Systemic Chemotherapy for Management of Recurrent Platinum-Sensitive Epithelial Ovarian Cancer: A Review

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1 SMGr up Systemic Chemotherapy for Management of Recurrent Platinum-Sensitive Epithelial Ovarian Cancer: A Review Ahmed Abu-Zaid 1 *, Marah Nayfeh 1, Sana Almairi 1, Nida Zubairi 1, Aseel Eljabali 1, Mohammed Abuzaid 2, Osama Alomar 3 and Hany Salem 1,3 1 College of Medicine, Alfaisal University, Saudi Arabia 2 Department of Obstetrics & Gynecology, King Fahad Medical City, Saudi Arabia 3 Department of Obstetrics & Gynecology, King Faisal Specialist Hospital and Research Centre, Saudi Arabia *Corresponding author: Ahmed Abu-Zaid, College of Medicine, Alfaisal University, P.O. Box 50927, Riyadh 11533, Saudi Arabia, Tel: ; Fax: ; (s): aabuzaid@live.com & aabuzaid@alfaisal.edu Published Date: September 20, 2017 ABSTRACT Epithelial ovarian cancer (EOC) is the fifth principal cause of cancer-related mortality in women. Roughly 75% of women with EOC present with an advanced-stage disease, and the classical first-line management is optimal cytoreduction (whenever technically feasible) followed by an adjuvant platinum-based chemotherapy. In spite of the relatively high response rates to first-line chemotherapy, around 70-85% of patients develop disease recurrence. These patients eventually require an additional systemic medical treatment, and its selection is based on the platinumfree interval (PFI) - that is, the time period from completion of platinum-based chemotherapy to beginning of disease progression. Patients with a PFI greater than a time period of 6 months are regarded as platinum-sensitive. The aim of study is to review the systemic chemotherapy 1

2 regimens (mono therapy and combination therapy) used for the management of patients with recurrent platinum-sensitive EOC. The rationale is to review the available literature, compare different systemic chemotherapeutic agents, and provide updated conclusive recommendations. The review will not include data pertaining to recurrent platinum-resistant EOC, or the novel molecularly targeted therapies. Keywords: Platinum-free interval; Platinum-sensitive; Ovarian; Cancer; Chemotherapy INTRODUCTION Epithelial ovarian cancer (EOC) is the fifth principal cause of cancer-related mortality in women [1]. It has been estimated that roughly 75% of women with EOC present with advancedstage disease (III-IV) which is associated with an unfortunate prognosis [2]. The classical first-line management for advanced-stage disease is optimal cytoreduction (whenever technically feasible) followed by an adjuvant platinum-based chemotherapeutic regimen [2,3]. In spite of the relatively high response rates to first-line chemotherapy, around 70-85% of patients relapse, progress to locally advanced unresectable or metastatic inoperable disease, or even develop drug-resistant disease [2,4]. Patients with recurrent EOC will eventually require an additional systemic medical treatment. The selection of systemic medical treatment is largely based on the response to the first-line chemotherapy - that is, the platinum-free interval (PFI) [5]. The PFI is defined as the interval from the completion of first-line platinum-based chemotherapy to the beginning of disease progression [5]. Patients with a PFI less than or equal to a time period of 6 months are regarded as platinumresistant, whereas patients with a PFI greater than a time period of 6 months are regarded as platinum-sensitive [5]. Recently, BRCA germ-line status, tumor histology, and existence of hypothetically actionable mutations are additional parameters considered in the selection of systemic treatment [6,7]. Herein, in this chapter, we review the systemic chemotherapy regimens (mono therapy and combination therapy) used for the management of patients with recurrent platinumsensitive EOC. The rationale is to review the available literature, compare different systemic chemotherapeutic agents, and provide updated conclusive recommendations. The review will not include data pertaining to recurrent platinum-resistant EOC. Also, the review will not include the novel molecularly targeted therapies, such as angiogenesis inhibitors (e.g., bevacizumab), PARP inhibitors (e.g., rucaparib) and others. SYSTEMIC CHEMOTHERAPY Several non-randomized and randomized controlled phase II/III clinical trials have been conducted to explore the efficacy and safety of mono therapy or combination systemic chemotherapy for management of patients with recurrent platinum-sensitive EOC. 2

