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Potential Regional Differences for the Tolerability Profiles of Fluoropyrimidines

Daniel G. Haller, Jim Cassidy, Stephen J. Clarke, David Cunningham, Eric Van Cutsem, Paulo M. Hoff, Mace L. Rothenberg, Leonard B. Saltz, Hans-Joachim Schmoll, Carmen Allegra, Joseph R. Bertino, Jean-Yves Douillard, Bengt G. Gustavsson, Gerard Milano, Michael O'Connell, Youcef Rustum, Josep Tabernero, Frank Gilberg, Florin Sirzén, Chris Twelves

From the Abramson Cancer Center at the University of Pennsylvania, Philadelphia; NSABP Foundation, Pittsburgh, PA; University of Texas, M.D. Anderson Cancer Center, Houston, TX; Vanderbilt-Ingram Cancer Center, Nashville, TN; Memorial Sloan-Kettering Cancer Center, New York; Roswell Park Cancer Institute, Buffalo, NY; NCI-Navy Medical Oncology Branch, National Cancer Institute, Bethesda, MD; The Cancer Institute of New Jersey, New Brunswick, NJ; Glasgow University, Glasgow; Royal Marsden Hospital, London; University of Leeds and Bradford NHS Trust, Bradford, United Kingdom; University of Sydney and Sydney Cancer Centre, Sydney, Australia; University Hospital Gasthuisberg, Leuven, Belgium; Martin Luther University, Halle, Germany; Centre René Gauducheau, St Herblain; Centre Antoine-Lacassagne, Nice, France; Gothenburg University, Gothenburg, Sweden; Vall d'Hebron University Hospital, Barcelona, Spain; and F. Hoffmann-La Roche, Basel, Switzerland

Corresponding author: Chris Twelves, MD, Cancer Research UK Clinical Centre, St James University Hospital, Beckett St, Leeds, LS9 7TF United Kingdom; e-mail: c.j.twelves{at}leeds.ac.uk; or c.twelves{at}bradford.ac.uk

Purpose 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.

Conclusion 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.

Supported by Roche.

Presented in part at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006 and the 8th World Congress of Gastrointestinal Cancer, Barcelona, Spain, June 28 to July 1, 2006.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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