Sage Journals: Discover world-class research

Abstract

The US FDA has recently approved the combination of carboplatin and gemcitabine as a second-line therapy for recurrent platinum-sensitive ovarian cancer. This article briefly reviews the pharmacokinetics and mechanism of action of gemcitabine and its synergistic effect with platinum. An overview of the literature on the role of gemcitabine in the treatment of epithelial ovarian cancer is also presented.

Keywords

carboplatin cisplatin gemcitabine ovarian cancer paclitaxel recurrent ovarian cancer

The majority of patients with epithelial ovarian cancer experience a complete clinical response after their initial treatment with surgical debulking and platinum-based chemotherapy. However, more than 75% of the patients with a complete response will suffer from recurrence within 5 years [1,2]. If recurrence occurs more than 6 months after the last platinum treatment, patients are considered to have a potentially platinum-sensitive disease [3,4], which exhibits a 30% response rate to single-agent carboplatin and carries an overall better prognosis [5,6]. On the other hand, if recurrence occurs less than 6 months after the last platinum treatment, patients are considered to have platinum-resistant disease, which is less likely to respond to second-line regimens and carries a poor prognosis [7].

Current treatment goals for recurrent ovarian cancer include: treating symptoms if present and prolonging the progression-free survival (PFS), with an aim to improve the overall survival (OS) of patients. This needs to be done whilst carefully balancing chemotherapy-related toxicity, patient's quality of life and the expected survival benefit from therapy. In order to achieve these goals, new cytotoxic agents and combination chemotherapy regimens are being investigated.

Gemcitabine is a synthetic nucleoside analog of cytidine with broad activity in solid tumors. Over the last 10 years, studies have confirmed the potential role of gemcitabine in the treatment of ovarian cancer. These studies led to the European (2004) and US (2006) approval of carboplatin plus gemcitabine for patients with ovarian cancer recurring more than 6 months after the completion of platinum therapy. Other studies have explored the role of gemcitabine in platinum-resistant recurrent ovarian cancer and as part of the first-line regimen for newly diagnosed patients.

Gemcitabine

Introduction to gemcitabine

Gemcitabine (2′-deoxy-2′,2′-difluorocytidine monohydrochloride) is a pyrimidine analog (Figure 1) with broad activity in solid tumors, including lung, pancreatic and breast cancers [8]. Gemcitabine is cell-phase specific, killing cells in the S phase and blocking the progression from G1 to S. Intracellularly, gemcitabine is transformed into two active metabolites: diphosphate (dFdCDP) and triphosphate (dFdCTP) nucleosides. Gemcitabine diphosphate inhibits ribonucleotide reductase, causing a reduction in the concentrations of deoxynucleotides, while gemcitabine triphosphate competes with dCTP for incorporation into DNA and stops further elongation of the DNA strand (Figure 2) [9,10].

Figure 1.

Gemcitabine.

Figure 2.

Metabolic pathways for self-potentiation of gemcitabine nucleotides.

Gemcitabine is administered intravenously with a volume of distribution that increases with the length of infusion. The half-life of gemcitabine for short infusions ranges from 42–94 min, and for long infusions varies from 245–638 min, depending on the patient's age and gender. Gemcitabine is mainly excreted through the kidneys and its clearance is lower in women and the elderly [11].

Combination of gemcitabine & platinum

In vitro studies showed a synergistic activity of gemcitabine plus cisplatin compared with either agent alone in platinum-sensitive and platinum-resistant cell lines [12,13]. Cisplatin acts by binding to DNA, forming mono-adducts and bifunctional platinum adducts. Gemcitabine increases the formation of platinum-adducts [14] and decreases the removal of interstrand and intrastrand cisplatin adducts [15]. This synergism seems to be due to the ability of gemcitabine to inhibit the repair of platinum-induced DNA lesions. For example, inhibiting the excision repair cross-complementation group 1 (ERCC1) gene in platinum-resistant colon cancer cells with ERCC1 overexpression diminished the synergistic cyotoxity of gemcitabine and cisplatin [16]. As a result, investigators explored the combination of carboplatin and gemcitabine for recurrent ovarian cancer.

Villella and colleagues reported a 55% response rate using gemcitabine plus carboplatin in patients with recurrent ovarian cancer. Even patients with initial platinum resistance experienced a 42% overall response rate [17].

Gemcitabine for recurrent ovarian cancer

Single-agent gemcitabine in recurrent ovarian cancer

Studies have shown that single-agent gemcitabine is active against recurrent ovarian cancer [18 –26] ( Table 1 ). Gemcitabine was given as a 30-min intravenous infusion with doses ranging between 800 and 1250 mg/m² on days 1, 8 and 15 of a 21-day cycle. The patients included were mostly heavily pretreated and suffering from platinum-resistant disease. Reported response rates ranged between 4 and 27%. Most responses were partial, with complete responses occasionally reported. The duration of the responses ranged between 4 and 10.6 months. Treatment was well tolerated overall, with neutropenia being the most common dose-limiting toxicity. When compared with other commonly used single-agent second-line therapies in platinum-resistant patients, gemcitabine seems to have a comparable response rate to topotecan (12–22%) [27,28] and liposomal doxorubicin (12–26%) [29,30]. In a recent study, 195 patients with recurrent platinum-resistant, taxane-pretreated disease were randomized to receive either gemcitabine or liposomal doxorubicin. The two regimens showed comparable efficacy in terms of PFS, disease control rate and response rate. However, the study, was underpowered to prove equivalency [31].

Table 1.

Single-agent gemcitabine for recurrent ovarian cancer.

Study	Number of patients	Overall response (%)	PFS (months)	Response duration (months)	OS (months)	Ref.
Lund (1995)	51	19	2.8	8.1	−	[18]
Shapiro (1996)	38	11	5	7	9	[19]
Friedlander (1998)	38	14	3	10.6	7	[20]
Silver (1999)	27	11	5	7	−	[21]
Von Minckwitz (1999)	40	22	3.6	9	8.5	[22]
D'Agostino (2003)	50	17	4.2	−	−	[23]
Markman (2003)	51	16	−	4	7	[24]
Bilgin (2003)	22	27	3	−	−	[25]
Penson (2005)	28	4	1.7	−	−	[26]

OS: Overall survival; PFS: Progression-free survival.