3 Mono therapy (Single-Agent) Systemic Chemotherapy Several single-agent systemic chemotherapies have been evaluated in patients with recurrent platinum-sensitive EOC. Such agents included: pegylated liposomal doxorubicin (PLD), etoposide, gemcitabine (GEM), nanoparticle albumin-bound paclitaxel (nab-paclitaxel), trabectidine and topotecan. Whenever available, clinical parameters that will be examined include: disease-free survival (DFS), progression-free survival (PFS), time to progression (TTP), overall survival (OS), duration of response (DOR), overall response rate (ORR), complete response (CR), partial response (PR), disease stabilization (DS), and disease progression (DP). Table 1: A summary of major phases II/III studies on single-agent systemic chemotherapy in patients with recurrent platinum-sensitive EOC. Ref Authors Phase Year Single-Agent Chemotherapy n [8] Gordon et al. III 2001 ORR (%) DS (%) TTP (mon) PFS (mon) OS (mon) PLD NR Topotecan NR [9] Gordon et al. III 2004 PLD 109 NR NR NR NR 27 Topotecan 110 NR NR NR NR 17.5 [10] Ferrandina et al. III 2008 PLD NR 14 GEM NR 12.8 [11] Katsumata et al. II 2008 PLD NR NR [12] Rose et al. II 1998 Etoposide NR NR [13] Cantù et al. I/II 2002 Paclitaxel NR CAP NR [14] Teneriello et al. II 2009 nab-paclitaxel NR 8.5 NR [15] Sessa et al. II 2005 Trabectidine NR NR [16] Krasner et al. II 2007 Trabectidine NR [17] Del Campo et al. II 2009 Trabectidine (1.5 mg/m 2 over 24 hrs) q3w Trabectidine (1.3 mg/m 2 over 3 hrs) q3w NR NR NR NR [19] Morris et al. II 2008 Topotecan NR 21.2 CAP: cyclophosphamide doxorubicin and cisplatin; DS: disease stabilization; GEM: gemcitabine; HRS: hours; MON: months; N: sample size; NAB-PACLITAXEL: nanoparticle albumin-bound paclitaxel; NR: not reported; ORR: overall response rate; OS: overall survival; PFS: progressionfree survival; PLD: pegylated liposomal doxorubicin; Q3w: three times per week; Ref: reference; TTP: time to progression Pegylated liposomal doxorubicin (PLD) In 2001, Gordon et al. [8] (phase III trial) randomized 474 patients with platinum-sensitive and platinum-resistant EOC to receive either PLD (50 mg/m 2, one-hour infusion every 28 days) 3

4 [n=239] or topotecan (1.5 mg/m 2 /d for 5 successive days every 21 days) [n=235]. For all patients, the PLD group achieved higher (statistically insignificant) ORR (19.7 vs. 17.0%) and median OS (60 vs weeks) than the topotecan group. Sub-analysis of platinum-sensitive patients only [n=220], the PLD group [n=109] achieved statistically significant benefits in terms of OS (108 vs weeks, p=0.008) and PFS (28.9 vs weeks, p=0.037) than the topotecan group [n=111]. The topotecan group demonstrated higher occurrence of hematologic adverse events, and they were influenced by administration of blood/growth factor products or dosage alteration. The study concluded that PLD is favorable over topotecan based on the suitable dosing, equivalent efficacy and acceptable safety profile. In 2004, Gordon and colleagues [9] provided a long-term survival data for the earlier abovementioned phase III clinical trial [8]. Survival data were mature (87% of patients died, n=413). For all patients, patients treated with PLD achieved an 18% decrease in the hazard of mortality (median survival: 62.7 vs weeks, p=0.050) than patients treated with topotecan. For patients with recurrent platinum-sensitive EOC (n= 219), patients treated with PLD [n=109] had a statistically significant 30% decrease in the risk of mortality (median survival: 108 vs. 70 weeks, p=0.017) than patients treated with topotecan [n=110]. There was no survival difference among patients with recurrent platinum-resistant EOC. The study concluded that PLD yields longer survival benefits than topotecan in patients with recurrent platinum-sensitive EOC. In 2008, Ferrandina et al. [10] (phase III clinical trial) randomized 153 patients with recurrent EOC who experienced relapse within 12 months following completion of an initial platinum-based chemotherapy. Patients were randomized to receive either GEM (1 g/m 2 on days 1, 8, and 15 every 28-day cycle) [n=77] or PLD (40 mg/m 2 every 28 days) [n=76]. PLD group achieved a higher median OS (14 vs. 12.8, p=0.048) than the GEM group. Similarly, PLD group achieved a higher ORR (29 vs. 16%, p=0.056) than the GEM group. There was no statistically significant difference in TTP (p=0.411) among both groups. With respect to drug-related side effects, GEM group had statistically significant rates of grade III/IV neutropenia (p=0.007). On the other hand, PLD group had higher, although not statistically significant, rates of palmar-plantar erythrodysesthesia (6 vs. 0%, p=0.061) than the GEM group. The study concluded that GEM is not favorable over PLD in the context of TTP. That being said, GEM may be considered as a potential rescue treatment in management of patients with recurrent EOC. In 2008, Katsumata and colleagues [11] (phase II clinical trial by the Japanese Gynecologic Oncology Group) explored the efficacy of PLD (50 mg/m 2 ) every 28 days in 73 patients with recurrent EOC. Only 11 patients were platinum-sensitive (16%). Among the platinum-sensitive patients, only 10 patients were evaluable. The CR, PR, DS and DP occurred in 0, 3, 3 and 4 patients, respectively. The study concluded that PLD is somehow effective in the platinum-sensitive patient population. However, additional studies are needed. 4

