The efficacy and safety of CapeOX plus bevacizumab therapy followed by capecitabine plus bevacizumab maintenance therapy in patients with metastatic colorectal cancer: a multi-center, single-arm, phase II study (CCOG-0902)

This multicenter, single-arm, phase 2 trial was conducted by the Chubu Clinical Oncology Group (CCOG) in 18 hospitals of Japan. The criteria for inclusion in this study were age at least 20 years; histologically proven adenocarcinoma of the colon or rectum; unresectable metastasis; no previous chemotherapy for metastatic disease; at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1; an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1; and adequate bone marrow, liver, and renal functions. Patients may register if they have received adjuvant chemotherapy with fluoropyrimidine and cancer recurrence has occurred 6 months or more after the last dose. Patients who have received oxaliplatin-based adjuvant chemotherapy may not register. Patients with brain metastasis, clinically significant cardiovascular disease, second malignancies, bowel obstruction, PNS more than grade 1, uncontrolled diabetes mellitus or hypertension were excluded. Patients completed written informed consent before participating, and the ethics committees of Nagoya University Hospital and each participating facility approved the study. This trial was registered with the University Hospital Medical Information Network in 15 March 2010 (UMIN000006478).

Induction therapy: Patients received CapeOX plus bevacizumab therapy for 4 cycles, which consisted of intravenous oxaliplatin (130 mg/m²) and bevacizumab (7.5 mg/kg) on day 1 in combination with oral capecitabine (1000 mg/m² twice daily) given as intermittent treatment for 14 days followed by 7 days treatment-free interval, every 3 weeks. Maintenance therapy: Capecitabine plus bevacizumab therapy which consisted of intravenous administration of bevacizumab (7.5 mg/kg) on day 1 and capecitabine (1000 mg/m² twice daily), was initiated for patients with stable disease or a superior response after 4 cycles of the induction therapy. Reintroduction therapy: Reintroduction of oxaliplatin was scheduled after 8 cycles of the maintenance therapy. Oxaliplatin was also reintroduced in the event of tumor progression before 8 cycles of the maintenance therapy (in a case where tumor progression was observed before 8 cycles of the maintenance therapy). The reintroduction therapy continued until disease progression, unacceptable toxicity, or the patient refusal.

The primary objective of this study was PFS, defined as the time from the date therapy was initiated until the date of disease progression or death from any cause. The secondary objectives were the following: OS, defined as the time from the date that therapy was initiated until the date of death from to any cause; duration of disease control (DDC), defined as PFS in the patients without disease progression before oxaliplatin reintroduction or the patients with progression at the first evaluation after oxaliplatin reintroduction. In the case achieved disease progression before oxaliplatin reintroduction and tumor response or stabilization at the first evaluation after oxaliplatin reintroduction, DDC was defined as the sum of the initial PFS and the PFS of the reintroduction [8]; overall response rate (ORR), defined as the proportion of patients whose best response was complete response (CR) or partial response (PR); disease control rate (DCR), defined as the proportion of patients whose best response was CR, PR or stable disease (SD); reintroduction rate of oxaliplatin, defined as the proportion of patients who received the reintroduced CapeOX plus bevacizumab therapy; and the incidence of adverse events, including the frequency and severity of PSN. Tumor size and response according to RECIST, version 1.1, based on chest-to-pelvic region computed tomography (CT) once every 8 weeks were evaluated by the local review in each participating facility. Adverse events were assessed using National Cancer Institute Common Toxicity Criteria (NCI-CTC), version 3.0.

A power analysis was conducted before the study. Assuming that the threshold for PFS was 7.2 months and the expected PFS was 10.4 months, referring to data from the previous clinical trials [4, 7], with the enrollment period of 2 years and the follow-up period of 3 years, 47 patients were required to ensure an alpha level of 0.05 (one-sided) and a detection power (1-β) of 80%. The sample size for this study was 50 to account for possible loss to follow-up.

