We undertook an open-label, non-randomized, multicenter clinical phase II trial in 12 institutions in Hiroshima, Japan. We enrolled individuals who met the following eligibility criteria: (1) histologically proven colorectal adenocarcinoma; (2) unresectable advanced/metastatic CRC; (3) aged 20–80 years; (4) Eastern Cooperative Oncology Group performance status (PS) of 0 or 1; (5) presence of assessable lesions as confirmed on computed tomography or magnetic resonance imaging; (6) no previous chemotherapy or radiotherapy; (7) could take drugs orally; (8) adequate hematological, renal, and hepatic functions, as defined by a leucocyte count of 3–12 × 109/L; neutrophil count of at least 2.0 × 109/L; platelet count of at least 100 × 109/L; hemoglobin level of at least 9.0 g/dL; total serum bilirubin concentration of no more than 1.5 mg/dL; serum aspartate aminotransferase/serum alanine aminotransferase concentration of no more than 100 U/L; serum creatinine concentration of no more than 1.2 mg/dL; creatinine clearance >60 mL/min; urinary protein score of no more than 1+; and an international normalized ratio of no more than 1.5 and (9) estimated life expectancy of >3 months.
We excluded individuals if they had a history of serious allergies to any medications, active infections, serious concurrent disease, substantially impaired cardiac function, gastrointestinal ulcers or bleeding, sensory neuropathy, serious diarrhea, ascites or pleural effusion needing medication, brain metastases, a history of gastrointestinal perforation within the 6 months before enrollment, a history of thromboembolism or interstitial pneumonia, a history of surgery within the 28 days before enrollment, a blood coagulation disorder, were on anticoagulation medication, a history of hemoptysis, or had a primary lesion associated with a severe stricture that precluded passage of an endoscope. We also excluded individuals if they had previously or were presently receiving oxaliplatin-based regimens as adjuvant chemotherapy.
The current study was conducted in accordance with the declaration of Helsinki. All patients provided written informed consent after having been informed about the purpose and investigational nature of the study. The institutional review boards or ethics committees of each of the participating centers reviewed and approved the protocol. This study was registered in the UMIN Clinical Trial Registry as UMIN000004976.
On day 1 of each 3-week cycle, patients assigned to receive SOX plus bevacizumab received a 7.5 mg/kg intravenous infusion of bevacizumab (for 30–90 min), followed by an intravenous infusion of 130 mg/m2 oxaliplatin (for 2 h). S-1 was taken orally twice daily from after dinner on day 1 to after breakfast on day 15, followed by a 7-day break. The dose of S-1 was assigned according to body surface area: patients with a body surface area of less than 1.25 m2 received 80 mg/day; those with a body surface area between 1.25 m2 and less than 1.5 m2 received 100 mg/day; and those with a body surface area of at least 1.5 m2 received 120 mg/day. Cycles were repeated for each patient until the criteria for withdrawal of the study treatment were met.
In view of the neurological toxicity of oxaliplatin, treatment could be skipped when patients had received at least 600 mg/m2 overall, even when no grade 3 toxic effects were recorded. If patients had grade 2 or higher proteinuria or grade 2 or higher bleeding before the scheduled starting day of each cycle, they received only SOX treatment; bevacizumab could be resumed in subsequent cycles if the treatment criteria were satisfied. The dose of cytotoxic drugs (oxaliplatin and S-1) was reduced by one level if the neutrophil count was less than 0.5 × 109/L at any time during a cycle, the neutrophil count was less than 1.0 × 109/L on the first day of a cycle, grade 3 or higher febrile neutropenia developed, or the platelet count was less than 50 × 109/L. In the event of grade 3 or higher diarrhea, the dose of S-1 was reduced by one level. If the platelet count was between 50 × 109 and 75 × 109/L at any time during a cycle, or between 75 × 109 and 100 × 109/L on the first day of a cycle, the oxaliplatin dose was reduced by one level. S-1 was withheld when the neutrophil count was less than 1 × 109/L; the platelet count was less than 75 × 109/L; the serum creatinine concentration was more than 1.5 mg/dL; suspected infection was diagnosed due to a fever of at least 38 °C; or diarrhea, mucositis, or stomatitis of grade 2 or higher developed. S-1 was subsequently reinitiated when the neutrophil count was at least 1 × 109/L; the platelet count was at least 75 × 109/L; the serum creatinine concentration was less than 1.5 mg/dL; no fever of 38 °C or higher suggesting infection was evident; and diarrhea, mucositis, and stomatitis were no higher than grade 1.
The primary endpoint of this study was response rate (RR), and the secondary endpoints were PFS, overall survival (OS), and safety.
RR was calculated for patients who had measurable lesions using the Response Evaluation Criteria in Solid Tumor (RECIST; version 1.1) (Eisenhauer et al. 2009). RR and disease control rate (DCR) were analyzed for the patients with target lesions. After initiation of study treatment, target and non-target lesions were assessed every 8 weeks in the same way as at baseline, using the same imaging conditions.
PFS was defined as the interval from the date of enrollment to the date on which progressive disease was first confirmed or the date of death from any cause, whichever came first. OS was defined as the interval from the date of enrollment to the date of death from any cause or last follow-up. Adverse events were graded according to the Common Terminology Criteria for Adverse Events (CTCAE; version 4.0).
We also evaluated the proportion of patients achieving disease control (a complete or partial response or stable disease), the proportion of patients having a curative resection, the time to treatment failure (TTF, interval from the date of enrolment to the date of a PFS event or withdrawal from the study for any reason), and adverse events.
All endpoints analyses except for the safety analysis were performed on the intent-to-treat set. The safety analysis included all treated patients who received at least one dose of the experimental drug. The required sample size was calculated to be at least 55 patients on the null hypothesis of a RR of 30 % versus the alternative hypothesis of a RR of 50 %, with a power of 80 %, and a 95 % significance level (one sided). Survival curves were estimated using the Kaplan–Meier method. All statistical analyses were performed using the IBM SPSS Statistic 20.0 software package.