Originally published as JCO Early Release 10.1200/JCO.2003.11.122 on September 8 2003

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Randomized Phase III Study of High-Dose Fluorouracil Given As a Weekly 24-Hour Infusion With or Without Leucovorin Versus Bolus Fluorouracil Plus Leucovorin in Advanced Colorectal Cancer: European Organization of Research and Treatment of Cancer Gastrointestinal Group Study 40952

C-H. Köhne, J. Wils, M. Lorenz, P. Schöffski, R. Voigtmann, C. Bokemeyer, M. Lutz, U. Kleeberg, K. Ridwelski, R. Souchon, M. El-Serafi, U. Weiss, O. Burkhard, H. Rückle, M. Lichinitser, T. Langenbuch, W. Scheithauer, B. Baron, M.L. Couvreur, H.J. Schmoll

From the Department of Internal Medicine I, University of Dresden, Dresden; Modizinische Hochschule Hannover, Hannover; Marien hospital Universitätsklinik, Herne; Eberhard Karls University, Tübingen; Caritasklinik St. Theresia, Saarbrücken; H.O.P.A., Hamburg; Akadem Lehrkrankenhaus der MLU Halle Wittenberg, Dessau; Allgemeines Krankenhaus Hagen GmbH, Hagen; Klinikum Lippe Lengo GmbH, Lengo; Medizinische Poliklinik der Universität, Würzberg; Martin Luther Universität Halle Wittenberg, Halle, Germany; EORTC Data Center, Brussels, Belgium; Allgeneines Krankenhaus, Vienna, Austria; N.N. Blokhin Cancer Research Center, Moscow, Russia; National Cancer Institute, Cairo, Egypt.

Address reprint requests to Claus-Henning Köhne, MD, Department of Internal Medicine I, University of Dresden, Fetscherstr 74, 01307 Dresden, Germany; e-mail: claus-henning.koehne{at}uniklinikum-dresden.de.

Purpose: This trial was conducted to determine whether high-dose fluorouracil (FU) given as a weekly 24-hour infusion is more active than bolus FU + leucovorin (LV), and whether high-dose infusional FU can be modulated by LV.

Patients and Methods: A total of 497 patients with previously untreated metastatic colorectal cancer were randomly assigned to receive bolus FU 425 mg/m² intravenously + LV 20 mg/m² on days 1 to 5 and repeated on day 28 (FU + LV), or FU 2,600 mg/m² as a 24-hour infusion alone (FU_24h) or in combination with 500 mg/m² LV (FU_24h + LV)—all given weekly x6 followed by a 2-week rest period. Survival was the major study end point.

Results: With a median follow-up of more than 3 years, survival did not differ among the treatment groups (median FU + LV, 11.1 months [95% CI, 10.2 to 15.0 months]; FU_24h, 13.0 months [95% CI, 10.4 to 15.4 months]; FU_24h + LV, 13.7 months [95% CI, 12.0 to 16.4 months]; P = .724). Progression-free survival (PFS) was significantly longer for FU_24h + LV (median FU + LV, 4.0 months [95% CI, 3.4 to 4.9]; FU_24h, 4.1 months [95% CI, 3.4 to 5.0]; FU_24h + LV 5.6 months [95% CI, 4.4 to 6.7]; P = .029). The response rates in the subgroup of patients with measurable disease were 12%, 10%, and 17% for FU + LV, FU_24h, and FU_24h + LV, respectively (not significant). Occurrence of grade 3 and 4 diarrhea was higher in the FU_24h + LV arm (22%) compared with the FU_24h (6%) or FU + LV (9%) arms; however, stomatitis (11% in FU + LV v 3% in FU_24h v 5% in FU_24h + LV arms) and hematologic toxicity were higher in the bolus FU + LV arm. Global quality of life did not differ within the three arms.

Conclusion: Neither FU_24h + LV nor FU_24h prolong survival, relative to bolus FU + LV. Leucovorin increases PFS if added to FU_24h, but increases toxicity.

Deceased.

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