Investigational New Drugs

, Volume 22, Issue 3, pp 335–341 | Cite as

A phase II study of high-dose 24 hour continuous infusion 5-FU and leucovorin and low-dose PALA for patients with advanced pancreatic adenocarcinoma: A Southwest Oncology Group Study

  • Robert P. Whitehead
  • Jacqueline K. Benedetti
  • James L. Abbruzzese
  • Bach Ardalan
  • J. Wendall Goodwin
  • Stanley P. Balcerzak
  • Wolfram E. Samlowski
  • Heinz-Josef Lenz
  • John S. Macdonald
Article

Abstract

Purpose: The purpose of this phase II multi-institutional study was to define the efficacy and toxicity of infusional 5-FU in combination with PALA and leucovorin in patients with advanced pancreatic cancer. Patients and methods: Patients were required to have histologically confirmed pancreatic cancer that was locally advanced, unresectable or disseminated. The treatment regimen consisted of weekly 5-FU 2600 mg/m2 given concurrently with leucovorin at 500 mg/m2. Both drugs were administered by 24-hour continuous infusion. PALA was administered 24 hours prior to the administration of 5-FU/LV at a dose of 250 mg/m2 IV over 15 minutes weekly. Patients were continued on the assigned treatment regimen until progression of disease, unacceptable toxicity, or the patient declined further therapy. Results: This study accrued 30 patients. Four of these patients were ineligible. All 26 eligible patients were evaluated for toxicity. One patient had inadequate assessment of response and was considered a non-responder. Three of the twenty-six eligible patients had partial responses, for a response rate of 12% (95% confidence interval 2% to 30%). All 26 eligible patients have died and the median overall survival was 7 months (95% confidence interval: 5.2 to 9 months). Four patients experienced grade 4 toxicities, including bilirubin increase (2 patients), vomiting (1 patient) and non-local skin ulceration (1). Two patients discontinued therapy due to toxicity. Conclusion: The dual modulation of 5-FU with PALA and leucovorin in the dose and schedule used here, has a response rate similar to other single agents in pancreatic cancer and can result in some long term survival while having relatively mild toxicity.

