Phase II clinical trial of 5-fluorouracil, trimetrexate, and leucovorin (NFL) in patients with advanced pancreatic cancer

  • Agustin A. Garcia
  • Lawrence Leichman
  • Joaquina Baranda
  • Lalita Pandit
  • Heinz-Josef Lenz
  • Cynthia G. Leichman
Research Article


Background. Advanced pancreatic cancer has limited treatment options. 5-fluorouracil (5-FU) is frequently used in the treatment of pancreatic cancer. Preclinical studies suggest synergism between trimetrexate (TMTX), 5-FU, and leucovorin (NFL).

Aim. We conducted a phase II trial to evaluate the activity and safety of NFL in pancreatic cancer.

Method. Eligible patients (n=21) with untreated advanced pancreatic cancer were treated with 110 mg/m2 intravenous (IV) THTX on day 1 and 200 mg/m2 IV leucovorin prior to 500 mg/m2 IV 5-FU on day 2. Oral leucovorin (15 mg every 6 h for seven doses) started intravenous 24 h later.

Results. Treatment was administered for 6 wk followed by a 2-wk rest period. Response was evaluated every 8 wk. All patients were evaluable for response and toxicity. Most patients (80%) had distant metastases. Forty-five cycles of chemotherapy were administered. The most common serious toxicities were Grade 3 diarrhea (23.8%) and nausea and vomiting (14.2%). The response rate was 4.1% (95% CI, 0–23%), median survival was 6.8 mo, and 1-yr survival was 19%.

Conclusion. Treatment with NFL is well-tolerated in patients with advanced pancreatic cancer. The median survival and 1-yr survival in these patients with poor prognosis compares favorably with other treatment options.

