Perspective Article

Enabling clinical use of linear energy transfer in proton therapy for head and neck cancer – A review of implications for treatment planning and adverse events study

¹ Department of Radiation Oncology, Mayo Clinic, Phoenix, AZ 85054, USA
² Department of Radiation Oncology, The University of Miami, Miami, FL 33136, USA
³ College of Mechanical and Power Engineering, China Three Gorges University, Yichang, Hubei 443002, PR China
⁴ Department of Radiation Oncology, Guangzhou Concord Cancer Center, Guangzhou, Guangdong 510555, PR China
⁵ Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen 518172, PR China
⁶ Department of Oncology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050023, PR China
⁷ School of Computing, The University of Georgia, Athens, GA 30602, USA
⁸ New York Proton Center, New York, NY 10035, USA
⁹ Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
¹⁰ Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
¹¹ Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA

^* Corresponding author: liu.wei@mayo.edu

Received: 11 October 2024
Accepted: 2 January 2025

Abstract

Proton therapy offers significant advantages due to its unique physical and biological properties, particularly the Bragg peak, enabling precise dose delivery to tumors while sparing healthy tissues. However, the clinical implementation is challenged by the oversimplification of the relative biological effectiveness (RBE) as a fixed value of 1.1, which does not account for the complex interplay between dose, linear energy transfer (LET), and biological endpoints. Lack of heterogeneity control or the understanding of the complex interplay may result in unexpected adverse events and suboptimal patient outcomes. On the other hand, expanding our knowledge of variable tumor RBE and LET optimization may provide a better management strategy for radioresistant tumors. This review examines recent advancements in LET calculation methods, including analytical models and Monte Carlo simulations. The integration of LET into plan evaluation is assessed to enhance plan quality control. LET-guided robust optimization demonstrates promise in minimizing high-LET exposure to organs at risk, thereby reducing the risk of adverse events. Dosimetric seed spot analysis is discussed to show its importance in revealing the true LET-related effect upon the adverse event initialization by finding the lesion origins and eliminating the confounding factors from the biological processes. Dose-LET volume histograms (DLVH) are discussed as effective tools for correlating physical dose and LET with clinical outcomes, enabling the derivation of clinically relevant dose-LET volume constraints without reliance on uncertain RBE models. Based on DLVH, the dose-LET volume constraints (DLVC)-guided robust optimization is introduced to upgrade conventional dose-volume constraints-based robust optimization, which optimizes the joint distribution of dose and LET simultaneously. In conclusion, translating the advances in LET-related research into clinical practice necessitates a better understanding of the LET-related biological mechanisms and the development of clinically relevant LET-related volume constraints directly derived from the clinical outcomes. Future research is needed to refine these models and conduct prospective trials to assess the clinical benefits of LET-guided optimization on patient outcomes.