Hepatocellular carcinoma (HCC) is commonly known as the “king of cancers”. Research on its pathogenesis, diagnosis and treatment is in full swing. This article reviews the molecular biology of hepatocellular carcinoma, as well as new advances in liver transplantation and non-surgical therapies. The original article was published in the journal Gut in 2014. The content is compiled below.
Abstract
Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis. New findings suggest that in addition to viral hepatitis and alcoholic liver disease, nonalcoholic liver disease syndrome is also an important cause of hepatocellular carcinoma. The molecular pathogenesis of hepatocellular carcinoma is extremely complex and heterogeneous. To date, clinical treatment has not taken into account the relevant molecular biological information.
Patients with cirrhosis need regular imaging because the imaging criteria for early stage liver cancer are well defined (1-2 cm nodules) and current therapies can effectively treat early stage liver cancer. Whether the surgical option for liver cancer is resection or transplantation depends on the local medical resources, the level of care and the feasibility of organ donation. This review focuses on the criteria for liver transplantation, summarizing controversies and new evidence.
In mid-stage liver cancer, several treatment options are available, including radiofrequency ablation, transhepatic artery chemoembolization (TACE), and transhepatic artery radiotherapy (TARE). However, the clinical effectiveness of these therapies is still debatable. For patients with advanced hepatocellular carcinoma, systemic therapy with sorafenib remains the best option at this time.
Therefore, although several studies have shown that combination therapy with multiple treatment options failed to improve clinical outcomes in patients, further research on combination therapy is still needed. In addition, the article mentions the stratification of patients for selective use of second-line treatment options, which may help explain the failure of previous studies.
Hepatocellular carcinoma (HCC) is a worldwide disease with more than 700,000 new patients each year. the main risk factors for HCC include HBV or HCV infection, and alcoholic cirrhosis. Non-alcoholic steatohepatitis is a recently emerged risk factor. Smoking increases the risk, but coffee may reduce it. The mortality rate of the disease is almost equal to the incidence in most countries, which indicates the lack of effective treatment for liver cancer at present.
In Japan, liver cancer surveillance is being actively pursued, leading to early detection and early treatment of a large number of liver cancers, and the mortality rate has been lower than the incidence rate.
More than 90% of liver cancer patients are transformed from chronic liver disease (cirrhosis). Therefore, HCC can be avoided by avoiding the development of chronic liver disease. Vaccination and antiviral therapy are beneficial interventions. However, if antiviral therapy is started after the development of cirrhosis, the preventive efficacy will be lost. Long-term interferon therapy does not reduce the risk of hepatocellular carcinoma. The prophylactic efficacy of metformin, propranolol and retinoic acid needs to be confirmed by prospective studies.
In this review, we describe the progress and future challenges in three main areas: molecular events in tumor development, predictors of tumor prognosis, and current treatment options.
Current status of molecular biology research in liver cancer
Molecular medicine is held in great hope, as it would be of great benefit to treatment if the molecular origins of cancer could be revealed. The biomedical community hopes that it will be possible to (A) easily stratify patients, (B) identify common and dominant oncogenic pathways and (C) target and personalize therapeutic approaches. Some of these goals have been achieved in some cancers, but progress toward the above goals has been slow in most tumors.
Cancer is far more complex than we realize. There are many genes and heterogeneities of genetic information that are quite difficult to analyze from a systems biology perspective. The nature of genetic information is also highly variable. For example, genetic analysis includes transcriptomes, miRNA expression profiles, long non-coding RNAs , copy number differences, deep exome sequencing, quantification of hemizygotes and pure deletions with promoter methylation.
To further explain genetic mutations, mutations are currently divided into two categories, major and minor mutations. However, the distinction between the two is not easy. The cancer genome must also be compared with non-tumor tissues to identify cancer-specific alterations. The course of cancer changes over time. As a result, the key genetic features of the cancer change with it. Unfortunately, many of the specimens available for genetic analysis are primarily derived from surgical specimens and therefore reflect only a subset of patients.
The genetic heterogeneity of cancer is fascinating; not only do differences exist between patients, but also between tumor nodes in the same patient, and even within a single node. For example, one study examined three nodes in one patient using whole genome sequencing. Two major mutations were identified in one node, while different major mutations were identified in the other two nodes.
