S-1 Superior to Capecitabine in Metastatic Colorectal Cancer

The incidence of hand-foot syndrome occurred significantly less often in patients treated with S-1 compared to capecitabine in patients with metastatic colorectal cancer.

Robert Jan Kwakman, MD, PhD candidate

The incidence of hand-foot syndrome (HFS) occurred significantly less often in patients treated with S-1 compared to capecitabine in patients with metastatic colorectal cancer (mCRC), according to findings from the phase III SALTO study that were presented at the 2017 European Cancer Congress.

All-grade investigator assessed HFS decreased in patients treated with S-1. HFS was reported in 73% of patients receiving capecitabine versus 45% receiving S-1 (P= .0005). Grade 2 HFS was seen in 30% versus 14% (P= .02), and grade 3 HFS occurred in 21% versus 4% (P= .003) of patients receiving capecitabine versus S-1, respectively.

“Although not life-threatening, low-grade HFS may impair quality of life, and HFS grades 2 and 3 can greatly limit the patient’s ability to perform tasks associated with adult daily life,” said Robert Jan Kwakman, MD, PhD candidate, Department of Medical Oncology, Academic Medical Center, Amsterdam, The Netherlands, while presenting the results on behalf of colleagues in the Dutch Colorectal Cancer Group.

“S-1 has a lower incidence of HFS compared to capecitabine and has demonstrated comparable efficacy results to other fluoropyrimidines in Asian patients with gastrointestinal cancer, ” he noted.

Patients in the open-label, multicenter SALTO study had previously untreated mCRC, World Health Organization performance status of 0 to 2, and a median age of 73 years. The investigators randomly assigned 81 patients to capecitabine at 1250 mg/m2(< 70 years) or 1000 mg/m2(≥70 years) and 80 patients to S-1, both administered at 30 mg/m2twice daily for 2 weeks of a 3-week cycle. Optional treatment with 7.5 mg bevacizumab was available to all patients. Patients were stratified by whether they received bevacizumab, normal versus abnormal baseline lactate dehydrogenase, performance status, and institution.

Patients also completed diaries that recorded whether they experienced any HFS symptoms, the severity, and the impact of the symptoms on their ability to perform daily activities.

The primary endpoint was investigator-assessed incidence of all-grade HFS; secondary endpoints included investigator-assessed grade 3 HFS, patient-assessed all-grade and grade 3 HFS, the incidence of other toxicities, progression-free survival (PFS), response rate, overall survival (OS), and the relative dose intensity.

“This study met its primary endpoint, with a significantly lower incidence of all-grade HFS for S-1 compared to capecitabine,” commented Kwakman.

By patients’ assessment, the incidence of HFS was also significantly lower with S-1; 84% versus 58% of 110 patients reported all-grade HFS symptoms (P= .004) and grade 3 HFS was reported by 18% versus 5% of capecitabine and S-1 patients, respectively (P= .05).

“There were no significant differences in efficacy outcomes between treatment groups,” said Kwakman.

At a median follow-up of 16.1 months, the median PFS was similar at 8.19 months with capecitabine compared to 8.39 months with S-1 (P= .93). The response rate was also similar with both treatments (P= .19).

With either capecitabine or S-1, median PFS was prolonged in the 95 patients that also received bevacizumab to 8.79 months compared with 6.37 months in 66 patients not receiving bevacizumab (P= .10).

Although 12-month OS was comparable at 67% versus 62% with capecitabine and S-1 arms, respectively, a nonsignificant trend towards lower 18-month OS rates with S-1 was observed of 50% versus 39% in the respective groups (P= 0.23). Kwakman pointed out: “36 patients in the capecitabine arm received 55 subsequent treatment regimens compared to 32 patients in the S-1 arm who received 38 subsequent regimens, which could have impacted long-term OS.”

Similar toxicity profiles were observed in both treatment groups with 100% of patients overall experiencing an event. Toxicities grade ≥3 occurred in 61% of patients receiving capecitabine and in 65% of patients receiving S-1. These toxicities were nearly all gastrointestinal and included diarrhea, stomatitis, nausea, vomiting, and fatigue; the incidence of grade ≥3 toxicity differed between treatments only for anorexia, which was reported in 3% and 13% of patients receiving capecitabine and S-1, respectively (P= .03).

“S-1 is known to have an incidence of gastrointestinal toxicities in Western patients compared with Asian patients, who show a higher incidence of hematological toxicities,” he commented.

Kwakman also noted: “Significantly fewer dose reductions were required in the S-1 group, which received a higher median relative dose intensity.” The median relative dose-intensity with capecitabine was 89% compared to 95% with S-1, and dose reductions were necessary for 69% of capecitabine patients versus 41% of S-1 patients (P= .0008).


Kwakman JJM, Simkens LHJ, Van Rooijen JM, et al. Randomised phase 3 study of S-1 versus capecitabine, with bevacizumab optional in both arms, in the first-line treatment of metastatic colorectal cancer (mCRC), the SALTO study of the Dutch Colorectal Cancer Group. Presented at: 2017 European Cancer Congress; January 27-30, 2017; Amsterdam, The Netherlands. Abstract 2BA.