
tive ncuroimaging. The radiographic responses are defined
along the lines of other oncology trials as outlined in Table 2
[9], This study design optimizes conditions for defining
which agents arc active or inactive for newly diagnosed
malignant gliomas.
New agents that arc cytostatic represent another challenge
in the design of clinical trials. Since the predominant effect of
these agents is stabilization of tumor size, radiographic response
rates are a suboptimal outcome measure. Specifically, direct
visualization by computerized tomography (CT) or magnetic
resonance imaging (MR1) may be insensitive to capillary num
ber, density, blood flow, and tumor metabolic activity. Despite
the limitations of progression-free and overall survival in the
context of phase II studies, these endpoints currently serve as the
primary outcome measures in the assessment of most cytostatic
agents There is a need to identify biological correlates of
activity in these types of studies. Data collected from surrogate
studies such as positron emission tomography (PET) scanning.
MR spectroscopy, and biopsy with attention to blood vessel
morphology and number may be relevant in these regards.
Important issues for phase III trials include stratified ran
domization for the known prognostic factors (Kamofsky
Performance Score [KPS], age, histology) to minimize the
chance of unbalanced distribution of these factors in the differ
ent arms of the study [10], Centralized neuropathology review
and use of pathologic criteria known to have a high inter-rater
correlation (WHO criteria = 94% correlation) are also impor
tant [11. 12], High inter-rater reliability ensures accurate case
identification and minimizes misclassification bias.
Analysis of phase HI outcomes should begin with exam
ination of predefined primary and secondary outcome mea
sures between the different treatment groups. Further
analysis may include multivariate modeling to identify sub
groups responsive to therapy. Such subgroup analyses should
not serve as the basis for definitive treatment recommenda
tions, but instead should be seen as hypothesis-generating for
future studies.
Finally, oncology study outcomes (including brain tumor
trials) have traditionally consisted of survival and time to pro
gression of disease. However, patient-derived data based on
quality of life (QOL) surveys arc becoming more common
and desirable. Combination of QOL data with survival data
(Q-TWiST analyses [nmc without symptoms or toxicity)) will
be an important means of comparing treatments, especially if
survival times are similar [13]. Several QOL measures have
been validated in malignant glioma patients (FACT-BR
[Functional Assessment of Cancer Therapy-Brain sub
scale] and the EORTC QLQ-C30 [European Organisation
for Research and Treatment in Cancer Quality of Life Ques
tionnaire]) and could be incorporated into a phase 111 study as
an outcome [14,15]. KPS is not a sufficient measure and docs
not correlate with QOL measures [14. 16]
Attention to the basic principles of clinical trial design
will optimize conditions for identifying active agents in phase
II studies and allow such drags to undergo more definitive
testing in randomized controlled trials.
Cytotoxic Agents
Methylating Agents
Temozolomide
Temozolomide is an imidazotctrazinone with activity attributed to the
formation of a reactive methyldiazo
nium cation and methylation of 06guanine in DNA (Fig. 1). Clinical
responses to temozolomide are closely
linked to the activity of 06-alkylguaninc-DNA alkyltransferasc (AGT), a
DNA repair protein that removes 06alkylguanine adducts in DNA [17],
Features of temozolomide that are
attractive for use in tumors of the CNS
include excellent oral bioavailability
Figure I. Temozolomide.
and good penetration of the blood-brain
barrier (BBB) [18].
The activity of temozolomide is highly dependent on
dosing schedule, with multiple administrations being more
New Treatment Strategies for Malignant Gliomas
211
Table 3. Summary of clinical trials of temozolomide for malignant gliomas
Remarks
“Dramatic clinical improvement” reported.
/Author
Path
Study
# Patients
Dose
CR(%)
PR(%)
Newland? [19]
GBM AA
Ph-1 Rcc
3
200 i.v.;
5/28 d 4-
0(0)
2(67)
Brock [20]
GBM AA
Ph-1 Rcc
17
75 p.o;
7 wks X
0(0)
7(41)
An additional 6/17 maintained stable disease.
Regimen permitted >2 fold drug exposurc/cydc
over standard dose.
Newlands [21]
GBM AA
Ph-1/11: N
Ph-l/n: Rcc
27
48
200 p.o.;
5/28 d 4
0(0)
0(0)
8(30)
12(25)
Survival advantage not demonstrated.
Seven patients not assessable by ncuroimaging.
Bower [22]
GBM AA
Ph-II: N(5)
Rcc(98)
103
200 p.o.;
5/28 d +
0(0)
5(9)
Only 57 of these patients evaluated with
MR,CT of brain. 87° a maintained stable disease.
Levin [23]
AA
Ph-II: Rec
161
200 p.o.;
5/28 d +
-(-)
42 (42)
Ardvsis of first 100 patients only. No breakdo. f CR versus PR. 24% of patients
maintained stable disease.
Friedman [24]
GBM AA
Ph-II: N
33
200 p.o.;
5/28 d +
3(9)
14(43)
No survival data. AGT protein expression may
identify patients m whom tumors are resistant
to temozolomide.
CR = complete response; PR = partial response; N = neoadjuvant (prior to radiation); Rec - recurrent. GBM = glioblastoma multiforme. AA = anaplastic astrocytoma;
i.v. = intravenously, p.o. - orally; d-days; wks = weeks:+150-200 mg/nd daily on days 1-5 each 28-day cycle; *75 mguf daily for seven weeks; AGT = 06-alkylguanme-DNA
alkyltransferase
effective than a single dose. It is administered orally at 200
mg/m: daily for five days on a four-wcck cycle. Peak plasma
concentration is achieved within 30-60 min of oral adminis
tration and the compound has an elimination half-life of one
to two hours. Elimination is largely via renal excretion as
intact drug and a carboxylic acid metabolite that has equiva
lent cytotoxicity. Myclosupprcssion, which is dose limiting at
1,200 mg/m:, and nausea and vomiting arc the most frequent
adverse events [18].
Clinical trials of temozolomide in malignant gliomas
arc summarized in Table 3 [19-24], Phase II trials have
reported partial responses (PR) in 9%-43% of cases. This
activity has been especially promising for AA. New direc
tions for the use of this drug will likely focus on optimizing
dosage and delivery to the CNS For example, temozolo
mide is compatible with chronic administration as patients
have tolerated this drug for up to three years [18],
Additionally, combination with the “pseudosubstratc” 06BG (O6-benzylguanine) is a promising approach since 06BG irreversibly inactivates AGT and potentially increases
the efficacy of temozolomide treatment [17],
Topoisomerase I Inhibitors
The camptothccin analogs CPT-I I, topotccan, and 9aminocamptothecin (9-AC) exert their cytotoxic effects by
inhibiting topoisomerase I. Normally, topoisomerase I tyro
sine undergoes a reversible trans-cstcnfication reaction
with the 3' end of the DNA strand. This cleaves the strand
long enough to allow passage of a newly synthesized strand
through the cut, after which time topoisomerase 1 normally
rcseals the cleavage. The cytotoxic effect of camptothecins
is exerted during replication by their ability to bind and sta
bilize this DNA-topoisomcrasc I complex. An irreversible
double-stranded DNA break occurs at the time of collision
of the replication fork and cleaved DNA strand (Fig. 2)
However, the correlation of cellular topoisomerase 1 levels
to drug sensitivity has been difficult to establish [25],
Topoisomerase I inhibitors studied as potential treatments
of gliomas include CPT-11, topotecan. and 9-AC. The in vitro
activity of these camptothecins in human colon carcinoma
HT-29 cells has been compared with the following cytotoxic
potency established: SN-38 (metabolite of CPT-I 1) > camp
tothccin > 9-AC > topotccan > CPT-I I [26]. In GB-1 and U87MG glioma cell lines, SN-38 induced apoptosis and
demonstrated significantly stronger antitumor effects than
did CPT-11 [27],
CPT-II
CPT-11 undergoes hydrolysis or dc-esterification to
form the active metabolite SN-38. which is approximately
100-1,000 times as potent as CPT-II as an inhibitor of
topoisomerase I (Fig. 3) [25, 27] Because SN-38 is 95%
bound to plasma proteins compared to only 65% for CPT11, the precise contribution of SN-38 to the activity of
CPT-I I is unclear. SN-38 can be further metabolized to the
inactive SN-38 glucuronide (SN-38G) by hepatic UDP-glucuronyltransfcrase (UDP-GT) [28], In an animal model,
pretreatment with the AED valproic acid resulted in a 99%
inhibition of the formation of SN-3SG, leading to a 270%
increase in the area under the plasma concentration-time
A vgcropoulos, Batchelor
212
Figure 3. A) CPT-ll. B) SN-38.
Figure 2. Topoisomerase I. A) The mechanism of topoisomerase I
action. (1) Increasing tension and supercoiling of DNA. (2)
Topoisomerase I hinds to one DNA strand and cuts it (cleavage reac
tion). (3) The intact strand of DNA passes through the neck, result
ing in the relaxation of the torsional strain. (4) Topoisomerase I
reseals the broken strand (religation step) and dissociates from the
DNA molecule. B) Collision of the replication fork with the camptothecin-stabilized cleavable complex results in an irreversible dou
ble-strand break in the DNA. Top I = topoisomerase J; C =
camptothecin; solid lines = parent DNA; dotted lines = daughter
DNA. Used with permission from (25).
curve of SN-38 compared with controls [29], This observa
tion has led to the exclusion of patients requiring valproic
acid from most clinical trials of CPT-11.
The initial and terminal half-lives of CPT-11 arc approxi
mately 6 h and 10-14 h, respeeth .'v. Elimination occurs pri
marily in the bile and secondarily in the urine. The main
toxicitics observed with CPT-11 are an acute cholinergic syn
drome. delayed onset diarrhea, neutropenia, nausea, vomiting,
fatigue, and alopecia. The usual dosing schedule is 125
mg/m'/wcck for four weeks followed by a two-weck rest [25].
Hare investigated more than 40 drugs in a CNS
xenograft model using multiple adult and pediatric glioma
cell lines and found CPT-ll to be the most active agent
tested [30]. An initial clinical trial of CPT-11 in 60 patients
with recurrent malignant glioma resulted in 10/49 (20%)
PR in GBM patients and 1/8 (12.5%) PR in AA patients
[31]. Ten patients with GBM and three with A A demon
strated stable disease beyond two cycles. Single agent CPT11 for recurrent malignant gliomas is now the subject of
three phase 11 NCI-sponsored trials.
Topotecan
Topotecan is a topoisomerase I inhibitor that under
goes a reversible pH-depcndent hydrolysis of its lactone
ring to produce the pharmacologically active form of the
drug (Fig. 4). it is then rapidly converted to its inactive car
boxylate form at physiologic pH [32, 33]. Topotecan has a
New Treatment Strategies for Malignant Gliomas
213
tumors as oligodendrogliomas, brain metastases, and primary
CNS lymphoma.
9-A min •icamptothccin (9-A C)
Hochberg conducted a phase I/II dose escalation study
of 9-AC in 59 patients, 31 with newly diagnosed GBM and
28 with recurrent high-grade astrocytomas [8]. Although
ineffective, the authors noted no grade III or IV myelosuppression in patients receiving concurrent "cytochrome P450
system inducing” AEDs. Although the trial was terminated.
plasma levels of the drug may have been insufficient to
achieve cytotoxic activity.
Alkylating Agents
Oxaliplatin
Figure 4. Topotccan.
half-life of two to four h following doses of 0.5 to 1.5
mg/m2 administered as a 30-min infusion, and approxi
mately 35% of the drug is protein bound [34]. The antitu
mor effect of topotccan appears to be greater when the drug
is administered over a prolonged period of time compared
with an intermittent schedule of drug administration [35].
The drug penetrates the BBB with a cerebrospinal fluid
(CSF) to serum ratio of 0.3 [36]. The main toxicitics of
topotccan arc leukopenia and thrombocytopenia; diarrhea
and vomiting arc less than with CPT-11. Elimination is pri
marily renal and patients with creatinine clearances less
than 50 ml per min should not be treated with this drug [25].
The results of clinical trials using topotccan in patients
with malignant brain tumors arc in Table 4 [37-40]. In these
studies, myclosupprcssion was a significant complication and
topotccan was found to have minimal activity in this setting.
Because of excellent BBB penetration and the novel mecha
nism of action, other studies of topotccan in brain tumors arc
under way, including trials for such potentially chcmoscnsitivc
Cisplatin and carboplatin have been used both i.v. and
intra-arterially as first-line chemotherapy for malignant
glioma with survival rates similar to BCNU [41. 42],
However, significant myclosupprcssion (carboplatin) and
nephrotoxicity (cisplatin) have limited the usefulness of
these drugs Oxaliplatin ([trans-(L)-1.2-r/inminocyclo/rcxanc] oxalatoplatinum (II)) is a cytotoxic platinum com
plex that has shown activity against colorectal cancer in
combination and as a single agent in phase II and phase 111
clinical trials (Fig. 5) [43,44]. Oxaliplatin’s dach ring com
plex results in the formation of platinum-DNA adducts.
which are more effective at
blocking DNA replication
than those formed by cis
platin. Because ototoxicity,
nephrotoxicity, cardiac toxi
city, and alopecia have not
been observed in adults
treated with oxaliplatin
alone, this agent is an Figure 5. Oxaliplatin.
Table 4. Summary of clinical trials using topotccan in malignant gliomas
Author
Path
Study
# Patients
Dose
CR(%)
PR(%)
Remarks
Macdonald [37)
GBM (15)
AA (16)
Ph-II Rec
31
1.5 i.v.;
5/21 d 4-
0(0)
2(6)
68% maintained stable disease.
Blaney [38]
GBM
Ph II Rec
9
7.5 i.v.;
1/21 d *
0(0)
0(0)
Two patients maintained stable disease for 12
weeks and one for 16 weeks.
Eisenhauer [39]
GBM AA
Ph-II Rec
12
1.5 i.v.;
5/21 d +
1(8)
1(8)
—
Kyritsis [40]
GBM AA
Ph-II Rec
29
0.4 i.v.;
28 d cy A
0(0)
3(12)
15% of patients with stable disease.
CR = complete response; PR = partial response; Rec - recurrent; GBM = glioblastoma multiforme, AA = anaplastic astrocytoma; i.v. = intravenously, d = days; t 1.5 mg nr
daily on days 1-5 each 21-day cycle; 5 5-7.5 mg/m2 as a single 24-h continuous infusion on day I of each 21-day cycle; ± Continuous i v infusion every 28 days with a
starting dose of 0.4 mg/mVday.
Avgcropoulos. Batchelor
attractive candidate for use in brain tumors [45, 46], The
cumulative dose limiting toxicity in adults is sensory neu
ropathy (12%). In those patients who developed sensory
neuropathy of grade 2 or higher, symptoms regressed in
82% at four months and completely resolved in 41% at eight
months after the drug was discontinued [45],
Experience with oxaliplatin for treatment of malignant
gliomas is limited. Misset reported a PR in two of six
patients (33%) with GBM [47], Soulie reported a complete
response (CR) in one of nine patients (11%) with recurrent
GBM [48], Both of these series incompletely defined pre
treatment status and patient outcomes and used varying
dosages of oxaliplatin. A phase II trial of neoadjuvant oxali
platin at 130 ntg/m! every three weeks is planned for newly
diagnosed GBM.
Biological Agents
Protein Kinase C Inhibitors
Protein kinase C (PKC) is a phosphohpid-dependent,
cytoplasmic, serine threonine kinase responsible for signal
transduction in response Io various growth factors, hormones.
and neurotransmitters. Once activated, PKC phophorylatcs
proteins and triggers many cellular responses including mem
brane transport, gene expression, and cellular differentiation/proliferation [49J. PKC inhibition has been investigated
as a therapeutic strategy for malignant gliomas because of its
critical intermediary role in the malignant transformation,
proliferation, and invasiveness of glial cells [50, 51]. Two
methods of PKC inhibition that have been studied in clinical
trials for malignant gliomas arc i.v. treatment with antisense
oligonucleotides and oral tamoxifen.
214
molecule [54], ISIS 3521 is the subject of an ongoing phase
11 trial for treatment of recurrent malignant glioma
There are several potential limitations associated with the
systemic administration of antisense oligonucleotides. First,
the delivery of antisense compounds to tumor cells beyond an
intact BBB may be impeded due to the highly negative charge,
acid lability, and large molecular weight of S-oligos [55],
Second, this therapeutic compound accumulates in the liver,
kidneys, and throughout the reticuloendothelial system and rel
atively small amounts may be left to traverse the BBB and
enter the tumor. Continuous i v. infusion may be necessary to
achieve sufficient and sustained delivery of antisense oligonu
cleotides to the tumor [52], Effective treatment of tumor cells
exhibiting cell-cycle dependent susceptibility to an antisense
compound (depending on the molecular target) may require this
delivery method. Third, multiple genes are important in cell
proliferation, invasiveness, and survival. Targeting PKC alone
may not result in cytotoxicity or sustained tumor response.
Finally gene expression changes over time and blocking one
critical cell pathway may activate yet another. Some of these
limitations may be bypassed by direct tumoral infusion
Tamoxifen
Tamoxifen is an agent widely used for adjuvant treat
ment of breast carcinoma. When administered in sufficient
doses, tamoxifen yields an estrogen receptor-independent
antmeoplastic effect by inhibiting PKC [56]. Tamoxifen
also induces transforming growth factor beta I and inhibits
ouabain-sensitive Na-K ATPase, Mg-ATPase, calmodulin
dependent protein kinase, and certain calcium channels [57,
58]. The clinical relevance of these mechanisms has not
been fully defined.
Antisense Oligonucleotides
Oligonucleotides are short sequences of nucleotides
(usually at least 15 bases in length) designed to hybridize
with complementary messenger RNA (mRNA) and prevent
translation of the RNA message at the ribosome (Fig 6).
Unmodified oligonucleotides arc unstable in the circulation
primarily due to degradation by ubiquitous cellular nucle
ases. and have a half-life of about five min [52). Substituting
one of the oxygens in the phosphate groups with a sulfur
atom (phosphorothioate modification) makes these frag
ments (S-oligos) resistant to cleavage, increases the half-life
to approximately one hour, and allows for continuous i.v
infusion. Upon administration, S-oligos arc presumed to
enter cells by cndocytosis [53],
ISIS 3521 is a phosphorothioate oligonucleotide that
binds to the 3' untranslated region of PKC mRNA with high
affinity and inhibits the production of protein kinase C-ax.
a PKC isoenzyme, by promoting cleavage of the hybridized
Figure 6. Antisense RNA. Antisense oligonucleotides bind the target to the mes
senger RNA (mRNA) sense strand, thus blocking successful translation ofthe cor
responding protein. High-affinity binding (formation ofthe RNA duplex) results in
gene inactivation cither through steric blocking of the ribosome complex or by
triggering mRNA cleavage by RNase H. This diagram presumes that the target
gene is regulated by transcription from the sense RNA strand.
New Treatment Strategics for Malignant Gliomas
215
Table 5. Summary of clinical trials using tamoxifen m recurrent malignant gliomas
Study
Ph-I
II Patients
Dose
Med Survival
*
32
20 mgp.o. BID
GBM (6)
AA(5)
GBM (53)
Ph-1
II
Ph-1
26
18
9
160-200 mg
p.o. daily
40 mg p.o. daily
80 mgp.o. daily
160 mg p.o. daily
17 wks
KPS <60 8 wks
KPS >70 21 wks
24 wks
Brain stem
gliomas (5)
GBM (20)
AA (12)
GBM/AA
Anecdotal
5
Not reported
Ph-11
32
Ph-I
7
7
80(F)-100 (M)
mg p.o. BID
60 mg p.o. BID
100 mg p.o. BID
Author
Path
Fertosick [59]
GBM (29)
AA(3)
Couldwell [GQ]
Vertaside [61]
Freeman [62]
Couldwell [63]
Pollack [64]
12 wks
18 wks
Not reached at
time of publication
Not reported
GBM 29 wks
AA 64 wks
11 wks
Remarks
7/32 pts remained stable on tamoxifen for >6 mos
PR in three pts—these responders survived longer
than 12 mos with clinical improvement
Significant reduction in peritumoral edema.
PR in 4/5 pts. SD in one pt. Remissions of up to
26 mos.
PR in four AA and four GBM pls with SD in six as
measured by MRI and PET
SD in four pts for at least three months. Longest
survivor was 17 months.
•After initiation of therapy.
Pls = patients; Ph = phase: PR = partial response, SD = stable disease, GBM = glioblastoma mulliformc; AA = anaplastic astrocytoma, p o. = orally, mos. = months:
wks = weeks; M = male; F = female: KPS - Kamofsky Performance Status; PET = positron emission tomography.
Because of the sensitivity of glioma cell lines to
tamoxifen-induced PKC inhibition, this drug has been the
subject of several clinical trials (Tabic 5) [59-64] These
trials have enrolled patients with largely inoperable,
recurrent malignant gliomas Median survivals have
ranged from 11-64 weeks from the initiation of tamoxifen
therapy with partial radiographic responses varying
widely between series (0%-80%) [65].
There appears to be a consistent relationship between
higher tamoxifen doses, higher radiographic response rates,
and longer survival [61] This is exemplified by
Couldwell’s description of a 49-ycar-old male with recur
rent glioblastoma treated with tamoxifen 20 mg orally twice
a day [60], Six weeks later, progressive disease was docu
mented on brain MRI and the patient was then treated with
tamoxifen 100 mg orally twice a day This resulted in clin
ical improvement, a radiographic PR, and a greater than
ninc-month survival.
Micromolar concentrations of scrum tamoxifen can be
achieved within several days by “loading" with 1,000 mg
per day prior to the administration of the maintenance dose
[64] Tamoxifen has been shown to attain high concentra
tions in brain metastases and surrounding brain tissues in
patients with breast cancer [66]. Levels of tamoxifen within
the middle of the in vitro therapeutic range have also been
demonstrated in a tumor biopsy specimen from a patient
with malignant glioma treated with this drug [60].
PKC inhibition for the adjuvant treatment of malignant
gliomas is a strategy still under investigation. Another PKC
inhibitor under development is staurosporine. This drug is
more effective at halting the proliferation of glioma cell
lines at lower docs than tamoxifen [67], Clinical trials with
this agent have not yet been reported.
Cell Signal Transduction Inhibitors
Pcptidomimctic drugs developed to target critical interme
diaries in cell signal transduction pathways represent another
novel class of ai.tincoplastic drugs. The main focus has been
on inhibiting ras, a family of GTP-binding cytoplasmic pro
teins with a pivotal role in the development and progression of
many human cancers (Fig. 7). Permanent activation of the
ras-signaling pathway requires insertion of proteins into the
plasma membrane. This in turn requires attachment of a famesyl group (15 carbon lipid tail) to the protein, a reaction cat
alyzed by the enzyme, famesyl transferase. Inhibition of this
step by a famesyl transferase inhibitor (FT1) is a potentially
useful antincoplastic strategy [68, 69], In animal models,
tetrapeptide FTIs specific for ras have successfully interrupted
the transmission of signals from activated cell surface growth
factor receptors to downstream intracellular partners. FTIs arc
cytostatic and have demonstrated in vitro activity against a
number of human tumor cell lines
There is a sound rationale for the study of FTIs in malig
nant gliomas, as up to 70% of these tumor specimens overex
press ras oncoproteins [70] Moreover, ras-dependent receptors
(epidermal growth factor receptor, platelet-derived growth faclor/reccptor, and insulin growth factor'receptor-1) have been
implicated in brain tumorigcncsis [71] Finally, because FTIs
are cytostatic and known to have synergistic effects on tumor
cell lines when used in conjunction with siandard chemothera
peutic agents, the most effective clinical application of these
drugs may be as part of a multiple drug combination (72].
Avgcropoulos. Batchelor
216
Figure 7. Cell signal transduc
tion. Ros is illustrated attached
to the plasma membrane by a
famcsyl anchor. This protein
occupies a pivotal position in
cellular replication. However.
some ras-associated receptors
such as PDGFare known to act
via multiple pathways. The exis
tence of multiple parallel path
ways ofsignal transduction is a
theoretical limitation offarnesyl transferuse inhibitors as
antineoplastic therapy. Used
with permission from [68],
Immunotherapy
Cytokines
Interferons possess direct tumor cytotoxicity and a capac
ity for immune modulation. They may act indirectly to recruit
and activate leukocytes, augment expression of cell surface
molecules, and induce the production of other intermediate
cytokines. Studies have demonstrated that human interferon
alpha and beta inhibit tumor growth in rodent glioma models,
and a large number of phase I and II clinical trials investigat
ing these interferons have been reported os er the past decade
[73-76] Limitations of these studies have included selection
bias, inadequate sample size, and incompletely documented
progression-free survival and radiographic response rates.
Despite these shortcomings, other groups have reported
encouraging response rates and survival times [77-79],
Rajkumar reported results of a phase I study evaluating
radiation combined with recombinant interferon alpha-2A
and BCNU as initial therapy for patients with high-grade
glioma [SO], Five of nine patients evaluable for radiographic
response had a PR, with a median survival of the entire cohort
approaching four years. In a phase II study evaluating alpha
interferon and BCNU for patients with recurrent high-grade
glioma, Brandes reported on 21 patients who had not received
prior chemotherapy [81], A PR was obtained in 7/21. and 6/21
maintained stable disease, although overall median survival
was seven months. Both of these studies reported "substantial
but acceptable” constitutional symptoms.
Adoptive Immunotherapy
The cellular immune response in malignant glioma
patients is significantly depressed as demonstrated by
impaired blastogenic response of peripheral blood lympho
cytes and reduced interleukin 2 (IL-2) production and IL-2
receptor expression of mitogen-stimulated T cells.
Peripheral blood lymphocytes from glioma patients can be
activated in vitro by IL-2, and these lymphokinc-aclivated
killer cells (LAK cells) are capable of killing both autolo
gous and allogenic glioma cells [82],
Hayes treated 15 recurrent malignant glioma patients
with intracavitary LAK cells and IL-2 in six-wcck cycles
dtrough a modified Ommaya reservoir placed at the time of
rcopcration [83], Four radiographic responses (two CR and
two PR) and a median survival of 53 weeks after rcopcration
were reported. Eight of these patients survived more than one
year. These data should be interpreted cautiously as some
patients received surgery and/or chemotherapy subsequent to
LAK/IL-2 administration.
Plant: reported 10 patients with progressive primary or
recurrent malignant glioma who were treated with systemic
T cell adoptive immunotherapy [84]. These patients were vac
cinated with irradiated autologous tumor cells, and T cells
from draining inguinal lymph nodes were then harvested,
stimulated, and expanded. Following i.v. T cell transfer ther
apy, radiographic regression that lasted at least six months was
demonstrated in two patients with recurrent tumors, and one
patient demonstrated stable disease that lasted more than 17
months. Four of eight patients with recurrent tumor were alive
more than one year after surgery for recurrence.
The source, specificity, and number of T cells arc essen
tial determinants of efficacy. There are significant limitations
of this treatment strategy. First, diminished immune responses
arc generated against antigens introduced into the CNS.
Second, the BBB effectively impedes T cells from reaching
217
their target. Third, many gliomas release substances such as
tumor growth factor P and IL-10 that cause immunosuppres
sion. Finally, the brain might not tolerate the inflammation
associated with an immune reaction [84],
Gene Therapy
Gene therapy is an attractive strategy for the treatment of
brain tumors because of the lack of systemic toxicity and tlic
ease of application during stereotactic procedures or cran
iotomy. Direct introduction of genes without any cellular or
viral vector can be accomplished via aerosol, systemic deliv
ery, or microccllular injection Indirect gene delivery by trans
plantation of genetically engineered cells or inoculation of a
recombinant defective virus is more clinically relevant and
constitutes a highly efficient means of transferring DNA to a
target cell [85],
The most common experimental paradigm for genetic
treatment of brain tumors has been delivery of the herpes
simplex virus thymidine kinase (HSV-tk) gene to the tumor
using an adenovirus vector (Fig. 8). Adenoviruses arc highly
stable, nonenvelopcd, double-stranded DNA-containing
viruses with a low rate of genomic instability and, therefore,
low risk of insertional mutagenesis. Adenoviruses transfer
their DNA by binding to a specific cell surface receptor.
entering the cytoplasm by cndocytosis, and then forming a
pore in the endosome to translocate genetic material to the
nucleus [86]
In principle, the HSV-tk construct should only be deliv
ered to dividing cells (i.e., tumor cells and not neurons). The
thymidine kinase that is being produced by these cells can
phosphorylate nucleoside analogs such as ganciclovir to
form nucleotide-like precursors that will block replication of
DNA. Although the transduction process alone is not cyto
toxic, cellular production of thymidine kinase confers sus
ceptibility to those cells subsequently exposed to ganciclovir.
The so-called “bystander effect" is the result of diffusion of
phosphorylated nucleosides away from dying cells to adja
cent nontransduced tumor cells resulting in their death [86].
Ram treated 15 patients with recurrent malignant brain
tumors using intratumoral injection of murine cells modified
to produce retroviral vectors containing the HSV-tk con
struct [87], Nine of these 15 patients had GBM and were
treated to cither a single focus or multiple foci of disease.
Three of the nine patients exhibited cither a CR or PR. with
smaller lesions most likely to respond. Potential limitations
of this strategy include lack of transduction of distant tumor
cells, transduction of endothelial cells, and immunologic
rejection of the murine vector cells.
Izquierdo used retrovirus-mediated gene therapy to treat
five patients with anaplastic glioma and two of these patients
showed a PR [88], In a follow-up study the investigators
New Treatment Strategies for Malignant Gliomas
reported that they had been unable to reduce the tumor size
of recurrent glioblastoma patients with tumor volumes
larger than 100 cm' by applying the standard HSV-tk/ganciclovir therapy or to prolong patient survival for more than
eight months [89J. These observations underscore the need
for more effective delivery and distribution strategics
Ideally, gene therapy with a replication-competent ade
noviral vector should result in intracellular viral replication
and exclusive cytolysis of targeted cancer cells. In theory,
newly released virions from a lysed cell could then infect both
neighboring and distant cells but selectively replicate only in
cancer cells. ONYX-015 (dl 1520) is an adenovirus construct
designed to be differentially lethal to tumor cells with mutated
or deleted p53, a tumor suppressor gene important in the early
transformation of most gliomas [90].
Figure 8. Gene therapy. A) The shuttle vector containing the expression
cassette with the foreign gene of interest is cotransfected with the plasmid
containing the adenoviral genome. B) The vector containing the aden
ovirus genome is missing the packaging sequence and cannot produce
virus. The shuttle vector also cannot replicate and produce virus because it
is missing u large piece of the adenoviral genome. For virus production.
the shuttle vector containing the packaging sequence and the expression
cassette must recombine with the adenovirus genome. C) The recombinant
virus can replicate in human embryonic kidney 293 cells. Replicating virus
is easily identified by the lysis of cells in tissue culture. After growth and
plaque purification, large quantities of recombinant adenovirus can be
processed over a cesium chloride density gradient. D) After dialysis, repli
cation-defective adenovirus can be usedfor in vivo transfections. Used with
permission from [86].
21K
Avgcropoulos, Batchelor
A key feature of the ONYX construct is the genetic dele
tion of an adenoviral protein (El B 55K) that binds to the N-terminus ofp53 and blocks its activity. Since E1B 55K is deleted
in this construct, the cellularp53 system can respond to “thera
peutic” infection by promoting cell-cycle arrest in p53-positive
cells (a nonlcthal infection) or cytolysis in p53-ncgative cells
[91]. Initially encouraging cell line and animal study results
using ONYX-015 virus have been tempered, however, by
recent reports of wild-type p53 dependent cytolysis [92-95]
Fueyo has also demonstrated that overexpression of E2F-1, a
promoter of inappropriate cell entry into the S-phasc that is
upregulated by ONYX-015, triggers apoptosis and suppresses
tumor growth in vitro and in vivo independently of cellular p53
status [96]. These new data suggest that molecular mechanisms
concerning replication competent adenoviral vectors need to be
defined prior to use in a clinical setting.
Angiogenesis Inhibitors
Tumors promote the formation of new blood vessels
when they surpass 1-2 ml in greatest diameter (less than 10
*
cells) (Fig. 9) [97, 98], This is accomplished by altering the
physiologic balance between positive and negative regulators
of angiogenesis [99]. Tumor neovascularization occurs
through a number of mechanisms including overexpression
and i .obilization of angiogenic proteins from the extracel
lular matrix and recruitment of host cells such as macro
phages, which in tum produce their own angiogenic proteins
[100]. Key angiogenic proteins include vascular endothelial
growth factor (VEGF), basic fibroblast growth factor
A
(bFGF). platelet-derived growth factor (PDGF), and
tcnascin. Endogenous inhibitors of angiogenesis include
angiostatin, endostatin, and thrombospondin [101].
When the angiogenic process is triggered, a cascade of
events including activation of endothelial cells, proteolytic
degradation ofthe extracellular matrix and basement membrane,
proliferation and migration of endothelial cells, endothelial
tube formation, and fusionreassembly of the extracellular
matrix occur [102]. Vascular basement membrane degrada
tion allows endothelial cells to migrate into the surrounding
tissue and form vascular structures [103]. The basement
membrane consists of both fibrous and nonfibrous proteins
including heparan sulfate proteoglycans, which can bind and
enable growth factors such as bFGF and VEGF [104]. This
complex degradative process involves many enzymatic sys
tems that result in the release of stored growth factors and,
in tum, promote further angiogenesis. Matrix metallopro
teinases, serine proteases (plasminogen activators), and
cathepsins are among the enzyme classes implicated in this
process [105].
Most experience with antiangiogenesis treatments in
brain tumors has been with matrix metalloproteinase
inhibitors (MMPls). The MMPs arc a family of over a
dozen secreted and membrane-bound zinc endopepti
dases. They require activation by other proteolytic
enzymes in order to digest an extracellular matrix. MMPs
are upregulated in primary and metastatic brain tumors
and correlate with malignant progression [104. 106], One
of the MMPs. MMP-9, is thought to play a critical role in
Early tumor
growth
(o) Viable tumor cell
Qj Apoptotlc tumor cell
(•) TPS3 mutation
009 Urokinase receptor
VEGF receptor
)( avP3 Integrln
tiSh Tissue lactor
Figure 9. Tumor angiogenesis. A) Small tumor, less than 1 mm3 in diameter with high rate ofapoptosis, cannot growfurther without new
blood supply. B) Hypoxic environment and genetic instability allow evolution of tumor clones with loss of p53 function. These cells have
lower apoptotic rate, and produce angiogenicfactors, inducing new vasculature (angiogenic “switch ”). There is also reduction in antiangiogenic factors. C) Tumor vasculature is abnormal. Leaky vessels allow passage offibrinogen, and tissue factor is expressed on tumor
endothelium producingfibrin deposits. VEGF receptors and urokinase receptor integrins are upregulated. Endothelial cells are dividing.
D) These processes allow invasion and metastasis to distant sites. Used with permission from [101].
219
tumor cell invasion, and, irronc study, was detected in the
CSF of patients with brain tumors but not in control
patients [103}.
Marimastt'l is an orally available MMPI that blocks
the ability of tumor cells to disrupt the extracellular
matrix, prevents the ingrowth of new blood vessels, and
inhibits glial tumor growth and spread in animal cancer
models [107]. A multiccnter phase III trial ofMarimastat in
recurrent malignant gliomas has recently been completed.
Thalidomide is an antiangiogcnic agent that decreases
the expression of beta integrin subunits produced by leuko
cytes. Because these integrins arc crucial for cell-matrix
interactions, thalidomide is felt to inhibit cell migration
accounting for its antiangiogcnic (and teratogenic) activity
[108] Its clinical utility as a long-term treatment for malig
nant gliomas remains under investigation. Yung reported
findings from a phase II trial of the antiangiogcnic agent
thalidomide in patients with recurrent high-grade gliomas
[109]. Of the 32 evaluable patients, there were two PRs,
two minor responses, and a median time to progression of
eight weeks. The assessment of cytostatic antiangiogenesis
agents as potential treatments for malignant glioma poses
significant challenges in clinical trial design, as discussed
earlier in Clinical Trial Design.
Delivery Strategies
RMP-7
The BBB impedes passage of circulating compounds
that are hydrophilic, ionized, greater than 18 A in diameter,
or more than 180 Da in molecular weight [110], This
excludes many conventional chemotherapy drugs such as
cyclophosphamide and the anthracyclincs. As the integrity
of the BBB is partially compromised tn brain tumor-associ
ated blood vessels, it is controversial whether hydrophilic
drugs have difficulty traversing this physiologic barrier.
However, restoration of the BBB by coadministration of
corticosteroids may impede delivery of these agents [111].
Mannitol disruption of the BBB was described almost two
decades ago and continues to be a technically difficult
method used for the delivery of high-dose chemotherapy
[112], More recently, RMP-7, a bradykinin analogue, has
been developed to transiently increase BBB permeability
while avoiding some of the risks inherent with the mannitol
procedure.
RMP-7 stimulates endothelial B2 receptors, which
results in intracellular calcium influx, contraction of capil
lary endothelial cells, and loosening of tight junctions
[113]. In addition, RMP-7 increases vesicular transport and
transcellular penetration. These effects led to increased per
meability of the BBB in animal studies with lanthanum, a
New Treatment Strategies for Malignant Gliomas
139 molecular weight tracer substance [114], RMP-7 has a
longer plasma half-life than bradykinin although it exerts its
effects over a narrow time frame so that the timing of
chemotherapy administration in relation to RMP-7 is criti
cal [I15J. RMP-7 preferentially “opens” the BBB in the
tumor area [116], Despite this, vasogenic edema as an
adverse event rarely occurs unless serum proteins
extravasatc into the brain parenchyma. Transient decreases
in arterial blood pressure have been observed with highdose RMP-7 administration in a swine model, but the drug
appears to be well tolerated otherwise [113].
The infusion of intracarotid RMP-7 followed by carboplatin in a rat glioma model produced longer survival than in
those rats treated with carboplatin alone (115] The amount
of carboplatin used in this experiment was substantially less
than an equivalent i.v. dose in humans. RMP-7 also increased
permeability to carboplatin in dexamethasone-treated tumors
although to a lesser extent than rau> not exposed to steroids.
In an irradiated dog brain model, RMP-7 appeared to have a
selective effect on an impaired BBB, but did not appear to
affect the extent or volume of radiation-induced cerebral
edema [117],
Gregor reported preliminary data from two phase II tri
als investigating RMP-7 administered with i.v. carboplatin
in recurrent malignant glioma patients [118]. A statistically
significant survival hazard ratio of approximately 2 in favor
of the RMP-7/carboplatin-trcatcd patients was seen in the
87 patients enrolled. There was also an implication that
these patients had improved QOL.
Polymers
Since 90% of malignant gliomas recur within I -2 cm of
the original site, local therapy may be an effective strategy
[119], This observation has served as the basis of focal radi
ation treatments such as brachytherapy, proton beam ther
apy, and radiosurgery. Another method is the use of
polymers to deliver drugs via diffusion from micropores in
the polymer matrix or by the release of drug from within the
interstices of a degradable matrix.
One BOND polymer design is a 1.45-cm diameter
wafer disk that consists of a biodegradable polymer com
ponent (poly bis(p-carboxyphenoxy) propane and sebacic
acid or PCPP-SA) uniformly impregnated with 7.7 mg of
BCNU (1,3-bis (2-chlorocthyl)-1-nitrosourea) The usual
dose is eight wafers, which are to be placed in the margins
of the surgical resection cavity. BCNU is released from the
wafer over two to three weeks and subsequently diffuses
into surrounding brain tissue to produce an antineoplastic
effect by alkylating DNA and RNA [120],
Although comparable human data are lacking, recent
work by Fung with intraparcnchymal BCNU impregnated
Avgcropoulos, Batchelor
polyanhydridc pellets in cynomolgus monkeys revealed high
drug levels (0.5-3.5 mM) within 3 mm of the implant over a
period of approximately one month [121], Pharmacokinetic
studies demonstrated that BCNU area under the concentra
tion time curve (AUC) was 4-1,200 times higher than the
AUC achieved with i.v. administration of a higher dose. The
applicability of this animal study is unclear.
In a randomized, double-blind, placebo-controlled clinical
trial in adults undergoing surgical resection for recurrent
malignant glioma. 222 patients were assigned to receive surgi
cally implanted biodegradable polymer disks with or without
3.85% BCNU (by weight) [122], Among patients with
glioblastoma, treatment with placebo polymer resulted in 64%
mortality at six months, compared to a 44% six-month mortal
ity for those treated with the BCNU polymer (p = 0.02).
Limitations of this study include the fact that no survival
advantage was shown over historical controls treated with i.v.
BCNU, BCNU polymer produced no survival prolongation in
patients with pathologic diagnoses other than GBM, and max
imal feasible resection and initial KPS were strong predictors
of survival irrespective of treatment with the BCNU implants.
Furthermore, the clinical relevance of the six-month compari
son is questionable. Follow-up data demonstrated no signifi
cant difference in survival between BCNU polymer and
placebo groups at approximately 40 weeks. Dose-escalation
trials incorporating wafers with higher concentrations of
BCNU by weight are ongoing.
A prospective, randomized, double-blind study of BCNU
polymer versus placebo at the time of initial surgery for malig
nant gliomas was recently reported by Aaltonen [120], All 32
patients in the study received involved field radiation therapy
following surgery. For 27 patients with grade IV tumors, the
median time from surgery to death was 40 weeks for the
placebo group and 53 weeks for the active treatment group (p
= 0.008). The two-year survival for patients receiving BCNU
polymer was 30% as compared to 6% in the placebo-controlled
polymer patients. Adverse events in the BCNU polymer arm
were relatively few. These results should be intcqircted with
caution as (he original study planned to enroll 100 patients and
was stopped prematurely due to administrative Issues; there
were more AAs in the BCNU polymer arm; and there was no
comparison to i.v. BCNU.
Many other chemo- and immunotherapies arc being devel
oped for interstitial delivery [123, 124], Carboplatin is one
220
such candidate that has shown activity against gliomas when
administered i.v. but has limited use because of myelotoxicity.
Carboplatin polymer was implanted in an experimental glioma
rat model [125], In this setting, median survival increased
threefold over controls and it was shown that the best intracra
nial polymer dose was significantly more effective than the
best systemic dose tested. Similarly with cisplatin, mean survival was significantly prolonged as compared to control ani
mals and animals treated with placebo polymer. At autopsy no
evidence of triable tumor was noted in the animal survivors
[126], The relevance of these animal models to human glioma
patients remains uncertain.
Conclusion
Malignant gliomas remain a poorly understood form of
cancer associated with high rates of morbidity and mortality.
Nevertheless, prospects for the future are better than ever
before. Developments in molecular biology have led to a
clearer understanding of the mechanisms of tumor develop
ment, growth, and resistance to therapy. As a result, new treat
ment strategies are emerging that target steps in the molecular
pathogenesis of these tumors. Antiangiogenesis agents, anti
sense oligonucleotides, and signal transduction inhibitors are
all examples of such therapies now entering clinical trials
Improved cytotoxic agents that penetrate the BBB (topoiso
merase I inhibitors, temozolomide, oxaliplatin) are other
promising therapeutic agents. Finally, strategies to circumvent
the BBB (polymers, bradykinin analogues, gene therapy) are
important advances that have also shown efficacy in early clin
ical trials. Future treatment strategics for malignant gliomas
will likely involve synergistic combinations of agents aimed at
different pathways in the molecular pathogenesis of this type
of cancer.
The pace and breadth of discovery in molecular biology
promise a steady supply of novel agents as well as refine
ments of existing ones. One of the important challenges for
the future is the development and implementation of sound
clinical research methods that will enable investigators to
identify active treatment regimens. Although the traditional
outcomes of survival and time to progression remain impor
tant, incorporation of neuropsychological outcomes and valid.
reliable QOL instruments assume great importance for future
studies. Extending and improving QOL should be the com
plementary goals of any new agent for malignant gliomas.
References
1
Salomon M, Scholtz H, Kaplan RS el al. Long-term survival
in patients with malignant astrocytoma. Neurosurgery
1994;34:213-219.
2
Fine HA, Dear KB, Loeffler JS et al. Mcta-analysis of radi
ation therapy with and without adjuvant chemotherapy for
malignant gliomas in adults. Cancer 1993;71:2585-2597.
221
New Treatment Strategies for Malignant Gliomas
3
Salcman M. Survival in glioblastoma: historical perspective.
Neurosurgery 1980;7:435-439.
4
20
Huncharek M, Muscat J. Treatment of recurrent high grade
astrocytoma; results of a systematic review of 1415 patients.
Anticanccr Res 1998;18:1303-1312.
Brock CS, Newlands ES, Wedge SR et al. Phase I trial of
temozolomide using an extended continuous oral schedule.
Cancer Res 1998;58:4363-4367.
21
Perry JR, DeAngelis LM, Schold SC Jr et al. Challenges in the
design and conduct of phase HI brain tumor therapy trials.
Neurology 1997;49:912-917..
Newlands ES, O’Reilly SM, Glaser MG et al. The Charing
Cross Hospital experience with temozolomide in patients with
gliomas. Eur J Cancer I996;32A:2236-224I.
22
Bower M, Newlands ES, Bleehen NM ct aL Multicentre CRC
phase II trial of temozolomide in recurrent or progressive high
grade glioma. Cancer Chemother Pharmacol 1997;40:484-488.
23
Levin VA, Yung A, Prados M et al. Temodal (temozolo
mide) at first relapse in anaplastic astrocytoma patients. J
Neurooncol I997;35(suppl I):185a.
24
Friedman HS, McLendon RE, Kerby T et al. DNA mismatch
repair and O6-aIkyIguaninc-DNA alkyltransfcrase analysis
and response to Temodal in newly diagnosed malignant
glioma. J Clin Oncol 1998;16:3851-3857.
25
Rothenberg ML. Topoisomerase I inhibitors: review and
update. Ann Oncol 1997;8:837-855.
26
Tanizawa A, Fujimori A, Fujimori Y ct al. Comparison of
topoisomerase I inhibition, DNA damage, and cytotoxicity
of camptothccin derivatives presently in clinical trials. J Natl
Cancer Inst 1994;86:836-842.
27
Nakatsu S, Kondo S, Kondo Y ct al. Induction of apoptosis
in multi-drug resistant (MDR) human glioblastoma cells by
SN-38, a metabolite of the camptothecm derivative CPT-I I.
Cancer Chemother Pharmacol 1997;39:417-423.
28
Chabot GG. Clinical pharmacokinetics of irinotecan. Clir
Pharmacokinct 1997;33:245-259.
29
Gupta E, Wang X, Ramirez J et al. Modulation of glu
curonidation of SN-38, the active metabolite of irinotecan, by
valproic acid and phenobarbital. Cancer Chemother Pharmacol
1997;39:440-444.
30
Weitzncr M, Meyers C, Gclkc C et al. The Functional
Assessment of Cancer Therapy (FACT) scale Development
of a brain subscale and rcvalidation of the general version
(FACT-G) in patients with primary brain tumors. Cancer
1995;75:1151-1161.
Hare CB, Elion GB, Houghton PJ ct al. Therapeutic efficacy
of the topoisomerase I inhibitor 7-cthyl-10-(4-[ I-pipendino]l-pipcridino)-carbonyloxy-camptothccin against pediatric
and adult central nervous system tumor xenografts. Cancer
Chemother Pharmacol 1997;39:187-191.
31
Osoba D, Aaronson NK, Muller M et al. Effect of neurolog
ical dysfunction on health-related quality of life in patients
with high-grade glioma. J Ncurooncol 1997;34:263-278.
Colvin OM, Cokgor I, Ashley DM ct al. Irinotecan treatment
of adults with recurrent or progressive malignant glioma.
Proc Am Soc Clin Oncol 1998; 171493a.
32
16
Hutchinson TA, Boyd NF, Feinstein AR. Scientific problems
in clinical scales, as demonstrated in the Kamofsky Index of
Performance Status. J Chronic Dis 1979;32:661-666.
Sung C, Blaney S, Cole D et al. A pharmacokinetic model of
topotccan clearance from plasma and cerebrospinal fluid.
Cancer Res 1994;54:5118-5122.
33
17
Wedge SR, Newlands ES. 06-bcnzylguanine enhances the
sensitivity of a glioma xenograft with low O6-alkylguanineDNA alkyltransfcrase activity to temozolomide and BCNU.
Br J Cancer 1996;73:1049-1052.
Crcemcrs GJ, Bolis G, Gore M et al. Topotccan, an active
drug in the second-line treatment of epithelial ovarian can
cer results of a large European phase II study. J Clin Oncol
1996;14:3056-3061
34
18
Newlands ES, Stevens MF, Wedge SR et al. Temozolomide: a
review of its discox :ry, chemical properties, pre-clinical devel
opment and clinical trials. Cancer Treat Rev 1997;23:35-61.
Dennis MJ, Bcijncn JH, Grochow LB et al. An overview of
the clinical pharmacology of topotccan. Semin Oncol
I997;24(suppl 5):S5-I2-S5-I8.
35
19
Newlands ES, Blackledge GRP, Slack JA et al. Phase 1 trial of
temozolomide (CCRG 81045. M&B 39831: NSC 362856).
Br J Cancer 1992;65:287-291.
Creemers GJ, Gerrits CJ, Eckardt JR et al. Phase I and phar
macologic study of oral topotccan administered twice daily
for 21 days to adult patients with solid tumors. J Clin Oncol
1997;15:1087-1093.
5
6
Kaplan RS. Complexities, pitfalls, and strategics for evaluat
ing brain tumor therapies. Curr Opin Oncol 1998; 10:175-178.
7
Fctcll MR, Grossman SA, Fisher JD et al. Preirradiation
paclitaxel in glioblastoma multiforme: efficacy, pharmacol
ogy, and drug interactions. New Approaches to Brain Tumor
Therapy Central Nervous System Consortium. J Clin Oncol
1997;15:3121-1128.
8
Hochberg F, Grossman SA, Mikkelsen T et aL Efficacy of 9aminocamptothccm (9-AC) in adults with newly diagnosed
glioblastoma multiforme (GBM) and recurrent high grade
astrocytomas (HGA). Proc Am Soc Clin Oncol 1998; 17:388.
9
Macdonald DR, Cascino TL, Schold SC et al. Response cri
teria for phase II studies of supratentorial malignant glioma.
J Clin Oncol 1990;8:1277-1280.
10
Burger PC, Vogel FS, Green SB et al. Glioblastoma multi
forme and anaplastic astrocytoma: pathologic criteria and
prognostic implications.Cancer 1985;56:1106-1 111.
11
Coons SW, Johnson PC, Schcithaucr BW et al. Improving
diagnostic accuracy and intcrobscrvcr concordance in the
classification and grading of primary gliomas. Cancer
1997;79:1381-1393.
12
Daumas-Duport C, Scheithauer B, O’Fallon J et al. Grading
of astrocytomas. A simple and reproducible method Cancer
1988;62:2152-2165.
13
Schwartz CE, Cole BF, Gclbcr RD. Measuring patient-cen
tered outcomes in neurologic disease. Extending the Q-TWiST
method. Arch Neurol 1995;52:754-762.
14
15
Axgcropoulos, Batchelor
222
36
Managold C, Pawal JV, Scheithauer W cl al. Response of
SCLC brain metastases to topotecan (SK&.F 104864) therapy.
Ann Oncol 1996;7(suppl 5): 106.
53
Gcrwitz AM, Stein CA, Glazer PM. Facilitating oligonu
cleotide delivery: helping antisense deliver on its promise.
Proc Natl Acad Sci USA 1996;93:3161-3163.
37
Macdonald D, Cairncross G, Stewart D ct al. Phase II study
of topotecan in patients with recurrent malignant glioma.
National Clinical Institute of Canada Clinical Trials Group.
Ann Oncol 1996;7:205-207.
54
38
Blaney SM, Phillips PC. Packer RJ et al. Phase II evaluation
of topotecan for pediatric central nervous system tumors.
Cancer 1996;78:527-531.
Dean NM, McKay R, Condon TP et al. Inhibition of protein
kinase C-ax expression in human A549 cells by antisense
oligonucleotides inhibits induction of intracellular adhesion
molecule 1 (ICAM-1) mRNA by phorbol esters. J Biol
Chcm 1994;269:16416-16424.
55
Smith CUM. Elements of Molecular Ncurobiology. New
York: John Wiley and Sons, 1996:60.
39
Eisenhauer EA, Wainman N, Boos G ct al. Phase II trials of
topotecan in patients with malignant glioma and soft tissue
sarcoma. Proc Am Soc Clin Oncol 1994:13: A4S8.
56
Pollack IF, Randall MS, Kristofik MP ct al. Effect of tamox
ifen on DNA synthesis and proliferation of human malignant
glioma lines m vitro. Cancer Res 1990:50:7134-7138.
40
Kyritsis A, Ncwlands ES, Brock CS ct al. Phase II trial of
topotecan as a continuous intravenous infusion in patients with
high grade gliomas. Proc Am Soc Clin Oncol 1997; 16:A1404.
57
O'Brian CA, Liskamp RM, Solomon DH et al. Inhibition of
protein kinase C by tamoxifen. Cancer Res 1985;45124522465.
41
Dropcho E, Rosenfeld S, Morawetz R ct al. Preradiation
intracarotid cisplatin treatment of newly diagnosed anaplastic
gliomas. J Clin Oncol 1992;10:452-458.
58
Butta A. MacLcnnan K, Flander KC et aL Induction of trans
forming growth factor beta I in human breast cancer in vivo fol
lowing tamoxifen treatment. Cancer Res 1992:52:4261-4264.
42
Gruber ML, Glass J, Choudhn H et al. Carboplatin
chemotherapy before irradiation in newly diagnosed
glioblastoma multiformc. Am J Clin Oncol 1998;21:338-340.
59
43
Bccouam Y, Rougicr P. Clinical efficacy of oxaliplatin
monotherapy: phase II trials in advanced colorectal cancer.
Semin Oncol 1998;25(suppl 5):23-31.
Vertosik FT, Sclkcr RG, Pollack IF et al. The treatment of
intracranial malignant gliomas using orally administered
tamoxifen therapy: preliminary' results tn a series of “failed”
patients. Neurosurgery 1992;30:897-903.
60
Levi F, Zidani R, Missel JL. Randomised multicentrc trial of
chronothcrapy with oxaliplatin, fluorouracil, and folinic acid
in metastatic colorectal cancer. Lancet 1997;350:681-686.
Couldwell WT, Weiss MH, DeGiorgio CM ct aL Clinical and
radiographic response in a minority of patients with recurrent
malignant gliomas treated with high-dose tamoxifen.
Neurosurgery 1993;32:485-489
61
Extra JM, Marty M, Bricnza S et al. Pharmacokinetics and
safety profile of oxaliplatin. Semin Oncol 1998;25(suppl
5): 13-22.
Vcrtosick FT Jr, Selker RG, Arena V. A dose-escalation study
of tamoxifen therapy in patients with recurrent glioblastoma
muhiforme. J Neurosurg 1994;80:385A.
62
Freeman A, Hetherington M, Egclhoff J et al. Preliminary
results: diffuse intrinsic brain stem gliomas of childhood
respond to tamoxifen. Proc Am Assoc Cancer Res
1994:35:470.
63
Couldwell WT, Hinton DR, Sumock AA et al. Treatment of
recurrent malignant gliomas with chronic oral high-dose
tamoxifen. Clin Cancer Res 1996;2:619-622.
64
Pollack IF, DaRosso RC, Robertson PL et al. A phase I study
of high-dose tamoxifen for the treatment of refractory malig
nant gliomas of childhood. Clin Cancer Res 1997;3:1109-1115.
65
Preul MC, Caramanos Z, Shenouda G ct al. In vivo biochem
ical effects of tamoxifen on recurrent malignant astrocy
tomas: characteristics of response and failure. J Neurosurg
I996;84:352A-353A.
66
Lien EA, Wester K, Lonning PE et al. Distribution of tamox
ifen and metabolites into brain tissue and brain metastases in
breast cancer patients. Br J Cancer 1991;63:641-645.
67
Baltuch GH, Couldwell WT, Villemure JG et al. Protein kinase
C inhibitors suppress cell growth in established and low-pas
sage glioma cell lines. A comparison between staurosporine and
tamoxifen. Neurosurgery 1993;33:495-501.
68
Boral AL, Dcssain S, Chabner BA. Clinical evaluation of bio
logically targeted drugs: obstacles and opportunities. Cancer
Chemother Pharmacol 1998;42(suppl):S3-S21
44
45
46
Bricnza S, Vignoud J, Itzhaki M et al Oxaliplatin (1-OHP):
global safety in 682 patients. Proc Am Soc Clin Oncol
1995;14:A5I3.
47
Missel JL, Kidam J. Gasuaburu C et al. Oxaliplatinum (I-OHP):
experimental and clinical studies. In: Howell SB, ed. Platinum
and Other Metal Coordination Compounds in Cancer
Chemotherapy New York: Plenum Press, 1991:369-375.
48
Soulie P, Raymond E, Bricnza S et al. Oxaliplatin: the first
DACH platinum in clinical practice. Bull Cancer
1997;84:665-673.
49
Nishizuka Y. The molecular heterogeneity of protein kinase
C and its implications of cellular regulation. Nature
1988;334:661-665.
50
Couldwell WT, Uhm JH, Antel JP ct al. Enhanced protein
kinase C activity correlates with the growth of malignant
glioma in vitro. Neurosurgery 1991;29:880-887.
51
Baltuch GH. Yong VW. Signal transduction for proliferation
of glioma cells in vitro occurs predominantly through a protein
kinase C-mediatcd pathway. Brain Res 1996;710:143-149.
52
Agrawal S, Tcmsamani J, Galbraith W et al. Pharmacokinetics
of antisense oligonucleotides. Clin Pharmacokinct
1995;28:7-16.
223
New Treatment Strategies for Malignant Gliomas
69
Kang MS, Stcmerick DM, Zwolshcn JTI ct al. Famesyl-dcrived
inhibitors of ras famesyl transferase. Biochcm Biophys Res
Common 1995;217:245--249.
87
Ram Z, Culver KW, Oshiro EM et al. Therapy of malignant
brain tumors by intratumoral implantation of retroviral
vector-producing cells. Nat Med 1997;3:1354-1361
70
Brede! M, Pollack IF, Freund JM et al. Inhibition of Ras and
related G-proteins as a therapeutic strategy for blocking
malignant glioma growth. Neurosurgery 1998;43:124-131.
88
Izquierdo M, Martin V, de Felipe P ct al. Human malignant
brain tumor response to herpes simplex thymidine kinase
(HSVtkJ/ganciclovir gene therapy. Gene Ther 1996:3:491-495.
71
Feldkamp MM, Lau N, Guha A Signal transduction pathways
and their relevance in human astrocytomas. J Neurooncol
1997;35:223-248.
89
Izquierdo M, Cortes ML, Martin V ct aL Gene therapy in
brain tumours: implications of the size of glioblastoma on its
curability. Acta Neurochir Suppi (Wien) 1997;68:11 i-117.
72
Moasser MM, Scpp-Lorenzino L, Kohl NE et al. Famesyl
transferase inhibitors cause enhanced mitotic sensitivity to taxol
and cpothiloncs. Proc Natl Acad Sci USA 1998;95:1369-1374.
90
73
Fetell MR, Housepian EM, Oster MW et al'. Intratumor admin
istration of beta-interferon in recurrent malignant gliomas. A
phase I clinical and laboratory study. Cancer 1990;65:78-83.
Mercer WE, Shields MT, Amin M ct al. Negative growth
regulation in a glioblastoma tumor cell line that conditionally
expresses human wild-type p53. Proc Natl Acad Sci USA
1990;87:6166-6170.
91
Yung WK, Prados M, Levin VA et aL Intravenous recombi
nant interferon beta in patients with recurrent malignant
gliomas: a phase I/H study. J Clin Oncol 199l;9.1945-1949.
Bischoff JR, Kim DH, Williams A et al. An adenovirus
mutant that replicates selectively in p53-deficient human
tumor cells. Science 1996;274:373-376.
92
Buckner JC, Brown LD, Kugler JWct al. Phase II evaluation
of recombinant interferon alpha and BCNU in recurrent
glioma. J Neurosurg 1995;82:430-435.
Hall AR, Dix BR, O’Carroll SJ ct al. p53-dependcnt cell
deatli/apoptosis is required for a productive adenovirus
infection. Nat Med 1998;4:1068-1072.
93
Goodrum F, Omclles D. p53 status docs not determine out
come of E1B 55-kilodalton mutant adenovirus lytic infection.
J Virol 1998;72:9479-9490
94
Linke SP. Cancer. Has the smart bomb been defused? Nature
1998,395:13, 15
95
Lane DP. Killing tumor cells with viruses—a question of
specificity. Nat Med 1998;4:1012-1013.
74
75
76
Chang SM, Barker FG II, Huhn SL ct al High dose oral
tamoxifen and subcutaneous interferon alpha-2a for recurrent
glioma. J Neurooncol 1998;37:169-176.
77
Yung WK, Castellanos AM, Van Tassel P ct al. A pilot study
of recombinant interferon beta (IFN-bcta scr) in patients with
recurrent glioma. J Neurooncol 1990;9.29-34.
78
Allen J, Packer R, Bleycr A ct al. Recombinant interferon
beta: a phase I-II trial tn children with recurrent brain tumors.
J Clin Oncol 1991;9:783-788.
96
Fueyo J, Gomez-Manzano C, Yung WK et aL Ovcrexprcssion
of E2F-1 in glioma triggers apoptosis and suppresses tumor
growth m vitro and in vivo. Nat Med 1998;4:685-690.
79
Yung WK, Prados M, Levin VA ct al. Intravenous recombi
nant interferon beta in patients with recurrent malignant
gliomas: a phase I/II study. J Clin Oncol 1991 ;9-1945-1949.
97
Li VW, Folkerth RD, Watanabe H et al. Microvessel count and
cerebrospinal fluid basic fibroblast growth factor m children
with brain tumors. Lancet 1994;344:82-86
80
Rajkumar SV, Buckner JC, Schomberg PJ ct al. Phase 1 eval
uation of radiation combined with recombinant interferon
alpha-2a and BCNU for patients with high-grade glioma. Int
J Radiat Oncol Biol Phys 1998;40:297-302
98
Folkman J. Tumor angiogenesis: therapeutic implications. N
Engl J Med 1971;285:1182-1186.
99
Hanahan D, Folkman J. Patterns and emerging mechanisms
of the angiogenic switch during tumorigenesis Cell
1996;86:353-364.
100
Folkman J. Clinical applications of research on angiogenesis.
N Engl J Med 1995;333:1757-1763.
101
Harris A. Antiangiogenesis for cancer therapy. Lancet
I997;349(suppl II):13-I5.
102
Lund EL, Spang-Thomsen M, Skovgaard-Poulsen H ct al.
Tumor angiogenesis—a new therapeutic target in gliomas.
Acta Neurol Scand 1998;97:52-62.
103
Friedberg MH, Glantz MJ, Klcmpner MS et al Specific matrix
metalloproteinase profiles in the cerebrospinal fluid correlated
with the presence of malignant astrocytomas, brain metastases,
and carcinomatous meningitis. Cancer 1998;82:923-930
104
Giese A, Westphal M. Glioma invasion in the central nervous
system. Neurosurgery 1996;39:235-252
105
Jekuncn AP, Kairemo KJ. Inhibition of malignant angiogenesis.
Cancer Treat Rev 1997;23:263-286.
81
Brandes A A. Scelzi E, Zampicri P et al Phase II trial with
BCNU plus alpha interferon in patients with recurrent
high-grade gliomas. Am J Clin Oncol 1997;20:364-367.
82
Kaye AH, Laws ER. Brain Tumors. New York: Churchill
Livingstone, 1997:118.
83
Hayes RL, Koslow M, Hiesiger EM et al. Improved long term
survival after intracavitary intcrleukin-2 and lymphokinc-activated killer cells for adults with recurrent malignant glioma.
Cancer 1995;76:840-852.
84
Plautz GE, Barnett GH, Miller DW et al. Systemic T cell
adoptive immunotherapy of malignant gliomas. J Neurosurg
1998;89:42-51.
85
Ridet JL, Privat a. Gene therapy in the central nervous sys
tem: direct versus indirect gene delivery. J Neurosci Res
1995;42:287-293.
86
Smith GM. Adenovirus-mediated gene transfer to treat
neurologic disease. Arch Neurol 1998;55:1061-1064.
224
Avgeropoulos, Batchelor
106
Nakagawa T, Kubota T, Kabuto M et al. Secretion of'matrix
metalloproteinase-2 (72 kD gelatinasc/type IV collagenase =
gelatinase A) by malignant human glioma cell lines: implica
tions for the growth and cellular invasion of the extracellular
matrix. J Neurooncol 1996:28:13-24.
107
Brown PD, Giavazzi R. Matrix metalloproteinase inhibition:
a review of anti-tumor activity. Ann Oncol 1995;6 :967-974
108
116
Matsukado K, Nakano S, Bartus RT et al. Steroids decrease
uptake of carboplatin in rat gliomas—uptake improved by
intracarotid infusion of bradykinin analog, RMP-7. Acta
Neurochir Suppl (Wien) 1997;70:159-161.
117
Fike JR, Gobbel GT, Mesiwala AH et al. Cerebrovascular
effects of the bradykinin analog RMP-7 in normal and
irradiated dog brain J Neurooncol 1998:37:199-215.
McCarty MF. Thalidomide may impede cell migration in
primates by down-regulating integrin beta-chains: potential
therapeutic utility in solid malignancies, proliferative
retinopathy, inflammatory disorders, neointimal hyperplasia,
and osteoporosis. Med Hypotheses 1997:49:123-131.
118
Gregor A, Lind M, Osborn C. RMP-7 and carboplatin in
recurrent malignant glioma J Neurooncol 1997;35(suppl
54)200a.
119
Hochberg FH, Pruit A. Assumptions in the radiotherapy of
glioblastoma. Neurology J 980:30:907-911.
109
Yung WKA. A NCNSC phase II trial of thalidomide, an
antiangiogenic agent, in patients with recurrent malignant
gliomas. J Neurooncol 1997;35(suppl 56)
*_206a.
120
110
Sanovich E, Bartus RT, Friden PM ct al. Pathway across
blood-brain barrier opened by the bradykinin agonist, RNfP-7.
Brain Res 1995;705:125-135.
Valtonen S, Timoncn U, Toivancn P et al. Interstitial
chemotherapy with carmustine-loaded polymers for high-grade
gliomas: a randomized double-blind study. Neurosurgery'
1997;41:44-48; discussion 48-49.
121
Fung LK, Ewend MG, Sills A ei al. Pharmacokinetics of
interstitial delivery of carmustme, 4-hydroperoxycyclophosphamide, and paclitaxel from a biodegradable polymer
implant in the monkey brain. Cancer Res 1998;58:672-684.
Ill
Reichman HR, Farrell CL, Del Maestro RF Effects of steroids
and nonsteroid anti-inflammatory agents on vascular perme
ability in a rat glioma model. J Ncurosurg 1986:65:233-237.
122
112
Ncuwelt EA, Barnett PA, Bigner DD ct al. Effects of adrenal
cortical steroids and osmotic blood-brain barrier opening on
methotrexate delivery to gliomas in the rodent: the factor of
the blood-brain barrier Proc Natl Acad Sci USA
1982;79:4420-4423.
Brem H, Piantadosi S, Burger PC cl al. Placebo-controlled
trial of safely and efficacy of intraoperative controlled deliv
ery by biodegradable polymers of chemotherapy for recurrent
gliomas. The Polymer-brain Tumor Treatment Group. Lancet
1995;345:1008-1012.
123
113
Riley MG, Kim NN, Watson VE ct al. Intra-arterial administra
tion of carboplatin and the blood brain barrier pcrmcabilizing
agent, RMP-7: a toxicologic evaluation in swine. J Neurooncol
1998:36:167-178.
Walter KA, Gahan MA, Gur A ct al. Interstitial Taxol delivered
from a biodegradable polymer implant against experimental
malignant glioma. Cancer Res 1994;4:2207-2212.
124
Sanovich E, Bartus RT, Friden PM ei al. Pathway across
blood-brain barrier opened by the bradykinin agonist, RMP-7.
Brain Res 1995;705:125-135.
Judy KD, Olivi A, Buahin KG ct al. Controlled release of a
cyclophosphamide derivative with polymers is effective
against rat gliomas. J Neurosurg 1995;82:103-108.
125
Matsukado K, Inamura T, Nakano S et al. Enhanced
tumor uptake of carboplatin and survival in gliomabcaring rats by intracarotid infusion of bradykinin ana
log,
RMP-7.
Neurosurgery
1996;39:125-133;
discussion 133-134.
Olivi A, Ewend MG, Utsuki T ct al Interstitial delivery of
carboplatin via biodegradable polymers is effective against
experimental glioma in the rat. Cancer Chemother Pharmacol
1996:39:90-96.
126
Kong Q, Kleinschmidt-Demasters BK, Lillehei KO.
Intralesionally implanted cisplatin cures primary brain tumor
in rats. J Surg Oncol 1997;64:268-273.
114
115
Caqtop
Topotecan Hydrochloride 2.5 mg.
...providing solutions
ABRIDGED
Presentation:
PRODUCT
Each carton of Cantop contains:
One single dose vial of Cantop
Topotecan Hydrochloride : 2.5 mg
in Lyophilized powder form.
Composition:
One ampoule of water for Injection
Water for Injection q.s. to 2.5 mg
For reconstitution during administration.
Composition:
INFORMATION
(AUC) show linear relationship with increasing dosages. No evidence of
drug accumulation is seen with daily 30 minute infusions for five consecutive
days. The mean total body clearance of the lactone form is 30 L/h/m’, with a
mean elimination half-life of 3 hours. Renal clearance accounts for
approximately 40% of the dose administered with large inter individual
variability. Renal dysfunction may decrease topotecan plasma clearance.
Creatinine clearance is significantly, but poorly correlated with Cantop
(Topotecan Hydrochloride) clearance. Hepatic impairment does not appear
to influence the Cantop (Topotecan Hydrochloride) disposition.
Indications:
Cantop (Topotecan Hydrochloride) is indicated in the treatment of:
* Metastatic carcinoma of the ovary after failure of initial or subsequent
chemotherapy.
* Small cell lung cancer sensitive disease after failure of first line
chemotherapy. In clinical studies submitted to support approval, sensitive
disease is defined as disease responding to chemotherapy but subsequently
progressing after atleast 60 days (in the phase III study) or atleast90 days (in
the phase II study) after chemotherapy.
Contraindications: Cantop (Topotecan Hydrochloride) is contraindicated in
patients with hypersensitivity to Cantop (Topotecan Hydrochloride). Its
usage is not recommended during pregnancy or lactation. It is also
contraindicated in patients with severe bone marrow depression.
Dosage: Cantop (Topotecan Hydrochloride) is intended for use only as an
intravenous infusion after reconstitution and dilution. The recommended
dose is 1.5 mg/m'/day administered as intravenous infusion over 30 minutes,
for 5 consecutive days. This cycle should be repeated after 3 weeks starting
from day 1 for minimum of 4 cycles. In the event of severe neutropenia, the
dose should be reduced by 0.25 mg/m’/day, in subsequent cycles.
Alternatively administration of G-CSF may be considered to regulate the
severity of myelosuppression.
Mode of action : Cantop (Topotecan Hydrochloride), an antineoplastic
agent, is a semisynthetic derivative of camptothecin and is topoisomerase I
inhibitor, an enzyme which relieves torsional strain during DNA replication.
The cleavable complex normally formed between DNA and topoisomerase I
is stabilised by Topotecan, with resultant breaks in single stranded DNA
Pharmacokinetics: Cantop (Topotecan Hydrochloride) undergoes a
reversible pH dependant hydrolysis in its lactone moiety which is
biologically active, into inactive hydroxy acid form. The peak plasma
concentration and the area under plasma concentration versus time curves
ADVERSE REACTIONS:
Haematological Reactions: Myelosuppression characterised primarily by
neutropenia is dose limiting toxicity in therapy with Cantop (Topotecan
Hydrochloride). Grade-IV neutropenia may occur in a majority of cases,
during first course of administration. In subsequent courses, the incidence
may come down to some extent but requires attention of the clinician. The
nadir neutrophil count may be encountered between day 8-11. However,
neutropenia associated with Cantop (Topotecan Hydrochloride) therapy is
non-cumulative in nature. Febrile neutropenia occuring in few patients
may require hospitalisation.
Thrombocytopenia is also encountered in moderate number of patients
receiving Cantop (Topotecan Hydrochloride) therapy. The nadir count is
usually observed between day 10-15. In few cases, platelet transfusion may
be necessitated.
Severe anaemia amounting to haemoglobin < 8 gm/dL may also be observed
in patients receiving Cantop (Topotecan Hydrochloride) therapy
Warning and Precautions: Prior to the first course of Cantop (Topotecan
Hydrochloride), patients must have a baseline neutrophil count of > 1500
cells/ mm1 and a platelet count of 100000 cells/ mm1 Peripheral blood a
counts should be monitored regularly during therapy with Cantop
(Topotecan Hydrochloride).
Stability: Unopened vials of Cantop (Topotecan Hydrochloride) are stable
until the date indicated on the package when stored between 20“ and 25° C.
As the vials contain no preservative, contents should be used immediately
after reconstitution.
Reconstituted vials of Cantop (Topotecan Hydrochloride) diluted for infusion
are stable at approximately 20’and 25“ C and ambient lighting condition for
24 hours.
can“
Topotecan Hydrochloride 2.5 mg.
.. .providing solutionis
PREPARATION FOR ADA/UNISTRATION
RECONSTITUTION:
DILUTION:
(A) Preparation of Cantop premix soln.
(B) Preparation of the
(Topotecan 2.5 mg/2.5ml)
Infusion solution.
A-l Take out the Cantop vial
B-1 Based on the required
and Water for injection (WFI)
dose of the patient expressed
ampoule from the carton.
in mg, aseptically withdraw
the premix solution using a
graduated syringe fitted with
needle.
A-2 Using a syringe fitted with
needle aseptically withdraw the
entire WFI from the ampoule.
B-2 Inject the required premix
solution into the infusion bag
or bottle containing either 5%
0.9%
dextrose
solution
or
A-3 Inject the entire content of
sodium
chloride
(normal
syringe into the Cantop vial.
saline) solution.
A-4 Remove the syringe and
needle and shake the mixture
manually for 15 seconds or till
the lyophilized powder dissolves
in the WFI.
A-5 This premix solution contains
2.5mg/2.5 ml (1.0 mg/ml) Topotecan.
B-3 The final concentration of
infusion solution should be
between 25 to 50 mcg/ml
(For example a 2.5 mg
solution can be diluted to 100
to 50 ml). Shake the infusion
bag or bottle using a rocking
motion.
Administration : The Cantop (Topotecan Hydrochloride) infusion solution should be aseptically
administered intravenously immediately after preparation as a 30 minutes infusion under room
temperature and normal lighting condition.
For further information please write to: Cantop Cell, Dr. REDDY'S LABORATORIES LTD.,
8-2-337, Road No. 3, Banjara Hills, Hyderabad 500 034. Phone: 049-3358471; Fax: 040-3358472; email: drlpmt@hotn
'pl
T.BAKER
HAZARD SYMBOLS
For your safety and as a precautinary measure, we strongly recommend that all of our products should only be handled by
qualified individuals knowing proper handling procedures of the chemicals listed and familiar with their potential hazards.
Certain chemicals are extremely harmful, toxic and/or otherwise hazardous in nature
Hazard Symbols and Risk warnings are displayed on our Product Lables in accordance to the International Rules & Procedures
practised. The absence of a warning must not be interpreted as an indication of safety. Therefore, in all circumstances users
should check whether additional precautions are necessary
FLAMMABLE
EXPLOSIVE
6
w
Hazard
Caution
Hazard
Caution
CORROSIVE
Hazard
Caution
IRRITANT
HARMFUL
OXIDIZING
X
X
: This symbol designates substances which may explode under
definite conditons
Caution
Hazard
TOXIC
1 Spontaneously falmmabie substances
2. Highly flammable gasses
3. Substances sensitive to moisture
4. Flammable liquids (with flash point below 21°C)
Store in cool places Keep away from open flame, source of heat
and sparks.
Hazard
Caution
Hazard
Caution
Hazard
Caution
Avoid shock, friction, sparks and heat.
: The subsances are very hazardous to health when breathed.
swallowed or in contact with the skin and may even lead to
death.
: Avoid contact with the human body and immediately consult a
doctor in cases of malaise.
• Living tissues as well as equipment are dstroyed on contact
with these chemicals.
Do not breathe vapours and avoid contact with body and
clothing
. This symbol designates substances which may have an irritant
effect on skin, eyes and respiratory organs.
Avoid inhalation and direct contant with the body
: Inhalation, ingestion and continues exposure of skin by these
chemicals is harmful
: Avoid inhalation and direct contact with human body
: Oxidising substances can ignite combustible material or worsen
existing fires and thus make fire-fighting more difficult
Keep away from Air and moisture.
General Conditions of Sale
All sales and transactions entered into by Lab & General Exports (P) Ltd ("Seller) for "T. Baker" Brand of Lab
chemicals and reagents shall be subject to the following general conditions of sale except where other specific
terms have been agreed. The terms and conditions as stated herein are subject to change.
Issuing purchase order for the seller's products will be considered as buyer's consent to the seller's terms and
conditions, irrespective of the buyer's own conditions of purchase.
ORDERS
For all orders accepted, seller's will arrange prompt despatch. For items which may not be readily available,
sellers will intimate the probable delivery schedule and if acceptance to the buyer, despatch would be made
accordingly. The sellers reserve the right to refuse the acceptance of order where (a) delivery may not be
possible due to transportation barriers (b) items ordered may not be available in ready stock and are in short
supply (c) restrictions have been imposed by authorities for export and or import by respective countries of
despatch/destination.
PRICES
All prices indicated in our price list are wholesale. All prices are quoted in American dollars. All prices are
exclusive of Frieght, packing any tax, customs duty, import tariff, value added tax. Prices quoted in this list are
subject to fluctuation without notice. The seller's reserve the right to accept the order at their own discretion and
to invoice the goods at the prevailing prices on the date of delivery/dispatch. Any UN specified or DOT USA
special packaging will be added extra to the buyers account. Our stockists, agents and dealers are free to resell
the goods at their own prices.
QUOTATIONS AND ORDER ACCEPTANCE
For all enquiries and requests received, the seller will provide quotations as per prices ruling. Quotations can
also be provided for non-listed items, bulk quantities and bulk packings. Orders received by telephone, fax or
electronic data exchange shall be binding only after we have issued written confirmation of the same. The seller
will accept orders from government, educational and commercial organisations only. Orders placed by private
individuals shall not be entertained. We reserve the right to deliver/alter our standard packaging size or type in
the likely event of the standard package size or type not being available at the time of despatch. All orders are
accepted subject to force majeure.
SHIPPING AND DELIVERY
For all consignments sold on FOB basis. The risk passes to customer as soon as the goods leave our premises.
This is also applicable when delivery is made by our own transport service. If the delivery is postponed for any
reason, storage of the goods in our own or third party warehouse shall also be at the customer's risk and
responsibility. On intimation to the buyer concerning the readiness of the goods for shipment on FOB basis, the
buyer must ensure full insurance cover for any loss or damage. For orders on C&F basis, the buyer must ensure
full insurance cover from the time of delivery or despatch from the premises. For consignments on GIF terms,
the risk passes to the buyer on arrival at the destination point. Where possible, shipments shall be made as per
specified method of the buyer. However, the sellers reserve the right to change the same depending on existing
regulations. A special charge shall be levied to meet customized demand regarding special packaging and
method of despatch. While the sellers endeavor to supply goods within specified schedules, the seller cannot
guarantee a fixed time of delivery. If delay in delivery is caused by circumstances beyond the control of the seller,
the time for delivery shall be extended by a reasonable period except where it becomes impossible to supply the
goods.
PRODUCT QUALITY AND PACKING
All products are analysed in seller’s QC Laboratory. The purity of seller’s products is defined in certificates of
guarantee, analyse and specifications, which are printed on product labels. Certificate of Guarantee, analysis
and specifications shall be provided by the seller on specific request of customer. Such certificates shall be
provided free of cost. Purity definitions and typical specifications of all products can be supplied on request.
Specifications are subject to change and minor variations from any value listed therein should not cause a
dispute. While every effort and utmost care is taken to meet the requirements of quality and exact specification
and to ensure that all data are correct. Seller cannot assume any responsibility for their accuracy. Our packing is
done under stringent quality control measures and strict adherence to label specifications.
COMPLAINTS AND WARRANTY
All chemicals listed in the price list are for laboratory use only. The seller assumes no responsible in respect of
the usage of our products in medicinal, pharmaceutical, agricultural, food, household or cosmetic applications
unless specifically agreed by us prior to delivery. The seller has no liability and is not responsible for any loss or
damage whatsoever arising out of use and or handling of its products.
All complaints concerning quantity and wrong deliveries must be made to seller within 14 days from the date of
receipt of the goods. Failure to notify within the specified period shall be constructed as acceptance of the
goods. The seller shall replace all goods and or refund the purchase price of such goods which are proved to be
wrongly supplied. Claims concerning breakage should be notified to the transport/insurance company.
PAYMENT CONDITION
For all purchases payments are to be made in advance for 100% invoice value or made through a confirmed,
irrevocable letter of credit opened in seller’s favour by any prime bank. Letter of credit to be payable at sight at
the counters of Seller's Bank, Syndicate Bank, Shoolay Branch, Residency Road, Bangalore-560 025. INDIA.
ARBITRATION
All disputes and differences which may arise out of contractual commitments shall be settled in accordance with
the Indian abritration and conciliation act, 1996, by a sole arbitrator agreed between the parties. The venue of
the arbitration shall be at Bangalore, India. Courts at Bangalore, India alone shall have jurisdiction over the
arbitration proceedings.
USA OFFICE
MEDLAB CHEMICALS
8901, Tonnelle Avenue,
North Bergen, N.J. 07047
Tel. + 1-201-869-8282 Fax + 1-201-869 8230
Toll free + 1-888-302-9494, Fax : +1-877-302-9495
Visit us at: www.medlabchemicals.com
e-mail: medlab@medlabchemicals.com
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
T 0003 Acacia (Gum arabic) Lab - Grade
T0715 Acetic acid glacial HPLC
CAS 9000-01-5
500
gm
4.10
T0137 Acetaldehyde Lab - Grade
500
1
CAS 75-07-0
CHjCHO
UN-1089 IMDG-3.1/1
500
ml
6x500 ml
3.85
23.10
CAS 60-35-5
F.W.59.07
79°-81°C
Passes test
99%
Maximum Limits
Chloride (Cl)
Heavy metal (as Pb)
Residue after ignition
Iron (Fe)
Water (H3O)
0.002%
0.001%
0.02%
0.002%
0.3%
500
gm
6x500 gm
5.10
500
T 0701
F.W. 135.16
115°+2°C
99%
gm
7.00
Acetic Acid Glacial Lab - Grade
CAS 64-19-7
CHjCOOH
UN-2789 IMDG-8/II
F.W. 60.05
min. 99.5%
min. 15.8 deg C
117-119degC
0.1%
Assay (aclcimetric)
E.P.
B.P.
Formic Acid
14.00
42.00
125
ml
4x125 ml
T 0877 Acetone Lab - Grade
99.0%
500
ml
6x500 ml
1
6x1
It
It
2.5
It
F.W.58.08
2.05
10.25
4.10
20.50
9.90
T0882 Acetone ACS/AFt
CAS 67-64-1
CH3COCH3
UN-1090 IMDG-3.1/11
Solubility in water
99.5%
F.W.58.08
Passes test
Maximum Limits
T0592 Acetanilide for synthesis Lab - Grade
CAS 103-84-4
C,H5NHCOCH3
Melting point
6.10
11.40
ml
It
CAS 67-64-1
UN 1090 IMDG-3.1/11
CH3COCH3
T0162 Acetamide Lab - Grade
Melting Range
Solubility in Benzene
•F.W.60.05
T 0800 Aceto Carmine solution
F.W. 44.05
0.15%
Acidity (CH3COOH)
ch3conh2
99.8%
CAS 64-19-7
UN-2789 IMDG - 8/II
CHjCOOH
Color (APHA)
Residue after Evaporation
Titrable Acid
Titrable Base
Aldehyde (as HCHO)
Isopropyl alcohol
Methanol
Substances Reducing Permanganate
Water
500
6x500
1
6x1
2.5
ml
ml
It
It
It
10
0.001%
0.0003 meq'g
0.0006 meq/g
0.002%
0.05%
0.05%
Passes test
0.5%
2.40
12.00
4.45
22.25
10.90
T0979 Acetonitrile Lab - Grade
CAS 75-05-8
CH,CN
UN-1648, IMDG-3.2/H
T0706 Acetic acid glacial ACS/AR
CAS 64-19-7
UN - 2789 IMDG - 8/II
C?H„O2
Dilution Test
H,
pH (10% soln)
99.7%
F.W.60.05
Passes test
Color (APHA)
Residue after Evaporation
Acetic anhydride ((CH3CO)3O)
Chloride (Cl)
Sulfate (SO4)
Heavy metals (as Pb)
Iron (Fe)
Substances Reducing Dichromate
Substances Reducing permanganate
Titrable Base
10
0.001%
0.01%
1 ppm
1 ppm
0.5 ppm
0.2 ppm
Passes test
Passes test
0.0004 meq/g
Maximum Limits
500
6x500
ml
ml
1
It
2.5
It
F.W.41.05
80-82 deg C
min. 99.0%
0.2%
Neutral to litmus.
B.P.
Assay (GC)
2.60
13.00
5.00
11.00
500
2.5
3.85
17.40
ml
It
T0984 Acetonitrile ACS/AR
CAS 75-05-8
UN-1648 IMDG-3.2/II
CH3CN
Appearance
99.5%
F.W.41.05
Clear
Color (APHA)
Residue after Evaporation
Titrable Acid
Titrable Base
Water
500
ml
6x500 ml
2.5
It_____________ _ ______
10
0.005%
8 jieq/g
0.6 peq/g
0.3%
6.85
34 25
31.40
Maximum Limits
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
1
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
T 0983 Acetophenone Lab-Grade
CAS 98-86-2
C6HSCOCH3
Freezing Point
99.0%
T 5315 Aluminum ammonium sulfate Lab-Grade
CAS 7784-26-1
AINHJSOJ,
F.W.120.15
19°-20°C
500
Maximum Limit
T 3601
Residue after Evaporation
0.01%
250
ml
6x250 ml
500
ml
3.50
17.50
6.25
Insoluble matter
Chloride (Cl)
Calcium (Ca)
Heavy metals (as Pb)
Iron(Fe)
Potassium (K)
Sodium (Na)
3.75
6.85
T13981 Balsam Canada -Neutral Clear solution
CAS - 8007-47-4
Light yellowish brown viscous transparent liquid.
Refractive index at 25 deg C
1.52 -1 54
30
100
ml
ml
T5461
2.70
13.50
99.0%
F.W. 133.34
Heavy metals (as Pb)
Iron (Fe)
0.01%
Substances not Pptd by NH.OH
0.005%
W. 72 OG
F.
Min. 99.0%
<0.2%
T 5468
97.0%
F.W.241.43
Maximum Limits
Heavy metals (as Pb)
Arsenic (As)
Insoluble matter
Iron (Fe)
Substances not Pptd. by NH.OH
Sulfate (SO,)
T3800 Albert's Stain 'A' solution
ml
ml
Aluminium chloride hydrated Lab -Grade
CAS 7784-13-6
UN-1726 IMDG-8/II
AICi,.6H.O
8.90
0.5%
2.70
13.70
500
gm
6x500 gm
ml
1.30
3.90
T3805 Albert's Stain 'B' solution
125
ml
4x125 ml
0.05%
0.01%
Maximum Limits
CAS 79-10-7
C3H4°2
UN - 2218, IMDG - 8/II
125
4x125
0.001%
Aluminium chloride anhydrous Lab-Grade
CAS 7446-70-0
UN-1726 IMDG-8/II
AJCIj
1.70
4.20
Assay (GC)
H;O
F.W.453.33
0.005%
0.001%
0.05%
0.001%
500
gm
6x500 gm
T3G20 Acrylic Acid Lab-Grade
500
98.0-102.0%
Maximum Limits
F.W.369.94
-90%
gm
gm
1.85
gm
CAS 7784-26-1
AINH.(SOJ2.1214,0
CAS 10127-02-3
C.l. NO. 46005
5
10
F.W.453.33
T5320 Aluminium ammonium sulfate ACS/AR
Acridine Orange Lab-Grade
DYE CONTENT
99.0%
6.00
30.00
500
gm
6x500 gm
1.30
3.90
0.0005%
0 0005%
0.01%
0.005%
0.2%
0.02%
T5473 Aluminium chloride hydrated ACS/AR
T 3810 Alkaline Copper Solution (folin & Wu)
125
4x125
ml
ml
CAS 7784-13-6
UN-1726 IMDG-8/II
AICI3.6H2O
0.45
1.35
T 4440 Alizarin for microscopy pH indicator Lab-Grade
Melting point
[C.I.58000]
F.W.240.20
pH 5.5 to pH 6.3
(Yellow to red)
pH 10.1 toph 12.1
(red to purple)
287°-289°C
gm
gm
2.85
8.85
CAS 72-48-0
c,.h8o.
Visual T ransition intervals
25
100
2
99.5%
F.W.241.43
Maximum Limits
T 5821
Ammonia
Acidity (HCI)
0.002%
0.1%
500
gm
6x500 gm
10.00
50.00
Aluminium Oxide Active Neutral Lab-Grade
CAS 1344-28-1
AI20.
Chloride
500
gm
F.W. 101.96
0.1%
4.20
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
1
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T BAKER LAB CHEMICALS
T5809 Aluminium potassium sulfate Lab-Grade
CAS 7784-24-9
AIK(SO4)2.12H?O
(Ammonium hydroxide)
99.5-100.50%
F.W.474.39
Maximum Limits
Ammonium salts
Fluoride
Heavy metals (as Pb)
Selenium
Passes test
0 003%
0 001%
0.003%
500
gm
6x500 gm
1.25
6.25
T5814 Aluminium potassium sulfate ACS/AR
CAS 7784-24-9
AIK(SO4)2.12H2O
99.0%
F.W.474.39
Maximum Limits
t
Insoluble matter
Chloride (Cl)
Ammonium (NH4)
Heavy metals (as Pb)
Iron (Fe)
Sodium (Na)
0.005%
5 ppm
0.005%
0.001%
0.001%
0.02%
500
gm
6x500 gm
6.00
30.00
T 5990 Aluminium sulfate Lab-Grade
CAS 7784-31-8
AI2(SO4)3.(14-18)H2O
500
1.75
T5995 Aluminium sulfate ACS/AR
500
500
6x500
1
2.5
5
ml
ml
It
It
It
5.40
T9914 Ammonia solution sp.gr OP ! 0 L ab-Grade
CAS 12124-07-9
NH4Br
pH of a 5% solution @ 25°C
500
F.W.35.05
ml
ml
It
It
It
It
0.0005%
0.02%
Passes test
1.35
6.75
2.40
5.25
18.25
9.20 -
6.85
34.25
2.50
gm
T 10076 Ammonium carbonate ACS/AR
CAS 506-87-6;
(NHJ2CO3
Insoluble matter
Nonvolatile matter
Chloride (Cl)
Sulfur compounds (as SOJ
Heavy metals (as Pb)
Iron (Fe)
Maximum Limits
0.0005%
' 0.0005%
CAS506-87-G;
Consists of approximately equi molecular proportions of
(NHJ2CO3
30-34%
CAS 1336-21-6
UN-3318IMDG-2.3
NH2
500
6x500
1
2.5
4x2.5
5
0.005%
0.01%
Passes test
(limit about 0.002%)
Passes test
(limit about 0.005%)
0 005'-
T 10071 Ammonium carbonate Lab-Grade
Maximum Limits
Heavy metals (as Pb)
Nonvolatile residue
Readily oxidizable substances
F.W.97.94
4.5-6.0
99.0%
Insoluble matter
Residue after Ignition
Bromate (BrO3)
(Ammonium hydroxide)
27-30%
1.60
8.00
3.00
6.25
10.90
T 9992 Ammonium bromide Lab-Grade
500
gm
6x500 gm
[C.I.2C470]
F.W.616.50
618nm
gm
0.002%
0.002%
0.5 ppm
2 ppm
2 ppm
0.5 ppm
0.2 ppm
Passes test
0.2%
0.001%
Amido biack 10 B Lab-Grade
100
Residue after Ignition
Carbon dioxide (CH2)
Chloride (Cl)
Phosphate (PO4)
Total sulfur (as SO4)
Heavy metals (as Pb)
Iron (Fe)
Substances Reducing Permanganate
Maximum Limts
0.01%
0.005%
2.55
CAS 1064-48-8
C22H14N6O3S2Na2
Absorption Max. (in water)
F.W.35.05
Passes test
Sulfate (SO.)
Barium (Ba)
Heavy metals (as Pb)
Iron (Fe)
98.0-102.0%
gm
28.0-30.0%
Iodide (I)
Maximum Limits
Insoluble matter
Chloride (Cl)
Substances not Pptd. by Ammonium
hydroxide (as SO4)
Heavy metals (as Pb)
Iron (Fe)
0.002%
CAS 1336-21-6
UN-3318 IMDG-2.3
NH2
Appearance
Maximum Limits
98.0%
gm
CAS 7784-31-8
AI2(SO4)3.(14-18)H2O
T9919 Ammonia solution sp.gr 0. 910 ACS/AR
30.0%
0.005%
0.01 %
5 ppm
0.002%
5 ppm
5 ppm
500
gm
6x500 gm
5.70
28.50
T10093 Ammonium ceric nitrate Lab-Grade
CAS 16774-21-3
(NHJJCefNOJJ
100
gm
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
98.0%
F.W.548.23
7.40
3
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
T10098 Ammonium ceric nitrate ACS/AR
100
T10465 Ammonium dichromate ACS/AR
□Jk-
CAS 16774-21-3
(NH4)JCe(NO3)J
F.W.548.23
99.0%
8.55
gm
T10110 Ammonium ceric sulfate Lab-Grade
CAS 10378-47-9
(NH4)4[Ce(SO4)J.2H2O
100
F.W.632.53
98.0%
gm
5.90
T10115 Ammonium ceric sulfate ACS/AR
CAS 10378-47-9
(NH4)4[Ce(SO4)J.2H2Q
100
gm
8.25
CAS 12125-02-9
NH4CI
99%
F.W.53.49
500
gm
6x500 gm
5
kg
1.55
7.75
13.40
T10135 Ammonium chloride ACS/AR
CAS 12125-02-9
NH,CI
pH of a 5% solution @ 25°C
13.75
gm
T10481 Ammonium dihydrogen orthophosphate
Lab-Grade
500
98-101%
F.W.115.03
gm
3.70
T10486 Ammonium dihydrogen orthophosphate ACS/AR
CAS 7722-76-1
NH4H2PO4
98.0%
pH of a 5% solution @ 25°C ■
F.W.115.03
3.S-4.4
Maximum Limits
F.W.53.49
4.5-5.5
99.5%
Maximum Limits
0.005%
0.01%
2 ppm
0.002%
0.002%
5 ppm
2 ppm
Insoluble matter
Residue after ignition
Phosphate (PO4)
Sulfate (SO4)
Calcium and Magnesium Ppt.
Heavy metals (as Pb)
Iron (Fe)
500
0 005%
3 0%
0.005%
0.01%
0.002%
0.002%
0.005%
Insoluble matterand ammonium hydroxide Pptd.
Loss on drying at 105°C
Chloride (Cl)
Sulfate (SO4)
Calcium (Ca)
Iron (Fe)
Sodium (Na)
CAS 7722-76-1
NH4H2PO4
T 10130 Ammonium chloride Lab-Grade
F.W.252.07
99.5%
Maximum Limits
500
F.W.632.53
99.0%
■“
CAS 7789-09-5
UN-1439 IMDG - 5-t/ll
(NH4)2Cr2O,
Insoluble matter
Ammonium hydroxide Ppt.
Chloride (Cl)
Nitrate (NO,)
Sulfur compounds (as SO4)
Heavy metals (as Pb)
Iron (Fe)
Potassium (K)
Sodium (Na)
’
0.005%
0.005%
5 ppm
0.001%
0.005%
5 ppm
0.001%
0.005%
0.005%
4.70
23.50
500
gm
6x500 gm
3.25
gm
T10603 Ammonium ferric sulfate Lab-Grade
T10316 tri-Ammonium citrate Lab-Grade
CAS 3458-72-8
(NH4)3C6H5O7
500
97-103%
CAS 7783-83-7
NH4Fe(SO4)2.12H2O
F.W.243.22
7.85
gm
Assay
Chloride
Oxalate
Maximum Limits
98.5-101.00%
0.001 %
0.01 %
Insoluble matter
Chloride (Cl)
Nitrate (NO3)
Copper (Cu)
Ferrous iron (Fe
* 2)
9.25
46.25
T10460 Ammonium dichromate Lab-Grade
UN-1439 IMDG-5.I/1I
S
1
(NH4)2Cr2O,
500
4
gm
3.00
98.5-102.0%
97%
F.W.252.07
5.25
F.W.482.20
Pale violet crystals
0.01%
0.001%
0.01%
0.003%
Passes test
(limit about 0.001%)
Substances not Pptd. by Ammonium hydroxide
0.05%
Zinc (Zn)
0.003%
3.55
17.75
500
gm
6x500 gm
CAS 7789-09-5
F.W.482.18
T 10608 Ammonium ferric sulfate ACS/AR
F.W.243.22
500
gm
6x500 gm
98-101%
gm
CAS 7783-83-7
NH4Fe(SO4)2.12H2O
Appearance
T 10321 tri-Ammonium citrate ACS/AR
CAS 3458-72-8
(NH^HjO,
500
T10660 Ammonium ferrous sulfate Lab-Grade
CAS 7783-85-9
(NH4)2Fe(SO4)2.6H2O
500
gm
98.5%
F.W.392.13
1-85
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
T 11221 Ammonium molybdate aCS/AH
T 10665 Ammonium ferrous sulfate ACS/AR
CAS 7783-85-9
(NH,)2Fe(SO.)2.6H2O
98.5%
F.W.392.13
Insoluble matter
Phosphate (PO.)
Copper (Cu)
Ferric iron (Fe3-)
Manganese (Mn)
Substances not Pptd. by Ammonium hydroxide
Zinc (Zn)
0.01%
0.003%
0.003%
0.01%
0.01%
0.05%
0.003%
4.00
20.00
500
gm
6x500 gm
95%
F.W.37.04
6.50
gm
T10677 Ammonium fluoride ACS/AR
I——I
CAS 12125-01-8
UN-2505 IMDG - 6.I/III
NH.F
98 0%
F W.37 04
0.005%
0.01%
0.001%
0.005%
5 ppm
5 ppm
Insoluble matter
Residue after ignition
Chloride (Cl)
Sulfate (SO.)
Heavy metals (as Pb)
Iron (Fe)
41.00
gm
T 10800 Ammonium hydrogen carbonate Lab-Grade
(Ammonium bicarbonate)
CAS 1066-33-7
NH.HCO3
500
98.5%
F.W.79.06
2.00
gm
T10805 Ammonium hydrogen carbonate ACS/AR
(Ammonium bicarbonate)
CAS 1066-33-7
NH.HCO,
pH of a 5% solution @ 25CC
99.0%
500
gm
6x500 gm
CAS 6484-52-2
UN 1942 IMDG-5.1/111
NH.NO,
F.W.80.04
98.0%
1.85
gm
T11332 Ammonium nitrate ACS/AR
CAS 6484-52-2
UN-1942 IMDG- 5.1/III
NH.NO3
pH of a 5% solution © 25CC
F.W.80.04
4.5-6.0
98%
Maximum Limits
0.005%
0.01%
5 ppm
Passes test
(limit about 5 ppm)
5 ppm
0.002%
5 ppm
2 ppm
Insoluble matter
Residue after ignition
Chloride (Cl)
Nitrite (NO.,)
Phosphate (PO.)
Sulfate (SO,)
Heavy metals (as Pb)
Iron (Fe)
3.70
500
gm
6x500 gm
T11381 Ammonium oxalate Lab-Grade
F.W.79.06
7.0-7.8
CAS 6009-70-7
(NH.)3C2O..H2O
500
Maximum Limits
Chloride (Cl)
Heavy metals (as Pb)
Insoluble matter
Iron (Fe)
Residue after ignition
Sulfate (SO.)
4.25
21.25
20.00
100.00
gm
gm
gm
gm
T11327 Ammonium nitrate Lab-Grade
500
Maximum Limits
250
0.005%
0.002%
Passes test
(limit about 0.003%)
0.001%
Arsenate, Phosphate and Silicate (as SiO )
5 ppm
Phosphate (PO.)
0.02%
Sulfate (SO.)
0.001%
Heavy metals (as Pb)
0.02%
Magnesium and other Alkaline earths
Insoluble matter
Chloride (Cl)
Nitrate (NO3)
100
6x100
500
6x500
T 10672 Ammonium fluoride Lab-Grade
500
F.W. 1235.86
81-83%
Maximum Limits
Maximum Limits
CAS 12125-01-8
UN-2505 IMDG -6.I/III
NH.F
CAS 12054-85-2
(NH.).Mo,O...4H.O
0.0005%
0.001%
0.005%
0.0005%
0.01%
0.001%
6.10
30.50
99.0%
F.W. 142.11
2.70
gm
T11386 Ammonium oxalate ACS/AR
CAS 6009-70-7
(NH.)2C2O..H2O
99.0-101.0%
F.W. 142.11
Maximum Limits
Insoluble matter
Residue after ignition
Chloride (Cl)
Sulfate (SO.)
Heavy metals (as Pb)
Iron (Fe)
500
gm
6x500 gm
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
0.005%
0.02%
0.002%
0.002%
5 ppm
2 ppm
3.85
19.25
5
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
T 11409 Ammonium persulfate Lab-Grade
A
CAS 7727-54-0
UN -1444 IMDG - 5.1,'ll!
