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

Jon Espen Dale; Silvia Molinelli; Barbara Vischioni; Viviana Vitolo; Maria Bonora; Giuseppe Magro; Andrea Mairani; Azusa Hasegawa; Tatsuya Ohno; Olav Dahl; Francesca Valvo; Piero Fossati

doi:10.3389/fonc.2020.531344

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

Front Oncol. 2020 Nov 24:10:531344. doi: 10.3389/fonc.2020.531344. eCollection 2020.

Authors

Jon Espen Dale^{1

2}, Silvia Molinelli³, Barbara Vischioni³, Viviana Vitolo³, Maria Bonora³, Giuseppe Magro³, Andrea Mairani^{3

4}, Azusa Hasegawa^{3

5}, Tatsuya Ohno⁶, Olav Dahl¹, Francesca Valvo³, Piero Fossati^{3

7}

Affiliations

¹ Department of Clinical Science, Faculty of Medicine, University of Bergen, Bergen, Norway.
² Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
³ National Center of Oncological Hadrontherapy, Pavia, Italy.
⁴ Heidelberg Ion-Beam Therapy Center, Heidelberg, Germany.
⁵ Osaka Heavy Ion Therapy Center, Osaka, Japan.
⁶ Department of Radiation Oncology, Gunma University Graduate School of Medicine, Gunma, Japan.
⁷ MedAustron Ion Therapy Center, Wiener Neustadt, Austria.

Abstract

Background and purpose: 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.

Material and methods: 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.

Results: 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)).

Conclusion: 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.

Keywords: brainstem tolerance; carbon ion radiotherapy; dose constraints; local effect model; microdosimetric kinetic model; normal tissue complication probability; relative biological effectiveness (RBE).