Biweekly intensified ambulatory chronomodulated chemotherapy with oxaliplatin, fluorouracil, and leucovorin in patients with metastatic colorectal cancer.
OBJECTIVE
This study sought to determine the feasibility and antitumor efficacy of an intensified three-drug chronomodulated regimen with maximum delivery at 4:00 AM for fluorouracil (5-FU)-leucovorin (folinic acid [FA]) and at 4:00 PM for oxaliplatin (I-OHP).


METHODS
Fifty patients with metastatic colorectal cancer were enrolled in the trial. The first treatment course consisted of daily administration of 5-FU (700 mg/m2/d), FA (300 mg/m2/d), and L-OHP (25 mg/m2/d) for 4 days with a multichannel programmable pump. Courses were repeated every 14 days, with 5-FU escalation by 100 mg/m2/d if toxicity was less than grade 2.


RESULTS
World Health Organization (WHO)-modified grade 3 or 4 diarrhea (40% of patients and 7% of courses) or stomatitis (28% of patients and 4% of courses) or grade 2 cumulative peripheral sensitive neuropathy (28% of patients) were dose-limiting. Median 5-FU and L-OHP dose-intensities (DIs), were increased by 32% and 18%, respectively, as compared with our previous 5 days on-16 days off schedule. The overall objective response rate was 48% (95% confidence limits [CL], 34% to 62%), being 40% (24% to 57%) in 37 previously treated patients and 69% (48% to 90%) in 13 chemotherapy-naive patients. A 5-FU DI > 1,400 mg/m2/wk over four courses was associated with a near doubling of the response rate. Residual metastases were surgically removed in 13 patients (26%). Median progression-free survival and survival durations were 9.3 months (95% CL, 6.6 to 11.2) and 17.8 months (95% CL, 14.1 to 21.4), respectively.


CONCLUSIONS
This highly effective fully ambulatory outpatient regimen deserves further testing in randomized trials both in chemotherapy-naive patients and before surgery to remove metastases.
Bertheault-Cvitkovic
F
F
Centre de Chronothérapie, Service des Maladies Sanguines, Immunitaires et Tumorales, France.
Jami
A
A
Ithzaki
M
M
Brummer
P D
PD
Brienza
S
S
Adam
R
R
Kunstlinger
F
F
Bismuth
H
H
Misset
J L
JL
Lévi
F
F
D000293:Adolescent; D000328:Adult; D000368:Aged; D000553:Ambulatory Care; D000931:Antidotes / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D015179:Colorectal Neoplasms / Q000473:pathology*; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin
D000931:Antidotes; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D002955:Leucovorin; D005472:Fluorouracil