Y. L. B. Klaver1,2, M. S. Hoogeman1,3, Q. R. Lu4, R. A. Amos5, M. A. Hawkins5, and C. B. Simone II6; 1HollandPTC, Delft, Netherlands, 2Department of Radiotherapy, Leiden University Medical Center, Leiden, Netherlands, 3Department of Radiotherapy, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, Netherlands, 4Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, 5Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom, 6New York Proton Center, New York, NY
Purpose/Objective(s): The FLASH effect, defined as normal tissue sparing while maintaining tumor control with ultra-high dose rate (UHDR) irradiation, has been demonstrated preclinically in different tumor sites and normal tissues. As we approach the next phase of clinical testing, optimizing a clinical study design is of paramount importance incorporating available preclinical data and considering technological constraints. The purpose of this study is to provide recommendations on the prerequisites, study design, and endpoints for next clinical trials that will explore the clinical potential of proton (p) FLASH. We hypothesized that consensus would be reached for the optimal patient population and other clinical and biological domains but not for the technical delivery of pFLASH. Materials/
Methods: Delphi methodology was used to develop expert consensus. An international expert group was composed using predefined expertise criteria consisting of 21 clinicians, medical physicists and biologists, well balanced in professions and across Europe versus North America. Statements on preclinical and technical prerequisites and clinical trial design were scored on a 5-point Likert scale or as multiple choice in 2 online questionnaire rounds. To reach consensus, an agreement from at least 66% of the entire group was needed. Strong consensus required =80% agreement. Results: Response rates were 100% in both questionnaire rounds. For the design of the next pFLASH trials, consensus was achieved that adult patients only should be included with a minimal expected overall survival of 1 year in a palliative setting or, preferably, with oligometastatic disease treated with ablation. It was strongly agreed that the FLASH effect should first be studied as a single treatment modality with toxicity reduction as primary endpoint. Consensus was that ex vivo experiments cannot substitute the need for in vivo data proving reduction of normal tissue toxicity and isoeffectiveness in tumor response before starting a clinical trial in a specific treatment site. Consensus was reached on the use of clinical target and organs at risk constraints, minimum pencil beam dose rates, dose rate optimization, accuracy and evaluation and quality assurance. No consensus was reached on use of single versus multiple beams, single versus multiple fractions and minimum fractionation dose. Conclusion: This Delphi study resulted in an international multidisciplinary expert consensus and recommendations on requirements for preclinical evidence, technical developments, quality assurance and study design for the next clinical trials investigating the clinical value of pFLASH. There is a need for additional data regarding fractionation and FLASH treatment planning. Results of this study can be used to develop a roadmap for future clinical trials.
