Cardiovascular Event Reporting in Modern Cancer Radiation Therapy Trials

Our plain-English summary of Cardiovascular Event Reporting in Modern Cancer Radiation Therapy Trials, by R.N. Prasad, M. McIntyre, A. Guha, et al (Advances in Radiation Oncology, 2022).

The study

• Authors: R.N. Prasad, M. McIntyre, A. Guha, R.R. Carter, V.O. Yildiz, E. Paskett, M. Lustberg, P. Ruz, T.M. Williams, O. Kola-Kehinde, E.D. Miller, D. Addison
• Journal: Advances in Radiation Oncology
• Published: 2022;7(2):100888
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in cancer survivors, particularly after chest radiation therapy (RT). However, the extent to which CVD events are consistently reported in contemporary prospective trials is unknown.

Methods And Materials: From 10 high-impact RT, oncology, and medicine journals, we identified all latter phase trials from 2000 to 2019 enrolling patients with breast, lung, lymphoma, mesothelioma, or esophageal cancer wherein chest-RT was delivered. The primary outcome was the report of major adverse cardiac events (MACEs), defined as incident myocardial infarction, heart failure, coronary revascularization, arrhythmia, stroke, or CVD death across treatment arms. The secondary outcome was the report of any CVD event. Multivariable regression was used to identify factors associated with CVD reporting. Pooled annualized incidence rates of MACEs across RT trials were compared with contemporary population rates using relative risks (RRs).

Results: The 108 trials that met criteria enrolled 59,070 patients (mean age, 58.0 ± 10.2 years; 46.0% female), with 273,587 person-years of available follow-up. During a median follow-up of 48 months, 468 MACEs were reported (including 96 heart failures, 75 acute coronary syndrome, 1 revascularization, 94 arrhythmias, 28 strokes, and 20 CVD deaths; 307 occurred in the intervention arms vs 144 in the control arms; RR, 1.96; P < .001). Altogether, 50.0% of trials did not report MACEs, and 37.0% did not report any CVD. The overall weighted-trial incidence was 376 events per 100,000 person-years compared with 1408 events per 100,000 person-years in similar nontrial patients (RR, 0.27; P < .001). There were no RT factors associated with CVD reporting.

Conclusion: In contemporary chest RT-based clinical trials, reported CVD rates were lower than expected population rates.

© 2021 The Author(s).

In plain English

This study examined how often heart and blood-vessel problems were reported in chest radiation cancer trials. The authors found 108 phase 2 and 3 trials from 2000 to 2019, enrolling 59,070 patients with lung cancer, esophageal cancer, lymphoma, mesothelioma or breast cancer. Only 2 trials, with 526 patients, involved mesothelioma, and asbestos was not studied. Half of the trials (50.0%) did not report major adverse cardiac events, and 37.0% did not report any cardiovascular events. Of 468 major cardiac events, 307 were in intervention arms and 144 in control arms (relative risk 1.96, 95% confidence interval 1.60 to 2.39). The rest could not be assigned to an arm. In trials reporting such events, the rate was 376 per 100,000 person-years, versus 1408 per 100,000 person-years in a population without overt clinical cardiovascular disease. Comparing the trial rate with that population's rate gave a relative risk of 0.27 (95% confidence interval 0.24 to 0.30). In multivariable analysis, no trial feature predicted whether heart problems were reported. The authors concluded that reported rates appeared to trail expected population rates and suggested underreporting. They noted their comparison population was imperfect.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Review and pooled analysis of published phase 2 and 3 clinical trials. The authors compared the cardiac events these trials reported with expected rates in a general population cohort (the Multi-Ethnic Study of Atherosclerosis, MESA).
• Who was studied: 108 phase 2 or 3 trials published 2000 to 2019 in ten journals. Each trial had more than 100 patients and at least 1 year of follow-up. Together they enrolled 59,070 patients with lung cancer, esophageal cancer, lymphoma, mesothelioma or breast cancer, with 273,587 person-years of follow-up. Mesothelioma accounted for 2 trials with 526 patients.
• Exposure: Chest radiation therapy, given in at least 1 arm of each trial, for lung cancer, esophageal cancer, lymphoma, mesothelioma or breast cancer. Asbestos exposure was not studied.
• Main results:
  • Across all 108 trials, 50.0% did not report major adverse cardiac events (MACEs) during follow-up, and 37.0% did not report any cardiovascular events.
  • 468 MACEs were reported across the trials: 96 heart failures, 94 arrhythmias, 75 acute coronary syndrome events, 28 strokes, and 20 cardiac-arrest or sudden deaths. The remainder were unspecified grade 3 or higher cardiac toxic effects.
  • In trials with observed MACEs, 307 events were in the intervention arms and 144 in the control arms (RR, 1.96; 95% CI, 1.60-2.39; P < .001). The remaining MACEs could not be attributed to a specific arm.
  • Across all trials, 1221 cardiovascular events (major and other) were noted: 791 in intervention arms and 407 in control arms (RR, 1.78; 95% CI, 1.58-2.01).
  • In the 50.0% of trials that reported MACEs, covering 124,432 years of patient follow-up, the weighted average reported MACE rate was 376 per 100,000 person-years. The comparison population, persons without overt clinical cardiovascular disease, had a rate of 1408 per 100,000 person-years. The trial rate relative to the comparison population's rate gave a relative risk of 0.27 (95% CI, 0.24-0.30; P < .001), which the authors described as a 3.75-fold lower rate of reported events.
  • In multivariable analysis, no specific trial characteristic was associated with reporting of cardiovascular disease. Year of trial initiation and mode of radiation delivery were also not associated with reporting.
  • In univariate analysis (Table 1), cancer type (P = .01) and whether radiation dose escalation or de-escalation was tested (P = .04) were associated with cardiovascular disease reporting. Neither was significant in the multivariable models (P = .056 and .24).
  • Of the 2 mesothelioma trials (526 patients), 1 (50.0%) reported cardiovascular disease.
• The authors' conclusion: The authors concluded that, in contemporary chest radiation trials, reported cardiac event rates appeared to trail expected rates in the general population. In their discussion, they suggested systematic underreporting or underappreciation of cardiovascular events, and they called for further research.
• Limitations the authors state:
  • The cancer populations were heterogeneous, which may have affected true rates of cardiac events.
  • Only initial trial reports were used. Some trials may have reported additional toxicity data in later publications.
  • Palliative, phase 1, smaller and shorter-term studies were excluded.
  • Cardiovascular disease in the trials was defined using standardized but subjectively estimated CTCAE grades rather than objective metrics.
  • There was no valid cancer-specific comparison population. The MESA cohort does not perfectly match the cardiovascular risk distribution of the pooled trial population.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Esophageal Cancer, Incidence, Relative Risk, Clinical Trial.

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