A Systematic Review of LET-Guided Treatment Plan Optimisation in Proton Therapy: Identifying the Current State and Future Needs

Abstract

The well-known clinical benefits of proton therapy are achieved through higher target-conformality and normal tissue sparing than conventional radiotherapy. However, there is an increased sensitivity to uncertainties in patient motion/setup, proton range and radiobiological effect. Although recent efforts have mitigated some uncertainties, radiobiological effect remains unresolved due to a lack of clinical data for relevant endpoints. Therefore, RBE optimisations may be currently unsuitable for clinical treatment planning. LET optimisation is a novel method that substitutes RBE with LET, shifting LET hotspots outside critical structures. This review outlines the current status of LET optimisation in proton therapy, highlighting knowledge gaps and possible future research. Following the PRISMA 2020 guidelines, a search of the MEDLINE® and Scopus databases was performed in July 2023, identifying 70 relevant articles. Generally, LET optimisation methods achieved their treatment objectives; however, clinical benefit is patient-dependent. Inconsistencies in the reported data suggest further testing is required to identify therapeutically favourable methods. We discuss the methods which are suitable for near-future clinical deployment, with fast computation times and compatibility with existing treatment protocols. Although there is some clinical evidence of a correlation between high LET and adverse effects, further developments are needed to inform future patient selection protocols for widespread application of LET optimisation in proton therapy.

Sacral-Nerve-Sparing Planning Strategy in Pelvic Sarcomas/Chordomas Treated with Carbon-Ion Radiotherapy

“…Besides the multi-model dosimetric evaluation, in the last few years, there has been growing interest in evaluating the impact of high LETd distribution of carbon ions for tumors such as chondrosarcomas, chordomas, and pancreatic tumors and non-squamous head and neck cancers [46][47][48][49][50][51]. Some of the information on LETd-guided optimization is already been published for proton beam therapy [52]. In a mixed radiation field of CIRT, LETd might not be the best representation of the LET spectra in the voxel.…”

Assessment of fluence- and dose-averaged linear energy transfer with passive luminescence detectors in clinical proton beams

“…The enhanced RBE of protons is tied to the ionization density, which is typically quantified through the linear energy transfer (LET). Consequently, the LET has become an additional physical dimension in treatment planning, leading to the development of concepts such as LET painting (Bassler et al 2014) or using averaged LET (LET) as input for RBE parameterization (Unkelbach et al 2016, Bertolet and Carabe 2020, McIntyre et al 2023.…”

Particle tracking, recognition and LET evaluation of out-of-field proton therapy delivered to a phantom with implants

“…Nowadays, modern TPSs used in proton or heavy ion facilities are focus on a LET-based model that should be used in the final treatment optimization process to increase the spare of the healthy tissue (Liu et al 2013, Gu et al 2021. The LET of the particles that are crossing a pixeled detector is of interest for primary and secondary radiation spectral characterization especially when recent developments of TPS allow for LET treatment planning (Nabha et al 2022, McIntyre et al 2023, Novak et al 2023, Stasica et al 2023.…”