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A Phase I Pharmacologic and Pharmacogenetic Trial of Sequential 24-Hour Infusion of Irinotecan Followed by Leucovorin and a 48-Hour Infusion of Fluorouracil in Adult Patients with Solid Tumors

Authors' Affiliations: ¹ Gastrointestinal Tumor Section, Cancer Therapeutics Branch, and ² Medical Oncology Clinical Research Unit, ³ Center for Cancer Research, ⁴ Cancer Prevention Program, ⁵ National Cancer Institute, ⁶ Division of Hematology and Medical Oncology, National Naval Medical Center, Bethesda, Maryland

Requests for reprints: Jean Grem, Section of Hematology/Oncology, Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE 68198-7680. Phone: 402-559-6210; Fax: 402-559-6520; E-mail: jgrem{at}unmc.edu.

Purpose: In preclinical studies, sequential exposure to irinotecan (CPT-11) then fluorouracil (5-FU) is superior to concurrent exposure or the reverse sequence; a 24-hour infusion of CPT-11 may be better tolerated than shorter infusions.

Experimental Design: CPT-11 was first given at four levels (70-140 mg/m²/24 hours), followed by leucovorin 500 mg/m²/0.5 hours and 5-FU 2,000 mg/m²/48 hours on days 1 and 15 of a 4-week cycle. 5-FU was then increased in three cohorts up to 3,900 mg/m²/48 hours.

Results: Two patients had dose-limiting toxicity during cycle 1 at 140/3,900 of CPT-11/5-FU (2-week delay for neutrophil recovery; grade 3 nausea despite antiemetics); one of six patients at 140/3,120 had dose-limiting toxicity (grade 3 diarrhea, grade 4 neutropenia). Four of 22 patients with colorectal cancer had partial responses, two of which had prior bolus CPT-11/5-FU. The mean 5-FU plasma concentration was 5.1 µmol/L at 3,900 mg/m²/48 hours. The end of infusion CPT-11 plasma concentration averaged 519 nmol/L at 140 mg/m²/24 hours. Patients with UDP-glucuronosyltransferase (UGT1A1; TA)6/6 promoter genotype had a lower ratio of free to glucuronide form of SN-38 than in patients with 1 (TA)7 allele. Thymidylate synthase genotypes for the 28-base promoter repeat were 2/2 (13%), 2/3 (74%), 3/3 (13%); all four responders had a 2/3 genotype.

Conclusions: Doses (mg/m²) of CPT-11 140/24 hours, leucovorin 500/0.5 hours and 5-FU 3,120/48 hours were well tolerated.

Key Words: uridine glucuronosyltransferase 1A1 • thymidylate synthase • glucuronidation