Irinotecan combined with bolus fluorouracil, continuous infusion fluorouracil, and high-dose leucovorin every two weeks (LV5FU2 regimen): a clinical dose-finding and pharmacokinetic study in patients with pretreated metastatic colorectal cancer.
OBJECTIVE
To determine the maximum-tolerated dose (MTD) and recommended dose of irinotecan (CPT-11) in combination with fluorouracil (5-FU) and leucovorin (LV), using a biweekly LV5FU2 regimen and increasing doses of CPT-11, and to assess the efficacy of this combination in pretreated patients with colorectal cancer (CRC).


METHODS
All patients had metastatic CRC and a World Health Organization performance status of 0 or 1. CPT-11 was administered over a 90-minute infusion every 2 weeks at a range of dose levels (100, 120, 150, 180, 200, 220, and 260 mg/m(2)). LV5FU2 was started 1 hour after the end of the biweekly CPT-11 infusion and was also administered on day 2.


RESULTS
Fifty-five patients were entered onto this trial; 549 cycles were administered. The MTD was not reached at 260 mg/m(2), and a dose level of 300 mg/m(2) was added. The MTD as defined in the protocol was not reached at this dose level either, but all patients had cycles delayed and/or required a dose reduction. This dose was deemed to be the MTD. To take into account both the toxicity of and compliance with the biweekly schedule, the recommended CPT-11 dose was established at 180 to 200 mg/m(2). Antitumor activity was observed at almost all dose levels, with an objective response rate of 22%. Median time to progression was 6.3 months and overall survival was 15 months.


CONCLUSIONS
The biweekly CPT-11/LV5FU2 combination is feasible and safe, without overlapping toxicity. CPT-11 at 180 to 200 mg/m(2) in combination with LV5FU2 has been selected as the recommended dose for further studies.
Ducreux
M
M
Institut Gustave Roussy, Villejuif, France.
Ychou
M
M
Seitz
J F
JF
Bonnay
M
M
Bexon
A
A
Armand
J P
JP
Mahjoubi
M
M
Méry-Mignard
D
D
Rougier
P
P
D000328:Adult; D000368:Aged; D000931:Antidotes / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000931:Antidotes; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin