High-dose, single-agent irinotecan as first-line therapy in the treatment of metastatic colorectal cancer.
OBJECTIVE
The efficacy and safety of single-agent, high-dose irinotecan (CPT-11, Campto) 500 mg/m(2) every 3 weeks were investigated as first-line treatment for advanced colorectal cancer (CRC).


METHODS
Patients were enrolled into the study to receive a first cycle of therapy with irinotecan at a dose of 350 mg/m(2) every 3 weeks, which could be escalated to 500 mg/m(2) for the second and subsequent cycles depending on toxicity. Efficacy, safety and pharmacokinetics were determined in the intent to treat (ITT) population and the high-dose population (i.e. patients who had received at least three cycles of irinotecan, the second and third at 500 mg/m(2)).


RESULTS
Of 49 patients enrolled into the study (ITT population), 31 (63%) received at least three cycles of treatment with cycles 2 and 3 at an irinotecan dose of 500 mg/m(2) (the high-dose population). The response rates (RR) for the ITT and high-dose populations were 24.5% and 35.5%, respectively. The main grade 3/4 toxicities per cycle in the ITT and high-dose populations were neutropenia 22% and 17%, febrile neutropenia 5% and 3%, and diarrhoea 12% and 7%, respectively. The pharmacokinetics of irinotecan and its metabolite SN-38 were investigated in 31 patients in cycle 1 and 22 patients in cycle 2. Irinotecan clearance and SN-38 exposure were not sufficiently correlated with toxicity in cycle 1 to identify patients for dose increase in subsequent cycles. The exposure to irinotecan and SN-38 increased in proportion to dose from 350 to 500 mg/m(2).


CONCLUSIONS
These results suggest that high-dose irinotecan can be safely administered as first-line monotherapy to approximately two-thirds of patients who present with advanced CRC following a selective first cycle.
Ychou
M
M
CRLC Val d'Aurelle, 31 Rue de la croix verte, 34298 Montpellier cedex 05, France. mychou@valdorel.fnclcc.fr
Raoul
J L
JL
Desseigne
F
F
Borel
C
C
Caroli-Bosc
F X
FX
Jacob
J H
JH
Seitz
J F
JF
Kramar
A
A
Hua
A
A
Lefebvre
P
P
Couteau
C
C
Merrouche
Y
Y
D000230:Adenocarcinoma / Q000188:drug therapy / Q000556:secondary*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000188:drug therapy*; D003967:Diarrhea / Q000139:chemically induced; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012004:Rectal Neoplasms / Q000188:drug therapy*; D012074:Remission Induction; D012449:Safety; D059004:Topoisomerase I Inhibitors; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009363:Neoplasm Proteins; D011355:Prodrugs; D059004:Topoisomerase I Inhibitors; D016179:Granulocyte Colony-Stimulating Factor; D000077146:Irinotecan; D002166:Camptothecin