Abstract

Background: Molecular targeted agents, such as bevacizumab and cetuximab, have been shown to improve the overall survival of metastatic colorectal cancer (mCRC) patients. However, we still do not know the best sequence in which to use the molecular targeted agents for mCRC, especially in K-ras wild-type cases. Methods: From July 2006 to November 2010, 63 chemotherapy-naive patients who were diagnosed with mCRC and received an oxaliplatin-based regimen as the first line, did not respond to a bevacizumab-containing regimen used as the first or second line, and received cetuximab or continued bevacizumab, were eligible for this analysis. Thirty-two patients received cetuximab as the third or fourth line chemotherapy due to the K-ras wild-type (Group A). Also, thirty-one patients continued a bevacizumab-containing regimen in spite of disease progression (Group B). Results: The difference in the rate of serious adverse events was not significant between the two groups, but the rate of overall adverse events tended to be higher in Group A than in Group B. The median overall survival (MST) was significantly higher in Group A than Group B (30.8 months and 23.13 months (95%CI: 15.80 - 30.47), respectively) (P = 0.031). Group A patients were all K-ras wild-type, and 21 of Group B were K-ras mutant type. Compared with Group B patients with the K-ras mutant type, MST of Group A patients was significantly longer (30.8 months and 25.73 months, respectively) (P = 0.025). Conclusion: Using cetuximab after progression with bevacizumab might be an effective sequence to improve the overall survival of K-ras wild-type mCRC patients. However, we need further prospective studies to identify the best sequence of chemotherapy for mCRC patients.

Keywords

Colorectal; Bevcizumab Cetuximab; K-ras

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1. Introduction

Colorectal cancer is the second most common cause of cancer death worldwide. A little more than a decade ago, fluorouracil (FU) was the only approved drug for this disease, but, over the last decade, irinotecan and oxaliplatin became available, and the development of novel therapies that target critical biological pathways has greatly expanded treatment options for patients with metastatic colorectal cancer (mCRC).

Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor (VEGF), combined with fluoropyrimidine-based chemotherapy, is now the standard first line treatment for mCRC [1-3]. Bevacizumab provides a survival benefit as a first and second line therapy for metastatic colorectal cancer (mCRC). And cetuximab, a chimeric IgG1 monoclonal antibody against epidermal growth factor receptor (EGFR), improves the median progression-free survival (PFS) of patients resistant to irinotecan monotherapy in combination with irinotecan and improves the median overall survival of mCRC patients in whom all available standard treatments have failed [4,5].

The K-ras genotype affects the response to anti-EGFR treatments [6-10]. In K-ras mutant type patients, after progression on both an irinotecan-based and oxaliplatinbased regimen, no other standard therapy options have existed up to the present. In the BRiTEs and ARIES study, a survival benefit was observed in mCRC patients who received the administration of bevacizumab beyond first progression (BBP) [11,12], but BBP has remained controversial [13,14]. So far, limited data on the efficacy of cetuximab after chemotherapy failure including bevacizumab are available [15]. In this analysis, we evaluated the benefit of using bevacizumab followed by cetuximab, and BBP for mCRC patients, retrospectively.

2. Materials and Methods

2.1. Patients and Procedure

From July 2006 to November 2010, 63 chemotherapytolerarting patients who were diagnosed with mCRC and received an oxaliplatin-based regimen as the first line, did not respond to a bevacizumab-containing regimen used as the first or second line therapy, and received cetuximab or a continued bevacizumab-containing regimen, were eligible for this analysis (Figure 1). Patients who had received prior bevacizumab, cetuximab, or other EGFRor VEGF-directed agents, were excluded. Thirtytwo patients received cetuximab as a third or fourth line chemotherapy due to the K-ras wild-type (Group A). Also, 31 patients continued a bevacizumab-containing regimen in spite of disease progression (Group B). All Patients were followed-up every 3 months with the evaluation of tumor markers (serum CEA and CA19-9) and CT scan of the abdomen and chest according to Response Evaluation Criteria in Solid Tumors (RECIST) [16]. For safety assessment, adverse events were graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE) version 3.0.

2.2. K-ras Mutation Analysis

DNA was extracted from paraffin-embedded colorectal cancer samples after the histological control (HES) for at least 50% tumor cells. Mutations at codons 12 and 13 were assessed by means of direct sequencing (Applied Biosystems). Mutation of the K-ras gene was analyzed by T. N. (Okayama University, Surgery, Japan).

2.3. Statistical Analysis

Categorical and continuous study variables were compared between the two groups using the χ² test and independent-sample t-test. Overall and disease-free survival probabilities were calculated using the Kaplan-Meier method and compared using log-rank tests. A P-value ≦0.05 was considered significant. Multivariate analysis was performed using a Cox proportional hazards model to identify independent prognostic factors of survival in all patients.

On multivariate analysis, factors with P 0.15 on univariate analysis were tested, and, at the end, P 0.05 was considered significant. All statistical analyses were performed using SPSS 19.0.

3. Results

The median duration of follow-up was 23.7 months. Patients’ characteristics are shown in Table 1. There were no significant differences between the two groups. All 63 patients received an oxaliplatin-based combination regimen (e.g., mFOLFOX6 (30), mFOLFOX6 + bevacizumab (Bev) (20), Xelox (5), Xelox + Bev (8)). All patients also received a bevacizumab-containing regimen as the second line. Thirty-two patients had the K-ras wild-type and agreed to receive cetuximab (Cet)-containing chemotherapy for third or fourth line (Group A). Thirty-one patients continued bevacizumab-containing regimen for the third line (Group B). In Group B, 10 of the 31 patients were K-ras wild-type. The reasons for not receiving anti-EGFR therapy were: 1) Before 2009.4, when cetuximab was first approved in Japan for use (4 cases), 2) Appropriate informed consent was not obtained (5 cases), and 3) Considered as anti-EGFR therapy-intolerable (1 case). The median number of cycles of the

bevacizumab-containing regimen was 9 (range, 2 - 30) in Group A and 10 (range, 5 - 33) in Group B. In Group A, the median number of cycles of cetuximab was 12.5 (range, 3 - 37).

Table 2 shows adverse events grade 2 in both groups. Overall, the safety profile of cetuximab, bevacizumab, irinotecan, and oxaliplatin was consistent with prior studies (1 - 5, 11, 12). Toxicities related to AntiEGFR drugs, such as skin rash (50%) and paronychia (37.5%), were more frequent in Group A. Hypertension (29.0%) occurred more frequently in Group B, probably due to the continuous usage of Bev. The incidence of arterial and venous thromboembolic events was equally distributed between the two groups. Gastrointestinal perforation did not occur in either group. No grade 4 adverse effects were observed.

Conflicts of Interest

The authors declare no conflicts of interest.

References