Making a case for cancer research in India

When confronted with a complex clinical scenario, I often refer to standard oncology guidelines, published by the National Comprehensive Cancer Network and the American Society of Clinical Oncology.12 These guidelines are the distillation of evidence from multiple prior studies. Invariably, these studies have been carried out in a non-Indian patient population, yet the guidelines are widely followed in India. Certainly, there are Indian guidelines, for example, the Indian Council of Medical Research (ICMR) consensus guidelines; however, they generally echo the international guidelines rather than providing specific recommendations for Indian patients.3 The lacunae in oncology research in India start from a basic deficiency of good quality epidemiological data. This is gradually changing with the establishment of the Indian National Cancer Registry Program, started in 1981 by the ICMR.4 Currently, there are 27 population-based cancer registries and some hospital-based cancer registries. As a result of the data generated by these registries, we now know that the cancer incidence in the northeastern states of India is not low as was initially perceived but is actually higher (age-adjusted incidence rate AAIR of 100–250 cases per 100,000 population) than the national average (AAIR of 80–100 cases per 100,000 population), giving the North East the dubious title of the 'national cancer capital of India.'5 The limitations of the cancer registries include the fact that they do not cover the entire population and often do not include treatment and outcome data, as is done in the Surveillance, Epidemiology and End Results Program database maintained by the National Cancer Institute of America.6 Other gaps include a lack of adequate diagnostic and therapeutic information ranging from machinery, surgical and radiation technologies, and medicines, both chemotherapeutics and biologics. Our standard oncologic practice has been adopted without being adequately tested in the Indian research setting. Compare this to the gefitinib approval story in the USA: the Food and Drug Administration granted accelerated approval to gefitinib based on the response rate in the Phase II IDEAL trials;78 however, when the mandated Phase III ISEL trial failed to show a survival benefit,9 they withdrew the approval for new patients, even though gefitinib continued to be approved and marketed in Europe and Asia. Sometimes, clear ethnic differences exist between oncology patients from different countries. Over 50% of our lung cancer patients are non-smokers, which is in stark contrast to reports from other countries.10 The rate of epidermal growth factor receptor mutation in non-small cell lung cancer (NSCLC) varies from 10%-15% in North Americans and Europeans, to 25%–30% in Asians.1112 The toxicity spectrum also varies. In the landmark trials that established the use of first-line pemetrexed-platinum for non-squamous NSCLC, hyponatremia was not a reported side-effect, yet 35% of our advanced NSCLC patients developed ≥Grade 3 hyponatremia when treated with this regimen.131415 Over 52% of our locally advanced head-and-neck squamous cell carcinoma patients treated with high-dose cisplatin chemoradiotherapy developed ≥Grade 3 hyponatremia,16 while hyponatremia was not a reported toxicity in the landmark trials of Bernier et al. and Cooper et al.1718 Hyponatremia may be a unique toxicity that occurs in our Indian patients. Several possible explanations exist for the deficiencies in oncology research in India. There is a lack of collaboration between various stakeholders, including between institutions, between clinicians and basic scientists, between academia and the pharmaceutical industry, between investigators in different Indian states, and between Indian and international researchers. Funding is practically nonexistent, especially for interventional trials, drug trials, and instruments. Several government agencies do provide research funding like the Department of Biotechnology and the ICMR. However, most of these funds are for basic research. The results of basic and translational research are not implemented in the clinic. There is a lack of trained workforce to run clinical trials, starting from lack of research training of investigators and lack of trained research coordinators, research nurses, and data entry operators. There are very few trained biostatisticians who have an in-depth understanding of oncology trials. There is a lack of expert regulatory bodies and, for the existing regulatory bodies, there is a lack of transparency in their functioning. There is a tremendous patient load in busy academic centers. Lack of protected research time and absence of focus of the administration on research add to the demotivation. The major academic oncology centers in India have failed to take on the mantle of research leadership. There certainly has been some seminal work done in India over the past 10 years. High-impact work has been done by Dr. Dikshit from Tata Memorial Center (TMC) and the India State Disease Burden Initiative Cancer Collaborators in epidemiology;1920 Dr. Shankaranarayanan and