Tài liệu Cancer Research in ICMR Achievements in Nineties ppt

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Cancer Research in ICMR
Achievements in Nineties



The process of carcinogenicity presents a major challenge to scientists and
provides limited tools for its control. Indian health services are also not adequately
equipped with facilities and expertise for management of cancers. Mortality and
morbidity due to tobacco use is very high. In view of the national priorities, the focus of
research in the field of cancer has been on the aetiology with identification of preventable
risk factors, understand the mechanism of carcinogenesis and on operational research for
control of tobacco use and common cancers through existing infrastructures. The multi-
disciplinary research involved clinical, epidemiological as well as basic sciences
including modern molecular techniques. The cancer registries helped in understanding
the magnitude & trends in cancer occurrence and plan control activities. The above
mentioned task force projects helped in addressing national priorities. However, high
importance was also accorded to supporting projects submitted by individual scientists,
which spanned practically all specialties concerned with cancer and different sites in the
body.

National Cancer Registry Programme

The National Cancer Regsitry Programme (NCRP) was initiated in 1982, with
three population based (existing Mumbai registry and new registries at Bangalore and
Chennai), and three hospital based registries (at Chandigarh, Dibrugarh &
Thiruvananthapuram). Further expansion saw the initiation of urban population based
cancer registries at Bhopal & Delhi; rural population based cancer registry at Barshi
(Maharashtra); & hospital cancer registries at Mumbai, Bangalore & Chennai.
Chandigarh registry functioned till 1992. At present the network has 6 population based
and 5 hospital based cancer registries. Coordinating unit at Bangalore & Delhi, with the
help of a steering commitee, carries out the monitoring and coordination of activities. The
data from cancer registries helped in highlighting the magnitude and common sites of
cancer in India, and was useful in planning the National Cancer Control Programme.

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Network of National Cancer Registry Programme

In 1994, the crude incidence rates of cancer in India varied between 57.5 and 78.6
per 100,000 men; and between 57.7 and 89.7 per 10,000 women in urban registry areas.
The age standardized incidence rates range from 98.7 to 138.3 per 100,000 men; and
from 108.0 to 143.4 per 100,000 women in urban areas. The crude incidence rate for
cancers at all sites in rural Barshi was reported to be 32.9 per 100,000 men and 49.7 per
100,000 women. The age standardized incidence rate in Barshi was 41.1 and 56.3 per
100,000 men & women, respectively.

0
20
40
60
80
100
120
140
Incidence Rate
Barshi
Bangalore
Bhopal
Chennai
Delhi
Mumbai
Incidence Rate of Cancer in India, Men (1994)
Crude Inci. Rate Age Stand. Rate


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0
20
40
60
80
100
120
140
160
Incidence Rate
Barshi
Bangalore
Bhopal
Chennai
Delhi
Mumbai
Incidence Rate of Cancer in India, Women (1994)
Crude Inci. Rate Age Stand. Rate


Global comparison shows that India has high incidence rates of cancers of oral
cavity, pharynx, & cervix. The age standardized cancer incidence in Indian registries as
compared to incidence in certain developed countries is about half to one third in men
and about half in women. Based on the data from population based cancer registries in
Bangalore, Bombay & Madras, the estimated number of new cancer cases for the year
1992 was 644,600. Considering no change in age specific incidence, 806,000
cases are expected to occur during the year 2001.

About half of the cases among men and one fifth of cases among women, pertain
to sites mainly attributable to tobacco use. Overall, about one-third of cancers in India
pertain to tobacco related sites. The most common cancer among men is lung & bronchus
in Mumbai, Delhi & Bhopal; stomach cancer in Bangalore & Chennai & hypopharygeal
cancer in Barshi. However, all these cancers occupy important ranks in all the registries.
The other important cancers sites among men are that of oral cavity, pharynx, larynx &
rectum. Cancer of cervix followed by breast cancer are the commonest cancers among women in
Barshi, Bangalore, Bhopal & Chennai. Breast cancer is the commonest cancer followed
by cervix, in Delhi & Mumbai. Other common forms of cancer among women are mouth,
oesophagus, ovary, & stomach. Incidence of cancer of gall bladder is very high in Delhi.

