编者按：“2018年CSH-EASL DAY”于“2018年中华医学会肝病学分会学术年会”期间举行，意大利博洛尼亚大学Fabio Piscaglia教授代表欧洲肝脏研究学会（EASL）在会上分享了肝细胞癌（HCC）领域的最新进展。Piscaglia教授致力于研究肝脏疾病、门静脉高压症，以及肝移植，他在这些领域探索出超声检测的多种应用模式。会后，《国际肝病》就HCC的监测、分期、治疗等问题采访了Piscaglia教授。

 

《国际肝病》：目前指南建议肝硬化患者接受HCC监测，每6个月进行超声检查，或者同时检测AFP。是否有较具前景的早期HCC检测新方法？

 

Piscaglia教授：我们现有的证据还不足以支持提出一种适用于所有患者的全球策略，未来，我们可能会看到一些“个体化医学（personalized medicine）”的应用。例如，肝细胞特异性造影剂MRI在早期发现肝脏结节中的应用。虽然该检测在明确HCC诊断方面不及常规的含钆造影剂MRI，但其对肝脏异常的判断非常敏锐。由于MRI检查的成本高且常规使用注射造影剂监测未患癌患者不太现实，所以我不认为未来MRI可常规用于HCC监测，但可用于超声检查效果不佳的患者。

 

甲胎蛋白（AFP）检测曾一度因为存在假阳性风险而不被指南推荐。这种假阳性风险与活动性肝炎有关，但今天我们有了治疗乙型肝炎的药物且大多数丙型肝炎患者都接受了治疗，所以AFP的假阳性风险有所降低。有文章表明，在已接受和正在接受乙型肝炎治疗的患者中，AFP水平的少量但逐渐增加提示患者未来会进展为HCC。

 

因此，未来，我们可能会看到超声检查联合甲胎蛋白检测，或者超声检查联合PIVKA检测，用于没有活动性肝炎的患者，这种联合监测具有较低的假阳性风险。然而，当下，我们仍然必须使用标准推荐，即所有肝硬化患者每六个月进行超声检查，仅为肝脏可见性不佳患者寻找替代方法。

 

: Current guidelines usually recommend patients with cirrhosis should undergo HCC surveillance using ultrasound with or without alphafetoprotein (AFP), every 6 months. Are there any new tools showing promise for early detection of HCC?

 

Prof. Piscaglia: The evidence we have today is not strong enough to propose any global strategy for all patients. In the foreseeable future, we might see some personalized medicine. 

 

For instance, we know that MRI with hepatocyte-specific contrast agents is sensitive to detecting abnormalities, but probably no better than conventional gadolinium-based MRI to establish a definitive diagnosis. But if we aim to identify more nodules at an early stage, this could be the most sensitive approach. However, the prospects for routine use are slim in my view due to cost issues, as MRI is expensive. Also the use of injectable contrast agents in surveillance in patients who would not be developing cancer is not ideal. So I don’t foresee a future for all patients, but there may potentially be a role in those patients where ultrasound scans do not work well. 

 

In the past, alpha-fetoprotein was dropped from the guidelines because of the risk for false positives. This was related to active hepatitis, but today we have drugs to treat hepatitis B and most patients with hepatitis C are treated. There have been papers showing that in patients who have been and are under treatment for hepatitis B, small but progressive increases in alpha-fetoprotein are suggestive of future development of HCC. So, in the future, we could see a combination of ultrasound with alpha-fetoprotein, or with another marker, PIVKA, the modified factor V in the absence of vitamin K, for those patients who have no active hepatitis, and are consequently at lower risk of false positives. Today, however, we have to use the standard recommendation of ultrasound every six months for all of our patients. We need to ask the scan operators to report on the visibility of the liver, and then seek out alternative methods only for those patients in whom the explorability of the liver is unsatisfactory.

 

《国际肝病》：临床实践中，常用的HCC分期及治疗分配系统有哪些，您更喜欢哪种系统？

 

Piscaglia教授：目前，全球有多个分期系统，但我们需要一个不仅能够对患者进行预后分层，而且还能将每个分期与特定的治疗方案联系起来的系统，然而少有分期系统能满足这些要求，准确指定一线治疗方案。

 

在西方国家，最常采用的是巴塞罗那临床肝癌（BCLC）分期系统，包括五个阶段：最早期、早期、中期，晚期和终末期，为确定患者的预后和分配治疗提供了指导。最早期和早期的患者分期非常明确，但中期和晚期的患者仍存在较大差异，例如，不同的晚期肿瘤进展类型，无论是肝外转移或局部进展还是症状性肿瘤，其预后都不同，对应的治疗方案实际上也是有差异的。

