Hadrontherapy for cancer. An overview of HTA reports and ongoing studies

Introduction: There is growing interest in the use of both proton beam therapy (PBT) and carbon ion radiation therapy (CIRT), which are types of hadrontherapy. Although neither are new technologies they have been subject to assessment by several Health Technology Assessment (HTA) agencies over the past years. The main claimed benefit of PBT and CIRT is a reduction in toxicity compared to conventional radiation therapy, resulting in fewer harms and a lower risk of induced secondary malignancies. Such an advantage would be particularly relevant to children and young adults. Sizeable hadrontherapy centres expansion is underway worldwide, while evidence supporting claims of superiority over conventional radiation therapy is thought to be currently insufficient. Objectives: The report is aimed at presenting the state of the art of clinical research in both PBT and CIRT, by summarising the evidence findings from most recent and uptodate HTA reports and by providing a description of all currently ongoing clinical studies. Methods: The search for HTA reports was carried out on 3 databases to identify reports published between January 2011 and June 2019. The quality of the identified reports was assessed using the AMSTAR instrument. The search for ongoing studies was carried out on four public registers in July 2019. All identified ongoing studies were included. Results: The overview of available evidence for PBT is drawn from five HTA reports on a total of 16 oncology indications, including 295 primary studies of any study design. One HTA report also included eight guidelines. All included HTA reports concluded that the quality of research is low and that there is insufficient evidence to support the claimed benefits of PBT. Seventytwo non-comparative ongoing studies and 25 comparative ongoing studies were identified. Seventeen were randomized controlled studies comparing Proton Beam Therapy with current practice. The search for HTA reports assessing the use of CIRT in oncology identified five reports, two of which were up to date and of good quality reporting data from primary studies. The largest report identified 56 studies on 13 indications, but only 27 studies (including only one randomised trial) could be included in a qualitative synthesis, providing no evidence of differences in efficacy and safety of CIRT compared to photontherapy. The other report focused on the effects of CIRT on chordomas and chondrosarcomas, highlighting the heterogeneity and inconsistency of available data mostly coming from low-quality studies. Thirtyseven ongoing studies were identified, 5 of which were RCT versus conventional treatment and 32 were single-arm studies. Table A summarises the findings, by clinical indication, from the included HTA reports and from the overview of ongoing clinical research. The Table reports the current level of certainty on superiority of PBT or CIRT compared to photon radiation therapy and the likelihood that future research results would resolve current uncertainty. Conclusions. Despite the growing number of studies being published and the growing number of PBT and/or CIRT centres opening or at a planning stage, there is persistent uncertainty on the added clinical benefit of hadrontherapy treatments over conventional radiation therapy. Clinical research currently underway may not contribute to solve this uncertainty. There is a lack of agreement on the appropriate study design to assess the effects of hadrontherapies and lack of coordination between centres in the production of joint research protocols to generate the necessary evidence. This has led to the production of numerous small, poorly designed and reported studies. These shortcomings might confine the use of PBT and CIRT to experimental treatments and require that patients willing to undergo PBT or CIRT be fully informed of the risks and uncertainties of the outcomes.