The growing burden of cancer in India: epidemiology and social context.

Cancer can have profound social and economic consequences for people in India, often leading to family impoverishment and societal inequity. Reported age-adjusted incidence rates for cancer are still quite low in the demographically young country. Slightly more than 1 million new cases of cancer are diagnosed every year in a population of 1.2 billion. In age-adjusted terms this represents a combined male and female incidence of about a quarter of that recorded in western Europe. However, an estimated 600,000-700,000 deaths in India were caused by cancer in 2012. In age-standardised terms this figure is close to the mortality burden seen in high-income countries. Such figures are partly indicative of low rates of early-stage detection and poor treatment outcomes. Many cancer cases in India are associated with tobacco use, infections, and other avoidable causes. Social factors, especially inequalities, are major determinants of India's cancer burden, with poorer people more likely to die from cancer before the age of 70 years than those who are more affluent. In this first of three papers, we examine the complex epidemiology of cancer, the future burden, and the dominant sociopolitical themes relating to cancer in India.

Cancer research in India: national priorities, global results.

Over the past 20 years, cancer research in India has grown in size and impact. Clinicians, scientists, and government and state policy makers in India have championed cancer research, from studies to achieve low-tech, large-scale health outcomes to some of the most advanced areas of fundamental cancer science. In this paper, we frame public policy discussions about cancer with use of an in-depth analysis of research publications from India. Cancer research in India is a complex environment that needs to balance public policy across many competing agendas. We identify major needs across these environments such as those for increased research capacity and training and protected time for clinical researchers; for more support from states and enhanced collaborative funding programmes from government; for development of national infrastructures across a range of domains (ie, clinical trials, tissue banking, registries, etc); and for a streamlined and rational regulatory environment. We also discuss improvements that should be made to translate research into improvements in cancer outcomes and public health.

Delivery of affordable and equitable cancer care in India.

The delivery of affordable and equitable cancer care is one of India's greatest public health challenges. Public expenditure on cancer in India remains below US$10 per person (compared with more than US$100 per person in high-income countries), and overall public expenditure on health care is still only slightly above 1% of gross domestic product. Out-of-pocket payments, which account for more than three-quarters of cancer expenditures in India, are one of the greatest threats to patients and families, and a cancer diagnosis is increasingly responsible for catastrophic expenditures that negatively affect not only the patient but also the welfare and education of several generations of their family. We explore the complex nature of cancer care systems across India, from state to government levels, and address the crucial issues of infrastructure, manpower shortages, and the pressing need to develop cross-state solutions to prevention and early detection of cancer, in addition to governance of the largely unregulated private sector and the cost of new technologies and drugs. We discuss the role of public insurance schemes, the need to develop new political mandates and authority to set priorities, the necessity to greatly improve the quality of care, and the drive to understand and deliver cost-effective cancer care programmes.

Trends in cancer incidence in Chennai city (1982-2006) and statewide predictions of future burden in Tamil Nadu (2007-16).

BACKGROUND: This paper investigates cancer trends in Chennai and predicts the future cancer burden in Chennai and Tamil Nadu state, India, using data on 89 357 incident cancers from the Chennai registry during 1982-2006, published incidence rates from the Dindigul Ambilikkai Cancer Registry during 2003-06 and population statistics during 1982-2016. METHODS: Age-specific incidence rates were modelled as a function of age, period and birth cohort using the NORDPRED software to predict future cancer incidence rates and numbers of cancer cases for the period 2007-11 and 2012-16 in Chennai. Predictions for Tamil Nadu state were computed using a weighted average of the predicted incidence rates of the Chennai registry and current rates in Dindigul district. RESULTS; In Chennai, the total cancer burden is predicted to increase by 32% by 2012-16 compared with 2002-06, with 19% due to changes in cancer risk and a further 13% due to the impact of demographic changes. The incidence of cervical cancer is projected to drop by 46% in 2015 compared with current levels, while a 100% increase in future thyroid cancer incidence is predicted. Among men, a 21% decline in the incidence of oesophageal cancer by 2016 contrasts with the 42% predicted increase in prostate cancer. The annual cancer burden predicted for 2012-16 is 6100 for Chennai, translating to 55 000 new cases per year statewide (in Tamil Nadu). Breast cancer would dislodge cervical cancer as the top-ranking cancer in the state, while lung, stomach and large bowel cancers would surpass cervical cancer in ranking in Chennai by 2016. CONCLUSION: In order to tackle the predicted increases in cancer burden in Tamil Nadu, concerted efforts are required to assess and plan the infrastructure for cancer control and care, and ensure sufficient allocation of resources.

Cancer survival in Chennai (Madras), India, 1990-1999.

The Madras metropolitan tumour registry was established in 1981, and registration of incident cancer cases is entirely done by active method. Data on survival for 20 cancer sites or types registered during 1990-1999 are reported. Follow-up has been carried out predominantly by active methods with a median follow-up time ranging between 2-28 months for different cancers. The proportion of histologically verified diagnosis for various cancers ranged between 45-100%; death certificates only (DCOs) comprised 0-5%; 68-95% of total registered cases were included for survival analysis. Complete follow-up at five years ranged between 83-96%. The 5-year age-standardized relative survival rates for common cancers were cervix (60%), breast (47%), stomach (8%), oesophagus (9%), lung (6%) and mouth (36%). The 5-year relative survival by age group portrayed either an inverse relationship or fluctuated. A majority of cases were diagnosed with regional spread of disease, and survival decreased with increasing extent of disease. The absolute difference in 5-year relative survival of most cancers diagnosed in 1984-1989 and1990-1999 ranged between 2-3%, with lesser survival in the latest period in most instances.

Evolution in the management of locally advanced cervical cancer: the experience of Cancer Institute (WIA), Chennai, India.

OBJECTIVE: To conduct a retrospective analysis of disease free survival (DFS) of locally advanced cervical cancer (LACC) in relation to evolution of treatment and related factors. METHODS: A total of 3,892 cases of LACC treated at the Cancer Institute (WIA), Chennai, India, during 1990-1999 were analyzed. Management of LACC including concurrent chemo-radiation (CCRT) has evolved through trials conducted at the institute. DFS and risk of second cancer were elicited using actuarial and Kaplan-Meier methods, respectively. RESULTS: A majority belonged to stage III (54%) and complete follow-up at 5-years was 90%. DFS at 5, 10 and 15-years were 58%, 49% and 42% for stage IIB and 43%, 35% and 31% for stage III, respectively. External beam radiotherapy (EBRT) alone as treatment modality reported the poorest 5-year DFS (37%). Addition of chemotherapy to EBRT resulted in marginal increase in survival (41%) but inclusion of brachytherapy to EBRT enhanced survival (58%) significantly (p<0.001). CCRT with brachytherapy as a planned component resulted in the best DFS (69%), irrespective of disease stage. In a carefully selected group of patients who were suitable for salvage surgery, the long-term DFS was 71%, 63% and 63% at 5, 10 and 15 years, respectively, for stages IIB and III together. Complete response was achieved in 67% and 15% of them recurred. Remote metastasis occurred in 13%. The cumulative risk of developing any second cancer was 0.5% at 5 years, 1.9% at 10 years and 2.8% at 15 years of follow up. CONCLUSION: Our data indicates satisfactory treatment outcome even in advanced disease and with the present state of knowledge, the recommended standard treatment for LACC is careful pre-treatment evaluation followed by CCRT which includes brachytherapy.

Adrenocortical carcinomas: a 12-year clinicopathologic study of 15 cases.

Adrenal cortical carcinomas are rare neoplasms and the definitive diagnostic criteria are distant metastasis and / or local invasion. Due to advances in imaging techniques, adrenal cortical neoplasms are discovered earlier and are smaller, increasing the need for more accurate diagnosis and pathologic indicators of prognosis. A twelve year retrospective clinicopathologic analysis of 15 histopathologically proven cases of adrenocortical carcinomas was done. Clinical details including radiologic findings, endocrine manifestations and gross finding were analysed. Hematoxylin and eosin stained slides were reviewed. Emphasis was on application of Weiss criteria. All fifteen tumors fulfilled Weiss criteria of malignancy, ie. all 15 possessed 3 or more of these criteria of malignancy. Functional tumors showed a greater representation of mixed cell type. It was concluded that Weiss criteria is easy to apply and that a combined evaluation of clinical features, size, weight and microscopic appearance seems necessary for the diagnosis of adrenocortical carcinomas.

Treatment of acute lymphoblastic leukaemia in countries with limited resources; lessons from use of a single protocol in India over a twenty year period [corrected].

In the 1970s, survival rates after treatment for acute lymphoblastic leukaemia (ALL) in children and young adults (less than 25 years) in India were poor, even in specialised cancer centres. The introduction of a standard treatment protocol (MCP841) and improvements in supportive care in three major cancer centres in India led to an increase in the event-free survival rate (EFS) from less than 20% to 45-60% at 4 years. Results of treatment with protocol MCP841 between 1984 and 1990 have been published and are briefly reviewed here. In addition, previously unpublished data from 1048 patients treated between 1990 and 1997 are reported. Significant differences in both patient populations and treatment outcome were noted among the centres. In one centre, a sufficiently large number of patients were treated each year to perform an analysis of patient characteristics and outcome over time. Although steady improvement in outcome was observed, differences in the patient populations in the time periods examined were also noted. Remarkably, prognostic factors common to all three centres could not be defined. Total white blood cell count (WBC) was the only statistically significant risk factor identified in multivariate analyses in two of the centres. Age is strongly associated with outcome in Western series, but was not a risk factor for EFS in any of the centres. Comparison of patient characteristics with published series from Western nations indicated that patients from all three Indian centres had more extensive disease at presentation, as measured by WBC, lymphadenopathy and organomegaly. The proportions of ALLs with precursor T-cell immunophenotypes, particularly in Chennai, were also increased, even when differences in the age distribution were taken into consideration (in <18-year olds, the range was 21.1-42.7%), and in molecular analyses performed on leukaemic cells from over 250 patients less than 21-years-old with precursor B-cell ALL, a lower frequency of TEL-AML1-positive ALL cases than reported in Western series was observed. The worse outcome of treatment in Indian patients compared with recent Western series was probably due to the higher rate of toxic deaths in the Indian patients, and possibly also due to their more extensive disease - which is, at least partly, a consequence of delay in diagnosis. Differences in the spectrum of molecular subtypes may also have played a role. The higher toxic death rates observed are likely to have arisen from a combination of more extensive disease at diagnosis, co-morbidities (e.g., intercurrent infections), differences in the level of hygiene achievable in the average home, poor access to acute care, and more limited supportive care facilities in Indian hospitals. Toxic death was not associated with WBC at presentation, and hence would tend to obscure the importance of this, and, potentially, other risk factors, as prognostic indicators. Since the prevalence of individual risk factors varies in different populations and over time, their relative importance would also be expected to vary in different centres and in different time periods. This was, in fact, observed. These findings have important implications for the treatment of ALL in countries of low socioeconomic status; it cannot be assumed that risk factors defined in Western populations are equally appropriate for patient assignment to risk-adapted therapy groups in less affluent countries. They also demonstrate that heterogeneity in patient populations and resources can result in significant differences in outcome, even when the same treatment protocol is used. This is often overlooked when comparing published patient series.

PCR-heteroduplex analysis of TCR gamma, delta and TAL-1 deletions in T-acute lymphoblastic leukemias: implications in the detection of minimal residual disease.

Detection of MRD remains one of the major goals in the treatment of acute lymphoblastic leukemia (ALL). We have used the polymerase chain reaction (PCR)-heteroduplex (HD) analysis to assess and confirm the clonal expansion of T cell receptor (TCR) gamma and delta gene rearrangements in 24 T-ALL patients at diagnosis. 52.4% revealed Vdelta1-Jdelta1; 48% Vdelta2-Ddelta3; 62.5% Vgamma1-Jgamma1 and 46% both Vdelta1-Jdelta1 and Vgamma1-Jgamma1 clonal rearrangements. 6/24 patients had TAL-1 deletion. These clonal markers were used to monitor MRD in remission/relapse bone marrow samples for periods ranging from 6 to 75 months after diagnosis. Patients who relapsed and died revealed a continuous PCR-HD positivity in their clinical remission bone marrow samples. HD analysis established identical diagnostic clone at relapse. Patients who are in long-term clinical and morphological remission achieved PCR-HD negativity in their 8-12 months bone marrow remission samples and continue to be PCR-HD negative. MRD monitored in six patients with two diagnostic PCR--HD positive clonal markers reveal an identical pattern ensuring circumvention of false positive and negative results. Thus, we conclude that PCR followed by HD analysis is a useful technique to monitor MRD in remission/relapse samples in ALL patients.

Neuregulin 1-alpha expression in locally advanced breast cancer.

The human Neuregulin 1 (NRG1) gene encodes several alternatively spliced ligands that bind to both c-erbB-3 and c-erbB-4, members of the family of type 1 tyrosine kinase growth factor receptors. Antibodies raised to a synthetic peptide recognize selectively the alpha variant of NRG1. The NRG1-alpha isoforms' expression was studied in 115 locally advanced adenocarcinomas of the breast using immunohistochemistry. Absent or low levels of NRG1-alpha were found to be associated with poorer prognosis compared to tumours that had moderate to high levels of the protein.

Epidemiology of cancer of the cervix: global and national perspective.

Cancer of the uterine cervix is one of the leading causes of cancer death among women worldwide. The estimated new cancer cervix cases per year is 500,000 of which 79% occur in the developing countries. Cancer cervix occupies either the top rank or second among cancers in women in the developing countries, whereas in the affluent countries cancer cervix does not even find a place in the top 5 leading cancers in women. The truncated rate (TR) in the age group 35-64 years in Chennai, India, is even higher (99.1/100,000; 1982-95) than rate reported from Cali, Colombia (77.4/100,000, 1987-91). The cervical cancer burden in India alone is estimated as 100,000 in 2001 AD. The differential pattern of cervical cancer and the wide variation in incidence are possibly related to environmental differences. Aetiologic association and possible risk factors for cervical carcinoma have been extensively studied. The factors are: Sexual and reproductive factors, socio-economic factors (education and income), viruses e.g., herpes simplex virus (HSV), human papillomavirus (HPV), human immunodeficiency virus (HIV) in cervical carcinogenesis and other factors like smoking, diet, oral contraceptives, hormones, etc. The accumulated evidence suggests that cervical cancer is preventable and is highly suitable for primary prevention. Sexual hygiene, use of barrier contraceptives and ritual circumcision can undoubtedly reduce cervical cancer incidence. Education, cervical cancer screening of high risk groups and improvement in socio-economic status can reduce cervical cancer morbidity and mortality significantly.

PIP: Cancer of the uterine cervix is one of the leading causes of cancer death among women worldwide. The estimated number of new cervical cancer cases per year is 500,000, of which 79% occur in developing countries. Cervical cancer is ranked highest or second-highest among cancers in women in developing countries, whereas in affluent countries cervical cancer does not even rate within the top 5 leading cancers in women. The truncated rate in the age group 35-64 years in Chennai, India, is even higher (99.1/100,000; 1982-95) than the rate reported from Cali, Colombia (77.4/100,000; 1987-91). The cervical cancer burden in India alone is estimated to reach 100,000 by 2001. The differential patterns of cervical cancer and the wide variation in incidence are possibly related to environmental differences. Etiologic associations and possible risk factors for cervical carcinoma have been extensively studied. The factors are: sexual and reproductive factors; socioeconomic factors (education and income); viruses (e.g., herpes simplex virus, human papillomavirus, HIV); and other factors such as smoking, diet, oral contraceptives, hormones, etc. The accumulated evidence suggests that cervical cancer is preventable and is highly suitable for primary prevention. Sexual hygiene, use of barrier contraceptives, and ritual circumcision can undoubtedly reduce cervical cancer incidence. Education, cervical cancer screening of high-risk groups, and improvement in socioeconomic status can reduce cervical cancer morbidity and mortality significantly.

