Hand–Foot Syndrome Incidence Lower With S-1 Than Capecitabine In Western mCRC Patients

Phase III trial results suggest that S-1 could be used instead of capecitabine in Western colorectal cancer patients with distant metastases

medwireNews: The oral fluoropyrimidine S-1 could be a “useful alternative” to capecitabine in Western patients with metastatic colorectal cancer (mCRC), say Dutch researchers who found a significant reduction in the incidence of hand–foot syndrome (HFS) with S-1, but not at the cost of efficacy.

Cornelis Punt, from the University of Amsterdam, and fellow investigators say that HFS has been observed in up to 77% of patients enrolled in capecitabine clinical trials, adding that although the adverse event is not life threatening, it can lead to considerable discomfort and functional impairment.

They explain that compared with capecitabine, treatment with S-1 is associated with a lower HFS rate, but the majority of studies have been conducted in Asian populations “who have a markedly different metabolism and toxicity profile compared to Western populations.”

In the phase III SALTO trial, which enrolled Dutch mCRC patients scheduled to undergo first-line fluoropyrimidine monotherapy, any grade HFS as assessed by local investigators occurred in 45% of 80 patients randomly assigned to receive S-1 30 mg/m2 on days 1–14 of each 21-day cycle. This was significantly lower than the 73% rate observed among their 81 counterparts given capecitabine on the same schedule at a dose of 1250 mg/m2 or 1000 mg/m2 depending on whether they were younger than or at least 70 years of age, respectively.

The corresponding rates of grade 3 HFS were 4% and 21%, also a significant difference, the team reports in the Annals of Oncology.

The findings were similar when patient-reported incidence of the adverse event was considered, with any grade and grade 3 HFS reported by a respective 58% and 5% of those in the S-1 group, compared with rates of 84% and 18% in the capecitabine group.

Other adverse events of grade 3 or worse occurred at a comparable rate in the two treatment arms, with the exception of grade 3 anorexia, which was significantly more common in the S-1 than the capecitabine group (13 vs 3%).

Patients given S-1 were significantly less likely to require a dose reduction than those who received capecitabine (40 vs 66%), but the rates of toxicity-related discontinuation were similar.

This was also the case for efficacy outcomes, with no significant difference between the groups in terms of overall survival, progression-free survival, objective response rate or disease control rate after a median follow-up of 20.2 months. The researchers caution, however, that the study was not adequately powered for these endpoints.

Nonetheless, they write: “Our results show that treatment with S-1 is associated with a statistically significant and clinically relevant lower incidence of HFS compared to capecitabine in Western mCRC patients, without compromising efficacy.”


Kwakman JJM, Simkens LHJ, van Rooijen JM, et al. Randomised phase III trial of S-1 versus capecitabine in the first-line treatment of metastatic colorectal cancer: SALTO study by the Dutch Colorectal Cancer Group. Ann Oncol; Advance online publication 5 April 2017. doi: https://doi.org/10.1093/annonc/mdx122

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