(NH4).S2O,
500
98.0°;
T 11751 Ammonium thiocyanate Lab-Grade
FW.228.19
3.4C
gm
T11414 Ammonium persulfate ACS/AR
CAS 7727-54-0
UN -1444 IMDG - 5.1/111
o2o
(i\ri4\)2o
<J8
qq co'
yo.ovo
F.W.228.19
0.005%
0.05%
0.04 meq/g
0.001%
0.005%
0.001%
0.5 ppm
500
gm
6x500 gm
4.25
21.25
T 11640 Ammonium sulfate Lab-Grade
CAS 7783-20-2
(NH4)2SO4
500
99%
500
98O'»
F.W.76.12
149°C
gm
4.20
T11756 Ammonium thiocyanate ACS/AR
Maximum Limits
Insoluble matter
Residue after ignition
Titrable free acid
Chloride and Chlorate (as Cl)
Heavy metals (as Pb)
Iron (Fe)
Manganese (Mn)
CAS 1762-95-4
NH.SCN
Melting point
CAS 1762-95-4
NH,SCN
Appearance
pH of a 5% solution @ 25°C
99%
F.W.76.12
Colorless or white crystals
4.5-6.0
Maximum Limits
Insoluble matter
Residue after ignition
Chloride (Cl)
Sulfate (SO,)
Heavy metals (as Pb)
Iron (Fe)
Iodine-Consuming substance
0.005%
0.025%
0.005%
0.005%
5 ppm
3 ppm
0.004 meq/g
500
gm
6x500 gm
5.55
27.75
T 12567 Aniline Lab-Grade
F.W.132.12
gm
1.30
CAS 62-53 3
UN-1547 IMDG 61/11
CSH NH.
F.W.93.13
4.10
T11645 Ammonium sulfate ACS/AR
CAS 7783-20-2
(NH4)2SO4
pH of a 5% solution @ 25°C
99%
F.W.132.12
5.0-6.0
Maximum Limits
0.005%
0.005%
5 ppm
0.001°,'o
5 ppm
5 ppm
5 ppm
Insoluble matter
Residue after ignition
Chloride (Cl)
Nitrate (NOj
Phosphate (PO4)
Heavy metals (as Pb)
Iron (Fe)
3.25
16.25
29.25
500
gm
6x500 gm
5
kg
500
98%
gm
F.W.184,15
25.70
T11692 Ammonium (+) tartrate ACS/AR
CAS 3164-29-2
(CHCOHJCOONHJj
99.0%
6
99.5%
' F.W.93.13
Maximum Limits
Color (APHA)
Residue after ignition
Chlorobenzene (C6H5CI)
Hydrocarbons
Nitrobenzene (CcH,.NO.)
250
0.005%
0.01%
Passes test
Passes test
(limit about 0.001%)
6.85
34.25
6x500 ml
CAS 2094-91-9
Abs.max (Methanol)
25
100
gm
gm
581 nm
.
4.00
12.00
T12593 Aniline blue (water soluble) Lab-Grade
F.W.184.15
Maximum Limits
Calcium (Ca)
Chloride (Cl)
Heavy metals (as Pb)
Iron (Fe)
Residue after Ignition
Sulfate (SO4)
0.02%
0.005%
0.001%
0.001%
0.01%
0.002%
gm
27.50
500
UN-1547 IMDG 6.I/II
C5H5NH2
T 12590 Aniline blue (spirit -..-•i-jble) Lab- Gr ' :!■?
T11687 Ammonium (+) tartrate Lab-Grade
CAS 3164-29-2
[CH(OH)COONHJ2
T 12572 Aniline ACS/AR
[C.I.42755]
CAS 28631-66-5
C^N/O^Na,
Dye Content (Titanometry)
Aos.max (■•.atcr + 5 rr! 0.1 N HC1)
25
100
gm
gm
F.W.737.74
> 25%
594-610
'
2.00
6.00
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
(INTERNATIONAL PR'CE LIST IN US. COLLARS)
T. BAKER LAB CHEMICALS
T 13388 Antimony trichloride ACS/AR
'T12602 Aniline hydrochloride Lab-Grade
CAS 142-04-1
C6H,NH2.HCI
UN-1548 IMDG-6.1/111
CAS 10025-91-9
UN -1733 IMDG-8/II
SbCI,
F.W. 129.59
99-100.5%
198-200 deg C
Assay
M.P.
250
6.25
gm
T 12672 Aniline sulfate Lab-Grade
CAS 542-16-5
(C,HsNH,)2H2SO,
F.W.284.33
Min 99 0%
002%
Assay (acidimelric)
Chloride
250
8.85
gm
CAS 118-92-3
NHjCjH.COOH
Melting range
25
98%
Insoluble in chloroform
Sulfate (SOJ
Arsenic (As)
Copper (Cu)
Iron (Fe)
Lead (Pb)
Substances not Pptd. by hydrogen sulfide
(as Sufate)
500
gm
6x500 gm
F.W.228.12
0.05%
0.005%
0.02%
0.001%
0.002%
0.005%
18.40
92.0
T 13413 Antimony trioxide Lab Grade
CAS 1309-64-1
Sb2O3 '
T13041 Anthranilic acid ACS/AR
99.0%
Maximum Limits
99.0%
F.W.291 52
Maximum Limits
F.W.137.13
within 1°C
including 147°C
Arsenic (As)
Chloride (Cl)
Iron (Fe)
0.1%
0 005%
0.002%
4.30
500
gm
6x500 gm
11.00
55.00
gm
T 13061 Anthraquinone Lab-Grade
CAS 84-65-1
(C6H4CO)2
500
T 13923 Arsenic Trioxide Lab-Grade
F.W.208.22
98%
gm
9.10
T13175 Antimony (metal) lumps Lab-Grade
CAS 7440-36-0
Sb
100
500
99%
3.40
13.75
T 13309 Antimony potassium (+) tartrate Lab-Grade
CAS 28300-74-5
UN - 1551 IMDG - 6.I/III
K(SbO)C,H4O4
99.0-103.0%
250
500
F.W.667.87
7.70
31.00
gm
gm
T13314 Antimony potassium (+) tartrate ACS/AR
CAS 28300-74-5
UN-1551 IMDG - 6.I/III
K(SbO)C4H4O,
F.W.324.92
99.0%
Maximum Limits
0.020 meq/g
2.7%
0.015%
Titrable acid or base
Loss on drying
Arsenic (As)
4.40
18.50
92.50
100
gm
500
gm
6x500 gm
T 13383 Antimony trichloride Lab-Grade
CAS 10025-91-9
UN-1733 IMDG-8/II
SbCI
500
gm
6x500 gm
CAS 1327-53-3
UN-1561 IMDG-6.1/11
500
2.85
gm
T15278 Barium carbonate Lab-Grade
CAS 513-77-9
UN-1564 IMDG-6.1/11
BaCO3
99-101%
500
gm
6x500 gm
F.W.197.34
6.10
30.50
T15283 Barium carbonate ACS/AR
CAS 513-77-9
UN-1564 IMDG-6.1/11
BaCOj
99.0-101.0%
F.W. 197.34
Insoluble in dilute hydrochloric acid
Chloride (Cl)
Water soluble titrable base
Oxidizing substances (as NO5)
Sulfide (S)
Substances not Pptd. by sulfuric acid
Calcium (Ca)
Heavy metals (as Pb)
Iron (Fe)
0.002%
Strontium (Sr)
0.015%
0.002%
0.002 meq/g
0.005%
0.001%
0.25%
0.05%
0.001 %
Maximum Limits
500
gm
6x500 gm
98.5%
F.W. 197.84
min. 95%
0.05%
Assay (iodometric)
Iron
F.W. 121.75
gm
gm
as2o,
0.7%
20-50
102.50
F.W.228.12
14.10
70.50
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T15287 Barium chloride extra pure Lab-Grade
CAS 10326-27-9
BaClj2H2O
99-102%
500
gm
6x500 gm
T 15794 Barium nitrate ACS/AR
F.W.244.26
2.15
10.75
T 15292 Barium chloride ACS /AR
CAS 10326-27-9
BaCI_2H2O
Lossondrying @ 150°C
pH of a 5% solution @ 25°C
99.0%
F.W.244.26
14.0-16.0%
5.2-8.2
Insoluble matter
Oxidizing substances (as NO3)
Substances not Pptd. by sulfuric acid
Calcium (Ca)
Heavy metals (as Pb)
Iron (Fe)
Strontium (Sr)
0.005%
0.005%
0.05%
0.05%
5 ppm
2 ppm
0.1%
Maximum Limits
500
gm
6x500 gm
4.10
20.50
500
F.W.253.37
gm
15.60
T 15305 Barium chromate ACS/AR
CAS 10294-40-3
BaCrO4
100
F.W.253.37
CAS 6211-24-1
CHBaNOS
Z4 ZU
Z b Z
F.W.633.9
gm
gm
3.00
12.00
97%
500
gm
6x500 gm
F.W.315.47
2.25
11.25
T15789 Barium nitrate Lab-Grade
CAS 10022-31-8
UN-1446 IMDG-5.1/11
Ba(NO3)2
500
gm
Insoluble matter
Chloride (Cl)
Substances not Pptd. by sulfuric acid
Calcium (Ca)
Heavy metals (as Pb)
Iron (Fe)
Strontium (Sr)
0.01%
5 ppm
0.05%
0.05%
5 ppm
2 ppm
Maximum Limits
500
gm
4.00
T 15845 Barium oxide Lab-Grade
CAS 1304-28-5
UN-1884 IMDG 6.1/111
BaO
100
95%
gm
88%
F.W.169.34
Chloride (Cl)
Heavy metals (as Pb)
Insoluble in HO
Iron (Fe)
Substances not Pptd. by Sulfuric acid
0.02%
0.002%
1.0%
0.05%
1.0%
Maximum Limits
500
7.50
gm
99%
T16089 Benedict’s Reagent (Qualitative) Lab-Grade
Sensitivity test:
0.5% Glucose
1.0% Glucose
1.5% Glucose
>2.0% Glucose
- bluish green
- yellow
- brownish yellow
- brick-red colour
1.35
ml
T16190 Benzaldehyde Lab-Grade
CAS 100-52-7
UN-1990 IMDG-9/III
CjHjCHO
98.5%
F.W.261.34
2.10
F.W. 106.12
6.40
32.00
500
ml
6x500 ml
T16195 Benzaldehyde ACS/AR
CAS 100-52-7
UN-1990 IMDG-9/III
C6H5CHO
Maximum Limits
Chlorinated compounds (as Cl)
Hydrochloride acid
Nitrobenzene
Solubility
500
8
F.W. 153.33
8.50
CAS 1304-29-6
BaO2
500
T15500 Barium hydroxide Lab-Grade
CAS 12230-71-6
Ba(OH)2.8H2O
F.W.261.34
5.0-8.0
12.25
gm
T15447 Barium diphenylamine sulfonate Lab-Grade
5
25
99.5%
T15896 Barium peroxide Lab-Grade
T15300 Barium chromate Lab-Grade
CAS 10294-40-3
BaCrO4
CAS 10022-31-8
UN-1446 IMDG-5.I/II
Ba(NO3)2
pH of a 5% solution @ 25°C
ml
99%
F.W. 106.12
Passes test
Passes test
Passes test
Passes test
10.25
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T. BAKER LAB CHEMICALS
T 17007 Benzoic acid Lab-Grade
T 16344 Benzanilide Lab-Grade
CAS 93-98-1
C6H5CONHC6H5
100
500
99%
F.W. 197.24
3.85
15.40
gm
gm
CAS 65-85-0
UN-2769 IMDG-6.I/II
C;H.O?
500
5
99.5%
F.W. 122.12
3.10
28.00
gm
kg
T16398 Benzene crystallizable Lab-Grade
T 17012 Benzoic acid ACS/AR
CAS 71-43-2
C.H.
UN-1114 IMDG-3.2/II
Maximum Limits
Color (APHA)
Residue after evaporation
Substances darkened by sulfuric acid
Thiophene
Sulfur compounds (as S)
Water (H2O)
500
2.5
10
0.001%
Passes test
Passes test
(limit about 1 ppm)
0.005%
0.005%
1.60
6.55
ml
It
CAS 71-43-2
UN-1114 IMDG-3.2/H
CSH„
99.9%
99.0%
F.W.78.11
Maximum Limits
Residue after ignition
Insoluble in methanol
Chlorine compounds (as Cl)
Heavy metals (as Pb)
Substances reducing permanganatePasses test
500
gm
Color (APHA)
Residue after evaporation
Substances darkened by sulfuric acid
Thiophene
10
0.001%
Passes test
Passes test
(limit about 1 ppm)
0.005%
0.005%
500
2.5
1.75
7.40
ml
It
CAS 119-61-9
(C6H5)2CO
Melting point
F.W.182.22
within 2°C
including 48.5°C + 0.1cC
99.0%
99.7%
F.W.78.11
Color (APHA)
Residue after evaporation
Substances darkened by sulfuric acid
Sulfur compounds (as S)
Water (H2O)
10
0.001%
Passes test
0.005%
0.005%
Maximum Limits
2.25
11.25
CAS 71-43-2
UN-1114 IMDG-3.2/II
C6H6
99.8%
Ultraviolet absorbance (1 cm cell vs. water)
X(nm) 280 290 300 330 350 380-400
Limit 1.00 0.30 1.10 0.04 0.02
0.01
Sulfur compounds (as S)
Water (H2O)
500
6x500
1
ml
ml
It
T 17403 Benzoyl chloride Lab-Grade
CAS 98-88-4
UN-1736 IMDG-8/II
C6H5COCI
500
ml
99%
.
F.W.140.57
5.50
CAS 98-88-4
UN-1736 IMDG-8/II
C8H5COCI
Freezing point
99.0%
F.W. 140.57
-2.0° toO.O-C
0.005%
0.002%
0.001%
0.001%
Residue after ignition
Phosphorous compounds (as P)
Heavy metals (as Pb)
Iron (Fe)
8.80
ml
500
6x500 ml
T 17711 Benzyl acetate Lab-Grade
T 16437 Benzene for spectroscopy
Color (APHA)
Residue after evaporation
Substances darkened by sulfuric acid
Thiophene
10.85
gm
Maximum Limits
500
ml
6x500 ml
Maximum Limits
500
T 17408 Benzoyl chloride ACS/AR
T 16422 Benzene thiophene free ACS/AR
CAS 71-43-2
UN-1114 IMDG-3.2/II
C,H,
0.005%
0.005%
0.005%
5 ppm
17.00
Maximum Limits
Sulfur compounds (as S)
Water (H2O)
F.W.122.12
122°-123°C
T 17068 Benzophenone Lab-grade
T 16403 Benzene crystallizable ACS/AR
■jlKkl
'O'
CAS 65-85-0
UN-2769 IMDG-6.1/11
C,H6O2
Freezing point
F.W.78.11
CAS 140-11-4
UN-1736 IMDG-8/II
CH3CO2CH2CsH5
Chloridated compounds
500
10
0.001%
Passes test
Passes test
(limit about 1 ppm)
0.005%
0.05%
98.0%
ml
F.W.150.18
Passes test
4.80
T17739 Benzyl alcohol Lab-Grade
CAS 100-51-6
UN-1736 IMDG-8/II
C,HaO
500
2.5
ml
It
99%
F.W. 108.14
4.80
20.00
4.00
20.00
7.70
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T. BAKER LAB CHEMICALS
T17744 Benzyl alcohol ACS/AR
CAS 100-51-6
C;H,O
99.0%
F.W. 108.14
Maximum Limits
Color (APHA)
Residue after Ignition
Acetophenone (C6H5COCH3)
Benzaldehyde (CtH5CHO)
500
2.5
20
0.005%
0.02%
0.01%
ml
It
6.00
28.00
T17806 Benzyl benzoate Lab-Grade
CAS 120-51-4
CSH.COOCH2C6HS
500
98%
5.50
ml
-40%
Max. 5%
0.30
0.50
CAS 10035-06-0
Bi(NO3)2.5H2O
98%
F.W.485.07
4.50
20.00
gm
gm
CAS 7787-68-0
Bi2(SO4)3
90%
125
ml
4x125 ml
3.10
9.90
19.20
T 20875 Biuret Reagent indicator solution
125
ml
4x125 ml
1.25
3.75
T 21030 Boric acid Lab-Grade
99.5%
F.W.61.83
2.70
22.80
gm
kg
T 21035 Boric acid ACS/AR
99.5%
628-632 nm
0.60
0.90
gm
gm
T 20906 Brilliant Green 1% Aqueous solution
125
ml
4x125 ml
1.70
5.10
(C.l. NO. 24890)
pH 6.4-9.4 yellow-orange -red
5
10
1.50
2.30
gm
gm
T 21487 Bromine Lab-Grade
F.W.706.18
gm
CAS 10043-35-3
H3BO3
2.00
6.00
T 20951 Brilliant Yellow Lab-Grade
T 20867 Bismuth sulfate Lab-Grade
500
5
125
ml
4x125 ml
(C.l. No. 42040) absorption max
gm
gm
CAS 10043-35-3
H3BO3
T 21005 Borax Carmine (Grenacher) aqueous
staining solution
5
10
T 20572 Bismuth (111) nitrate Lab-Grade
250
3.40
10.20
T 20901 Brilliant Green Indicator Lab-Grade
C.l.NO. 21010
CAS 1051-38-6
C^HjX^HCI
F.W.461.40
DYE content
LOD(HOdegC)
100
500
125
ml
4x125 ml
T 21010 Brilliant Cresyl Blue indicator solution
F.W.212.25
T 20305 Bismark Brown Lab-Grade
5
10
T 21000 Borax Carmine (Grenacher) alcoholic
staining solution
F.W.61.83
CAS 7726-95-6
UN -1744 IMDG - 8/I
Br2
5x20
250
99.0%
F.W. 159.82
6.60
10.80
ml
ml
T 21492 Bromine ACS/AR
CAS 7726-95-6
UN-1744 IMDG-8/I
Br,
99.5%
Maximum Limits
F.W. 159.82
0.005%
0.05%
0.001%
Passes test
0.001%
2 ppm
5 ppm
Residue after evaporation
Chloride (Cl)
Iodine (I)
Organic bromine compounds
Sulfur compounds (as S)
Heavy metals (as Pb)
Nickel (Ni)
Maximum Limits
Insoluble in methanol
Nonvolatile with methanol
Chloride (Cl)
Phosphate (PO4)
Sulfate (SO4)
Calcium (Ca)
Heavy metals (as Pb)
Iron (Fe)
500
6x500
10
gm
gm
0.005%
0.05%
0.001%
0.001%
0.01%
0.005%
0.001%
0.001%
250
ml
1400
T21807 Bromobenzene Lab-Grade
CAS 108-86-1
UN-2514 IMDG-3.3/HI
C6H5Br
98.0%
F.W.157.01
6.80
8.10
40.50
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T. BAKER LAB CHEMICALS
T 23401 Bromothymol Blue powder Lab-Grade
T21851 Bromocresol Green Lab-Grade
CAS 76-59-5
CAS 76’60-8
F.W. 624.40
F.W. 698.04
C2|H,4Br4O5S
pH transition range:
pH 3.8 to 5.4
Abs.max pH 3.8
pH 5.4
LOD(110degC)
1
5
yellowish green to blue
438-443 nm
615-618 nm
3%
1
5
1.90
7.50
gm
gm
T 21856 Bromocresol Green indicator solution standard
pH transition range:
pH 3.8 to 5.4
C„HaBr2O$S
pH transition range:
pH 5.8 - 7.6
Abs. max:
pH 5.8
pH 7.6
1.05
3.15
F.W. 540.24
C2,H,0Br2S
pH transition range:
pH 5.2-6.8
Abs.max
pH 5.2
pH 6.8
1
5
T 23370 Buffer Tablet pH 4.0 Lab-Grade
10
tab
10x10 tab
T 23380 Buffer Tablet pH 9.2 Lab-Grade
427-431 nm
588-590 nm
0.50
2.00
10
tab
10x10 tab
CAS 123-86-4
UN-1123 IMDG - 3.2/1I
CH3COO(CH,)3CH3
Greenish yellow to blue violet
1.00
3.00
1.50
5.50
1.00
3.00
F.W.116.16
Color (APHA)
Residue after Evaporation
Titrable acid
Substances Darkened by sulfuric acid
Water (H2O)
n-Butyl alcohol (C4H9OH)
n-Butyl formate (HCOOC4H9)
n-Butyt propionate (C2H5COOC4Ha)
10
0.001%
0.0016 meq/g
Passes test
0.1%
0.2%
0.1%
0.1%
11.00
55.00
500
ml
6x500 ml
T 24458 n-Butyl alcohol Lab-Grade
T 23320 Bromophenol Red Lab-Grade
pH 5.2-7.0, yellow-reddish purple
gm
gm
99.5%
Maximum Limits
T 23309 Bromophenol blue indicator solution
125
ml
4X125 ml
F.W.116.16
3.10
ml
CAS 123-86-4
UN-1123 IMDG - 3.2/1!
CHjCOOtCHj^CHj
F.W.669.98
Passes test
pH 3.0 to pH 4.6
(Yellow to blue)
grn
gm
97%
T 24874 n-Butyl acetate ACS/AR
T 23304 Bromophenol blue ACS/AR pH indicator
CAS 115-39-9
C,9H,0O5SBr4
Clarity of solution
Visual transition interval
1.45
13.00
T 24869 n-Butyl acetate Lab-Grade
500
5.50
17.25
tX-ZJ
CAS 71-36-3
UN-1120 IMDG-3.3/III
(CH3)(CH2)3OH
500
2.5
T 23325 Bromophenol red indicator solution
125
ml
4X125 ml
1.45
13.00
greenish yellow - blue violet
125
ml
4x125 ml
5
25
1.45
13.00
T 23375 Buffer Tablet pH 7.0 Lab-Grade
T 21866 Bromocresol purple indicator solution standard
5
1.05
3.15
10
tab
10x10 tab
gm
gm
pH transition range:
pH 5.2 to 6 8
0.90
3.40
gm
gm
125
ml
4X125 ml
T 21861 Bromocresol purple Lab-Grade
CAS 115-40-2
430-435 nm
615-618 nm
T 23406 Bromo Thymol blue indicator solution
yellowish green to blue
125
ml
4x125 ml
yellow -blue
ml
It
98%
F.W.74.12
2.40
11.00
100
3.00
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T. BAKER LAB CHEMICALS
T 24463 n-Butyl alcohol ACS/AR
CAS 71-36-3
UN-1120 IMDG-3.34II
(CH3)(CH2)3OH
T 26583 iso-Butyl methyl ketone ACS/AR
99.5%
CAS 108-10-1
(CHjJjCHCHjCOCH,
Appearance
F.W.74.12
Maximum Limits
10
0.005%
0.0008 meq/g
Passes test
0.2%
0.1%
ml
ml
It
4.70
23.70
20.00
Color (APHA)
Residue after Evaporation
Titrable acid
Water
6
CAS 5743-04-4
(CHjCOOJjCd^HjO
500
F.W.74.12
6.50
ml
CAS 78-83-1
(CH3)2CH.CH2OH
500
99%
T 112582iso-Butyl alcohol ACS/AR
F.W.74.12
Passes test
Maximum Limits
500
6x500
250
500
3.70
18.50
98%
500
4.70
23.50
Melting point
100
500
0.003%
6.85
34.25
500
2.5
12
ml
It
99%
F.W. 100.16
21.40
99%
F.W.228.35
7.50 1'1
35.50
99.5%
Insoluble matter
Nitrate and Nitrite (as NO3)
Sulfate (SO,)
Ammonium (NH,)
Copper (Cu)
Iron (Fe)
Lead (Pb)
Substances not Pptd. by Hydrogen sulfide
(as sulfates)
Zinc(Zn)
F.W.74.12
Within 1,5’C
including 82.0cC±0.1°C
Min24"C
100
500
T 26578 iso-Butyl methyl ketone Lab-Grade
CAS 108-10-1
(CHjJjCHCHjCOCHj
F.W. 172.42
gm
gm
CAS 7790-78-5
CdCI2.2'/2H2O
500
ml
6x500 ml
62-66%
T 29102 Cadmium chloride hydrate ACS/AR
Maximum Limits
Residue after Evaporation
12.50
24.00
gm
CAS 7790-78-5
CdCI2.272H2O
T 24745 tert-Butyl alcohol ACS/AR
99.0%
0.001%
0.010%
0.001%
0.005%
0.005%
T 29097 Cadmium chloride hydrated Lab-Grade
F.W.74.12
500
ml
6x500 ml
CAS 75-65-0
(CH3)3COH
Boiling range
F.W.266.52
gm
gm
CAS 513-78-0
CdCO3
10
0.001%
0.0005 meq/g
0.1%
ml
ml
CAS 75-65-0
(CH3)3COH
99%
T 29084 Cadmium carbonate Lab-Grade
T 24740 tert-Butyl alcohol Lab-Grade
MB
15.10
Chloride (Cl)
Insoluble matter
Iron(Fe)
Lead(Pb)
Sulfate (SO,)
2.40
Color (APHA)
Residue after Evaporation
Titrable acid
Water (H2O)
gm
CAS 5743-04-4
(CH3COO)2Cd.2H2O
F.W.74.12
99%
F.W.266.53
Maximum Limits
ml
CAS 78-83-1
(CH3)2CH.CH2OH
Solubility in water
98%
T 29043 Cadmium acetate dihydrate ACS/AR
T112577iso-Butyl alcohol Lab-Grade
e
4.20
21.00
18.50
T 29038 Cadmium acetate dihydrate Lab-Grade
500
99.7%
15
0.005%
0.002 meq/g
0.1%
500
ml
6x500 ml
2.5
It
T 24466 n-Butyl alcohol for spectroscopy
CAS 71-36-3
UN-1120 IMDG - 3.8/III
(CH3)(CH2)3OH
F.W. 100.16
Clear
Maximum Limits
Color (APHA)
Residue after Evaporation
Titrable acid
Aldehydes
Butyl ether
Water (H2O)
500
6x500
2.5
99%
F.W.228.35
0.005%
0.003%
0.005%
0.005%
0.0005%
0.0005%
0.005%
0.2%
0.1%
11.50
45.70
gm
gm
T 29328 Cadmium nitrate Lab-Grade
CAS 10022-68-1
Cd(NO3)2.4H2O
X
100
500
cm
gm
99%
F.W.308.48
3.00
13.40
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T. BAKER LAB CHEMICALS
T 29951 Calcium carbonate precipitated ACS/AR
T 29333 Cadmium nitrate ACS/AR
CAS 10022-68-1
Cd(NO3)2.4H2O
CAS 471-34-1
CaCO3
F.W.308.47
Ammonium (NH,)
Chloride (Cl)
Copper (Cu)
Insoluble matter
Iron (Fe)
Lead (Pb)
Sulfate (SO,)
Zinc(Zn)
0.003%
0.005%
0.002%
0.005%
0.001%
0.005%
0.003%
0.05%
gm
23.50
500
500
98-103%
gm
F.W.769.52
15.10
99%
F.W.769.52
Maximum Limits
Insoluble matter
Loss on drying at 150°C
Chloride (Cl)
Nitrate and Nitrite (as NO3)
Arsenic (As)
Copper (Cu)
Iron (Fe)
Lead (Pb)
Substances not Pptd. by Hydrogen sulfide
(as Sulfates)
Zinc (Zn)
CAS 10035-04-8
CaCI2.2H2O
98.5%
Arsenic (as As)
Fluoride (F)
Heavy metals (as Pb)
Lead (Pb)
Magnesium and Alkali Salts
500
0.15%
0.1%
500
gm
gm
2.50
CAS 75-15-0
CS2
UN-1131 IMDG-3.1/1
F.W. 100.09
0.2%
0.0003%
0.005%
0.002%
0.0003%
2%
1%
0.0003%
0.004%
0.002%
0.0005%
4.0%
T 31804 Carbon Disulfide Lab-Grade
F.W. 76.14
min. 99.9%
45-47.5 deg C (95%)
Assay
Boiling Range
Maximum Limits
Acid insoluble substances
Arsenic (As)
Fluoride (F)
Heavy metals (as Pb)
Lead (Pb)
Loss on drying @200°C
Magnesium and Alkali salts
F.W.147.01
99.0-107.0%
Maximum Limits
T 29946 Calcium carbonate extra pure Lab-Grade
CAS 471-34-1
CaCO3
4.80
24.00
T 29962 Calcium chloride dihydrate Lab-Grade
0.005%
1.0%
0.001%
0.003%
0.0002%
0.002%
0.001%
0.003%
21.40
500
0.01%
0.01%
0.002 meq/g
0.001%
0.0015%
0.005%
0.002%
0.01%
0.003%
0.005%
0.001%
0.003%
0.02%
0.01%
0.1%
0.1%
500
gm
6x500 gm
T 29479 Cadmium sulfate ACS/AR
CAS 7790-84-3
3CdSO,.8H2O
'
Insoluble in dilute hydrochloric acid
Ammonium hydroxide Ppt.
Water soluble titrable base
Chloride (Cl)
Fluoride (F)
Oxidizing substances (as NO3)
Copper (Cu)
Sulfate (SO,)
Ammonium (NH,)
Barium (Ba)
Heavy metals (as Pb)
Iron (Fe)
Magnesium (Mg)
Potassium (K)
Sodium (Na)
Strontium (Sr)
T 29474 Cadmium sulfate Lab-Grade
CAS 7790-84-3
3CdSO,.8H2O
F.W. 100.09
99.0%
Maximum Limits
Maximum Limits
2.40
T 30408 Calcium hydroxide Lab-Grade
CAS 1305-62-0
Ca(OH)2
500
1.40
F.W.74.09
gm
2.45
T 30413 Calcium hydroxide ACS/AR
TSjTI
CAS 1305-62-0
Ca(OH)2
95-98%
F.W.74.09
-------- Maximum Limits
Insoluble in Hydrochloric acid
Chloride (Cl)
Sulfur compounds (as SO,)
Heavy metals (as Pb)
Iron (Fe)
Magnesium and Alkali salts (as Sulphate)
500
gm
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
0.03%
0.03%
0.1%
0.003%
0.05%
1.0%
8.50
13
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
T31250 Carmine Lab-Grade
T 30833 Calcium oxide selected lumps ACS/AR
CAS 1305-78-8
CaO
F.W.56.08
95.0%
Maximum Limits
Ammonium hydroxide Ppt.
Chloride (Cl)
Heavy metals (as Pb)
Insoluble in acetic acid
Iron(Fe)
Loss on Ignition
Nitrate (NO3)
Sulfate (SO,)
Znc(Zn)
500
6x500
1.0%
0.005%
0.01%
1.0%
0.1%
5.0%
0.01%
0.1%
0.015%
7.70
38.50
gm
gm
T 30830 Calcium oxide powder Lab-Grade
CAS 1305-78-8
CaO
500
95%
F.W.56.08
gm
1.90
T 31196 Calcium sulfate dihydrate ACS/AR
CAS 10101-41-4
CaSO,.2H2O
98.0-102.0%
F.W.172.17
Maximum Limits
Insoluble in dilute Hydrochloride acid0.02%
Chloride (Cl)
0.005%
Nitrate (NO3)
To pass test
(limit about 0.005%)
Carbonate (COJ
To pass test
Heavy metals (as Pb)
0.002%
Iron(Fe)
0.001%
Magnesium and alkali salts (as Sulfate)
0.3%
500
gm
6x500 gm
9.35
46.75
T 31201 Carbol Fuchsin powder Lab-grade
CAS 4197-24-4
1
5
0.25
1.00
T 31254 Casein Soluble Lab-Grade
500
gm
min. 12.0%
7.0%
10.80
T 31206 Carbol Fuchsin (Dilute) staining solution
(Ziehl Neelsen strong solution)
125
ml
4X125 ml
1.05
3.15
T 31221 Carbol Fuchsin (Strong) staining solution
(Ziehl Neelsen strong solution)
125
4X125
ml
ml
1
5
gm
gm
2.50
9.70
i 31858 Carbon Tetra Chloride Lab-Grade
CAS 56-23-5
CCI,
UN-1846 IMDG-6.1/II
99.9%
500
12x500 ml
1
It
2.5
It
F.W. 153.82
2.60
27.00
4.70
10.90
T 31863 Carbon Tetra Chloride ACS/AR
CAS 56-23-5
CO,
UN-1846 IMDG-6.1/II
Maximum Limits
Color (APHA)
Residue after evaporation
Water soluble titrabic acid
Free chlorine (Cl)
Sulfur compounds (as S)
99.9%
F.W.153.82
10
0.001%
0.0005 meq/g
Passes test
Passess test
(limit about 0.005%)
Passes test
Iodine-Consuming substances
■passes test
Substances darkened by sulfuric acid
passes test
Suitability for use in dithizone test
3.00
15.00
11.90
500
ml
6x500 ml
2.5
It
1.25
3.75
CAS 56-23-5
ca4
99.9%
F.W. 153.82
UN-1846 IMDG-6.1/II
Ultraviolet absorbance (1cm cell vs. water)
(nm)265 270 280 290 300 330-400
Limit 1.00 0.35 0.10 0.05 0.02 0.01
Maximum Limits
10
Color (APHA)
0.001%
Residue after Evaporation
0.005 meq/g
Water-soluble titrable acid
passes test
Free Chlorine (Cl)
passes test
Sulfur compounds (as S)
(limit about 0.005%)
Iodine Consuming substances
passes test
Substance darkened by Sulfuric acid
passes test
Suitability for use in Dithizone tests
passes test
500
11.00
ml
T 31893 Carbon Tetra Chloride for HPLC
CAS 56-23-5
CCl,
UN-1846 IMDG-6.1/11
500
14
- 50%
565-570 (525-532) nm
T 31883 Carbon Tetra Chloride for spectro Scopy
gm
gm
CAS 9005-46-3Nitrogen content
LCD (105 deg C)
C.l. NO. 75470
CAS 1390-65-4
Carminic acid (spectro)
Absorption max. (DMSO)
ml
99.9%
F.W.153.82
5.50
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T BAKER LAB CHEMICALS
T 35405 Chloroform ACS/AR
T 32555 Chlorine Water saturated Lab-Grade
500
ml
CAS 67-66-3
UN • 1888 IMDG - 6.1/111
CHCI.
99.0-99.4%
1.20
T 32428 Ceric sulfate Lab-Grade
CAS 13590-82-4
Ce(SO.)2.4H2O
85%
10%
0.001%
Passes test
(limit about 0.005%)
Passes test
Acid and Chloride
Passes test
Free chlorine (Cl)
0.05 ppm
Lead(Pb)
Passes test
Substances darkened by sulfuric acid
Passes test
Suitability for use in dithizone tests
Color (APHA)
Residue after evaporation
Acetone and Aldehyde (as (CHJ2COJ
F.W.528.43
Maximum Limits
Insoluble matter
Iron (Fe)
Phosphate (PO.)
0.1%
0.1%
9.1%
100
6.40
gm
T 32433 Ceric sulfate ACS/AR
CAS 13590-82-4
Ce(SO.)2.4H2O
500
6x500
1
2.5
F.W.528.43
94%
Maximum Limits
Insoluble matter
Chloride (Cl)
Iron (Fe)
Phosphate (PO.)
0.1%
0.001%
0.1%
0.01%
gm
7.00
100
500
gm
6x500 gm
99%
F.W.112.56
Maximum Limits
CAS 10060-12-5
CrClj.eHjO
T 36355 p-Chlorobenzoic acid Lab-Grade
CAS 74-11-3
CICcH,COOH
100
500
99%
F.W.156.57
3.00
11.40
gm
gm
99.0%
F.W.266.45
Maximum Limits
4.50
22.50
500
ml
6x500 ml
19.25
T 39008 Chromium (III) chloride hexahydrate ACS/AR
30%
0.02%
0.004 meq/g
Color (APHA)
Residue after evaporation
Titrable acid
4.25
21.25
8.25
18.80
ml
ml
It
It
T 39003 Chromium (111) chloride hexahydrate
Lab-Grade
T 33416 mono-Chlorobenzene ACS/AR
CAS 108-90-7
UN-1134 IMDG 0 3.3/III
C6H5CI
F.W.119.38
Maximum Limits
Insoluble matter
Sulfate (SO.)
Iron (Fe)
0.01%
0.01%
0.01%
500
gm
6x500 gm
30.25
151.25
T 39068 Chromium (III) nitrate nonahydrate
Lab-Grade
O'
CAS 7789-02-8
Cr(NO3)3.9H2O
99%
F.W.400.15
T 35400 Chloroform Lab-Grade
CAS 67-66-3
UN -1888 IMDG - 6.1/111
CHCL,
500
ml
6x500 ml
1
It
2.5
It
26.10
130.50
500
gm
6x500 gm
99.5%
F.W.119.38
2.80
14.00
5.00
11.50
T 39082 Chromium (III) oxide green Lab-Grade
CAS 1308-38-9
Cr2O3
500
99%
F.W.151.99
6.50
gm
T 39087 Chromium (III) oxide green ACS/AR
CAS 1308-38-9
Cr2O.
99%
F.W.151.99
Maximum Limits
Water soluble salts (Wt.%)
0.2%
500
15.00
gm
T 38976 Chromium trioxide Lab-Grade
CAS 1333-82-0
UN -1463 IMDG-5.1/11
CiO3
500
gm
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
99%
F.W.99.99
4.25
15
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
©
T. BAKER LAB CHEMICALS
T 38981 Chromium trioxide ACS/AR
CAS 1333-82-0
UN-1463 IMDG-5.1/11
CrO3
T 40100 Cobalt (II) acetate tetrahydrate Lab-Grade
CAS 6147-53-1
(CH3COO)2Co.4HjO
99.0%
F.W.99.99
Maximum Limits
Insoluble matter
Chloride (Cl)
Nitrate (NO3)
Sulfate (SO4)
Sodium (Na)
Iron, Aluminium, Barium
0.01%
0.005%
0.05%
0.005%
0.2%
0.03%
500
99%
F.W.148.16
gm
21.40
T 39793 Citric acid anhydrous Lab-Grade
CAS 5949-29-1
' C6HaO7
500
6X500
99.5%
F.W.210.14
4.10
20.50
gm
gm
T 39798 Citric acid anhydrous ACS/AR
CAS 5949-29-1
CsH,O7
99.7%
F.W.210.14
Insoluble matter
Residue after Ignition
Chloride (Cl)
Oxalate (C2O4)
0.005%
0.02%
0.001%
Passes test
(limit about 0.05%)
Phosphate (PO.)
0.001%
Sulfate (SOJ
0.002%
Iron (Fe)
3 ppm
Lead (Pb)
2 ppm
Substances carbonizable by Hot sulfuric acid
(Tartrates, etc.)
Passes test
6.25
31.25
500
gm
6x500 gm
T 39796 Citric acid monohydrate Lab-Grade
500
99%
gm
F.W.237.93
Min. 98%
0.03%
'
0.01%
F.W.210.14
4.40
99.0-102.0%
F.W.210.14
Maximum Limits
Insoluble matter
Residue after Ignition
Chloride (Cl)
Oxalate (C2O4)
0.005%
0.02%
0.001%
Passes test
(limit about 0.05%)
Phosphate (POJ
0.001%
Sulfate (SO4)
0.002%
Iron (Fe)
3 ppm
Lead (Pb)
2 ppm
Substances carbonizable by Hot sulfuric acid
(Tartrates, etc.)
Passes test
500
gm
6x500 gm__________________________
9.40
gm
T 40390 Cobalt oxide ACS/AR
CAS 1308-06-1
Co3O4
F.W.240.8
70.0%
Maximum Limits
Chloride (Cl)
Iron(Fe)
Nickel (Ni)
Substances not Pptd. by (NH4)2S
Sulfate (SOJ
0.01%
0.1%
0.2%
0.5%
0.2%
50
82.50 •
gm
CAS 10026-24-1
CoSO4.7HjO
6-80
34 00
F.W.281.0
98.0%
500
gm
6x500 gm
35.70
178.50
T 40489 Cobalt (II) sulfate heptahydrate ACS/AR
CAS 10026-24-1
CoSO4.7H2O
F.W.281.0
99%
Maximum Limits
Chloride (Cl)
Copper (Cu)
Insoluble matter
Lead (Pb)
Nickel (Ni)
Substances not Pptd. by (NH4)2S
Zinc (Zn)
500
T 39801 Citric acid monohydrate ACS/AR
CAS 5949-29-1
CH.Oj.HjO
CAS 7791-13-1
CoCIj.6H2O
T 4 3484 Cobalt (H) sulfate heptahydrate Lab-Grade
Maximum Limits
CAS 5949-29-1
C6HbO7.HjO
39.00
195.00
T 40178 Cobalt (11) Chloride Lab-Grade
100
T 39570 Cinnamic acid Lab-Grade
F.W.249.08
500
gm
6x500 gm
Assay (ex co)
Sulphate
Iron
500
gm
6x500 gm
CAS 140-10-3
C6H5CH:CHCOOH
99.0%
■
gm
0.001%
0.002%
0.01%
0.005%
0.1%
0.2%
0.02%
45.00
T 40715 Congo red pH indicator Lab-Grade
CAS 571-58-0
[C.1.22120]
CjjHjjN, I la,O..S,
F.W.696.68
Absorpiicn Max.(in water plus 1ml 1%Na2CO ,)
497 nm
25
100
gm
gm
1.00
3.50
T 40720 Congo Red indicator solution
125
ml
4x125 ml
1.00
3.00
T 40725 Cotton Blue indicator solution
125
mi
4x125 ml
3.00
9.00
__________ _____________ _________ _ _____ ____ ___ ,
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
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T. BAKER LAB CHEMICALS
T 41200 Cotton Blue for m.s Lab-Grade
25
100
T 41667 Cupric chloride dihydrate ACS/AR
gm
gm
4.70
14.25
CAS 95-48-7
UN-2076 IMDG-6.1 /II
ch3c6h_oh
F.W.108.14
500
ml
6x500 ml
5.70
28.50
8.50
ml
CAS 1733-12-6
C21HibOjS
Absorption Max.(in Borate Buffer; pH 9)..
Visual Transition intervals
1.10
4.25
T 41327 Crystal violet for microscopy Lab-Grade
96-100.5.0%
[C.I.42555]
F.W.407.99
Maximum Limits
Water
Residue on Ignition
Alcohol-Insoluble substances
Arsenic (As)
Lead (Pb)
Zinc (Zn)
25
100
7.5%
1.5%
1.0%
- 0.001%
0.003%
0.05%
1.50
4.70
gm
gm
ml
ml
F.W.239.10
7.10
35.50
gm
gm
T 41662 Cupric chloride dihydrate Lab-Grade
500
gm
14.50
72.50
500
99.0%
gm
F.W.241.60
5.00
CAS 3251-23-8
Cu(NOJ)2.3H2O
99.5%
F.W.241.60
Maximum Limits
Insoluble matter
0.01%
Chloride (Cl)
0.002%
Sulfate (SO4)
0.01%
Substances not Pptd. by hydrogen sulfide
(as Sulfate)
0.05%
Lead(Pb)
0.001%
Iron(Fe)
0.005%
Ammonium sulfide metals other than Iron (as Ni)
Passes test
(limit about 0.01%)
8.00
40.00
500
gm
6x500 gm
T 41933 Cupric oxide Lab-Grade
CAS 1317-38-0
CuO
500
97%
F.W.79.55
14.25
gm
99.0%
F.W.79.55
Maximum Limits
CAS 12069-69-1
CuCO3.Cu(OH)2H2O
CAS 10125-13-0
UN-2802 IMDG-8/III
CuCI2.2H2O
CAS 3251-23-8
Cu(NO3)2.3H2O
CAS 1317-38-0
CuO
T 41648 Cupric carbonate basic Lab-Grade
500
6x500
0.10%
0.005%
0.01 %
T 41938 Cupric oxide ACS/AR
T 41242 Crystal violet staining solution (gram's)
125
4x125
0.01%
0.015%
0.005%
T 41881 Cupric nitrate trihydrate ACS/AR
F.W.382.44
570 (367) nm
pH 2.0 to pH 3.0
(Orange to Yellow)
pH 7.2 to pH 8.8
(Yellow to Red)
gm
gm
CAS 548-62-9
CaHMCIN3
Insoluble matter
Nitrate (NO3)
Sulfate (SO4)
Substances not Pptd. by hydrogen sulfide
(as Sulfate)
Iron (Fe)
Ammonium sulfide metals other than Iron
T 41876 Cupric nitrate trihydrate Lab-Grade
F.W.108.14
99%
T 41283 Cresol red pH indicator Lab-Grade
5
25
F.W.170.48
500
gm
6x500 gm
T 41222 p-Cresol Lab-Grade
500
99.0%
Maximum Limits
T 41215 o-Cresol Lab-Grade
CAS 106-44-5
UN-2076 IMDG-6.1/11
CH3C6H4OH
CAS 10125-13-0
UN-2802 IMDG-8/lll
CuCI2.2H2O
99%
F.W.170.48
6.25
Insoluble in dilute Hydrochloric acid
Carbon compounds (as C)
Chloride (Cl)
Nitrogen compounds (as N)
Sulphur compounds (as SO4)
Free Alkali
Sulfate (SO4)
Substances not Pptd. by hydrogen sulfide
(as Sulfate)
Ammonium hydroxide precipitate
500
gm
6x500 gm
0.02%
0.01 %
0.005%
0.002%
0.02%
Passes test
0.01%
0.2%
0.1%
45.60
228.00
T 42139 Cupric sulfate penta hydrate Lab-Grade
CAS 7758-99-8
CuSO4.5HjO
500
gm
6x500 gm
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
99%
F.W.249.68
2 30
14.00
17
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T. BAKER LAB CHEMICALS
T 42144 Cupric sulfate ACS/AR
CAS 7758-99-8
CuSO4.5H2O
99.5%
T 46192 Dextrine white Lab-Grade
F.W.249.68
Maximum Limits
Insoluble matter
Chloride (Cl)
Nitrogen compounds (as N)
Substances not Pptd. by hydrogen sulfide
(as Sulfates)
Iron (Fe)
Ammonium sulfide metals other than Iron
500
gm
6x500 gm
0.005%
0.001%
0.001%
0.1%
0.003%
0.005%
4.50
6
500
99.0%
F.W.84.16
ml
CAS 110-82-7
UN - 1145 IMDG 3.1/11
C6Hu
Appearance
99.0%
F.W.84.16
Clear
Color (APHA)
Residue after evaporation
Substances darkened by sulfuric acid
Water (H20)
10
0.002%
Passes test
0.02%
Maximum Limits
500
gm
4.80
T 83600 Dextrose anhydrous Lab-Grade
CAS 50-99-7
c.h,2os
F.W.180.16
gm
kg
1.55
13.00
500
5
CAS 50-99-7
C6K2Os
Specific rotation, [a].
T 431>11 Cyclohexane ACS/AR
6
500
T 83605 Dextrose anhydrous ACS/AR
T 43206 Cyclohexane Lab-Grade
CAS 110-82-7
UN-1145 IMDG-3.1/11
C6H,2
CAS 9004-53-9
(C.H,0O5)„-xH2O
ml
6.00
F.W.180.16
+52.5° to +53.0°
Maximum Limits
0.005%
0.2%
0.02%
0.002 meq/g
0.01%
0.005%
Passes test
5 ppm
5 ppm
Insoluble matter
Loss on drying @ 105°C
Residue after Ignition
Titrable acid
Chloride (Cl)
Sulfate and sulfite (as SO4)
Starch
Heavy metals (as Pb)
Iron (Fe)
1.80
9.00
500
gm
6x500 gm
T 83612 Dextrose monohydrate ACS/AR
CAS 5996-10-1
C6H1?O6.HjO
F.W.198.17
Maximum limits
T 43221 Cyclohexane for spectroscopy
uj
CtH12
99.7%
F.W.84.16
Ultraviolet absorbance (1cm cell vs.water)
X(nm) 210 220 230 240 250 260 300-400
Limit
1.00 0.50 0.20 0.08 0.03 0.02 0.01
Maximum Limits
Color (APHA)
Residue after Evaporation
Substances Darkened by Sulfuric acid
Water
10
0.001%
Passes test
0.02%
7.50
37.50
500
ml
6x500 ml
T 43316 Cyclohexanone Lab-grade
CAS 108-94-1
UN -1915 IMDG-3.3/1II
C,H,0O
500
2.5
99.0%
F.W.98.15
T 43321 Cyclohexanone ACS/AR
MH
CAS 108-94-1
UN-1915 IMDG-3.3/III
CeH10O
Appearance
500
gm
6x500 gm
T 54480 Diazo A Reagent indicator solution
2.50
7.50
125
ml
4x125 ml
2.50
7.50
125
ml
4x125 ml
T 54493 Diethanolamine Lab-Grade
CAS 111-42-2
C4H„NO2
500
ml
6x500 ml
99.5%
1.75
8.75
T 54485 Diazo B Reagent indicator solution
3.60
16.00
ml
It
0.00002%
0.005%
' 0.0005%
0.005%
0.0005%
Passes test
0.005%
Arsenic (As)
Chloride (Cl)
Heavy metals (as Pb)
Insoluble matter
Iron (Fe)
Starch
Sulfate and sulfite (as SO,)
98%
F.W.105.14
4.80
24.00
F.W.98.15
Clear
Maximum Limits
Water (H20)
10
0.05%
0.05%
500
ml
12x500 ml
6.80
74.00
Color (APHA)
Residue after evaporation
—-
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T BAKER LAB CHEMICALS
IT 54498 Diethanolamine ACS/AR
CAS 111-42-2
C4H„NO2
Apparent equivalent weight
99.5%
T 65530 Dimethyl sulfoxide Lab-Grade
CAS 67-68-5
CH3SOCH3
F.W.105.14
104.0-106.0
Maximum Limits
15
0.005%
1.0%
1.0%
0.15%
Color (APHA)
Residue after Ignition
Monoethanolamine
Triethanolamine
Water (H2O)
.500
ml
6x500 ml
2.5
It
CAS 67-68-5
CH3SOCH3
Appearance
■
CAS 109-89-7
UN-1154 IMDG-3.1/11
(C2H.)2NH
99.5%
500
ml
6x500 ml
2.5
It
6
99.5%
500
ml
6x500 ml
500
500
500
ml
6x500 ml
2.5
It
99.5%
F.W.74.12
0.0001%
10
1 ppm
0.001%
0.0002 meq/g
0.001%
Passes test
4.20
21.00
19.50
EBB
CAS 123-91-1
UN-1165 UMDG - 3.2/1I
C4H3O2
99%
100
gm
F.W.88.11
8.25
41.25
T 66894 1,4-Dioxan ACS/AR
CAS 123-91-1
C4H3O2
Freezing point
99.5%
F.W.88.11
Min.11.0°C
Maximum Limits
20
0.005%
0.005%
0.0016rheq/g
0.01%
0.05%
Color (APHA)
Peroxide (as H2O2)
Residue after evaporation
Titrable acid
Carbonyl (as HCHO)
Water (H2O)
9.70
42.50
F.W.116.12
Approx.240°C
Passes test
Maximum Limits
Insoluble in alcohol
Residue after Ignition
10.70
T 66889 1,4-Dioxan Lab-Grade
T 63713 Dimethyl glyoxime ACS/AR
CAS 95-45-4
(CH3C(NOH)C(NOH)CH3
99%
Melting point
Suitability for nickel determination
F.W.212.12
.
gm
500
ml
6x500 ml
Maximum Limits
Color (APHA)
Peroxide (as H2O2)
Residue after Ignition
Titrable acid
Carbonyl (as HCHO)
Substances darkened by sulfuric acid
9.60
F.W.74.12
T 56005 Diethyl ether ACS/AR
CAS 60-29-7
UN-1155 IMDG-3.1/1
(C.H^O
Peroxide Inhibitor (BHT)
F.W.168.11
gm
CAS 99-34-3
C^4N2O6
3.50
15.25
MH
98%
T 66183 3-5-Dinitrobenzoic acid Lab-Grade
11" 56000 Diethyl ether Lab-Grade
CAS 60-29-7
UN-1155 IMDG-3.1/1
(C^O
9.40
47.00
T 66152 m-Dinitrobenzene for synthesis Lab-Grade
CAS 99-65-0
UN-1597 IMDG-6.1/11
C6H,(NO2)2
F.W.73.14
-r
7.10
35.50
F.W.78.13
Clear
500
ml
6x500 ml
T 55064 Diethylamine ACS/AR
CAS 109-89-7
UN-1154 IMDG-3.1/11
(CjH^NH
99.5%
Residue after evaporation
0.01%
Titrable acid
0.001 meq/g
Substances darkened by Potassium hydroxide
Passes test
Water (H2O)
0.1%
F.W.73.14
4.10
20.50
18.00
7.70
38.70
36.70
.
