Spatial correlation of linear energy transfer and relative biological effectiveness with suspected treatment-related toxicities following proton therapy for intracranial tumors.

Abstract

The enhanced relative biological effectiveness (RBE) at the end of the proton range might increase the risk of radiation-induced toxicities. This is of special concern for intracranial treatments where several critical organs at risk (OARs) surround the tumor. In the light of this, a retrospective analysis of dose-averaged linear energy transfer (LETd ) and RBE-weighted dose (DRBE ) distributions was conducted for three clinical cases with suspected treatment-related toxicities following intracranial proton therapy. Alternative treatment strategies aiming to reduce toxicity risks are also presented. The clinical single-field optimized (SFO) plans were recalculated for 81 error scenarios with a Monte Carlo dose engine. The fractionation DRBE was 1.8Gy (RBE) in 28 or 30 fractions assuming a constant RBE of 1.1. Two LETd - and α/β-dependent variable RBE models were used for evaluation, including a sensitivity analysis of the α/β parameter. Resulting distributions of DRBE and LETd were analyzed together with normal tissue complication probabilities (NTCPs). Subsequently, four multi-field optimized (MFO) plans, with an additional beam and/or objectives penalizing protons stopping in OARs, were created to investigate the potential reduction of LETd , DRBE , and NTCP. The two variable RBE models agreed well and predicted average RBE values around 1.3 in the toxicity volumes, resulting in an increased near-maximum DRBE of 7-11Gy (RBE) compared to RBE=1.1 in the nominal scenario. The corresponding NTCP estimates increased from 0.8%, 0.0%, and 3.7% (RBE=1.1) to 15.5%, 1.8%, and 45.7% (Wedenberg RBE model) for the three patients, respectively. The MFO plans generally allowed for LETd , DRBE , and NTCP reductions in OARs, without compromising the target dose. Compared to the clinical SFO plans, the maximum reduction in the near-maximum LETd was 56%, 63%, and 72% in the OAR exhibiting the toxicity for the three patients, respectively. Although a direct causality between RBE and toxicity cannot be established here, high LETd and DRBE correlated spatially with the observed toxicities, whereas setup and range uncertainties had a minor impact. Individual factors, which might affect the patient-specific radiosensitivity, were however not included in these calculations. The MFO plans using both an additional beam and proton track-end objectives allowed the largest reductions in LETd , DRBE , and NTCP, and might be future tools for similar cases.