Controversies in clinical trials in proton radiotherapy: The present and the future

Proponents of proton radiotherapy have cited the dose distribution characteristics of proton beams as evidence of its superiority over photon radiotherapy. Outcomes after photon radiotherapy remain suboptimal owing to poor local control and normal-tissue toxicity in many clinical indications. Critics of proton radiotherapy have noted the relative lack of prospective data from clinical trials showing a benefit for proton radiotherapy despite its theoretical advantages. Questions remain with regard to physical uncertainties in proton dose delivery and variations in their radiobiological effect in different tissues and tumors. Although prospective data have been scant in the past, clinical trials using proton radiotherapy are now being conducted with increasing frequency. However, very few of these are randomized controlled trials comparing protons directly with photons. Randomized controlled trials should remain the ideal tool for research in proton radiotherapy: they should be focused on areas where clinical equipoise is present, ideally in tumor sites where there is a low risk of systemic failure, a high risk of local progression, and/or a high risk of toxicity with conventional therapy. Proton radiotherapy centers should develop prospective registries with the goal of long-term data collection on an international basis to support the evidence provided by observational studies and comparative effectiveness research trials.