Linear energy transfer-inclusive models of brainstem necrosis following proton therapy of paediatric ependymoma

Andreas H Handeland; Daniel J Indelicato; Lars Fredrik Fjæra; Kristian S Ytre-Hauge; Helge Egil S Pettersen; Ludvig P Muren; Yasmin Lassen-Ramshad; Camilla H Stokkevåg

doi:10.1016/j.phro.2023.100466

Linear energy transfer-inclusive models of brainstem necrosis following proton therapy of paediatric ependymoma

Phys Imaging Radiat Oncol. 2023 Jun 29:27:100466. doi: 10.1016/j.phro.2023.100466. eCollection 2023 Jul.

Authors

Affiliations

¹ Department of Physics and Technology, University of Bergen, Bergen, Norway.
² Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.
³ Department of Radiation Oncology, University of Florida, Jacksonville, FL, USA.
⁴ Department of Medical Physics, Oslo University Hospital, Norway.
⁵ Danish Centre for Particle Therapy, Aarhus University Hospital, Aarhus, Denmark.
⁶ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

Abstract

Background and purpose: Radiation-induced brainstem necrosis after proton therapy is a severe toxicity with potential association to uncertainties in the proton relative biological effectiveness (RBE). A constant RBE of 1.1 is assumed clinically, but the RBE is known to vary with linear energy transfer (LET). LET-inclusive predictive models of toxicity may therefore be beneficial during proton treatment planning. Hence, we aimed to construct models describing the association between brainstem necrosis and LET in the brainstem.

Materials and methods: A matched case-control cohort (n = 28, 1:3 case-control ratio) of symptomatic brainstem necrosis was selected from 954 paediatric ependymoma brain tumour patients treated with passively scattered proton therapy. Dose-averaged LET (LET_d) parameters in restricted volumes (L_50%, L_10% and L_0.1cm³, the cumulative LET_d) within high-dose thresholds were included in linear- and logistic regression normal tissue complication probability (NTCP) models.

Results: A 1 keV/µm increase in L_10% to the brainstem volume receiving dose over 54 Gy(RBE) led to an increased brainstem necrosis risk [95% confidence interval] of 2.5 [0.0, 7.8] percentage points. The corresponding logistic regression model had area under the receiver operating characteristic curve (AUC) of 0.76, increasing to 0.84 with the anterior pons substructure as a second parameter. 19 [7, 350] patients with toxicity were required to associate the L_10% (D > 54 Gy(RBE)) and brainstem necrosis with 80% statistical power.

Conclusion: The established models of brainstem necrosis illustrate a potential impact of high LET regions in patients receiving high doses to the brainstem, and thereby support LET mitigation during clinical treatment planning.

Keywords: Brainstem necrosis; Ependymoma; Linear energy transfer; Normal tissue complication probability; Pediatric; Proton therapy; Relative biological effectiveness.