Dr. Shastri from TMC in prevention, screening, and early detection;21222324 Dr. Dutt from TMC in genomic profiling;25 Dr. Badwe and Dr. D'Cruz from TMC in surgical oncology;262728 Dr. Jalali and Dr. Srivastava from TMC in radiation oncology;2930 Dr. Gupta and Dr. Prabhash from TMC; and Dr. Sharma from AIIMS in medical oncology.163132 This list is by no means comprehensive. But the bottom-line remains that very few landmark trials have been done in India. We certainly can and should do exponentially better. With multiple responsibilities competing for our time and attention including patient care, administrative duties, and teaching of residents and fellows, it is easy for research to take a backseat. As clinicians, our primary training is in patient care, and that is what provides instant gratification. However, only through appropriate research activity can we understand the true scope of the cancer problem, identify and then rectify deficiencies in the system. Through oncology research in India, we could identify unique issues that our cancer patients face. We can better understand the ethnic differences between patients, the differential response to treatments, and the differential survival in various malignancies. This is the first step toward improving oncologic outcomes. Certain cancers such as oral cavity, cervical, and penile cancers are common in India; at least for these cancers, we should lead the research. Other areas uniquely suited to research in the Indian context include drug repurposing, using medications in low and frequent dosing (metronomic scheduling), and the role of alternative branches of medicine such as Ayurveda, homeopathy, and Unani. In terms of direct patient care, we believe that patients on clinical trials have the best possible outcomes, regardless of what the specific research question is, and we should strive for a future when most of our patients are enrolled in a study. As clinicians, we make a difference in the lives of the patients we treat daily in the clinic. This impact is immediately tangible. However, this impact is limited; a very busy clinician could treat between 10 and 30 new patients a day, which works out to approximately 5000 new patients a year. To illustrate the potential impact that research could have, let us take the example of the N0 trial, done on approximately 500 Indian patients with early-stage oral cavity cancer.28 According to GLOBOCAN 2012, there are 77,003 new oral cavity cancer patients annually in India and 300,000 worldwide.33 Approximately 20%–40% of these patients will have early-stage disease.34 Thus, the N0 trial results will potentially impact 23,000 early-stage oral cavity cancer patients in India and 90,000 patients globally per year. There are some immediate actionable points that can improve the research situation in India. There should be changes in the national policy, making cancer research part of the agenda. Technology is widely available and utilized in India. Cancer registries should be established to cover an adequate population and cancer reporting should be enabled, paralleling how the Aadhaar card has been enabled for various government and nongovernment services. In all major cancer centers, there should be compulsory audits, including treatment and outcomes. Training in research methodology and establishment of a research mindset should start from undergraduate training. There should be a commitment from regulatory bodies for timely approval of trials and to encourage scientific rigor in the conduct of trials. Academic cancer centers should be rewarded for conducting and publishing practice-changing trials. Within institutions, high-quality research could be incentivized; for example, academic promotion or a commitment to fund the next trial conducted by that group of investigators. Resources should be established, in the form of workforce, funding, space, and infrastructure. Funding bodies should consider important clinical studies and should commit some funding for clinical trials. Most importantly, patients should be involved as stakeholders in the design and conduct of meaningful clinical research. When surveyed, 66.4% of Indian patients stated that clinical research benefits society.35 A national public opinion poll by Research! America found that 72% of Americans would be likely to participate in a clinical trial if recommended by their doctor, yet only 22% said that a doctor or health-care provider had discussed clinical trials with them and only 16% said that they or a family member had participated in a clinical trial.36 It is estimated that worldwide, <5% of adult cancer patients are enrolled in clinical trials.37 My hope is that the Indian oncology community and the Government of India understand sooner rather than later the importance of high-quality oncology research and that we start providing our own patients and the rest of the world with answers to the innumerable questions that currently plague the practice of oncology. When that happens, I hope to one day be able to quote George Orwell, “We shall meet in a place where there is no darkness” (1984). Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.