The intra-tumor heterogeneity may reflect the presence of different cancer stem cells that exhibit different tumorigenicity and independent genomes. Thus, not only does each patient have his or her own cancer genome, but individual tumor nodes within the same patient have unique genomes. Genetic heterogeneity in hepatocellular carcinoma may also be due to differences in etiology and differences in the genetic background of patients, making it rather difficult to compare patients from different regions of the world.
Unfortunately, even if oncogenic pathways are identified through genetic studies, they are difficult to use for targeted therapy. Our current pharmacological techniques allow for well-designed kinase inhibitors, but not for blocking protein-protein interactions. For example, although the WNT / β-linked protein pathway can directly contribute to hepatocarcinogenesis, there are no corresponding drugs available so far.
Cancer cells need mutations in their own oncogenes to survive. This is called oncogene accumulation. One of the goals of genetic research is to identify such oncogenes for targeted therapy. The most typical example is melanoma, in which the commonly expressed mutation is in the BRAF gene (V600E). Patients presenting with this mutation are sensitive to Velofinil tablets. This is a good example of personalized medicine in oncology.
The microenvironment is also key in tumor biology. Recent data suggest that hepatocyte growth factor secreted by adjacent stromal cells can counteract the killing effect of virofenicin tablets on cancer cells. Therefore, cancer therapy cannot target genetic mutations alone, but the nature of the microenvironment should also receive attention.
Given the complexity of tumor genetics, making meaningful progress is quite difficult. None of the current guidelines for liver cancer mention genetic tools. In the following sections, we will dissect the available genetic information and highlight the commonalities in the findings.
1. Risk stratification
(1) Risk stratification for liver cancer
Several genome-wide association studies (GWAS) have explored the relevance of single nucleotide polymorphisms and hepatocellular carcinoma. These pathways affect pathways including oxidative stress and detoxification, iron metabolism, inflammatory cytokine chemokine systems, and DNA synthesis and repair mechanisms. Interestingly, functional polymorphisms of the epidermal growth factor receptor (EGFR) are also associated with the risk of HCC.
Given the effectiveness of EGFR inhibitors, such drugs may be used as chemopreventive therapy. Finally, cellular mutations in precancerous lesions of cirrhosis and early hepatocellular carcinoma activate the telomerase reverse transcriptase promoter. These mutations can be used to identify patients at high risk for HCC.
(2) Risk stratification for HCC recurrence
The biggest problem affecting the radical treatment (i.e., ablation, surgical resection) of hepatocellular carcinoma is the recurrence of hepatocellular carcinoma. Researchers delved into the expression profiles of treated liver cancer tissue versus non-tumor tissue to assess this risk. Unexpectedly, both tumor and non-tumor tissues were predisposed to tumor recurrence.
These data suggest that most tumor recurrences after radical treatment may not be metastases from the original tumor, but rather a redevelopment from cirrhosis to hepatocellular carcinoma. In addition, it has been shown that advanced hepatocellular carcinoma contains more proto-oncogene mutations within the peritumor cells.
Studies have also identified interleukin-6 (IL -6) to be associated with inflammatory cytokine-driven carcinogenesis. Interruption of IL-6 signaling reduced tumor growth in experimental rats. Inhibition of IL-6 may be a secondary preventive measure.
Microvascular invasion of hepatocellular carcinoma is a risk factor for recurrence. Given this information, a molecular marker predicting vascular invasion would be useful to stratify the risk of recurrence in patients with hepatocellular carcinoma. Differences in the expression of this molecular marker have been reported to predict microvascular invasion, but this index does not predict recurrence of hepatocellular carcinoma. Therefore the value of the clinical application of this molecular marker has not been determined.
An alternative approach is to combine clinical, pathological and gene expression data to predict recurrence of hepatocellular carcinoma. The expression profile of proliferative molecules combined with the expression profile of undesirable non-tumor tissues plus the pathological features of satellite foci can predict the recurrence of hepatocellular carcinoma.
2.Carcinogenic pathways
(1) mRNA expression profile and genome-wide methylation profile
A large number of studies have been conducted in this area. Mainly, there are three major pathways, including WNT/β-linked protein pathway, proliferative pathway and hepatoblastoma-like pathway. The molecular features of these three pathways are extensive and there are no areas of overlap between studies. Therefore, although they have been very informative, they are unlikely to be applicable to clinical practice.
In addition, they have not elucidated specific, targetable oncogenic pathways. The same is true for the current genome-wide methylation profiles.
