Comparison of Continuous Infusions and Bolus Injections of 5.Fluorouracil with or without Leucovorin: Implications for Inhibition of Thymidylate Synthase

  • Godefridus J. Peters
  • Giovanni Codacci-Pisanelli
  • Clasina L. van der Wilt
  • Jan A. M. van Laar
  • Kees Smid
  • Paul Noordhuis
  • Herbert M. Pinedo
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 339)

Abstract

Although 5-fluorouracil (5FU) is in clinical use for more than three decades, it is not clear what is the most efficacious schedule of 5FU administration [1, 2]. For systemic treatment with 5FU a number of different schedules are in clinical use (Table 1). The two major schedules for bolus injections do not show significant differences in either toxicity or antitumor activity. For the prolonged administration schedules, however, the pattern of toxicity changes. For weekly bolus injections, myelotoxicity (mainly leukopenia) is usually dose-limiting; however, at the prolonged administration schedules the pattern of toxicity changes with mucositis and diarrhea as serious site-effects for continuous infusions. In addition, the handfoot syndrome is frequently observed at protracted infusions of several weeks, as well as other skin lesions (see ref. in Table 1). Interestingly the addition of LV to both the bolus injections and the continuous infusions, caused a marked increase in gastrointestinal toxicity. In several schedules this increase of toxicity was the only result of the modulatory agent, with no apparent effect on the antitumor activity.

Keywords

Continuous Infusion Bolus Injection Plasma Pharmacokinetic Biochemical Modulation Advanced Colorectal Carcinoma 
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.
This is a preview of subscription content, log in to check access.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    H.M. Pinedo and G.J. Peters. 5-Fluorouracil: biochemistry and pharmacology, J. Clin. Oncol. 6: 1653–1664 (1988).PubMedGoogle Scholar
  2. 2.
    G.J. Peters and C.J. van Groeningen, Clinical relevance of biochemical modulation of 5-fluorouracil, Ann. Oncology 2: 469–480 (1991).Google Scholar
  3. 3.
    C.J. van Groeningen, G.J. Peters, and H.M. Pinedo, Modulation of 5-fluorouracil toxicity with uridine. Sem. Oncology 19 (Sup 3): 148–154 (1992).Google Scholar
  4. 4.
    P. Piedbois, M. Buyse, Y. Rustum, D. Machover, C. Erlichman, R.W. Carlson, F. Valone, R. Labianca, J.H. Doroshow, and N. Petrelli, Modulation of Fluorouracil by Leucovorin in Patients With Advanced Colorectal Cancer: Evidence in Terms of Response Rate, J. Clin. Oncol 10: 896–903 (1992).Google Scholar
  5. 5.
    P.J. O’Dwyer, A.R. Paul, J. Walczak, L.M. Weiner, S. Litwin, and R.L. Comis, Phase II study of biochemical modulation of fluorouracil by low-dose PALA in patients with colorectal cancer, J. Clin. Oncol. 8: 1497–1503 (1990).PubMedGoogle Scholar
  6. 6.
    B. Ardalan, S. Gurckarn, and H. Silberman, 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 cancer, J. Clin. Oncol., 6: 1053–1058 (1988).PubMedGoogle Scholar
  7. 7.
    W.P. Peters, G. Weiss, and D.W. Kufe, Phase-I trial of combination therapy with continuous-infusion MMPR and continuous-infusion 5FU, Cancer. Chemother. Pharmacol. 13: 136–138 (1984).PubMedCrossRefGoogle Scholar
  8. 8.
    P.I. Raju, Y. Maruyama, J. MacDonald, and P. DeSimone, Treatment of Unresectable Pancreatic Carcinoma Using Irradiation with Concurrent Intravenous 5-FU Infusion Therapy, Cancer. Invest. 6: 263–266 (1988).PubMedCrossRefGoogle Scholar
  9. 9.
    A. Shah, W. MacDonald, J. Goldie, G. Gudauskas, and B. Brisebois, 5-FU Infusion in Advanced Colorectal Cancer: A Comparison of Three Dose Schedules, Cancer. Treatment. Rep. 69: 739–742 (1985).Google Scholar
  10. 10.
    D.L. Trump, MJ. Egorin, A. Forrest, J.K.V. Willson, S. Remick, and K.D. Tutsch, Pharmacokinetics and Pharmacodynamic Analysis of Fluorouracil During 72-Hour Continuous Infusion With and Without Dipyridamole, J. Clin. Oncol. 9: 2027–2035 (1991).PubMedGoogle Scholar
  11. 11.
