The burden of liver cancer is increasing worldwide (1). World Health Organization estimates that more than 1 million people will die from liver cancer in 2030 (2). The observed variation in racial and geographic distribution of HCC is mainly related to specific risk factors. For example, Asia and Africa have high prevalence due to hepatitis C virus (HCV) and hepatitis B virus (HBV) infection; while the incidence in the US and Western Europe has increased during past decade with Hepatitis C reaching maturity and non-alcoholic fatty liver rising as distinctive risk factor. As major predisposing conditions for HCC are well identified, high-risk groups can be followed with screening.
Hepatocellular carcinoma HCC is unique because its prognosis depends on both stage of the tumor and severity of the underlying liver disease. Curative options like liver transplantation (LT) and surgical resection are available only in early stages (3,4). However recently there is significant advances in available locoregional treatments and systemic therapies for advanced HCC.
Hepatocellular carcinoma worldwide (Figure 1)
The high mortality ratio of liver cancer made it fourth leading cause of cancer death globally. A total of 841,000 (4.7%) new HCCs are estimated to have occurred in 2018 in addition to 782,000 (8.2%) HCC related deaths (5). The overall incidence of HCC is heterogeneous probably due to variation in prevalence of hepatitis virus and environmental factors. Approximately 80% of HCC cases occur in sub-Saharan Africa and Eastern Asia following the similar high prevalence pattern of chronic hepatitis B virus carriers in these regions. Thailand, Indonesia, Jamaica, Haiti, New Zealand, and Alaska fall under Intermediate-incidence areas; whereas Japan, North and South America, most of Europe, Australia, and Middle East are reported to be low-incidence regions (less than 3 cases reported per 100,000 populations per year) for HCC where hepatitis C is the major risk factor (6). Incidence in Japan has dropped drastically with significant reduction in their HCV population. Similarly, HCC incidence in China is on decline owing to increasing vaccination against hepatitis B (7). In all the parts of world, HCC occurs two to three times more often in males than in females with more disparity in high incidence regions.
In United states, incidence of HCC has tripled over the last four decades, possible from maturity of chronic hepatitis C patient pool. Burden of HCC is expected to reach 22 million cases in the next two decades (8). Interestingly, rising prevalence of obesity and associated fatty liver disease are believed now for this predicted increase in HCC patients (9). Population-based studies in the US have shown distribution of HCC differs amongst various racial and ethnic groups like Asians/Pacific Islanders (APIs) have higher rates of HCC compared with other Caucasians and Hispanics (10). In United States, reported average five-year survival for HCC is 14% and it is likely to be poorer in developing countries (11).
Addressing the risk factors
Hepatitis B virus infection is still the predominant risk factor for HCC, mainly in Asian countries, where more than half of the world’s HCC population live (12). Apart from causing cirrhosis, Hepatitis B virus itself plays critical role in development of HCC (13). In vitro studies have shown that Hepatitis B virus can cause activation of oncogenes while integrating into host DNA (14). Chronic hepatitis B carriers without evidence of cirrhosis also can develop liver cancer (15). Incidence of HCC in patients with chronic HBV in East Asia is reported to be 0.2 per 100 person-years in chronic HBV carriers, and 3.7 per 100 person-years for those with compensated cirrhosis (16,17). Multiple host factors like male gender, older age, family history of HCC, use of alcohol or tobacco and virus-related factors like HBV genotype C, pre-core HBV mutations and coinfection with HCV, HDV or HIV increase the risk of HBV related HCC (18,19).
Most important risk factor related to HCC development is HBV viral load and maintaining undetectable circulating HBV virus with oral antivirals has shown to reduce the incidence of development of HCC (20). Another strategy to reduce HBV related HCC incidence is vaccination against HBV infection (21). The best example of this is Taiwan where 30 years after the initiation of universal newborn vaccination, HBV carrier rates have fallen from 10–17% to 0.7–1.7% and rates of HCC have fallen by 80% (22,23). Still, there is a need to eradicate HBV infection and new research targeting the cell receptor, cccDNA of HBV etc., appears promising (24,25).
Most of the HCC in developed countries is related to chronic HCV. HCV increases the risk of developing HCC almost 17-fold. Cirrhosis is the major risk factor for HCC development. This risk is further increased in combination with alcohol abuse, coinfection with HBV, diabetes mellitus, older age, African American race and smoking. HCV infection remains asymptomatic most of the life, early detection by screening followed by treatment is crucial to reduce the incidence of HCV associated cirrhosis and subsequent risk of development of liver cancers.
Current CDC guidelines for screening in the general population include recommendation for individuals in the baby boomer birth cohort with highest HCV prevalence (people born between 1945 and 1965) and those at high risk of acquisition of HCV (history of intravenous drug use, blood transfusion or solid organ transplantation before 1992 and clotting factors before 1987, chronic hemodialysis, health care workers and children born of HCV-positive mothers) (26,27). Risk-based HCV screening is reported to be inadequate and there is always need for better HCV screening strategies. Fortunately, development of all oral, highly effective, Directly Antiviral Agents (DAA) therapy against HCV has revolutionized the management of chronic HCV infection with 95–98% success rate (28). Treatment of all patients with HCV is recommended, because progression to cirrhosis is associated with substantial risk of HCC development and/or costs for lifelong HCC surveillance (29). Also, recent study by Singal et al. have shown that treatment with DAAs is associated with increased survival amongst HCV related HCC population (30).
Nonalcoholic fatty liver disease (NAFLD)
NAFLD is hepatic manifestoing of the metabolic syndrome —obesity, dyslipidemia and diabetes mellitus type 2. NASH (non-alcoholic steatohepatitis) is more aggressive form of NAFLD with inflammation which can progress to cirrhosis with subsequent development of HCC (31) Global prevalence of NAFLD is reported around 25%, with the highest rates in South America (31%) and the Middle East (32%), followed by Asia (27%), the United States (24%), and Europe (23%) with lowest in Africa (32). Further, NASH is now becoming one of the most common etiologies for chronic liver disease worldwide (33). Risk of developing HCC from NASH-cirrhosis can range from 2.4% to 12.8% (34). Data of diabetes and HCC have shown relative risks of 2.0–2.5 independent of other risk factors (35-37). Similarly, a meta-analysis of metabolic syndrome and HCC reported a significant relative risk of 1.81 (38,39).
Possible strategies to prevent HCC development in patients with NAFLD/NASH concentrate on lifestyle changes to prevent progression of liver fibrosis (31). Potential newer therapies for NASH are still in clinical trials with inconsistent results and we are still waiting for successful medications for NASH (40). At present, only diet and weight have shown best outcomes with improvement of liver enzymes and fibrosis (41,42). Other medications hypothesize to reduce the risk of NASH related HCC are metformin and statins (43,44). However, their antineoplastic effects still need more clinical evidence. Given the increasing prevalence NASH associated HCC; efforts should continue to better understand the implications and risks of NAFLD-NASH for HCC.
Evidence suggests that certain occupational and environmental factors also play role in development of HCC. Among those are exposure to aflatoxin, contamination of ground water by industrial waste like inorganic arsenic, workplace exposure to polycyclic aromatic hydrocarbons. Aflatoxin is predominantly produced by fungi which can contaminate food or water. Aflatoxin B1 is the most potent liver carcinogen (45). There is definite interaction between Aflatoxin B1 and HBV on HCC risk (46). The fraction of HCC cases attributable to aflatoxin exposure has been estimated to be 4.6–28.2% (47). Porru et al. showed increased risk of HCC amongst workers chronically exposed to organic solvents like toluene and xylene (48). In epidemiological studies, groundwater contamination with inorganic arsenic has been reported with increased risk of HCC (49).
As we learn more about theses environmental and occupational hazards, there will be additional opportunities to intervene and prevent HCC worldwide.
