Inclusion and exclusion criteria
Patients who met the following eligibility criteria were enrolled in this study: (1) histologically confirmed stage IIIA, IIIB, or IIIC gastric cancer ; (2) patients receiving curative gastrectomy with a D2 lymph node dissection or greater ; (3) macroscopic tumor type was neither Borrmann type 4 nor large (≥ 8 cm) type 3; (4) no prior chemotherapy or radiation therapy, including treatment for other types of cancer; (5) performance status of 0–1 on Eastern Cooperative Oncology Group classification; (6) no gastric stump cancer; (7) no esophageal invasion or invasion of ≤ 3 cm; (8) able to receive chemotherapy within 4–8 weeks after surgery; (9) aged between 25 and 75 years; (10) sufficient oral intake; (11) adequate organ function (white blood cell [WBC] count ≥ 3,500/mm3 and < 12,000/mm3, neutrophil count ≥ 2,000/mm3, hemoglobin level ≥ 9.0 g/dl, platelet count ≥ 100,000/mm3, total bilirubin level ≤ 1.5 mg/dl, aspartate transaminase (AST) and alanine aminotransferase (ALT) levels ≤ 100 IU/l; (12) creatinine level ≤ 1.2 mg/dl, creatinine clearance > 60 ml/min in the Cockcroft-Gault equation; and (13) written informed consent provided by the patient to participate in the study.
The following patients were excluded: (1) synchronous or metachronous (within 5 years) duplication cancers other than carcinoma in situ; (2) contraindications to S-1, cisplatin, and docetaxel; (3) current treatment with systemic steroids; (4) continued use of flucytosine, phenytoin, or warfarin; (5) a history of serious drug hypersensitivity; (6) serious comorbidities (intestinal paralysis, intestinal obstruction, interstitial pneumonia or pulmonary fibrosis, neuropathy, uncontrolled diabetes, heart failure, renal failure, or hepatic failure, etc.); (7) severe mental disorders; (8) history of myocardial infarction or unstable angina pectoris within 6 months; (9) diarrhea (watery stool); (10) pregnancy or breastfeeding; (11) hepatitis B surface antigen positivity; and (12) those deemed ineligible for this study by the investigator or sub-investigator.
This study was approved by the Shimane University Institutional Committee on Ethics and was conducted in accordance with the Declaration of Helsinki and the Japanese Ethical Guidelines for Clinical Studies. This study was registered with the University Hospital Medical Information Network Clinical Trials Registry, number 000012785. Written informed consent was obtained from the patients prior to the study.
Thirty patients were enrolled in this study between March 2013 and December 2017. The characteristics of the patients are summarized in Table 1. There were 26 men and 4 women, with a median age of 69 years (range, 51–79 years). Total gastrectomy, proximal gastrectomy, and distal gastrectomy were performed in 12 patients (40%), 2 patients (6.7%), and 16 patients (53.3%), respectively. Histologically, 2 patients (6.7%) had well-differentiated adenocarcinoma, 12 (40%) had moderately differentiated adenocarcinoma, and 16 (53.3%) patients had undifferentiated adenocarcinoma. In regard to cancer staging, 12 patients (40.0%) had stage IIIA, 9 patients (30.0%) had stage IIIB, and 9 patients (30.0%) had stage IIIC.
Adjuvant chemotherapy was initiated 4–8 weeks after the gastrectomy. The first cycle of chemotherapy consisted of S-1 monotherapy, which was administered twice daily at the following oral doses based on the patient’s body surface area (BSA): 40 mg (BSA < 1.25 m2), 50 mg (BSA ≥ 1.25 m2), or 60 mg (BSA ≥ 1.5 m2), from day 1 to day 14, followed by a 7-day rest. Cycles 2 and 3 adhered to the following schedule: oral administration of S-1 (same dose as that of the first cycle) twice daily from day 1 to day 14, a 14-day rest, followed by intravenous infusion of cisplatin at 35 mg/m2 for 2 hours and intravenous infusion of docetaxel at 35 mg/m2 for 2 hours on days 1 and 15. After 2 cycles, S-1 was administered for up to 1 year. To avoid cisplatin-induced renal dysfunction, adequate hydration with normal saline (> 2000 ml) was administered on days 1 and 15.
Antiemetic analgesics were routinely prescribed to prevent nausea and vomiting. On day 1, all patients received aprepitant 125 mg orally 60 min before cisplatin infusion plus intravenous palonosetron (0.75 mg) and dexamethasone (12 mg) approximately 30 minutes prior to receiving cisplatin. On days 2 and 3, all patients received oral aprepitant 80 mg once daily after breakfast. Rescue antiemetics, such as 5-hydroxy-tryptamine-3 (5-HT3) receptor antagonists, were prescribed to treat prominent, unbearable nausea and vomiting. These prophylactic antiemetics were used in accordance with the Japan Society of Clinical Oncology Guidelines for Antiemetics in Oncology 2010 .
The patient’s symptoms and physical examination results were obtained. The assessment and grading of blood test were done according to the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0 (https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm#ctc_40).
Subsequent chemotherapy was postponed if a patient did not meet the following criteria: WBC count ≥ 3,000 mm3, neutrophil count ≥ 1,500 mm3, hemoglobin level ≥ 8.0 g/dl, platelet count ≥ 75,000 mm3, total bilirubin level ≤ 1.5 mg/dl, AST and ALT levels ≤ 100 IU/l, and creatinine concentration < 1.2 mg/dl. After confirming non-hematological toxicities, body temperature, general fatigue, anorexia, stomatitis, diarrhea, watery eyes, and neuropathy were graded (0 or 1) for adjuvant chemotherapy, and other non-hematological toxicities were graded as 2 or lower.
The dose of S-1 was reduced by 20 mg/day when any adverse events mentioned above were observed during the previous cycle. Patients in whom the dose of S-1 was already reduced to 80 mg per day were withdrawn from the study when adverse events reoccurred. The doses of docetaxel and cisplatin were reduced from 35 to 20 mg/m2 in case of any adverse events. Moreover, if patients could not resume subsequent cycles within 4 weeks due to toxicities, they were withdrawn from the study.
During the study, physical examination, complete blood cell counts, and biochemical examination were performed on the first day of each chemotherapy cycle, and every 3 months thereafter. Computed tomography was performed every 6 months for the first 3 years, and yearly thereafter.
The primary endpoint of this study was the completion rate of two courses of S-1 in combination with DCS chemotherapy. Secondary endpoints were OS, recurrence-free survival (RFS), cumulative 1-year S-1 completion rate, and the safety of the chemotherapy regimen. OS was defined as the time from registration to the date of death from any cause. RFS was defined as the interval from registration until objective tumor recurrence. OS and PFS were estimated using the Kaplan-Meier method. Data for patients who remained event-free at clinical time were censored on the day they were last reviewed. Relative dose intensity (RDI) was defined as the administered dose divided by the planned dose.
All statistical analyses were conducted using JMP software for Windows (version 14.0; SAS Institute, Cary, NC, USA).