A review of the current evidence for maintenance therapy in ovarian cancer

Gynecologic Oncology 115 (2009) 290–301

Contents lists available at ScienceDirect

Gynecologic Oncology j o u r n a l h o m e p a g e : w w w. e l s e v i e r. c o m / l o c a t e / y g y n o

Review

A review of the current evidence for maintenance therapy in ovarian cancer Talia Foster a, T. Michelle Brown a, Jane Chang b, Hans D. Menssen b, Marissa B. Blieden a, Thomas J. Herzog c,⁎ a b c

Abt Bio-Pharma Solutions, Inc., USA Bayer HealthCare Pharmaceuticals, USA Columbia University Medical Center, USA

a r t i c l e

i n f o

Article history: Received 24 April 2009 Available online 31 August 2009 Keywords: Ovarian cancer Maintenance therapy Review Economics Quality of life Systematic review

a b s t r a c t Objectives. Ovarian cancer (OC) typically is diagnosed at advanced stages, in which the primary goal of therapy is to prolong progression-free survival (PFS) and overall survival (OS). In recent years, maintenance therapy has been tested for this purpose in advanced OC (AOC). Literature on maintenance therapy in AOC was systematically reviewed to assess current knowledge regarding the impact of this therapeutic approach. Methods. A MEDLINE search was performed 2/2009 for articles published 1/2001–1/2009 pertaining to OC maintenance therapy guidelines, patterns, and outcomes. A second search used keywords specific to maintenance and included primary studies published in the last 10 years. Of 406 sources identified, 36 primary studies and 16 review articles were included in this systematic review. A third search used the keyword “consolidation” to find maintenance articles not identified through other searches; of 48 additional sources, 13 primary studies and 6 reviews were included. A fourth search of non-MEDLINE-indexed sources yielded 14 additional relevant publications from the same time period. Results. Among practice guidelines identified, only the National Comprehensive Cancer Network (NCCN) 2008 guidelines provide recommendations regarding maintenance therapy, assigning it a category 2B recommendation. No studies were identified that reported current treatment patterns or economic outcomes in maintenance therapy; quality of life data were reported in one study. A variety of agents have been tested for maintenance, with paclitaxel the most commonly evaluated. The Southwest Oncology Group—Gynecologic Oncology Group 178 trial has found that 12 cycles of paclitaxel extend PFS (by 7 months) compared to 3 months paclitaxel, but could not adequately evaluate OS. Conclusions. Maintenance therapy may improve clinical outcomes in AOC, but additional research is needed to demonstrate an OS advantage. Future studies should investigate the long-term clinical benefit of maintenance treatment and its impact on resource utilization and health-related quality of life. © 2009 Published by Elsevier Inc.

Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . Recommended and current use of maintenance therapy . . Outcomes with and without maintenance therapy . . . . . . . Clinical outcomes . . . . . . . . . . . . . . . . . . . . . Paclitaxel. . . . . . . . . . . . . . . . . . . . . . . . . Platinum agents . . . . . . . . . . . . . . . . . . . . . Other agents . . . . . . . . . . . . . . . . . . . . . . . Patient-reported outcomes . . . . . . . . . . . . . . . . Economic outcomes. . . . . . . . . . . . . . . . . . . . Directions for future research . . . . . . . . . . . . . . . . . Efficacy and toxicity of other maintenance agents . . . . . Quality of life data from patients using maintenance therapy Economic studies of maintenance therapy for OC . . . . . .

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⁎ Corresponding author. 161 Ft. Washington Ave., 8th Floor, New York, NY 10032, USA. Fax: +1 212 305 3412. E-mail address: [email protected] (T.J. Herzog). 0090-8258/$ – see front matter © 2009 Published by Elsevier Inc. doi:10.1016/j.ygyno.2009.07.026

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Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction Ovarian cancer (OC) accounts for more deaths than any other gynecologic malignancy, an estimated 15,520 in the U.S. during 2008. Despite the fact that this cancer is highly treatable when caught early and confined to the ovary, less than one-fifth of cases are diagnosed while still in this early stage [1]. As a result, relative survival for females is only 75% at one year and 45% at five years [2]. For women diagnosed with OC in stage III, 5-year survival rate ranges between 31% (stage IIIC) and 51% (stage IIIA) [1]. For such patients with advanced ovarian cancer (AOC), the primary goal of therapy is to prolong progression-free survival (PFS) and overall survival (OS). A strategy gaining attention in recent years is to initiate maintenance therapy as soon as AOC patients achieve their first remission. While no definitive study data have established maintenance therapy as standard in AOC, the results from the Gynecological Oncology Group (GOG) 178 study have revealed some promise in prolonging time until relapse with the use of a paclitaxel for 12 months compared to 3 months [3]. Biologic or non-cytotoxic therapy also may offer activity as a maintenance agent in OC. Because many of these therapies are more tolerable than cytotoxic drugs, they have the potential for both efficacy and low toxicity for use in maintenance, and minimal impact on health-related quality of life (HRQL) [4]. With the rapid increase in research on biologic/non-cytotoxic therapies in the last five years, much of the progress in studying potential therapies for use in maintenance for OC has taken place during this recent period. A systematic review of the recent literature pertaining to maintenance therapy in AOC was performed. The objectives for the review were to evaluate the recommended and current use of maintenance therapy; clinical, patient-reported, and economic outcomes with and without maintenance therapy; and directions for future research in this area. Methods MEDLINE-indexed publications were reviewed using the following search strategy: (ovarian cancer⁎[ti] OR ovarian carcinoma⁎[ti] OR ovarian adenocarcinoma⁎[ti]) AND (treatment pattern⁎ OR prescribing pattern⁎ OR (utilization⁎ NOT “glucose utilization”) OR “maintenance therapy” OR management OR economic⁎ OR pharmacoeconomic⁎ OR cost OR costs OR expenditure⁎) NOT (“case”[ti] OR case reports[pt]) NOT pregnan⁎ NOT (review[pt] AND 1998:2003[dp]) The limits for this search included: Field: Title/Abstract, Limits: Publication Date from 2001/01/01 onward (search conducted 17 February 2009), only items with abstracts, Humans, English. The search yielded 398 publications. The phrase “maintenance treatment⁎” added to the existing algorithm increased this number by one, and seven additional citations were identified by conducting another search of the OC literature using the terms “maintenance treatment⁎” or “maintenance therap⁎” and allowing primary studies published in the last 10 years. The abstracts of all 406 citations were examined to identify whether the publications should be retrieved in full text for further review. In this manual examination of the literature, we sought articles that pertained to maintenance therapy, which we defined as extended therapy given on a regular schedule to patients who have achieved clinical complete remission. Consolida-