The PFS, the primary objective of this study, was estimated using the Kaplan–Meier method, and the median PFS and its 95% confidence interval were estimated. Other time-to-endpoint variables, DDC and OS, were estimated using the same method. The ORR, DCR and incidence the toxicities were calculated as proportions with exact confidence intervals. Statistical analyses were performed using SPSS, version 23 (SPSS Inc., Chicago, IL, USA).

Fifty-four patients from 18 institutions were enrolled in this study between April 2010 and October 2011. Two patients were excluded after enrollment because of ineligibility. The remaining 52 patients who received the protocol treatment were included in the evaluation of efficacy and safety. Baseline characteristics of the 52 patients are presented in Table 1.

The initial CapeOX plus bevacizumab therapy was administered to 52 patients, including 50 patients who accomplish 4 cycles of the induction therapy. The maintenance therapy, capecitabin and bevacizumab, was administered to 45 patients (86.5%). Twenty-two of those patients could accomplish 8 cycles of maintenance therapy. Oxaliplatine was reintroduced in 29 patients (55.8%), including 20 patients accomplished 8 cycles of the maintenance therapy and 9 patients with disease progression during the maintenance therapy. A consort chart of patients is presented in Fig. 1. The median number of treatment cycles was 4 (1–4 cycles) for the initial CapeOX plus bevacizumab therapy, 7 (1–8 cycles) for the capecitabin plus bevacizumab maintenance therapy, and 5 (1–22 cycles) for the reintroduced CapeOX plus bevacizumab therapy. The median time-to-treatment failure of the protocol treatment was 9.9 months (95% confidence interval [CI]: 5.9–13.8 months).

The relative dose intensity of oxaliplatin in the initial and reintroduced CapeOX plus bevacizumab therapy were 92.3 and 78.5%, respectively, and the cumulative dose of oxaliplatin during the overall treatment period was 1052 mg (470–4346 mg). The protocol treatment was discontinued because of the following circumstances: disease progression in 28 patients (53.8%), adverse events in 11 (21.2%), and resection of metastasis in 5 (9.6%).

Treatment status is summarized in Table 2.

After a median follow-up period of 49.5 months (range: 6.3–63.9 months), the disease progressed in 49 patients (94.2%) and 35 deaths (67.3%) occurred in the 52 patients enrolled. Median PFS, the primary endpoint, and DDC were 12.4 months (95% CI, 10.0–14.8 months) and 13.4 months (95% CI, 12.2–14.6 months), respectively (Fig. 2a). There was no significant difference between these two survival outcomes (HR 0.932, 95% CI 0.627–1.385, p = 0.727). The median OS was 30.6 months (95% CI, 27.6–33.5 months) (Fig. 2b). The ORR for the initial CapeOX plus bevacizumab therapy, maintenance capecitabin plus bevacizumab therapy, and reintroduced CapeOX plus bevacizumab therapy were 55.8, 17.8, and 31.0%, respectively. The DCR for those therapies were 96.2, 80.0, and 89.7%, respectively. The tumor response to each phase of treatment is summarized in Table 3.

The incidence of treatment-related adverse events is presented in Table 4. The frequencies of hematological and non-hematological adverse events above grade three were 13.5 and 38.5%, respectively, for the overall treatment period. PSN occurred in 33 patients (63.5%), including two patients (3.8%) with PSN grade 3. Grade-3 PSN occurred in one patient at the end of the induction therapy and one patient after fourth cycle of the reintroduction therapy. The frequencies of PNS after 4 cycles of the initial CapeOX plus bevacizumab therapy and after 8 cycles of the maintenance therapy were 42 and 9%, respectively (Fig. 3). During the induction and maintenance therapy, no patients required treatment discontinuation due to PSN. The incidence of hand-foot syndrome and bevacizumab-related toxicities is presented in Fig. 3a and b, respectively. These toxicities occurred in relatively constant rate of patients throughout all treatment period, however, treatment was discontinued in 3 patients (5.8%) due to HFS and 4 patients (7.7%) due to bevacizumab-related toxicities.