Surgery
Treatment Options With Group 1 Drugs
Treatment Options With Group 2 Drugs
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 has not been studied in the setting of a randomized clinical trial.

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 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 deemednot useful.

Considerably higher response rates and response durations are achievable at retreatment with platinums alone or in combination when the disease is potentially platinum sensitive rather than when it is platinum resistant.

Platinum-sensitive recurrence

A small randomized study showed a significant difference in response rates and in duration of response in favor of a platinum-containing regimen over paclitaxel.[2] Several larger 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). These trials differed with respect to platinum-free interval, number of prior regimens allowed, and whether exposure to a prior taxane was required. 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.[3][Level of evidence: 1iiA]

The combination of carboplatin plus epirubicin has also been tested in randomized trials, but a survival advantage has not been observed for the combination versus carboplatin alone. Carboplatin plus pegylated liposomal doxorubicin has been studied in phase II trials but the results are only available in abstract form.[7] While platinum plus taxane is considered the standard option for a platinum-sensitive recurrence, particularly in the absence of residual neurotoxicity, the superior results might have as readily been achieved with this combination by using the single agents given sequentially, or with any of the combinations shown in Table 2.

Platinum-refractory or platinum-resistant recurrence

For patients with platinum-refractory or platinum-resistant disease, the drugs listed in Group 1 (below) constitute the currently preferred treatment options based on stronger evidence of single-agent activity and/or a more favorable therapeutic index than the drugs listed in Group 2.

Treatment with paclitaxel historically provided the first agent with consistent activity in patients with platinum-refractory or platinum-resistant recurrences.[8-12] Subsequently, randomized studies have indicated that the use of topotecan achieved results that were comparable to those achieved with paclitaxel.[13] More recently, topotecan was compared with pegylated liposomal doxorubicin in a randomized trial of 474 patients, nearly 50% of whom had platinum-sensitive disease, and demonstrated similar response rates, PFS, and OS at the time of the initial report.[14]

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.[15-17] Objective responses are reported in patients with platinum-refractory disease. Substantial myelosuppression follows administration. Other toxic effects include nausea, vomiting, alopecia, and asthenia.



2. Pegylated liposomal doxorubicin. 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.[18]

   Liposomal doxorubicin and topotecan have been compared in a randomized trial of 474 patients with recurrent ovarian cancer.[14] 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.[14][Level of evidence: 1iiA] Survival was longer for the patients with platinum-sensitive disease who received liposomal doxorubicin.[19]




3. Docetaxel. This drug has shown activity in paclitaxel-pretreated patients and is a reasonable alternative to weekly paclitaxel in the recurrent setting.[20]



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.[21-23]



5. Paclitaxel. 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.[13]

(This group includes drugs that are not fully confirmed to have activity in a platinum-resistant setting, have a less desirable therapeutic index, and do not have a level of evidence higher than 3iiiDiv.)

1. Etoposide. Oral low doses of etoposide have generated response rates from 6% to 26%. Studies have not determined efficacy relative to other drugs.[24-27]



2. Alkylating drugs (i.e., cyclophosphamide, ifosfamide, melphalan, treosulfan, and thioTepa). Ifosfamide has shown modest activity in patients with epithelial ovarian cancer, including disease that is platinum refractory. A GOG study demonstrated three clinical complete responses and five partial responses (overall response rate was 20%) in 41 evaluable patients whose disease was either refractory to platinum or had relapsed following platinum-based chemotherapy.[28] Toxic effects include myelosuppression, nephrotoxicity, hemorrhagic cystitis, and toxic encephalopathy. Other phase II studies confirm the activity of ifosfamide in patients with epithelial ovarian cancer. In one phase II study, seven objective responses were observed in 52 patients (objective response rate was 13.5%). Of the seven patients who responded, five had tumors that were platinum refractory.[29] Data on other alkylating drugs are mostly from the preplatinum era or from outside the United States.



3. Hexamethylmelamine (HMM, altretamine). Several reports of orally administered HMM as salvage chemotherapy after failure of cisplatin-based combination regimens are encouraging.[30-34] Response rates in platinum-resistant patients are 12% to 14%. Mild to moderate toxic effects and peripheral neuropathy are often observed following treatment with HMM.



4. Irinotecan. Most trials with this topoisomerase I inhibitor derivative of camptothecin have been conducted in Japan. Some activity, particularly against clear cell carcinoma, has been claimed.



5. Oxaliplatin. In a phase II randomized study, this platinum analog showed activity similar to that seen with paclitaxel; however, there was little activity in the platinum-resistant setting.[35,36] Combinations with pegylated liposomal doxorubicin, however, are well tolerated and active.



6. Vinorelbine. This vinca derivative has shown activity in some series but only modest activity in the platinum-resistant setting.[37] Aggravation of intestinal hypomotility (ileus) and need for a central line further inhibit its use.



7. Fluorouracil and capecitabine. In patients with platinum-resistant recurrent disease, an objective response rate of 10% to 17% has been reported.[38,39]



8. Tamoxifen. Some patients will respond to tamoxifen. In one study, 18% of patients responded to a dose of 20 mg twice daily.[40] A response is more likely in patients with detectable levels of cytoplasmic estrogen receptor on their tumors.

Summary of treatment options

1. 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 cisplatin or carboplatin should be considered.[41,42]



2. For patients with platinum-refractory or 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), treatment with paclitaxel, liposomal doxorubicin, docetaxel, topotecan, or gemcitabine should be considered.[43] Other drugs listed above have also had some claims of antitumor activity.



3. No studies have clearly demonstrated that secondary cytoreduction confers a survival advantage, and its role remains controversial; however, 100 patients with recurrent or progressive disease after standard cytoreduction and platinum-based chemotherapy were re-explored.[44,45] The 61 patients who had successful cytoreduction (greatest residual tumor diameter <2 cm) had a statistically significant prolongation of survival.[1] Multivariate analyses revealed the cytoreduction to be the most important variable influencing survival. Whether the success of cytoreduction is related to the biologic nature of the tumor is not known.

   When disease-related symptoms can be abrogated, surgical intervention may improve the quality of life, such as the reversal of small or large bowel obstruction. Palliation, however, is rarely achieved when there are multiple areas of partial or complete obstruction, when the transit time is prolonged as a result of diffuse peritoneal carcinomatosis, or when anatomy requires a bypass that results in the short bowel syndrome.[44]




4. Other agents shown to have activity in phase II trials:
   • Gemcitabine.
   • Fluorouracil and leucovorin.
   • Tamoxifen.
   • Etoposide.
   • Ifosfamide.
   • Hexamethylmelamine (HMM).
   • Capecitabine.[46]
   • Bevacizumab. Although phase II studies have shown single-agent activity for this antibody to vascular endothelial growth factor (VEGF), bowel perforations have occurred, primarily in patients who had partial bowel obstruction.[47,48]



5. Drug combinations. Pilot studies have reported tolerance and activity for combinations of doxorubicin plus topotecan, gemcitabine plus doxorubicin, oxaliplatin plus topotecan, oxaliplatin plus doxorubicin, and a number of other combinations with drugs listed above. There is no evidence that drug combinations are superior to single agents in the platinum-resistant setting.



6. A number of tyrosine kinase inhibitors alone and in combination with Group 1 drugs. A number of pilot studies with erlotinib, lapatinib, sunitinib, imatinib, sorafenib, and additional VEGF small-molecule inhibitors are under way.

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

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