5 Etoposide In 1998, Rose et al. (phase II clinical trial by a Gynecologic Oncology Study Group) [12] examined the role of prolonged oral etoposide (30-60 mg/m 2 /d for 3 weeks, every 4 weeks) in 99 patients with platinum-sensitive and platinum-resistant EOC. There were 41 patients with platinumsensitive EOC. The ORR was 34.1%, as follows: 19.5% PR and 14.6% CR rates. The median DOR, progression-free interval (PFI) and OS were 7.5, 6.3+, and months, respectively. A total of 97 patients were evaluable for toxicity. Grade III/ IV drug-related hematologic side effects predominated. The most repeatedly encountered of them (in a descending order) were grade IV neutropenia (25%), grade III neutropenia (20%), anemia (13.4%), grade III thrombocytopenia (5%) and grade IV thrombocytopenia. Only one patient experienced leukemia. Three drug-related mortalities were recorded, as follows: neutropenic sepsis (n=2) and thrombocytopenic bleeding due to an overdose (n=1). The study concluded that etoposide is therapeutic in both types of recurrent EOC. Gemcitabine (GEM) One study was conducted in 2008 by Ferrandina et al. [10]. This study is reported earlier. Paclitaxel In 2002, Cantù and partners [13] (phase I/II trial) randomized a total of 97 patients with recurrent platinum-sensitive EOC to receive either monotherapy paclitaxel (175 mg/m 2 IV over 3 hours) or cyclophosphamide, doxorubicin and cisplatin (CAP; 500 mg/m 2, 50 mg/m 2 and 50 mg/ m 2 (CAP) IV, respectively). The paclitaxel group had 50 patients whereas the CAP group had 47 patients; median number of cycles was 6 for both groups. At a median follow up of 49 months, the CAP group achieved a higher statistically significant median PFI (15.7 vs. 9 months, p=0.038) and OS (34.7 vs months, p=0.043) than the paclitaxel group. Regarding ORR, the PR and CR rates in the CAP group were 25 and 30%, respectively. Conversely, the PR and CR rates in the paclitaxel group were 28 and 17%, respectively (p=0.062). Drug-related adverse events of grade III/IV leukopenia (34 vs. 4%), grade II/IV neutropenia (36 vs. 13%) and grade II/III nausea/ vomiting (51 vs. 17%) were higher in the CAP group more than the paclitaxel group. On the other hand, toxicities of allergic reactions (15 vs. 2%) and grade I/II myalgia (19 vs. 4%) were higher in the paclitaxel group more than the CAP group. The study concluded that mono therapy paclitaxel is not superior to a platinum-based regimen in patients with recurrent platinum-sensitive EOC. Large-sized multicenter studies are warranted. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) In 2009, Teneriello et al. [14] (phase II clinical trial) studied the role of nab-paclitaxel (260 mg/m 2 IV for 30 min on day 1 of each 21-day cycle, for either a total of 6 cycles or occurrence of disease progression) in 47 patients with recurrent platinum-sensitive EOC. There were only 44 evaluable patients, and the ORR was 64%, as follows: PR (n=13, 30%) and CR (n=15, 34%). 5

6 Among patients who were evaluated according to Response Evaluation Criteria In Solid Tumor (RECIST) only [n=11], ORR was 45.5%, as follows: PR (n=4, 36.4%) and CR (n=1, 9.1%). Among non-measurable disease patients [n=11] with elevated CA-125 (>70 U/mL), the ORR was 82%, as follows: PR (n=2, 18.2%) and CR (n=7, 63.6%). Among patients evaluated with both RECIST and CA-125 parameters, the ORR was 64%, as follows: PR (n=7) and CR (n=7). The median DOR and PFS were 1.3 and 8.5 months, respectively. The most commonly encountered grade III/IV drugrelated side effects were neuropathy (9%) and neutropenia (24%). The study concluded that nab-paclitaxel yields beneficial therapeutic outcomes with a tolerable toxicity profile. However, additional research studies of nab-paclitaxel in combination with platinum-based therapy are necessary. Trabectidine In 2005, Sessa et al. [15] (European multi-center phase II clinical trial) evaluated the efficacy and safety of trabectidine (1,300 mcg/m 2 for 3-hour infusion every 3weeks) in 59 patients with recurrent platinum-sensitive (n=29) and platinum-resistant (n=30) EOC. In platinum-sensitive patients, the ORR and median TTP were 43% and 7.9 months, respectively. There were only 2 responses (7%) documented in the platinum-resistant patients. Overall, the most frequently reported side effects were asthenia, neutropenia and self-limited elevations in aminotransferases, not necessitating alteration or ceasing of treatment. The study concluded that trabectidine is potentially safe and active in patients with recurrent platinum-sensitive EOC. Further research studies are needed either as single-agent or in combination with other therapeutic agents. In 2007, Krasner and colleagues [16] (multicenter phase II trial) evaluated the efficacy and safety of trabectidine (0.58 mg/m 2 for an 3-hour infusion weekly for 3 weeks of a 4-week cycle) in 147 patients with recurrent platinum-sensitive (n=62, evaluable patients) and platinum-resistant (n=79, evaluable patients) EOC. In platinum-sensitive patients, the ORR and median PFS were 29% and 5.1 months, respectively. In platinum-resistant patients, the ORR and median PFS were 6.3% and 2 months, respectively. The most common chemotherapy-related adverse effects (in an ascending order) were: nausea (5%), vomiting (5%), fatigue (5%), neutropenia (8%), and reversible hepatic alanine transferase (10%). The study concluded that trabectedin has favorable therapeutic and tolerable safety profiles in patients with recurrent platinum-sensitive EOC. In 2009, Del Campo and partners[17] (randomized, open-label, phase II clinical trial) administered trabectidine to 107 patients with recurrent platinum-sensitive EOC. One group (group A, n=54) of patients received trabectidine at 1.5 mg/m 2 over 24 hours, whereas the other group (group B, n=53) received trabectidine at 1.3 mg/m 2 over 3 hours. Both groups received the dose every 3 weeks. Group A had higher ORR (38.9 vs. 35.8%), nausea/vomiting (24 vs. 15%), fatigue (15 vs. 10%), and transient non-cumulative neutropenia (55 vs. 37%) than Group B. Conversely, Group B had higher median TTP (6.8 vs. 6.2 months) and elevated transient noncumulative alanine aminotransferase (59 vs. 55%) than Group A. The study concluded that both regimens were fairly active and rationally well-endured in patients with recurrent platinumsensitive EOC. The encouraging results warrant additional confirmatory research. 6

