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July 14, 2017. Hand-foot syndrome (HFS) is a dreaded complication of capecitabine, one of the most prescribed oral chemos (and often the radiosensitizer of choice). Yesterday’s JAMA Onc pub reports outcomes of a randomized trial evaluating the efficacy of pyridoxine concurrent to single-agent Xeloda. Sadly, it’s not the next leucovorin: there were no differences in rates of HFS when the intervention and placebo arms went toe-to-toe. However, a big determinant of toxicity was found in folate levels...as in, the higher the serum and/or red blood cell levels, the higher the risk of HFS. This makes sense since folate depletes its metabolizer thymidylate synthase (TS) which is a major target of capecitabine. And lower TS levels mean higher capecitabine potency. At this point there are no folate levels at which a lower starting dose is recommended, but it seems like a smart tool to help predict those at extreme-ity risk.