    A. Thyss, G. Milano, N. Renée, J. Vallicioni, M. Schneider, and F. Demard, Clinical pharmacokinetic study of 5-FU in continuous 5-day infusions for head and neck cancer, Cancer. Chemother. Pharmacol. 16: 64–66 (1986).PubMedCrossRefGoogle Scholar
  12. 12.
    Ph. Rougier, H. Ammarguellat, M. Ghosn, G. Piot, M. Benhamed, J.M. Tigaud, Ph. Laplaige, C. Theodore, J. Kac, J. Goldberg, P. Carde, and J.P. Droz, Phase II Trial of 7-Day Continuous 5-Fluorouracil Infusion in the Treatment of Advanced Colorectal Carcinoma, Oncology 49: 35–39 (1992).PubMedCrossRefGoogle Scholar
  13. 13.
    J.S. Macdonald, Continuous Low-Dose Infusion of Fluorouracil: Is the Benefit Worth the Cost? J. Clin. Oncol. 7 (4): 412–414 (1989).PubMedGoogle Scholar
  14. 14.
    S.M. Grunberg, C. Clay, and D.V. Spicer, Tolerance of Extended (28 Day) Continuous Infusion of 5-Fluorouracil in Advanced Head and Neck Cancer, Sel. Cancer. Ther. 7: 17–21 (1991).PubMedCrossRefGoogle Scholar
  15. 15.
    V.P. Barbounis, H.P. Kalofonos, A.J. Munro, C.G. McKenzie, J.M. Sackier, and A.A. Epenetos, Treatment of Colorectal Cancer and Other Malignancies with Continuous Infusion of 5-Fluoromacil, Anticancer, Res. 9: 33–40 (1989).Google Scholar
  16. 16.
    S. Huan, R. Pazdur, A. Singhakowinta, B. Samal, and V.K. Vaitkevicius, Low-Dose Continuous Infusion 5-Fluorouracil: Evaluation in Advanced Breast Carcinoma, Cancer 63: 419–422 (1989).PubMedCrossRefGoogle Scholar
  17. 17.
    R. Hansen, E. Quebbeman, P. Ritch, C. Chitambar, and T. Anderson, Continuous 5-Fluorouracil (5FU) Infusion in Carcinoma of the Pancreas: A Phase II Study, Am. J. Med. Sci. 295: 91–93 (1988).PubMedCrossRefGoogle Scholar
  18. 18.
    C.G. Leichman, L. Leichman, C.P. Spears, PJ. Rosen, F. Muggia, S. Jeffers, and W. Waugh, Biological Modification of protracted infusion of 5-fluorouracil with weekly leucovorin: A dose seeking clinical trial for patients with disseminated gastrointestinal cancers, Cancer Chemother. Pharmacol. 26: 57–61 (1990).PubMedCrossRefGoogle Scholar
  19. 19.
    H.A.M. Sinnige, A.G. Nanninga, R.C.J. Verschueren, D.Th. Sleijfer, E.G. E. de Vries, P.H.B. Willemse, and N.H. Mulder, A Phase I-II Study of 14-days Continuous Infusion of 5-Fluorouracil with Weekly Bolus Leucovorin in Metastatic Colorectal Carcinoma, Eur. J. Cancer 28A: 885–888 (1992).Google Scholar
  20. 20.
    S.C. Remick, J.L. Grem, P.H. Fischer, K.D. Tutsch, D.B. Alberti, L.M. Nieting, M.B. Tombes, J. Bruggink, J.K.V. Willson, and D.L. Trump, Phase I Trial of 5-Fluorouracil and Dipyridamole Administered by Seventy-two-Hour Concurrent Continuous Infusion, Cancer Res. 50: 2667–2672 (1990).PubMedGoogle Scholar
  21. 21.
    B. Ardalan, K. Stridhar, R. Reddy, P. Benedetto, S. Richman, S. Waldman, L. Morrell, L. Feun, N. Savaraj, and A. Livingstone, Phase I Study of High Dose 5-Fluorouracil and High Dose Leucovorin with Low Dose Phosphonacetyl-L-Aspartic Acid in Patients with Advanced Malignancies, Int. J. Radiation Oncology Biol. Phys. 22: 511–514 (1992).CrossRefGoogle Scholar
  22. 22.
    P.J. O’Dwyer, G.R. Hudes, J. Colofiore, J. Walczak, J. Hoffman, F.P. LaCreta, R.L. Comis, D.S. Martin, and R.F. Ozols, Phase I Trial of Fluorouracil Modulation by N-Phosphonacetyl-L-aspartate and 6-Methylmercaptopurine Riboside: Optimization of 6-Methylmercaptopurine Riboside Dose and Schedule Through Biochemical Analysis of Sequential Tumor Biopsy Specimens, J. Natl. Cancer Inst. 83: 1235–1240 (1991).PubMedCrossRefGoogle Scholar
  23. 23.
    J.A. Kish, J.F. Ensley, J. Jacobs, A. Weaver, G. Cummings, and M. Al-Sarraf, A randomized trial of cisplatin (CACP) + 5-fluorouracil (5-FU) infusion and CACP + 5-FU bolus for recurrent and advanced squamous cell carcinoma of the head and neck, Cancer 56: 2740–2744 (1985).PubMedCrossRefGoogle Scholar
  24. 24.
    J.J. Lokich, J.D. Ahlgren, JJ. Gullo, J.A Philips, and J.G. Fryer, A Prospective Randomized Comparison of Continuous Infusion Fluorouracil With a Conventional Bolus Schedule in Metastatic Colorectal Carcinoma: A Mid-Atlantic Oncology Program Study, J. Clin. Oncol. 7: 425–432 (1989).PubMedGoogle Scholar
  25. 25.
    C.H.N. Veenhof, R.L. Poorter, PJ.M. Bakker, D.MJ. Biermans-Van Leeuwe, P. Noordhuis, G. Codacci-Pisanelli, and G.J. Peters, Fourteen days continuous 5-Fluorouracil (5-FU) infusion and low dose oral calcium leucovorin (LV) in patients with gastrointestinal cancer. Proc. Amer. Soc. Clin. Oncol. 11: 181 (Abstract 539) (1992).Google Scholar
  26. 26.
    R.M. Hansen, P.S. Ritcn, J.A. Libnoch, and T. Anderson, Continuous 5-Fluorouracil Infusion and Alpha Interferon in Advanced Cancers: A Report of Initial Treatment Results, Am. J. Med. Sci. 301: 246–249 (1991).PubMedCrossRefGoogle Scholar
  27. 27.
    N. Anderson, J. Lokich, M. Bern, S. Wallach, C. Moore, and D. Williams, A Phase I Clinical Trial of Combined Fluoropyrimidines With Leucovorin in a 14-Day Infusion: Demonstration of Biochemical Modulation, Cancer 63: 233–237 (1989).PubMedCrossRefGoogle Scholar
  28. 28.
    C-H. Könne-Wömpner, H-J. Schmoll, A. Harstrick, and Y.M. Rustum, Chemotherapeutic Strategies in Metastatic Colorectal Cancer: An Overview of Current Clinical Trials, Sem. Oncol. 19 (Suppl 3): 105–125 (1992).Google Scholar
  29. 29.
    B. Drewinko and L.-Y. Yang, Cellular Basis for the Inefficacy of 5-FU in Human Colon Carcinoma, Cancer Treatment Rep. 69: 1391–1398 (1985).Google Scholar
  30. 30.
    P.M. Calabro-Jones, J.E. Byfield, and J.F. Ward, Time-dose relationships for 5-fluorouracil cytotoxicity against human epithelial cancer cells in vitro, Cancer Res. 42: 4413–4420 (1982).PubMedGoogle Scholar
  31. 31.
    G.J. Peters, E. Laurensse, A Leyva, J. Lankelma, and H.M. Pinedo, Sensitivity of human, murine and rat cells to 5-fluorouracil and 5′deoxy-5-fluorouridine in relation to drug metabolizing enzymes, Cancer Res. 46: 20–28 (1986).PubMedCrossRefGoogle Scholar
  32. 32.
    Y.P.A.M. Keepers, P.E. Pizao, G.J. Peters, J. van Ark-Otte, B. Winograd, and H.M. Pinedo, Growth-inhibition kinetics — schedule and concentration dependency — of anticancer agents in colon cancer cells, Proc. Amer. Assoc. Cancer Res. 32: 386 (Abstract 2292) (1991).Google Scholar
  33. 33.
    C.L. van der Wilt, H.M. Pinedo, J. Cloos, P. Noordhuis, K. Smid, and G.J. Peters, Effect of folinic acid on 5-fluorouracil activity and expression of thymidylate synthase. Sem. Oncology 19 (Sup 3): 16–25 (1992).Google Scholar
  34. 34.