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tion therapy is also sometimes understood to include therapy that would meet these criteria, and so we included as maintenance therapy any “consolidation” therapy that would qualify using the same definition. Three hundred and forty-six articles were eliminated because they did not primarily address maintenance therapy, three because they were review articles or phase I trials published in 2003 or earlier, three because they pertained to preclinical research, two because maintenance therapy was given to fewer than 20 patients, and one because it was a case report. Using the search strategies described above, 36 primary studies and 16 review articles were identified and studied. Because we sought to capture literature on consolidation therapy that meets our definition of maintenance therapy but omits the keyword “maintenance,” we performed a separate search (March 2009) for articles using the keyword “consolidation” that matched the search criteria above but were not captured by those searches. The 48 articles identified in this approach were examined in full text to determine whether “consolidation” therapy mentioned in the abstract was maintenance therapy. Twenty-six articles were eliminated because they did not address maintenance therapy, and three were excluded because maintenance therapy was given to fewer than 20 patients. From this additional search, 13 primary studies and 6 review articles were added to the review. Searches were conducted in the “grey” literature (not published in peer-reviewed, MEDLINE-indexed medical journals) for any information pertaining to treatment guidelines, patterns, or outcomes of postsurgical treatment in OC, including any reference to maintenance or consolidation therapy. Searches were conducted on meeting abstracts (e.g. the American Society for Clinical Oncology), disease organizations (e.g. the American Cancer Society), and government websites (e.g. the National Institutes of Health). Searches also were conducted on the Google search engine using the keywords “ovarian cancer” AND (maintenance OR consolidation). Further, a search of guidelines related to post-surgical treatment of OC was performed on the website maintained by the National Guideline Clearinghouse. From these searches, eight primary studies and seven other relevant materials were identified and included in this report. An algorithm describing this process is depicted in Fig. 1. Results Recommended and current use of maintenance therapy Among clinical practice guidelines identified, only the National Comprehensive Cancer Network (NCCN) guidelines published in 2008 provide recommendations regarding maintenance therapy in AOC. In discussing the appropriate number of chemotherapy cycles for AOC, the guidelines state that no evidence supports the use of more than six cycles of initial chemotherapy [5]. However, the NCCN also cites the Southwest Oncology Group—Gynecologic Oncology Group (termed SWOG-GOG) 178 study [3], that showed for the first time an improvement in PFS using 12 cycles of maintenance paclitaxel (PFS 28 months) compared to 3 cycles of paclitaxel (PFS 21 months) in AOC patients who achieved complete clinical remission on initial chemotherapy (HR = 2.31; p = 0.0035). When this result was discovered in a planned interim analysis, the study was ended prior to full accrual because the primary endpoint (PFS) had been reached. Patients were permitted to switch from the inferior arm (3 cycles of maintenance paclitaxel) to receive 12-month maintenance therapy. There was no difference in OS (p = 0.63), which in part may have been explained by patient crossover [6]. The NCCN assigns a category 2B recommen-

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Fig. 1. Literature retrieval strategy.

dation (some disagreement, or evidence obtained solely through panel members' own experiences) to postremission chemotherapy based on these findings. The Physician Data Query (PDQ®) released by the National Cancer Institute is the only other institutional statement to address the topic of maintenance therapy. This document states that trials have evaluated the value of maintenance therapy in epithelial OC, but most have found no benefit. This statement makes reference to the SWOG-GOG 178 trial, but issues no recommendation based on these results [7].

A number of published reviews making recommendations based on recent research address the use of maintenance therapy. Ultimately, these reviews discuss two points: 1. The lack of evidence showing any benefit of maintenance therapy with single-agent chemotherapies, immunotherapies such as interferon (INF)-alpha and vaccines targeting CA-125, hormonal therapies, and prolonged administration of induction chemotherapies; and 2. The implications of the SWOG-GOG 178 trial. Most conclude that because this trial focused on PFS instead of OS, the clinical benefit of maintenance therapy could not be determined, and the evidence does not support routine use of maintenance paclitaxel in

Fig. 2. Post-surgical treatment patterns and outcomes with and without maintenance therapy. Dotted lines represent pathways not recommended in guidelines and/or not commonly considered in published reviews. PFS = progression-free survival; OS = overall survival; 5-yr = five year survival rate. References: A: [1,5]; B: [97,98]; C: [2,97]; D: [86,90]; E: [86–88]; F: [98]; G: [87–91]; H: [99]; I: [10,100]; J: [87–91]; K: [99–105]; L: [90]; M: [29,52]; N: [92]; O: [3,29,41,52,62]; P: [71,93–95]; Q: [106]; R: [93,96]; S: [71,94].

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Table 1 Efficacy and safety outcomes in agents used in clinical trials of maintenance therapy. Therapies

Efficacy

Paclitaxel 2

3 cycles of paclitaxel monotherapy (175 mg/m over 1 h every 21 days) (n = 13) versus 12 cycles of paclitaxel monotherapy (175 to 135 mg/m2 over 1 h every 21 days) (n = 13)

6 cycles maximum intravenous (IV) paclitaxel (175 mg/m2 every 21 days) or observation (n = 200)

Initial platinum/paclitaxel, randomized to either three (n = 109) or 12 (n = 97) cycles of maintenance paclitaxel (175 mg/m2 over 3 h every 28 days) Weekly IV paclitaxel (median dose of 80 mg/m2 for up to 12 weeks) Weekly IV paclitaxel (60 mg/m2 for 21 weeks) (n = 41)

Initial IP/IV or IV platinum/paclitaxel, followed by 135 mg/m2 IV paclitaxel, once every 4 weeks for 12 12 cycles Paclitaxel combinations Initial sequence of carboplatin mono-therapy (the Calvert formula was used to determine dose; up to three courses) and then paclitaxel monotherapy (175 mg/m2 over 3 h every 28 days) (n = 53) IV paclitaxel (135 mg/m2 over 24 h or 175 mg/m2 over 3 h) and carboplatin (AUC 4.5 or 5) every 3 weeks for 3 cycles (following six initial cycles) (n = 57)

Paclitaxel (135 mg/m2 over 24 h on day 1) and cisplatin (75 mg/m2 over 15 min on day 2) or paclitaxel (same dose) and carboplatin (AUC 6 over 30 min on day 2) (n = 42) Platinum agents Extended initial therapy with carboplatin in AOC (the Calvert formula was used to determine dose; 3 cycles every 2 months then 2 cycles every 3 months 1 year) (n = 22) Intraperitoneal (IP) cisplatin (90 mg/m2 every 3 weeks) (n = 76) IP cisplatin (100 mg/m2 every three 3 weeks) (n = 30)

Other agents Subcutaneous IL-2/RA maintenance for one to 5 years (1.8 × 106 106 IU, 5 days/ week) and 13-cis-retinoic acid (0.5 mg/kg body weight 5 days/week) (n = 44) INF-alpha (4.5 mega-units subcutaneously administered 3 days/week) (n = 300) INF-alpha (50 × 106 106 IU, weekly for 6 weeks) (n = 35)

Oregovomab (2 mg diluted in 50 mL of sodium chloride intravenous injection over 20 min.) [83]. (2 mg intrathecally administered) [37 38] (n = 324)

Tanomastat (800 mg bid orally) (n = 243)

PFS median was 11 months. OS not reached in 38 months.

PFS median was 24 months (p = 0.0062). OS not reached in 43 months (p = 0.0019). [31] No PFS or OS benefits in AOC. PFS was 34.5 months in paclitaxel arm versus 34 months in observation arm. 3-year OS was 88% for observation and 78% for paclitaxel. [29] 28 months PFS in 12-cycle arm, compared with 21 months in the 3-cycle arm (p = 0.0035). [3] Median PFS was 27 months. 2-year survival was 94%. [37] Not reported.

Not reported.

