Impact of range uncertainty on clinical distributions of linear energy transfer and biological effectiveness in proton therapy

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Purpose Increased radiation response after proton irradiation, such as late radiation‐induced toxicity, is determined by high dose and elevated linear energy transfer (LET). Steep dose‐averaged LET (LETd) gradients and elevated LETd occur at the end of proton range and might be particularly sensitive to uncertainties in range prediction. Therefore, this study quantified LETd distributions and the impact of range uncertainty in robust dose‐optimized proton treatment plans and assessed the biological effect in normal tissues and tumors of patients. Methods For each of six cancer patients (two brain, head‐and‐neck, and prostate), two nominal treatment plans were robustly dose optimized using single‐ and multi‐field optimization, respectively. For each plan, two additional scenarios with ±3.5% range deviation relative to the nominal plan were derived by global rescaling of stopping‐power ratios. Dose and LETd distributions were calculated for each scenario using the beam parameters of the corresponding nominal plan. The variability in relative biological effectiveness (RBE) and probability of late radiation‐induced brain toxicity (PIC) was assessed. Results The optimization technique (single‐ vs multi‐field) had a negligible impact on the LETd distributions in the clinical target volume (CTV) and in most organs at risk (OARs). LETd distributions in the CTV were rather homogeneous with arithmetic mean of LETd below 3.2 keV/µm and robust against range deviations. The RBE variability within the CTV induced by range uncertainty was small (≤0.05, 95% confidence interval). In OARs, LETd hotspots (>7 keV/µm) occurred and LETd distributions were inhomogeneous and sensitive to range deviations. LETd hotspots and the impact of range deviations were most prominent in OARs of brain tumor patients which translated in RBE values exceeding 1.1 in all brain OARs. The near‐maximum predicted PIC in healthy brain tissue of brain tumor patients was smaller than 5% and occurred adjacent to the CTV. Range deviations induced absolute differences in PIC up to 1.2%. Conclusions Robust dose optimization generates LETd distributions in the target volume robust against range deviations. The current findings support using a constant RBE within the CTV. The impact of range deviations on the considered probability of late radiation‐induced toxicity in brain tissue was limited for robust dose‐optimized treatment plans. Incorporation of LETd in robust optimization frameworks may further reduce uncertainty related to the RBE‐weighted dose estimation in normal tissues.

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