'
Maximum Limits
T 55059 Diethylamine Lab-Grade
-"AT1
F.W.78.13
T 65535 Dimethyl sulfoxide ACS/AR
8.80
44.00
500
ml
6x500 ml
99%
0.05%
0.05%
T 67430 Diphenyl L^b-Grade
CAS 92-52-4
C,2H10
100
gm
98%
F.W.154.21
3.40
6.10
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T. BAKER LAB CHEMICALS
T 67517 Diphenylamine ACS/AR
CAS 122-39-4
(C6Fy,NH
Melting point
Senstitivity to nitrate
Solubility in alcohol
99%
T 71815 Esbach's Reagent indicator solution
F.W. 169.23
52.5°-54.0°C
Passes test
Passes test
Maximum Limits
Residue after Ignition
Nitrate (NO3)
0.03%
Passes test
100
gm
6x100 gm
Refractive index (n)xD
—*
4.40
ml
“““
4.45
ml
CAS 141-43-5
UN-2491 IMDG -8/III
CHjOHCHjNHj
F.W.61.08
99%
ml
ml
Color (APHA)
Iron (Fe)
Heavy metals (as Pb)
Water (H2O)
1.50
4.50
500
1.50
4.50
CAS 548-24-3
C_HfBr,NJMa_O.
6
3.10
10.50
125
ml
4x125 ml
1.05
3.15
T 71296 Eosin yellow for microscopy Lab-Grade
[45380]
F.W.691.86
CAS 548-26-5
C20H6Br4Na2Os
3.15
10.00
gm
gm
T 71300 Eosin Yellow stain solution (2% w/v)
125
ml
4x125 ml
T 71800 Eriochrome Black T Indicator solution
1-50
4.50
T 71803 Eriochrome black T ACS/AR
CAS 1787-61-7
Cx_H,2N3NaO7S
Clarity of solution
Suitability as complexometric indicator
F.W.88.11
99%
2.25
11.25
9.70
CAS 141-78-6
UN-1173 IMDG-3.2/II
CH3COOC2H5
99%
F.W.88.11
Color (APHA)
Residue after evaporation
Water (H2O)
Titrable acid
Substances darkened by sulfuric acid
10
0.003%
0.2%
0.0009 meq/g
Passes test
Maximum Limits
4.00
20.00
18.50
500
ml
6x500 ml
2.5
It
T 51900 Ethylene Chloride Lab-Grade
105
3.15
125
ml
4x125 ml
CAS 141-78-6
UN-1173 IMDG-3.2/II
CHjCOOCjHj
T76 577 Ethyl acetate ACS/AR
d
T 70905 Eosin Blue stain solution (2% w/v)
6.35
ml
500
ml
6x500 ml
2.5
It
[45400]
F.W.624.09
gm
gm
15
5 ppm
5 ppm
0.30%
T 76672 Ethyl acetate Lab-Grade
T 70900 Eosin blue for microscopy Lab-Grade
20
F.W.61.08
Maximum Limits
125
ml
4x125 ml
25
100
99%
T 71977 mono-Ethanolamine ACS/AR
1.515-1.525
T 68725 Ehlrich's Reagent
25
100
CAS 141-43-5
UN-2491 IMDG - 8/III
CHjOHCHjNHj
500
T 68775 Drabkin's Reagent
125
4x125
1.40
4.20
T 71972 mono-Ethanolamine Lab-grade
5.70
28.50
T 68710 D.P.X. Mountant Lab-Grade
250
125
ml
4x125 ml
CAS 107-06-2
CICHjCH,CI
Assay (GC)
B.P.
Free Chlorine
500
ml
6x500 ml
2.5
It
F.W. 98.96
Min. 99.0%
82-84 deg C(95%)
0.002%
2.10
10.50
10.00
[14645]
F.W.461.38
Passes test
Passes test
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T. BAKER LAB CHEMICALS
T106791 Ethylene glycol monomethyl ether
T 74352 Ethylenediamine tetraacetic acid
disodium salt ACS/AR
CAS 6381-92-6
C,0H,4OeNa2N2.2HJO
pH of a 5% solution @ 25°C
98%
F.W.372.24
4.0-6.0
G3
ch3och2ch2oh
Maximum Limits
Maximum Limits
Insoluble matter
Nitrilotriacetic acid [(HOCOCH2)3N)
Heavy metals (as Pb)
Iron(Fe)
100
6x100
500
6x500
0.005%
0.1%
0.005%
0.01%
2.00
10.00
9.40
47.00
gm
gm
gm
gm
1.50
4.50
T106795Eucalyptus Oil
T79870 Fast Green indicator solution
1.50
4.50
99%
C.l. NO. 42000
F.W. 927.02
CsoH^Np,
Dye Content (Titanometry, dries)
Abs. max. (H2O)
F.W.62.07
2.60
11.40
ml
It
T 71883 Ethylene glycol ACS/AR
99%
3.70
18.50
16.40
T 72344 Ethylene glycol monoethyl ether ACS/AR
F.W.90.12
0.9290-0.9330
Maximum Limits
0.005%
0.1%
Acidity (as CH3COOH)
Water (H2O)
5.80
29.00
ml
ml
T 106785 Ethylene glycol monomethyl ether
Lab-Grade
CAS 109-86-4
UN-1188 IMDG - 3.3/1II
CHjOCHjCHjOH
500
2.5
ml
It
500
99%
0.20
0.80
gm
gm
F.W.76.10
500
23.70
3.85
ml
T79878 Fehling Solution 'B' Lab-Grade
500
ml
7.10
T 79882 Ferric chloride anhydrous Lab-Grade
j
—*
■
CAS 7705-08-0
UN-1173 IMDG-8/III
FeCI3
500
96%
F.W.162.21
gm
1.80
T 79887 Ferric chloride anhydrous ACS/AR
*=l
99.5%
-90%
616-620 nm
T79874 Fehling Solution 'A' Lab-Grade
10
0.005%
0.005%
0.5 ppm
0.1 ppm
0.10%
500
ml
6x500 ml
2.5
It
1
5
F.W.62.07
1.1151-1.1156
Maximum Limits
Color (APHA)
Residue after evaporation
Acidity (as CH3COOH)
Chloride (Cl)
Iron (Fe)
Water (H2O)
1.00
3.00
T79890 Fast Green (Malachite green)Lab-Grade
T 71878 Ethylene glycol Lab-Grade
500
6x500
3.25
9.75
125
ml
4x125 ml
125
ml
4x125 ml
CAS 110-80-5
UN-1171 IMDG-3.3/III
C2H5O.CH2CH2OH
Specific gravity @ 20720cC
6.80
34.00
500
ml
6x500 ml
T 74335 E.D.T.A. Solution N/50
CAS 107-21-1
CH2(OH)CH2OH
Specific gravity @ 20°/20°C
10
0.002 meq/g
0.1%
125
ml
4x125 ml
125
ml
4x125 ml
500
2.5
F.W.76.10
99.5%
Color (APHA)
Titrable acid
Water (H2O)
T 74330 E.D.T.A. Solution N/10
CAS 107-21-1
CH2(OH)CH2OH
UN - 1188 IMDG - 3.3/III
CAS 7705-08-0
UN -1773 IMDG - 8/UI
FeCI3
98%
F.W. 162.21
Maximum Limits
Alkalies and Earths (as SO4)
Copper (Cu)
Ferrous chloride (FeCI2)
Insoluble in HCI
Nitrate (NO3)
Phosphorous compounds (as PO4)
Sulfate (SO4)
Zinc (Zn)
0.3%
0.05%
1.5%
1.0%
0.01%
0.03%
0.01%
0.05%
500
16.50
gm
T 79886 Ferric chloride hexahydrate Lab-Grade
CAS 10025-77-1
FeCI3.6H2O
500
gm
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
97%
F.W.270.3
5.40
21
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T. BAKER LAB CHEMICALS
T 79891 Ferric chloride hexahydrate ACS/AR
CAS 10025-77-1
FeCI3.6H2O
T 81971 Formic acid 85% Lab-Grade
F.W.270.3
98%
Maximum Limits
0.01%
0.01%
0.01%
0.01%
0.003%
Passes test
(limit about 0.002%)
Substances not Pptd. by Ammonium hydroxide
(as Sulfates)
0.1%
Zinc(Zn)
0.003%
Insoluble matter
Nitrate (NO3)
Phosphorous compounds (as POJ
Sulfate (SO.)
Copper (Cu)
Ferrous Iron (Fe'!)
500
gm
10.00
T 30" 78 Ferric nitrate Lab-Grade
CAS 7782-61-8
UN-1466 IMDG -5.1/111
FetNO^.SHjO
98%
F.W.404.0
Ferrous iron
Chloride (Cl)
0.01%
0.01%
gm
2.00
T 80655 Ferrous sulfate heprahydrate Lab-Grade
CAS 7782-63-0
FeSO..7H;O
500
99%
F.W.278.01
gm
1.25
T 80660 Ferrous sulfate heptahydrate ACS/AR
CAS 7782-63-0
FeSO4.7H2O
F.W.278.02
99.0%
Maximum Limits
Insoluble matter
Chloride (Cl)
Phosphate (PO J
Copper (Cu)
Ferric Iron (Fe1-)
Manganese (Mn)
Substances not Pptd. by Ammonium hydroxide
Znc(Zn)
500
gm
6x500 gm
0.01%
0.001%
0.001%
0.005%
0.1%
0.05%
0.05%
0.005%
5.50
27.50
T 81852 Formaldehyde solution 37-41 % w/v ACS/AR
CAS 50-00-0
UN -1198 IMDG-3.3/III
HCHO
Preservative (CH3OH)
37-41%
F.W.30.03
10-15%
Maximum Limits
Color (APHA)
Residue after Ignition
Titrable acid
Chloride (Ct)
Suffate (SOJ
Heavy metals (as Pb)
Iron(Fe)
500
ml
6x500 ml
2.5
it
22
CAS 64-18-6
UN-1779 IMDG-8/II
HCOOH
Dilution test
10
0.005%
0.006 megg
5 ppm
0.002%
5 ppm
5 ppm
120
&00
5.00
F.W. 46.03
Passes test
85%
Maximum Limits
0.4%
0.001%
0.004%
Acetic acid
Heavy metal (as Pb)
Sulfate (SO.)
2.90
13.00
T 81972Formic acid 90% Lab-Grade
CAS 64-18-6
UN-1779 IMDG-8/II
HCOOH
f
Maximum Limits
500
*
=?
“•<
F.V'.46 03
33.0%
4.35
ml
T 81977Formic acid 90% ACS/AR
CAS 64-18-6
UN-1779 IMDG-8/II
HCOOH
Dilution Test
F.W.46.03
Passes test
88.0%
Maximum Limits
Color (APHA)
Residue after Evaporation
Acetic acid (CH3COOH)
Ammonium (NH.)
Chloride (Cl)
Sulfate (SO.)
Sulfite (SO3)
Heavy Metals (as Pb)
Iron (Fe)
500
6x500
15
0.002%
0.4%
0.005%
0.001%
0.002%
Passes test
5 ppm
5 ppm
5.40
27.00
ml
ml
T 81974 Formic acid 98-100%Lab-Grade
CAS 64-18-6
HCOOH
UN-1779 IMDG-8/ll
500
2.5
ml
It
.
8.85
39.50
T 82500 d- Fructose Lab-Grade
CAS 57-48-7
Specific rotation (a)- D
Lead
500
gm
-92 to - 88 deg
0.0002%
9.25
T 82505 d-Fructose ACS'AR forbtochemistiy & microbiology
CAS 57-48-7
C,H.3O5
Acidity
Color of solution
F.W. 180.16
To pass test
To pass test
Maximum Limits
Glucose
Loss on drying
Residue on Ignition
Chloride (Ct)
Scifate (SOJ
Arsenic (As)
Caidum and Magnesium (as Ca)
Heavy Metals (as Pb)
H/droxymeT /furfural
250
gm.
0.2%
0.5%
0.5%
0.018%
0.025%
0.0001%
0.005%
0.0005%
To pass test
9.10
Lab & Genera! Exports (Pvt) Ltd. 11/1, Hosur Road. Bangalore-560 029. India
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T. BAKER LAB CHEMICALS
T 84601 Gram's Stain No. 3 (Acetone Alcohol)
T 82600Gentian Violet 2% (Aqueous)
500
ml
T83359Gibberelic acid Lab-Grade
CAS 77-06-5
CwHaO6
90%
ml
ml
1-50
4 50
T 84701 Gram's Stain No. 4 (Safranine 'O').
F.W.346.38
gm
1
125
4x125
5.25
125
4x125
3.40
ml
ml
1.50
4.50
T 88700 Hematoxylin stain solution (Delafield)
T 83945Glycerin Lab-Grade
CAS 56-81-5
C3H$(DH)3
500
2.5
98%
125
4x125
F.W.92.10
ml
It
5.10
23.40
125
4x125
99.5%
F.W 92.10
Passes test
10
0.005%
0.003%
0.001%
Passes test
Fatty acid esters (as Butyric acid)0.05%
Silver reducing substances
Substances darkened by sulfuric acid
Heavy Metals (as Pb)
Water (H2O)
500
6x500
2.5
Passes test
Passes test
2 ppm
0.5%
6.00
30.00
28.00
ml
ml
It
T 84357Glycine Lab-Grade
CAS 56-40-6
C2H5NO2
500
6x500
F.W.75.07
98.5%
10.50
52.50
gm
gm
T 84362 Glycine ACS/AR
CAS 56-40-6
C2H5NO2
F.W.75.07
98.5%
Maximum Limits
Residue after Ignition
Heavy metals (as Pb)
Chloride (Cl)
Sulphate (SO4)
Ammonium (NH4)
Substancas darkened by sulfuric acid
Hydrolyzable substances
100
0.1%
0.002%
0.005%
0.005%
0.005%
Passes test
Passes test
gm
4.25
T 84401 Gram's Stain No. 1 (Crystal Violet)
125
4x125
ml
ml
1.10
3.30
125
4x125
125
4x125
ml
ml
3.60
10.80
ml
ml
3.60
10.80
T 88893 Hexane 65-70 C Fraction from petroleum
Lab-Grade
6
CAS 110-54-3
UN-1208 IMDG-3/1/11
CH,(CH2)4CH3
500
6x500
2.5
ml
ml
It
1.50
7.50
7.00
T 88898 Hexane 65-70C Fraction from petroleum ACS/AR
CAS 110-54-3
UN-1208 IMDG-3.1/11
CHjtCH^CH,
Maximum Limits
Color (APHA)
Residue after Evaporation
Water soluble Titrable acid
Sulfur compounds (as S)
Thiophene
500
6x500
2.5
10
0.001%
0.0003 meq/g
0.005%
Passes test
2.40
12.00
11.25
ml
ml
It
T 88913 Hexane fraction from petroleum for HPLC
CAS 110-54-3
UN -1208 IMDG-3.1/11
CH^CH^CH,
Maximum Limits
Color (APHA)
Residue after Evaporation
Titrable acid (H2O soluble)
Sulfur compounds (as S)
Thiophene
Water (H2O)
1
6x1
T 84501 Gram's Stain No. 2 (Gram's Iodine)
ml
ml
T88710Hematoxylin stain solution (Harris)
Maximum Limits
Color (APHA)
Residue after Ignition
Chlorinated compounds (as Cl)
Sulfate (SO„)
Acrolein, Glucose and Ammonium compounds
3.10
9 30
T 88705Hematoxylin stain solution (Ehrlich)
T83950Glycerin ACS/AR
CAS 56-81-5
C3H5(OH)3
Neutrality
ml
ml
It
It
W
2 ppm
0.03 peq/g
• 0.005%
To pass test
0.01%
9.25
46.25
1.25
3.75
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T. BAKER LAB CHEMICALS
T 90054 Hydrazine Hydrate 99% ACS/AR
CAS 7803-57-8
UN-2030 IMDG-8/11
NH,NH22H2O
85%
T 90244Hydrochloric acid 35.4% ACS/AR
F.W.50.06
CAS 7647-01-0
UN-1789 IMDG-8/II
HO
36.5-38%
F.W.36.46
Maximum Limits
500
6x500
ml
ml
9.70
48.50
T90063 Hydrazine Hydrochloride Lab-Grade
CAS 5341-61-7
NH,NH,2HCI
100
6x100
98%
F.W.104.98
4.25
21.25
gm
gm
T 90084Hydrazine Sulfate Lab-Grade
CAS 10034-93-2
NH2NH2H2SO4
100
500
99%
F.W.130.12
gm
gm
1.40
5.60
CAS 10034-93-2
99.5%
100
500
6x500
F.W.130.12
0.005%
0.05%
0.005%
0.002%
0.001%
Insoluble matter
Residue after Evaporation
Chloride (Cl)
Heavy metals (as Pb)
Iron (Fe)
2.40
9.60
48.00
gm
gm
gm
T 90312Hydrobromic acid abt 48% Hbr ACS/AR
CAS 10035-10-6
UN-1788 IMDG-8/II
HBr
48-49%
500
6x500
7.80
39.00
CAS 7722-84-1
UN-2014 IMDG-5.1/11
h2o2
500
6x500
29-32%
F.W.34.01
2.70
13.50
ml
ml
T 90383 Hydrogen Peroxide 30% 100 vol. ACS/AR
CAS 7722-84-1
UN -2014 IMDG-5.1/11
H2O2
500
6x500
29-32%
ml
ml
F.W.34.01
10
0.002%
0.0006 meq/g
3 ppm
2 ppm
2 ppm
5 ppm
5 ppm
1 ppm
0.5 ppm
3.25
16.25
T 94359 8-Hydroxyquinoline ACS/AR
36.5-38%
Heavy metals (as Pb)
Iron (Fe)
Nonvolatile Residue
Oxidizing substances (as Cl2)
Reducing substances (as SO3)
Sulfate (SO,)
Organic compounds
24
0.40
1.20
T 90378 Hydrogen Peroxide 30% 100 vol. Lab-Grade
Color (APHA)
Residue after evaporation
Titrable acid
Chloride (Cl)
Nitrate (NO3)
Phosphate (PO,)
Sulfate (SO,)
Ammonium (NH,)
Heavy metal (as Pb)
Iron (Fe)
F.W.36.46
Passes test
Maximum Limits
ml
ml
It
It
It
4.30
15.1.0
7.00
24.00
ml
ml
0.002%
0.05%
0.003%
0.001%
0.003%
5 ppm
1 ppm
0.01 ppm
T 90239Hydrochloric acid 35-38% Lab-Grade
2x500
8x500
2.5
4x2.5
5
125
4x125
Maximum Limits
ml
ml
CAS 7647-01-0
UN-1789 IMDG-8/11
HQ
Specific gravity
ml
ml
It
It
F.W.80.91
Maximum Limits
Residue after Ignition
Chloride (Cl)
Iodide (I)
Phosphate (PO,)
Sulfate and Sulfite (as SO,)
Heavy metals as (as Pb)
Iron (Fe)
Selenium (Se)
2x500
8x500
2.5
4x2.5
10
5 ppm
0.005%
1 ppm
1 ppm
5 ppm
1 ppm
3 ppm
0.01 ppm
1 ppm
0.2 ppm
T 90301 Hydrochloric Acid solution 5%
T 90089Hydrazine Sulfate ACS/AR
nh2nh2h2so.
Maximum Limits
Color (APHA)
Residue after ignition
Bromide (Br)
Sulfate (SO.)
Sulfite (SO3)
Extractable organic substances
Free Chlorine (Cl)
Ammonium (NH,)
Arsenic (As)
Heavy metals (as Pb)
Iron (Fe)
0.0001%
0.0005%
0.5%
0.003%
0.007%
0.5%
Passes test
CAS 148-24-3
HOC2KN
99-101%
Melting point
Suitability for Magnesium Determination
F.W.145.16
72.5°-74.0°C
Passes test
Maximum Limits
Insoluble in Alcohol
Residue after Ignition
Sulfate (SO,)
100
500
gm
gm
0.05%
0.05%
Passes test
8.80
39.00
4.10
14.40
5.70
18.00
8.40
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
T 94501 Indigo Carmine ACS/AR
T 99150 Lactose Monohydrate ACS/AR
for Bacteriological purpose
CAS 5989-81-1
gm
gm
10
25
c,2hho„.h2o
Maximum Limits
Insoluble matter
Residue after ignition
Dextrose
Passes test
Sucrose
Heavy metals (as Pb)
Iron (Fe)
CAS 87-51-4
F.W. 175.19
CJ l:NO-
Assay'acidimetric)
1
S
min. 96%
2.30
9.25
gm
gm
500
6x500
IT 94651 Iodine Solution Lugol's
125
4x125
1.80
5.40
ml
ml
F.W 207.19
500
F.W 207.19
99.8%
F.W.253.81
0.01%
0.005%
100
6x100
500
6x500
8.50
42.50
41.40
207.00
Pb
gm
gm
gm
gm
125
4X125
X
T 97526 Karl Fischer Heagent Composit single
solution (Pyridine Free) Lab-Grade
17.00
85.00
*T 99040 Lactic acid Lab-Grade
85-90%
ml
8.00
Maximum Limits
Passes test
500
6x500
F.W.379.33
0.01%
5 ppm
0.005%
0.002%
0.05%
0001%
4.40
gm
gm
T 99440Lead (II) Acetate Basic anhydrous for
sugar analysis according to home Lab-Grade
K
CAS -51404-69-4
UN-1616 IMDG-6.1/111
(CH3COO)2Pb.Pb(OH)2
1
2.5
72-74%
F.W.566.5
7.00
15.00
kg
kg
CAS 1319-46-6
(PbCO3)2.Pb(OH2)
500
Residue after ignition
Chlorida (Cl)
Sulfate (SO.)
Heavy metals (as Pb)
Iron (Fe)
0.02%
0.001%
0.002%
5 ppm
5 ppm
ml
ml
10.70
53 50
500
6x500
99-103%
T 99400 Lead (II) Carbonate basic Lab-Grade
T 99045 Lactic acid ACS/AR
CAS 50-21-5
CHjCHOHCOOH
85-90%
Substances darkened by sulfuric acid
CAS 6080-56-4
UN-1616 IMDG - 6.1/111
(CH3COO)2Pb.3H,O
Insoluble matter
Chloride (Cl)
Nitrate and Nitrite (as NO.)
Copper (Cu)
Substances not precipitated by
hydrogen sulfide (as sulfates)
Iron (Fe)
17.00
85.00
ml
ml
2.85
8.50
Maximum Limits
for moisture determination
ml
ml
gm
gm
T 99296 Lead (II) Acetate trihydrate ACS/AR
IT 97523 Karl Fischer Reagent A&B set
(Pyridine Free) Lab-Grade
500
6.80
CAS 7439-92-1
Nonvolatile matter
Chlorine and bromine (as Cl)
CAS 50-21-5
CH3CHOHCOOH
gm
T 99206Lead Metal granular Lab-Grade
Maximum Limits
500
6x500
4.80
24.00
gm
gm
CAS 7439-92-1
3.50
IT 95667lodine Resublimed ACS/AR
500
6x500
Passes test
5 ppm
5 ppm
Pb
ml
CAS 7553-56-2
l2
0.005%
0.03%
T 99201 Lead Metal shots Lab-Grade
IT 95651 Iodine 0.1 N Solution
500
F.W.360.32
4-6%
Water (H2O)
C 94601 3-Indole acetic acid Lab-Grade
gm
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
F.W.775.60
10.50
25
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
T 99445 Lead (II) Carbonate basic ACS/AR
CAS 1319-46-6
(PbCO3)2.Pb(OH2)
T100600Leishman's stain solution for blood smears
F.W.775.60
Maximum Limits
Insoluble in dilute acetic acid
Chloride (Cl)
Nitrate and nitrite (as NOJ
0.02%
0.002%
Passes test
(limit about 0.005%)
Substances not precipitated by hydrogen
sulfide (as sulfates)
Cadmium (Cd)
Iron (Fe)
Zinc (Zn)
500
0.2%
0.002%
0.005%
0.003%
145.00
gm
T 99412 Lead (II) Chloride Anhydrous Lab-Grade
CAS 7758-95-4
PbCI2
500
97%
F.W.278.10
11.10
gm
T99445 Lead (11) Chromate
CAS 7758-97-6
PbCrO4
500
F.W.323.21
10.50
T99536Lead Dioxide Lab-Grade
500
F.W.239.20
5.40
99%
gm
CAS 10099-74-8
UN-1469 IMDG-5.1/11
Pb(NOj)2
500
6x500
F.W.331.21
99.5%
F.W.331.21
85%
F.W.685.60
3.40
98%
gm
gm
F.W.223.20
3.10
15.50
T 99983 Lead (II) Sulfate Lab-Grade
CAS 7446-14-2
PbSO,
500
gm
1
24
pkt
pkt
1.60
29.00
.
T 100630Litmus Red indicator paper
one pkt contains 100 leaves
1
24
1.60 I
29.00 1
pkt
pkt
highly concentrated solution
125
4x125
1.00
3.00
mi
ml
125
4x125
ml
ml
500
1.00
3.00
98%
F.W.86.85
27.10
gm
T101262Litmus pH indicator Lab-Grade
25
100
6.25
19.00
gm
gm
T103010Magnesium metal ribbon Lab-Grade
CAS 7439-95-4
Mg
T 99817Lead (II) Oxide yellow Lab-Grade
500
6x500
one pkt contains 100 leaves
approx. F.W.3300 |
6.00
30.00
gm
CAS 1317-36-8
PbO
T 100625Litmus Blue indicator paper
CAS 1393-92-6
T 99812Lead Oxide red Lab-Grade
500
1.25
3.75
ml
ml
CAS 7550-35-8
UBr
3.00
gm
gm
CAS 1314-41-6
Pb3O4
125
4x125
T100712Lithium Bromide anhydrous Lab-Grade
T 99761 Lead (II) Nitrate ACS/AR
HH
"
T100610Light Green stain solution
T 100640Litmus Red indicator solution
T99756Lead (II) Nitrate Lab-Grade
500
1.00
3.00
highly concentrated solution
94%
gm
CAS 10099-74-8
UN-1469 IMDG-5.1/11
Pb(NO,)2
ml
ml
T 1G0635Litmus Blue indicator solution
98%
gm
CAS 1309-60-0
UN -1872IMDG - 5.1/111
PbO2
125
4x125
25
6x25
99.7%
gm
grn
F.W.24.31
1.65
8.00
T103021 Magnesium Carbonate Lab-Grade
CAS 39409-82-0
Soluble mater
Chloride
Calcium
Iron
125
500
gm
gm
1.0%
0.05%
1%
0.04%
1.25
3.80
T103026Magnesium Carbonate ACS/AR
97%
F.W.303.25
11.10
100
500
gm
gm
4-80
19.00
Lab & General Exports (Pvt) Ltd. 11/1, Hosur HoaJ7BangaIdre-S60 aZSTlndia'
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T BAKER LAB CHEMICALS
TF103139Magnesium chloride hexahydrate
Lab-Grade
T104216 Manganese (II) Acetate Tetrahydrate
ACS/AR
CAS 6156-78-1
(CH3COO)2Mn.4H2O
CAS 7791-18-6
MgCI2.6H2O
F.W.203.30
Min. 89%
0.002%
0.004%
Assay (ex Cl)
Iron
Phosphate
500
99%
F.W.245.09
Maximum Limits
Chloride (Cl)
Heavy metal (as Pb)
Insoluble matter
Iron(Fe)
Sulfate (SO,)
gm
0.003%
0.001%
0.01%
0.001%
0.005%
IT 103144 Magnesium chloride hexahydrate ACS/AR
CAS 7791-18-6
MgCI2.6H2O
99-102%
F.W.203.30
Maximum Limits
Insoluble matter
Nitrate (NO3)
Phosphate (PO,)
Sulfate (SO,)
Ammonium (NH,)
Barium (Ba)
Calcium (Ca)
Heavy metal (as Pb)
Iron (Fe)
Manganese (Mn)
Potassium (K)
Sodium (Na)
Strontium (Sr)
0.005%
0.001%
5 ppm
0.002%
0.002%
0.005%
0.01%
5 ppm
5 ppm
5 ppm
0.005%
0.005%
0.005%
gm
gm
1.55
7.75
500
6x500
T104272Manganese (II) chloride Tetrahydrate
ACS/AR
CAS 13446-34-9
MnCI,.4H,O
98-101%
pH of a 5% solution at 25°C
F.W.197.90
3.5-6.0
Maximum Limits
Insoluble matter
Sulfate (SO,)
Calcium (Ca)
Heavy metals (as Pb)
Iron (Fe)
Magnesium (Mg)
Potassium (K)
Sodium (Na)
Zinc (Zn)
500
6x500
•
0.005%
0.005%
0.005%
5 ppm
5 ppm
0.005%
0.01%
0.05%
0.005%
3.45
17.25
gm
gm
T103442 Magnesium nitrate hexahydrate ACS/AR
CAS 13446-18-9
99-102%
Mg(NOX6H3O
pH of a 5% solution at 25°C
F.W.256.41
5.0-8.2
T104070Manganese dioxide tech 85% Lab-Grade
CAS 1313-13-9
MnO2
Maximum Limits
Insoluble matter
Chloride (Cl)
Phosphate (PO,)
Sulfate (SO,)
Ammonium (NH,)
Barium (Ba)
Calcium (Ca)
Heavy metal (as Pb)
Iron (Fe)
Manganese (Mn)
Potassium (K)
Sodium (Na)
Strontium (Sr)
500
6x500
gm
gm
0.005%
0.001%
5 ppm
0.005%
0.003%
0.005%
0.01%
5 ppm
5 ppm
5 ppm
0.005%
0.005%
0.005%
500
Maximum Limits
CAS 10034-96-5
MnSO,.H2O
98-101%
Loss on ignition
Substances reducing permanganate
F.W.246.48
5.0-8.2
0.005%
5 ppm
0.002%
0.002%
2 ppm
0.02%
5 ppm
5 ppm
5 ppm
0.005%
0.005%
0.005%
gm
gm
3.00
15.00
500
6x500
1.20
F.W.169.02
10-12%
Passes test
Maximum Limits
5.50
27.50
Insoluble matter
Chloride (Cl)
Nitrate (NO,)
Ammonium (NH,)
Arsenic (As)
Calcium (Ca)
Heavy metal (as Pb)
Iron (Fe)
Manganese (Mn)
Potassium (K)
Sodium (Na)
Strontium (Sr)
gm
F.W.86.94
T 104517Manganese (ll) Sulfate
monohydrate ACS/AR
T 103713Magnesium sulfate heptahydrate ACS/AR
CAS 10034-99-8
MgSO,.7H2O
98.0-102.0%
pH of a 5% solution at 25°C
80%
Insoluble matter
Chloride (Cl)
Calcium (Ca)
Heavy metal (as Pb)
Iron (Fe)
Magnesium (Mg)
Nickel (Ni)
Potassium (K)
Sodium (Na)
Zinc (Zn)
0.01%
0.005%
0.005%
0.002%
0.002%
■ 0.005%
0.02%
0.01%
0.05%
0.005%
gm
gm
7.00
35.00
500
6x500
T104601 Maleic Acid Lab-Grade
■■
CAS 110-16-7
F.W.116.07
HOOC.CH:CH.COOH
Assay (acidimetric)
M.P.
250
gm
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
99.5 to 100.5%
136-141 degC
2.20
27
(INTERNATIONAL PRICE LIST If JS. DOLLARS)
T. BAKER LAB CHEMICALS
T104651 D (-) Mannitol ACS/AR
CAS 69-65-8
M.W. 182. 17
CcH,.Ot
Specific rotation (a)wD
Assay
Acidity (CH3COOH)
Chloride
Iron
reducing sugars (glucose)
500
T105468Mercuric Nitrate ACS/AR
CAS 7783-34-8
UN-1625 IMDG-6.1/11
Hg(NO3)..H2O
+140 to +143 deg
Min. 99%
0.005%
0.001%
0.0005%
0.05%
gm
15.75
T104695 Menthol crystals Lab-Grade
CAS 2216-51-5
C,0H„O
100
Residue after reduction
Chloride (Cl)
Sulfate (SO.)
Iron(Fe)
Mercurous mercury (as Hg)
100
500
'
0.01 %
0.002%
0.002%
0.001%
0.2%
22.00
88.00
gm
gm
T105490Mercuric Oxide red ACS/AR
F.W.156.27
18.60
gm
F.W.342.62
98%
Maximum Limits
CAS 21908-53-2
UN-1641 IMDG-6.1/11
HgO
F.W.216.59
99%
Maximum Limits
T105319Mercuric acetate Lab-Grade
CAS 1600-27-7
UN-1624 IMDG 6.1/11
(C2H3O.)2Hg
100
F.W.156.27
12.00
gm
100
500
T105353Mercuric chloride Lab-Grade
CAS 7487-94-7
UN-1624 IMDG. 6.1/11
HgCI,
250
98%
F.W.271.50
7.15
gm
99.5%
F.W.271.50
Passes test
Maximum Limits
Residue after reduction
Iron (Fe)
0.02%
0.002%
gm
gm
4.95
11.15
100
250
T105449Mercuric Iodide red ACS/AR
CAS 7774-29-0
Hgl?
99%
Solubility in potassium iodide solution
F.W.454.40
Passes test
Maximum Limits
Mercurous mercury (as Hg)
Soluble mercury salts (as Hg)
0.1%
0.05%
100
500
6x500
16.50
66.00
330.00
gm
gm
gm
100
500
28
gm
gm
58-62%
gm
gm
16.50
66.00
T105505 Mercuric Oxide yellow ACS/AR
CAS 21908-53-2
UN-1641 IMDG-6.1/11
HgO
99%
Insoluble in dilute hydrochloric acid0.03%
Residue after reduction
Chloride (Cl)
Sulfate (SO.)
Nitrogen compounds (as N)
Iron (Fe)
100
500
F.W.216.59
F.W.342.62
5.45
22.00
0.05%
0.025%
0.01%
0.005%
0.003%
20.50
82.00 .
gm
gm
T105526Mercuric Sulfate Lab-Grade
CAS 7783-35-9
UN-1645 IMDG-6.1/11
HgSO.
250
99%
gm
F.W.296.65
11-15
T10E>531 Mercuric Sulfate ACS/AR
CAS 7783-35-9
UN-1645 IMDG-6.1/11
HgSO.
98%
’ F.W.296.65
Maximum Limits
Residue after reduction
Chloride (Cl)
Nitrate (NO3)
T105463Mercuric Nitrate Lab-grade
CAS 7783-34-8
UN-1625 IMDG 6.1/11
Hg(NO3)2.H2O
0.025%
0.025%
0.015%
0.005%
0.005%
Maximum Limits
T105358Mercuric chloride ACS/AR
CAS 7487-94-7
UN-1624 IMDG-6.1/II
HgClj
Soluble in ethyl ether
Insoluble in dilute hydrochloric acid0.03%
Residue after reduction
Chloride (Cl)
Sulfate (SO.)
Nitrogen compounds (as N)
Iron (Fe)
Iron (Fe)
Mercurous mercury (as Hg)
250
gm
0.02%
0.003%
Passes test
(limit about 0.005%)
0.005%
0.15%
55.00
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
IT. BAKER LAB CHEMICALS
T109587Methylene blue for microsocopy Lab-Grade
T105678Mercurous Nitrate Lab-Grade
CAS 14836-60-3
UN-1627 IMDG-6.1/11
Hg?(NO3)2.xH2O
100
CAS 26283-09-0
C,6H„N3SCI.3H2O
99%
F.W.561.22
7.50
gm
98%
25
100
1-90
5.15
gm
gm
T109592 Methylene blue Loftier solution
‘ 105683 Mercurous Nitrate ACS/AR
0-3
UN-1645 IMDG-6.1/11
Hg2(NO3)2.2H2O
(C.l. 52015)
F.W.319.86
F.W.561.22
125
4x125
ml
ml
.
1.30
3.90
Maximum Limits
Insoluble matter
Residue after reduction
Chloride (Cl)
Sulfate (SO.)
Iron(Fe)
Mercuric mercury (as Hg)
100
500
0.005%
0.01%
0.005%
0.005%
0.001%
0.5%
T109600 Methyl Orange solution
pH 2.9-4.6 orange to yellow
22.00
88.00
T109605 Methyl Red indicator solution
gm
gm
125
4x125
107726 Methanol (Methyl Alcohol) Lab-Grade
CAS 67-56-1
UN-1230 IMDG-3.2/II
r.NJAH
500
6x500
1
2.5
F.W.32.04
1.50
7.50
2.55
5.15
ml
ml
It
It
CAS 67-56-1
UN-1230 IMDG-3.1/11
CH3OH
99.8%
Appearance
Substances darkened by sulfuric acid
Substances reducing permanganate
F.W.32.04
Clear
Passes test
Passes test
Maximum Limits
Titrable acid
Titrable base
10
0.1%
0.001%
Passes test
0.001%
each of acetone,
formaldehyde, and
acetaldehyde
0.0003 meq/g
0.0002 meq/g
ml
ml
It
It
It
1.90
9.50
3.55
17.75
7.45
Color (APHA)
Water (H2O)
Residue after evaporation
Solubility in water
Carbonyl compounds
TT107618Methyl acetate Lab-Grade
LTT-J
CAS 79-20-9
UN-1231 IMDG-3.2/II
CH3COOCH3
500
1.05
3.15
ml
ml
1.05
3.15
90%
C.l. NO. 13020
CAS 493-52-7
M.W. 269.31
0,^0,
pH transition range:
pH 4.5 - 6.2
Absorption max:
pH 4.5
pH 6.2
25
red-violet to brownsih yellow
523 - 526 nm
430 - 434 nm
2.60
gm
T109630 Methyl Violet indicator solution .
125
4x125
ml
ml
1.15
3.45
T 52297Methylene Chloride Lab-Grade
CAS 75-09-2
UN-1593 IMDG-6.1/111
CH2CI2
500
2.5
99%
ml
It
F.W.84.93
3.30
15.30
T 52302Methylene Chloride ACS/AR
CAS 75-09-2
UN -1593 IMDG- 6.1/111
CH2CI2
Appearance
99.5%
F.W.84.93
Clear
Maximum Limits
F.W.74.08
T108273 Methyl benzoate Lab-Grade
CAS 93-58-3
C6H5COOCH3
ml
ml
T 109610 Methyl Red Stain powder Lab-Grade
99%
TT107731 Methanol ACS/AR
500
6x500
1
6x1
2.5
125
4x125
Color (APHA)
Residue after evaporation
Titrable acid
Water (H2O)
Free Halogens
500
2.5
ml
It
10
0.002%
0.0003 meq/g
0.02%
Passes test
4.30
19.90
F.W.136.14
12.50
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
29
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
T115351 Naphthalene flakes Lab-Grade
T24470Methyl Ethyl Ketone Lab-Grade
6
CAS 78-93-3
UN-1193 IMDG-3.2/11
C2HSCOCH3
500
6x500
2.5
CAS 91-20-3
F.W. 128.17
F.W.72.11
99%
3.00
15.00
14.15
ml
ml
It
*
15
0.0025%
0.0005 meq/g
0.20%
4.90
24.50
ml
ml
T111773 Methyl Orange pH indicator ACS/AR
CAS 547-58-0
C,.Hl4N3NaO3S
Clarity of Solution
Visual Transition interval
(C.1.13025)
F.W.327.33
Passes test
pH 3.2 to 4.4
(red to yellow)
gm
grn
1.50
7.50
T113072 Methyl Salicylate Lab-Grade
CAS 119-36-8
CBH8O3
98-100.5%
Solubility in 70% alcohol
Specific gravity @25°/25°C
Refractive Index @20°C
Angular Rotation
F.W.152.15
Passes test
1.180-1.185
1.535-1.538
Optically inactive
0.004%
Passes test
Heavy metals (as Pb)
Organic volatile impurities
5.70
F.W. 284.19
- 70%
520 nm
Dye Content
Abs. max (water)
0-90
3.75
gm
gm
4.60
T135371 b-NaphthoI powder Lab-G'ade
CAS 135-19-3-
: F.W. 144 7
C^OH
Assay
M.P.
1 -Naphthol
500
min. 98:
121-123 degC
0.5%
gm
5.75
T116618 Neutral red pH indicator ACS/AR
CAS 553-24-2
C,5H,7CIN.
[C.I.50040]
F.W.288.78
gm
gm
4.45
8.90
T116701 Nickel Ammonium Sulfate Lab-Grade
CAS 7785-20-8
F.W.394.97
(NH4)2Ni(SO4)2.6H2O
Assay
Chloride
500
min 98.5%
0.003%
11.00
gm
45%
■ F.W.376.24
Reagent for protein test
0.005%
0.005%
0.3%
0.04%
0.03%
0.005%
0.06%
Chloride (Cl)
Iron (Fe)
Sulfate (SO.)
Lead (Pb)
Sodium (Na)
Copper (Cu)
Zinc (Zn)
500
6x500
T113085 Million's Reagent solution
15.30
76.50
gm
gm
T116730 Nickel (II) chloride hexahydrate ACS/AR
2.00
8.00
CAS 7791-20-0
NiCI2.6H2O
500
6x500
30
gm
Maximum Limits
CbHbnbob
ml
ml
100
CAS 12607-70-4
NiCO3.2Ni(OH)24H2O
(Ammonium Purpurate)
C.l. 56085.
CAS 3051-09-0
F.W. 144.17
Min. 99%
94-96 deg C
Assay
M.P.
T116717 Nickel (II) carbonate extra pure Lab-Grade
T113101 Murexide indicator powder Lab-Grade
125
4x125
2.35
10
25
Maximum Limits
1
5
gm
500
F.W.72.11
99%
Color (APHA)
Residue after evaporation
Titrable acid
Water
25
6x25
Min 99%
79-82 deg C
CAS 90-15-3
C..H.OH
Maximum Limits
500
6x500
Assay (GC)
M.P.
T115364 a-Naphthol Lab-Grade
T24475 Methyl Ethyl Ketone ACS/AR
CAS 78-93-3
UN-1193 IMDG-3.2/11
C2H5COCH3
c„hb
gm
gm
95%
F.W.237.71
10.00
50.00
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
T116853 Nickel (11) Nitrate hexahydrate Lab-Grade
T116991 Ninhydrin indicator solution
CAS 13478-00-7
Ni(NO3)2.6HaO
UN - 2725 IMDG - 5.1/ill
125
4x125
F.W.290.79
Min. 98%
0.005%
0.02%
Assay (ex.Ni)
Chloride
Iron
500
T117318 Nitric acid 69-72% Lab-Grade
CAS 7697-37-2
UN-2031 IMDG-8/II
HNO3
■—--J
CAS 13478-00-7
UN-2725 IMDG-5.1/lil
NUNOJj.eHjO
500
6x500
2x500
8x500
2.5
4x2.5
99%
gm
gm
F.W.290.79
13.15
65.75
“A
CAS 10101-97-0
NiSO4.6H2O
98.-104%
CAS 7697-37-2
UN-2031 IMDG-8/II
HNO3
Appearance
69-71%
F.W.63.01
Coloriess and free form
suspended matter or
sediment.
Maximum Limits
Color (APHA)
Residue after Ignition
Chloride (Cl)
Sulfate (SO4)
Arsenic (As)
Heavy metals (as Pb)
Iron (Fe)
F.W.262.85
98-104%
0.01%
0.002%
Assay
Chloride
Heavy metals (Pb)
8.00
gm
T116986 Nickel (II) sulfate ACS/AR
CAS 10101-97-0
NiSO4.6H2O
4.80
16.50
6.70
23.00
ml
ml
It
It
T117323 Nitric acid 69-72% ACS/AR
’T116981 Nickel (li) sulfate Lab-Grade
500
F.W.63.01
68.5-69.5%
gm
T116858 Nickel (II) nitrate hexahydrate ACS/AR
Magi
2.75
8.25
ml
ml
98.0-102.0%
2x500
8x500
2.5
4x2.5
F.W.262.85
Maximum Limits
Insoluble matter
Chloride (Cl)
Nitrogen compounds (as N)
Calcium (Ca)
Cobalt (Co)
Copper (Cu)
Iron(Fe)
Magnesium (mg)
Manganese (Mn)
Potassium (K)
Sodium (Na)
0.005%
0.001%
0.002%
0.005%
0.002%
0.005%
0.001%
0.005%
0.002%
0.01%
0.05%
500
6x500
20.50
102.50
gm
gm
5.00
17.50
8.25
28.50
ml
ml
It
It
T117654 Nitrobenzene Lab-Grade
LSSJ
CAS 98-95-3
UN-1662 IMDG-6.1/11
CtHsNO2
500
99%
ml
570-580 nm
F.W.123.11
3.20
T117659 Nitrobenzene ACS/AR
CAS 98-95-3
UN-1662 IMDG-6.1/11
C6H5NO2
F.W.123.11
Maximum Limits
Residue after evaporation
Water-soluble titrable acid
Chloride (Cl)
T117005 Nigrosine Water soluble Lab-Grade
C.I. 50420
CAS 8005-03-6
Abs.max (50% ethanol)
10
5 ppm
0.5 ppm
1 ppm
0.01 ppm
0.2 ppm
0.2 ppm
500
ml
0.005%
0.0005 meq/g
5 ppm
6.60
T117701 Oleic Acid Lab-Grade
10
25
gm
gm
1.00
2.00
T117201 Ninhydrin powder ACS/AR
,-aaI
CAS 485 -47-2F.W. 178.14
C0H4 03H2 0
Assay
Sulphated ash
5
10
gm
gm
min. 99%
0.1%
6.50
12.90
CAS 112-80-1
F.W.282-47
Ct7HMCOOH
Assay (GC)
Iodine value
65-70%
85-93
ml
2.75
500
T117905 Orcein Stain powder Lab-Grade
CAS 1400-62-0
1
gm
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
7.75
31
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
T117675 Orange G Solution (aqueous)
T123301 Peppermint Oil Lab-Grade
gm
2.50
7.50
125
• ml
4x125 ml
T123440 Peptone Lab-Grade
T117690 Orcinol (reagent for sugars) Lab-grade
Total Nitrogen
a-Amini Nitrogen
CAS 6153-39-5
100
12.50
22.80
gm
gm
CAS 6153-56-6
(COOH)2.2H2O
99.5102.5%
S’ dances darkened by hot sulfuric acid
CAS 7501-90-3
UN-1873 iMDG -5 1.1
HCIO,
0.005%
0.01%
0.002%
0.005%
0.001%
0.001%
5 ppm
2 ppm
•ron.Fr'
3.30
16.50
gm
500
6x500
Maximum Limits
Viscosity @40°C
Readily carbonisable substances
Limit of Polynuclear compounds
Solid Paraffin
500
1
2.5
33.5 cs
Passes test
Passes test
Passes test
ml
It
It
2.75
5.00
12.15
\
T123261 Paraformaldehyde Lab-Grade
«
**
L
J
CAS 30525-89-4
UN-2213 IMDG-4.1/III
(H.CHO) „
Formaldehyde content
Maximum Limits
Acidity (as HCOOH)
Ash
Iron (Fe)
Water
500
32
gm
95%
f
w ao ha
91.0-93.0%
0.03%
0.01%
0.0002%
9.0%
10
0.003%
5 ppm
0.001%
0.001%
0.001%
1 ppm
1 ppm
Heavy nv.LJs (as Pb)
Iron (Fe)
500
6x500
7.00
0.818-0.880
Passes test
F.W.100.46
69-72%
Color (APHA)
Residue after ignition
Silicate and phosphate (as SiOJ
Chloride (Cl)
Nitrogen compounds (as M)
Sulfate (SO . ’
Passes test
Passes test
Passes test
T123053 Mineral oil light (Paraffin liquid light)
Lab-Grade
12.00
60.0
Maximum Limits
Maximum Limits
It
10
0.003%
5 ppm
0.001%
0.001%
0.001%
1 ppm
1 ppm
ml
ml
CAS 7601-90-3
UN-1873 IMDG-5.1/1
HCIO4
Min.34.5 cs
0.845-0.905
Passes test
CAS 8021-95-1
Specific Gravity @ 25°C
Neutrality
F.W. 100.46
T124820Perchloric acid 70% ACS /AR
T123050Mineral oil heavy (Paraffin liquid heavy)
Lab-Grade
1
60-62%
Color (APHA)
Residue after ignition
Silicate and phosphate (as SiO2)
Chloride (Cl)
Nitrogen compounds (as N)
Sulfate (SOJ
Heavy metals (as Pb)
Iron (Fe)
F.W. 126.07
Passes test
Insoluble matter
Residue after ignition
Chloride (Cl)
Sulfate (SOj
Calcium (Ca)
Nitrogen comoounds (as N)
rea-’y metu:'. fas l’*»;
Readily carbonizable substances
Limit of Polynuclear compounds
Solid Paraffin
5.00
Maximum Limits
Maximum Limits
CAS 8021-95-11
Viscosity @40°C
Specific Gravity @25°C
Neutrality
gm
T124817Perchloric acid 60% ACS/AR
T1223620xalic acid ACS/AR
6x500
14.2 -15.5%
3.5%
F.W.124.15
CH3C,H,(OH)2
5
10
3.00
13.15
65 75
ml
ml
T125021 Petroleum ether 40-60°C ACS/AR
ft
CAS 8032-32-4
UN-1268 IMDG-3.1/11
Boiling range
Maximum Limits
Acidity
Color (APHA)
Residue after evaporation
500
6x500
Passes test
10
0.001%
4.15
20.75
ml
ml
T125028 Petroleum ether 60-80°C ACS/AR
CAS 8032-32-4
UN-1268 IMDG -3.2/11
Boiling range
Odor
Appearance and color
Acidity
Maximum Limits
Residue after evaporation
Heavy Oils and Fats (Spot test)
Sulfur (Doctor test)
500
6x500
2.5
ml
ml
It
60°-80°C
Passes test
Passes test
Passes test
0.001%
Passes test
Negative
2.00
10.00
9.00
3.45
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T BAKER LAB CHEMICALS
T114110 Phosphomoly bdic Acid Reagent indicator solution
7T123035Petroleum ether 80-100°C ACS/AR
CAS 8032-32-4
UN-1268 IMDG -3.3/H
Boiling range
500
80°-100°C
ml
8.25
1.50
4 50
ml
ml
T128540 o-Phosphoric acid Lab-Grade
CAS 7664-38-2
UN -1805 IMDG-8/III
H3PO4
7T125608 Pheno! crystal ACS/AR
CAS 108-95-2
UN-1671 IMDG-6.1/11
CSH.OH
Freezing Point (Dry)
Clarity of solution
125
4x125
F.W.94.11
Min.4C 5°C
Passes test
99%
6x500
2.5
F.W.98.00
4.40
22.00
20.15
ml
Maximum Limits
Residue after evaporation
Water
0.05%
500
6x500
5.15
25.75
gm
gm
7T125621 Phenolphthal;; i powder Lab-Grade
CAS-77-09-8
F.W. 318.33
min. 98%
Assay (dried)
pH transition '-"ne:
pH 8.2-9.8
Abs. max (p 4 9.8)
125
colourless to red violet
551-554 nm
gm
5.00
T125626 Phenolphthale in indicator solutioni%aicohoiic
125
4x125
ml
ml
1.00
3.00
71125701 Phenol Red Water Soluble indicator powder
Lab-Grade
CAS 143-74-8
F.W. 354.38
C„H.:O5S
I
1
5
gm
gm
2.00
8.00
0.95
2.85
ml
ml
CAS 7664-33-2
UN-1805 IMDG - 8/1II
H PO4
Color (APHA)
Insoluble matter, calcium, magnesium and
ammonium hydroxide precipitate
Chloride (Cl)
Nitrate (NOJ
Sulfate (SOJ
Volatile acids (as CH3COOH)
Antimony (Sb)
Arsenic (As)
Heavy metal (as Pb)
Iron (Fe)
Manganese (Mn)
Potassium (K)
Sodium (Na)
Reducing substances
500
6x500
F.W.98.00
85.0%
Maximum Limits
10
0.005%
3 ppm
5 ppm
0.003%
0.001%
0.002%
1 ppm
0.001%
0.003%
0.5 ppm
0.005%
0.025%
Passes test
ml
ml
5.70
28.50
T122270 o-Phosphoric acid for steel industries
Lab-Grade
CAS 7664-38-2
UN-1805 IMDG-3/III
H3PO4
500
F.W.98.00
85.0%
ml
6.00
T128626 Phosphorous oxychloride Lab-Grade
T125706 Phenol Red indicator Solution standard
125
4x125
T128545o-Phosphoric acid ACS/AR
CAS 10025-87-3
UN -1810 IMDG-8/II
POCI3
500
98-101%
F.W. 153.33
ml
10.00
T114120Phosphomolybdic acid ACS/AR
CAS 51429-74-4
H3PO4.12MoO?.24H2O
98%
F.W.336.74
Maximum Limits
Insoluble matter
Chloride (Cl)
Sulfate (SO4)
Ammonium (NH4)
Calcium (Ca)
Heavy metal (as Pb)
Iron (Fe)
0.01%
0.02%
0.025%
0.01%
0.02%
0.005%
0.005%
gm
gm
gm
8.00
31.45
157.25
25
100
6x100
T128679Phosphorous pentoxide ACS/AR
CAS 1314-56-3
P2O5
98%
F.W. 141.94
Maximum Limits
Insoluble matter
Phosphorus trioxide (P2O3)
Ammonium (NH4)
Heavy metal (as Pb)
500
gm
ILab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
0.02%
Passes test
(limit about 0.02%)
0.01%
0 01%
12.15
33
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T. BAKER LAB CHEMICALS
T130174 Potassium acetate ACS /AR
T162732 Phosphotungstic acid Lab-Grade
CAS 12501-23-4
H3PO,.12WO3.xH2O
CAS 127-08-2
Maximum Limits
pH of 5% solution at 25°C
ch3cook
Ammonium (NH,)
Chloride (Cl)
Heavy metal (as Pb)
Insoluble matter
Iron (Fe)
Nitrate (NO3)
Sulfate (SO.)
