肝癌监测：请问甲胎蛋白有作用？

StephenW

Hepatocellular Carcinoma Surveillance: Does Alpha-Fetoprotein Have a Role? [url=]Ashwini Mehta[/url]
, [url=]Amit G. Singal[/url]
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas

Published Online: July 28, 2015
Philip S. Schoenfeld, Section Editor, John Y. Kao, Section Editor


DOI:            http://dx.doi.org/10.1053/j.gastro.2015.07.017 |

Share on mendeleyShare on facebookShare on twitterShare on emailMore Sharing Services

Article Info

• Abstract
• Full Text
  

Chang T, Wu Y, Tung S, et al. Alpha-fetoprotein measure benefits hepatocellular carcinoma surveillance in patients with cirrhosis. Am J Gastroenterol 2015;110:836–844.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide and one of the leading causes of death in patients with cirrhosis (Gastroenterology 2012;142:1264–1273 e1). Several societies recommend HCC surveillance for patients with cirrhosis given its association with higher rates of early tumor detection, curative treatment received, and overall survival (Hepatology 2010;53:1–35). Ultrasonography and alpha-fetoprotein (AFP) are the most common tests for HCC surveillance in clinical practice. However, the accuracy of AFP has been critically challenged, and there is growing debate about its continued use in HCC surveillance programs.

The study by Chang et al addressed this important issue through a retrospective cohort study of patients with cirrhosis who were undergoing HCC surveillance in Taiwan between 2002 and 2010 (Am J Gastroenterol 2015;110:836–844). Among 5664 potentially eligible patients, 1597 were retained for analyses after excluding those with history of HCC, prevalent HCC within 18 months of enrollment, concurrent extrahepatic neoplasms, and/or follow-up duration of <18 months. Patients routinely received HCC surveillance with ultrasonography and AFP every 3-6 months, with diagnostic workup typically initiated when mass lesions were seen on ultrasonography or AFP levels were increased.

Most patients (n = 1398; 88%) had hepatitis B virus (HBV) and/or hepatitis C virus (HCV) cirrhosis, and most (n = 1233, 77%) had Child-Pugh class A cirrhosis. Over a median of 4.8 years (range, 1.4–14), 363 (22.7%) developed HCC, of whom 213 (59%) were early or very early stage HCC as defined by Barcelona Clinic Liver Cancer criteria. HCC was the factor most strongly associated with an increased AFP (relative risk [RR], 13.2; 95% CI, 9.6–18.2); however, false-positive AFP levels were significantly more likely in HCV- (RR, 6.9; 95% CI, 1.6–29.5) or HBV-infected (RR, 5.6; 95% CI, 1.3–24.7) patients than those with nonviral liver disease.

Most patients had HCC (334/363; 92%) detected by ultrasonography, regardless of AFP level. However, 29 patients (8%) presented with increasing AFP alone (ie, no mass on ultrasonography). The sensitivity and specificity of ultrasonography alone were 92.0% (95% CI, 89.2–94.8) and 74.2% (95% CI, 71.8–76.7), respectively. Combining ultrasonography and AFP, at a cutoff of 20 ng/mL, significantly increased sensitivity (P < .001) compared with ultrasonography alone. In subgroup analysis, the significant increase in sensitivity was observed in patients with viral cirrhosis (P < .001) but not those with nonviral cirrhosis (P > .10). The combination of ultrasonography and AFP had a sensitivity of 99.2% (95% CI, 98.2–100) with minimal decrease in specificity (68.3%, 95% CI, 65.7–70.9). Adding an additional criterion of AFP to increase ≥2 times from nadir maintained sensitivity at 99.2% (95% CI, 98.2–100) and increasing specificity to 71.6% (95% CI, 69.0–74.0).

Comment

The effectiveness of HCC surveillance in clinical practice is contingent on the availability of surveillance tools with high sensitivity for early HCC detection. The most recent guidelines from the American Association for the Study of Liver Diseases and European Association for the Study of the Liver recommend using ultrasonography alone to achieve this goal given concerns about the suboptimal sensitivity and specificity of AFP (Hepatology 2010;53:1–35). Although ultrasonography is highly efficacious in well-controlled settings, this study by Chang et al contributes to the growing evidence base that its effectiveness in clinical practice may be more heterogeneous (Am J Gastroenterol 2015;110:836–844).

