Introduction

Nasopharyngeal carcinoma is a form of malignancy at the tissue of the upper section of the pharynx behind the nose – the nasopharynx region.^{Reference He, Lee, Liang, Lee, Chen and Chan1} Globally, the disease accounts for 65 000 deaths yearly and has a regionally varied incidence rate.^{Reference Ferlay, Shin, Bray, Forman, Mathers and Parkin2} In endemic regions, such as Southern China, Southeast Asia and the Middle East, there are over 20 cases of nasopharyngeal carcinoma per 100 000 people, although it is rare in North America and Europe.^{Reference Chang and Adami3}

Based on the World Health Organization classification, nasopharyngeal carcinoma is histologically categorised into three subtypes: type I is characterised by keratinising differentiated squamous cell carcinoma (SCC); type II (or 2a) is distinguished by non-keratinising differentiated SCC; and type III (or 2b) is typified by non-keratinising undifferentiated basaloid SCC.^{Reference Barnes, Eveson, Reichart and Sidransky4} The latter, more chemosensitive type III/2b is predominant among Asian cases, whereas types I and II/2a are mostly found in Western countries.^{Reference Fandi, Altun, Azli, Armad and Cvitkovic5}

Risk factors for nasopharyngeal carcinoma include genetic factors, viral infection (Epstein–Barr virus), environmental factors, lifestyle influences (smoking) and the consumption of certain preserved foods.^{Reference Chan6} The early stages of malignancy usually involve invasion of nasopharyngeal carcinoma cells to surrounding tissue and cervical lymph nodes.^{Reference Cho7,Reference Chou, Lin, Kim, You, Xu and He8} Despite the radio-sensitivity of nasopharyngeal carcinoma tumours, patients with advanced disease stages show poor survival.^{Reference Rusthoven, Lanning, Jones, Amini, Koshy and Sher9–Reference Teo, Yu, Lee, Leung, Kwan and Yu12} Improved therapeutic techniques, such as concurrent chemotherapy with or without neo-adjuvant or adjuvant intensity-modulated radiotherapy (RT), and high-resolution magnetic resonance image monitoring, have been the standard treatment protocol for locally advanced nasopharyngeal carcinoma.^{Reference Prawira, Oosting, Chen, Delos Santos, Saluja and Wang13–Reference Fendri, Khabir, Mnejja, Sellami-Boudawara, Daoud and Frikha15} Nevertheless, relapse and metastasis still occur in approximately 20–50 per cent of patients.^{Reference Hughes, Scott, Kew, Cheung, Leung and Ahuja16}

Studies have shown that nasopharyngeal carcinoma patients with the same disease classification present with different prognoses.^{Reference Han, Lin, Pan, Chen, Zhang and Zhang17,Reference Chua, Nicholls, Sham and Au18} This suggests that consideration of ethnicity^{Reference Su and Wang19} and biomolecular factors associated with survival outcome^{Reference Shi, Pataki, Macmillan, Pintilie, Payne and O'Sullivan20} may be necessary to accurately distinguish nasopharyngeal carcinoma patients for individualised and tailored treatment. Hence, it is important to identify prognostic factors (particularly molecular and genetic factors) that correspond closely to the actual clinical outcomes for the improvement of therapies, to yield a better treatment outcome.

One candidate biomarker of potential prognostic significance to nasopharyngeal carcinoma is the cyclo-oxygenase-2 gene. Expression of cyclo-oxygenase-2 has clinical and prognostic significance in cancers of the head and neck.^{Reference Yang, Jia, Guo, Ren, Hu and Xie21} Its involvement in nasopharyngeal carcinoma carcinogenesis is most probably during the formation of the inflammatory microenvironment associated with tumorigenesis and malignancy. Cyclo-oxygenase-2 over-expression is associated with metastasis to the lymph nodes in nasopharyngeal carcinoma patients,^{Reference Grivennikov, Greten and Karin22} and is thought to mediate this process by promoting interactions between cancer cells and myeloid-derived suppressor cells.^{Reference Li, Ye, OuYang, Zhang, Zhang and Li23}

Cyclo-oxygenase-2 is a key enzyme in the conversion of arachidonic acid to prostaglandins, and is poorly expressed (if detectable at all) in most normal tissues, but is rapidly induced by pro-inflammatory cytokines, growth factors, carcinogens and tumour promoters.^{Reference Dannenberg, Altorki, Boyle, Dang, Howe and Weksler24–Reference Simonsson, Björner, Markkula, Nodin, Jirström and Rose27} Over-expression of cyclo-oxygenase-2 in various cancers has been linked to angiogenesis, invasion and apoptotic resistance, suggesting an involvement in inflammation-induced tumorigenesis, and an influence on the outcome and survival of cancer cells.^{Reference Li, Ye, OuYang, Zhang, Zhang and Li23,Reference Greenhough, Smartt, Moore, Roberts, Williams and Paraskeva25,Reference Gupta, Nguyen, Chiang, Bos, Kim and Nadal28–Reference Peng, Zhou, Wang, Mou and Zhao32} Interestingly, the functional abrogation of cyclo-oxygenase-2, via cyclo-oxygenase inhibitor, reverses cancer progression. Actions of cyclo-oxygenase inhibitor and non-steroidal anti-inflammatory drugs have been reported to reduce the incidence and progression of tumours in animal models.^{Reference Vosooghi and Amini33–Reference Ben-Batalla, Cubas-Cordova, Udonta, Wroblewski, Waizenegger and Janning35}

To date, there has been no comprehensive review of cyclo-oxygenase-2 in terms of its prognostic value for nasopharyngeal carcinoma. It is difficult to make inferences based on existing literature linking the expression of cyclo-oxygenase-2 to nasopharyngeal carcinoma tissues because of differences in experimental study methodology and relatively small sample sizes, which have resulted in inconsistent findings. Herein, we report a systematic review and meta-analysis study conducted (in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (‘PRISMA’) checklist) to establish the relationship of cyclo-oxygenase-2 expression with the survival outcome and treatment response of nasopharyngeal carcinoma patients.