title: Mortality associated with irinotecan plus bolus fluorouracil/leucovorin: summary findings of an independent panel.
abstract: OBJECTIVE
  To review and assign attribution for the causes of early deaths on two National Cancer Institute-sponsored cooperative group studies involving irinotecan and bolus fluorouracil (5-FU) and leucovorin (IFL).
  
  
  METHODS
  The inpatient, outpatient, and research records of patients treated on Cancer and Leukemia Group B protocol C89803 and on North Center Cancer Treatment Group protocol N9741 were reviewed by a panel of five medical oncologists not directly involved with either study. Each death was categorized as treatment-induced, treatment-exacerbated, or treatment-unrelated.
  
  
  RESULTS
  The records of 44 patients who experienced early deaths on C89803 (21 patients) or N9741 (23 patients) were reviewed. Patients treated with irinotecan plus bolus 5-FU/leucovorin had a three-fold higher rate of treatment-induced or treatment-exacerbated death than patients treated on the other arm(s) of the respective studies. For C89803, these rates were 2.5% (16 of 635) for IFL versus 0.8% (five of 628) for bolus weekly 5-FU and leucovorin. For N9741, these rates were 3.5% (10 of 289) for IFL, 1.1% (three of 277) for oxaliplatin plus bolus and infusional 5-FU and leucovorin, and 1.1% (three of 275) for oxaliplatin plus irinotecan. Multiple gastrointestinal toxicities that often occurred together were characterized into a gastrointestinal syndrome. Sudden, unexpected thromboembolic events were characterized as a vascular syndrome. The majority of deaths in both studies were attributable to one or both of these syndromes.
  
  
  CONCLUSIONS
  Close clinical monitoring, early recognition of toxicities and toxicity syndromes, aggressive therapeutic intervention, and withholding therapy in the presence of unresolved drug-related toxicities is recommended for patients receiving IFL or other intensive chemotherapy regimens.
authors.affiliation: Vanderbilt-Ingram Cancer Center, Nashville, TN 37232-6307, USA. mace.rothenberg@mcmail.vanderbilt.edu
authors.forename: M L
authors.initials: ML
authors.lastname: Rothenberg
authors.forename: N J
authors.initials: NJ
authors.lastname: Meropol
authors.forename: E A
authors.initials: EA
authors.lastname: Poplin
authors.forename: E
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: S
authors.initials: S
authors.lastname: Wadler
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives / Q000627:therapeutic use*; D002423:Cause of Death; D005472:Fluorouracil / Q000008:administration & dosage; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D017408:Guidelines as Topic; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage; D009026:Mortality; D016032:Randomized Controlled Trials as Topic; D012307:Risk Factors; D013577:Syndrome; D013997:Time Factors; D014652:Vascular Diseases / Q000139:chemically induced
chemical_list: D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin