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  In this article
 »  Abstract
 » Introduction
 »  the Complexities...
 » Worldwide Scenario
 »  Scenario in Less...
 »  Scenario and Pra...
 »  Future Perspecti...
 » Conclusion
 »  References

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  Table of Contents  
Year : 2020  |  Volume : 57  |  Issue : 2  |  Page : 139-143

Rare cancers in India: A road less travelled

1 Department of Medical Oncology and Hemato-oncology, Narayana Superspeciality Hospital, Gurugram, Haryana, India
2 Department of Medical Oncology, All India Institute of Medical Sciences, New Delhi, India

Date of Submission01-May-2019
Date of Decision21-May-2019
Date of Acceptance15-Jun-2019
Date of Web Publication29-Apr-2020

Correspondence Address:
H S Darling
Department of Medical Oncology and Hemato-oncology, Narayana Superspeciality Hospital, Gurugram, Haryana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_384_19

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 » Abstract 

Globally, rare cancers as a group are commoner than any single common cancer. They represent an unmet medical need, and this issue gets further amplified in India due to various reasons, including the limited accessibility of healthcare system to the population at large. The scarce available data yet only represents the tip of the iceberg, due to poor registration and incomplete medical cover. Rare cancers, as a consequence, are driven further away from attention of the policy.makers and financial authorities. Poor research prospectives and lesser administrative support restrict the research in this field. There is an urgent need for initiating studies exclusively on rare cancers in India, considering their prevalence and deprived management, as many countries are already pursuing work in this field. All such inadequacies ultimately affect the patient outcomes. In this review, after discussing these aspects, we suggest a stepwise approach to improve the care of rare cancers in India.

Keywords: Clinical trials, definition, healthcare, incidence, India, rare cancers

How to cite this article:
Darling H S, Rastogi S. Rare cancers in India: A road less travelled. Indian J Cancer 2020;57:139-43

How to cite this URL:
Darling H S, Rastogi S. Rare cancers in India: A road less travelled. Indian J Cancer [serial online] 2020 [cited 2021 Jan 24];57:139-43. Available from:

 » Introduction Top

Cancer can have profound social and economic consequences, especially in developing countries. Social factors, especially inequalities, are major determinants of cancer outcomes, with poorer people more likely to die from cancer than the affluent.[1],[2] With the advent of better technology, decreasing cost, increasing affordability and availability of lesser toxic or more effective drugs, the prognosis of many common cancers is improving year by year. However, it is not that aptly applicable to the rare cancers. Collectively, rare cancers not only affect a large population, but also their prognosis is worse than their more common counterparts.[3] Major advances in healthcare occur through conduction of large randomised trials on different modalities and newer drugs with different novel mechanisms of action. This necessitates the involvement of research investment by pharmaceutical enterprises. This goes without saying that these projects require large numbers of patients both for the trial to have statistical significance as well as the new drug to have substantial market scope. Due to small numbers of patients in individual rare cancers, large studies are difficult and pharmaceutical companies are less interested in such trials for obvious reasons. Financial constraints potentiate this problem in India, jeopardising further the feasibility of research and treatment of rare cancers. As of now, the clear definition and concept of rare cancers, as a separate group, is almost non-existent in India and other developing countries. In this review, we have tried to look upon the problems in research, diagnosis and treatment of rare cancers in India, within the context of limited literature available worldwide. This review, while trying to be non-nihilistic, deals with the significant burden and unasked questions about rare cancer management in India.

 » the Complexities of Definition Top

Rare cancers are rare individually, but collectively they constitute 20%-30% of all cancers.[4],[5] Different societies and studies have adopted different definitions of a rare cancer. There is no universally agreed upon definition, eg. the United States-National Cancer Institute (US-NCI) definition is fewer than 15 cases per one hundred thousand people per year, whereas RARECARE (Europe) has adopted as those with fewer than 6 cases per one hundred thousand people per year. International Rare Cancers Initiative (IRCI) has defined rare cancers as the cancers having a prevalence of less than 2 cases per one hundred thousand.[4] Currently in India, there is no such definition and/or consortium that deals with rare cancers. Intriguingly, rare cancers also include the uncommon subtypes of common cancers such as Li-Fraumeni associated breast cancer, ALK positive subtype of lung cancer, rare variant of kidney cancers etc. Rare cancer definition and classification in India 'can't be copied' from other countries as the incidence of cancers varies from country to country. For example, cancers like cervical cancer and gall bladder cancers are relatively common in India, as compared to western countries. Similarly, melanoma is apparently less commonly reported in India as compared with western countries.

