Trial of Ovarian Chemotherapy Regimens Fails to Provide Clarity

Joan L. Walker, MD

Three different chemotherapy regimens, each combined with bevacizumab, failed to demonstrate an advantage for patients with advanced ovarian cancer or build on results of a landmark trial reported more than a decade ago.

Results of the Gynecologic Oncology Group (GOG) 252 trial showed median progression-free survival (PFS) of approximately 27 to 29 months in patients with optimal stage II-III disease treated with regimens consisting of different combinations of intravenous (IV) and intraperitoneal (IP) cisplatin, carboplatin, and paclitaxel, in combination with bevacizumab. An analysis limited to patients with optimal stage III tumors and no gross residual disease produced median PFS values of 31 to 34 months.

By comparison, the decade-old GOG 172 trial comparing IP and IV chemotherapy regimens in ovarian cancer produced a median PFS of 23.8 months with IP cisplatin, including 60.4 months in patients who had no visible residual disease after surgery. Follow-up for survival will continue in GOG 252, as reported at the 2016 Society of Gynecologic Oncology Annual Meeting.

“Reduced doses of paclitaxel and cisplatin, as well as crossover, may have compromised the efficacy,” explained Joan L. Walker, MD, a gynecologic oncologist at the University of Oklahoma Health Sciences Center in Oklahoma City. “Dose-dense paclitaxel may have improved efficacy well enough to allow us to abandon IP chemotherapy, so should we wait or should we combine both? That’s the question. However, neuropathy might limit that. Bevacizumab interactions also may have clouded our analysis.”

GOG 252 involved women with stage II-III epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. All patients underwent optimal surgical debulking to 1 cm or less residual disease by surgeon report.

Patients were randomized to three chemotherapy regimens:

• IV paclitaxel 80 mg/m², IV carboplatin AUC 6, and bevacizumab 15 mg/kg (reference arm)
• IV paclitaxel 80 mg/m², IP carboplatin AUC 6, and15 mg/kg bevacizumab
• IV paclitaxel 135 mg/m², IP cisplatin 75 mg/m², IP paclitaxel 60 mg/m², and 15 mg/kg bevacizumab

Differences in the cisplatin arm from the GOG 172 study include a dose reduction from 100 mg to 75 mg and a shorter infusion time from 24 hours to 3 hours (outpatient).

The primary endpoint was PFS. Data were analyzed from 1560 patients with a median age of 58. Patients with stage III disease accounted for 84% of the study population, and 72% of patients had grade 3 serous ovarian cancer. Walker noted that 57% of the patients had no visible residual disease by surgeon report. An analysis of CT assessment of completeness of surgery is pending.

In both carboplatin arms, 90% of patients completed at least 6 cycles of platinum therapy compared with 84% of patients randomized to the cisplatin-containing regimen. In all 3 arms, 87% to 88% of patients completed at least 6 cycles of the taxane.

The primary analysis showed a median PFS of 26.8 months for patients with optimal stage II-III disease in the IV carboplatin reference arm, 28.7 months among patients who received IP carboplatin, and 27.8 months for patients who received IP cisplatin. Follow-up for overall survival will continue, Walker said.

Two thirds or more patients in each arm developed grade 3 neutropenia. Grade 3 thrombocytopenia occurred in 6.3% and 8.4% the IV and IP carboplatin groups, respectively, as compared with 9% in the cisplatin arm. Grade 3 hypertension occurred in 12% to 14% of patients in the carboplatin arms and 20.5% of patients randomized to the cisplatin-containing regimen. Grade 3 nausea and vomiting occurred in 11.2% of the cisplatin group and in about 5% in the two carboplatin arms. Grade 2 sensory neuropathy occurred in more than 20% of patients in all three arms of the trial.

“All arms had substantial toxicity,” Walker said. “Neurotoxicity was equally high in all arms. We reserve judgment on recommendations until survival is available. IP cisplatin probably shouldn’t be combined with bevacizumab because it causes severe hypertension.”

An analysis of patient-reported outcomes (PROs)—quality of life, neuropathy, nausea, fatigue, and abdominal discomfort—showed consistently lower scores among patients in the cisplatin arm,. PRO scores did not differ appreciably between the two carboplatin arms, with the exception of slower improvement in abdominal discomfort in patients treated with IP carboplatin.

Walker JL, Brady MF, DiSilvestro PA, et al. A phase III clinical trial of bevacizumab with IV versus IP chemotherapy in ovarian, fallopian tube and primary peritoneal carcinoma NCI-supplied agent(s): bevacizumab (NSC #704865, IND #7921) NCT01167712 a GOG/NRG trial (gog 252). Presented at: 2016 SGO Annual Meeting. March 19-22, 2016. San Diego, CA. Late-breaking abstract.

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