Recurrent or Persistent Ovarian Epithelial, Fallopian Tube, and Primary Peritoneal Cancer Treatment
Overall, approximately 80% of patients diagnosed with ovarian epithelial, fallopian tube, and primary peritoneal cancer will relapse after first-line platinum-based and taxane-based chemotherapy and may benefit from subsequent therapies. Early detection of persistent disease by second-look laparotomies after completion of first-line treatment is no longer practiced; when the outcomes in the 50% of institutions practicing such procedures were informally compared with the outcomes in institutions not using such procedures, additional lack of support for them grew, as was found in the case for patients entered in GOG-0158. However, the practice of close follow-up of patients completing treatment by serial CA-125s at intervals of 1 to 3 months was nearly universally adopted. In patients who are in clinical complete remission, increases in CA-125 from their initial treatment represent the most common method to detect disease that will eventually relapse clinically.
A trial by the Medical Research Council and European Organization for Research and Treatment of Cancer (MRC-OV05, which is now closed) examined the consequences of early institution of treatment for recurrence versus treatment delayed until clinical symptoms appeared. Patients in clinical complete remission after platinum-based chemotherapy were registered and followed with CA-125s only and clinical visits. Upon detection of a twofold elevation over the normal range, patients were randomly assigned to disclosure of the result (and early treatment for recurrence) versus continued blinding and treatment upon development of signs and symptoms indicative of clinical relapse. The number of randomly assigned patients was to exceed 500 in order to yield a superior survival outcome at 2 years with early institution of therapy; this required 1,400 registrations, which were accrued between May 1996 and August 2005. Among 1,442 registrants, 29% continued to show no evidence of relapse, 19% relapsed without evidence of CA-125 doubling beyond normal or at the same time, and another 4% died before becoming eligible for random assignment. Registrants had stage III and stage IV disease in 67% of the cases, whereas these stages represented 80% of the randomly assigned patients. The median survival of all patients registered was 70.8 months.
Median survival for patients randomly assigned to early treatment (n = 265) was 25.7 months compared with 27.1 months for patients in the delayed-treatment group (n = 264) (hazard ratio [HR], 0.98; 95% confidence interval [CI], 0.8–1.2). The median delay in instituting second-line chemotherapy was 4.8 months, and the median delay in instituting third-line chemotherapy was 4.6 months. Treatments for second-line chemotherapy were comparable among the two groups (mostly platinum- and taxane-based), whereas third-line treatments were less often applied to the delayed-treatment group. The study concluded that there was no benefit in the detection of early presence of disease by CA-125; this is consistent with the failure of second-look surgeries to provide improved outcomes after early detection of persistent disease. Monitoring CA-125 levels in follow-up may play a role in identifying appropriate candidates for secondary cytoreduction, although this strategy awaits confirmation with a randomized trial.
Local Modalities: Surgery and Radiation Therapy
Cytoreduction is often employed, but such intervention is only now 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:
- 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 platinum sensitive).
- Platinum-refractory or platinum-resistant recurrence: for patients who progress prior to cessation of induction therapy (platinum refractory) or within 6 months after cessation (platinum resistant); in these patients, platinums are generally deemed not sufficiently useful to be part of the treatment plan.
|Eligibility (mo)||Regimen||Patient Number||Comparator||Comments on Outcome (mo)|
|OS = overall survival; PFS = progression-free survival; PLD = pegylated liposomal doxorubicin.|
|aTrabectedin has been approved for use in treating recurrent ovarian cancer in Europe and Canada.|
|bOS data were not mature at the time the manuscript was published.|
|Most Commonly Used|
|Platinum sensitive (>6)||Cisplatin or carboplatin + paclitaxel||802||Single or nontaxane + platinums||PFS 11 vs. 9; OS 24 vs. 19 |
|Platinum sensitive (>6)||Carboplatin + gemcitabine||356||Carboplatin||PFS 8.6 vs. 5.8; OS 18 vs. 17 |
|Platinum sensitive (> 6)||Carboplatin + pegylated liposomal doxorubicin||976||Carboplatin + paclitaxel||PFS 11.3 vs. 9.4; OS 30.7 vs. 33.0 [7,8]|
|Platinum sensitive (>6)||Carboplatin + epirubicin||190||Carboplatin||Powered for response differences; OS 17 vs. 15 |
|Platinum sensitive (≥12)||Cisplatin + doxorubicin + cyclophosphamide||97||Paclitaxel||PFS 15.7 vs. 9; OS 34.7 vs. 25.8 |
|Platinum sensitive + resistant||PLD + trabectedina||672||PLD||PFS 7.3 vs. 5.8; OS 20.5 vs. 19.4b|
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. 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 3), 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 greater patient intolerance. Oxaliplatin, initially introduced with the hope that it would overcome platinum resistance, has activity mostly in platinum-sensitive patients  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. 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.
Several randomized trials have addressed whether the use of a platinum in combination with other chemotherapy agents is superior to single agents (see Table 3). In an analysis of data examining jointly the results of three trials performed by the Medical Research Council/Arbeitsgemeinschaft Gynaekologische Onkologie (MRC/AGO) and ICON investigators (known as ICON-4), a platinum-plus-paclitaxel combination yielded a superior outcome, in terms of response rates, progression-free survival (PFS), and overall survival (OS), compared with carboplatin as a single agent or other platinum-containing combinations as controls. Platinum plus paclitaxel was compared with several control regimens, although 71% used carboplatin as a single agent in the control, and 80% used carboplatin plus paclitaxel. Prolonged PFS (HR, 0.76; 95% CI, 0.66–0.89; P = .004) and OS (HR, 0.82; 95% CI, 0.69–0.97; P = .023) were improved in the platinum-plus-paclitaxel arm.; [Level of evidence: 1iiA] The AGO had previously compared the combination of epirubicin plus carboplatin with 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, 0.72; 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).
Carboplatin plus paclitaxel has been considered the standard regimen for platinum-sensitive recurrence in the absence of residual neurological toxic effects. The GOG-0213 trial is comparing this regimen with the experimental arm that adds bevacizumab to carboplatin plus paclitaxel.
In a phase III trial, carboplatin plus PLD (CD) was compared with carboplatin plus paclitaxel (CP) in patients with platinum-sensitive recurrence (>6 months). The primary endpoint was PFS with a median PFS for the CD arm of 11.3 months versus 9.4 months for the CP arm (HR, 0.823; 95% CI, 0.72–0.94; P = .005).[Level of evidence: 1iiDiii] Long-term follow-up revealed no difference in OS rates between the two arms (30.7 months for CD vs. 33.0 months for CP). The CP arm was associated with increased severe neutropenia, alopecia, neuropathy, and allergic reaction; the CD arm was associated with increased severe thrombocytopenia, nausea, and hand-foot syndrome. Given its toxicity profile and noninferiority to the standard regimen, CD is an important option for patients with platinum-sensitive recurrence.
Platinum-Refractory or Platinum-Resistant Recurrence
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 4. 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.[15-19] Subsequently, randomized studies have indicated that the use of topotecan achieved results that were comparable with 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.[20,22-24] 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 intravenously (IV) once every 21 to 28 days demonstrated 1 complete response and 8 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, 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.[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.[28-30] (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 with 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 patients who were randomly assigned to treatment with topotecan and 13.2% for 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 plus chemotherapy.
The AURELIA (Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer) (NCT00976911) trial was an open-label randomized trial designed to evaluate the effect of adding bevacizumab to standard chemotherapy in patients with platinum-resistant recurrent ovarian cancer. Eligible patients had platinum-resistant disease (progression within 6 months of finishing a platinum-containing regimen), and no more than two prior regimens. Patients with platinum-refractory disease (those with progression during receipt of a platinum-containing regimen), and those with clinical or radiological signs of bowel involvement were ineligible. Patients were prescribed one of three chemotherapy regimens, based on physician preference:
- Pegylated liposomal doxorubicin (PLD) 40 mg/m2 by IV on day 1 every 4 weeks.
- Paclitaxel 80 mg/m2 by IV on days 1, 8 15 and 22 every 4 weeks.
- Topotecan 4 mg/m2 by IV on days 1, 8 and 15 every 4 weeks; or, 1.25 mg/m2 by IV on days 1 through 5 every 3 weeks.
Patients were then randomly assigned to receive either chemotherapy alone or chemotherapy with bevacizumab (10 mg/kg every 2 weeks, or 15 mg/kg every 3 weeks if on the 3-week-dosing schedule). Crossover to a bevacizumab-containing regimen was allowed at progression for those patients in the chemotherapy-only arm. PFS was the primary outcome, with response rate, OS, safety and quality of life used as secondary endpoints. Enrollment included 361 patients, with a median follow-up of 13.9 months in the chemotherapy-only arm and 13.0 months in the chemotherapy-plus-bevacizumab arm. Patients in the bevacizumab arm exhibited longer PFS (HR, 0.48; 95% CI, 0.38 to 0.60); median PFS was 3.4 months in the chemotherapy-alone arm versus 6.7 months in the chemotherapy-plus-bevacizumab arm. The objective response rate was 12.6% in the chemotherapy-alone arm versus 30.9% in the chemotherapy-plus-bevacizumab arm. There was no statistically significant difference in OS between the regimens (13.3 months for the chemotherapy-alone regimen vs. 16.6 months for the chemothearpy-plus-bevacizumab regimen). Patients in the chemotherapy-plus-bevacizumab arm had an increased incidence of hypertension and proteinuria, when compared with patients in the chemotherapy-only arm. Gastrointestinal (GI) perforation was only 2% in those receiving chemotherapy plus bevacizumab, which reflects the study’s stringent exclusion criteria. Quality of life, as measured by improvement in the GI-symptom subscale, was also improved in the patients on the bevacizumab-plus-chemotherapy arm.
- 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 1 or 2 previous treatments (these last patients had received 1 additional platinum-based regimen because of an initial interval of 12 months or longer 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 2 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 5 of 44 patients experienced bowel perforations, 1 of them fatal; 7 partial responses had been observed. This increased risk of bowel perforations was associated with three or more previous treatments.[35-37][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 4 patients had intestinal perforations.
- Pemetrexed. A randomized, double-blinded phase II European trial with 102 patients evaluated pemetrexed at 2 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% of the patients had received 5 or more regimens previously. 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.
|Drugs||Drug Class||Major Toxicities||Comments|
|Etoposide||Topoisomerase II inhibitor||Myelosuppression; alopecia||Oral; rare leukemia dampens interest|
|Cyclophosphamide and several other bischloroethylamines||Alkylating agents||Myelosuppression; alopecia (only the oxazaphosphorines)||Leukemia and cystitis; uncertain activity after platinums|
|Hexamethylmelamine (Altretamine)||Unknown but probably alkylating prodrugs||Emesis and neurologic toxic effects||Oral; uncertain activity after platinums|
|Irinotecan||Topoisomerase I inhibitor||Diarrhea and other gastrointestinal symptoms||Cross-resistant to topotecan|
|Oxaliplatin||Platinum||Neuropathy, emesis, myelosuppression||Cross-resistant to usual platinums, but less so|
|Vinorelbine||Mitotic inhibitor||Myelosuppression||Erratic activity|
|Fluorouracil and capecitabine||Fluoropyrimidine antimetabolites||Gastrointestinal symptoms and myelosuppression||Capecitabine is oral; may be useful in mucinous tumors|
|Tamoxifen||Antiestrogen||Thromboembolism||Oral; minimal activity, perhaps more in subsets|
Treatment Options for Patients with Recurrent or Persistent Disease
- Secondary cytoreduction has been advocated, but it remains controversial. The GOG-0213 trial, active in 2008, is attempting to define its role.
- For patients with platinum-sensitive disease (i.e., ≥6–12 mo 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 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.
- Other agents that have shown activity in phase II trials are listed in Table 4 and may also be used alone or in combination with other drugs, but such treatments are best done in prospective trials.
Current Clinical Trials
Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent ovarian epithelial cancer, fallopian tube cancer and primary peritoneal cavity 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.
- Ozols RF, Bundy BN, Greer BE, et al.: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J Clin Oncol 21 (17): 3194-200, 2003. [PUBMED Abstract]
- Rustin GJ, van der Burg ME, Griffin CL, et al.: Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomised trial. Lancet 376 (9747): 1155-63, 2010. [PUBMED Abstract]
- 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]
- Monk BJ, Herzog TJ, Kaye SB, et al.: Trabectedin plus pegylated liposomal Doxorubicin in recurrent ovarian cancer. J Clin Oncol 28 (19): 3107-14, 2010. [PUBMED Abstract]
- Parmar MK, Ledermann JA, Colombo N, et al.: Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 361 (9375): 2099-106, 2003. [PUBMED Abstract]
- Cantù MG, Buda A, Parma G, et al.: Randomized controlled trial of single-agent paclitaxel versus cyclophosphamide, doxorubicin, and cisplatin in patients with recurrent ovarian cancer who responded to first-line platinum-based regimens. J Clin Oncol 20 (5): 1232-7, 2002. [PUBMED Abstract]
- Pfisterer J, Plante M, Vergote I, et al.: Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J Clin Oncol 24 (29): 4699-707, 2006. [PUBMED Abstract]
- Wagner U, Marth C, Largillier R, et al.: Final overall survival results of phase III GCIG CALYPSO trial of pegylated liposomal doxorubicin and carboplatin vs paclitaxel and carboplatin in platinum-sensitive ovarian cancer patients. Br J Cancer 107 (4): 588-91, 2012. [PUBMED Abstract]
- 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]
- Muggia FM: Overview of carboplatin: replacing, complementing, and extending the therapeutic horizons of cisplatin. Semin Oncol 16 (2 Suppl 5): 7-13, 1989. [PUBMED Abstract]
- Piccart MJ, Green JA, Lacave AJ, et al.: Oxaliplatin or paclitaxel in patients with platinum-pretreated advanced ovarian cancer: A randomized phase II study of the European Organization for Research and Treatment of Cancer Gynecology Group. J Clin Oncol 18 (6): 1193-202, 2000. [PUBMED Abstract]
- Markman M, Markman J, Webster K, et al.: Duration of response to second-line, platinum-based chemotherapy for ovarian cancer: implications for patient management and clinical trial design. J Clin Oncol 22 (15): 3120-5, 2004. [PUBMED Abstract]
- Gordon AN, Tonda M, Sun S, et al.: Long-term survival advantage for women treated with pegylated liposomal doxorubicin compared with topotecan in a phase 3 randomized study of recurrent and refractory epithelial ovarian cancer. Gynecol Oncol 95 (1): 1-8, 2004. [PUBMED Abstract]
- Pujade-Lauraine E, Wagner U, Aavall-Lundqvist E, et al.: Pegylated liposomal Doxorubicin and Carboplatin compared with Paclitaxel and Carboplatin for patients with platinum-sensitive ovarian cancer in late relapse. J Clin Oncol 28 (20): 3323-9, 2010. [PUBMED Abstract]
- Kohn EC, Sarosy G, Bicher A, et al.: Dose-intense taxol: high response rate in patients with platinum-resistant recurrent ovarian cancer. J Natl Cancer Inst 86 (1): 18-24, 1994. [PUBMED Abstract]
- McGuire WP, Rowinsky EK, Rosenshein NB, et al.: Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 111 (4): 273-9, 1989. [PUBMED Abstract]
- Einzig AI, Wiernik PH, Sasloff J, et al.: Phase II study and long-term follow-up of patients treated with taxol for advanced ovarian adenocarcinoma. J Clin Oncol 10 (11): 1748-53, 1992. [PUBMED Abstract]
- Thigpen JT, Blessing JA, Ball H, et al.: Phase II trial of paclitaxel in patients with progressive ovarian carcinoma after platinum-based chemotherapy: a Gynecologic Oncology Group study. J Clin Oncol 12 (9): 1748-53, 1994. [PUBMED Abstract]
- Trimble EL, Adams JD, Vena D, et al.: Paclitaxel for platinum-refractory ovarian cancer: results from the first 1,000 patients registered to National Cancer Institute Treatment Referral Center 9103. J Clin Oncol 11 (12): 2405-10, 1993. [PUBMED Abstract]
- ten Bokkel Huinink W, Gore M, Carmichael J, et al.: Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 15 (6): 2183-93, 1997. [PUBMED Abstract]
- Gordon AN, Fleagle JT, Guthrie D, et al.: Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 19 (14): 3312-22, 2001. [PUBMED Abstract]
- Kudelka AP, Tresukosol D, Edwards CL, et al.: Phase II study of intravenous topotecan as a 5-day infusion for refractory epithelial ovarian carcinoma. J Clin Oncol 14 (5): 1552-7, 1996. [PUBMED Abstract]
- 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]
- 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]
- McGonigle KF, Muntz HG, Vuky J, et al.: Combined weekly topotecan and biweekly bevacizumab in women with platinum-resistant ovarian, peritoneal, or fallopian tube cancer: results of a phase 2 study. Cancer 117 (16): 3731-40, 2011. [PUBMED Abstract]
- 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]
- 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]
- 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]
- 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]
- 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]
- Mutch DG, Orlando M, Goss T, et al.: Randomized phase III trial of gemcitabine compared with pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer. J Clin Oncol 25 (19): 2811-8, 2007. [PUBMED Abstract]
- Pujade-Lauraine E, Hilpert F, Weber B, et al.: Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J Clin Oncol 32 (13): 1302-8, 2014. [PUBMED Abstract]
- Burger RA, Sill MW, Monk BJ, et al.: Phase II trial of bevacizumab in persistent or recurrent epithelial ovarian cancer or primary peritoneal cancer: a Gynecologic Oncology Group Study. J Clin Oncol 25 (33): 5165-71, 2007. [PUBMED Abstract]
- Cannistra SA, Matulonis UA, Penson RT, et al.: Phase II study of bevacizumab in patients with platinum-resistant ovarian cancer or peritoneal serous cancer. J Clin Oncol 25 (33): 5180-6, 2007. [PUBMED Abstract]
- Vasey PA, McMahon L, Paul J, et al.: A phase II trial of capecitabine (Xeloda) in recurrent ovarian cancer. Br J Cancer 89 (10): 1843-8, 2003. [PUBMED Abstract]
- Monk BJ, Han E, Josephs-Cowan CA, et al.: Salvage bevacizumab (rhuMAB VEGF)-based therapy after multiple prior cytotoxic regimens in advanced refractory epithelial ovarian cancer. Gynecol Oncol 102 (2): 140-4, 2006. [PUBMED Abstract]
- Kaye SB: Bevacizumab for the treatment of epithelial ovarian cancer: will this be its finest hour? J Clin Oncol 25 (33): 5150-2, 2007. [PUBMED Abstract]
- Garcia AA, Hirte H, Fleming G, et al.: Phase II clinical trial of bevacizumab and low-dose metronomic oral cyclophosphamide in recurrent ovarian cancer: a trial of the California, Chicago, and Princess Margaret Hospital phase II consortia. J Clin Oncol 26 (1): 76-82, 2008. [PUBMED Abstract]
- Vergote I, Calvert H, Kania M, et al.: A randomised, double-blind, phase II study of two doses of pemetrexed in the treatment of platinum-resistant, epithelial ovarian or primary peritoneal cancer. Eur J Cancer 45 (8): 1415-23, 2009. [PUBMED Abstract]
- Miller DS, Blessing JA, Krasner CN, et al.: Phase II evaluation of pemetrexed in the treatment of recurrent or persistent platinum-resistant ovarian or primary peritoneal carcinoma: a study of the Gynecologic Oncology Group. J Clin Oncol 27 (16): 2686-91, 2009. [PUBMED Abstract]