Cardiotoxicity as an Endpoint in Prospective Clinical Trials Involving Chest Radiation Therapy.

Abstract

PURPOSE/OBJECTIVE(S)\nChest radiation therapy (RT) has been associated with increased cardiac morbidity and mortality in a number of retrospective studies, including the landmark Darby study published in 2013 that demonstrated a linear increase in cardiac mortality with increasing mean heart radiation dose. The adverse effects of RT on the heart have led to an increased focus on minimizing radiation dose to the heart or its substructures during radiation planning. However, the extent to which cardiotoxicity has been incorporated as an endpoint in prospective RT studies remains unknown. We hypothesized that cardiotoxicity has increased in frequency as an endpoint in oncology trials involving thoracic RT since publication of the Darby study in 2013, and we sought to quantify this change in trial design.\n\n\nMATERIALS/METHODS\nWe queried clinicaltrials.gov for all phase II/III interventional studies conducted from 1/1/2006 until 2/1/2021 which included RT for breast, esophageal, lymphoma, mesothelioma, thymoma, or lung cancer with a planned enrollment of ≥100 patients. Studies were categorized into the pre-Darby era (enrollment started prior to 1/1/2014) or the post-Darby era (enrollment after 1/1/2014). We determined whether each eligible study included cardiotoxicity as a specific primary or secondary endpoint. The primary endpoint was to compare the rate of studies with a cardiotoxicity endpoint in the pre-Darby versus post-Darby era using the Chi-square test (P < 0.05 considered significant).\n\n\nRESULTS\nOverall, 1,822 trials were reviewed and 256 met the study criteria. Of the trials included, 32% were for esophageal cancer, 31% for lung cancer, 28% for breast cancer, and 7% lymphoma/thymoma/mesothelioma. Overall, 5% (N\u202f=\u202f13) included cardiotoxicity as an endpoint: 6 breast cancer, 3 lung cancer, 3 esophageal cancer, and 1 lymphoma study. There was no statistically significant increase in the inclusion of cardiotoxicity as an endpoint in the pre-Darby versus post-Darby era (3.9% vs. 5.9%, P\u202f=\u202f0.46). The greatest absolute increase in inclusion of cardiotoxicity as an endpoint was seen for lung cancer (0% vs. 6%, P\u202f=\u202f0.17) and breast cancer (5.7% vs. 10.8%, P\u202f=\u202f0.43) studies, though these increases remained insignificant.\n\n\nCONCLUSION\nAmong prospective clinical trials involving chest RT, cardiotoxicity remains an uncommon endpoint despite its prevalence as a primary source of toxicity following treatment. Breast cancer RT trials had the highest rates of including cardiotoxicity endpoints in the pre- and post-Darby era, though this rate remained low at 10%. Despite increased recognition that cardiac toxicity is prevalent after chest RT, there has been no detectable increase in the inclusion of cardiotoxicity endpoints in prospective clinical trials. In order to better characterize cardiac toxicities, future prospective studies involving chest RT should include cardiotoxicity endpoints.