Differential Lung Tissue Response and Patient Outcomes Between Protons and Photons Receiving Regional Nodal...

The purpose of this paper is to quantify radiation-induced lung density changes in patients with breast cancer treated with proton therapy and compare the effect to photon therapy, assessing both temporal dynamics and spatial distribution of these changes.

We prospectively collected serial noncontrast computed tomography scans on a cohort of 91 patients at 6- and 12-month post-radiation therapy. All patients were co-enrolled on a randomized clinical trial and a correlative substudy at Massachusetts General Hospital between 2017 and 2023. Deformably registered planning and follow-up (FU) computed tomography scans were analyzed using voxel-wise Hounsfield unit (HU) changes binned by dose (5 Gy relative biological effectiveness [RBE] increments) within the ipsilateral lung. Dose-response relationships were modeled using the Lyman-Kutcher-Burman model to estimate the dose associated with 50% of the observed maximum lung density changes in HU (TD₅₀) and slope (m) parameters as comparative metrics between modalities. Bootstrap analysis with 10,000 iterations was used to determine confidence intervals and assess statistical significance. RBE was calculated as the ratio of photon to proton TD₅₀ values per voxel. Demographic and clinical variables were tested to rule out confounding.

A total of 71 patients had complete FU imaging (36 protons and 35 photons). Proton therapy demonstrated significantly lower TD₅₀ values than photon therapy at both FU visits, indicating greater radiation sensitivity. The right-sided free-breathing cohorts showed TD₅₀ of 33.4 Gy(RBE) for protons versus 45.1 Gy for photons at 8.5 months, with RBE of 1.35 (95% CI, 1.18-1.44), decreasing to 1.27 (95% CI, 1.14-1.36) at second follow-up. The overall population showed TD₅₀ of 34.5 Gy(RBE) for protons versus 43.6 Gy for photons at first follow-up with an RBE of 1.27 (95% CI, 1.14-1.33), decreasing to 1.24 (95% CI, 1.12-1.33) at second follow-up. No significant confounders were identified. Temporal analysis revealed an earlier onset of HU changes with protons, but there were no significant associations between patient pulmonary toxicities and TD₅₀ values. No patients developed clinically relevant pneumonitis or fibrosis. Cough and dyspnea rates were similar between groups (P > .40), with no correlations between HU changes and symptoms.

Despite equivalent clinical pulmonary outcomes, proton therapy demonstrates greater subclinical lung tissue changes than photon therapy. These findings support ongoing evaluation of potentially linear energy transfer- and RBE-based optimization strategies in proton therapy planning and highlight the need for personalized approaches accounting for RBE variability.