It is well established alcohol intake with resulting cirrhosis has causal relationship with development of HCC (50). HBV and HCV, in conjunction with alcohol, have synergistic effects on HCC risk (51-53). A metanalysis of alcohol and liver cancer estimated a 16% increased risk of liver cancer among consumers of 3 or more drinks per day and 22% increased risk among consumers of 6 more drinks per day (54). High alcohol consumption is thought to be contributing to the highest HCC prevalence in Mongolia (55).
Several epidemiological studies have revealed correlation between smoking and HCC. A meta-analysis on HCC and cigarette smoking, demonstrated the relative risk to be 1.51 for current smokers and 1.12 for former smokers (56).
This highlights impact of lifestyle factors on HCC prevalence.
American Association of the Study of Liver Diseases (AASLD) recommends enrollment in HCC surveillance program for all patients with cirrhosis regardless of etiology and high-risk chronic HBV carriers with ultrasound (US) with or without alpha-fetoprotein (AFP). High risk hepatitis B carriers are patients even without cirrhosis if they are Africans older than 20 years of age, Asians older than 40 years of age, or if they have a family history of HCC. US have the advantage of being noninvasive and inexpensive, but is operator dependent. Systemic reviews demonstrate US alone has sensitivity for HCC from 30–70% (57,58). Zhang et al. in their landmark randomized control study in chinses hepatitis B population (n=18,816) reported 30% reduction in mortality with abdominal US and alpha-fetoprotein (AFP) every 6 months as screening strategy (59). Other observation studies support this surveillance strategy, showing a survival benefit (60,61). At present, the concern is adherence to such surveillance program as data from Surveillance, Epidemiology, and End Results registry shows that less than 20% of patients who developed HCC had received regular surveillance (62).
AFP alone should not be used as screening test due to low sensitivity (63,64). However, complete exclusion of AFP as cost effective screening tool is controversial and European Association for the Study of the Liver (EASL) and AASLD did recommend the use of US with AFP for surveillance (65,66).
The diagnostic tests most commonly used for diagnosis of HCC are quadruple phase multidetector CT scan and dynamic contrast-enhanced MRI. On CT and MRI, typical HCC lesion shows intense arterial uptake followed by loss on enhancement or “washout” with demonstration of capsule during portal vein and/or equilibrium phase imaging (67,68). Generally, AFP levels greater than 500 u/L in high risk patient suggest HCC but negative values do not rule out HCC. Other biomarkers like AFP-L3% (ratio of AFP-L3 to total AFP) and Des-gamma-carboxy prothrombin (DCP-abnormal form of prothrombin) have shown some promise but data is not sufficient for their routine use in diagnosis of HCC (69,70).
For HCC >1 cm. if the single imaging characteristics are not typical, then a second sequential contrast enhanced imaging study is recommended. If both the imaging modalities are non-diagnostic then only biopsy is required. Sub-centimeter liver nodules being less likely malignant; needs follow up with imaging at interval of 3 to 6 months. Biopsy has its own falsies like high false negative rate, risk of bleeding and implantation metastasis (71). It is recommended to have expert pathology review and use of special immune-stains (glypican 3, heat shock protein 70, glutamine synthetase 91) on biopsies (72). AASLD guidelines recommend step wise approach for liver lesion with dynamic imaging to decreases the number of potential biopsies.
Management (Figure 2)
Hepatocellular carcinoma is lethal as most patients present with advanced disease with median survival around one year (73). In the past few years, advancement in locoregional treatments and emerging molecular targeted therapies, have improved short-term survival but resection and liver transplant are still the cornerstone of curative options for HCC (74). Selection of particular therapy depends on tumor size/location, underlying liver dysfunction, performance status, local expertise and availability. Multidisciplinary team evaluation, consisting of hepatologists, surgeons, intervention radiologist, oncologists and pathologists are recommended for the best decision planning of HCC.
A number of staging systems are available for use in HCC, but the Barcelona Clinic Liver Cancer classification is the most widely preferred staging system. It is the only one that considers liver function, stage of tumor, and performance status of patients with HCC (75,76).
