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.

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.

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.

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.

Cancer registration in Madras Metropolitan Tumour Registry, India.

The Madras Metropolitan Tumour Registry (MMTR) was established at the Cancer Institute (WIA), Madras, in 1981-1982. Cancer is not a notifiable disease in India, and hence registration per force has to be active. The MMTR covers a population of 3.8 million. Mortality statistics are obtained from the Department of Vital Statistics, death registers in hospitals and by active follow-up of registered cases. A total of 28,980 (13,012 males, 15,968 females) cases were registered during 1982-1991. The average annual world-standardised age-adjusted rates (AAR) per 100,000 are 104.2 in males and 129.0 in females. The lifetime cumulative risk (0-74 years) of cancer in Madras is one in eight. Stomach (AAR:15.2) is the leading site of malignancy among males, followed by cancers of the lung (AAR:9.8) and oral cavity (AAR:9.4). Among females, cancer of the cervix (AAR:44.0) is the commonest, followed by breast (AAR:21.7) and oral cavity cancers (AAR:9.8).

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.

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.

Immunophenotyping of acute lymphoblastic leukaemia in Madras, India.

At the Cancer Institute, Madras, India, we have performed immunophenotyping in 125 untreated cases of acute lymphoblastic leukaemia using a panel of 16 monoclonal antibodies and the avidin-biotin immunoperoxidase technique in a haematology autoanalyser (Technicon Hi system). Our results demonstrate a marked difference in the phenotypic pattern of ALL compared to Western countries, the predominant finding being a relative excess of T-ALL and a paucity of C-ALL cases. Age distribution of C-ALL reveals a peak at 2-6 years in paediatric ALL cases.

Immunophenotypic analysis of T-cell acute lymphoblastic leukaemia in Madras, India.

Immunophenotypic analysis of 285 newly diagnosed previously untreated, unselected, acute lymphoblastic leukaemia cases carried out at the Cancer Institute (W.I.A) in Madras reveals that 126 (44.2%) cases showed T-immunophenotype. The study was conducted using flow-cytometric immunofluorescent or immunoperoxidase methods using an extensive panel of monoclonal antibodies comprising CD1, 2, 3, 4, 5, 7, 8, 57, 19, 20 kappa, lambda, IgG, M, D, CIg, CD10, HLA-DR, CD13, 14, 33, 34 and CD61. The study group comprised 73 (57.9%) paediatric cases (<15 years) and 53 (42.1%) adult cases (>15 years). Based on their reactivity with various anti-T-cell monoclonal antibodies, all T-ALL cases were assigned to one of the intrathymic differentiation compartments. 56.2% of paediatric T-ALLs arise from intrathymic compartment II, 34.2% from compartment III and 9.6% from compartment I. Among adults, 45.3% arise from compartment I. 33.9% from compartment III and 20.8% from compartment II. The most frequently observed CD antigens in our study group are CD7, 5, 2 and 3. A correlative study of socioeconomic status reveals that 67.5% of T-ALL cases occurred among lower socioeconomic strata.

Lifestyle and risk of stomach cancer: a hospital-based case-control study.

BACKGROUND: Stomach cancer (SC) is the most frequent cancer among males and third most common cancer among females in Madras, India. The incidence rate of SC is higher in Southern India compared to Northern India. METHODS: A hospital-based case-control study on 388 incident cases of SC was carried out in Madras as part of a multicentre study in India to identify the risk factors for SC. Cases were matched to cancer controls based on age (+/- 5 years), sex, religion and mother tongue. Categorical variables for income group, level of education and area of residence were included in all models to control for confounding. RESULTS: Smokers had a twofold risk of SC (95% confidence interval [CI] = 1.25-3.78) compared to non smokers and the risk seen among current smokers (odds ratio [OR] = 2.5; 95% CI: 1.36-4.44) was significantly different from that seen among exsmokers (OR = 1.5; 95% CI: 0.67-3.54). The risk among those who smoke bidi (OR = 3.2; 95% CI: 1.80-5.67) was higher than that seen among cigarette (OR = 2.0; 95% CI: 1.07-3.58) and chutta (OR = 2.4; 95% CI: 1.18-4.93) smokers. Significant dose response relationships were observed with age began smoking bidi (P < 0.001) and with lifetime exposure to bidi (P < 0.001), cigarette (P < 0.01) and chutta (P < 0.05) smoking. The habits of drinking alcohol and chewing did not emerge as risk factors. An interaction effect was not seen between the lifestyle habits. Attributable risk (AR) for smoking among exsmokers was 33% and current smokers 60%. Population AR for smoking was 31%. CONCLUSION: Smoking tobacco is an independent risk factor for SC.

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.

Tobacco-related cancers in Madras, India.