A survival study of cervical cancer in Chennai, India.

A total of 4304 cervical cancer cases registered during 1982-89 in Chennai registry, India, were analyzed. Relative survival at 1, 3 and 5 years were 90%, 72% and 60% respectively. Age at diagnosis and extent of disease emerged as statistically significant prognostic factors (p<0.001). Five-fold higher risk of death was seen among those above 64 years vs. <45 years and those with distant metastasis vs. localized disease at diagnosis. Cancer control programs focusing on health education would motivate women to attend hospital at an early stage of disease for better survival.

A study on serum carotenoid levels in breast cancer patients of Indian women in Chennai (Madras), India.

Two-hundred and six breast cancer cases were histologically confirmed breast cancer diagnoses at the Cancer Institute in Chennai (Madras), India. One-hundred and fifty hospital controls were patients who had cancer at any site other than breast and gynecological organs, and 61 healthy controls were persons accompanying patients in the Cancer Institute. Serum levels of carotenoids such as beta-carotene, lycopene, cryptoxanthin, and zeaxanthin & lutein were determined by HPLC. Serum levels of total carotenes and total carotenoids including beta-carotene, which reflects food intake of colored vegetables and fruits and has a protective role for certain sites of cancer, were significantly lower among breast cancer cases and hospital controls compared to healthy controls, especially in post-menopausal women. Serum carotenoid levels appeared to change with menopausal status. Serum beta-carotene levels tended to be lower among breast cancer cases than among hospital controls in premenopausal women. Serum xanthophyll levels were significantly lower among breast cancer cases than among healthy controls in post-menopausal women, but not in premenopausal women. Serum levels of retinol and alpha-tocopherol among breast cancer cases were not significantly different from those in post-menopausal healthy controls, but were higher than those in hospital controls. Serum estrone levels were significantly higher among breast cancer cases than among healthy controls, but serum levels of estradiol and estriol were not. In conclusion, Indian women with cancer of breast or of other sites might have low intake of green-yellow vegetables rich in fiber and carotenoids such as beta-carotene and zeaxanthin & lutein.

Survival from contralateral breast cancer.

First primary, or unilateral, breast cancer (UBC) cases diagnosed in 1960-89 at the Cancer Institute (WIA), Chennai, India were followed-up until December 31, 1994. Patients with UBC (n = 3163) and those who developed second cancer in the contralateral breast (CBC) after the initial breast cancer (n = 67 or 2.1% of UBC) were analysed. Compared to UBC patients, those who developed CBC were younger at the time of diagnosis of initial breast cancer and had higher frequency of breast cancer among the family members. The relative survival rate takes into account competing causes of death and was estimated as the ratio of observed survival rate to the expected survival rate. The cumulative relative survival from UBC at 5 and 10 years were 51% and 41%, respectively, and the corresponding rates for CBC were 47% and 30%; the survival difference seen between UBC and CBC patients was not statistically significant. The survival rates among younger, middle-aged and older women were significantly different from each other in UBC but not in CBC patients. Both UBC and CBC with early stage disease had a better survival compared to late stage disease. Survival advantage was also seen among both UBC and CBC patients with family history of breast cancer compared to those without. The multivariate analysis by the life table proportional hazards model showed that the age at diagnosis is an independent prognostic factor for breast cancer. The study results should be interpreted in the light of small sample size of second cancers.

Risk factors for contralateral breast cancer in Chennai (Madras), India.