7 In 2013, Del Campo and colleagues [18] conducted a retrospective pooled analysis of three phase II trials of single-agent trabectidine [15-17] in management of patients with relapsed EOC (n=295). They compared the above-mentioned 3 different dosing regimens, namely, 3-hour infusion weekly every 3 weeks of a 4-week cycle, 3-hour infusion once every 3 weeks (q3w), and 24-infusion q3w. The weekly regimen was associated with lower ORR (16 vs. 36%; p=0.0001), disease stabilization (46 vs. 66%; p=0.0007) and shorter median PFS (2.8 vs. 5.6 months, p<0.0001) than both q3w regimens. There were similar clinical outcomes documented for the 3-hour and 24-hour infusions q3w regimens. Slightly worse drug-related side effects, with respect to vomiting, fatigue and neutropenia, were observed for the 24-hour infusion q3w regimen as opposed to the 3-hour infusion q3w regimen. The review concluded that mono-therapy trabectidine (administered as a 3-hour infusion q3w) is the recommended dosing, and its potency and drug-related adverse events satisfactorily parallel other active salvage chemotherapies. Topotecan One study was conducted in 2001 by Gordon et al [8]. A follow-up long-term survival data was conducted in 2004 by Gordon and partners [9]. Both studies are reported earlier. In 2008, Morris et al [19] (phase II clinical trial) explored the efficacy and safety of topotecan (4 mg/m 2 weekly as tolerated until disease progression) in 41 patients with recurrent platinumsensitive EOC. A median of 9 topotecan cycles were administrated and ranged from as low as 1 to as high as 45 cycles. Overall, the drug schedule was well-endured; there were no incidences of grade IV anemia or thrombocytopenia. However, around 9 (22%) and 7 (17%) patients developed grade III/IV fatigue and neutropenia, respectively. There was a total of 38 patients who were assessable for drug-related response. A sum of 1, 8, 13, and 16 patients developed CR (3%), PR (21%), DP (34%), and DS (42%), respectively. The study concluded that weekly dosing of topotecan was efficacious, well-endured, and yield analogous outcomes to that of the classical 5-day regimen. Iproplatin In 1991, Weiss and colleagues [20] explored the role of iproplatin (initial dose: 270 mg/m 2, range: mg/m 2 as per toxicity) as a second-line salvage therapy in 105 patients with recurrent platinum-sensitive and platinum-resistant EOC. There were 101 patients who had measurable disease. The DOR ranged from 2 to 20 months.in patients who were resistant to carboplatin, the ORR was 12% (total=2/18, PR=2, CR=0) whereas in patients who were resistant to cisplatin, the ORR was 12% (total=7/60, PR=4, CR= 3). Most importantly, in platinum-sensitive patients treated with cisplatin, the ORR was 26% (total=5/19, PR=2, CR= 3). The most frequently reported side effects (in an ascending order) were diarrhea (40%), anemia (68%), leukopenia (76%) and thrombocytopenia (93%). The study concluded that iproplatin is not advised as therapeutic second-line chemotherapy in patients with platinum-sensitive as well as platinumresistant EOC (due to cross-reactivity with platinum-based agents, namely carboplatin and cisplatin). 7

8 COMBINATION SYSTEMIC CHEMOTHERAPY REGIMENS Numerous combinations of systemic chemotherapies have been investigated in patients with recurrent platinum-sensitive EOC. Such combinations included: platinum-based and nonplatinum-based regimens. Table 2: A summary of major phases II/III studies on combination chemotherapy in patients with recurrent platinum-sensitive EOC. Ref Authors Phase Year Single-Agent Chemotherapy n ORR (%) DS (%) TTP (mon) PFS (mon) PLD NR 16 NR 14 [21] Parmar et al. I/II 2003 Paclitaxel plus a platinum-based chemotherapy NR NR [23] Rose et al. II 2005 Carboplatin plus paclitaxel NR 14 NR OS (mon) [25] Bafaloukos et al. II 2010 Carboplatin plus paclitaxel NR 10.8 NR 29.4 Carboplatin plus PLD NR 11.8 NR 24.7 [26] Pujade-lauraine et al. III 2010 Carboplatin plus paclitaxel 509 NR NR NR Carboplatin plus PLD 467 NR NR NR [28] Wanger et al. III 2012 PLD plus carboplatin 467 NR NR NR NR 30.7 Paclitaxel plus carboplatin 509 NR NR NR NR 33 [29] Ferrero et al. II 2007 Carboplatin plus PLD NR [30] Weber et al. II 2009 Carboplatin plus PLD NR [31] Pfisterer et al. III 2006 [32] Bolis et al. III 2001 Carboplatin NR Carboplatin plus gemcitabine NR Carboplatin NR Carboplatin plus epidoxorubicin NR [33] van der Burg et al. II 1991 Cyclophosphamide plus carboplatin NR 8 12 [34] Zanaboni et al. II/III 1991 Cisplatin plus epirubicin or etoposide NR NR NR 13.5 [35] Monk et al. III 2010 [36] Poveda et al. III 2011 Trabectidine plus PLD NR NR PLD NR NR Trabectidine plus PLD 123 NR NR NR PLD 91 NR NR NR [38] Joly et al. II 2009 Gemcitabine plus topotecan NR NR 15.6 DS: disease stabilization; MON: months; N: sample size; NR: not reported; ORR: overall response rate; OS: overall survival; PFS: progression-free survival; PLD: pegylated liposomal doxorubicin; REF: reference; TTP: time to progression. 8

