Project 1: Understanding normal tissue toxicity to identify patients most likely to benefit from proton therapy.

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PROJECT 1 - PROJECT SUMMARY A potential benefit of proton beam therapy compared to conventional therapy is expected for many treatment sites if solely judged by the dose distribution, i.e. physical parameters. Biological differences between protons and photons are currently only considered by applying a constant weighting factor to proton doses, i.e. a proton relative biological effectiveness (RBE) of 1.1. There is an urgent need for additional research to examine whether spatial variations in dose and RBE within organs at risk can explain adverse treatment outcomes. The potential difference in normal tissue toxicity between proton and photon irradiation can only be assessed with studies with a substantial amount of clinical data because the frequencies of most overt toxicities in radiation therapy is low, thus causing variations to be typically within the noise of patient specific radiosensitivity. There is a significant amount of clinical data available at our two institutions and equally as important, expertise in assessment of toxicities based on blood, imaging and dosimetric biomarkers. We hypothesize that there are fundamental differences in normal tissue toxicities between proton and photon radiation due not only to differences in the distribution of dose but also variations in RBE for normal tissue toxicities, which are currently poorly understood. We aim to 1) understand the differences in normal tissue toxicities between protons and photons by assessing dose response relationships, 2) identify biomarkers to inform relative normal tissue complication probabilities to replace simple RBE concepts, and 3) advance precision medicine concepts to proton radiotherapy by identifying patients that will benefit. Ultimately our approach will lead to novel outcome modeling concepts applicable to both proton and photon therapy.