SAN ANTONIO — Rectovaginal nodularity turned out to be the only significant risk factor for bowel complications in a retrospective single-institution study of 112 women treated with bevacizumab for recurrent epithelial ovarian cancer.
Ten women (9%) developed bowel perforations in the study, and five died within 30 days—a mortality rate of 50% for this serious complication. Fistulas were diagnosed in two patients (1.8%): one enterocutaneous fistula and one fistula-in-ano.
To the investigators' surprise, a host of potential causes—among them, the number of previous bevacizumab (Avastin) regimens, carcinomatosis, bowel involvement on CT scan, and history of small bowel obstruction—produced no significant associations with bowel complications. Rectovaginal nodularity increased risk more than threefold (odds ratio 3.64, P = .04), however.
After hearing the data presented at the Society of Gynecologic Oncologists' annual meeting on women's cancer, an audience member asked Dr. Debra L. Richardson, the lead author, whether the 50% mortality rate she reported was excessive. Most of the patients were heavily pretreated, she responded, and three patients chose not to pursue any further interventions at a late stage in their disease.
Though potentially deadly, the risk of bevacizumab-related bowel complications should not preclude use of the agent in advanced ovarian cancer, Dr. Richardson added in an interview. If other treatment options are available, she might hold off introducing bevacizumab. If not, she would discuss the risk with the patient.
“If bevacizumab is the only treatment option, I think it still may be worthwhile as long as the patient is well counseled about this risk,” she said.
Dr. Richardson and her coauthors at the Ohio State University in Columbus undertook the chart review because high rates of bowel complications have been seen when bevacizumab is used in patients with recurrent epithelial ovarian cancer. Bowel perforation and fistula have been reported in 0%–11% of patients given monotherapy, and 0%–9% of patients when bevacizumab is used in combination with other cytotoxic agents. Of particular concern, these rates are higher than with bevacizumab use in other cancers, including colorectal cancers.
Despite this toxicity, she noted, bevacizumab continues to be used because it has produced response rates of 10%–21% as monotherapy and 24%–78% when used in combination with other drugs for recurrent ovarian cancer.
The chart review looked at all patients treated with at least one dose of bevacizumab. Dr. Richardson reported that 112 patients (median age 60 years) who met study requirements received 160 different bevacizumab regimens. Nearly a third, 31%, had received more than one bevacizumab regimen. The most common cytotoxic combination was with weekly paclitaxel (34%) followed by combinations of bevacizumab with gemcitabine and carboplatin or cisplatin.
Patients had a median of four prior chemotherapy regimens, and they received a median of six cycles of bevacizumab with a median total dose of 8,313 mg. The population included 18 patients with a history of small bowel obstruction, 31 with rectovaginal nodularity, 78 with a CT scan prior to starting bevacizumab, 10 with a CT scan showing bowel involvement, and 21 with carcinomatosis.
The bowel perforations occurred 2–25 days (0.5–5 cycles) after starting bevacizumab, Dr. Richardson reported. Three of the patients who developed perforations had previously been treated with bevacizumab, and 30% of perforated patients died within 7 days. After the perforations were diagnosed, she continued, four patients opted for surgery and three of them survived 30 days as did two patients treated with intravenous antibiotics.
As for why rectovaginal nodularity turned out to be the only significant risk factor, Dr. Richardson cited the small size of the study as one possibility. Another is that only large-volume disease is associated with bevacizumab-related bowel perforation, she said, and yet another that current imaging is not large enough to detect bowel involvement.
Dr. Richardson disclosed no conflicts of interest.
Bevacizumab continues to be used because it has produced response rates of 10%–21% as monotherapy. DR. RICHARDSON