9 Platinum-Based Combination Systemic Chemotherapy Regimens Cisplatin and carboplatin were the two most commonly platinum-based drugs employed in the combination systemic chemotherapy regimens. Paclitaxel plus a platinum-based chemotherapy In 2003, Parmar and colleagues [21] (international, randomized, multicenter, phase I/II, the ICON4/AGO-OVAR-2.2 clinical trial) randomized 802 patients with recurrent platinum-sensitive EOC to receive either paclitaxel plus a platinum-based chemotherapy (n=392) or a conventional platinum-based chemotherapy (n=410). A total of 530 patients died after a median follow up of 42 months. A total of 717 patients developed progressive disease or died. The paclitaxel plus platinum-based chemotherapy group achieved a higher statistically significant 2-year survival rate (57 vs. 50%, p=0.02), median OS (29 vs. 24 months), 1-year PFS rate (50 vs. 40%, p=0.0004), and median PFS (13 vs. 10 months) than the conventional platinum-based chemotherapy group. The study concluded that a regimen of paclitaxel plus platinum-based chemotherapy is superior to a conventional platinum-based chemotherapy regimen, in terms of OS and PFS, in patients with recurrent platinum-sensitive EOC. Carboplatin plus paclitaxel In 1998, Rose and partners [22] (phase II clinical trial) evaluated the role of re-treatment with paclitaxel (135 mg/m 2 as a 24-hour infusion) plus carboplatin (area under curve [AUC] of 5-6) every 21 days in 25 patients with recurrent platinum-sensitive EOC. Only 20 patients had measurable and assessable disease, of which 4 (20%) and 14 (70%) patients experienced PR and CR, respectively. The ORRs were 91% and 89% for measurable and assessable diseases, respectively. The median PFI for measurable/assessable and non-assessable disease was 9 and 7 months, respectively. At a ranging interval between 2 and 15 months (median 9.0 months) after secondary remedy, 15 patients (60%) were reported to have relapse. Moreover, at a ranging interval between 2 and 21 months (median 10 months), 2 patients (8%) were reported to be dead. The study concluded that carboplatin plus paclitaxel combination is associated with higher ORR and long PFI in patients with recurrent platinum-sensitive EOC. In 2005, Rose et al. [23] (phase II clinical trial) examined the role of paclitaxel (80 mg/m 2 over 1 hour infusion on days 1, 8 and 15) plus carboplatin (AUC of 5 on day 1 only) in 28 patients with recurrent platinum-sensitive EOC. A median of 6 courses was administered and ranged from as low as 1 to as high as 13 cycles. Paclitaxel dose decreased to 60 mg/m 2 were deemed necessary in around 85% of patients. Grade III thrombocytopenia, grade III neutropenia, grade IV thrombocytopenia, grade IV neutropenia and neutropenic fever were observed in 5, 14, 0, 1 and 1 patients, respectively. Around 77% of the evaluable patients (n=20/26) demonstrated response to treatment, of which 15 and 5 patients exhibited CR and PR, respectively. The study concluded that a regimen of weekly paclitaxel (60mg/m 2 ) plus carboplatin (AUC of 5) is largely endured and therapeutic in patients with recurrent platinum-sensitive EOC. 9