 » Worldwide Scenario Top

Rare cancers miss the attention of researchers and academicians all over the world. Cancer epidemiology varies with region, country, behavioural and cultural differences and age distribution of the study population. Therefore, a cancer rare at one region can be common at another region. Number of conferences and academic activities are lesser on rare cancers. Low number of patients with a particular rare cancer makes the clinical trials difficult, lessening the therapeutic options on an evidence basis. Off-label practice creates reimbursement issues. Overall, rare cancers represent 20% of cancers diagnosed in the US. Previous studies using the RARECARE definition demonstrated that rare cancers represent 22% of cancer diagnoses in Europe (27 countries), 17% of cancers in the Netherlands, and 15% of diagnoses in Japan. Similarly, Greenlee et al. estimated that 25% of all cancers diagnosed in US adults during 1995 through 2004 were rare.[4] The scenario of rare cancers is changing but at a very slow pace through RARECARE, IRCI organizations and implementation of Orphan Drug Act. Limited literature is available regarding rare cancers in different parts of the globe. In US, rare cancers comprise more than 100 cancers, two-thirds (71%) of cancers occurring in children and adolescents compared with less than 20% of cancers in 65 years and older; 59% of rare cancers are diagnosed in advanced stage at presentation compared with 45% of common cancers. Five-year relative survival is also poorer than in common cancers among both males (55% vs 75%) and females (60% vs 74%).[4]

IRCI, established in 2011, is a joint effort by Cancer Research UK, the National Institutes of Health Research Clinical Research Network: Cancer, NCI, the European Organisation for Research and Treatment of Cancer, the Institut National Du Cancer, Clinical Oncology Society of Australia, Japan Clinical Oncology Group and Canadian Cancer Trials Group on taking forward the research on rare cancers. It brings together international experts on rare cancers and member organizations that have the capacity to perform clinical trials across national boundaries, provides a platform to prioritize global rare cancer research strategies and works to overcome barriers and facilitates worldwide industrial collaboration.[6] Multiple trials are already going on in metastatic anal cancer, small bowel adenocarcinoma, penile cancer, salivary gland cancer and melanoma. These trials are open across international boundaries and parallel trials are added to increase the numbers in case sufficient recruitment does not happen in a given time, for example, in small intestine adenocarcinoma, BALLAD trial is already recruiting since 2015, and later JCOG has opened a parallel trial JCOG 1502C in May 2017.[1]

The Orphan Drug Act of 1983 from the US and EC141/2000 and 847/2000 from the European Union (EU) legislation have been recognized as major steps toward promoting drug research on rare diseases. Since that time, about 400 medicines representing more than 447 separate indications have been approved to treat rare diseases, compared to fewer than 10 in the 1970s.[4] Among the 34 drugs approved by United States Food and Drug Administration in 2017, 21 new drug approvals were for rare cancers.[7] However, at least outside the US, their accessibility remains an issue. For instance, as per a survey reported by the European Commission in 2004, only 9 of 25 EU member states had access to all 10 orphan drugs approved in previous years and all but one failed to have them on the national reimbursement lists. The situation appears to be even more grim in developing countries.[8]

 » Scenario in Less Developed Nations Top

Currently the focus of the developed world is to improve statistical tools and collaborations for answering the questions pertaining to rare diseases. This is exemplified by EURAMOS trial with transatlantic collaboration. Recently, various statistical models like Multi-Arm Multi-Stage (MAMS) trial designs and Bayesian models are being adopted for such kind of research along with innovative clinical study designs.[9] However, the simplest answer to such clinical trial collaboration lies in including developing countries as well. Ideally these trials should enrol all patients world over. As 85% of the world population lives in developing countries,[10] enrolling patients from developing countries will itself increase the numbers and trials can be completed in shorter time with lesser cost. Per se, the best treatment in oncology is enrolment in a clinical trial, hence, by expanding the trial access to developing countries will serve dual purpose, providing the state-of-the-art treatment as well as the completion of the trial.

