In the year 2001, an estimated 29,200 new cases of pancreatic cancer were expected to be diagnosed in the U.S.1 Over the past few decades, there has not been a significant change in the incidence of this disease. The 5-year survival remains at < 4–5%, making pancreatic cancer the fourth leading cause of cancer mortality in the U.S.2 To our knowledge, radical surgery currently is the only curative therapy for pancreatic cancer. However, only 5–25% of patients present with potentially resectable disease.2 Approximately 50% of all patients with pancreatic cancer present with locally advanced disease that is nonresectable because of the involvement of the celiac axis or superior mesenteric artery or vein. Approximately 50% of patients will present with overt metastatic pancreatic cancer. The median survival time after pancreatic resection is 13–20 months with < 10–20% of patients being long-term survivors.2, 3 One of the factors contributing to this high mortality is the presence of metastases at the time of diagnosis and the lack of effective systemic therapies for pancreatic cancer. Improvements in the survival outcome of pancreatic cancer therefore are very much dependent on the development of newer and more effective systemic agents.
Progress in the treatment of pancreatic cancer in the past several decades has been very modest. Several new agents with activity against this disease have been identified. Of these, gemcitabine appears to be the most promising when used in combination with other drugs. Gemcitabine and cisplatin combinations have been tested in several studies. The major toxicity reported to occur with the gemcitabine-cisplatin combination is myelosuppression, which is greater than that encountered with single-agent gemcitabine. However, episodes of neutropenic fever or spontaneous bleeding are reported to be very infrequent. Pilot Phase II studies combining gemcitabine with cisplatin have shown improved outcomes in objective response rates and survival; however, these findings must be confirmed in larger randomized studies. Cancer 2002;95:908–11. © 2002 American Cancer Society.
Rationale for Gemcitabine-Platinum Combinations
Gemcitabine is a useful drug in the treatment of metastatic pancreatic cancer. However, objective tumor response and survival in patients receiving gemcitabine were reported to be low.4–6 Objective responses were observed in 6–11% of patients. The overall survival in patients treated with gemcitabine was 4–6 months. Combination therapy with gemcitabine therefore has been studied to improve the outcome of patients with pancreatic cancer. Over the past few years, there has been an increase in the clinical use of gemcitabine plus cisplatin in the treatment of solid tumors, notably lung cancer.7–11 The choice of such a combination of drug therapy was based on theoretic considerations and the results of laboratory experiments.12, 13 There also was evidence of some activity of single-agent cisplatin in this disease. A Phase II study of single-agent cisplatin at a dose of 100 mg/m2 in 33 assessable patients with advanced pancreatic cancer was reported by Wils et al.14 The objective response rate was 21% with a median duration of response of 5 months.
Cisplatin acts by forming DNA-DNA cross-links (intrastrand and interstrand) and DNA-protein cross-links, whereas resistance to cisplatin is believed to be mediated by excision repair of the affected DNA. Gemcitabine incorporates into nucleic acids, leading to masked chain termination. By combining gemcitabine with cisplatin, a better therapeutic effect may be achieved, and resistance to one or both drugs might be bypassed. Preclinical in vitro and in vivo combination studies with cisplatin indicated schedule-dependent and model-dependent synergistic and additive effects of the two agents. The incorporation of gemcitabine into DNA might facilitate the formation of cisplatin-DNA adducts. The combination of gemcitabine and cisplatin has inhibited DNA excision-repair processes to a greater extent than gemcitabine alone, indicating that incorporation of the gemcitabine nucleotide into the DNA strand reduces the efficiency of proofreading exonucleases. Moreover, deoxyribonucleotide and ribonucleotide pools that both are important for DNA repair function are seriously depleted by gemcitabine. Thus, it is believed that the combination of gemcitabine with cisplatin can be at least additive, provided that the right schedule is chosen that gives the best balance between acceptable toxicity and enhanced antitumor activity.15
In addition, gemcitabine and cisplatin have nonoverlapping dose-limiting toxicities (DLTs) that facilitate their use in combination. Although hematologic toxicity is the major DLT associated with gemcitabine, gastrointestinal toxicity, neurotoxicity, and nephrotoxicity are reported to be the DLTs of cisplatin. There also is evidence that gemcitabine is noncross-resistant to cisplatin in patients with ovarian cancer.16 Therefore, these drugs have the desired features that are needed to obtain synergistic activity, including different side effect profiles and mechanisms of action.
