Skip to main content

Advertisement

SpringerLink
Log in

Modulation von 5-Fluorouracil durch Leucovorin bei fortgeschrittenen kolorektalen Karzinomen

Modulation of 5-fluorouracil with leucovorin in advanced colorectal carcinoma

  • Published:
Acta Chirurgica Austriaca Aims and scope Submit manuscript

Zusammenfassung

Trotz umfangreicher klinischer Untersuchungen konnte in den letzten 20 Jahren die medikamentöse Palliativtherapie fortgeschrittener kolorektaler Karzinome nicht entscheidend verbessert werden. Als Standardtherapie galt bisher eine Monotherapie mit 5-Fluorouracil (5-FU), das in 15 bis 20% der Fälle zu einer objektiven Tumorregression führt. Die therapeutische Effizienz kann allerdings durch Modulation der 5-FU-Wirkung durch Leucovorin (LV) gesteigert werden. Im Rahmen von Phase-II-Studien wurden Ansprechraten zwischen 20 und 40% mitgeteilt und in randomisierten Studien mit der Kombination 5-FU/LV gegenüber 5-FU allein ein Überlebensgewinn erzielt. Allerdings sind optimale Dosierung und Form der Applikation von 5-FU/LV noch nicht bekannt. An toxischen Nebenwirkungen sind vor allem Stomatitis, Diarrhöe und Myelosuppression bekannt. Im Rahmen der Therapie mit 5-FU/LV wurden auch toxische Todesfälle berichtet. In einer eigenen Untersuchung wurde mit einer kontinuierlichen Dauerinfusion von 5-FU (500 mg/m2) über 5 Tage und LV (200 mg/m2/d als Bolus) bei 26 auswertbaren Patienten lediglich in 12% der behandelten Patienten eine partielle Remission erzielt. Das mediane Überleben der Gesamtgruppe betrug 15 Monate. Die therapiebedingte Toxizität war allerdings gering, es wurde kein toxischer Todesfall beobachtet.

Zur endgültigen Beurteilung der Kombination 5-FU/LV sind weitere klinische Studien erforderlich.

Summary

In spite of intensive investigation there has been no significant improvement in the chemotherapy of patients with metastatic colorectal cancer. Monotherapy with 5-fluorouracil (5-FU) remains the standard treatment yielding a 15 to 20% response rate. The therapeutic efficacy of 5-FU may be enhanced by leucovorin (LV). In phase II trials response rates of 20 to 40% were reported and in some randomized studies comparing 5-FU and 5-FU/LV a survival benefit was achieved with the combination. However, the optimal dose, schedule and route of administration of 5-FU/LV remain to be determined. Causing substantial mucositis, diarrhoe and myelosuppression toxic deaths occurred under 5-FU/LV treatment. In a phase II-study we administered 5-FU as a continuous infusion (500 mg/m2) in a 5-day course, LV was given as i.v. bolus (200 mg/m2/d). 12% of 26 patients, evaluable for response, reached a partial remission. The overall median survival was 15 months. The treatment related toxicity was mild, no drug-related death was observed.

Further studies are needed to identify the optimal 5-FU/LV-treatment.

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

Literatur

  1. Arbuck SG: 5-FU/leucovorin: Biochemical modulation that works? Oncology 1987;1:61–71.

    PubMed  CAS  Google Scholar 

  2. Au J L-S, Rustum YM, Ledesma EJ, et al: Clinical pharmacology studies of concurrent infusion of 5-fluorouracil and thymidine in treatment of colorectal carcinomas. Cancer Res 1982;42:2930–2937.

    PubMed  CAS  Google Scholar 

  3. Bertino JR, Sawicki WL, Lindquist CA, et al: Schedule dependent antitumor effects of methotrexate and 5-fluorouracil. Cancer Res 1977;37:327–328.

    PubMed  CAS  Google Scholar 

  4. Bruckner HW, Roboz T, Spigelman M, et al: An efficient Leucovorin-5-fluorouracil sequence: Dosage escalation and pharmacological monitoring, in Bruckner HW, Rustum YM (eds): Advances in cancer chemotherapy. The current status of 5-fluorouracil-leucovorin calcium combination. New York. Park Row Publishers, Wiley & Sons, 1984, pp 49–54.