10 In 2009, Hoekstra and associates [24] performed a retrospective chart review exploring the role of weekly paclitaxel (80 mg/m 2 on days 1, 8, 15) and monthly carboplatin (AUC 5 on day 1) of a 28-day cycle in 20 patients with recurrent EOC. A total of 15 patients were regarded as platinum-sensitive whereas 5 patients were regarded as platinum-resistant. For all patients, the ORR was 85% (n=17/20), as follows: PR (12%, n=2/17) and CR (78%, n=15/17). Specifically, in platinum-sensitive patients, the ORR was 94% (n=14/15). Even after a median follow up of 2 years and 4 months, median survival could not be documented. Only 35% of patients (n=7) exhibited neutropenia of grade III-IV drug-related adverse events. Moreover, 25% of patients displayed platinum hypersensitivity; however, they progressed with successful treatment through administration of a carboplatin desensitization procedure. The study concluded that a regimen of weekly paclitaxel plus monthly carboplatin is effective and potentially safe in patients with recurrent platinum-sensitive EOC. Large-sized multicenter study is warranted. In 2010, Bafaloukos and colleagues [25] (phase II clinical trial, Hellenic Cooperative Oncology Group study) randomized 189 patients with recurrent platinum-sensitive EOC to receive either PLD (45 mg/m 2 once every 28 days) plus carboplatin (AUC of 5) [Group A, n=93] or paclitaxel (175 mg/m 2 once every 21 days) plus carboplatin (AUC of 5) [Group B, n=96]. There were no statistically significant differences between both groups regarding ORR (51 vs 58%), CR rate (23 vs. 34%), median OS (24.7 vs months), and median TTP (11.8 vs months). Although there was no drug-related fatality reported, termination of treatment was statistically significantly higher in Group B than Group A (13.5 vs. 3%, p=0.016). For both groups, neutropenia was the most frequently documented side effect (Group A vs. Group B: 35 vs. 30%). Group A had higher statistically significant rates of the following side effects than group B: severe thrombocytopenia (11 vs. 2%, p=0.016) and grade II palmar-plantar erythrodysesthesia (38 vs. 9%, p<0.001). Conversely, Group B had higher statistically significant rates of the following side effects than group A: grade III neurotoxicity (7 vs. 0%, p=0.029) and grade III alopecia (20 vs. 5%, p=0.003). The study concluded that PLD plus carboplatin is an active treatment in patients with recurrent platinum-sensitive EOC with low associated frequencies of alopecia and neurotoxicity side effects. A phase III clinical trial is deemed necessary to further assess the efficacy and safety of the combination regimen. In 2010, Pujade-Lauraine and colleagues [26] (multicenter, non-inferiority, CALYPSO phase III clinical trial) randomized 976 patients with recurrent platinum-sensitive EOC into 2 groups, namely, group A and group B. Group A (n=467) received PLD (30 mg/m 2 ) plus carboplatin (AUC of 5) every 28 days, whereas group B (n=504) received paclitaxel (175 mg/m 2 ) and carboplatin (AUC of 5) every 21 days for at least 6 cycles. The median follow-up was 22 months. Group A achieved a higher statistically significant PFS (11.3 vs. 9.4 months, p=0.005) than Group B. Despite the OS data insufficient for final analysis, a sum of 334 patients passed away during treatment. Grade II-III hand-foot syndrome (12.0 v 2.2%), nausea (35.2 vs. 24.2%) and grade II/III mucositis (13.9 vs. 7%) were noticed more frequently in Group A than Group B. Conversely, non-blood related 10

11 adverse side effects (36.8 vs. 28.4%), grade II alopecia (83.6 vs. 7%), hypersensitivity reactions (18.8 vs. 5.6%) and sensory neuropathy (26.9 vs. 4.9%) were noticed more frequently in Group B than Group A. The study concluded that the regimen of PLD plus carboplatin is superior to the regimen of paclitaxel plus carboplatin in terms of PFS and safety profile. In 2011, Joly et al. [27] monitored the rate of hypersensitivity reactions (HSRs) in the abovementioned CALYPSO phase III clinical trial [26]. Data available for 466 and 502 patients in Group A and Group B, respectively. It was noted that Group A had a higher rate of HSRs than Group B within the first chemotherapeutic schedule (46 vs. 16%). However, overall, Group B experienced a higher statistically significant rate of HSRs than group A (33.1 vs. 15.5%, p<0.001). Chemotherapy regimen and age were sub-analyzed as multivariate predictors of allergy. At the conclusion of the study, it was reported that the combination PLD plus carboplatin as well as older age 70 years old were associated with a low frequency of HSRs in patients with recurrent platinum-sensitive EOC. In 2012, Wagner et al. [28] released the final OS analysis of the CALYPSO phase III clinical trial [26]. The median follow-up was 49 months. There was no statistically significant difference of OS between Group A and Group B (30.7 vs. 33 months, p=0.94). The study concluded that PLD plus carboplatin is associated with postponed disease progression and equivalent OS outcomes to paclitaxel plus carboplatin regimen in patients with recurrent platinum-sensitive EOC. Carboplatin plus pegylated liposomal doxorubicin (PLD) In 2007, Ferrero and colleagues [29] (retrospective GINECO phase II clinical trial) administered carboplatin (AUF of 5) plus PLD (30 mg/m 2 ) every 4 weeks for a maximum of 9 cycles in 104 patients with recurrent platinum-sensitive EOC. The median PFS, OS and ORR were 9.4 months, 32 months and 63%, respectively. Non-hematologic drug-related adverse events were mostly of grade I/II; grade III/IV neutropenia happened in 51% of patients whereas febrile neutropenia happened in only 3% of patients. Alopecia and neurotoxicity were of low frequency. The study concluded that carboplatin plus PLD is active and offers clinical benefits in terms of prolonged OS, prolonged PFS and well-endured safety profile. In 2009, Weber and colleagues [30] (prospective GINECO phase II clinical trial) administered carboplatin (AUF of 5) plus PLD (30 mg/m 2 ) every 4 weeks for a maximum of 6 cycles of occurrence of disease progression, in 81 patients with recurrent platinum-sensitive EOC. The median PFS, OS and ORR were 13.6 months, 38.9 months and 65.4%, respectively. Hematological drug-related adverse events were more frequently reported than non-hematological ones. Neither drugrelated fatality nor cardiotoxicity were observed. The study concluded that carboplatin plus PLD is an active treatment and well-endured in patients with recurrent platinum-sensitive EOC. In 2010, a study was conducted by Bafaloukos and colleagues [25]. This study is reported earlier. 11