Researchers have adopted several schedules for the combination of gemcitabine and cisplatin. Fractionation of the total dose of cisplatin per cycle has been undertaken to prolong the exposure of the tumor cells to cisplatin and to reduce the toxicity associated with higher single doses of this drug. Such an approach also facilitated the use of this regimen in the outpatient therapy setting.
Studies over the past few years have focused on gemcitabine-based combination chemotherapy, especially with platinum compounds for patients with advanced pancreatic cancer (Table 1). Three studies have addressed the combination of gemcitabine with cisplatin,17–19 given the potential for the biochemical modulation of DNA-platinum adduct repair by gemcitabine.20 In a Phase II study conducted at Wayne State University in Detroit, a total of 42 patients, 4 of whom had locally advanced unresectable disease and 38 of whom had metastatic disease, received a total of 211 cycles of therapy. The patients (median age, 61.5 years) were treated in the outpatient setting with a combination of gemcitabine, 1000 mg/m2 over 30 minutes, administered intravenously (i.v.) on Days 1, 8, and 15 of each cycle; and cisplatin, 50 mg/m2 administered i.v. after gemcitabine infusion on Days 1 and 15. The cycles were repeated every 28 days. The response rate (complete and partial responses) of the registered patients was 26% (95% confidence interval [95% CI], 0.14–0.42). The median overall survival time was 7.1 months (95% CI, 6.3–9.1 months), with 64% of patients alive at 6 months and 19% alive at 12 months; the median time to disease progression was 5.4 months (range, 0.9–20.8 months). The major toxicities in the patients in the study were neutropenia and thrombocytopenia, plus one episode of neutropenic fever.17
|Combinations||No. of patients||Response rate (%)||Median survival (mo)||Reference|
|Gemcitabine/cisplatin||41||11||8.2||Heinemann et al.18|
|42||26||7.1||Philip et al.17|
|52||31||NA||Colucci et al.19a|
|16||31||9.6||Brodowicz et al.21|
|Gemcitabine/oxaliplatin||64||29||NA||Louvet et al.24|
|Gemcitabine/cisplatin/epirubicin/5-FU||49||58||11||Reni et al.25|
In another Phase II study of a similar design in Germany, 41 patients with either locally advanced or metastatic pancreatic cancer were treated with gemcitabine and cisplatin.18 The gemcitabine dose was 1000 mg/m2 on Days 1, 8, and 15 and cisplatin was given at a dose of 50 mg/m2 on Days 1 and 15 of a 28-day cycle. The overall response rate in 35 evaluable patients was 11% (95% CI, 3.2–26.7%), and the median survival was 8.2 months (95% CI, 6.1–10.6 months). Another Phase II study from Austria demonstrated an objective response rate of 31% and a median survival of 9.6 months.21 The regimen was comprised of gemcitabine, 1000 mg/m2 and cisplatin, 35 mg/m2 on Days 1, 8, and 15. Cycles were repeated every 28 days. A randomized Phase II trial conducted in Italy compared gemcitabine at a dose of 1000 mg/m2 over a 30-minute infusion alone (Arm A) with gemcitabine given in combination with cisplatin (Arm B) in 103 chemotherapy-naive patients with advanced pancreatic cancer.19 In both treatment arms, weekly gemcitabine was administered for the first 7 weeks followed by 1 week of rest and then for 3 of 4 weeks. In Arm B, cisplatin at a dose of 25 mg/m2 was administered weekly for 3 of 4 weeks. The response rate was 10% in the gemcitabine arm compared with 31% in patients who received the combination. Hematologic toxicity was greater in the combined therapy arm.
