DOUBLING OF RISK FOR BLEEDING WITH SORAFENIB AND SUNITINIB

October 27, 2009 — Treatment of cancer patients with the targeted agents sorafenib (Nexavar, Bayer and Onyx) and sunitinib (Sutent, Pfizer) is associated with a significant increase in the risk for bleeding, a new meta-analysis concludes.

The risk for bleeding was doubled by the use of these agents, the authors report in the October issue of Lancet Oncology.

Bleeding is already mentioned as a warning in the labeling of both products, but the findings from this meta-analysis — which consisted of 6779 patients — go "beyond the label," said senior author Toni Choueiri, MD, from the Dana-Farber Cancer Institute, Harvard Medical School, in Boston, Massachusetts. The quantification of risk is new, and so is the finding that the risk is statistically significant, he told Medscape Oncology.

"Clinicians should be aware of the possibility of increased bleeding, especially in patients at high risk," the authors note.

"The risk of bleeding might be higher and more relevant in the older and frailer population, in whom even a grade 2 bleed is of clinical importance," they note. Also, the risk for bleeding might be increased in patients who are receiving chemotherapy, because this leads to bone marrow suppression and thrombocytopenia, and by the concurrent use of anticoagulant (e.g., warfarin) or antiplatelet (e.g., aspirin, clopidogrel, ticlopidine) treatment.

Currently, clinicians are "barely aware" of the risk for bleeding with these drugs, Dr. Choueiri said. It might be necessary to stop certain therapies before using these agents, or to proceed with caution in patients who are taking concomitant medication, he added.

Consequence of Their Mode of Action

Sorafenib and sunitinib both act as inhibitors of vascular endothelial growth-factor (VEGF) tyrosine kinase, and both were originally approved for use in advanced renal cell carcinoma. Sorafenib is also approved for use in hepatocellular carcinoma, and sunitinib has an additional indication for gastrointestinal stromal tumors. Both drugs are being tested in a variety of other cancers, and so "an increase in their use is expected in the near future," the authors note.

"Recognition of patterns of toxic effects and understanding the mechanism of action of these drugs is important so that early and adequate intervention or prevention can be done," they write.

An increased risk for bleeding has been reported for another drug that inhibits VEGF — bevacizumab (Avastin) — but by a different mechanism. Bevacizumab is a humanized monoclonal antibody directed against serum VEGF ligand, the authors note.

VEGF is important for the survival of endothelial cells and helps to maintain the architecture and integrity of the microvasculature, the authors explain. If VEGF is blocked, the repair and renewal capacity of endothelial cells in response to trauma could be altered, increasing the risk for hemorrhage.

Doubling in Risk for All Grades of Bleeding Events

The meta-analysis — which the authors believe is the first on this issue — included 23 clinical trials. The calculation of relative risk involved 1325 patients receiving VEGF receptor inhibitors (748 receiving sorafenib and 577 receiving sunitinib), and 1215 patients in the control group receiving placebo.

The relative risk for all grades of bleeding events associated with sorafenib and sunitinib (for randomized clinical trials only) was 2.0 (1.14–3.49; P = .015).

"The overall incidence of risk of all-grade bleeding events was 16.7%, with no difference recorded between sorafenib or sunitinib or type of malignant disease," the authors report.

However, a further analysis suggested that among patients treated with sorafenib, the incidence of all-grade bleeding was higher in those with renal cell carcinoma than with other tumors.

The risk for high-grade bleeding events was not significantly higher; the overall incidence was 2.4%, the authors report. The most important of these seemed to be grade 5 cerebral and pulmonary hemorrhages.

Dr. Choueiri and colleagues suggest several explanations for the fact that the risk for high-grade bleeding events was raised only slightly, including the small number of these events and the differences in the way that bleeding events were graded by the trials.

The incidence of high-grade bleeding events for sorafenib and sunitinib (2.4%) is similar to that reported for bevacizumab (2.7%) in a meta-analysis presented earlier this year at the American Society of Clinical Oncology 45th Annual Meeting (Abstract 9584). In that case, this increase in risk for high-grade bleeding events was significant, the authors note, as was the increase in the risk for all grades of bleeding events (36.3%). However, they add, in another meta-analysis of bevacizumab (in which only industry-sponsored trials were selected), the risk for bleeding was slightly higher than that in the control group (hazard ratio, 1.69; P = .09) and was not significantly increased (J Natl Cancer Inst. 2007;99:1232-1239).

The risks for bleeding with bevacizumab are not well quantified, and this adverse effect is not well known, in contrast to some of the other adverse effects seen with this agent, such as thromboembolism, hypertension, bowel perforation, and proteinuria, Dr. Choueiri noted.