Impact of RBE variations on risk estimates of temporal lobe necrosis in patients treated with intensity-modulated proton therapy for head and neck cancer

Abstract

Background

Temporal lobe necrosis (TLN) is a potential late effect after radiotherapy for skull base head and neck cancer (HNC). Several photon-derived dose constraints and normal tissue complication probability (NTCP) models have been proposed, however variation in relative biological effectiveness (RBE) may challenge the applicability of these dose constraints and models in proton therapy. The purpose of this study was therefore to investigate the influence of RBE variations on risk estimates of TLN after Intensity-Modulated Proton Therapy for HNC.

Material and Methods

Seventy-five temporal lobes from 45 previously treated patients were included in the analysis. Sixteen temporal lobes had radiation associated Magnetic Resonance image changes (TLIC) suspected to be early signs of TLN. Fixed (RWD_Fix) and variable RBE-weighed doses (RWD_Var) were calculated using RBE = 1.1 and two RBE models, respectively. RWD_Fix and RWD_Var for temporal lobes were compared using Friedman’s test. Based on RWD_Fix, six NTCP models were fitted and internally validated through bootstrapping. Estimated probabilities from RWD_Fix and RWD_Var were compared using paired Wilcoxon test. Seven dose constraints were evaluated separately for RWD_Fix and RWD_Var by calculating the observed proportion of TLIC in temporal lobes meeting the specific dose constraints.

Results

RWD_Var were significantly higher than RWD_Fix (p < 0.01). NTCP model performance was good (AUC:0.79-0.84). The median difference in estimated probability between RWD_Fix and RWD_Var ranged between 5.3% and 20.0% points (p < 0.01), with V_60GyRBE and D_Max at the smallest and largest differences, respectively. The proportion of TLIC was higher for RWD_Fix (4.0%–13.1%) versus RWD_Var (1.3%–5.3%). For V_65GyRBE ≤ 0.03 cc the proportion of TLIC was less than 5% for both RWD_Fix and RWD_Var.

Conclusion

NTCP estimates were significantly influenced by RBE variations. D_max as model predictor resulted in the largest deviations in risk estimates between RWD_Fix and RWD_Var. V_65GyRBE ≤ 0.03 cc was the most consistent dose constraint for RWD_Fix and RWD_Var.

Keywords:

• Proton therapy
• head and neck neoplasm
• cerebral necrosis
• toxicity
• relative biological effectiveness
• normal tissue complication probability

Disclosure statement

Engeseth has nothing to disclose. Hysing has nothing to disclose. Yepes has nothing to disclose. Pettersen has nothing to disclose. Mohan has nothing to disclose. Fuller reports grants from National Institutes of Health, grants, personal fees, nonfinancial support and other from Elekta AB, personal fees from American Association of Physicists in Medicine, personal fees from Oregon Health & Science University, outside the submitted work. Stokkevåg has nothing to disclose. Wu has nothing to disclose. Zhang has nothing to disclose. Dr. Frank reports grants from Hitachi, personal fees from Varian, grants from Eli Lilly, personal fees from Boston Scientific, outside the submitted work. Dr Gunn has nothing to disclose.

Additional information

Funding

Engeseth received funding from Trond Mohn Foundation [TMS:BFS2017TMT07]. Dr. Fuller received/receives direct funding and salary support during the period of study execution from: the National Institutes of Health (NIH) NIBIB Research Education Programs for Residents and Clinical Fellows Grant [R25EB025787-01]; NIDCR Academic Industrial Partnership Grant [R01DE028290]; NCI Early Phase Clinical Trials in Imaging and Image-Guided Interventions Program [1R01CA218148]; an NIH/NCI Cancer Center Support Grant (CCSG) Pilot Research Program Award from the UT MD Anderson CCSG Radiation Oncology and Cancer Imaging Program [P30CA016672-44]; and an NSF Division of Civil, Mechanical, and Manufacturing Innovation (CMMI) grant [NSF 1933369]. Dr. Fuller has received direct industry grant support, honoraria, and travel funding from Elekta AB unrelated to this project. Direct infrastructure support is provided by the multidisciplinary the Radiation Oncology/Cancer Imaging Program [P30CA016672-44] of the MD Anderson Cancer Center Support Grant [P30CA016672] and the MD Anderson Program in Image-guided Cancer Therapy.