Quantification of Plasma Epstein–Barr Virus DNA in Patients with Advanced Nasopharyngeal Carcinoma

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Abstract
We investigated the clinical significance of plasma concentrations of Epstein–Barr virus (EBV) DNA in patients with advanced nasopharyngeal carcinoma. Ninety-nine patients with biopsy-proven stage III or IV nasopharyngeal carcinoma and no evidence of metastasis (M0) received 10 weekly chemotherapy treatments followed by radiotherapy. Plasma samples from the patients were subjected to a real-time quantitative polymerase-chain-reaction assay. EBV genotypes of paired samples from plasma and primary tumor were compared. Plasma EBV DNA was detectable before treatment in 94 of the 99 patients, but not in 40 healthy controls or 20 cured patients. The median concentrations of plasma EBV DNA were 681 copies per milliliter among 25 patients with stage III disease, 1703 copies per milliliter among 74 patients with stage IV disease, and 291,940 copies per milliliter among 19 control patients with distant metastasis (P<0.001). Patients with relapse had a significantly higher plasma EBV DNA concentration before treatment than those who did not have a relapse (median, 3035 vs. 1202 copies per milliliter; P=0.02). The consistent genotyping of EBV DNA between paired samples of plasma and primary tumor suggested that the circulating cell-free EBV DNA may originate from the primary tumor. Unlike the rebound of plasma EBV DNA concentrations in the patients who had a relapse, the plasma EBV DNA concentration was persistently low or undetectable in patients with a complete clinical remission. Overall survival (P<0.001) and relapse-free survival (P=0.02) were significantly lower among patients with pretreatment plasma EBV DNA concentrations of at least 1500 copies per milliliter than among those with concentrations of less than 1500 copies per milliliter. Patients with persistently detectable plasma EBV DNA had significantly worse overall survival (P<0.001) and relapse-free survival (P<0.001) than patients with undetectable EBV DNA one week after the completion of radiotherapy. Quantification of plasma EBV DNA is useful for monitoring patients with nasopharyngeal carcinoma and predicting the outcome of treatment.

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