The incidence of pancreatic cancer in France increased by approximately 70% between 1980 and 2000. According to European registry data, only 4% of patients with pancreatic cancer survive for 5 years. Long-term survival is limited to patients with resectable tumors, who account for only 10% to 20% of patients. The vast majority of patients present with locally advanced or metastatic disease, creating a large population of patients in need of palliative chemotherapy. Single-agent gemcitabine(Drug information on gemcitabine) (Gemzar) is considered standard of care in chemotherapy for pancreatic cancer. The antimetabolite agent pemetrexed(Drug information on pemetrexed) (Alimta) shows activity in pancreatic cancer and would appear to be a suitable candidate for partnering with gemcitabine in this setting. Current Chemotherapy for Pancreatic Cancer Fluorouracil(Drug information on fluorouracil) (5-FU)-based regimens had long been the mainstay of chemotherapy for advanced pancreatic cancer. A phase III trial reported by Burris et al in 1997 showed significant benefits of gemcitabine vs 5-FU in this setting, with gemcitabine treatment improving 1-year survival (18% vs 2%). A recent meta-analysis of chemotherapy in pancreatic cancer has confirmed this superiority, with 5-FU- based chemotherapy shown to be superior to best supportive care in terms of median overall survival, and single- agent gemcitabine shown to be superior to 5-FU and other chemotherapeutic agents. A current issue in identifying optimal chemotherapy in this setting is whether gemcitabine-based combinations are superior to gemcitabine as a single agent. A number of phase II trials of gemcitabine in combination with other agents (eg, cisplatin, 5-FU, docetaxel [Taxotere], oxaliplatin(Drug information on oxaliplatin) [Eloxatin], and irinotecan(Drug information on irinotecan) [Camptosar]) have yielded response rates of 20% to 30% and have reported 1-year survival rates of up to 30%. However, to date, no phase III trial has shown superiority of combination treatment over single-agent gemcitabine in terms of overall survival. For example, increased progression-free survival was found in trials of gemcitabine/ cisplatin(Drug information on cisplatin) vs gemcitabine reported by Colucci et al (5 vs 2 months, P = .048) and Heinemann et al (4.6 vs 2.5 months, P = .016), with no difference in overall survival found in either study (7 vs 4.7 months and 7.6 vs 6.0 months, respectively). Berlin et al reported greater progression- free survival in a phase III trial (Eastern Cooperative Oncology Group [ECOG] EE2297) with gemcitabine plus 5-FU (3.4 vs 2.2 months, P = .022) with no difference in overall survival (6.7 vs 5.4 months); Rocha-Lima et al reported no difference in time to progression (3.5 vs 3.0 months) or overall survival (6.3 vs 6.6 months) with gemcitabine/irinotecan vs gemcitabine. A trial of gemcitabine/ oxaliplatin (GEMOX) vs gemcitabine reported by Louvet et al showed that GEMOX achieved significantly better results than gemcitabine in terms of response rate, clinical benefit, and progression-free survival, but the difference did not reach the significant level for overall survival. These phase III studies are summarized in Table 1. In addition, biological agents (marimastat, BAY 12-9566, tipifarnib [Zarnestra]) have been combined with gemcitabine in four phase III trials with no improvement in outcome compared with gemcitabine alone being observed. Rationale for Combination of Pemetrexed and Gemcitabine Pemetrexed is an antimetabolite that targets several enzymes in the pyrimidine and purine synthesis pathways, including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. It has shown clinical activity in multiple tumor types, including pancreas cancer, and in treatment-refractory/ resistant tumors. The dose-limiting toxicity of pemetrexed is myelosuppression, with other toxicities including fatigue, rash, mucositis, and diarrhea. Folic acid(Drug information on folic acid) and vitamin B12 supplementation is now routinely given in clinical trials to reduce the risk of severe toxicity. The drug has a convenient administration schedule consisting of a 10-minute intravenous (IV) infusion every 3 weeks. In a phase II trial, Miller et al administered pemetrexed at a dose of 600 mg/m2 every 3 weeks without vitamin supplementation as first-line treatment to 42 chemotherapy-naive patients with advanced pancreatic cancer.[ 10] The patients had a median age of 60 years, and 79% had stage IV disease. The objective response rate was 5.7%, with one patient having a complete response lasting for 16.2 months and one having a partial response lasting 6.9 months. The stable disease rate was 40%; five patients with stable disease were alive at the time of analysis, with survival durations of 6+ to 19+ months. Median survival was 6.5 months, and the 1-year survival rate was 28%. Treatment was well tolerated. Grade 3/4 hematologic toxicities included neutropenia in 17%/24% of patients, leukopenia in 31%/12%, thrombocytopenia in 10%/7%, and anemia in 14%/5%. Grade 3 aspartate aminotransferase and alanine aminotransferase elevations occurred in 15% and 7.5% of patients, respectively, grade 3 nausea occurred in 17%, and grade 3/4 vomiting occurred in 2%/5%. The demonstration of pemetrexed's activity in advanced pancreas cancer prompted exploration of the potential for combining pemetrexed and gemcitabine in this setting. In addition to the single-agent activity of both, the rationale for combination includes the fact that the two agents are antimetabolites that act via different mechanisms of action. The combination shows synergistic effects in vitro, with cytotoxic effects greatest when gemcitabine exposure occurs before pem- etrexed exposure (suggesting that gemcitabine inhibition of thymidylate synthase could enhance inhibition of this enzyme by pemetrexed). Both agents have favorable side-effect profiles when used as monotherapy, suggesting the potential for use of full doses of each in combination. Adjei et al reported from their phase I study in patients with solid tumors that the recommended dose of the combination was gemcitabine at 1,250 mg/m2 on days 1 and 8 and pemetrexed at 500 mg/m2 on day 8 every 21 days. The combination produced promising responses in the phase I trial, with 12 partial responses observed in 35 evaluable patients. The combination was subsequently evaluated in a phase II trial in pancreatic cancer. Phase II Trial of Gemcitabine/ Pemetrexed in Pancreatic Cancer In an open-label phase II trial of Kindler et al, patients with histologically or cytologically confirmed stage III or IV adenocarcinoma of the pancreas not amenable to curative resection were treated with gemcitabine at 1,250 mg/m2 by 30-minute infusion on days 1 and 8 plus pemetrexed at 500 mg/m2 by 10-minute infusion on day 8 at 90 minutes after gemcitabine every 21 days.[12,13] To be eligible for inclusion in the study, patients had to have no prior systemic chemotherapy; prior use of 5-FU as a radiosensitizer was allowed if treatment occurred > 4 weeks prior to enrollment, and prior radiation to < 25% of bone marrow was permitted if treatment was completed > 4 weeks prior to enrollment. All patients received dexamethasone(Drug information on dexamethasone) pretreatment to prevent skin rash. Routine vitamin B12 supplementation was initiated after the study had been under way for 2 months. The study utilized a two-stage sequential design. In the first part of the study, 21 patients were enrolled; if fewer than two patients had tumor response, the study was to be stopped. An additional 20 patients were to be enrolled in the second part of the trial; if fewer than five patients overall had a tumor response, the regimen was to be deemed unsuitable for additional investigation. A total of 42 patients (64% male) with a median age of 60 years (range: 34-79 years) were enrolled in the study. The majority of patients (95%) had stage IV disease, and most patients had Karnofsky performance scores of 80 (36%) or 90 (55%). In total, 12% of patients had prior adjuvant therapy (5-FU in all cases). A total of 212 treatment cycles were given in the study, with a range of 1 to 17; five patients received 10 or more cycles. Results are shown in Tables 2 and 3. The objective response rate was 15%, with six partial responses being observed. Median time to disease progression was 3.6 months. Median survival was 6.5 months (Figure 1), and the 1-year survival rate was 29%. Neutropenia was the primary hematologic toxicity, with grade 3/4 toxicity occurring in 22%/51% of patients. Severe nonhematologic toxicity was infrequent. Gemcitabine/Pemetrexed: Phase III Trial The promising findings in this study, particularly with regard to survival, prompted Richards et al to conduct a phase III trial (N = 585) examining the gemcitabine/pemetrexed combination. In this international trial encompassing 19 countries, patients with locally advanced or metastatic adenocarcinoma of the pancreas with bidimensionally measurable disease who have received no prior chemotherapy have been randomized to receive either (1) gemcitabine at 1,000 mg/m2 on days 1, 8, and 15 every 28 days or (2) gemcitabine at 1,250 mg/m2 on days 1 and 8 and pemetrexed at 500 mg/m2 on day 8 after gemcitabine administration every 21 days. Investigators stratified patients according to (1) ECOG performance status (0/1 vs 2), (2) stage II/III vs IV, (3) center, and (4) homocysteine. According to standard clinical practice, patients in the combination arm received folic acid and vitamin B12 supplementation, as well as dexamethasone (to prevent skin rash). The primary outcome measure was overall survival; secondary outcome measures consisted of progression- free survival, response rate, quality of life, and toxicity. Median overall, 1-year, and progression- free survival did not differ significantly between the gemcitabine/ pemetrexed and gemcitabine arms (6.2 vs 6.3 months, 21.4% vs 20.1%, and 3.9 vs 3.3 months, respectively). The intent-to-treat overall response was significantly increased in the gemcitabine/pemetrexed arm (14.8% vs 7.1%; P = .004), as was median time to progression (5.2 vs 3.6 months; P = .042). Overall quality of life (assessed with the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 [EORTC QLQ-C30]) was well preserved in both arms. Significantly greater grade 3/4 toxicity was seen in the gemcitabine/pemetrexed arm: neutropenia (45.1% vs 12.8%), thrombocytopenia (17.9% vs 6.2%), anemia (13.9% vs 2.9%), febrile neutropenia (9.9% vs 0.4%) (all P < .001), and fatigue (15% vs 6.6%; P < .05). Otherwise, both regimens were well tolerated by study patients. The authors concluded that gemcitabine monotherapy remained the standard for first-line therapy in patients with locally advanced or metastatic pancreatic cancer. Conclusion Pancreatic cancer remains a challenge for the oncologist. Since the approval of gemcitabine for treatment of pancreatic cancer, no phase III trial has shown an improvement in overall survival with gemcitabine-based combination therapy over gemcitabine single- agent therapy in this setting. While the combination of pemetrexed and gemcitabine demonstrated promising activity in a phase II trial in patients with advanced pancreatic cancer, a phase III trial comparing gemcitabine/ pemetrexed with gemcitabine alone did not report significant differences in survival. In this trial, the combination of pemetrexed/gemcitabine did improve overall response and time to progression. Further investigation may be required to determine whether the addition of novel agents to the current standard of gemcitabine might improve survival and quality of life in advanced pancreatic cancer.