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

TL;DR

This review discusses recent advances in LET calculation and integration into proton therapy planning for head and neck cancer, aiming to improve treatment outcomes and reduce adverse events by accounting for variable biological effects.

Contribution

It introduces dose-LET volume histograms and DLVC-guided optimization as novel tools for better treatment planning considering LET effects.

Findings

LET-guided robust optimization reduces high-LET exposure to organs at risk.

DLVH enables correlation of dose, LET, and clinical outcomes.

DLVC-guided optimization improves plan quality over traditional methods.

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.