Advancing Proton FLASH Radiation Therapy: Innovations, Techniques, and Clinical Potentials

Yangguang Ma; Tengda Zhang; Balaji Selvaraj; Jiajian Shen; Shouyi Wei; Chingyun Cheng; Hao Gao; Per Rugaard Poulsen; Heng Li; Eric Diffenderfer; Jan Schuemann; Liyong Lin; Zachary Morris; Benjamin Durkee; Jürgen Hesser; Haibo Lin; Charles B Simone 2nd; Minglei Kang; Hui Wu

doi:10.1016/j.ijrobp.2025.05.076

Advancing Proton FLASH Radiation Therapy: Innovations, Techniques, and Clinical Potentials

Int J Radiat Oncol Biol Phys. 2025 Jun 11:S0360-3016(25)00594-2. doi: 10.1016/j.ijrobp.2025.05.076. Online ahead of print.

Authors

Yangguang Ma¹, Tengda Zhang², Balaji Selvaraj³, Jiajian Shen⁴, Shouyi Wei⁵, Chingyun Cheng⁶, Hao Gao⁷, Per Rugaard Poulsen⁸, Heng Li⁹, Eric Diffenderfer¹⁰, Jan Schuemann¹¹, Liyong Lin¹², Zachary Morris¹³, Benjamin Durkee¹⁴, Jürgen Hesser¹⁵, Haibo Lin¹⁶, Charles B Simone 2nd¹⁷, Minglei Kang¹⁸, Hui Wu¹⁹

Affiliations

¹ Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. Electronic address: mayangguang_2002@126.com.
² MIISM, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin, USA. Electronic address: tzhang646@wisc.edu.
³ New York Proton Center, New York, New York, USA. Electronic address: bselvaraj@nyproton.com.
⁴ Department of Radiation Oncology, Mayo Clinic, Phoenix, Arizona, USA. Electronic address: Shen.Jiajian@mayo.edu.
⁵ New York Proton Center, New York, New York, USA. Electronic address: awei@nyproton.com.
⁶ Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin, USA. Electronic address: chingyun.cheng@humonc.wisc.edu.
⁷ Department of Radiation Oncology, University of Kansas Medical Center, Kansas, USA. Electronic address: hgao2@kumc.edu.
⁸ Danish Centre for Particle Therapy, Aarhus University Hospital, Aarhus, Denmark; Department of Oncology, Aarhus University Hospital, Aarhus, Denmark. Electronic address: per.poulsen@rm.dk.
⁹ Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; The Johns Hopkins Proton Therapy Center, Johns Hopkins University School of Medicine, Washington, DC, USA. Electronic address: hengli@jhu.edu.
¹⁰ Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address: Eric.Diffenderfer@pennmedicine.upenn.edu.
¹¹ Physics Division, Department of Radiation Oncology, Massachusetts General Hospital & Harvard Medical School, Boston, Massachusetts, USA. Electronic address: JSCHUEMANN@mgh.harvard.edu.
¹² Department of Radiation Oncology and Winship Cancer Institute, Emory University, Atlanta, Georgia, USA. Electronic address: liyong.lin@emoryhealthcare.org.
¹³ Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin, USA. Electronic address: zmorris@humonc.wisc.edu.
¹⁴ Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin, USA. Electronic address: bydurkee@humonc.wisc.edu.
¹⁵ MIISM, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. Electronic address: juergen.hesser@medma.uni-heidelberg.de.
¹⁶ New York Proton Center, New York, New York, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address: hlin@nyproton.com.
¹⁷ New York Proton Center, New York, New York, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address: csimone@nyproton.com.
¹⁸ Department of Human Oncology, University of Wisconsin-Madison, Madison, Wisconsin, USA; New York Proton Center, New York, New York, USA. Electronic address: mkang@humonc.wisc.edu.
¹⁹ Department of Radiation Oncology, the Affiliated Cancer Hospital of Zhengzhou University& Henan Cancer Hospital, Zhengzhou, Henan, China. Electronic address: zlyywuhui202@zzu.edu.cn.

PMID: 40513679
DOI: 10.1016/j.ijrobp.2025.05.076

Abstract

Proton FLASH radiation therapy (RT) is an emerging technique that offers highly conformal doses similar to conventional intensity-modulated proton therapy (IMPT) but with the added potential benefit of protecting organs at risk (OARs) through the FLASH-sparing effect. This review examines recent advancements in proton FLASH-RT, including transmission beams (TB), single-energy Bragg peak (SEBP), single-energy spread-out Bragg peak (SESOBP), hybrid FLASH, and multiple-energy spread-out Bragg peak (MESOBP). These proton FLASH technologies are discussed in detail, highlighting their advantages, limitations, and dosimetric comparisons with IMPT and other FLASH techniques. While TB achieves dose conformity through multifield optimization, it also has unnecessary exit doses, SEBP and SESOBP offer improved OAR protection and superior target conformity at the cost of using range compensators (RCs) and/or ridge filters (RFs). Additionally, hybrid FLASH-RT combines TB and Bragg peak methods to target the tumor core and edges separately, whereas MESOBP FLASH leverages ultra-fast energy switching. Despite these advancements, only non-conformal TB FLASH-RT has been applied clinically with single fields for palliative RT due to the complexity of other methods and uncertainties about the FLASH effect. This review summarizes the technical details of these FLASH-RT methods and discusses their utilization across various anatomical sites.

Keywords: FLASH; proton radiotherapy; range modulators; ultra-high dose rate, single energy Bragg peak.

Publication types

Review