VEGFR TKIs may increase cardiovascular toxicity, stroke risk in renal cell carcinoma

Sunitinib and sorafenib appeared associated with an increased risk for cardiovascular events and stroke in older patients with advanced renal cell carcinoma, according to the results of a population-based study.

“A growing understanding of the biology of renal cell carcinoma has led to … FDA approval of several agents targeting the vascular endothelial growth factor receptor [VEGFR] tyrosine kinase,” Sekwon Jang, MD, director of melanoma and cutaneous oncology therapeutics and research and director of quality at Inova Comprehensive Cancer and Research Institute in Fairfax, Virginia, and colleagues wrote.

These include sorafenib (Nexavar, Bayer), approved in December 2005, and sunitinib (Sutent, Pfizer), approved in January 2006.

“However, despite improvements in survival, there are concerns about possibly significant cardiovascular complications associated with VEGFR TKIs,” Jang and colleagues wrote.

The researchers assessed whether this risk was elevated risk among older patients with renal cell carcinoma.

Jang and colleagues used the SEER–Medicare linked database to identify patients aged 66 years or older diagnosed with renal cell carcinoma between 2000 and 2009. They determined the incidence of cardiovascular adverse events, including congestive heart failure and cardiomyopathy, as well as acute myocardial infarction, stroke, and cardiovascular deaths.

The final analysis included data from 670 patients (sunitinib, n = 396; sorafenib, n = 163; sunitinib and sorafenib, n = 111), with a comparison cohort of 788 patients who did not receive either agent.

More than half of patients had one or more comorbid conditions. Further, 48% received at least one other systemic therapy, including bevacizumab (Avastin, Genentech; 30.9%) or pazopanib (Votrient, Novartis; 3.4%) in addition to sunitinib or sorafenib.

Cardiovascular events occurred in 171 patients treated with sunitinib or sorafenib (overall incidence rate = 1.02; 95% CI, 0.88-1.19). Patients who received both agents had a lower overall incidence rate (0.56; 95% CI, 0.37-0.8) than patients who received either agent alone.

Sunitinib or sorafenib use led to an increased risk for cardiovascular events (HR = 1.38; 95% CI, 1.02-1.87) ― especially stroke (HR = 2.84; 95% CI, 1.52-5.31) ― compared with the control cohort.

The risk for congestive heart failure or cardiomyopathy was increased among patients who received sunitinib only (HR = 1.53; 95% CI, 1.01-2.33).

In a subgroup analysis, patients aged between 66 years and 74 years at diagnosis demonstrated the highest risk for stroke (HR = 6.94; 95% CI, 2.52-19.09).

“Clinicians should be aware of this adverse effect to prevent or detect its development, provide early interventions, and balance the therapeutic benefit with adverse events,” Jang and colleagues wrote.

The researchers identified limitations to their study, including the potential overestimation of congestive heart failure due to Medicare misclassification. Further, they could not determine why patients in the comparison cohort did not take either drug. – by Cameron Kelsall

 Disclosure: Jang reports no relevant financial disclosures. Other researchers report grant support and personal fees from Cell Therapeutics, Genentech, Novartis and Pfizer.