The Ethics Committee for Biomedical Research of the Jikei Institutional Review Board approved the protocol [29-041 (8657)], and all patients or their family members provided written informed consent. Between 2013 and 2018, sixteen patients (twelve males, four females) with unresectable colorectal cancer who were administered TAS-102 as third-line chemotherapy in our institution were retrospectively enrolled in this study. The mean age was 65.4 (range: 46-79) years (Table 1). These 16 patients were given oxaliplatin with oral S-1 (tegafur, gimeracil, oteracil potassium) (SOX) as first-line chemotherapy, followed by the administration of irinotecan with oral S-1 (IRIS) as second-line chemotherapy. Patients were only included in this study if they demonstrated adequate organ function (4,000≤leukocytes<12,000/mm3; thrombocytes, ≥100,000/ mm3; total serum bilirubin, ≤1.5 mg/dl; aspartate aminotransferase (AST) and alanine aminotransferase (ALT), <100 IU/l; and creatinine, ≤1.5 mg/dl). Patients with a history of drug hypersensitivity or serious surgical and non-surgical complications were excluded. The cutoff values for serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) concentrations were 50 ng/ml, which is tenfold of the normal limit  of 5 ng/ml, and 37 U/ml, respectively. The cutoff value for the neutrophil-lymphocyte ratio (NLR) was 3.0 .
Physical examinations, routine blood analyses, and CEA and CA19-9 measurements were performed every month before chemotherapy. Computed tomography (CT) was performed every two months or when a patient’s serum CEA value on the treatment day was higher than it was before the initial chemotherapy. The responses of the measurable and accessible disease sites were evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST) .
SOX  was employed as the first-line treatment. Oxaliplatin at 130 mg/m2 was administered on the first day followed by 14-day administration and 6-day withdrawal of oral S-1 (Taiho Pharmaceutical, Tokyo, Japan) at 80 mg or 100 mg per day according to the patient’s body surface area (BSA). Specifically, 80 mg/day S-1 was administered to those patients with BSA<1.5 m2, and 100 mg/day S-1 was administered to those patients with BSA>1.5 m2. S-1 was administered orally twice daily after meals.
Irinotecan with oral S-1 (IRIS)  was employed as the second-line treatment. Irinotecan at 120 mg/m2 was administered on the first day followed by 14-day administration and 6-day withdrawal of oral S-1 (Taiho Pharmaceutical, Tokyo, Japan) at 80 mg or 100 mg per day according to the patient’s BSA. Specifically, 80 mg/day S-1 was administered to those patients with BSA<1.5 m2, and 100 mg/day S-1 was administered to those patients with BSA>1.5 m2. S-1 was administered orally twice daily after meals.
In the third-line treatment, TAS-102 at 35 mg/m2 was administered twice daily after morning and evening meals 5 days a week for 2 weeks followed by a 14-day rest period, thus completing one treatment cycle. The regimen was repeated every 4 weeks.
Adverse events were classified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.03 .
Continuous variables are expressed as the mean and range. The Wilcoxon rank-sum test was used for the comparison of continuous variables, and the chi-square test was used for the comparison of categorical data. Postoperative survival time was examined by the Kaplan-Meier method and log-rank analysis. Variables affecting postoperative survival were analyzed using the Cox proportional hazards regression. A P-value of less than 0.05 indicated significance. All data were analyzed with IBM SPSS Statistics, version 24.0 (IBM Japan, Ltd, Tokyo, Japan).