Controversy Remains on Addition of VEGF Inhibition Before Interval Debulking in Ovarian Cancer

Roman Rouzier, MD

The addition of bevacizumab (Avastin) to neoadjuvant platinum-based chemotherapy led to a significantly increased rate of complete resection at interval debulking in advanced ovarian cancer, according to results reported at the 2016 ESMO Annual Congress in Copenhagen.

After receiving the neoadjuvant chemotherapy with the angiogenesis inhibitor, nearly 60% of patients with FIGO stage III/IV ovarian cancer underwent complete resection, compared with a reference rate of 51% of patients who underwent interval debulking after receiving platinum-based neoadjuvant chemotherapy.

However, the invited discussant of the poster, Ignace Vergote, MD, PhD, who was also the lead investigator of the study that provided the reference values for complete surgical resection, cited some issues with the trial design and the investigators' conclusions.

“The interval debulking was done after four cycles [of neoadjuvant therapy], despite in all other randomized trials the interval debulking was performed after three cycles,” said Vergote, director of gynecologic oncology at University Hospitals Leuven in Belgium. “Comparing the complete resection rate after four cycles versus after three cycles is not really fair. You should have more complete resections. Secondly, this study is small. It is only 95 randomized patients.”

On the other hand, Roman Rouzier, MD, highlighted the fact that the study's primary objective was met, such that the complete resection rate was significantly higher than the previously reported reference rate.

"Adding bevacizumab to neoadjuvant carboplatin-paclitaxel chemotherapy achieved an encouraging complete resection rate at interval debulking surgery in patients with initially unresectable FIGO stage IIIc/IV ovarian, tubal, or peritoneal adenocarcinoma," Rouzier, director of senology and gynecology at the Institut Curie in Saint-Cloud, France, and colleagues concluded in the poster presentation.

The report represented a continuation of the clinical investigation of adding bevacizumab to standard chemotherapy to improve the complete resection rate at interval debulking. Preliminary data established the safety and feasibility of adding three cycles of bevacizumab to four cycles of carboplatin-paclitaxel chemotherapy.

To continue the investigation, Rouzier et al enrolled 95 patients with initially unresectable FIGO IIIc/IV ovarian cancer and randomized them 2:1 to four cycles of conventional neoadjuvant chemotherapy, with or without three cycles of bevacizumab (the chemotherapy-only group serving as a calibration group). Patients were evaluated 28 days after completion of cycle 4, and interval debulking surgery was performed if deemed appropriate by the treating surgeon.

Using published data for complete surgical resection after neoadjuvant chemotherapy, the investigators derived a reference rate of 46.3% for all patients and 51.2% for those who actually underwent interval surgical debulking. Rouzier and colleagues considered a complete resection rate of <45% as evidence of insufficient efficacy of adding bevacizumab to neoadjuvant chemotherapy and 65% as evidence of clinical efficacy.

The 95 patients had a median age of 63. More than 90% had ECOG performance status 0-1, and 70% had FIGO IIIc ovarian cancer. The ovary was the primary site in 95% of cases. Histology was serous in 95% of the cases and poorly differentiated (high grade) in 94%. The median CA-125 level was 1,045 U/mL.

Subsequently, 40 of 58 (69%) patients in the bevacizumab arm underwent interval debulking surgery, and 34 patients (58.6%) attained complete resection. The rate of complete resection was associated with a lower confidence limit of 47.0%, significantly higher than the prespecified minimum threshold of 45%. A sensitivity analysis limited to the 40 bevacizumab-treated patients who underwent interval debulking surgery yielded a complete resection rate at interval debulking of 85.5%. An analysis of 52 patients who received at least two cycles of bevacizumab resulted in a complete resection rate at interval debulking of 63.5%.

In the calibration group, interval debulking surgery was performed in 22 patients (60.0%), resulting in a complete resection rate of 51.4%.

“The percentage of patients who undergo interval debulking surgery is really not much higher. When I look at the R0 (complete resection) rate—51% in the control arm, 58% in the bevacizumab arm&mdash;I don’t see a real difference,” said Vergote when comparing the calibration and bevacizumab arms.

Vergote also noted that his own study is an older study, making comparison with a contemporary study somewhat complicated.

“On the basis of these results, I think we can say that the adding a VEGF inhibitor to carboplatin-paclitaxel chemotherapy prior to interval debulking is safe, but there is no proof—yet, because we don’t have all the data&mdash;that the addition of a VEGF inhibitor improves the complete resection rate after interval debulking,” Vergote concluded.

Vergote I, Tropé CG, Amant F, et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med. 2010;363:943-953.