Cardiotoxicity of Sunitinib Greater than Expected (2008)

SAN FRANCISCO—Patients taking sunitinib should undergo routine cardiac monitoring, say researchers reporting at the Genitourinary Cancers Symposium here, who found that the tyrosine kinase inhibitor is associated with a greater risk of heart failure than previously thought. The meeting is cosponsored by the American Society of Clinical Oncology, the American Society for Therapeutic Radiology and Oncology, and the Society of Urologic Oncology. Seven of 48 patients (15%) treated with sunitinib in the single-institution study developed symptomatic Grade 3 or 4 heart failure, said Melinda L. Telli, MD, a postdoctoral fellow in medical oncology at Stanford University School of Medicine. In some cases, the cardiotoxicity was irreversible, and three patients died “in close temporal relationship to being diagnosed with heart failure,” she said. Dr. Telli noted that the study is the second in several months to link sunitinib to symptomatic heart failure. In December, researchers reported an 8% incidence of symptomatic heart failure among 75 patients taking sunitinib for GIST (Chu TF et al: Lancet 2007;370:2011–2019). Cardiac Profile An oral, small-molecule, multi-targeted receptor, tyrosine kinase inhibitor, sunitinib is approved for the treatment of renal cell carcinoma and gastrointestinal stromal tumor (GIST). Reports of sunitinib-associated cardiac side effects are not new. Hypertension is a known side effect that is listed on the drug labeling. Animal studies have shown that sunitinib can be toxic to cardiac cells and that this effect may be exacerbated by high blood pressure, she said. In the pivotal Phase III study that led to approval of sunitinib for renal cell carcinoma, 21% of patients experienced declines in ejection fraction to below normal. The cardiotoxicity, however, was reversible and was not associated with adverse clinical outcomes (Motzer RJ: NEJM;2007:356:115–124). Study Details After observing a higher than expected incidence of symptomatic heart failure among their patients, Dr. Telli and colleagues decided to conduct a retrospective analysis of patients treated with sunitinib at Stanford University Comprehensive Cancer Center between July 2004 and July 2007. Pfizer, which manufactures sunitinib, helped fund the research. Eighty-five percent of the patients had renal cell carcinoma, and 15% had GIST. The mean age of the patients, 81% of whom were male, was 61. Fifty percent of the patients had pre-existing hypertension, and 17% developed hypertension while on treatment. While taking sunitinib, 38% were taking an angiotensin-converting enzyme inhibitor or an angiotensin-receptor blocker, and 25% were taking a beta blocker. Six percent of patients had a history of congestive heart failure or cardiomyopathy, and six percent had coronary artery disease. Seven patients (15%) developed symptomatic left ventricular dysfunction or heart failure during sunitinib treatment. These effects were observed as early as 22 days and as late as 435 days after initiation of sunitinib therapy. Five of the seven patients required hospitalization at the time of their diagnosis for heart failure. Three of the patients had persistent cardiac dysfunction despite discontinuation of sunitinib and initiation of standard heart-failure therapy. Two patients were transferred to palliative care and died “soon after,” Dr. Telli said. A third patient was admitted to the intensive care unit with fulminate heart failure and died after 60 days. In further analysis, factors associated with cardiotoxicity included a history of heart failure or cardiomyopathy, a history of coronary artery disease, and a body-mass index (BMI) less than 25 kg/mg2. “This was true even among those patients with a remote history of heart disease and normal heart function at the time of initiation of sunitinib,” Dr. Telli said, adding that there was also a nonsignificant trend toward increased risk in women. While the study was limited by its retrospective design and small size, it may have underestimated the number of affected people, since physicians did not plan to do cardiac monitoring, she said. “Routine cardiac monitoring of these patients is not really being done. We believe our data support the need for routine cardiac monitoring in patients receiving sunitinib.” ‘Real-World’ Experience Dr. Telli said that clinical trials may give a somewhat skewed view of a drug's side effects, in part because patients with significant comorbidities are often excluded. Two-thirds of patients in the current study were treated with sunitinib outside of the context of a clinical trial, making them more representative of patients “in the real world,” she said. “Determining what factors place patients at increased risk of cardiotoxicity will ultimately allow us to administer this medication more safely to patients for whom the benefits of treatment clearly outweigh the risks. This is especially important because sunitinib is being investigated in over 30 cancer types.” Dosing Question An important question raised by the findings, she said, is whether “dose is important. Since all patients receive a standard dose of sunitinib regardless of gender or weight, it is possible that higher doses could be more toxic in patients with lower BMIs. “This could help to explain the potential increased risk among women, as women tend to have lower BMIs compared with men,” Dr. Telli said. She cautioned that a number of newer targeted cancer treatments, such as sorafenib, also appear to be associated with adverse cardiac effects. “I would be hesitant to rechallenge patients at this point without more data. “A lot of these drugs are new to us, as are their toxicities. Questions about how best to sequence treatments in a patient who has a history of previous heart attack or heart disease, we just don't know [the answer to] right now,” Dr. Telli said. Still, Only a ‘Small Observational Experience’ Robert Dreicer, MD, Chairman of the ASCO Steering Committee for the meeting and Chairman of the Department of Solid Tumor Oncology at the Cleveland Clinic's Taussig Cancer Center, agreed that a critical question going forward is how to best sequence drugs as they become available. But he cautioned against “overdoing the toxicity issue—This is a small observational experience,” he said. The higher than expected rates of cardiotoxicity are “a consequence of more patients being treated and a better understanding of side effects, not a consequence of huge rates of people developing heart disease,” Dr. Dreicer said in an interview. Another symposium official, Howard M. Sandler, MD, Professor of Radiation Oncology and Urology at the University of Michigan Health System, agreed that the small size of the study raises questions about broad applicability. Nevertheless, the findings do appear to support routine cardiac monitoring of patients given sunitinib, he said.Figure: MELINDA L. TELLI, MD: “Our data support the need for routine cardiac monitoring in patients receiving sunitinib.”