 

EASL指南明确指出，BCLC分期系统只是医生和多学科团队为患者制定最佳治疗方案的一般框架，强调向个体化医学的转变，考虑患者个体的肝功能损伤程度。我们通常将Child-Pugh评分与MELD评分结合起来，明确患者的合并症，以获知患者是否需要或禁忌选择手术治疗，另外还需确定中期肿瘤的大小。所以，有很多其他因素可能使我们不选择BCLC的主要治疗建议，在我们的患者中大概有一半的这样的病例，这与个体化医疗有关。

 

我想再次强调EASL的建议：治疗方案需由多学科团队一起制定。团队可采用分期迁移的治疗对策，即如果患者不适合其所在阶段的推荐治疗，则可采用下一分期的治疗方案，这可能是从疗效较强的方案过渡到疗效较弱的方案；在适当的情况下，团队还可以采用针对更早期患者的治疗方案，对肿瘤的治疗效果可能更好。

 

: What are the most commonly used systems for staging HCC and treatment allocation in routine clinical practice? Which one do you prefer?

 

Prof. Piscaglia: There have been several staging systems designed around the world. These reflect the fact that different countries carry out surveillance differently and that the severity of tumors at diagnosis is different, so one staging system may not be as good at predicting prognosis as others. However, when we adopt a staging system in our practice, we need to utilize one that is not only able to stratify patients by prognosis, but also link each stage to a specific treatment. This applies only to few staging systems. These accurately specify the recommended first-line treatment option. 

 

In the West, the most widely adopted is the BCLC (Barcelona-Clinic Liver Cancer), which has five stages - the very early, early, intermediate, advanced and terminal stages. This provides a framework for establishing the prognosis of patients and to allocate treatment. We know the staging is very well defined in the very early and early categories, but there are still quite broad divisions of patients in the intermediate and advanced stages. For instance, we know that the type of tumor development in the advanced stage, whether it is extrahepatic metastases or local progression or a symptomatic tumor, defines a different prognosis. This is the system we utilize in current daily practice, even though we know it is far from perfect, especially in the intermediate and advanced stages in terms of defining treatment options. 

 

However, the EASL Guidelines specify clearly that this is just a general framework to be used by the physician and the multidisciplinary team to decide the best treatment for any specific patient. This emphasizes the move towards personalized medicine, which takes the degree of liver dysfunction into consideration. We usually combine the Child-Pugh score with the MELD score. We have to define patient comorbidities, which may indicate or contraindicate surgery as an option. We should define the extent of the tumor bulk in the intermediate stage. So there are many other factors that may lead us away from the primary treatment recommendation from the BCLC in maybe half of our cases. This is all related to personalized medicine. 

 

I would like to emphasize again the EASL recommendation that the choice needs to be made by the multidisciplinary team. This team can adopt a stage migration approach, recommending the next stage of treatment if the patient is not suitable for the treatment recommended for their stage. This may be from a more curative treatment to a less curative treatment. They can also endorse, where appropriate, an approach specific to an earlier stage that may be more effective and curative for that individual tumor.

 

《国际肝病》：您怎么看各种维生素或矿物质膳食补充剂在预防HCC中的作用？

 

Piscaglia教授：在我看来，肠道正常状态的改变对一般健康，特别是肝脏健康有很大的影响，添加补充剂的改良饮食对此可能会有较大的改善作用。但是迄今为止，我们只知道咖啡可以降低罹患HCC的风险，在对心血管系统没有不良影响的情况下，咖啡的摄入量与HCC的风险降低有关，这是饮食方式如何影响HCC风险的一个很好的例子。我认为，补充剂有预防HCC的潜能，但目前的科学证据还不足以推荐使用任何一种特定的补充剂。

 

: What’s your opinion about the role of dietary supplements such as all kinds of vitamins and minerals for the prevention of HCC?

 

Prof. Piscaglia: In my view, what happens in our gut has a strong influence on general health, and especially liver health. So I think a modified diet that may include supplements may have a strong effect. So far, we only know that coffee reduces the risk of HCC. This has been well demonstrated, and an example of how what we eat or drink influences the risk of HCC. The decrease in HCC is related to the amount of coffee consumed, provided there are not adverse effects on the cardiovascular system. I foresee a potential for supplements, but the current scientific evidence is insufficient to recommend any specific supplements.