Safety outcomes Cumulative side effect of neurotoxicity. [9,23–25] Grade 3 neutropenia was reported in one patient. Grade 4 neutropenia and thrombocytopenia was reported in two patients. 23% developed grade 2 + neuropathy. [32] Grades 3–4 neutropenia or anemia were not reported. Grade 3 thrombocytopenia was reported in one patient. 54% developed grade 2 + neuropathy. [32] Grade 2 or greater neurotoxicity was reported in 25% of patients treated with paclitaxel; other toxicities were mild. [29]

Neuropathy more severe in 12-cycle arm (10% versus 4% had grade 4 neuropathy). [3] 1 patient developed grade 3 neutropenia and another reported grade 3 neuropathy. [37] In an interim report, there was one case of grade 4 anemia and grade 2 reversible peripheral neurotoxicity in 7.4%. [38] Neuropathy was the most common cause of discontinuation. [26]

OS shorter than that of historical stage IV controls. [30]

Reasonably well tolerated. 50% of patients had some grade of hematologic toxicity. [30]

Median disease free survival was 15 months (versus 22 months for those without maintenance, p = 0.703). Mean OS was 69 months (versus 73 months for those without maintenance, p = 0.891). [28] The actuarial median disease-free survival was 25 months (versus 26 months with no treatment, p = .80). [27]

Grade 3 or 4 leukopenia was significantly more common in patients receiving maintenance therapy (50.9% versus 21.6%, p = 0.004). [28]

Median PFS was 36 months; mean OS was 83 months. [41]

Acceptable toxicity in 22 women given a one-year extension of initial carboplatin. [41]

Same survival time as patients randomized to observation. PFS HR = 0.89; OS HR = 0.82. [43] Median disease-free survival was 50 months. Mean survival was 69.1 months. [45]

Common side effects included vomiting, rise in serum creatinine, abdominal pain, and neurotoxicity. [43,45] The most common grades 3–4 toxicities were emesis (63%), abdominal pain (23%), and nephrotoxicity (7%). [45]

Significantly better PFS and OS than in matched controls. Median PFS was 50.5 months (p b 0.0001); median OS was 102.5 months (p b 0.0001). [52] No benefit. Median PFS was 10.3 months (HR = 0.96; p = 0.73); median OS was 27 months (HR = 1.06; p = 0.65). [53] Median PFS was 47 months (versus 94 months in the observation arm, p = 0.56). [50] No benefit. PFS was 13.3 months (p = 0.71) and 10.3 months (p = 0.29) in each study. In subgroup of successful firstline treated patients (n = 34) PFS was 24.0 months (p = 0.59; HR = 0.54). [55,57,58] No benefit. Median PFS was 10.4 months (p = 0.67); median OS was 13.9 months (p = 0.53). [59]

Low toxicity. [52]

No significant increase of grades 3–4 toxicity in maintenance arm. [27]

Flu-like symptoms and fatigue were significantly more common in the INF-alpha group versus placebo (p b 0.001). [53] There were no grade 4 adverse events. 40% of patients experienced at least one grade 3 adverse event. [50] Well tolerated; adverse events similar between oregovomab and placebo arms. serious adverse events (19% versus 14%) and grade 3/4 toxicity (25% versus 20%) were more common in placebo than oregovomab arm. [55,57,58]

Well tolerated; toxicities generally grades 1 and 2. [59] (continued on next page)

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Table 1 (continued) Therapies

Efficacy

Safety outcomes

Gefitinib (250 mg orally once daily) (n = 32)

Not reported

Bevacizumab (15 mg/kg IV every 21 days) continued as monotherapy (n = 58) Etoposide (50 mg m− 2 per day for 21 days every 4 weeks) plus cisplatin (50 mg IV over 3 h on days 1,15, 29, and 43 of 6 week cycles); etoposide continued for 6–9 cycles in patients with response or stable disease (n = 98) Pertuzumab (420 mg IV every 3 weeks) (n = 84)

Not reported.

Toxicities were mild and generally affected the skin (in 31%) and gastrointestinal system (in 22%). [61] During the extended-use phase, this agent was associated with mild toxicities, including myalgia. [62] Mild toxicities. [84]

Oral altretamine (260 mg/m2/day in 4 doses for 14 days every 4 weeks for 6 cycles) (n = 97)

Pegylated liposomal doxorubicin (40 mg/m2 every 28 days for 4 cycles) (n = 29) Epidoxorubicin (120 mg/m2 to 90 mg/m2, depending on platelet count, every 21 days for 4 cycles) (n = 64) Cisplatin (100 mg/m2 on day 1, excluded for later patients), etoposide (150 mg/m2 on day 1), and mitoxantrone (25 mg/ m2 on day 2) every 4 weeks for three 3 cycles (n = 68) Monoclonal Anti-Idiotype Antibody ACA125 (2 mg injection every 2 weeks for four 4 cycles, then monthly) (n = 42) Oral bicalutamide (50 mg daily) and subcutaneous goserelin (3.6 mg every 4 weeks) (n = 35)

Highly effective. Median PFS was 14 months; median OS was 26 months. [84]

Not reported.

Well tolerated as treatment and maintenance for relapsed disease. Grade N 3 neutropenia occurred in 30% of patients randomized to pertuzumab plus a platinum-based combination versus 38% of patients on the platinum combination alone. [63] Prolonged PFS and OS. Median PFS was Well tolerated. The most common grade 3 toxicities were 28 months, median survival for patients malaise/fatigue (7%), nausea (6%), and vomiting (3%). with suboptimally debulked disease was No post-treatment adverse events were reported. 39 months, [50] [50,85] Median PFS was 15 months. Median OS was Palmar-plantar erythrodysesthesia was 31 months. [49] the most common toxicity (30%). [49] 3-year percent OS was 79.0% (versus 78.7%, 6 (9%) did not complete treatment because for no treatment, log-rank test, p = 0.93) of toxicity. [60] [60] Median PFS was 34 months; median OS was 51% of patients experienced at least one grades 3–4 toxicity. 73 months. 5-year survival was 58% [44] The most common toxicities include leucopenia, catheter-related abdominal pain, nausea, and vomiting. [44] Mean survival was 15 months. [51] Treatment was generally well tolerated. [51]

PFS 11.4–11.9 months (depending on number of remissions). Treatment did not appear to extend PFS. [48] 2 Median PFS was 37 months (versus Cisplatin (50 mg/m ) and doxorubicin (50 mg/m2) or 116 months for whole abdominal radiation, epirubicin (60 mg/m2) (n = 72) p = 0.034; and 32 months for no treatment). 5-year survival rates were not significantly different between groups. [39] Oral erlotinib (150 mg/day) until progression (n = 27) Median PFS was 14.8 months; median OS was 37.0 months. [47] 2 Median disease-free survival was 5-Fluorouracil (500 mg/m /day intravenously for 5 days), followed by cisplatin (100 mg/m2 on the 6th or 7th day, never 66 months (versus 73 months for exceeding a total dose of 160 mg). This was repeated every observation, p = 0.64); Median OS was 28 days for 3 cycles. (n = 61) 95 months (versus 96 months for observation, p = 0.66). [40]

Grade 1 alkaline phosphatase (54%), fatigue (57%), and hot flashes (42%) were the most common toxicities. [48] The radiotherapy group experienced treatment-related toxicities most frequently. Most common adverse events in chemotherapy group were intestinal problems and bone marrow problems. [39] The most common toxicities were grade 2 alopecia (24%), rash (18%), and fatigue (15%). [47] 62.3% experienced nausea and vomiting, grades 3–4 in 44.3%. Other common adverse events were leukopenia (21.3%) and mucositis (11.5%). [40]

The efficacy and safety outcomes associated with agents used in the clinical trials of maintenance therapy in ovarian cancer.

