BACKGROUND AND PURPOSE: A constant relative biological effectiveness (RBE) of 1.1 is used in clinical proton therapy (PT) to convert prescribed photon doses into isoeffective proton doses. However, the RBE is not constant
it is a dynamic parameter highly influenced by factors such as linear energy transfer, tissue type, biological endpoint, and dose/fraction. Preclinical in vivo proton RBE studies using fractionated doses and late damage endpoints are almost nonexistent. The aim is to test the hypotheses that the RBE varies between single and fractionated doses and that the late damage development differs between proton and photon irradiation using a 6 MV linac as a reference modality in a murine leg model. MATERIALS AND METHODS: The right hindlimb of unanesthetized mice was irradiated with single or four fractions of protons or 6 MV photons. Over one year after treatment, the mice were analyzed every fourteenth day using a joint contracture assay to investigate severe radiation-induced late damage. RESULTS: The results indicated a higher RBE for severe late damage endpoint of 1.25 ± 0.06 (1.13-1.36) for fractionated doses than single doses, exhibiting an RBE of 1.16 ± 0.08 (1.00-1.31). The onset of late damage is earlier for protons than photons for doses higher than 47 Gy and fractionated doses above 50 Gy (12.5 Gy per fraction). CONCLUSION: The findings demonstrate that fractionated doses enhance the RBE for a late damage endpoint and lead to an earlier onset of severe late effects than its photon counterpart in vivo.