0.02%
0.03%
0.005%
0.02%
0.003%
0.01%
0.02%
100
6x100
27.15
135.75
gm
gm
T162700Phosphotungstic Acid Reagent indicator
solution
125
4x125
T128813Phthalic acid 99.5% ACS /AR
99.5%
Maximum Limits
Insoluble matter
Chloride (Cl)
Phosphate (PO,)
Sulfate (SO.)
Calcium, magnesium, and R2O3 precipitate
Heavy metals (as Pb)
Iron (Fe)
Sodium (Na)
500
6x500
gm
gm
500
F.W.166.13
6.50
T128814 Phthalic anhydride for synthesis Lab-Grade
CAS 85-44-9
UN-2214 IMDG-8/III
C6H,(CO)2O
Appearance
99-100.2%
Melting point
F.W.148.12
White flaky crystals
3°C range
including 131GC
0.01%
0.002%
0.003%
5 ppm
5 ppm
Residue after ingnition
Chloride (Cl)
Sulfate (SO,)
Heavy metal (as Pb)
Iron (Fe)
3.75
18.75
gm
gm
T130157 Potassium metal (in liquid paraffin) Lab-Grade
CAS 7440-09-7
UN - 2257 IMDG - 4.3/11
K
Sodium (Na)
Rubidium (Rb)
Insoluble matter
Bromide (Br)
Nitrogen compounds (as N)
Sulfate (SO,)
Heavy metal (as Pb)
Iron (Fe)
Sodium (Na)
500
F.W.39.102
0.75%
0.01 %
Maximum Limits
gm
10.70
T130412Potassium bromide Lab-Grade
CAS 7758-02-3
KBr
99%
pH of a 5% solution in water @20°C
Chloride (Cl)
Iodide (I)
Sulfate (SO,)
Bromate (BrO3)
Total Nitrogen (N)
Heavy metal (as Pb)
Iron (Fe)
Calcium, Magnesium and R2O3
Sodium (Na)
Insoluble matter
500
F.W.119.00
5.5-8.5
gm
0.002%
0.15%
0.001%
0.005%
500
240.00
0.2%
0.001%
0.005%
0.001%
0.005%
0.0005%
0.0005%
0.005%
0.02%
0.005%
6.00
T130417 Potassium bromide ACS/AR
CAS 7758-02-3
KBr
99.0%
pH of a 5% solution at 25°C
Insoluble matter
Bromate (BrOJ
Chloride (Cl)
Iodate (IO,)
Iodide (I)
Nitrogen compounds (as N)
Sulfate (SO4)
Barium (Ba)
Calcium, magnesium, and R2O3 precipitate
Heavy metal (as Pb)
Iron (Fe)
Sodium (Na)
500
6x500
34
0.005%
Passes test
(limit about 0.005%)
0.001%
0.005%
5 ppm
0.002%
0.01%
Maximum Limits
98%
Chloride (Cl)
Fluorine (F)
Iron(Fe)
Sulfur (S)
gm
F.W.167
5.0-9.0
Maximum Limits
Maximum Limits
500
6x500
7.00
35.00
Maximum Limits
0.05%
0.02%
0.001%
0.005%
0.005%
0.001%
0.001%
0.5%
gm
0.005%
0.003%
0.001%
0.002%
0.01%
5 ppm
5 ppm
0.03%
T130410 Potassium bromate ACS /AR
Maximum Limits
Insoluble matter
Residue after ignition (as SO,)
Chloride (Cl)
Nitrate (NO3)
Sulfate (SO,)
Heavy metals (as Pb)
Iron (Fe)
Water (H2O)
F.W.98.14
6.5-9.0
CAS 7758-01-2
UN-1484 IMDG - 5.1/11
KBrO3
99.7-100.3%
pH of a 5% solution at 25°C
ml
ml
CAS 88-99-3
C6H,(COOH)2
99%
gm
gm
F.W.119.00
5.0-8.8
0.005%
0.001%
0.2%
0.001%
0.001%
0.005%
0.005%
0.002%
0.005%
5 ppm
5 ppm
0.02%
10.75
53.75
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
T130734tri-Potassium citrate Lab-Grade
11130503 Potassium carbonate anhydrous
Lab-Grade
CAS 584-08-7
K.2CO3
99.0-100.5%
F.W.138.21
Maximum Limits
Heavy metals (as Pb)
Insoluble substances
Lead
Loss on drying
500
0.002%
Passes test
10mg/kg
1%
2.80
gm
IT 130508 Potassium carbonate anhydrous ACS/AR
CAS 584-08-7
KjCOj
99.0%
F.W.138.21
Insoluble matter
Chloride (as Cl)
Nitrogen compounds (as N)
Phosphate (PO.)
Silica (SiO2)
Sulfur compounds (as SO.)
Ammonium hydroxide precipitate
Calcium and magnesium precipitate
Arsenic (As)
Heavy metal (as Pb)
Iron (Fe)
Sodium (Na)
0.01%
0.003%
0.001%
0.001%
0.005%
0.004%
0.01%
0.01%
1 ppm
5 ppm
5 ppm
0.02%
Maximum Limits
500
4.75
gm
T130510Potassium chloride Lab-Grade
CAS 7447-40-7
KCI
99-100.5%
Passes test
1.0%
Passes test
Passes test
Passes test
0.001%
Passes test
500
6x500
1.80
9.00
gm
gm
CAS 7789-00-6
KjCrO,
500
6x500
99%
gm
gm
500
6x500
F.W.194.19
5.90
29.50
Passes test
0.001%
passes test
4.90
24.50
gm
gm
T130739tri-Potassium citrate ACS/AR
CAS 6100-05-6
K,C,HbO,.H2O
99.0%
pH of a 5% solution © 25°C
F.W.324.41
8.0-9.0
Maximum Limits
0.001%
0.005%
0.001%
0.001%
0.01%
0.001%
Ammonium (NH.)
Calcium (Ca)
Chloride (Cl)
Heavy metal (as Pb)
Insoluble matter
Iron (Fe)
500
6x500
6.15
30.75
gm
gm
T130802Potassium dichromate Lab-Grade
CAS 7778-50-9
KjCr2O,
99.0%
F.W.294.18
4.90
gm
T130807Potassium dichromate ACS/AR
CAS 7778-50-9
K.Cr.O,
99.0%
F.W.294.18
Maximum Limits
Insoluble matter and ammonium hydroxide
precipitate
Loss on drying
Chloride (Cl)
Sulfate (SO.)
Calcium (Ca)
Sodium (Na)
500
T130714 Potassium chromate Lab-Grade
F.W.324.41
3.0-6.0%
Passes test
Maximum Limits
Tartrate
Heavy metals
Organic volatile impurities
500
F.W.74.55
Maximum Limits
Acidity or Alkalinity
Loss on drying @ 105°C
Iodide or Bromide
Calcium and Magnesium
Sodium
Heavy metals
Organic volatile impurities
CAS 6100-05-6
l<,C6H5O7.H2O
99.0-100.5%
Loss on drying @ 180°C
Alkalinity
.
0.005%
0.05%
0.001%
0.005%
0.003%
0.02%
5.60
gm
T131826 Potassium dihydrogen orthophosphate
anhydrous Lab-Grade
CAS 7778-77-0
KH2PO.
98-100.5%
F.W.136.09
Maximum Limits
T130719Potassium chromate ACS/AR
CAS 7789-00-6
KjCrOj
99.0%
pH of a 5% solution at 25°C
F.W.194.19
8.6-98
Maximum Limits
Insoluble matter
Chloride (Cl)
Sulfate (SO.)
Calcium (Ca)
Sodium (Na)
500
gm
0.005%
0.005%
0.03%
0.005%
0.02%
Loss on drying @ 105°C
Insoluble substances
Fluoride
Arsenic(As)
Heavy metal
Lead
Organic volatile impurities
500
gm
1.0%
0.2%
0.001%
0.0003%
0.002%
0.0005%
Passes test
4.55
8.15
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
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T. BAKER LAB CHEMICALS
T131831 Potassium dihydrogen orthophosphate
anhydrous ACS/AR
CAS 7778-77-0
KH2PO4
pH of a 5% solution at 25°C
99%
T131353 Potassium hydrogen phthalate ACS/AR
CAS 877-24-7
COOHC5H4COOK 99.95-100.05%
pH of a 0.05m solution at 25.0 +0.2°C
F.W.136.09
4.1-4.5
Maximum Limits
Insoluble matter
Chlorine compounds (as Cl)
Sulfur compounds (as S)
Heavy metal (as Pb)
Iron (Fe)
Sodium (Na)
Maximum Limits
Insoluble matter, calcium and ammonnium
hydroxide precipitate
Loss on drying over sulfuric acid
Chloride (Cl)
Nitrogen compounds (as N)
Sulfate (SO4)
Heavy metals (as Pb)
Iron (Fe)
Sodium (Na)
500
0.01%
0.2%
0.001%
0.001%
0.003%
0.001%
0.002%
0.005%
gm
500
6x500
T1313?
5.90
500
98.5-102.0%
8.60
43.00
.ssium hydroxide flakes Lab Grade
S .310-58-3
. ’ "3IMDG-8/II
7.00
T131020Potassium ferrocyanide ACS/AR
CAS 14459-95-1
K4Fe(CN)6.3H?O
98.5-102.0%
500
6x500
F.W.422.39
0.005%
0.01%
Passes test
(limit about 0.01%)
9.00
45.00
gm
gm
T131031 Potassium fluoride anhydrous Lab-Grade
------ ■
CAS 7789-23-3
UN-1812IMDG-6.1/1II
KF
500
F.W.58.10
9.45
T131279Potassium hydrogen carbonate Lab-Grade
99.5-101.5%
F.W.100.12
Maximum Limits
Loss on drying (over silica gel)
Normal Carbonate
Heavy metal (as Pb)
Organic volatile impurities
500
0.3%
2.5%
0.001%
1 asses test
gm
5.50
T131348Potassium hydrogen phthalate Lab-Grade
CAS 877-24-7
COOHC6H4COOK
500
gm
3.00
24.30
T131383Pctassii!m hydroxide pell
““
CAS 1310 58-3
UN-1H13IMDG-8/II
KOH
Maxi rum Limits
Insoluble substances
Heavy metals
500
6x500
5
99.5%
s Lab-Grade
85.0%
F.W.56.11
Passes test
'
0.003%
gm
gm
kg
3.30
16.50
30.0C
T131394Potassium hydroxide pellets ACS/AR
CAS 1310-58-3
UN-1813 IMDG - 8/II
KOH
97%
gm
CAS 298-14-6
KHCO3
gm
kg
■ST?
Maximum Limits
Insoluble matter
Chloride (Cl)
Sulfate (SOJ
F.W.56.11
85%
F.W.422.39
gm
0.005%
0.003%
0.002%
5 ppm
5 ppm
0.005%
gm
gm
T131015Potassium ferrocyanide Lab-Grade
CAS 14459-95-1
K/efCN^.SHjO
F.W.204.22
4 00-4.02
bo.O/o
F.W.56.11
Maximum Limits
Potassium carbonate (K.CO3)
Chloride (Cl)
Nitrogen compounds (as N)
Phosphate (PO4)
Sulfate (SO4)
Ammonium hydroxide precipitate
Heavy metal (as Ag)
Iron iFe)
Nickel (Ni)
Sodium (Na)
500
6x500
5
2.0%
0.01%
0.001%
5 ppm
0.003%
0.02%
0.001%
0.001%
0.001%
0.05%
4.60
23.00
41.00
gm
gm
kg
T131487Potassium iodide Lab-Grade
F.W.204.22
CAS 7681-11-0
KI
5.60
Maximum Limits
99.0-101.5%
Arsenic (As)
Heavy metal (as Pb)
lodate(IO,)
Loss on Drying
Nitrate, Nitrite and Ammonia
Thiosulfate and Barium
250
500
gm
gm
F.W. 166.0
0.0003%
0.001%
0.004%
1.0%
Passes test
Passes test
14.45
28.00
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
(INTERNATIONAL PRICE LIST IN US. DO .LARS)
T. BAKER LAB CHEMICALS
T131833 Potassium oxalate ACS/AR
'T131492 Potassium iodide ACS/AR
CAS 7681-11-0
KI
99.9%
pH of a 5% solution at 25°C
CAS 6487-48-5
(COOK)2H2O
98.5-101.0%
Substances darkened by hot sulfuric acid
Neutrality
F.W. 166.0
6.0-9.2
Maximum Limits
Insoluble matter
Loss on drying at 150°C
Chloride and bromide (as Cl)
Iodate (IO3)
Nitrogen compounds (as N)
Phosphate (PO.)
Sulfate (SO,)
Barium (Ba)
Calcium , magnesium, and R2O3 precipitate
Heavy metals (as Pb)
Iron (Fe)
Sodium (Na)
100
250
6x250
gm
gm
gm
0.005%
0.2%
0.01%
3 ppm
0.001%
0.001%
0.005%
0.002%
0.005%
5 ppm
3 ppm
0.005%
Maximum Limits
Insoluble matter
Chloride (Cl)
Sulfate (SO.)
Ammonium (NH.)
Heavy metal (as Pb)
Iron (Fe)
Sodium (Na)
500
6x500
CAS 7757-79-1
I i. '486 IMDG-5.1/111
;<IIO3
99.0-100.5%
i .fe dmum Limits
Ch'orate
I -avy metal (as Pb)
•ad
i .ssonorying @ 105°C
500
gn
2.20
T131717 Potassium nitrate ACS/AR
A
CAS 7757-79-1
UN-1486 IMDG-5.1/1II
KNO3
99.0%
pH of a 5% solution at 25°C
F.W.101.10
4.5-8.5
•
6.30
31.50
gm
gm
CAS 7722-64-7
UN-1490 IMDG-5.1/11
KMnO.
99.0-100.5%
F.W. 158.03
Maximum Jmits
F.W.101.10
Passes test
0.002%
0.001%
1%
0.01%
0.002%
0.01%
0.002%
0.002%
0.001%
0.02%
T131918 Potassium permangante Lab-Grade
6.30
14.90
74.50
T13I712P:' Tssium nitrate Lab-Grade
RRH
HH
F.W.184.23
Passes test
Passes test
Loss on di "ng (over silica gel)
Insoluble s ibstances
0.5%
0.2%
500
6x500
3.90
19.50
gm
T131923 Potassium permangante ACS/AR
gn|
LzWC-.n
CAS 7722-64-7
UN-1490 IMDG-5.1/11
IZUnH
QQO//o
yy
F.W. 158.03
Maximum Limits
0 2%
0.005%
0.005%
0.02%
Insoluble matter
Chloride and chlorate (as Cl)
Nitrogen compounds (as N)
Sulfate (SO.)
500
6x500
7.90
39.50
gm
gm
Maximum Limits
Insoluble matter
Chloride (Cl)
Iodate (IO3)
Iodate and nitrite
0.005%
0.002%
5 ppm
Passes test
(limit about 5ppm IO3;
about 0.001 %NO2)
Phosphate (PO.)
5 ppm
Sulfate (SO.)
0.003%
Calcium, magnesium, and R2O, precipitate
0.01%
Heavy metal (as Pb)
5 ppm
Iron (Fe)
3 PPm
Sodium (Na)
0.005%
500
6x500
gm
gm
3.30
16.50
Assay (oxidimetric)
Chloride
Iron
500
6x500
gm
gm
CAS 12208-13-8
KSb(OH),
9-4%
F.W.262.90
Maximum Limits
Water-insoluble matter
Sodium (Na)
0.01%
0.05%
gm
gm
13.75
55.00
100
500
T132223 Potassium sodium (+) tartrate ACS/AR
CAS 6381-59-5
C.H.O6NaK.4H2O
99-102%
pH of a 5% solution at 25°C
F.W.282.22
6.0-8.5
Maximum Limits
"T131828 Potassium oxalate Lab-Grade
CAS 6487-48-5
(COOK)2H2O
T132021 Potassium pyroantimonate ACS/AR
F.W.184.23
Min. 99%
0.005%
0.005%
5.45
27.25
Insoluble matter
Chloride (Cl)
Phosphate (PO.)
Sulfate (SO.)
Ammonium (NH.)
Calcium (Ca)
Heavy metals (as Pb)
Iron(Fe)
500
gm
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
0.005%
0.001%
0.002%
0.005%
0.002%
0.005%
5 ppm
0.001%
’
20.90
37
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
TJ.33476iso-Propyl alcohol for HPLC
T132290Potassium sulphate ACS/AR
CAS 7778-80-5
KjSO,
pH of a 5% solution at 25°C
F.W.174.26
5.5-S.5
99%
Maximum Limits
0.01%
0.001%
5 ppm
2 ppm
0.02%
5 ppm
5 ppm
0.02%
Insoluble matter
Chloride (Cl)
Nitrogen compounds (as N)
Arsenic (As)
Calcium, magnesium, and R2O3 precipitate
Heavy metal (as Pb)
Iron (Fe)
Sodium (Na)
500
2.90
gm
T132392Potassium thiocyanate ACS/AR
F.W.97.18
Colorless or white
crystals
5.3-8.7
99%
pH of a 5% solution at 25°C
Maximum Limits
0.005%
0.01%
0.005%
0.005%
0.003%
5 ppm
2 ppm
0.005%
Passes test
(Not more than 0.2 ml of
0.1 N iodine solution per
gram)
Insoluble in water
Insoluble in alcohol
Chloride (Cl)
Sulfate (SO,)
Ammonium (NHJ
Heavy metals (as Pb)
Iron (Fe)
Sodium (Na)
Iodine-consuming substances
500
6x500
16.90
84.90
gm
gm
6
99%
F.W.60.10
0.783-0.787
1.376-1.378
Maximum Limits
Passes test
0.005%
Acidity
Nonvolatile residue
500
6x500
2.5
2.15
10.75
9.15
ml
ml
It
T133461 iso-Propyl alcohol ACS/AR
CAS 67-63-0
UN-1274 IMDG-3.2/II
(CH^CHOH
Solubility in water
99.5%
F.W.60.10
Passes test
Maximum Limits
Color (APHA)
Residue after evaporation
Water (H2O)
Titrable acid or base
500
6x500
2.5
38
ml
ml
It
CAS 67-63-0
UN-1274 IMDG-3.2/II
(CH3)2CHOH
99.7%
F.W.60.10
Solubility in water
Passes test
Ultraviolet Absorbance (1 cm cell vs. water)
X(nm) 205 220 230 245 254
280-400
Limit
1.00 0.30 0.15 0.08 0.02
0.01
Maximum Limits
Color (APHA)
Residue after Evaporation
Titrable acid or base
Water (H2O)
500
1
10
2 ppm
0.1 peq/g
0.05%
5.10
9.10
ml
It
CAS 71-23-8
CH/XjCHjOH
UN-1274 IMDG -3.2/II
F.W. 60.10
Min 99%
0.2%
96-99 deg C 95%)
Assay (GC)
H2O
Boiling Range
5.75
T133378 Propylene glycol ACS/AR
CAS 57-55-6
CH3CH(OH)CH2OH
99.5%
F.W. 76.10
Maximum Limits
10
0.005%
0.0005 meq/g
1 ppm
0.2%
Color (APHA)
Residue after ignition
Titrable acid
Chloride (Cl)
Water (H2O)
500
5.15
ml
T135509Pyridine Lab-Grade
T133456iso-Propyl alcohol Lab-Grade
CAS 67-63-0
UN-1274 IMDG-3.2/il
(CH3)2CHOH
Specific gravity @25°C
Refractive Index @20°C
'JEJL
T133444 n-Propyl Alcohol Lab-Grade
(Pottassium Supho-cynide)
CAS 333-20-0
KSCN
Appearance
kSB
10
0.001%
0.2%
0.0001 meq/g
CAS 110-86-1
UN-1282 IMDG -3.2/II
C5H5N
500
98%
F.W.79.10
9.45
ml
T133514 Pyridine ACS/AR
CAS 110-86-1
UN-1282 IMDG-3.2/II
W
Solubility in water
Maximum Limits
Residue after evaporation
Water (H2O)
Chloride (Cl)
Sulfate (SO,)
Ammonia (NH3)
Copper (Cu)
Reducing substances
500
6x500
ml
ml
99%
F.W.79.10
Passes test
0.002%
0.1%
0.001%
0.001%
0.002%
Passes test
(limit abour 5 ppm)
Passes test
12.90
64.50
2.80
14.00
11.90
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
T142263Silver nitrate Lab-Grade
IT139210 Resorcinol ACS/AR
I
X
ESH
Q
CAS 108-46-3
UN-2876 IMDG - 6.1/III
C6H.(OH)2
99-100.5%
Melting Point
Solubility
F.W.110.11
109°-111°C
Passes test
100
6x100
500
6x500
Maximum Limit
Residue alter Ignition
0.05%
gm
gm
7.40
29.50
100
500
CAS 477-73-6
F.W.350.85
5
10
1 -35
2.40
gm
gm
ml
ml
F.W. 138.12
Min. 99%
157-162degC
gm
4.90
25
ml
ml
ml
ml
ml
ml
0.002%
2 ppm
2 ppm
0.001%
11.45
57.25
40.00
200.00
F.W.311.80
12.60
98%
F.W.311.80
Maximum Limits
Insoluble matter and silver chloride0.02%
Nitrate (NOj)
Substance not precipitated by HCI0.03%
Iron(Fe)
25
6x25
1.50
4.50
98%
gm
CAS 10294-26-5
Ag2SO4
3.30
9.90
0.001%
0.001%
gm
gm
21.45
107.25
T142507Sodium (metal) in liquid paraffin Lab-Grade
A
.’o“’
T142130 Semens Diluting Fluid solution
125
4x125
5 ppm
Passes test
T142397Silver sulfate ACS/AR
'T142120 Selivoriaff's Reagent solution
125
4x125
F.W. 169.84
Passes test
gm
gm
gm
gm
CAS 10294-26-5
Ag2SO.
T142110 Schiff's Reagent solution for detection
of Aldehydes
125
4x125
yy /o
T142392Silver sulfate Lab-Grade
CAS 69-72-7
C.H,(OH)COOH
500
CAS 7761-88-8
UN-1493 IMDG-5.1/11
AgNU3
Clarity of solution
25
6x25
100
6x100
1.30
3.90
ri41235Salicylic Acid Lab-Grade
Assay
M.P.
37.75
188.75
180.00
900.00
gm
gm
gm
gm
Chloride (Cl)
Free acid
Substances no precipitated by HCI0.01%
Sulfate (SO.)
Copper (Cu)
Iron (Fe)
Lead (Pb)
-90%
530-534 nm
T142100 Safranine stain indicator solution
125
4x125
F.W. 169.84
Maximum Limits
c20h„n4ci
Dye content (spectro.dried)
Abs. max (50% ethanol)
99.8%
T142268Silver nitrate ACS/AR
i ~^1
o
“140101 Safranine Lab-Grade
CAS 7761-88-8
UN-1493 IMDG-5.1/11
AgNOj
CAS 7440-23-5
UN-1428 IMDG -4.3/1
Na
F.W.22.90
Maximum Limits
125
3.75
T142230 Silver Nitrate N/10 solution
Calcium (Ca)
Chloride (as Cl)
100
gm
500
gm
.
0.04%
0.005%
2.40
930
T142546Sodium acetate anhydrous Lab-Grade
125
4x125
ml
ml
1.80
5.40
T142240 Silver Nitrate N/50 solution
" jp
125
4x125
ml
ml
CAS 127-09-3
CH COONa
Assay (non-aqueous)
100
3.00
500
gm
ILab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
F.W.82.03
Min.98%
3.60
39
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
T144859Sodium hydrogen carbonate ACS/AR
T144997 Sodium hydrogen sulphate ACS/AR
(Sodium Bicarbonate)
CAS 144-55-8
NaHCO,
99.7-100.3%
F.W.84.01
Maximum Limits
Insoluble matter
Chloride (Cl)
Phosphate (PO.)
Sulfur compounds (as SO,)
Ammonium (NH,)
Calcium, magnesium, and R.O, precipitate
Heavy metals (as Pb)
Iron (Fe)
Potassium (K)
500
6.500
0.015%
0.003%
0.001%
0.003%
5 ppm
0.02%
5 ppm
0.001%
0.00514
3.30
16.50
gm
gm
T144949di-Sodium hydrogen orthophosphate
Lab-Grade
anhydrous
CAS 7558-79-4
Na?HPO,
98-100.5%
F.W. 141.96
Maximum Limits
5.0%
0.4%
0.06%
0.2%
16 ppm
0.002%
Loss on Drying © 105°C
Insoluble substances
Chloride (Cl)
Sulfate (SO,)
Arsenic (As)
Heavy metals (as Pb)
500
gm
T144954di-Sodium hydrogen orthophosphate
99%
F.W. 141.96
8.7-9.3
Maximum Limits
0.01%
0.2%
0.00214
0.002%
0.005%
0.001%
0.002%
Insoluble matter
Loss on drying at 105°C
Chloride (Cl)
Nitrogen compounds (as N)
Sulfate (SO,)
Heavy metals (as Pb)
Iron (Fe)
500
6x500
4.75
23.75
gm
gm
T144959di-Sodium hydrogen orthophosphate
dihydrate
Lab-Grade
CAS 10028-24-7
Na/tPO.^HjO
500
99%
gm
F.W. 177.99
4.00
T144964 di-Sodium hydrogen orthophosphate
dihydrate ACS/AR
CAS 10028-24-7
Na2HPO,.2H;O
99.5%
pH of a 5% solution in CO2 free water
Maximum Limits
Chloride (Cl)
Sulfate (SO,)
Iron (Fe)
500
6x500
gm
gm
F.W. 177.99
9.0-9.2
0.001%
0.005%
0.001%
5.60
28.00
39.0-42.0%
Maximum Limits
Insoluble matterand Ammonium hydroxide ppt.
Chloride (Cl)
Phosphate (PO,)
Calcium and Magnesium Ppt.
.
Heavy metal (as Pb)
Iron (Fe)
500
0.01%
0.001%
0.001%
0.005%
5 ppm
0.002%
27.50
gm
T145030 Sodium hydroxide flakes Lab-Grade
CAS 1310-73-2
UN-1823 IMDG-8/11
NaOH
500
1
5
96%
F.W.40.0
gm
kg
kg
1.35
2.35
9.60
T145035 Sodium hydroxide flakes ACS/AR
CAS 1310-73-2
NaOH
F.W.40.0
UN-1823 IMDG-8/ll
Assay
Chloride
Sulphate
500
anhydrous ACS/AR
CAS 7558-79-4
Na.HPO,
pH of a 5% solution at 25°C
CAS 7681-38-1
UN-1821 IMDG-8/III
NaHSO,
Acidity (as H2SO,)
Min. 96%
0.1%
0.01%
2.20
gm
T145037 Sodium hydroxide pellets Lab-Grade
CAS 1310-73-2
UN -1823IMDG-8/II
NaOH
500
5
gm
kg
97%
F.W.40 0
.
1.75
14.00
T145042 Sodium hydroxide pellets ACS/AR
CAS 1310-73-2
UN-1823 IMDG-8/II
NaOH
F.W.40.0
98%
Maximum Limits
1.0%
0.005%
0.001%
0.001%
0.003%
0.02%
0.002%
0.001%
0.1 ppm
0.001%
0.02%
Na,CO3
Chloride (Cl)
Nitrogen compounds (as N)
Phosphate (PO.)
Sulfate (SO,)
Ammonium hydroxide precipitate
Heavy metals (as Ag)
Iron (Fe)
Mercury (Hg)
Nickel (Ni)
Potassium (K)
500
5
250
21.45
gm
kg
T145372Sodium hypophosphite Lab-Grade
CAS 10039-56-2
NaHjPO2.H2O
500
98-101%
FV
gm
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029- India
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T BAKER LAB CHEMICALS
T146007Sodium nitrate ACS/AR
IF 145377Sodium hypophosphite ACS/AR
CAS 10039-56-2
NaH2PO2.H2O
99.0%
F.W.105.99
Maximum Limits
Arsenic (A)
Chloride (Cl)
Heavy metal (as Pb)
Insoluble matter
Iron (Fe)
0.0001%
0.01%
0.0005%
0.01%
0.0005%
gm
gm
16.50
82.50
500
6x500
T145507Sodium lauryl sulfate Lab-Grade
CAS 151-21-3
CH3(CH2)10CH2OSO3Na
99%
F.W.288.38
Maximum Limits
1.0%
0.003%
0.1%
0.0001%
Moisture (KF)
Insoluble in water
Chloride (Cl)
Phosphate (PO,)
500
6.60
gm
T145760Sodium Molybdate Lab-Grade
CAS 10102-40-6
Na2MoO,.2H20
F.W.241.95
98-102%
6-10
0.02%
0.05%
Assay (ex Mo)
pH (10% soln)
Chloride
Sulphate
100
500
4.00
20.00
gm
gm
H 145765 Sodi J n molybdate ACS/AR
CAS 10% ’-40-6
H? M?O, LH/0
98 102%
r.W.241.95
Maxim .m L imits
insoluble matter
Chloride (Ci,
Phosphate (°C.,
Sulfate (S "
A r coniu . 'r. .
Hr avy me< s (a.: °b)
Iron (re)
100
500
6x500
gm
gm
gm
0 905%
0 005%
■- npm
. j J
0.001%
5 ppm
0.001%
5.15
18.60
93.00
CAS 7631-99-4
UN-1498 IMDG-5.1/111
NaNO3
0.005%
0.001%
5 ppm
Passes test
(limits about 5 ppm lO.about 0.001% NO2)
Phosphate (PO,)
5 ppm
Sulfate (SOJ
0.003%
Calcium , magnesium, and R2O3 precipitate
0.005%
Heavy metals (as Pb)
5 ppm
Iron (Fe)
3 ppm
Insoluble matter
Chloride
Iodate (IOJ
Iodate and nitrite
500
6x500
2.80
14.00
gm
gm
T146015 Sodium Nitrite Lab-Grade
CAS 7632-00-0
F.W. 69.00
UN-1500 IMDG - 5.1/111
NaNO,
Assay (ex NO2)
Chloride
Sulphate
500
min. 98%
0.02%
0.03%
2.10
gm
T146020Sodium nitrite ACSAR
CAS 7C32-00-0
UN -1500 IMDG-5.1/111
NaNO,
F.W.69.00
Maximum Limits
Insoluble matter
Chloride (Cl)
Sulfate (SO,)
Calcium (Ca)
Heavy metals (as Pb)
Iron (Fe)
Potassium (K)
0.01%
0.005%
0.01%
0.01%
0.001%
0.001%
0.005%
gm
gm
2.35
11.75
500
6x500
T146169 Sodium nitroprusside ACS/AR
CAS 13755-38-9
Na.[Fe(CN)5NO].2H?O
99%
Insoluble Matter
Chloride (Cl)
Sulfate (SO,)
100
500
Jk :
CAS 7631-99-4
o ;
NaNO3
----- UN-1498 IMDG - 5.1/111
Assay (ex NO3)
Chloride
500
gm
F.W.84.99
Min. 98%
0.01%
1.95
F.W.297.95
Maximum Limits
0.01%
0.02%
Passes test
(limit about 0.01%)
T146C02Sodium Nitrate Lab-Grade
‘
F.W.84.99
99.0%
Maximum Limits
gm
6.90
27.60
T146363Sodium,periodate Lab-Grade
CAS 7790-28-5
NalO,
100
98%
F.W.213.89
gm
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
43
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
T146922Sodium sulfite anhydrous ACS/AR
T146368Sodium periodate ACS/AR
CAS 7790-28-5
NalO,
99.8%
F.W.213.89
Other halogens (as Cl)
Manganese (Mn)
0.02%
3 ppm
100
6x100
12.30
61.50
gm
gm
T146390Sodium persulfate Lab-Grade
CAS 7775-27-1
UN-1505IMDG-5.1/111
NaAO.
F.W.238.09
Maximum Limits
Chloride (Cl)
Lead (Pb)
Iron (Fe)
0.005%
0.005%
0.01%
gm
5.75
T146395Sodium persulfate ACS/AR
CAS 7775-27-1
UN-1505 IMDG-5.1/111
Na,S2O,
F.W.238.09
gm
500
6x500
500
T 147062Sodium thiosulphate pentahydrate
Lab-Grade
CAS 10102-17-7
Na2S2O3.5H2O
Calcium (Ca)
Arsenic (As)
Heavy metals (as Pb)
Lead
Selenium
F.W.248.17
Passes test
3 ppm
0.002%
0.001%
0.003%
gm
1.70
99%
CAS 10102-17-7
Na2S2O3.5H2O
F.W.270.14
6.60
T146891 Sodium sulfate anhydrous Lab-Grade
500
99-100.5%
Maximum Limits
T 147067Sodium thiosulphate pentahydrate ACS/AR
gm
CAS 7757-82-6
Na^O,
4.30
21.50
gm
gm
8.25
T146853Sodium succinate Lab-Grade
CAS 6106-21-4
(CHjCOONaJj.eHjO
0.005%
Passes test
0.03 meq/g
0.02%
1 ppm
0.001%
0.001%
Insoluble matter
Free acid
Titrable free base
Chloride (Cl)
Arsenic (As)
Heavy metals (as Pb)
Iron (Fe)
500
500
F.W. 126.04
98%
Maximum Limits
Maximum Limits
500
CAS 7757-83-7
Na2SO3
99%
F.W.142.04
gm
1.95
99.5%
F.W.248.17
Maximum Limits
0.005%
0.002%
0.1%
Passes test
(limit about 1 ppm
Insoluble matter
Nitrogen compounds (as N)
Sulfate and sulfite (as SO,)
Sulfide (S)
500
5.15
gm
T147113 Sodium tripolyphosphate Lab-Grade
CAS 7758-29-4
Na5O10P3
T146896Sodium sulfate anhydrous ACS/AR
CAS 7757-82-6
Na,SO4
99.0%
pH of a 5% solution at 25°C
500
F.W.142.04
5.2-9.2
Maximum Limits
Insoluble matter
Loss on ignition
Chloride (Cl)
Nitrogen compounds (as N)
Arsenic (As
Calcium. magnesium, and R2O3 precipitate
Heavy metals (as Pb)
Iron(Fe)
500
6x500
0.001%
0.5%
0.001%
5 ppm
1 ppm
0.02%
5 ppm
0.001%
3.15
15.75
gm
gm
T146905Sodium Sulfide flakes Lab-Grade
NajS.XHjO
CAS 1313-84-4
UN-1385 IMDG-4.2/II
Assay
500
4
gm
Min. 52%
2.45
4.20
gm
T147265Sodium tungstate hydrate Lab-Grade
CAS 10213-10-2
NajWO4.2H2O
100
500
98%
F.W.329.86
3.45
13.80
gm
gm
T 147270Sodium tungstate hydrate ACS/AR
CAS 10213-10-2
Na.WO4.2H2O
99.0-101%
Maximum Limits
Insoluble matter
Titrable free base
Chloride (Cl)
Molybdenum (Mo)
Nitrogen compounds (as N)
Sulfate (SO4)
Arsenic (As)
Heavy metals and iron (as Pb)
100
gm
F.W.329.86
0.01%
0.02%
0.005%
0.001%
0.001%
0.01%
5 ppm
0.001%
4.75
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T BAKER LAB CHEMICALS
T148337Strontium nitrate anhydrous Lab-Grade
IT 147732Stannous chloride ACS/AR
CAS 10025-69-1
SnCI?.2H2O
F.W.225.63
97%
Maximum Limits
Passes test
Passes test
(limit about 0.003%)
2 ppm
Solubility in hydrochloric acid
Sulfate (SO,)
Arsenic (As
Substances not precipitated by
hydrogen sulfide (as sulfates)
Iron (Fe)
Other metals (as Pb)
100
500
6x500
3.45
13.80
69.00
gm
gm
gm
CAS 7759-02-6
SrSO,
500
F.W. 183.68
9.00
gm
T148330Succinic acid ACS/AR
99.0%
8.00
gm
CAS 9005-25-8
(C.H.AL
pH of a 2% solution @ 25°C
Sensitivity
Solubility
5.0-7.0
Passes test
Passes test
Maximum Limit
Residue after Ignition
0.4%
500
6x500
10.75
53.75
gm
gm
98%
F.W.284.48
4.90
gm
0.01%
0.02%
0.001%
0.001%
0.003%
0.001%
5 ppm
5 ppm
Insoluble matter
Residue after ignition
Chloride (Cl)
Phosphate (SO,)
Sulfate (SO,)
Nitrogen compounds (as N)
Heavy metals (as Pb)
Iron (Fe)
100
500
6.60
26.10
gm
gm
T148863Sucrose Lab-Grade
CAS 57-50-1
C„H„O,
500
6x500
17147890Stearic acid for synthesis Lab-Grade
99.9%
T148868 Sucrose ACS/AR
CAS 57-50-1
c.AP,,
99%
500
F.W. 147.63
8.30
gm
TT148221 Strontium chloride Lab-Grade
CAS 10025-70-4’
SrCL.6H,O
500
98-101%
F.W.266.62
4.60
gm
99.0-103.0%
F.W.266.62
Maximum Limits
Insoluble matter
Sulfate (SO.)
Barium (Ba)
Calcium (Ca)
Heavy metals (as Pb)
Iron (Fe)
Magnesium (Mg)
0.005%
0.001%
0.05%
0.05%
5 ppm
5 ppm
2 ppm
gm
11.00
500
Insoluble matter
Loss on Drying @ 105°C
Residue after Ignition
Titrable acid
Chloride (Cl)
Sulfate and Sulfite (as SO,)
Heavy metal (as Pb)
Iron (Fe)
Invert sugar
500
gm
0.005%
0.03%
0.01%
0.0008 meq/g
. 0.005%
0.005%
5 ppm
5 ppm
0.05%
6.90
T149186Sulfanilic acid ACS/AR
T148226Strontium chloride ACS/ACR
CAS 10025-70-4
SrClr6HaO
F.W.342.3
66.3° to 66.8°
Maximum Limits
TT148298 Strontium carbonate Lab-Grade
99%
F.W.342.3
2.00
10.00
gm
gm
Specific rotation [a)0
CAS 1633-05-2
SrCO,
F.W.118.09
Maximum Limits
TT147860Starch soluble ACS/AR
500
F.W.211.63
4.45
gm
CAS 110-15-6
HOOCCH2CH,COOH
CAS 9005-25-8
(C6H,0O5)o
CAS 57-11-4
CH3(CH2)10COOH
500
99%
T148492Strontium sulfate Lab-Grade
0.05%
0.003%
0.01%
T 147855Starch soluble Lab-Grade
500
CAS 10042-76-9
UN-1507 IMDG-5.1/111
SrfNOJ,
CAS 121-57-3
NHa.C,H,.SO,H
98.0-102.0%
F.W.173.19
Maximum Limits
Residue after ignition
Insoluble in sodium carbonate solution
Chloride (Cl)
Nitrite (NO,)
Sulfate (SO,)
100
500
6x500
gm
gm
gm
L«ab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
0.01%
0.02%
0.002%
0.5 ppm
0.01%
8.25
33.00
165.00
45
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
T155420Thiourea ACS/AR
T149625Sulfur powder Lab-Grade
*
CAS 62-56-6
CAS 7704-34-9
S
100
500
F.W.32.06
gm
gm
0.45
1.60
T149656Sulfuric acid 98% Lab-Grade
CAS 7664-93-9
UN-1830 IMDG-8/11
H2SO4
min. 99.0%
0.01%
0.0005%
gm
gm
13 15
65.75
500
6x500
98%
.
F.W. 76.12
NH2CSNH2
Assay
Sulphate
Iron
F.W.98.07
T155501 Thymol Crystals Lab-Grade
2x500
8x500
2.5
4x2.5
5
4.40
15.40
6.10
21.25
8.50
ml
ml
It
It
It
T149661 Sulfuric acid 98% ACS/AR
l£
S 7664-93-9
UN - 1830 IMDG-8/11
H2SO4
95-0-98.0%
F.W.98.07
Maximum Limits
Color (APHA)
Residue after ignition
Chloride (Cl)
Nitrate (NO3)
Ammonium (NH4)
Substances reducing permanganate
Arsenic (As)
Heavy metals (as Pb)
Iron (Fe)
Mercury (Hg)
2x500
8x500
2.5
4x2.5
5
10
5 ppm
0.2 ppm
0.5 ppm
2 ppm
2 ppm as SO,
0.01%
1 ppm
0.2 ppm
5 ppb
ml
ml
It
It
It
5.00
17.50
7.20
25.00
10.10
T149670 Sulphosalicylic Acid 3% solution
125
4x125
ml
ml
F.W. 150.22
C,oH„O
Assay (GC)
M.P.
min. 99.5%
min. 49 deg C
Acidity (HCI)
0.073%
25
100
4.70
14.30
pH transition range:
pH 1.2 - 2.8
pH 7.8 - 9.5
125
4x125
Violet red to brownish yellow
.Greenish yellow to blue
1.20
3.60
ml
ml
T155621 Thymol Blue powder Lab-Grade
pH transition range:
CAS 76-61-9
F.W. 466.60
cJ7h30o5s
pH transition range:
pH 1.2 - 2.8
pH 7.8-9.5
Violet red to brownish yellow
Greenish yellow to blue
0.70
2.90
gm
gm
T 155430Thymoiphthaleine indicator solution
CAS 109-99-9
UN-2056 IMDG-3.1/11
C4H„O
gm
gm
T155651 Thymol Blue solution Standard
1
5
T152591 Tetrahydrofuran ACS /AR
H
CAS 89-83-8
99.0%
Maximum Limits
20
0.015%
0.03%
0.05%
10.00
Color (APHA)
Peroxide (as H2O2)
Residue alter evaporation
Water
500
ml
T155450Titaii yellow solution
pH 12.0-13.0
125
1x125
red
.nl
ml
150
350
chloride Lab-Grade
CAS 7719-09-7
UN-1836 IMDG 8/I
SOCI2
500
T155980o-Tolidine ACS/AR
99-101%
ml
F.W.118.97
6.00
T155415Thiourea Lab-Grade
CAS 62-56-6
NH2CSNH2
500
48
gm
CAS 119-93-7
[NH^Ctyt
Melting range
Sensitivity to Chlorine
Maximum Limit
Residue after Ignition
99-101%
F.W.76.12
25
100
gm
gm
97.5%
F.W.212.30
129°-131°c
Passes tost
0.1%
1.80
5.45
7.90
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T BAKER LAB CHEMICALS
T164501 Wright Stain Lab-Grade
TT156106Toluene ACS/AR
6
CAS 108-88-3
UN-1294 IMDG-3.2/II
C6H5CH3
99.5%
F.W.92.14
Color (APHA)
Residue after evaporation
Substance darkened by sulfuric acid
Sulfur compounds (as S)
Water (H2
10
0.001 %
Passes test
0.003%
0.03%
CAS 68988-92-1
Absorptivity (1 %/1 cm: methanol dried):
(g) max. 640-651 nm :1200-1400
(g) max. 521-524 nm : 650-850
Maximum Limits
500
6x500
2.5
ml
ml
It
CAS 79-01-6
UN-1710IMDG06.1/III
CHCI=CCI2
500
6x500
2.5
99%
125
4x125
500
Color (APHA)
Residue after evaporation
Substances darkened by sulfuric acid
Sulfur compunds (as S)
Water (H2O)
F.W.149.19
ml
CAS 121-44-8
UN-1296 IMDG-3.2/II
(C2H5).N
500
2.5
99%
500
2.5
AI
F.W.101.19
Maximum Limits
Water (H2O)
Iron(Fe)
Lead(Pb)
500
6x500
6.60
33.00
1T163250 Universal indicator solution pH 2.0-10.0
Lab-Grade
500
ml
1-00
Maximum Limits
Insoluble matter
Residue after ignition
Chloride (Cl)
Sulfate (SO4)
Heavy metals (as Pb)
Iron (Fe)
500
6x500
gm
gm
F.W.106.17
2.35
11.40
ml
It
125
4x125
0.01%
0.01%
5 ppm
0.001%
0.001%
0.001%
F.W.106.17
2.40
11.50
2 50
7 50
ml
ml
T16S011 Zinc (metal) dust Lab-Grade
ran
CAS 7440-66-6
UN-1436 IMDG-4.3/11
500
F.W.60.06
Not below 132cC
nor above 135'C
98.5%
ml
It
90%
2h
99.5%
98.5%
T167250Xylenol Orange indicator solution 0.1%
1T163263Urea ACS/AR
CAS 57-13-6
(NH2)2CO
Melting point
It
CAS 1330-20-7
UN-1307 IMDG-3.2/II
c6H,(CH3)2
500
2.5
0.05%
0.0001%
0.0001%
ml
ml
ml
T167221 Xylenes Sulfur free Lab-Grade
- -v-■ .
99.5%
10%
0.002%
Passes test
0.003%
0.05%
2.75
13.75
12.45
ml
CAS 1330-20-7
UN-1307 IMDG-3.2/II
C.H/CHJ.
