Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 27, Issue 2, pp 131–134 | Cite as

Phase I trial of 5-fluorouracil, leucovorin, and cisplatin in combination

  • Peter J. O'Dwyer
  • Mark J. Cornfeld
  • Ruth Peter
  • Robert L. Comis
Original Articles Cisplatin, 5-Fluorouracil, Leucovorin, Combination Chemotherapy, Phase I

Summary

The ongoing evaluation of combination chemotherapy with 5-fluorouracil (5-FU) and cisplatin in several tumors prompted a phase I clinical trial of cisplatin with 5-FU modulated by leucovorin. A total of 26 patients were treated with varying doses of 5-FU by continuous i.v. infusion for 5 days; 200 mg/m2 leucovorin was given by daily bolus injection for 5 days; and 20 mg/m2 cisplatin was infused over 2 h on each day of treatment. Courses were repeated every 21–28 days. The starting dose of 5-FU was 300 mg/m2. Poor-risk patients (extensive prior radiation, performance status of 2 or worse) did not tolerate the initial dose; the maximum tolerated dose of 5-FU in this group was 200 mg/m2 daily. Good-risk patients tolerated 300 mg/m2, but a majority had excessive toxicity at higher doses. The dose-limiting toxicity was gastrointestinal (mucositis/diarrhea) and/or myelosuppression; additional side effects included were nausea and vomiting (≤grade 2) and ataxia (one patient). Among 13 patients with colorectal cancer, 4 partial responses were observed. The marked reduction in the tolerable dose of 5-FU occasioned by the addition of modulating doses of leucovorin is noteworthy. The response observed support further investigation of this regimen in phase II trials.