AOC patients outside of clinical trials. Dearnley and McMeekin suggest caution when opting for maintenance rather than being motivated by the feeling that for patients at risk, “doing something is better than doing nothing at all” [8]. In contrast, Herzog et al. suggested that “maintenance therapy may be a valuable option and should be discussed with patients until further data are available” [9]. Reviewers anticipate new results from the next GOG trial of maintenance paclitaxel (GOG 212) to determine its effect on OS and quality of life [8,10–18]. Outcomes with and without maintenance therapy Clinical outcomes Unless diagnosed at the earliest stages, which is rare in the absence of a screening test, OC carries an unfavorable prognosis. Recent epidemiological studies and clinical trials have reported that patients treated for stage III disease progress after approximately 16 to 24 months, and die after 26 to 66 months [19–21]. In stage IV, the equivalent outcomes are 9 and 15 months [21]. Five years after diagnosis, one third to one half of patients with stage III OC survive, and 18% of those with stage IV [1]. Typical patterns of treatment, progression, and survival in OC are depicted in Fig. 2. With the increasing trend to approach metastatic cancers as a disease that may be controlled with maintenance therapy, this approach has gained interest as a strategy to potentially extend survival in OC. The question of whether PFS is an acceptable endpoint in

studies of OC maintenance therapy was considered by a panel (the OC Endpoints Workshop) recently convened by the Food and Drug Administration (FDA), the American Society for Clinical Oncology (ASCO), and the American Association for Cancer Research (AACR). The panel agreed that OS should remain the most important endpoint for chemotherapy trials, which should be sized to measure OS. However, PFS may be acceptable for agents that are highly tolerable, will not affect subsequent cytotoxic therapy, merit quick approval, and are being tested using a blinded design to thwart assessment bias. The value of PFS as an endpoint was not specifically discussed within the context of maintenance therapy [22]. A large number of agents have been or are being tested for use as maintenance therapy in AOC (see Table 1 and 2). In particular, non-cytotoxic drugs have been considered especially promising as they may avoid toxicity associated with use of a maintenance treatment [4]. Paclitaxel Paclitaxel has been investigated more than any other agent for use in maintenance therapy. Its safety is well supported, with allowance for its cumulative side effect of neurotoxicity [9,23–25]. This was the chief reason for discontinuation of paclitaxel maintenance in a recent study enrolling 102 women with stage III OC, usually within the first few cycles among those who discontinued [26]. Evidence regarding its efficacy in maintenance therapy for AOC comes from several studies published over the last six years.

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Table 2 Maintenance therapy trials in ovarian cancer registered on ClinicalTrials.gov. Title

Study Study population phase

Intervention

Trial status

An RCT of concurrent and maintenance cediranib in women with platinum-sensitive relapsed ovarian cancer Efficacy study of maintenance IT-101 therapy for ovarian cancer patients A randomized placebo-controlled phase II study of continuous maintenance treatment with BIBF 1120 following chemotherapy in patients with relapsed ovarian cancer Green tea intake for the maintenance of complete remission in women with advanced ovarian carcinoma (DBGT-OC-CR)

II/III

Ovarian cancer

Ongoing

II

Ovarian cancer

II

Relapsed ovarian cancer

Cediranib: once-daily oral tablet starting dose 30 mg up to 18 months IT-101 (12 mg/m2/dose) IT-101 (15 mg/m2/ dose): every other week until disease progression BIBF1120 for up to 9 months

II

Advanced ovarian cancer

I/II

Ovarian or primary peritoneal cancers Fallopian tube, ovarian, or peritoneal cavity cancers

DCVax-L vaccination with CD3/CD28 costimulated autologous T-cells for recurrent ovarian or primary peritoneal cancer A phase I–II study of OSI-774 (Tarceva, Erlotinib) with docetaxel/ carboplatin followed by maintenance therapy with Tarceva as treatment for newly diagnosed stages III/IV epithelial ovarian cancer, primary peritoneal or fallopian tube cancer

Comparison of Nexavar (sorafenib) /placebo as maintenance therapy for patients with advanced ovarian or primary peritoneal cancer Efficacy multi-center trial of immunotherapy vaccination with abagovomab to treat ovarian cancer Patients (MIMOSA) Comparing two treatments for ovarian cancer: standard chemotherapy plus enzastaurin, or placebo

ICON6- A double-blind, placebo-controlled, three arm randomised multi-center Gynecological Cancer InterGroup Trial of AZ2171, in combination with platinum-based chemotherapy and as a single-agent maintenance therapy, in patients with ovarian cancer relapsing more than 6 months following completion of first-line platinum-based treatments

I/II

II II/III II

Ovarian cancer, fallopian tube neoplasms, or peritoneal neoplasm

III

Fallopian tube, ovarian, or peritoneal cavity cancers

Determine if either of 2 doses of study drug given with a low-dose of II cyclophosphamide after a complete or partial response to a platinumbased second-line therapy in women with recurrent ovarian carcinoma results in a longer time to progression when compared to the first time to progression Paclitaxel or polyglutamate paclitaxel or observation in treating patients III with stage III or stage IV ovarian epithelial or peritoneal cancer Bevacizumab study with carboplatin and paclitaxel in ovarian, II fallopian tube or primary peritoneal cancer

Study of combination immunotherapy for the generation of HER-2/ Neu specific cytotoxic T cells Carboplatin and paclitaxel with or without bevacizumab in treating patients with stage III or stage IV ovarian epithelial, primary peritoneal cancer, or fallopian tube cancer (GOG-0218)

Advanced ovarian or primary peritoneal cancers Ovarian cancer

I/II III

Carboplatin and paclitaxel with or without bevacizumab after surgery in treating patients with recurrent ovarian epithelial cancer, primary peritoneal cavity cancer, or fallopian tube cancer (GOG-0213)

III

Carboplatin and paclitaxel with or without bevacizumab in treating patients with newly diagnosed ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cavity cancer (ICON7)

III

A Study of carboplatin and gemcitabine plus bevacizumab in patients with ovary, peritoneal, or fallopian tube carcinoma (OCEANS)

III

DOXIL for consolidation therapy in ovarian cancer

II

Ovarian cancer

Ovarian cancer or peritoneal cavity cancer Advanced ovarian, peritoneal, or fallopian tube cancers

Ongoing Completed

Double-brewed green tea: liquid, 4 Celsius; 500 mL ID, 3 h after meals and 1 h before next meal; for 18 months or until relapse Maintenance DCVax-L and T cells

Ongoing

Docetaxel IV over 1 h and carboplatin IV over 30 min on day 1, pegfilgrastim subcutaneously on day 2, and oral erlotinib once daily on days 3–16. Treatment repeats every 21 days for up to 6 courses. Patients with stable or responding disease receive oral erlotinib once daily for up to 12 months. Sorafenib (Nexavar, BAY43-9006) 400 mg twice a day and in continuous administration Maintenance abagovomab 2 mg/mL SC (subcutaneously) for 4 years or until relapse Enzastaurin (1125 mg loading dose then 500 mg, oral, daily, six 21 day cycles or up to 3 years), carboplatin (AUC 5, IV, q 21 days, six 21 day cycles), paclitaxel (175 mg/m2, IV, q 21 days, six 21 day cycles) Carboplatin (IV over 30–60 min), oral cediranib (daily on days 1–21), and paclitaxel (IV over 3 h on day 1); treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients then receive oral cediranib alone daily for 60 weeks (until a total of 18 months after randomization) Tucotuzumab celmoleukin (EMD 273066) (dose an schedule information not available)

Ongoing

Paclitaxel (IV over 3 h on day 1) and paclitaxel poliglumex (IV over 10–20 min on day 1.) Bevacizumab (cycle 2; 6 cycles re-evaluated and follow up), carboplatin and paclitaxel (cycle 1 and continuous through entire regimen; treated every 3 weeks) Ovarian or breast cancer on HER2 CTL vaccine (intradermally every month for 6 maintenance trastuzumab total doses) (plus trastuzumab) Advanced ovarian, Paclitaxel (IV over 3 h) and carboplatin (IV over peritoneal, or fallopian tube 30 min on day 1). Beginning in course 2, patients cancers also receive bevacizumab or placebo (IV over 30– 90 min) on day 1. Treatment repeats every 21 days for 6 courses. Beginning in course 7, patients receive bevacizumab or placebo alone IV over 30– 90 min on day 1. Treatment repeats every 21 days for up to 22 courses in the absence of disease progression or unacceptable toxicity. Recurrent ovarian epithelial Paclitaxel (IV over 3 h or docetaxel IV over 1 h) cancer, primary peritoneal and carboplatin (over 30 min on day 1), with or cavity cancer, or fallopian without bevacizumab (IV over 30–90 min on day tube cancer 1); treatment repeats every 21 days. Newly diagnosed ovarian Paclitaxel (IV over 3 h) followed by carboplatin (IV epithelial cancer, fallopian over 30–60 min) on day 1, preceded or not by tube cancer, or primary bevacizumab (IV over 30–90 min). Treatment peritoneal cavity cancer repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. Platinum-sensitive recurrent IV repeating doses of carboplatin and gemcitabine epithelial ovarian, primary with and without bevacizumab. peritoneal, or fallopian tube carcinoma Ovarian neoplasm Liposomal doxorubicin (every 2 weeks)

Ongoing

Ongoing Ongoing Ongoing

Ongoing

Terminated due to poor recruitment

Ongoing Ongoing

Ongoing Ongoing

Ongoing

Ongoing

Ongoing

Ongoing

(continued on next page)

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Table 2 (continued) Title

Study Study population phase

Intervention

Weekly topotecan therapy in patients with ovarian cancer

II

Ovarian cancer

Avastin and erlotinib as first-line consolidation chemotherapy after carboplatin, paclitaxel, and avastin (CTA) induction therapy for advanced ovarian, fallopian tube, and primary peritoneal cancer, and papillary serous Mullerian tumors Study of bevacizumab followed by bevacizumab consolidation for ovarian cancer

II

Ovarian, fallopian tube, primary peritoneal, and papillary serous mullerian Mullerian cancers Advanced ovarian carcinoma, primary peritoneal carcinoma, and ovarian carcinosarcoma Ovarian, primary peritoneal or fallopian tube cancer Advanced ovarian or primary peritoneal cancer Epithelial ovarian, tubal, or peritoneal cancer

Topotecan (4 mg/ m2 weekly × 8 weeks for one Terminated 1 cycle followed by a break in the 9th week) for a maximum of 3 cycles. Avastin (every 3 weeks) with or without erlotinib Ongoing (daily) for 1 year.

An ovarian, primary peritoneal or fallopian tube cancer study for patients that have not received prior chemotherapy Cisplatin induction with paclitaxel consolidation for stages III–IV epithelial ovarian and primary peritoneal cancer A phase I study of ovarian cancer peptides plus GM-CSF and adjuvant (Montanide ISA-51) as consolidation following optimal debulking and systemic chemotherapy for women with advanced stage ovarian, tubal or peritoneal cancer Carboplatin taxol avastin in ovarian cancer Intraperitoneal hyperthermic chemotherapy in epithelial ovarian carcinoma Adjuvant whole abdominal intensity modulated radiotherapy (IMRT) for high risk stage FIGO III patients with ovarian cancer (OVAR-IMRT-01) Combination chemotherapy in treating patients with stage III ovarian epithelial cancer or gastrointestinal cancer

II

III II I

II II

Ovarian cancer Stage IIIC ovarian cancer

I

Stage III ovarian cancer

II

Stage III ovarian or gastrointestinal cancer

Monoclonal antibody therapy in treating patients with residual disease from stage III or stage IV ovarian epithelial, fallopian tube, or peritoneal cancer following surgery and chemotherapy

II

Advanced ovarian, peritoneal, or fallopian tube cancers

Combination chemotherapy plus IM-862 in treating patients with resected stage III ovarian cancer or primary peritoneal cancer

II

Ovarian or peritoneal cavity cancer

Multi-center clinical trial of intravenous OvaRex MAb-B43.13 as post-chemotherapy consolidation for ovarian carcinoma Topotecan in treating patients with advanced ovarian epithelial, fallopian tube, or primary peritoneal cancer

II

Ovarian cancer

I

Combination chemotherapy and autologous peripheral stem cell transplant in treating patients with stage III, stage IV, or recurrent ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer

I

Advanced ovarian, peritoneal, or fallopian tube cancers Advanced ovarian, primary peritoneal, or fallopian tube cancers

Oregovomab with or without cyclophosphamide in treating patients with stage III or stage IV ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer that responded to second-line chemotherapy

n/a

Advanced ovarian, peritoneal cavity, or fallopian tube cancers

Clinical trial for ovarian cancer (OvaRex®)

III

Advanced ovarian, peritoneal, or fallopian tube cancers

Overall, investigations of paclitaxel maintenance administered every three weeks only have shown survival benefits with 12 cycles, and no survival benefits with 6 cycles or less. Two similar, nonrandomized studies performed in Korea used three cycles of a paclitaxel/ platinum combination, neither finding significant benefit. Lee et al. found no significant difference in disease-free survival (p = 0.80), or in toxicity, (p values for all comparisons range from p = 0.173 to p = 0.616), between 42 patients who agreed to receive maintenance therapy and 39 who had chosen no further treatment (paclitaxel as 135 mg/m2 every 21 days, cisplatin 75 mg/m2 every 21 days or carboplatin area under the curve 6 every 21 days) [27]. Kim et al. also

Trial status

Avastin (15 mg/kg IV every 21 days for 12 12 cycles)

Ongoing

Paclitaxel (135 mg/m2, IVPB/3 h every 28 days for 1 year) Paclitaxel (maintenance schedule not specified)

Ongoing

OCPM immunotherapeutic vaccine subcutaneously on weeks 0, 1, 2, 3, 5 and 6 and then receive the immunizations every 1 month for 6 months or disease recurrence Bevacizumab (every 21 days for 1 year) Hyperthermic chemotherapy (schedule not specified) Intensity modulated radiation therapy (IMRT) to a total dose of 30 Gy in 1.5 5 Gy fractions

Ongoing

IP floxuridine on days 1–3 followed by IP cisplatin and/or carboplatin on day 3. Treatment continues every 3 weeks for 4–6 courses in the absence of disease progression or unacceptable toxicity. IV oregovomab (OvaRex MAb-B43.13) on day 0. Treatment continues at 4, 8, 20, 32, 44, and 56 weeks, and then every 3 months in the absence of disease progression or unacceptable toxicity. Treatment with IM-862 (oglufanide disodium) begins within 10 days of chemotherapy initiation and continues until clinical evidence of disease progression or until 3 days before second-look surgery. IV oregovomab (OvaRex MAb-B43.13) 2 mg monthly, then every 12 weeks for 2 years. Oral topotecan twice daily for 21 days every 4 weeks for up to 6 months in the absence of unacceptable toxicity or disease progression. Patients receive paclitaxel IP on day 1, cyclophosphamide IV on day 2, and filgrastim (GCSF) subcutaneously (SC) beginning on day 3 and continuing until apheresis is completed. Patients undergo apheresis until ≥2.5 × 106 CD34-positive cells/kg are collected. Two weeks later, patients receive cisplatin IP and melphalan IV on days 11 and 4 and topotecan hydrochloride by continuous infusion over 120 h on days. Patients receive cyclophosphamide IV on day 6 and oregovomab IV over 20 min on day 9 or 10. Patients then receive oregovomab alone at weeks 6 and 10 and then every 12 weeks for up to 2 years (10 doses) in the absence of disease progression or unacceptable toxicity. Oregovomab (OvaRex MAb-B43.13) (schedule not specified)

Completed

Ongoing Ongoing Ongoing

Ongoing

Ongoing

Ongoing

Terminated Completed

Ongoing

Completed

Terminated

found no significant difference in disease-free survival or in OS, but grade 3 or 4 leukopenia was more prevalent among the 57 patients administered maintenance than among the 37 patients who received no therapy, (paclitaxel as 135 mg/m2 for a 24-h period or 174 mg/m2 for a 3-h period every 21 days, and carboplatin area under the curve 4.5 or 5 every 21 days) [28]. Another recent and substantially larger (n = 200) study, by Conte et al. [29], found no PFS or OS benefits in AOC patients randomized to six cycles or less of paclitaxel maintenance (175 mg/m2 every 21 days) versus no maintenance. Nearly a quarter of this group received only two to five cycles, largely because of toxicity or refusal. Additionally, 14% of the controls received

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paclitaxel [29]. Markman et al. [30] also found negative results in a trial of 53 stage IV patients who received an experimental approach to initial and maintenance chemotherapy. An initial sequence of carboplatin monotherapy and then paclitaxel monotherapy was modified for an individual based on evidence of response during treatment, in that patients who met specific response criteria would receive additional courses of these agents. Paclitaxel maintenance was given to some individuals with evidence of response to the program. The participants in this trial had OS shorter than that of historical controls [30]. In contrast, studies administering paclitaxel maintenance for 12 cycles have shown survival benefits. Micha et al. [31] found significant improvements in survival using a prospective, but small and nonrandomized, design to investigate paclitaxel for AOC patients who responded to primary platinum regimens. Thirteen patients received three cycles of paclitaxel monotherapy (175 to 135 mg/m2 over 1 h every 21 days), and 13 received 12 cycles. Both PFS and OS were significantly longer (medians 24 months and not reached in 43 months) in the 12-cycle group than in the 3-cycle group (11 and 38 months), although Micha et al. noted that the 12-cycle regimen carries considerable risk for neuropathy [31,32]. As mentioned, the most influential study in maintenance therapy for OC is the SWOG-GOG 178 randomized phase 3 trial of paclitaxel, reported by Markman et al. [30]. The trial enrolled women with clinical CR to initial platinum/paclitaxel, and randomized them to either three or 12 cycles of maintenance paclitaxel (175 mg/m2 over 3 h) delivered every four weeks. The trial was stopped prior to full enrollment when in a pre-planned evaluation, the data revealed a longer PFS in the 12-cycle arm, 28 months compared with 21 months in the 3-cycle arm (HR = 2.31; p = 0.0035) [3]. Following the early closure of the study, patients on the 3 months maintenance arm were allowed to receive 12 months of maintenance treatment. Early stoppage of the study was appropriate considering that one of the pre-specified primary endpoints, i.e. PFS, had been met, but ideally it may have been preferable for the study to continue to fully assess the effect of longer paclitaxel maintenance on OS [6,9,33,34]. An update in 2006 found that the difference in OS between the groups was not statistically significant (p = 0.63) [6]. The SWOG-GOG 178 trial has garnered criticism for a variety of reasons, including the use of PFS as a primary endpoint, the cost and cumulative neurotoxicity of the maintenance treatment, and the theory that maintenance might lower the chance that chemotherapy would be effective at relapse. These criticisms have been discussed by Herzog et al. [9]. One comment by McMeekin et al. has been that maintenance may not add meaningful survival because some patients already have been cured after first-line therapy, and many patients selected for maintenance have disease that is slow to recur and responsive to second-line therapy. These authors suggest that maintenance therapy could be viewed simply as an earlier initiation of second-line therapy, and that timing constitutes the only difference between a maintenance schedule and more typical initiation of second-line therapy upon recurrence. McMeekin et al. propose that studies of maintenance therapy should include an arm in which patients receive no maintenance and are instead treated with secondline therapies once disease recurs [8]. To provide some comparison along these lines with the SWOG-GOG 178 trial, McMeekin et al. conducted a retrospective analysis of registry data from 44 patients in whom second-line chemotherapy was reserved until the time of recurrence. McMeekin et al. used the same criteria as SWOG-GOG 178 for patient eligibility, and the same definitions of PFS and OS. In this study, the median time between initial remission and start of thirdline therapy was 43 months compared to 40 months for third-line therapy with maintenance since the median PFS was 28 months after 12 months of paclitaxel maintenance in SWOG-GOG 178. The authors note that randomized comparisons will be needed to determine when to use second-line/maintenance therapy [35].

297

In order to evaluate the potential benefit of prolonged taxane maintenance compared to observation, GOG 212 is enrolling a similar population to SWOG-GOG 178 with a primary endpoint of OS. Unlike GOG 178, GOG 212 has three arms: observation, 12 months of paclitaxel, or 12 months of the novel taxane PPX (paclitaxel proteinbound particles). The latter compound is in a class of new taxanes and taxane-like molecules that either overcome drug resistance or promote drug delivery to the tumor, and may have improved tolerability [9]. PPX, which has shown high response rates in studies of first-line and maintenance therapy, also offers the advantages of shorter infusion time and no need for premedication [9,36]. Results of GOG 212 likely will determine whether maintenance therapy with paclitaxel benefits patients with AOC who achieve clinical CR with paclitaxel/platinum combinations [9]. In the meantime, some authors have suggested that these patients should be informed about the results of SWOG-GOG 178 and offered the option of weighing the benefits against the toxicity of paclitaxel maintenance [6,9]. In addition to the studies of paclitaxel given on a schedule of one cycle every three weeks, two studies of paclitaxel maintenance given weekly were identified. One study of women with AOC (n = 24) or primary peritoneal carcinoma (n = 7) given weekly paclitaxel for up to 12 weeks, (paclitaxel at a max of 80 mg/m2 once per week), yielded a median PFS of 27 months, with good tolerability [37]. A preliminary report from a phase II study in Italy of 21 courses of weekly paclitaxel, (60 mg/m2 once per week), also indicated good tolerability even in a heavily pretreated population [38]. Platinum agents Research on maintenance with IV platinum agents in AOC has not yielded survival benefits in two randomized and two nonrandomized studies. A trial randomizing 98 stage III patients in complete surgical and pathologic remission, (initial treatment included four courses of cisplatin as 50 mg/m2 and doxorubicin as 50 mg/m2 or epirubicin as 60 mg/m2), to consolidation with whole abdominal radiation, no further treatment, or maintenance with 6 courses of cisplatin plus either doxorubicin or epirubicin, (cisplatin as 50 mg/m2 and doxorubicin as 50 mg/m2 or epirubicin as 60 mg/m2), found the best PFS in the radiation group (p = 0.034). At five years, 56% of the radiation group had no progression, versus 35–36% of the chemotherapy group and untreated controls [39]. Another study randomized 122 patients to either no further treatment or three cycles of fluorouracil/cisplatin, (fluorouracil as 500 mg/m2 per day, cisplatin at 100 mg/m2 on the 6th or 7th day of a 28 day cycle), and found no difference in either DFS (p = 0.42) or OS (p = 0.66), which was 95–96 months in both groups [40]. Dearnley and McMeekin have commented that this long survival time emphasizes the favorable prognosis of patients enrolled in trials of maintenance therapy and the resulting need for a control group [8]. The two Korean studies of maintenance paclitaxel/platinum mentioned above did not use a randomized design, and controls were selected as patients who refused the therapeutic intervention; neither found significant PFS or OS differences between treatment and control groups, (Kim et al. OS (p = 0.891), PFS (p = 0.703) and Lee et al. OS (p = 0.79), PFS (p = 0.80)) [27,28]. Concerns have been raised about potential cumulative toxicity with platinum agents, but tolerability was generally favorable in the above studies, and one trial of extended initial therapy with carboplatin in AOC, conducted by Safra et al., recorded acceptable toxicity in 22 women given a one-year extension of initial carboplatin [41]. Intraperitoneal (IP) cisplatin also has been studied as maintenance therapy. However, reviewers have noted that trials of IP therapy are difficult to control and conduct, and that these studies have enrolled a fairly heterogeneous patient population [8,42]. The first randomized trial of IP maintenance therapy, by Piccart et al., found that patients in complete remission following intravenous (IV) cisplatin-based treatment who were randomized to maintenance with IP cisplatin had the same survival time as patients randomized to observation [42,43].

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Other studies of IP cisplatin have not used control arms or compared to IV cisplatin maintenance; these studies have reported prolonged survival but high toxicity. A study by Tournigand et al. [44] administered three cycles of IP chemotherapy (cisplatin as 100 mg/m2 every four weeks, mitoxantrone as 25 mg/m2 every four weeks and etoposide as 50 mg m− 2 per day for 21 days every four weeks) to 68 patients who had received platinum and anthracycline-based induction. While mean PFS was 34 months and median OS 73 months, half of participants experienced grade 3/4 toxicities, including leukopenia, nausea and vomiting, and pain from the catheter [44]. Similarly, Topuz et al. studied three cycles of IP cisplatin, (100 mg/m2 every 21 days), given to 30 women in remission for stage III disease and reported a median DFS of 50 months, but with most patients having grade 3/4 vomiting [45]. Other agents A number of other treatments have been tested as maintenance therapies in OC including INF-alpha, gefinitib, erlotinib, interleukin-2 (IL-2) and 13-cis-retinoic acid (RA) combination, goserelin and bica lutamide combination, etoposide, mitoxantrone/cisplatin/etoposide combination, epidoxorubicin, pegylated liposomal doxorubicin (PLD), tanomastat, altretamine, abagovomab, bevacizumab, and oregovomab [46]. Some of these studies tested only toxicity, some tested efficacy using noncomparative designs, and others also compared efficacy with that of non-maintenance populations. Small studies testing efficacy with no comparison group yielded wide ranges of PFS and OS. Median PFS endpoints included 34 months (with IP mitoxantrone/cisplatin/etoposide), 28 months (altretamine in stage III OC), 15 months (PLD after suboptimal debulking), 14.8 months (daily erlotinib), and 11 months (goserelin/bicalutamide in second or higher remission) [47–50]. Reported OS among these noncomparative studies included 73 months (with IP mitoxantrone/cisplatin/ etoposide), 37.0 months (daily erlotinib), 31 months (PLD after suboptimal debulking), and 19.9 months (abagovomab third-line with positive immune response) [44,47,49,51]. Of the comparative efficacy studies, sonly one by Recchia et al. [52] found improvement in survival: in a prospective study of 44 AOC patients, IL-2 (1.8 × 106 IU, 5 days/week) and 13-cis-retinoic acid (RA) (0.5 mg/kg body weight 5 days/week) maintenance administered subcutaneously for one to five years produced significantly better PFS and OS than those observed in 82 matched controls treated with standard therapy during the same time period. The median PFS in the treatment arm was 50.5 months, versus 15.5 months in the control arm (p b 0.0001). The median OS was 102.5 months in the treatment arm, versus 29.6 months in the control arm (p b 0.0001). This therapy also was associated with low toxicity [52]. Other studies comparing efficacy outcomes in maintenance populations to those of non-maintenance populations found no benefit of maintenance therapy. Hall et al. [53] conducted a phase 3 trial of 300 AOC patients post-initial surgery/chemotherapy who were randomized to INF-alpha (4.5 mega-units subcutaneously administered 3 days/ week) or to observation; no benefit was found in either event-free or OS. The median PFS was 10.3 months (HR = 0.96; p = 0.73), and the median OS was 27 months (HR = 1.06; p = 0.65) [53]. The same comparison was made and lack of survival benefit observed in a SWOG trial that began enrolling patients in 1988 and subsequently was closed in 1999 after very slow accrual of 70 evaluable patients, although the authors caution against drawing efficacy conclusions from this trial [54]. Multiple trials also have been conducted using maintenance with oregovomab, an immunotherapeutic agent investigated in patients expressing the tumor-associated antigen CA-125. No survival benefits have been reported in these trials comparing oregovomab to placebo. Berek et al. [55] randomized 145 patients to maintenance with either placebo or oregovomab (2 mg diluted in 50 mL of sodium chloride intravenous injection over 20 min) (2 mg intrathecally administered). Patients received this treatment until two years or recurrence. There

was no significant difference in time to relapse, which was 13.3 months for oregovomab and 10.3 months for placebo (p = 0.71) [55]. In a subgroup of patients in whom first-line treatment was successful, (n = 34) PFS was 24.0 months (p = 0.59; HR= 0.54). A five-year follow up survey of participants in this trial could not definitively assess survival post-relapse as the sample size was too small to determine the significance of the comparison. At this time point, 47% of oregovomab patients (n = 73) and 37% of placebo patients (n = 72) were alive, with median survival estimates of 57.5 months for oregovomab and 48.6 months for placebo [56]. More recently, Berek et al (2008) conducted a larger (n = 371) phase III, randomized, double-blind study of oregovomab, which also found no benefit of this agent as maintenance following first-line treatment; time to relapse was 10.3 months for oregovomab and 12.9 months for placebo (p = 0.29) [57,58]. Other comparative studies yielding no survival benefits with maintenance therapy included a phase III trial by Hirte et al. [59] randomizing 243 patients to maintenance with placebo or tanomastat (800 mg bid orally), a biphenyl matrix metalloprotease inhibitor. Median PFS was 10.4 months for the treatment arm versus 9.2 months for the placebo arm (p = 0.67); median OS was 13.9 months versus 11.9 months in favor of the treatment arm (p = 0.53) [59]. A phase II trial randomized 64 patients to 4 months of epidoxorubicin, (120 mg/m2 every 21 days) and 74 patients to no treatment and found no significant difference in 3-year OS (p = 0.93) [60]. Safety outcomes of several agents as maintenance therapy have been reported and are shown in Table 1 (tanomastat [59], gefinitib [61], bevacizumab [62], and pertuzumab [63]). Patient-reported outcomes Ovarian cancer significantly impacts physical, social, spiritual, and functional well-being [64–66]. Little is known about the influence of maintenance therapy on patient-reported outcomes in AOC. As survivorship issues in AOC become increasingly important, there is a greater need for further inquiry into the effects and benefits of maintenance therapy on HRQL [64]. Of the studies identified for this review, only one reported HRQL data on maintenance therapy in OC, and found limited evidence of a HRQL benefit of the agent tested. A phase III trial by Hirte et al. [59] compared tanomastat maintenance versus placebo in 243 women with AOC. Participants showed low compliance with completion of the quality of life questionnaire (the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30), with only 81% responding at 12 and 24 weeks. Women randomized to tanomastat showed significantly worse scores for physical and cognitive domains at week 12, and physical and emotional domains at week 24 [59]. Herzog et al. recommend balancing any survival benefit obtained for a study evaluating maintenance therapy against the added toxicity and potential impact on patients' HRQL from the additional chemotherapy [9]. These authors criticize the SWOG-GOG 178 trial of maintenance paclitaxel because it did not address HRQL [15]. At the OC Endpoints Workshop, panel members noted that the natural history of OC involves a decrement in HRQL which would inherently confound its assessment among patients on maintenance therapy, because most patients who withdraw from a study because of disease progression will likely have reduced HRQL compared to baseline [67]. Herzog et al. also have suggested that without HRQL data, inference can be made from available toxicity data [9]. However, a contrasting view was obtained from the OC Endpoints Workshop, where panel members concluded that toxicity data are not an acceptable alternative to HRQL assessment. Members commented that toxicity data are rated by clinicians, but that patients' own HRQL assessments consider both positive and negative outcomes of treatment. Notably, some evidence suggests that patients prefer to receive chemotherapy even if clinical benefits may be low, and HRQL may improve as a result. One study evaluating patient preferences in OC found that most women preferred

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to continue chemotherapy regardless of likely benefit, with 25% never considering discontinuation even when the median survival period was less than one week [68]. In another study of OC patients' expectations of treatment, while clinical response to palliative chemotherapy was low, there was substantial improvement in patients' emotional function and global HRQL [69].

299

Economic studies of maintenance therapy for OC A cost analysis would yield a simple estimate of the cost of acquiring and administering maintenance therapy with a selected agent, or a comparison between agents. Studies of medical records or databases could be used to determine whether there are offsets to the costs of maintenance therapy, such as fewer acute hospitalizations.

Economic outcomes Conclusions No economic studies in maintenance therapy for OC were identified. This topic only has been discussed with reference to the SWOG-GOG 178 trial, which has been criticized as to whether the 7 months of extended PFS associated with paclitaxel maintenance was worth its additional cost. This criticism was countered by Herzog et al., who have noted that the health-care system has accepted the cost of smaller gains in PFS resulting from first-line taxanes and platinum agents, although not from maintenance studies that may obscure endpoints [9,70,71]. The direct costs of OC have been assessed by relatively few studies during the past 10 years. Most were published in the early-tomid-2000 s and assess the direct medical costs of treatment with liposomal doxorubicin (LD) and topotecan in North America and Europe [72,73]. Indirect costs related to lost work productivity, caregiver time, and other non-medical costs are less frequently assessed in health economic analyses than direct costs, but in OC, a study of both direct and indirect costs was published in 2001 by Calhoun et al. [74]. The authors surveyed OC patients regarding resource use, work loss, and caregiver impact related to chemotherapy-related hematologic or neuropathic toxicities. When costs were applied to the information furnished by survey respondents, indirect costs accounted for up to 86% of the total (direct plus indirect) costs of these AEs [74]. A number of models have assessed the cost-effectiveness of various components of OC chemotherapy; nearly all have been published since 2006 [74–78]. While these models take a variety of different payer perspectives, they generally support the current standard of taxane/ platinum combinations for first-line treatment. Second-line treatment appears moderately cost-effective depending on the setting, but additional lines of therapy may not provide sufficient value [79–82]. Directions for future research A review of the OC literature reveals that the role of maintenance therapy after initial treatment is not established. Maintenance therapy may improve outcomes in this population, but more research is needed to determine the most efficacious and cost-effective approach. Current trials such as GOG 212 will be key in establishing OS benefits of paclitaxel maintenance; in addition, GOG 212 will provide a comparison of paclitaxel and PPX as the maintenance agent to the current standard of observation. Efficacy and toxicity of other maintenance agents IL-2 and RA have yielded promising survival results in prospective testing, with low toxicity [52]. Intraperitoneal cisplatin has not received adequate testing as maintenance therapy in randomized studies using a homogeneous patient population and an appropriate comparison group, and high toxicity has been a major issue. A maintenance agent should be tolerable and not impair patients' quality of life. For this reason, it is fruitful to test non-cytotoxic agents that have proven tolerable in long-term use, with attention to the potential for any cumulative damage. Quality of life data from patients using maintenance therapy HRQL data should be compared among patients using and not using maintenance; among patients who demonstrate PFS or OS benefits and those who do not; and among patients using different agents.

This systematic review of the literature pertaining to maintenance therapy in AOC shows that there is continued interest in evaluating this treatment approach. Based on the available literature, it appears that maintenance therapy may improve outcomes, but definitive survival improvement has yet to be demonstrated. Currently, one study of IL-2 and RA maintenance therapy has shown OS benefit compared to observation [52]. Twelve-or three-month courses of paclitaxel maintenance have been assessed in a randomized study (SWOG-GOG 178), and revealed a seven-months improved progression-free survival in the longer paclitaxel maintenance arm. An ongoing GOG trial will assess the effect of paclitaxel maintenance compared to observation on OS in advanced OC. Other agents are earlier in clinical testing for maintenance use, and they include multikinase inhibitors (cediranib, sorafenib), an angiogenesis inhibitor (bevacizumab), a triple angiokinase inhibitor (BIBF 1120), a mouse anti-idiotype monoclonal antibody (abagovomab), a camptothecin-polymer conjugate (IT-101), a serine threonine kinase inhibitor (enzastaurin), and paclitaxel poliglumex (a taxane combined with a biodegradable polymer). Furthermore, there are little or no HRQL or economic data from studies of OC patients receiving maintenance therapy. The current review of the literature in maintenance therapy of AOC indicates that the best recommendation for individual patients is to be counseled about the potential benefits and risks of prolonged paclitaxel therapy demonstrated in the SWOG-GOG 178 study and/or consider enrollment in currently available trials. Maintenance use in the routine treatment of AOC likely will remain low until there is a clear advantage in OS demonstrated in future trials. Conflict of interest statement This independent research was sponsored by Bayer HealthCare Pharmaceuticals.

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