Final results of a phase 2 study indicated that the use of the
VEGF-targeting aflibercept significantly reduced the occurrence of malignant
ascites in women with advanced ovarian cancer; however, the drug confers a high
risk for fatal bowel perforation.
The study was a double blind, placebo-controlled, parallel-group design
that included 55 patients with advanced chemoresistant ovarian cancer and
recurrent malignant ascites. The patients had undergone a median of four prior
lines of chemotherapy. Patients were randomly assigned to treatment with
aflibercept (Eylea, Regeneran Pharmaceuticals) 4 mg/kg every 2 weeks or
placebo. The primary endpoint was time to repeat paracentesis.
Data indicated that patients assigned to aflibercept had significantly
longer time to first paracentesis compared with patients assigned placebo (55.1
days vs 23.3 days; P=.0019). Median time to repeat paracentsesis was 39
days for those assigned to aflibercept and 18 days for those assigned to
placebo. Two patients assigned to aflibercept went the entire 6-month double
blind period without needing repeat paracentesis.
Treatment with aflibercept was not without side effects, the most common
of which were dyspnea, fatigue or asthenia, and dehydration. In addition, three
patients assigned to aflibercept died of bowel perforation.
In an accompanying editorial, Gerhild Becker, MD, and Hubert
E. Blum, MD, of the University Medical Center Freiburg in Freiburg,
Germany, wrote: “Careful patient selection could reduce the incidence of
gastrointestinal perforations. However, 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.”
For more information:
- Gotlieb WH. Lancet Oncol.
2011;doi:10-1016/S1470-2045(22)70338-2.
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Bradley J. Monk
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This paper adds to our already substantial understanding of
anti-angiogenesis therapy in advanced ovarian cancer. The advantages of this
paper were its randomized and placebo-controlled design. There were no new
findings, but again, it confirms prior observations. First, anti-VEGF therapy
is active in ovarian cancer. The current study showed control of symptomatic
ascites, but three randomized phase 3 trials (GOG 218, ICON-7 and OCEANS) have
shown that anti-angiogenesis therapy results in durable tumor control and
prolonged PFS. Second, there appears to be little or no improvement in OS with
anti-VEGF therapy. The current study showed a HR of 1.02. It was underpowered,
but a trend in OS would have been encouraging. Finally, the major side effect
that is more common in ovarian cancer than other solid tumors is
gastrointestinal perforation. One of the major predictors of perforation is
multiple lines of prior chemotherapy. Among heavily pretreated women with
recurrent ovarian cancer, the gastrointestinal perforation rate is about 10%,
as seen in the current study. It was 11% in a previous phase 2 trial (Cannistra
SA. J Clin Oncol. 2007;25:5180-5186.). So we know that
aflibercept, like bevacizumab, is active in inhibiting angiogenesis since it
prolongs OS in advanced colon cancer. Indeed, it also is active but toxic in
ovarian cancer, again like bevacizumab. Moving forward, we need to identify
biomarkers that predict efficacy to enrich the possibility of an improvement in
OS. We also need to learn if anti-angiogenesis-based therapy is better used
front line or second line.
– Bradley J. Monk, MD, FACS, FACOG
Professor, Division of Gynecologic Oncology,
Creighton University School of Medicine
St. Joseph’s Hospital and Medical Center
Disclosure: Dr. Monk reports no relevant financial
disclosures.