12 Also, in 2010, another study was conducted by Pujade-Lauraine and colleagues [26]. This study is reported earlier. In 2011, a study was conducted by Joly et al. [27]. This study is reported earlier. In 2012, a study was conducted by Wagner et al. [28]. This study is reported earlier. Carboplatin plus gemcitabine (GEM) In 2006, Pfisterer and partners [31] (phase I/II trial, an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GC) randomized 356 patients with recurrent platinum-sensitive EOC to receive either a single-agent carboplatin (n=178) or combination carboplatin plus gemcitabine (n=178) every 21 days. A median of 6 cycles was reported in both groups. With a median follow up of 17 months, the combination carboplatin plus gemcitabine group achieved higher statistically significant PFS (8.6 vs. 5.8 months, p=0.0031) and ORR (47.2 vs. 30.9%, p=0.0016) than the singleagent carboplatin group. There were no statistical differences among both groups with respect to median OS and quality of life (QoL) scores. Myelosuppression was substantially more frequent in the combination regimen; however, without subsequent increase in myelosuppression-related complications, for example, infections and fever-related neutropenia. The study concluded that combination regimen of carboplatin plus gemcitabine is associated with enhanced clinical outcomes such as PFS and ORR without incurring deleterious effects on QoL in patients with recurrent platinum-sensitive EOC. Carboplatin plus epidoxorubicin In 2001, Bolis and colleagues [32] (phase III clinical trial) randomized 190 patients with recurrent platinum-sensitive EOC to receive either single-agent carboplatin (300 mg/m 2 every 4 weeks for 5 cycles) [Group A, n=95] or carboplatin (300 mg/m 2 ) plus epidoxorubicin (120 mg/m 2 ) every 4 weeks for 5 cycles [Group B, n=95]. For the single-agent carboplatin group, the DOR, CR and PR were 16 months, 36% and 20.2%, respectively. On the other hand, for carboplatin plus epidoxorubicin group, the DOR, CR and PR were 20 months, 31.8% and 29.9%, respectively. Among both groups, there were no statistical significance with respect to DOR, CR and PR. The single-agent carboplatin group had a lower 3-year percentage of survival (29 vs. 42%, no statistical significance) than the carboplatin plus epidoxorubicin group. With respect to drug-related adverse events, the single-agent carboplatin group had lower rates of grade III/ IV thrombocytopenia, leukopenia and anemia. Conversely, the carboplatin plus epidoxorubicin group had a higher rate of grade III alopecia (around 90%). The study concluded that both regimens did not exhibit noticeable therapeutic differences, and the hematological side effects were more common in the combination regimen. 12

13 Carboplatin plus cyclophosphamide In 1991, van der Burg and partners [33] (phase II clinical trial) administered cyclophosphamide (100 mg/m 2 orally on days 1-7) plus carboplatin (300 mg/m 2 IV on day 8) in 30 patients with platinum-sensitive EOC. Only 28 patients were eligible for response assessment. The ORR, CR, PR, DS and DP rates were 32%, 18%, 14%, 53% and 14%, respectively. The median PFS and OS were 8 and 12 months, respectively. Overall, the combination regimen was well-endured, and thrombocytopenia was the most significant drug-related toxicity. The study concluded that cyclophosphamide plus carboplatin should be considered for palliative purposes only. Weekly cisplatin plus epirubicin or etoposide In 1991, Zanaboni and colleagues [34] (retrospective study) administered weekly cisplatin plus epirubicin or etoposide in 40 patients with platinum-sensitive EOC. The ORR, DOR and median OS were 60% (CR: 25%), 7 months and 13.5 months, respectively. The drug-related side effects were acceptable. The study concluded that weekly cisplatin plus epirubicin or etoposide showed an evidence of effectiveness and was well-tolerated. Non-platinum-based Combination Systemic Chemotherapy Regimens There are a few studies that have explored the role of non-platinum-based doublets in the management of patients with recurrent platinum-sensitive EOC. Trabectidine plus pegylated liposomal doxorubicin (PLD) In 2010, Monk and colleagues [35] (OVA-301, phase III clinical trial) randomized 672 patients with recurrent platinum-sensitive and platinum-resistant EOC to receive either trabectidine (1.1 mg/m 2 3-hour infusion) plus PLD (30 mg/m 2 IV) every 21 days [Group A, n=337] or single-agent PLD [Group B, n=335] every 28 days. For all patients, the trabectidine plus PLD group achieved higher statistically significant median ORR (27.6 vs. 18.8%, p=0.0080) and median PFS (7.3 vs. 5.8 months, p=0.0190) than the single-agent PLD group. For patients with recurrent platinumsensitive EOC [n=431], similar outcomes were obtained; the trabectidine plus PLD group [n=218] achieved higher statistically significant median ORR (35.3 vs %, p=0.0042) and median PFS (9.2 vs. 7.5 months, p=0.0170) than the single-agent PLD group [n=213]. As for the platinumresistant EOC patients, there were no statistically significant differences between both groups with regards to ORR and PFS. When compared to the single-agent PLD group, the trabectidine plus PLD group had high frequencies of neutropenia and grade III/IV high transaminase levels, and low frequencies of mucositis and hand-foot syndrome. The study concluded that combination trabectidine plus PLD regimen is associated with clinical advantages in terms of ORR, PFS and better drug-related safety profile in patients with recurrent platinum-sensitive EOC. In 2011, Poveda and colleagues [36] (OVA-301 phase III clinical trial) reported the outcomes of the OVA-301 study [35] for the 214 patients with platinum-sensitive EOC. The trabectidine plus 13

