Advanced Ovarian Cancer: Phase III Randomized Study
Advanced Ovarian Cancer: Phase III Randomized Study
Background Topotecan has single-agent activity in recurrent ovarian cancer. It was evaluated in a novel combination compared with standard frontline therapy.
Methods Women aged 75 years or younger with newly diagnosed stage IIB or greater ovarian cancer, Eastern Cooperative Oncology Group Performance Status of 1 or less, were stratified by type of primary surgery and residual disease, treatment center, and age; then randomly assigned to one of the two 21-day intravenous regimens. Patients in arm 1 (n = 409) were administered four cycles of cisplatin 50 mg/m on day 1 and topotecan 0.75 mg/m on days 1–5, then four cycles of paclitaxel 175 mg/m over 3 hours on day 1 followed by carboplatin (area under the curve = 5) on day 1. Patients in arm 2 (n = 410) were given paclitaxel plus carboplatin as in arm 1 for eight cycles. We compared progression-free survival (PFS), overall survival, and cancer antigen-125 normalization rates in the two treatment arms. A stratified log-rank test was used to assess the primary endpoint, PFS. All statistical tests were two-sided.
Results A total of 819 patients were randomly assigned. At baseline, the median age of the patients was 57 years (range = 28–78); 81% had received debulking surgery, and of these, 55% had less than 1 cm residual disease; 66% of patients were stage III and 388 (47.4%) patients had measurable disease. After a median follow-up of 43 months, 650 patients had disease progression or died without documented progression and 406 had died. Patients in arm 1 had more hematological toxicity and hospitalizations than patients in arm 2; PFS was 14.6 months in arm 1 vs 16.2 months in arm 2 (hazard ratio = 1.10, 95% confidence interval = 0.94 to 1.28, P = .25). Among patients with elevated baseline cancer antigen-125, fewer in arm 1 than in arm 2 had levels return to normal by 3 months after random assignment (51.6% vs 63.3%, P = .007)
Conclusions Topotecan and cisplatin, followed by carboplatin and paclitaxel, were more toxic than carboplatin and paclitaxel alone, but without improved efficacy. Carboplatin plus paclitaxel remains the standard of care for advanced epithelial ovarian cancer.
Cisplatin plus paclitaxel, and subsequently carboplatin plus paclitaxel, have become the most widely accepted first-line chemotherapy regimens for advanced epithelial ovarian cancer. Despite the improvements in outcome afforded by this treatment, the great majority of women with ovarian cancer will relapse and eventually die of their disease. One approach to try to improve this treatment is to add a third active agent to the carboplatin–paclitaxel combination. The camptothecin analog, topotecan, has shown activity in the treatment of recurrent ovarian cancer, including platinum-resistant disease. However, combining topotecan with carboplatin and paclitaxel as a triplet therapy is problematic due to myelosuppression. To address this problem, the NCIC Clinical Trials Group (NCIC CTG) tested an approach of sequential doublets of cisplatin plus topotecan followed by carboplatin—paclitaxel as a means of integrating this third agent into the standard regimen. The activity seen in the phase II study of this combination was sufficient to warrant phase III investigation. This report outlines the results of a randomized phase III study that compares standard carboplatin plus paclitaxel to the triple drug combination regimen including topotecan. The trial was conducted by the NCIC CTG, the European Organization for Research and Treatment of Cancer–Gynecologic Cancer Group (EORTC-GCG) and the Grupo de Investigación de Cáncer de Ovario (GEICO) cooperative groups under the auspices of the Gynecologic Cancer Intergroup in women with newly diagnosed advanced epithelial ovarian or fallopian tube or primary peritoneal cancers.
Abstract and Introduction
Abstract
Background Topotecan has single-agent activity in recurrent ovarian cancer. It was evaluated in a novel combination compared with standard frontline therapy.
Methods Women aged 75 years or younger with newly diagnosed stage IIB or greater ovarian cancer, Eastern Cooperative Oncology Group Performance Status of 1 or less, were stratified by type of primary surgery and residual disease, treatment center, and age; then randomly assigned to one of the two 21-day intravenous regimens. Patients in arm 1 (n = 409) were administered four cycles of cisplatin 50 mg/m on day 1 and topotecan 0.75 mg/m on days 1–5, then four cycles of paclitaxel 175 mg/m over 3 hours on day 1 followed by carboplatin (area under the curve = 5) on day 1. Patients in arm 2 (n = 410) were given paclitaxel plus carboplatin as in arm 1 for eight cycles. We compared progression-free survival (PFS), overall survival, and cancer antigen-125 normalization rates in the two treatment arms. A stratified log-rank test was used to assess the primary endpoint, PFS. All statistical tests were two-sided.
Results A total of 819 patients were randomly assigned. At baseline, the median age of the patients was 57 years (range = 28–78); 81% had received debulking surgery, and of these, 55% had less than 1 cm residual disease; 66% of patients were stage III and 388 (47.4%) patients had measurable disease. After a median follow-up of 43 months, 650 patients had disease progression or died without documented progression and 406 had died. Patients in arm 1 had more hematological toxicity and hospitalizations than patients in arm 2; PFS was 14.6 months in arm 1 vs 16.2 months in arm 2 (hazard ratio = 1.10, 95% confidence interval = 0.94 to 1.28, P = .25). Among patients with elevated baseline cancer antigen-125, fewer in arm 1 than in arm 2 had levels return to normal by 3 months after random assignment (51.6% vs 63.3%, P = .007)
Conclusions Topotecan and cisplatin, followed by carboplatin and paclitaxel, were more toxic than carboplatin and paclitaxel alone, but without improved efficacy. Carboplatin plus paclitaxel remains the standard of care for advanced epithelial ovarian cancer.
Introduction
Cisplatin plus paclitaxel, and subsequently carboplatin plus paclitaxel, have become the most widely accepted first-line chemotherapy regimens for advanced epithelial ovarian cancer. Despite the improvements in outcome afforded by this treatment, the great majority of women with ovarian cancer will relapse and eventually die of their disease. One approach to try to improve this treatment is to add a third active agent to the carboplatin–paclitaxel combination. The camptothecin analog, topotecan, has shown activity in the treatment of recurrent ovarian cancer, including platinum-resistant disease. However, combining topotecan with carboplatin and paclitaxel as a triplet therapy is problematic due to myelosuppression. To address this problem, the NCIC Clinical Trials Group (NCIC CTG) tested an approach of sequential doublets of cisplatin plus topotecan followed by carboplatin—paclitaxel as a means of integrating this third agent into the standard regimen. The activity seen in the phase II study of this combination was sufficient to warrant phase III investigation. This report outlines the results of a randomized phase III study that compares standard carboplatin plus paclitaxel to the triple drug combination regimen including topotecan. The trial was conducted by the NCIC CTG, the European Organization for Research and Treatment of Cancer–Gynecologic Cancer Group (EORTC-GCG) and the Grupo de Investigación de Cáncer de Ovario (GEICO) cooperative groups under the auspices of the Gynecologic Cancer Intergroup in women with newly diagnosed advanced epithelial ovarian or fallopian tube or primary peritoneal cancers.