Although scarce data on individual rare cancers are available from emerging countries, the concept of rare cancers as a separate group is still almost non-existent. Also because of unstructured and poorly controlled data collection, the limited available data from developing countries may not be true representative of the disease in the region concerned.[8],[11] Depending upon the demographic statistics, many cancers which are rare in the developed countries, may be quite common in developing countries. For example, for gall bladder cancer, the highest incidence and mortality rates are in Chile.[12] The comparative incidence of gall bladder cancer is 21.5/1,00,000 in Delhi (India), 13.8/1,00,000 in Karachi (Pakistan) and 27/1,00,000 in Chile.[13] Oral cavity and nasopharyngeal cancers are rare in US, whereas the former is very common in the Indian subcontinent, and the latter is much common in Hong Kong.[4],[14] Even lung cancer is a rare cancer in west Africa (with an age standardised incidence rate of 3.5 per 1,00,000 per year), whereas its highest incidence (76.5 per 1,00,000 per year) is found in Polynesia and eastern Europe.[15]

 » Scenario and Practical Issues in India Top

Research for rare cancers across the world is painfully slow, as studies on rare cancers are lengthy, tedious and cost-consuming. In India, where the outcome of common cancers is also not at par with the developed countries, rare cancers obviously take a backseat. Consequently, liberal financial grants are not sanctioned for these cancers. Classifications, diagnostic and pathological guidelines are also not clear and standardised in these cancers. Research is minimal and new drugs do not enter into pre-clinical studies and clinical trials. Due to these lacunae, rare cancers and relevant drugs are seldom in news or limelight, which discourages the young researchers to enter these fields. Very few articles on rare cancers in India can be found on internet search.[11],[16] Akin to the ORDI (Organization for Rare Diseases India), there is a need for establishing a dedicated organization for rare cancers in India.

Rare cancer epidemiology of India is different from the rest of the world. Surprisingly, the list of US common cancers of 19 varieties do not include the many common cancers of India such as head and neck cancer, cervical cancer, gall bladder cancer and cholangiocarcinoma.[4] Melanomas are uncommon in India and other non-melanoma skin cancers are also rare. Adenocarcinomas of the esophagus and stomach, squamous cell carcinoma of esophagus and head and neck, cervical carcinoma and Hodgkin lymphoma are all in the list of rare cancers in US, but they are quite commonly seen in practice in India.[4]

There is overwhelming discrepancy in sarcoma diagnosis in peripheral centres versus tertiary care centres in India. Having said this, majority of patients are compelled to take treatment from peripheral centres because of limited infrastructure in tertiary care centres. Limited pathological expertise on rare cancers may delay or altogether miss the diagnosis. Ancillary diagnostic tests for rare diseases are also a problem in most of the centres. This can be exemplified by lack of SDH immunohistochemistry for gastrointestinal stromal tumour, paraganglioma and even the c-kit mutation and PDGFRA are not widely available. MIBG scan for neuroblastoma and DOTANOC scan for neuroendocrine tumours, and FISH, PCR and NGS for higher molecular analysis are only available in a few specialist centres.

A rare cancer may be of lesser priority for researchers or profit-driven industry but it does not justify an inferior treatment for a patient from an oncologist. Diagnosis at advanced stages, paucity of clinical trials and lesser drugs for rare cancers leads to worrisome outcomes. Even if newer or novel drugs or modalities are approved in these cancers, these may not be readily available or affordable in India. Clinicians may also not be adequately trained or experienced in using these drugs or in managing rare cancers. For instance, drugs like mitotane, ipilimumab, dabrafenib, vandetinib, cabozantinib, trametinib and carboxypeptidase G2 are still not available in Indian market. Specialized procedures such as total skin electron beam therapy for mycosis fungoides, intraarterial chemotherapy for retinoblastoma, hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei and isolated limb perfusion for soft tissue sarcoma are also an exception in majority of the centres.

