血浆EB病毒DNA浓度预测鼻咽癌远处转移的研究

背景与目的：鼻咽癌治疗失败的主要原因之一是远处转移,近年多项放化疗综合治疗的临床研究未显示出明显的远处转移率的降低和远期生存的获益,综合治疗适宜个体及最佳模式尚未确立。血浆EB病毒DNA（EBV DNA）浓度是一项能反映鼻咽癌分期、治疗反应、预后的灵敏、特异的分子生物学指标。我们设计此前瞻性研究。探讨通过鼻咽癌患者血浆EBV DNA浓度预测远处转移的发生．为个体化的综合治疗模式的选择提供分子学指标。方法：69例初治鼻咽癌患者分别在治疗前和治疗结束时采用荧光定量PCR方法检测血浆EBV DNA浓度。所有患者按计划随访。进行远期疗效及生存的评价。Kaplan-Meier法计算无转移生存率及总生存率,多因素分析用Cox回归模型。结果：远处转移患者治疗前血浆EBV DNA中位浓度（27 000copies／m1）及治疗后EBVDNA检出率（55．56％）均高于持续缓解者（4 000 copies／ml,5．56％）及局部复发者（3 850 copies／ml,0％）（P值分别为0．039,0．001）。以治疗前20 000 copies／ml、治疗后0 copies／ml为界值点．EBV DNA低浓度患者的无复发生存率、无转移生存率及总生存率均高于高浓度患者,差异有显著性。Cox回归分析显示治疗前EBV DNA浓度（P=0．050,RR=3．95）、治疗后EBVDNA浓度（P=0．001,RR=11．74）均是影响无转移生存的危险因素。进一步将患者治疗前后EBVDNA浓度变化综合进行生存分析,结果表明治疗后EBV DNA浓度能否降到0是影响无转移生存最重要的预后因素（P=0．000）。结论：鼻咽癌患者治疗前、后血浆EBV DNA浓度,尤其是治疗后能否降到0．能预测远处转移的发生,有望为放化综合治疗筛选高危患者,指导放化结合模式的选择。

Prognostic impact of plasma Epstein-Barr virus DNA concentration on distant metastasis in nasopharyngeal carcinoma

BACKGROUND & OBJECTIVE: Distant metastasis is one of the main causes of treatment failure in nasopharyngeal carcinoma (NPC). Trials of combined modality treatment could not demonstrate obvious decrease of the rate of distant metastasis and survival rate, therefore eligible individualized and best combined modality treatment has not been established. Plasma Epstein-Barr virus (EBV) DNA is a sensitive and specific molecular marker, which may reflect the stage, response to treatments and prognosis of NPC. This prospective study was to investigate whether the plasma EBV DNA concentration could be used to predict distant metastasis in NPC, and thus to provide us a molecular marker for individualized combined modality treatment. METHODS: Blood samples from 69 patients with primary NPC were collected before and after radiotherapy. The content of EBV DNA in the plasma samples was detected by real-time quantitative PCR. All patients received consequent follow up and long-term efficacy and survival assessment. The correlation of pre/post treatment EBV DNA concentrations to survival was analyzed by Kaplan-Meier method. The prognostic factors were evaluated by Cox proportional hazards model. RESULTS: Both pretreatment EBV DNA median concentration (27,000 copies/ml) and post-treatment EBV DNA detecting rate (55.56%) in patients with distant metastasis were higher than those with continuous remission (4,000 copies/ml, 5.56%) and those with local relapse (3,850 copies/ml, 0%)(P = 0.039 and 0.001, respectively). With a cut-off value of 20,000 copies/ml and 0 copies/ml respectively for pretreatment and post-treatment EBV DNA concentration, patients with lower EBV DNA concentration had statistically preferable progression-free survival (PFS), metastasis-free survival(MFS) and overall survival (OS) than those with higher EBV DNA concentration. Cox regression analysis demonstrated that both pretreatment EBV DNA (P = 0.050; RR = 3.95) and post-treatment EBV DNA (P = 0.001; RR = 11.74) were risk factors for MFS. Further analysis of pretreatment and post-treatment EBV DNA concentration revealed that whether EBV DNA concentration could be decreased to 0 after treatment dominated metastasis-free survival (P = 0.000). CONCLUSION: Plasma EBV DNA concentration before and after treatment, especially whether post-treatment concentration could be decreased to 0 may predict distant metastasis, which helps to select patients with high risks and determine the combined modality treatment.