Requirements and Study Design for the Next Proton FLASH Clinical Trials: an International Multidisciplinary Delphi Consensus

Yvonne L B Klaver; Mischa S Hoogeman; Q Richard Lu; Jeffrey D Bradley; J Isabelle Choi; Matthew J Ferris; Cai Grau; Chandan Guha; Haibo Lin; Liyong Lin; Anthony E Mascia; Astrid M Moerman; Per R Poulsen; Lewis Z Shi; Brita Singers Sørensen; Sibo Tian; Marie-Catherine Vozenin; Christopher D Willey; Sumin Zhou; Richard A Amos; Maria Hawkins; Charles B Simone 2nd

doi:10.1016/j.ijrobp.2025.03.047

Requirements and Study Design for the Next Proton FLASH Clinical Trials: an International Multidisciplinary Delphi Consensus

Int J Radiat Oncol Biol Phys. 2025 Mar 31:S0360-3016(25)00306-2. doi: 10.1016/j.ijrobp.2025.03.047. Online ahead of print.

Authors

Yvonne L B Klaver¹, Mischa S Hoogeman², Q Richard Lu³, Jeffrey D Bradley⁴, J Isabelle Choi⁵, Matthew J Ferris⁶, Cai Grau⁷, Chandan Guha⁸, Haibo Lin⁹, Liyong Lin¹⁰, Anthony E Mascia¹¹, Astrid M Moerman¹², Per R Poulsen¹³, Lewis Z Shi¹⁴, Brita Singers Sørensen¹⁵, Sibo Tian¹⁰, Marie-Catherine Vozenin¹⁶, Christopher D Willey¹⁷, Sumin Zhou¹⁸, Richard A Amos¹⁹, Maria Hawkins²⁰, Charles B Simone 2nd⁵

Affiliations

¹ HollandPTC, Delft, The Netherlands; Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands. Electronic address: y.klaver@hollandptc.nl.
² HollandPTC, Delft, The Netherlands; Department of Radiotherapy, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
³ Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
⁴ Department of Radiation Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania.
⁵ Department of Radiation Oncology, New York Proton Center, New York, New York; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.
⁶ Department of Radiation Oncology, University of Maryland School of Medicine, Baltimore, Maryland; Maryland Proton Treatment Center, Baltimore, Maryland.
⁷ Danish Center for Particle Therapy, Aarhus University Hospital, Aarhus, Denmark.
⁸ Department of Radiation Oncology, Montefiore University Hospital, Bronx, New York.
⁹ Department of Radiation Oncology, New York Proton Center, New York, New York; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Radiation Oncology, Montefiore University Hospital, Bronx, New York.
¹⁰ Department of Radiation Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
¹¹ Cincinnati Children's Hospital Medical Center, Cancer and Blood Disease Institute, Division of Oncology, Cincinnati, Ohio.
¹² HollandPTC, Delft, The Netherlands.
¹³ Danish Center for Particle Therapy, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
¹⁴ Departments of Microbiology, Pharmacology & Toxicology; The Immunology Institute; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama; Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
¹⁵ Danish Center for Particle Therapy, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Experimental Clinical Oncology, Aarhus University, Denmark.
¹⁶ Radiotherapy and Radiobiology Sector, Radiation Therapy Service, University Hospital of Geneva, Geneva, Switzerland.
¹⁷ Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama.
¹⁸ Radiation Oncology Department, University of Nebraska Medical Center, Omaha, Nebraska.
¹⁹ Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom.
²⁰ Department of Medical Physics and Biomedical Engineering, University College London, London, United Kingdom; Clinical Oncology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.

PMID: 40174648
DOI: 10.1016/j.ijrobp.2025.03.047

Abstract

Purpose: The FLASH effect, defined as normal tissue sparing while maintaining tumor control with ultra-high dose-rate irradiation, has been demonstrated preclinically in different tumors and tissues. Although the biological mechanisms are unclear, there is a need for clinical trials investigating the value of proton FLASH irradiation (pFLASH). The purpose of this study was to establish an expert consensus regarding prerequisites, study design, and endpoints for the next clinical trials exploring the clinical potentials of pFLASH.

Methods and materials: Delphi methodology was used to develop a systematic expert consensus. An international expert panel was composed of 21 clinicians, physicists, and biologists, well-balanced in expertise and geography, using predefined inclusion criteria. Statements were scored on a 5-point Likert scale in 2 rounds of online questionnaire voting. The definition of consensus was set a priori.

Results: The response rate was 100% in both rounds. Preclinical in vivo demonstration of the FLASH effect in normal tissue while maintaining tumor response was deemed essential before starting a clinical trial in a specific tumor site. The next clinical pFLASH trials are advised to include adult patients only, with a minimal expected overall survival of 1 year for palliative settings or, preferably, oligometastatic disease in the ablative setting. The pFLASH effect should be studied in a single treatment modality setting with toxicity reduction as the primary endpoint. Recommendations were formulated on the use of clinical targets and organs at risk constraints, requirements for evaluation and reporting, and accuracy levels and pretreatment verification of dose rates. No consensus was reached on the use of multiple beams, multiple fractions, and fraction dose.

Conclusions: There is a need for additional data regarding the influence of fractionation and multiple beam planning. The results of this study can be used to develop roadmaps to guide future clinical trial design.