Elsevier

The Lancet

Volume 370, Issue 9604, 15–21 December 2007, Pages 2011-2019
The Lancet

Articles
Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib

https://doi.org/10.1016/S0140-6736(07)61865-0Get rights and content

Summary

Background

Sunitinib, a multitargeted tyrosine-kinase inhibitor, which is approved by both US and European Commission regulatory agencies for clinical use, extends survival of patients with metastatic renal-cell carcinoma and gastrointestinal stromal tumours, but concerns have arisen about its cardiac safety. We therefore assessed the cardiovascular risk associated with sunitinib in patients with metastatic gastrointestinal stromal tumours.

Methods

We retrospectively reviewed all cardiovascular events in 75 patients with imatinib-resistant, metastatic, gastrointestinal stromal tumours who had been enrolled in a phase I/II trial investigating the efficacy of sunitinib. The composite cardiovascular endpoint was cardiac death, myocardial infarction, and congestive heart failure. We also examined sunitinib's effects on left ventricular ejection fraction (LVEF) and blood pressure. We investigated potential mechanisms of sunitinib-associated cardiac effects by studies in isolated rat cardiomyocytes and in mice.

Findings

Eight of 75 (11%) patients given repeating cycles of sunitinib in the phase I/II trial had a cardiovascular event, with congestive heart failure recorded in six of 75 (8%). Ten of 36 (28%) patients treated at the approved sunitinib dose had absolute LVEF reductions in ejection fraction (EF) of at least 10%, and seven of 36 (19%) had LVEF reductions of 15 EF% or more. Sunitinib induced increases in mean systolic and diastolic blood pressure, and 35 of 75 (47%) individuals developed hypertension (>150/100 mm Hg). Congestive heart failure and left ventricular dysfunction generally responded to sunitinib being withheld and institution of medical management. Sunitinib caused mitochondrial injury and cardiomyocyte apoptosis in mice and in cultured rat cardiomyocytes.

Interpretation

Left ventricular dysfunction might be due, in part, to direct cardiomyocyte toxicity, exacerbated by hypertension. Patients treated with sunitinib should be closely monitored for hypertension and LVEF reduction, especially those with a history of coronary artery disease or cardiac risk factors.

Introduction

Small-molecule inhibitors, designed to inhibit tyrosine kinases that are mutated or are overexpressed in cancer cells, have improved the management of cancers such as chronic myeloid leukaemia, renal-cell carcinoma, and gastrointestinal stromal tumours.1 This targeted approach has resulted in improved antitumour activity with fewer toxic effects than traditional chemotherapies for many patients. However, tyrosine-kinase inhibitors also inhibit normal variants of tyrosine kinases in non-cancerous cells, which can lead to unexpected toxicities, including cardiotoxic effects.2, 3, 4, 5 Tyrosine-kinase inhibitor-related cardiac dysfunction can be difficult to recognise in early clinical trials.6, 7, 8, 9 Furthermore, symptoms of congestive heart failure are often non-specific and can be wrongly attributed to malignant disease alone.

Sunitinib (Sutent, Pfizer, New York, NY, USA) is a US Food and Drug Administration-approved and European Union-approved, multitargeted tyrosine-kinase inhibitor that extends survival in patients with gastrointestinal stromal tumours or renal-cell carcinoma.10, 11, 12 Its targets include vascular endothelial-cell growth-factor receptors 1–3, platelet-derived growth-factor receptors α and β, FMS-like tyrosine kinase-3, KIT (stem-cell factor receptor), colony-stimulating factor-1 receptor, and the product of the human RET gene.13, 14, 15, 16, 17 Sunitinib is being assessed for activity in more than 25 different tumour types in more than 120 registered clinical trials, enrolling about 20 000 patients.18

Most of our knowledge of the cardiac effects of sunitinib comes from cancer efficacy trials that assessed overall safety.10, 11, 12, 16, 19 Although two cases of congestive heart failure were reported in a phase I study,19 Demetri and co-workers12 reported no systematic mean reduction in left ventricular ejection fraction (LVEF) in a phase III clinical trial in patients with gastrointestinal stromal tumours. Motzer and colleagues11 reported modest reductions in LVEF without clinical sequelae in renal-cell carcinoma patients. Although this study hinted at the potential for cardiotoxic effects, the absence of studies designed mainly to assess sunitinib-associated cardiovascular dysfunction leaves many questions about potential cardiotoxic effects unanswered. Our aims were therefore to review cardiac adverse events in patients with imatinib-resistant, metastatic, gastrointestinal stromal tumours on sunitinib. We also aimed to establish the mode of action of sunitinib in mouse models and cardiac myocyte cultures.

Section snippets

Patients

Between April, 2002 and June, 2004, 97 patients with imatinib-resistant, gastrointestinal stromal tumours were given repeating cycles of sunitinib as part of an open-label, single-arm, dose-escalation phase I/II trial at the Dana-Farber Cancer Institute, Massachusetts General Hospital, and Memorial Sloan-Kettering Cancer Center to assess drug efficacy and tolerability. A total of 75 patients (51 [68%] men, mean age 54·3 [SD 11·5] years) were enrolled at the Dana-Farber Cancer Institute and

Results

Table 1 shows baseline characteristics for the entire cohort. All patients discontinued imatinib or other systemic anticancer agents at least 2 weeks before starting sunitinib. All had a baseline LVEF of 50 EF% or more and none had a history of congestive heart failure. Four patients had a history of coronary artery disease (mean baseline LVEF 56 [SD 4] EF%), but were without symptoms for at least 1 year before enrolment. Patients received sunitinib at or below the eventual approved dose of 50

Discussion

The principal finding of our study was that 11% of 75 patients with imatinib-resistant, metastatic, gastrointestinal stromal tumours given sunitinib for a median of 33·6 weeks developed cardiac adverse events. The most common event was New York Heart Association class III–IV congestive heart failure, which was reported in 8%. Analysis of patients given the approved sunitinib dose showed a steady reduction in LVEF during the first four cycles (24 weeks). Sunitinib also induced increases in blood

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