Tobacco is the single most important cause of avoidable morbidity and early mortality in many countries. Tobacco-related cancer (TRC) cases constitute 48.2% in men and 20.1% in women of the total cancers seen in India per year. The age-adjusted rate (AAR) of TRC ranges from 44 to 67 among males and from 23 to 27 among females in different registries in India. Of these cases, only 15% were in the lung. The religion-specific risk ratio of the TRC sites in Madras suggests that when Muslims were compared with Hindus pharynx and lung were the two sites that showed higher risk in males, while the pharynx, lung and oesophagus had higher risk in females. When Christians were compared with Hindus, lung cancer was found to have higher risk and cancer of the oesophagus lower risk in males, while cancer of the mouth had lower risk in females. The overall percentage increase in AAR of TRCs in males was 39.7 and in females was 20.1 for the period 1987-91, compared with 1982-86, with variation in the percentage increase in all the TRC sites in Madras. The change in the incident rate of TRCs seen in Madras is consistent with the change in the per capita consumption of tobacco over the years.

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.

Preoperative multimodal therapy for locally advanced non-inflammatory breast cancer.

The present study is a comparison of two sequential groups of advanced locoregional (T3, T4) non-inflammatory breast cancers. The first group was of 164 cases treated between 1965 and 1975 who received radiotherapy followed by surgery (Group I). The second group was of 211 cases treated between 1976 and 1984, who received radiotherapy combined with multidrug chemotherapy followed by surgery (Group II). The 5 and 10 year disease-free survival in the two groups are 47.5% vs 60.6% (P less than 0.005) and at 10 years 35.9% vs 44.1% respectively (P less than 0.005). Tumour sterility in the resected breast was more than doubled in the chemotherapy group (18.9% vs 42.1%). The impact of the addition of chemotherapy on survival was seen only in the node-positive group, the 5-year disease-free survival in node-positive cases being 44.7% compared to 28.2% when chemotherapy was not used (P less than 0.007). Remote metastases at 5 years in node positive cases also showed a significantly lower rate in the CT + RT arm against the RT-only arm (36.4% vs 54.3%) (P less than 0.005). The results clearly demonstrate the advantage of a multimodality approach in the management of Stage III breast cancers.

Radiation, pepleomycin and hyperthermia in the therapy of locally advanced squamous cell carcinomas of the buccal mucosa.

Oral squamous cell carcinoma is the commonest male (29%) and the second commonest female (18%) malignancy in South India. At first attendance 93% of the tumours are stage T3 or T4. They are essentially locoregional, remote metastases being rare (0.75%). Radiotherapy alone yields a poor survival (19% 5 year NED). Radiopotentiation by chemical sensitizers and cytotoxic drugs has been attempted since 1960, the best results being obtained by a combination of irradiation and bleomycin. There was, however, persistent failure in about 40% of cases. The present three-armed trial attempted to improve the results of radiotherapy and bleomycin by the addition of hyperthermia. A total of 101 T3 and T4 buccal squamous cancers were entered in the trial over a period of nearly three years. Entry closed in August 1987 and the last case was evaluated in October 1987, hence only response data are available. Hyperthermia did not confer any benefit.

Antibiotics in febrile neutropenia: a randomized prospective comparison of two combinations.

BACKGROUND: Problems of initial empirical antibiotic therapy in febrile neutropenia are further complicated by other factors such as cost and the pattern of infective organisms in a particular institution. We, therefore, conducted a randomized study comparing the efficacy of two sets of antibiotics which differed in their spectrum of action, availability and price. METHODS: Sixty episodes of febrile neutropenia in 40 patients who were not on any prophylactic antibiotics were randomized into one of two arms--cefotaxime and gentamicin or ciprofloxacin and gentamicin. Depending upon the response by 72 hours, they were crossed over to the other arm or continued with the same combination. Empirical antifungal therapy was added in those who did not become afebrile. RESULTS: Infection was documented either clinically, bacteriologically or radiologically in 42% of the febrile episodes. The commonest organism isolated was Klebsiella and the commonest organism producing bacteraemia was the Staphylococcus. The temperature was reduced to normal without cross-over in 53% of the febrile episodes with cefotaxime and gentamicin and in 60% with ciprofloxacin and gentamicin (p > 0.05). After cross-over the temperature came down in 30% of the episodes with cefotaxime and gentamicin (initial combination) and 40% with ciprofloxacin and gentamicin (initial combination; p > 0.05). The overall response rate without empirical antifungal therapy was 83% in the patients on cefotaxime and gentamicin (initial combination; p > 0.05). While both the arms of the study had a 100% response rate, there was no significant difference between the efficacy of the antibiotic combinations. The ciprofloxacin-gentamicin combination is one-third as expensive as cefotaxime-gentamicin and is more readily available. CONCLUSION: We recommend the use of ciprofloxacin and gentamicin as the initial drug combination and cefotaxime and gentamicin only when the former is not effective.

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.

Methodology for long term follow-up of cancer cases in a developing environment.

The utility of data collected on patients will be rendered insignificant without adequate follow-up information. Efficient methods should be used to follow cases in order to get vital status information in Hospital(HBCR) and Population Based Cancer Registries (PBCR). Based on our experience we have evolved methods to follow cancer cases and this has been discussed in this paper. Active follow up of cases has enhanced follow-up rate from 50% to more than 85% at HBCR and "death in period" from 19% to 41% during the period 1982 to 1991 in PBCR. Active follow-up is mandatory for the cases registered at HBCR. In addition to collecting data from VSD on cancer deaths, active follow-up is desirable to get maximum death information on cases registered at PBCR in a developing environment. Computerization of follow-up data is necessary in order to further improve the efficiency of the follow-up system.