Brainstem NTCP and Dose Constraints for Carbon Ion RT-Application and Translation From Japanese to European RBE-Weighted Dose.

The Italian National Center of Oncological Hadrontherapy (CNAO) has applied dose constraints for carbon ion RT (CIRT) as defined by Japan's National Institute of Radiological Sciences (NIRS). However, these institutions use different models to predict the relative biological effectiveness (RBE). CNAO applies the Local Effect Model I (LEM I), which in most clinical situations predicts higher RBE than NIRS's Microdosimetric Kinetic Model (MKM). Equal constraints therefore become more restrictive at CNAO. Tolerance doses for the brainstem have not been validated for LEM I-weighted dose (D LEM I). However, brainstem constraints and a Normal Tissue Complication Probability (NTCP) model were recently reported for MKM-weighted dose (D MKM), showing that a constraint relaxation to D MKM|0.7 cm3 <30 Gy (RBE) and D MKM|0.1 cm3 <40 Gy (RBE) was feasible. The aim of this work was to evaluate the brainstem NTCP associated with CNAO's current clinical practice and to propose new brainstem constraints for LEM I-optimized CIRT at CNAO. We reproduced the absorbed dose of 30 representative patient treatment plans from CNAO. Subsequently, we calculated both D LEM I and D MKM, and the relationship between D MKM and D LEM I for various brainstem dose metrics was analyzed. Furthermore, the NTCP model developed for D MKM was applied to estimate the NTCPs of the delivered plans. The translation of CNAO treatment plans to D MKM confirmed that the former CNAO constraints were conservative compared with D MKM constraints. Estimated NTCPs were 0% for all but one case, in which the NTCP was 2%. The relationship D MKM/D LEM I could be described by a quadratic regression model which revealed that the validated D MKM constraints corresponded to D LEM I|0.7 cm3 <41 Gy (RBE) (95% CI, 38-44 Gy (RBE)) and D LEM I|0.1 cm3 <49 Gy (RBE) (95% CI, 46-52 Gy (RBE)). Our study demonstrates that RBE-weighted dose translation is of crucial importance in order to exchange experience and thus harmonize CIRT treatments globally. To mitigate uncertainties involved, we propose to use the lower bound of the 95% CI of the translation estimates, i.e., D LEM I|0.7 cm3 <38 Gy (RBE) and D LEM I|0.1 cm3 <46 Gy (RBE) as brainstem dose constraints for 16 fraction CIRT treatments optimized with LEM I.

Dale JE ，Molinelli S ，Vischioni B ，Vitolo V ，Bonora M ，Magro G ，Mairani A ，Hasegawa A ，Ohno T ，Dahl O ，Valvo F ，Fossati P ... -  《Frontiers in Oncology》

Conversion and validation of rectal constraints for prostate carcinoma receiving hypofractionated carbon-ion radiotherapy with a local effect model.

Wang W ，Li P ，Sheng Y ，Huang Z ，Zhao J ，Hong Z ，Shahnazi K ，Jiang GL ，Zhang Q ... -  《Radiation Oncology》

RBE-weighted dose conversions for patients with recurrent nasopharyngeal carcinoma receiving carbon-ion radiotherapy from the local effect model to the microdosimetric kinetic model.

Zhang L ，Wang W ，Hu J ，Lu J ，Kong L ... -  《Radiation Oncology》

Organs at risk dose constraints in carbon ion radiotherapy at MedAustron: Translations between LEM and MKM RBE models and preliminary clinical results.

Carbon ion radiotherapy (CIRT) treatment planning is based on relative biological effectiveness (RBE) weighted dose calculations. A large amount of clinical evidence for CIRT was collected in Japan with RBE estimated by the modified microdosimetric kinetic model (MKM) while all European centres apply the first version of the local effect model (LEM). Japanese schedules have been used in Europe with adapted prescription dose and organs at risk (OAR) dose constraints. Recently, less conservative adapted LEM constraints have been implemented in clinical practice. The aim of this study was to analyse the new set of LEM dose constraints for brain parenchyma, brainstem and optic system considering both RBE models and evaluating early clinical data. 31 patients receiving CIRT at MedAustron were analysed using the RayStation v9A planning system by recalculating clinical LEM-based plans in MKM. Dose statistics (D1cm3, D5cm3, D0.1cm3, D0.7cm3, D10%, D20%) were extracted for relevant critical OARs. Curve fitting for those values was performed, resulting in linear quadratic translation models. Clinical and radiological toxicity was evaluated. Based on derived fits, currently applied LEM constraints matched recommended MKM constraints with deviations between -8% and +3.9%. For particular cases, data did not follow the expected LEM vs MKM trends resulting in outliers. Radiological (asymptomatic) toxicity was detected in two outlier cases. Respecting LEM constraints does not automatically ensure that MKM constraints are met. Constraints for both RBE models need to be fulfilled for future CIRT patients at MedAustron. Careful selection of planning strategies is essential.

Grosshagauer S ，Fossati P ，Schafasand M ，Carlino A ，Poljanc K ，Radakovits T ，Stock M ，Hug E ，Georg P ，Pelak M ，Góra J ... -  《-》

The sensitivity of radiobiological models in carbon ion radiotherapy (CIRT) and its consequences on the clinical treatment plan: Differences between LEM and MKM models.

Carbon ion radiotherapy (CIRT) relies on relative biological effectiveness (RBE)-weighted dose calculations. Japanese clinics predominantly use the microdosimetric kinetic model (MKM), while European centers utilize the local effect model (LEM). Despite both models estimating RBE-distributions in tissue, their physical and mathematical assumptions differ, leading to significant disparities in RBE-weighted doses. Several European clinics adopted Japanese treatment schedules, necessitating adjustments in dose prescriptions and organ at risk (OAR) constraints. In the context of these two clinically used standards for RBE-weighted dose estimation, the objective of this study was to highlight specific scenarios for which the translations between models diverge, as shortcomings between them can influence clinical decisions. Our aim was to discuss planning strategies minimizing those discrepancies, ultimately striving for more accurate and robust treatments. Evaluations were conducted in a virtual water phantom and patient CT-geometry, optimizing LEM RBE-weighted dose first and recomputing MKM thereafter. Dose-averaged linear energy transfer (LETd) distributions were also assessed. Results demonstrate how various parameters influence LEM/MKM translation. Similar LEM-dose distributions lead to markedly different MKM-dose distributions and variations in LETd. Generally, a homogeneous LEM RBE-weighted dose aligns with lower MKM values in most of the target volume. Nevertheless, paradoxical MKM hotspots may emerge (at the end of the range), potentially influencing clinical outcomes. Therefore, translation between models requires great caution. Understanding the relationship between these two clinical standards enables combining European and Japanese based experiences. The implementation of optimal planning strategies ensures the safety and acceptability of the clinical plan for both models and therefore enhances plan robustness from the RBE-weighted dose and LETd distribution point of view. This study emphasizes the importance of optimal planning strategies and the need for comprehensive CIRT plan quality assessment tools. In situations where simultaneous LEM and MKM computation capabilities are lacking, it can provide guidance in plan design, ultimately contributing to enhanced CIRT outcomes.

Góra J ，Grosshagauer S ，Fossati P ，Mumot M ，Stock M ，Schafasand M ，Carlino A ... -  《Journal of Applied Clinical Medical Physics》