5-FU leucovorin PALA pancreas cancer phase II 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ: Cancer statistics 2003. CA A Cancer Journal for Clinicians 53: 5–26, 2003PubMedGoogle Scholar
  2. 2.
    Cornell GN, Cahow CE, Frey C, McSherry C, Beal JM: Clinical experience with 5-fluorouracil (NSC-1893) to the treatment of malignant disease. Cancer Chemother Rep 9: 23–30, 1960PubMedGoogle Scholar
  3. 3.
    Hurley JD, Ellison EH: Treatment of advanced cancer with 5-fluorouracil. Annals Surg 152: 568–582, 1960Google Scholar
  4. 4.
    Schnall SF, Macdonald JS: Chemotherapy of adenocarcinoma of the pancreas. Seminars in Oncology 23: 220–228, 1996PubMedGoogle Scholar
  5. 5.
    Martin DS, Kemeny NE: Modulation of fluorouracil by N-(phosphonacetyl)-L-asparate: A review. Seminars in Oncology 19: (2, Suppl 3), 49–55, 1992Google Scholar
  6. 6.
    Moran RG, Scanlon KL: Schedule-dependent enhancement of the cytotoxicity of fluoropyrimidines to human carcinoma cells in the presence of folinic acid. Cancer Research 51: 4618–4623, 1991PubMedGoogle Scholar
  7. 7.
    Grem JL, Hoth D, Hamilton MJ, King SA, Leyland-Jones B: An overview of the current status and future directions of clinical trials of 5-fluorouracil and folinic acid. Cancer Treatment Reports 71: 1249–1264, 1987PubMedGoogle Scholar
  8. 8.
    The Advanced Colorectal Cancer Meta-Analysis Project. Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: Evidence in terms of response rate. Journal of Clinical Oncology 10: 896–903, 1992Google Scholar
  9. 9.
    Ullman B, Lee M, Martin DW Jr, Santi DV: Cytotoxicity of 5-fluoro-2′-deoxyuridine: Requirement for reduced folate cofactors and antagonism by methotrexate. Proc Natl Acad Sci USA 75(2): 980–983, 1978PubMedGoogle Scholar
  10. 10.
    Evans RM, Laskin JD, Hakala MT: Effect of excess folates and deoxyinosine on the activity and site of action of 5-fluorouracil. Cancer Res 41: 3288–3295, 1981PubMedGoogle Scholar
  11. 11.
    Houghton JA, Maroda SJ Jr, Philips JO, Houghton PJ: Biochemical determinants of responsiveness to 5-fluorouracil and its derivatves in xenografts of human colorectal adenocarcinomas in mice. Cancer Res 41: 144–149, 1981PubMedGoogle Scholar
  12. 12.
    Meropol NJ, Creaven PJ, Petrelli NJ: Metastatic colorectal cancer: Advances in biochemical modulation and new drug development. Seminars in Oncology 22(5): 509–524, 1995PubMedGoogle Scholar
  13. 13.
    Petrelli N, Douglass HO Jr, Herrera L, Russell D, Stablein DM, Bruckner HW, Mayer RJ, Schinella R, Green MD, Muggia FM, Megibow A, Greenwald ES, Bulowski RM, Harris J, Levin B, Gaynor E, Loutfi A, Kalser MH, Barkin JS, Benedetto P, Wooley PV, Nauta R, Weaver DW, Leichman LP for the Gastrointestinal Tumor Study Group: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: A prospective randomized phase III trial. J Clin Oncol 7: 1419–1426, 1989PubMedGoogle Scholar
  14. 14.
    DeCaprio JA, Mayer RJ, Gonin R, Arbuck SG: Fluorouracil and high-dose leucovorin in previously untreated patents with advanced adenocarcinoma of the pancreas: Results of a phase II trial. J Clin Oncol 9: 2128–2133, 1991PubMedGoogle Scholar
  15. 15.
    Poon MA, O’Connell MJ, Moertel CG, Wieand HS, Cullinan SA, Everson LK, Krook JE, Mailliard JA, Laurie JA, Tschetter LK, Wiesenfeld M: Biochemical modulation of fluorouracil: Evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 7: 1407–1418, 1989PubMedGoogle Scholar
  16. 16.
    Crown J, Casper ES, Botet J, Murray P, Kelsen DP: Lack of efficacy of high-dose leucovorin and fluorouracil in patients with advanced pancreatic adenocarcinoma. J Clin Oncol 9: 1682–1686, 1991PubMedGoogle Scholar
  17. 17.
    Grem JL, King SA, O’Dwyer PJ, Leyland-Jones B: Biochemistry and clinical activity of N-(Phosphonacetyl)-L-aspartate: A review. Cancer Research 48: 4441–4454, 1988PubMedGoogle Scholar
  18. 18.
