Relative Biological Effectiveness Uncertainties and Implications for Beam Arrangements and Dose Constraints in Proton Therapy.

Current clinical implementation of proton radiation therapy assumes a constant relative biological effectiveness (RBE) value of 1.1 throughout the treatment field, for both the target and organs at risks. Although few in vivo clinical data suggest that this approximation is clinically significant, in vitro studies demonstrate the dependency of RBE on dose, fractionation, proton energy, and linear energy transfer, as well as patient radiosensitivity and definition of endpoint. This article provides a brief review on the principles and individual factors contributing to RBE uncertainties, with emphasis on clinical practice. Clinical considerations regarding the effect of RBE uncertainties and implications for beam arrangements in proton therapy treatment planning are discussed through clinical examples for treatments of prostate cancer and posterior fossa tumors as well as craniospinal irradiation for medulloblastoma. Approaches on biological optimization in proton therapy are presented, including a discussion on linear energy transfer-based optimization as an alternative method for biological optimization and its implementation both in multicriteria optimization and inverse optimization modules.