This study was a multicenter phase II clinical study to examine the efficacy and safety of intermittent oxaliplatin administration in patients with unresectable CRC receiving CAPOX plus bevacizumab as first-line therapy. The primary endpoint was progression-free survival (PFS); secondary endpoints were time to treatment failure (TTF), overall survival (OS), response rate (RR), and safety.
Patient eligibility criteria
Patients were enrolled in the study if they fulfilled the following inclusion criteria: 1) provided written informed consent; 2) CRC was definitively diagnosed histologically and was metastatic and unresectable, the disease had not received previous chemotherapy or radiation therapy, advanced CRC patients who had received no intervention expect surgical procedures, and recurrent CRC patients who had not been administered any therapy to the recurrent site; 3) at least one lesion was evaluable by radiological examinations within 28 days before registration; 4) age ≥ 20 years old and provided informed consent; 5) Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1; and 6) vital organ function (listed below) within 14 days prior to entry: adequate hematological (white blood cell count: > 3000/mm3; neutrophil count: > 1500/mm3; platelet count: > 10.0 × 104/mm3; hemoglobin > 9.0 g/dl), hepatic (total bilirubin < 1.5 × the upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 × ULN, or < 5 × ULN in the case of hepatic metastases), and renal function (serum creatinine clearance < 1.5 × ULN; proteinuria < 2+).
Patients were excluded if there was 1) suspicion of brain metastasis or brain cancer confirmed by radiological imaging, such as head computed tomography or magnetic resonance imaging; 2) cerebrovascular disease or related symptoms within 1 year or a history of suspected complications of arterial thromboembolism, such as cerebrovascular disease or thromboembolism once within 1 year or twice; 3) bleeding diathesis (history of hemoptysis, including cavitation and/or necrosis in lung metastases confirmed by imaging), coagulopathy, or abnormality in coagulation factors, such as a prothrombin time-international normalized ratio (PT-INR) ≥ 1.5; 4) history of gastrointestinal perforation within 1 year or uncontrollable peptic ulcers, uncontrollable infection, diarrhea, and hypertension; 5) symptomatic cardiovascular disease or symptomatic disease previously treated and history of myocardial infarction within 1 year; 6) women who were pregnant, possibly pregnant, wishing to become pregnant, or nursing; or 7) not appropriate for the study at the physician’s assessment.
An eligibility report form was sent to the registration center at the Graduate School of Medicine, Department of Frontier Surgery, Chiba University (Chiba, Japan). Information regarding the necessary follow-up tests was then sent to the investigator from the registration center. The registration period was from February 2011 to January 2014, and the ongoing follow-up period was 2 years from enrollment of the last subject.
The protocol treatment was started within 14 days after enrollment for eligible patients. Patients received five cycles of CAPOX plus bevacizumab therapy. Intravenous oxaliplatin (130 mg/m2) was administered over 120 min, bevacizumab (7.5 mg/kg) was administered by a 30-min intravenous infusion on day 1 of the 3-week cycle, and oral capecitabine (2000 mg/m2) was administered daily on days 1–14 every 3 weeks. This regimen constituted cycles 1–5.
Five cycles (cycles 6–10) were given without oxaliplatin. Capecitabine (2000 mg/m2 daily on days 1–14 every 3 weeks) plus bevacizumab (7.5 mg/kg on day 1 of the 3-week cycle) therapy was initiated for patients with disease control (complete response (CR), partial response (PR), and stable disease (SD)) after the induction therapy.
Reintroduction of oxaliplatin was scheduled after 10 cycles of induction and maintenance therapy. Oxaliplatin was then reintroduced for five cycles, so that a total of 15 cycles was administered as the protocol treatment. Protocol treatment was continued as long as it did not conflict with the criteria for discontinuing treatment. However, the following defined the end of the protocol treatment: (1) The 15 cycles (induction therapy followed by maintenance therapy and then reintroduction therapy) prescribed in the protocol were completed. However, if progressive disease (PD) was confirmed before completing five cycles in the maintenance therapy, the end of protocol treatment was defined as the end of oxaliplatin reintroduction therapy. (2) The patient became operable as a result of treatment efficacy (with the day of surgery defined as the end of protocol treatment).
Dose reduction and withdrawal criteria
The types and severities of adverse events (AEs) were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 , and PSN was assessed in accordance with the Neurotoxicity Criteria of Debiopharm (DEB-NTC) [29–31]. Dose reduction for subsequent courses was performed according to AEs that occurred during the previous course. The dose could be reduced twice, after which protocol treatment was discontinued if a third dose reduction was required. The dose could not be increased again after being reduced.
Patients were observed carefully for previously reported typical adverse drug reactions to bevacizumab and oxaliplatin, including hemorrhage, thrombosis, gastrointestinal perforation, increased blood pressure, hemotoxicity, and PSN. The dose of capecitabine was reduced for grade ≥ 3 neutropenia, thrombocytopenia, diarrhea, hand-foot syndrome, stomatitis, skin toxicity, or other nonhematologic toxicities or for a second or subsequent occurrence of hand-foot syndrome. If PSN occurred, dose reduction or treatment withdrawal was performed.
If grade ≥ 3 hematological AEs (neutropenia, thrombocytopenia, other hematological toxicities) occurred, the doses of oxaliplatin and capecitabine were reduced as follows: oxaliplatin was reduced to 100 mg/m2, and capecitabine was reduced to 1500 mg/m2. If a similar AE occurred subsequently, the doses were reduced further to 85 mg/m2 and 1000 mg/m2, respectively. If PSN occurred, dose reduction or treatment withdrawal was performed.
Criteria for starting the next cycle and discontinuation criteria
The clinical findings and laboratory test values (listed below) were evaluated in all patients on the first planned day (Day 1) of each treatment cycle. If all of the following criteria were not fulfilled, treatment was postponed until the criteria were met: 1) adequate hematological indices: white blood cell count > 3000/mm3 and < 12,000/mm3; neutrophil count > 1500/mm3; platelet count > 75,000 mm3; hemoglobin > 9.0 g/dL; 2) hepatic indexes: total bilirubin < 1.5 × ULN; ALT and AST < 2.5 × ULN, or < 5 × ULN in the case of hepatic metastases; 3) renal function: serum creatinine below the institutional ULN; and 4) PSN: grade ≤ 2.
The protocol treatment was discontinued if any of the following occurred: the development of any AEs (defined as grade ≥ 2 hypersensitivity); the criteria for starting the next cycle were not met within 4 weeks (28 days) after the planned day of initiating treatment because of an AE; further toxicity meeting the dose reduction criteria after two dose reductions; discontinuation considered necessary by the investigator because of an AE (even if the criteria were not met); the patient requested to discontinue treatment; death during protocol treatment; or a protocol violation was found after enrollment, making the patient ineligible .
Statistical determination of target sample size
In the NO16966 study , a phase III clinical study of FOLFOX4 or CAPOX with/without bevacizumab, the median PFS by on-treatment analysis, excluding PD cases from at least 29 days after the final administration of the study drug, was 10.4 months. In the MACRO trial , a phase III clinical study conducted to confirm first-line CAPOX plus bevacizumab followed by CAPOX plus bevacizumab or single-agent bevacizumab as maintenance therapy, the median PFS for CAPOX plus bevacizumab was 10.4 months, and that for single-agent bevacizumab was 9.7 months. Therefore, the threshold PFS in this study was assumed to be 7 months considering PFS in the phase III study of FOLFOX4 with bevacizumab  and CAPOX with bevacizumab , and the anticipated PFS was set at 10.5 months. The level of significance was 0.05 at a power of 80%, and the required number of cases determined using the Southwest Oncology Group’s one-arm survival design (http://www.swogstat.org/statoolsout.html) was 42 patients. The target number of cases in this study was 50 patients, considering a dropout rate of 10%.
PFS (as the primary objective of this study) and TTF (as the secondary endpoint) were estimated using the Kaplan–Meier method. The median PFS and TTF were calculated, and their two-sided 95% confidence interval (CI) was determined. Regarding the RR, the antitumor effect was calculated, and the exact CI was used for the interval estimation. Statistical analyses were performed using SPSS, version 23 (IBM Corp., Armonk, NY, USA). Statistical significance was established at the P<0.05 level.