PITChing (professional organisations, innovative trial designs and collaborative approach) for evidence generation for proton therapy

Although there is a discerning lack of consensus regarding PBT’s benefits in several indications, it has been accepted as the preferred choice in paediatric cancers, complex spinal tumours, tumours requiring re-irradiation and certain CNS tumours with a reasonable consensus. For rest of the clinical indications it is widely believed that there is equipoise to merit randomised controlled trials (RCT). There are several ongoing RCTs comparing photons and protons in North America [1], and almost all of them are struggling to recruit patients. Several authors have articulated these challenges that are mainly relevant in the context of USA’s healthcare [2]. The central theme of all these concerns has been economics mainly in the form of lack of insurance coverage for several cancer sites. However, these set of challenges are likely to be different across regions globally. In most LMIC such as India, health care system is based on shared decision-making model and the financial standing of the patient dictates the decision regarding the use of PBT. Unfortunately, the funding opportunities in these countries are limited and the “RCT culture” (the drive to conduct or participate in trials) is restricted to a few institutions [3].

Much of the available evidence for PBT through RCTs have been obtained using the older passive scattering techniques which many believe will be rendered obsolete. Evaluation of evolving technologies is extremely challenging primarily because of resources and time constraints. By the time the results of the current RCTs are in public domain, the technology is likely to evolve and results may become irrelevant. So the RCTs from centres that have used treatment plans with relatively large spot sizes, no image guidance or large margins may not represent the true potential of modern PBT. Also, timing of a trial is extremely crucial as learnt from the RCT on non-small cell lung cancer [4]. The investigators noted a learning curve in treatment planning during the trial accrual, which could have altered the outcome of this study.

In the context of global and regional challenges in evidence generation for PBT, we would like to propose a definitive action plan to bring across major stakeholders such as governmental and non-governmental institutions in high-income countries (HIC) and LMIC, industry and professional organizations across the globe to address the challenges of evidence generation. The action plan proposed by us will be a multi-pronged approach involving relevant stakeholders, innovative study designs, potential funding mechanisms, and most importantly seamless coordination between all these factors to carry forward collaborative PBT trials to fruition by generation of high-quality evidence for PBT.

Clinical trial study designs and methodologies which enhance the value proposition of a trial with optimal sample size, reduced resource and capital expenditure with a concentric approach towards patient centric outcomes and quality of life are the need of the hour. Pragmatic clinical trial designs, adaptive designs, Bayesian methods, model-based approaches for patient selection, seeking biological surrogates for toxicities, risk-based monitoring, patient engagement during trial design etc. are steps in the right direction. Since most PBT trials need long follow-up periods, initiatives such as Intermediate Clinical Endpoints in Cancer of the Prostate (ICECaP) are much needed. Similarly, intermediate surrogates for late effects (ISLE)- should be sought to identify patients at higher risk to develop late effects [5]. Most or all of the next generation trials must include cost effectiveness (CE) analysis as the thresholds are constantly evolving.

In LMIC, the overall cost of the proton treatment is likely to be a fraction of that in North America and Europe. Also, the cost of running a trial itself is much lower bringing down the overall funding requirement significantly lower compared to that in USA. Hence the output per dollar spent on clinical trials is far superior in LMIC. So economically speaking, it is prudent to fund a well-designed study in countries like India to quickly address a clinical question. Several institutions have previously funded major practice changing studies outside of North America [6] and the same standards can be applied to these studies. Investigators in HIC and emerging proton therapy centres in LMIC stand to benefit mutually by virtue of such collaborative proton therapy research. The HIC stand to benefit in terms of lower operational costs and timely completion of trials. While LMIC stand to gain in terms of financial assistance to conduct resource intensive clinical trials, faster evidence generation and eventually better utilisation of an expensive technology for deserving patients.

The barriers to evidence generation in PBT are sufficiently formidable however the way ahead is encouraging and can be accomplished so as to say. It requires concerted efforts from all the stakeholders across the globe. Each of the barriers here must be acknowledged and efforts made to overcome them. Unfortunately, it is fanciful to think this will happen any time soon.