Sorafenib, sunitinib, and pazopanib—the three FDA-approved vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs)—have been found to carry a heightened risk of fatal complications for users. Although the risk remains low, clinicians and patients nonetheless need to be aware of these dangers and design cancer treatments accordingly.

In a meta-analysis of 10 randomized controlled trials involving 4,679 patients, sorafenib (Nexavar; approved for the treatment of kidney and liver cancers), sunitinib (Surent; for the treatment of kidney cancer and GI stromal tumor), and pazopanib (Votrient; for kidney cancer) were associated with an increased risk of fatal adverse events. VEGFR TKIs have become the cornerstone of treatment for several malignancies, according to Toni Choueiri, MD, of the Dana-Farber Cancer Institute in Boston, Massachusetts, and coinvestigators. But as the researchers noted in their Journal of Clinical Oncology report, these agents have also been linked with an increased risk of potentially life-threatening side effects such as arterial thrombotic events, bleeding, and congestive heart failure.

To determine the risk of fatal adverse events, Choueiri’s team analyzed data from 2,856 patients using sorafenib, 1,388 using sunitinib, and 435 using pazopanib. The incidence of fatal adverse events related to VEGFR TKIs was 1.5%, compared with a 0.7% incidence in patients given standard treatments or placebos. The majority of patients who died succumbed to fatal bleeding; the second most common cause of death was heart attack or heart failure. Liver failure also occurred.

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Subgroup analysis revealed no difference in the rate of fatal adverse events between the different agents or tumor types.

“There is no doubt for the average patient, these drugs have benefits and are FDA-approved for these indications,” explained Choueiri in a statement. “While the absolute incidence of these fatal side effects is very small, the relative risks are higher and patients and practitioners need to be aware of it.”

Choueiri pointed out that VEGFR TKIs should be used cautiously in patients who have had a heart attack, that clinicians should give full consideration to the potential risk before using the medications in persons at slightly high risk for heart attack or bleeding, and that clinicians should consider whether the patient requires close monitoring while taking one of these medications. In addition, a person might need to stop taking the VEGFR TKI temporarily, and might need to avoid elective surgery while on such therapy.