Ovarian Epithelial Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI] - Recurrent or Persistent Ovarian Epithelial Cancer Treatment
Table 3. Regimens Used in First Relapse continued...
Treatment with paclitaxel historically provided the first agent with consistent activity in patients with platinum-refractory or platinum-resistant recurrences.[14,15,16,17,18] Subsequently, randomized studies have indicated that the use of topotecan achieved results that were comparable to those achieved with paclitaxel. Topotecan was compared with PLD in a randomized trial of 474 patients and demonstrated similar response rates, PFS, and OS at the time of the initial report, which was contributed primarily by the platinum-resistant subsets.
Drugs used to treat platinum-refractory or platinum-resistant recurrence:
- Topotecan. In phase II studies, topotecan administered intravenously on days 1 to 5 of a 21-day cycle yielded objective response rates ranging from 13% to 16.3% and other outcomes that were equivalent or superior to paclitaxel.[19,21,22,23] Objective responses are reported in patients with platinum-refractory disease. Substantial myelosuppression follows administration. Other toxic effects include nausea, vomiting, alopecia, and asthenia. A number of schedules and oral formulations are under evaluation. (Refer to the PDQ summary on Nausea and Vomiting for more information.)
The combination of weekly topotecan and biweekly bevacizumab was evaluated in a phase II study that showed an objective response rate of 25% (all partial responses) in a platinum-resistant patient population. The most common grade 3 and grade 4 toxicities were hypertension, neutropenia, and gastrointestinal (GI) toxicity, though no bowel perforations occurred.
- PLD. A phase II study of encapsulated doxorubicin given IV once every 21 to 28 days demonstrated one complete response and eight partial responses in 35 patients with platinum-refractory or paclitaxel-refractory disease (response rate, 25.7%). In general, liposomal doxorubicin has few acute side effects other than hypersensitivity. The most frequent toxic effects are usually observed after the first cycle and are more pronounced following dose rates exceeding 10 mg/m2 per week and include stomatitis and hand-foot syndrome. Neutropenia and nausea are minimal, and alopecia rarely occurs.
Liposomal doxorubicin and topotecan have been compared in a randomized trial of 474 patients with recurrent ovarian cancer. Response rates (19.7% vs. 17.0%; P = .390), PFS (16.1 wk vs. 17.0 wk; P = .095), and OS (60 wk vs. 56.7 wk; P = .341) did not differ significantly between the liposomal doxorubicin and topotecan arms, respectively.[Level of evidence: 1iiA] Survival was longer for the patients with platinum-sensitive disease who received liposomal doxorubicin.
- Docetaxel. This drug has shown activity in paclitaxel-pretreated patients and is a reasonable alternative to weekly paclitaxel in the recurrent setting.
- Gemcitabine. Several phase II trials of gemcitabine as a single agent administered IV on days 1, 8, and 15 of a 28-day cycle have been reported. The response rate ranges from 13% to 19% in evaluable patients. Responses have been observed in patients whose disease is platinum refractory and/or paclitaxel refractory as well as in patients with bulky disease. Leukopenia, anemia, and thrombocytopenia are the most common toxic effects. Many patients report transient flu-like symptoms and a rash following drug administration. Other toxic effects, including nausea, are usually mild.[27,28,29] (Refer to the anemia section in the PDQ summary on Fatigue and refer to the PDQ summary on Nausea and Vomiting for more information.)
A randomized trial of gemcitabine versus PLD showed noninferiority and no advantage in therapeutic index of one drug over the other.
- Paclitaxel. Patients generally received paclitaxel in front-line induction regimens. Retreatment with paclitaxel, particularly in weekly schedules, indicates an activity comparable to those of the preceding drugs. If there is residual neuropathy upon recurrence, this may shift the choice of treatment towards other agents.
In a phase III study, 235 patients who did not respond to initial treatment with a platinum-based regimen but who had not previously received paclitaxel or topotecan, were randomly assigned to receive either topotecan as a 30-minute infusion daily for 5 days every 21 days or paclitaxel as a 3-hour infusion every 21 days. The overall objective response rate was 20.5% for those patients who were randomly assigned to treatment with topotecan and 13.2% for those patients who were randomly assigned to treatment with paclitaxel (P = .138). Both groups experienced myelosuppression and GI toxic effects. Nausea and vomiting, fatigue, and infection were observed more commonly following treatment with topotecan, whereas alopecia, arthralgia, myalgia, and neuropathy were observed more commonly following paclitaxel. (Refer to the PDQ summary on Gastrointestinal Complications for information on gastrointestinal toxic effects; refer to the PDQ summary on Nausea and Vomiting and the PDQ summary on Fatigue; and, refer to the PDQ summary on Pain for information on arthralgia, myalgia, and neuropathy.)
- Bevacizumab. Three phase II studies have shown activity for this antibody to vascular endothelial growth factor (VEGF).
The first study (GOG-0170D) included 62 patients who had received only one or two prior treatments (these last patients had received one additional platinum-based regimen because of an initial interval of 12 months or greater after first-line regimens and also had to have a performance status of 0 or 1). Patients received a dose of 15 mg/kg every 21 days; there were two complete responses and 11 partial responses, a median PFS of 4.7 months, and an OS of 17 months. This activity was noted in both platinum-sensitive and platinum-resistant subsets.
The second study only included patients with platinum-resistant disease using an identical dose schedule, but the study was stopped because five of 44 patients experienced bowel perforations, one of them fatal; seven partial responses had been observed. This increased risk of bowel perforations was associated with three or more prior treatments.[33,34,35][Level of evidence: 3iiiDii]
The third study (CCC-PHII-45) included 70 patients who received 50 mg of oral cyclophosphamide daily, in addition to bevacizumab (10 mg/kg every 2 wk); 17 partial responses were observed and four patients had intestinal perforations.
- Pemetrexed. A randomized, double-blind, phase II European trial with 102 patients evaluated pemetrexed at two doses: standard (500 mg/m2) versus high-dose (900 mg/m2) IV every 3 weeks. The response rate was 9.3% for the standard dose and 10.4% for the high dose. The toxicity profile favored the standard dose with fatigue, and nausea and vomiting, as the most common severe toxicities.
A phase II study by the Gynecologic Oncology Group utilized pemetrexed (900 mg/m2) IV every 3 weeks in 51 patients with platinum-resistant recurrent disease. The response rate was 21% in a heavily pretreated population in which 39% had five or more prior regimens. Myelosuppression and fatigue were the most common severe toxicities.
Other drugs used to treat platinum-refractory or platinum-resistant recurrence
This group includes drugs that are not fully confirmed to have activity in a platinum-resistant setting, have a less desirable therapeutic index, and have a level of evidence lower than 3iiiDiv.