title: Phase I/II study of irinotecan, 5-fluorouracil, and l-leucovorin combination therapy (modified Saltz regimen) in patients with metastatic colorectal cancer.
abstract: BACKGROUND
  A combination of irinotecan 125 mg/m2, 5-fluorouracil (5-FU) 500 mg/m2, and leucovorin (LV) 20 mg/m2 (Saltz regimen; treatment on days 1, 8, 15, and 22 every 6 weeks) is widely used for the treatment of metastatic colorectal cancer. A modified schedule with chemotherapy on days 1 and 8 of a 21-day cycle was recommended in 2001 because of early treatment-related mortality. We conducted a phase I/II study of this modified Saltz regimen as first-line therapy in Japanese patients with metastatic colorectal cancer to assess the maximum tolerated dose (MTD) and the recommended dose of 5-FU when given with fixed doses of l-LV and irinotecan, and to evaluate the efficacy and the feasibility of this regimen.
  
  
  METHODS
  Irinotecan, 5-FU, and l-LV were administered on days 1 and 8 of a 21-day cycle. Irinotecan 100 mg/m2 was given intravenously over the course of 90 min on day 1, followed by l-LV 10 mg/m2, and then 5-FU. The dose of 5-FU was escalated from 400 mg/m2 (level 1) to 500 mg/m2 (level 2). If neither level met the criteria for the MTD, the recommended dose was defined as level 2, and dose escalation was discontinued, because the maximum approved weekly dose of irinotecan alone in Japan is 100 mg/m2 and the dose of 5-FU in the original Saltz regimen was 500 mg/m2.
  
  
  RESULTS
  One patient had grade 4 neutropenia with fever at level 1, and four patients had grade 3 neutropenia at level 2. There was no treatment-related death. Level 2 did not meet the criteria for the MTD. The relative dose intensities of the first five cycles were 91% for both 5-FU and irinotecan at level 1 and 86% for 5-FU and 93% for irinotecan at level 2. The response rates were 58% for all patients, and 69% for patients at level 2. CONCLUSION. Our results confirm that the modified Saltz regimen is safe and efficacious for Japanese patients. The recommended doses for phase II studies are irinotecan 100 mg/m2, 5-FU 500 mg/m2, and l-LV 10 mg/m2.
authors.affiliation: Gastrointestinal Oncology Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
authors.forename: Ayumu
authors.initials: A
authors.lastname: Goto
authors.forename: Yasuhide
authors.initials: Y
authors.lastname: Yamada
authors.forename: Ayumu
authors.initials: A
authors.lastname: Hosokawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Ura
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Arai
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hamaguchi
authors.forename: Kei
authors.initials: K
authors.lastname: Muro
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shimada
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shirao
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000139:chemically induced; D016896:Treatment Outcome
chemical_list: D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin