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  Table of Contents  
ORIGINAL ARTICLE
Year : 2014  |  Volume : 51  |  Issue : 7  |  Page : 113-116
 

A meta analysis of cetuximab plus oxaliplatin based chemotherapy regimen for metastatic colorectal cancer


1 Department of Clinical Pharmacy, The Central Hospital of Jinhua City, Jinhua Zhejiang Province 321000, China
2 Department of Oncology, The Central Hospital of Lishui City, Lishui Zhejiang Province 323000, China
3 Department of Pharmacy, The Second Hospital of Jinhua City, Jianhua Zhejiang Province 321017, China

Date of Web Publication27-Mar-2015

Correspondence Address:
S W Lv
Department of Clinical Pharmacy, The Central Hospital of Jinhua City, Jinhua Zhejiang Province 321000
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.154101

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 » Abstract 

Background: Oxaliplatin based chemotherapy regimen was one of the most used chemotherapy modality for metastatic colorectal cancer. The purpose of this meta-analysis was to assess the clinical activity and toxicities of cetuximab plus oxaliplatin-based chemotherapy regimen for metastatic colorectal Cancer. Methods: We searched the clinical studies about the cetuximab plus oxaliplatin-based chemotherapy regimen versus oxaliplatin-based chemotherapy alone for metastatic colorectal cancer in the databases of PubMed, EMBASE, Cochran, and CNKI. The data of response and toxicities were extracted and pooled by random or fixed effects model. And publication bias was evaluated by begg's funnel plot and egger's regression test. Results: Seven papers were included in this study. Adding cetuximab to oxaliplatin-based chemotherapy regime can significant increase response rate in K-RAS mutation metastatic colorectal patients (odds ratio [OR]: 1.45, 95% confidence interval [CI]: 1.17-1.80, Z = 3.38, P = 0.001) and metastatic colorectal patients without knowing the K-RAS status (OR: 1.36, 95% CI: 1.11-1.65, Z = 1.89, P = 0.003). But for patients with mutated K-RAS, the improvement for objective response rate was not statistical significant (OR: 0.70, 95% CI: 0.49-1.01, Z = 3.00, P = 0.058) when adding cetuximab to oxaliplatin-based chemotherapy regime. The pooled results indicating the rash and diarrhea risk was significantly increased in the combined treatment group (P < 0.05). The toxicity of peripheral neuritis was decreased by adding the cetuximab (P < 0.05). And other toxicities were not statistical different between the two groups (P > 0.05). Significant publication bias was found in toxicities evaluation. Conclusion: Cetuximab plus oxaliplatin-based chemotherapy regimen significant increase the response rate for metastatic colorectal cancer. But the some toxicities such rash and diarrhea risk was also increased.


Keywords: Cetuximab, chemotherapy, meta-analysis, metastatic colorectal cancer, oxaliplatin


How to cite this article:
Zhu Y L, Lou J, Guo J Y, Huang Z, Lv S W. A meta analysis of cetuximab plus oxaliplatin based chemotherapy regimen for metastatic colorectal cancer. Indian J Cancer 2014;51, Suppl S3:113-6

How to cite this URL:
Zhu Y L, Lou J, Guo J Y, Huang Z, Lv S W. A meta analysis of cetuximab plus oxaliplatin based chemotherapy regimen for metastatic colorectal cancer. Indian J Cancer [serial online] 2014 [cited 2020 Aug 9];51, Suppl S3:113-6. Available from: http://www.indianjcancer.com/text.asp?2014/51/7/113/154101



 » Introduction Top


Cetuximab, a chimeric (mouse/human) monoclonal antibody, [1] is an epidermal growth factor receptor (EGFR) inhibitor used for the treatment of metastatic colorectal cancer, [2],[3] advanced nonsmall cell lung cancer [4],[5] and head and neck carcinoma. [6] Cetuximab is recommended for the treatment of patients with EGFR-mutation, K-RAS wild-type metastatic colorectal cancer, in combination with platinum-based chemotherapy, or as a single agent in patients who have failed for platinum-based chemotherapy. Studies indicated that cetuximab was active in metastatic colorectal cancer with approximately 10% of patients achieve an objective tumor response to cetuximab. [7] And other studies indicated that the response rate was higher than 10%. [8] To explicated the activity and toxicities of cetuximab plus oxaliplatin-based chemotherapy regimen for metastatic colorectal cancer we performed this meta-analysis by pooling the open published data.


 » Methods Top


The clinical studies about the cetuximab plus oxaliplatin-based chemotherapy regimen versus oxaliplatin-based chemotherapy alone for metastatic colorectal cancer were search in the databases of PubMed, EMBASE, Cochran, and CNKI. The search items were used as cetuximab or erbitux), oxaliDlatin, (randomized controlled trial) or (controlled clinical trial), colorectal and (tumour* or tumor* or carcinoma* or adenoma* or neoplasm* or cancer*). The searching procedure was done and cross-checked by two reviewers independently. All of the data were extracted independently by two reviewers according to the selection criteria. The disagreement between the two data extraction reviewers was resolved by discussion.

