A Model-Based Approach to Predict Short-Term Toxicity Benefits With Proton Therapy for Oropharyngeal Cancer

Purpose : The aim of this study was to generate normal tissue complication probability (NTCP) models in patients treated with either proton beam therapy (PBT) or intensity-modulated radiotherapy (IMRT) for oropharynx cancer, and to use a model-based approach to investigate the added value of PBT in preventing treatment complications. Methods : For patients with advanced-stage oropharynx cancer, treated with curative intent (PBT, n=30; IMRT, n=175), NTCP models were developed using multivariable logistic regression analysis with backward selection. For PBT-treated patients, an equivalent IMRT plan was generated, to serve as a reference to determine the benefit of PBT in terms of NTCP. The models were then applied to the PBT treated patients to compare predicted and observed clinical outcomes (calibration-in-the large). Five binary endpoints were analyzed at 6-months post-treatment: dysphagia ≥ grade 2, dysphagia ≥ grade 3, xerostomia ≥ grade 2, salivary duct inflammation ≥ grade 2, and feeding tube dependence. Corresponding toxicity grading was based on CTCAEv4. Paired t-tests and Wilcoxon rank tests were used to compare mean NTCP results for endpoints between PBT and IMRT. Results: NTCP models developed based on outcomes from all patients were applied to those receiving PBT. NTCP-values were calculated for the equivalent IMRT plans for all PBT treated patients, revealing significantly higher NTCP-values with IMRT. PBT was associated with statistically significant reductions in the mean NTCP values for each endpoint at 6-months post treatment, with the largest absolute differences in rates of > grade 2 dysphagia and > grade 2 xerostomia. Conclusion : NTCP models predict significant improvements in the probability of short-term, treatment-related toxicity with PBT compared to IMRT for oropharyngeal cancer. This study demonstrated an NTCP model-based approach to compare predicted patient outcomes when randomized data are not available. hypothesize that improvements in dosimetric normal tissue sparing with PBT will translate to lower toxicity compared to treatment with IMRT. This (institution review board approved) study included patients with locally-advanced oropharyngeal carcinoma treated with curative intent multi-modality therapy from two institutions who had at least one year of follow-up. The cohort from the XXXXX consisted of 30 patients with oropharyngeal carcinoma treated with surgery followed by adjuvant proton radiotherapy, with or without chemotherapy (decision to offer chemotherapy was consistent with standard of care, such as the presence of positive margin and/or extranodal extension [19]) between 2013 and 2016. The cohort from the XXXXXX consisted of 175 patients mainly with locally-advanced oropharyngeal carcinoma treated with definitive photon radiotherapy with or without chemotherapy. Approaches to predict upfront the potential clinical gains of a new technology or approach in radiation delivery are needed in a rapidly advancing field. This study reports on an outcomes-based predictive model of anticipated gains (xerostomia and dysphagia) for proton therapy in the treatment of oropharynx cancer. These results and this approach can be used to complement prospective trials, or to rationalize novel treatment approaches when randomized data are not yet available.