In addition to the operator-dependent nature of ultrasonography, its performance may be influenced by patient characteristics, such as liver nodularity. A prior study using a multicenter Italian database found that ultrasonography failure rate for detecting HCC varied between centers (range, 10%–64%), with higher failure rates associated with male gender, Child B or C cirrhosis, high AFP levels, and surveillance intervals of >6 months (Clin Gastroenterol Hepatol 2014;12:1927–1933.e2). Inadequate sensitivity of surveillance tools is the most common reason for late-stage tumor detection among patients followed in tertiary care centers (Am J Gastroenterol 2013;108:425–432). With less than one-half of all HCC being detected at an early stage, it is clear that better surveillance tests are needed. Although several novel biomarkers are being investigated, most are in phase II-III biomarker development and years away from being available widely for use in clinical practice (Best Pract Res Clin Gastroenterol 2014;28:843–853). AFP is currently the only biomarker to have undergone all 5 phases of biomarker development. Similarly, ultrasonography is the only imaging modality to be evaluated adequately as a surveillance imaging modality. Although some advocate use of CT or MRI for HCC surveillance, their widespread use is limited by costs and harms, such as radiation exposure. Therefore, current efforts should be focused on optimizing the delivery and effectiveness of surveillance using ultrasonography and AFP.

The study by Chang et al suggests that using ultrasonography and AFP in combination significantly increases surveillance sensitivity for HCC compared with ultrasonography alone (92% vs 99%; P < .001; Am J Gastroenterol 2015;110:836–844). However, these data describe the performance of ultrasonography and AFP for HCC detection at any stage, whereas the goal of HCC surveillance is to detect tumors at an earlier stage, when curative options are available (Hepatology 2010;53:1–35). A prior effectiveness trial suggested adding AFP to ultrasonography can also increase significantly surveillance sensitivity for early HCC (32% vs 63%; P < .001), but these data still require validation in other studies (Cancer Epidemiol Biomarkers Prev 2012;21:793–799). Given the correlation between AFP and HCC tumor stage/size, it is possible that AFP could detect advanced HCC missed on ultrasonography without improvement in early tumor detection. Only 59% of HCC in the study by Chang et al were detected at an early stage, and it is unclear if the 29 cases detected by AFP alone were early or advanced tumors (Am J Gastroenterol 2015;110:836–844). Future studies evaluating ultrasonography and AFP for HCC surveillance should report test performance characteristics for early HCC detection.

Although adding AFP ≥20 ng/mL to ultrasonography significantly increased sensitivity compared with ultrasonography alone, the best performance characteristics were observed when using longitudinal AFP measurements. Requiring an increase in AFP level of ≥2 from its nadir in the prior year maintained high sensitivity of surveillance while increasing specificity. This finding confirms prior studies that suggested longitudinal AFP measurements may have greater diagnostic accuracy than 1-time measurements for HCC detection, particularly in patients with HCV cirrhosis, where AFP elevations are often due to disease activity rather than HCC (Clin Gastroenterol Hepatol 2013;11:437–440). Alternatively, others have suggested the accuracy of AFP for HCC surveillance can be improved by using different cutoffs based on liver etiology or adjusting AFP level for patient age, alanine aminotransferase level, and platelet count (Clin Gastroenterol Hepatol 2014;12:870–877; Gastroenterology 2014;146:1249–1255.e1).

In subgroup analysis, AFP increased sensitivity for HCC detection in patients with HCV or HBV cirrhosis, but not those with nonviral liver disease. The authors concluded AFP may not be beneficial in patients with alcohol or nonalcoholic steatohepatitis (NASH); however, lack of significance in this subgroup may simply be related to small sample size (n = 199). In fact, patients with NASH who are obese may be particularly prone to ultrasonography failure and stand to benefit from the addition of serum biomarkers. Further studies are needed to evaluate the sensitivity of ultrasonography and potential benefit of AFP in patients with NASH because the burden of NASH is growing worldwide.

Increasing surveillance sensitivity must be weighed carefully with trade offs in specificity, because high rates of false-positive tests can result in unnecessary diagnostic evaluation and resultant harms. In this study, adding AFP to ultrasonography resulted in a minimal decrease in specificity, which could be mitigated further by incorporating longitudinal AFP data. In fact, most patients who underwent CT or MRI for false-positive surveillance tests did so because of ultrasonography results (91%), with only 33 patients (9%) undergoing diagnostic evaluation for false-positive AFP levels. These data highlight the possibility that the harms of ultrasonography may be greater in clinical practice than prior efficacy studies given “unnecessary” diagnostic evaluation for indeterminate ultrasonography results. Similarly, the harms of AFP may be lower in clinical practice, because providers may not pursue diagnostic evaluation in all cases after accounting for factors, such as AFP trend, alanine aminotransferase levels, and liver disease etiology.

