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.
OBJECTIVE
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.


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 2600 mg/m2 as a 24-hour infusion alone (FU24h) or in combination with 500 mg/m2 LV (FU24h + 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]; FU24h, 13.0 months [95% CI, 10.4 to 15.4 months]; FU24h + LV, 13.7 months [95% CI, 12.0 to 16.4 months]; P =.724). Progression-free survival (PFS) was significantly longer for FU24h + LV (median FU + LV, 4.0 months [95% CI, 3.4 to 4.9]; FU24h, 4.1 months [95% CI, 3.4 to 5.0]; FU24h + 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, FU24h, and FU24h + LV, respectively (not significant). Occurrence of grade 3 and 4 diarrhea was higher in the FU24h + LV arm (22%) compared with the FU24h (6%) or FU + LV (9%) arms; however, stomatitis (11% in FU + LV v 3% in FU24h v 5% in FU24h + LV arms) and hematologic toxicity were higher in the bolus FU + LV arm. Global quality of life did not differ within the three arms.


CONCLUSIONS
Neither FU24h + LV nor FU24h prolong survival, relative to bolus FU + LV. Leucovorin increases PFS if added to FU24h, but increases toxicity.
Köhne
C-H
CH
Department og Internal Medicine I, University of Dresden, Dresden, Germany. claus-henning.koehne@uniklinikum-dresden.de
Wils
J
J
Lorenz
M
M
Schöffski
P
P
Voigtmann
R
R
Bokemeyer
C
C
Lutz
M
M
Kleeberg
C
C
Ridwelski
K
K
Souchon
R
R
El-Serafi
M
M
Weiss
U
U
Burkhard
O
O
Rückle
H
H
Lichnitser
M
M
Langenbuch
T
T
Scheithauer
W
W
Baron
B
B
Couvreur
M L
ML
Schmoll
H J
HJ
D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000009:adverse effects* / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D002955:Leucovorin / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011788:Quality of Life; D015996:Survival Rate; D016896:Treatment Outcome
D002955:Leucovorin; D005472:Fluorouracil