title: Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group.
abstract: BACKGROUND
  The combination of fluorouracil and leucovorin has until recently been standard therapy for metastatic colorectal cancer. Irinotecan prolongs survival in patients with colorectal cancer that is refractory to treatment with fluorouracil and leucovorin. In a multicenter trial, we compared a combination of irinotecan, fluorouracil and leucovorin with bolus doses of fluorouracil and leucovorin as first-line therapy for metastatic colorectal cancer. A third group of patients received irinotecan alone.
  
  
  METHODS
  Patients were randomly assigned to receive irinotecan (125 mg per square meter of body-surface area intravenously), fluorouracil (500 mg per square meter as an intravenous bolus), and leucovorin (20 mg per square meter as an intravenous bolus) weekly for four weeks every six weeks; fluorouracil (425 mg per square meter as an intravenous bolus) and leucovorin (20 mg per square meter as an intravenous bolus) daily for five consecutive days every four weeks; or irinotecan alone (125 mg per square meter intravenously) weekly for four weeks every six weeks. End points included progression-free survival and overall survival.
  
  
  RESULTS
  Of 683 patients, 231 were assigned to receive irinotecan, fluorouracil, and leucovorin; 226 to receive fluorouracil and leucovorin; and 226 to receive irinotecan alone. In an intention-to-treat analysis, as compared with treatment with fluorouracil and leucovorin, treatment with irinotecan, fluorouracil, and leucovorin resulted in significantly longer progression-free survival (median, 7.0 vs. 4.3 months; P=0.004), a higher rate of confirmed response (39 percent vs. 21 percent, P<0.001), and longer overall survival (median, 14.8 vs. 12.6 months; P=0.04). Results for irinotecan alone were similar to those for fluorouracil and leucovorin. Grade 3 (severe) diarrhea was more common during treatment with irinotecan, fluorouracil, and leucovorin than during treatment with fluorouracil and leucovorin, but the incidence of grade 4 (life-threatening) diarrhea was similar in the two groups (<8 percent). Grade 3 or 4 mucositis, grade 4 neutropenia, and neutropenic fever were less frequent during treatment with irinotecan, fluorouracil, and leucovorin. Adding irinotecan to the regimen of fluorouracil and leucovorin did not compromise the quality of life.
  
  
  CONCLUSIONS
  Weekly treatment with irinotecan plus fluorouracil and leucovorin is superior to a widely used regimen of fluorouracil and leucovorin for metastatic colorectal cancer in terms of progression-free survival and overall survival.
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: L B
authors.initials: LB
authors.lastname: Saltz
authors.forename: J V
authors.initials: JV
authors.lastname: Cox
authors.forename: C
authors.initials: C
authors.lastname: Blanke
authors.forename: L S
authors.initials: LS
authors.lastname: Rosen
authors.forename: L
authors.initials: L
authors.lastname: Fehrenbacher
authors.forename: M J
authors.initials: MJ
authors.lastname: Moore
authors.forename: J A
authors.initials: JA
authors.lastname: Maroun
authors.forename: S P
authors.initials: SP
authors.lastname: Ackland
authors.forename: P K
authors.initials: PK
authors.lastname: Locker
authors.forename: N
authors.initials: N
authors.lastname: Pirotta
authors.forename: G L
authors.initials: GL
authors.lastname: Elfring
authors.forename: L L
authors.initials: LL
authors.lastname: Miller
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage*; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D009061:Mouth Mucosa; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000139:chemically induced; D016016:Proportional Hazards Models; D011788:Quality of Life; D013280:Stomatitis / Q000139:chemically induced; D016019:Survival Analysis
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin