Mechanisms and Review of Clinical Evidence of Variations in Relative Biological Effectiveness in Proton Therapy.

Proton therapy is increasingly being used as a radiation therapy modality. There is uncertainty about the biological effectiveness of protons relative to photon therapies as it depends on several physical and biological parameters. Radiation oncology currently applies a constant and generic value for the relative biological effectiveness (RBE) of 1.1, which was chosen conservatively to ensure tumor coverage. The use of a constant value has been challenged particularly when considering normal tissue constraints. Potential variations in RBE have been assessed in several published reviews but have mostly focused on data from clonogenic cell survival experiments with unclear relevance for clinical proton therapy. The goal of this review is to put in vitro findings in relation to clinical observations. Relevant in vivo pathways determining RBE for tumors and normal tissues are outlined, including not only damage to tumor cells and parenchyma but also vascular damage and immune response. Furthermore, the current clinical evidence of varying RBE is reviewed. The assessment can serve as guidance for treatment planning, personalized dose prescriptions, and outcome analysis.