title: Potential regional differences for the tolerability profiles of fluoropyrimidines.
abstract: OBJECTIVE
  We conducted a retrospective analysis of safety data from randomized, single-agent fluoropyrimidine clinical trials (bolus fluorouracil/leucovorin [FU/LV] and capecitabine) to test the hypothesis that there are regional differences in fluoropyrimidine tolerability.
  
  
  METHODS
  Treatment-related safety data from three phase III clinical studies were analyzed by multivariate analysis: two comparing capecitabine with bolus FU/LV in metastatic colorectal cancer (MCRC) and one comparing capecitabine plus oxaliplatin (XELOX) with bolus FU/LV as adjuvant treatment for colon cancer. The United States (US) was compared with non-US countries (all three studies) and with the rest of the world and East Asia (adjuvant study).
  
  
  RESULTS
  In the MCRC studies (n = 1,189), more grade 3/4 adverse events (AEs; relative risk [RR], 1.77), dose reductions (RR, 1.72), and discontinuations (RR, 1.83) were reported in US versus non-US patients. Likewise, in the adjuvant colon cancer study (n = 1,864), more grade 3/4 AEs (RR, 1.47) and discontinuations (RR, 2.09) were reported in US versus non-US patients. After further dividing non-US patients into those in East Asia and the rest of the world, differential RRs for related grade 3/4 AEs, grade 4 AEs, and serious AEs were again observed, with East Asian patients having the lowest and US patients the highest RR.
  
  
  CONCLUSIONS
  Regional differences exist in the tolerability profiles of fluoropyrimidines. More treatment-related toxicity was reported in the US compared with the rest of the world for bolus FU/LV and capecitabine in first-line MCRC and adjuvant colon cancer. In the adjuvant setting, a range of fluoropyrimidine tolerability was observed, with East Asian patients having the lowest, and US patients the highest, RR.
authors.affiliation: Abramson Cancer Center at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Haller
authors.forename: Jim
authors.initials: J
authors.lastname: Cassidy
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Clarke
authors.forename: David
authors.initials: D
authors.lastname: Cunningham
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Paulo M
authors.initials: PM
authors.lastname: Hoff
authors.forename: Mace L
authors.initials: ML
authors.lastname: Rothenberg
authors.forename: Leonard B
authors.initials: LB
authors.lastname: Saltz
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Schmoll
authors.forename: Carmen
authors.initials: C
authors.lastname: Allegra
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Bertino
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Douillard
authors.forename: Bengt G
authors.initials: BG
authors.lastname: Gustavsson
authors.forename: Gerard
authors.initials: G
authors.lastname: Milano
authors.forename: Michael
authors.initials: M
authors.lastname: O'Connell
authors.forename: Youcef
authors.initials: Y
authors.lastname: Rustum
authors.forename: Josep
authors.initials: J
authors.lastname: Tabernero
authors.forename: Frank
authors.initials: F
authors.lastname: Gilberg
authors.forename: Florin
authors.initials: F
authors.lastname: Sirzén
authors.forename: Chris
authors.initials: C
authors.lastname: Twelves
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D000069287:Capecitabine; D017024:Chemotherapy, Adjuvant; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000208:ethnology / Q000473:pathology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D005060:Europe; D005202:Asia, Eastern; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects* / Q000031:analogs & derivatives*; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000208:ethnology; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000139:chemically induced* / Q000208:ethnology; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D011355:Prodrugs / Q000008:administration & dosage / Q000009:adverse effects*; D012111:Residence Characteristics; D012189:Retrospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014481:United States; D014803:Vitamin B Complex / Q000008:administration & dosage; D028761:Withholding Treatment
chemical_list: D000964:Antimetabolites, Antineoplastic; D009944:Organoplatinum Compounds; D011355:Prodrugs; D000077150:Oxaliplatin; D003841:Deoxycytidine; D014803:Vitamin B Complex; D000069287:Capecitabine; D002955:Leucovorin; D005472:Fluorouracil