In Silico Interim Adaptation of Proton Therapy in Head and Neck Cancer by Simultaneous Dose and Linear Energy Transfer Escalation.

Abstract

The outcome of proton therapy for head and neck cancer (HNC) varies considerably. We investigated the feasibility of adapting proton therapy plans based on ¹⁸F-fluorodeoxyglucose-positron emission tomography-defined biologic tumor volumes (BTVs) reflecting remaining aggressive tumor subvolumes 2 weeks into treatment (interim). Recognizing the potential to improve proton therapy response with increasing linear energy transfer (LET), we simulated a combined dose-LET escalation to the BTVs and compared it to pure dose escalation. In addition, the impact of relative biological effectiveness (RBE) was evaluated by comparing the constant RBE of 1.1 (RBE_1.1) with a variable-RBE model. A semiautomated method was used to segment the BTV from ¹⁸F-fluorodeoxyglucose-positron emission tomography-defined for 9 patients with HNC, assuming high standardized uptake value at interim to reflect tumor radioresistance. An in-house Monte Carlo-based recalculation and reoptimization tool simulated proton therapy plans with both constant RBE_1.1 and variable-RBE, aimed to deliver 68 Gy (RBE) to high-risk target volumes, 10% dose escalation to the BTV, and a LET boost to the BTV. Dose distributions were prioritized over LET optimization goals. Results were quantified by dose and LET distributions to target volumes and organs at risk, as well as normal tissue complication probabilities (NTCPs) for xerostomia and dysphagia. Dose-LET adapted proton therapy plans achieved 10% dose escalation and mean dose-averaged LET (LET_d) increases to the BTV above 1.0 keV/μm, with no significant LET increases to organs at risk. NTCP for xerostomia and dysphagia from dose-LET and dose-only escalation were similar. However, NTCPs increased 6% to 10% when variable-RBE was used instead of the constant RBE_1.1. Our in silico study showed that dose-LET escalation in proton therapy integrating a variable-RBE model may improve proton therapy for patients with HNC. Clinical evaluation of such a biological image-based dose-LET escalation in proton therapy of HNC remains to be investigated.