Role of gemcitabine in ovarian cancer treatment

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1 Annals of Oncology 17 (Supplement 5): v188 v194, 2006 doi: /annonc/mdj979 Role of gemcitabine in ovarian cancer treatment D. Lorusso, A. Di Stefano, F. Fanfani & G. Scambia* Department of Oncology, Catholic University of the Sacred Heart, Campobasso, Rome, Italy symposium article Newer agents and combinations are needed in order to improve current results in ovarian cancer treatment. Gemcitabine is a novel agent that has shown promising activity as a single agent in the treatment of platinumresistant ovarian cancer and a favorable toxicity profile. Because of its clinical and preclinical synergism with platinum analogues, Gemcitabine has been combined with Carboplatin as a convincing approach in the treatment of platinum-sensitive recurrent ovarian cancer patients. Further combination of Gemcitabine and other agents, including paclitaxel, are also feasible and have been actively studied in order to establish the role of Gemcitabine in the management of treated and untreated ovarian cancer patients. Key words: gemcitabine, ovarian cancer background Ovarian carcinoma accounts for 4% of all malignant tumors and represents the leading cause of death among all gynecological malignancies in Western countries [1]. In the United States in 2003, new cases of ovarian cancer were estimated and women are expected to die from the disease; in Western Europe every year about new cases and 24,600 deaths from ovarian cancer are registered [1]. Actually the standard treatment of ovarian cancer is represented by radical surgical debulking followed by carboplatin-paclitaxel combination chemotherapy [2] Despite the improvements in the management of ovarian cancer during the past 20 years and the development of new cytotoxic drugs with initial high response rates, more than 60% of patients with advanced ovarian cancer experience a relapse, or develop resistant disease, and die from progressive disease [3 5]. The probability of response to second line chemotherapy depends on several factors among which the most important is the platinum-free interval [6]. In Platinum-sensitive patients (patients which recur more than 6 months from the end of a Platinum-based chemotherapy) the chosen treatment is generally represented by the re-challenge with a second line Platinum-based treatment which may induce a response rate up to 70%, superior to what reported with all other currently available anti-neoplastic drugs [7]. Many drugs have shown activity in the treatment of recurrent Platinum-resistant (patients that recur during a Platinum-based chemotherapy or within 6 months from the end of the treatment) ovarian cancer patients (Table 1). Platinum-resistant patients present a very poor prognosis with short-lasting response and survival; in this subset of patients the response rate reported for different treatments is *Correspondence to: Dr G. Scambia, Gynecologic Oncology Unit, Catholic University of the Sacred Heart, Largo A. Gemelli, 8, Rome, Italy. Tel/Fax: ; giovanni.scambia@libero.it quite similar, varying from 14% to 34% and, at present, no drug may be considered the treatment of choice. The principal end-point of salvage treatment in this subset of patients is represented by the palliation of symptoms and the maintenance of acceptable quality of life [7]. All present new drugs or combinations, potentially active and with an acceptable toxicity profile, are continuously evaluated in this subset of patients in order to convert a higher response rate in a longer survival [8]. In the last years Gemcitabine (29,29-difluorodeoxycytidine, dfdc) a synthetic nucleoside analog of cytidine, has emerged as an attractive option in ovarian cancer treatment [9]. As a false nucleotide, incorporation of Gemcitabine into DNA block processing and chain elongation by the DNA polymerase complex producing a cytostatic effect with G1 block in the cell cycle. Gemcitabine triphosphate metabolite is also incorporated into RNA, thus inhibiting RNA synthesis [10]. The efficacy of Gemcitabine in inhibiting the growth of human ovarian carcinoma cells has been evaluated both in in vitro and in vivo models [11 14]. gemcitabine monotherapy in the treatment of recurrent ovarian cancer As a single agent, Gemcitabine has been extensively evaluated at doses ranging from 800 to 1250 mg/m 2 administered as a 30-min infusion on days 1, 8, and 15 of a 28-day cycle [15 26, Table 2). Using this dosage and schedule, the most frequently occurring dose-limiting toxicities associated with Gemcitabine treatment are hematologic, with neutropenia occurring more often than thrombocytopenia. Fortunately, the hematologic toxicity is not cumulative and can be easily managed with dose reductions, omissions of day 8 or 15 administrations or delays in subsequent therapy. Non hematologic toxicities include transient increases in hepatic transaminases, fever, myalgia, flu-like symptoms, and extremity ª 2006 European Society for Medical Oncology

