title: Randomized multicenter phase II trial of oxaliplatin plus irinotecan versus raltitrexed as first-line treatment in advanced colorectal cancer.
abstract: OBJECTIVE
  Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs act synergistically, a randomized phase II study was initiated to investigate the therapeutic potential and tolerance of this combination in the front-line setting.
  
  
  METHODS
  Ninety-two patients with previously untreated, measurable disease were randomized to receive biweekly oxaliplatin 85 mg/m(2) plus irinotecan 175 mg/m(2) or raltitrexed 3 mg/m(2) given on day 1 every 3 weeks. Upon development of progressive disease, second-line treatment with the opposite arm was effected.
  
  
  RESULTS
  Patients allocated to oxaliplatin/irinotecan had a significantly better radiologically confirmed response rate (43.5% v 19.6%; P =.0025) and longer progression-free survival (median, 7.1 v 5.0 months; P =.0033). Improvement in overall survival, however, did not reach the level of significance (median, 16.0 v 16.5 months; P =.3943). The response rate after cross-over was 33.3% (eight of 24) for assessable patients treated with oxaliplatin/irinotecan compared with 14.2% (three of 21) for those treated with second-line raltitrexed. Oxaliplatin/irinotecan caused more hematologic and gastrointestinal toxicities, necessitating dose reductions in 10 of the first 20 patients. After adjustment of the irinotecan starting dose from 175 to 150 mg/m(2), tolerance of treatment was acceptable; the most commonly encountered events (all grades) were neutropenia (81%), alopecia (65%), nausea/emesis (62%), peripheral sensory neuropathy (62%), and diarrhea (46%).
  
  
  CONCLUSIONS
  Oxaliplatin/irinotecan seems beneficial as first-line therapy in advanced colorectal cancer, with an acceptable toxicity profile at the reduced irinotecan dose level. Its promising therapeutic potential is supported by the high response activity noted in the raltitrexed control arm after cross-over, which may also explain the lack of a difference in overall survival.
authors.affiliation: Department of Internal Medicine I, Division of Oncology, Vienna University Medical School. Waeringer Guertel 18-20, A-1090 Vienna, Austria. werner.scheithauer@akh-wien.ac.at
authors.forename: Werner
authors.initials: W
authors.lastname: Scheithauer
authors.forename: Gabriela V
authors.initials: GV
authors.lastname: Kornek
authors.forename: Markus
authors.initials: M
authors.lastname: Raderer
authors.forename: Herbert
authors.initials: H
authors.lastname: Ulrich-Pur
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Fiebiger
authors.forename: Claudia
authors.initials: C
authors.lastname: Gedlicka
authors.forename: Birgit
authors.initials: B
authors.lastname: Schüll
authors.forename: Stefan
authors.initials: S
authors.lastname: Brugger
authors.forename: Bruno
authors.initials: B
authors.lastname: Schneeweiss
authors.forename: Fritz
authors.initials: F
authors.lastname: Lang
authors.forename: Alfred
authors.initials: A
authors.lastname: Lenauer
authors.forename: Dieter
authors.initials: D
authors.lastname: Depisch
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018592:Cross-Over Studies; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010166:Palliative Care; D011799:Quinazolines / Q000627:therapeutic use; D015996:Survival Rate; D013876:Thiophenes / Q000627:therapeutic use
chemical_list: D000964:Antimetabolites, Antineoplastic; D009944:Organoplatinum Compounds; D011799:Quinazolines; D013876:Thiophenes; D000077150:Oxaliplatin; D000077146:Irinotecan; C068874:raltitrexed; D002166:Camptothecin