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 Agents that target the mTOR axis, which have become particularly important in treating advanced renal cell carcinoma (RCC), have significant adverse cardiovascular effects, a Stanford University team reports.
"The main finding of our study is that cardiovascular side effects of targeted cancer therapies -- particularly the ever-growing class of tyrosine kinase inhibitors -- are extremely common, and far more common than most practitioners appreciate," Dr. Ronald Witteles commented in an email to Reuters Health.
In a paper this month in JACC: Heart Failure, Dr. Witteles and colleagues note that in the last six years, the U.S. Food and Drug Administration has approved the tyrosine kinase inhibitors (TKI) sunitinib, axitinib, sorafenib, and pazopanib; the anti-VEGF (vascular endothelial growth factor) agent bevacizumab; and the mTOR (mammalian target of rapamycin) inhibitors everolimus and temsirolimus for various malignancies.
Among these agents available for the treatment of RCC, sunitinib has been linked most often to cardiovascular toxicity - but not in the phase III trials that led to FDA approval. Instead, the researchers say, "subsequent retrospective and prospective studies have since illuminated the significantly elevated risk of heart failure."
To look into this issue, the team assessed the incidence and severity of adverse cardiovascular effects in 159 patients with advanced metastatic RCC who received targeted therapies at the Stanford Cancer Institute in Stanford, California between 2004 and 2011. Since 2007, most of these patients underwent regular, prospective cardiac monitoring.
TKIs were used in 92% of patients, and sunitinib was the most commonly used agent (64% of patients). Some form of cardiovascular toxicity occurred in 116 (73%) of the patients, most often related to hypertension requiring antihypertensive therapy.
Excluding hypertension, 52 patients (33%) experienced some other cardiotoxicity, ranging from asymptomatic increases in levels of NT-proBNP (N-terminal prohormone of brain natriuretic peptide) to severe heart failure, the investigators report.
Among the 41 patients who received mTOR inhibitors, 17% of those treated with everolimus developed grade 1 heart failure, and 24% of temsirolimus recipients developed grade 3 hypertension, the report indicates.
So how does Dr. Witteles view the benefit-risk balance with use of the targeted therapies? "I certainly don't believe that these agents shouldn't be used, as they often have tremendous efficacy as cancer therapy," he responded, "but patients and physicians need to be aware of the likelihood of cardiovascular side effects so that early treatment can be initiated."
In fact, the team found a very high rate of asymptomatic cardiotoxicity. "In our study," the authors said, "asymptomatic cardiotoxicity, as defined by an elevated NT-proBNP level and/or a decrease in systolic function as estimated by left ventricular ejection fraction, was identified in 43 patients (27%). Given their asymptomatic status, these patients would likely not have been identified without screening."
Screening often allowed for asymptomatic cases to be referred to a heart failure specialist and to begin medical therapy with beta blockers and renin-angiotensin inhibitors. "Accordingly," Dr. Witteles and colleagues conclude, "we propose guidelines for monitoring therapy in this population to potentially improve detection and guide treatment."


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