早治疗是提高肝癌患者生存率的关键。第58届欧洲肝脏研究学会年会（EASL2023）暨2023年EASL大会（EASL Congress 2023）上，意大利博洛尼亚大学Fabio Piscaglia教授在“Treatment of early stage HCC in 2023”专题会议中介绍了早期细胞癌（HCC）的治疗选择新进展，《国际肝病》有幸在大会现场邀请到Fabio Piscaglia教授分享HCC治疗策略， HCC预防复发策略，以及新兴技术肿瘤分子特征分析的研究现状及前景。
 

 

《国际肝病》

早期肝细胞癌的治疗选择较多，临床如何为患者选择最佳治疗方案呢，能否请您谈一谈？

 

Fabio Piscaglia教授：目前有多种针对早期诊断的单发小肝癌的治疗选择，以帮助延长患者的生存期。明确最佳治疗方案需要三步。

 

第一，治疗需要实现彻底的肿瘤清除，即达到完全缓解。

 

第二，治疗过程中需要保证患者肝功能完整，因为大多数肝癌患者也同时患有肝硬化等慢性肝病。若彻底清除了肿瘤但导致肝功能受损，患者生存期可能会受到影响。我们的目标是在尽可能延长生存期的同时，为患者提供最佳的生活质量。

 

第三，最佳治疗方案的抉择上需要权衡完全缓解和肝功能保护之间的利弊，并了解复发的风险。即使在组织学上实现肿瘤完全缓解（completed tumor response），中高风险的早期患者在三年内的复发率仍然高达50%。因此，了解复发风险是确定最佳治疗方案的一个重要依据。我们通常根据卫星灶（satellite nodules）、微血管侵犯（MVI）和肿瘤分级（如果有肿瘤组织学信息）来进行判断。因此，在进行切除或消融化疗之前，很难准确预测预后，通常我们只使用肿瘤大小和甲胎蛋白水平（AFP）来评估。

 

此外还要综合考虑患者的肝功能状况，包括是否处于Child-Pugh A代偿期，以及Child-Pugh A5之前是否有代偿情况，是否处于Child-Pugh A6或B7。通过多学科团队，包括外科医生、移植外科医生、介入放疗操作者、放射科医师、肝病学家、肿瘤学家和放射治疗师，我们会讨论每位患者的情况，综合考虑肿瘤大小、甲胎蛋白水平和肝功能等因素，然后确定最佳治疗方案。需要记住的是，患者通常需要接受多种治疗，在复发时可能需要采取其他治疗措施。因此，我们需要制定长期的策略，以最大限度地延长患者的生存期。

 

There are many different treatment options, and this will therefore allow long survival, provided that you make an early diagnosis which is a small single tumor. How to decide the best treatment option depends on three different steps. The first one is how to achieve the most radical oncological treatment, so achieving complete response. The second is to preserve liver function, because most of the patient with the hepatocellular carcinoma suffer cancer and chronic liver diseases in the cirrhotic stage. Therefore, if you treat completely the tumor but you worsen liver function, the patient will live shorter. While the aim is to maximally prolong patient survival with the best quality of life. In order to complement the best choice, balancing making a tradeoff between radicality and preservation of live function, it would be best to know the risk of recurrence because patients in the early stage who achieve a completed tumor response who are an intermediate or high risk of recurrence based on histological features still suffer a recurrence rate up to 50% at three years. Therefore, if you decide which treatment is best, it would be better if you have the information about the probability of risk. To date, we still are based only on the presence of satellite nodules, microvascular invasion and tumor grading, when histology is available. So before resection today or ablation of chemicalization, there are very little information to predict the prognosis. We usually only use the tumor size and level of alpha fetoprotein.

 

Therefore, putting together this information, what is the precise liver function of the patient? Not only Child-Pugh A compensated, but Child-Pugh A5 ever they compensated in the Child-Pugh A6 or B7. These are all might be all compensated conditions together with the tumor size and alpha fetoprotein, we discuss in a multidisciplinary team, which means there is the surgeon, transplant surgeon, the interventional operators, the interventional audiologist, the hepatologist, the oncologist, radiotherapist. Then we can decide for each patient the best treatment. Having in mind that the patient will not receive only one treatment because at the time of recurrence, most likely he has to receive other treatments. Therefore, we have to make a strategy for the long term in order to prolong maximum survival.

