Long-term weekly treatment of colorectal metastatic cancer with fluorouracil and leucovorin: results of a multicentric prospective trial of fluorouracil dosage optimization by pharmacokinetic monitoring in 152 patients.
OBJECTIVE
A relationship between fluorouracil (5-FU) dose and response has been previously shown in advanced colorectal cancer. In a previous study with 5-FU stepwise dose escalation in a weekly regimen, and pharmacokinetic monitoring, we defined a therapeutic range for 5-FU plasma levels: 2,000 to 3,000 microg/L (area under the concentration-time curve at 0 to 8 hours [AUC0-8], 16 to 24 mg x h/L). The current study investigated 5-FU therapeutic intensification with individual dose adjustment in a multicentric phase II prospective trial.


METHODS
Weekly high-dose 5-FU was administered by 8-hour infusion with 400 mg/m2 leucovorin. The initial dose of 5-FU (1,300 mg/m2) was adapted weekly according to 5-FU plasma levels, to reach the therapeutic range previously determined.


RESULTS
A total of 152 patients entered the study from December 1991 to December 1994: 117 patients with measurable metastatic disease and 35 with assessable disease. Toxicity was mainly diarrhea (39%, with 5% grade 3) and hand-foot syndrome (30%, with 2% grade 3). Among 117 patients with measurable disease, 18 had a complete response (CR), 48 a partial response (PR), 35 a minor response (MR) and stable disease (SD), and 16 progressive disease (PD). Median overall survival time was 19 months. The 5-FU therapeutic plasma range was rapidly reached with a variable 5-FU dose in the patient population: mean, 1,803 +/- 386 mg/m2/wk (range, 950 to 3,396). Thirteen patients were immediately in the toxic zone, whereas 51 required a > or = 50% dose increase.


CONCLUSIONS
Individual 5-FU dose adjustment with pharmacokinetic monitoring provided a high survival rate and percentage of responses, with good tolerance.
Gamelin
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E
Service d'Oncologie Médicale et de Pharmacologie Clinique, Centre Paul Papin, Angers, France. cppapin@unimedia.rf
Boisdron-Celle
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M
Delva
R
R
Regimbeau
C
C
Cailleux
P E
PE
Alleaume
C
C
Maillet
M L
ML
Goudier
M J
MJ
Sire
M
M
Person-Joly
M C
MC
Maigre
M
M
Maillart
P
P
Fety
R
R
Burtin
P
P
Lortholary
A
A
Dumesnil
Y
Y
Picon
L
L
Geslin
J
J
Gesta
P
P
Danquechin-Dorval
E
E
Larra
F
F
Robert
J
J
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary*; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D003110:Colonic Neoplasms / Q000473:pathology*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D012004:Rectal Neoplasms / Q000473:pathology*; D016019:Survival Analysis
D002955:Leucovorin; D005472:Fluorouracil