Systematic review of methodology used in clinical studies evaluating the benefits of proton beam therapy.

Background: Proton beam therapy (PBT) delivers high-energy radiation to target tumours while sparing surrounding normal tissues. The dosimetric advantages of PBT over traditional photon radiotherapy may be clear but the translation of this benefit into clinically meaningful reductions in toxicities and improved quality-of-life (QoL) needs to be determined. Randomised controlled trials (RCTs) are considered the gold standard for generating the highest-level evidence in medicine. The objectives of this systematic review were to provide an overview of published clinical studies evaluating the benefits of PBT, and to examine the methodology used in clinical trials with respect to study design and outcomes.

Methods: PubMed, EMBASE and Cochrane databases were systematically searched for published clinical studies where PBT was a cancer treatment intervention. All randomised and non-randomised studies, prospective or retrospective, were eligible for inclusion.

Results: In total, 219 studies were included. Prospective studies comprised 89/219 (41%), and of these, the number of randomised phase II and III trials were 5/89 (6%) and 3/89 (3%) respectively. Of all the phase II and III trials, 18/24 (75%) were conducted at a single PBT centre. Over one-third of authors recommended an increase in length of follow up. Research design and/or findings were poorly reported in 74/89 (83%) of prospective studies. Patient reported outcomes were assessed in only 19/89 (21%) of prospective studies.

Conclusions: Prospective randomised evidence for PBT is limited. The set-up of national PBT services in several countries provides an opportunity to guide the optimal design of prospective studies, including RCTs, to evaluate the benefits of PBT across various disease sites. Collaboration between PBT centres, both nationally and internationally, would increase potential for the generation of practice changing evidence. There is a need to facilitate and guide the collection and analysis of meaningful outcome data, including late toxicities and patient reported QoL.