Statistical analysis

STATA/SE 11.0 (http://www.stata.com; Stata Corporation, College Station, TX, USA) were used for statistical analysis. Statistical heterogeneity across studies was assessed by Chi-square test, [9] and the inconsistency was calculated by I2 . [10] If heterogeneity was significant (χ2 , P < 0.1 or I2 > 50%), the random-effect method (Dersimonian-Laird method) was used to pool the data. Inversely, without significant heterogeneity across the individual studies, fixed-effect method was used.


 » Results Top


Study characteristics

Through searching the databases, we find 389 studies related to this meta-analysis. By checking the title, abstract and full-text paper, 382 studies were excluded. Finally, a total of 7 eligible studies met all selection criteria for the pooled analyses. The general characteristics of the studies included in the meta-analysis were demonstrated in [Table 1].
Table 1: Characteristics of studies included in the meta‑analysis

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K-RAS mutation rate

Four studies reported the K-RAS status of the included studies. The K-RAS mutation rate ranges from 46.9% to 57.3% with the median mutation rate of 52.0%.

Heterogeneity analysis

The odds ratio (OR) was used to demonstrate the objective response rate (ORR) between the combined treatment and alone treatment group. We test the statistical heterogeneity of OR for the ORR in K-RAS wild patients, K-RAS mutation patients, and mixed patients. The statistical heterogeneity was obvious in K-RAS wild (I2 = 58.9%, P = 0.063), K-RAS mutation (I2 = 66.0, P = 0.053) and mixed (I2 = 49.0, P = 0.098) subgroups. The pooled method was employed by random effect model.

Response rate

Significant heterogeneity was found in pooling the OR for ORR. The combined results showed adding cetuximab to oxaliplatin-based chemotherapy regime can significant increase response rate in K-RAS mutation metastatic colorectal patients (OR: 1.45, 95% confidence interval [CI]: 1.17-1.80, Z = 3.38, P = 0.001). For metastatic colorectal patients without knowing the K-RAS status, adding cetuximab to oxaliplatin-based chemotherapy regime can also improve the ORR compared to oxaliplatin-based chemotherapy regime alone (OR: 1.36, 95% CI: 1.11-1.65, Z = 1.89, P = 0.003). But for patients with mutated K-RAS, the improvement for ORR was not statistical significant (OR: 0.70, 95% CI: 0.49-1.01, Z = 3.00, P = 0.058) when adding cetuximab to oxaliplatin-based chemotherapy regime [Figure 1].
Figure 1: Forest plot of objective response rate for cetuximab plus oxaliplatin-based chemotherapy regime in the treatment of metastatic colorectal cancer with fixed effect model

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Toxicities and safety

Six studies reported the toxicity of neutrophils, the median incidence of grade III-IV neutrophils was 23% and 26% in the combined group and control group respectively. 6 articles reported the rash, the median incidence of grade III-IV neutrophils was 16.0% and 0.4% in the combined group and control group respectively. The median incidence of grade III-IV peripheral neuritis was reported by 4 articles with the incidence of 12.6% and 15.0% in combined treatment and control group respectively. The grade III-IV debilitation toxicity was reported by 4 studies with its incidence of 12.3% and 7.3% respectively. For nausea and vomiting side effects, 5 studies provided the incidence with 7.1% (nausea), 6.6% (vomiting) and 7.6% (nausea), 6.6% (vomiting) in the combined group and control group respectively. The incidence of grade III-IV diarrhea was 25.1% and 17.4% respectively reported by 4 studies. The median and range of incidence for the related toxicities were showed in [Figure 2]. The pooled results indicating the rash and diarrhea risk was significantly increased in the combined treatment group (P < 0.05). The toxicity of peripheral neuritis was decreased by adding the cetuximab (P < 0.05). And other toxicities were not statistical different between the two groups (P > 0.05), [Table 2].
Figure 2: Box-and-whisker plot for the median toxicities of the two groups

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Table 2: The pooled toxicities of the two groups

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Publication bias

The publication bias was evaluated by funnel plot and egger's regression test. For ORR, the funnel plot was symmetrical [Figure 3] and egger's regression test (t = 0.87, P = 0.41) showed no publication bias. In the case of toxicities, the funnel plot was asymmetrical [Figure 4] and egger's regression test (t = 2.37, P = 0.02) showed significant publication bias.
Figure 3: The funnel plot for evaluating the publication bias for objective response rate

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Figure 4: The funnel plot for evaluating the publication bias for toxicities

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 » Discussion Top


The main findings of this meta-analysis are the combination treatment of cetuximab plus oxaliplatin-based chemotherapy regimen can improve the tumor response in K-RAS wild-type patients and metastatic colorectal cancer patients without knowing the K-RAS status. But for metastatic colorectal cancer patients with mutated K-RAS gene, the adding cetuximab treatment modality does not increase the tumor response rate (P > 0.05). The results indicated that wild-type K-RAS metastatic colorectal patients can benefit from the cetuximab plus oxaliplatin-based chemotherapy regimen. But the K-RAS mutated metastatic colorectal carcinoma patients cannot benefit from the treatment of cetuximab plus oxaliplatin-based chemotherapy regimen which was in accordance with previously study. [17] We further find that for without knowing K-RAS status patients, the ORR was also increased by adding the cetuximab into the oxaliplatin-based chemotherapy regimen. This result seems to be contradictory. We think the reason for this result could be explained by the small weight of K-RAS mutated patients data and small cases number included in this meta-analysis. The weight for K-RAS mutated patients' data was smaller than the K-RAS wild-type patients' data, the effect size of OR for K-RAS mutated patients was covered by the data from K-RAS wild-type patients. And the small number of individual studies included in this meta-analysis made the statistical power limited which could not distinguish between K-RAS wild-type patients and without knowing K-RAS status patients.

For toxicities assessment in this meta-analysis, we find that the severe rash and diarrhea risk was significantly increased in the combined treatment group (P < 0.05). The toxicity of peripheral neuritis was decreased by adding the cetuximab (P < 0.05). And other toxicities were not statistical different between the two groups (P > 0.05). But the toxicities evaluation of this meta-analysis was not stable for its obviously publication bias.

 
 » References Top

1.
Goldberg RM. Cetuximab. Nat Rev Drug Discov 2005;Suppl: S10-1.  Back to cited text no. 1
    
2.
Gomez D, De Rosa A, Addison A, Brooks A, Malik HZ, Cameron IC. Cetuximab therapy in the treatment of metastatic colorectal cancer: The future frontier? Int J Surg 2013;11:507-13.  Back to cited text no. 2
    
3.
Jones C, Taylor MA, McWilliams B. The role of cetuximab as first-line treatment of colorectal liver metastases. HPB (Oxford) 2013;15:11-7.  Back to cited text no. 3
    
4.
Carillio G, Montanino A, Costanzo R, Sandomenico C, Piccirillo MC, Di Maio M, et al. Cetuximab in non-small-cell lung cancer. Expert Rev Anticancer Ther 2012;12:163-75.  Back to cited text no. 4
    
5.
Nieder C, Pawinski A, Dalhaug A, Andratschke N. A review of clinical trials of cetuximab combined with radiotherapy for non-small cell lung cancer. Radiat Oncol 2012;7:3.  Back to cited text no. 5
    
6.
Numico G, Franco P, Cristofano A, Migliaccio F, Spinazzé S, Silvestris N, et al. Is the combination of Cetuximab with chemo-radiotherapy regimens worthwhile in the treatment of locally advanced head and neck cancer? A review of current evidence. Crit Rev Oncol Hematol 2013;85:112-20.  Back to cited text no. 6
    
7.
Jiang Z, Li C, Li F, Wang X. EGFR gene copy number as a prognostic marker in colorectal cancer patients treated with cetuximab or panitumumab: A systematic review and meta analysis. PLoS One 2013;8:e56205.  Back to cited text no. 7
    
8.
Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, et al. Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: The OPUS study. Ann Oncol 2011;22:1535-46.  Back to cited text no. 8
    
9.
Dersimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88.  Back to cited text no. 9
    
10.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327:557-60.  Back to cited text no. 10
    
11.
Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, et al. Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. J Clin Oncol 2013;31:1931-8.  Back to cited text no. 11
    
12.
Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, et al. Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: Results of the randomised phase 3 MRC COIN trial. Lancet 2011;377:2103-14.  Back to cited text no. 12
    
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Tveit KM, Guren T, Glimelius B, Pfeiffer P, Sorbye H, Pyrhonen S, et al. Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of metastatic colorectal cancer: The NORDIC-VII study. J Clin Oncol 2012;30:1755-62.  Back to cited text no. 13
    
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Borner M, Koeberle D, Von Moos R, Saletti P, Rauch D, Hess V, et al. Adding cetuximab to capecitabine plus oxaliplatin (XELOX) in first-line treatment of metastatic colorectal cancer: A randomized phase II trial of the Swiss Group for Clinical Cancer Research SAKK. Ann Oncol 2008;19:1288-92.  Back to cited text no. 16
    
17.
Codacci-Pisanelli G, Spinelli G, Tomao S. K-RAS mutations and cetuximab in colorectal cancer. N Engl J Med Overseas Ed 2009;360:835.  Back to cited text no. 17
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2]



 

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