 

《国际肝病》

目前对于肝细胞癌分子特征的研究逐渐深入，您怎么评价这些工具的价值和局限性，可为临床实践带来哪些获益？

 

Fabio Piscaglia教授：肿瘤的分子特征分析是一个相当新的领域。由于分子出现异常（derangement of the molecules），例如炎症分子，不同类型的高密度细胞癌（hypercellular carcinoma）至少可以分为四种不同的分子特征亚型。

 

目前，这项技术仍然处于研究阶段，还未投入临床应用，因为不能仅仅根据分子特征来做出治疗选择或预测预后，且通常我们只能从肿瘤本身来获取这些信息。因此，通常情况下，患者会接受肿瘤切除手术。实施肿瘤切除即已经对治疗方案做出了决策，这意味着我们并没有直接利用分子特征来指导治疗策略。

 

然而，这个领域非常有趣，因为通过识别不同类型的肿瘤，我们有可能找到一些新药物的靶点。因此，如果这些研究结果取得成功，将来也许能够根据分子特征来确定最佳治疗方案，特别是针对不同患者选择最适合的药物。但是我必须承认，目前这只是一个研究的方向。

 

The molecular profiling of the tumors is a quite new condition. There have been at least four different subtypes of molecular profile in different classes of hypercellular carcinoma due to the derangement of the molecules like the inflammatory type. Today there is no clinical implication because this is still for research, because we don't take decision about the choice or prognosis simply according to the molecular profile, even because we usually have this information only on the tumor itself. Therefore, usually patients have been resected. So we had already choosing the therapy. So it means we don't utilize it upfront to decide the strategy. However, this is a very interesting field of research because potentially by identifying some classes of tumors we might identify some targets for new drugs. Therefore, potentially in the future, if these results will be successful, you might have the possibility to identify the class, the molecular profile class, and choose the best treatment, especially the best drug for one differently from another patient. But at present I must acknowledge this is only a research field.

 

《国际肝病》

肝癌的复发率较高。目前对于预防复发，有哪些值得关注的研究？能否谈谈您在预防肝癌复发方面的临床经验和心得？

 

Fabio Piscaglia教授：对于实现肿瘤完全缓解的早期肿瘤患者而言，三年内的复发率相对较高，约为40%到60%，五年内则达到60%到70%。复发可分为两种类型。通常在最初几年内观察到的复发是初始肿瘤（initial tumor）的微小转移（micro-metastasis）。然而，如果初始肿瘤病灶在硬化的肝脏中，则可能出现其他独立肿瘤，这被称为de novo癌。因此，我们在减少复发方面有两个目标。

 

第一，我们应尽力避免de novo癌的发展，这主要通过治疗潜在肝病来实现，例如通过治疗丙型肝炎以达到持续病毒学应答，抑制乙肝病毒的复制并将其载量降至零，通过改变生活方式和减重治疗非酒精性脂肪肝，或者戒酒。通过改善肝脏基础疾病，我们可以减少再生刺激和肝脏新病灶的发展。

 

第二，初始肿瘤扩散到其他部位时，即使治愈了初始肿瘤，其他部位仍可能存在肿瘤细胞，因此需要给予能够杀死这些细胞的抗肿瘤治疗，以防止其进展为肝转移。目前，我们已经尝试了对晚期肿瘤有效的药物，希望它们也能对这些微小肿瘤产生作用。这些微小肿瘤只是细胞的散播，肉眼尚不可见。这些微小肿瘤可能在接下来的几个月或几年内出现进展。

 

然而，首次尝试使用索拉非尼进行的靶向治疗不幸失败，没有改善患者的无复发生存期（RFS）。最近，阿替利珠单抗与贝伐珠单抗的联合疗法在中位RFS上取得了显著改善。这是一个重要的进展，但仍不是最终目标。我们需等待最终数据，同时还有其他正在进行的研究，包括一些免疫检查点抑制剂和抗血管生成药物的组合，或者仅使用免疫检查点抑制剂的疗法。我们迫切期待这些结果的出现。

 

通过综合类似试验的不同结果，甚至可以区分抗血管生成药物和免疫治疗在预防转移方面的作用，并希望能够治愈这些微小的循环肿瘤细胞。同时，我们还必须考虑设计新的试验，因为在切除肿瘤后立即开始给予治疗，有时循环肿瘤细胞数量太少，无法触发免疫反应。因此，一种新的预防复发方法是在进行肿瘤学治疗之前先开始药物治疗，这被称为围手术辅助治疗。这个领域非常令人兴奋且具有巨大的潜力。

 

So, the recurrence rate in patients who have been completely treated for an early stage tumor is relatively high because it is in the range of 40% to 60% at three years. And if you extend your observation time to five years, it is almost 60% to 70%. The recurrence is of two types. Usually within the first few years you observe recurrence which are micro-metastasis of the initial tumor. But when the initial tumor is developed in a cirrhotic liver, also other independent tumors may arise. These are called de novo tumors. So obviously, if we want to limit the recurrence, we have two targets. On one side we should address to limit the development of de novo tumors. This is made mainly by treating the underlying liver disease. So, for instance, achieving sustained virological response by treating hepatitis C or treating replication of hepatitis B and bringing to zero the replication of hepatitis B or changing lifestyle and losing weight in patient with nonalcoholic fatty liver disease or stopping drinking alcohol. So if you improve the background liver condition, then you will reduce the stimulus to regeneration and to development of new liver lesions.

 

On the other side, when we have the diffusion of the initial tumor by the spreading of cells. It means that if you cure the initial tumor, there are tumoral cells elsewhere and you want to give a treatment that can kill these cells to avoid that they progress to liver metastasis. This instead has to be done with oncological treatments. Nowadays, what has been attempted is to give drugs that work for advanced tumors, hoping that they will work also for these microtumors, invisible tumors, because these are only cells spreading but still not visible, otherwise we would have treated them by oncological treatments. They may develop in the next months or few years. The first attempt with TKI with sorafenib unfortunately failed, so there was no change in the recurrence free survival. Very recently, the combination of Atezolizumab plus Bevacizumab demonstrated an improvement in median recurrence free survival time.

 

This is a big advantage, but it's still not the ultimate aim. We still have to see the final data, but there are still other ongoing studies which include some combinations of immunocheckpoint inhibitors and antiangiogenic drugs or immunocheckpoint inhibitors alone. So we are eagerly waiting for these results, because combining different results for similar trials will be very helpful even to distinguish the role of antiangiogenics, which might even only delay the appearance of allegiance from immunotherapy, which we hope could cure these tiny circulating tumor cells. So we needed to wait for these trials. But we also have to think about designing new trials because if you resect a tumor and you start giving a treatment, sometimes the circulating cells are too little to trigger an immune response.

 

So the new modality to approach the prevention of recurrence is starting the pharmacological treatment, even before the oncological treatment, which is called perioperative adjuvant treatment. These are the hope for the future in case that the incoming trials will be concluded without too strong results or even if these results are good, this could be a modality to further improve these findings. Therefore, at present I can only say we can wait for this new data, but the field is very exciting and with a great potential.

 

《国际肝病》

总体而言，对于肝癌的临床诊治，您建议采取何种模式？

 

Fabio Piscaglia教授：在全球不同地区，关于肝癌的诊断存在一些差异，这其中部分原因来自不同地区诊治指南的差异。例如欧洲指南只推荐在肝硬化患者中，对于≥1 cm的结节采用非侵入性标准，而美国的指南则推荐在慢性肝炎患者中，尤其是慢性乙型肝炎患者中采用非侵入性标准。个人而言，我倾向于遵循欧洲的指南，因为在肝硬化患者中，患有肝细胞癌的先验概率（apriori probability）或先验风险要高得多，这样可以避免误诊。这些指南认可CT、MRI或增强超声以及活检。其中我认为活检要重要一些。总的来说，EASL指南与全球其他指南差异不大。

 

其次是对患者进行分期，基本上都是通过结合肝功能、肿瘤大小和数量来进行。所有指南在分期方面是一致的。目前最常用的是巴塞罗那肝癌治疗指南（Barcelona Clinic Liver Cancer guidelines，BCLC），但它们只能起到一定的指导作用，不能作为对任何具体患者的强烈推荐。针对具体患者的管理应根据当地专业建议进行。因此，指南只是一种指导框架。在我看来，它们应该纳入基于治疗的分层决策中，在保证患者肝功能完好的前提下，为患者提供最有效的抗肿瘤治疗。单纯依靠指南很难做到这一点。

 

因此，只要条件允许且对整个患者群体有生存获益，我们在治疗方案中将优先考虑肝移植，其次是手术切除、经皮消融或血管内治疗，最后才考虑药物治疗。不过，我们经常结合这些治疗方法，甚至在BCLC中也会应用阶段迁移策略（stage migration strategy），即从更强的高层次到较低层次的抗肿瘤治疗，或者反过来从低到高，因为一些患者可能接受更激进的治疗。唯一的注意事项是肝功能的保护，肝储备功能必须最大限度地保持以延长患者生存期。

 

由于患者可能需要接受肿瘤切除、再切除手术、消融治疗、经动脉化疗、一线系统治疗、二线、三线治疗等。为了使这些治疗成功，患者必须保持Child-Pugh A的代偿状态。因此，每种治疗都应在保证肝功能完好的前提下进行。迄今为止，可能没有一个分期系统完全适合回答对于任何给定患者的这些问题。因此，需要有专业知识的医生参考指南而非依赖指南对患者进行治疗，因为指南的内容无法满足每一位患者的具体临床需求。

 

There are some differences in different part of the world in order how to achieve the diagnosis. Because some guidelines, for instance, like European guidance only endorse the adoption of noninvasive criteria for nodules ≥ 1 cm in cirrhosis. While the American endorse it also for patients with chronic hepatitis, especially chronic hepatitis B. So the situation is a bit variable. Personally, I would stick with the European guidelines because the apriori probability or a prior risk of having an HCC is much higher in patient with cirrhosis and these will avoid false positive. And these guidelines endorse CT, MRI or contrast enhanced ultrasound and biopsy. And we should resort to biopsy more. Therefore, these are the European Association for the Study of the Liver guidelines, but they do not differ much from other guidance worldwide.

 

Then you stage the patient and the staging is done everywhere, combining liver function, tumor size and number. All the guidance agree on this. At present, the most commonly utilized are the Barcelona Clinic Liver Cancer guidelines, but they must be considered a sort of frame, but they cannot be held as in strong recommendation for any given patient. Any given patient must be managed according to the local expertise comorbidities. Therefore the guidelines are a sort of frame, but in my view they should be incorporated in what is held a hierarchical stepwise decision on the treatment, trying to give to the patient the strongest level of oncological treatments, providing that the liver function is preserved. This is difficult to be held in a guideline.

 

So we'll start from liver transplantation whenever it's possible and when it produces a survival benefit to the entire community of your patients. Then it goes to surgical section, percutaneous ablation, endovascular treatments and then drugs. However, often we combine these treatments and we must apply even within the BCLC, the stage migration strategy, not only what is called from left to right, from stronger higher hierarchy to lower hierarchy of oncological capacity of treatment, but even right to left, because patients, some individual patients might be treated with more radical treatments. The only caveat that we have to keep in mind is that we must preserve liver function. The liver functional reserve must be preserved at maximum, because today a patient, to prolong survival, may need to undergo resection, maybe a re-resection, ablation, transarterial chemicalization, first line systemic treatment, second line, third line treatment. In order to successfully receive all this treatment, he must remain compensated in Child-Pugh A. Therefore, each treatment is to be delivered, keeping in mind the idea of preserving liver function. And to date, probably no staging system is perfectly suited to answer these questions for any given patient. Therefore, there is a need of local expertise who are inspired by the guidelines but do not follow strictly the guidance, which cannot recognize any single individual given patient.

 

 

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