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

Simple Summary The increasing global demand and accessibility for proton beam therapy has been fueled by its recognised clinical benefits over traditional radiotherapy, primarily its ability to precisely target tumors while sparing more healthy tissue. However, the effectiveness of proton treatment plans can be compromised by four key variables: patient motion, patient setup, proton range, and radiobiological effects. A promising solution for mitigating radiobiological uncertainty is a novel method known as Linear Energy Transfer (LET) optimisation. This systematic review is aimed at compiling data related to the clinical motivation for, and various methodologies of, LET optimisation in proton beam therapy. It will present the current standing of LET optimisation in the field, and provide recommendations for future research and clinical deployment.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 & REG; 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.