Aflibercept reduces ovarian ascites but carries bowel perforation risk
MedWire News: The vascular endothelial growth factor (VEGF) inhibitor aflibercept significantly reduces malignant ascites in women with ovarian cancer but carries a risk for fatal bowel perforation, results of a phase II, placebo-controlled trial show.
The researchers suggest that aflibercept should be used with caution for advanced disease and the benefit-risk balance should be thoroughly discussed with each patient.
"Efforts to improve the safety of VEGF blockers in this population of patients with very advanced cancer might include further understanding of the risk factors for intestinal perforation and individualization of VEGF blockade treatment," comment Walter Gotlieb (McGill University, Montréal, Quebec, Canada) and colleagues in the journal Lancet Oncology.
Ascite formation can result from obstruction of lymph vessels by tumor cells, resulting in incomplete absorption of intraperitoneal fluid and protein, the authors explain.
There is no generally accepted gold standard for the management of malignant ascites and the most common therapeutic strategies in clinical practice are paracentesis and diuretic drugs.
It is believed that VEGF increases permeability, leading to ascites formation. Serum concentrations of VEGF are significantly higher in patients with ovarian cancer than in healthy individuals, and malignant ascites contain up to 10-fold higher levels of VEGF than matched serum, the authors write.
Aflibercept is a soluble decoy receptor consisting of portions of human VEGF receptors 1 and 2 fused to the constant region of human immunoglobulin (Ig)-G1. Aflibercept binds and neutralizes VEGF-A isoforms, VEGFB, and inhibits placental growth factor, which plays a part in tumor angiogenesis and inflammation.
To assess the efficacy and safety of aflibercept, Gotlieb et al initiated a double-blind, placebo-controlled, parallel-group, phase II study.
In all 55 patients with advanced chemoresistant ovarian cancer and recurrent symptomatic malignant ascites were randomly allocated to receive treatment with either intravenous aflibercept 4 mg/kg every 2 weeks (n=29) or placebo (n=26). Patients were treated for a minimum of 60 days, until repeat paracentesis had occurred.
Gotlieb et al report that mean time to repeat paracentesis was significantly longer with aflibercept than with placebo, at 55.1 versus 23.3 days, and giving a significant difference of 31.8 days.
Notably, two patients in the aflibercept group did not need repeat paracentesis during 6 months of double-blind treatment.
The most common grade 3 or 4 treatment-emergent adverse events in afilbercept- and placebo-treated patients were dyspnea (20 vs 8%), fatigue or asthenia (13 vs 44%), and dehydration (10 vs 12%).
The frequency of fatal gastrointestinal events was higher with aflibercept (three intestinal perforations) than with placebo (one intestinal fistula leading to sepsis).
In an accompanying comment Gerhild Becke and Hubert Blum (University Hospital Freiburg, Germany) say that symptom relief has to be weighed against discomfort and potentially life-threatening adverse events.
The write: "Before a general recommendation of aflibercept for the treatment of malignant ascites can be made, further studies, including comparative effectiveness research, are needed to compare the effectiveness of the different therapeutic strategies in daily clinical practice."
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By Andrew Czyzewski