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  Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 55  |  Issue : 2  |  Page : 196-200
 

Cetuximab in combination with chemoradiotherapy for nasopharyngeal carcinoma: A meta-analysis


1 Department of Oncology, Second Hospital of Lanzhou University, Lanzhou, Gansu Province, China
2 Department of Orthopedics, Second Hospital of Lanzhou University, Lanzhou, Gansu Province, China

Date of Web Publication31-Dec-2018

Correspondence Address:
Dr. Feixue Song
Department of Oncology, Second Hospital of Lanzhou University, Lanzhou, Gansu Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_446_17

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 » Abstract 


AIMS AND OBJECTIVES: The aims and objectives of this study are to investigate the efficacy and safety of chemoradiotherapy (CCRT) with or without cetuximab in nasopharyngeal carcinoma (NPC). METHODS: We searched the Cochrane Library, PubMed, Embase, CNKI, VIP, Chinese biomedicine literature database, and WANFANG database for relevant articles. The methodological quality of included studies was evaluated, and data were analyzed using RevMan 5.0 software. RESULTS: Ten relevant articles (783 patients) were identified. The results were complete response rate; the response rate was significantly better in the cetuximab plus CCRT (C225+CCRT) group than the CCRT group. The partial response and 3-year-overall survival rates were not significantly different between the two groups. Regarding adverse effects, myelosuppression was observed in the CRRT group and the C225+CCRT group; the main toxicity was mucositis and rash, but no significant statistical difference was observed. CONCLUSION: The combination of cetuximab and CCRT was more effective for NPC than CCRT alone and had no serious side effects.


Keywords: Cetuximab, chemoradiotherapy, meta-analysis, nasopharyngeal carcinoma


How to cite this article:
Wang N, Wang K, Song F, Liu Y. Cetuximab in combination with chemoradiotherapy for nasopharyngeal carcinoma: A meta-analysis. Indian J Cancer 2018;55:196-200

How to cite this URL:
Wang N, Wang K, Song F, Liu Y. Cetuximab in combination with chemoradiotherapy for nasopharyngeal carcinoma: A meta-analysis. Indian J Cancer [serial online] 2018 [cited 2019 Nov 13];55:196-200. Available from: http://www.indianjcancer.com/text.asp?2018/55/2/196/249199





 » Introduction Top


Nasopharyngeal carcinoma (NPC) is a common type of head and neck tumor in Southeast Asia.[1] Its occurrence and development are closely related to genetic, ethnic, regional, and environmental factors, as well as viral infection; it has a high incidence and recurrence rate.[2] NPC is sensitive to radiotherapy.[3] However, recurrence after radiotherapy is the main reason for the treatment failure of NPC. Chemoradiotherapy (CCRT) can kill tumor cells directly, and not only reduce tumor load but also synchronize tumor cells, enhancing its sensitivity to radiotherapy.[4] In recent years, with the development of molecular biology, molecular mechanisms of invasion and metastasis in NPC have become known, making molecular-targeted drugs possible.[5] A study found that epidermal growth factor receptor (EGFR) is often highly expressed in NPC.[6] Overexpression of EGFR in squamous cell carcinoma of the head and neck is closely related to lower local control rate after radiotherapy.[7] Cetuximab, a monoclonal antibody that specifically blocks the EGFR, can modulate apoptosis thus enhancing the effects of radiation and chemotherapy.[8],[9] Therefore, we present a meta-analysis to evaluate the efficacy and safety of cetuximab in combination with CCRT in the treatment of NPC.


 » Methods Top


Literature search

We searched the Cochrane Library, Pubmed, Embase, CNKI, VIP, Chinese biomedicine literature database and WANFANG database for relevant articles comparing CCRT with or without cetuximab in NPC, we used the search terms: “chemotherapy,” “radiotherapy,” “radiochemotherapy,” “chemoradiotherapy,” “cetuximab,” “nasopharyngeal carcinoma,” “nasopharynx cancer,” and “randomized controlled trial.” We also used search engines to search related references of included studies. There was no limit on the language of publication.

Inclusion and exclusion criteria

We included studies if they met the following criteria: randomized controlled trials (RCTs or non-RCTs) comparing CCRT plus cetuximab with CCRT alone, patients undergoing primary treatment, diagnosis of NPC confirmed by pathology, and no distant metastases.

Evaluation method

The first author searched all relevant published trials. Two review authors independently assessed the titles and abstracts to ensure that the trials met the inclusion criteria, and disagreements were resolved by discussion. The remaining investigators assessed the details of the intervention and outcome parameters, name of the first author, country of origin, mean age of patients, number of patients, disease stage, study design, blinding, and follow-up.

Statistical analysis

Statistical analyses were performed with Review Manager (version 5.0). Dichotomous variables were analyzed using relative risk (RR) with 95% confidence intervals (CIs); weighted mean difference or means and standard deviations (SDs) were calculated for continuous data. Statistical heterogeneity was assessed using I2. Data analysis was conducted using the fixed-effects model, if there was significant heterogeneity, random-effects model was used.


 » Results Top


Search results

We identified 680 trials. After reviewing the titles and abstracts, review and original articles without comparison of cetuximab plus CCRT (C225+CCRT) with chemoradiation alone were excluded. After reviewing the full text, articles reporting incomplete outcome measurements were excluded. Finally, 10 studies,[10],[11],[12],[13],[14],[15],[16],[17],[18],[19] totaling 783, patients were included. The ten studies[10],[11],[12],[13],[14],[15],[16],[17],[18],[19] reported the effectiveness comparing CCRT with or without cetuximab. [Table 1] shows the characteristics of the included studies.
Table 1: Characteristics and quality assessment of included studies

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Meta-analysis results

The complete response rate

Nine studies (671 participants) reported the CR. No heterogeneity was observed (I2 = 0%, P = 0.52). Hence, fixed-effects model was used, and significant statistical difference was observed [RR, 1.97; 95% CI, 1.57–2.46, P < 0.00001, [Figure 1].
Figure 1: The complete response rate of cetuximab plus chemoradiotherapy versus chemoradiotherapy (fixed-effect model)

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The partial response rate

Nine studies (671 participants) reported the partial response rate. No heterogeneity was observed (I2 = 0%, P = 0.68). Hence, fixed-effects model was used, but no significant statistical difference was observed [RR, 0.95; 95% CI, 0.77–1.16, P = 0.59, [Figure 2].
Figure 2: The partial response rate of cetuximab plus chemoradiotherapy versus chemoradiotherapy (fixed-effect model)

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The response rate

Nine studies (671 participants) reported the response rate. No heterogeneity was observed (I2 = 0%, P = 0.63). Hence, a fixed-effects model was used, and significant statistical difference was observed [RR, 1.32; 95% CI, 1.20–1.46, P < 0.00001, [Figure 3].
Figure 3: The response rate of cetuximab plus chemoradiotherapy versus chemoradiotherapy (fixed-effect model)

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The 3-year overall survival rate

Three studies (300 participants) reported the 3-year overall survival (OS). Heterogeneity was observed (I2 = 66%, P = 0.06). Hence, a random-effects model was used, but no significant statistical difference was observed [RR, 1.09; 95% CI, 0.86–1.39, P = 0.48, [Figure 4].
Figure 4: The 3-year overall survival rate of cetuximab plus chemoradiotherapy versus chemoradiotherapy (random-effect model)

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Myelosuppression

Eight studies (711 participants) reported myelosuppression. Heterogeneity was observed (I2 = 50%, P = 0.05). Hence, a random-effects model was used, and a significant statistical difference was observed [RR, 0.77; 95% CI, 0.60–0.98, P = 0.04, [Figure 5].
Figure 5: The side effect of myelosuppression of cetuximab plus chemoradiotherapy versus chemoradiotherapy (random-effect model)

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Mucositis

Ten studies (783 participants) reported mucositis. Heterogeneity was observed (I2 = 64%, P = 0.003). Hence, a random-effects model was used, but no significant statistical difference was observed [RR, 1.27; 95% CI, 0.86–1.88, P = 0.23, [Figure 6].
Figure 6: The side effect of mucositis of cetuximab plus chemoradiotherapy versus chemoradiotherapy (random-effect model)

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Rash

Ten studies (783 participants) reported rash. Heterogeneity was observed (I2 = 82%, P < 0.00001). Hence, a random-effects model was used, but no significant statistical difference was observed [RR, 1.46; 95% CI, 0.88–2.44, P = 0.15, [Figure 7].
Figure 7: The side effect of rash of cetuximab plus chemoradiotherapy versus chemoradiotherapy (random-effect model)

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Gastrointestinal reaction

Ten studies (783 participants) reported gastrointestinal reaction. Heterogeneity was observed (I2 = 72%, P = 0.004). Hence, a random-effects model was used, but no significant statistical difference was observed [RR, 0.78; 95% CI, 0.60–1.01, P = 0.05, [Figure 8].
Figure 8: The side effect of gastrointestinal reaction of cetuximab plus chemoradiotherapy versus chemoradiotherapy (random-effect model)

