【作者】 孙平；

【导师】 郑启昌；

【作者基本信息】 华中科技大学 ， 普通外科， 2013， 博士

【摘要】 背景：在全世界范围内，肝细胞癌（Hepatocellular carcinoma，HCC）占恶性肿瘤发病率第五位，占恶性肿瘤相关死亡率第三位，且由于病毒性肝炎、肥胖等的流行，HCC发病率不断上升。而据预测，有一半HCC新增病例和死亡发生于中国，慢性乙型肝炎（Hepatitis B virus，HBV）和慢性丙型肝炎（Hepatitis C virus，HCV）是HCC的主要病因。现阶段，对于肿瘤早期、肝储备功能尚可的患者，手术切除或消融是主要的治愈手段，但根治性治疗后，5年复发率仍然达到70%，且目前尚无有效手段预防HCC复发。已有许多研究证明抗病毒治疗可预防HCC的发生，推测抗病毒治疗应能预防HCC根治后复发，延长生存，但现有的研究结果却未获得一致结论。目的：1.评估HBV/HCV相关HCC根治后抗病毒治疗对复发和生存的影响；2.评估辅助抗病毒治疗的安全性；3.分层分析：辅助干扰素（Interferon，IFN）抗病毒治疗的有效性和安全性；辅助核苷（酸）类似物抗病毒治疗的有效性和安全性；HBV相关HCC根治后辅助抗病毒治疗的有效性和安全性；HCV相关HCC根治后辅助抗病毒治疗的有效性和安全性。方法：我们系统检索了截止2012年12月19日以下四大电子数据库的所有文献：MEDLINE (PubMed)，EMBASE，Cochrane Library databases和Science Citation IndexExpanded。同时手工检索纳入文献和相关综述的参考文献，不限制语言和文献种类。只有比较HCC根治后辅助抗病毒治疗和安慰剂或无任何辅助治疗的随机对照实验（Randomized controlled trials，RCT）才纳入本研究。2名研究者独立筛选文献、提取数据和评估偏倚风险。对于生存数据（时间事件指标），选取风险比（Hazard ratio，HR）及其95%可信区间（Confidence interval，CI）作为效应指标；统计分析使用RevMan5.1和Stata11.0软件；所有研究均采用意向性治疗（Intention-to-treat，ITT）原则分析数据。结果：9个RCT纳入本研究（其中3个低偏倚风险；6个偏倚风险不确定）；共纳入954名病人，经随机分组后，493名进入辅助抗病毒治疗组；461名进入对照组。所有纳入的研究均使用传统IFN行辅助抗病毒治疗，没有研究使用聚乙二醇干扰素或核苷（酸）类似物。与对照组相比，辅助IFN治疗组无复发生存（HR=0.81，95%CI=0.68～0.95；p=0.01）和总生存（HR=0.59，95%CI=0.46～0.76；p<0.0001）均明显改善。亚组分析显示：HCV相关HCC患者可从辅助IFN治疗中明显获益，而HBV相关HCC患者间则无统计学差异。由于中重度药物副作用，如白细胞减少、中性粒细胞减少、血小板减少、肝脏毒性等，28.3%的病人需要减量，8.2%的病人需要停药。结论：我们的研究表明，HBV/HCV相关HCC根治后辅助IFN抗病毒治疗很可能使患者获益，尤其是对于HCV相关HCC患者。需要进行更多高质量的随机对照试验，研究更强有力的抗病毒药物，单独使用或联用，用于辅助治疗病毒相关性HCC，尤其是HBV相关HCC。未来的研究还需要更多关注患者生活质量和药物副作用等。更多还原

【Abstract】 Background: Hepatocellular carcinoma (HCC) is the fifth most common cancer and thethird most frequent cause of cancer-related death worldwide. Due to the prevalence of theviral hepatitis, obesity, and so on, the incidence rates of HCC are increasing all over theworld. Half of these cases were estimated to occur in China. Hepatitis B virus (HBV) andhepatitis C virus (HCV) are the main cause of HCC. Nowadays, for patients with earlytumor stage and compensated liver function, surgical resection or ablation is the maincurative treatment choice. But approximately70%of patients suffered from recurrenceafter curative treatment within five years. Besides, there was not any effective strategy toprevent HCC recurrence. Antiviral regimens have been shown to improve the liverpathology and reduce the risk of HCC in patients with chronic viral hepatitis. It ishypothesized that adjuvant antiviral therapy following curative treatment of HCC wouldprevent recurrence and meanwhile improve survival. But available published work reportscontroversial results.Aim:1. To evaluate the effect of adjuvant antiviral therapy on recurrence and survivalafter curative treatment of HBV/HCV-related HCC;2. To evaluate the safety of adjuvantantiviral therapy;3. Stratified analyses: adjuvant interferon (IFN) therapy versus placebo orno treatment, adjuvant nucleos(t)ide analogs (NA) therapy versus placebo or no treatment,subgroup of HBV-related HCC and subgroup of HCV-related HCC will be analyzed if thenecessary data is provided. Methods: We conducted a systematic search using electronic databases (PubMed,EMBASE, Cochrane Library databases and Science Citation Index Expanded) for all thepublished studies without restriction of language or publication type (last date of searchingpublished work:19December,2012). Reference lists of all identified papers (includedstudies and relevant reviews) were checked for additional studies suitable for inclusion. Allrandomized controlled trials comparing adjuvant antiviral therapy versus placebo or notreatment were considered for this review. Two authors independently identified the trialsfor inclusion, extracted data and assessed the risk of bias. Results were expressed as HazardRatio (HR) for time-to-event outcomes with95%confidence intervals (CI). The statisticswere performed by RevMan version5.1and STATA version11.0. All studies wereanalyzed using the ’intention to treat’ principle.Results: We included nine trials (three of low risk of bias and six of unclear risk of bias)with954patients randomized:493to the adjuvant antiviral therapy group and461to thecontrol group. All the included studies used conventional IFN as adjuvant antiviral therapy;none of them used pegylated IFN or NA. There were significant improvements forrecurrence free survival (HR=0.81,95%CI=0.68~0.95; P=0.01) and overall survival(HR=0.59,95%CI=0.46~0.76; P <0.0001) in the adjuvant IFN group compared withthe control group. Subgroup analysis also showed a significant difference favoring IFNtherapy in HCV-related HCC patients, but for HBV-related patients, the difference failed toreach statistical significance between the two groups. A dose reduction was needed in28.3%of patients and discontinuation of IFN therapy happened in8.2%of patients due tomoderate to severe side-effects like leucocytopenia, neutropenia, thrombocytopenia andhepatic toxicity.Conclusion: Our study suggested potential benefits of adjuvant IFN therapy followingcurative treatment of HBV/HCV-HCC, especially for HCV-related HCC. Further high-quality randomized controlled trials of more potent adjuvant antiviral regimens, eitherused alone or in combination, for virus-related HCC, especially HBV-related HCC, areneeded. Future trials should also focus on other clinically relevant aspects, such as qualityof life and adverse effects.更多还原