Due to poor structural organization of health facilities and resources, rare cancers are diagnosed late, never diagnosed or misdiagnosed, late or never treated and are hardly ever notified. This is mostly seen in endocrine malignancies, soft tissue sarcomas, and small intestinal adenocarcinomas. Patients have to travel long distances due to low number of cancer centres. It is not only the issue of new drug development and availability, but the understanding of the rare cancer itself requires a full-fledged emphasis, including the appropriate role and/or type of surgery, radiation therapy, appropriate pathological classification, molecular studies for diagnosis and targeted approach or novel schedules for currently available treatments. These questions are less likely to be addressed by trials sponsored by pharmaceutical companies and could be preferentially addressed by investigator-initiated academic research.

This apathy towards rare cancers is also compounded by financial aspect and affordability issues. Rare cancer treatment may include relatively more tests, visits, second opinions, experimental therapies, uncertainties in diagnosis, treatment and prognosis, resulting in increased costs. This becomes more taxing for a patient already struggling with financial difficulties. Moreover, newer drugs may not be covered under the ambit of government approvals or policies. Insurance companies often do not cover these drugs and off-label use remains very restricted. For example, use of sunitinib in alveolar soft part sarcoma becomes difficult to procure and there are no compassionate schemes that might help patients. This is a vicious cycle, further impeding the new drug development and clinical research on rare cancers.

 » Future Perspectives and Suggestions for a Better Landscape for Rare Cancers Top

Molecular technologies and newer research models are attempting to understand the genetic makeup of various rare cancers, searching for the targetable mutations. Checkpoint inhibitors are also rapidly expanding their reign across various cancers. Research and well-designed clinical trials are the best way ahead in the field of cancer. To begin with, a nationwide consortium to address the issue of rare cancers is needed, with prime focus on maximal registration of rare cancer cases. It will help generate a dataset, which can be utilized to develop a clear definition, measure the disease burden, classify rare cancers in India and chalk out future plans. The authentic data shall attract international clinical trials and pharmaceutical companies to invest in Indian market. This will advance research and also make the newer drugs available in India. The governments, policy makers and non-government organizations need to come forward to support the research in this field. We propose a stepwise approach to streamline the rare cancer care in India:

  1. To establish a rare cancer consortium with a defined vision and mission
  2. To standardize a clear definition of rare cancer as per Indian scenario
  3. To enlist rare cancers according to Indian definition
  4. To ensure registry of maximum rare cancer cases
  5. To educate the stakeholders in oncology through CMEs, interactive sessions
  6. To participate in international clinical trials on rare cancers
  7. To channelize government and non-government resources to fund the research and management of rare cancers
  8. To develop indigenous guidelines for treatment of various rare cancers complying with Indian scenario.

 » Conclusion Top

Apart from just making the healthcare available to the masses, the equality and quality of healthcare is also of utmost importance. A lot of work needs to be done on rare cancers in this direction in India. Government and legislative measures such as tax policies, financial incentives (such as specific grants to support research), marketing, and accessibility to approved drugs can go a long way to yield desired outcome in these 'inadvertently neglected and academically deprived' cancers. Sensitizing the stakeholders in health sector through interactive meetings and discussions can hasten the financial grants, sanctions and approvals. The prime focus should be on research in this field, which will yield a revenue in the form of discovery, development and availability of newer drugs to Indian patients as well as improve the diagnostic and therapeutic potential. India being a large population has a drawback of poor administrative control, but at the same time has a big market and demographic potential, which must be exploited by young researchers, with the aid of authorities.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

 » References Top

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DeSantis CE, Kramer JL, Jemal A. The burden of rare cancers in the United States. CA Cancer J Clin 2017;67:261-72.  Back to cited text no. 4
Shin DW, Cho J, Yang HK, Kim SY, Lee SH, Suh B, et al. Oncologist perspectives on rare cancer care: A nationwide survey. Cancer Res Treat 2015;47:591-9.  Back to cited text no. 5
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