Local Modalities: Surgery and Radiation Therapy
Platinum-Sensitive Recurrence
Platinum-Refractory or Platinum-Resistant Recurrence
Treatment Options for Patients with Recurrent or Persistent Disease
Current Clinical Trials

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Cytoreduction is often employed,[1] but such intervention only now is being studied in the setting of a randomized clinical trial (GOG-0213). The role of radiation therapy in patients with recurrent ovarian cancer has not been defined.

Systemic treatment options for patients with recurrent disease are subdivided as follows:

1. Platinum-sensitive recurrence: for patients whose disease recurs more than 6 months after cessation of the induction (usually retreated with a platinum—cisplatin or carboplatin— and referred to as potentially platinum sensitive).
2. Platinum-refractory or platinum-resistant recurrence: for patients who progress prior to cessation of induction (platinum refractory) or within 6 months after cessation (platinum resistant); in these patients, platinums are generally deemed toxic and not sufficiently useful to be part of the treatment plan.

Carboplatin was approved in 1987 for the treatment of patients with ovarian cancer whose disease recurred after treatment with cisplatin, based on improved survival with etoposide or 5-fluorouracil.[7] In a randomized phase II trial of paclitaxel, a currently used second-line drug, the cisplatin-containing combination of cisplatin plus doxorubicin plus cyclophosphamide (CAP) yielded a superior survival outcome. This, and subsequent studies (see Table 2), have reinforced using carboplatin as the treatment core for patients with platinum-sensitive recurrences. Cisplatin is occasionally used, particularly in combination with other drugs, because of its lesser myelosuppression, but this advantage over carboplatin is counterbalanced by its greater intolerance. Oxaliplatin, initially introduced with the hope that it would overcome platinum resistance, has activity mostly in platinum-sensitive patients [8] but has not been compared with carboplatin alone or in combinations. With all platinums, outcome is generally better the longer the initial interval without recurrence from the initial platinum-containing regimens.[9] Therefore, on occasion, patients with platinum-sensitive recurrences relapsing within 1 year have been included in trials of nonplatinum drugs. In one such trial, comparing the pegylated liposomal doxorubicin (PLD) to topotecan, the subset of patients who were platinum sensitive had better outcomes with either drug (and in particular with PLD) relative to the platinum-resistant cohort.[10]

Several randomized trials have addressed whether the use of a platinum in combination is superior to single agents (see Table 2). A platinum-plus-paclitaxel combination yielded a superior outcome in terms of response rates, progression-free survival (PFS), and overall survival (OS) in comparison to carboplatin as a single agent or other platinum-containing combinations as control in an analysis of data analyzing jointly the results of three trials performed by the Medical Research Council/Arbeitsgemeinschaft Gynaekologische Onkologie (MRC/AGO) and ICON investigators (known as ICON4). Platinum plus paclitaxel was compared to several control regimens, though 71% used carboplatin as a single agent in the control, and 80% used carboplatin plus paclitaxel. Prolonged PFS (hazard ratio [HR] = 0.76; 95% confidence interval [CI], 0.66–0.89; P = .004) and overall survival (HR = 0.82; 95% CI, 0.69–0.97; P = .023) were improved in the platinum-plus-paclitaxel arm.[6][Level of evidence: 1iiA][3] The AGO had previously compared the combination of epirubicin plus carboplatin to carboplatin alone and had not found significant differences in outcome.

Another trial by European and Canadian groups compared gemcitabine plus carboplatin to carboplatin. The PFS of 8.6 months with the combination was significantly superior to 5.8 months for the carboplatin alone (HR = .72; 95% CI, 0.58–0.90; P = .003). The study was not powered to detect significant differences in OS, and the median survival for both arms was 18 months (HR = 0.96; CI, 0.75–1.23; P = .73).[5]

Accordingly, because of this randomized experience, carboplatin plus paclitaxel is considered the standard regimen for platinum-sensitive recurrence in the absence of residual neurotoxicity. The GOG-0213 trial will be comparing this regimen to the experimental arm that adds bevacizumab to carboplatin plus paclitaxel.

Clinical recurrences that take place within 6 months of completion of a platinum-containing regimen are considered platinum-refractory or platinum-resistant recurrences. Anthracyclines (particularly when formulated as PLD), taxanes, topotecan, and gemcitabine are used as single agents for these recurrences based on activity and their favorable therapeutic indices relative to agents listed in Table 3. The long list underscores the marginal benefit, if any, generally conveyed by these agents. Patients with platinum-resistant disease should be encouraged to enter clinical trials.

Treatment with paclitaxel historically provided the first agent with consistent activity in patients with platinum-refractory or platinum-resistant recurrences.[11-15] Subsequently, randomized studies have indicated that the use of topotecan achieved results that were comparable to those achieved with paclitaxel.[16] Topotecan was compared with pegylated liposomal doxorubicin in a randomized trial of 474 patients and demonstrated similar response rates, PFS, and OS at the time of the initial report, contributed primarily by the platinum-resistant subsets.[17]

Drugs used to treat platinum-refractory or platinum-resistant recurrence:

1. 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.[16,18-20] 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.



