Roccarina Davide, Majumdar Avik, Thorburn Douglas, Davidson Brian R, Tsochatzis Emmanuel, Gurusamy Kurinchi Selvan
Sheila Sherlock Liver Centre, Royal Free Hospital and the UCL Institute of Liver and Digestive Health, London, UK, NW3 2QG.
Department of Surgery, Royal Free Campus, UCL Medical School, Pond Street, London, UK, NW3 2QG.
Cochrane Database Syst Rev. 2017 Mar 10;3(3):CD011649. doi: 10.1002/14651858.CD011649.pub2.
There is significant uncertainty in the treatment of intermediate-stage hepatocellular carcinoma which is defined by the Barcelona Clinic Liver Cancer (BCLC) as hepatocellular carcinoma stage B with large, multi-nodular, Child-Pugh status A to B, performance status 0 to 2, and without vascular occlusion or extrahepatic disease.
To assess the comparative benefits and harms of different interventions used in the treatment of intermediate-stage hepatocellular carcinoma (BCLC stage B) through a network meta-analysis and to generate rankings of the available interventions according to their safety and efficacy. However, we found only one comparison. Therefore, we did not perform the network meta-analysis, and we assessed the comparative benefits and harms of different interventions versus each other, or versus placebo, sham, or no intervention (supportive treatment only) using standard Cochrane methodology.
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised clinical trials registers to September 2016 to identify randomised clinical trials on hepatocellular carcinoma.
We included only randomised clinical trials, irrespective of language, blinding, or publication status, in participants with intermediate-stage hepatocellular carcinoma, irrespective of the presence of cirrhosis, size, or number of the tumours (provided they met the criteria of intermediate-stage hepatocellular carcinoma), of presence or absence of portal hypertension, of aetiology of hepatocellular carcinoma, and of the future remnant liver volume. We excluded trials which included participants who had previously undergone liver transplantation. We considered any of the various interventions compared with each other or with no active intervention (supportive treatment only). We excluded trials which compared variations of the same intervention: for example, different methods of performing transarterial chemoembolisation.
We used standard methodological procedures expected by Cochrane. We calculated the hazard ratio (HR) with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on available-participant analysis with Review Manager. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis using Stata, and assessed the quality of the evidence using GRADE.
Three randomised clinical trials, including 430 participants, met the inclusion criteria for this review; however, data from two trials with 412 participants could be included in only one primary outcome (i.e. mortality). All three trials were at high risk of bias. All three trials included supportive care as cointervention. The comparisons included in the two trials reporting on mortality were: systemic chemotherapy with sorafenib versus no active intervention; and transarterial chemoembolisation plus systemic chemotherapy with sorafenib versus transarterial chemoembolisation alone. The trials did not report the duration of follow-up; however, it appeared that the participants were followed up for a period of about 18 to 30 months. The majority of the participants in the trials had cirrhotic livers. The trials included participants with intermediate-stage hepatocellular carcinoma arising from viral and non-viral aetiologies. The trials did not report the portal hypertension status of the participants. The mortality was 50% to 70% over a median follow-up period of 18 to 30 months. There was no evidence of difference in mortality at maximal follow-up between systemic chemotherapy versus no chemotherapy (hazard ratio 0.85, 95% CI 0.60 to 1.18; participants = 412; studies = 2; I = 0%; very low quality evidence). A subgroup analysis performed by stratifying the analysis by the presence or absence of transarterial chemoembolisation as cointervention did not alter the results. None of the trials reported on serious adverse events other than mortality, health-related quality of life, recurrence of hepatocellular carcinoma, or length of hospital stay. One of the trials providing data was funded by the pharmaceutical industry, the other did not report the source of funding, and the trial with no data for the review was also funded by the pharmaceutical industry. We found two ongoing trials.
AUTHORS' CONCLUSIONS: Currently, there is no evidence from randomised clinical trials that people with intermediate-stage hepatocellular carcinoma would benefit from systemic chemotherapy with sorafenib either alone or when transarterial chemoembolisation was used as a cointervention (very low quality evidence). We need high-quality randomised clinical trials designed to measure differences in clinically important outcomes (e.g. all-cause mortality or health-related quality of life).
中期肝细胞癌的治疗存在很大不确定性，巴塞罗那临床肝癌（BCLC）将其定义为B期肝细胞癌，具有肿瘤大、多结节、Child-Pugh肝功能分级为A至B级、体能状态为0至2级，且无血管闭塞或肝外疾病。
通过网状Meta分析评估用于治疗中期肝细胞癌（BCLC B期）的不同干预措施的相对获益和危害，并根据安全性和有效性对现有干预措施进行排序。然而，我们仅发现一项比较研究。因此，我们未进行网状Meta分析，而是采用标准的Cochrane方法评估不同干预措施之间，或与安慰剂、假手术或无干预（仅支持治疗）相比的相对获益和危害。
我们检索了Cochrane对照试验中心注册库（CENTRAL）、MEDLINE、Embase、科学引文索引扩展版、世界卫生组织国际临床试验注册平台以及截至2016年9月的随机临床试验注册库，以识别肝细胞癌的随机临床试验。
我们仅纳入中期肝细胞癌患者的随机临床试验，无论语言、是否设盲或发表状态如何，无论是否存在肝硬化、肿瘤大小或数量（只要符合中期肝细胞癌标准）、是否存在门静脉高压、肝细胞癌的病因以及未来残余肝体积。我们排除了纳入曾接受肝移植患者的试验。我们考虑了相互比较或与无活性干预（仅支持治疗）比较的各种干预措施。我们排除了比较同一干预措施不同变体的试验：例如，不同的经动脉化疗栓塞实施方法。
我们采用Cochrane期望的标准方法程序。我们基于Review Manager的可用参与者分析，使用固定效应和随机效应模型计算风险比（HR）及95%置信区间（CI）。我们根据Cochrane评估偏倚风险，使用Stata通过试验序贯分析控制随机误差风险，并使用GRADE评估证据质量。
三项随机临床试验，共430名参与者，符合本综述的纳入标准；然而，两项共412名参与者的试验数据仅可纳入一个主要结局（即死亡率）。所有三项试验均存在高偏倚风险。所有三项试验均将支持性护理作为联合干预措施。两项报告死亡率的试验中的比较包括：索拉非尼全身化疗与无活性干预；经动脉化疗栓塞联合索拉非尼全身化疗与单纯经动脉化疗栓塞。试验未报告随访持续时间；然而，参与者似乎随访了约18至30个月。试验中的大多数参与者患有肝硬化。试验纳入了由病毒和非病毒病因引起的中期肝细胞癌患者。试验未报告参与者的门静脉高压状态。在18至30个月的中位随访期内，死亡率为50%至70%。在最大随访期时，全身化疗与不化疗之间死亡率无差异的证据（风险比0.85，95%CI 0.60至1.18；参与者 = 412；研究 = 2；I² = 0%；极低质量证据）。按是否将经动脉化疗栓塞作为联合干预措施进行分层分析的亚组分析未改变结果。除死亡率、健康相关生活质量、肝细胞癌复发或住院时间外，没有试验报告严重不良事件。提供数据的一项试验由制药行业资助，另一项未报告资金来源，而本综述无数据的试验也由制药行业资助。我们发现两项正在进行的试验。
目前，随机临床试验没有证据表明中期肝细胞癌患者单独使用索拉非尼全身化疗或在使用经动脉化疗栓塞作为联合干预措施时会获益（极低质量证据）。我们需要高质量的随机临床试验来衡量临床上重要结局（如全因死亡率或健康相关生活质量）的差异。
