Aflibercept and Its Role in the Treatment of Colorectal Cancer—Letter

We enjoyed the informative review by Ciombor and colleagues (1) on ziv-aflibercept®, an intravenously administered antiangiogenic drug that inhibits VEGF and placental growth factor (PIGF). Aflibercept in combination with 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) is U.S. Food and Drug Administration (FDA)–approved for the treatment of patients with metastatic colorectal cancer after progression with oxaliplatin-containing regimen. As indicated in the review, known adverse effects reported with aflibercept are characteristic of those seen with agents targeting VEGF receptor (VEGFR) and include hypertension, hemorrhage, and arterial or venous thromboembolic events. In a phase II study of aflibercept in patients with lung cancer, decreased left ventricular ejection fraction (LVEF) to 35% after cycle 2 was observed in one of 98 enrolled patients (2). Although studies evaluating aflibercept have not reported acute heart failure, we observed a nonischemic cardiomyopathy in a 66-year-old patient after receiving two doses of aflibercept plus FOLFIRI for metastatic colorectal cancer in the absence of antecedent cardiovascular disease. Seventeen days following his last aflibercept treatment, the patient presented to his local emergency room with severe dyspnea and fatigue in the absence of chest pain or other symptoms. Physical examination indicated congestive heart failure and the initial echocardiogram revealed normal left ventricular chamber size and wall thickness, but with global hypokinesia and severe left ventricular dysfunction (ejection fraction of 17%). Cardiac MRI showed normal perfusion sequences without early delayed enhancement, except for a faint linear area of delayed enhancement in the septum. The findings were consistent with nonischemic cardiomyopathy that was treated medically and completely reversed at 3 months, as indicated by normal left ventricular function (ejection fraction of 62%) and resolution of previously visualized delayed myocardial enhancement on MRI. The cardiomyopathy was attributed to aflibercept given the temporal association with its administration, MRI perfusion findings that would be atypical for myocarditis, and known cardiovascular toxicities of anti-VEGF agents.

Along with its role in cancer growth and metastasis, VEGF is involved in the maintenance of cardiovascular homeostasis. Inactivation of endogenous VEGF with an adenoviral vector encoding a decoy VEGF receptor led to a net reduction in capillary density, and promoted left ventricle dilatation and a loss in contractile function in mice (3). Although elucidation of the specific mechanism of aflibercept-induced cardiotoxicity awaits further study, we emphasize the need for vigilance in using aflibercept as heart failure represents a potentially life threatening toxicity. In studies of cancer patients treated with VEGF inhibitors, multivariate analysis found that the only significant independent predictor of a cardiovascular event, including heart failure, was a prior history of coronary artery disease (4). We propose consideration of baseline functional cardiac evaluation in patients receiving aflibercept as subclinical cardiac dysfunction may be under-recognized.