Key Words

Pancreatic cancer chemotherapy 5-fluorouracil leucovorin trimetrexate 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Jemal A, Thomas A, Murray T, et al. Cancer Statistics. CA Cancer J Clin 2002;52:23–47.PubMedCrossRefGoogle Scholar
  2. 2.
    Ahlgren JD. Chemotherapy for pancreatic cancer. Cancer 1996;78:654–663.PubMedGoogle Scholar
  3. 3.
    Carter SK, Comis RL. The integration of chemotherapy into a combined modality approach for cancer treatment. VI. Pancreatic adenocarcinoma. Cancer Treat Rev 1975;2:193–214.PubMedCrossRefGoogle Scholar
  4. 4.
    Cullinan S, Moertel CG, Wieand HS, et al. A phase III trial on the therapy of advanced pancreatic carcinoma. Evaluations of the Mallinson regimen and combined 5-fluorouracil, doxorubicin, and cisplatin. Cancer 1990;65:2207–2212.CrossRefGoogle Scholar
  5. 5.
    Rougier M, Ducreux M, Douillard JY, et al. Efficacy of 5FU + cisplatin (FUP) compared to bolus 5FU (FU) in advanced pancreatic carcinoma (APC): a randomized trial from the French Anticancer Centers Digestive Group (FNL-CCDG). Proc Am Soc Clin Oncol 1999;18:1050 (abstract).Google Scholar
  6. 6.
    Burris 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 1997;15:2403–2413.PubMedGoogle Scholar
  7. 7.
    Rothenberg M, Moore MJ, Cripps MC, et al. A phase II trial of gemcitabine in patients with 5-FU-refractory pancreas cancer. Ann Oncol 1996;7:347–353.PubMedGoogle Scholar
  8. 8.
    Casper ES, Green MR, Kelsen DP, et al. Phase II trial of gemcitabine (2,2′-difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Inv New Drugs 1994;12:29–34.CrossRefGoogle Scholar
  9. 9.
    Carmichael J, Fink U, Russell RCG, et al. Phase II study of gemcitabine in patients with advanced pancreatic cancer. Br J Cancer 1995;73:101–105.Google Scholar
  10. 10.
    Heinemann V. Gemcitabine: progress in the treatment of pancreatic cancer. Oncology 2001;60:8–18.PubMedCrossRefGoogle Scholar
  11. 11.
    Martin DS. Introduction to 5-fluorouracil modulation. Cancer Invest 1990;8:257–258.CrossRefGoogle Scholar
  12. 12.
    Peters GJ, Schornagel JH, Milano GA. Clinical pharmacokinetics of antimetabolites. Cancer Surveys 1993;17:123–149.PubMedGoogle Scholar
  13. 13.
    Fleming GF, Schilsky RL. Antifolates: the next generation. Sem Oncol 1992;19:707–719.Google Scholar
  14. 14.
    Pyrhonen S, Kuitunen T, Nyandoto P, et al. Randomized comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Brit J Can 1995;71:587–591.Google Scholar
  15. 15.
    Advanced colorectal cancer meta-analysis project. Meta-analysis of randomized trials testing the biochemical modulation of fluorouracil by methotrexate in metastatic colorectal cancer. J Clin Oncol 1994;12:960–969.Google Scholar
  16. 16.
    Lin JT, Bertino JR. Update of trimetrexate, a folate antagonist with antineoplastic and antiprotozoal properties. Cancer Inv 1991;9:159–172.CrossRefGoogle Scholar
  17. 17.
    Jackson RC, Leopold WR, Hamelehle KL, et al. Preclinical studies with trimetrexate: a review of conclusions and unanswered questions. Sem Oncol. 1988;15:1–7.Google Scholar
  18. 18.
    Romanini A, Li WW, Colofiore JR, et al. Leucovorin enhances cytotoxicity of trimetrexate/fluorouracil, but not methotrexate/fluorouracil, in CCRF-CEM cells. JNCI 1992;84:1033–1038.PubMedCrossRefGoogle Scholar
  19. 19.
    Elliot WL, Howard CT, Dykes DJ, et al.. Sequence and schedule-dependent synergy of trimetrexate in combination with 5-fluorouracil in vitro and in mice. Cancer Res 1989;49:5586–5590.Google Scholar
  20. 20.
    Sobrero A, Romanini A, Russello O, et al. Sequence-dependent enhancement of HCT-8 cell kill by trimetrexate and fluoropyrimidines: implications for the mechanism of this interaction. Eur J Can Clin Oncol 1989;25:977–982.CrossRefGoogle Scholar
  21. 21.
    Conti JA, Kemeny N, Seiter K, et al. Trial of sequential trimetrexate, fluorouracil, and high-dose leucovorin in previously treated patients with gastrointestinal carcinoma. J Clin Oncol 1994;12:695–700.PubMedGoogle Scholar
  22. 22.
    Blanke CD, Kasimis B, Schein P, et al. Phase II study of trimetrexate, fluorouracil, and leucovorin for advanced colorectal cancer. J Clin Oncol 1997;15:915–920.PubMedGoogle Scholar
  23. 23.
    Szelenyi H, Hohenberger P, Lochs H, et al. Sequential trimetrexate, 5-fluorouracil and folinic acid are effective and well tolerated in metastatic colorectal carcinoma. The phase II study group of the AIO. Oncology 2000;58:273–279.PubMedCrossRefGoogle Scholar
  24. 24.
    Cullinan SA, Moertel CG, Fleming TR, et al. A comparison of three chemotherapeutic regimens in the treatment of advanced pancreatic and gastric carcinoma: fluorouracil vs fluorouracil and doxorubicin vs fluorouracil, doxorubicin, and mitomycin. JAMA 1985;253:2061–2067.PubMedCrossRefGoogle Scholar
  25. 25.
    Takada T, Kato H, Matsushiro T, et al. Comparison of 5- fluorouracil, doxorubicin and mitomycin C with 5-fluorouracil alone in the treatment of pancreatic-biliary carcinomas. Oncology 1994;51:396–400.PubMedCrossRefGoogle Scholar
  26. 26.
