The monoclonal antibody aflibercept, a vascular endothelial growth factor blocker, prevented the recurrence of malignant ascites in a phase II clinical trial involving 55 patients with advanced ovarian cancer, according to a report published online Dec. 21 in Lancet Oncology.

Compared with placebo, aflibercept extended the time to repeat paracentesis, increased the duration of paracentesis-free survival, and reduced the frequency of paracentesis during 60 days of follow-up. It also improved symptoms of abdominal bloating, discomfort, and pain, and allowed patients to move more comfortably, said Dr. Walter H. Gotlieb of McGill University and Jewish General Hospital, Montreal, and his associates.

"Anti-VEGF [vascular endothelial growth factor] treatments such as aflibercept appear to reduce the formation of malignant ascites and could dramatically improve the quality of life for patients with this debilitating complication. But clinicians must exercise caution in their use of aflibercept because of the significantly increased risk of fatal bowel perforation," Dr. Gotlieb noted in a press statement accompanying the report.

There were three fatal gastrointestinal perforations among study subjects who received aflibercept and one among those who received placebo. This complication has been reported previously in a pilot study of the drug, as well as in studies of the related monoclonal antibody bevacizumab, the investigators noted.

In this double-blind trial, women with advanced ovarian epithelial cancer that was resistant to a median of four types of chemotherapy were enrolled at 23 sites in Belgium, Canada, Hungary, India, Israel, the United Kingdom, and the United States. Most had serous cancer and poorly differentiated tumors. The study subjects had experienced recurrent malignant ascites and required up to four paracenteses per month to relieve their symptoms.

The subjects were randomly assigned to receive IV aflibercept (29 women) or placebo (26 women) every 2 weeks for at least 60 days, but for no longer than 6 months. They were allowed to cross over to open-label treatment at 6 months.

The primary end point was the time to repeat paracentesis. This interval was significantly longer with aflibercept (55 days) than with placebo (23 days).

Paracentesis-free survival also was significantly longer with aflibercept (42 days) than with placebo (18 days). Notably, two women who received the active drug did not require any repeat paracentesis during 6 months of treatment.

The median frequency of paracentesis procedures within 60 days of beginning treatment was 2 (range, 0-9 procedures) with aflibercept, which was significantly less than the median frequency of 4 procedures (range, 0-17 procedures) that were required with placebo.

In addition, the women who received the active drug reported greater improvement on a questionnaire that assessed abdominal pain, abdominal bloating, abdominal discomfort, and restricted movement, the investigators said (Lancet Oncol. 2011 [doi:10.1016/S1470-2045(11)70338-2]).

There were no significant differences between aflibercept and placebo in overall survival or progression-free survival.

All the women who received aflibercept and all but two of those who received placebo reported adverse effects that commonly occur with advanced intraperitoneal disease, chiefly nausea, vomiting, diarrhea, fatigue, asthenia, peripheral edema, dyspnea, and cough. Potentially serious adverse effects possibly related to VEGF blockade were more common in the aflibercept group, and included venous thromboembolism, hypertension, proteinuria, and bowel perforation.

There was "an imbalance" between the aflibercept and placebo groups in the number of deaths related to study treatment (four vs. zero) and in the number of fatal gastrointestinal perforations (three vs. one).

"Anti-VEGF treatments such as aflibercept appear to reduce the formation of malignant ascites."

All three intestinal perforations in the aflibercept group occurred early in the course of treatment (during the first or second treatment cycle), and two occurred in the context of disease progression. One of these patients had experienced two recent episodes of intestinal obstruction and another had a deep tumor mass infiltrating the sigmoid.

Six deaths among women receiving aflibercept were unrelated to cancer progression: one due to suspected pulmonary embolus possibly related to the study drug, and one each due to dyspnea, intestinal perforation, pneumonia, aspiration pneumonia, and an unknown cause. In comparison, there were two deaths in the placebo group, which were due to sepsis and aspiration.

Four patients who received aflibercept developed grade 3 or 4 liver abnormalities, as did one patient who received placebo.

The study results "clearly show the effectiveness of VEGF blockade in the reduction of ascites formation." However, the number of bowel perforations "point[s] to an unfavorable benefit-risk balance for this therapeutic anti-VEGF intervention in heavily pretreated patients with ovarian cancer," Dr. Gotlieb and his associates said.

"A patient population not as advanced in their disease or without a history of bowel obstruction or with alternative regimens might have a different benefit-risk balance," they added.

This study was sponsored by Sanofi Oncology. Dr. Gotlieb reported ties to Sanofi-Aventis, and his associates reported ties to numerous industry sources.

Aflibercept Prevents Ascites Recurrence in Advanced Ovarian Cancer