American Journal of Cancer

, Volume 4, Issue 6, pp 395–416 | Cite as

Gemcitabine

A Review of its Use in the Management of Pancreatic Cancer
Adis Drug Evaluation

Summary

Abstract

Gemcitabine (Gemzar®), an intravenously administered deoxycitidine analog, is approved in the US and several European countries for the treatment of locally advanced (unresectable) or metastatic adenocarcinoma of the pancreas, including fluorouracil-refractory disease.

Although gemcitabine demonstrates only modest activity against pancreatic tumors (like most other cytotoxic agents), and rarely prolongs median survival beyond 7 months, it has a relatively mild toxicity profile, which is particularly important in the context of palliative treatment. Gemcitabine was superior to fluorouracil in alleviating tumor-related symptoms and extending survival in a randomized, multicenter trial; it was at least as effective as other single agents (e.g. exatecan and marimastat), but less effective than a four-drug combination (fluorouracil, leucovorin, epirubicin plus carboplatin [FLEC]) in prolonging survival in similar studies. There is the suggestion that survival outcomes with the drug may be enhanced using an extended, slow infusion rate, as opposed to a short, standard infusion rate. Adding another anticancer agent to gemcitabine, however, has to date yielded mostly disappointing results relative to gemcitabine alone in phase III trials. Of the doublet combinations tested, only gemcitabine plus capecitabine and gemcitabine plus erlotinib significantly increased survival (preliminary data), while only gemcitabine plus oxaliplatin significantly improved symptom alleviation, relative to gemcitabine alone; however, a four-drug regimen of cisplatin plus epirubicin, fluorouracil, and gemcitabine (PEFG) significantly improved both outcomes. Administering gemcitabine concurrently with radiotherapy is being evaluated in the setting of locally advanced, unresectable disease. Additionally, gemcitabine and/or gemcitabine-based chemoradiotherapy are being investigated as (neo)adjuvant treatments in patients with resectable disease; disease-free survival was improved relative to observation in the first randomized trial of adjuvant gemcitabine (preliminary data).

In conclusion, systemic gemcitabine monotherapy has been widely investigated in the treatment of patients with advanced, inoperable pancreatic cancer, and is well tolerated and moderately effective in these individuals. Research is ongoing into ways of maximising treatment outcomes with gemcitabine; these approaches include combining the drug with novel chemotherapeutic agents, integrating it into chemoradiotherapy regimens, using it in patients with resectable disease, and administering it by intra-arterial infusion. Pending confirmation of promising preliminary results with certain gemcitabine-based combination chemotherapies, gemcitabine monotherapy remains the widely accepted standard of care for advanced, nonresectable pancreatic cancer.

Pharmacologic Properties

Gemcitabine is a deoxycitidine analog prodrug that inhibits DNA synthesis through the self-potentiating actions of its active diphosphate and triphosphate derivatives, which are formed after the uptake and intracellular phosphorylation of the parent drug by nucleoside kinases.

Gemcitabine demonstrates linear pharmacokinetics over the dose range 53–1000 mg/m2; the recommended dosage is 1000 mg/m2once weekly, administered by a 30-minute intravenous infusion. The maximum concentration of gemcitabine triphosphate in peripheral blood mononuclear cells (PBMCs) was attained within 30 minutes of the end of the infusion and increased in proportion to the gemcitabine dose (up to 350 mg/m2). Gemcitabine triphosphate formation within PBMCs was saturable at higher gemcitabine doses, although this phenomenon can be overcome using an extended, slow infusion rate (i.e. 10 mg/m2/min). Gemcitabine systemic exposure was significantly reduced with intra-arterial as opposed to intravenous administration of the drug.

Plasma protein binding of gemcitabine is minimal, and the drug is not extensively distributed into tissues after short infusions (<70 minutes). Gemcitabine is rapidly deaminated intracellularly; up to 98% of the administered dose is excreted in the urine within 1 week. Unchanged parent drug (<10%) and the inactive 2′-deox-y-2′,2′-difluorouridine metabolite account for 99% of the excreted dose. The terminal elimination half-life of gemcitabine after short infusions ranges from 42–94 minutes depending on age and sex; however, dosage adjustments are not necessary on the basis of these characteristics.

Therapeutic Efficacy

In a pivotal, randomized, multicenter trial, the recommended dosage regimen of gemcitabine was superior to the previous standard of care fluorouracil (given as an intravenous bolus) in the first-line treatment of patients with advanced, inoperable pancreatic cancer. Gemcitabine was more effective than fluorouracil in alleviating three common debilitating, tumor-related signs and symptoms (pain, functional impairment, weight loss), and conferred a small survival advantage. Relative to other single agents (exatecan, marimastat, BAY 12-9566), gemcitabine had a similar or superior effect on overall survival in randomized, multicenter, phase III studies in patients with locally advanced (unresectable) or metastatic pancreatic cancer. Systemic gemcitabine was, however, inferior to combination chemotherapy with FLEC, administered intra-arterially, in this regard. As a second-line treatment, gemcitabine demonstrated useful palliative efficacy in patients with fluorouracil-refractory pancreatic cancer in a pivotal noncomparative, multicenter trial.

The strategy of adding other cytotoxic or targeted anticancer agents (e.g. fluorouracil [with or without folinic acid], pemetrexed, cisplatin, oxaliplatin, irinotecan, exatecan, marimastat, tipifarnib, G17DT, virulizin, or LY293111) to gemcitabine has largely produced disappointing results in terms of improving overall survival relative to gemcitabine monotherapy in randomized, multicenter, phase II or III studies in patients with locally advanced (unresectable) or metastatic pancreatic cancer (n = 92–688). However, preliminary reports indicate that, when used as the second drug in a gemcitabine-containing doublet, capecitabine (in the larger of two studies) and erlotinib confer a survival advantage over gemcitabine alone. Similarly, combination chemotherapy with PEFG significantly improved survival relative to gemcitabine monotherapy (and was superior for the primary endpoint of progression-free survival at 4 months).

Gemcitabine monotherapy did not prolong median survival beyond 7.3 months in pivotal and phase III clinical trials. However, survival may be enhanced using an extended, slow infusion of the drug as opposed to the standard (30-minute) infusion.

In the only prospective, randomized studies reported to date, gemcitabine-based chemoradiotherapy was superior to fluorouracil-based chemoradiotherapy, and gemcitabine plus doxifluridine-based chemoradiotherapy was similar to paclitaxel plus doxifluridine-based chemoradiotherapy, in the treatment of patients with locally advanced, unresectable pancreatic cancer.

According to preliminary results of a randomized, multicenter, phase III study, adjuvant chemotherapy with gemcitabine significantly increased the median duration of disease-free survival (relative to observation) in previously untreated patients with resected pancreatic cancer, regardless of whether the resection margin was positive or negative, or whether lymph nodes were involved.

Tolerability

Gemcitabine, either as monotherapy or in combination with other anticancer agents, was generally well tolerated when administered as a first-line treatment for locally advanced (unresectable) or metastatic pancreatic cancer. Fewer than 5% of patients receiving the recommended gemcitabine dosage regimen discontinued treatment because of adverse events (e.g. fever, pain, asthenia, nausea/vomiting) in a large-scale investigational new drug (compassionate use) treatment program (n = 3023).

Myelosuppression was the primary dose-limiting toxicity in clinical trials, with grade 3 or 4 neutropenia occurring in up to 41% of patients, and grade 3 or 4 leukopenia, thrombocytopenia and anemia each occurring in up to 16% of patients with advanced pancreatic cancer who typically received the recommended gemcitabine dosage regimen in phase III studies (n = 107–668). Myelosuppression was increased with an extended, slow infusion of gemcitabine relative to a standard 30-minute infusion of the drug in a randomized, multicenter, phase II trial, although the number of consequent dose reductions and omissions were similar for both protocols.

Compared with gemcitabine monotherapy, the incidence of some grade 3 or 4 adverse events (e.g. hematological toxicities) was significantly increased with four-drug regimens containing (PEFG) or not containing (FLEC) gemcitabine, and with pemetrexed, exatecan, or oxaliplatin as the second drug in a gemcitabine-containing doublet.

The incidence of neutropenia and thrombocytopenia in patients receiving gemcitabine plus capecitabine was numerically higher than that in patients receiving gemcitabine alone, and the incidence of diarrhea and rash in patients receiving gemcitabine plus erlotinib was numerically higher than that in patients receiving gemcitabine plus placebo, although statistical analyses were not provided.

Similar tolerability profiles for gemcitabine-based chemoradiotherapy versus fluorouracil-based chemoradiotherapy (the current standard of care) and gemcitabine plus doxifluridine-based chemoradiotherapy versus paclitaxel plus doxifluridine-based chemoradiotherapy were seen in small, randomized trials in patients with advanced pancreatic cancer.

Pharmacoeconomic Considerations

Economic models incorporating clinical outcome and resource use data from a randomized, single-blind study of gemcitabine versus fluorouracil suggest that first-line treatment of advanced pancreatic cancer with gemcitabine, as opposed to fluorouracil or best supportive care only, is cost effective in relation to other accepted healthcare interventions in the UK from a national healthcare payer’s perspective, and in Sweden from a societal perspective. These analyses took into account direct costs only; the impact of indirect or intangeable costs (e.g. quality of life) was not assessed.

Keywords

Pancreatic Cancer Gemcitabine Capecitabine Pemetrexed Advanced Pancreatic Cancer 

Notes

Acknowledgments

At the request of the journal, Eli Lilly and Company Limited provided a non-binding review of this article.

