Cardiovascular Implications of Vascular Endothelial Growth Factor Inhibition Among Adolescents/Young Adults in ECOG-ACRIN E2805

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Wendy J. Bottinor Division of Cardiovascular Medicine, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia

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Yael Flamand Department of Data Science/ECOG-ACRIN Biostatistics Center, Dana-Farber Cancer Institute, Boston, Massachusetts

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Naomi B. Haas Division of Medical Oncology, Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

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Anne M. ONeill Department of Data Science/ECOG-ACRIN Biostatistics Center, Dana-Farber Cancer Institute, Boston, Massachusetts

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Robert S. DiPaola Division of Medical Oncology, Department of Internal Medicine, University of Kentucky, Lexington, Kentucky

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Pearl Subramanian School of Medicine, Hofstra University, New York, New York

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David Cella Department of Medical Social Sciences, Northwestern Medicine, Chicago, Illinois

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W. Gregory Hundley Division of Cardiovascular Medicine, Department of Internal Medicine, Pauley Heart Center, Virginia Commonwealth University, Richmond, Virginia

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Lynne I. Wagner Department of Social Sciences and Health Policy, Wake Forest School of Medicine, Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, North Carolina

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John M. Salsman Department of Social Sciences and Health Policy, Wake Forest School of Medicine, Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, North Carolina

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Bonnie Ky Division of Cardiology, Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania

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Background: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among adolescents and young adults (AYAs) diagnosed with cancer. The aim of this study was to assess the incidence and predictors of left ventricular systolic dysfunction (LVSD) and hypertension among AYAs receiving VEGF inhibition compared with non-AYAs. Methods: This retrospective analysis used data from the ASSURE trial (ClinicalTrials.gov identifier: NCT00326898), in which participants with nonmetastatic, high-risk, renal cell cancer were randomized to sunitinib, sorafenib, or placebo. The incidence of LVSD (left ventricular ejection fraction decrease >15%) and hypertension (blood pressure ≥140/90 mm Hg) were compared using nonparametric tests. Multivariable logistic regression examined the association between AYA status, LVSD, and hypertension while adjusting for clinical factors. Results: AYAs represented 7% (103/1,572) of the population. Over a study treatment period of 54 weeks, the incidence of LVSD was not significantly different among AYAs (3%; 95% CI, 0.6%–8.3%) versus non-AYAs (2%; 95% CI, 1.2%–2.7%). The incidence of hypertension was significantly lower among AYAs (18%; 95% CI, 7.5%–33.5%) compared with non-AYAs (46%; 95% CI, 41.9%–50.4%) in the placebo arm. In the sunitinib and sorafenib groups, the incidence of hypertension for AYAs compared with non-AYAs was 29% (95% CI, 15.1%–47.5%) versus 47% (95% CI, 42.3%–51.7%), and 54% (95% CI, 33.9%–72.5%) versus 63% (95% CI, 58.6%–67.7%), respectively. AYA status (odds ratio, 0.48; 95% CI, 0.31–0.75) and female sex (odds ratio, 0.74; 95% CI, 0.59–0.92) were each associated with a lower risk of hypertension. Conclusions: LVSD and hypertension were prevalent among AYAs. CVD among AYAs is only partially explained by cancer therapy. Understanding CVD risk among AYA cancer survivors is important for promoting cardiovascular health in this growing population.

Submitted August 9, 2022; final revision received March 3, 2023; accepted for publication March 6, 2023.

Author contributions: Conceptualization: Bottinor, Flamand, Haas, ONeill, Salsman, Ky. Data curation: Haas, Subramanian. Formal analysis: Flamand, ONeill. Validation: Flamand, ONeill. Writing—original draft: Bottinor, Flamand, Salsman, Ky. Writing—review and editing: Haas, ONeill, DiPaola, Cella, Hundley, Wagner.

Disclosures: The authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Research reported in this publication was supported by ECOG-ACRIN (award number UG1CA189828-06-VCU1). This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD, and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under award numbers U10CA180820, U10CA180794, UG1CA189828, UG1CA233270, UG1CA233196, UG1CA233320, and UG1CA189869. The research reported in this publication was also supported by CTSA award No. KL2TR002648 from the National Center for Advancing Translational Sciences, Tomorrow’s Research Fund St. Baldrick’s Scholar Award (award number 636214), and American Heart Association (award number 19CDA34760181).

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the supporting institutions.

Correspondence: Wendy J. Bottinor, MD, MSCI, Virginia Commonwealth University, Department of Internal Medicine, Division of Cardiovascular Medicine, Gateway Building, 1200 East Marshall Street, Richmond, VA 23298. Email: wendy.bottinor@vcuhealth.org

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