Sunitinib and Cardiovascular Toxicity
Abstract & Commentary
By William B. Ershler, MD
Synopsis: In a retrospective review of 175 sunitinib-treated renal cell carcinoma patients, grade 3 hypertension was observed in approximately 10% and grade 3 left ventricular dysfunction and/or congestive heart failure in 7%. Preexisting hypertension and coronary artery disease were significant independent predictors of cardiovascular toxicity.
Source: Di Lorenzo G, et al. Cardiovascular toxicity following sunitinib therapy in metastatic renal carcinoma: a multicenter analysis. Ann Oncology. 2009;20:1535-1542.
The treatment of metastatic renal cell carcinoma (RCC) has changed dramatically during the past few years. Sunitinib malate is one of several new agents (including sorafenib tosylate, bevacizumab, temsirolimus, and everolimus) that have improved clinical outcomes in randomized phase III trials by inhibiting the vascular endothelial growth factor and related pathways.1,2 Sunitinib is a tyrosine kinase inhibitor, and recent data have shown that cardiotoxicity represents a potentially important side effect in patients treated with this class of agents.3,4 In the current report, Lorenzo et al reviewed cardiac adverse events in patients with metastatic renal cell carcinoma (RCC) who underwent treatment with this sunitinib.
For this, the medical records of 175 patients with metastatic RCC treated with sunitinib at eight Italian institutions were retrospectively reviewed. Alterations in left ventricular ejection fraction (LVEF) and blood pressure were evaluated. Patients with preexisting cardiac risk factors were specifically scrutinized for increased expression of cardiac changes.
Grade 3 hypertension was seen in 17 patients (9.7%); in 12 of these 17, hypertension developed after receiving the third sunitinib cycle. Among these 17 patients, 12 (70.6%) also experienced left ventricular systolic (LVEF) dysfunction. In all, 33 of the 175 patients (18.9%) developed some degree of cardiac abnormality, of which 12 were classified as grade 3 LVEF dysfunction and/or congestive heart failure (CHF) (6.9%). Significant univariate associations for predictors of CHF were history of hypertension (p = 0.008), history of coronary heart disease (p = 0.0005), and prior treatment with an angiotensin-converting enzyme inhibitor (p = 0.04). Multivariate analysis suggested that a history of coronary artery disease [odds ratio (OR) 18, 95% confidence interval (CI) 4-160, p = 0.005] and hypertension (OR 3, 95% CI 1.5-80, p = 0.04) were the only significant independent predictors of CHF.
Commentary
Thus, patients undergoing sunitinib, especially those with a previous history of hypertension and coronary heart disease, are at increased risk for cardiovascular events and should be monitored for exacerbations of their hypertension and for evidence of LVEF dysfunction during treatment. This report is more or less a confirmation of other earlier reports, yet it represents a fairly large cohort of sunitinib-treated patients with a single tumor type, and it is the first such series where all patients were treated outside of a clinical trial; thus, it more likely represents current clinical practice. Yet, when compared with other reports, the findings are quite consistent and the message for clinicians is coming through quite clearly. For example, Chu et al assessed cardiac risk in sunitinib-treated patients with metastatic gastrointestinal stromal tumors (GIST),5 and found that 8% developed New York Heart Association class III-IV heart failure and 47% developed hypertension, with grade 3 hypertension occurring in 17% of the patients by cycle 3. In another retrospective review of 48 patients treated with sunitinib for either RCC or GIST, Telli et al found that 15% developed symptomatic grade 3/4 heart failure.6 The patient characteristics in these three reports were quite different with regard to prior cardiovascular history, exposure to prior tyrosine kinase therapy, and even the type of tumor treated, yet the appearance of both CHF and hypertension was relatively comparable. Symptomatic heart failure and significant hypertension occur in approximately 10%-20% of patients, with hypertension commonly recognized during or after the third cycle.
The mechanism of tyrosine kinase-associated cardiovascular toxicity remains unresolved. It is notable that, like that observed with trastuzumab treatment in breast cancer patients and distinct from anthracycline-associated cardiovascular toxicity, sunitinib cardiovascular toxicity does not appear to be dose-related. Thus, careful cardiac monitoring is warranted in all patients, but particularly those with a prior history of coronary artery disease or hypertension. For patients with preexisting hypertension, consideration should be given to increasing dose of their current hypertensive, or even adding an additional anti-hypertensive, while being treated with sunitinib. If hypertension persists, sunitinib should be held until blood pressure comes under control and reintroduction of sunitinib, perhaps at a lower dose, could be considered; however, alternative approaches at this point might offer a better risk/benefit ratio.
References
1. Rini BI. Vascular endothelial growth factor-targeted therapy in metastatic renal cell carcinoma. Cancer. 2009;115:2306-2312.
2. Sosman J, Puzanov I. Combination targeted therapy in advanced renal cell carcinoma. Cancer. 2009;115: 2368-2375.
3. Force T, et al. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer. 2007;7: 332-344.
4. Kerkela R, et al. Cardiotoxicity of the cancer therapeutic agent imatinib mesylate. Nat Med. 2006;12: 908-916.
5. Chu TF, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet. 2007;370:2011-2019.
6. Telli ML, et al. Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate. Ann Oncol. 2008;19:1613-1618.
In a retrospective review of 175 sunitinib-treated renal cell carcinoma patients, grade 3 hypertension was observed in approximately 10% and grade 3 left ventricular dysfunction and/or congestive heart failure in 7%.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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