Potential regional differences for the tolerability profiles of fluoropyrimidines.
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.
Haller
Daniel G
DG
Abramson Cancer Center at the University of Pennsylvania, Philadelphia, PA, USA.
Cassidy
Jim
J
Clarke
Stephen J
SJ
Cunningham
David
D
Van Cutsem
Eric
E
Hoff
Paulo M
PM
Rothenberg
Mace L
ML
Saltz
Leonard B
LB
Schmoll
Hans-Joachim
HJ
Allegra
Carmen
C
Bertino
Joseph R
JR
Douillard
Jean-Yves
JY
Gustavsson
Bengt G
BG
Milano
Gerard
G
O'Connell
Michael
M
Rustum
Youcef
Y
Tabernero
Josep
J
Gilberg
Frank
F
Sirzén
Florin
F
Twelves
Chris
C
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
D000964:Antimetabolites, Antineoplastic; D009944:Organoplatinum Compounds; D011355:Prodrugs; D000077150:Oxaliplatin; D003841:Deoxycytidine; D014803:Vitamin B Complex; D000069287:Capecitabine; D002955:Leucovorin; D005472:Fluorouracil