In the study by Penson and colleagues, which reported the lowest response rate, the patients received 700–800 mg/m² only on days 1 and 8 of a 21-day cycle, which is less than what patients received in the other trials, while 50% of them had liver metastatic disease [26].

Combination gemcitabine & platinum in platinum-sensitive recurrent epithelial ovarian cancer

A Phase I/II dose-escalating study was conducted by the Arbeitsgemeinschaft Gynäkologische Onkologie studiengruppe Ovarialkarzinom (AGO-OVAR) investigators using gemcitabine plus carboplatin in patients with platinum-sensitive recurrent ovarian cancer. The dose-limiting toxicity was myelosupression, mostly thrombocytopenia. The maximal tolerated dose of gemcitabine was 1000 mg/m² given on days 1 and 8 of a 3-week schedule combined with carboplatin area under the curve (AUC) 4 given on day 1 [32]. This study was followed by two Phase II trials that confirmed the efficacy and tolerability of this regimen ( Table 2 ) [33,34].

Table 2.

Gemcitabine plus carboplatin in patients with platinum-sensitive recurrent ovarian cancer.

Study	Type	Carboplatin (AUC on day 1)	Gemcitabine (mg/m² on days 1 and 8 of 21-day cycle)	Number of patients	Overall response (%)	PFI (months)	OS (months)	Ref.
Dubois (2001)	Phase I/II	4–5	800–1000	26	62.5	10	18	[32]
Papadimitriou (2004)	Phase II	5	1000	37	40.5	9	24.5	[34]
Kose (2004)	Phase II	4	1000	40	62.5	9.6	−	[33]

AUC: Area under the curve; OS: Overall survival; PFI: Progression-free interval.

A large, intergroup, randomized, controlled trial comparing gemcitabine plus carboplatin with carboplatin alone in patients with platinum-sensitive recurrent ovarian cancer has recently been completed ( Table 3 ) [35]. A total of 356 patients were randomly assigned to receive either carboplatin AUC 4 on day 1 and gemcitabine 1000 mg/m² on days 1 and 8 of a 21-day cycle, or carboplatin AUC 5 only every 21 days. The combination of carboplatin and gemcitabine had a significantly higher response rate and PFS. The hazard ratio (HR) for OS was 0.96 (95% confidence interval [CI]: 0.75–1.23; p = 0.7349). However, this study was not powered to detect survival benefit. The carboplatin plus gemcitabine group had more grade 3/4 hematological toxicities, mostly neutropenia, and significantly higher rates of blood and platelet transfusions and granulocyte growth factor administration. However, the rate of febrile neutropenia and the need for antibiotics was the same and quality-of-life questionnaires showed no difference between the two groups. This study led to FDA approval of carboplatin plus gemcitabine for platinum-sensitive recurrent ovarian cancer on July 14, 2006.

Table 3.

Summary of the randomized, controlled trial comparing carboplatin plus gemcitabine with carboplatin alone in patients with platinum-sensitive recurrent ovarian cancer.

Parameter	Carboplatin	Carboplatin plus gemcitabine
Number of patients	178	178
Dose	AUC 5 on day 1	C: AUC 4 on day 1G: 1000 mg/m² on days 1 and 8
Frequency	Every 21 days	Every 21 days
Median number of cycles	6	6
Response rate*	30.9%	47.2%
Median PFI (months)*	5.8	8.6
Median OS (months)	17.3	18
Anemia (Grade 3 + 4)*	8%	27.4%
Neutropenia (Grade 3 + 4)*	12%	70.3%
Thrombocytopenia (Grade 3 + 4)*	11.4%	34.9%

Reached statistical significance.

AUC: Area under the curve; C: Carboplatin; G: Germcitabine; OS: Overall survival; PFI: Progression-free interval.

Combination gemcitabine & platinum in platinum-resistant recurrent ovarian cancer

Given the rising evidence of the synergistic cytotoxicity of cisplatin plus gemcitabine in ovarian cancer cell lines, and the ability of gemcitabine to overcome platinum resistance by inhibiting DNA repair [12 –16], the combination of gemcitabine plus platinum was used in patients with platinum-resistant ovarian cancer ( Table 4 ). While earlier studies reported impressive response rates (43–64%) [36 –38], the recently published Gynecologic Oncology Group (GOG) 126L Phase II trial had a response rate of only 16% [39]. However, a total of 54% of the patients had a stable disease. This disparity in response rates may be related to the fact that patients in the GOG study had recurred shortly after their first platinum-based regimen. This concurs with the findings of our recent retrospective analysis of 114 patients with recurrent ovarian and primary peritoneal cancers. The treatment-free interval following primary therapy, the number of previous platinum-based courses, and the most recent platinum-free interval correlated with response to treatment with combination gemcitabine and platinum [40]. Another possible reason for the lower response rate in the Phase II trial is the use of 28-day cycles in the GOG study as opposed to 21-day cycles in the previous studies in order to decrease the reported high hematological toxicity of the treatment [36,37].

Table 4.

Gemcitabine plus cisplatin in patients with platinum-resistant recurrent ovarian cancer.

Study	Type	Cisplatin (mg/m²)	Gemcitabine (mg/m² on days 1 and 8 of 21 day cycle)	Number of patients	Overall response (%)	PFI (months)	OS (months)	Ref.
Rose (2003)	Retrospective	30	750	35	43	6	12	[36]
Nagourney (2003)	Phase II	30	600–750	14	57	6	20.2	[37]
Tewari (2004)	Retrospective	30	450–600	22	64	3.9	11.4	[38]
Brewer (2006)	Phase II	30	600–750*	57	16	5.4	14.9	[39]

mg/m² on days 1 and 8 of 28-day cycles.

