Tuesday, August 9, 2011

Meta-analysis defines risk of congestive heart failure with sunitinib - Reuters Health • The Doctor's Channel Daily Newscast Videos - The Doctor's Channel

Well, this is worrying.

NEW YORK (Reuters Health) - Pooled data suggest that cancer patients who are treated with sunitinib (Sutent; Pfizer) have about a 2-fold increased relative risk of developing high-grade congestive heart failure (CHF) and about a 3-fold increased risk of developing high-grade CHF. The absolute risks are about 4% and less than 2%.

With the clinical use of sunitinib “expected to expand greatly, I think this is something to be concerned about in several situations,” Dr. Toni K. Choueiri, from Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, noted in an interview with Reuters Health.

“I think it is reasonable to evaluate the cardiac function of patients before sunitinib,” he explained, “especially older patients and those with a history of heart problems. It doesn't mean I won't give sunitinib to these patients; it means I will monitor them and counsel them about signs of CHF because a lot of times it can present as vague symptoms, or I might use an alternative drug.”

Sunitinib and the Heart

Sunitinib is approved for the treatment of metastatic renal cell carcinoma (RCC) and imatinib-resistant GI stromal tumor (GIST). It is currently being investigated in more than 30 tumor types in more than 300 clinical trials, Dr. Choueiri and colleagues note in a paper in the Journal of Clinical Oncology, published online August 1.

CHF associated with sunitinib use has been reported sporadically in several cancer trials but the true risk associated with its use remains undefined. Dr. Choueiri and colleagues conducted a meta-analytic review of 16 clinical trials of sunitinib involving 6935 patients with RCC and non-RCC tumors. There were 4 phase III trials and 11 phase II trials. One study was an expanded access protocol.

In sunitinib-treated patients, the overall incidence of any CHF and high-grade CHF was 4.1% and 1.5%, respectively, the investigators report.

The relative risk of any CHF and high-grade CHF with sunitinib compared with placebo was statistically significant, at 1.81 and 3.30, respectively. There was no evidence of publication bias for incidence or relative risk of CHF events, the investigators note.

Whether CHF observed in sunitinib-treated patients is a dose-dependent or reversible effect remains to be determined. There is some evidence in the literature that a decline in left ventricular ejection fracture with sunitinib may indeed be reversible, the investigators note.

Class Effect

Sunitinib is a small-molecule tyrosine kinase inhibitor that blocks the intracellular domain of the vascular endothelial growth factor (VEGF) receptor. The VEGF pathway is critical in maintaining functional cardiac myocardium, the investigators point out in their report.

They say their findings support “emerging data” suggesting that members of this class of drugs may carry increased risk cardiac toxicity. For instance, a recent meta-analysis of the anti-VEGF antibody bevacizumab found a greater than 3-fold increased risk of CHF in patients with breast cancer.

Sunitinib has also been shown to increase the risk of hypertension, in line with other VEGF inhibitors, such as sorafenib and bevacizumab. As hypertension is a well known risk factor for CHF, it's possible that sunitinib use increased CHF through this mechanism, the investigators note.

Summing up, Dr. Choueiri and colleagues say clinicians need to be aware of the risk of CHF with sunitinib treatment to provide early intervention and balance therapeutic benefit with this potentially life-threatening adverse effect.

Incidence and Risk of Congestive Heart Failure in Patients With Renal and Nonrenal Cell Carcinoma Treated With Sunitinib
J Clin Oncol 2011;29. Published online August 1, 2011.

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