    Google Scholar 

  5. Budd GT, Fleming TR, Bukowski RM, et al: 5-fluorouracil and folinic acid in the treatment of metastatic colorectal cancer: A randomized comparison. A Southwest Oncology Group Study. J Clin Oncol 1987;5:272–277.

    PubMed  CAS  Google Scholar 

  6. Byrne PJ, Treat J, Mc Fadden M, et al: Therapeutic efficacy of the combination of 5-fluorouracil and high-dose leucovorin in patients with advanced colorectal carcinoma: Single daily intravenous dose for five days, in Bruckner HW, Rustum YM (eds): Advances in cancer chemotherapy. The current status of 5-fluorouracil-leucovorin calcium combination. New York. Park Row Publishers, Wiley & Sons. 1984, pp 65–68.

    Google Scholar 

  7. Chua L, Andalan B, Sridhor KS, et al: A Phase II study of short term protracted infusion with high dose 5-fluorouracil (5-FU) with leucovorin (LV) in colorectal carcinoma. Proc Am Soc Clin Oncol 1990;9:106.

    Google Scholar 

  8. Costanzo FD, Bartolucci R, Sofra M, et al: 5-fluorouracil alone versus high dose folinic acid and 5-FU in advanced colorectal cancer: A randomized trial of the Italian Oncology Group for Clinical Research. Proc Am Soc Clin Oncol 1989;8:106 (abstr).

    Google Scholar 

  9. Danenberg PV, Langenbach RJ, Heidelberger C: Structures of reversible and irreversible complexes of thymidilate synthetase and fluoropymiridine nucleotides. Biochemistry 1977;13:926–933.

    Article  Google Scholar 

  10. Doroshow JH, Multhauf P, Leong L, et al: Prospective randomized comparison of fluorouracil versus fluorouracil and high-dose continuous infusion leucovorin calcium for the treatment of advanced measurable colorectal cancer in patients proviously unexposed to chemotherapy. J Clin Oncol 1990;8:491–501.

    PubMed  CAS  Google Scholar 

  11. Erlichman C, Fine S, Wong A, et al: A randomized trial of fluorouracil and folinic acid in patients with metastatic colorectal carcinoma. J Clin Oncol 1988;6:469–475.

    PubMed  CAS  Google Scholar 

  12. Grem JL, Hoth DF, Hamilton JM, et al: Overview of current status and future direction of clinical trials with 5-fluorouracil in combination with folinic acid. Cancer Treat Rep 1987;71:1249–1264.

    PubMed  CAS  Google Scholar 

  13. Heidelberger C, Chaudhari NK, Danneberg P, et al: Fluorinated pyrimidine. A new class of tumor inhibitory compounds. Nature 1957;179:663–666.

    Article  PubMed  CAS  Google Scholar 

  14. Houghton JA, Moroda SJ, Phillips JO, et al: Biochemical determinants of responsiveness to 5-fluorouracil and its derivates in xenografts of human colorectal adenocarcinomas in mice. Cancer Res 1981;41:144–149.

    PubMed  CAS  Google Scholar 

  15. Labianca R, Pancera G, Beretta G, et al: A randomized study of intravenous fluorouracil plus or minus folinic acid in advanced metastatic colorectal carcinoma. Proc Am Soc Clin Oncol 1989;8:118 (abstr).

    Google Scholar 

  16. Leichman C, Leichman L, Spears P, et al: Phase II study of protracted infusion 5-fluorouracil (5-FU) with weekly leucovorin (LV) in disseminated, measurable adenocarcinoma of the large bowel. Proc Am Soc Clin Oncol 1990;9:129.

    Google Scholar 

  17. Loehrer PJ, Turner S, Kubilis P, et al: 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 1988;6:642–648.

    PubMed  Google Scholar 

  18. Lokich J, Ahlgren J, Gullo J, et al: A randomized trial of standard bolus 5-FU versus protracted infusional 5-FU in advanced colon cancer. Proc Am Soc Clin Oncol 1987;6:81 (abstr).

