Sequence effect of irinotecan and fluorouracil treatment on pharmacokinetics and toxicity in chemotherapy-naive metastatic colorectal cancer patients.
OBJECTIVE
To investigate the sequence effect of irinotecan and a 48-hour infusion of fluorouracil (5-FU) modulated by leucovorin (LV) on the plasma pharmacokinetics of irinotecan and its metabolites, the toxicity profile of this combination, and irinotecan's maximum-tolerated dose (MTD).


METHODS
Thirty-three metastatic colorectal cancer patients were randomized to receive a 60-minute infusion of irinotecan before or after a 48-hour infusion of 5-FU modulated by LV. The reverse sequence was used after 21 days for the second cycle. 5-FU 3,500 mg/m2 was preceded by l-LV 250 mg/m2. Irinotecan 150 mg/m2 (starting dose) was administered to the first three patients. The dose was escalated by 50 mg/m2 in subsequent groups of three to six patients to determine the MTD for both sequences. Pharmacokinetic analysis of irinotecan and its metabolites was performed after each cycle.


RESULTS
Toxicities were affected by the sequence of administration of irinotecan and 5-FU, with an improved tolerability for irinotecan followed by 5-FU. The irinotecan MTD was reached at 300 mg/m2 when irinotecan followed 5-FU and at 450 mg/m2 when it preceded 5-FU. In seven of 23 patients who received both sequences at identical irinotecan doses, the dose-limiting toxicity was observed only when irinotecan followed 5-FU. Pharmacokinetic analysis revealed that the administration sequence significantly affected the SN-38 area under the concentration-versus-time curve (AUC), which was 40.1% lower (P <.05) when irinotecan preceded 5-FU.


CONCLUSIONS
The sequence of treatment with irinotecan and infusional 5-FU affects the tolerability of this combination. This can be explained in part by a reduced SN-38 AUC when irinotecan preceded infusional 5-FU. Well-defined 5-FU/irinotecan regimens are needed because the administration sequence or the interval between the agents might affect treatment tolerance and perhaps also activity.
Falcone
A
A
Division of Medical Oncology, Department of Oncology, Civil Hospital, Livorno, Italy. a.falcone@do.med.unipi.it
Di Paolo
A
A
Masi
G
G
Allegrini
G
G
Danesi
R
R
Lencioni
M
M
Pfanner
E
E
Comis
S
S
Del Tacca
M
M
Conte
P
P
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism; D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin