Advertisement

Clinical Experience with CF-FUra

  • Leslie R. Laufman
  • Wayne D. BrenckmanJr.
  • Kathy A. Stydnicki
  • E. D. Morgan
  • Mary Collier
  • Victoria B. Knick
  • David S. Duch
  • Robert Mullin
  • Robert Ferone
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 131)

Abstract

Two trials of CF-FUra in patients with metastatic colorectal cancer were performed, both using a 3 day loading dose and then weekly maintenance doses to minimize toxicity. The first trial used CF by IV infusion with constant dose of FUra 400 mg/m2, and the second trial used oral CF with escalating doses of FUra.

In the first trial, 45 eligible patients (20 with and 25 without prior therapy) were treated. Toxicity usually consisted of diarrhea or weakness and was controlled by delaying or decreasing 5FU dose. Subjective responses occurred in 75% of patients but did not correlate with antineoplastic effect. objective responses were seen in 36% and stabilization of disease in 31% of patients, and correlated with prolonged survival. Median survival was 8 months for patients with prior treatment and 10 for those without, and 12 month survival was 32% and 40%, respectively. There was no correlation between the development of toxicity and response or survival.

The second trial was recently conducted in cooperation with Duke University to determine toxicity and efficacy of oral CF with IV FUra prior to a randomized trial of this combination versus placebo with IV FUra. Eighteen patients were treated and serum levels of folates were obtained on 10. First toxicity occurred at FUra doses ranging from 375 to 850 mg/m2, and consisted of diarrhea in 9, lethargy in 7, nausea/ vomiting in 4, dermatitis in 4, conjunctivitis in 2, hypersalivation in 2, stomatitis in 1, and profound granulocytopenia in 1. Response rate was 35% and stabilization was 35% with median survival of 14 months and 12 month survival of 56%.