    G.J. Peters, E. Laurensse, A. Leyva, and H.M. Pinedo, Purine nucleosides as cell-specific modulators of 5-fluorouracil metabolism and cytotoxicity, Eur. J. Cancer Clin. Oncol. 23: 1869–1881 (1987).PubMedCrossRefGoogle Scholar
  35. 35.
    J.C. Nadal, C.J. van Groeningen, H.M. Pinedo, and G.J. Peters, Schedule-dependency of in vivo modulation of 5-fluorouracil by leucovorin and uridine in murine colon carcinoma, Invest. New Drugs 7: 163–172 (1989).PubMedCrossRefGoogle Scholar
  36. 36.
    G.J. Peters, J. van Dijk, E. Laurensse, C.J. van Groeningen, J. Lankelma, A. Leyva, J.C. Nadal, and H.M. Pinedo. In vitro biochemical and in vivo biological studies of the uridine “rescue” of 5-fluorouracil, Brit. J. Cancer 57: 259–265 (1988).PubMedCrossRefGoogle Scholar
  37. 37.
    C.L. van der Wilt, K. Smid, H.M. Pinedo, and G.J. Peters, Elevation of thymidylate synthase following 5-fluorouracil treatment is prevented by addition of leucovorin in murine colon tumors, Cancer Res. 52: 4922–4928 (1992).PubMedGoogle Scholar
  38. 38.
    C.L. van der Wilt, J. van Laar, F. Gyergyay, K. Smid, and G.J. Peters, Biochemical modification of the toxicity and antitumor effect of 5-fluorouracil and cis-platinum by WR-2721 (ethiofos) in mice, Eur. J. Cancer, in press.Google Scholar
  39. 39.
    C.J. van Groeningen, H.M. Pinedo, J. Heddes, R.M. Kok, A.P.J.M. de Jong, E. Wattel, G.J. Peters and J. Lankelma, Pharmacokinetics of 5-fluorouracil assessed with a sensitive mass spectrometric method in patients during a dose escalation schedule, Cancer Res. 48: 6956–6961 (1988).PubMedGoogle Scholar
  40. 40.
    G.J. Peters, J. Lankelma, R.M. Kok, P. Noordhuis, C.J. van Groeningen, S. Meijer, and H.M. Pinedo, Long retention of high concentrations of 5-fluorouracil in human and murine tumors compared to plasma, Cancer Chemother. Pharmacol., in press.Google Scholar
  41. 41.
    T. Yoshida, E. Araki, M. Iigo, T. Fujii, M. Yoshino, Y. Shimada, D. Saito, H. Tajiri, H. Yamaguchi, S. Yoshida, M. Yoshino, H. Ohkura, M. Yoshimori, and N. Okazaki, Clinical significance of monitoring serum levels of 5-fluorouracil by continuous infusion in patients with advanced colonic cancer, Cancer Chemother. Pharmacol. 26: 352–354 (1990).PubMedCrossRefGoogle Scholar
  42. 42.
    M. Slavik, J. Wu, D. Einspahr, and C. Riley, Clinical pharmacokinetics of 5-fluorouracil low dose continuous intravenous infusion, Proc. Amer. Assoc. Cancer Res. 32: 173 (Abstract 1030) (1991).Google Scholar
  43. 43.
    C. Erlichman, S. Fine, and T. Elhakim, Plasma Pharmacokinetics of 5-FU Given by Continuous Infusion With Allopurinol, Cancer Treatment Rep. 70: 903–904 (1986).Google Scholar
  44. 44.
    S. Fujii, Y. Shimamoto, H. Ohshimo, T. Imaoka, M. Motoyama, M. Fukushima, and T. Shirasaka, Effects of the Plasma Concentration of 5-Fluorouracil and the Duration of Continuous Venous Infusion of 5-Fluorouracil with an Inhibitor of 5-Fluorouracil Degradation on Yoshida Sarcomas in Rats, Jpn. J. Cancer Res. 80: 167–172 (1989).PubMedCrossRefGoogle Scholar
  45. 45.
    W.M. Hryniuk, A Figueredo, and M. Goodyear, Applications of Dose Intensity to Problems in Chemotherapy of Breast and Colorectal Cancer, Semin. Oncol. 14 (Suppl 4): 3–11 (1987).PubMedGoogle Scholar
  46. 46.
