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Journal of Cancer Research and Therapeutics, Vol. 5, No. 1, January-March, 2009, pp. 1-2 Editorial Inverse planning for the T1 - T2 conundrum in translation research Sarin, Rajiv Prof. Radiation Oncology and I/C Cancer Genetics Unit, Director, ACTREC, Tata Memorial Centre, Navi Mumbai - 410 210, India Code Number: cr09001 Translational research is the current flavor in all disciplines of medicine and more so in oncology. Better understanding of the biology underlying the development or progression of diverse cancers is being fervently translated into molecular diagnostics, targeted drugs and cancer vaccines. Similarly, advancement in diverse areas of technology is producing an ever-increasing range of new equipment and techniques for cancer imaging, radiation therapy and surgery. Translating a biological or technological concept into a new drug, device, equipment or vaccine is the first component of Translation Research or T1. While T1 research attracts funding, dominates scientific literature and captures the public imagination, it is the second translation or T2 which determines the degree of benefit that would accrue to the wider community in a given timeframe. In the ' Bench to Bedside to Community' paradigm, T2 forms the complicated and poorly controlled process of integrating the T1 product or technology in the routine preventive or clinical care of the intended beneficiaries across a wide range of public, private, academic and other healthcare settings. There are several barriers in the speed, extent, and quality of the second translation and this is not limited to economic factors. Other equally important barriers include the complexities involved in remodeling healthcare systems and overcoming organizational inertia; upgrading knowledge, skills and attitude of the health professionals and finally public expectation, acceptance and access. At long last, T2 is being given a special status and the NIH roadmap outlines, "The second area of translation concerns research aimed at enhancing the adoption of best practices in the community". In the affluent industrialized nations, T2 translation is dominated by efforts to integrate the T1 research findings into new healthcare practices and policies as the new evidence based standard of care. Unfortunately 80% of the world's citizens live in countries with limited resources where T2 translation has to first deal with wider implementation of the pre-existing standards of care and sometimes be content with just increasing the population covered by an arbitrarily defined 'minimum standard of care'. [1] The problem is compounded by the absence of population-based time trends on cancer morbidity and mortality in these countries. This hampers any kind of realistic assessment of societal health benefit with new screening, diagnostic or therapeutic approaches introduced in a particular region or country. One could theoretically model the likely societal health benefit with various oncological interventions based on the proportion of cases with a particular cancer in that society that would be considered eligible for this intervention; the proportion of the eligible cases who are likely to actually undergo this intervention; and the dampening effect of heterogeneous or suboptimal healthcare systems. While a model is as good as the underlying assumptions, it could be used for inverse planning where social scientists and community practitioners could project the expected challenges in T2 translation of different T1 approaches in their communities. This in turn should influence which T1 research approaches should be pursued more vigorously. In the absence of viable T1 alternatives it would help accelerate innovation in various T2 approaches. The T1 - T2 conundrum is exemplified by the barriers in reaping societal benefits from a recent breakthrough in T1 research, the vaccine against Human Papilloma Virus (HPV). HPV is the causative agent for cervical cancers and this vaccine could prevent development of cervical cancer if given to adolescent girls before their sexual debut. The T2 barriers in the developing countries where the vast majority of the global cervical cancer deaths occur, are not just its cost or programmatic challenges in vaccine delivery, but more importantly the socio-cultural barriers in dealing with adolescent female sexual health. Inverse planning to make a real impact in developing countries would suggest that further T1 research should focus on developing either therapeutic vaccine that could be integrated in the maternal health program to eradicate established HPV infection in young mothers; treat pre-cancerous cervical lesions with appropriate methods or develop a better preventive vaccine which could be safely integrated in the universal childhood immunization program to provide immunity against HPV infections in later decades of life. Hence the best way forward may be to embark on a different T1 approach which is more amenable to community level T2 translation in developing countries. Community based cancer prevention trials often take into account the social milieu where the study would be conducted and where the research findings would be applied. In contrast, clinical trials to evaluate cancer therapeutics create an artificial healthcare delivery environment as part of a tightly controlled experiment. Trials for approval of new drugs or devices are specifically designed, executed and monitored to give very high quality oncology and general supportive care to patients who have been carefully selected with maximum likelihood of response and least likely to experience toxicity. The case selection, quality of oncology and supportive care and facilitation for patient logistics could be very different for patients treated outside controlled trial settings. Not surprisingly, the clinical benefits of new drugs or technologies as projected in controlled clinical or technological experiments are diluted, sometimes to a great extent, when they are used in very heterogeneous community or hospital based routine practice in different parts of the world. In south Asia, the cancer with maximum morbidity and mortality is the advanced cancer of the head and neck region with its associated pain, malnutrition, dehydration and anemia. While the T1 research community in the West is excited about new targeted therapies for advanced head and neck cancers, the T2 community in developing countries is striving to ensure that simple cisplatin based chemotherapy with good quality radiotherapy is given safely to the majority of the deserving patients. Another barrier for T2 translation is the slow rate of transfer of clinical excellence achieved in centers of excellence to a large number of centers and practitioners. While the clinical benefit from clinical excellence is not always self-evident, in some cancers it has been clearly shown that high quality multidisciplinary care in centers of excellence or high volume centers can improve clinical outcome and survival. In less populous and geographically compact countries like the UK, central referral of all cases of less common conditions like retinoblastoma or choriocarcinoma to one or two centers of excellence can achieve this. However for populous or large countries such as India, any center of excellence can cater to the needs of a small minority of the affected population. Hence for a national impact of clinical excellence achieved in such centers it should be disseminated to a large number of hospitals and practitioners. While a cascade effect may be wishful thinking, innovative training courses, hands-on workshops, evidence-based meetings, practice surveys, cross audits and telemedicine programs could gradually bring about this T2 translation. Inverse planning could help in designing trials particularly amenable for T2 translation and in developing clinical excellence models well suited for rapid T2 translation. Trials should be designed taking into account the health status and co-morbidities frequently associated with our common cancers and the prevalent healthcare infrastructure. While we would continue to crave for scintillating science or studies which could demonstrate large health benefits from complex and well controlled approaches in select population, parallel efforts are required for pragmatic trials with patients and therapeutic environments that bear greater resemblance to reality. The gain with such a T1 approach is likely to be smaller but the net benefit to the society could be far greater because of the ease of the second translation across diverse healthcare systems in the country. Large and populous countries like India would require ingenious ways to make clinically proven and pragmatic oncological approaches for common cancers easily accessible and affordable to all its citizens. Inverse planning can be a guiding force to change mindsets and develop policies which could partly solve the T1 - T2 conundrum. References
Copyright 2009 - Journal of Cancer Research and Therapeutics |
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