End-of-range Radiobiological Effect on Rib Fractures in Patients Receiving Proton Therapy for Breast Cancer.

PURPOSE: A prospective trial of proton therapy for breast cancer revealed an increased rib fracture rate of 7%, which is higher than the expected rate based on the literature on photon therapies. We aim to evaluate the hypothesis that the increased relative biological effectiveness (RBE) at the distal edge of proton beams is the reason. METHODS AND MATERIALS: We combined the cohort from the prospective clinical trial and a retrospective cohort from a database. Monte Carlo simulations were performed to recalculate the physical dose and dose-averaged linear energy transfer (LETd). The first 10 ribs and fracture areas in patients with fractures were contoured and deformably registered. The LETd-weighted dose was used as a surrogate for biological effectiveness and compared with the conventional fixed RBE of 1.1. Dose to 0.5 cc of the ribs (D0.5) was selected to analyze the dose-response relationship using logistic regression. We chose an alpha/beta ratio of 3 to calculate the biological effective dose in Gy3(RBE). RESULTS: Thirteen patients from the 203 patients in the cohorts exhibited a total of 25 fractures. The LETd in fractured areas is increased (6.1 +/- 2.0 keV/mum, mean +/- standard deviation), suggesting possible end-of-range radiobiological effect with increased RBE. The D0.5 of the fractured ribs is 80.3 +/- 9.4 Gy3(RBE) with a generic factor of 1.1 and is relatively low compared to historical photon results. On the other hand, the D0.5 of the fractured ribs is 100.0 +/- 12.5 Gy3(RBE) using the LETd-based model with a dose-response curve that is more consistent with historical photon data. CONCLUSIONS: The increased rib fracture rate seen in our trial is probably associated with the increased LETd and RBE at the distal edge of proton beams. This phenomenon warrants further investigation and possible integration of LETd into treatment planning and optimization in proton therapy.