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 » Discussion Top


Although the incidence of NPC is low in the world, it is a common malignant disease of the head and neck in Southern China. Although its pathogenesis is still unclear, it is currently accepted that Epstein-Barr virus infection is the most widely studied etiological factor.[20] The prognosis of patients with NPC remains poor because a majority of patients present with locally advanced stages at diagnosis.[21] The nonkeratinizing type is a common type of NPC; it is different from other head and neck cancers because of its unique epidemiology, natural behavior, and high risk of distant metastasis.[22] The treatment of locally advanced head and neck tumors remains a challenge. Several studies have demonstrated that adding cisplatin concurrently to radiotherapy can improve progression-free survival (PFS), (OS, and organ preservation; however, only approximately 50% of the patients survived more than 5 years.[23] With the development of molecular-targeted therapy, EGFR has received much attention in various cancers and has become a promising new therapeutic target. Significant number of studies have shown that EGFR overexpression in 80% of the patients with locoregionally advanced NPC was associated with poor prognosis.[24] Cetuximab, an EGFR-targeting monoclonal antibody, has shown therapeutic benefit in head and neck cancers improving survival when combined with radiochemotherapy in patients with locoregionally advanced non-NPC head and neck squamous cell carcinoma.[8] Studies showed that cetuximab can enhance the growth-inhibitory effect of cisplatin in NPC cell lines[25] and has clinical activity when combined with carboplatin in the treatment of recurrent NPC.[26]

The aim of the meta-analysis was to systematically estimate the efficacy and safety of CCRT plus cetuximab or not in NPC.

There are several potential limitations in this study. First, it has certain heterogeneity; five outcomes used a random-effects model. Second, the included trials were of poor methodological quality, and none of them were multicenter clinical trials or multinational samples. Hence, it might have an unreliable conclusion. Third, the included studies reported incomplete outcome measurements. Chinese literature did not mention the PFS. Fourth, the follow-up duration was short. Fifth, there was a selection bias in this meta-analysis, all the included studies originated from China.

In conclusion, the results of this meta-analysis showed that the C225+CCRT group was more effective in CR and RR than CCRT group. Regarding toxicity, there was a relatively high rate of mucositis and rash in the C225+CCRT group, but no significant statistical difference was observed. In myelosuppression, CRRT group had a higher occurrence rate. Due to the abovementioned limitations of this meta-analysis, further high quality, large sample, multicenter RCTs reporting outcomes of C225+CCRT versus CCRT are warranted.

Acknowledgment

The authors would like to thank Yuliang Wang for assistance with the analysis of the data and Bin Xiong for valuable discussion.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Li GH, Zhu B, Yang F, Ma CK, Yang DQ. Use of cetuximab in combination with pulsed reduced dose-rate radiotherapy in a patient with recurrence of nasopharyngeal carcinoma in the neck. Exp Ther Med 2012;3:869-72.  Back to cited text no. 1
    
2.
Chan SL, Ma BB. Novel systemic therapeutic for nasopharyngeal carcinoma. Expert Opin Ther Targets 2012;16 Suppl 1:S63-8.  Back to cited text no. 2
    
3.
Shen C, Gao Y, Xu T, Wang X, Ying H, Hu C, et al. Carcinoma of the nasopharynx in young patients: A single institution experience. Clin Oncol (R Coll Radiol) 2009;21:617-22.  Back to cited text no. 3
    
4.
Uzel EK, Karaçam S, Eliçin O, Uzel O. Comparison of two different IMRT planning techniques in the treatment of nasopharyngeal carcinoma. Effect on parotid gland radiation doses. Strahlenther Onkol 2013;189:552-8.  Back to cited text no. 4
    
5.
Wang J, Yang J, Li BB, He ZW. High cytoplasmic expression of the orphan nuclear receptor NR4A2 predicts poor survival in nasopharyngeal carcinoma. Asian Pac J Cancer Prev 2013;14:2805-9.  Back to cited text no. 5
    
6.
Chung CH, Ely K, McGavran L, Varella-Garcia M, Parker J, Parker N, et al. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol 2006;24:4170-6.  Back to cited text no. 6
    
7.
Zimmermann M, Zouhair A, Azria D, Ozsahin M. The epidermal growth factor recepter (EGFR) in head and neck cancer: Its role and treatment implications. Radiat Oncol 2006;1:11.  Back to cited text no. 7
    
8.
Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567-78.  Back to cited text no. 8
    
9.
Sharafinski ME, Ferris RL, Ferrone S, Grandis JR. Epidermal growth factor receptor targeted therapy of squamous cell carcinoma of the head and neck. Head Neck 2010;32:1412-21.  Back to cited text no. 9
    
10.
Wu CZ. Curative effects of cetuximab combined with concurrent chemo-and radiotherapy on recurrent nasopharyngeal carcinoma. Med J Natl Defending Forces Southwest China 2013;23:509-12.  Back to cited text no. 10
    