Common Cancers in among Men in India
Rank

Bangalore Bhopal Chennai Delhi Mumbai Barshi
1
Stomach
10.9
Lung
14.5
Stomach
15.4
Lung
13.2
Lung
14.3
Hypopharynx
6.1
2
Oesophagus
9.4
Tongue
10.6
Lung
10.9
Larynx
9.7
Oesophagus
11.0
Oesophagus
4.9
3
Lung
9.2
Hypopharynx
8.5
Oesophagus
9.2
Prostate
7.1
Larynx
8.5
Penis
3.4
4

4
Hypopharynx
6.4
Oesophagus
8.3
Mouth
7.3
Oesophagus
6.6
Hypopharynx
8.2
Mouth
3.1
5
Prostate
5.1
Mouth
7.5
Hypopharynx
5.7
Uri Bladder
6.3
Prostate
7.5
Larynx
2.7
Common Cancers in among Women in India
Rank

Bangalore Bhopal Chennai Delhi Mumbai Barshi
1
Cervix
30.8
Cervix
24.9
Cervix
41.9
Breast
29.0
Breast
27.1
Cervix
27.7
2
Breast
21.4
Breast
22.2
Breast
22.4
Cervix
29.0
Cervix
19.5
Breast
8.0
3
Mouth
9.9
Ovary
6.1
Mouth
8.0
Gall Bladder
8.4
Oesophagus
8.2
Oesophagus
2.1
4
Oesophagus
9.0
Mouth
5.8
Stomach
7.0
Ovary
8.4
Ovary
7.2

5
Stomach
5.8
Oesophagus
5.8
Oesophagus
6.4
Lymphoma
4.9
Mouth
4.6

Figures are age-standardized rates for the specific cancer sites.
Figures for Bangalore, Chennai & Mumbai are for the years 1982-94. For other registries the figures are for the years
1988-94.

Time trend analysis of the data from population based cancer registries over the
last decade shows a small but significant increase in the overall incidence of cancer in all
the urban cancer registries, both among men & women. Though there are large year-to-
year variations, data suggests that among men incidence increased for oesophagus in
Bangalore & Chennai; leukaemia in Bangalore, Chennai & Barshi; gall bladder, colon &
brain in Mumbai & Delhi; prostate in Mumbai, Chennai & Delhi; urinary bladder &
lymphomas in Mumbai & Chennai; lungs, stomach & recturm in Chennai & Delhi;
tongue, oropharynx & larynx in Chennai; mouth in Delhi; and kidney in Mumbai. Among
women increased incidence has been observed for cancer of breast in Bangalore,
Mumbai, Chennai, Delhi & Bhopal ; gall bladder in Mumbai, Chennai & Delhi;
leukaemia in Bangalore, Mumbai & Chennai; colon in Bangalore & Mumbai; lymphoma
in Bangalore & Chennai; uterus & urinary bladder in Mumbai & Chennai; brain in
Mumbai & Delhi; rectum in Chennai & Delhi; mouth in Mumbai; and oesophagus,
stomach, lungs & ovary in Chennai.

A decreased incidence over last decade has been observed for cancer
of mouth among men in Bangalore; and pharynx among men in Mumbai. Among women
decrease incidence has been observed for cervix in Bangalore & Chennai; mouth in
Bangalore; and stomach in Mumbai. The work at rural registry at Barshi has contributed
in bringing down the proportion of patients with late stages. The proportion of women
with early stage (stage 1 & II) cervical cancer has increased from 32.6% in 1987-88 to
48% in 1991.

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Trends in Age standardized Cancer Incidence Rates among Men
in India (1982 to 1994)
0
20
40
60
80
100
120
140
160
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
Age Standardized Incidence Rate
Bangalore Mumbai Chennai Delhi Bhopal Barshi



Trends in Age standardized Cancer Incidence Rates among
Women in India (1982 to 1994)
0
20
40
60
80
100
120
140
160
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
Age Standardized Incidence Rate
Bangalore Mumbai Chennai Delhi Bhopal Barshi



The age specific incidence rates of cancer gradually increase with age. There is a
decline in incidence rate in old age in all registries, except Bombay. There are small
variations in age specific incidence rates in different registries, except Barshi where the
rates are consistently lower after 40 years of age. The incidence rates in the rural registry
of Barshi are of special interest, as these are likely to throw light on rural-urban
differentials in cancer occurrence. Incidence rate of cancer of penis as recorded by this
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registry is the highest in the country. The incidence rates of mouth, hypopharynx,
oesophagus, rectum & larynx are comparable to some urban registries. The incidence rates
of smoking related cancers in men, all tobacco related cancers in women, and cancers of
not easily accessible sites in both sexes are lower than urban registries.