OS: Overall survival; PFI: Progression-free interval.

In another study, a more intense regimen consisting of biweekly gemcitabine 1000 mg/m² and cisplatin 40 mg/m² on days 1 and 15, repeated every 4 weeks, was well tolerated and effective (response rate [RR] = 31.5%) in 35 evaluable patients with platinum-refractory ovarian cancer [41]. The authors found that patients with a progression-free interval less than 3 months after platinum-therapy had lower response rates to gemcitabine and cisplatin (15.8 vs 50%, p = 0.03) than patients with longer intervals. Recently, Lehoczky and colleagues published their experience using carboplatin plus gemcitabine in 22 heavily pretreated patients (median of four regimens) with recurrent platinum-resistant ovarian cancer. Carboplatin was given at a dose of AUC 4 on day 1, and gemcitabine was given at a dose of 1000 mg/m² on days 1 and 8 of a 3-week cycle. The authors reported a 39% overall response rate with only one complete response and a median progression-free interval of 3 months [42].

Combination gemcitabine & paclitaxel in recurrent ovarian cancer

In vitro studies showed that gemcitabine can significantly antagonize the cytotoxic effects of paclitaxel if administered simultaneously or before paclitaxel, but not if administered after paclitaxel [43]. This may be explained by the fact that gemcitabine blocks progression from G1 to S in the cell cycle, decreasing the number of cells reaching the G2 and M phases, where they will be susceptible to paclitaxel.

A Phase I dose-finding study by Iaffaioli showed the feasibility and safety of combination gemcitabine and paclitaxel in 14 patients with advanced recurrent ovarian cancer. The investigators used a fixed dose of gemcitabine of 1000 mg/m² on days 1 and 8 of a 21-week cycle, and an escalating dose of paclitaxel starting at 90 mg/m² on day 1 of the cycle. The maximum tolerated dose was 240 mg/m² of paclitaxel. All patients received granulocyte colony-stimulating factors [44].

In another Phase I study, the sequence and dose of the regimen were evaluated. The administration of gemcitabine before paclitaxel resulted in the elevation of liver enzymes, which prompted the investigators to abandon this sequence in favor of administering paclitaxel prior to gemcitabine [45]. Table 5 summarizes the studies evaluating gemcitabine plus paclitaxel in patients with recurrent ovarian cancer [44 –46].

Table 5.

Gemcitabine plus paclitaxel in patients with recurrent ovarian cancer.

Study	Type	Gemcitabine	Paclitaxel	Number of patients	Overall response (%)	Response duration (weeks)	PFI (months)	OS (months)	Ref.
Iaffaioli (2000)	Phase I	1000 mg/m² on days 1,8 of 21-day cycle	90 – 240 mg/m² on day 1	14	46	32	−	−	[44]
Poole (2006)	Phase I	1000 – 1250 mg/m² on days 1,8 of 21-day cycle	130 – 175 mg/m² on day 1 or 8	39	41	−	−	−	[45]
Garcia (2004)	Phase II	1000 mg/m² on days 1,8,15 of 28-day cycle	80 mg/m² on days 1,8,15 of 28-day cycle	35	40	−	5.7	13.1	[46]

OS: Overall survival; PFI: Progression-free interval.

Other combination chemotherapy regimens that contain gemcitabine for recurrent ovarian cancer

Preclinical in vivo studies in athymic mice bearing cisplatin-resistant human ovarian cancer xenografts showed that treatment with gemcitabine plus liposomal doxorubicin produced a significant enhancement of antitumor activity compared with monotherapy using the same doses [47]. In the last few years, several Phase I and Phase II studies confirmed the tolerability and efficacy of combination gemcitabine and liposomal doxorubicin for recurrent ovarian cancer ( Table 6 ). The majority of patients in these studies had platinum-resistant disease. Hematological toxicity and palmar–plantar erythrodysesthesia were the most commonly reported toxicities. Response rates ranged from 22–33% [48 –52].

Table 6.

Gemcitabine plus liposomal doxorubicin in patients with recurrent ovarian cancer.

Study	Type	Gemcitabine (mg/m² on days 1 and 8 of 21-day cycle)	Liposomal doxorubicin (mg/m² on day 1)	Number of patients	Overall response (%)	Response duration (months)	OS (months)	Ref.
D'Agostino (2002)	Phase I	600–1000	20–35	23	21.7	−	−	[48]
Goff (2003)	Phase I/II	700	20‡	40	24	5	12	[49]
Skarlos (2005)	Phase II	650*	25	37	22	2.7	8.4	[50]
Ferrandina (2005)	Phase II	1000	30	106	25.5	−	−	[51]
Petru (2006)	Phase II	650*	30	31	33	3.8	15.8	[52]

mg/m² on days 1,8 of 28-day cycle.

‡

mg/m² on days 1 and 8.

OS: Overall survival.

Trials using combination gemcitabine and topotecan for patients with recurrent ovarian cancer used different regimens and had variable results [53 –55]. The GOG Phase I trial by Chen and colleagues was closed early owing to the high rates of neutropenia, thrombocytopenia and stomatitis ( Table 7 ) [55].

Table 7.

Gemcitabine plus topotecan in patients with recurrent ovarian cancer.

Study	Type	Gemcitabine	Topotecan	Number of patients	Response	OS	Ref.
Greggi (2001)	Phase I/II	400–800 mg/m² on days 1 and 3 of a 21-day cycle	0.7–0.9 mg/m² on days 1–5	24	12.3%	−	[53]
Sehouli (2002)	Phase II	800 and 600 mg/m² on days 1 and 8, respectively	0.5–1 mg/m² on days 1–5	21	64%	21.1	[54]
Chen (2006)	Phase I	800 mg/m² on days 1, 8 and 15 of a 28-day cycle	0.5 mg/m² on days 2–5	10	−	−	[55]

OS: Overall survival.