2 Annals of Oncology edema and are reversible. Nausea, vomiting, fatigue, and headache were generally mild and not dose dependent. Peripheral neuropathy has been rarely (<2%) reported. While subclinical pneumonitis can occur, severe pneumonitis with risk of pulmonary fibrosis and respiratory insufficiency is rare [23]. The single-agent experiences from 12 studies and a total of 411 individual participants with recurrent ovarian cancer are summarized in Table 2. In these studies, the majority of participants appeared to have platinum-resistant disease and Table 1. Salvage chemotherapy in recurrent platinum refractory ovarian cancer patients Drug RR (%) PFS (weeks) OS (median, weeks) Topotecan Paclitaxel Docetaxel Liposomal Doxorubicin Oral Etoposide Gemcitabine Oxaliplatin Hexamethylmelamine Ifosfamide Vinorelbine Tamoxifen RR, Response Rate; PFS, Progression Free Survival; OS, Overxall Survival. Table 2. Phase I and II studies on Gemcitabine as a single agent for salvage treatment of ovarian cancer Study [ref] No. of Patients RR (%) Dose (mg/m 2 ) TTP (mo) OS (mo) Lund [15] Silver [16] Morgan-Ihrig [17] Shapiro [18] D Agostino [19] Markman [20] Coenen [21] Friedlander [22] Markman [23] Von Minckwitz [24] Neijt [25] Kudelka [26] Total * RR, Response rate; *, Mean response (%); TTP, Median time to progression; OS, Median overall survival. symposium article was heavily pretreated. In more recent studies, participants also had prior exposure to paclitaxel. Overall response rates varied from 14% to 22%, with an average of 16.5% across the all series. The median duration of response ranged from 4.0 to 10.6 months. Most of the responses were partial, although a small number of complete responses have also been reported. Probably a dose-response relationship for Gemcitabine in ovarian cancer does not exist, and doses higher than 1000 mg/ m 2 in heavily pre-treated patients are not advised because of the risk of severe myelosuppression. Of interest is that an additional 30% of the patients experienced stable disease for an overall clinical benefit rate of approximately 50%. These studies demonstrate that Gemcitabine has a wellproven activity in Platinum/Paclitaxel resistant ovarian cancer patients and seems to present no cross-resistance with Platinum compounds. gemcitabine and platinum combinations in the treatment of recurrent, platinum-resistant ovarian cancer Gemcitabine has been variously combined with other drugs in the treatment of recurrent ovarian cancer. The combination of Gemcitabine with Cisplatin has been extensively studied in several solid tumors because of the in vitro evidence in ovarian cancer cell line A 2780 and ADDP of a synergism based on the incremented Platinum-DNA adducts induced by Gemcitabine incorporation into the DNA [27]. Moreover, recent evidences suggest that Gemcitabine could be able to overcome Platinum-resistance probably through the inhibition of the enzymatic complex ERCC1 responsible for the repair of the DNA damage, and usually overexpressed in Platinum-resistant patients [28]. In this context the results of four Phase II clinical trials, investigating the role of gemcitabine in overcoming platinumresistance are very interesting (Table 3). Rose et al. [29] treated 36 Platinum-resistant patients (Platinum free interval < 6 months) with a combination of Cisplatin 30 mg/m 2 and Gemcitabine 750 mg/m 2 on days 1,8 q 21; a total number of 259 cycles (median 4 cycles, range 1 20) was administered without evidence of intolerable toxicity. Among the 35 evaluable patients 4 complete responses and 11 partial responses were registered (42.9%), with a median duration of response of 11 months (range 4 14) and a median time to progression of 6 months (range 1 14). The authors underline the interesting evidence of a response in 4 out of the 6 patients previously not responding to Cisplatin treatment. Table 3. Clinical trials on CisPlatinum/Gemcitabine combination in the salvage treatment of platinum-resistant ovarian cancer Author [ref] Dose (mg/m 2 ) gg1,8 q 21 Number of patients (response rate) Time to progression months (range) Nagourney [30] Gemcitabine 750 Cisplatin (70%) 6 ( ) 20.2 Rose [29] Gemcitabine 750 Cisplatin (43%) 6 (1 14) 12 Median overall survival (months) Volume 17 Supplement 5 May 2006 doi: /annonc/mdj979 v189