References

  1. 1.
    Shore S, Raraty MG, Ghaneh P, et al. Review article: chemotherapy for pancreatic cancer. Aliment Pharmacol Ther 2003Dec; 18(11–12): 1049–69PubMedCrossRefGoogle Scholar
  2. 2.
    American Cancer Society. Cancer facts and figures 2005. Atlanta: American Cancer Society [online]. Available from URL: http://www.cancer.org [Accessed 2005 Sep 21]
  3. 3.
    Burris III HA, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 1997Jun; 15: 2403–13PubMedGoogle Scholar
  4. 4.
    Kulke MH. Recent developments in the pharmacological treatment of advanced pancreatic cancer. Expert Opin Investig Drugs 2003Jun; 12(6): 983–92PubMedCrossRefGoogle Scholar
  5. 5.
    Ko AH. Cancer of the pancreas [online]. Available from URL: http://www.cancersupportivecare.com/pancreas.html [Accessed 2005 Nov 11]
  6. 6.
    Gunzburg WH, Lohr M, Salmons B. Novel treatments and therapies in development for pancreatic cancer. Expert Opin Investig Drugs 2002Jun; 11(6): 769–86PubMedCrossRefGoogle Scholar
  7. 7.
    Noble S, Goa KL. Gemcitabine: a review of its pharmacology and clinical potential in non-small cell lung cancer and pancreatic cancer. Drugs 1997Sep; 54: 447–72PubMedCrossRefGoogle Scholar
  8. 8.
    Plunkett W, Huang P, Xu YZ, et al. Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin Oncol 1995Aug; 22(4 Suppl. 11): 3–10PubMedGoogle Scholar
  9. 9.
    Eli Lilly and Company Limited. Gemzar 200mg powder for solution for infusion: summary of product characteristics [online]. Available from URL: http://emc.medicines.org.uk [Accessed 2005 Jul 1]
  10. 10.
    Shewach DS, Lawrence TS. Radiosensitization of human solid tumor lines with gemcitabine. Semin Oncol1996 1996; 23: 65–71PubMedGoogle Scholar
  11. 11.
    Plate JM, Plate AE, Short S, et al. Effect of gemcitabine on immune cells in subjects with adenocarcinoma of the pancreas. Cancer Immunol Immunother 2005Sep; 54(9): 915–25PubMedCrossRefGoogle Scholar
  12. 12.
    Nowak AK, Robinson BW, Lake RA. Synergy between chemotherapy and immunotherapy in the treatment of established murine solid tumors. Cancer Res 2003; 63: 4490PubMedGoogle Scholar
  13. 13.
    Abbruzzese JL, Grunewald R, Weeks EA, et al. A phase I, clinical, plasma and cellular pharmacology study of gemcitabine. J Clin Oncol 1991Mar; 9: 491–8PubMedGoogle Scholar
  14. 14.
    Eli Lilly and Company. Gemzar(r) (Gemcitabine HCL) for injection prescribing information [online]. Available from URL: http://pi.lilly.com/us/gemzar.pdf [Accessed 2005 Sep 19]
  15. 15.
    Grunewald R, Abbruzzese JL, Tarassoff P, et al. Saturation of 2′-2-difluorodeoxycitidine 5′-triphosphate accumulation by mononuclear cells during a phase I trial of gemcitabine. Cancer Chemother Pharmacol 1991Jan; 27: 258–62PubMedCrossRefGoogle Scholar
  16. 16.
    Hochster HS. Newer approaches to gemcitabine-based therapy of pancreatic cancer: fixed-dose-rate infusion and novel agents. Int J Radiat Oncol Biol Phys 2003; 56(4 Suppl): 24–30PubMedCrossRefGoogle Scholar
  17. 17.
    Tempero M, Plunkett W, Ruiz vanHaperen V, et al. Randomized phase II comparison of dose-intense gemcitabine: thirty-minute infusion and fixed dose rate infusion in patients with pancreatic adenocarcinoma. J Clin Oncol 2003Sep 15; 21(18): 3402–8PubMedCrossRefGoogle Scholar
  18. 18.
    Shamseddine AI, Khalifeh MJ, Mourad FH, et al. Comparative pharmacokinetics and metabolic pathway of gemcitabine during intravenous and intra-arterial delivery in unresectable pancreatic cancer patients. Clin Pharmacokinet 2005; 44(9): 957–67PubMedCrossRefGoogle Scholar
  19. 19.
    Venook A, Egorin MJ, Rosner GL, et al. Phase I and pharmacokinetic trial of gemcitabine in patients with hepatic or renal dysfunction: Cancer and Leukemia Group B 9565. J Clin Oncol 2000; 18: 2780–7PubMedGoogle Scholar
  20. 20.
    Correale P, Cerretani D, Marsili S, et al. Gemcitabine increases systemic 5-fluorouracil exposure in advanced cancer patients. Eur J Cancer 2003Jul; 39(11): 1547–51PubMedCrossRefGoogle Scholar
  21. 21.
    Bramhall SR, Rosemurgy A, Brown PD, et al. Marimastat as first-line therapy for patients with unresectable pancreatic cancer: a randomized trial. J Clin Oncol 2001; 19: 3447–55PubMedGoogle Scholar
  22. 22.
    Cantore M, Fiorentini G, Luppi G, et al. Gemcitabine versus FLEC regimen given intra-arterially to patients with unresectable pancreatic cancer: a prospective, randomized phase III trial of the Italian Society for Integrated Locoregional Therapy in Oncology. J Chemother 2004Dec; 16(6): 589–94PubMedGoogle Scholar
  23. 23.
    Cheverton P, Friess H, Andras C, et al. Phase III results of exatecan (DX-8951f) versus gemcitabine in chemotherapy-naive patients with advanced pancreatic cancer [abstract no. 4005]. J Clin Oncol 2004; 22(14 Suppl.): 4005. Plus oral presentation at the 40th Annual Meeting of the American Society of Clinical Oncology: Late Breakers: 6; 2004 Jun 5–8; New Orleans (LA)Google Scholar
  24. 24.
    Moore MJ, Hamm J, Dancey J, et al. Comparison of gemcitabine versus the matrix metalloproteinase inhibitor BAY 12-9566 in patients with advanced or meta-static adenocarcinoma of the pancreas: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 2003Sep 1; 21(17): 3296–302PubMedCrossRefGoogle Scholar
  25. 25.
    Berlin ID, Catalano P, Thomas JP, et al. Phase III study of gemcitabine in combination with fluorouracil versus gemcitabine alone in patients with advanced pancreatic carcinoma: Eastern Cooperative Oncology Group trial E2297. J Clin Oncol 2002Aug 1; 20: 3270–5PubMedCrossRefGoogle Scholar
  26. 26.
    Colucci G, Giuliani F, Gebbia V, et al. Gemcitabine alone or with cisplatin for the treatment of patients with locally advanced and/or metastatic pancreatic carcinoma: a prospective, randomized phase III study of the Gruppo Oncologico dell'Italia Meridionale. Cancer 2002Feb 15; 94: 902–10PubMedCrossRefGoogle Scholar
  27. 27.
    Unningham D, Chau I, Stocken D, et al. Phase III randomised comparison of gemcitabine (GEM) versus gemcitabine plus capecitabine (GEM-CAP) in patients with advanced pancreatic cancer [abstract no. PS11]. Eur J Cancer Supplements 2005Oct; 3(4): 4. Plus oral presentation at the 13th European Cancer Conference; 2005 Oct 30–Nov 3; ParisCrossRefGoogle Scholar
  28. 28.
    Heinemann V, Quietzsch D, Gieseler F, et al. A phase III trial comparing gemcitabine plus cisplatin vs. gemcitabine alone in advanced pancreactic carcinoma [abstract no. 1003]. Proc Am Soc Clin Oncol 2003; 22: 250. Plus oral presentation at the 39th Annual Meeting of the American Society of Clinical Oncology; 2003 May 31–Jun 3; Chicago (IL)Google Scholar
  29. 29.
    Herrmann R, Bodoky G, Ruhstaller T, et al. Gemcitabine (G) plus capecitabine (C) versus G alone in locally advanced or metastatic pancreatic cancer: a randomized phase III study of the Swiss Group for Clinical Cancer Research (SAKK) and the Central European Cooperative Oncology Group (CECOG) [abstract no. 4010]. J Clin Oncol 2005; 23Suppl. 16: 1092. Plus oral presentation at the 41st Annual Meeting of the American Society of Clinical Oncology; 2005 May 13–17; Orlando (FL)Google Scholar
  30. 30.
    Louvet C, Labianca R, Hammel P, et al. Gemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial. J Clin Oncol 2005May 20; 23(15): 3509–16PubMedCrossRefGoogle Scholar
  31. 31.
    Oettle H, Richards D, Ramanathan RK, et al. A phase III trial of pemetrexed plus gemcitabine versus gemcitabine in patients with unresectable or metastatic pancreatic cancer. Ann Oncol 2005; 16: 1639–45PubMedCrossRefGoogle Scholar
  32. 32.
    'Reilly EM, Abou-Alfa GK, Letourneau R, et al. A randomized phase III trial of DX-8951f (Exatecan mesylate; DX) and gemcitabine vs. gemcitabine alone in advanced pancreatic cancer [abstract no. 4006]. J Clin Oncol 2004Jul 15; 22Suppl. 14: 315. Plus oral presentation at the 40th Annual Meeting of the American Society of Clinical Oncology; 2004 Jun 5–8; New Orleans (LA)Google Scholar
  33. 33.
    Reni M, Cordio S, Milandri C, et al. Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol 2005Jun; 6(6): 369–76PubMedCrossRefGoogle Scholar
  34. 34.
    Riess M, Helm A, Niedergethmann I, et al. A randomised, prospective, multicentre, phase III trial of gemcitabine, 5-fluorouracil (5-FU), folinic acid vs. gemcitabine alone in patients with advanced pancreatic cancer [abstract no. 4009]. J Clin Oncol 2005Jun 1; 23(16 Pt 2): 1092. Plus oral presentation presented at the 40th Annual Meeting of the American Society of Clinical Oncology; 2004 Jun 5–8; New Orleans (LA)Google Scholar
  35. 35.
    Rocha Lima CM, Green MR, Rotche R, et al. Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 2004Sep 15; 22(18): 3776–83CrossRefGoogle Scholar
  36. 36.
    tathopoulos G, Aravantinos G, Syrigos K, et al. A randomized phase III study of irinotecan/gemcitabine combination versus gemcitabine in patients with advanced/metastatic pancreatic cancer [abstract no. 4106]. 41st Annual Meeting of the American Society of Clinical Oncology; 2005 May 13–17; Orlando (FL)Google Scholar
  37. 37.
    Lorus announces results of Virulizin(R) phase III clinical trial [online]. Available from URL: www.prnewswire.com [Accessed 2005 Nov 8]Google Scholar
  38. 38.
    Bramhall SR, Schulz J, Nemunaitis J, et al. A double-blind placebo-controlled, randomised study comparing gemcitabine and marimastat with gemcitabine and placebo as first line therapy in patients with advanced pancreatic cancer. Br J Cancer 2002Jul 15; 87(2): 161–7PubMedCrossRefGoogle Scholar
  39. 39.
    Moore MJ, Goldstein D, Hamm J, et al. Erlotinib improves survival when added to gemcitabine in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of Canada Clinical Trials Group [abstract no. 77 plus oral presentation]. 2005 Gastrointestinal Cancers Symposium; 2005 27–29 Jan; Miami (FL)Google Scholar
  40. 40.
    Shapiro J, Marshall J, Karasek P, et al. G17DT + gemcitabine [Gem] versus placebo + Gem in untreated subjects with locally advanced, recurrent or metastatic adenocarcinoma of the pancreas: results of a randomized, double-blind, multinational, multicenter study [abstract no. 4012]. J Clin Oncol 2005Jun 1; 23(16 Pt 2): 1098. Plus oral presentation at the 41st Annual meeting of the American Society of Clinical Oncology; 2005 May 13–17; Orlando (FL)CrossRefGoogle Scholar
  41. 41.
    VanCutsem E, van deVelde H, Karasek P, et al. Phase III trial of gemcitabine plus tipifarnib compared with gemcitabine plus placebo in advanced pancreatic cancer. J Clin Oncol 2004Apr 15; 22(8): 1430–8PubMedCrossRefGoogle Scholar
