FDA Warns of Possible Bevacizumab Fistula Complication

ROCKVILLE, Md., April 23 -- The FDA and Genentech have issued a warning about the possible formation of tracheoesophageal fistulas as a complication of an off-label use of bevacizumab (Avastin).

Two of 29 patients in a trial of the drug for limited-stage small-cell lung cancer, a non-approved indication, developed a tracheoesophageal fistula and one died, the agency said.

A third patient suffered upper aerodigestive tract hemorrhage and death of unknown cause in which a tracheoesophageal fistula was suspected but not confirmed, the agency said.

The multicenter, non-randomized phase II trial, which was closed to new accruals on March 12, combined four cycles of concurrent irinotecan (Campto), carboplatin (Paraplatin), radiation therapy, and bevacizumab, followed by maintenance bevacizumab for up to six months, said a Genentech "Dear Healthcare Provider" letter.

All of the adverse events occurred during the bevacizumab maintenance phase, the letter said.

The rate of tracheoesophageal fistula in patients with small-cell lung cancer is estimated to be less than 1%, far lower than the nearly 7% seen in the study, the Genentech letter said.

But because of the small size of the study, and its non-randomized nature, the company said, it's not possible to say whether the observed toxicity was caused by bevacizumab or other risk factors, such as intra-thoracic organ sensitivity from chemotherapy or radiotherapy alone.

The company added that as of March 22, six cases of tracheoesophageal fistula have been reported in other lung and esophageal cancer studies, using bevacizumab and either chemotherapy alone or with concurrent radiation.

The current prescribing information for bevacizumab contains a warning and case descriptions of gastrointestinal tract perforation in patients treated for colorectal and other cancers.

Gastrointestinal perforation, sometimes associated with intra-abdominal abscess, can occur at any time during treatment with bevacizumab, the prescribing information says, and is not correlated with duration of exposure.

The rate of gastrointestinal perforation in bevacizumab-treated patients with colorectal cancer was 2.4%, while in patients with non-small cell lung cancer, it was 0.9%.

Bevacizumab should be stopped permanently if gastrointestinal perforation occurs, the label says. Physicians should consider gastrointestinal perforation as the differential diagnosis if a bevacizumab patient develops abdominal pain.

Bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF), is approved, with intravenous 5-fluorouracil-based (5-FU) chemotherapy, for first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum.

It's also approved, with carboplatin and paclitaxel, for first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic non-squamous non-small cell lung cancer (NSCLC).