RESUMO
Contemporary anticancer therapies frequently have different efficacy and side effects in men and women. Yet, whether women are well-represented in pivotal trials supporting contemporary anticancer drugs is unknown. Leveraging the Drugs@FDA database, clinicaltrials.gov, MEDLINE, and publicly available FDA-drug-reviews, we identified all pivotal (phase II and III) non-sex specific trials supporting FDA-approval of anticancer drugs (1998-2018). Observed-enrollment-rates were compared to expected-population-rates derived from concurrent US-National-Cancer-Institute's Surveillance-Epidemiology-and-End-Results (SEER) reported rates and US-Census databases. Primary outcome was the proportional representation of women across trials, evaluated by a participation-to-prevalence ratio (PPR), according to cancer type. Secondary outcome was the report of any sex-specific analysis of efficacy and/or safety, irrespective of treatment-arm. Overall, there were 148 trials, enrolling 60,216 participants (60.5 ± 4.0 years, 40.7% female, 79.1% biologic, targeted, or immune-based therapies) evaluating 99 drugs. Sex was reported in 146 (98.6%) trials, wherein 40.7% (24,538) were women, compared to 59.3% (35,678) men (p < .01). Altogether, women were under-represented in 66.9% trials compared to the proportional incidence of cancers by respective disease type; weight-average PPR of 0.91 (relative difference: -9.1%, p < .01). Women were most under-represented in gastric (PPR = 0.63), liver (PPR = 0.71), and lung (PPR = .81) cancer trials. Sex-based safety data was reported in 4.0% trials. There was no association between adequate female enrollment and drug efficacy (HR: 0.616 vs. 0.613, p = .96). Over time, there was no difference in the percentage of women recruited into clinical trials. Among pivotal clinical trials supporting contemporary FDA-approved cancer drugs, women were frequently under-represented and sex-specific-efficacy and safety-outcomes were commonly not reported.
RESUMO
PURPOSE: Radiation therapy (RT) associates with long-term cardiotoxicity. In preclinical models, RT exposure induces early cardiotoxic arrhythmias including atrial fibrillation (AF). Yet, whether this occurs in patients is unknown. METHODS AND MATERIALS: Leveraging a large cohort of consecutive patients with esophageal cancer treated with thoracic RT from 2007 to 2019, we assessed incidence and outcomes of incident AF. Secondary outcomes included major adverse cardiovascular events (MACE), defined as AF, heart failure, ventricular arrhythmias, and sudden death, by cardiac RT dose. We also assessed the relationship between AF development and progression-free and overall survival. Observed incident AF rates were compared with Framingham predicted rates, and absolute excess risks were estimated. Multivariate regression was used to define the relationship between clinical and RT measures, and outcomes. Differences in outcomes, by AF status, were also evaluated via 30-day landmark analysis. Furthermore, we assessed the effect of cardiac substructure RT dose (eg, left atrium, LA) on the risk of post RT-related outcomes. RESULTS: Overall, from 238 RT treated patients with esophageal cancer, 21.4% developed incident AF, and 33% developed MACE with the majority (84%) of events occurring ≤2 years of RT initiation (median time to AF, 4.1 months). Cumulative incidence of AF and MACE at 1 year was 19.5%, and 25.7%, respectively; translating into an observed incident AF rate of 824 per 10,000 person-years, compared with the Framingham predicted rate of 92 (relative risk, 8.96; P < .001, absolute excess risk 732). Increasing LA dose strongly associated with incident AF (P = .001); and those with AF saw worse disease progression (hazard ratio, 1.54; P = .03). In multivariate models, outside of traditional cancer-related factors, increasing RT dose to the LA remained associated with worse overall survival. CONCLUSIONS: Among patients with esophageal cancer, radiation therapy increases AF risk, and associates with worse long-term outcomes.