Asymptomatic Late-phase Radiographic Changes Among Chest-Wall Patients Are Associated With a Proton RBE Exceeding 1.1

Clinical practice assumes a fixed proton relative biological effectiveness (RBE) of 1.1, but in vitro experiments demonstrate higher RBEs at the distal edge of the proton spread-out Bragg peak, that is, in a region that falls within the lung for chest-wall patients. We performed retrospective qualitative and quantitative analyses of lung-density changes-indicative of asymptomatic fibrosis-for chest-wall patients treated with protons or photons. Our null hypothesis was that, assuming a fixed RBE of 1.1, these changes would be the same for the 2 cohorts, supporting current RBE practice. Our alternative hypothesis was that radiographic abnormalities would be greater for the proton cohort, suggesting an RBE > 1.1.

We analyzed follow-up computed tomography (CT) scans for 20 proton and photon patients. All were prescribed 50.4 Gy (RBE) in 28 fractions, assuming a fixed RBE of 1.1 for protons and 1 for photons. Deformable registrations enabled us to calculate density changes in the normal lung, specifically (1) median Hounsfield unit (HU) values among posttreatment CT scans and (2) changes in median HU values between pretreatment and posttreatment CT scans, both as a function of grays (RBE). In addition, qualitative abnormality grading was performed by a radiologist.

Proton patients exhibited higher values of HU/Gy (RBE) (endpoint 1) and ΔHU/Gy (RBE) (endpoint 2): P = .049 and P = .00019, respectively, were obtained (likelihood ratio tests of full linear mixed-effects models against models without "modality"). Furthermore, qualitative radiologic scoring indicated a significant difference between the cohorts (Wilcoxon P = .018; median score, 3 of 9 for protons and 1.5 of 9 for photons).

Our data support the hypothesis that the proton RBE for lung-density changes exceeds 1.1. This RBE elevation could be attributable to (1) the late, normal tissue endpoint that we consider or (2) end-of-range proton linear energy transfer elevation-or a combination of the two. Regardless, our results suggest that variations in proton RBE prove important in vivo as well as in vitro.