A comprehensive ten years (1984 to 1993) report of the hospital cancer registries
under NCRP shows that microscopic verification of the diagnosis of cancers ranged from
70% to 95% among men and from 72% to 96% among women. The cases diagnosed on
clinical examination alone varied from 1% to 23% among men and 2% to 26% among
women. At the time of initial reporting, the disease had spread to regional tissues or
metastasis had occurred in most of the cases. The proportion of patients who did not
receive any treatment varied from 16% to 46% among men, and from 15% to 40% among
women. Detection at the stage of localized disease varied from 5% to 24% among men
and from 6% to 23% in women. Radiotherapy was the commonest modality of treatment
at all stages; surgery was used for localized cancers and chemotherapy for patients having
distant spread.

0%
20%
40%
60%
80%
100%
Mumbai
Bangalore
Chennai
Thiruvananthapuram
Chandigarh
Dibrugarh
Proportion of Patients according to Clinical Extent of Disease
Hospital Cancer Registries under NCRP, Men
Localised Regional Distant Others




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0%
20%
40%
60%
80%
100%
Mumbai
Bangalore
Chennai
Thiruvananthapuram
handigarh
Dibrugarh
Proportion of Patients according to Clinical Extent of Disease
Hospital Cancer Registries under NCRP, Women
Localised Regional Distant Others




Institute of Cytology and Preventive Oncology, New Delhi

The Institute of Cytology and Preventive Oncology (ICPO) carried out two long
term prospective studies on uterine cervical dysplasia (UCD I and UCD II), to understand
the natural history of cervical cancer, for the first time on a sizeable cohort. Various risk
factors, both biologic and behavioural, were identified and the role of different microbial
aetiologies such as Herpes simplex virus (HSV), Human papilloma virus (HPV) and
reproductive tract infections (RTIs) was examined. The role of genetic factors and
micronutrients in the process of cervical carcinogenesis was also probed. The Institute
gave for the first time alternative strategies/modalities for early detection of cervical
cancer both unaided and aided visual inspection. The Institute proposes to organise a
national workshop for early detection of cervical cancer. The studies demonstrated strong
association of HPV high risk type for cervical precancerous and cancerous lesions and
demonstrated the role of certain transcriptional factors in the regulation of E6 and E7
oncogene expression. Further it was also informed that Her-2/neu oncogene was found to
be frequently amplified and in cervical cancer and a novel tumour suppressor gene on 5p
at D5S406 has also been identified which could act as a genetic marker for the
identification of high risk dysplasias. Over years ICPO developed the required
infrastructures to carry out in depth studies for cervical cancer such as accredited
cytology laboratory for teaching, training and diagnostic purposes, centralised colposcope
facilities, day care clinic for management of precancerous lesions and molecular
oncology and genetic infrastructure. The Institute has initiated a multi disciplinary study
on breast cancer with the main emphasis for studying risk factors involved in breast
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carcinogenesis and a pilot study for identifying susceptible genes in the families of breast
cancer cases.

Cumulative Rates of Progression to Severe Dysplasia/ CIS
Mild Moderate Mild+Moderate Period
of
Follow
Up
No. of
Women
at Risk
Cumulative
Progression
Rate
No. of
Women
at Risk
Cumulative
Progression
Rate
No. of
Women at
Risk
Cumulative
Progression
Rate
6
51 0.03 29 0.09 80 0.08
12
44 0.06 24 0.22 68 0.12
18
40 0.08 20 0.22 60 0.13
24
36 0.08 15 0.26 51 0.14
30
30 0.10 13 0.26 43 0.16
36
24 0.14 11 0.26 35 0.18
42
21 0.14 8 0.32 29 0.21
48
15 0.14 8 0.32 23 0.21
54
13 0.14 5 0.32 18 0.21




A novel tumour suppressor gene site at D55406 at 5p15
Has been identified by ICPO and may be specific to cervical
cancer. This genetic alteration is independent of HPV infection.

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More than 80% cervical cancer tissues have
been observed to be associated with HPV.
HPV DNA 16 has been found to be most
common, in integrated or in episomal form.



Oncogene Her-2/neu amplification is commonly observed in cervical cancer.

