A phase I-II trial of five-day continuous intravenous infusion of 5-fluorouracil delivered at circadian rhythm modulated rate in patients with metastatic colorectal cancer.
The toxicity of 5-fluorouracil (5-FU) was decreased by two to eight-fold if this drug was injected in mice near the middle of the day (rest span) rather than in the middle of the night (activity span). If the rhythm in 5-FU toxicity is linked to the sleep-wakefulness endogenous circadian cycle across species, the least toxic time in man would correspond to 4.00 hours at night. The availability of a single-reservoir programmable-in-time external ambulatory pump (Chronopump, Autosyringe, Hooksett, USA) allowed us to perform a first test of this hypothesis. Five-FU was infused for 5 consecutive days, via an implanted venous access port, with peak drug delivery at 4.00 hours and no infusion from 18.00 to 22.00 hours. Each course was repeated after a free interval of 16 days. Intrapatient dose escalation was planned from 4 to 9 g/m2/course (800 to 1800 mg/m2/day x 5 days) if toxicity was less than grade 2 according to the World Health Organization (W.H.O.). Thirty-five patients with metastatic colorectal cancer were treated; 15 (41%) had received previous therapy, 22 (63%) had W.H.O. performance status of 2 or greater, and 19 (54%) had two or more sites involved. Grade 2 or greater toxicity was encountered in less than 5% of the courses, indicating an adequate control of toxicity via dose adjustment. Oral mucositis, diarrhea, and/or hand-foot syndrome limited dose escalation, and their incidence was dose dependent. Median maximal tolerated dose was 7.5 mg/m2/course in 30 patients assessed for this endpoint.(ABSTRACT TRUNCATED AT 250 WORDS)
Laboratoire Rythmes Biologiques et Chronothérapeutique, Institut du Cancer et d'Immunogénétique, Hôpital P. Brousse, Villejuif, France.
F
F
Lévi
A
A
Soussan
R
R
Adam
J P
JP
Caussanel
G
G
Metzger
C
C
Jasmin
H
H
Bismuth
M
M
Smolensky
J L
JL
Misset
D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D002940:Circadian Rhythm; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007262:Infusions, Intravenous / Q000379:methods; D008297:Male; D009362:Neoplasm Metastasis
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil