The patients were enrolled between March 2014 and October 2014. The follow-up period was one year from the last case registration. Patients were enrolled at the Wakayama Medical University Hospital (Wakayama, Japan) and its associated teaching hospitals, National Hospital Organization Minami Wakayama Medical Center (Wakayama, Japan), Wakayama Rosai Hospital (Wakayama, Japan) and Izumiotsu Municipal Hospital (Osaka, Japan). Patients on the 5-days-on/2-days-off regimen who met all of the following criteria were eligible for the present study, regardless of sex: Histologically or cytologically diagnosed with CRC; capecitabine used as adjuvant chemotherapy; age between 20 and 80 years; Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; principal organ functions sufficiently maintained (see criteria below); first-line treatment; written informed consent to participate in the study.

Furthermore, patients were required to be CRC stage III or high-risk stage II and undergoing curative operation followed by adjuvant chemotherapy (staging criteria in accordance with the TNM Classification of Malignant Tumors, 7th edition) (9). According to the American Society of Clinical Oncology guidelines (10) and the European Society for Medical Oncology guidelines (11), high-risk stage II CRC has <12 lymph nodes, T4 lesions, perforation, poorly differentiated histology, vascular or lymphatic or perineural invasion, and clinical presentation with intestinal occlusion or perforation.

The study was performed in accordance with the Declaration of Helsinki and the Ethical Guidelines for Clinical Research and has been approved by the Ethics Committee of Wakayama Medical University (Wakayama, Japan). Written informed consent was obtained from all patients prior to enrollment in this study.

Regarding the laboratory test results, the following criteria were also required to be satisfied: White cell count >1,500/mm³; neutrophil count ≥1,500/mm³; platelet count ≥100,000/mm³; hemoglobin ≥9.0 g/dl; total bilirubin ≤1.5 mg/dl; aspartate transaminase, alanine aminotransferase ≤100 IU/l; serum creatinine ≤1.5 mg/dl.

Exclusion criteria. Patients who met any of the following criteria were excluded from participation in the study: Pregnant or lactating; likely to, or planning to, become pregnant; history of malignancy; uncontrollable congestive heart failure, hypertension, angina pectoris, arrhythmia; severe drug hypersensitivity; side effects (or possible side effects) of fluoropyrimidine-type drugs with suspicion that dihydropyrimidine dehydrogenase deficiency may have developed; uncontrollable infection; oral ingestion difficulty; otherwise inappropriate for enrollment based on the researcher's judgment. Protocol treatment was not started in cases of rapid exacerbation after registration, protocol violation or discovery of ineligibility after registration.

Toxicities were graded according to the common terminology criteria for adverse events version 4.0(12). Patients visited the hospital on the first day of admission and were checked for adverse events by blood examination and clinical examination. If a G3 adverse event was identified, the patient visited the clinic weekly until the adverse events were alleviated. If there were no G3 adverse events, the patient visited the clinic every three weeks. Adverse effects of capecitabine were checked by YM, SY, MO, YK and HY. If any discrepancies arose, all members discussed them in order to reach a consensus.

The patients enrolled were treated with capecitabine (2,500 mg/m²/day), which was taken on five consecutive days, followed by an interval of two days (5-days-on/2-days-off schedule). This trial was single-arm study and comparison was performed with a retrospectively enrolled conventional treatment group. The retrospective conventional treatment group was composed of 21 consecutive patients who received conventional treatment. They underwent surgery between January 2011 and March 2016 and received capecitabine treatment (2,500 mg/m²/day) taken on 14 consecutive days every 21 days according to the conventional schedule, prior to March 2014. One course lasted for three weeks, and eight courses (24 weeks) were administered in total. To assess the feasibility of the treatment schedule, sex, age, agreed date of acquisition of adverse events, ECOG PS, body height, body weight, body surface area, location of CRC, surgical procedure, lymph node dissection range, tumor diameter, histopathological classification, patient history, and comorbidities within one year were recorded. To examine hematologic side effects of the protocol treatment, baseline peripheral blood counts were measured and biochemical examination of blood was performed within 14 days prior to the start of drug administration.

General characteristics, clinical findings (subjective symptoms and objective signs), peripheral blood counts, blood chemistry values, tumor markers and incidence of HFS were typically recorded between weeks three and five during treatment. Imaging evaluation was performed at three months by computed tomography or magnetic resonance imaging. QOL evaluation (EORTC QLQ-C30) (13,14) was performed prior to chemotherapy and after two, four, six and eight courses of treatment.

Treatment completion was defined as the completion of the eight three-week cycles on the 5-days-on/2-days-off schedule according to protocol in patients who were registered and began treatment within eight weeks post-operatively. None of the patients received neo-adjuvant chemotherapy.

Discontinuation meant that the intake of the drug was completely terminated. Treatment was stopped for any of the following reasons: i) Decision made by the clinician to terminate protocol treatment due to AEs; ii) patient decided to discontinue treatment according to the protocol for reasons associated with AEs; iii) patient decided to stop treatment according to the protocol due to reasons not associated with AEs; iv) mortality during treatment.

Statistical analysis regarding patient characteristics was performed using non-parametric methods, including the Chi-squared test and Fisher's exact probability test. Statistical analysis regarding the treatment course, completion rate and relative dose intensity was performed using Fisher's exact probability test. For the time to treatment failure (TTF), evaluation was performed using Kaplan-Meier analysis and the log-rank test was used to identify statistically significant differences between the groups. The Cox proportional hazard ratios for the risk of treatment failure were calculated with a 95% confidence interval (CI). P<0.05 was considered to indicate statistical significance.

A total of 27 patients [18 males and 9 females; median age, 67 years (range 47-80 years)] were enrolled. There was no significant difference in the age and sex ratio of patients between the 5-days-on/2-days-off regimen group and the retrospectively included conventional regimen group. The follow-up period was one year from the last case registration. These patients underwent curative surgery and were diagnosed either as pathological stage III or high-risk stage II CRC. A total of 6 patients were excluded: One was changed to a different chemotherapy, one declined to participate in the trial, two patients started treatment from a dose lower than that prescribed in the study protocol, one was excluded due to bowel-diverting stoma operation and one lost the medicine after registration. A total of 21 patients were therefore eligible and treated with capecitabine (2,500 mg/m²/day), which was taken for five days followed by an interval of two days (5-days-on/2-days-off schedule). One course lasted for three weeks, and eight courses (24 weeks) were administered. The median age of patients on the 5-days-on/2-days-off schedule was 67 years (range, 38-80 years). The patients had a PS of 0 or 1. Rectal cancer patients accounted for 23.8% (Table I). To compare the age, sex, PS, lymph node dissection, location of cancer, stage, invasion, lymphatic invasion, venous invasion and histological classification between the 5-days-on/2-days-off regimen group and conventional regimen group, two-sided P-values were calculated and P<0.05 was considered significant. A significant difference between the two groups was only identified in the stage (Table I).

The most common treatment-associated AEs were HFS (13 patients, 61.9%), anemia (7 patients, 33.3%), pigmentation (6 patients, 28.5%), hyperbilirubinemia (6 patients, 28.5%) and aspartate aminotransferase increase (6 patients, 28.5%; Table II). The major G3/4 AE was HFS only (9.5%). Although AEs in the conventional group were only investigated retrospectively, most common AEs were HFS (5 patients, 23.9%) and hyperbilirubinemia (2 patients, 9.5%). The AEs in the conventional group are provided in Table III. When comparing the AEs between the two groups, it appeared that HFS was more common in the 5-days-on/2-days-off regimen but G3/4 AEs were less common.

To address whether the 5-days-on/2-days-off regimen allows patients to continue adjuvant chemotherapy of stage III or high-risk stage II CRC, the median number and range of treatment courses in the 5-days-on/2-days-off regimen were compared with those of the conventional regimen. The median number of treatment courses in the 5-days-on/2-days-off regimen group was significantly higher than that in the conventional regimen group (P=0.0438). In terms of completion rate, 20 out of 21 patients (95.2%) received the complete scheduled treatment according to the 5-days-on/2-days-off regimen. On the other hand, of the 21 patients following a conventional schedule, only 15 patients (71.4%) completed the entire scheduled treatment (Table IV). Although the result was not significantly different (P=0.0931), the 5-days-on/2-days-off treatment tended to have better feasibility than the conventional regimen, and regarding the completion of the new vs. conventional regimen, the odds ratio was 8.0 (95% CI: 0.87-73.7). When the TTF of the 5-days-on/2-days-off group was compared with that of the conventional group, the 5-days-on/2-days-off regimen group had a significantly lower risk of failure of the scheduled treatment (P=0.0389; HR=0.15; 95% CI: 0.047-0.92; Fig. 1).

The median relative dose intensity was 1.0 (range, 0.15-1) in the 5-days-on/2-days-off group and 1 (range, 0.125-1) in the conventional group, respectively. Table V presents the various reasons for discontinuation and dose reduction in the conventional group. A dose reduction was required for seven patients (33.3%) in the 5-days-on/2-days-off group due to AEs. One of these seven patients discontinued the treatment. In the conventional group, four patients (19%) reduced the capecitabine dose but completed all eight courses. The other six patients (28.6%) stopped the regimen without dose reduction.

The results obtained with the EORTC QLQ-C30 are presented in Fig. 2. The QLQ-C30 questionnaire consists of two scales: A functional scale (Fig. 2A) and a symptom scale (Fig. 2B), each scoring from 0 to 100. Higher scores are considered to indicate a better result on the functional scale and lower scores are better on the symptom scale. On the two scales, there was no significant change in any of the QOL functions and symptoms in the 5-days-on/2-days-off group over the course of the treatment (P>0.05).

To address the degree of toxicity occurring under the 5-days-on/2-days-off regimen, the toxicities of the 5-days-on/2-days-off regimen were compared with those of other larger studies, including the Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) (5) and Kyushu Study group of Clinical Cancer (KSCC)0803(7) (Fig. 3). The X-ACT and KSCC0803 trials were performed using the 2-weeks-on/1-week-off regimen. Toxicities of all grades (Fig. 3A) and G3/4 toxicities (Fig. 3B) were compared among the three studies. The AEs in the present study, except for HFS, had a lower frequency and severity than those in the X-ACT and KSCC0803 trials. In the present study, low-grade HFS occurred at the same frequency but fewer cases of high-grade HFS were noted as compared with those in the X-ACT and KSCC0803 trials.