International Journal of Radiation Oncology*Biology*Physics
Clinical InvestigationHigh-Sensitivity C-Reactive Protein Complements Plasma Epstein-Barr Virus Deoxyribonucleic Acid Prognostication in Nasopharyngeal Carcinoma: A Large-Scale Retrospective and Prospective Cohort Study
Introduction
Nasopharyngeal carcinoma (NPC) is endemic in southern China and Southeast Asia, with a peak incidence of 50 cases per 100,000 individuals (1). According to data reported by the GLOBOCAN on Cancer Research, there were more than 84,000 new NPC cases and 51,600 NPC-related deaths in 2012, with 80% of the cases located in Asia, especially China, and 5% in Europe and the United States (2). Radiation therapy is the primary treatment modality for NPC. Although the TNM staging system is still the most important prognostic indicator for NPC patients, a mysterious heterogeneity remains with regard to the outcomes of NPC patients with apparently equivalent Union for International Cancer Control classifications 3, 4. Recently the quantification of pretreatment plasma Epstein-Barr virus (EBV) DNA has been increasing in clinical use for the diagnosis, risk stratification, monitoring, and prediction of NPC prognosis 5, 6, 7, 8, 9. However, even in patients with equivalent pretreatment EBV DNA levels, NPC remains a biologically heterogeneous disease. Hence, we sought to identify additional markers that could complement EBV DNA.
One inflammation biomarker, high-sensitivity C-reactive protein (hs-CRP), which is increased in diseases characterized by chronic inflammation, such as cardiovascular disease, diabetes, and cancer (10), may be useful for assessing the prognosis of NPC. High-sensitivity CRP production increases in the liver in response to elevated cytokine levels after exposure to an inflammatory stimulus (11). Elevated CRP has been associated with poor survival in gastroesophageal (12), colorectal (13), inoperable non–small-cell lung (14), and breast cancers (15). As an EBV-related disease, NPC is associated with chronic inflammation. Elevated levels of various cytokines 16, 17 and CRP (18) have been observed in NPC patients. Although one retrospective study (18) has reported that elevated CRP levels are predictive of worse survival for NPC patients, the findings were based solely on 2-dimensional radiation therapy without adjusting for other factors, such as systemic inflammation, concurrent disease, and smoking status. Therefore, this study, which included both retrospective and prospective analyses, was conducted to confirm whether baseline hs-CRP levels are able to accurately predict the prognosis of a large population of NPC patients. We also examined whether combining hs-CRP and pretreatment plasma EBV DNA levels may refine the prognostic stratification of NPC patients.
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Patients
A total of 4609 nonmetastatic patients with primary NPC were consecutively recruited from January 2007 to December 2009 at the study institute. Of these patients, two-thirds (n=3113) were randomly assigned by a computer to a training set, and the remaining third (n=1556) were randomly assigned to an internal validation set. Moreover, another independent cohort of 1618 newly diagnosed NPC patients was enrolled between January 2011 and December 2011 as a prospective validation set to confirm the
Patient characteristics, determination of final cutoff value for hs-CRP, and its association with clinical stage and EBV DNA
The characteristics of the 6287 patients with NPC are listed in Table 1, with median follow-up times of 51 (interquartile range [IQR] 40-62), 50 (IQR 40-62), and 29 months (IQR 26-32) for the training set (n=3113), internal validation set (n=1556), and prospective validation set (n=1618), respectively. The patient outcomes are presented in Table 1.
The hs-CRP cutoff value for patient outcome was determined by receiver operating characteristic curve analysis of the training set. As shown in
Discussion
To our knowledge, this is the first large population study of 3 independent cohorts examining the role of a systemic inflammation biomarker alone or in combination with plasma EBV DNA in an attempt to refine the prognostic stratification of NPC patients. We observed significant associations between elevated pretreatment hs-CRP alone and in combination with plasma EBV DNA with DFS, DMFS, and OS.
In this study, multivariate analysis revealed that pretreatment hs-CRP and EBV DNA levels were
Acknowledgments
The authors thank the patients who participated in this study, and Professor Qing Liu for statistical assistance.
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This study was partly supported by the Ministry of Science and Technology of China (grant 2011CB504300), the National Natural Science Foundation of China (grants 81025014, 81230045, 91019015, 81201629, 30600755, and 81072226), the 863 Project (grant 2012AA02A501), the National Key Basic Research Program of China (grant 2013CB910304), the Sci-Tech Project Foundation of Guangdong Province (grants 2011B080701034 and 2011B031800161), the Sci-Tech Project Foundation of Guangzhou City (grant 2011J4300100), the Sun Yat-sen University Clinical Research 5010 Program, and the Fundamental Research Funds for the Central Universities.
L,-Q.T., C.-F.L., and Q.-Y.C. contributed equally to this work.
X.G., H.-Q.M., and M.-S.Z. contributed equally to this work.
Conflict of interest: none.