National indication protocol for proton radiotherapy in esophageal cancer patients in the Netherlands

BACKGROUND: Chemoradiotherapy (CRT) plays a key role in treating esophageal cancer (EC) but is associated with significant toxicity. Proton radiotherapy (PRT) may reduce this risk by limiting radiation dose to organs at risk. In the Netherlands, PRT is reimbursed only when eligibility criteria defined in a National Indication Protocol for Proton Therapy (NIPP) are met. This study describes the development and implementation of such a protocol for EC based on model-based selection. MATERIALS AND METHODS: A national multidisciplinary working group was formed aiming to develop the NIPP protocol through literature review, evaluation of prediction models, external model validation, and stakeholder engagement. RESULTS: Cardiac events and overall survival were identified as the most clinically relevant endpoints. As no existing models met the quality criteria for model-based selection, a validated 2-year mortality prediction model originally developed for lung cancer was externally validated in EC patients treated with definitive (dCRT) or neoadjuvant (nCRT) CRT. The model performed well after updates to the intercept (both cohorts) and slope (nCRT). Model-based selection was defined as a = 5 % predicted absolute reduction in 2-year mortality with PRT versus photon radiotherapy, using Mean Heart Dose (MHD) and Gross Tumor Volume (GTV) as predictors. Additional selection criteria included WHO performance status 0-2 and exclusion of cT4, cN3, or cM1 status. The NIPP was approved by the Dutch Society of Radiation Oncology in June 2021 and by the Dutch Health Care Institute in October 2021. National implementation and prospective outcome evaluation are ongoing via the ProTRAIT registry. CONCLUSION: A national indication protocol enabling model-based selection for PRT in EC was successfully implemented in the Netherlands. The NIPP describes eligibility criteria for proton therapy reimbursement and enables reimbursement for individual patients who are expected to benefit from PRT.