NTCP modelling and external validation of early side effects for proton therapy of brain tumours

Purpose: To identify patients who are likely to benefit most from proton beam therapy (PBT), based on the potential reduction in normal tissue complication probability (NTCP) compared to photon therapy. The NTCP models required for this decision were developed using clinical data on early side effects for patients with brain tumours who underwent PBT.

Material and methods: Two cohorts of adult patients with brain tumours who received PBT were included in this study: 113 patients treated at University Proton Therapy Dresden were used for model training and 71 cases from West German Proton Therapy Centre Essen were used for external validation. Moreover, volumetric modulated arc therapy (VMAT) plans were retrospectively created for all patients to predict the potential reduction in NTCP when applying PBT. The radiation-induced early side effects alopecia, erythema, pain and fatigue were investigated. The occurrence of these side effects was correlated with different DVH parameters of associated organs at risk (OAR), such as skin and remaining brain. NTCP models were created using logistic regression and the area under the receiver operating characteristic curve (AUC) was used to assess their prognostic ability.

Results: The NTCP models revealed significant correlations between the incidence of alopecia grade 2 (figure a) as well as erythema grade≥1 and the DVH parameters D1%, D2%, V15Gy and V20Gy of the skin. The V20Gy models showed a very good discrimination on external validation for both endpoints (AUC≥0.75, figure b). No correlations between DVH parameters of the remaining brain and the incidence of fatigue or pain were found. Dose comparison between PBT and VMAT showed large differences in both training and validation cohort, especially in the remaining brain. The mean brain dose of the PBT plans was significantly lower compared to VMAT (median training: 6.9Gy vs 18.6Gy, median validation: 8.5Gy vs 16.0Gy; p<0.001). For alopecia grade 2, plan comparison between PBT and VMAT predicted a potential median NTCP reduction for PBT of approx. 5% (range: -39% – 32%) in the training and 1% (range: -25% – 37%) in the validation cohort. A reduction of NTCP for alopecia grade 2 for PBT by more than 10% was observed for 12/113 patients in training and for 9/71 patients in validation.

Conclusion: Plan comparison showed a large reduction in dose to the brain using PBT instead of VMAT. We found significant correlations between the occurrence of early side effects and DVH parameters of associated OARs for patients with brain tumours receiving PBT. A relevant reduction of NTCP (>10%) for PBT was calculated for approx. 10 % of the patients. However, due to the large range of NTCP reduction, patient individual calculations are mandatory. After inclusion of more relevant late side effects and neurocognitive changes, these models may be used to identify patients who are likely to benefit most from PBT [1].

[1] Langendijk JA et al. (2013) Radiother Oncol 107, 267-273.