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Surgery
Hepatocellular carcinoma (HCC) is one of the major malignant diseases worldwide, characterized by growing incidence and high mortality rates despite apparent improvements in surveillance programs, diagnostic and treatment procedures, molecular therapies, and numerous research initiatives. Most HCCs occur in patients with liver cirrhosis, and the competing mortality risks from the tumor and the cirrhosis should be considered. Presently, previously identified risk factors, such as hepatitis virus infection, hepatic inflammation and fibrosis, and metabolic syndrome, may be used as chemoprevention targets. The application of precision medicine for HCC management challenges the one-size-fits-all concept; moreover, patients should no longer be treated entirely according to the histology of their tumor but based on molecular targets specific to their tumor biology. Next-generation sequencing emphasizes HCC molecular heterogeneity and aids our comprehension of possible vulnerabilities that can be exploited.
- hepatocellular carcinoma
- precision medicine
- Hepatitis B
1. Introduction
Hepatocellular carcinoma (HCC) is one of the major malignant diseases worldwide, characterized by unrestrainedly growing incidence, a low resectability rate, a high recurrence rate after curative-intent procedures, limited response to medical treatment, and, finally, a grave outcome. Today, more than 850,000 new cases are diagnosed annually, and it is expected that the burden of this disease might soon exceed an annual incidence of 1 million cases [1,2]. Moreover, HCC has one of the highest mortality rates among malignant tumors; the number of deaths recorded annually is close to the number of new cases diagnosed every year [3]. This proportion makes HCC an uncontrollable disease despite apparent improvements in surveillance programs, diagnostic and treatment procedures, molecular therapies, and numerous research initiatives. In the United States, the overall 5-year survival is less than 12%, making HCC the fastest rising cause of cancer-related deaths [4].
Disappointment with the results of HCC treatment is also reflected in the considerable differences between countries, which provide a disparate quality of healthcare regarding screening and surveillance programs, available treatment options, and reimbursement policies of state-funded health insurance.
Most HCCs occur in patients with underlying chronic liver disease and inflammation, i.e., liver cirrhosis. Therefore, clinicians should consider the competing mortality risks from the tumor and cirrhosis [5]. In western countries, chronic hepatitis C virus (HCV) infection; alcohol; and metabolic syndrome comprising obesity, diabetes, and nonalcoholic steatohepatitis (NASH) are all considered to be the leading risk factors [6]. In the eastern world, a background of chronic hepatitis B virus (HBV) infection is responsible for an increasing load of HCC cases [7,8].
In most centers worldwide, the treatment allocation is based on the modified Barcelona clinic liver cancer (BCLC) staging system endorsed by the European and American Association for the Study of the Liver [1,9]. The assessment of tumor burden, liver function, and general health status guides the selection of the best treatment modality for each patient with HCC [9]. However, no more than a third of HCC patients are candidates for curative-intent treatment options. For most patients, the diagnosis is established late, when limited treatment options are available, which results in poor treatment outcomes [9].
The application of precision medicine in HCC management challenges the one-size-fits-all concept; moreover, patients should no longer be treated entirely according to the histology of their tumor but based on molecular targets specific to their tumor biology [10,11]. Next-generation sequencing (NGS) emphasizes HCC molecular heterogeneity and aids our comprehension of possible vulnerabilities that can be exploited [12]. However, one of the major obstacles to implementing precision medicine for HCC patients is a reluctance to perform diagnostic biopsies [13]. One reason for this is that diagnostic imaging combined with α-fetoprotein is highly sensitive and specific for HCC. Another reason is the risk of tumor seeding via the biopsy tract [13,14]. Although biopsies offer limited histologic information that would impact clinical decision making, molecular information obtained by NGS may provide a critical breakthrough in the future treatment of HCC patients [12].
2. Hepatitis B
In the eastern world, chronic HBV infection is a dominant etiology, although HBV-associated HCC is declining [28]. Different from HCV infection, HBV DNA integration into the host genome causes direct cis/trans activation of oncogenic signals and carcinogenesis without requiring a fibrotic tissue microenvironment [29]. It was already reported that several predisposing factors, such as serum HBV DNA levels, certain HBV strains (e.g., genotype C in Asian and genotype F in Alaskan), and mutations in the HBV genome (e.g., precore and basal core promoter regions), are associated with increased HCC risk [29,30,31].
The established primary HCC prevention measure is a universal HBV vaccination reducing neonatal HBV vertical transmission [32,33]. The secondary prevention involves antiviral therapy. A meta-analysis of 2082 patients employing interferon-based regimens showed a reduction in the occurrence of cirrhosis and HCC development (RRs, 0.65 and 0.59, respectively) [34]. The use of nucleotide analogs (NAs) further reduced HCC incidence from 7.4% to 3.9% and from 13.3% to 1.1% in two trials on 651 and 2795 patients, respectively [35,36,37]. However, the impact of newer-generation, first-line NAs, entecavir and tenofovir, is ambiguous because studies from Asia reported an HCC risk reduction of 30% in cirrhotic and 80% in noncirrhotic patients, whereas evidence from the western world is still limited [38,39,40]. Regarding tertiary prevention (the use of antiviral therapy after the curative-intent liver resection or thermal ablation), a meta-analysis of 6350 patients reported lower recurrence-free survival (HR, 0.66) with the use of NAs [41]. The same finding is reported in another more recent trial with 200 patients (HR, 0.65) [42]. However, even if viral replication is attenuated by the NAs treatment, HCC risk is still present. It was confirmed that even if the HBV DNA level is consistently < 2000 IU/mL as a result of NAs treatment, the HCC incidence was significantly higher than the HCC incidence in inactive chronic hepatitis B patients, indicating that cancer risk is not completely eliminated by current antiviral therapies [43].
3. First-Line Therapy
3.1. Sorafenib
Sorafenib is an oral multi-TK-receptor inhibitor that suppresses angiogenic vascular endothelial growth factor receptors (VEGFRs), platelet-derived growth factor receptor-β (PDGFRβ), and drivers of cell proliferation (RAF1, BRAF, and KIT) [134].
After the survival benefit for advanced HCC patients was demonstrated in the Phase 2 trial, a large, double-blind, placebo-controlled Phase 3 study was conducted to confirm prolonged survival after sorafenib [133,135]. This trial demonstrated a 31% decrease in relative risk of death (HR 0.69, 95% CI 0.55–0.87; p < 0.001) in the sorafenib group compared to that of the placebo group. The median survival was prolonged from 7.9 months in the placebo group to 10.7 months in the sorafenib group. Another Phase 3 study investigated survival outcomes in Asian patients with predominantly HBV-related HCC [136]. The study confirmed a similar benefit concerning the overall survival. However, the adverse events (AEs) rate was 15% in the sorafenib group and 7% in the placebo group.
Sorafenib is documented as a well-tolerated therapy. The most commonly observed drug-related AEs are diarrhea, hand–foot skin reaction, fatigue, and hypertension [133]. The safety and efficacy of sorafenib provided the frame for further clinical research involving patients at earlier HCC stages. In the randomized Phase 3 trial, the time to progression of patients with unresectable HCC managed by a combination of sorafenib and TACE was not prolonged [137]. Similarly, in the adjuvant settings after surgical resection or local ablation, sorafenib did not improve recurrence-free survival [138]. Phase 3 SARAH72 and SIRveNIB73 were designed to compare the survival of patients with advanced HCC between sorafenib and internal radiation with 90Y microspheres [139,140]. The studies showed similar overall survival between the treatment arms, although both studies demonstrated better response rate and quality of life in the radioembolization group.
Indications for sorafenib administration are preserved liver function (Child–Pugh class A) and advanced BCLC stage. Sorafenib is also indicated for HCC patients at the intermediary BCLC stage after disease progression following TACE treatment or in cases where TACE is not technically feasible. Sorafenib treatment should be interrupted if imaging studies confirm the signs of disease progression. Second-line therapy is then recommended.
3.2. Lenvatinib
Lenvatinib was introduced by the Tsukuba Research Laboratory in Japan as an angiogenesis-inhibitor [141]. Levantinib is a multi-TK-receptor inhibitor targeting VEGFR, fibroblast growth factor receptors (FGFR), PDGRα, KIT, and RET [2]. The drug was tested in Phase 2 and Phase 3 trials for the treatment of advanced HCC [142,143].
An open-label, Phase 3, multicenter, noninferiority trial was designed primarily to evaluate overall survival after lenvatinib and sorafenib therapy in advanced HCC, and it showed that the median survival for lenvatinib (13.6 months) was noninferior to sorafenib (12.3 months) [143]. In addition, lenvatinib demonstrated higher objective and tumor response rates than sorafenib. In the subgroup analysis of HBV-related HCC, lenvatinib prolonged overall survival for 5 months compared to that of sorafenib, and the objective response rate was also increased. In 2018, lenvatinib was approved as a first-line therapy for advanced HCC by the US FDA based on the previously mentioned results. Lenvatinib and sorafenib were not compared so far regarding cost-effectiveness, and there are no proposed biomarkers to predict drug responses.
The most common registered AEs during lenvatinib administration are hypertension, diarrhea, and loss of appetite with decreased weight [142,143].
Lenvatinib is indicated as an alternative drug to sorafenib in the first-line treatment of advanced-stage HCC (except in cases where more than half of the liver is affected by tumor) or in patients at intermediate HCC stage progressing after
4. Atezolizumab plus Bevacizumab
Atezolizumab is a programmed death 1 (PD-1) inhibitor that selectively targets PD-L1 hindering interaction with receptors PD-1 and B7-1 [144]. Bevacizumab is a monoclonal antibody that targets VEGF, leading to inhibition of angiogenesis and tumor growth [145,146].
Although PD-1 inhibitors demonstrated promising clinical results for HCC in Phase 1/2 studies with the response rates ranging from 15% to 20%, improved overall survival was not found in Phase 3 studies [147,148,149,150].
The rationale for the combination of VEGF and PD-1 inhibitors in HCC is related to the effect of impaired VEGF-mediated immunosuppression within the tumor and its microenvironment by VEGF inhibitors, leading to enhanced anti-PD-1 efficacy [151,152]. Moreover, anti-VEGF therapy promotes T-cell infiltration in tumors [153,154].
The clinical benefit of the combination of VEGF and PD-1 inhibitors in HCC was confirmed by the Phase 3, randomized trial IMbrave150 comparing atezolizumab plus bevacizumab over sorafenib [155]. The study enrolled patients with an ECOG 0 or 1 and good liver function (CP class A) [156]. The presence of autoimmune disease and untreated esophageal varices were critical exclusion criteria [155]. Atezolizumab plus bevacizumab was superior to sorafenib regarding mPFS (6.8 vs. 4.3 months, HR: 0.59, p < 0.001) and overall survival at 12 months, 67.2% (95% CI, 61.3 to 73.1) vs. 54.6% (95% CI, 45.2 to 64.0) [156]. Regarding safety, 15% of patients had to stop the combination therapy for AEs vs. 10% of patients who were on sorafenib treatment [156]. Upper gastrointestinal bleeding occurred in 6.4% of patients treated by combination therapy [156]. Based on these promising results, NCCN Guidelines Version 5.2020 Hepatocellular Carcinoma recommended atezolizumab plus bevacizumab for the first-line treatment of advanced HCC [156].
5. Donafenib
Donafenib is a derivative of sorafenib, and it has the same features as sorafenib: it is an oral, multikinase inhibitor of VEGFR, PDGFRβ, and RAF1 kinases [157].
The clinical benefit of this novel drug was confirmed by a head-to-head, Phase 2–3 study that evaluated the efficacy and safety of first-line donafenib compared with that of sorafenib in 668 Chinese patients with advanced HCC [157]. The primary end point was OS. The study showed that donafenib significantly prolonged OS, 12.1 vs. 10.3 months, respectively (HR, 95% confidence interval, 0.699–0.988; 0.83; p = 0.0245) [157]. Moreover, donafenib demonstrated an improved safety and tolerability that, according to the authors, contributed to improved patient adherence. Grade 3 or 4 AEs and common side-effects, such as hand-foot syndrome and diarrhea, occurred less frequently in patients receiving donafenib compared to that of patients on sorafenib (38% vs. 50%; p = 0.0018) [157].
From June 2021, donafenib was approved in China to treat unresectable HCC patients who did not receive systemic treatment. However, it is not yet available in the United States.
6. Second-Line Therapy
Second-line therapy is intended for advanced HCC patients who experience disease progression after first-line therapy or in cases of drug intolerance.
7. Regorafenib
Regorafenib is a multikinase inhibitor with an ultrastructure similar to sorafenib, and it expresses a stronger affinity toward VEGFR [158]. Results from the Phase 3 RESORCE trial indicated better overall survival after regorafenib compared to that of placebo (10.6 vs. 7.8 months) in HCC patients who tolerated and progressed on sorafenib [159]. Moreover, regorafenib was associated with improved objective response rate and progression-free survival. Drug-related AEs were hand-foot skin reactions, diarrhea, and hypertension. Subsequent cost-effectiveness analysis suggested that regorafenib is not cost-effective because of the modest incremental benefit in contrast to high incremental cost [160]. Despite these observations, the FDA and the European Medical Agency approved regorafenib in second-line therapy for patients progressing on sorafenib.
8. Cabozantinib
Cabozantinib is a multitargeted TK inhibitor with a specific affinity to the hepatic growth factor receptor MET responsible for HCC carcinogenesis and sorafenib resistance [161]. The randomized Phase 3 trial compared cabozantinib with placebo in previously treated patients with advanced HCC [162]. Treatment with cabozantinib improved OS (8 to 10.2 months) and progression-free survival (1.9 to 5.2 months) compared to that of placebo. High-grade AE (Grade 3 or 4) occurred in 68% of patients in the cabozantinib group and in 36% of the placebo group. During the study, the most common events were palmar-plantar erythrodysesthesia, hypertension, increased aspartate aminotransferase levels, fatigue, and diarrhea. These AEs can be successfully managed by the adopted strategy of supportive care and dose modifications [163]. The comparative cost-effectiveness studies from Germany and the United States found that cabozantinib is not cost-effective compared to that of the best supportive care [164]. Furthermore, cabozantinib was not shown to be cost-effective in almost all scenarios using sensitivity analyses.