4.15
18.30
IT 158725Triethylamine for synthesis ACS/AR
6
F.W.106.17
T167214Xylenes rectified Lab-Grade
F.W.101.19
ml
It
CAS 121-44-8
UN-1296 IMDG-3.2/11
(C2H5)3N
500
6x500
2.5
4.60
IT 158720Triethylamine for synthesis Lab-Grade
S3.5%
Maximum Limits
3.60
18.00
15.45
95%
1.00
3.00
ml
ml
CAS 1330-20-7
UN-1307 IMDG-3.2/11
C.HJCH^
TT158700Triethanolamine Lab-Grade
CAS 102-71-6
N(CH2CH2OH)3
1.55
6.30
T167228Xylenes ACS/AR
F.W.131.39
ml
ml
It
gm
grn
T164505 Wright's Staining solution
2.55
12.75
11.30
TT157981 Trichloroethylene for synthesis Lab-Grade
X
5
25
gm
F.W.65.39
5.30
T169016Zinc (metal) dust ACS/AR
nan
CAS 7440-66-6
UN-1436 IMDG -4.3/II
Zh
500
95%
gm
F.W.65.39
5.75
5.45
27.25
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
47
(INTERNATIONAL PRICE LIST IN US. DOLLARS)
T. BAKER LAB CHEMICALS
T169005Zinc (metal) granulated (As Free) Lab-grade
T169582Zinc oxide ACS/AR
CAS 1314-13-2
ZnO
99.0%
F.W.81.39
Maximum Limits
500
T169010Zinc (metal) granulated (As Free) ACS/AR
rg~j
ffg
“"
CAS 7440-66-6
Zn
99.8%
Suitability for Determination of Arsenic (As)
F.W.65.37
Passes test
Maximum Limits
0.01%
0.01%
Iron (Fe) Lead (Pb)
500
6.90
gm
T169024Zinc acetate Lab-Grade
CAS 5970-45-6
(CH3COO)2Zn.2H2O
500
98.5%
500
6x500
F.W.219.50
3.60
gm
CAS 7446-20-0
ZnSO,.7H2O
0.005%
5 ppm
0.005%
0.5 ppm
0.005%
5 ppm
0.002%
0.005%
0.01%
0.01%
Insoluble matter
Chloride (Cl)
Sulfate (SO,)
Arsenic (As)
Calcium (Ca)
Iron (Fe)
Lead (Pb)
Magnesium (Mg)
Potassium K)
Sodium (Na)
500
F.W.219.50
6.0-7.0
Maximum Limits
500
6x500
Insoluble matter
Chloride (Cl)
Nitrate (NO,)
Ammonium (NH,)
Arsenic (As)
Calcium (Ca)
Iron (Fe)
Lead (PB)
Magnesium (Mg)
Manganese (Mn)
Potassium (K)
Sodium (Na)
65%
500
5.00
gm
99.0-103.0%
500
6x500
gm
gm
Assay
500
gm
500
48
gm
99.0%
4.15
20.75
Chip Chap Educational Electronic Kit
20.00 Each
M 101
Light Lab Kit (Optics 40 experiments)
55.00 Each
M102
Electric Kit (60 experiments)
24.00 Each
M103
Maglite Kit (20 experiements)
8.00 Each
F.W. 136.29
Min. 94-96%
M104
Bell Kit
6.00 Each
2.70
M105
Electric Wiring Kit
6.00 Each
M106
Tele Kit
9.00 Each
T169577Zinc oxide Lab-Grade
CAS 1314-13-2
ZnO
0.01%
5 ppm
0.002%
0.001%
1 ppm
0.005%
0.001%
0.003%
0.005%
3 ppm
0.01%
0.05%
M 100
T169158Zinc Chloride dry Lab-Grade
CAS 7646-85-7
ZnOs
UN-2331 IMDG -8/III
F.W.287.56
Maximum Limits
Maximum Limit
0.5%
F.W.287.56
2.15
gm
CAS 7446-20-0
ZnSO,.7H2O
T169143Zinc carbonate basic Lab-Grade
Sulfate (SO,)
99%
T169727Zinc sulfate heptahydrate ACS/AR
5.75
28.75
gm
gm
CAS 12539-71-8
ZnCO,.2ZnO.3H2O
4.60
23.00
gm
gm
T169722Zinc sulfate heptahydrate Lab-Grade
T169029Zinc acetate ACS
CAS 5970-45-6
(CH3COO)2Zn.2H!0
98.0%
pH of a 5% solution at 25°C
0.01%
Passes test
0.001%
0.003%
0.01%
2 ppm
0.005%
0.001%
0.005%
0.005%
5 ppm
0.01%
0.05%
Insoluble in dilute sulfuric acid
Alkalinity
Chloride (CIO
Nitrate (NO,)
Sulfur compounds (as SO,)
Arsenic (As)
Calcium (Ca)
Iron (Fe)
Lead (Pb)
Magnesium (Mg)
Manganese (Mn)
Potassium (K)
Sodium (K)
5.90
gm
F.W.81.39
3.75
Lab & General Exports (Pvt) Ltd. 11/1, Hosur Road, Bangalore-560 029. India
T BAKER LAB CHEMICALS
Manufacturer of Laboratory & Fine Chemicals
Metal
Non-metal
1 H
2/1 la
Be 4
0 He “
22.989768
Al
4/IVb
3/IIIb
„ 20 ’’ Sc 21
Ca
40.078
44 955910
47 867
-8-10-2
5/Vb
6/Vlb
2
Cr
45 50-9415
’ 51.9961
-8-13-1
12/1 lb
7/VIIb 8/VIII
9/VIII 10/VIII ||/Ib
25 ■3 Ee26 " co27 3 W28 ;! r 29I ’ r, 30
*- Cu
Zn
3 Ni
.7 54.93805
Vannaum
Potass urn
1 Rb37
- Sr 38 .3 y 39
85.4678
-18-8-1
87.62
-18-8-2
Strontium
’ Cs55
132 90543
-18-8-1
C«.cm
Ba 56
-18-8-2
Bar.um
88.90585
-18-9-2
Yttnun
+3
41
40 Mo
* “ ’6
*5 Nb
92.90638
-18-10-2
Zirconium
Nobium
57-71
4
'
Lantha
*
nide
178.49
-32-10-2
Hatn ten
” Fr 87 ^Ra88 89-103
Hf72
4.RI!W
(226.0254)
w
la
Tantalum
183.84
-32-12-2
Tun-;-.ton
106
105
♦Unh
♦Ha
(262 114)
*
Actinide
Hahn-yn
(263.118)
-32-12-2
llr< ^‘ -n
.3
Actinides
Rh45
102.90550
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LAB & GENERAL EXPORTS (P) LTD.
11/1, HOSUR ROAD
BANGALORE-560 029, INDIA
TEL -(91) 80-5536800/5521830, 5536052
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T)iS' 13 13
Dr. Reddy's
LABORATORIES
DoceteRe .
^aaaaBBBBMBaaaan^B Docetaxel 20 mg & 80 mg
.
■
.—
Va^ue beyond paz\~/
6NN(5va™@ for & remoter lLBFE
For the use only of o Registered Medical Practitioner or a Hospital or a laboratory
OoceteRe.. ABRIDGED PRODUCT INFORMATION:
Doce'Cld 20 F>g & 60 mg
|
Description
Docetaxel (DOCETERE) is a new semi synthetic analogue of Paclitaxel with promising antitumour activity.
Composition
Each single dose vial contains:
Docetaxel Trihydrate equivalent to Docetaxel anhydrous
Polysorbate 80
Mode of Action
Docetere 80
Docetere 20
80 mg.
2.0 mL.
20 mg.
0.5 mL.
DOCETERE enhances polymerization of the tubulin into stable microtubules and inhibits their depolymerization. This
induces theformation of stable microtubule bundles leading to cell death.
Indications
Adverse Reactions
DOCETERE in indicated in the treatment of patients with metastatic breast cancer and non-small cell lung cancer.
Neutropenia, fluid retention, peripheral neuropathy, hypersensitivity reactions, nail changes, asthenia, mucositis and
alopecia.
Storage
Unopened vials should be stored under refrigeration at a temperature of 2°- 8°C. Solvent for Docetaxel injection
concentrate should be stored in a cool place, protected from light.
Presentations
DOCETERE 80 mg. carton containing single dose Oocetaxel-80 mg. vial and a carton containing solvent for Docetaxel
injection concentrate - 6 mL.
DOCETERE 20 mg. carton
:
single dose Docs', axd-20 mg. vials and carton containing solvent for Docetaxel
injection concentrate- 1.5ml.
’ARATlON FO#
(A) PREPARATION OF THE DOCETETRE
PREMIX SOLUTION
(10 mg. DOCETAXEL/mL
A-1 Remove the required number of
DOCETERE vials from the refrigerator
and allow to stand at room
temperature for 5 minutes.
A-2 Use a syringe fitted with needle,
aseptically withdraw the entire
contents of the solvent from
"SOLVENT FOR DOCETAXEL" vial.
A-3 Inject the entire contents of the
syringe into the corresponding
DOCETEREvial
ADMINISTRATION
;
-- .’riDN SOLUTION
B-1 More than one premix vial may be necessary to obtain the required
dose for the patient. Based on the required dose for the patient
expressed in mg., aseptically withdraw the corresponding premix
volume containing 10 mg./mL. docetaxel from the appropriate
number of premix vials using graduated syringes fitted with a
needle. For example, a dose of 140 mg. docetaxel would require 14
mL docetaxel premix solution.
B-2 Inject the required premix volume into a 250 mL infusion bag or
bottle containing either 5% glucose solution or 0.9% sodium
chloride solution. If a dose greater than 240 mg. of docetaxel is
required, use a larger volume of the infusion vehicle so that a
concentration of 0.9 mg./mL. docetaxel is not exceeded.
B-3 Mixthe infusion bag or bottle manually using a rocking motion.
A-4 Remove the syringe and needle and
shake the mixture manually for 15
seconds.
B-4 The DOCETERE infusion solution should be aseptically administered intravenously as soon
as possible after preparation as a 1 hour infusion under room temperature and normal
A-5 Allow the premix vial to stand for 5
minutes at room temperature and
then check that the solution is
homogenous and clear. (Foaming is
normal even after 5 minutes due to
the presence of polysorbate 80 in the
formulation. The premix solution
contains 10 mg. / mL docetaxel and is
stable for 8 hours in a refrigerator or
at roomtemperature.
lighting conditions.
B-5 As with all parenteral products, DOCETERE premix solution and infusion solution should be
visually inspected priorto use, solutions containing a precipitate should be discarded.
DISPOSAL
All materials that have been utilised for dilution and administration should be disposed
of according to standard procedures.
For further information, please write to: Docetere Cell, Dr. REDDY'S LABORATORIES LTD.,
8-2-337, Road No. 3, Banjara Hills, Hyderabad-500 034. Phone: 040-3358471 Fax: 040-3358472 email: drlpmt@hotmail.com
A Phase II Study of Docetaxel in Patients With
Paclitaxel-Resistant Metastatic Breast Cancer
By Vicente Valero, Stephen E. Jones, Daniel D. Von Hoff, Daniel J. Booser, Robert G. Mennel, Peter M. Ravdin,
Frankie A. Holmes, Zia Rahman, Margaret W. Schottstaedt, John K. Erban, Laura Esparza-Guerra, Robert H. Earhart,
Gabriel N. Hortobagyi, and Howard A. Burris III
Purpose: To evaluate the efficacy and safety of doce
taxel in patients with paclitaxel-resistant metastatic
breast cancer (MBC).
Patients and Methods: Docetaxel (100 mg/m2) was
administered every 3 weeks to 46 patients registered at
four centers. Patients had previously received < two
chemotherapy regimens for MBC. All patients had pro
gressive disease while receiving paclitaxel therapy.
Treatment was repeated until there was evidence of
disease progression or for a maximum of three cycles
after best response.
Results: Objective responses were seen in eight of
44 assessable patients (18.1 %; 95% confidence interval
[Cl], 6.7% to 29.5%). Seven patients had partial re
sponses and one patient responded completely. Re
sponse rates were not significantly different by previ
ously received paclitaxel dose or resistance. No
responses were seen in 1 2 patients who had previously
received paclitaxel by 24-hour infusion, but the re-
sponse rate in 32 patients who had received paclitaxel
by 1 - to 3-hour infusion was 25%. The median response
duration was 29 weeks and the median time to disease
progression was 10 weeks. Median survival was 10.5
months. Clinically significant (severe) adverse events
included neutropenic fever (24% of patients), asthenia
(22%), infection (13%), stomatitis (9%), neurosensory
changes (7%), myalgia (7%), and diarrhea (7%).
Conclusion: Docetaxel is active in patients with pacli
taxel-resistant breast cancer, particularly in those who
failed to respond to brief infusions of paclitaxel. Re
sponse rates were comparable to or better than those
seen with other therapies for patients with paclitaxelresistant MBC. This confirms preclinical studies, which
indicated only partial cross-resistance between pacli
taxel and docetaxel.
OCETAXEL AND PACLITAXEL are cytotoxic agents
that interfere with microtubular function by promot
ing tubulin polymerization and inhibiting the depolymeriza
tion of microtubules. Although their mechanism of action is
similar, the preclinical and clinical activity profiles of the
two compounds have several notable differences.1'5 Doce
taxel is a more potent promoter of tubulin polymerization
and a more potent inhibitor of microtubule depolymerization
than paclitaxel.6-7 In addition, docetaxel has a greater affinity
than paclitaxel for the tubulin-binding site and it promotes
structurally different microtubules than does paclitaxel.5'6-8
The intracellular biologic activity of the taxanes is related to
their concentration and duration of exposure, especially in
taxane-resistant cell lines. The cellular uptake of docetaxel is
greater than that of paclitaxel and its efflux rate is about three
times slower than that of paclitaxel.9 These differences may
result in higher intracellular concentration and longer expo
sure to docetaxel, which may. among other biologic differ
ences. lead to greater cytotoxic activity. In many in vitro
murine and human preclinical models, including chemother
apy-resistant cell lines, docetaxel demonstrated greater
antitumor activity than paclitaxel at equitoxic doses.4-1012
Docetaxel was capable of inducing bcl-2 phosphorylation
and apoptotic cell death at 100-fold lower concentrations
than paclitaxel.13 Docetaxel was also shown to be more
potent than paclitaxel in many tumor models in vivo.3-14'16
Docetaxel was less schedule-dependent than paclitaxel and
showed a stronger correlation between dose and plasma
concentration and area under the plasma concentration-time
curve (AUC).1'2- *- 17 Finally, preclinical studies indicated
only partial cross-resistance between paclitaxel and doce
taxel in cell lines in which resistance to paclitaxel had been
induced.114
Clinical differences between docetaxel and paclitaxel are
more difficult to define because no randomized phase 111
study comparing these agents has been completed. Both
drugs were active in first- and second-line treatment of
patients with metastatic breast, ovarian, and lung cancers.
Phase II studies showed greater efficacy for docetaxel
D
From The University of Texas M.D. Anderson Cancer Center,
Houston: Texas Oncology Physician Association. Dallas: Cancer
Therapy and Research Center. San Antonio. TX: New England Medical
Center. Boston. MA: and Rhone-Poulenc Rorer Pharmaceuticals. Inc.
Collegeville. PA.
Submitted February 26. 1998: accepted June 29. 1998.
Supported by a gram from Rhone-Poulenc Rorer Pharmaceuticals.
Inc. Collegeville. PA.
Address reprint requests la Vicente Valero. MD. The University of
Texas M.D. Anderson Cancer Center. Department of Breast Medical
Oncology. Box 56. 1515 Holcombe Blvd. Houston. TX 77030-4095:
Email \ valero@tndacc.org .
© 1998 by American Society of Clinical Oncology.
0732-183X798/1610-603483.00/0
3362
J Clin Oncol 16:3362-3368. © 1998 by American Soci
ety of Clinical Oncology.
Journal of Clinical Oncology Vol 16, No 10 (October), 1998: pp 3362-3368
3363
DOCETAXEL IN PACLITAXEL-RESISTANT BREAST CANCER
relative to paclitaxel in patients with anthracycline-resistant
breast cancer.1 In patients with anthracycline-resistant meta
static breast cancer (MBC) treated with docetaxel at a dose
of 100 mg/m2 infused over 1 hour every 3 weeks, objective
response rates ranged from 32% to 5I%.18'20
The use of paclitaxel in anthracycline-resistant patients
has also been studied. When the same definition of anthracycline resistance was used, paclitaxel doses of 175 to 300
mg/m2 administered over 3 to 24 hours resulted in response
rates that ranged from 6% to 30%.2122 These preclinical and
clinical results led to implementation of the present prospec
tive phase II study al four centers in the United States. The
objectives of the study were to evaluate the objective
response rate, duration of response, and toxicity of docetaxel
in patients with paclitaxel-resistant metastatic breast cancer.
The final stud) results are reported here.
PATIENTS AND METHODS
Eligibiliiy Criteria
Eligibility criteria included histologically confirmed, advanced breast
cancer resistant to paclitaxel therapy in female patients
18 years of
age. Patients were required to have at least one bidimcnsionally
measurable indicator lesion that had not been irradiated, a Karnofsky
performance status
60%. no peripheral neuropathy 2: National
Cancer Institute (NCI) grade 2. no symptomatic pleural effusion, and to
have undergone no more than two previous chemotherapy regimens for
advanced disease (in addition to any adjuvant and/or neoadjuvant
therapy), with a paclitaxel-based regimen having been the most recent
treatment Patients had to have adequate bone marrow function
(absolute neutrophil count 2: 1.500 cells/pL. platelet count > 100.000
cells/pL). hepatic function (norma) total bilirubin., AST
1.5 times
upper limit of normal, and alkaline phosphatase live times upper limit
of normal), and kidney function (creatinine concentration
2.0
mg/dL). Patients mtbi have had no radiation therapy within 3 weeks
before study entry.
An interval of at least 21 days was required between the end of
previous paclitaxel therapy and protocol entry. Paclitaxel resistance was
defined as the patient's having experienced progressive disease while
receiving paclitaxel with at least two cycles at doses of 135 to 250
mg/m2 Primary resistance to paclitaxel was defined as no tumor
response (disease progression) Secondary resistance was defined as
stable disease, partial response, or complete response to paclitaxel
preceding disease progression. Patients who had progressive disease
after they discontinued paclitaxel therapy were not eligible for this
protocol. Prestudy information to confirm disease progression on
paclitaxel was reviewed by the principal investigators at each site.
Before treatment began, all patients were advised of the investigational
nature of the study and signed an institutional review board-approved
informed consent.
Treatment Plan
Patients were pretreated with 8 mg of dexamethasone orally twice
daily for 5 days beginning on the day before each docetaxel infusion.
The starting do-e of docetaxel was 100 mg/m2 over I hour into a
peripheral or central vein. Arterial blood pressure, pulse rate, and
respiratory rate were measured before administration of docetaxel.
every 15 minutes during administration, and 2 hours afterward. Dose
reductions were made in subsequent cycles according to the system that
showed the greatest degree of toxicity. A maximum of two 25%’ dose
reductions for toxic effects (level 1,75 mg/m2; level 2, 55 mg/m2) were
allowed per patient. Docetaxel administration was repeated every 21
days until there was evidence of progressive disease or unacceptable
toxicity, or for a maximum of three cycles after best response. Patients
who enjoyed an objective response or stable disease were to receive at
least six cycles of docetaxel. Patients with stable disease were to be
removed from the study after six cycles or given additional cycles at the
discretion of the investigator. Patients with rapidly progressive disease
(ic. new lesions or a > 25% increase in sum of products of perpendicu
lar diameters of measurable indicator lesions) were removed from the
study after one cycle of therapy and were categorized as having
progressive disease.
Study Evaluations
Pretreatment evaluations consisted of a complete medical history and
physical examination, which included neurologic evaluation, complete
blood cell count, biochemical profile, urinalysis. ECG, chest x-ray. bone
scan, and computed tomographic scans of chest, abdomen, and brain ( if
indicated). At the end of every cycle, patients underwent a chest x-ray
and biochemical profile, physical examination, tumor measurements.
and toxicity evaluations. Patients had a complete blood cell count
weekly during the first two cycles and then once before every' cycle
thereafter. Neurologic examinations were performed every two cycles.
Imaging studies were done to assess objective response every two
treatment cycles. An ECG was performed every four cycles.
Toxic effects were graded according to the NCI common toxicity
criteria.25 Other toxic effects were graded as mild (asymptomatic or
minor symptoms; no treatment required) moderate (moderately symp
tomatic. minor treatment required), or severe (symptomatic and interfer
ing with function: major treatment required).
Response Criteria
Responses were graded by standard criteria (complete response.
partial response, stable disease or no change, and progressive disease).24
The duration of complete response was calculated from the time of the
first documentation of complete remission to the first documentation of
progressive disease. The duration of partial response was calculated
from the first docetaxel infusion to the first occurrence of progression.
The time to progression was calculated .from the time of the first
docetaxel infusion to the first objective evidence of tumor progression
Responses were confirmed by an independent team of two oncologists
and a radiologist.
Statistical Analysis
Continuous data were summarized using descriptive statistics. Confi
dence intervals (Cis) were constructed at the 95% level and KaplanMeier estimations were performed to analyze censored data. Subgroup
analyses were performed on patients who had previous therapy with
low-dose paclitaxel (< 175 mg/m2) and those who had been treated
with high-dose paclitaxel (> 175 ing/m2). Patients were grouped
according to duration of previous paclitaxel infusion (1 to 3 hours v 24
hours) lor response analysis. For some analyses, patients were also
grouped on the basis of primary or secondary paclitaxel resistance All
treated patients were analyzed lor safety.
3364
VALERO ET AL
Table 1. Patient Characteristics
RESULTS
Patient Characteristics
Previous Paclitaxel Dose
Overall
Characteristics
No.
No of patients
%
s 175 mg/m7
> 175 mg/m7
No.
No.
%
%
46
30
16
26- 78
47 .5
26-78
29-61
48.5
43 0
Age, years
Range
Median
Kamofsky status
Unknown
1
2.2
60-80
16
29
34 8
1
10
63.0
90-100
33
0
0
6
37.5
19
33.3
63 4
10
62.5
No. of organs involved
1
7
152
6
20 0
1
6.3
2
20
19
43 5
12
40.0
50.0
41.3
12
40.0
8
7
Visceral
35
76.1
24
80 0
11
68 8
Liver
25
54.3
17
56.7
50 0
Lung
Pleura
15
32.6
11
36.7
8
4
2
4.3
1
3.3
1
63
Bone
17
37.0
10
33.3
7
43.8
Lymph nodes
21
45.7
13
43.3
10
6
Breast
11
21 7
23.9
5
20.0
167
8
4
50 1
Skin
Soft tissue
10
21.7
6
1
2.2
13
32
S3
43.8
Site of disease
25 0
25.0
20.0
6
4
25.0
1
3.3
0
0
28.3
10
33.3
3
18.8
69.6
19
63 3
13
81.3
375
Previous chemotherapy
Neoadjuvant/
adjuvant only
Advanced disease
only
Neoadjuvant and/or
adjuvant and
advanced
No of previous regi
mens
1
2
4.3
2
67
0
0
2
26
56 5
13
43 3
13
81 3
3
18
39.1
15
50 0
3
18 8
41
89.1
27
90.0
14
87.5
Previous antnracycline
exposure
Previous paclitaxel
resistance
Primary
Secondary
Between April 1994 and December 1995. 46 patients
were enrolled onto the study at four centers. Patient charac
teristics are listed in Table I. The majority of patients
(76.1%) had visceral-dominant disease with multiple disease
sites. Most patients (95.6%) had-received two or more
chemotherapy regimens. Sixteen patients in the low-dose
group (s 175 mg/m3) had received a median cumulative
paclitaxel exposure of 700 mg/m3 (range. 318 to 3.833
mg/m3) and 30 patients in the high-dose group (> 175
mg/m3) had been exposed to a median cumulative dose of
1.212.5 mg/m3 (range. 400 to 4.355 mg/m3). Overall, the
median cumulative paclitaxel exposure of the 46 patients in
the study was 810 mg/m3 (range. 318 to 4.355 mg/m3).
Twelve patients had received paclitaxel by 24-hour infusion
regimens and 34 had received 3-hour infusion regimens;
none had received 96-hour infusions. The median time
between the last dose of paclitaxel and the first dose of
docetaxel was 1 month (range. 0.6 to 7.2); for 16 patients more
than 1 month elapsed between the two taxane treatments.
18
39.1
14
46.7
4
25.0
28
60.9
16
53.3
12
75.0
Response
The overall response rate of the intcnt-to-lreat population
of 46 patients was 17.4% (95% Cl. 7.8% to 31.4%).
Forty-four patients were assessable for efficacy. Two pa
tients were ineligible, one because of other malignancy and
one because disease progression on paclitaxel could not be
proved. One of these patients' response to docetaxel treat
ment was stable disease and one was partial response.
Among the 44 patients who were assessable, two patients
could not be assessed for response. Both were considered
nonresponders. One of the other two patients had no
follow-up data and another patient received only one
treatment cycle.
The following analysis is based only on the patients who
were assessable for efficacy. Among 44 assessable patients.
the overall objective response rate was 18.1% (95% CI.
6.7% to 29.5%) (Table 2). One complete response and seven
Table 2. Objective Response Rate in Assessable Patients By Previous Paclitaxel Dose and Resistance
Previous Paclitaxel Dose
Overall
£ 175 mg/m7
> 175 mg/m7
(N - 44)
(n -■ 28)
(n = 16)
Secondary
Primary
Resistance
(n = 17]
Resistance
(n » 27)
Response
No
%
No
%
No
%
No
%
No.
%
Overall response rate
8
18.1
3
10.7
5
31.2
3
1
7
2.2
15 9
1
3.5
0
0
1
5
0
18.5
Complete response
17.6
5.9
2
7.2
5
31.2
11 7
12.5
35.2
55.3
8
47.2
5
8
14
18.5
2
9
2
6
Partial response
Stable
14
31.9
12
42 8
Progression
22
50
13
46.5
0
29.2
52.3
3365
DOCETAXEL IN PACUTAXEL-RESISTANT BREAST CANCER
<n = «>
Fig 1.
Survival analysis (intent to
treat).
partial responses were observed. The time to response of
individual patients ranged from 3 to 20 weeks (median. 6.5).
The patient who experienced a complete response required 3
weeks to achieve a partial response and 9 weeks to attain a
complete response.
The median duration of response was 29 weeks (range. 22
to 53). The median time to disease progression was 10 weeks
(range. 3 to 53) Patients' previous paclitaxel dose level did
not affect these results. The median survival time (intent to
treatlwas 10.5 months (range. 1.2 to 30+). A survival curve
for all patients is presented in Fig 1.
Objective response rates by previous paclitaxel dose and
resistance are listed m Table 2. When classified by duration
of previous paclitaxel infusion, the response rate was 0% in
the 24-hour infusion group (n = 12) and 25% in the I - to
3-hour infusion group (n = 32). This difference was not
statistically significant.
Safety Profile
A toial of 199 cycles was assessable for toxic effects in 46
patients: docetaxel was administered at a dose of 100 mg/nr
for 129 cycles. 75 mg/nr for 65 cycles, and 55 mg/nr for
five cycles. The docetaxel dose was reduced from 100
mg/nr to 75 mg/nr in 19 patients (because of febrile
neutropenia in nine, infection in three, stomatitis in one.
diarrhea and rash in one. and neuropathy in five), and from
75 mg/nr to 55 mg/nr in four patients (because of infection
in two and neuropathy in two).
Overall. 64.7% of the patients received at least three
cycles of docetaxel. Nine delays occurred that were longer
than 7 days (one because of a patient's upper respiratory
infection, two because of stomatitis, one because of febrile
neutropenia, one as a result of transient neuromotor symp
toms. and four for unspecified reasons). The median cumula
tive dose of docetaxel was 3SS mg/nr (range. 8S to 949
mg/nr) and the median relative dose-intensity was 92% of
the planned dose.
Three patients were withdrawn from the study because of
neurosensory toxicity: one patient after four cycles, because
of grade 3 neurotoxicity; one patient after eight cycles.
because of grade 2 neurotoxicity; and one patient after two
cycles, because she developed grade 2 neurotoxic symp
toms. The latter two withdrawals were minor protocol
violations. There were no drug-related deaths. One patient
died 7 days after she received her initial docetaxel treatment
because of her breast cancer's rapidly progressive pulmo
nary involvement.
Hematologic Toxicitv
Patients' hematologic toxic reactions are listed in Table 3.
Neutropenia was observed in 95% of patients and during
89.4% (126 of 141) of assessable cycles. Grade 4 neutrope
nia was seen in 72% (33 of 46) of patients. When evaluated
by previous paclitaxel dose, grade 4 neutropenia was seen in
80.8% of low-dose and 75.0% of high-dose paclitaxel
Table 3. Hematologic Toxic Reactions (46 patients)
Grode 3
Nadir
Variable
Leukocytes, x 103/|iL
Neutrophils, x 103/|xL
Platelets, X 103/;iL
Hemoglobin, g/dL
Infection
Grade 4
Median
Range
No
%
No.
%
1 3
0 4 to 6 1
24
11
24
02
0 0 to 5.7
23 to 549
6 to 12.4
5
1
52
13
195
9.9
3
6
33
72
2
7
0
0
1
2
13
0
0
3366
VALERO ET Al
patients. The median duration of neutropenia was 7 days
(range. 2 to 28). In only one cycle did grade 4 neutropenia
last longer than 7 days. The median nadir for both leukope
nia and neutropenia was reached in 7 days (range. 5 to 14).
Febrile neutropenia, defined as fever greater than 3S.0°C,
related possibly or probably to the study drug, and concomi
tant with neutropenia (< 500 cells/pL) that required intrave
nously administered antibiotics and/or hospitalization, was
observed in 11 patients (24%) and in 12 of 199 cycles
(6.0%). Febrile neutropenia occurred in 27% (eight of 30) of
patients and 7% (nine of 121) of cycles in the low-dose
paclitaxel group, and in 19% (three of 16) of patients and 4%
(three of 78) of cycles in the high-dose paclitaxel group.
Grade 3 infection occurred in six patients (13%) and in
seven of 199 cycles (4%). but no cases of grade 4 infection
or septic death were observed.
thematous papular rash. Dermatitis occurred in 11 patients
(23.9%) and a nail disorder in nine patients (19.6%). This
included six (20.0%) patients who had dermatitis and four
patients (13.3%) who experienced nail changes in the
low-dose paclitaxel group, and five patients (31.3%) with
dermatitis and five (31.3%) with a nail disorder in (he
high-dose group.
Nonhematologic non-NCI-gradeable toxicitics were asthe
nia in 32 patients (69.6%) and myalgia in 22 patients
(47.8%). Asthenia was moderate in 16 patients (34.8%) and
severe in 10 (21.7%). In the low-dose paclitaxel group. 19
patients (63.3%) had asthenia (nine moderate and six
severe). In the high-dose paclitaxel group. 13 patients
(81.3%) had asthenia (seven moderate and four severe).
Myalgia was moderate in 15 patients (32.6%) and severe in
three. There was no difference between the low-dose and
high-dose groups (46.7% and 50%, respectively).
Fluid retention occurred in 23 patients (50.0%). In seven
patients, it was moderate and in two patients (4.4%) it was
severe; both were a combination of edema and effusion.
There was no difference between previous paclitaxel dose
groups (low-dose 53.3% v high-dose 43.8%). The cumula
tive doses that preceded severe fluid retention in these two
patients were 300 and 500 mg/m2 (three and five cycles).
respectively. Overall, the median cumulative dose to onset
of moderate or severe fluid retention was 297 mg/m2 (range.
88 to 626 mg/m2). In the low-dose paclitaxel group, the
median cumulative dose to onset of fluid retention was 297
mg/m2 (88 to 626 mg/m2), and in the high-dose paclitaxel
group it was 292 mg/m2 (272 to 311 mg/m2). No patients
were withdrawn from the study because of fluid retention.
Chronic docetaxel-associated adverse events such as fluid
retention, asthenia, and neurosensory/neuromotor events
were classified according to previous cumulative paclitaxel
dose to learn whether the two taxanes might have additive
effects (Table 5). Generally, the percentage of patients who
Nonhematologic Toxic Effects
Nonhematologic NCl-gradeablc toxic effects possibly or
probably related to the study medication are listed in Table 4.
The most common toxic effects were neurosensory ones
(73.9%) and stomatitis (52.2%). but most were mild or
moderate (grade 1 to 2). No NCI grade 4 nonhematologic
toxic effect was reported. No grade 3 or grade 4 hypersensi
tivity reactions occurred; one grade 1 and one grade 2
hypersensitivity reaction were reported.
Neurosensory' toxicity was observed in 34 patients (73.9%).
but only three patients experienced severe (grade 3) neuro
sensory events. No difference was seen in the incidence of
neurotoxic effects between patients previously treated with
high-dose paclitaxel (69%) versus those previously treated
with low-dose paclitaxel (77%).
None of the skin toxic reactions (rash or nail changes)
observed in 20 patients (43.5%) were classified as severe.
The most commonly encountered skin reactions included a
diffuse macular erythema, acral erythema, and focal ery
Table 4. Acute Nonhematologic Toxic EFIects
Previous Paclitaxel
Doses 17.5mg/m?
(n = 30|
All Patients
|N = 46)
Total
Grode 3
Total
Previous Paclitaxel
Dose > 175 mg/mJ
(n = 16)
Grode 3
Grode 3
Total
No
%
No.
%
No.
%
No.
%
No
%
No.
%
34
73.9
3
6.5
23
76.7
2
6.7
68.8
1
63
2
6.7
Stomatitis
6
24
11
4
52 2
4
8.7 .
6.7
8
50.0
22
478
2
4.3
533
46.7
2
Nausea
16
14
2
6.7
67
8
50.0
3
18.8
—
10.0
16.7
5
31.1
—
NCI Term
Neurosensory
Neuromolor
—
13.0
—
Vomiting
7
15.2
2
4.3
4
13.3
2
Diarrhea
Fever in absence of infection
21
3
65
17 4
3
40.0
5
Skin/nail
20
43.5
16
12
14
53.3
18
45.7
39.1
8
-
46.7
-
—
25.0
6
37.5
6
37.5
2
12.5
—
18.8
3
-
3367
DOCETAXEL IN PACUTAXEL-RESISTANT BREAST CANCER
Table 5. Patients With Adverse Events, Classified by Previous Cumulative
Paclitaxel Dose
Cumulative
Previous
Paclitaxel Dose
(mg/m2)
Neuro
sensory
Fluid
Neuro
motor
Aslhenia
Skin
Retention
No.
%
No.
%
No.
%
No.
%
No.
%
0-400 (n = 8)
6
75
79
0
4
0
29
63
38
29
5
63
57
3
4
2
20
14
40
2
6
43
2
20
14
8
4
57
70
71
5
8
4
6
43
> 400-800 (n = 14)
11
>800-1,200 (n = 10)
> 1,200 (n = 14)
7
10
Total events
34
2
8
23
11
40
23
experienced an adverse event associated with docetaxel
treatment did not increase with an increase in the cumulative
paclitaxel dose.
Q
DISCUSSION
This open-label multicenter phase II clinical trial evalu
ated drug efficacy and drug safety prolile of patients treated
with docetaxel for paclitaxel-resistant metastatic breast
cancer. Paclitaxel resistance was delined stringently, and
most patients had significant previous paclitaxel exposure.
The overall objective response rate of 18.1% and the
intent-to-treat objective response rate were similar. Previous
paclitaxel dose and type of resistance (primary v secondary)
did not affect the response rate. A higher response rate was
seen in' the patients who had received paclitaxel by I- to
3-hour infusions compared with those who had received
24-hour infusions (25% v 0%). but this did not reach
statistical significance. Activity was seen even in patients
with poor prognostic factors, including those with liver
metastases, extensive previous therapy, and anthracyclineresistance/exposure.
(
Tire results of this study showed that docetaxel is active in
^^atients with paclitaxel-resistant breast cancer and they
confirmed the indications of preclintcal studies that pacli
taxel and docetaxel have only partial cross-resistance in cell
lines in which resistance to paclitaxel was induced.3 The
relative differences between the two laxanes in potency and
efficacy may play a role in the absence of complete
cross-resistance between the two drugs. Docetaxel, for
example, exhibits much higher potency than paclitaxel in
induction of bcl-2 phosphorylation, which suggests docetax
el's relatively greater potential for inducting apoptotic death
in cancer cells.13 Whether any specific mechanism of
resistance is more important for paclitaxel resistance than
for docetaxel resistance is not known. Cells that develop
resistance to paclitaxel through mechanisms that involve
microtubule processes may remain sensitive to docetaxel if
the bcl-2 phosphorylation mechanism remains sensitive to
docetaxel.
Only two reports have been published of phase II trials
with patients who had strictly defined paclitaxel resistance.
The response rate for docetaxel in our study was comparable
to that seen with 96-hour continuous infusion of paclitaxel
(27%)25 and with dose-intensive vinorclbine (25%).26 In the
former study.25 earlier brief infusions of paclitaxel had failed
in all patients. No patient had received 24-hour infusions.
The toxic effects of 96-hour paclitaxel in this population
were comparable to that seen in our study; overall, in terms
of both risks and benefits, the results are equivalent between
the former25 study and the present trial. A 96-hour paclitaxel
infusion regimen may not be feasible in all general oncology
practices, but it can be accomplished in specially equipped
centers.
Livingston et al26 administered vinorelbine at doses of 30
to 35 mg/m2/wk with continuous granulocyte colonystimulating factor (G-CSF) support. The patients’ median
survival time was 33 weeks. Noting the unfavorable pharma
coeconomics of this regimen, the authors do not advocate
routine administration of concurrent G-CSF and vinorelbine
tn this setting.
Moderate to severe neutropenia was common in our study.
with neutropenic fever the most frequent major adverse
event. Because of the incidence of neutropenic fever (in
23.9% of patients, 6% of cycles), either a lower dose of
docetaxel (75 mg/m2) or the use of prophylactic colonystimulating factors (granulocyte-macrophage-CSF or G-CSF)
or antibiotics (ciprofloxacin or levofloxacin) should be
considered in patients who have been heavily pretreated or
who have risk factors of severe neutropenia (such as
extensive previous radiation therapy and known inability to
tolerate myelosuppressive treatment).
The incidence of neurosensory toxicity (of any grade) was
higher than is usually reported with single-agent docetaxel.
but the incidence of severe neurotoxicity was comparable.1-2
In contrast, the incidence of hypersensitivity reactions, fluid
retention, and skin toxicity related to previous paclitaxel
exposure was lower than those initially reported.1’2 27 How
ever. in this study, patients on the docetaxel regimens had
been premedicated with dexamethasone, which clearly de-'
creased or ameliorated these adverse events.2-27 2S Recently.
a 3-day dexamethasone regimen was reported to be as
effective as a 5-day regimen in ameliorating docetaxelinduced toxicity, with less severe steroid-related side ef
fects.29
In summary, the results of this mullicenter trial show'ed
that docetaxel is active in patients with paclitaxel-resistant
breast cancer The response rates observed were comparable
3368
or superior to those seen with other salvage therapies.
Adverse events were similar to those seen in previous
docetaxel studies. There was no evidence for additive
cumulative toxic effects of the two taxanes. Although the
results of this trial demonstrated the absence of complete
cross-resistance to docetaxel in paclitaxel-resistant breast
cancer patients, they do not imply absence of cross
resistance in patients who may have been treated with
paclitaxel for other neoplastic diseases.
ACKNOWLEDGMENT
We acknowledge the assistance of Ramon P. Hernandez. Hao Zhang.
Pamcia C. Nastase. Carla M. Kozak, and Chris Kwiccinski in the
conduct of this study and of Lore Feldman, editor, and Judy Dillon.
secretary, in the preparation of this report.
REFERENCES
1. Verweij J. Clavel M. Chevallier B- Paclitaxel (Taxol) and doce
taxel (Taxotere): Not simply two of a kind. Ann Oncol 5:495-505. 1994
2. Cortes JE, Pazdur R: Docetaxel. J Clin Oncol 13:2643-2655,1995
3 Lavelle F. Bissery MC. Combeau C. ct al: Preclinical evaluation
of docetaxel (Taxotere) Semin Oncol 22:3-16. 1995 (.suppl 4)
4. Bissery MC. Nohynek G. Sanderink G-J. ct al: Docetaxel
(Taxotere): A review of preclinical and clinical experience. Part 1:
Preclinical experience. Anticancer Drugs 6'339-368. 1995
5. Rowinsky E: The taxanes: Dosing and scheduling considerations.
Oncology 11 7-19, 1997 (suppl)
I 6. Ringel I. Horwitz SB: Studies with RPR 56976 (Taxotere). A
semisynthetic analogue of Taxol. J Natl Cancer Inst 83:288-291. 1991
7. Diaz JF. Andreau JM: Assembly of purified GDP-tubulin into
microtubules induced by Taxol and Taxotere: Reversibility, ligand
stoichiometry, and competition. Biochemistry 32:2747-2755 1993
8. Andreau JM. Diaz JF. Gil R. et al; Solution structure of
microtubules induced by the side chain Taxol analogue Taxotere to 3 nm
resolution. J Biol Chem 269:31785-31792. 1994
9 Riou JF. Petitgenet O. Combeau C, et al. Cellular uptake and
efflux of docetaxel and paclitaxel in P388 cell line Proc Am Assoc
Cancer Res 35:2292, 1994 (abstr)
10. Keland LR. Abel G: Comparative in vitro cytotoxicity of Taxol
and Taxotere against cisplatin-sensitive and -resistant human ovarian
carcinoma cell lines. Cancer Chemothcr Pharmacol 30'444-450. 1992
11. Hanauske AR, Degen D. Hilsenbeck SG. et al: Effects of
Taxotere and Taxol in vitro colony formation of freshly explanted
human tumor cells. Anticancer Drugs 3:121-124, 1992
12 Riou JF. Naudin A. Lavelle F Effects of Taxotere on murine and
human tumor cell lines. Biochem Biophys Res Commun 187:164-170.
1992
13. Haidar S. Basu A. Croce CM. Bcl2 is the guardian of microtu
bule integrity- Cancer Res 57:229-233. 1997
14. Bissery MC. Guenard D. Gueritte-Voegelein F. et al: Experimen
tal antitumor activity of Taxotere (RP 56976. NSC 628503). a Taxol
analogue Cancer Res 51 4845-4852. 1991
15. Nicoletti MI. Lucchini V. DTncalci M. ct al: Comparison of
paclitaxel and docetaxel activity on human ovarian carcinoma xeno
grafts. Eur J Cancer 30A:691-696. 1994
16. Vogel M, Hilsenbeck SG. Debenbrock H. ct al Preclinical
activity of Taxotere (RP 56976. NSC 628503) against freshly explanted
clonogenic human tumour cells: Comparison with Taxol and conven
tional antincoplastic agents. Eur J Cancer 29A.2009-2014 1993
17 Gianni L. Munzone E. Capri G. ct al- Paclitaxel in metastatic
breast cancer. A trial of two doses by 3-hour infusion in patients with
recurrence after prior therapy with anthracyclines. J Natl Cancer Inst
87:1169-1175. 1995
IS. Valero V. Holmes FA, Walters RS. et al: Phase II trial oi
docetaxel: A new highly effective antincoplastic agent in the manage
ment of patients with anthracycline-resistant breast cancer. J Clin Oncol
13.2886-2894. 1995
19. Ravdin PM. Burris HA III. Cook G. et al: Phase II of docetaxel in
advanced anthracycline-resistant or anthracencdionc-rcsistant breast
cancer. J Clin Oncol 13:2879-2885. 1995
20. Adachi I. Watanabe T. Takasima et al: A late phase II study of RP
569776 (docetaxel) in patients with advanced or recurrent breast cancer
BrJ Cancer 73:210-216. 1996
21. Seidman AD. Hudis CA. Raptis G. et al: Paclitaxel for breast
cancer: The Memorial Sloan-Kettering Cancer Center experience
Oncology 11:20-28. 1997 (suppl 2)
22. Vermorken JB. ten Bokkel Humink WW. Mandjes IAM. ct al
High-dose paclitaxel with granulocyte colony-stimulating factor in
patients with advanced breast cancer refractory' to anthracycline therapy
A European Cancer Center trial. Semin Oncol 4:16-22, 1995 (suppl 8)
23. Ajani J A. Welch SR. Raber MN. ct al: Comprehensive criteria
for assessing therapy-induced toxicity. Cancer Invest 8:147-159. 1990
24. Hayward JL. Rubens RD, Carbone PP. et al: Assessment of
response to therapy in advanced breast cancer. Br J Cancer 35:292298.1977
25. Seidman AD. Hochhauser D. Gollub M. et al: Ninety-six hour
paclitaxel infusion after progression during short taxane exposure: A
phase II pharmacokinetic and pharmacodynamic study in metastatic
breast cancer. J Clin Oncol 14 1877-1884. 1996
26. Livingston RB. Ellis GK, Gralow JR. et al. Dose-intensive
vinorelbine with concurrent granulocyte colony-stimulating factor
support in paclitaxel-refractory' metastatic breast cancer. J Clin Oncol
15:1395-1400. 1997
27. Ravdin PM. Valero V, Nabholtz J-P. et al: Efficacy of a 5-day
corticosteroid premedication in ameliorating Taxotere-induced fluid
retenction. Proc Am Soc Clin Oncol 15:115. 1996 (abstr)
28. Taxotere Package Insert. Rhone-Poulenc Rorer. Collegeville. PA
29. Riva A. Fumoleatf P. Roche H, et al: Efficacy and safety of
different corticosteroid premedications in breast cancer patients treated
with Taxotere. Proc Am Soc Clin Oncol 16:188a, 1997 (abstr)
The
IE)
I N
THE
I_____________________________________________________
M A IL
CT
_____________________________________ ___
^l^his issue of Cancer Care is
dedicated to children with cancer. This
is the area where there is much more
hope of survival after cancer. There ore
statistics to prove that there are
thousands of adults who suffered from
cancer in childhood who ore now
leading normal and healthy lives.
Some children do succumb to this
dreaded disease but this is due to the
site of the cancer and how late it has
been diagnosed. Immence progress
has been mode in the treatment of
cancer and we are sure more and more
children will survive. In India, the
statistics show, more children die of
malnutrition and other communicable
diseases than of cancer.
Not that this is any consolation. CPAA
is aware of the pain of the loss and the
despair felt by the parents when a
Sunaina or a Jigar who were respond
ing so well to chemotherapy and were
fighting so gallantly, suddenly lose the
battle.
'
i
Hope is eternal. We also Hope to find
the answers one day.
Madam,
I have read with interest the write
up which appeared in EXPRESS
WEEK dated 9/05/98. lam
indeed touched by the humanitar
ian work you are carrying on for
the cause of cancer patients,
particularly the poor. May god
bless you and all your co-workers
in your noble venture.
E.F.Noronha
Bangalore - 560 041
Respected Madam,
I toke this opportunity by thanking
CPAA for giving me such o
wonderful opportunity to serve as
a volunteer for distribution of
Rose, gifts etc Io Cancer Patients
on Cancer Rose-Day the 22nd
September
22nd September - Cancer Rose
Day - Rose Distribution Day - o
day of silver lining for CPAA a
day Io remember for cancer
patients young ond old, when
they hove been conveyed through
Roses, Toys, gifts etc that we, the
citizen of Mumbai CARE for them.
And of course a day to treasure
for us.
Shri Vasant B. Dalal
Andheri (West)
Mumbai - 400 058
Respected Modam,
I, the undersigned, R.M.Agrowal,
grand father of Payal Agrawal,
Sarla Kolhi
who is oged 17 years, ot present
boarding at 'Borges Memorial
Home, Bandra, ond undergoing
treatment at Tato Memorial, beg
to express my heartfelt
gratitude, for your selfless
services rendered to the
attendants of patients, coming
from various parts of not only
India, but abroad
The work your association
does is really appreciated.
add to the glory of the
W|
association, your ever smiling
and cheerful handling,
politeness and very
sympathetic talk, no doubt
reduces the tension of the
needy persons like us.
R.M.Agrowal
Bhillai - 490 001.
Dear Ms. Alka Kapadia,
Couple of years back, my wife
and I took an Insurance cover
promoted by Bombay based
Cancer Patients Aid Associa
tion. In December 1997 my
wife had to undergo hysterec
tomy for a moderate adeno
carcinoma of endometrium, at
Breach Candy Hospital
Bombay. This took me for
first time to the office of
C.PA.A. to lodge with them my
wife's Insurance claim The
claim, in toto, was settled in
record lime of 10-15 days!
Experiencing the service
orientation of C.PA.A. one
gets highly motivated and
enthused. I hope and pray
C.PA.A. continues this good
work ond pursue their cause of
serving distressed humanity.
A.N. Sann
Hyderabad - 500 034
International union
against cancer
iji Venkotesh and Alka
Kapadia of CPAA Mumbai,
attended the UICC Congress at
Rio in 1998. It was an opportunity
for Viji to interact with the other
members of the COPES Steering
Committee. Viji who is already a
BCC member, was invited to join
the Steering Committee from
August 1998 to December 1999.
accessible to all groups ond
agencies working for the cause of
cancer care the world over . . this
website will be a store house of
informational resources and it is
the responsibility of each member
to see to it that cancer
organisations of the geographical
areas they represent are able to
benefit from this exercise.
COPES (Campaign,
Organisation, Public Education
and Patient Services) Programme
is committed to the UICC member
organisations and to the establish
ment of a worldwide network of
collaborating voluntary cancer
control agencies; to assuring that
they are efficiently organised to
effectively carry out their mandate
in cancer control and to the
provision of service to cancer
patients.
Each member of COPES has
given the feed back and input as
Io the nature and volume of
demands from each country and
now are busy gathering informa
tion as to what are the existing
The main objectives of this.
fcpgramme are, to facilitate
Wmmunication and information
sharing between voluntary cancer
societies throughout the world, as
well as to initiate and support
cancer societies by providing
training opportunities for their staff
and volunteers, particularly in the
area of public education and
patient services.
At Rio, one of the first decisions
was Io set up a website specifically
for the COPES arm and make it
to implement an effective
learning and shoring procedure — whether it is providing
practical assistance to patients,
setting up specific support
programmes or educating the
youth and community at large.
Everyone working in this field is
involved in one or more of the
above areas of cancer care.
CPAA also successfully
developed and implemented
quite a few effective and result
oriented community
programmes which will serve
as wonderful models for others
to learn and adapt from.
Activities
Bringing a smile
to those in pain
Another look at Patient Care
Sonia Klaus al
Inloks Hospital
Pune, cheering a
patient.
ne of our
prime channels to alleviate
pain and assist cancer patients
is to give free aid and disburse
medicines. This in effect means
looking info the family circum
stances to decide how helpful
we can be in each case. In
addition we at CPAA believe,
that a disease like cancer hits
not only the body but the mind
and soul of-not only the
patient, but the entire family I
Hence over the years we have
begun associating closely with
activities that will bring some
’ oments of cheer to the
aiients. CPAA is notionally
committed to this charier, and
the enunciation is in different
chnsimos
at Ernest Borges Home
ways in the different branches.
Part of this effort is observed
through Rose Day on Septem
ber 22 when CPAA visits
hospitals and patients and
extends an invitation to as
many volunteers and
celebrities to join the teams to
spread the message of Care
and Hope.
'Patients Day-Out' was held at
a 'Fun Doy' at Mumbai and
Delhi when patients mixed with
celebrities, were given gifts and
treats. A wonderful time was
had by all. X mas father visited- ••
the Ernest Borges Home in
Mumbai and Inlaks
Sunil Shehy's Astro Mischief, Mumbai.
A day m space for children with cancer.
nteers of CPAA
Kiron Bedi on
? Day al Delhi
rVV®
___ retxsS - \rt
v
with d
Inlaks
rT- [.
Ambani at
dren's word
lumbai dn
Hospital, Pune, to give gifts Io
the young patients. Little
patients had a wonderful time at
Sunil Shetty's Astro Mischief in
Mumbai.
Our efforts are aimed at making
the patients feel that they are like
other normal people who also
fall sick and are not pariahs to
be shunned by society.
ancer Patients Aid Association gave medicines worth Rs.17.75 lakhs in
Mumbai alone during January to December 1998. Other help given in kind is
in the form of rations, clothes, nutritional supplements, toys, wheel chairs,
educational scholarships, prosthesis, ambulance service etc. Delhi chapter which
was started in 1980 was able to give aid worth Rs.3,77,822.00 to 755 patients,
out of which 324 were new cases taken up in 1998. Bangalore donated
medicines worth Rs.2,15,71 7.00 in 1998 to 420 patients. Scan charges,
ambulance services nutrients etc. worth Rs.45,000.00 were also given. Pune was
able to aid 379 people in 1998 with medicines, counselling and care.
Child patients enjoying themselves at
Fantasy Land, Mumbai
A look at some stars
CPA A is proud of
I n keeping with
CPAA's philosophy
of Total
Management, we
are involved with
patients from diag
nosis and awareness
to rehabilitation and
being productive
citizens of the
nation. We believe
in self-worth and
self-respect to be
maintained, without
which life is not
worth living. CPAA
is happy to profile
I some of the people
we-have been able
jo help
*and
work with.
joy and that of her family.
Padmanabhan Thevar,
17 years old, a cose of
Vidhi Doshi, 13 years old,
a cose of relapsed Acute
Lymphoblastic Leukemia now
completely cured after o
Bone Marrow Transplant at
the Royal Marsden Hospital,
U.K. She is the first benefi
ciary of our tie-up with British
Airways 'Donate your miles
Scheme'. She and her father
were given free tickets for her
treatment abroad by British
Airways. We helped her with
a list of Charitable
Organisations in U.K. along,
with on appeal addressed to
each of them for financial
assistance.
Sangita Bhise, 14
years
old, a cose of Retinoblas
toma hailing from Kolhapur,
undergoing treatment at TATA
MEMORIAL HOSPITAL
(TMH). In addition to
supporting her treatment, we
helped rectify her gross
disfigurement by organising
an artificial eye implant for
her which has mode her look
really normal - much to her
Hodgkins Disease now
completely cured after
treatment in TMH. We fully
supported his treatment
g
(adopted him) and have
’
raised funds to pay for his
Computer fees at NUT. He's
doing very well - being an
intelligent and hardworking
young boy. He's simulta
neously doing his graduation
in Commerce as well.