    Cullinan S, Moertel CG, Wieand HS, et al. A phase III trial on the therapy of advanced pancreatic carcinoma: evaluations of the Mallinson regimen and combined 5-fluorouracil, doxorubicin, and cisplatin. Cancer 1990;65:2207–2212.CrossRefGoogle Scholar
  27. 27.
    Gastrointestinal Tumor Study Group. Phase II studies of drug combinations in advanced pancreatic carcinoma: fluorouracil plus doxorubicin plus mitomycin C and two regimens of streptozotocin plus mitomycin C plus fluorouracil. The Gastrointestinal Tumor Study Group. J Clin Oncol 1986;4:1794–1798.Google Scholar
  28. 28.
    Oster MW, Gray R, Panasci L, et al. Chemotherapy for advanced pancreatic cancer. A comparison of 5-fluorouracil, adriamycin, and mitomycin (FAM) with 5-fluorouracil, streptozotocin, and mitomycin (FSM). Cancer 1986;57:29–33.PubMedCrossRefGoogle Scholar
  29. 29.
    Louvet C, Andre T, Hammel P, et al. A Phase II trial of bimonthly leucovorin, 5-fluorouracil and gemcitabine for advanced pancreatic adenocarcinoma (FOLFUGEM). Ann Oncol 2001;12(5):675–679.PubMedCrossRefGoogle Scholar
  30. 30.
    Marantz A, Jovtis S, Almira E, et al. Grupo de Tumores Gastrointestinales. Phase II study of gemcitabine, 5-fluorouracil, and leucovorin in patients with pancreatic cancer. Sem Oncol 2001;28(3 suppl 10):44–49.CrossRefGoogle Scholar
  31. 31.
    Rauch DP, Maurer CA, Aebi S, et al. Activity of gemcitabine and continuous infusion fluorouracil in advanced pancreatic cancer. Oncology 2001;60(1):43–48.PubMedCrossRefGoogle Scholar
  32. 32.
    Kurtz JE, Kohser F, Negrier S, et al. Gemcitabine and protracted 5-FU for advanced pancreatic cancer. A phase II study. Hepato-Gastroenterology 2000;47(35):1450–1453.PubMedGoogle Scholar
  33. 33.
    Oettle H, Arning M, Pelzer U, et al. A phase II trial of gemcitabine in combination with 5-fluorouracil (24-hour) and folinic acid in patients with chemonaive advanced pancreatic cancer. Ann Oncol 2000;11(10):1267–1272.PubMedCrossRefGoogle Scholar
  34. 34.
    Matano E, Tagliaferri P, Libroia A, et al. Gemcitabine combined with continuous infusion 5-fluorouracil in advanced and symptomatic pancreatic cancer: a clinical benefit-oriented phase II study. Brit J Can 2000;82(11):1772–1775.CrossRefGoogle Scholar
  35. 35.
    Berlin JD, Adak S, Vaughn DJ, et al. A phase II study of gemcitabine and 5-fluorouracil in metastatic pancreatic cancer: an Eastern Cooperative Oncology Group Study (E3296). Oncology 2000;58(3):215–218.PubMedCrossRefGoogle Scholar
  36. 36.
    Reni M, Passoni P, Panucci MG, et al. Definitive results of a phase II trial of cisplatin, epirubicin, continuous-infusion fluorouracil, and gemcitabine in stage IV pancreatic adenocarcinoma. J Clin Oncol 2001;19(10):2679–2686.PubMedGoogle Scholar
  37. 37.
    Berlin JD, 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 2002;20(15):3270–3275.PubMedCrossRefGoogle Scholar
  38. 38.
    Petty RD, Nicolson MC, Skaria S, et al. A phase II study of mitomycin C, cisplatin and protracted infusional 5-fluorouracil in advanced pancreatic carcinoma: efficacy and low toxicity. Ann Oncol 2003;14(7):1100–1105.PubMedCrossRefGoogle Scholar
  39. 39.
    Maisey N, Chau I, Cunningham D, et al. Multicenter randomized phase III trial comparing protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin in inoperable pancreatic cancer. J Clin Oncol 2002;20(14):3130–3136.PubMedCrossRefGoogle Scholar
  40. 40.
    Storniolo AM, Enas MH, Brown CA, et al. An investigational new drug treatment program for patients with gemcitabine: results for over 3000 patients with pancreatic carcinoma. Cancer 1999;85:1261–1268.PubMedCrossRefGoogle Scholar
  41. 41.
    Jabboury K, Wong A, Hendricks S, et al. Phase I/II weekly sequential trimetrexate and 24-hour fluorouracil/leucovorin infusion in advanced malignancy. Proc Amer Assoc Can Res 1999;40:553(abstract).Google Scholar
  42. 42.
    Cartwright TH, Cohn A, Varkey JA, et al. Phase II study of oral capecitabine in patients with advanced or metastatic pancreatic cancer. J Clin Oncol 2002;20(1):160–164.PubMedCrossRefGoogle Scholar
  43. 43.
    Campos LT, Alvarez RH, Sanford M, et al. Gemcitabine (GEM) and capecitabine (CPC) in advanced pancreatic cancer (APC) and solid tumors. A single institution experience. Proc Am Soc Clin Oncol 2001;20:2315(abstract).Google Scholar
  44. 44.
    Scheithauer W, Schull B, Ulrich-Pur H, et al. Biweekly high-dose gemcitabine alone or in combination with capecitabine in patients with metastatic pancreatic adenocarcinoma: a randomized phase II trial. Ann Oncol 2003;14(1):97–104.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc 2003

Authors and Affiliations

  • Agustin A. Garcia
    • 1
  • Lawrence Leichman
    • 2
  • Joaquina Baranda
    • 3
  • Lalita Pandit
    • 4
  • Heinz-Josef Lenz
    • 1
  • Cynthia G. Leichman
    • 2
  1. 1.Norris Comprehensive Cancer CenterUniversity of Southern CaliforniaLos Angeles
  2. 2.Salick Health Care, Inc.Los Angeles
  3. 3.The Cancer Center of IrvineIrvine
  4. 4.Department of Veterans AffairsKansas City (VAMC)Kansas City

Personalised recommendations