    Google Scholar 

  19. Machover D, Goldschmidt E, Chollet P, et al: Treatment of advanced colorectal and gastric adenocarcinomas with 5-fluorouracil and high dose folinic acid. J Clin Oncol 1986;4:685–696.

    PubMed  CAS  Google Scholar 

  20. Madajewicz S, Petrelli N, Rustum YM, et al: Phase I~II trial of high-dose calcium leucovorin and 5-fluorouracil in advanced colorectal cancer. Cancer Res 1984;44:4467–4469.

    Google Scholar 

  21. Moertel CG, Reitemeier RJ: Advances in Gastrointestinal Cancer: Clinical Management and Chemotherapy. New York, Harper & Row, 1969, pp 86–107.

    Google Scholar 

  22. Moertel CG: Chemotherapy of gastrointestinal cancer. N Engl J Med 1978;299:1049–1051.

    Article  PubMed  CAS  Google Scholar 

  23. Nobile MT, Vidili MG, Sobrero A, et al: 5-fluorouracil alone or combined with high dose folinic acid in advanced colorectal cancer patients: A randomized trial. Proc Am Soc Clin Oncol 1988;7:97 (abstr).

    Google Scholar 

  24. O'Dwyer PJ, Paul AR, Peter R, et al: Biochemical modulation of 5-fluorouracil (5-FU) by PALA: Phase II study in colorectal cancer. Proc Am Soc Clin Oncol 1989;8:107.

    Google Scholar 

  25. Petrelli N, Douglass HO jr, Herrera L, et al: The modulation of fluorouracil with leucovorin in metastatic colorectal carcinoma: A prospective randomized phase III trial. J Clin Oncol 1989;7:1419–1426.

    PubMed  CAS  Google Scholar 

  26. Poon MA, O'Connel MJ, Moertel CG, et al: Biochemical modulation of fluorouracil: Evidence of significant improvement of survival and quality of life in patients with advanced colorectal carcinoma. J Clin Oncol 1989;7:1407–1418.

    PubMed  CAS  Google Scholar 

  27. Rustum YM, Campbell J, Petrelli N, et al: Clinical biochemical pharmacology of 5-formyltetrahydrofolate in combination with 5-fluorouracil in patients with advanced colorectal carcinoma: Correlation with clinical response, in Bruckner HW, Roboz T, Spigelman M, et al (eds): An efficient leucovorin-5-fluorouracil sequence: Dosage escalation and pharmacological monitoring, in Bruckner HW, Rustum YM (eds): Advances in cancer chemotherapy. The current status of 5-fluorouracil-leucovorin calcium combination. New York, Park Row Publishers, Wiley & Sons, 1984, pp 77–82.

    Google Scholar 

  28. Santi DV: A biochemical rationale for the use of 5-fluorouracil in combination with leucovorin, in Bruckner HW, Rustum YM (eds). Advances in cancer chemotherapy. The current status of 5-fluorouracil-leucovorin calcium combination. New York, Park Row Publishers, Wiley & Sons, 1984, pp 1–4.

    Google Scholar 

  29. Sugarbaker PH, Gunderson LL, Wittes RE: Colorectal cancer, in De vita jr, Hellman S, Rosenberg SA (eds). Cancer: Principles and Practice of Oncology. New York, Lippincott, 1985, pp 795–884.

    Google Scholar 

  30. Valone FH, Friedman MA, Wittlinger PS, et al: Treatment of patients with advanced colorectal carcinomas with fluorouracil alone, high-dose leucovorin plus fluorouracil, or sequential methotrexate, fluorouracil and leucovorin: A randomized trial of the Northern California Oncology Group. J Clin Oncol 1989;7:1426–1427.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Onkologischen Ambulanz und Bettenstation der Landeskrankenanstalten Salzburg, Müllner Hauptstraße 48, A-5020, Salzburg

    H. Hausmaninger

Authors
  1. H. Hausmaninger
    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

Hausmaninger, H. Modulation von 5-Fluorouracil durch Leucovorin bei fortgeschrittenen kolorektalen Karzinomen. Acta Chir Austriaca 23, 230–234 (1991). https://doi.org/10.1007/BF02663232

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02663232

Schlüsselwörter

Key-words

Search

Navigation