14 PLD group achieved a higher statistically significant median PFS (7.4 vs. 5.5 months, p=0.0152; 35% reduction in the risk of DP) and median OS (23 vs. 17months, p=0.0015; 41% reduction in the risk of death) than the single-agent PLD group. Both groups (76 and 77%, respectively) were administered subsequent platinum-based therapy, and the trabectidine plus PLD group had a higher statistically significant median OS (13.3 vs. 9.8 months, p=0.0357) than the singleagent PLD group. The study concluded that trabectidine plus PLD yields clinical advantages with respect to PFS and OS in the general population, generally, and in the platinum-sensitive population, specifically. In 2012, Monk and partners [37] reported the OS analysis of OVA-301 phase III clinical trial [35]. The study was powered to demonstrate a 33% increase in the OS after 520 deaths occurred. The median follow-up was approximately 47.5 months. The trabectidine plus PLD group had a higher statistically significant median OS (p=0.0285) than the single-agent PLD group; the platinumsensitive group had the most pronounced advantage of OS as opposed to the platinum-resistant group (p=0.0027). The analysis included several unexpected outcomes and further secondary analyses/hypotheses were generated. At the conclusion of the study, it was determined that the final analysis of OS did not match the protocol-defined condition for statistical significance, and the PFI influenced the OS, rendering the interpretation of results uncertain. Gemcitabine plus topotecan In 2009, Joly and partners [38] (a French multicenter phase II clinical trial) administrated weekly gemcitabine (1000 mg/m 2 ) plus topotecan (2.5 mg/m 2 ) on days 1, 8, and 15 of a 28-day cycle to 77 patients with platinum-sensitive and platinum-resistant EOC. A total of 66 patients were evaluable for response, and 17% and 4% of patients developed grade III and IV neutropenia, respectively. Around 60% of patients were administered the complete regimen of the combination therapy as a result of developing moderate neutropenia and thrombocytopenia. For all patients, the ORR was 14%. As compared to platinum-resistant (n=30), the platinum-sensitive (n=36) EOC patients had higher ORR (20 vs. 7%), median DOR (6.4 vs. 4.9%), DS (69 vs. 63%) and median OS (15.6 vs. 7.5 months). However, the platinum-resistant group had a higher decrease in the rate of pain/symptomology (64 vs. 39%) than the platinum-sensitive group. The study concluded that weekly administration of gemcitabine plus topotecan is associated with moderate ORR and satisfactory quality of life (QoL) in terms of disease- and symptom-control. CONCLUSIONS Epithelial ovarian cancer (EOC) remains a principal cause of cancer-related mortality in women. In spite of the primary therapy (surgical cytoreduction and platinum-taxane combination regimen), majority of patients (85%) with advanced-stage EOC will relapse and require an additional systemic medical treatment. 14

15 The selection of systemic medical treatment is largely based on the response to the first-line chemotherapy -that is, the platinum-free interval (PFI): o Patients with a PFI 6 months are regarded as platinum-resistant. o Patients with a PFI 6 months are regarded as platinum-sensitive. Patients with recurrent platinum-sensitive EOC should be considered for secondary cytoreduction (whenever technically feasible) and re-treatment with a platinum-based regimen. In patients with recurrent platinum-sensitive EOC, platinum-based regimens are recommended over non-platinum-based regimens. Platinum-based combination chemotherapy is preferred over monotherapy as it is associated with improved objective response rate (ORR), progression-free survival (PFS), and to some degree, superior overall survival (OS). Recommended platinum-based combination regimens are carboplatin plus paclitaxel (first priority), carboplatin plus gemcitabine, or carboplatin plus pegylatedliposomal doxorubicin (PLD). The selection of the platinum-based combination regimen should be based on availability, affordability, therapeutic efficacy and toxicity profile. Availability and affordability of novel molecularly targeted therapies, such as angiogenesis inhibitors and poly-adp ribose polymerase (PARP) inhibitors as a maintenance therapy, remains a healthcare problem. Combination novel molecularly targeted therapy and systemic chemotherapy is an active and exciting area for research. Future research should strive to explore molecular mechanisms of recurrence, and subsequently recognize significant molecular targets for therapeutic interventions. References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, CA Cancer J Clin. 2015; 65: Foley OW, Rauh-Hain JA, Del Carmen MG. Recurrent epithelial ovarian cancer: an update on treatment. Oncology (Williston Park). 2013; 27: Wu YS, Shui L, Shen D, Chen X. Bevacizumab combined with chemotherapy for ovarian cancer: an updated systematic review and meta-analysis of randomized controlled trials. Oncotarget. 2017; 8: González Martín A, Bratos R, Márquez R, Alonso S, Chiva L. Bevacizumab as front-line treatment for newly diagnosed epithelial cancer. Expert Rev Anticancer Ther. 2013; 13: Teplinsky E, Herzog TJ. The efficacy of trabectedin in treating ovarian cancer. Expert Opin Pharmacother. 2017; 18: Alvarez RD, Karlan BY, Strauss JF. Ovarian cancers: Evolving paradigms in research and care : Report from the Institute of Medicine. Gynecol Oncol. 2016; 141: Alvarez RD, Matulonis UA, Herzog TJ, Coleman RL, Monk BJ, et al. Moving beyond the platinum sensitive/resistant paradigm for patients with recurrent ovarian cancer. Gynecol Oncol. 2016; 141:

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