BEVACIZUMAB INCREASES HEART FAILURE RISK

Less than a month after the US Food and Drug Administration announced it was revoking bevacizumab's indication for metastatic breast cancer, citing myriad serious toxicities, more bad news for the embattled drug has emerged.

A study led by Toni K. Choueiri, MD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, reports that advanced breast cancer patients treated with bevacizumab are at increased risk for congestive heart failure (CHF).

The study was published online January 4 in the Journal of Clinical Oncology. Dr. Choueiri and colleagues report a nearly 5-fold increase in the risk for CHF in bevacizumab-treated patients, compared with control subjects.

However, an accompanying editorial is critical of the paper, and urges "extreme caution" in interpreting these results.

Meta-Analysis of 5 Trials

To collect their data, Dr. Choueiri and colleagues conducted a PubMed search of articles published from 1966 to March 2010, and abstracts presented at the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium annual meetings. They eventually selected 5 trials, comprising 3784 patients with metastatic breast cancer, for their final analysis.

The trials were E2100, AVADO, RIBBON-1, RIBBON-2, and a randomized phase 3 trial comparing capecitabine with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer (J Clin Oncol. 2005;23:792-799).

All these trials excluded patients with uncontrolled hypertension, clinically significant CHF, cerebrovascular disease or peripheral vascular disease, and unstable angina or a recent history of myocardial infarction. They included patients previously treated with anthracycline, and 1 trial in which patients were treated with concomitant anthracycline.

In 2 of the trials, patients had HER2-positive disease and had received previous treatment with trastuzumab.

The analysis showed close to a 5-fold increase in the risk for CHF in bevacizumab-treated patients, compared with control subjects.

Of the 2366 patients who received bevacizumab, 36 had high-grade CHF, for an overall incidence rate of 1.6% (95% confidence interval [CI], 1.0% to 2.6%). Among the 1418 control or placebo patients, 4 had CHF events, for an incidence rate of 0.4% (95% CI, 0.2% to 1.0%).

"To our knowledge, this is the first large report to show a significant increase in the risk of CHF in bevacizumab-treated patients with metastatic breast cancer," the authors write. "Patients with metastatic breast cancer may be at an especially increased risk of CHF because of prior concomitant exposure to other cardiotoxic medications in the adjuvant or metastatic settings."

Editorial Critical of Study

However, an accompanying editorial is somewhat critical of the paper, saying it has several limitations, and urging "extreme caution" in interpreting its results.

One of the editorialists, Sandra M. Swain, MD, medical director of the Washington Cancer Institute at Washington Hospital Center in DC, explained to Medscape Medical News in an interview that the editorial is critical "because the paper is just an analysis of 5 trials. It's not unique research; they're just getting data from papers that have been either published or only presented. Performing a meta-analysis with retrospectively collected heart failure data adds little to our current body of evidence."

A big limitation is previous anthracycline use among the patients. In the meta-analysis, the rate of anthracycline exposure among patients in the trials ranged from 30% to 100%.

Patients with previous anthracyclines already have a damaged heart, so it is possible that the bevacizumab could add to that. Or, it could just be related to the anthracyclines, period, and not at all related to the bevacizumab," Dr. Swain said.

Moreover, large randomized trials of bevacizumab in metastatic colorectal cancer, lung cancer, and renal cell cancer have not reported any cases of heart failure, Dr. Swain pointed out.

The lack of information about individual patients is another important limitation, she said.

"I personally don't agree with writing these kinds of papers, because — as even [the authors point] out — you're not looking at the individual patient. There was no information about the underlying risk factors that predispose to heart failure in individual patients. They didn't put in anything about cumulative [doxorubicin] dose for each patient, radiation, heart disease history, diabetes, or any of the other things that could contribute to heart failure. None of those things were evaluated, or if they were evaluated, they weren't presented."

Although the study has flaws, there are still ways that bevacizumab could be cardiotoxic, Dr. Swain said.

"Vascular endothelial growth factor is important for blood vessels, so you decrease your perfusion and decrease your ability to repair any kind of injury. If, for example, you have gotten a drug like doxorubicin that affects the heart, and then get bevacizumab afterward, you may have a limited ability to repair any kind of injury and you could develop heart failure. So there certainly are a lot of preclinical and physiologic reasons why you could have heart failure," she said.

The other adverse effect with bevacizumab that has been very clearly demonstrated and that could lead to heart failure is its effect on blood pressure. "Bevacizumab does confer a significant risk of hypertension, and there is no controversy about that. That is very clear, and the hypertension could contribute to heart failure," Dr. Swain said.

Awaiting Adjuvant Trial Results

The final word on bevacizumab's role in heart failure in advanced breast cancer will come when data from adjuvant trials are analyzed, Dr. Swain suggested.

The adjuvant trials include E5103, which was actually stopped briefly in 2009 because of fears of heart failure, but was started again, she said. They also include BEST, and BEATRICE. Together, these 3 trials should provide answers to this question, she reported.

"These trials will really give us the data because those patients are evaluated prospectively with different heart imaging. We should really wait for those trials before we pass sentence on bevacizumab with regard to heart failure. There are certainly reasons why it can occur, and it obviously did occur in some patients. The question is: Is it related to the bevacizumab or is it the anthracycline, or is it the combination of both these things, or is it because the patients had left-sided radiation? There are a lot of questions."

Dr. Choueiri reports financial relationships with Bayer/Onyx Pharmaceuticals, Novartis, GlaxoSmithKline, Genentech, Eisai, and Aveo. Dr. Swain reports that she was on an advisory board for Genentech and Roche and is the principal investigator of a National Surgical Adjuvant Breast and Bowel Project trial sponsored by Roche, but was not compensated in either instance.