Cardiovascular Event Reporting in Clinical Trials Involving Chest Radiation Therapy

Abstract

Cardiovascular disease (CVD) is a serious consequence of anticancer therapy particularly following chest radiation therapy (RT). These events have been increasingly recognized to develop much earlier than previously anticipated and serve as a leading source of mortality. Yet, the extent to which CVD events are consistently reported in contemporary prospective trials is unknown. We hypothesized that CVD events are inconsistently reported in cancer trials involving chest RT. Querying 10 high-impact oncology or internal medicine journals, we identified all phase II/III trials from 2000-2019 wherein chest RT was delivered for lung, esophageal, lymphoma, mesothelioma, or breast cancer in at least 1 arm with enrollment of ≥100 patients and minimum 1-year follow up. The primary endpoint was the report of major adverse cardiovascular events (MACE) defined as myocardial infarction (MI), stroke, heart failure (HF), coronary revascularization, arrhythmia, or CVD death across all arms. The secondary endpoint was reporting of any CVD event. Rates of MACE across all trials were compared with incidence rates of CVD in a contemporary population of persons free of clinical CVD, as derived from the NIH-funded Multi-Ethnic Study of Atherosclerosis (MESA) observational cohort using relative risk (RR) ratios. Population risk differences for MACE were estimated. Overall, 111 trials with 59,624 patients and 367,142 person-years of follow-up met study criteria (mean age 57.8 +/- 10.6 years, 58.1% female). With a median follow-up of 48 months, 63% of trials reported any CVD. The incidence of any reported CVD events by cancer type ranged from lowest in breast cancer to highest in lung followed by esophageal (Table). In total, 471 MACE events were reported including 96 HF, 94 arrhythmia, 78 MI, 28 stroke, and 20 cardiac-arrest/sudden deaths. The remaining MACE incidents were unspecified grade 4+ cardiac toxicities. 310 MACE events occurred in the intervention arms vs. 144 in the control arms (p = 0.054) with 17 events in unspecified arms. The overall clinical trial incidence was 128 MACE events per 100,000 person-years (84.4 per 100,000 person-years in the intervention arm) compared to 1408 events per 100,000 person-years in MESA [RR: 0.24, CI:0.22-0.27, p<0.0001] translating to a risk difference of 0.54 (p<0.0001). Among pivotal RT based clinical trials, reported CVD rates are much lower than expected population rates. Highest rates of CVD reporting are among lung trials followed by esophageal with the lowest rates in breast cancer. Going forward, study design for future trials involving chest RT should ensure that CVD events are consistently reported.Abstract 108; TableTrialsPatientsCVD Not Reportedp ValueOverall11159,6244137%Cancer Type0.041Lung4742%17,8851838%Esophageal1413%3,588214%Lymphoma1715%9,563318%Mesothelioma22%526150%Breast3027&27,9561757%Other11%10600% Open table in a new tab