  42. 42.
    Kulke MH, Niedzwiecki D, Tempero MA, et al. A randomized phase II study of gemcitabine/cisplatin, gemcitabine fixed dose rate infusion, gemcitabine/ docetaxel, or gemcitabine/irinotecan in patients with metastatic pancreatic cancer (CALGB 89904) [abstract no. 4011]. J Clin Oncol 2004; 22(14S): 4011. Plus oral presentation at the 40th Annual Meeting of the American Society of Clinical Oncology; 2005 Jun 5–8; New Orleans (LA)Google Scholar
  43. 43.
    Feliu J, Mel R, Borrega P, et al. Phase II study of a fixed dose-rate infusion of gemcitabine associated with uracil/tegafur in advanced carcinoma of the pancreas. Ann Oncol 2002Nov; 13(11): 1756–62PubMedCrossRefGoogle Scholar
  44. 44.
    Feliu J, Lopez Alvarez MP, Jaraiz MA, et al. Phase II trial of gemcitabine and UFT modulated by leucovorin in patients with advanced pancreatic carcinoma. Cancer 2000Oct 15; 89: 1706–13PubMedCrossRefGoogle Scholar
  45. 45.
    Kim TW, Kang HJ, Ahn JH, et al. Phase II study of gemcitabine, UFT and leucovorin in patients with advanced pancreatic cancer. Acta Oncol 2002; 41(7-8): 689–94PubMedCrossRefGoogle Scholar
  46. 46.
    Lee J, Park JO, Kim WS, et al. Phase II study of gemcitabine combined with uracil-tegafur in metastatic pancreatic cancer. Oncology 2004; 66: 32–7PubMedCrossRefGoogle Scholar
  47. 47.
    Kralidis E, Aebi S, Friess H, et al. Activity of raltitrexed and gemcitabine in advanced pancreatic cancer. Ann Oncol 2003Apr; 14(4): 574–9PubMedCrossRefGoogle Scholar
  48. 48.
    VanLaethem JL, VanMaele P, Verslype C, et al. Raltitrexed plus gemcitabine (TOMGEM) in advanced pancreatic cancer: results of a Belgian multicentre phase II study. Oncology 2004; 67(5-6): 338–43PubMedCrossRefGoogle Scholar
  49. 49.
    Arends JJ, Sleeboom HP, Leys MBL, et al. A phase II study of raltitrexed and gemcitabine in patients with advanced pancreatic carcinoma. Br J Cancer 2005Feb 14; 92(3): 445–8PubMedGoogle Scholar
  50. 50.
    Xiros N, Papacostas P, Economopoulos T, et al. Carboplatin plus gemcitabine in patients with inoperable or metastatic pancreatic cancer: a phase II multicenter study by the Hellenic Cooperative Oncology Group. Ann Oncol 2005May; 16(5): 773–9PubMedCrossRefGoogle Scholar
  51. 51.
    Novarino A, Chiappino I, Bertelli GF, et al. Phase II study of cisplatin, gemcitabine and 5-fluorouracil in advanced pancreatic cancer. Ann Oncol 2004Mar; 15(3): 474–7PubMedCrossRefGoogle Scholar
  52. 52.
    El-Rayes BF, Zalupski MM, Shields AF, et al. Phase II study of gemcitabine, cisplatin, and infusional fluorouracil in advanced pancreatic cancer. J Clin Oncol 2003Aug 1; 21(15): 2920–5PubMedCrossRefGoogle Scholar
  53. 53.
    Ryan DP, Kulke MH, Fuchs CS, et al. A Phase II study of gemcitabine and docetaxel in patients with metastatic pancreatic carcinoma. Cancer 2002Jan 1; 94(1): 97–103PubMedCrossRefGoogle Scholar
  54. 54.
    Tomao S, Romiti A, Massidda B, et al. A phase II study of gemcitabine and tamoxifen in advanced pancreatic cancer. Anticancer Res 2002Jul 31; 22: 2361–4PubMedGoogle Scholar
  55. 55.
    Stathopoulos GP, Mavroudis D, Tsavaris N, et al. Treatment of pancreatic cancer with a combination of docetaxel, gemcitabine and granulocyte colony-stimulating factor: a phase II study of the Greek Cooperative Group for Pancreatic Cancer. Ann Oncol 2001Jan; 12: 101–3PubMedCrossRefGoogle Scholar
  56. 56.
    Schneider BP, Ganjoo KN, Scitz DE, et al. Phase II study of gemcitabine and docetaxel in combination for advanced pancreatic cancer: a Hoosier Oncology Group study [abstract no. 546]. 38th Annual Meeting of the American Society for Clinical Oncology; 2002 May 18–21; Orlando (FL)Google Scholar
  57. 57.
    Shepard RC, Levy DE, Berlin JD, et al. Phase II study of gemcitabine in combination with docetaxel in patients with advanced pancreatic carcinoma (E1298): a trial of the Eastern Cooperative Oncology Group. Oncology 2004; 66: 303–9PubMedCrossRefGoogle Scholar
  58. 58.
    Jacobs AD, Otero H, Picozzi Jr VJ, et al. Gemcitabine combined with docetaxel for the treatment of unresectable pancreatic carcinoma. Cancer Invest 2004; 22(4): 505–14PubMedCrossRefGoogle Scholar
  59. 59.
    Tuinmann G, Hegewisch-Becker S, Zschaber R, et al. Gemcitabine and mitomycin C in advanced pancreatic cancer: a single-institution experience. Anticancer Drugs 2004Jul; 15(6): 575–9PubMedCrossRefGoogle Scholar
  60. 60.
    Ianniello GP, Orditura M, Rossi A, et al. Gemcitabine plus epirubicin in advanced pancreatic cancer: a phase II multicenter trial. Oncol Rep 2001Sep-2001 31; 8: 1111–5PubMedGoogle Scholar
  61. 61.
    Scheithauer W, Kornek GV, Raderer M, et al. Phase II trial of gemcitabine, epirubicin and granulocyte colony-stimulating factor in patients with advanced pancreatic adenocarcinoma. Br J Cancer 1999Aug; 80: 1797–802PubMedCrossRefGoogle Scholar
  62. 62.
    Maples WJ, Stevenson J, Sumrall SV, et al. Advanced pancreatic cancer: a multiinstitutional trial with gemcitabine and thalidomide [abstract no. 4082]. J Clin Oncol 2004; 22(14 Suppl.): 4082. Plus oral presentation at the 40th Annual Meeting of the American Society of Clinical Oncology; 2004 Jun 5–8; New Orleans (LA)Google Scholar
  63. 63.