Overall, the study by Chang et al tackles an important issue in HCC surveillance. Ultrasonography was able to detect 92% of HCC, which was significantly improved by combining with AFP with minimal loss in specificity. However, nearly 40% of tumors were diagnosed beyond an early stage, highlighting the need for better surveillance tools in the future. In the interim, using ultrasonography and AFP in combination may be the best surveillance strategy to optimize early HCC detection.

StephenW

肝癌监测：请问甲胎蛋白有作用？
阿什维尼·梅塔
阿米特G.葛
内科，得克萨斯大学西南医学中心，得克萨斯州达拉斯系
发布时间：2015年7月28日
菲利普S.舍恩菲尔德，部分编辑，约翰Y.花王，科编辑
DOI：http://dx.doi.org/10.1053/j.gastro.2015.07.017 |
分享到mendeleyShare到Facebook分享到Twitter上emailMore共享服务
showArticle信息

    抽象的
    全文

常T，吴Y，通S等人。甲胎蛋白措施，有利于肝细胞肝癌监测肝硬化患者。牛J Gastroenterol 2015年; 110：836-844。

肝细胞癌（HCC）是世界癌症相关死亡的第三大原因，死亡患者的主要原因肝硬化一（消化内科2012; 142：1264年至1273年E1）。几个社团推荐HCC监测的肝硬化患者由于其与肿瘤的早期发现，接受根治性治疗和总生存率较高协会（肝病2010; 53：1-35）。超声和​​α-甲胎蛋白（AFP）是在临床实践中HCC监测最常见的测试。然而，AFP的精确度已经批判质疑，并有关于它在肝癌监测计划继续使用越来越多的辩论。

通过对肝硬化患者谁是2002年到2010年间发生HCC监测在台湾的回顾性队列研究昌等人的研究解决这一重要问题（牛J Gastroenterol 2015年; 110：836-844）。在5664潜在的符合条件的患者，1597被保留用于分析不包括肝癌18个月入学的内普遍存在肝癌，肝外并发肿瘤病史后，和/或后续的<18个月时间。患者经常接受HCC监测超声检查，每3-6个月AFP，与诊断检查通常开始时，肿块被视为在超声或AFP水平增加。

大多数患者（n = 1398; 88％）有乙型肝炎病毒（HBV）和/或丙型肝炎病毒（HCV）肝硬化，和最（N = 1233，77％）有Child-Pugh分级类甲肝硬化。在4.8岁（范围1.4-14）的中位数，363（22.7％）发展为HCC，其中213（59％）为早期或非常早期的阶段肝癌巴塞罗那临床肝癌的标准定义。肝癌是有增加的AFP（相对危险[RR]，13.2; 95％CI，9.6-18.2）最密切相关的因素;然而，假阳性甲胎蛋白水平与HCV有显著更可能（RR，6.9; 95％CI，1.6-29.5）或HBV感染（RR，5.6; 95％CI，1.3-24.7）的患者比那些非病毒肝疾病。

大多数患者肝癌（三百六十三分之三百三十四; 92％），超声检测，无论AFP水平。然而，29例（8％）呈现增加单独AFP（即，没有质量上的超声检查）。超声检查的敏感性和特异性独显92.0％（95％CI，89.2-94.8）和74.2％（95％CI，71.8-76.7），分别。结合B超和AFP，在20毫微克/毫升截止，与单纯超声相比显著的敏感性增加（P <0.001）。在亚组分析，灵敏度显著增加，观察患者的病毒性肝硬化（P <0.001），但那些与非病毒性肝硬化（P> 0.10）。 B超和AFP的结合，有99.2％（95％CI，98.2-100）与特异性降低最小（68.3％，95％CI，65.7-70.9）的敏感性。法新社添加一个附加标准提高≥2为99.2％（95％CI，98.2-100），增加特异性从低谷时期保持敏感性71.6％（95％CI，69.0-74.0）。
注解

在临床实践中HCC监测的有效性取决于监控工具，具有高灵敏度的早期肝癌检测的可用性。在由美国协会最近的指南肝病和欧洲协会的研究，为肝病的研究建议使用超声独自实现这一目标对次优敏感性AFP（肝病2010年和特异性给予关注; 53：1-35 ）。虽然超声是在良好控制的设置高度有效，本研究由Chang等有助于越来越多的证据基础，其在临床实践中的有效性可以是更多的异构（牛J Gastroenterol 2015; 110：836-844）。