11.
Tang DH, Zhang YX, Cai J. The clinical efficacy of cetuximab combined with radiotherapy and chemotherapy in the treatment of locally advanced nasopharyngeal carcinoma. Antitumor Pharm 2013;3:119-21.  Back to cited text no. 11
    
12.
Wang DX. Cetuximab combined radiation and chemotherapy in the treatment of advanced nasopharyngeal carcinoma. Mod Diagn Treat 2015;26:2465-6.  Back to cited text no. 12
    
13.
Zhou LH. Analysis of efficacy of cetuximab with concurrent chemoradiation therapy in 63 patients with advanced nasopharyngeal carcinoma. China Prac Med 2013;8:131-2.  Back to cited text no. 13
    
14.
Zeng T, Zhang YL, Li JJ. Analysis of the efficacy of cetuximab combined with chemotherapy and radiotherapy in the treatment of advanced nasopharyngeal carcinoma. Chin J Front Med Sci 2016;8:45-8.  Back to cited text no. 14
    
15.
Fu X, Meng MS, Chen XF, Li YX, Wu WY. IMRT Combined with cetuximab in treating advanced nasopharyngeal carcinoma. China Pharm 2015;24:41-3.  Back to cited text no. 15
    
16.
Wu X, Huang J, Liu L, Li H, Li P, Zhang J, et al. Cetuximab concurrent with IMRT versus cisplatin concurrent with IMRT in locally advanced nasopharyngeal carcinoma: A retrospective matched case-control study. Medicine (Baltimore) 2016;95:e4926.  Back to cited text no. 16
    
17.
Zheng ZH, Li SE, Luo WJ. Analysis on the curative effect of cetuximab combined with concurrent cisplatin chemotherapy and intensity modulated radiation therapy for locally advanced nasopharyngeal carcinoma. China Foreign Med Treat 2013;34:3-4.  Back to cited text no. 17
    
18.
Yang ZY, Wan H, Chen CX, Yuan H, Wang P, Liu J. Study on the efficacy of cetuximab in combination with cisplatin chemotherapy and intensity modulated radiotherapy in treatment of patients witil nasopharyngeal carcinoma. J Clin Exp Med 2016;15:45-8.  Back to cited text no. 18
    
19.
Zhao ZQ, Yang XN, Xu ZH, Li J, Wang H, Yin LH. Curative effects of cetuximab combined with intensity modulated radiation therapy on advanced nasopharyngeal carcinoma. Med J Natl Defending Forces Southwest China 2015;25:750-3.  Back to cited text no. 19
    
20.
Gu J, Yin L, Wu J, Zhang N, Huang T, Ding K, et al. Cetuximab and cisplatin show different combination effect in nasopharyngeal carcinoma cells lines via inactivation of EGFR/AKT signaling pathway. Biochem Res Int 2016;2016:7016907.  Back to cited text no. 20
    
21.
Zhang X, Du L, Zhao F, Wang Q, Yang S, Ma L, et al. A phase II clinical trial of concurrent helical tomotherapy plus cetuximab followed by adjuvant chemotherapy with cisplatin and docetaxel for locally advanced nasopharyngeal carcinoma. Int J Biol Sci 2016;12:446-53.  Back to cited text no. 21
    
22.
Lee AW, Lin JC, Ng WT. Current management of nasopharyngeal cancer. Semin Radiat Oncol 2012;22:233-44.  Back to cited text no. 22
    
23.
Pignon JP, le Maître A, Maillard E, Bourhis J, MACH-NC Collaborative Group. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): An update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009;92:4-14.  Back to cited text no. 23
    
24.
Ma BB, Poon TC, To KF, Zee B, Mo FK, Chan CM, et al. Prognostic significance of tumor angiogenesis, Ki 67, p53 oncoprotein, epidermal growth factor receptor and HER2 receptor protein expression in undifferentiated nasopharyngeal carcinoma – A prospective study. Head Neck 2003;25:864-72.  Back to cited text no. 24
    
25.
Sung FL, Poon TC, Hui EP, Ma BB, Liong E, To KF, et al. Antitumor effect and enhancement of cytotoxic drug activity by cetuximab in nasopharyngeal carcinoma cells. In Vivo 2005;19:237-45.  Back to cited text no. 25
    
26.
Chan AT, Hsu MM, Goh BC, Hui EP, Liu TW, Millward MJ, et al. Multicenter, phase II study of cetuximab in combination with carboplatin in patients with recurrent or metastatic nasopharyngeal carcinoma. J Clin Oncol 2005;23:3568-76.  Back to cited text no. 26
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8]
 
 
    Tables

  [Table 1]



 

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