Evaluation Of Radiographic Pulmonary Changes And Cytokine Expressions On A Prospective Longitudinal Clinical Trial After Radiation Therapy For Breast Cancer: A Comparison Of Proton Vs. Photon Therapy

Radiotherapy (RT) with regional nodal irradiation for breast cancer (BC) results in improved disease control and survival, but also lung exposure to RT. Proton therapy (PT) often results in improved lung dosimetry compared to conventional x-ray techniques (XRT) but a clinical benefit in terms of decreased lung toxicity has not yet been quantified. We have developed and implemented methodologies to analyze radiation induced lung injury (RILI) from serial chest CT scans to assess early, asymptomatic pulmonary changes in relation to lung dose and RT technique. These radiographic changes were correlated using Pearson’s correlation coefficient, with the blood cytokines (MCP-1, IL-1α, IL-1β, IL-1RA, IL-6, IL-8, VEGF, FGF-2, TNF-α, IFNα2, IFNγ) acquired at the same time points to identify asymptomatic breast cancer patients at high-risk for RILI. Post-RT chest CT scans and blood cytokines were acquired and analyzed at 1, 3, 6, 12 and 24-months on an ongoing IRB-approved protocol. CT images from RT simulation serve as a pre-RT baseline. For this preliminary analysis, 21 patients were assessed, with 80.95% (17 of 21; 6 XRT, 11 PT) and 57.1% (12 of 21; 5 XRT, 7 PT) attaining 6 month and 1-year follow-up, respectively. In-house software was used to segment the lung volume, register each scan to the simulation CT, transform the RT dose to each post-RT scan, and compute the (1) dose-volume histogram and (2) percent volume of ipsilateral lung fibrosis over time. The radiographic changes were also graded as 0-3 according to Lind et al. and correlated with blood cytokines (MCP-1, IL-1α, IL-1β, IL-1RA, IL-6, IL-8, VEGF, FGF-2, TNF-α, IFNα2, IFNγ) acquired at the same time points to identify asymptomatic breast cancer patients at high-risk for RILI. The median ipsilateral lung V20Gy was 32.1% (range 24.6%-39.7%) with XRT vs 18.8% (9.9%-26.3%) with PT. The incidences of grade 2-3 RILI post-RT were 66.7% (4 of 6) and 54.5% (6 of 11) at 6 months for patients treated with XRT and PT respectively and were 100% (5 of 5) and 42.9% (3 of 7) at 1 year, respectively. The percent volume of ipsilateral lung fibrosis post-RT were 0.2% (0.0%-0.6%) and 0.5% (0.0%-2.1%) at 6 months for patients treated with XRT and PT, respectively, and 0.25% (0.01%-0.54%) and 0.05% (0.0%-0.9%) at 1 year, respectively. The most significantly correlated cytokine with volume of fibrosis at 6 months (14 patients) was MCP-1 (60%) and at 12 months (9 patients) was VEGF (-67%). No patients developed pulmonary symptoms during follow-up. Both ipsilateral lung V20Gy and differential cytokine expressions seem to contribute to asymptomatic RILI. At 6 months MCP-1, a promoter of collagen synthesis, and at 12 months, vascular pruning as evidenced by decreased expressions of VEGF appear to dominate the formation of lung fibrosis. Additional follow-up evaluations are forthcoming from this ongoing study.