Comparing biological effectiveness guided plan optimization strategies for cranial proton therapy: potential and challenges

BACKGROUND: To introduce and compare multiple biological effectiveness guided (BG) proton plan optimization strategies minimizing variable relative biological effectiveness (RBE) induced dose burden in organs at risk (OAR) while maintaining plan quality with a constant RBE. METHODS: Dose-optimized (DOSEopt) proton pencil beam scanning reference treatment plans were generated for ten cranial patients with prescription doses ≥ 54 Gy(RBE) and ≥ 1 OAR close to the clinical target volume (CTV). For each patient, four additional BG plans were created. BG objectives minimized either proton track-ends, dose-averaged linear energy transfer (LET(d)), energy depositions from high-LET protons or variable RBE-weighted dose (D(RBE)) in adjacent serially structured OARs. Plan quality (RBE = 1.1) was assessed by CTV dose coverage and robustness (2 mm setup, 3.5% density), dose homogeneity and conformity in the planning target volumes and adherence to OAR tolerance doses. LET(d), D(RBE) (Wedenberg model, α/β(CTV) = 10 Gy, α/β(OAR) = 2 Gy) and resulting normal tissue complication probabilities (NTCPs) for blindness and brainstem necrosis were derived. Differences between DOSEopt and BG optimized plans were assessed and statistically tested (Wilcoxon signed rank, α = 0.05). RESULTS: All plans were clinically acceptable. DOSEopt and BG optimized plans were comparable in target volume coverage, homogeneity and conformity. For recalculated D(RBE) in all patients, all BG plans significantly reduced near-maximum D(RBE) to critical OARs with differences up to 8.2 Gy(RBE) (p < 0.05). Direct D(RBE) optimization primarily reduced absorbed dose in OARs (average ΔD(mean) = 2.0 Gy; average ΔLET(d,mean) = 0.1 keV/µm), while the other strategies reduced LET(d) (average ΔD(mean) < 0.3 Gy; average ΔLET(d,mean) = 0.5 keV/µm). LET-optimizing strategies were more robust against range and setup uncertaintes for high-dose CTVs than D(RBE) optimization. All BG strategies reduced NTCP for brainstem necrosis and blindness on average by 47% with average and maximum reductions of 5.4 and 18.4 percentage points, respectively. CONCLUSIONS: All BG strategies reduced variable RBE-induced NTCPs to OARs. Reducing LET(d) in high-dose voxels may be favourable due to its adherence to current dose reporting and maintenance of clinical plan quality and the availability of reported LET(d) and dose levels from clinical toxicity reports after cranial proton therapy. These optimization strategies beyond dose may be a first step towards safely translating variable RBE optimization in the clinics.