    Neri B, Cini G, Doni L, et al. Weekly gemcitabine plus Epirubicin as effective chemotherapy for advanced pancreatic cancer: a multicenter phase II study. Br J Cancer 2002Aug 27; 87(5): 497–501PubMedCrossRefGoogle Scholar
  64. 64.
    Xiong HQ, Rosenberg A, LoBuglio A, et al. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II trial. J Clin Oncol 2004Jul 1; 22(13): 2610–6PubMedCrossRefGoogle Scholar
  65. 65.
    Safran H, Iannitti D, Ramanathan R, et al. Herceptin and gemcitabine for metastatic pancreatic cancers that overexpress HER-2/neu. Cancer Invest 2004; 22(5): 706–12PubMedCrossRefGoogle Scholar
  66. 66.
    Kindler HL, Friberg G, StadlerWM, et al. Bevacizumab plus gemcitabine is an active combination in patients with advanced pancreatic cancer: interim results of an ongoing phase II trial from the University of Chicago Phase II Consortium [abstract no. 86]. 2004 Gastrointestinal Cancers Symposium: Current Status and Future Directions for Prevention and Management; 2004 Jan 22–24; San Francisco (CA)Google Scholar
  67. 67.
    Alberts SR, Schroeder M, Erlichman C, et al. Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II trial. J Clin Oncol 2004Dec 15; 22(24): 4944–50PubMedCrossRefGoogle Scholar
  68. 68.
    Alberts SR, Foster NR, Morton RF, et al. PS-341 and gemcitabine in patients with metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group (NCCTG) randomized phase II study. Ann Oncol 2005; 16: 1654–61PubMedCrossRefGoogle Scholar
  69. 69.
    Corrie P, Mayer A, Shaw J, et al. Phase II study to evaluate combining gemcitabine with flutamide in advanced pancreatic cancer patients. Br J Cancer 2002Sep 23; 87(7): 716–9PubMedCrossRefGoogle Scholar
  70. 70.
    Xiong HQ, Hess KR, Kayaleh OR, et al. A phase II trial of gemcitabine and celecoxib for metastatic pancreatic cancer [abstract no. 4174]. 41st Annual Meeting of the American Society of Clinical Oncology; 2005 May 13–17; Orlando (FL)Google Scholar
  71. 71.
    Richards DA, Oettle H, Vervenne WL, et al. Randomized, double-blind phase II trial comparing gemcitabine (GEM) plus LY293111 vs GEM plus placebo in advanced adenocarcinoma of the pancreas [abstract no. 4092]. J Clin Oncol 2005Jun 1; 23(16 Pt 1): 330Google Scholar
  72. 72.
    Rothenberg ML, Moore MJ, Cripps MC, et al. A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 1996Apr; 7(4): 347–53PubMedCrossRefGoogle Scholar
  73. 73.
    A study to test the effectiveness of virulizin(R) given in combination with standard chemotherapy for pancreatic cancer [online]. Available from URL: http://clinicaltrials.gov [Accessed 2005 Nov 25]
  74. 74.
    Magnino A, Gatti M, Massucco P, et al. Phase II trial of primary radiation therapy and concurrent chemotherapy for patients with locally advanced pancreatic cancer. Oncology 2005Jul 13; 68(4-6): 493–9PubMedCrossRefGoogle Scholar
  75. 75.
    Okusaka T, Ito Y, Ueno H, et al. Phase II study of radiotherapy combined with gemcitabine for locally advanced pancreatic cancer. Br J Cancer 2004Aug 16; 91(4): 673–7PubMedGoogle Scholar
  76. 76.
    deLange SM, vanGroeningen CJ, Meijer OWM, et al. Gemcitabine-radiotherapy in patients with locally advanced pancreatic cancer. Eur J Cancer 2002Jun; 38: 1212–7PubMedCrossRefGoogle Scholar
  77. 77.
    Blackstock AW, Bernard SA, Richards F, et al. Phase I trial of twice-weekly gemcitabine and concurrent radiation in patients with advanced pancreatic cancer. J Clin Oncol 1999Jul; 17: 2208–12PubMedGoogle Scholar
  78. 78.
    Lee HR, Park JO, Lim DH, et al. Concurrent chemoradiation therapy with 24-hour infusional gemcitabine in locally advanced pancreatic cancer: a phase II study [abstract no. 750]. Eur J Cancer Supplements 2005Oct; 3(2): 214Google Scholar
  79. 79.
    Blackstock WA, Tepper JE, Niedwiecki D, et al. Cancer and Leukemia Group B (CALGB) 89805: phase II chemoradiation trial using gemcitabine in patients with locoregional adenocarcinoma of the pancreas. Int J Gastrointest Cancer 2003; 34(2-3): 107–16PubMedCrossRefGoogle Scholar
  80. 80.
    VanLaethem JL, Haustermans K, Hammel P, et al. Adjuvant therapy for pancreatic cancer: current status and future directions. Oncologia 2004; 27(4): 198–204Google Scholar
  81. 81.
    Berlin JD, Rothenberg ML. Chemotherapeutic advances in pancreatic cancer. Curr Oncol Rep 2003; 5: 219–26PubMedCrossRefGoogle Scholar
  82. 82.
    Li CP, Chao Y, Chi KH, et al. Concurrent chemoradiotherapy treatment of locally advanced pancreatic cancer: gemcitabine versus 5-fluorouracil, a randomized controlled study. Int J Radiat Oncol Biol Phys 2003Sep 1; 57(1): 98–104PubMedCrossRefGoogle Scholar
  83. 83.
    Leong T, Michael M, Ganju V, et al. Phase I trial of capecitabine and gemcitabine with concurrent radical radiotherapy in locally advanced pancreatic cancer: interim results [abstract no. 779]. Eur J Cancer Supplements 2005Oct; 3(2): 222Google Scholar
  84. 84.
    Martenson JA, Vigliotti APG, Pitot HC, et al. A phase I study of radiation therapy and twice-weekly gemcitabine and cisplatin in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2003Apr 1; 55: 1305–10PubMedCrossRefGoogle Scholar
  85. 85.
    Muler JH, McGinn CJ, Normolle D, et al. Phase I trial using a time-to-event continual reassessment strategy for dose escalation of cisplatin combined with gemcitabine and radiation therapy in pancreatic cancer. J Clin Oncol 2004Jan 15; 22(2): 238–43PubMedCrossRefGoogle Scholar