    S.G. Arbuck, Overview of Clinical Trials Using 5-Fluorouracil and Leucovorin for the Treatment of Colorectal Cancer, Cancer 63: 1036–1044 (1989).PubMedCrossRefGoogle Scholar
  47. 47.
    G. Codacci-Pisanelli, C.L. van der Wilt, P. Noordhuis, R. Kok, F. Franchi, H.M. Pinedo, and G.J. Peters, Pharmacodynamics and antitumour activity of continuous infusion (ci.) of 5-Fluorouracil in mice, Proc. Amer. Assoc. Cancer Res. 33: 533 (Abstract 3184) (1992).Google Scholar
  48. 48.
    L.D. Nord and D.S. Martin, Loss of Murine Tumor Thymidine Kinase Activity in vivo Following 5-Fluorouracil (FUra) Treatment by Incorporation of FUra into RNA, Biochem. Pharmacol. 42: 2369–2375 (1991).PubMedCrossRefGoogle Scholar
  49. 49.
    T.-L. Chen and C. Erlichman, Biochemical modulation of 5-fluorouracil with or without leucovorin by a low dose of brequinar in MGH-U1 cells, Cancer Chemother. Pharmacol. 30: 370–376 (1992).PubMedCrossRefGoogle Scholar
  50. 50.
    N. Kemeny, J.A. Conti, K. Sciter, D. Niedzwiecki, J. Botet, D. Martin, P. Costa, J. Wiseberg, and W. McCulloch, Biochemical Modulation of Bolus Fluorouracil by PALA in Patients With Advanced Colorectal Cancer, J. Clin. Oncol. 10: 747–752 (1992).PubMedGoogle Scholar
  51. 51.
    S. Wadler, B. Lembersky, M. Atkins, J. Kirkwood, and N. Petrelli, Phase II trial of fluorouracil and recombinant interferon alfa-2a in patients with advanced colorectal carcinoma: an Eastern cooperative oncology group study, J. Clin. Oncol. 9: 1806–1810 (1991).PubMedGoogle Scholar
  52. 52.
    R. Pazdur, J.A Ajani, Y.Z. Patt, R. Winn, D. Jackson, B. Shepard, R. DuBrow, L. Campos, M. Quaraishi, J. Faintuch, J.L. Abruzzese, J. Gutterman, and B. Levin, Phase II study of fluorouracil and recombinant alfa-2a in previously untreated advanced colorectal carcinoma. J. Clin. Oncol. 8: 2027–2031 (1990).PubMedGoogle Scholar
  53. 53.
    N. Kemeny, A. Younes, K. Sciter, D. Kelsen, P. Sammarco, L. Adams, S. Derby, P. Murray, and C. Houston, Interferon alfa-2a and 5-fluorouracil for advanced colorectal carcinoma. Assessment of activity and toxicity. Cancer 66: 2470–2475 (1990).PubMedCrossRefGoogle Scholar
  54. 54.
    J.D. Ahlgren, O. Trocki, J.J. Gullo, R. Goldberg, W.A. Muir, R. Sisk, and L. Schacter, Protracted Infusion of 5-FU with Weekly Low-Dose Cisplatin as Second-Line Therapy in Patients with Metastatic Colorectal Cancer Who Have Failed 5-FU Monotherapy, Cancer Invest. 9: 27–33 (1991).PubMedCrossRefGoogle Scholar
  55. 55.
    J.E. Byfield, 5-Fluorouracil radiation sensitization: A brief review, Invest. New Drugs 7: 111–116 (1989).PubMedCrossRefGoogle Scholar
  56. 56.
    W.J.M. Hrushesky, More Evidence for Crcadian Rhythm Effects in Cancer Chemotherapy: The Fluoropyrimidine Story, Cancer Cells 2: 65–68 (1990).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1993

Authors and Affiliations

  • Godefridus J. Peters
    • 1
  • Giovanni Codacci-Pisanelli
    • 2
  • Clasina L. van der Wilt
    • 1
  • Jan A. M. van Laar
    • 1
  • Kees Smid
    • 1
  • Paul Noordhuis
    • 1
  • Herbert M. Pinedo
    • 3
  1. 1.Dept. OncologyFree University HospitalAmsterdamthe Netherlands
  2. 2.3rd Dept. Intern. MedicineUniv. Roma “La Sapienza”Italy
  3. 3.Netherlands Cancer Institutethe Netherlands

Personalised recommendations