除了超声的操作者相关的性质，它的性能可通过患者特征，如肝结节的影响。采用多中心的意大利数据库中的前一项研究发现，超声检查故障率检测肝癌中心之间变化（范围，10％-64％），与男性，儿童B或C肝硬化，高AFP水平，并监督相关的较高的失败率间隔> 6个月（临床Gastroenterol肝脏病杂志2014年; 12：1927-1933.e2）。监控工具的灵敏度不足是最常见的原因是患者晚期肿瘤检测，随后在三级医疗中心（牛J Gastroenterol 2013; 108：425-432）。与在早期阶段被检测不到的二分之一的所有HCC的，很明显，需要更好的监视测试。尽管一些新的生物标志物正在被调查，大多数是在阶段II-III生物标志物的开发和年距可被广泛用于临床实践（最佳PRACT RES临床Gastroenterol 2014; 28：843-853）。 AFP是目前已经经历了所有的5个阶段的生物标志物发展的唯一标志物。同样地，超声是唯一的成像方式可以充分评估作为监视成像模态。虽然一些人主张使用CT或MRI肝癌监视，它们的广泛使用是由成本和损害，如放射线照射的限制。因此，目前的努力应该侧重于利用B超和AFP优化监测的交付和有效性。

Chang等人的研究表明，使用超和AFP联合显著增加了HCC监测的敏感性与单纯超声组（92％比99％，P <0.001;牛J Gastroenterol 2015年; 110：836-844）。然而，这些数据描述了超声和AFP肝癌检测的性能，在任何阶段，而HCC监测的目的是检测肿瘤在早期阶段，当治疗选项（肝脏病2010; 53：1-35）。一种先有效性试验建议增加法新社超声检查也能显著增加对早期肝癌监测的敏感性（32％比63％，P <0.001），但这些数据仍需要验证在其他研究中（癌症流行病学杂志生物标志物上一页2012; 21：793 -799）。鉴于AFP和肝癌肿瘤分期/大小之间的关系，有可能是AFP可以检测晚期肝癌错过了超声检查无好转的早期肿瘤检测。在早期阶段检测到只有59％的肝癌研究中Chang等，目前还不清楚，如果通过AFP检测29例单纯是早期或晚期肿瘤（牛J Gastroenterol 2015年; 110：836-844）。未来的研究评估超声和AFP肝癌监测应报告为早期肝癌检测测试的性能特点。

虽然添加AFP≥20毫微克/毫升与单纯超声相比，超声显著的敏感性增加，表现最好的特点是用纵向AFP测量时观察到。需要一个从它的最低点，而上年同期增加了≥2AFP水平保持监控的高灵敏度，同时提高特异性。这一发现证实了先前的研究，暗示纵向AFP测量可能有更大的诊断准确率比HCC检测1次测量，尤其是在患者的丙型肝炎肝硬化，其中AFP升高往往是由于疾病的活动，而不是肝癌（临床Gastroenterol肝脏病杂志2013; 11 ：437-440）。可替代地，其他人所说AFP的精度HCC监测可以通过使用基于肝病因或调节AFP水平为患者年龄，谷丙转氨酶水平，和血小板计数（临床Gastroenterol肝脏病2014不同截断得到改善; 12：870-877;消化科2014年; 146：1249-1255.e1）。

在亚组分析，AFP患者HCV或乙肝肝硬化的敏感性增加肝癌的检测，而不是那些非病毒性肝病。作者总结AFP未必有利患者酒精或非酒精性脂肪性肝炎（NASH）;然而，在该亚组缺乏显着性可以简单地与小样本大小（N = 199）。事实上，NASH患者谁是肥胖的可能特别容易出现超声失败和站从添加血清生物标志物中获益。需要进一步的研究来评估B超和AFP的潜在利益患者的敏感性纳什，因为纳什的负担增长的全球。

增加监测的灵敏度必须仔细与特异性折衷权衡，因为假阳性率高可能导致不必要的诊断评估和由此产生的危害。在这项研究中，增加的AFP到超声导致降低最小特异性，这可以进一步通过结合纵向AFP数据来减轻。事实上，大多数患者谁接受CT或MRI检查假阳性监控测试做超声检查的结果（91％）是因为，只有33接受诊断评估的假阳性甲胎蛋白水平的患者（9％）。这些数据突出的可能性，B超的危害可能更大在临床实践中所给的“不必要”的诊断评估不确定的超声检查结果前药效学研究。同样地，AFP的危害可能是低在临床实践中，因为占因素，如AFP趋势，谷丙转氨酶水平和肝脏疾病的病因之后提供商可能不追求诊断评价在所有情况下。

总的来说，这项研究由张等人在铲球HCC监测的一个重要问题。超声检查能够检测肝癌，这是显著与AFP结合特异性最小的损失提高了92％。然而，近40％的肿瘤被诊断超越初级阶段，强调有必要在未来能有更好的监视工具。在此期间，利用超声和AFP的组合可能是最好的监测策略，优化早期肝癌检测。