Dr. Weeks’ Comment: Avastin now is linked to increased risk for treatment-related death. How was it released before this was discovered?
Bevacizumab Linked to Fatal Adverse Effects in Cancer Patients
February 1, 2011 — More bad news is on the horizon for bevacizumab (Avastin). Just over a month after the US Food and Drug Administration proposed withdrawing its breast cancer indication, a new study has shown that the drug might be associated with an increased risk for treatment-related death.
The meta-analysis, which appears in the February 2 issue of theJournal of the American Medical Association, found that the overall incidence of fatal adverse events with bevacizumab in combination with chemotherapy was 2.5%; the incidence was 1.7% in patients who received chemotherapy alone.
Overall, adding bevacizumab to chemotherapy or biologic therapy was associated with an increased relative risk for fatal adverse events of 1.46 (95% confidence interval [CI], 1.09 to 1.94; P = .01). However, this association varied significantly with the type of chemotherapeutic agents that were combined with bevacizumab (P = .045).
The relative risk for fatal adverse events was 3.5-fold higher among patients receiving taxanes or platinum agents; there was no increased risk when bevacizumab was used in combination with other agents.
The incidence of fatal adverse events also varied among the different types of cancers. This variation, note the authors, reflected the nature of underlying tumor biology or associated treatment. However, the relative risk for fatal adverse events specifically associated with bevacizumab did not vary significantly by tumor type.
Dr. Shenhong Wu
On the basis of these results, senior author Shenhong Wu, MD, PhD, assistant professor of medicine at Stony Brook University in New York, noted that caution might be needed when prescribing bevacizumab. This includes closer patient monitoring, more careful patient selection, and a weighing of the risk/benefit ratio in all patients.
Even though the absolute risk for treatment-related mortality seems to be low, it is important for physicians and patients to recognize the risks and benefits associated with this agent, Dr. Wu and colleagues conclude.
“I think it is important for physicians to discuss this issue before the therapy,” Dr. Wu told Medscape Medical News. “Further trials are needed to select patients for survival benefit and less serious side effects.”
Failures and Success
Bevacizumab has had a somewhat checkered history of failures and successes. For example, as previously reported by Medscape Medical News, a phase 3 trial showed that the addition of bevacizumab to standard therapy in early breast cancer had no benefit. Another phase 3 trial did not demonstrate a benefit in early colon cancer.
On the positive side, bevacizumab appeared to extend progression-free survival in advanced colorectal cancer and recurrent glioblastoma multiforme. It has also been approved for the treatment of metastatic renal cell carcinoma, although an overall survival benefit has not yet been observed.
In an accompanying editorial, Daniel F. Hayes notes that bevacizumab studies have produced results that are inconsistent and decidedly mixed when it comes to a survival benefit.
“Why, despite the impressively solid preclinical data and the promising early clinical results, has bevacizumab not been more successful in improving overall survival?” asks Dr. Hayes, from the University of Michigan Comprehensive Cancer Center in Ann Arbor.
Boon or Bust?
The answer to that and other questions are not easily discernible, he notes, pointing out that some investigators have questioned whether progression-free or disease-free survival, as opposed to overall survival, is the best end point for large-scale cancer therapeutic trials. “The biology of anti-[vascular endothelial growth factor] therapy may make the choice of end points a critical issue,” he writes.
“Careful review of response rates to bevacizumab suggest that bevacizumab works well, but only in selected patients,” Dr. Hayes notes.
However, the meta-analysis shows that bevacizumab therapy is associated with a higher rate of fatal adverse events, even though it is not associated with the degree of adverse effects encountered with most chemotherapies, he points out. Considering that optimal treatment with bevacizumab might require years of frequent treatment, the higher rate of fatal adverse events could negate any survival benefits.
Is bevacizumab a boon or a bust?
“Is bevacizumab a boon or a bust?” asks Dr. Hayes, andswering that “the jury is still out. Although bevacizumab has benefit, it is currently not possible to determine in whom or for how long.”
Therefore, he adds, “oncologists are forced to dilute the potential effects of bevacizumab by exposing all treated patients, and society, to enormous costs and occasional life-threatening toxic effects. These unfortunate circumstances are sad for those who pay the bills — and sadder for patients with solid tumors.”
For the meta-analysis, Dr. Wu and colleagues identified 16 randomized controlled trials that comprised a total of 10,217 patients with a variety of advanced solid tumors. In all of the studies considered eligible for inclusion, bevacizumab was used in combination with chemotherapy or biologic therapy, and was compared with chemotherapy alone or biologic therapy alone.
Data on 5589 patients who received bevacizumab were available for analysis. Within this cohort, there were 148 fatal adverse events. The highest incidence was observed in a phase 2 lung cancer study (13.4%; 95% CI, 7.1% to 23.8%), and the lowest incidence was observed in a phase 3 breast cancer trial in which no events were reported.
The most common specific causes of fatal adverse events were hemorrhage (23.5%), neutropenia (12.2%), gastrointestinal tract perforation (7.1%), pulmonary embolism (5.1%), and cerebrovascular accident (5.1%).
Partial funding was provided by the Research Foundation of the State University of New York at Stony Brook. Dr. Wu reports being a speaker for Onyx, Novartis, and Pfizer; and receiving honoraria from Onyx, Pfizer, Novartis, Amgen, and Genentech. His coauthors have disclosed no relevant financial relationships.
The editorial was supported by Fashion Footwear Charitable Foundation of New York/QVC Presents Shoes on Sale and by Komen for the Cure. Dr. Hayes has disclosed stock ownership in Oncimmune LLC and Halcyon Diagnostics Inc. He has received occasional honoraria for consulting from Compendia Bioscience, Chugai Pharmaceuticals, and Biomarker Strategies. He receives research funding support from GlaxoSmithKline, Pfizer, Novartis, and Veridex (Johnson & Johnson). He has disclosed no relevant financial relationships with Genentech or Roche.
JAMA. 2011;305:487-494, 506-508. Abstract