Oral administration of the amino acids cystine and theanine attenuates the adverse events of S-1 adjuvant chemotherapy in gastrointestinal cancer patients

This study was approved by the Institutional Review Board of Sendai City Medical Center (approval number: 2012-0010), and consent was obtained from each patient after the study was sufficiently explained. The study was performed in accordance with the Declaration of Helsinki. The subjects comprised patients who underwent R0 surgery for either colon or gastric cancer at the surgery department of the Sendai City Medical Center and who were expected to receive postoperative S-1 adjuvant chemotherapy for 4 weeks with a 2-week drug-free interval. Patients were enrolled in the study if they were in PS0 or PS1, were 20 years of age or above, submitted written consent, and fulfilled the following criteria on their pre-registration laboratory tests: white blood cell (WBC) count >3,000/mm³, neutrophil count >1,500/mm³, platelet count >100,000/mm³, hemoglobin level >9.0 g/dl, total bilirubin level <2.0 mg/dl, aspartate aminotransferase (AST) level <100 IU, alanine aminotransferase (ALT) level <100 IU, and estimated glomerular filtration rate (eGFR) >60 ml/min. The patient registration period lasted from July 2012 to June 2014, and the intended number of enrolled subjects was 70.

The study design was a prospective randomized trial, and the subjects were allocated using the envelope method. The administration of S-1 (Taiho Pharmaceutical, Tokyo, Japan) was scheduled to be initiated within 6 weeks after surgery. The subjects in the C/T group were orally administered an amino acid supplement, which contained 700 mg cystine and 280 mg theanine (total weight, 1.7 g; Ajinomoto, Tokyo, Japan), once a day starting 1 week before and ending at the same time as the administration of S-1 (a total of 35 days) (Fig. 1). The control group received S-1 without cystine and theanine. The subjects in both groups were examined at the outpatient clinic immediately before starting S-1 chemotherapy. They underwent blood sampling, and it was confirmed that they fulfilled the inclusion criteria. The subjects visited the hospital 14 days after starting S-1 chemotherapy and at the end of the first treatment course (28 days after starting S-1 chemotherapy); during the visits, they underwent blood sampling and answered questions about AEs. The subjects were observed until the end of the first treatment course. A physician in charge of the outpatient clinic graded the AEs according to the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. If AEs that were of a grade 2 severity or more severe occurred during the chemotherapy, the administration of S-1 was suspended or discontinued, and the period in which S-1 was administered at the prescribed dose (i.e., not including the period when the dose was reduced) was recorded. Consultations regarding AEs were given by telephone and during hospital visits, and the administration of S-1 was immediately discontinued if the AE was judged to be of a grade 2 severity or more severe. The evaluation items included the incidence of AEs, which was determined through blood tests and medical interviews, and the completion rate of the first course of chemotherapy at the prescribed dose.

The hypothesis was that the completion rate of the first course of chemotherapy would be increased from 45 % (less than half) to 80 % by administration of cystine and theanine. It was calculated that 66 samples would be required. Expecting the loss of several samples, 70 samples were included in this study.

All data were expressed as a percentage or the mean ± standard deviation (SD). The incidence of AEs and completion rate of chemotherapy were evaluated using Fisher’s exact test. The number of days that the prescribed dose of S-1 was administered in each group was compared using the t test. All statistical procedures were performed at a significance level of p < 0.05 using the Prism software package (GraphPad Software, La Jolla, CA, USA).