INCREASED RISK OF ARTERIAL THROMBOEMBOLISM WITH SUNITINIB AND SORAFENIB

April 5, 2010 — Treatment of cancer patients with the targeted agents sunitinib (Sutent, Pfizer) and sorafenib (Nexavar, Bayer and Onyx) is associated with a significant increase in the risk for arterial thromboembolic events, according to a meta-analysis published online March 29 in the Journal of Clinical Oncology.

The meta-analysis, which consisted of 10,255 patients with a variety of cancers, found that the incidence of arterial thromboembolic events (ATEs) associated with sunitinib and sorafenib was 1.4% (95% confidence interval [CI], 1.2% - 1.6%), and that the relative risk for ATEs was 3.03% (95% CI, 1.25 - 7.37; P = .015), compared with control patients randomized to placebo.

"The overall incidence is very low — less than 5%. The relative risk is higher and is statistically significant, suggesting a 3-fold greater risk for developing ATEs with sorafenib or sunitinib, compared with controls," lead investigator Toni K. Choueiri, MD, director of the kidney cancer center at Dana-Farber/Brigham and Women's Cancer Center in Boston, Massachusetts, told Medscape Oncology. "These cases were in clinical trials. Could the incidence be higher in the general population? Probably, but we don't know. However, we have to recognize that ATEs do occur — that's the first thing."

Increased Bleeding Also a Risk

In October 2009, as reported by Medscape Oncology, Dr. Choueiri and colleagues published a study showing that the treatment of cancer patients with sunitinib and sorafenib doubled their risk of bleeding.

At the time, Dr. Choueiri noted that the risk for bleeding might even be higher in older and frailer cancer patients and in those receiving chemotherapy. He also stated that clinicians had scant awareness of the problem of bleeding with these drugs.

In the current study, he and his team analyzed 10 phase 2 and 3 trials published between January 1966 and July 2009 found with a PubMed search, and abstracts presented at the American Society of Clinical Oncology and the European Society of Medical Oncology meetings held between 2004 and 2009.

Six of the trials were on renal cell carcinoma; the others were on hepatocellular cancer, gastrointestinal stromal tumor, nonsmall-lung cancer, and neuroendocrine tumor.

The most reported event was cardiac ischemia or infarction (7 trials), followed by cerebral ischemia (3 trials). Two trials reported both cardiac and cerebral ischemia.

The doses of sunitinib and sorafenib, as well as the dosing schedules, were approved by the US Food and Drug Administration and consisted of sunitinib 50 mg orally once daily on a 4-weeks-on 2-weeks-off schedule, and sorafenib 400 mg orally twice daily.

The incidence of ATEs with sunitinib and sorafenib were similar — 1.3% (95% CI, 1.0% - 1.6%) for sunitinib and 1.7% (95% CI, 1.1% - 2.4%) for sorafenib. This difference was not statistically significant (P = .35).

Nor were there significant differences with regard to the type of malignancy or the type of clinical trial, Dr. Choueiri said.

The Good and the Bad of VEGF Inhibition

Speculating on the reasons for the increased incidence of ATEs, Dr. Choueiri told Medscape Oncology that he believes it is because these drugs disrupt the hemostatic balance.

"These drugs inhibit tumor angiogenesis, which has resulted in a major therapeutic advance for many cancers. The [vascular endothelial growth factor] VEGF pathway is vital for tumor angiogenesis, but it also plays an important part in regulating endothelial cells," he said. "Endothelial cells are important in vascular homeostasis for maintaining normal blood viscosity and preventing abnormal bleeding or abnormal clotting. If the balance is tipped toward clotting, arterial thromboembolic events, such as stroke and myocardial infarction, can occur. If it goes the other way, bleeding can occur."

VEGF also increases the production of nitric oxide, which has several vascular protective effects, such as antiplatelet activity and the inhibition of leukocyte adhesion.

"If you inhibit VEGF with these drugs, you disrupt, not in a major way but in a statistically significant way as we show in our study, this hemostatic balance and you tip it toward thrombosis or bleeding."

He added that he believes that this is a class effect. "I don't think folks can claim that one drug has less of an effect than the other."

Study Furthers Understanding of Vascular Effects

Commenting on this study for Medscape Oncology, Ming Hui Chen, MD, MMSc, an oncocardiologist who specializes in the cardiac care of cancer patients at Harvard Medical School in Boston, said that this study furthers our understanding the vascular effects of the small-molecule tyrosine kinase inhibitors.

She added that the study supports the observation of earlier trials that showed cardiac ATEs such as myocardial infarction.

With greater awareness of the ATE risk of these important anticancer agents, "clinicians and patients alike can partner in the early detection and management of any thrombolic events that occur," Dr. Chen added.

Cancer Patients Need These Drugs

Dr. Choueiri said care should be taken when using sunitinib and sorafenib, especially in patients who might be vulnerable to their effects.

"We should not stop using the drugs. Absolutely not. They have made an enormous difference to the way we treat these cancers. But we do have to exert caution, especially in a predisposed population," he told Medscape Oncology. "These would include people who have had a previous stroke, older people, those with uncontrolled hypertension, diabetes, a history of thrombolic events, and so on. The first thing is to know that ATEs can occur. The next most important thing is to monitor your patients. Don't just give them the drug and then see them 2 months later. Bring them back frequently and monitor closely."

Dr. Choueiri and Dr. Chen have disclosed no relevant financial relationships. In the paper, Dr. Choueri reports having had relationships with Bayer Pharmaceuticals/Onyx Pharmaceuticals, GlaxoSmithKline, Abbott Laboratories, Genentech, Agennix, Novartis, and Pfizer, but adds that he has received no compensation for these relationships.

J Clin Oncol. Published online March 29, 2010. Abstract