Jayshree Rajput, 23 years
old, daughter of our expired
cancer patient. We got her
enrolled into a beautician's
course and got her a job
subsequently. When she was
confident of her experience
and expertise, we helped
raise funds for her Io set up a
beauty parlour in a place on
rent. No we are trying to gid
her help from the Nehru
Rozger Yojna to set up a
beauty parlour on a perma
nent basis.
Chamundeshwari Patil,
25 years old, completely
cured of Hodgkins disease
after treatment at TMH. We
supported her treatment,
fixed up accommodation at a
Working Women's Hostel for
her, gave her a job as
Administrative Assistant,
raised funds to pay her MCA
course fees at NUT. After 6
months, she went back home
to Raichur. Had the fees
transferred to NIIT's branch
in Raichur. She is now just
married and is setting off to
on January 5lh 1999
and will join the NUT there.
Irfan Razak, 27 years old,
a completely cured case of
ALL from BYL Nair Hospital,
hailing from Surat. In
addition to all the medical,
dietary and Vehicular help
we gave him, we olso
successfully socio
economically rehabilitated
him. We have raised funds
to partly pay for an
Autorickshaw for him. The
balance money wos
arranged through a bank
loan. He is now a full
fledged autorickshaw driver
and is very happy with his
success.
Sudhir Nikharge, 26
years old, a case of osteosar
coma from TMH. He has
undergone a total knee
replacement surgery. The
prosthesis cost o whopping
lakhs. We raised the
•Wds through countless
appeals to Trusts, Commer
cial Organisations, media
and Publications and the
general public. He is a
Chartered Accountant and
we have fixed up a job for
him with a foreign bank but he insists he'll join only
after he feels cent percent
restored back to normalcy.
deserted him after his concer
diagnosis) helped him with
basic sustenance require
ments, got him a job at our
Rehabilitation Centre in the
Marketing Section, since he
had a background in this,
prior to his illness. We
arranged a Coca Cola
Booth at Andheri
Lokhandwala Complex for
him and he is, doing very
well now.
Urmi Mody, 6 years old, a
cured case of ALL from TMH.
This friendly ond chirpy child
is a real treat for the eyes.
CPAA has supported her
entire treatment. Seeing her
extrovert nature and good
communication skills, CPAA
helped her get a role in a TV
Serial, much Io her delight.
Madaswamy Konar, 24
Manoj Thakker, 40 years
old, a case of cheek concer
caused by constant chewing
of gutka treated at TMH and
now totally cured. He was
referred to us post treatment. Helped raise
funds to pay off his pending
medical bills, provided
extensive emotional support,
(as his wife and child had
years old, o case of rectum
concer from BYL Nair
Hospital. CPAA supported
his entire treatment. He has
to use colostomy hags
lifelong and CPAA is
supporting him for the same.
We have raised funds for him
to get enrolled for a
Computer Course.
Jigar Waghela, 5 years
old, a case of ALL from B J
Wadia Children's Hospital.
Jigar, the heart-throb of all
who set eyes on him, was
totally supported by CPAA for
his treatment. Initially, he
was responding excellently to
the treatment. Due to this,
plus the fact that he wos a
cute and even - tempered
child, he was selected as our
Rose Day 'mascot' for 3
consecutive years. Unfortu
nately, he suffered a bad
relapse in early 1998 ond
expired just a week before
Rose Day '98 CPAA wos of
emotional and practical
support to his heart - broken
parents. CPAA arranged for
Rs.8000/- towards the lost
rites to bid him a dignified
farewell. We are also in the
process of getting Jigar's
father a job.
Santosh Kumar, 4 years
suffering from small round
cell and tumours of the Pelvis
has been looked after by
CPAA since a year and may
have to undergo surgery. His
mother Pappoma who has
another three children, has
tremendous courage and
indefatigable fortitude. We
salute her immense optimism
and wish Santosh Kumar, all
the best.
2
The Perfect Opportunity to create
awareness of the harm caused by
tobacco consumption
World No
Tobacco Day is a
national activity
taken on by all
branches of CPAA,
who use different
methods and
means to capture
the attention of the
relevant audience
— the impression
able youth.
I he primary objective of
CPAA's awareness drive in
May is to bring the scourge of
tobacco to light. This allows
for attention Io one of the
primary causes of oral cancer
— which constitutes 30 to 50
percent of all cancers in
Indio.
In Mumbai on
art competition
was held for
children on this
day It was
astounding to see
the depth of their
understanding and
awareness of the
great harm that
tobacco causes." It is
unlikely that they will become
addicts. The presence of
Rhea Pilloi Dutt was very
encouraging for the young
competitors. Anupam Kher,
who was the chief guest, gave
away the prizes.
CPAA Bangalore held a No
Tobacco March led by a jeep
with Geeta Gopolakrishanon
belting out anti-tobacco
slogans. Cricketers like Rahul
Dravid and Snnath and
veteran cricketers like Brijesh
Patel, Syed Kirmani, marched
with anti smoking placards, fl
Senior Artists Vasudev, Arakal;
Vani Ganpathy marched
wearing T-shirts with the
slogan "Tobacco is out, you're
in".
At Mota Royal Arcade where
the march ended, questions of
the public on cancer
were answered by
Oncologists. What
kept the crowd in
place were special
songs on tobacco
specially penned for
the occasion.
Tobacco Statistics
The objective of these
events are to trigger
off 'An Anti Tobacco
Movement' and
spread Cancer
Awareness by
relating tobacco
consumption to
cancer.
Tobacco kills nearly 10,000
people ever day. According to
the World Health
Organisation it is predicted
that over 500 million people
currently alive will be killed by
tobacco.By the year 2020,
according to current trends,
seven million of the tobacco
related deaths out of the ten
million that are being pro
jected, will be occurring in
developing countries like ours.
Two million Indian children get
addicted to tobacco.
Did you know that...
BOTH. ''1
Tobacco causes 10 lakhs deaths
annually in India. • One to
bacco-related death occurs every
10 seconds. •Tobacco contains
over 4,000 different chemicals,
■ 43 of these are proven
*
carcinogens.
Passive smokers
are at a higher risk of getting
*
cancer.
Cigarettes and beedies
kill one in every five of *us. 500
million people alive today will be
killed by tobacco. The widespread
usage of tobacco in its various
forms is responsible for the fact
that oral cancer is the no. 1
cancer among Indian males.
*
6
billion cigarettes are smoked
*
annually.
Heavy smokers who
smoke more than two packs a day
have a death rate which is 140
percent greater than non smokers.
•The relaxed feeling felt by smok
ers is a pseudo-relaxation. In
fact, nicotine causes an increase
in the pulse rate and blood
pressure.
9
Awareness
Childhood Cancers
Dr. Rakesh Mittal , M.D.: D.M. Consultant, Medical & Pediatric Oncologist
I ediafric and adolescent cancer cases
represent a small proportion of world
wide cancer burden. In western countries,
about 10.4% of all deaths in children are
from cancer and it constitutes about
2% of all cancer cases. The Indian
figure is not very clear. But if is not a major
cause of death. In our country diseases like
diarrhea, malnutrition, and infections
constitute major causes of death. The exact
magnitude of childhood cancer in India is not
exactly known because there is no nation
wide survey. But because of sheer volume of
pediatric cases, the number of children
suffering from childhood cancer is enormous.
Causes of childhood cancers
A question that often arises in the minds of
parents when their child is newly diagnosed
with cancer is "Did this happen because of
something I did or passed on to my child ?"
But generally it is not so. The percentage of
childhood cancer that ore caused by a clearly
inherited predisposition or significant
environmental exposure is very low. There
are no known causes of cancer in most of the
cases. The factors, which have been
implicated in the causes of childhood cancer
are certain viruses, radiation, chemicals, and
genetic factors.
Types of childhood cancers
Childhood cancers can broadly be divided in
to two types of cancer:
Hematological malignancies
Non hematological malignancies
Hematological malignancies:There are two main types of hematological
malignancies. Leukemias (blood cancers). In
which we have acute and chronic type.
Lymphomas. They are Hodgkins disease and Non
Hodgkins Lymphomas. Among leukemias the most
common type is acute lymphoblastic leukemia,
which constitute about 70% of all childhood
leukemias. The other type is acute myeloid
leukemia, which is bout 20-25% of all leukemias.
Among lymphomas most common ore high grade
Non Hodgkins lymphomas.
Non hematological cancers
or solid cancers:Solid cancers of childhood are the cancers of
various organs like brain, liver, kidney, bones,
muscle, adrenal glands, and testis or ovary.
Among solid cancers the most common are
tumors of brain (brain tumors) kidney (Wilms
tumor), muscles (Rhabdomyosarcomas), and
bones (Osteosarcoma) and germ cell tumors of
gonads.
In children, leukemias, brain tumors, and lympho
mas are the most frequent tumor types. Hemato
logical malignancies constitute about 1/3 of all
cancers while rest are solid tumors.
Differences between childhood
and adult cancer in the hematological
cancers
The main difference is that among leukemias, tPA
predominant type in children is acute leukemias w
while in adults it is chronic leukemias (CML,CLL).
Among lymphomas, in children the predominant
type is high-grade lymphomas while in adults it is
low-grade lymphomas.
Among solid tumors, the main difference is in the
type of tissues involved. In adults it is predomi
nantly squamous cell carcinoma (superficial), while
in children it is mesenchymal cells (deeper cells).
The other major difference seen is that in children
the effect of environment factors like smoking,
diet, dr pollution is not seen. The effects of
genetic factors are more in childhood cancers.
The early warning signs seen in adults are not seen
m children. In children the signs and symptoms of
malignancy are common symptoms like lever,
headache, lymph node enlargement, weight loss
etc. Hence there is no role of screening for
childhood cancers. The childhood cancers ore
more aggressive than adult cancers and this is the
reason they are more responsive to chemotherapy,
hence their survival is belter.
Signs and symptoms of
childhood cancer.
As mentioned above it is difficult to diagnose
childhood cancers in its early stage because the
signs and symptoms of childhood cancer are
relatively nonspecific and may mimic a variety of
other, more common childhood disorders. For a
pediatric oncologist, the index of suspicion for a
diagnosis of cancer is high, while for primary core
physician, the opposite is more often true.
Management of childhood cancers.
Management of childhood cancers is a
multimodality treatment strategy. We have three
modalities of treatment for all cancer patients
namely, surgery, radiotherapy, and chemotherapy.
For different malignancies, the various modalities
ore combined in an appropriate manner depend
ing upon the sensitivity of malignancy to a
particular modality. For hemotologial
malignancies the main modality of treatment is
chemotherapy while for solid cancers normally all
the modalities ore combined.
Results of treatment of
childhood cancers.
Since the introduction of chemotherapy for
childhood leukemia nearly 50 years ago, the
prognosis of childhood cancer has improved
dramatically. The long-term survival, which was
less than 10% four decades ago, is now in the
range of 60-70%. Apart from advances in the
field of chemotherapy, surgery, and radiotherapy,
other factors which have made a difference in the
increased survival are improvement in the
supportive core and introduction of newer methods
of diagnosis. The most notable difference can be
seen in Acute Lymphoblastic Leukemia, Hodgkins
Disease, Non-Hodgkins Lymphoma, Wilms tumor,
Rhabdomysarcoma, Germs cell tumors and Bone
tumors. In some childhood cancer 5 years survival
may be called as cure, while in others there may
be relapses even after many years. The malignan
cies where treatment has not mode much impact
are Acute Myeloid Leukemia, ond Neuroblastoma.
The childhood malignancy is no more a universally
fatal disease. If diagnosed early and given a
proper trealinenl for sufficiently long time then we
can easily cure it. Interestingly, in western
countries there is a large number of adult
population who suffered from one or other type of
childhood cancer and are leading a normal life.
In fact in the management of childhood cancers,
now the main concern other then curing the
disease is to prevent long term complications.
Because these children when cured of their
cancers are going to lead o normal adult life, ond
there should not be any stigmata of their
childhood cancer on their adult life in the form of
any physical or psychological disability.
Future of Childhood malignancies.
The future of the cure of childhood malignancies
looks very bright. What is needed is refinement
and better utilization of available modalities of
treatment. Then there is need to look for new
innovative methods of treatment. Most notable in
this are gene therapy and immunotherapy. Time is
not far when childhood malignancies will no more
be considered as a dreadful disease. The
treatment will be like that of any other childhood
disease.
Awareness
Q & A on Cancers
in children
happen nowadays as doctors
are aware of the possible
hazards and take appropriate
precautions.
Cancers themselves are not
usually hereditary. (The only
important exception to this is
retinoblastoma, a type of eye
concer, which is often
inherited.)
A
What are the symptoms of
childhood cancer ?
Bright and beautiful Sunoino ■ a victim
of Medulo Blastoma
Do children really
get cancer ?
Yes, although the types of cancer
which occur in children are
rather different from those
which occur commonly in adults.
Altogether, about one child in
600 will develop cancer before
the age of 15 years. Of the
cancers which occur, about one
third ore leukemia. The next most
common are the brain tumours,
but cancer can occur in any part
of the body. Cancer can occur at
any age; very occasionally the
tumour is already present at birth.
What causes
childhood cancer ?
Very little is known about this.
Unlike adult cancers, there is no
clear evidence
that they can
be caused by environmental
agents such as chemicals. In the
post, some may have been
caused by excessive exposure Io
x-roys but this is unlikely to
These depend mainly on where
the tumour is situated. Brain
tumours often cause persistent
headaches, vomiting or
dizziness. Other tumors appear
as a lump, for example, in the
neck or in the abdomen. Often,
there is no pain and, even
when pain is present, it is rarely
severe. Although there are
many ways in which cancer can
present, there are often
alternative, less serious
explanations for some unusual
symptoms. However, if you are
in doubt or worried, take the
child to your doctor for an
examination. If necessary, tests
should be arranged or the child
referred to a specialist or
hospital.
Can anything be done
for childhood cancer?
There have been many
important discoveries made in
the treatment of cancer in the
last few years. As a result, many
forms of childhood cancer can
now be cured. Some forms of
cancer are more likely to
respond to treatment than'
others. With some types, nearly
100% of cases are cured with
appropriate therapy. Overall,
more than half the children
who have cancer ore cured,
ond can look forward to a
normal active life.
What is the treatment?
This varies according to the
type of cancer, its site within
the body ond the extent to
which it has spread to distant
parts. The three main kinds of
treatment used are surgery,
radiotherapy (x-ray treatment)
and chemotherapy (Treatment
with anti-cancer drugs). With
some localised tumours,
surgery alone may be oil that is
required to provide a cure but
most cases will require
radiotherapy or chemotherapy
or both. Radiotherapy takes a
few weeks to complete.
Chemotherapy is given
intermittently, over a period
varying from a few months to
two years. While on chemo
therapy, children will be able MT
take part in normal activities.
Are the children
actually cured?
Despite what some people
believe, cancer can be
permanently cured. There is an
increasing number of adults
around nowadays who are
perfectly healthy and normal
and have had cancer in
childhood. They are able to
work normally, marry ond have
children. Il is extremely
unlikely that they will pass on
cancer to their own children.
A look at 1998
CPAA's Diagnostic Camp Statistics
1987-1998 (MARCH)
Total number of camps held
Number of Individuals screened
Males
Tobacco Users
Females
Tobacco Users
Suspected cases
Detected
-2,183
— 78,315
— 53,862
-43,200
-24,555
-4,780
-8,466
— 84
5 Point Target for Awareness
& Counselling
•Volunteer Service at TMH
•CPAA Website
• Head & Neck Group Sessions
at TMH
• FDA Meet
•Ambulance Services
ancer Patients
Aid Association's Awareness
and Education Programmes
have started to cater to a
new group...children and
young adults. A frightening
increase in tobacco
consumption trends in this
age group and relentess
targetting of these young
sters by the tobacco
companies has left us with
no option but to reach out
to these youngsters who are
being duped into making
uninformed choices.
• Awareness Material brought out:
- ’asters
- ’amplets
- BSE, Warning Signs
- nformation on CPAA)
•CPAA Website
• Ernest Borges Home Play Group
©Wadia Hospital Support Group
• Head and Neck Support Group
•CPAA cell at TMH
• Naigaum /Airoil spade work
• Head & Neck Oncology Conference
Workshop.
Reaching out to young adults has
been worked out with help from
the NSS Programme Officers
Training project of the TISS.
Access to students has not been a
problem and regular Awareness
Programme are being held in
colleges all over the city. On
another level CPAA has also been
working on a project which will
create cancer and tobacco
awareness in secondary school
children.
At TATA Hospital, Wadia Hospital
and Ernest Borges Home, our
patient related programmes are
well attended and appreciated.
Volunteers Deepali Kapoor and
Urmila Ausekeor run a weekly
counselling cell for Head & Neck
patients, an important component
of the Support Group, and
Deepali also runs another weekly
session for patients referred to the
Palliative Clinic (Both of these ot
Tata Hospital).
It has to be mentioned that the
CPAA staff from the Diagnostic
and Policy Depts are very sincere
volunteers for the Tata Hospital
counselling desk and are doing a
tremendous job. An informal
workshop on counselling and
listening skill was organised for
the CPAA staff. Deepali Kapoor
(herself a trained professional
counsellor) conducted the one
day session. With more such
sessions CPAA staff will be
equipped with all the necessary
skills...they already have the most
important one...commitment.
DIAGNOSTIC CENTRE
AWARENESS
LECTURES / CAMPS
MUMBAI
TOTAL NO. OF CAMPS/CLINICS/CIPS
TOTAL NO. OF MALES SCREENED
TOTAL NO OF FEMALES SCREENED
: 259
: 3890
: 3459
TOTAL
:
7349
TOTAL FOLLOW UP CASES
DETECTED CASES OF CANCER
TOTAL PAP SMEAR TAKEN
:
:
1712
3
2735
Awareness lectures were held in
Lonavala for the Cadets, Sailors and
Sailor's wives, this will be Followed by
a camp there (INS SHIVAJI) in March.
Matunga, for the Central Railway
employees Hindustan Mills
Patel wadi in Jogeshwari (350 familiesopen air lecture 9 pm 10
pm...incredible audience)
Trainee Volunteers from SNDT
Cosmopolitan Education Society Art
College Andhen Gurunanak College
Sion-Kollwadas NAL, ISRO, BEML
OFFICES IN BANGALORE
HAL OFFICERS WIVES, BANGALORE
dvnng,ne
'
Line for Registration for o free
Detection check-up camp in Mumbai
Viji Venkofesh at on awareness
lecture ot a Camp tor street
children
PUNE
□ Total No. of Potienls
given free medical aid
□ Total No. of Free Cancer
Detection Comps held
□ Total No. men checked
□ Tofol No. of females checked
CPAA, Mumbai organises Awareness Comp
for street children
lo,T.o"^*C
warrior
Shreyo is 5 '/? years old and the
only child of middle class parents.
Looking ot them, one is struck by
the happy picture they make but
when one talks to them, one
realises the unified courage they
radiate —a courageous family
indeed I
2 '/? years ago, when Shreya was
only 3 years old, she wos
diagnosed as having Acute
Lymphoblastic Leukemia - a
common, but curable childhood
cancer. The parents brought her
to the Bangalore Institute of
Oncology, where she has been
taking treatment for the past 2 'h
years and is presently free of
disease.
Today Shreya is
a smart,
confident,
poised child,
excellent at her
studies (She
stands 1 st in
class) and very
popular with
everybody. This
has been
possible only
because of the
considerable
help and
support that she
has received.
First and foremost from the
parents - they have borne her
illness with exemplary courage
and equanimity; never have they
lost hope in their child or their
doctors. Secondly, from the
hospital and Physicians - they
have been totally supportive of
Shreya and her family. Thirdly, and
very importantly - various
individuals and organisations like
CPAA have come forward to help
her. Although this is a curable
disease, it is very expensive
(financially, emotionally and
physically). Only the presence of
o very strong support system can
ensure that the patient completes
the prescribed treatment. Lastly
and most importantly - Shreya
herself, has been a model patient,
taking the treatment with a
maturity far beyond her years.
Apart from a little nervousness
about the invasive aspects of
treatment she bore
it all very well and
jumped back to
her normal self
within 2-3 days of
treatment.
Shreya and her
family ore an
inspiration to all of
us al the hospital,
the staff, the
doctors and mostly
to other patients in
the hospital.
Shreyo with Dr.Romesh ot the survivor's
Meet organised by BIO
Dr. Nalini Rao,
Dr. Shekar Patel
Dr. B S Srinath
accompanied
by the med-cal $taH
of Bangalore Institute
Oncology
angalore Institute of
Oncology (BIO) observed the
10" anniversary of its establish
ment in a unique way by inviting
over 300 survivors of this
dreaded disease to prove that life
is possible after cancer.
It was wonderful to see the
doctors, who are always seen as
serious fighters of the disease, as
entertainers who sang and
danced helped by the Nursing
and Technical Staff of this premier
institution.
The objective of this
innovative programme was
to reiterate the fact that...
Cancer is curable.
Cancer need not be
deadly._____________
Cancer is like any
other disease which
can be controlled
and cured.__________
Cancer patients need
acceptance by friends
and relatives — not
their pity.
Fund Raising
Reaching Out :
To each a different tune
CPAA has tried to
reach out special
segments of one
community with a
focussed appeal.
The objectives are
two fold.
To expand the
reach and
spread
awareness
ince CPAA is not
funded by any agency,
foreign or local — it has to
continually raise funds to
meet its objective of Total
Management of Cancer.
Antakshari by Annu Kapur and
Pallavi Joshi. The event was
held in Mumbai and
Bangalore and was im
mensely popular and success
ful in both places
The challenge in raising
funds is to take up events
which are different,
innovative and give value for
the money expended by
sponsors as well as the
audience. Our biggest event
in 1998 was the Live
The great energy and
charisma of Annu Kapur, his^j)
generosity in doing the shows
free, the fairness and sincere
effort of Mrs. Kapur at the
auditions, all went to make a
To generate
funds for the
cause.
Prasad Bidapa and Kalpana Kor al the
Press meet organised by CPAA.
Shobno De talking erf her
involvement with CPAA at the
opening of Close-Up
Anlokshori in Bongolore.
tremendous show.
Mumbai, a great metropolis,
with a tradition of charitable
events also held Ila Arun
Show and organised a
celebrity Dinner. Mrs. Birla
who was the chief guest
donated Rs. 1 lakh to the
^Mjse. We must profusely
Wnk the celebrities who
participate fully in all our
functions thus making our
events scintillating and
glamorous.
concerts with the co
operation and support of
Mr.Arun Goyal al the Essex
farms. Anup Jalota and
Brian Silas held the
audience captivated with
their melodious music.
Although from two different
streams, they are appreciotea
Fund-raising and Awareness
through competitions like
painting story-writing etc are
held by all CPAA branches
Delhi has been able to raise
A Helping Hand
Tina Amboni al CPAA's
Rehabilitation Centre
oncer
Patients Aid
Association's
Rehabilitation
Centre in Mumbai
is becoming a
centre of activities for concer
patients in remission and their
families os this is one place
where a helping hand is
available for everyone.
Like all the other Divisions in
CPAA, the Rehabilitation
Centre is also self-sufficient
and manages its finances
independently
enjoying these little treats.
Our patrons and well-wishers
Mr.Madanlal Dolmia and
Mr.B.J.Sanghvi distributed
Diwali gifts and Bonus to 100
patients and relatives at
CPAA's rehabilitation centre.
Pumps for allotting stalls put
up by Coca-Cola for our
patients.
Jackie Shroff al the Society
Collection Exhibition al Pune in
October '98
CPAA also arranges to take
out rehabilitation patients to all
our functions such as Fantasy
Land Picnic ond X mas party at
Oberoi and also to Annu
Kapur's Antakshari. It is really
wonderful to see the patients.
Our designer stationery and
terracotta items were exhibited
and sold at various outlet
including Oberoi Hotel, Aakor
Art Gallery, Concern India
Foundation, Sydenham
College etc. The Society
Collection Exhibition at
Mumbai ond Pune is where
our products ore really
appreciated and selllike hot
cakes.
A big thank you to IOC
1 tor ^^8
A J,A«Oec!98
Madanlol Dalmio and B J. Songhvi distributing gifts and bonus to some of the patients
and their relatives who are under training at the centre.
New Patients/Relafives Adopted
30
Total No. of Patients Helped
100 per month
Ration Distributed to
1,331 patients
.Total Rations Distributed
;Wheaf, Rice, Milk Powder, Dal etc)
5,500 kgs
Patients Wages
Patients Education & Vocational Training
Rs. 12,50,000
Aid given to Patients
Rs. 2,15,000
Rs. 2,50,000
(Medical, Conveyance, Diet etc.
Patients given Breast Prosthesis
35 cases
The Press Says...
Corporate Giants add
weight to tobacco drive
The campaign to spread
awareness about cancer has
received a shol in the arm
with several Indian companies
coming forward with financial
assistance. In a step which
could go a long way in
controlling cancer as a
disease in India, the Cancer
Totients Aid Association
(CPAA) has come up with a
major project titled "Prevent
Cancer Epidemic India
2010". They will be aided by
some Indian companies, non
governmental organisations
and advertising agencies.
Taking the lead is Rs. 1,000
crore group Gujarat Ambuja
Cements Ltd., (GACL). A
special cell is being created in
the CPAA for educating
children in schools ond
colleges against the ill-effects
of gutko and smoking.
Youngsters are the primary
target group since a recent
^fudy showed that over 80
Percent cases of gutko
consumption starts during the
teens. Stating that his
organisation is keen to keep
up a continuous campaign,
Y.K. Sapru founder chairman
of CPAA said " With three
million cancer patients and
another sixty thousand added
every year, we are already
way behind in managing this
epidemic. This is our last
chance to protect ourselves
from the powerful interna
tional lobby and the local
The Bombay Times -
medical aid," she added. CPAA
has also tied up with British
Airways to send children abroad
for treatment.
20’ Moy 1998
Bangalore Times
gutka and paan masala lobby. It's
time cigarette companies pay
towards cancer care."
31" July 1998
No bars on health care
Celebrating Life
Deputy Inspector-General (Jails)
Ashok Kininge says "Abstinence
has to come from within. The
prisoners must realise that such
habits can cause serious harm. I
am going to introduce such
comps in all jails because health
management there is very
important.
CPAA has conducted such camps
in Thane and Arthur Road Jails.
An awareness lecture precedes
the camp, followed by another
comp six months later.
The Cancer Patients Aid
Association (CPAA) an
independent charitable
organisation which has been
working in Delhi since 1980,
organised a day out for cancer
patients at the Appu Ghor. Bhupi
and Sanjay Raina entertained
patients with a special
programme while Shotrughan
Sinha, Shovona Narayanan and
Manpreet Brar mingled with the
special guests for the day.
Midday
3D December 1998
DELHI TIMES - The Times of India -
* May 1998
27
11
Saying it with a rose
The Cancer Patients Aid Associa
tion is a voluntary organisation
helping cancer pptients since
1969. The Bangalore chapter
was started in 1994, but to dale,
the CPAA has been able to reach
out to only 1 per cent of the 6
lakh cancer patients in India.
"We believe in the total manage
ment of cancer — free medica
tion, counselling, awareness,
detection and rehabilitation," said
Sarla Kohli, regional director of
CPAA. "Many patients have
found jobs through CPAA.
Children of patients who have
succumbed to the disease have
been placed in families and
children with cancer are given
1 ovedlo'N^ ^ehugety
L taWs *°ne ° 3 Close-Up .
B
°
u
H
eoWrtnoconc
........t—
■ V
8. Jonuoiy
G'kjihg tjcps
eet Manju Gupta Director
Rehabilitation since 1988, who has been
a newsreader on Mumbai Doordarshan,
did a course in Mass Communication in
USA and then joined Sloane Kettering in
the PR department and worked there for
10 years.
On her return to India she made an
audio visual film for CPAA which gave a
big boost io us since people could see
the work in which we were involved.
Manju then decided to help run the
Rehabilitation Centre for cancer patients.
When she took charge she decided that
the centre would not be another run of
the mill affair but a one - stop restoration
therepy. People should not buy the
products out of pity for the patients but
also because-we give quality at
competitive rates.
Since then the terracotta and designer
stationery items made al the centre are
much coveted and people wait for the
Sesety exhibition in which the CPAA stall
is'a complete sell-out.
The tailoring department has an order to
supply linen to the Taj Group of Hotels
all over India.
Manju takes part in TV shows, looks after
all the needs of the patients who come to
CPAA and makes sure that they are all
encouraged to become self-sufficient
The human being and his dignity is our
primary concern" she says.
CANCER
PATIENT’S AID
ASSOCIATION
At Mumbai
Gulshan Hodiwala
King George V. Memorial
Dr E. Moses Road, Mahalaxhmi,
Mumbai - 400 001
Tel: (022) 4924000 / 4928775
Fax: (022) 4973599
Siloo Jasdanwala
5, Malhotra House, Opp. GPO
Mumbai - 400 001
Tel: 022 - 269 8964 / 269 3790
Fax: 022 - 269 7255
At Delhi
Madhu Hukku
C-l / 807 Mayfaif Towers
Charmwood Village, Near Suraj
Kund Dist. Faridabad, Hariyana,
Tel: 0129 - 252881
Manju Dar
AB870, Sarojini Nagar
New Delhi - 110 023
At Bangalore
Sarla Kolhi
1330, 13th Cross, Indiranagar
2nd Stage, Bangalore - 560 038
Tel: 080 - 525 1005
At Pune
Dolly Rizvi
5, Angel Appts. 9, Kalyani Nagar
Yerwada , Pune - 411 014
Tel: 020 - 682224 / 680066.
Published by: Cancer Patient's Aid Association
Designed by Paul Fernandes
PRINTED AT MODERN PRINTING PRESS
M
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®
WORLD
TARMAC INSECURITY: Armed troops move
into the area, but only after the attack
ther the police nor international security
forces, which patrol a different part of the
airport, intervened. Later that night, when
the Saudi charter jets showed up to trans
port the pilgrims, several of the suspected
killers flew with them. Karzai has asked the
Saudis to hand over General Abdullah Jan
Tawhidi, a military intelligence chief, and
General Kalandar Beg, a deputy defense
minister, along with other suspects. The
Saudis have agreed to help. In all, says a
Karzai aide, more than 20 Afghan officials
were involved in Rahman’s murder.
As he presides over a nation still seek
ing a semblance of normality, Karzai is
struggling to contain the damage. He
claims that the motives for Rahman’s death
were “personal, not political." But Rah
man, like Karzai, was a royalist, and some
diplomats believe the killing was the
Northern Alliance’s way of demonstrating
opposition to the planned return to
Afghanistan this spring of Mohammed Za
hir Shah, 87, the exiled monarch. An
stranded, hungry, thirsty and freezing in Afghan patriarch was heard muttering at
their white cotton robes and sandals. Their the funeral: “This killing is a clear warning
plight was largely a result of Rahman’s in to Zahir Shah’s people.”
competence: his staff had failed to fill out
Across town was another sign of dis
the necessary paperwork for two Saudi tress. At Kabul Stadium—the scene of
jumbo jets to land at Kabul and whisk the ghastly Taliban executions in the past—
pilgrims off to Mecca.
Afghans squared off against international
Rahman, meanwhile, had gassed up peacekeepers in a football game, the first
an Antonov turboprop belonging to Ari- live entertainment in the capital in nearly
ana, the national car
a decade. The event
rier, for a private
was marred by stone
jaunt to India with
throwing, tear-gas fir
friends. When the
ing and beatings as
shivering pilgrims saw
foreign troops strug
Rahman and his fur
gled to hold back
clad pals climb aboard,
thousands trying to
it was easy for the as
cram into the already
sassins, mingling with
brimming 30,000-seat
stadium. Against the
the hajis, to roust the
crowd into action.
warlords, Karzai is
Several people charged
similarly outmanned.
Though he can count
the runway and threw
on widespread sup
themselves in front
port from both the
of the turboprop’s
SHAKY ALLIANCE: The assassination of
wheels. The pilot Rahman, top, puts further strain on the West and Afghans sick
stopped, and Rahman brittle coalition led by Karzai, below
of the fighting and bul
made the mistake
lying, his rivals have
weapons and the incli
that cost him his life:
he opened the hatch
nation to use them.
Murder is a timeto shoo away the
pilgrims.
honored tool of Afghan
Then the assassins
politics, but this is one
stormed tire plane.
crime that Karzai can
Whipping out knives,
not afford to let go un
they stabbed and beat
punished—or he could
be its next victim.
Rahman to death. Nei-
flurder in the Airport
After one of his top officials is killed, Afghanistan’s
leader struggles to keep his fragile nation united
By TIM MCGIRK KABUL
TANDING IN THE COLD RAIN ON A
rocky hillside cemetery outside Kab
ul, Afghan leader Hamid Karzai
watched grimly as the body of his as
sassinated minister, Abdul Rahman, was
lowered into the ground. “We will capture
his killers,” Karzai vowed, “and we will
punish them.”
Grabbing the culprits may be the easy
part. Punishing them is a different matter.
The suspects include senior military and
int^igence officials in Karzai’s fragile
coajplon government who belong to the
I ^’qrthem Alliance, an Afghan faction that
Jsjn’t want Karzai in the first place. By go| ing after the killers, the country’s interim
leader is headed for a showdown with the
powerful warlords who control Afghan' istan’s foreign affairs, military and security
forces—and even his own palace guards.
His green-striped cape sodden with rain
’ during the funeral ceremony, Karzai never
looked so alone.
The death of Rahman, the tourism
and aviation minister, is a tragically clas
sic Afghan murder drama. And it raises
fears that Karzai’s coalition, welded in
part by foreign aid and B-52 bombers,
might be falling apart. Karzai s aides
claim the minister’s killers tried to mask
. the assassination by making it seem spon. taneous. It occurred last Thursday at
! Kabul’s airport, where for two days, 800
pilgrims on their way to the hajj had been
S
TIME, FEBRUARY 25,2002
29
MEDICINE
New detection techniques and treatments are
exciting—and confusing. A guide to saving lives
By CHRISTINE GORMAN
43, wasn't particularly
worried
when
a routine
mam
had
had
a tumor
yearsBut
earlier
that
turned
out
to seven
be benign.
this
mogram
up
something
her
radiologistturned
thought
was
fishy. She
time was different. A biopsy confirmed that
Ulene, the niece of former Today show med
ical expert Art Ulene, had ductal carcinoma in
situ, or dcis, a growth that is variously de
scribed as either an early-stage breast cancer or
a precancerous lesion. “It was very confusing,”
says Ulene, a color stylist for Walt Disney TV
Animation. “I needed to know more.”
What she soon learned was that the kind of
cancer she had—a group of malignancies so
tiny that they were rarely seen before the ad
vent of mammograms powerful enough to spot
them—is at the heart of a raging debate in the
cancer community. Doctors know what to do
ancy ulene,
N
when they find tumors the size of marbles or
plums. That’s what surgery, radiation and
chemotherapy are for. But what do you do with
cancers the size of pencil points? Do you treat
them as you would a massive tumor? Do you
leave them alone? Should you even be looking
for them in the first place?
This year, according to the American Cancer
Society, some 200,000 women (and 1,500 men)
will learn that they have breast cancer—up from
a little more than 100,000 two decades ago.
While the death rate from the disease has
dropped modestly over the past decade, there is
a growing sense of frustration among cancer ex
perts. Part of the problem is dcis. Thirty years
ago, these miniature tumors, which usually
don’t spread into the rest of the body, were di
agnosed in some 6% of breast-cancer patients.
Today the ratio is closer to 20%, largely because
of advances in detection techniques. Yet the
treatmen t of choice is still surgery’ followed by ra
diation. “We may be far overtreating our pa-
Photolllustration for TIME by Howard Schatz
MEDICINE
tients,” says Dr. Julie Gralow, an oncologist
at the Fred Hutchinson Cancer Research
Center in Seattle. “We've now got women
being diagnosed with tumors that probably
never would have been treated if we didn’t
have mammography. They probably would
have lived long, natural, healthy lives never
knowing they had breast cancer.”
The long-simmering debate over the
value of routine mammograms flared up
again last month because of new questions
about whether the test has been sufficient
ly proved to save lives (see box'). But the
mammography squabble masks a deeper
problem: advances in screening and J
diagnostic technology have outpaced fl
treatments, leaving cancer patients and ft
their doctors struggling to make treat- \
ment choices neither are prepared
to make.
That’s the bad news. The good news is
that the situation is on the mend. Basic re
search into the molecular- chemistry of can
cer is well funded and advancing steadily,
delivering better diagnoses and smarter
drugs. Meanwhile, a series of dramatic im
provements in the tools of treatment are
moving into clinical trials, promising
patients kinder, gentler ways to treat their
cancers. Among the highlights:
► Surgeons are developing several tech
niques that destroy tumors while sparing
more breast tissue—without reducing the
chances of survival. (This can be particu
larly important for small-breasted women
who don’t necessarily have a lot of tissue to
spare in the first place.)
► Doctors are experimenting with new
ways to deliver lethal radiation that more
closely targets the tumor and takes just a
few days at most—compared with the more
usual six-week regimen—to finish the job.
► Researchers who are trying to minimize
the need for chemotherapy are finding that
patients can avoid chemo altogether ifjust
one or two cancer cells are discovered in a
lymph node—apparently these cells are not
active enough to cause any further trouble.
ost of these new approach-
es
still
need to
befail.
more
will
undoubtedly
Thefully
ulti
mate
prize,
which
could
be
widely
Some
ofyears,
them
testedtheadopted.
before
be
available within
next 10they
to 15can
would be a diagnostic test that determines
which genes in a particular tumor have gone
awry. As doctors are increasingly aware, it’s
not just a tumor’s size but its underlying bi
ology that determines how quickly it will
grow. Genetic tests may one day accurately
M
32
IUIA DIZ AE AANPCD A pair of color-enhanced mammograms showing a
|jIfUlA VI* VflNWCSu microcalcifications, red dots, right, that in this car
identify those tumors that are likely to
spread and those that are not. The tests may
also tell doctors to which drugs your partic
ular tumor is most vulnerable.
Before peering any further into the fu
ture, however, it helps to know a little biol
ogy. Most breast cancers begin in the milk
ducts, narrow passageways that radiate
throughout the breast. A few cells, for rea
sons that are not completely understood,
start accumulating genetic mistakes that
cause them to grow abnormally. Eventually
the cells develop into dcis. The good thing
about dcis cells is that they haven’t spread
beyond the milk duct. The bad thing is that
they are malignant. “Some people call dcis
precancer, but it’s not precancer,” says Dr.
Dennis Slamon, director of breast-cancer
research at the ucla School of Medicine.
“It’s preinvasive. It’s cancer that hasn’t in
vaded outside the breast ducts.”
After a tumor starts to break out of its
milk duct, it’s often still quite small.
About the smallest tumor a mammogram
can pick up is 0.5 cm to 1 cm in diameter.
TIME, FEBRUARY 25,2002
By contrast, the average cancers that arr
felt either by women or their physician:
are around 2.5 cm. Even though mam-mo
grams still miss about 10% of all tuUirs
it’s their ability to spot smaller luma
which are generally easier to treat, tK,
keeps women coming back for their an
nual appointment.
Once the cancer puts down roots in the
lymph nodes, the prognosis gets worse. The
lymph nodes act as a kind of sewer systeir
for many types of toxins and wastes. Tu
mors growing in the lymph nodes have <
greater chance of breaking off and traveling
to the bones, brain, lungs or other pails ol
the body, where they can seed new
growths, called metastases. Here again
doctors used to think that any breast cancel
that had spread to the lymph nodes musl
have been growing a long time. Now they
realize that the fact the cancer has shown up
in the lymph nodes may have more to do
with how aggressive it was from the start
than with how long it has been growing.
That’s what makes dcis treatment so
M AM MOGRAP H Y
What All the Fuss Is About
controversial. What if most of the tiny tumors that show up in high-resolution mamimams are the ones that grow the slowest
oiWaybe even disappear of their own acd? It probably doesn’t matter too much
v quickly you treat these slow-growing
: tumors; most women would survive. And if
that’s the case, wouldn’t it make sense to
leave those tumors alone until you could fig
ure out whether they are going to grow?
Some breast-cancer experts even speculate
that more women may die with these tu
mors in their breast than because of them.
An intriguing study on invasive tumors,
begun in 1988, provides some clues. The
trial included about 1,200 women whose tu
mors were less than 2 cm across with no ev
idence of malignancy in their lymph nodes
and whose cancer cells looked, under the
microscope, as if they weren’t particularly
dangerous. Although these women did not
receive the “watchful waiting" approach pi
oneered in prostate-cancer patients, they
weren’t treated as aggressively as they
might have been. For five years after their
U
can easily be removed, mammograms
find growths that are already malignant
and that are more difficult to remove.
Whether or not the cancer grows
another year or two before it becomes a
lump that can be felt may ultimately not
make much of a difference to long-term
survival.
Wasn’t this issue decided long ago?
You would have thought so. Since the
1960s, mammograms have been
tested with seven different randomly
controlled clinical trials. Most of these
trials concluded that early detection
via routine mammograms significantly
reduces a woman’s risk of dying
from breast cancer—by as much as
30%. But some critics suspect that
those results might have been
unintentionally skewed by scientists
seeing only the results they hoped to
see. The two Danish researchers
judged these old studies by today's
standards of what constitutes a good
clinical trial and concluded that five of
the studies were so shoddy or primitive
that their conclusions could not be
trusted. The data from the remaining
two studies, taken together, showed
no lifesaving benefit from routine
mammography.
Do mammograms have any other
drawbacks? Sure. They are associated
with a high rate of false positives—
readings that come back abnormal
even when no cancer is present. The
result is a lot of anxious women getting
called back for another mammogram or
told they have to undergo a biopsy.
How is that possible? Mammograms
are not perfect. Even the best miss 10%
of breast cancers. Unlike pap smears,
which detect precancerous lesions that
ivasive tumor, circled at left, and an array of
ignaled the presence of ductal carcinoma in situ (DCIS)
1
,i
I
'
Do routine mammograms actually
save lives? For the past two years,
academics have been furiously
arguing the question. Two Danish
scientists are convinced that they
don't. A host of medical and advocacy
groups in the U.S. is just ascertain
that they do.
tumors were surgically removed, doctors
did nothing more unless there was a recur
rence. Though .11% of the women did in fact
develop a second cancer, their survival rate
(and this is the key) was comparable to that
of another group of women who had under
gone chemotherapy (with or without the
drug tamoxifen) at the time of their surgery.
O
ONE
IS
RECOMMENDING
A
wholesale “cut and wait” ap
proach for breast cancer—partic
ularly on the basis of a single
study. For one thing, waiting to
see how aggressive a cancer tru
ly is makes a lot more sense for men in their
80s than for women in their 40s.
The question about what to do with
dcis is also rife with extenuating factors. If
dcis never left the breast ducts, physicians
could safely ignore it. No one knows for
sure, but at least one study suggests that per
haps 40% of dcis lesions will develop into
invasive tumors that, if left untreated, could
eventually prove fatal. That means that
N
TIME. FEBRUARY25, 2002
Will we ever know the truth about
mammograms? There’s a push to make
public the raw data from some of the
original studies. Without new studies,
that's probably the closest we are likely
to come in the near future to a scientific
answer.
Should I cancel my next appointment?
Absolutely not! Mammograms find
more tumors at earlier stages of
development than any other screening
test currently available. That gives
women options they might not
otherwise have—forgoing
chemotherapy, for example, or opting
for breast-sparing surgery and
hormonal therapy. And, who knows,
they might just save your life.
—C.G.
maybe 60% of dcis cases never threaten a
woman’s health—and therefore these
growths do not need to be removed.
Before the routine use of mammo
grams, most cases of dcis were discovered
accidentally, often during other surgeries.
Thanks to better screening, the absolute
number of dcis cases has jumped seven
fold in the U.S. over tire past three decades.
“At the moment, we don’t know which
women diagnosed with dcis might be able
to get by with minimal treatment,” says Dr.
Eric Winer, director of breast oncology at
the Dana-Farber Cancer Institute in
Boston. As a result, most doctors agree that
it’s prudent to treat all dcis cases as if they
are dangerous. (In the past couple of years,
however, some surgeons have started
treating the tiniest, least aggressive dcis le
sions by excision alone, forgoing radiation,
provided they can get wide, cancer-free
margins around the tumor.)
That’s not the only dilemma with dcis.
Radiologists don’t actually see a dcis le
sion—they see its footprint in the calcified
33
Anatomy of a Tumoi
Every breast cancer is a little different, but many follow a
fairly standard course. How each is treated depends on how
early it is discovered, how aggressively it is spreading and
‘how it responds to antihormone treatments and other drugs
PRECANCEROUS
*
Rf
,
'
\ Normal
• The cells lining the duct
are orderly and well
fferentiated
yperplasia
A few extra cells
cumulate
leal ductal hyperplasia
The cells start looking
more and more abnormal
DCIS with Microcalcifications
STAGEI t
■ THE DEFINITION
■ THE DEFINITION
Cells that look like cancer but have not in
vaded surrounding tissue are called ductal
carcinoma in situ (cancer confined to the
duct). The lesions may be tiny as pinpoints
and may pop up throughout the breast
Some of the cells from the —
tumor, which now measures
2 cm or less, spill out of the
duct. There is no evidence of .»
cancer in the lymph nodes
J
■ THE OPTIONS
■ THE OPTIONS
Patients whose lesions are tightly
focused can be treated with
lumpectomy and radiation. Some
surgeons think surgery alone may be
sufficient in certain cases
Mastectomy or lumpectomy
&
plus radiation. Lymph nodes
j
are biopsied. Chemotherapy
|
or tamoxifen may be
recommended for some women :
■ THE OUTLOOK
■ THE OUTLOOK
Very good. Virtually no one dies of breast
cancer within five years of treatment for
DCIS. No one knows what percentage of
DCIS lesions eventually become invasive
Anywhere from 95% to
98% of women are doing fine
five years after treatment.
Most will live much longer
STAGE III
„ , ' T.UMQR
STAGEIV
■ THE DEFINITION
The cancer has really taken
hold in the lymph nodes.
Even a tumor less than
1 cm in size is considered
Stage III if several lymph
nodes are involved
ducts
Lymi
Nod
■ THE OPTIONS
Aureola
Lobules
..
*■
Mastectomy or
lumpectomy plus
radiation.
Chemotherapy.
Tamoxifen for those
cancers that respond
to estrogen
Muscles
■ THE OUTLOOK
Ribs
Depending on tumor
size and other
characteristics,
49% to 56% of
women live at
least five years
after diagnosis
-
Sec
TIME Graphic by Ed Gabel
Sources: M. D. Anderson Cancer
Center; National Cancer Institute
Liver
MEDICINE
WHERE IT
STRIKES
Tumors most
frequently form in
the breast’s upper
hemisphere, but
they can appear
anywhere
SWGEH
■ THE DEFINITION
Msjpt tumors in this category
nV sure 2-5 cm but have not
spread to the lymph nodes
S^jllE options
Waitectomy or lumpectomy plus
radiation. Chemotherapy is used for
any cancers that have spread to the
lymph nodes and may even be
indicated for larger node-negative
tumors. Tamoxifen is prescribed for
those cancers that respond to estrogen
■ THE OUTLOOK
Depending on tumor size and
other characteristics, 76% to 88%
of women live at least five years
after their diagnosis
■ THE DEFINITION
(
The cancer has spread beyond
the breast, leading to
secondary tumors in the liver,
lungs, brain or elsewhere
|
■ THE OPTIONS
;
Most treatments are aimed at
relieving symptoms or
prolonging life a few months or
years. Surgery or radiation to
remove or at least try to shrink
any tumors. Chemotherapy.
Herceptin for those cancers
that express an excess of the
Her2 receptor. Tamoxifen or an
aromatase inhibitor, if they
haven't already been used, for
those tumors that respond to
estrogen. (Clinical trials of both
herceptin and aromatase
inhibitors in earlier stages of
breast cancer are under way)
■ THE OUTLOOK
; Studies indicate an average
survival time of 18 months
to 24 months. From 15% to
20% live at least five years
after diagnosis
remains of dead and dying cells. What rector of the Weill Cornell Breast Center in
makes mammography as much an art as a New York City. The remaining tissue can
science is that these so-called micro then be rearranged to fill in the void.
calcifications are often just a normal part of
Doctors have also developed a new
breast anatomy. It’s the pattern of micro technique for determining whether a can
calcifications—whether new ones appear cer has spread to the lymph nodes. Instead
suddenly or line up in particular forma of taking 15 to 20 lymph nodes from in and
tions like soldiers in a row—that suggests around the armpit for further examina
something more sinister.
tion—a procedure that can lead to prob
For a variety of reasons, radiologists in lems with swelling and disability of the
the U.S. tend to err on the side of caution. arm—they are focusing on certain key
That is, they identify lots of “abnormali spots called sentinel nodes. The surgical
ties,” of which only 2% to 11% prove to be team injects a blue dye into the tissue from
cancerous—either nets or an invasive tu which it has just removed a tumor and
mor. Sometimes a second mammogram or traces its path through the lymph system.
an ultrasound provides the necessary reas The first node or two that the dye reaches
surance. Other times, a biopsy—which en are presumably also the first nodes in
tails the removal of some breast tissue—is which any cancer cells would take up res
required to resolve any ambiguity. Here idence. The sentinel nodes are removed
the odds of finding cancer rise to about and closely examined. If they are free of
25%, which means that 75% of biopsies cancer, chances are all the other nodes are
come back negative.
clear. Preliminary evidence suggests that
For years many women got an ugly this is indeed the case, though two ran
scar along with their answer because most domized controlled trials of tire technique
biopsies began with a wide surgical inci are under way to make sure.
sion. Nowadays, more breast centers offer
such minimally invasive biopsies as the
ventually, women may be able to
Mammotome, which relies on careful posi
forgo surgery entirely. Doctors at
tioning of the breast to remove the least
the M.D. Anderson Cancer Center
amount of tissue. “We’re trying to reserve
at the University of Texas in Hous
surgery for treatment, not diagnosis,” says
ton and the Weill Cornell Center in
Dr. Joshua Gross, chief of breast imaging at
New York City are experimenting
Beth Israel Medical Center in New York- with high-frequency radio waves that can
City. “So many women I see have scars all literally cook tumors from the inside. Using
over their breasts. The scars aren’t from be ultrasound to guide them, doctors insert a
ing treated. They’re from doctors finding multipronged probe into a tumor. The
out if a woman even needs to be treated.”
prongs open up like the spokes of an um
Thirty years ago, surgery meant mas brella and melt malignant cells without
tectomy-removal of the entire breast. By burning surrounding breast tissue. So far,
the 1980s, studies had shown that for tu the procedure has been performed only on
mors that had not spread, only the portion women who were planning to get a mas
immediately surrounding the cancerous tectomy or lumpectomy anyway. But early
growth needed to be cut away—provided results have been encouraging enough that
the operation was followed by radiation physicians hope to test it as a stand-alone
therapy to destroy any wayward cancer procedure this year.
cells the surgeon may have missed. Today,
One of tlie drawbacks to minimally in
as more women are being treated for ever vasive surgeiy, in the eyes of many women,
smaller tumors, doctors are finding that is that it is usually followed by radiation.
even these so-called lumpectomies can be Currently, doctors shoot high-powered
further refined.
beams across the affected breast five days a
The new minimalist approach begins week for six or seven weeks. But it has be
with the first cut, which many surgeons come increasingly clear, particularly with
now place near the nipple, under the arm smaller tumors, that if the cancer recurs, it
or in the lower portion of the breast so that usually does so in the original spot from
any scars are much less obvious. Because which the tumor had been removed. By fo
many small tumors are confined to the duct cusing radiation more precisely on the place
or its immediate vicinity, doctors have where the original tumor occurred, says Dr.
learned they don’t need to remove so much Silvia Formenti, chairwoman of radiation
of the overlying fatty tissue as they used to. oncology' at New York University School of
“Taking out too much fat was what led to Medicine, “we think we can make radiation
the concavities and deformities we saw in better and easier for the patient.”
the past,” says Dr. Alexander Swistel, di- I
Taking a page from treatment manuals
E
TIME, FEBRUARY 25,2002
35
THE CUTTING EDGE
OFCANCER
TREATMENT
Surgery, radiation and
chemotherapy are still
the first line of defense against
breast cancer. But exciting
new techniques are entering
clinical trials and, if they
work, may eventually replace
the old standards with kinder,
gentler treatments
nut Grapiuc
by T<1 Gab
*.-!
Sources: AcuwJy. Praxniu I Impedes, M. D. AiMkison
Cancer CerilM, Hosctla InplumwlKs
for prostate cancer, a few doctors have im
planted tiny radioactive “seeds” in the
breast to ensure that the maximum amount
of radiation is delivered near the tumor
site. They leave a small, balloon-tipped
catheter in the breast after a lumpectomy.
The balloon is filled from the outside with
the radioactive material for five to 10 min
utes twice a day. After five days, both
catheter and contents are removed.
Don’t have five days to spare? Doc
tors in the U.S. and Europe think they
may be able to deliver all the radiation
that's needed while a woman is still on
the operating table. In an experiment
conducted on 15 women in England,
physicians inserted a tiny coil into the
cavity created by the removal of a tumor.
The bottom of the coil was shielded in
lead to protect the heart and lungs, while
the breast tissue was stretched around
tumor mumoN
r '
■ HOW IT’S DONE
■ HOW IT'S DONE
Cancers can be frozen or vaporized with
lasers or high-energy radiowaves
delivered by a probe through a tiny
incision. In one technique, the probe
opens like an umbrella inside the breast
Tumors can be examined with a miniature
fiber-optic camera that is inserted
through the nipple and into a milk duct.
Eventually surgeons may be able to treat
tumors through the same tiny probe
■ AVAILABILITY
■ AVAILABILITY
Already used for liver tumors. Clinical
trials for breast cancer are under way,
but could take five years to complete
The fiber-optic scope was okayed by the j
FDA last summer. Using it for treatment
may be less than five years away
*
the coil. As the surgical team left the room
to avoid exposure, the device delivered a
full course of radiation treatment at once.
After 25 minutes, the coil was removed. In
18 months of follow-up, none of the
breast cancers have recurred.
Unfortunately, some cancers do reap
pear, sometimes far from their original
site. This is where chemotherapy can
make a difference. Once again, it’s not al
ways clear who will benefit most. A con
crete example helps explain:
Many doctors would recommend che
motherapy to a woman whose tumor mea
sures 2 cm across, even if it has shown no
sign of spreading to the lymph nodes. Why?
There is always the possibility that some
cancer cells have already escaped to tire
rest of the body through the bloodstream.
How often does that happen? Statisti
cians estimate that 20 of every 100 women
who get only mastectomy (or lumpectomy
plus radiation) for a 2-cm tumor that has
not spread to the lymph nodes would, all
other things being equal, suffer a recur
rence sometime in the next five to 10
years. Fourteen of those tumors would
have come back regardless of whether any
additional therapies had been tried. The
remaining six would have been prevented
by chemotherapy. “For a 6% improve
ment, that’s a lot of women who have to
accept chemotherapy,” says Dr. Gralow at
the Fred Hutchinson Cancer Research
Center in Seattle. But there is no way to
figure out in advance which six tumors ac
tually needed to be treated.
That may change as scientists learn
more about the genetic alterationMJnat
transform a normal cell into a malign^ \
one. Last month a group of scientists fi^J
the U.S. and the Netherlands published a
PREVENTION
Estrogen: A Villain and a Possible Savior
here is no single cause for
breast cancer, but one major
factor is estrogen. That's a
shocking thought. The same
hormone that softens our skin,
thickens our hair and fills out our
hips and breasts also feeds
disfiguring tumors. Rates of breast
cancer are highest in developed
nations, in part, scientists believe,
because with better nutrition we
reach menses earlier and
menopause later, allowing
estrogen to course through our
bodies for that much longer.
T
If there is a bright side to all
this, it is that estrogen is now
pointingthe way to new breast
cancer treatments. One of the
most exciting developments in the
field is a new class of drugs called
aromatase inhibitors, which for
postmenopausal women are
already in use against late-stage
tumors and may prove even more
effective when tumors are caught
early. Aromatase inhibitors block
the action of an enzyme that these
women need to produce estrogen.
Two new studies suggest that the
drugs can shrink tumors before
surgery and also perhaps prevent
breast cancer from recurring. More
than 20,000 women are enrolled in
clinical trials designed to show just
how effective the aromatase
inhibitors are in early cancer and
how best to use them.
These drugs could one day
replace tamoxifen, which is
routinely given to women at high risk
for recurring tumors, and raloxifene,
a newer drug that was originally
designed to prevent osteoporosis
but also appears to block breast
cancer. Known as “designer
estrogens," tamoxifen and
raloxifene work by taking the plac
of the body's natural estrogen on
the surface of breast-cancer cells
preventing the real thing from
stimulating tumor growth.
Five years ago, doctors and
their patients hailed tamoxifen,
which was the first drug approver
for reducing the risk of getting
breast cancer (rather than just
treating it). But tamoxifen isfar
from perfect. It increases the risk
uterine cancer and potentially fat
blood clots. Raloxifene appears t
provoke fewer side effects, but tt
results from a head-to-head stuc
■ HOW IT’S DONE
■ HOW IT’S DONE
■ HOW IT’S DONE
With microarrays, scientists can study
patterns of gene activity using strands of
cancer DNA and predict which tumors are
likely to spread. The technique may someday
be used to design customized treatments
As scientists come to understand at the
molecular level precisely how tumors form,
they are designing a new generation of
smart drugs that bind to specific receptors
or block particular proteins
■ AVAILABILITY
■ AVAILABILITY
■ AVAILABILITY
have been completed. The procedure is
awaiting FDA approval
Clinical trials for breast cancer are starting
this year; treatment may be widely available
within the decade
Herceptin, the first of these smart
drugs for breast cancer, is available for
certain advanced cancers
the so-called micrometastases that pathol
ogists are starting to discover in some
women's lymph nodes. Once again, better
detection techniques have revealed mi
nute clumps of cancer—0.2 mm across—
that are smaller titan anyone had ever
seen before.
expert panel. “Now we try to target and
control our treatment.”
Ideally, Singletary would like to be able
to tailor each woman’s treatment to the
characteristics of her particular tumor. Al
ready scientists have identified a biological
marker called the HER2 receptor, whose
presence usually signifies a very aggressive
cancer. For the past four years, a drug called
Herceptin has been given to women with
metastatic tumors that make a lot of the
HER2 protein. Now trials are being con
ducted to see if Herceptin, which may have
some deleterious effects on the heart, will
nonetheless help other women with smaller
tumors that haven’t yet spread.
Herceptin is only a beginning, says
ucla’s Slamon, who identified the HER2
receptor. There are bound to be other
cancer proteins that pharmaceutical
manufacturers can use as targets as they
After a lumpectomy, a tiny radioactive
bead is delivered directly into the tumor
site through a small balloon-tipped
catheter. Treatment takes a matter of
days, not weeks
QjJ cal trials on 70 patients nationwide
•
paper in the research journal Nature de
scribing a molecular test they have devel
oped that may predict, at the time of
surgery, which cancers will be likely to
metastasize—and therefore might benefit
from chemotherapy. Using so-called dna
microarrays, the researchers analyzed
some 25,000 genes from the breast can
cers of 100 women. By winnowing the
number of relevant markers to about 70
genes, they produced a dna profile that
correlated closely with the women’s actu
al outcomes. “There’s not much that
stands in the way of this test being used
clinically,” says Stephen Friend, one of
the paper’s authors and a co-founder of
the.jfiotech firm Rosetta Inpharmatics.
Cljlal trials could begin, he believes,
• "'thin the year.
<7 Such a test might prove particularly
helpful in determining what to do about
paring the two drugs won't be
Hable until 2009.
Meanwhile, researchers are
ng better at predicting who is
t likely to benefit from which
gner estrogen. Raloxifene, it
s out, is most effective for the
-menopausal women who have
rally high levels of estrogen.
r tests suggest that tamoxifen
s little or no benefit to women
carry the BRCA1 mutation, one
a generic mutations known to
a an inherited form of breast
er, but it can help lower the
if breast cancer in women
ing a variation of the gene
d BRCA2. For now, women who
NTIL RECENTLY, THE PRESENCE OF
any cancer in a lymph node
would be a clear signal that
chemotherapy was required. But
at the upcoming meeting of the
American Society of Clinical On
cology in May, a group of cancer experts
will recommend that these minute malig
nancies be left alone, as long as the original
breast tumor is small. “We used to seek out
and destroy every cell,” says Dr. Eva Sin
gletary, a breast surgeon at the M.D. An
derson Center in Houston, who chairs the
U
are taking tamoxifen should
continue doing so. Butinthefuture,
doctors will almost certainly have
more drugs to choose from. They
may, for example, use designer
estrogens and aromatase inhibitors
in sequence to try to keep breast
cancer cells off-balance.
The ultimate goal, of course, is
to keep breast cancer from taking
hold in the first place, and estrogen
will play a role in achieving that.
One idea that researchers have
begun to test is temporarily
suppressing the body’s natural
estrogen and thus providing birth
control along with protection from
breast cancer. This could be
accomplished by combining an
ovulation-stopping drug with tiny
doses of female hormones to
protect tissues like bone and
brain. A pilot study conducted
at the University of Southern
California in women with a family
history of breast cancer showed
that such a dosage regimen
reduced breast density, making
mammograms easier to read.
An added benefit: the treatment
cut their menstrual cycles to three
a year.
—By Shannon Brownlee.
Reported by Sora Song/New York
TAMOXIFEN: Prevents natural
hormones from feeding tumors
MEDICINE
develop new, more selective drugs.
“Using a combination of [these kinds of]
therapies earlier in the disease could
have a dramatic impact on outcomes,”
Slamon says.
It might also lay to rest any debate
over the benefits of mammography; in the
final analysis, early detection is only as
good as the treatments that follow. You
want to know which women’s lives will be
saved by surgery, radiation, chemothera
py or hormone treatment. Otherwise, you
risk doing more harm than good.
That’s why it helps, when trying to
sort through the current unsettled state of
affairs in breast cancer, to take the long
view. “There’s always a trend or an issue
that everyone’s chasing after,” says Fran
Visco, president of the National Breast
Cancer Coalition. “I do think we’re at a
place where we can begin asking some of
those questions regarding targeted therapy. But I don’t think we’re going to get the
answers next month or next year.”
A LIGHTER TOUCH:
Dr. Kambiz Dowlat of
Chicago readies a laser for
vaporizing breast tumors
In the meantime,
women like Nancy Ulene
who discover they have
breast cancer have to de
cide what to do with their
lives and their breasts
based on information cur
rently available. There are
days when many women
would probably agree with
Ulene’s assessment that it’s oo
all a “crapshoot” anyway.
After much soul-searching,
she finally opted for a par
tial mastectomy and tamoxifen. It may not
happen today. It may not happen tomorrow. But eventually those decisions will
start to get easier. —Reported by Janice M.
Horowitz, Alice Park and Sora Song/New York
and Jeanne McDowell/Los Angeles
FOR MORE INFORMATION
The National Cancer Institute’s hot line at .
1-800-4-CANCER can answer questions
about cancer diagnosis and treatment and
offer tips for preventing breast cancer. On the
Web, visit www.cancer.gov
Who fte®(fc Breasts, Anyway?
By MOLLY IVINS
n Having breast cancer is
|O| massive amounts of no
fun. First they mutilate
9 9 you; then they poison you;
then they burn you. I have been
on blind dates better than that.
One of the first things you
notice is that people treat you
differently when they know you
have it. The hushed tone in which
they inquire, "How are you?” is
unnerving. If I had answered
honestly during 90% of the nine
months I spent in treatment, I
would have said, "If it weren’t for
being constipated, I’d be fine." In
fact, even chemotherapy is not
nearly as hard as it once was,
although it still made all my hair
fall out. My late friend Jocelyn
Gray found the ultimate proof
that there is no justice: "Not just
my hair, but my eyebrows, my
eyelashes—every hair on my
body has fallen out, except for
these goddam little mustaches
at the corner of my mouth I have
always hated.”
Another thing you get as a
cancer patient is a lot of football
coach patter. "You can beat this;
Molly Ivins wasfound to have
Stage III inflammatory breast
cancer in 1999
you can win; you're strong;
you’re tough; get psyched." I
suspect that cancer doesn't give
a rat’s ass whether you have a
positive mental attitude. It just
sits in there multiplying away,
whether you are admirably stoic
or weeping and wailing. The only
reason to have a positive mental
attitude is that it makes life
better. It doesn't cure cancer.
My friend Judy Curtis
demanded totally uncritical
support from everyone around
her. “I smoked and drank
through the whole thing," she
says. “And I hated the lady from
the American Cancer Society."
My role model.
The late Alice Trillin wrote
some brilliant essays on being a
cancer patient, and I found her
theory of “the good student"
especially helpful. When you are
not doing well at cancer—barfing
and getting bad blood tests and
generally not sailing through the
whole thing with grace and
panache—you have a tendency
to think, Help, I’m flunking
cancer, as though it were your
fault. Your doctor also tends to
look at you as though he
is disappointed.
Especially if you start to
die on him.
You don’t get
through this without
friends. Use them. Call
them, especially other
women who have been
through it. People like to
help. They like to be able
to do something for you.
Let them. You will also
get sick of talking about
cancer. One way to hold
down the solicitous calls is to
give your friends a regular
update by e-mail, if you have it. If
you work, I recommend that you
keep right on doing so (unless
you hate your job). Most
companies are quite good about
giving you time off when you
need it, and working keeps you
from sitting around and worrying.
Losing a part of a breast or
all of one or both has, obviously,
serious psychological
consequences. Your self-image,
your sense of yourself as a
woman, your sense of your
sexual attractiveness are going
to be rocked whether or not you
have enough sense to realize
that tits aren’t that important. I
am one of those people who are
out of touch with their emotions.
I tend to treat my emotions like
unpleasant relatives—a long
distance call once or twice or
year is more than enough. If I |J\
got in touch with them, they
might come to stay. My friend
A \1
Mercedes Pena made me get in w
touch with my emotions just
before I had a breast cut off.
Just as I suspected, they were
awful. "How do you Latinas do
this—all the time in touch with
your emotions?" I asked her.
"That’s why we take siestas,"
she replied.
As a final indignity, I have
just flunked breast reconstruc
tion. Bad enough that I went
through all that pain for the sake
of vanity, butthen I got a
massive infection and had to
have both implants taken out.
I’m embarrassed about it,
although my chief cancer
mentor. Marlyn Schwartz (who
went to the Palm for lunch after
every chemo session), has
forbidden this particular
emotion. So now I’m just a
happy, flat-chested woman.
□
MEDICINE
To Test or Not to Test?
The mammogram wars are raging again. The facts
aien t all in yet, but don’t cancel your appointment
By CHRISTINE GORMAN
reast cancer researchers have
been arguing for two years about an
issue that most women, in the U.S. at
least, thought was settled: whether
routine mammograms save lives. Given
that tens of millions of these tests are per
formed each year, tire women who
ge'&em deserve some clarity on the
isstm. Instead they’re getting an oldfashioned academic feud with lots of
y | and very little light.
The debate flared up again last
week when an independent adviso
ry panel to the U.S. National Cancer
Institute concluded that a harsh cri
tique by two Danish researchers of
the data supporting mammogra
phy's benefits had enough merit that
its conclusions should be addressed
in the cancer database maintained
by the nci. For now, the cancer in
stitute is not changing its basic rec
ommendation that women age 40
and older undergo routine mammo
grams. But it is planning to review
the policy. “This is a very' complex is
sue,” says Dr. Peter Greenwald, di
rector of cancer prevention at the
nci. “It doesn't mean that it’s wrong
[to >Kt a mammogram], just that it’s
lesswertain than we thought.”
)jln trying to sort out what women
s«-iuld make of this controversy—and
whether they need to keep their next
mammogram appointment—it helps
to have a little background. The most
important tiring to keep in mind is
that the debate is about mammo
grams used to screen healthy women.
Researchers are not talking about
mammograms that are ordered after
a lump has been discovered. Nor are
they talking about women previous
ly treated for breast cancer or those who
are at high risk because of, for example, a
strong family history of the disease.
The authors of the Danish study,
which was published in tire journal Lancet
last October, focused on routine mam
mography of healthy women. They re
viewed seven large clinical trials—several
of them 30 years old-that were designed
B
to figure out whether such mammograms
actually saved lives. Using the most up-todate standards of what makes a good clin
ical trial, they concluded that five of the
studies were so primitive or of such poor
quality that their conclusions could not be
trusted. Those five included ones that
found that routine mammograms reduce a
review was flawed and that several studies
were too hastily thrown out. Others point
ed out that both mammography and breast
cancer treatments are better now than they
were in the 1970s and ’80s, when some of
those studies were conducted. Some breast
cancer advocates have even wondered
whether the Danish researchers might
have had an economic or a political incen
tive to downplay the benefits of what are
fairly expensive screening programs.
When you cut through all the argu
ments and counterarguments, what you
realize is that everyone expects too much of
mammograms. Even the best miss 10% to
15% of breast cancers. Mammograms are
also associated with a high rate of
false positives—particularly among
younger women. In the U.S. only 2%
to 11% of all “abnormalities” found in
a routine screening actually turn out
to be cancer. That translates into a lot
of anxious women who are called
back for another mammogram or
advised to undergo either a needle
aspiration or a biopsy. These can
lead to problems such as scarring, in
fections and the complications of un
necessary surgery.
Despite these drawbacks, there
are very real benefits to mammo
grams. The earlier a cancer is found,
the more options a woman usually
has with regard to treatment—some
thing the Danish review did not ad
dress. Many women with smaller tu
mors, for example, may be able to
forgo chemotherapy, opting for
breast-sparing surgery and hormon
al treatment. To these women, a few
anxiety-provoking false positives may
seem like a small price to pay.
True, some slow-growing tumors
will be treated when they probably
don’t need to be. And maybe someday
doctors will know how to identify
those cases and say with confidence,
“We don't need to touch this cancer
because it won’t kill you until you're
85.” But we’re not there yet.
As with so many things in medi
cine, doctors and patients are left
making decisions based on incom
plete information. “We have to be honest
about saying that [routine] mammography
may not save your life,” says Dr. Patricia
Ganz, a professor at the schools of medi
cine and public health at the University of
California at Los Angeles. But it can give a
woman who discovers she has breast can
cer options she might not otherwise have.
And who wouldn’t want that?
a
By focusing on whether women
who get mammograms live longer
than those who don’t, scientists
may have missed the point
woman’s risk of dying from breast cancer
by 30%. The two remaining studies found
no benefit. The authors’ conclusion: there
is no reliable evidence that women who
get mammograms live any longer than
women who don’t.
The reaction in the medical communi
ty was immediate—and fierce. Critics ar
gued that the methodology of the Danish
TIME, FEBRUARY 11. 2002
39
T?l S'In
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An Ounce of Prevention
Cancer doctors met last month to share the latest research on
keeping tumors at bay. Here are the findings By Alice Park
S CANCER SPECIALISTS
from around the world
gathered last month in
Orlando, Florida, for
the annual meeting of the
American Society of Clinical
Oncology, a new sense of
optimism was in the air. It's not
that cancer has been cured—
there are too many different
types of malignancies to hope
for a universal treatment
A
Rather, it’s that doctors are
beginning to piece together
new strategies for keeping
cancer from recurring and, in
some cases, preventing it from
taking root in the first place.
As asco president Dr. Larry
Norton puts it, “Cancer is not a
bolt of lightning. It’s more like a
thunderstorm. We have plenty
of time to close the windows if
we know what to do.”
One of those windows
opens up right after a patient’s
initial treatment. It’s
becoming clear that whatever
form that treatment takes—
surgery, chemotherapy, radia
66
tion, medication—what doctors
and patients do in the weeks
afterward may determine
whether a cancer comes back.
Breast cancer is a prime
example. For more than two
decades, women with earlystage, estrogen-sensitive breast
cancers have been treated with
surgery followed by a combi
nation of tamoxifen and chemo
therapy. Adding tamoxifen
seemed to make sense, since it
blocks estrogen’s cancer
promoting effects. It turns out,
however, that tamoxifen may act
as a spoiler, preventing the
chemotherapy agents from
entering cancer ceDs and doing
their job. In a paper presented
at the conference, researchers
reported on a finding that
should change the way doctors
treat patients from now on; after
eight years of follow-up exams,
women who waited until their
chemotherapy was complete
before taking tamoxifen were
18% more likely to survive with
out a recurrence than women
who took them together.
In another study, women
with early-stage breast cancer
that had spread to several
lymph nodes significantly cut
the risk of recurrence simply
by replacing one of the standar d
chemotherapy agents with a
drug called docetaxel (Tax
otere). By blocking cancer
cells’ division and growth
process, docetaxel reduces
the risk of tumor recurrence 50%.
And in a preliminary
but promising finding in
lung cancer, doctors
discovered that a special
form of vitamin A might
reverse some of the
changes in lung tissue
caused by smoking. In a
small study, former
smokers who took the
vitamin A derivative
produced higher levels of
a protein thought to be
important in suppressing
tumor growth than ex
smokers who took a
placebo.
Because cancer
research is moving
quickly, it pays for cancer
survivors—and their loved
ones—to be vigilant. Think of
cancer as a chronic condition,
one you will have to stay on top
of for the rest of your life. (This
is also true for people at high
risk for cancer who have been
lucky enough to escape it so
far.) Ask your doctor regularly
if you’re doing everything you
can to keep die tumors at bay.
The latest studies suggest that
prevention really is the best
medicine.
For more, visit www.asco.org
or e-mail alcpark@aol.com
TIME, JUNE 10,2002
NO BONES ABOUT IT Regular
tea drinking may strengthen
bones, say researchers in Tai
wan. After surveying more than
1,000 men and women 30 and
I in
older, scientists found that peo
ple who drank an average of
nearly two cups of tea—black,
green or oolong—daily for 10
years had a 6.2% greater hip
1 bone density than occasional
drinkers. Scientists suspect that
fluoride, flavonoids and phyto
estrogens—a few of the 4,000
health-affecting chemical com
pounds found in tea—may help
; preserve bone-mineral density.
i 2
is
]
[
i
I
i
;
[
]
|
1
ALZHEIMER’S HOPE? Re
searchers have discovered a
substance that appears to pre
vent the formation of amyloid
plaques, which are implicated in
such diseases as Alzheimer’s,
amyloidosis and Type 2 dia
betes. Doctors hope to start a
clinical trial within weeks using
the experimental drug CPHPC
on Alzheimer’s patients.
CINDERELLA SYNDROME It
may be good for the soul, but
researchers say housework
doesn't do much for the heart.
University of Bristol scientists
studied 2,341 British women
ages 60 to 79 and found that
heavy housework—vacuuming,
washing windows and floors—
had no effect on their health or
weight. Women who spent 214
hours a week doing such chores
may have burned extra calories
but were neither less obese nor
had lower resting heart rates
than those who did no cleaning
i S at all.
—By Sora Song
Ii 2o Sources: Archives of Internal Medicine; Nature:
i a- Journal of Epidemiology and Community Health
FwJ[21:Awareness
Subject:
.Awareness
Date: Wed. 19 Sep 2001 11:36:33 -0400
■,
From: pmehta@imicef.org (Pankaj Mehta)
To: chaya_mehta@hotmaii.com, msamd@blr.vsni.net.in, kajaibanik@hotmail.com,
kbajracharya@unicefrosa.org.np, mdupar@yahoo.com, rsachdev@bigfoot.com,
SGCHARA@VSNL. COM, uhoque@unicefrosa. org.np
Forward Header
A handsome, middle-aged man walked quietly into the cate and sat down. Betore he
ordered, he couldn't help but notice a group of younger men at the table next to
him.. It was obvious they were making fun of something about him, and it wasn't
unts.1 he remembered he was wearing a amal^. pmx rxbbo.. o*.
,—**
e ^.a^,el c±
chat he became aware of what the joke was all about.
The man brushed off the reaction as ignorance, but the smirks began to get to
look9d
of th9 cud9 m9n . scpis.c9 in th99y9, pl?.c9d his hsnd b.9H9ath
trio cs-jobon cine scksa, Quizzically, "This?"
With that the men all began to laugh out loud. The man he addressed said, as he
fought back laughter, "Hey, sorry man, but we were just commenting on how pretty
cibbon looks Eig2.ic.st youc blii9 jsckot!"
The middle aged man calmly motioned for the joker to come over co his cable, and
invited him to sit down. As uncomfortable as he was, the guy obliged, not really
sure why. In a soft voice, the middle aged man said,
”I wear thia ribbon co bring awareness aoouc oreast cancer.
I wear it m my
mother’s honour”.
"Oh. sorry dude. She died of breast cancer?"
"No, she didn’t. She’s alive and well. But her breasts nourished me as an
infant, and were a sofc resting pxace for my head when I was scared or lonely as
a little boy. I’m very grateful for my mother’s breasts, and her health."
"ITrnm " the stranger red ied "Yeah. "
"And I wear this ribbon to honour my wife, the middle aged man went on.
"And she's okay, too?", the other guy asked.
■
"Oh, yes. She's tine. Her breasts have been a great source ot loving pleasure
for both of us, and with them she nurtured beautiful daughter 23 years ago. I am
grateful for my wife's breasts, and for her health."
"Uh huh. And I guess you wear it to honour your daughter, also?"
"No. It's too late to honour ray daughter by wearing it now. My daughter died of
breast cancer one month ago. She thought she was too young to have breast
cancer, so when she accidentally noticed a small lump, she ignored it. She
thought that since it wasn't painful, it must not be anything to worrv about."
Shaken and ashamed, the now sober stranger said, "Oh, man, I'm so sorry mister".
9/19/01 3:02 PM
Pwdl?l-AwarCTess
r
my uauautei a memory, too, i proudly wear this ntcie riooon, wnicn
allows me the opportunity to enlighten others. Now, go home and talk to your
wife and your daughters, your mother and your friends. And here .
. The middle-aged man reached in his pocket and handed the other man a little pink
ribbon. The guy looked at it, slowly raised his head and asked, "Can ya help me
put it on?"
Tills is breast cancer awareness month. Do regular breast self—exams and have
annual mammograms if you are a woman over the age of 40. And encourage those
women you love to do the same. Please send this on to anyone you would like to
remind of the importance of breast cancer awareness.
A CANDLE LOSES NOTHING BY LIGHTING ANOTHER.CANDLE, PLEASE KEEP 'THIS CANDLE
GOING! This one I do ask that you send on.
2 of 2
9/19/01 3:02 PM
Page 1 of5
Main identity
From:
"Erin Purvis" <mojxkpdd@y3hoo com>
To:
Cc:
<pwr@vsnl.com>
<sochara@vsn!.com>; <ga!@vsnl.com>, <bhas.kardk@vsnl.com>, <fbrtpapl@vsnl.corn>;
<sswaii<a@vsni.com>; <vacation@vsni.com>
Monday. December 01. 2003 3:36 PM
US STOCK MARKET - HTDS Medical Research—CANCER Trials ariana
Sent:
Subject:
US Steck Market - Stock Profile of the Week
Symbol: HTDS
Market: PK
Sector MEDICAL RESEARCH
BARCHART Rates HTDS an 80% BUY - hllp://quoles.barch arl.com,-'texperi.asp?sym-HTDS
Before we begin our profile we have very exciting, breaking news...
r ubercin Passes Toxicity Trials - Ready To Proceed To Live Cancer Trials
BREAKING NEWS - DELRAY BEACH, Fla.-(BUSINESS WIRE)-Haid to Treat Diseases
Incorporated (Pink Sheets:HTDS) announces that Tubercin® has passed the toxicity tests
required to proceed to the live cancer trials. Testing Tubercin® on live Melanoma. Lung and
Breast cancer cells will begin immediately. The President and CEO, Mr. Cohn J. King, met with
the spokesperson of the medical group at their offices in Oklahoma City. Mr. King was advised
that the tests were conducted under strict FDA (Federal Drug Administration) guidelines. Full test
results will be available at the corporate offices as soon as the reports and findings arc printed.
n
)?■
"These are the most promising results to date regarding Tubercin® and we're looking forward to
additional positive results in the near future," stated Mr. King. "These tests prove that Tubercin®
is non-toxic and is the first step on the way to human clinical trials as well as the first positive
breakthrough conducted in the United States with an independent medical group for Tubercin®."
Operating out of Delray Beach. Florida. Hard to Treat Diseases Incorporated ("HTTD") holds the
international marketing rights, except South Korea, to Tubercin®. a patented immunostimuiant
developed for combating Cancer under medical patent (US Patent 6,274,356). The- unique
properties unlike oilier cancer products are clearly slated in the abslracl summary oi the palenl...
"A carbohydrate complex, which is a mixture of low molecular-weight polysaccharides of an
arabinomannan structure extracted from Mycobacterium tuberculosis, is highly effective in
treating various cancer patients without incurring any adverse side effects."
STOCK PROFILE OF THE- WEEK
HTDS is now al an emerging and potentially explosive stage. As slated in their press release.
Tubercin is now ready to proceed (after tests conducted under strict FDA guidelines) to human
clinical trials. While they have jumped one ver; big hurdle, they are still in the early stages of
development and now is a great lime for investors lo take heed.
12'3'03
Page 2 of 5
I UB1-.RCTN
Over ilie past ten years, epoch making anlicancer agents have continuously been introduced, but
the mortality of cancer patients have been rising in the U.S. and the European countries not to
mention Japan and Korea. The decisive measure to cope with cancer is surgery5.
When the cancer cells spread throughout the body instead of remaining on the original spot, the
treatment should take into consideration chemotherapy, radiation therapy and immunotherapy.
I he drawback of such therapies, however, is they incur damages not onlv on cancer cells, but also
on ths noimni cells.
Chemotherapy and radiation therapy are not suitable for applica tion on weakened patients,
especially those above 70. Historically, various forms of immunotherapy ha ve been performed.
falling short of therapeutic expectation. When Bacille calmetteguerin is used as an active no
specific immunotherapeutic agent, however, the patient's prognosis turns better through a
simulative action on immune system of the cancer case.
Professor T.H. Chung of Korea extracted carbohydrate complex Tubercin from microbacterium
tuberculosis to tie used as immunostimulant. 1 his was meant to activate the t -lymphocyte ot the
cancer patient to produce Ivmphokine. This process strengthened and promoted immuno
surveillance activities in deficient state and alleviated the pain and prolonged the life of cancer
patients.
Of late the pharmaceutical industry in advanced countries started to put on the market so called
cancer vaccines (active specific immunotherapy). The vaccines, bacterial extracts, as adjuvants,
with, autologous and or allogenic cancer cells to generate antibodies to cancer ceils, facilitating
the killer T-cells to recognize and destroy cancer cells.
fhe laboratory work to modify autologous or allogenic cancer cells arc not ordinary and simple.
When our lab work augments the active specific immunotherapeutic agents, the Tubercin will be
one of the best adjuvants. Meanwhile, the main point of AIDS is its virus killing T-cells and
Tubercin helps maintain healthy T-ceils. Consequently, we focus our effort on the application of
Tubercin to A IDS
TUBERCIN is derived from micro bacterium tuberculosis. As an immunostimulant. TUBERCIN
strengthens the human body's own immune system and assists the body in seeking out and
combating cancer cells. HTTD is potentially able io develop TUBERCIN into a low-cost product
to treat cancer patients on an international scale. Salient treatment, through the administration of
TUBERCIN, could positively affect thousands of lives in North America. In addition, Europe and
zisia nave millions gt iivcs at risk each year because oi viral diseases such as cancer.
I UBniiCTN IS A FuniShi’.i j PRODUC I. Tubercin as an mmunostimuiant has been administered
to human patients in stages t&e and four of terminal cancer. There have been no indications of
12/3/03
Page 3 of 5
any adverse side effects in human trials There has been encouraging results of patients with
1UBERCLN in the last fourteen years. Various forms of cancer were involved and many of the
patients survived.
A review oi clinical studies indicate TUBERCIN has no side ellecls and could possibly be
administered in conjunction with other such modalities for the treatment of cancer without any
adverse effects. The scientific presumption would be the distinct possibility of a strengthened
immunity system and rhe- administration of treatment such as chemotherapy at the later stages of
tumor growth would not be impeded by the weakened condition of the terminal cancer patient.
re inis end the Company has been assisted by outside consultants reviewing the research data and
human trials involving TUBERCIN to see specifically whereby incidents of dual treatment
produced favorable results in terms of moving toward indication of prolongation of the life of the
cancer patient.
There is recognition that morphine is an trusted pain killer, but in totality it cannot be said that it
has no side ellecls. In the maintaining of patient care, there is the strong possibility that
TUBERCIN could be also considered as a candidate for a pain management. The Company's
scientists describe TUBERCIN as having the high propensity of deadening the nerve endings in
specific areas of the body where cancer lias caused erosion and consequently much pain.
PATENTS
Presently, HTTD has the patent rights for Korea. Japan and the United States. The Korean patent
was issued on October 29, 1998 (Registration No. i 73362). The Japanese patent was issued on
lime 12, 1998 (Registration No. 2790447). The United States patent was issued on August 14,
2001 (Registration No.6,274.356). Currently, patents are pending for Canada and Europe (the
United Kingdom. France. Germany. Italy and Spain).
CANCER IN OUR TIME
In the 20th century, the number of cancer patients has been on the increase. Although many amicancer agents were developed and an enormous study on its essence continued, the mortality by
cancer still is increasing. Mankind may be chronically threatened with cancer in the 21st century.
Nine million new case of cancer occur annually and five million people die from breast cancer.
reports the World Health Organization. Dramatic increases in life expectancy and change in
lifestyle are estimated to increase the number of new cancer cases to 20 million annually by 2020
and cancer deaths to more than 10 million.
About 552,200 Americans - more than 1,500 people a day - are excepted to die of cancer this
year. In the United States, one of every four deaths is attributed io cancer. Cancer is the secondleading cause of death in the United Stales. Exceeded only by heart disease. About 5 million lives
have been lost to cancer since 1990 and about 13 million new cases have been diagnosed. In
2000. more then 1.2 million new cancer cases arc expected to be diagnosed. The number of
cancer cases will continue to grow, spurred by the aging population. By 2009, this patient group
could total 8.4 million. In 1997, about 6.3 million people worldwide died from some form of
cancer, and most major international cancer agencies expect this number to double by 2022.
12/3/03
Page 4 of 5
Please note that HTDS had abso’utlcy nothing to do with litis report and is not a participant in any
way.
No more advertisements: http: 7doubleoDt.biz/ootout.htnil
Stock Market Today is an independent research firm. This report is based on Stock Market
Today's independent analysis but also relies on information supplied by sources believed to be
reliable. This report may not be the opinion of HTDS management. Stock Market Today has also
been retained to research ano issue reports on Hti.tS. tsiock .bluitwi today may rroni cimv to time
purchase or sell HTDS common shares in the open market without notice. The information
contained in this report shall not constitute, an offer io sell or solicitation of any offer to purchase
any security. It is intended for information only. Some statements may contain so-called
"forward-looking statements". Many factors could cause actual results to differ. Investors should
consult with their Investment Advisor concerning HTDS. (Copyright 2003
Stock ivlarkct ioday
Ltd. All Riehls Reserved. 1 his newsletter was distributed by MMS, Inc. MrvlS was paid eight
hundred and fifty thousand shares HTDS stock io distribute this report. MMS is not affiiated with
Stock Market Today and is not responsible for newsletter content.
12/3/03
Page 5 of 5
fp \ S - i 3
BOOKS
SHINING SOUL: Being labeled a woman's
writer “never worried me for a minute,”
Shields says. “It's an important thing to be"
Dying of breast cancer, Carol Shields talks about her
life, her illness and her superb new novel, Unless
By LEV GROSSMAN
■ KNEW I WANTED HER TO BE A WRITER,”
^Msays Carol Shields. “I wanted her to be
about 40 years old. I wanted her to live
■ in a certain house. And I wanted some
thing terrible to happen to her.”
Perched on an overstuffed armchair
that looks like it might swallow her whole,
Shields is talking about Reta Winters, the
heroine of her new novel, Unless, but she
isn't being cruel—or if she is, it’s because
life itself is cruel. Shields needed some
thing terrible to happen to Reta because
something terrible was happening to her.
Shields, 66, is dying of breast cancer, and
Unless will be her last word.
She almost never wrote her first. The
daughter of a factory manager from Oak
Park, Illinois—the birthplace of Ernest
Hemingway, the bard of brawn—the tiny,
winsome Shields never imagined she could
become a writer at all. “I thought it was like
wanting to be a movie star!” she recalls. “1
never thought writers could be people like
me.” Instead, she married Don Shields, an
engineer, and moved to Canada, where she
had five children in 10 years.
But when her last child marched off to
kindergarten, something unexpected hap
pened. “It was very hard to find novels at
that time that had anything to do with my
life,” says Shields. “It was all about leaving
your home, leaving your children, not hav
ing children. So I started writing the kinds
of books that I wanted to read.” Her first
novel appeared when she was 40. With her
eighth she accomplished that rarest of lit
erary feats, a crossover hit: The Slone Di
aries was an international best seller and a
critical triumph, winning the 1995
Pulitzer Prize for fiction.
Last year, when she sat down to
write Unless, Shields knew what she
did not want: a cancer book. Instead,
she wrote about Reta, a middle-aged
novelist whose daughter Norah has
abruptly dropped out of college to
TIME, JUNE 10.2002
panhandle on a Toronto street comer. Norah
won’t speak; she wears a sign around her
neck that reads, simply, goodness. Reta is
Shields’ not-quite alter ego, and like Shields,
she is discovering a realm of pain she never
knew existed. “The whole sense of sadness,
of the end of things, of the broken vessel—
everything is there,” says Shields in her
quiet, serious voice.
Reta narrates her predicament in the
first person, circling it doggedly, chattily,
sometimes with a deliciously malicious
wit, taking us inside her domestic routines,
her comfortable, functional marriage, her
kaffeeklatsch, her struggles with her own
new book. (Along with everything else, Un
less is rich with practical advice for the
would-be novelist.) Shields swings easily
from comedy to tragedy and back again—
she says she doesn’t really beheve in the
distinction anyway—pausing in between
for a disquisition on the biology of the
trilobite (a prehistoric creepy-crawly), an
expert demolition of literary journalists
(no offense taken) and an angry letter to a
chauvinist academic.
But pain is never far: it’s the book’s
frozen, icy core, and the most vivid mo
ments in Unless demonstrate the oblique,
unexpected angles at which agony can en
ter our lives—as when Reta impulsively
scrawls MY heart is broken in the ladies’
room of a bar, or when she effortlessly en
capsulates postholiday gloom with a single
question: “Is there any task as joyless as un
decorating a tree?” Unless isn’t a grand fi
nale to Shields’ oeuvre; it’s not a monumental summing up. It’s a graceful coda,
an arabesque performed over an abyss.
Reta speaks to us in a voice both calm and
urgent. This is no time for prevarication,
she seems to say. This is the time for truth.
For Shields, lime is growing short. Com
fortably retired in an ivy-covered mansion in
Victoria, British Columbia, she is wrapping
up a few last obligations—a preface here, an
essay there. She goes antiquing with her
daughter, attends a local discussion group,
answers e-mail. She tires easily, her face go
ing gray with fatigue (her husband hovers
protectively), and she still writes in a sunny
upstairs study that used to be a
sewing room. She is even consid
ering an excursion into tlie sonnet.
She will write as long as she can. As
Reta puts it, “This matters, the re
making of an untenable world
through the nib of a pen; it matters
so much 1 can’t stop doing it.” E
BAYWOOD PUBLISHING COMPANY, INC.
AMITYVILLE, NEW YORK
Cancer Establishment Continues to Mislead Public: Epstein
Rebuts National Cancer Institute and American College of
Radiology Responses
F. The Cancer War and Its Critics, Washington Post
G. Epstein Rebuts the Washington Post Editorial
Dangers and Unreliability of Mammography: Breast Examination Is a
Safe, Effective, and Practical Alternative, With Rosalie Bertell and
E.
In Praise (Continued)
There is less and less effort to inform workers and their families, and the general
public, about avoidable environmental and occupational causes of cancer. This
book will make you pause and think—especially if you have, or a loved one has,
cancer.
Eula Bingham, Ph.D.
Professor Emerita of Environmental Health, University of Cincinnati Medical Center
Former Assistant Secretary of Labor, Occupational Safety and Health Administration
Dr. Epstein’s factual expose of the National Cancer Institute and American Cancer
Society—their conflicts of interest, co-option by the pharmaceutical and
petrochemical industries, and indifference to cancer prevention—is riveting.
Dr. Epstein reaches for the law to turn the issue of public health into one of human
rights. This book belongs on the bookshelf of every' lawyer and teacher of
environmental law or public health, in every law library, and on the reading lists
of all law school classes.
George S. Grossman
Professor of Law and Director, Law Library, University of California, Davus
As Cancer-Gate details, the National Cancer Institute and American CaWff
Society have narrowly focused their policies and resources on promoting highly
profitable Big Pharma “miracle” drugs in largely unsuccessful efforts to cure
cancer. What’s more, in defiance of the Human Rights Covenants, they have
denied the public its right to know of available information on the causes and
prevention of cancer.
Dr. Rosalie Bertell
Former President, International Institute of Concern for Public Health
Member, National Association for Public Health Policy,
International Science Oversight Committee
Professor Epstein’s scientifically accurate yet highly readable book is an
extraordinarily important depiction of the failure of President Nixon’s 1971 “War
on Cancer.” This has been due to concentration on highly questionable treatment
and a monumental neglect of preventing environmental and other avoidable
causes of cancer. Like the “War on Terrorism,” which has been sidetracked into a
war on Iraq and on human rights, the “War on Cancer” has enriched powerful
special interests and stifled the free flow of public information. This book
provides recommendations and inspiration for, al long last, transforming the
largely futile, and inflationary, cancer war into realistic strategies to prevent the
nation’s leading cause of suffering and premature death.
Dr. Epstein is a scientist/scholar/activist who devotes his life 24/7 to informing the
public about what really causes cancer, and how we can protect ourselves. In this
brilliant and compelling book, in spite of the silence of the National Cancer
Institute and attacks by industry, he has established guidelines on the public's
undeniable right to know about avoidable causes of cancer in the environment,
workplace, hormone replacement therapy and other prescription drugs, and
consumer products.
Barbara Seaman
Co-Founder, National Women’s Health Network
Author, The Doctor's Case Against the Pill
Cancer-Gate is Dr. Epstein's heroic effort to show us how to reduce our risks of
cancer. Motivated by compassion and concern, he does not fail to deeply impress.
In both print and film, he is as remarkable in his command of scientific data as in
his ability to present them in a way that is both convincing to the public health
community and accessible to the general public. He has shared these powerful
insights in my recent documentary, The Corporation.
Mark Achbar
Executive Producer and Co-Director, The Corporation
Recipient of 22 international awards
Dr. Epstein’s new masterpiece, Cancer-Gate, takes the onus from an industry that
tries to keep us in the dark about the war on cancer and puts the information right
into our hands. This well-researched book acts as a roadmap, showing what is
being done and what can be done regarding the war on cancer. The importance of
becoming proactive gets even more personal as Dr. Epstein reveals the role that
the cosmetics industry plays in the cancer epidemic, in my forthcoming
documentary America the Beautiful.
Darryl Roberts
Producer, Sensory Overload Productions
Table of Contents
Dedication
Foreword by Congressman David Obey
Preface
Acknowledgments
Introduction by Congressman John Conyers Jr.
Victor W. Sidel,
Distinguished University Professor of Social Medicine,
Montefiore Medical Center/Albert Einstein College of Medicine
Past President, American Public Health Association
Cancer has surpassed heart disease as America’s #1 killer, but the National Cancer
Institute continues to hope that miraculous “magic bullets” will save us. For more
than three decades, Prof. Samuel S. Epstein has shown that many kinds of cancer
can be prevented by simply eliminating carcinogens in the air, food, water, and
workplace. Vested interests have blocked this strategy. Sam Epstein is a national
treasure and his Cancer-Gate is simply magnificent—a battle cry for activists to
reclaim the failing war against cancer.
Ralph W. Moss, Ph.D.
President, Cancer Communications, Inc., Lemont, Pennsylvania
Director, The Moss Reports, and Author, The Cancer Industry
I Cancer Policy and Politics
1.
2.
Losing the War Against Cancer Who’s to Blame and What to Do
About It
Debate on Policies of the National Cancer Institute, American Cancer
Society, and American College of Radiology
A. Losing the “War Against Cancer”: A Need for Public Policy
Reforms
B. Mammography Radiates Doubts
C. National Cancer Institute Reaffirms Commitment to Prevention,
National Cancer Institute
D. American College of Radiology Refutes Epstein's Comments,
American College of Radiology
3.
Barbara Seaman
4.
5.
6.
7.
8.
9.
Evaluation of the National Cancer Program and Proposed Reforms
American Cancer Society: The World’s Wealthiest “Nonprofit”
Institution
Legislative .Proposals for Reversing the Cancer Epidemic and
Controlling Run-Away Industrial Technologies
The Crisis in U.S. and International Cancer Policy
Strategies for the Stop Cancer Campaign
REACH: An Unprecedented Science-Based European Initiativ^^r
Regulating Industrial Chemicals
PART II Poorly Recognized Carcinogens in Food
10.
Debate on Safety of Recombinant Bovine Growth Hormone
A. Potential Public Health Hazards of Recombinant Bovine Growth
Hormone
B. FDA Publishes Bovine Growth Hormone Data, Ann Gibbons,
Article in Science
C. Rebuttal of Gibbons's Article Challenging the Epstein Publication,
Vicente Navarro
Questions and Answers on Synthetic Bovine Growth Hormones
Unlabeled Milk from Cows Treated with Biosynthetic Growth
Hormones: A Case of Regulatory Abdication
13. The Chemical Jungle: Today’s Beef Industry
14. Preventing Pathogenic Food Poisoning: Sanitation, Not Irradiation
11.
12.
with Wenonah Hauter
PART III Pro-Industry Bias, Corporate Crime, and Poorly Recognized
Risks of Colorectal and Breast Cancers
Pro-industry Bias in Science
Corporate Crime: Why We Cannot Trust Industry-Derived Safety
Studies
17. Industrial Risks of Colorectal Cancer, With Bret A. Lashner
15.
16.
18.
Industrial Risks of Breast Cancer
PART IV Epilogue
Why Wc Are Still Losing the Winnable Cancer War
Appendix: Endorsers of Proposals for Cancer Policy Reform
References and Further Readings
Index
Praise for Recent Books by Samuel S. Epstein
Praise for Cancer-Gate
About the Author
Dr. Epstein, Professor Emeritus of Environmental and Occupationa
Medicine at the School of Public Health, University of Illinois at Chicago,
and Chairman of the Cancer Prevention Coalition, is an internationally
recognized authority on the causes and prevention of cancer. He has
published some 270 scientific articles and 11 books, including the prize
winning The Politics of Cancer (1978), The Safe Shopper's Bible (1995),
The Breast Cancer Prevention Program and The Politics of Cancel
Revisited (both 1998). His popular writings include numerous press
releases, and op-eds and letters in leading newspapers. Dr. Epstein also
has extensive media experience. He is the recipient of many prizes and
awards, and a member of the National Writers Union, AFL-CIO, and
National Association of Science Writers.
In Praise
Dr. Epstein penetrates the facades of the huge cancer institutions and organizations
and explodes the myth that they are protecting us from cancer-causing agents. In
Cancer-Gate, he demonstrates that he is a fearless fighter in the battle against
environmental carcinogens.
Ruth Winter
Past President, American Society of Journalists and Authors
Relentlessly, and with meticulous documentation. Dr. Epstein updates us on the
unresponsiveness of the National Cancer Institute and American Cancer Society to
avoidable causes of cancer. His urgent message—stop cancer before it starts—is
daily more imperative and must be heeded. This book is a must for every public
health student and professional.
Quentin D. Young, M.D.
Chairman, Health and Medicine Policy Research Group
Past President, American Public Health Association
About the Book
Cancer-Gate’s searing indictment of the National Cancer Institute
and American Cancer Society (ACS) for losing the war against
cMKer, launched by President Nixon in 1971, has been endorsed by over
100 leading independent scientific experts in cancer prevention and
public health, including past directors offederal research and regulatory
agencies, besides citizen activist groups.
Despite decades of false assurances, we are losing the winnable war
against cancer. The hand-in-glove generals of the federal NCI and the
“nonprofit” ACS have betrayed us. These institutions have spent tens of
billions of taxpayer and charity dollars, largely promoting ineffective
drugs for terminal disease, while virtually ignoring strategies for
preventing cancer, other than quitting smoking. As a result, cancer rates
have escalated to epidemic proportions, now striking nearly one in two
men and more than one in three women. Paradoxically, the more we spend
on fighting cancer, the more cancer we seem to get.
But, as Cancer-Gate shows, there is much more. In particular, the
NCI and ACS are rife with institutional, and even personal, conflicts of
interest with the cancer drug industry. For the ACS, these conflicts extend
flagrantly to the chemical industry. Unbelievably, PR for the ACS is
handled by Edelman, whose major clients are the tobacco and fast food
ai^^everage industries.
Cancer-Gate details how the NCI and ACS are sitting on mountains
of information on environmental and other avoidable causes of cancer
while failing to act on this and make it available to Congress and the
public. This silence even extends to frank suppression of information
Cancer-Gate explains how we can win the war against cancer with
strategies including “right-to-know” laws, ensuring public dissemination
of critical information on environmental carcinogens and other avoidable
causes of cancer, and Congressional reform and oversight to ensure that
the NCI protects the public rather than special interests.
Finally, Cancer-Gate tells you, the reader, how to fight back h
arming yourself with the information you need to protect your fam'l
from everyday carcinogens, and how to become an activist in the
against cancer.
Dr. Epstein is a legend in the field of cancer prevention. From his 1978 The P&i&cs
of Cancer through this latest brilliant work, Cancer-Gate, Epstein dcmonstiWK a
clear understanding of the cancer crisis and the only real solution—cancer
prevention. This year, 1,400,000 Americans will be diagnosed with cancer and
600,000 will die. If we had taken Epstein's advice on cancer prevention 30 years ago
we would not be facing this tragedy today.
Frank D. Wiewel
Founder, People Against Cancer
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