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Compared with fluorouracil monotherapy, modern multidrug combination therapies based on fluorouracil (eg, fluorouracil, leucovorin, and oxaliplatin [FOLFOX]) have been shown to dramatically improve outcomes for stage III and IV colorectal cancer in the adjuvant setting. As a consequence of being more effective, combination therapies also tend to be more toxic because the concomitant drugs potentiate the toxic effects of fluorouracil. The types of toxic effects observed, as well as the severity, have been shown to vary greatly between treatment regimens, which may not only differ in the combination of drugs prescribed, but also vary in dose, route of administration, and length of therapy. Deleterious germline variations in the dihydropyrimidine dehydrogenase (DPD) gene (DPYD) have been established as predictors of adverse effects to fluorouracil-based treatments. Three rare DPYD variants have been repeatedly associated with decreased DPD enzyme function and correlated with severe adverse fluorouracil-related toxic effects, DPYD*2A, p.I560S, and p.D949V1; however, a recent meta-analysis2 has cast doubt on whether risk variants for fluorouracil-related adverse effects are generalizable across all fluorouracil-based regimens.
Offer SM, Diasio RB. Biomarkers of Fluorouracil Toxicity: Insight From the PETACC-8 Trial. JAMA Oncol. 2016;2(5):662–663. doi:10.1001/jamaoncol.2015.5463
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