(2) MicroRNA (miRNA) profiles
miRNAs are small non-coding RNAs that regulate gene expression and can alter mRNA transcription and/or translation. miRNAs can regulate an average of about 200 target mRNAs and therefore have a wide range of cellular effects, such as cell differentiation, cell proliferation and avoidance of cell death. Analysis of miRNA expression patterns in hepatocellular carcinoma suggests that several miRNAs are dysregulated, however, the exact function of this dysregulation needs to be further investigated.
Llovet and colleagues analyzed the miRNA profiles of patients with HCV-associated hepatocellular carcinoma. These patients were from the United States, Italy and Spain. By unsupervised clustering analysis, three main subsets of miRNA alterations were identified including a subset related to β-linked proteins, a subset of interferon-related genes and a subset related to tyrosine kinase signaling pathway activation
In the last subset, miR – 517A was upregulated in hepatocellular carcinoma, and functional analysis indicated that it is a bona fide oncogenic miRNA. however, targeting of miRNAs for therapeutic treatment remains to be further investigated.
(3) Genome-wide investigation
A limited number of studies have performed genome-wide analyses in patients with liver cancer. Rossi and his colleagues analyzed the genome copy number of 125 patients who underwent resection for hepatocellular carcinoma and performed whole-genome sequencing in 24 of them, which were alcoholic cirrhosis patients.
Alterations in somatic mutations or pure deletions included the Wnt signaling/β-catenin signaling pathway, the p53 pathway, the phosphatidylinositol 3-kinase (PI3K)/Ras signaling pathway, oxidative and endoplasmic reticulum stress regulators, and chromatin repair mechanisms. It is noteworthy that hepatocellular carcinoma has different mutations with different etiologies. This suggests that different liver diseases have different mechanisms at the cancer initiation stage.
Inactivation of chromatin repair mechanisms is more common in patients with alcoholic cirrhosis, while mutations in interferon regulatory factor 2 (IRF2; a regulatory pathway of the p53 gene) are common in HBV patients.
Nakagawa and his colleagues performed whole-genome sequencing of Japanese patients with liver cancer. Twenty-seven of them were due to hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. They also identified mutations in the following pathways, including Wnt/β-linked protein, p53 gene and chromatin repair mechanisms. In addition, they identified point mutations in ERRFI1, which primarily represses the kinase structural domains of EGFR and ERBB2. Loss-of-function of ERRFI1 activates the EGFR signaling pathway, and mutations in ERRFI1 may serve as biomarkers for EGFR-targeted therapies.
The researchers also found that the HBV genome is inserted with a telomerase reverse transcriptase (TERT) gene, suggesting that telomerase activity is one of the mechanisms of hepatitis B virus carcinogenesis.
Luk and his colleagues performed a genome-wide analysis of 81 patients with recurrent liver cancer, looking primarily at HBV integration. These patients were all HBV-positive Chinese patients, and HBV integrated mainly into the following genes, including TERT, MLL4, cell cycle protein E1 (CCNE1), SUMO1/sentrin-specific peptidase 1 (SENP5), Rho-associated protein kinase 1 (ROCK1), and fibronectin 1 (FN1). This suggests that integration of hepatitis B virus is associated with the pathogenesis of hepatocellular carcinoma.
Researchers performed high-throughput sequencing of individual HCC genomes in HCV-positive HCC patients. Inactivation and nonsense mutations in TSC1 were identified in a subpopulation of tumor cell species. This suggests that in mammalian target of rapamycin (mTOR) drive is one of the oncogenic pathways.
Another high-throughput study analyzed 18 000 genes (exomes) expressing the protein. These specimens were derived from 10 patients with HCV-associated hepatocellular carcinoma. The study identified inactivating mutations in the AT-enriched interacting structural domain 2 ( ARID2 ) . Given the role of this protein in chromatin repair mechanisms, it could serve as a potential tumor suppressor gene, and by regulating the expression of this protein could slow down the progression of HCC.
These high-throughput studies have provided new therapeutic targets for the treatment of hepatocellular carcinoma. For example, mTOR inhibitors and epigenetic regulators. However, progress in this area has been very slow.
4. Key points: genetic research objectives
(1) Risk stratification: risk of developing hepatocellular carcinoma (HCC); risk of recurrence of hepatocellular carcinoma after clinical treatment; disease prediction for the presence of hepatocellular carcinoma.
(2) Identification of carcinogenic pathways: carcinogenesis; invasion and metastasis.
(3) Oncogene therapy for patients themselves
(4) Complexity of hepatocellular carcinoma gene profile: genomic alterations; genomic correlation studies of single nucleotide polymorphisms (GWAS); mRNA expression profile/characterization; miRNA expression profile/characterization; long non-coding RNA expression profile/characterization; copy number aberrations; exon mutation sequencing; pure deletions and heterozygotes; translocations.
(5) Epigenetics of DNA: promoter methylation status
New advances on hepatocellular carcinoma (HCC)
1. Screening and diagnosis
Hepatocellular carcinoma is the leading cause of death in patients with cirrhosis, and long-term disease-free survival must depend on early detection and treatment of hepatocellular carcinoma. Because a high-risk population for liver cancer has been identified, all scientific societies recommend regular ultrasound screening for high-risk patients, which allows for early treatment if diagnosed.
However, this limits screening to patients with normal liver function (Child-Pugh classification A and B) and no serious comorbidities. If nodules reach 10 mm, the diagnostic process should be initiated. alpha-fetoprotein ( AFP) and other tumor markers do not have clinical value for screening. This leaves a need for novel biomarkers for early stage liver cancer to improve the effectiveness of current screening.
Even with specific immunostaining methods, biopsies have false negative results (up to 40% when hepatocellular carcinoma ≤ 2 cm). The development of diagnostic imaging criteria is crucial. The diagnosis of hepatocellular carcinoma can be made when nodules within 10 mm are observed either in MR or CT and the arterial phase of the nodule is enhanced and the venous phase is diminished.
Although this method has a strong specificity, it has limited sensitivity. Current research is focused on the development of novel imaging techniques or liver-specific enhancers. The clinical application of enhancers should consider not only their tissue separation but also their potential toxicity.
2. Choice of treatment and predictors of clinical outcome
Patients and their families want to know the approximate life expectancy. Predictors of survival time include tumor load, liver function and symptoms associated with cancer (e.g., performance status (PS), karyotype) and response to treatment. The Barcelona Clinical Liver Cancer Criteria (BCLC) is widely accepted and used in clinical practice and scientific studies (Figure 2). It stratifies prognosis and first-line treatment options. Patients with very early or early-stage hepatocellular carcinoma (BCLC A) without avascular invasion should be considered for surgical resection, transplantation or ablation.
Tumor size is not a limiting factor for surgery, and surgical resection is a good option if HCC is large in size but without metastases without associated complications.BCLC grade B patients include asymptomatic multifocal hepatocellular carcinoma without vascular invasion and/or extrahepatic spread and normal liver function, then the first line of treatment is chemoembolization (TACE) through the hepatic artery.
This therapy is best limited to patients with compensated cirrhosis, as patients with decompensated stages can become further aggravated after treatment.
Theoretically, BCLC stage B includes a heterogeneous group of diseases. However, it is important that BCLC criteria are applied to patients without significant liver impairment. While these patients must be considered for liver transplantation in the absence of severe comorbidities, the Child-Pugh classification is commonly used to assess liver function and life expectancy, but neither it nor the MELD score can make a comprehensive evaluation. In addition, spontaneous bacterial peritonitis, intractable ascites, hyponatremia, and encephalopathy episodes are all references that suggest end-stage cirrhosis.
Therefore, even if a patient meets Child-Pugh classification B, evaluation by a hepatologist may classify such patients as having end-stage cirrhosis (BCLC D), and any anticancer therapy may be ignored.
The degree of tumor load is equally heterogeneous. Patients with multifocal hepatocellular carcinoma found to have both spread to both lobes and cancer-related symptoms after careful clinical evaluation should be classified as BCLC C. This stage also includes extrahepatic spread and/or vascular infiltration. They will benefit from treatment with sorafenib.
Finally, patients with end-stage disease ( BCLC D) are the endpoint of clinical treatment. They have an extremely poor prognosis. These patients are contraindicated for liver transplantation.
Biomarkers such as AFP, vascular endothelial growth factor, angiopoietin 2 or c CKit can be used as prognostic stratifiers. An increase in AFP while awaiting transplantation is associated with disease progression and predicts a poorer prognosis in intermediate to advanced liver cancer. Therefore, research trials can use these parameters for stratification followed by randomized sampling.
Tissue biomarkers such as keratin 19 are predictors of more severe disease. The timing and type of disease progression affects survival after treatment and can be used as a predictor.
3. Treatment: current challenges and future perspectives
The goal of treatment for liver cancer is to improve survival and quality of life. Whether emerging technologies can improve survival as a recommendation for treatment needs to be supported by a large number of studies.
For those patients with advanced disease, the development of local therapies (ablation, post-embolization chemotherapy/radiotherapy) may induce tumor necrosis and improve survival and the efficacy of sorafenib.
The indications and applications of treatment should be refined so that if patients are not suitable for first-line therapy, then they can receive the next stage of the treatment regimen (treatment regimen migration concept). Treatment of non-cirrhotic liver cancer follows the same principles, but the efficacy and outcome are unpredictable.
4. Summary of key points.
(1) New concepts about hepatocellular carcinoma (HCC)
Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis.
For hepatocellular carcinoma, it varies not only from patient to patient, but also from tumor to tumor in the same patient without using the site.
The genetics of the tumor also varies due to various underlying liver diseases (nature of the microenvironment) and patient background. Therefore, there are no uniform genetic tools available.
In combination with clinical, pathological and gene expression data may help in the prognosis of liver cancer. However, it remains unknown how these data will influence patient treatment choices.
Since most liver cancers are transformed by cirrhosis, the guidelines recommend ultrasound screening for these high-risk patients. Diagnostic efforts should be initiated when nodules larger than 10 mm are detected,.
For outcome prediction, treatment planning and research, the Barcelona Classification of Clinical Liver Cancer (BCLC staging system) is recommended.
The technical feasibility of the treatment approach does not improve patient survival. Evaluation of the effectiveness of treatment should consider the difference in survival between treated and untreated. (Favorable principles)
The era of liver transplantation – surgical treatment of liver cancer
Traditionally, liver resection and liver transplantation (LT) are often considered as separate treatments. The so-called “surgical treatment” of hepatocellular carcinoma. However, this is a controversial definition and does not have a specific clinical name. The clinical outcomes of hepatectomy and liver transplantation are difficult to generalize, as no single surgical modality can be appropriate for all hepatocellular carcinomas. Individual intent is a key factor in the procedure performed.
Hepatectomy and liver transplantation has a 5-year survival rate of 60-80%. It can be the first option for patients with early stage liver cancer and normal liver function. There are 4 basic issues discussed here.
1. Decision-making for liver transplantation
In the United States and Europe, the supply of patients waiting for liver transplantation greatly exceeds the supply of livers. Less than one-third of patients on the transplant request list have received a liver transplant.
With the gradual increase in patients with liver cancer, the decision to give a liver to a patient with liver cancer or to a non-cancerous patient is difficult. After the implementation of the Milan criteria (MC), the proportion of patients receiving liver transplants with liver cancer was about 27% in Europe and worldwide, with a peak of over 40%. Therefore, enhanced waiting list management is required (Table 1 ). the MELD score can accurately predict short-term clinical outcomes in cirrhosis. Liver transplantation for the sickest patients allows a prioritization strategy.
Conversely, tumors exhibit some heterogeneity and variability in treatment response hinders accurate prediction of disease progression, transplant effectiveness and survival. The use of complex statistical models has been advocated, but controversy persists, with opponents claiming that no method can be universally applied. (Table 2 )
2. Liver transplantation criteria for hepatocellular carcinoma
Liver transplantation criteria for hepatocellular carcinoma vary from region to region. However, the Milan criteria (MC) are the benchmark for patient selection and serve as a baseline for other criteria (Table 3 ). Meta-analysis confirmed the survival advantage (HR 1.7) and low risk of MC (single hepatocellular carcinoma ≤ 5 cm or HCC ≤ 3 nodes and ≤ 3 cm, imaging staging without macrovascular invasion).
Nevertheless, MC is too conservative and the criteria need to be expanded. The University of San Francisco criteria (UCSF ) have been partially validated, but it has a significant overlap with MC. It was only expanded by ≈5%.
One study followed more than 1500 patients who underwent liver transplantation for tumors. It was found that patient prognosis determination may be individualized. The greater the tumor load, the shorter the expected survival after transplantation. Clinical outcomes after liver transplantation were associated with different combinations of tumor size and number. Therefore, there is a “maximum of 7” guideline for patients with liver cancer without microvascular invasion. This “maximum of 7” pathological recommendation has been partially confirmed. However, further confirmation in prospective trials is needed.
Patients on the transplant list have been lost to liver transplantation due to progression of liver cancer. Hepatectomy, ablation, transarterial embolization and radiotherapy can slow disease progression prior to liver transplantation. However, strong evidence is lacking.
While this risk of waiting can be addressed by a prioritization policy, disease progression (uncontrolled liver failure or death) in non-oncology patients is different from progression (i.e., tumor progression and ineffective treatment) in liver cancer patients. This calls for a relatively equitable selection criteria for organ transplantation.
Over-prioritization of patients with liver cancer can lead to increased tumor recurrence after transplantation. To better balance pre- and post-transplant expectations, transplantation criteria for patients with liver cancer and identification of high-risk patients are issues that need to be addressed urgently.
In this regard, AFP presents the ability to predict patient prognosis. In a large multicenter French study, the addition of AFP to a prognostic scoring model for long-term clinical outcomes greatly improved the predictive performance of MC. aFP can also be used as part of liver transplant selection criteria. aFP (especially > 400 ng/mL) combined with total tumor volume (TTV ) has good long-term prognostic predictive power (Table 3).
In general, patients with hepatocellular carcinoma with AFP > 200 ng/mL have poorer clinical outcomes.
Any future expansion of the criteria should maintain an overall 5-year survival rate of ≥ 50%. However, the increase in patients suitable for liver transplantation will elevate organ requirements and prolong waiting times. Clearly, liver transplantation can be the best option for patients with liver cancer if organ shortage is not considered.
3. Liver cancer downgrading before liver transplantation: a real benefit or just another elective tool?
”Downgrading” is defined as improvement of HCC disease prior to liver transplantation to meet the requirements for liver transplantation. The criterion for “acceptable” is that the life expectancy of a downgraded liver transplant is similar to that of an ungraded patient who is eligible for transplant. Such a complex definition reflects the benefits of downgrading and represents the principle of this treatment: to obtain a more favorable chance of tumor transplantation through treatment.
Hepatic artery embolization chemotherapy is the most appropriate treatment modality for downgrading, followed by radiofrequency ablation (RFA), and hepatic artery embolization radiotherapy with surgical resection. Most approaches use the Milan criteria as the endpoint event for downgrading and are maintained for at least 3-6 months. However, the current lack of reproducible, validated methods, baseline staging, and downgrade assessment prevents these methods from being used in guidelines.
4. Post-transplant follow-up and treatment
There are no clear recommendations on what kind of screening should be performed after liver transplantation to detect and treat recurrence of liver cancer in a timely manner. The prognosis of early recurrence of hepatocellular carcinoma after hepatectomy is worse than that of late stage. Moreover, the treatment of hepatocellular carcinoma needs to be individualized. Tumor seeding due to tumor puncture diagnosis or ablation can be successfully resected with a high rate of long-term disease-free survival.
Retrospective studies have shown that surgical resection of recurrent tumors is beneficial. Recent reports indicate that in patients with untreatable hepatocellular carcinoma after transplantation, sorafenib treatment has a positive efficacy relative to historical data. However, the specific effect of treatment is unknown.
5.Treatment methods for very early stage liver cancer
Liver transplantation and surgical resection are the most effective treatments for very early stage hepatocellular carcinoma. In the past decades, a variety of treatment measures with good results have emerged. Current studies have shown that patients with very early stage liver cancer (individual tumors <2 cm in size; stage T1) with compensated cirrhosis have good long-term outcomes with non-transplantation therapy. This leads to surgical treatment becoming less important. Very early stage tumors can remain dormant for a period of cycles and their multiplication time may exceed 10-20 months.
With this in mind, surgical resection and ablation can achieve good survival rates, with a 5-year survival of 60-70%. Although there are no large studies comparing the efficacy of resection and ablation for hepatocellular carcinoma. However, studies have shown no significant benefit of ablation for very early stage hepatocellular carcinoma, and the cost is enormous.
For small tumors, we cannot choose whether ablation, resection or liver transplantation should be used. The recurrence of hepatocellular carcinoma, the patient’s condition, the status of the tumor and the suitability of the treatment are all important. Some guidelines recommend ablation as a means of waiting for liver transplantation in patients with recurrent tumors.
While other guidelines recommend surgical resection as the first option. Pathological examination may reveal LT if there is microvascular infiltration, but large clinical trials are still needed for treatment options for very early stage liver cancer.
6. Key points.
(1) Liver transplantation therapy for patients with hepatocellular carcinoma
There is no single treatment method that may be suitable for all patients with hepatocellular liver cancer (HCC). The patient’s own characteristics are crucial to the choice of clinical treatment.
The MELD score is a good predictor of survival in end-stage cirrhosis, but HCC lacks good predictive models for various therapies and liver transplantation.
The current principle of organ allocation is based on maximizing outcomes after transplantation (the principle of utility). The beneficial principle helps to avoid useless transplantation of very early (less than 2 cm in size) and advanced tumors.
The Milan criterion remains the criterion for patient selection compared to other criteria. Some experts have proposed a modest expansion of this criterion (University of California or up-to-7 criteria), if the availability of organs allows.
Tumor downstaging is possible prior to liver transplantation. According to the traditional Milan criteria, if the tumor load is reduced, the 5-year survival rate is comparable to that of liver transplantation without downstaging.
Non-surgical treatments for liver cancer
1.Local treatment
The goal of local treatment is to induce tumor necrosis, which is the conventional oncologic criterion for assessing treatment efficacy. the RECIST criteria do not provide an exhaustive response to tumor load reduction compared to necrosis. The goal of ablation is to achieve complete remission on ultrasound, CT or MRI-enhanced sections. In contrast, complete efficacy is rarely achieved with TACE considering the presence of residual tumor tissue.
The accumulation of iodine oil degree (an oily enhancer used prior to conventional TACE injection of gelatin sponges in obstructed arteries) does not accurately reflect tumor necrosis. subsequent development of the EASL label and mRECIST takes into account the use of dynamic CT or MRI to assess the degree of tumor necrosis. The degree of tumor necrosis is related to the efficacy of ablation or TACE.
There is no debate that tumors can be completely necrotic after ablation, but quantifying local necrosis is quite challenging if multiple foci of tumor are present, which is more complicated if systemic therapy is performed. This is a point to be highlighted in the pre-treatment conversation.
2. Ablation
Radiofrequency ablation (RFA) is now the first-line technique for ablation. Ethanol injection has a lower local control effect but is still useful when the residual biopsies of the tumor are small or when the tumor is in an awkward location. Both techniques achieve the same effectiveness and survival rates when treating individual tumors ≤2 cm. At tumors <3 cm, the efficacy of ablation is comparable to that of surgery. < p="">
Therefore, both approaches may be considered as preferred options, but age/related comorbidities and tumor location must be taken into account. The failure rate of both approaches rises when the liver cancer is > 3 cm, or when multiple lesions are present. In such cases, surgical resection or chemoembolization combined with ablative therapy should be recommended. However, the current data do not support this phenomenon. The efficacy of the combination therapy remains to be proven.
The recurrence rate after ablation is similar to that after surgical resection, although surgical resection achieves better local control. Unfortunately, there are no effective ways to reduce the risk of recurrence. Antiviral therapy may delay the development of secondary hepatocellular carcinoma in patients with HBV.
3. Transarterial chemoembolization (TACE) and transarterial radioembolization (TARE)
Hepatocellular carcinoma is mainly supplied with nutrients by arterial vessels, and the tumor can be treated by selective injection of anti-cancer drugs. tACE combines selective arterial embolization with injection of chemotherapeutic drugs. Cumulative Meta-analysis has confirmed TACE as a first-line option for patients with BCLC grade B. Excluding those patients with decompensated cirrhosis, the choice of appropriate technique and the discontinuation of TACE therapy in the presence of liver failure and lack of therapeutic response have led to a median survival of more than 4 years.
When patients present with multifocal lesions or meet extended criteria for liver transplantation, physicians can use this number as a benchmark to discuss the benefits of surgery with patients. Patient tolerability is improved through the use of drug-eluting beads. These beads block the arterial blood vessels allowing the chemotherapy drug to be released slowly. This enhances the local drug concentration and reduces the side effects of systemic therapy.
Because arterial blockage induces the release of vascular growth factors, TACE should be combined with an anti-angiogenic drug such as sorafenib. Although this combination is safe, its efficacy in enhancing tumor response and/or delaying tumor progression has not been demonstrated. In fact, the sequence of sorafenib in combination with TACE therapy has not been determined.
TARE is different from TACE. Its action is not based on blocking the artery, but on local radiation via beta-rays emitted by yttrium glass or resin spheres. This therapy is well tolerated. Cohort studies in different populations have shown similar efficacy to the combination of TACE and sorafenib. Especially in patients with portal vein thrombosis (PVT). Ongoing clinical randomized controlled trials include TARE as a first-line treatment option versus sorafenib and as a second-line treatment option versus placebo.
4. Criteria for evaluation of systemic therapy and efficacy
Sorafenib is currently the only effective systemic agent, an oral multikinase inhibitor with anti-angiogenic and anti-proliferative effects that has been shown to improve patient survival. Two randomized controlled trials confirmed the safety of sorafenib and were able to significantly improve patient survival by 30 percent. The success of sorafenib has modified the principles of cancer treatment.
According to traditional RECIST criteria, cancer patients need a reduction in tumor load in order to improve patient survival. But sorafenib does not require it. It enhances the utility of tumorigenic time to progression (TTP) as a criterion for evaluating efficacy, questioning the interruption of treatment due to mere radiological progression. However, the cessation of tumor progression is limited and heterogeneous. There is an urgent need to identify biomarkers or develop functional imaging techniques to predict efficacy.
As mentioned above, mRECIST suggests that methods to assess tumor necrosis (if present) and TTP to estimate efficacy need to be validated by prospective trials. In fact, changes in imaging do not directly respond to changes in survival. tTP is informative, but it needs to be refined because not all tumor imaging progression leads to impaired survival.
In randomized controlled trials, the second-line treatment regimen brivanib versus placebo found significant improvements in TTP but not survival in patients. Progression-free survival (PFS) in clinical settings may also be misunderstood. In trials comparing sunitinib and sorafenib, PFS was similar for both, but survival was worse for sunitinib.
Both TTP and PFS are unreliable if tumor load is present, which requires us to develop new tools to determine the early efficacy of the drug. The data we currently use to predict post-intervention survival (from surgery to systemic therapy) are based on the period from trial initiation to specific treatment.
There are no tools available to evaluate the normal progression of disease in patients with hepatocellular carcinoma. Recurrence after surgery has an impact on survival, but it is not known what the exact impact is. This would require a lot of research.
To date, there are no treatment options or combinations that can outperform sorafenib. Phase 3 clinical trials currently underway are testing sunitinib, linifanib, brivanib, or a combination of sorafenib and erlotinib in second-line therapy. The combination of sorafenib and chemotherapy or novel approaches may enrich the treatment options. Patients with high C – met expression have good efficacy with tivantinib treatment.
Large phase 3 clinical trials are currently underway for its use in 2nd line therapy. Immunological approaches to cancer treatment are also a potential therapeutic tool.
5. Key points.
(1) Non-surgical treatment of hepatocellular carcinoma
Local therapy aims to induce tumor necrosis, but necrosis is not equivalent to a reduction in tumor load. tumor necrosis is considered by both EASL criteria and mRECIST criteria, which can guide the assessment of treatment response.
Ablation is comparable to surgery when the tumor is <3 cm in diameter. Depending on age, comorbidities and tumor location it can be the first line of treatment.
Transarterial embolization (TACE) is a first-line option for patients with intermediate hepatocellular carcinoma (Barcelona Clinical Liver Cancer (BCLC) grade B). Restricted patient selection and appropriate techniques allow for prolonged survival cycles. For those patients with multiple lesions, surgery may be preferable.
Local radiotherapy by Y90 microspheres yields similar survival rates to TACE and sorafenib, especially in the setting of portal vein thrombosis. Clinical randomized trials are ongoing.
Sorafenib is currently the only systemic chemotherapeutic agent that improves patient survival and has a strong safety profile. The effectiveness of sorafenib treatment demonstrates that survival of cancer patients can be increased without reducing tumor burden. The validity of time to disease progression (TTP) as a measure to evaluate treatment needs to be improved and validated.
Post-progression survival (PPS) is a relevant parameter for patients receiving sequential therapies. It is influenced by the pattern of progression as well as by the impairment of liver function and the presence of symptoms. All these parameters should be taken into account during trial design and analysis.
In conclusion, the diagnosis and treatment of HCC has now undergone significant changes. Hopefully, prevention programs that reduce the impact of risk factors, early diagnosis and more effective treatment will eventually lead to a significant reduction in liver cancer-related deaths and make liver cancer less of a king of cancers.