Keywords

Colorectal Cancer Partial Response Marked Reduction Initial Dose Combination Chemotherapy 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Budd GT, Fleming TR, Bukowski RM, McCracken JD, Rivkin SE, O'Bryan RM, Balcerzak SP, Macdonald JS (1987) 5-Fluorouracil and folinic acid in the treatment of metastatic colorectal cancer: a randomized comparison. A Southwest Oncology Group study. J Clin Oncol 5: 272–277Google Scholar
  2. 2.
    Cantrell J, Hart R, Taylor R, Harvey J (1986) A phase II trial of continuous infusion 5-FU and weekly low dose cisplatin in colorectal carcinoma (abstract). Proc Am Soc Clin Oncol 5: 84Google Scholar
  3. 3.
    Doroshow JH, Bertrand M, Multhauf P, Leong L, Goldberg D, Margolin K, Carr B, Akman S, Hill R (1987) Prospective randomized trial comparing 5-FU versus 5-FU and high dose folinic acid (hdfa) for treatment of advanced colorectal cancer (abstract). Proc Am Soc Clin Oncol 6: 96Google Scholar
  4. 4.
    Dreyfuss AI, Clark JR, Wright JE, Norris CM, Busse PM, Lucarini JW, Fallon BG, Casey D, Andersen JW, Klein R, Rosowski A, Miller D, Frei E III (1990) Continuous infusion of high dose leucovorin with 5-fluorouracil and cisplatin for untreated stage IV carcinoma of the head and neck. Ann Intern Med 112: 167–172Google Scholar
  5. 5.
    Erlichman C, Fine S, Wong A, Elhakeim T (1988) A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol 6469–6475Google Scholar
  6. 6.
    Forestiere AA, Belliveau JF, Goren MP, Vogel WC, Posner MR, O'Leary GP (1988) Pharmacokinetic and toxicity evaluation of fiveday continuous infusion versus intermittent boluscis-diamminedichloroplatinum(II) in head and neck cancer patients. Cancer Res 48: 3869–3874Google Scholar
  7. 7.
    Hines JD, Adelstein DJ, Bast J, Speiss JL (1988) High-dose oral leucovorin and intravenous 5-fluorouracil in advanced metastatic colorectal carcinoma: results of a pilot-phase I study. Proc Am Soc Clin Oncol 7: 110Google Scholar
  8. 8.
    Kemeny N, Reichman B, Botet J, Rosenbluth R, Michaelson R, Vinciguerra V, Deonarine S (1987) Continuous infuson 5-fluorouracil and bolus cisplatin for metastatic colorectal cancer (abstract). Proc Am Soc Clin Oncol 6: 86Google Scholar
  9. 9.
    Kies MS, Rosen ST, Tsang T-K, Shetty R, Schneider PA, Wallemark CB, Shields TW (1987) Cisplatin and 5-fluorouracil in the primary management of squamous esophageal cancer. Cancer 60: 2156–2160Google Scholar
  10. 10.
    Kish J, Drelichman A, Jacobs J, Hochsner J, Kinzie J, Loh J, Weaver A, Al-Sarraf M (1982) Clinical trial of cisplatinum and 5-FU infusion as initial treatment for advanced squamous cell carcinoma of the head and neck. Cancer Treat Rep 66: 471–474Google Scholar
  11. 11.
    Kish J, Ensley J, Weaver A, Jacobs J, Cummings G, Al-Sarraf M (1984) Superior response rate with 96 hour 5-fluorouracil (5-FU) infusion vs 5-FU bolus combined with cisplatinum (CACP) in a randomized trial for recurrent and advanced head and neck cancer. Proc Am Soc Clin Oncol 3: 179Google Scholar
  12. 12.
    Kish JA, Ensley JF, Jacobs J, Weaver A, Cummings G, Al-Sarraf M (1985) A randomized trial of cisplatin plus 5-fluorouracil infusion and cisplatin plus 5-fluorouracil bolus for recurrent and advanced squamous cell carcinoma of the head and neck. Cancer, 56: 2740–2744Google Scholar
  13. 13.
    Lacave ANJ, Anton-Aparicio L, Gonzalez-Baron M, Estrada E, Fernandez-Hidalgo O, Baron FJ, Ribas A (1987) Cisplatin (CDDP) and 5-fluorouracil (5-FU) 120-h infusion for advanced gastric cancer: a phase II multicenter study. Proc Am Soc Clin Oncol 6: 91Google Scholar
  14. 14.
    Loehrer PJ, Turner S, Kubilis P, Hui S, Correa J, Ansari R, Stephens D, Woodburn R, Meyer S (1988) A prospective randomized trial of fluorouracil versus fluorouracil plus cisplatin in the treatment of metastatic colorectal cancer: a Hoosier Oncology Group trial. J Clin Oncol 6: 642–648Google Scholar
  15. 15.
    Machover D, Schwartzenberg L, Goldschmidt E, Tourani JM, Michalski B, Hayat M, Dorval T, Misset JL, Jasmin C, Maral R, Mathe G (1982) Treatment of advanced colorectal and gastric adenocarcinomas with 5-FU combined with high-dose folinic acid: a pilot study. Cancer Treat Rep 66: 1803–1807Google Scholar
  16. 16.
    Miller AB, Hoogstraten B, Staquet M, Winkler A (1981) Reporting results of cancer treatment. Cancer 47: 207–214Google Scholar
  17. 17.
    O'Connell MJ, Weiand HS (1988) A controlled clinical trial including folinic acid at 2 distinct dose levels in combination with 5-fluorouracil (5-FU) for the treatment of advanced colorectal cancer. Experience of the Mayo Clinic and the North Central Cancer Treatment Group (abstract). Proceedings, Symposium on the Expanding Role of Folates and Fluoropyrimidines in Cancer Chemotherapy, Buffalo, New York, April 28–29Google Scholar
  18. 18.
    Pandya KJ, Petrelli NJ, Lefkopoulou M, haller D (1987) Preliminary report of a phase II evaluation of mitomycin-C, vincristine, platinum, and 5-fluorouracil in advanced large bowel cancer: an Eastern Cooperative Oncology Group (abstract). Proc Am Assoc Cancer Res 28: 201Google Scholar
  19. 19.
    Petrelli N, Herrera L, Rustum Y, Burke P, Creaven P, Stulc J, Emrich LJ, Mittelman A (1987) A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal cancer. J Clin Oncol 5: 1559–1565Google Scholar
  20. 20.
    Petrelli N, Stablein D, Bruckner HJ, Megibow A, Mayer R, Douglass HO (1988) A prospective randomized phase III trial of 5-fluorouracil (5-FU) versus 5-FU+high dose leucovorin (hdcf) versus 5-FU+low dose leucovorin (ldcf) in patients (Pts) with metastatic colorectal adenocarcinoma: a report of the Gastrointestinal tumor study group (abstract). Proc Am Soc Clin Oncol 7: 94Google Scholar
  21. 21.
    Scanlon KJ, Safirstein RL, Thies H, Gross RB, Waxman S, Guttenplan JB (1983) Inhibition of amino acid transport bycis-diamminedichloroplatinum(II) derivatives in L1210 murine leukemia cells. Cancer Res 43: 4211–4215Google Scholar
  22. 22.
    Scanlon KJ, Newman EM, Priest DG (1986) Biochemical basis for cisplatin and 5-fluorouracil synergism in human ovarian carcinoma cells. Proc Natl Acad Sci USA 83: 8923–8925Google Scholar
  23. 23.
    Shionoya S, Lu Y, Scanlon KJ (1986) Properties of amino acid transport systems in K562 cells sensitive and resistant tocis-diamminedichloroplatinum(II). Cancer Res 46: 3445–3448Google Scholar
  24. 24.
    Stewart DJ, Benjamin RS, Zimmerman S, Caprioli RM, Wallace S, Chuang V, Calvo D, Samuels M, Bonura J, Loo TL (1983) Clinical pharmacology of intra-arterialcis-diamminedichloroplatinum(II). Cancer Res 43: 917–920Google Scholar
  25. 25.
    Ullman B, Lee M, Martin DW, Santi DV (1978) Cytotoxicity of 5-fluoro-2′-deoxyuridine: requirement for reduced folate co-factors and antagonism by methotrexate. Proc Natl Acad Sci USA 75: 980–983Google Scholar
  26. 26.
    Vokes EE, Choi KE, Schilsky RL, Moran WJ, Guarnieri CM, Weichselbaum RR, Panje WR (1988) Cisplatin, fluorouracil and high-dose leucovorin for recurrent or metastatic head and neck cancer. J Clin Oncol 6: 618–626Google Scholar

Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • Peter J. O'Dwyer
    • 1
  • Mark J. Cornfeld
    • 1
  • Ruth Peter
    • 1
  • Robert L. Comis
    • 1
  1. 1.Department of Medical OncologyFox Chase Cancer CenterPhiladelphiaUSA

Personalised recommendations