Hepatocellular carcinoma-the role of the underlying liver disease in clinical practice

Abstract

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related mortality. This particular type of cancer has the distinctive characteristic of mostly happening in individuals with an underlying liver disease. This makes the management of patients more challenging, since physicians must take into consideration two different conditions, the chronic liver disease and the tumor. The underlying liver disease has several implications in clinical practice, because different kinds of chronic liver disease can lead to varying degrees of risk of developing HCC, obstacles in surveillance, and differences in the efficacy of the treatment against HCC. A shift in the prevalence of liver diseases has been evident over the last few years, with viral hepatitis gradually losing the leading position as cause of HCC and metabolic dysfunction-associated steatotic liver disease gaining importance. Therefore, in an era of personalized medicine, it is imperative that physicians are aware of the underlying liver disease of individuals with HCC and its impact in the management of their tumors.

Key Words: Hepatocellular carcinoma, Etiology, Epidemiology, Surveillance, Therapy

Core Tip: Hepatocellular carcinoma (HCC) almost always develops in patients with chronic liver disease. The underlying liver disease has an important role in clinical practice, as it may have implications in the risk of developing HCC, as well as in surveillance, diagnosis and treatment of liver cancer. In an era of personalized medicine, it is imperative that physicians are aware of the underlying liver disease of individuals with HCC and that they plan the management of these patients accordingly.

INTRODUCTION

Liver cancer is the sixth most common malignancy worldwide and the second cause of cancer-related death, most of which correspond to hepatocellular carcinoma (HCC)[1-3]. HCC has the particular characteristic of developing almost exclusively in individuals with an underlying liver disease (particularly in those with cirrhosis), and the most common causes of liver disease associated with HCC are hepatis B virus (HBV) infection, hepatitis C virus (HCV) infection, alcohol-related liver disease and metabolic dysfunction-associated steatotic liver disease (MASLD)[4]. Therefore, every aspect of the management of HCC, from surveillance and diagnosis to treatment, should take into consideration not only the tumor itself, but also the underlying liver disease.

HBV and HCV infections are the most important causes of HCC globally[4-6]. Despite the availability of effective vaccines and treatments for HBV, as well as the development of highly-effective treatments for HCV, Bayesian models predict that their contribution as etiological factors for HCC will remain quite stable at least until 2030[7]. Among other mechanisms, including chronic inflammation, the continuous exposure of immune cells to viral antigens leads to a state of immune exhaustion, which contributes to hepatocarcinogenesis. In the case of HBV, there is also an oncogenic effect of the virus itself, which, by integrating its own DNA to that of the hepatocyte, confers a predisposition to gene modulation that, depending on insertion sites, can lead to early cancer. This helps explain why HCC develops in non-cirrhotic livers infected with HBV (including occult HBV), which rarely happens in HCV[5,8-10]. Together with vertical transmission and epigenetic factors, integration might also explain why HCC develops at earlier ages in patients with HBV, when compared to those with other underlying liver diseases[11,12]. Implementation of treatment for HBV and HCV are, therefore, of the utmost importance in order to reduce the risk of HCC, but it must be highlighted that treatment does not completely eliminate HCC risk, particularly in patients with advanced liver fibrosis[5,12,13].

Alcohol-associated cirrhosis is another important cause of HCC. According to a recent meta-analysis of 18 studies (148333 patients), the cumulative incidence of HCC in this population reaches 1%, 3% and 9% in 1, 5 and 10 years respectively. Moreover, that study suggested that diabetes, smoking, and advanced cirrhosis (as represented by variceal bleeding or hepatic decompensation) are associated with higher risks of hepatocarcinogenesis in these patients[14], which might help physicians to risk-stratify based on these risk factors during surveillance. In order to reduce the burden of alcohol-associated liver disease and consequently that of alcohol-related HCC, it is essential that public health policies are enforced and that an integrated management of alcohol-use disorder is offered to patients[15-18].

Among the main causes of HCC, MASLD is certainly that with the greatest increase in prevalence, as we were able to recently demonstrate, when comparing two South American cohorts a few years apart[19,20]. Almost one third of the global population is affected by MASLD[21], and this condition was responsible for 36300 new cases of HCC worldwide in 2019[4]. Although patients with MASLD-related cirrhosis seem to have a slightly lower risk of developing HCC (with an annual incidence of 0.5%-2.6%) when compared to patients with other causes of cirrhosis[22], mathematical models predict that the age-standardized incidence rate of MASLD-related HCC will increase from 0.92 to 1.18 per 100000 people between the years of 2018 and 2030[7]. Furthermore, similarly to what happens with HBV, MASLD may lead to HCC before the development of cirrhosis (approximately 38% of all MASLD-related HCC can occur in non-cirrhotic livers)[23], which makes surveillance in this population a greater challenge, even if the risk in individuals with cirrhosis is much higher[24]. While some genetic variants, especially the rs738409 variant of the patatin-like phospholipase domain containing protein 3 gene, might be associated with the development of MASLD-related HCC and could help explain its occurrence in patients without cirrhosis, the role of gene mutations still needs to be further understood and seem to vary across different ethnicities[22,25-27].

SURVEILLANCE AND DIAGNOSIS

The abovementioned role of the underlying liver disease in the development and risk of HCC impacts the efficacy and success of surveillance strategies. This is true, even in the setting of cirrhosis. Historically, individuals at risk for HCC have been categorized for surveillance as either having cirrhosis (from any cause) or HBV infection at certain age groups depending on their geographic area of origin[28]. Specifically, individuals from Asia and Africa are recommended to be screened at earlier ages. However, studies over the last decade have changed our understanding of HCC risk, with so far, little change on surveillance practice. MASLD has been shown to be an important risk factor for HCC even in the absence of cirrhosis, particularly in Hispanic populations living in the United States[29,30]. Interestingly, this does not seem to be the case in Latin America, where data from the European-South American Consortium to Assess Liver-Originated Neoplasia showed very few non-cirrhotic HCCs related to MASLD[19,20]. However, MASLD equally represents a major challenge of surveillance for HCC considering the extremely large size of the population affected by this condition. We now understand that those with diabetes and cardiovascular disease seem to be at increased risk within this cohort, but further tailoring of who should be screened and how often is still needed[31].

The continuous presence of inflammation, regardless of cause, also does play a role in HCC development, which can lead to a differential risk in individuals with cirrhosis related to alcohol and ongoing alcohol use compared to those with cirrhosis from HCV who successfully underwent viral treatment. Other factors that affect underlying liver disease such as infection with the human immunodeficiency virus or hepatitis D virus also play a major role in risk of HCC[32].

Moreover, even in the setting of HBV infection, the risk of HCC has been differentially reported, with studies from Asia placing the risk at 0.2 per 100 person-years, compared to Europe at 0.02 per 100 person-years, a 10-fold difference[12,33,34]. Africans and South Americans with HBV infection also express a higher risk of early age HCC occurrence[11,35]. While in the African continent this is thought to be due to aflatoxin exposure, it is unclear what leads to early HBV-associated HCC in Latin America. This led our group proposing the consideration of “immune-epidemiology” (the differential interaction between the virus and the immune system based on circumstances unique to each region and the risk of cancer) when assessing HCC surveillance in HBV[12]. There is, however, insufficient studies to further stratify surveillance in HBV depending on immune-epidemiology.

Underlying liver disease is also critical in the powerful interface of genetics and cancer, with specific inherited mutations increasing the risk of HCC when associated to specific liver diseases. Indeed, several studies have shown a direct association between a mutation in the membrane bound O-acetyltransferase domain containing 7 gene and HCC in individuals with MASLD, with little to no effect in HCC risk with other underlying conditions such as viral hepatitis[27,36,37]. Mutations in the signal transducer and activator of transcription gene have also been associated to HCC in Asian populations with a great majority of HBV-related HCC, while not showing any effect in populations with minimal contributions of HBV-related HCC[25,38]. Similarly, while the tolloid-like protein 1 rs17047200 variant has been associated with HCV-related HCC in Japan, that association was not confirmed in Latin American and European patients with different etiologies of HCC[26]. Therefore, in an era of personalized medicine, stratification of surveillance based on genetic markers also needs to take into account the underlying liver disease and the ethnicity or the geographical background of patients in their risk for cancer.

These issues highlight the complex interaction between the underlying liver disease, genetics and environment that all contribute uniquely to HCC development even in the setting of a major hepatocarcinogenesis contributor such as cirrhosis. Indeed, the diagnosis of cirrhosis, performed much earlier now in the elastography era has also shed light into a different risk of HCC (lower in some cases of specific liver diseases) than previously thought[39]. It is clear that surveillance practices that include the underlying liver disease, as well as ethnicity with genetic penetrance and geographic region will be needed to properly stratify patients at HCC risk in a cost-effective and patient-sensitive fashion.

TREATMENT

Despite the indisputable role of the underlying liver disease in hepatocarcinogenesis and in the management of patients with HCC, it might be challenging to pinpoint one cause of underlying liver disease in a particular patient, as many individuals have multiple risk factors for liver disease. For instance, the role of multiple risk factors in the development of liver disease has been recognized by the recent consensus that proposed changes to the nomenclature and definition of MASLD, when a new category was created, that of patients with MASLD and increased alcohol intake (MetALD)[40]. However, it is still important for physicians to be attentive to the factors that have led to underlying liver disease when planning the treatment of HCC, particularly when considering systemic therapies.

A variety of treatment options are now available for the treatment of HCC. Different treatment modalities must be integrated into an individualized overall concept as part of an interdisciplinary tumor board with representatives from hepatology, oncology, surgery (preferably with a focus on hepatobiliary surgery/transplantation), interventional radiology, nuclear medicine and radiotherapy. In addition to the tumor status (size, number, spread and vascular invasion), liver function, general performance status and co-morbidities must be included in the treatment decision for all patients with HCC. The concept of precision medicine has even led to the proposal of a novel algorithm for HCC treatment, based on a multiparametric and converse therapeutic hierarchy. The new model elicits a shift from currently accepted stage-centered therapeutic allocation systems to a patient-customized strategy that takes into consideration different parameters, among which the etiology of the underlying liver disease[41,42].

Systemic therapy is the preferred treatment modality in advanced stage and in intermediate stage when patients do not qualify for local therapies. Survival of patients treated with systemic agents has significantly improved over time and, with the approval of six treatment regimens by the European Medicines Agency (EMA) and eight regimens by the Food and Drug Administration (FDA), sequential therapy should be routinely considered for patients with advanced HCC.

For many years, tyrosine kinase inhibitors (TKIs), initially sorafenib (SOR) and more recently lenvatinib (LEN), were the only approved drugs for systemic treatment of HCC. Although no predictive biomarkers for response to SOR have ever been implemented in clinical practice, clinical factors such as a low neutrophil to lymphocyte ratio, disease limited to the liver and specifically chronic (untreated) hepatitis C infection favored a better response to the treatment with SOR in phase-III trials[43]. Of note, an individual patient data meta-analysis concluded that there was no evidence of any improvement in overall survival (OS) attributable to SOR for patients positive for HBV and negative for HCV[44]. On the other hand, in the pivotal trial of LEN, the majority of patients were recruited from Asia, with underlying HBV infection, preventing any firm conclusion from subgroup analysis in respect to the efficacy of LEN compared to SOR in other liver diseases[45]. Subsequent real-world studies observed a strikingly long survival in patients with MASLD-induced HCC treated with LEN. However, this needs to be confirmed in prospective studies[46,47].

The introduction of immunotherapy-based strategies marked the next breakthrough in the treatment of advanced HCC. Combinations of immune checkpoint inhibitors (ICI) with anti-vascular endothelial growth factor (VEGF) directed therapies significantly improved survival compared to SOR. First, the IMbrave150 study reported significantly longer OS with the combination of anti-programmed cell death ligand-1 (PD-L1) atezolizumab (AZ) plus anti-VEGF bevacizumab (BV) compared to SOR[48], and AZ/BV was subsequently endorsed as new standard of care in first-line advanced HCC by national and international guidelines[49,50]. In a personalized approach of patients with HBV-related HCC, initial data suggest that an alpha-fetoprotein decrease of more than 75% from baseline to the sixth week of treatment might be a good predictor of response to AZ/BV[51,52].

More recently, the combination of camrelizumab, a programmed cell death-1 (PD-1) inhibitor, and rivoceranib, a TKI with VEGF receptor 2 directed activity, also significantly improved survival compared to SOR, supporting the concept of ICI/VEGF targeted combinations in HCC[53]. In addition to ICI/VEGF combinations, antibodies against cytotoxic T-lymphocyte antigens (CTLA-4) have also been successfully evaluated in advanced HCC. The combination of nivolumab and ipilimumab has shown improved OS in HCC patients in the phase I/II CheckMate040 study[54,55]. The pure immuno-oncology combination achieved a high objective response rate with a promising OS of almost 23 months. Similar to ipilimumab, tremelimumab has also been studied as an anti-CTLA-4 antibody in HCC. Based on promising phase II data, the combination of durvalumab and tremelimumab (STRIDE) as well as a durvalumab monotherapy was compared with SOR as first-line therapy for advanced HCC in the HIMALAYA trial[56]. The study met its primary endpoints with a significant improvement in OS for the ICI combination therapy, and STRIDE has been approved by FDA and EMA and is now also endorsed by international guidelines[57,58].

For most patients, the combination therapy including a PD1/PD-L1 inhibitor will therefore represent the first-line treatment of choice. Hence, both AZ/BV and STRIDE may be considered[59,60]. Although AZ/BV was associated with more impressive results than STRIDE, cross-trial comparisons are unreliable due to distinct patient populations, and both regimens should be considered as effective first-line options. To date, no validated predictive markers have been identified for ICI therapy in HCC.

Based on pre-clinical data and a meta-analysis of three clinical trials, a potential negative predictive value of MASLD for ICI-efficacy in HCC patients was suggested[61]. The possibility that etiology was an important factor for response to ICI-based therapy was subsequently allegedly supported by the subgroup analysis of the IMbrave150 trial. In the non-viral subgroup, the hazard ratio (HR) for the combination was only 0.91, comparing unfavourably with the hepatitis B and C cohort. Of note, not only in IMbrave150, but also in the Checkmate-459 trial with nivolumab, the HR for OS was worse in patients with non-viral hepatitis compared with patients with viral hepatitis. However, what is also striking in the subgroup analysis of both trials is that the OS for the non-viral, SOR -treated patients was 18 months, which is considerably longer when compared to the viral hepatitis cohorts. Hence, the overperformance of the control group in the subgroup analysis of IMbrave150 and Checkmate-459 may explain, at least in part, the apparent lack of benefit of AZ/BV in non-viral patients. In addition, it should be noted that neither study distinguished patients with MASLD from those with alcohol-related liver disease. Our team has subsequently performed a meta-analysis of seven phase-III trials using a restricted maximum likelihood random effects model[62]. Our findings revealed a significant survival advantage across both non-viral and viral etiologies, with the largest estimated benefit for those with HBV. For the non-viral subgroup, the HIMALAYA trial reported the most significant benefit with ICIs, indicating the potential importance of CTLA-4 inhibition in this subpopulation.

CONCLUSION

The underlying liver disease plays an important role in hepatocarcinogenesis and, therefore, it has a substantial impact on the epidemiology of HCC. It also has practical implications regarding surveillance of HCC and its diagnosis. Nevertheless, despite very interesting (pre-) clinical observations, there is currently no sufficient evidence to conclude that the underlying liver disease has a clinically meaningful impact on the efficacy of systemic therapies in HCC. In this context, preclinical models will be helpful not only to understand the molecular mechanisms that may underlie differential efficacies, but also to develop hypothesis-based strategies to improve the efficacy of therapy in a specific subgroup such as patients with viral and non-viral liver diseases.