Keywords

Folinic Acid Serum Folate Antineoplastic Effect Chiral HPLC Serum Folate Level 
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.
    S. G. Arbuck, 5-FU/Leucovorin: Biochemical modulation that works?, Oncology 1: 61 (1987).PubMedGoogle Scholar
  2. 2.
    T. R. Buroker, C. G. Moertel, T. R. Fleming, et al., A controlled evaluation of recent approaches to biochemical modulation or enhancement of 5-fluorouracil therapy in colorectal carcinoma, J. Clin. Oncol. 3: 1624 (1985).PubMedGoogle Scholar
  3. 3.
    S. K. Carter, Large bowel cancer: The current status of treatment, JNCI 56: 3 (1976).PubMedGoogle Scholar
  4. 4.
    D. Machover, G. Schwarzenberg, E. Goldschmidt, et al., Treatment of advanced colorectal and gastric adenocarcinomas with 5FU combined with high dose folinic acid: A pilot study, Cancer Treat. Rep. 66: 1803 (1982).Google Scholar
  5. 5.
    H. W. Bruckner, T. Ohnuma, R. Hart, et al., Leucovorin (LV) potentiation of 5-fluorouracil (FU) efficiency and potency, Proc. Am. Assoc. Cancer Res. 23: 111 (1982).Google Scholar
  6. 6.
    L. R. Laufman, K. A. Krzeczowski, R. Roach, et al., Leucovorin-5fluorouracil: An effective treatment for metastatic colon cancer, J. Clin. Oncol. 5: 1394 (1987).PubMedGoogle Scholar
  7. 7.
    N. Petrelli, L. Herrera, Y. Rustum, et al., A prospective randomized trial of 5-fluorouracil versus 5-flurouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma, J. Clin. Oncol. 5: 1559 (1987).PubMedGoogle Scholar
  8. 8.
    C. Erlichman, S. Fine, A. Wong, et al., A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma, J. Clin. Oncol. 6: 469 (1988).PubMedGoogle Scholar
  9. 9.
    M. J. O’Connell and H. S. Wieand, A controlled clinical trial including folinic acid at two distinct dose levels in combination with 5-fluorouracil (5FU) for the treatment of advanced colorectal cancer: Experience of the Mayo Clinic and North Central Cancer Treatment Group, This Volume.Google Scholar
  10. 10.
    B. W. McGuire, L. L. Sia, J. D. Hayes, et al., Absorption kinetics of orally administered leucovorin calcium: Development of folates and folic acid antagonists in cancer chemotherapy, NCI Monograph 5: 47 (1987).Google Scholar
  11. 11.
    J. A. Straw, D. Szapary and W. T. Wynn, Pharmacokinetics of the diastereoisomers of leucovorin after intravenous and oral administration to normal subjects, Cancer Pes. 44: 3114 (1984).Google Scholar
  12. 12.
    J. D. Hines, D. J. Adelstein, J. Bast, et al., High-dose oral (PO) leucovorin (CF) and intravenous 5-fluorouracil (5FU) in advanced metastatic colorectal carcinoma: Results of a pilot-phase I study, Proc. Am. Soc. Clin. Oncol. 7: 110 (1988).Google Scholar
  13. 13.
    E. M. Newman and J. F. Tsai, Microbiological analysis of 5 formyl THE and other folates using an automatic 96 well plate reader, Analyt. Biochem. 154: 509 (1986).Google Scholar
  14. 14.
    D. S. Duch, S. W. Bowers and C. A. Nichol, Analysis of cofactor levels in tissues using high performance liquid chromatography, Anal. Biochem. 130: 385 (1983).Google Scholar
  15. 15.
    R. J. Mullin, B. R. Kieth and D. S. Duch, Distribution and metabolism of calcium leucovorin in normal and tumor tissue, This Volume.Google Scholar
  16. 16.
    E. E. Vokes, K E. Choi, R. L. Schilsky, et al, Cisplatin, fluorouracil, and high-dose leucovorin for recurrent or metastatic head and neck cancer, J. Clin. Oncol. 6: 618 (1988).PubMedGoogle Scholar
  17. 17.
    K. E. Choi and R. L. Schilsky, Resolution of the stereosiomers of LV and 5MTHF by chiral high performance liquid chromatography, Analytical Biochem. 168: 398 (1988).CrossRefGoogle Scholar
  18. 18.
    R. M. Evans, J. D. Laskin and M. T. Hakala, Effects of excess folates and deoxyinosine on the activity and site of action of 5-fluorouracil, Cancer Res. 41: 3288 (1981).PubMedGoogle Scholar
  19. 19.
    B. Ullman, M. Lee, D. W. Martin Jr., et al., Cytotoxicity of 5-fluoro-2’-deoxyuridine: Requirement for reduced folate cofactors and antagonism by methotrexate, Proc. Natl. Acad. Sci. USA 75: 980 (1978).PubMedCrossRefGoogle Scholar
  20. 20.
    K. Keyomarsi and R. G. Moran, Folinic acid augmentation of the effects of fluoropyrimidines on murine and human leukemic cells, Cancer Res. 46: 5229 (1986).PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Leslie R. Laufman
    • 1
    • 2
    • 3
  • Wayne D. BrenckmanJr.
    • 1
    • 2
    • 3
  • Kathy A. Stydnicki
    • 1
    • 2
    • 3
  • E. D. Morgan
    • 1
    • 2
    • 3
  • Mary Collier
    • 1
    • 2
    • 3
  • Victoria B. Knick
    • 1
    • 2
    • 3
  • David S. Duch
    • 1
    • 2
    • 3
  • Robert Mullin
    • 1
    • 2
    • 3
  • Robert Ferone
    • 1
    • 2
    • 3
  1. 1.Columbus CCOPColumbusUSA
  2. 2.Duke University Medical CenterDurhamUSA
  3. 3.Burroughs Wellcome Co.Research Triangle ParkUSA

Personalised recommendations