Variable-RBE-induced NTCP predictions for various side-effects following proton therapy for brain tumors - Identification of high-risk patients and risk mitigation.

Background and Purpose: Disregarding the increase of relative biological effectiveness (RBE) may raise the risk of acute and late adverse events after proton beam therapy (PBT). This study aims to explore the relationship between variable RBE (above 1.1)-induced normal tissue complication probabilities (NTCP) and patient-specific factors, identify patients at high risk of RBE-induced NTCP increase, and assess risk mitigation by incorporating RBE variability into treatment planning.
Materials and Methods: We retrospectively analyzed 105 primary brain tumor patients treated with PBT (RBE = 1.1). We calculated differences in estimated NTCP (ΔNTCP) using a variable RBE-weighted dose (D _RBE , Wedenberg model) and a constant RBE-weighted dose (D _RBE=1.1 ), across 16 NTCP models. These differences were correlated with patient-specific characteristics. Based on ΔNTCP, patients were classified as high risk (32 %) or low risk (68 %) for adverse events due to RBE-induced NTCP. This classification was compared with alternative classifications based on (a) relevant patient-specific characteristics, (b) D _RBE=1.1 , and (c) the difference between D _RBE and D _RBE=1.1 (ΔD), assessing the balanced accuracy. The potential to reduce RBE-induced NTCP through track-end and linear energy transfer (LET) optimization was evaluated in six example patients.
Results: Using a variable RBE instead of a constant one resulted in NTCP increases (up to 32 percentage points). Variable-RBE-induced NTCP increases were strongly negatively correlated with the distance between the clinical target volume (CTV) and the organ at risk (OAR) for most side-effects, and positively correlated with CTV volume for certain side-effects. High increases were associated with (a) specific patient factors, particularly the proximity of the CTV to OARs, (b) D _RBE=1.1 , and (c) ΔD, with a balanced accuracy of 0.88, 0.94, and 0.86, respectively. Optimization of track-ends and LET considerably reduced NTCP values, achieving a mean reduction of 31 % for optimized OARs.
Conclusion: The risk of variable-RBE-induced NTCP strongly depends on patient-specific factors and the considered side-effect. A small distance between the tumor and OARs notably increases the risk. Integrating biologically-guided objectives into treatment planning can effectively mitigate the risk.
Competing Interests: Declaration of competing interest For the present study, the authors received no external financial support, neither for the study design or materials used, nor for the collection, analysis, and interpretation of data, nor for the writing of the publication. OncoRay has a research collaboration with RaySearch Laboratories. Dr. Christian Hahn is employed at RaySearch Laboratories AB. In the past 5 years, Dr. Mechthild Krause received funding for her research projects by Merck KGaA (2014-2018 for preclinical study; 2018-2020 for clinical study), Medipan GmbH (2014-2018). Dr. Mechthild Krause is involved in an ongoing publicly funded (German Federal Ministry of Education and Research) project with the companies Medipan (2019-2022), Attomol GmbH (2019-2022), GA Generic Assays GmbH (2019-2022), Gesellschaft für medizinische und wissenschaftliche genetische Analysen (2019-2022), Lipotype GmbH (2019-2022) and PolyAn GmbH (2019-2022). Dr. Krause confirms that, to the best of their knowledge, none of the above-mentioned funding sources were involved in the preparation of this paper. All other authors have declared no conflicts of interest.
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