title: A phase I trial of CPT-11 in combination with 5-fluorouracil plus leucovorin chemotherapy for patients with metastatic colorectal cancer.
abstract: OBJECTIVE
  To establish a safe and practical chemotherapeutic regimen using CPT-11 in combination with 5-FU plus leucovorin (5-FU/LV) for patients with metastatic colorectal cancer in an outpatient setting, a phase I clinical trial was conducted. METHDOLOGY: Eligible patients received the RPMI regimen of I-LV (200 mg/m2, for 2 hours) plus 5-FU (333 mg/m2, bolus) weekly for 4 weeks followed by a 2-week rest. CPT-11 was administered over the 5-FU/LV therapy at the 1st and 3rd week of every treatment cycle before the bolus 5-FU. Dose escalation of CPT-11 from 25 to 100 mg/m2 was done for every cohort consisting of at least 3 patients to define a dose-limiting toxicity (DLT), maximal tolerated dose (MTD), and recommended dose (RD) for a phase II trial.
  
  
  RESULTS
  Twenty-one patients with metastatic colorectal cancer were enrolled. Hematologic toxicity was very infrequently observed. One patient enrolled at level 1 (25 mg/m2 CPT-11), but not the other patients, had muscle weakness at grade 3 and needed to be hospitalized. Hair loss at grade 1 was observed in 3 of 21 patients. Gastrointestinal toxicity, including nausea, was commonly observed throughout the dose levels. Diarrhea was frequently observed at doses higher than level 4 (60 mg/m2 CPT-11), and 2 of the 3 patients at dose level 6 (100 mg/m2 CPT-11) experienced diarrhea at grade 3 and needed to be hospitalized. As for the overall tumor responses, 3 partial responses (PR), 10 stable diseases, and 6 progressive diseases were observed, with 2 of the PRs occurring at dose level 5 (80 mg/m2 CPT-11).
  
  
  CONCLUSIONS
  These results suggest that our treatment regimen using CPT-11 in combination with 5-FU/LV is a safe regimen in an outpatient setting and effective for patients with metastatic colorectal cancer. The DLT is diarrhea at the MTD of 100 mg/m2 of CPT-11, and 80 mg/m2 CPT-11 is recommended for the next phase II trial.
authors.affiliation: Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine Hiroshima University, Hiroshima, Japan. shogo@hiroshima-u.ac.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Minami
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Kawabuchi
authors.forename: Manabu
authors.initials: M
authors.lastname: Emi
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D014803:Vitamin B Complex / Q000008:administration & dosage*
chemical_list: D000970:Antineoplastic Agents; D014803:Vitamin B Complex; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin