Between April 2005 and June 2010, 40 patients with MCRC were treated with bevacizumab plus chemotherapy as a second- or later-line treatment in Busan, South Korea. Patients who were eligible for the present study suffered from histologically-confirmed MCRC. Other inclusion criteria included an age of at least 20 years, and a life expectancy of > 3 mo. There were no limitations on the number of prior therapies or on the Eastern Cooperative Oncology Group (ECOG) performance status. However, adequate hematologic (an absolute neutrophil count > 1500/μL, hemoglobin > 9.0 g/dL, and a platelet count > 75 000/μL), hepatic (bilirubin < 2.0 mg/dL and transaminase levels < 3 times the upper normal limit), and renal functions (creatinine < 1.5 mg/dL and urinary excretion ≤ 500 mg of protein per day) were required.

The exclusion criteria included the presence of clinically significant cardiovascular disease, uncontrolled hypertension, central nervous system metastasis, major surgery within 6 wk, pregnancy or lactation, non-healing wounds, bleeding diatheses, the regular use of aspirin (> 325 mg/d) or other non-steroidal anti-inflammatory agents, pre-existing bleeding diatheses or coagulopathies, the need for full-dose anticoagulation or prior bevacizumab therapy.

Among the 40 patients in the present study, 12 patients received bevacizumab plus oxaliplatin-containing chemotherapy, 19 patients received bevacizumab plus irinotecan-containing chemotherapy, 8 patients received bevacizumab plus 5-FU and LV (FL), and 1 patient received bevacizumab alone. Bevacizumab plus FOLFOX or FOLFIRI chemotherapy was administered every 2 wk and consisted of the following: intravenous (IV) oxaliplatin (85 mg/m²) or irinotecan (150 mg/m²) over 2 h; IV LV (200 mg/m²) over 2 h, followed by a bolus of 5-FU (400 mg/m²); and infusional 5-FU (600 mg/m²) over 22 h, with FL repeated on day 1. The FL chemotherapy was administered every 4 wk [infusional 5-FU (375 mg/m²) over 24 h, and the IV LV (20 mg/m²)] was administered over 2 h for 5 d. Bevacizumab was administered intravenously at 5 mg/kg over 30 min to 90 min every 2 wk, prior to FOLFOX, FOLFIRI, or FL.

The objective of the present study was to evaluate the overall response rate (ORR), OS, progression-free survival (PFS), and toxicity of bevacizumab in patients who failed prior treatment. The tumor responses were assessed using Response Evaluation Criteria in Solid Tumors guidelines[17]. Progression was defined as a 20% increase at the time of disease progression.

The toxicities were graded using the NCI Common Terminology Criteria for Adverse Events (version 3.0)[18]. Radiographic assessments were performed at baseline (within 4 wk before starting chemotherapy) and every 6 wk to 8 wk. Radiologic evaluation consisted of a chest X-ray, bone scan, chest computed tomography (CT) scan, and abdominopelvic CT scan.

All of the patients who received at least three dose of therapy were included in the PFS and OS analyses. The OS was defined as the time elapsed between the initiation of the study therapy to the date of death from any cause. The PFS was defined as the time elapsed between the initiation of the study therapy to the date of the progressive disease (PD). Patients who died without a documented PD were considered to have had a PD at the time of death. Patients who were removed from therapy for toxicity without clinical or radiographic evidence of PD were censored. Patients who were lost to follow-up were censored at the last contact date. Survival curves were estimated using the Kaplan-Meier method.

The median age of the patients in the present study was 55.5 years. Forty patients received FOLFOX, FOLFIRI or FL, plus bevacizumab or bevacizumab alone, as a therapy. The metastatic sites were primarily located in the liver and/or lung (45.0%). Thirty one patients had previously undergone treatment with the FOLFOX regimen, twenty-five had undergone treatment with FOLFIRI, fifteen had undergone treatment with capcitabine alone and six had undergone treatment with FL. Seventeen patients (42.5%) were treated with bevacizumab combined chemotherapy as a second-line treatment, thirteen (32.5%) were treated as a third-line treatment, and ten (25.0%) were treated as a fourth- or later-line treatment. The majority of the patients were treated with Bevacizumab combined chemotherapy, including oxaliplatin (30.0%), irinotecan (47.5%), and fluoropyrimidine (20.0%). One patient (2.5%) was treated using bevacizumab alone, without the addition of other chemotherapy regimens. Additional patient demographics are summarized in Table 1.

Three patients had partial responses, resulting in an ORR of 7.5%. Twenty-one patients exhibited a stable disease (SD), and fifteen patients exhibited a PD. The response rates of second-line, third-line, and fourth- or later-line treatments were noted in Table 2.

The median duration of the OS and PFS was 14.0 mo and 6.13 mo, respectively (Table 3 and Figure 1). The median OSs were 16.60 mo, 14.07 mo and 13.00 mo for the second-line, third-line and fourth- or later-line treatments, respectively. The median PFSs were 7.23, 7.30, and 3.87 mo for the second-line, third-line and fourth- or later-line treatments, respectively.

Open in New Tab   Full Size Figure   Download Figure

Figure 1 Curves for the overall survival, and progression-free survival in patients with metastatic colorectal cancer after bevacizumab combined chemotherapy as a second- or later-line treatment. A: Curves for the overall survival in patients with metastatic colorectal cancer after bevacizumab combined chemotherapy as a second- or later-line treatment; B: Curves for progression-free survival in patients with metastatic colorectal cancer after bevacizumab combined chemotherapy as a second- or later-line treatment.

The addition of bevacizumab to 5-fluorouracil (5-FU)-based combination chemotherapy as the first-line treatment results in a clinically meaningful improvement in the survival of patients with metastatic colorectal cancer (MCRC).

Based on the inconclusive results from multicenter studies, the role of bevacizumab in the treatment of patients with disease that is refractory to 5-FU, irinotecan, and oxaliplatin is unclear.

In previous studies, bevacizumab combined chemotherapy as a second- or later-line treatment was shown to have controversial results. In the present study, three patients exhibited partial responses, resulting in an overall response rate of 7.5%. The median duration of the overall survival (OS) and progression-free survival (PFS) was 14.0 mo and 6.13 mo, respectively. The median OSs were 16.60, 14.07 and 13.00 mo for the second-line, third-line and fourth- or later-line treatments, respectively. The median PFSs were 7.23 mo, 7.30 mo, and 3.87 mo the second-line, third-line and fourth- or later-line treatments, respectively.

The results of the present study suggest that bevacizumab combined chemotherapy as a second- or later-line treatment is an active and tolerable treatment option for patients with MCRC after failure to previous chemotherapy.

The present study is a good descriptive retrospective study that evaluated the efficacy of bevacizumab plus chemotherapy in patients with MCRC who have failed prior chemotherapy without bevacizumab.