To reduce the duration of effective drug concentration and keeping an appropriate rest period could be effective method of improving safety. So we modified the schedule as 1-week S-1/LV, followed by 1-week rest period, the same as S-1/LV group in that randomized phase II study. The efficacy S-1/LV here was quite comparable with S-1/LV group in that randomized phase II study, in terms of ORR (41.0 vs. 43%), PFS (4.13 vs. 4.2 m), and TTF (3.70 vs. 4.1 m) . Fewer patients in our study received the second-line treatment (53.9 vs. 77%), which helped explain the relatively not so promising OS. Another reason was that there were 5 patients discontinuing treatment before progression not due to adverse events. Meanwhile, S-1/LV in this study saw very satisfactory safety. The frequencies of each type of AEs were generally lower than those in the phase II trial of mCRC and comparable with those in the randomized phase II trial of AGC [4, 5]. Encouragingly, grade 4 AEs occurred in 1 patient (2.6% neutropenia), similarly for the randomized study (2% grade 4 neutropenia and 2% leucopenia). Each type of the grade 3 AEs occurred in only 2.6–7.7% patients, similar to 2–13% for the randomized study . In our study, significantly fewer patients experienced dose reduction, or delayed courses , compared to patients with S-1 monotherapy in previous phase III trials [19, 26]. In our study, gastrointestinal reactions were more common than myelosuppression both in total (89.7 vs. 74.4%) and in grade 3–4 (15.4 vs. 10.3%), and dose reductions or interruptions were chiefly due to diarrhea, stomatitis, anorexia, and vomiting. We also observed dose-limiting toxicity was shifted from hematological to gastrointestinal when S-1 was administered with LV . Probably the capacity of oral intake and gastrointestinal tolerability would be the important indications for this regimen.