  86. 86.
    Wilkowski R, Thoma M, Schauer R, et al. Effect of chemoradiotherapy with gemcitabine and cisplatin on locoregional control in patients with primary inoperable pancreatic cancer. World J Surg 2004Oct; 28(10): 1011–8PubMedCrossRefGoogle Scholar
  87. 87.
    Micke O, Hesselmann S, Bruns F, et al. Results and follow-up of locally advanced cancer of the exocrine pancreas treated with radiochemotherapy. Anticancer Res 2005May-2005 30; 25(3A): 1523–30PubMedGoogle Scholar
  88. 88.
    Brunner TB, Grabenbauer GG, Klein P, et al. Phase I trial of strictly time-scheduled gemcitabine and cisplatin with concurrent radiotherapy in patients with locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2003Jan 1; 55: 144–53PubMedCrossRefGoogle Scholar
  89. 89.
    Epelbaum R, Gez E, Kuten A, et al. Irinotecan and gemcitabine (IrinoGem) combined with 3D conformai radiation therapy for locally advanced pancreatic cancer [abstract no. 775]. Eur J Cancer Supplements 2005Oct; 3(2): 221Google Scholar
  90. 90.
    Kornek GV, Potter R, Selzer E, et al. Combined radiochemotherapy of locally advanced unresectable pancreatic adenocarcinoma with mitomycin C plus 24-hour continuous infusional gemcitabine. Int J Radiat Oncol Biol Phys 2001Mar 1; 49: 665–71PubMedCrossRefGoogle Scholar
  91. 91.
    Safran H, Dipetrillo T, Iannitti D, et al. Gemcitabine, paclitaxel, and radiation for locally advanced pancreatic cancer: a phase I trial. Int J Radiat Oncol Biol Phys 2002Sep 1; 54: 137–41PubMedCrossRefGoogle Scholar
  92. 92.
    Chung HW, Bang SM, Park SW, et al. A prospective randomized study of gemcitabine with doxifluridine versus paclitaxel with doxifluridine in concurrent chemoradiotherapy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2004Dec 1; 60(5): 1494–501PubMedCrossRefGoogle Scholar
  93. 93.
    Neuhaus P, Oettle H, Post K, et al. A randomized, prospective, multicenter, phase III trial of adjuvant chemotherapy with gemcitabine vs. observation in patients with resected pancreatic cancer [abstract no. LBA4013]. J Clin Oncol 2005Jun 1; 23(16 Pt 2): 1092. Plus oral presentation presented at the 41st Annual meeting of the American Society of Clinical Oncology; 2005 May 13–17; Orlando (FL)Google Scholar
  94. 94.
    VanLaethem JL, Demols A, Gay F, et al. Postoperative adjuvant gemcitabine and concurrent radiation after curative resection of pancreatic head carcinoma: a phase II study. Int J Radiat Oncol Biol Phys 2003Jul 15; 56(4): 974–80PubMedCrossRefGoogle Scholar
  95. 95.
    Demols A, Peeters M, Polus M, et al. Adjuvant gemcitabine and concurrent continuous radiation (45 Gy) for resected pancreatic head carcinoma: a multicenter Belgian phase II study. Int J Radiat Oncol Biol Phys 2005Aug 1; 62(5): 1351–6PubMedCrossRefGoogle Scholar
  96. 96.
    Ozkok S, Dubova S, Yuzer Y, et al. Postoperative adjuvant gemcitabine alone and concurrent with radiation after resection of locally advanced pancreatic carcinoma [abstract no. 729]. Eur J Cancer Supplements 2005Oct; 3(2): 207. Plus oral presentation at the 13th European Cancer Conference; 2005 Oct 30–Nov 3; ParisGoogle Scholar
  97. 97.
    Allen AM, Zalupski MM, Robertson JM, et al. Adjuvant therapy in pancreatic cancer: phase I trial of radiation dose escalation with concurrent full-dose gemcitabine. Int J Radiat Oncol Biol Phys 2004Aug 1; 59(No. 5): 1461–7PubMedCrossRefGoogle Scholar
  98. 98.
    Wilkowski R, Thoma M, Duhmke E, et al. Concurrent chemoradiotherapy with gemcitabine and cisplatin after incomplete (R1) resection of locally advanced pancreatic carcinoma. Int J Radiat Oncol Biol Phys 2004Mar 1; 58(3): 768–72PubMedCrossRefGoogle Scholar
  99. 99.
    Joensuu TK, Kiviluoto T, Karkkainen P, et al. Phase I–II trial of twice-weekly gemcitabine and concomitant irradiation in patients undergoing pancreat-icoduodenectomy with extended lymphadenectomy for locally advanced pancreatic cancer. Int J Radiat Oncol Biol Phys 2004Oct 1; 60(2): 444–52PubMedCrossRefGoogle Scholar
  100. 100.
    Storniolo AM, Enas NH, Brown CA, et al. An investigational new drug treatment program for patients with gemcitabine: results for over 3000 patients with pancreatic carcinoma. Cancer 1999Mar 15; 85: 1261–8PubMedCrossRefGoogle Scholar
  101. 101.
    Mustacchi G, Beorchia A, MilaniS, et al. Gemcitabine and concomitant radiation for locally advanced or relapsed pancreatic cancer [abstract no. A2288]. 37th Annual Meeting of the American Society of Clinical Oncology; 2001 May 12–15; San Francisco (CA), 134Google Scholar
  102. 102.
    Ikeda M, Okada S, Tokuuye K, et al. A phase I trial of weekly gemcitabine and concurrent radiotherapy in patients with locally advanced pancreatic cancer. Br J Cancer 2002May 20; 86(10): 1551–4PubMedCrossRefGoogle Scholar
  103. 103.
    Poggi MM, Kroog GS, Russo A, et al. Phase I study of weekly gemcitabine as a radiation sensitizer for unresectable pancreatic cancer. Int J Radiat Oncol Biol Phys 2002Nov 1; 54: 670–6PubMedCrossRefGoogle Scholar
  104. 104.
    Hoffman JP, McGinn CJ, RossE, et al. A phase I trial of preoperative gemcitabine and radiotherapy followed by postoperative gemcitabine for patients with localized, resectable pancreatic adenocarcinoma. 16th Chemotherapy Foundation Symposium; 1998 Nov 11; New York (NY)Google Scholar