BACKGROUND: This is the first cohort study conducted in India to identify risk factors for contralateral breast cancer (CBC) among patients with first primary breast cancer. METHODS: Patients with first primary breast cancer diagnosed in 1960-1989 at the Cancer Institute (WIA) in Chennai, India, were followed-up until 31 December 1994. The risk of CBC was assessed among unilateral breast cancer (UBC) patients who survived for >12 months following the diagnosis of breast cancer and did not develop a second cancer (n = 2665) and among those who developed a CBC > or =12 months after the diagnosis of breast cancer (n = 39). RESULTS: The age-adjusted incidence of CBC among women with UBC was seven times the incidence (per single breast) in the general population. Among women with UBC the relative risk (RR) was 4.5 (95% CI: 1.1-19.6) comparing those with and without a history of breast cancer in the mother, and 2.8 (95% CI: 1.2-6.7) comparing age at first birth 21-25 versus earlier. The RR was 0.3 (95% CI: 0.1-0.6) comparing those with and without hormone therapy for their UBC. Radiotherapy for the UBC had no significant effect on the incidence of CBC. CONCLUSION: Positive family history of breast cancer and later age at first childbirth emerged as stronger risk factors for CBC than UBC. Hormone therapy reduces the risk of CBC.

PIP: The 3492 women with a first primary breast cancer diagnosed in 1960-89 at the Cancer Institute in Chennai, India, were enrolled in a cohort study to identify risk factors for contralateral breast cancer. The 788 women who died or developed contralateral breast cancer within 12 months of initial breast cancer diagnosis were excluded from the cohort. 17,317 women-years of observation (mean follow-up time, 7.4 years) on the remaining women were accrued by the end of 1994. The incidence of metachronous contralateral breast cancer was 2.3/1000 women-years. The age-adjusted incidence of contralateral breast cancer among women with unilateral breast cancer was 7 times the incidence per single breast in the general population (relative risk (RR), 7.4; 95% confidence interval (CI), 4.8-11.4). The risk of bilateral breast cancer was significantly increased over that for primary breast cancer among women with an affected mother (RR, 4.5; 95% CI, 1.1-19.6) and those 21-25 years of age at first childbirth compared with younger women (RR, 2.8; 95% CI, 1.2-6.7). A significant negative association between contralateral breast cancer and hormone therapy was recorded (RR, 0.3; 95% CI, 0.1-0.6). The risk factors age at menarche, number of children, age at menopause, menopausal status, and radiotherapy for the primary breast cancer did not significantly differ for second compared with first breast cancers.

Registration of cancer mortality data in a developing area: Chennai (Madras, India) experience.

OBJECTIVES: This study was carried out to evolve a method to improve the registration of cancer mortality data in Chennai (Madras, India). METHODS: Data on cancer deaths have been collected from the Vital Statistics Department (VSD) by a population-based cancer registry (PBCR) in Chennai only since 1982. The low mortality-to-incidence ratio during 1982-84 suggested under-registration of mortality data. Since 1985, the PBCR has taken special effort to ascertain the vital status of cancer cases by sending reply-paid postcards and/or making house visits. The data on all deaths occurring in Chennai, irrespective of stated cause of death in the death certificate, have been collected from the VSD since 1992. RESULTS: Deaths that occurred in Chennai and obtained by sending reply-paid postcards and/or making house visits were registered in VSD as non-cancer causes of death; hence, these data were not collected from VSD. The sensitivity and positive predictive values of death certificates on cancer diagnosis based on 1992 and 1993 mortality data were 57 percent and 99.5 percent, respectively. CONCLUSION: Since the accuracy of death certificate information on cancer diagnosis is relatively low in a developing country such as in India, collecting data on all deaths will improve the mortality data registration in PBCRs.

A study on pancreatic cancer in Chennai (Madras), India.

A total of 299 pancreatic cancer (PC) cases were registered in Chennai during 1982-1993 with an age-adjusted incidence rate (AAR) of 1.0 per 100,000. The present study shows an increasing trend in the risk of PC with an increase in the literacy level among males (P < 0.001). The relative survival rates at 1, 3 and 5 years were 35.7, 14.4 and 6.1%, respectively. Age at diagnosis, sex, religious group and literacy level did not emerge as significant prognostic factors for survival from PC. It is reiterated that emphasis should be placed on primary prevention of pancreatic cancer as opposed to early detection, by controlling the use of tobacco.