Chu TF, Rupnick MA, Kerkela R et al.Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370:2011-19

Harvard University, Cambridge, Massachusetts, United States
The Lancet (Impact Factor: 45.22). 12/2007; 370(9604):2011-9. DOI: 10.1016/S0140-6736(07)61865-0
Source: PubMed


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.
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.
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.
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.

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    • "In the majority of patients who develop LV dysfunction, symptoms improve after dose interruption, dose modification, and/or initiation of heart failure therapy. The reported time to improvement of LV EF was between 1 and 9.6 weeks.31 Although CHF is not a common toxicity reported for HD-IL2, myocardial dysfunction as a result of myocarditis is a known event.36 "
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    ABSTRACT: Although tyrosine kinase inhibitors (TKI) are the most common first-line therapy for metastatic renal cell carcinoma, high-dose interleukin-2 (HD-IL2) remains the only agent that provides durable complete responses. The optimal sequence of these agents remains uncertain. This retrospective multi-institutional study examined the safety and efficacy of HD-IL2 following TKI therapy. After IRB approval at 7 HD-IL2 centers, data relating to patient, disease, and treatment characteristics among 40 consecutive patients with metastatic renal cell carcinoma who were treated with HD-IL2 after at least 1 prior TKI therapy were retrospectively collected. The most common cardiac adverse events were grade 3 hypotension and vascular leak syndrome. Six patients (15%) experienced other grade ≥3 cardiac adverse events. There were 2 treatment-related deaths due to congestive heart failure, occurring in 1 patient with short TKI to HD-IL2 interval and another patient with an abnormal baseline cardiac stress test. Best responses included 2 CRs (5%, duration 40+ and 62+ mo), 3 PRs (8%, duration 6, 11, and 24 mo), 13 SD (32%, median duration 12 mo), 20 PD (50%), and 2 not evaluable patients. Median overall survival was 22 months. Administration of HD-IL2 could be safe and effective after TKI therapy; however, careful selection of patients is critical. We recommend baseline cardiac risk factor assessment, screening with both cardiac stress test and echocardiogram, and allowing a TKI to HD-IL2 interval of at least 2 months.
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    • "HFSR, also known as ''palmar plantar erythrodysesthesia'' or ''chemotherapy-induced acral erythema'', is characterized by thick, hyperkeratotic, and erythema/edema lesions with pain, a loss of feeling, and swelling and redness in the palms of hands and/or soles of feet, which occurs with chemotherapies and emerges with targeted therapies (Lacouture et al., 2008; Anderson et al., 2009; Lipworth et al., 2009). Although HFSR is not life threatening, such an adverse reaction is associated with significant tenderness affecting function and quality of life, which often leads to dose modification or discontinuation of treatment (Chu et al., 2007; George et al., 2009; Lee et al., 2009). Asian patients exhibit increased susceptibility to Y kinase inhibitor-induced HFSR (Anderson et al., 2009; George et al., 2009; Lee et al., 2009; Chen et al., 2011; Lee et al., 2012). "
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    ABSTRACT: Sunitinib, a multi-targeted receptor tyrosine kinase inhibitor (TKI) used for the treatment of renal cell carcinoma and gastrointestinal stromal tumor (GIST), is notorious for cutaneous adverse effects, such as hand-foot skin reaction (HFSR). To explore the underlying mechanism of HFSR, we enrolled 53 sunitinib-treated GIST patients, including 23 HFSR cases, and 30 tolerant controls. Among 29 biomarkers examined, soluble FasL showed significant increase in the plasma, blister fluids, and skin lesions of HFSR patients. The plasma levels of sFasL were significantly correlated with that of sunitinib in HFSR patients. In addition to FasL, augmented expression of Fas and active caspase 3 was also detected in the epidermis of HFSR patients. The increased FasL caused keratinocyte death, as the use of anti-FasL antibody specifically blocked cell apoptosis. Oral administration of sunitinib to mice increased skin susceptibility to mechanical injuries in a dose/time-dependent manner. The administration of sunitinib (40 mg/kg/day) for 4 weeks to mice caused the maximally affected skin area with erosion to ulceration response to tape-stripping.The skin biopsies of mice given sunitinib exhibited increased expression of Fas and FasL in the apoptotic keratinocytes in the epidermis. Our data revealed that Fas/FasL interaction mediates keratinocyte death in sunitinib-induced HFSR.Journal of Investigative Dermatology accepted article preview online, 06 May 2014; doi:10.1038/jid.2014.218.
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    • "Cardiac dysfunction is a known side effect of trastuzumab, with reported incidences of 3–7% when given as monotherapy and 27% when administered with anthracycline-containing chemotherapy [35]. Cardiac dysfunction has also been associated with sunitinib treatment, with reported incidences of 11–19% in patients with RCC or GIST [36-38]. Given that the drugs were used in combination in this study, LVEF was monitored frequently. "
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