10


A simple instrument, Magnavisualizer,
costing about Rs. 1,000 has been developed
at ICPO. The instrument is expected to be
helpful in visual examination of cervix.



Operational Research Projects for Control of Cervical Cancer

The twin center project (in Gujarat and Karnataka) aimed at assessing the efficacy
of clinical downstaging with selective cytology for control of cervical cancer. The project
was carried out in three PHC areas, with intervention in one PHC area being provided at
the subcentre level; while in the second PHC area, the strategy of imparting health
education to the women, and advising the eligible women to attend the PHC for a clinical
examination was adopted. The project is proposed to be carried out at a district level.
After an 18 months intervention, the proportion of women covered for health education at
Karnataka was 8.3% in the area with clinical examination in the field, and 22.0% in the
area with only health education in the field. The coverage for health education at Gujarat
was near total. The coverage for clinical examination of cervix was more in Gujarat, if
the examination was carried out in the field (28.3% vs 0.8%). The coverage for clinical
examination in Karnataka was 8.3% when the examination was done in the field, and 9.3%
in the PHC approach. The compliance of referral to cancer institute was poor, the major
reasons being, monetary difficulties, feeling of no obvious problem, and domestic
responsibilities. A total of 147 dysplasia cases were detected out of total of 2,044 women
screened in the area with clinical examination in the field, in Gujarat.

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0
1
2
3
4
5
6
7
8
9
Knowledge of Cancer (Max 2)
Treatment (Max 2)
Early detection & Pap Test (Max
Treatment (Max 2)
Visual Inspection (Max 6)
Pre- & Post-training Knowledge Score of Paramedical Workers,
Kheda Centre
Pre-training Post-training


Adequacy of Pap Smears at Karnataka Centre
97%
3%
Adequte Smears Inadequate Smears


The feasibility of involving health infrastructure for early detection of cervical
cancer, through scheme on Reorientation of Medical Education, was studied during late
80s and early 90s in Delhi. The project adopted the strategy of screening of community
with Pap smear collected by ANMs. Medical interns, medical officers of the PHC and
angawadi workers were also involved. Coverage in the age group above 35, during the
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effective intervention period of 38 months was 36.8%. Smears could not be collected in
11.9% of women covered under the project. Pap smears were adequate in 85.5% cases.
The study registered 19 cervical dysplasia cases and no case of malignancy was
encountered. Comparison of results from surveys on knowledge, attitude and practices
before and after intervention revealed 40% increase in knowledge about cervical cancer.


Viruses and Cervical Cancer

A study was carried out in early 1990s in Delhi, to determine the humoral and
cellular immune response against human papillomavirus (HPV) 16, in patients with
benign and malignant lesions of the uterine cervix and to correlate the response with the
clinical status of the patients. HPV 16 E7 and L1 proteins as well as synthetic peptides of
two B cell epitopes of HPV 16 E7 gene product was used for this purpose. However, No
correlation could be established between the severity of the disease and T cell responses.
The study suggested that peptides PI and PII are the two major immuno-dominant B cell
epitopes of the HPV16E7 and PII is more immuno-dominant compared to PI.


Environmental Carcinogen Testing Units

Environmental Carcinogen Testing Units (ECTU) are working towards
understanding the carcinogenic potential of various suspected carcinogens under Indian
conditions, and on monitoring of known carcinogens. The National Institute of
Occupational Health, Ahmedabad, is working on chemicals in work environment, while
The Food & Drug Toxicology Research Centre, National Institute of Nutrition (NIN) is
studying food items. The studies carried out by the National Institute of Occupational
Health, Ahmedabad, include, carcinogenicity of DDT and HCH, studies on workers
exposed to benzidine dyes, carcinogenic potential of HCH in animals exposed to
aflatoxin, presence of green symptoms in agriculture tobacco workers, role of black tea
extract on carcinogenesis in animals, development of microbial systems for assessing the
genotoxicity, genotoxic potential of air samples from high air pollution areas, and
chemical analysis of pan masala. It is proposed to conduct further experimental and
epidemiological work on pan masala, synthetic pyrithroids (like phenoxy herbicides used
extensively in Gujarat), and benzene exposure to high risk group (in view of decision to
ban leaded petrol in some cities).