    Grem JL, McAtee N, Steinberg SM, Hamilton JM, Murphy RF, Drake J, Chisena T, Balis F, Cysyk R, Arbuck SG, Sorensen JM, Chen AP, Goldstein L, Jordan E, Setser A, Goldspiel B, DeCarvalho M, Allegra CJ: A phase I study of continuous infusion 5-fluorouracil plus calcium leucovorin in combination with N-(Phosphonacetyl)-L-aspartate in metastatic gastrointestinal adenocarcinoma. Cancer Research 53: 4828–4836, 1993PubMedGoogle Scholar
  19. 19.
    Ardalan B, Glazer RL, Kensler TW, Jayaram HN, Van Pham T, Macdonald JS, Cooney DA: Synergistic effect of 5-fluorouracil and N-(phosphonacetyl)-L-aspartate on cell growth and ribonucleic acid synthesis in human mammary carcinoma. Biochem Pharmacol 30: 2045–2049, 1981PubMedGoogle Scholar
  20. 20.
    Spiegelman S, Sawyer R, Nayak R, Ritzi E, Stolfi R, Martin D: Improving the anti-tumor activity of 5-fluorouracil by increasing its incorporation into RNA via metabolic modulation. Proc Natl Acad Sci USA 77: 4966–4970, 1980PubMedGoogle Scholar
  21. 21.
    Martin DS, Stolfi RL, Sawyer RC, Spiegelman S, Casper ES, Young CW: Therapeutic utility of utilizing low doses of N-(phosphonacetyl)-L-aspartic acid in combination with 5-fluorouracil: A murine study with clinical relevance. Cancer Res 43: 2317–2321, 1983PubMedGoogle Scholar
  22. 22.
    Johnson RK, Clement JJ, Howard WS: Treatment of murine tumors with 5-fluorouracil in combination with de novo pyrimidine synthesis inhibitors PALA or pyrazofurin. Proceedings AACR 21: 292, 1980 (abstract)Google Scholar
  23. 23.
    Ardalan B, Singh G, Silberman H: A randomized phase I and II study of short-term infusion of high dose fluorouracil with or without N-(phosphonacetyl)-L-aspartic acid in patients with advanced pancreatic and colorectal cancers. J Clin Oncol 6: 1053–1058, 1988PubMedGoogle Scholar
  24. 24.
    Rosvold E, Schilder R, Walczak J, DiFino SM, Flynn PJ, Banerjee TK, Heim WJ, Engstrom PF, Ozols RF, O’Dwyer PJ: Phase II trial of PALA in combination with 5-fluorouracil in advanced pancreatic cancer. Cancer Chemother Pharmacol 29: 305–308, 1992PubMedGoogle Scholar
  25. 25.
    Tian E, Ardalan B, Benedetto P, Feun L, Morrell L, Waldman S, Hurley J, Savaraj N, Richman S, Livingstone A, Anac S: A phase II study of short term protracted infusion of high dose 5-fluorouracil (5-FU) with leucovorin (LV) and low dose phosphonacetyl-L-aspartic acid (PALA) in pancreatic carcinoma. Proc Am Soc Clin Oncol 11: 184, 1992 (abstract)Google Scholar
  26. 26.
    Green S, Weiss GR: Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 10: 239–253, 1992CrossRefPubMedGoogle Scholar
  27. 27.
    Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481, 1958Google Scholar
  28. 28.
    Green SI, and Dahlberg S: Planned versus attained design in Phase II clinical trials. Statistics in Medicine 11: 853–862, 1992PubMedGoogle Scholar
  29. 29.
    Burris HA III 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD: Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: A randomized trial. J Clin Oncol 15: 2403–2413, 1997PubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Robert P. Whitehead
    • 1
  • Jacqueline K. Benedetti
    • 2
  • James L. Abbruzzese
    • 3
  • Bach Ardalan
    • 4
  • J. Wendall Goodwin
    • 5
  • Stanley P. Balcerzak
    • 6
  • Wolfram E. Samlowski
    • 7
  • Heinz-Josef Lenz
    • 8
  • John S. Macdonald
    • 9
  1. 1.University of Texas Medical BranchGalveston
  2. 2.Southwest Oncology Group Statistical CenterSeattle
  3. 3.University of Texas, MD Anderson Cancer CenterHouston
  4. 4.School of MedicineUniversity of MiamiMiami
  5. 5.Ozarks Regional Clinical Oncology ProgramUSA
  6. 6.Ohio State University Health CenterColumbus
  7. 7.University of Utah Health Sciences CenterSalt Lake City
  8. 8.University of Southern California School of MedicineLos Angeles
  9. 9.St. Vincent’s Comprehensive Cancer CenterNew York

Personalised recommendations