2. PLD. A phase II study of encapsulated doxorubicin given intravenously 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.[21] Liposomal doxorubicin and topotecan have been compared in a randomized trial of 474 patients with recurrent ovarian cancer.[17] Response rates (19.7% vs. 17.0%, P = .390), PFS (16.1 weeks vs. 17.0 weeks; P = .095), and OS (60 weeks vs. 56.7 weeks, P = .341) did not differ significantly between the liposomal doxorubicin and topotecan arms, respectively.[17][Level of evidence: 1iiA] Survival was longer for the patients with platinum-sensitive disease who received liposomal doxorubicin.[10]



3. Docetaxel. This drug has shown activity in paclitaxel-pretreated patients and is a reasonable alternative to weekly paclitaxel in the recurrent setting.[22]



4. Gemcitabine. Several phase II trials of gemcitabine as a single agent administered intravenously 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.[23-25] A randomized trial of gemcitabine versus PLD showed noninferiority and no advantage in therapeutic index of one drug over the other.[26]



5. 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 gastrointestinal 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.[16]



6. Bevacizimab. 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).[27] 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.[28] This increased risk of bowel perforations was associated with three or more prior treatments.[29-31][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 weeks); 17 partial responses were observed and four patients had intestinal perforations.[32] Studies by the GOG are evaluating the efficacy of the drug added to the intial treatment and at first recurrence in the platinum-resistant setting.

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.)

1. Secondary cytoreduction has been advocated, but it remains controversial.[1] The GOG-0213 trial, actived in 2008, is attempting to define its role.



2. For patients with platinum-sensitive disease (i.e., a minimum of 5–12 months between completion of a platinum-based regimen and the development of recurrent disease), retreatment with a platinum or platinum-containing combination, such as carboplatin, should be considered (see Table 2).



3. For patients with platinum-refractory or platinum-resistant disease (i.e., disease that has progressed while on a platinum-based regimen or has recurred within 6 months of completion of a platinum-based regimen), clinical trials should be considered. For patients who are not entering a trial, treatment with one of the drugs listed above should be considered.



4. Other agents that have shown activity in phase II trials are listed in Table 3 and may also be used alone or in combination with other drugs, but such treatments are best done in prospective trials.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent ovarian epithelial cancer. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References

1. Hoskins WJ, Rubin SC, Dulaney E, et al.: Influence of secondary cytoreduction at the time of second-look laparotomy on the survival of patients with epithelial ovarian carcinoma. Gynecol Oncol 34 (3): 365-71, 1989.  [PUBMED Abstract]
   
   
2. Ferrero JM, Weber B, Geay JF, et al.: Second-line chemotherapy with pegylated liposomal doxorubicin and carboplatin is highly effective in patients with advanced ovarian cancer in late relapse: a GINECO phase II trial. Ann Oncol 18 (2): 263-8, 2007.  [PUBMED Abstract]
   
   
3. Bolis G, Scarfone G, Giardina G, et al.: Carboplatin alone vs carboplatin plus epidoxorubicin as second-line therapy for cisplatin- or carboplatin-sensitive ovarian cancer. Gynecol Oncol 81 (1): 3-9, 2001.  [PUBMED Abstract]
   
   
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19. Creemers GJ, Bolis G, Gore M, et al.: Topotecan, an active drug in the second-line treatment of epithelial ovarian cancer: results of a large European phase II study. J Clin Oncol 14 (12): 3056-61, 1996.  [PUBMED Abstract]
    
    
20. Bookman MA, Malmström H, Bolis G, et al.: Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. J Clin Oncol 16 (10): 3345-52, 1998.  [PUBMED Abstract]
    
    
21. Muggia FM, Hainsworth JD, Jeffers S, et al.: Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation. J Clin Oncol 15 (3): 987-93, 1997.  [PUBMED Abstract]
    
    
22. Berkenblit A, Seiden MV, Matulonis UA, et al.: A phase II trial of weekly docetaxel in patients with platinum-resistant epithelial ovarian, primary peritoneal serous cancer, or fallopian tube cancer. Gynecol Oncol 95 (3): 624-31, 2004.  [PUBMED Abstract]
    
    
23. Friedlander M, Millward MJ, Bell D, et al.: A phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer. Ann Oncol 9 (12): 1343-5, 1998.  [PUBMED Abstract]
    
    
24. Lund B, Hansen OP, Theilade K, et al.: Phase II study of gemcitabine (2',2'-difluorodeoxycytidine) in previously treated ovarian cancer patients. J Natl Cancer Inst 86 (20): 1530-3, 1994.  [PUBMED Abstract]
    
    
25. Shapiro JD, Millward MJ, Rischin D, et al.: Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel. Gynecol Oncol 63 (1): 89-93, 1996.  [PUBMED Abstract]
    
    
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