9. Ramucirumab
Ramucirumab is an anti-VEGFR2 monoclonal antibody that prevents the specific binding between VEGF and VEGFR2 to inhibit angiogenesis [129]. Antitumor activity against advanced HCC was demonstrated for the first time in a Phase 2 pilot study, and mild to moderate AEs were manageable and acceptable [165]. Encouraged by the results of the mentioned study, ramucirumab was tested as second-line therapy in the Phase 3 REACH trial that included advanced-stage HCC patients previously treated by sorafenib [166]. The primary endpoint was negative. Therefore, second-line treatment with ramucirumab did not significantly improve survival over placebo. A subgroup analysis of patients with AFP levels ≥400 ng/mL had a significantly better median overall survival with ramucirumab (7.8 months) than placebo (4.2 months). Thereafter, the randomized Phase 3 trial (REACH-2) demonstrated improved overall survival for ramucirumab compared to that of placebo in patients with HCC and α-fetoprotein concentrations of more than 400 ng/mL who previously received sorafenib [167]. In the Japanese REACH-2 subpopulation, ramucirumab improved progression-free survival and overall survival [168]. The REACH-2 trial indicated that ramucirumab is the first effective agent in the subpopulation of HCC patients selected by biomarker level.
Phase 3 trials confirmed the safety of ramucirumab. Ramucirumab is a well-tolerated drug in the study population. The safety profile of ramucirumab was manageable, including grade 3 or more AEs—hypertension, hyponatremia, and increased aspartate aminotransferase.
16. Immune Checkpoint Inhibitors
HCC is one of the inflammation-related carcinomas arising from a microenvironment infiltrated by T cells, natural killer cells, and myeloid cells. Complex interactions between immune cells and tumor cells determine the natural tumor behavior and response to therapy [169]. High immune infiltration, including T-cells (mainly CD8+) and low levels of macrophages, is associated with improved overall survival [170]. Contrarily, immune-suppressive T-cells, dysfunctional NK cells, tumor-associated macrophages, and myeloid-derived suppressor cells are more accumulated in HCC with poor prognosis. Immune checkpoint molecules, including cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death (PD-1), and its two known ligands, PD-L1 and PD-L2, are dominantly expressed on T cells. It is assumed that these molecules have an implication in HCC immune exhaustion [171]. Moreover, the underlying mechanism of immune checkpoint inhibitors is a blockade of negative feedback pathways of the immune system that mediate immunosuppression. The clinical implication of novel therapeutical targets is under investigation. Currently, available drugs are monoclonal antibodies to CTLA-4 (ipilimumab and tremelimumab), monoclonal antibodies to PD-1 (nivolumab, camrelizumab, and pembrolizumab), or PD- L1 (atezolizumab, avelumab, and duravalumab).
10. Pembrolizumab
The clinical efficacy of pembrolizumab was evaluated in the Phase 2 KEYNOTE-224 study, which enrolled 104 eligible patients (chronic HBV and HCV with Child–Pugh A liver function and HCC BCLC B or C stage) with confirmed disease progression after or intolerance to sorafenib [147]. The study reported an ORR of 17%; DCR was 62%, and the median DOR was not reached. However, pembrolizumab was a safe and well-tolerated drug with certain antitumor activity. Based on study results, in November 2018, pembrolizumab was granted FDA approval for advanced HCC patients with prior sorafenib treatment. The following Phase 3 KEYNOTE-240 trial was carried out, but the study did not meet its primary endpoint, and the pembrolizumab was not superior to placebo in terms of OS (13.9 vs. 10.6 months, HR = 0.78; p = 0.02) and PFS (3 vs. 2.8 months; HR = 0.77; p = 0.01) [149]. However, the results were consistent with those of KEYNOTE-224: the ORR was 18.3%, and DCR was 62,2%, while median OS was longer in the pembrolizumab arm compared to that of placebo, supporting a favorable risk-to-benefit ratio for pembrolizumab. No hepatitis B or C flares were identified [149]. In 2021, the FDA approved pembrolizumab for HCC patients not eligible for bevacizumab (front-line allocation to atezolizumab plus bevacizumab). In the meantime, the results from the ongoing Phase 3 KEYNOTE-394 trial in Asian patients are awaited.
This entry is adapted from the peer-reviewed paper 10.3390/jpm12020149
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