3 In the study of Nagourney et al. [30], 27 recurrent ovarian cancer patients were treated with Cisplatin 30 mg/m 2 and Gemcitabine 600 or 750 mg/m 2 (based on the number of previous treatments) on days 1, 8 q 21. The overall response rate registered was 70%: among the 14 Platinum-resistant patients (mean Platinum-free interval 8 months) 3 complete responses and 5 partial responses were documented accounting for a total response rate of 57%, with a median time-to-progression of 6 months. The authors concluded that the concomitant or sequential administration of Platinum and Gemcitabine may overcome the Platinum-resistance of the ovarian cancer cells. Finally Tewari et al. [31] reported a 64% response rate among the 15 platinum-resistant patients treated with the combination of Cisplatin and Gemcitabine. The encouraging results emerged from these studies supported the design of the Phase II GOG 126L trial aimed at evaluating the combination of Platinum and Gemcitabine in recurrent Platinum-resistant ovarian cancer patients. Preliminary results on 52 enrolled patients [32] showed a 15.8% response rate with a 54% stabilization of disease. gemcitabine in combination with other drugs in the treatment of recurrent platinum-resistant ovarian cancer The acceptable toxicity profile and proven efficacy of gemcitabine in relapsed ovarian cancer enable the development of the hypothesis stating that a specific choice of drugs with different mechanisms and non cross-resistance can increase the chance of response and prolong its duration and that of other outcome parameters (e.g., symptom control). Preclinical studies have shown that gemcitabine based combinations increase cytotoxicity and can potentially overcome drug resistance [33]. These characteristics make gemcitabine an attractive partner for combination with other cytostatic agents. Several studies have assessed the feasibility and efficacy of the combination of Gemcitabine with Paclitaxel (Table 4). In vitro studies demonstrated that Paclitaxel and Gemcitabine induce an antagonistic effect when administered simultaneously, while sequential infusion produces additive cytotoxic effects that do not depend on the sequence of the administration [34]. Other authors reported that the contemporaneous administration of the two drugs and the sequence Gemcitabine followed by Paclitaxel produces only antagonistic effects while the opposite sequence could induce a synergistic action probably through a mechanism of activation of apoptosis; besides, this effect is maximum when there is a 48-h wash-out between the infusion of the drugs [45]. Paclitaxel, in fact, blocks the cells in the G2-M phase of the cycle, thus producing an increase of synchronized Annals of Oncology G1-S phase cells which represents the specific cell cycle phase of Gemcitabine cytotoxic activity. Jungnelius et al. [36] conducted a phase I trial to investigate the optimal dose and schedule of Gemcitabine in combination with Paclitaxel in the salvage treatment of recurrent, platinum resistant ovarian cancer patients. The MTD was reached at Gemcitabine 1250 mg/m 2 on days 1 and 8 and Paclitaxel 175 mg/m 2 on day 8 of a 21 day cycle. The overall response rate was 41% including 14 partial and 2 complete responses among 39 evaluable patients. Garcia et al. [37] in a population of 35 recurrent, platinum resistant ovarian cancer patients with Gemcitabine 1000 mg/m 2 and Paclitaxel 80 mg/m 2 on days 1, 8, 15 of a 28 day cycle reported a 40% response rate with a median time to progression of 5.7 months and a median overall survival of 13.1 months. Because of its activity in ovarian cancer patients, the different mechanisms of action and the compatible toxicity profile, Topotecan seems to be a good candidate to combine with Gemcitabine in the second line setting (Table 5). Our Department conducted a phase I II trial in 24 recurrent Platinum resistant/refractory ovarian cancer patients, WHO received Topotecan day 1 5 plus Gemcitabine day 1,3 q 28 [38]. The starting dose level was Topotecan 0.7 mg/m 2 and Gemcitabine 200 mg/m 2 ; the following dose levels were 0.8/400; 0.9/600; 0.9/800 for Topotecan and Gemcitabine, respectively. The maximum tolerated dose (MTD) was reached at level 3, the dose-limiting toxicity being represented by febrile neutropenia and thrombocytopenia. Non hematological toxicity was mild and manageable. Among all patients two complete and one partial response occurred (RR 13%). Sehouli et al. performed a phase I study in 23 heavily pretreated patients with relapsed ovarian cancer and defined the recommended dose of topotecan as 0.5 mg/m 2 on days 1 5 and of gemcitabine as 800 mg/m 2 on day 1 and 600 mg/m 2 on day 8 every 3 weeks [39]. In the subsequent phase II study, an additional 21 patients with relapsed ovarian cancer were recruited, including 5 patients with platinum- and paclitaxelresistant disease [40]. Eleven patients were evaluable for clinical tumor response, of which there were three CRs, four PRs, two patients with stable disease, and two patients with progressive disease. The median progression-free survival was 8.8 months and the median overall survival was 21.1 months. Based on preclinical studies on breast cancer cell lines where a synergistic cytotoxic effect has been documented, the combination of Gemcitabine with Liposomal Doxorubicin appears very interesting. Our Department conducted a Phase II study [41] in 70 heavily pretreated (median number of previous chemotherapy lines 2, range 1 5) recurrent ovarian cancer patients in order to evaluate the efficacy and toxicity of this combination. Patients received Gemcitabine 1000 mg/m 2 on Table 4. Clinical trials on Taxanes/Gemcitabine combination in the salvage treatment of platinum-resistant ovarian cancer Author [ref] Dose (mg/m 2 ) Number of patients (response rate) Median overall survival (months) Median time to progression (months) Junnelius [36] Gem 1250 d1,8 Paclitaxel 175 d1 q (41%) Not reported Not reported Garcia [37] Gem 1000 Paclitaxel 80 days 1,8,15 q (40%) v190 Lorusso et al. Volume 17 Supplement 5 May 2006

4 Annals of Oncology symposium article days 1, 8 and liposomal doxorubicin 30 mg/m 2 on day 1, q21d. The treatment schedule derived from a previous Phase I trial [42]. Among the 67 patients evaluable for response, 7 complete responses and 16 partial responses were registered, for an overall response rate of 35% and an overall clinical benefit, taking into consideration the prolonged stabilization of disease, of 73.1%. The results have recently been updated in a larger series with a longer follow up; the study performed on 106 patients reported 9 complete responses (8.5%) and 27 partial responses (25.5%) which still represent the best response rate reported in the salvage treatment of ovarian cancer with regimens nonincluding platinum and/or taxanes (Table 6). After a median follow up duration of 46.5 weeks, in the overall series median OS was 60 weeks and median PFS was 28 weeks [Figure 1, 43]. Gemcitabine has been variously combined with other drugs (oral etoposide, vinorelbine, treosulfan, 44 46) in the treatment of recurrent ovarian cancer and, a part from oral etoposide combination which was judged as too toxic, all the doublets appear to be feasible and active. It remains to be defined the definitive role of combination therapy in platinum-resistant ovarian cancer treatment. platinum-gemcitabine combination in the treatment of recurrent platinumsensitive ovarian cancer patients Du Bois et al. [47] published the results of a prospective dose-finding Phase I II (0026-AGO OVAR 2.4) trial aimed at establishing the recommended doses and schedule of a combination of Gemcitabine and Carboplatin in a group of 25 recurrent Platinum-sensitive ovarian cancer patients (Platinumfree interval 6 months). Patients received chemotherapy at three different dose levels: level 1 Gemcitabine 800 mg/m 2 on days 1, 8 and Carboplatin 5 AUC on day 1 q 21; level 2 Gemcitabine 1000 mg/m 2 on days 1,8 and Carboplatin 5 AUC on day 1 q 21; level 2A Gemcitabine 1000 mg/m 2 on days 1, 8 and Carboplatin 4 AUC on day 1 q 21. The maximum tolerated dose (MTD) was reached at level 2A, the dose-limiting toxicity being represented by myelosuppression (G3-4 uncomplicated neutropenia 29%, G3-4 thrombocytopenia 21%). Among the 16 patients with measurable disease an overall response rate of 62.5% was registered (4 complete responses, 6 partial responses and 2 stabilizations of disease), with a median progressionfree survival of 10 months and a median overall survival of 18 months. Based on the promising results of the phase I study, a following phase II study on Gemcitabine 1000 mg/m 2 on days 1,8 in combination with Carboplatin 4 AUC on day 1 q 21 in patients with late recurrent, Platinum-sensitive ovarian cancer, was performed [JHRW, 48]. The authors reported a median time-to-progression of 9.6 months (range months), a median time to treatment failure of 9.3 months (range months) and an overall clinical response rate of 62.5% (6 complete responses and 19 partial responses) among the 40 enrolled patients; prolonged stabilizations of disease were also registered