Adjuvant S-1 chemotherapy after curative resection of gastric cancer.

To the Editor—In the February issue of Hong Kong Medical Journal, Yeo et al1 reported an informative study on the use of S-1 as adjunct chemotherapy after curative resection of gastric cancer. Since the active ingredient in S-1 is the prodrug tegafur, to be converted to 5-fluorouracil (5FU), much of the toxicity reduction depends on the degradation of 5FU by dihydropyrimidine dehydrogenase (DPD) encoded by the DPYD gene. Loss-of-function mutations in DPYD would lead to excessive toxicity and, on rare occasions, could be fatal. This applies also to prodrugs such as capecitabine.2 The incidence of DPYD variants leading to reduced DPD activity has been estimated to be 3% to 5% in a western population and complete loss of function at 0.2%.3 A Korean study showed that minor allele frequency of single nucleotide polymorphism varies across different ethnic groups, being lowest in Koreans, followed closely by Chinese and Japanese with Caucasians having a higher level.4 For the 3% to 5% of patients with reduced DPD activity, S-1 (tegafur/gimeracil/oteracil) has the built-in safety factor similar to an earlier tegafur combination UFT (tegafur/uracil). With UFT, tegafur gives a level of 5FU below the conventional therapeutic level. Yet efficacy is achieved by uracil, another component of UFT, which reduces the activity of DPD and results in partial DPD deficiency. A study has revealed that patients with partial DPD deficiency (due to heterozygotic DPYD mutations) could be treated successfully by UFT.5 Presumably S-1 could be used similarly. For the 0.2% of cases with homozygous defects in DPYD, perhaps Prof Yeo and her colleagues have already provided the answer in their paper when they quoted a Taiwan study in which a single-dose pharmacokinetic study tested the tolerability of S-1 in the individual patient.6 Using a small dose may appear contrary to traditional oncology practice, but in this particular situation it could be a practical and cost-effective way to avoid some alarming outcomes. I declare no conflicts of interest other than having also used small single doses of 5FU and have screened out two patients with very severe toxicity over the past 30 years.