Oxaliplatin, another platinum analog, has shown a sequence-dependent synergy with gemcitabine in leukemia and colon cancer cell lines.22 Phase I evaluation of the combination in patients with advanced stage solid tumors demonstrated myelosuppression to be the major toxicity with mild nonhematologic toxicities, mainly in the form of asthenia.23 A Phase II study of gemcitabine at a dose of 1000 mg/m2 by 10 mg/m2/minute i.v. infusion on Day 1 and oxaliplatin at a dose of 100 mg/m2 i.v. on Day 2 every 2 weeks in patients with locally advanced and metastatic pancreatic cancer was reported recently.24 The partial response rate was 26% and 31%, respectively, in locally advanced and metastatic disease. Survival at 6 months was 71%. Myelosuppression was the major toxicity with this treatment.
A Phase II study evaluated a combination of cisplatin, epirubicin, gemcitabine, and 5-FU (PEF-G) in 49 patients with TNM Stage IV pancreatic adenocarcinoma. The treatment regimen was 40 mg/m2 each of cisplatin and epirubicin given on Day 1, gemcitabine at a dose of 600 mg/m2 on Days 1 and 8 every 4 weeks, and 5-FU at a dose of 200 mg/m2/day as a protracted venous infusion. The objective response rate in 43 assessable patients was 58%, with a median survival of 11 months. The major observed toxicities were neutropenia in 51% of the cycles and thrombocytopenia in 28%.25
Preliminary results regarding gemcitabine-platinum combination chemotherapy suggest a modest superiority in treatment outcomes compared with single-agent gemcitabine. Nevertheless, toxicity generally is greater with combination therapy. Phase III studies therefore are needed to determine the benefits of combination chemotherapy over single-agent gemcitabine and provide guidance regarding the drug schedule that would provide the best therapeutic index. An ongoing four-arm Cancer and Leukemia Group B randomized Phase II trial (#89904) in patients with metastatic pancreatic cancer is investigating the effectiveness of gemcitabine given alone or in combination with cisplatin, docetaxel, or irinotecan. The major endpoints for this study are overall survival, time to disease progression, and toxicity. As a single agent, gemcitabine will be given at a fixed-rate infusion of 10 mg/m2/minute over 150 minutes on Days 1, 8, and 15. The gemcitabine-cisplatin combination arm will be comprised of gemcitabine administered as a 1000 mg/m2 weekly 30-minute i.v. infusion and cisplatin at a dose of 50 mg/m2 given every 2 weeks. A study comparing single-agent gemcitabine with the gemcitabine-cisplatin combination currently is underway in Germany. A similar study also is planned to test the combination of gemcitabine and oxaliplatin versus gemcitabine alone.
The role of the combination of gemcitabine and cisplatin in the treatment of locally advanced pancreatic cancer currently is being determined. A Phase I/II study of gemcitabine and cisplatin as induction therapy for patients with locally advanced pancreatic cancer currently is being evaluated by investigators at The New York University School of Medicine. Another Phase I study by the North Central Cancer Treatment Group is investigating the combination of gemcitabine and cisplatin administered concurrently with radiation in patients with locally advanced pancreatic cancer.
Conclusions and Future Directions
The combination of gemcitabine and cisplatin appears to have significantly greater activity than single-agent gemcitabine in Phase II studies, with tolerable toxicity. The antitumor activity of this combination needs to be confirmed in multiinstitutional or comparative trials. Ongoing studies will determine whether the gemcitabine-platinum combination is superior to single-agent gemcitabine. Additional work also is needed to improve the efficacy and tolerability of gemcitabine-platinum combinations. Fixed-rate infusion of gemcitabine and combinations with targeted therapies need to be investigated. Of particular interest are combinations with epidermal growth factor receptor antagonists, farnesyl transferase inhibitors, and cyclooxygenase-2 inhibitors. Finally, the role of the gemcitabine-platinum combination in the adjuvant and neoadjuvant setting will be worth investigating.