in 12 patients (30%). The main toxicities registered were hematological: G3 G4 neutropenia 77.5%, G3 G4 thrombocytopenia 17.5%; G3 G4 anemia 15.0%. No G4 non hematological toxicity was observed and only 5% of patients reported a G3 non hematological toxicity (mainly gastro-intestinal). In the recent ASCO meeting Pfisterer presented the results of a randomized multicenter Phase III AGO-NCIC-EORTC pilot study (AGO-OVAR 2.5; GCIG; 49). In the trial the combination of Gemcitabine 1000 mg/m 2 on days 1, 8 and Carboplatin 4 AUC on day 1 every 21 days was compared with a standard control arm represented by Carboplatin 5 AUC on day 1 q 21 as a single agent in a population of 356 recurrent Platinumsensitive ovarian cancer patients. Table 5. Clinical trials on Topotecan/Gemcitabine combination in the salvage treatment of Platinum-resistant ovarian cancer Author [ref] Dose (mg/m 2 ) Number of patients (response rate) Median overall survival (months) Grade 3 4 toxicity Greggi [38] Gem 600 d1,3 Topotecan 0.9 d1-5 q (13%) Not reported Platelets, febrile neutropenia Sehouli [39] Gem 800 d 1, 600 d8; Topotecan 0.5 d1-5 q (50%) 15.3 Platelets, leukopenia Sehouli [40] Gem 800 d 1, 600 d8; Topotecan 0.5 d1-5 q (64%) 21.1 Platelets, leukopenia Table 6. Response rate of Gemcitabine-Liposomal Doxorubicin combination treatment classified on the basis of the response to previous platinum-based chemotherapy (106 evaluable patients) Type of response Platinum- resistant patients Platinum- sensitive patients Total Complete response 2 (3.1%) 7 (17.1%) 9 (8.5%) Partial response 12 (18.5%) 15 (36.6%) 27 (25.5%) Stable disease 21 (32.3%) 15 (36.6%) 36 (34.0%) Progression 30 (46.1%) 4 (9.7%) 34 (32.1%) Evaluable patients Progression free survival Median, weeks Overall survival Median, weeks Volume 17 Supplement 5 May 2006 doi: /annonc/mdj979 v191

5 Annals of Oncology The primary objective of the study was the time to progression; secondary end-points were represented by overall response rate, duration of response, overall survival and evaluation of quality of life. The study produced the following results: With a median follow-up of 17 months, median PFS was 8.6 months for gemcitabine carboplatin and 5.8 months for carboplatin. The response rate for the gemcitabine carboplatin group was 47.2% and 30.9% for carboplatin group (P 1/ ).The HR for overall survival was 0.96 (95% CI ; P 1/ , Table 7). It is important to underline that this trial was not powered for statistical comparison of survival. Therefore, only with an exploratory analysis median overall survival resulted in 18.0 months for participants in the gemcitabine carboplatin arm and 17.3 months for those in the carboplatin arm. Grade 3 4 hematologic toxicities were significantly more frequent in the gemcitabine carboplatin arm than in the PFS (%) OS (%) p= p= Weeks Weeks Overall Resistant Sensitive B Overall Resistant Sensitive Figure 1. PFS (A) and OS (B) curves in the overall series and according to initial Platinum sensitivity. Table 7. AGO-OVAR 2.5 study: response rate A Experimental arm CARBOPLATIN+GEMCITABINE carboplatin arm; neutropenia was the predominant toxicity (neutropenia 70.3% vs. 12.0%; thrombocytopenia 34.9% vs. 11.4% e anemia 27.4% vs. 8.0%; all P values P <0.05). Although the use of granulocyte growth factors was significantly higher in the gemcitabine carboplatin arm (24%) than in the carboplatin arm (10%), the frequency of febrile neutropenia and use of intravenous antibiotic treatment did not differ significantly between arms the number of participants who stopped treatment due to hematologic events was low (10%) and similar between treatment arms. Patients in the gemcitabine carboplatin arm received more red blood cells (40%) and platelet transfusions (8%) than those in the carboplatin arm (8% and 3%, respectively). The overall incidence of nonhematologic toxicities was modest, with 5% of participants in either arm reporting nausea, vomiting, stipsi. Grade 2 alopecia was reported in 14.3% of participants receiving gemcitabine carboplatin and 2.3% of participants treated with carboplatin monotherapy. grade 2 neurotoxicity was registered in <2% of patients, which is significantly lower with respect to what reported with Paclitaxel in the same setting of patients [36]. Finally, as far as the evaluation of quality of life is concerned, no significant differences between the two treatment arms were registered in almost all the evaluation scales, even if, in the subgroup of symptomatic patients, patients treated with gemcitabine carboplatin reported significantly faster palliation of abdominal symptoms and a significantly improved global quality of life. The authors concluded that Gemcitabine combined with Carboplatin in the treatment of late recurrent ovarian cancer patients demonstrated to be active and safe and that the combination has a favourable risks/benefits relationship that makes it an acceptable option in the second line treatment of platinum sensitive ovarian cancer. gemcitabine-based combinations in the management of untreated ovarian cancer patients Many drugs are already under evaluation for the up-front treatment of ovarian cancer: Epirubicin, Docetaxel, oral Etoposide, Liposomal Doxorubicin, Topotecan, Oxaliplatin and Gemcitabine. Based on the activity demonstrated in second-line setting, Gemcitabine appears very promising and it is appropriate to Standard arm CARBOPLATIN No. patients Complete response 26 (14.6%) 11 (6.2%) Partial response 58 (32.6%) 44 (24.7%) Stable disease 68 (38.2%) 69 (38.8%) Progression of disease 14 (7.9%) 29 (16.3%) Mean time to progression (range) 8.6 ( ) 5.8 ( ) P v192 Lorusso et al. Volume 17 Supplement 5 May 2006

6 Annals of Oncology symposium article Table 8. Clinical studies with Cisplatinum/Gemcitabine combination in the first line treatment of ovarian cancer Author Regimen Patients (stage) Overall response rate Krakowski [50] Cisplatin 75 mg/m 2 d1 Gemcitabine 1250 mg/m 2 d1,d8 42 (III & IV) 20/28 (71%) (7 CR 13 PR) Nogue [51] Cisplatin 100 mg/m 2 d1 Gemcitabine 1250 mg/m 2 d1,d8 27 (III & IV) 18/27 (69%) (5CR 13 PR) Bauchnecht [52] Cisplatin 75 mg/m 2 d1 Gemcitabine 1250 mg/m 2 d1,d8 31 (III IV; >60 anni) 8/15 (53%) (NA) CR, Complete response; PR, Partial response; NA, Not Applicable. explore its role in combination with Platinum and Taxanes as initial treatment of advanced ovarian cancer. In this context 3 clinical trials [50 52] reporting a response rate ranging from 53% to 70% (Table 8) support the belief that the combination of Cisplatin and Gemcitabine could be very active in the first-line treatment of advanced ovarian cancer. Moreover, two phase I trials evaluated the efficacy of Gemcitabine in combination with Carboplatinum and Paclitaxel in first line treatment of advanced ovarian cancer. In a population of 24 untreated ovarian cancer patients receiving Gemcitabine 800 mg/m 2 on day 1 in combination with Carboplatin and Paclitaxel at standard doses, Hansen et al. [53] reported a response rate of 100% (58% complete responses), with a median time to progression of 16 months and a median overall survival not reached after 30 months. Poole et al. [54] in a population of 29 advanced ovarian cancer patients, with the same treatment schedule, reported a response rate of 89.7% (75.9% complete responses). In both studies the toxicity registered was mainly hematological and Grade 4 febrile neutropenia was described in 13% of cases. In any case the judgment on the relative efficacy of the combination of Gemcitabine with Platinum and Taxanes could not be considered conclusive before the completion of the ongoing phase III randomized trials on the Carboplatin/ Gemcitabine combination in the first-line treatment of ovarian cancer. The first Phase III trial [55] is a large international study sponsored by the Gynecological Oncology Group and by the International Collaborative Group in Ovarian Neoplasia (GOG182-ICON5), with 5 treatment arms in which different drugs with documented activity in ovarian cancer (Gemcitabine, Topotecan, Paclitaxel, Carboplatin and Liposomal Doxorubicin) are variously combined in association or in sequence in the first line treatment of advanced ovarian carcinoma. In the second study (GCIG, AGO, GINECO, NSGO trial) untreated advanced ovarian cancer patients are randomized to receive standard treatment with Carboplatin and Paclitaxel with or without Gemcitabine. These trials have recently completed the accrual, but no data are currently available. conclusions In conclusion, literature data provide sufficient information to support the efficacy and the safety of Gemcitabine in ovarian cancer treatment. Gemcitabine has been shown to have a significant activity with an acceptable toxicity profile in previously treated ovarian cancer patients as a single agent or in combination with other drugs. In particular, based on the demonstrated significant benefits of Gemcitabine in combination with Carboplatin, its acceptable toxicity profile and the tolerability of the treatment reached with the recommended adjustment of doses, this combination presents a favourable risk/benefits relationship in the treatment of late recurrent ovarian cancer patients. 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