ArticlesCardiotoxicity associated with tyrosine kinase inhibitor sunitinib
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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These authors contributed equally