Triplet therapy with gemcitabine, carboplatin and paclitaxel for patients with recurrent ovarian cancer showed very promising results in several studies, with overall response rates between 75 and 100% [56,57].

Gemcitabine as a first-line therapy for epithelial ovarian cancer

Single-agent gemcitabine was evaluated in previously untreated patients with Stage III/IV ovarian cancer. The response rate was limited to 18% [58]. A Phase I GOG trial showed that combining paclitaxel 135 mg/m², carboplatin AUC 5, and gemcitabine 800 mg/m² is feasible, with an acceptable toxicity profile [59]. Several Phase II studies evaluated different combination ( Table 8 ) [56,60 –69] and sequential (doublet) regimens ( Table 9 ) that included gemcitabine in previously untreated patients [61,63,70]. The reported response rates were encouraging, ranging from 57–91%. Toxicity was a limiting factor in some of these studies. For example, in the study by Micha and colleagues, 54% of patients had to discontinue gemcitabine due to severe myelotoxicity. In the sequential study by Steer and colleagues the treatment regimen was associated with unacceptable neurotoxicity (72%) that led the investigators to recommend against its use [71].

Table 8.

Gemcitabine in first-line regimens for epithelial ovarian cancer.

Study	Type	Regimen	Number of patients	Overall response (%)	PFS (months)	OS (months)	Ref.
Hansen (2002)	Phase II	Carboplatin Gemcitabine Paclitaxel	24	100	−	−	[56]
Nogue (2002)	Phase II	Cisplatin Gemcitabine	42	70.7	10.4	23.4	[60]
Belpomme (2003)	Phase II	Cisplatin Gemcitabine	42	57.1	13.4	24	[61]
Harries (2004)	Phase II	Carboplatin Gemcitabine Paclitaxel	53	77–84	19.5	−	[62]
Micha (2004)	Phase II	Carboplatin Gemcitabine Paclitaxel	57	90.4	15.5	40.8	[63]
du Bois (2005)	Phase II	Carboplatin Gemcitabine Paclitaxel	14	71.4	−	−	[64]
Gupta (2005)	Phase II	Cisplatin Gemcitabine Paclitaxel	46	64.4	12.3	26	[65]
Fuso (2006)	Phase II	Carboplatin Gemcitabine Paclitaxel	24	91	−	28	[66]
Hensley (2006)	Phase I/II	Carboplatin Gemcitabine Paclitaxel	27	81	27.3	43.6	[67]
Gallardo (2006)	Phase II	Cisplatin Gemcitabine	28	57.7	24.3	28.1	[68]
Tay (2006)	Phase II	Carboplatin Gemcitabine	20	83.3	11.6	29.2	[69]

OS: Overall survival; PFS: Progression-free survival.

Table 9.

Gemcitabine in sequential (doublet) regimens as first-line therapy for epithelial ovarian cancer.

Study	Type	Regimen (number of cycles)	Number of patients	Overall response (%)	PFS (months)	Ref.
Harries (2004)	Phase II	Carboplatin (4) thenGemcitabine + Paclitaxel (4)	53	77–84	19.5	[63]
Maenpaa (2006)	Phase II	Gemcitabine + Carboplatin (4) thenPaclitaxel + Carboplatin (4)	56	92	12.8	[70]
Steer (2006)	Phase II	Gemcitabine + Oxiloplatin (4) thenPaclitaxel + Carboplatin (4)	20	88	−	[61]

PFS: Progression-free survival.

These overall encouraging results led to the GOG 182/ICON5 study [72]. This is an international collaborative multicenter randomized, controlled trial that evaluated four new combination chemotherapy regimens as first-line therapy for patients with Stage III and IV ovarian cancer. Two of the five study arms contained gemcitabine. One was the combination of gemcitabine with carboplatin and paclitaxel. The second was a doublet regimen, where patients receive four courses of carboplatin and gemcitabine followed by four cycles of carboplatin and paclitaxel. The preliminary results of this trial showed that adding a third cytotoxic agent did not prolong progression-free or OS. Two other Phase III studies for previously untreated patients are currently in progress and have completed enrollment. The AGO-OVAR 9 study is comparing carboplatin plus paclitaxel with or without gemcitabine [73], and the Eli Lilly-sponsored S302 study is comparing carboplatin plus paclitaxel versus carboplatin plus gemcitabine, with or without consolidation therapy. Results of both studies are awaiting data maturation.

Conclusion

In order to achieve better response rates and disease progression survival, new agents and different combination therapy regimens are being evaluated in patients with epithelial ovarian cancer. Gemcitabine showed activity in primary and recurrent ovarian cancer, in both platinum-sensitive and -resistant disease. The toxicity of gemcitabine is well tolerated overall when given alone or in combination with other regimens, even in heavily pretreated patients. The commonly reported toxicities of gemcitabine include nausea and vomiting, abnormal liver enzymes, fever and edema, with myelosupression being the dose-limiting toxicity. The rare incidence of neurotoxicity allows gemcitabine to be used in combination with paclitaxel and in patients with paclitaxel-related neurotoxicity.

In patients with platinum-sensitive recurrent ovarian cancer, the International Collaborative Ovarian Neoplasm (ICON)4/AGO-OVAR trial showed that paclitaxel plus platinum-based chemotherapy results in a higher response rate and longer PFS and OS when compared with single-agent platinum (carboplatin or cisplatin). However, despite the fact that only 34% of the patients had received prior taxanes, the combination regimen was associated with high (20%) neurotoxicity, which may limit its use in patients with residual neurotoxicity from their primary therapy [74]. In another randomized, controlled trial, the combination of carboplatin and gemcitabine was superior to single agent carboplatin in terms of its response rate and PFS, with an equivalent quality of life [35]. This trial was not powered to detect differences in survival, which as an end point may be confounded by subsequent treatments.