  105. 105.
    Pipas JM, Mitchell SE, Barth RJ, et al. Phase I study of twice-weekly gemcitabine and concomitant external-beam radiotherapy in patients with adenocarcinoma of the pancreas. Int J Radiat Oncol Biol Phys 2001Aug 1; 50: 1317–22PubMedCrossRefGoogle Scholar
  106. 106.
    Blackstock AW, Tepper J, Kachnic L, et al. Adjuvant gemcitabine and concurrent radiation for resected pancreatic cancer: a phase II study. Proc Am Soc Clin Oncol 2003; 22: 266Google Scholar
  107. 107.
    McGinn CJ, Zalupski MM, Shureiqi I, et al. Phase I trial of radiation dose escalation with concurrent weekly full-dose gemcitabine in patients with advanced pancreatic cancer. J Clin Oncol 2001Nov 15; 19: 4202–8PubMedGoogle Scholar
  108. 108.
    Aristides M, Lees M, Botwood N, et al. Economic evaluation of gemcitabine in the treatment of pancreatic cancer in the UK. Eur J Health Econ 2003Sep; 4(3): 216–21PubMedCrossRefGoogle Scholar
  109. 109.
    Ward S, Morris E, Bansback N, et al. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of gemcitabine for the treatment of pancreatic cancer. Health Technol Assess 2001; 5(24): 1–70PubMedGoogle Scholar
  110. 110.
    Ragnarson-Tennvall G, Wilking N. Treatment of locally advanced pancreatic carcinoma in Sweden: a health economic comparison of palliative treatment with best supportive care versus palliative treatment with gemcitabine in combination with best supportive care. Pharmacoeconomics 1999Apr; 15: 377–84PubMedCrossRefGoogle Scholar
  111. 111.
    Trippoli S, Messori A. Cost-effectiveness of gemcitabine as first-line therapy for patients with advanced pancreatic cancer. Value Health 1999Jan 28; 2: 22CrossRefGoogle Scholar
  112. 112.
    Kozuch P, Petryk M, Bruckner HW. A comprehensive update on the use of chemotherapy for metastatic pancreatic adenocarcinoma. Hematol Oncol Clin North Am 2002Feb; 16: 123–38PubMedCrossRefGoogle Scholar
  113. 113.
    Ishii H, Furuse J, Nagase M, et al. Impact of gemcitabine on the treatment of metastatic pancreatic cancer. J Gastroenterol Hepatol 2005Jan; 20(1): 62–6PubMedCrossRefGoogle Scholar
  114. 114.
    Ishii H, Furuse J, Kinoshita T, et al. Treatment cost of pancreatic cancer in Japan: analysis of the difference after the introduction of gemcitabine. Jpn J Clin Oncol 2005Sep; 35(9): 526–30PubMedCrossRefGoogle Scholar
  115. 115.
    McGinn CJ, Lawrence TS, Zalupski MM. On the development of gemcitabine-based chemoradiotherapy regimens in pancreatic cancer. Cancer 2002Aug 15; 95Suppl. 4: 933–40PubMedCrossRefGoogle Scholar
  116. 116.
    Neoptolemos JP, Cunningham D, Friess H, et al. Adjuvant therapy in pancreatic cancer: historical and current perspectives. Ann Oncol 2003May; 14(5): 675–92PubMedCrossRefGoogle Scholar
  117. 117.
    Jacobs AD, Burris HA, Rivkin S, et al. A randomized phase III study of rubitecan (ORA) vs. best choice (BC) in 409 patients with refractory pancreatic cancer report from a North-American multi-center study [abstract no. 4013]. J Clin Oncol 2004Jul 15; 22(14 Suppl.): 4013. Plus oral presentation at the 40th Annual Meeting of the American Society of Clinical Oncology; 2004 Jun 5–8; New Orleans (LA)Google Scholar
  118. 118.
    National Cancer Institute. U.S. National Institutes of Health [online]. Available from URL: http://www.cancer.gov [Accessed 2005 Oct 18]
  119. 119.
    Nio Y, Hashimoto K, Yano S, et al. Phase II study on low dose gemcitabine plus oral chemotherapy with uracil-tegafur and cyclophosphamide in combination with radiotherapy against recurrent and advanced pancreatic cancer. Oncol Rep 2005Aug; 14(2): 401–8PubMedGoogle Scholar
  120. 120.
    Banu E, Oudard S, Banu A, et al. Cumulative meta-analysis of randomized trials comparing gemcitabine-based chemotherapy versus gemcitabine alone in patients with advanced or metastatic pancreatic cancer [abstract no. 4101]. J Clin Oncol 2005Jun 1; 23(16 Pt 2): 4101. Plus oral presentation presented at the 41st Annual Meeting of the American Society of Clinical Oncology; 2005 May 13–17; Orlando (FL)Google Scholar
  121. 121.
    US Food and Drug Administration. FDA approves Tarceva in combination with gemcitabine for first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer, [online]. Available from URL: http://www.fda.gov/cder/ [Accessed 2005 Nov 8]
  122. 122.
    Heinemann V, Hoehler T, Scipelt G, et al. Randomized comparison of capecitabine plus oxaliplatin (CapOx) versus capecitabine plus gemcitabine (CapGem) versus gemcitabine plus oxaliplatin (GemOx) in advanced pancreatic cancer [abstract no. 735]. Eur J Cancer Supplements 2005Oct; 3(2): 209. Plus oral presentation at the 13th European Cancer Conference; 2005 Oct 30–Nov 3; ParisGoogle Scholar
  123. 123.
    Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. New Engl J Med 2004Mar 18; 350: 1200–10PubMedCrossRefGoogle Scholar
  124. 124.
    Stocken DD, Buchler MW, Dervenis C, et al. Meta-analysis of randomized adjuvant therapy trials for pancreatic cancer. Br J Cancer 2005Apr 25; 92(8): 1372–81PubMedCrossRefGoogle Scholar

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© Adis Data Information BV 2005

Authors and Affiliations

  1. 1.Adis International Inc.YardleyUSA

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