The current study was conducted in a single center as an interventional, single-arm, phase II trial. The enrollment period was between April 2014 and November 2017. The study protocol was approved by the Ethics Committee of Toho University Omori Medical Center (approval numbers / approval date: no.25-216 / 27 November 2013, no.27-251 / 18 February 2015), and written informed consent was obtained from all registered patients. This study was registered in the UMIN Clinical Trials Registry as UMIN000013598 (further details can be accessed at https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000015887). Cancer staging was based on the tumor, node, metastasis (TNM) classification system (Union for International Cancer Control, 6th edition) . The Response Evaluation Criteria in Solid Tumors (RECIST) v1.1  were used to assess tumor response to preoperative treatment using computed tomography (CT) or magnetic resonance imaging (MRI). Tumor response to preoperative treatment was defined as: complete response (CR), complete disappearance of the target lesion; partial response (PR), at least 30% reduction in target lesion; progressive disease (PD), 20% increase in target lesion and absolute increase of 5 mm or more and/or appearance of new lesions; stable disease (SD), a state of neither PR nor PD. We used the Common Terminology Criteria for Adverse Events v4.0 to grade adverse events. Adverse events of preoperative CRT were evaluated by the physicians involved in this study at the start of each course.
The pathological complete response (pCR) rate was the primary endpoint of this study. Secondary endpoints included the treatment completion rate, downstaging rate, curative resection rate, anal sphincter preservation rate, safety, local recurrence rates, disease-free survival (DFS), histological efficacy , and overall survival (OS). The evaluation of downstaging was compared before and after CRT. The stage was denoted by a prefix, indicating clinical findings at diagnosis with “c,” clinical findings after preoperative treatment (i.e., yield of treatment) with “yc,”; the descriptions follow the TNM classification system and Japanese guideline for classification of colorectal cancer , which have been used in Japan since 2013 (http://www.jsccr.jp/whatsnew/kiyaku8.html). R0 resection was defined as “no distant metastasis and no residual tumor.” Local recurrence was defined as anastomotic and pelvic recurrence.
The inclusion criteria were the following: 1. histologically confirmed rectum adenocarcinoma (i.e., in Ra, which is the segment of the rectum from the height of the inferior border of the second sacral vertebra to the peritoneal reflection; Rb, which is the segment of the rectum located below the peritoneal reflection; or P, which is the anal canal; Ra-Rb, the notation is the location in Ra to Rb, with Ra as the main; Rb-P, the notation is the location in Rb to P, with Rb as the main; not in the rectosigmoid [Rs], which is the segment from the height of the sacral promontory to the inferior border of the second sacral vertebra) ; 2. preoperative CT or MRI findings indicative of a cT3-4 clinical stage and any N stage ; 3. resectable tumor; 4. no evidence of distant metastasis; 5. aged 20–80 years; 6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1; 7. no prior antitumor therapy; 8. adequate organ function according to laboratory findings (white blood cell count ≥4,000/mm3 and ≤12,000/mm3, neutrophil count ≥2,000/mm3, platelet count ≥100,000/mm3, hemoglobin ≥9.0 g/dl, glutamic oxaloacetic transaminase and glutamic pyruvic transaminase ≤upper limit of normal ´ 2.5, serum total bilirubin ≤1.5 mg/dl, serum creatinine ≤N (upper limit of normal range), creatinine clearance ≥50 ml/min/body as calculated using the Cockcroft-Gault equation ; 9. can receive therapeutics orally; and 10. those who provided written informed consent.
Patients were excluded from the study on the basis of the following 16 exclusion criteria: 1. unable to receive chemotherapy containing S-1; 2. history of radiotherapy in the pelvis; 3. clinically significant infections; 4. having serious complications; 5. experienced myocardial infarction within the last six months, previous serious medical illness, or allergies to drugs; 6. multiple malignant diseases; 7. requiring treatments for pleural effusion or ascites; 8. having current or previous brain metastases; 9. having symptoms of watery stool (diarrhea); 10. having fresh bleeding in the digestive organs; 11. circumstances requiring treatment with flucytosine, atazanavir sulfate, and warfarin; 12. evidence of mental disorders that interfere with enrollment in a clinical trial; 13. women who are pregnant or lactating, or who are trying to get pregnant; 14. men who want to have their own children; 15. in the need for systemic administration of corticosteroids; 16. judged unsuitable to participate in this study by physicians.
The dose of S-1 was 80 mg/m2/day. S-1 was administered orally, twice daily along with radiation therapy on days 1–5, 8–12, 15–19, 22–26, and 29–33. On days 36–40, 43–47, 50–54, and 57–61, S-1 was administered twice daily without radiotherapy. Radiation therapy consisted of 1.8 Gy/day on days 1–5, 8–12, 15–19, 22–26, and 29–33 (total dose of 45 Gy in 25 fractions) (Fig. 1). Resection in rectal cancer patients with D3 lymph node dissection was performed within 2–3 weeks after completion of S-1 therapy. Postoperative treatment for one year consisted of starting oral administration of tegafur-uracil (300 mg/m2/day) and leucovorin (75 mg/body/day), following a cycle of four weeks of oral administration and one week of no medication , within 4–6 weeks postoperatively.
Blood tests, including the tumor markers carcinoembryonic antigen and carbohydrate antigen 19-9, were performed once a month for one year after surgery. Imaging studies were performed every six months postoperatively using CT or abdominal ultrasonography. The median duration of follow-up in this study was 41 months (range, 4–74 months).
Study design and statistical methods
Using an expected CR rate of 20% and a threshold CR rate of 5%, the number of patients required for a one-sided α = 0.1 and β = 0.1 was calculated to be 28. The target number of patients was set to 30, with consideration given to ineligible cases. As approved by the Ethics Committee of Toho University Omori Medical Center (approval number: 25-216, 27-251), patients who participated in the previous phase I trial  were also re-enrolled for the current analysis. DFS and OS were evaluated using the Kaplan–Meier method with the statistical analysis software “EZR” .
Thirty patients were enrolled; however, two patients were deemed ineligible. One patient was due for a re-evaluation of wall-depth cT2 , and another patient was due for irradiation above the prescribed radiation dose; they were excluded from this study (Fig. 2).