The work so far carried out at ECTU at NIN, Hyderabad includes, studies on pan
masala, nitrosamines in foods, experimental iron deficiency and gastrointestinal tract
tumours, screening for protective factors in foods and biomarkers of genotoxicity,
determination of levels of nitrosamines in certain food groups and measure the quantity
of volatile nitrosamines formed from foods under stimulated gastric conditions. Future
proposed work includes assessment of mutagenicity of body fluids of habitual chewers of
pan masala, study of micronucleated cells and DNA adducts in peripheral blood
lymphocytes of patients suffering from precancers and cancers due to pan masala habit,
measurement of lysyl oxidase activity in buccal mucosa of OSF patients, and assessment
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of role of copper in etiopathogenesis of OSF. Suggestions from members of the expert
were invited to identify gaps in knowledge regarding mutagenicity/ carcinogenicity of
various substances, which were discussed by the expert group in April 1999. The group
recommended preparation of standard guidelines on methodology for certain laboratory
techniques, review of literature for role of biomass fuel, plastic material used for food
packaging, plain pan masala and edible oils and condiments, in mutagenicity/
carcinogenicity.


Support for Cancer Control

At the request of the Government of National Capital Territory of Delhi, the
ICMR helped them in development of a strategy for cancer control in Delhi. This
collaboration helped in identifying the requirements for training of the medical officers in
cancer control activities. Two day training programme was organized by ICMR and All
India Institute of Medical sciences.

An operational research project on control of cancer through multidisciplinary
approach is proposed for introduction of elements of control of common cancers of the
country through the existing health infrastructure. The project could not be initiated due
to lack of resources. The protocol for the project was discussed by an expert committee,
which recommended initiation of the project in a district of Delhi. The project is expected
to commence shortly.


Modern Biology and Cancer

Many cellular changes have been reported to be associated with malignant
process. Such studies may provide an important lead not only in aetiology of cancers, but
also for early diagnosis of the disease and prognosis with respect to treatment modalities.
It is important to comprehensively study the biological processes at cellular levels, before
a logical conclusion on such association can be made. It is proposed to initiate a study on
common cancers of India by combining epidemiological and molecular tools. The aim of
the study would be to correlate epidemiological risk factors with molecular, cellular and
biochemical changes identified through sensitive modern biological tools, and presence
of infectious agents through hybridization techniques, in order to find their role in
aetiology and progression of the disease.



Anti-tobacco Community Education

A multicentre project to study the feasibility of involving existing infrastructures
in anti-tobacco community education, was carried out at Bangalore, Trivandrum (both
through health care services), Goa (through schools), and Agra (through community
volunteers. The primary health workers also examined the oral cavity to identify and
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classify lesions. Pre-tested health education material was prepared by the project staff and
used by the existing infrastructure personnel. Pre-intervention and post-intervention
surveys on knowledge, attitude and practice of tobacco use, measured the effect of
intervention. The overall reduction in the prevalence of tobacco usage in Goa was 11.8%
among men and 9.1% among women in intervention zone 1; 13.4% among men and
13.3% among women in intervention zone 2; and 2.0% for men and 10.2% for women in
control zone. The proportional reduction in the rate of tobacco habit was 33.5% in men
and 45.5% in women of intervention zone 1; 32.6% in men and 50.4% in women of
intervention zone 2; and 8.5% in men and 33.3% in women of control zone. Based on the
experience of this project, Ministry of Education, state of Goa, included an 8 hour course
on tobacco as a part of co-curricular activities for standard five and above.

The intervention through community volunteers at Agra centre showed that
26.3% males and 10.5% females left tobacco and another 10.1% males and 4.3% females
as likely quitters (6 months have not passed after leaving tobacco), after an intervention
of about one year. The project at Trivandrum centre could not achieve optimum
participation of health care workers. The nine workers who worked on the project,
referred 408 patients out of which 258 reported, giving a compliance of 63.2%. About
59% of these were found to have cancers (10) or pre-cancers. Of the 10 cancer cases five
were in stage I & II. 29 old cases were also examined, out of which four recurrences
were detected. Intervention at Bangalore centre achieved a reduction of tobacco habit in
experimental area, amounting to 5.7% in the males and 6.9% in the females. The control
area I showed an increase of 3.8% among male and 7.8% among female, while in control
area II, among men there was a 2.9% increase in habit and 4.6% decrease among females.

33.5
32.6
8.5
45.5
50.4
33.3
0
10
20
30
40
50
60
% Reduction
Male Female
Proportionate Reduction in Tobacco Use in Goa
Intervention Zone 1 Intervention Zone 2 Control Zone