Phase II trial of chronomodulated infusion of high-dose fluorouracil and l-folinic acid in previously untreated patients with metastatic colorectal cancer.
OBJECTIVE
To study tolerability and efficacy of an intensified chronomodulated schedule of fluorouracil (5-FU) and l-folinic acid (l-FA) as first-line treatment of metastatic colorectal cancer, 5-FU was given near individually determined dose-limiting toxicity in a multicenter phase II trial.


METHODS
One hundred patients (68 men and 32 women, median age 62 years, World Health Organization performance status less-than-or-equal 2) with previously untreated and inoperable metastases received chronomodulated daily infusion of 5-FU/l-FA (from 10:00 PM to 10:00 AM with peak at 4:00 AM). 5-FU dose was escalated from 900 to 1,100 mg/m(2)/d with fixed dose of l-FA at 150 mg/m(2)/d for 4 days every 14 days.


RESULTS
5-FU dose escalation was achieved in 66% of the patients. Grade 3 to 4 toxicities mainly consisted of nausea or vomiting (14% of patients and 1.5% of courses), hand-foot syndrome (38% of patients and 8% of courses), mucositis (26% of patients and 4% of courses), and diarrhea (21% of patients and 2.3% of courses). Objective response rate (ORR) was 41% (95% confidence interval, 31.5% to 50.5%). Twenty patients underwent metastases surgery; among these, 12 had a complete resection. Median progression-free survival was 7 months. Median survival was 17 months; 28% of the patients were alive at 2 years and 18.6% at 3 years.


CONCLUSIONS
The ORR achieved with intensified chronomodulated delivery of 5-FU/l-FA was nearly twice as high as that earlier obtained by our cooperative group using less intensive 5-FU/FA chronotherapy.
Curé
H
H
Centre Jean Perrin and L'Institut National de la Santé et de la Recherche Médicale U484, Clermont-Ferrand, France.
Chevalier
V
V
Adenis
A
A
Tubiana-Mathieu
N
N
Niezgodzki
G
G
Kwiatkowski
F
F
Pezet
D
D
Perpoint
B
B
Coudert
B
B
Focan
C
C
Lévi
F
F
Chipponi
J
J
Chollet
P
P
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000633:toxicity; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000633:toxicity; D019454:Chronotherapy; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000633:toxicity; D006801:Humans; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage / Q000633:toxicity; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D015996:Survival Rate
D000964:Antimetabolites, Antineoplastic; D002955:Leucovorin; D005472:Fluorouracil