A phase III trial of bevacizumab (Avastin) with intravenous vs intraperitoneal chemotherapy showed no improvement in progression-free survival for first-line treatment of patients with optimally surgically resected stage II and III ovarian, peritoneal, or fallopian tube cancer.1 When compared with previous trials of intraperitoneal chemotherapy, including GOG 172, the progression-free survival for patients was described as “very disappointing” by Joan Walker, MD, lead author of the study.
“At 33.8 months, the progression-free survival for optimal and no-residual-disease participants was pretty good [in GOG 252], but compared to GOG 172, we did not come close,” said Dr. Walker, Professor and Interim Section Chief of Obstetrics and Gynecology at the University of Oklahoma Stephenson Cancer Center, Oklahoma City. “All arms had excessive toxicity,” she added.
GOG 252 Design
As Dr. Walker reported at the 2016 Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer, GOG 252 began in 2005 with the goal of understanding the “awesome” results of GOG 172. “We wanted to understand the contributions of intraperitoneal paclitaxel and intraperitoneal cisplatin, we wanted to have a new comparator arm, and we wanted to learn if we could improve the outcomes of these patients,” she explained.
Despite the positive results of GOG 172, there was a poor completion rate of six cycles of chemotherapy. With that in mind, Dr. Walker and colleagues attempted to develop less-toxic intraperitoneal regimens for testing, and two were eventually selected: an intraperitoneal carboplatin and a dose-reduced intraperitoneal cisplatin arm.
The researchers enrolled 1,560 patients (median age, 58 years) from July 2009 to November 2011. Eligible patients had stages II–IV epithelial ovarian, peritoneal, or fallopian tube carcinoma and were randomized to receive six cycles of chemotherapy in one of three arms:
- Arm 1: intravenous carboplatin AUC (area under the curve) 6/intravenous weekly paclitaxel at 80 mg/m2
- Arm 2: intraperitoneal carboplatin AUC 6/intravenous weekly paclitaxel at 80 mg/m2
- Arm 3: intravenous paclitaxel at 135 mg/m2 on day 1/intraperitoneal cisplatin at 75 mg/m2 on day 2/intraperitoneal paclitaxel at 60 mg/m2 on day 8.
In addition, each arm received intravenous bevacizumab at 15 mg/kg with cycles 2 through 6 of chemotherapy and then alone for cycles 7 through 22.
Comparatively Disappointing Results
As Dr. Walker reported, intraperitoneal therapy did not confer a statistically significant progression-free-survival advantage over intravenous therapy alone. For the respective arms, the outcomes were as follows:
- Median progression-free survival by intent-to-treat analysis was 24.9 (intravenous carboplatin), 27.3 (intraperitoneal carboplatin), and 26.0 months (intraperitoneal cisplatin)
- Median progression-free survival for stage II/III patients with 1 cm or less visible tumor was 26.8 (intravenous carboplatin), 28.7 (intraperitoneal carboplatin), and 27.8 months (intraperitoneal cisplatin)
- Median progression-free survival for stage III patients with no visible residual disease was 31.3 (intravenous carboplatin), 31.8 (intraperitoneal carboplatin), and 33.8 months (intraperitoneal cisplatin).
Dr. Walker noted that a computed tomography scan was required in all patients every 6 months—a first for an intraperitoneal study. Progression-free survival may have been influenced by that addition, she observed.
Intraperitoneal Chemotherapy in GOG 252 Trial
In the GOG 252 study of ovarian, fallopian tube, and peritoneal cancers, progression-free survival was not improved with intraperitoneal chemotherapy. Intravenous and intraperitoneal carboplatin using weekly, dose-dense paclitaxel were better tolerated than intraperitoneal cisplatin. The reduced-dose intraperitoneal cisplatin regimen does not appear to be as effective as previously reported high-dose cisplatin regimens.Although the progression-free survival of 33.8 months in arm 3 is respectable, compared with previous intraperitoneal studies, it’s “very disappointing,” she acknowledged.
“The results of GOG 172 were amazing. It had a 60.4-month median progression-free survival for no-visible-disease patients,” she said. “Dose reductions of paclitaxel and cisplatin as well as crossover may have compromised our efficacy,” Dr. Walker added, “and bevacizumab interactions may have clouded the analysis.”
Questions Remain
As Dr. Walker reported, dose-dense paclitaxel may have improved efficacy well enough to allow clinicians to abandon intraperitoneal chemotherapy. The question remains, she said, should we wait or combine intraperitoneal therapy with weekly paclitaxel?
As overall survival data for optimal and no-residual-disease participants will not be available for a few years, Dr. Walker reserved judgment on recommendations. However, intraperitoneal chemotherapy with cisplatin probably should not be combined with bevacizumab because the angiogenesis inhibitor may cause severe hypertension, she concluded. ■
Disclosure: The GOG 252 trial was supported by Genentech. Dr. Walker has not personally received funding for the trial.
Reference