Given the proven survival benefit for carboplatin plus paclitaxel, it is considered to be an acceptable choice in patients with recurrent platinum-sensitive ovarian cancer. However, carboplatin plus gemcitabine represents a very attractive alternative given the proven efficacy and the lower toxicity (less neurotoxicity and rare alopecia). It should be strongly considered for patients with significant residual neuropathy, those who do not tolerate paclitaxel and those who refuse paclitaxel therapy because of potential undesirable side effects like alopecia. Table 10 summarizes the results of the combination arm of each of the two trials.

Table 10.

Comparing the intervention arms of the two randomized, controlled trials evaluating combination regimens versus conventional single-agent platinum in patients with platinum-sensitive recurrent ovarian cancer.

Parameter	Parmar (2003)	Pfisterer (2006)
Intervention arm	Paclitaxel + platinum	Gemcitabine + carboplatin
Control arm	Conventional platinum-based therapy	Carboplatin
Number of patients in the intervention arm	392	178
Median age (years)	60	59
Neurotoxicity (grade 2–4)	20%	6.3%
Hematological toxicity	All types 29%	Anemia: 27.4%Neutropenia: 70.3%Thromobocytopenia: 34.9%
Alopecia (grade 2–4)	86%	14.3%
HR of progression free survival	0.76	0.72
HR for overall survival	0.82	0.96
Ref.	[74]	[35]

HR: Hazard ratio.

For patients with platinum-resistant ovarian cancer, combination regimens containing gemcitabine are well tolerated and seem to have higher response rates than single-agent therapies. However, these conclusions are based on retrospective and Phase II studies. Thus, randomized comparative trials are needed to determine the role of combination regimens containing gemcitabine in this group of patients.

The role of gemcitabine as a first-line therapy for ovarian cancer was evaluated in many Phase I and II studies using different combinations and doses. Despite the encouraging results of these studies, adding gemcitabine to first-line regimens offered no PFS or OS benefit in the GOG/ICON5 trial. Therefore, carboplatin plus paclitaxel remains the standard therapy for previously untreated patients with advanced ovarian cancer.

Future perspective

Chemotherapy strategies for recurrent ovarian cancer are gradually shifting towards using combination regimens as opposed to single-agent therapies. This is based on the improved response rates and PFS noted with several combination regimens in platinum-sensitive patients. In platinum-resistant patients, increasing numbers of Phase II trials evaluating combination regimens have been conducted or are on the way. However, combination chemotherapy may be associated with broader and more severe toxicities, which may limit its utility in some patients, such as elderly, heavily pretreated patients, or those with renal or liver dysfunction. Individualizing chemotherapy would allow clinicians to choose the regimens that are most likely to be effective for the individual patient's tumor, avoiding all the risks, toxicities and costs associated with the current treatment strategies that are based on treating the patient with the agents that have been shown in population-based studies to be the most effective. Genetic and epigenetic prognostic markers are being investigated. The development of markers predictive of response may allow a more educated guess when several options for planning chemotherapy are available. Agents that selectively target aberrant or overactive cell-signaling elements, apoptotic pathways, regulators of protein trafficking, and epigenetic DNA modifications are under investigation. Some of these agents may become an important adjunct to current treatment strategies of ovarian cancer.

Executive summary

Gemcitabine is a pyrimidine analog with proven activity against both platinum-sensitive and -resistant ovarian cancer.

Gemcitabine inhibits DNA repair, resulting in a synergistic activity when combined with platinum.

Combination gemcitabine and carboplatin is approved by the US FDA for treatment of platinum-sensitive recurrent ovarian cancer. The recommended dose is gemcitabine 1000 mg/m² on days 1 and 8 of a 21-day cycle, and carboplatin area under the curve 4 on day 1.

Both regimens (carboplatin plus paclitaxel and gemcitabine plus carboplatin) are acceptable choices for platinum-sensitive recurrent ovarian cancer. However, gemcitabine plus carboplatin is preferred in patients with residual neurotoxity or those who do not tolerate or refuse paclitaxel.

Adding gemcitabine to first-line regimens offered no progression-free or overall survival benefit in the GOG/ICON5 trial. The results of two more Phase III trials are still pending.

References

Papers of special note have been highlighted as either of interest (•) or of considerable interest (••) to readers.

du Bois

Luck

Meier

: A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J. Natl Cancer Inst. 95(17), 1320–1329 (2003).

Ozols

Bundy

Greer

: Phase III trial of carboplatin and paclitaxel compared with cisplatin and paclitaxel in patients with optimally resected stage III ovarian cancer: a Gynecologic Oncology Group study. J. Clin. Oncol. 21(17), 3194–3200 (2003).

Markman

Rothman

Hakes

: Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J. Clin. Oncol. 9(3), 389–393 (1991).

Gore

Fryatt

Wiltshaw

Dawson

: Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol. Oncol. 36(2), 207–211 (1990).

Ozols

Ostchega

Curt

Young

: High-dose carboplatin in refractory ovarian cancer patients. J. Clin. Oncol. 5(2), 197–201 (1987).

Canetta

Bragman

Smaldone

Rozencweig

: Carboplatin: current status and future prospects. Cancer Treat. Rev. 15(Suppl. B), 17–32 (1988).

Eisenhauer

Vermorken

van Glabbeke

: Predictors of response to subsequent chemotherapy in platinum pretreated ovarian cancer: a multivariate analysis of 704 patients. Ann. Oncol. 8(10), 963–968 (1997).

van Moorsel

Peters

Pinedo

: Gemcitabine: Future prospects of single-agent and combination studies. Oncologist 2(3), 127–134 (1997).

10.

Heinemann

Chubb

: Cellular elimination of 2″,2″-difluorodeoxycytidine 5″-triphosphate: a mechanism of self-potentiation. Cancer Res. 52(3), 533–539 (1992).

11.

Huang

Chubb

Hertel

Grindey

Plunkett

: Action of 2″,2″-difluorodeoxycytidine on DNA synthesis. Cancer Res. 51(22), 6110–6117 (1991).

12.

Gemzar® (for injection) prescribing information. Eli Lilly and Company, IN, USA (2006).

13.

van Moorsel

Pinedo

Veerman

: Mechanisms of synergism between cisplatin and gemcitabine in ovarian and non-small-cell lung cancer cell lines. Br. J. Cancer 80(7), 981–990 (1999).

14.

Peters

Bergman

van Haperen

Ruiz VW

Veerman

Kuiper

Braakhuis

: Interaction between cisplatin and gemcitabine in vitro and in vivo. Semin. Oncol. 22(4 Suppl. 11), 72–79 (1995).

15.

Peters

Van Moorsel

Lakerveld

: Effects of gemcitabine on cisplatinum-DNA adduct formation and repair in a panel of gemcitabine and cisplatinsensitive or -resistant human ovarian cancer cell lines. Int. J. Oncol. 28(1), 237–244 (2006).

16.

The mechanisms of the synergistic activity of gemcitabine plus cisplatin.

17.

Moufarij

Phillips

Cullinane

: Gemcitabine potentiates cisplatin cytotoxicity and inhibits repair of cisplatin-DNA damage in ovarian cancer cell lines. Mol. Pharmacol. 63(4), 862–869 (2003).

18.

Yang

Jiang

Shen

Plunkett

: Expression of ERCC1 antisense RNA abrogates gemicitabine-mediated cytotoxic synergism with cisplatin in human colon tumor cells defective in mismatch repair but proficient in nucleotide excision repair. Clin. Cancer Res. 6(3), 773–781 (2000).

19.

Villella

Marchetti

Odunsi

Rodabaugh

Driscoll

Lele

: Response of combination platinum and gemcitabine chemotherapy for recurrent epithelial ovarian carcinoma. Gynecol. Oncol. 95(3), 539–545 (2004).

20.

Lund

Hansen

Neijt

Theilade

Hansen

: Phase II study of gemcitabine in previously platinum-treated ovarian cancer patients. Anti-Cancer Drugs 6(Suppl 6), 61–62 (1995).

21.

Shapiro

Millward

Rischin

: Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel. Gynecol. Oncol. 63(1), 89–93 (1996).

22.

Friedlander

Millward

Bell

: A Phase II study of gemcitabine in platinum pre-treated patients with advanced epithelial ovarian cancer. Ann. Oncol. 9(12), 1343–1345 (1998).

23.

Silver

Piver

: Gemcitabine salvage chemotherapy for patients with gynecologic malignancies of the ovary, fallopian tube, and peritoneum. Am. J. Clin. Oncol. 22(5), 450–452 (1999).

24.

von Minckwitz

Bauknecht

Visseren-Grul

Neijt

: Phase II study of gemcitabine in ovarian cancer. Ann. Oncol. 10(7), 853–855 (1999).

25.

D'Agostino

Amant

Berteloot

Scambia

Vergote

: Phase II study of gemcitabine in recurrent platinum-and paclitaxel-resistant ovarian cancer. Gynecol. Oncol. 88(3), 266–269 (2003).

26.

Markman

Webster

Zanotti

Kulp

Peterson

Belinson

: Phase 2 trial of single-agent gemcitabine in platinum-paclitaxel refractory ovarian cancer. Gynecol. Oncol. 90(3), 593–596 (2003).

27.

Bilgin

Ozalp

Yalcin

Zorlu

Vardar

Ozerkan

: Efficacy of gemcitabine in heavily pretreated advanced ovarian cancer patients. Eur. J. Gynaecol. Oncol. 24(2), 169–170 (2003).

28.

Penson

Campos

Seiden

: A Phase II study of fixed dose rate gemcitabine in patients with relapsed mullerian tumors. Int. J. Gynecol. Cancer 15(6), 1035–1041 (2005).

29.

Bookman

Malmstrom

Bolis

: Topotecan for the treatment of advanced epithelial ovarian cancer: an open-label Phase II study in patients treated after prior chemotherapy that contained cisplatin or carboplatin and paclitaxel. J. Clin. Oncol. 16(10), 3345–3352 (1998).

30.

Hoskins

Eisenhauer

Beare

: Randomized Phase II study of two schedules of topotecan in previously treated patients with ovarian cancer: a National Cancer Institute of Canada Clinical Trials Group study. J. Clin. Oncol. 16(6), 2233–2237 (1998).

31.

Gordon

Fleagle

Guthrie

Parkin

Gore

Lacave

: Recurrent epithelial ovarian carcinoma: a randomized Phase III study of pegylated liposomal doxorubicin versus topotecan. J. Clin. Oncol. 19(14), 3312–3322 (2001).

32.

Muggia

Hainsworth

Jeffers

: Phase II study of liposomal doxorubicin in refractory ovarian cancer: antitumor activity and toxicity modification by liposomal encapsulation. J. Clin. Oncol. 15(3), 987–993 (1997).

33.

Mutch

Orlando

Teneriello

: Randomized Phase III trial of gemcitabine (Gem) versus pegylated liposomal doxorubicin (PLDox) for patients (pts) with platinum-resistant (Pt-R) taxane (tax)-pretreated ovarian cancer (OC) as 2nd or 3rd line chemotherapy. Gynecol. Oncol. 101(Suppl. 2), 14 (2006).

34.

Phase III trial showing no significant difference between pegylated liposomal doxorubicin and gemcitabine in platinum-resistant ovarian cancer.

35.

du Bois

Luck

Pfisterer

: Second-line carboplatin and gemcitabine in platinum sensitive ovarian cancer–a dose-finding study by the Arbeitsgemeinschaft Gynakologische Onkologie (AGO) Ovarian Cancer Study Group. Ann. Oncol. 12(8), 1115–1120 (2001).

36.

Kose

Sufliarsky

Beslija

: A Phase II study of gemcitabine plus carboplatin in platinum-sensitive, recurrent ovarian carcinoma. Gynecol. Oncol. 96(2), 374–380 (2005).

37.

Papadimitriou

Fountzilas

Aravantinos

: Second-line chemotherapy with gemcitabine and carboplatin in paclitaxel-pretreated, platinum-sensitive ovarian cancer patients. A Hellenic Cooperative Oncology Group Study. Gynecol. Oncol. 92(1), 152–159 (2004).

38.

Pfisterer

Plante

Vergote

: Gemcitabine plus carboplatin compared with carboplatin in patients with platinum-sensitive recurrent ovarian cancer: an intergroup trial of the AGO-OVAR, the NCIC CTG, and the EORTC GCG. J. Clin. Oncol. 24(29), 4699–4707 (2006).

39.

Phase III trial that showed better response and longer progression-free survival with combination carboplatin and gemcitabine in platinum-sensitive recurrent ovarian cancer.

40.

Rose

Mossbruger

Fusco

Smrekar

Eaton

Rodriguez

: Gemcitabine reverses cisplatin resistance: demonstration of activity in platinum- and multidrug-resistant ovarian and peritoneal carcinoma. Gynecol. Oncol. 88(1), 17–21 (2003).

41.

Nagourney

Brewer

Radecki

: Phase II trial of gemcitabine plus cisplatin repeating doublet therapy in previously treated, relapsed ovarian cancer patients. Gynecol. Oncol. 88(1), 35–39 (2003).

42.

Tewari

Monk

Hunter

Falkner

Burger

: Gemcitabine and cisplatin chemotherapy is an active combination in the treatment of platinum-resistant ovarian and peritoneal carcinoma. Invest. New Drugs 22(4), 475–480 (2004).

43.

Brewer

Blessing

Nagourney

Morgan

Hanjani

: Cisplatin plus gemcitabine in platinum-refractory ovarian or primary peritoneal cancer: a Phase II study of the Gynecologic Oncology Group. Gynecol. Oncol. 103(2), 446–450 (2006).

44.

Rose

: Differential response to gemcitabine and platinum combinations in patients with inherent and acquired platinum-resistant ovarian and peritoneal carcinoma Gynecol. Oncol. 104(3S), 42 (2007).

45.

Bozas

Bamias

Koutsoukou

: Biweekly gemcitabine and cisplatin in platinum-resistant/refractory, paclitaxel-pretreated, ovarian and peritoneal carcinoma. Gynecol. Oncol. 104(3), 580–585 (2007).

46.

Lehoczky

Pulay

: [Experience with gemcitabine-carboplatin chemotherapy in relapsed ovarian cancer]. Orv. Hetil. 147(30), 1405–1408 (2006).

47.

Sui

Xiong

Kraft

Fan

: Combination of gemcitabine antagonizes antitumor activity of paclitaxel through prevention of mitotic arrest and apoptosis. Cancer Biol. Ther. 5(8), 1015–1021 (2006).

48.

Iaffaioli

Tortoriello

Santangelo

: Phase I dose escalation study of gemcitabine and paclitaxel plus colony-stimulating factors in previously treated patients with advanced breast and ovarian cancer. Clin. Oncol. (R. Coll. Radiol.) 12(4), 251–255 (2000).

49.

Poole

Perren

Gawande

: Optimized sequence of drug administration and schedule leads to improved dose delivery for gemcitabine and paclitaxel in combination: a Phase I trial in patients with recurrent ovarian cancer. Int. J. Gynecol. Cancer 16(2), 507–514 (2006).

50.

Garcia

O'Meara

Bahador

: Phase II study of gemcitabine and weekly paclitaxel in recurrent platinum-resistant ovarian cancer. Gynecol. Oncol. 93(2), 493–498 (2004).

51.

Gallo

Fruscella

Ferlini

Apollonio

Mancuso

Scambia

: Preclinical in vivo activity of a combination gemcitabine/liposomal doxorubicin against cisplatin-resistant human ovarian cancer (A2780/CDDP). Int. J. Gynecol. Cancer 16(1), 222–230 (2006).

52.

D'Agostino

Ferrandina

Garganese

: Phase I study of gemcitabine and liposomal doxorubicin in relapsed ovarian cancer. Oncology 62(2), 110–114 (2002).

53.

Goff

Thompson

Greer

Jacobs

Storer

: Treatment of recurrent platinum resistant ovarian or peritoneal cancer with gemcitabine and doxorubicin: A Phase I/II trial of the Puget Sound Oncology Consortium (PSOC 1602). Am. J. Obstet. Gynecol. 188(6), 1556–1562 (2003).

54.

Skarlos

Kalofonos

Fountzilas

: Gemcitabine plus pegylated liposomal doxorubicin in patients with advanced epithelial ovarian cancer resistant/refractory to platinum and/or taxanes. A HeCOG Phase II study. Anticancer Res. 25(4), 3103–3108 (2005).

55.

Ferrandina

Paris

Ludovisi

: Gemcitabine and liposomal doxorubicin in the salvage treatment of ovarian cancer: updated results and long-term survival. Gynecol. Oncol. 98(2), 267–273 (2005).

56.

Petru

Angleitner-Boubenizek

Reinthaller

: Combined PEG liposomal doxorubicin and gemcitabine are active and have acceptable toxicity in patients with platinum-refractory and -resistant ovarian cancer after previous platinum-taxane therapy: a Phase II Austrian AGO study. Gynecol. Oncol. 102(2), 226–229 (2006).

57.

Greggi

Salerno

D'Agostino

: Topotecan and gemcitabine in platinum/paclitaxel-resistant ovarian cancer. Oncology 60(1), 19–23 (2001).

58.

Sehouli

Stengel

Oskay

: A Phase II study of topotecan plus gemcitabine in the treatment of patients with relapsed ovarian cancer after failure of first-line chemotherapy. Ann. Oncol. 13(11), 1749–1755 (2002).

59.

Chen

Fleming

Mitchell

Horowitz

: A Phase I trial of gemcitabine and topotecan in previously treated ovarian or peritoneal cancer: a Gynecologic Oncology Group study. Gynecol. Oncol. 100(1), 111–115 (2006).

60.

Hansen

: Gemcitabine, platinum, and paclitaxel regimens in patients with advanced ovarian carcinoma. Semin. Oncol. 29(1 Suppl. 1), 17–19 (2002).

61.

Liu

Hung

Hwang

: Triplet combination of gemcitabine, carboplatin, and paclitaxel in previously treated, relapsed ovarian and peritoneal carcinoma: an experience in Taiwan. Gynecol. Oncol. 94(2), 393–397 (2004).

62.

Underhill

Parnis

Highley

: Multicenter Phase II study of gemcitabine in previously untreated patients with advanced epithelial ovarian cancer. Anti-Cancer Drugs 12(8), 647–652 (2001).

63.

Look

Bookman

Schol

Herzog

Rocereto

Vinters

: Phase I feasibility trial of carboplatin, paclitaxel, and gemcitabine in patients with previously untreated epithelial ovarian or primary peritoneal cancer: a Gynecologic Oncology Group study. Gynecol. Oncol. 92(1), 93–100 (2004).

64.

Nogue

Cirera

Arcusa

: Phase II study of gemcitabine and cisplatin in chemonaive patients with advanced epithelial ovarian cancer. Anti-Cancer Drugs 13(8), 839–845 (2002).

65.

Belpomme

Krakowski

Beauduin

: Gemcitabine combined with cisplatin as first-line treatment in patients with epithelial ovarian cancer: a Phase II study. Gynecol. Oncol. 91(1), 32–38 (2003).

66.

Harries

Moss

Perren

: A Phase II feasibility study of carboplatin followed by sequential weekly paclitaxel and gemcitabine as first-line treatment for ovarian cancer. Br. J. Cancer 91(4), 627–632 (2004).

67.

Micha

J P

Goldstein

Rettenmaier

: Pilot study of outpatient paclitaxel, carboplatin and gemcitabine for advanced stage epithelial ovarian, peritoneal, and fallopian tube cancer. Gynecol. Oncol. 94(3), 719–724 (2004).

68.

du Bois

Belau

Wagner

: A Phase II study of paclitaxel, carboplatin, and gemcitabine in previously untreated patients with epithelial ovarian cancer FIGO stage IC-IV (AGO-OVAR protocol OVAR-8). Gynecol. Oncol. 96(2), 444–451 (2005).

69.

Gupta

John

Naik

: A multicenter Phase II study of gemcitabine, paclitaxel, and cisplatin in chemonaive advanced ovarian cancer. Gynecol. Oncol. 98(1), 134–140 (2005).

70.

Fuso

Amant

Neven

Berteloot

Vergote

: Gemcitabine–carboplatin–paclitaxel combination as first-line therapy in advanced ovarian carcinoma: a single institution Phase II study in 24 patients. Int. J. Gynecol. Cancer 16(Suppl. 1), 60–67 (2006).

71.

Hensley

Correa

Thaler

: Phase I/II study of weekly paclitaxel plus carboplatin and gemcitabine as first-line treatment of advanced-stage ovarian cancer: pathologic complete response and longitudinal assessment of impact on cognitive functioning. Gynecol. Oncol. 102(2), 270–277 (2006).

72.

Gallardo

Calderillo

Serrano

: A Phase II study of gemcitabine plus cisplatin in previously untreated advanced ovarian cancer. Anticancer Res. 26(4B), 3137–3141 (2006).

73.

Tay

Ilanchadran

Tan

: First-line gemcitabine and carboplatin in advanced ovarian carcinoma: a Phase II study. Br. J. Obstet. Gynaecol. 113(12), 1388–1392 (2006).

74.

Maenpaa

Grenman

Jalkanen

: Sequential gemcitabine-carboplatin followed by paclitaxel-carboplatin in the first-line treatment of advanced ovarian cancer: A Phase II study. Gynecol. Oncol. 101(1), 114–119 (2006).

75.

Steer

Chrystal

Cheong

: Gemcitabine and oxaliplatin followed by paclitaxel and carboplatin as first line therapy for patients with suboptimally debulked, advanced epithelial ovarian cancer. A Phase II trial of sequential doublets. The GO-First Study. Gynecol. Oncol. 103(2), 439–445 (2006).

76.

Bookman

: GOG0182-ICON5: 5-arm Phase III randomized trial of paclitaxel (P) and carboplatin (C) vs combinations with gemcitabine (G), PEG-lipososomal doxorubicin (D), or topotecan (T) in patients (pts) with advanced-stage epithelial ovarian (EOC) or primary peritoneal (PPC) carcinoma. J. Clin. Oncol. ASCO Annual Meeting Proceedings 24(18S) (2006) (Abstract 5002).

77.

Phase III trial showing no benefit from adding gemcitabine to carboplatin and paclitaxel in previously untreated patients.

78.

du Bois

Sehouli

Lund

: Paclitaxel-carboplatin-gemcitabine (TCG) as first-line treatment of ovarian cancer: a prospective multicenter Phase II study (AGO-OVAR 8) followed by a prospectively randomized Phase III GCIG Intergroup study (AGO-OVAR 9, GINECO-TCG, NSGO-OC-0102) comparing TCG with standard TC. Int. J. Gynecol. Cancer 15(S3), 224–225 (2005).

79.

Parmar

Ledermann

Colombo

: Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2.2 trial. Lancet 361(9375), 2099–2106 (2003).

Role of Gemcitabine in the Treatment of Ovarian Cancer

Abstract

Keywords

Gemcitabine

Introduction to gemcitabine

Combination of gemcitabine & platinum

Gemcitabine for recurrent ovarian cancer

Single-agent gemcitabine in recurrent ovarian cancer

Combination gemcitabine & platinum in platinum-sensitive recurrent epithelial ovarian cancer

Combination gemcitabine & platinum in platinum-resistant recurrent ovarian cancer

Combination gemcitabine & paclitaxel in recurrent ovarian cancer

Other combination chemotherapy regimens that contain gemcitabine for recurrent ovarian cancer

Gemcitabine as a first-line therapy for epithelial ovarian cancer

Conclusion

Future perspective

References