Disease	Colorectal cancer
Stage of Disease/Treatment	Metastatic/advanced
Prior Therapy	None
Type of Study	Phase II, single arm
Primary Endpoint	Deliverability
Secondary Endpoints	Time to progression, overall survival, safety
Additional Details of Endpoints or Study Design	The primary endpoint was completion rate of adjuvant chemotherapy.
Inclusion criteria: Eligibility criteria were histologically proven colorectal cancer; curatively resected metastatic liver tumors from colorectal cancer; no extrahepatic sites of disease; enrollment within 90 days after hepatic resection; age 20 years or more at the time of registration; Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1; and adequate organ function, as defined by absolute neutrophil count ≥1,500/mm3, hemoglobin ≥10 g/dL, platelet count ≥10.0 × 104/mm3, total bilirubin ≤1.5 mg/dL, serum transaminases ≤100 U/L, and serum creatinine ≤1.2 mg/dL.
This trial was carried out in accordance with the Helsinki Declaration and Ethical Guidelines for Clinical Studies and was approved by the institutional review boards of all participating institutions. All patients were required to give written informed consent before entering the study.
Study treatment and dose modification: Patients received one course of capecitabine followed by four courses of CAPOX for a total of five courses (15 weeks) as adjuvant chemotherapy after curative resection of CLM. Oral capecitabine was given at 1,000 mg/m2 twice daily for 2 weeks in a 3‐week cycle, whereas CAPOX consisted of oral capecitabine plus a 2‐hour intravenous infusion of oxaliplatin at 130 mg/m2 on day 1 in a 3‐week cycle. The dose was modified for each patient based on hematologic or nonhematologic toxicity. Treatment was delayed if, on the planned day of treatment, the following criteria were present: absolute neutrophil count <1,500/mm3, platelets <75,000/mm3, palmar‐plantar erythrodysesthesia syndrome grade >1, diarrhea grade >1, and other parameters at the attending physician's discretion. If adverse events of a high enough grade occurred during the previous course, the dose was reduced by one level (up to −2 level). Capecitabine doses could be reduced to 1,500 mg/m2 per day (−1 level) and 1,000 mg/m2 per day (−2 level). Oxaliplatin doses could be reduced to 100 mg/m2 (−1 level) and 85 mg/m2 (−2 level). Patients who could not tolerate oxaliplatin could continue to receive capecitabine monotherapy until a maximum total of five courses, disease relapse, or intolerable toxicity. Capecitabine and oxaliplatin could be reduced by two dose levels, but treatment was discontinued if subsequent reduction was indicated. In the event of grade 4 nonhematologic toxicities, treatment was definitively interrupted. Pretreatment evaluation included a medical history; physical examination; complete blood cell count and serum chemistry tests; and chest, abdominal, and pelvic computed tomography scans. Clinical examination and biochemical tests were required before and during each cycle.
All adverse events experienced during the study were recorded and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
Endpoints and statistical analysis: The primary endpoint was completion rate of adjuvant chemotherapy. Based on the treatment completion rate of the EORTC 40983 trial [11], which was conducted in the same subjects as this study, the threshold completion rate of protocol treatment was set to 45% and the expected completion rate was set to 70%. Given a one‐sided α of 0.1 and statistical power of 80%, a minimum of 25 patients was required. Secondary endpoints included RFS, OS, dose intensity, and safety. Dose intensity was calculated as the ratio of the actual to planned dose intensity in milligrams per square meter per week. The survival curve was estimated using the Kaplan‐Meier method. Safety and efficacy analyses were both conducted on an intention‐to‐treat population, defined as all patients enrolled in the study who received at least one dose of chemotherapy. RFS was defined as the time to the earlier of the date at which relapse was diagnosed or the date of death due to any cause, with the day of registration as the base date. OS was determined as the time to date of death due to any cause or last confirmation of survival, with the day of registration as the base date. Statistical data were obtained using SAS software, version 9.4 (SAS Institute Inc., Cary, NC).
Investigator's Analysis	Active and should be pursued further