Lack of Cardiotoxicity Endpoints in Prospective Trials Involving Chest Radiation Therapy: A Review of Registered, Latter-Phase Studies

Our plain-English summary of Lack of Cardiotoxicity Endpoints in Prospective Trials Involving Chest Radiation Therapy: A Review of Registered, Latter-Phase Studies, by R.N. Prasad, E.D. Miller, D. Addison, et al (Frontiers in Oncology, 2022).

The study

• Authors: R.N. Prasad, E.D. Miller, D. Addison, J.G. Bazan
• Journal: Frontiers in Oncology
• Published: 2022;12:808531
• Cited by: 4 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Chest radiation therapy (RT) has been associated with increased cardiac morbidity and mortality in numerous studies including the landmark Darby study published in 2013 demonstrating a linear increase in cardiac mortality with increasing mean heart radiation dose. However, the extent to which cardiotoxicity has been incorporated as an endpoint in prospective RT studies remains unknown.

Methods: We queried clincaltrials.gov to identify phase II/III trials in lung, esophageal, lymphoma, mesothelioma, thymoma, or breast cancer from 1/1/2006-2/1/2021 enrolling greater than 100 patients wherein chest RT was delivered in at least one treatment arm. The primary endpoint was the rate of inclusion of cardiotoxicity as a specific primary or secondary endpoint in the pre- (enrollment started prior to 1/1/2014) versus post-Darby era using the Chi-square test (p<0.05 considered significant). We also analyzed clinical trial factors associated with the inclusion of cardiotoxicity as an endpoint using logistic regression analysis.

Results: In total, 1,822 trials were identified, of which 256 merited inclusion. 32% were for esophageal, 31% lung, 28% breast, and 7% lymphoma/thymoma/mesothelioma cancers, respectively. 5% (N=13) included cardiotoxicity as an endpoint: 6 breast cancer, 3 lung cancer, 3 esophageal cancer, and 1 lymphoma study. There was no difference in the inclusion of cardiotoxicity endpoints in the pre-Darby versus post-Darby era (3.9% vs. 5.9%, P=0.46). The greatest absolute increase in inclusion of cardiotoxicity as an endpoint was seen for lung cancer (0% vs. 6%, p=0.17) and breast cancer (5.7% vs. 10.8%, p=0.43) studies, though these increases remained statistically non-significant. We found no clinical trial factors associated with the inclusion of cardiotoxicity as an endpoint.

Conclusions: Among prospective trials involving chest RT, cardiotoxicity remains an uncommon endpoint despite its prevalence as a primary source of toxicity following treatment. In order to better characterize cardiac toxicities, future prospective studies involving chest RT should include cardiotoxicity endpoints.

Copyright © 2022 Prasad, Miller, Addison and Bazan.

In plain English

This was a review of registered clinical trials, not a study of asbestos exposure. Mesothelioma was one of several cancers included. The authors searched the US registry clinicaltrials.gov for phase II or III trials from 1/1/2006 to 2/1/2021. Trials qualified if they gave chest radiation therapy as definitive treatment for breast, esophageal, lymphoma, mesothelioma, thymoma or lung cancer and planned to enroll more than 100 patients. The authors measured how often these trials listed heart damage (cardiotoxicity) as an endpoint. They compared trials that began enrolling before 1 January 2014 (the "pre-Darby era") with later ones. Of 1,822 trials reviewed, 256 met the criteria. Thirteen of the 256 (5%) included a cardiotoxicity endpoint: 6 breast, 3 lung, 3 esophageal and 1 lymphoma trial. The share was 3.9% in the earlier era and 5.9% in the later era (p=0.46). The authors reported this difference as not statistically significant. No trial characteristic they examined was associated with including such an endpoint. The authors concluded that future chest radiation trials should include cardiotoxicity endpoints. They noted that they searched only one registry and did not review trial protocols.

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 of trial registry entries comparing the rate of cardiotoxicity endpoints in trials whose enrollment started before 1/1/2014 (pre-Darby era) versus after (post-Darby era), using the Chi-square test and univariate logistic regression
• Who was studied: 256 phase II or III trials registered on clinicaltrials.gov (2006 to 2021), selected from 1,822 reviewed; 81 esophageal, 80 lung, 72 breast and 23 other (lymphoma, thymoma or mesothelioma)
• Exposure: Chest (thoracic) radiation therapy given as definitive therapy for breast, esophageal, lymphoma, mesothelioma, thymoma or lung cancer in trials planning more than 100 patients; no asbestos exposure was studied
• Main results:
  • 13 of 256 trials (5%) included a cardiotoxicity endpoint: 6 breast cancer (8%), 3 lung cancer (4%), 3 esophageal cancer (4%) and 1 lymphoma trial
  • Of these, 5 trials (2%) had cardiotoxicity as a primary endpoint and 8 (3%) as a secondary endpoint
  • The endpoints mostly measured serious late effects such as major adverse cardiac events (7 trials, 54%)
  • Across all cancer types, cardiotoxicity endpoints appeared in 3.9% of pre-Darby era trials versus 5.9% of post-Darby era trials (p=0.46), not statistically significant
  • Lung cancer trials went from 0.0% to 5.9% (p=0.17) and breast cancer trials from 5.7% to 10.8% (p=0.43); the authors reported these increases as not significant
  • Esophageal cancer trials went from 3.8% to 3.6%, and the other cancers (lymphoma, thymoma, mesothelioma) from 7.7% to 0.0%
  • On univariate logistic regression, none of the trial characteristics examined was associated with including a cardiotoxicity endpoint
• The authors' conclusion: The authors concluded that cardiotoxicity remains an uncommon endpoint in prospective chest radiation trials and that future such studies should include cardiotoxicity endpoints more often
• Limitations the authors state:
  • Smaller single-arm studies of blood and imaging markers of heart damage were not included
  • Only one registry (clinicaltrials.gov) was searched
  • Trial protocols were not reviewed to see whether trials without cardiac endpoints still monitored heart events
  • Splitting the two eras at a different date might have changed the significance of the trend

Topics

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

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