Bevacizumab Significantly Increases GI Perforations

Nick Mulcahy

May 27, 2009

May 27, 2009 — Bevacizumab (Avastin) significantly increases the risk of potentially life-threatening gastrointestinal (GI) perforations, compared with those treated with control medication — especially among patients with colorectal cancer and renal cell cancer, according to a new meta-analysis.

"In previous studies, there has been no significant association, even though a black-box warning has been issued," senior author Shenhong Wu, MD, told Medscape Oncology, explaining that earlier clinical trials were not powered to detect a significant relationship.

Dr. Wu is from the Division of Hematology and Medical Oncology at the Stony Brook Medical Center in New York. The meta-analysis was published online May 25 in the Lancet Oncology.

In an analysis of 17 randomized trials, patients treated with bevacizumab had twice the risk for GI perforation as patients treated with control medication (relative risk [RR], 2.14; 95% confidence interval [CI], 1.19 - 3.85; P = .011). The overall incidence of perforations was 0.9% among patients taking the drug.

The perforations can be fatal in many instances, owing to severe peritonitis, note the study authors. In the meta-analysis, mortality in patients with GI perforation related to bevacizumab was 21.7%, whereas mortality in patients with GI perforation related to control medication was 15.7%.

However, the incidence and relative risks of bevacizumab-related GI perforations are "possibly worse," said Barbara Burtness, MD, from the Department of Medical Oncology at the Fox Chase Cancer Center in Philadelphia, Pennsylvania, who was not involved with the meta-analysis, in an interview with Medscape Oncology.

This is one more piece of data about bevacizumab and GI perforations, but not the final word.

"This is one more piece of data about bevacizumab and GI perforations, but not the final word because it is a study of randomized controlled trials only," continued Dr. Burtness.

Dr. Burtness explained that "randomized controlled trials tend to exclude lots of types of patients and don't provide a complete picture of who gets the drug."

The new meta-analysis also leaves an important question unanswered, said Dr. Burtness. "Does the chemotherapy influence risk?" she asked, explaining that bevacizumab is used in combination with a variety of chemotherapy regimens.

"For instance, we know that irinotecan (Camptosar) is associated with more colitis and bowel injury in general. However, this analysis lumps together all sorts of chemotherapy regimens under each tumor type. So we have no way of evaluating the effect of the chemotherapies used in conjunction with bevacizumab," said Dr. Burtness.

Despite her reservations about the study itself and the incidence of GI perforations in general oncology populations, Dr. Burtness said that she believes that the drug was "widely and appropriately used, despite this side effect."

These findings do not affect the safety or efficacy profile of Avastin in its FDA-approved indications.

Genentech, the manufacturer of bevacizumab, noted that the meta-analysis findings are in keeping with previous results. "The authors found an absolute incidence of 0.6% to 1.1%, which is similar to what is in the label," Charlotte Arnold, a spokesperson for Genentech, told Medscape Oncology. "These findings do not affect the safety or efficacy profile of Avastin in its [US Food and Drug Administration]–approved indications," she added.

The drug is indicated for:

  • use in combination with intravenous 5-fluorouracil-based chemotherapy for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum;

  • use in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic nonsquamous nonsmall-cell lung cancer; and

  • use in combination with paclitaxel for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer.

 

Which Patients Are Most at Risk?

In the meta-analysis, the risk for GI perforation varied with bevacizumab dose and tumor type.

With regard to dose, the relative risks for GI perforation for patients receiving bevacizumab — 5 mg/kg and 2.5 mg/kg per week — were 2.67 (95% CI, 1.14 - 6.26) and 1.61 (0.76 - 3.38), respectively.

With regard to tumor type, the highest risks were observed among patients with colorectal cancer (RR, 3.10; 95% CI, 1.26 - 7.63) and renal cell cancer (RR, 5.67, 95% CI, 0.66 - 48.42), and the lowest were in patients with pancreatic cancer (RR, 0.92; 95% CI, 0.19 - 4.37).

"Our study might help to identify a subset of patients at high risk of bevacizumab-associated perforation," the authors conclude.

However, they add that any additional risk factors for GI perforation associated with bevacizumab are "poorly understood." An earlier single-variant analysis had indicated a possible higher risk among patients with intact primary tumors, a history of sigmoidoscopy or colonoscopy within 1 month of initiating bevacizumab therapy, or a history of previous adjuvant radiotherapy (Ann Surg Oncol. 2007;14:1860-1869).

It would be great to know which patients are at highest risk.

"It would be great to know which patients are at highest risk," commented Dr. Burtness.

For instance, Dr. Burtness explained, "we have a sense clinically that patients with lots of peritoneal disease might be at higher risk."

Genentech could help with further identifying risk factors, suggested lead author Dr. Wu. "Postmarketing studies on this issue will help greatly to understand the risk and benefits," he said.

Genentech's Ms. Arnold said that the company monitored GI perforations. "We continue to evaluate all safety events, including the risk of GI perforations, through postmarketing reports, ongoing registry trials, and our Avastin clinical-trial program, which includes more than 450 clinical trials across more than 30 tumor types," she said.

What to Look Out For

In addition to recommending that clinicians pay attention to bevacizumab's dose and a patient's tumor type, the authors also suggest that clinicians be aware of the timeframe of a patient's treatment. "Most gastrointestinal perforations occurred early in the course of bevacizumab treatment, usually within the first 6 months," they write.

Also, clinicians should carefully assess a patient's history to look for evidence of "past diverticulitis or ulcers, radiation exposure, recent sigmoidoscopy or colonoscopy, resection of the primary tumor, gastrointestinal obstruction, and multiple previous surgeries," write the authors.

Dr. Burtness advised telling patients to "look out for abdominal pain" and to have staff "be alert" to such patient complaints. "Refer all abdominal pain to the [emergency department]," she said.

"Our vigilance is higher now," said Dr. Burtness about the national readiness of staff at oncology centers to deal with complaints related to potential GI perforations.

In patients with GI perforation, bevacizumab should be permanently stopped per the drug's labeling, said Ms. Arnold.

However, the authors of the study and Dr. Burtness said this is not always advisable.

"This approach may be an oversimplified response to a diverse range of underlying causes, and might restrict the use of an otherwise effective drug in patients with metastatic cancer and very few treatment options," write the authors

What's Behind the Problem

The authors note that perforations can take place anywhere in the GI tract, including the stomach, small bowel, and colon. However, the precise mechanisms involved in bevacizumab-associated GI perforations are unknown, they point out.

The damage could be done by a variety of processes, they suggest. For instance, "bevacizumab might damage the structure and function of gastrointestinal vasculature, resulting in ischemic perforation of the normal bowel or anastomosis site," they write. Or the drug, which inhibits vascular endothelial growth factor, might prevent the "healing of gastrointestinal ulcers or colonic diverticulitis, which could subsequently develop into perforations," they add.

The study was funded by the Research Foundation of the State University of New York. Dr. Wu is partially supported by the Research Foundation of the State University of New York; has received honoraria from Onyx Pharmaceuticals, Novartis, and Wyeth; and is a speaker for Pfizer and Onyx. The other authors have disclosed no relevant financial relationships. Dr. Burtness has been a consultant to Array BioPharma, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Imedex, Pfizer, Rexahn Pharmaceuticals, and Roche Laboratories; and has received grant/research support from Bristol-Myers Squibb, Genentech, and Novartis.

Lancet Oncol. 2009. Published online before print May 25, 2009.

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