Skip to main content
SpringerLink
Log in

A phase II and pharmacokinetic study of 6S-leucovorin plus 5-fluorouracil in patients with colorectal carcinoma

  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Leucovorin (LV) is commonly used as a modulator of 5-fluorouracil (5-FU) cytotoxicity. In patients with colon cancer, the addition of LV to 5-FU improves response rates, and in some trials has improved survival in advanced disease and in the adjuvant setting. Leucovorin is generally administered as a racemic mixture, but the isomers differ substantially in pharmacokinetics and biological activity, with 6S-LV the predominant active component. The current study was undertaken to determine the effect of 6R on the pharmacokinetics of 6S-LV, and to characterize the toxicity and antitumor effect of 5-FU when administered with 6S-LV to patients with advanced colorectal carcinoma. Thirty patients were treated with weekly 5-FU plus high dose 6S-LV. To determine the effects of 6R-LV on the pharmacokinetics of 6S-LV, 20 patients were randomly assigned to receive either 250 mg/m2 6S-LV or 500 mg/m2 6R,S-LV as a 2 hour IV infusion on day −2, and the other preparation on day −1, with pharmacokinetics measured each day. The presence of 6R-LV had no effect on the AUC, Clp, Cmax, or terminal phase t1/2 of 6S-LV. The overall response rate was 40% (C.I. 23–60%). The most frequent toxicities were gastrointestinal. In this small cohort, scheduled and delivered dose intensity was positively associated with response (p=0.05). These results show that there is no pharmacokinetic advantage to the use of 6S-LV rather than 6R,S-LV as a modulator of 5-FU.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Grem JL: Fluoropyrimidines. In: Chabner BA and Collins JM (eds) Cancer Chemotherapy: Principles and Practice. JB Lippinott Company, Philadelphia, pp 180–224, 1990

    Google Scholar 

  2. Piedbois P, Buyse M, Rustum YM, Machover D, Erlichman C, Carlson RW, Valone F, Labianca R, Doroshow JH, Petrelli N: Modulation of fluorouracil by leucovorin in patients with advanced colorectal cancer: evidence in terms of response rate. J Clin Oncol 6:896–903, 1992

    Google Scholar 

  3. Poon MA, O'Connell MJ, Wieand HS, Krook JE, Gerstner JB, Tschetter LK, Levitt R, Kardinal CG, Mailliard JA: Biochemical modulation of fluorouracil with leucovorin: confirmatory evidence of improved therapeutic efficacy in advanced colorectal carcinoma. J Clin Oncol 9:1967–1972, 1991

    Google Scholar 

  4. Wolmark N, Rockette H, Fisher B, Wickerham DL, Redmond C, Fisher ER, Jones J, Mamounas EP, Ore L, Petrelli NJ, Spurr CL, Dimitrov N, Romond EH, Sutherland CM, Kardinal CG, DeFusco PA, Jochimsen P: The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-03. J Clin Oncol 11:1879–1887, 1993

    Google Scholar 

  5. Lee PP, Schilsky RL: Inhibition of thymidylate synthase by the diastereoisomers of leucovorin. Cancer Chemother Pharmacol 26:273–277, 1990

    Google Scholar 

  6. White JC, Bailey BD, Goldman ID: Lack of stereospecificity at carbon 6 of methyltetrahydrofolate. Transport in Ehrlich ascites tumor cells. J Biol Chem 253:242–245, 1978

    Google Scholar 

  7. Sirotnak FM, Chello PL, Moccio DM, Kisliuk RL, Combepine G, Gaumont Y, Montgomery JA: Stereo-specificity at carbon 6 of formyltetrahydrofolate as a competitive inhibitor of transport and cytotoxicity of methotrexatein vitro. Biochem Pharmacol 28:2993–2997, 1979

    Google Scholar 

  8. Schilsky RL, Ratain MJ: Clinical pharmacokinetics of high-dose leucovorin calcium after intravenous and oral administration. J Nat Cancer Inst 82:1411–1415, 1990

    Google Scholar 

  9. Creaven PJ, Petrelli NJ, Rustum YM, George M, Letvak L, Solomon J: Initial clinical trial of weekly 5-fluorouracil plus 6S-leucovorin. 7th NCI-EORTC Symposium on New Drugs in Cancer Therapy, Amsterdam, The Netherlands, 195, 1992

  10. Cancer Therapy Evaluation Program: Common toxicity criteria. In: NCI decision of cancer treatment guidelines for reporting of adverse drug reactions. Bethesda: NIH Publications, pp 6–9, 1989

  11. Rocci ML, Jusko WJ: LAGRAN program for area and moments in pharmacokinetic analysis. Computer Programs in Biomedicine 16:203–216, 1983

    Google Scholar 

  12. Schefler W: Statistics for the biological sciences. Addison-Wesley Publishing Co., Inc., 1979

  13. Buroker TR, O'Connell MJ, Wieand HS, Krook JE, Gerstner JB, Mailliard JA, Schaefer PL, Levitt R, Kardinal CG, Gesme DH: Randomized comparison of two schedules of fluorouracil and leucovorin in the treatment of advanced colorectal cancer. J Clin Oncol 12:14–20, 1994

    Google Scholar 

  14. Petrelli N, Herrera L, Rustum YM, Burke P, Creaven PJ, Stulc J, Emrich LJ, Mittelman A: 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 carcinoma. J Clin Oncol 10:1559–1565, 1987

    Google Scholar 

  15. Petrelli N, Douglass HO, Herrera L, Russell D, Stablein DM, Bruckner HW, Mayer RJ, Schinella R, Green MD, Muggia FM, Megibow A, Greenwald ES, Bukovvski RM, Harris J, Levin B, Gaynor E, Loutfi A, Kalser MH, Barkin JS, Benedetto P, Woolley PV, Nauta R, Weaver DW, Leichman LP: The modulation of flourouracil with leucovorin in metastatic colorectal carcinoma: a prospective randomized phase III trial. J Clin Oncol 7: 1419–1426, 1989

    Google Scholar 

  16. Bertrand R, Jolivet J: Lack of interference by the unnatural isomer of 5-formyltetrahydrofolate with the effects of the natural isomer in leucovorin preparations. J Natl Cancer Inst 81:1175–1178, 1989

    Google Scholar 

  17. Rustum YM: Toxicity and antitumor activity of 5-fluorouracil in combination with leucovorin. Cancer 63: 1013–1017, 1989

    Google Scholar 

  18. Grem JL, Chu E, Boarman D, Balsi FM, Murphy RF, McAtee N, Allegra CJ: Biochemical modulation of fluorouracil with leucovorin and interferon: preclinical and clinical investigations. Sem Oncol 19:36–44, 1992

    Google Scholar 

  19. Boarman DM, Allegra CJ: Intracellular metabolism of 5-formyltetrahydrofolate in human breast and colon cell lines. Cancer Res 52:36–44, 1992

    Google Scholar 

  20. Zhang Z-G, Rustum YM: Effects of diastereoisomers of 5-formyltetrahydrofolate on cellular growth. Sensitivity to 5-fluoro-2′-deoxyuridine, and methyleneterrahydrofolate polyglutamate levels in HCT-8 cells. Cancer Res 51:3476–3481, 1991

    Google Scholar 

  21. Grem JL, Jordan E, Robson ME, Binder RA, Hamilton JM, Steinberg SM, Arbuck SG, Beveridge RA, Kales AN, Miller JA, Weiss RB, McAtee N, Chen A, Goldspiel B, Sover E, Allegra CJ: Phase II study of fluorouracil, leucovorin, and interferon alfal-2a in metastatic colorectal carcinoma. J Clin Oncol 11:1737–1745, 1993

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medicine, Roswell Park Cancer Institute, 14263, Buffalo, NY, USA

    Neal J. Meropol, Elmer Berghorn & Patrick J. Creaven

  2. Department of Surgery, Roswell Park Cancer Institute, 14263, Buffalo, NY, USA

    Nicholas J. Petrelli & Miguel Rodriguez-Bigas

  3. Department of Experimental Therapeutics, Roswell Park Cancer Institute, 14263, Buffalo, NY, USA

    Youcef M. Rustum & Cheryl Frank

  4. Department of Biostatistics, Roswell Park Cancer Institute, 14263, Buffalo, NY, USA

    Leslie E. Blumenson

Authors
  1. Neal J. Meropol
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nicholas J. Petrelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Youcef M. Rustum
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miguel Rodriguez-Bigas
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Leslie E. Blumenson
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Cheryl Frank
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Elmer Berghorn
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Patrick J. Creaven
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Meropol, N.J., Petrelli, N.J., Rustum, Y.M. et al. A phase II and pharmacokinetic study of 6S-leucovorin plus 5-fluorouracil in patients with colorectal carcinoma. Invest New Drugs 13, 149–155 (1995). https://doi.org/10.1007/BF00872864

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00872864

Key words

Search

Navigation