Carefully selected patients do benefit from surgical resection. The ideal candidate for resection is patient with single tumor confined to the liver without any vascular invasion and preserved liver function (Child’s score A without significant portal hypertension), but this clinical situation is present is less than 5% (77). Present data shows that post-resection 5-year survival rate in selected candidate is as high as 70% (78). So far, reported perioperative mortality is approximately 2% (79,80). Most of these patients are at risk of post resection hepatic decompensation. Another concern is post resection tumor recurrence. There is no role of repeat resection for such tumor recurrences and only options left are salvage liver transplant or controlled by locoregional therapy or systemic chemotherapy (78).
For HCC, not resectable due to underlying liver dysfunction, liver transplant (LT) remains the best option as it also cures underlying liver disease. Studies have shown that HCC, confined to liver with size within the Milan criteria (one lesion less than 5 cm, or up to 3 lesions with each 3 cm or smaller), has post-transplant 5-yr survival rate >70% and a tumor recurrence rate <15% (81-83).
In United States, UNOS (United Network for Organ Sharing) uses the MELD (Model for End-stage Liver Disease) score for prioritizing LT for patients with decompensated cirrhosis. Though MELD score is good predictor of mortality in cirrhosis, this score fails to predict mortality in the patient with HCC as underlying liver disease may not have decompensated (84). Hence, candidates with HCC within Milan criteria and AFP <1,000 ng/mL, receive “MELD exception” score of 28 after staying on transplant waitlist for 6 months to facilitate early transplant. A significant drawback of LT for HCC is the long waiting time to get donor organ and hence various locoregional therapies like radiofrequency ablation (RFA), Trans arterial chemoembolization (TACE) or combinations are used to control the size of HCC and as bridge to transplant (85-88). UNOS has recently updated its transplant listing criteria for HCC beyond Milan criteria (89). Living donor liver transplant (LDLT) is also an option in high-volume well-equipped centers (90). Apart from tumor size and number, there is need for molecular markers of HCC to define tumor biology which can help in future liver transplant decision making (91).
In last decade, use of several forms of locoregional therapies like RFA, cryoablation, TACE, etc. have increased role in management of HCC. Locoregional therapies have shown success in patients with very early stage HCC or downsizing size of tumor burden before resection or transplant.
Radiofrequency ablation is most effective treatment to treat early stage HCC. In RFA, single or multiple needle electrodes are used to deliver electromagnetic waves to tumor causing thermal necrosis. RFA effect is size dependent. Studies show that RFA can achieve complete necrosis in 90% cases for HCC size 2 cm or smaller with local recurrence < 1% and 5 yr. survival ranging from 40–70% (92). Feng et al. in their study did not find any significant difference in survival between RFA and resection for single HCC up to 4 cm in diameter (93). However, recent meta-analysis of retrospective studies by Li et al. showed resection still has better long-term survival compared to RFA (94). However, there is no consensus as to whether RFA can replace surgical resection as first-line treatment for small tumors.
RFA is preferred for small HCC located away from major vessels and diaphragm to avoid potential damage to adjacent tissues and loss of efficacy due to large blood vessels causing the heat-sink phenomena. Further, RFA can be associated with pain, bleeding, hepatic abscess, hepatic decompensation and in such situations percutaneous ethanol injection (PEI) was used PEI was popular in past due to less adverse events and being cost effective. But PEI has major drawback of high local recurrence rate requiring multiple sessions. Three independent meta-analyses have shown that RFA achieves better local control and increased survival benefits in patients with small HCC compared to PEI (95-97). As a result, RFA has progressively replaced PEI as the preferred locoregional therapy over years. Recently major technical advances in RFA like cooled tip probe or expanded tip probe has promising outcome to become effective alternative to surgery in future (98).
Microwave ablation and electroporation
Microwave ablation is one more technique of local ablation, in which an implanted electrode induces an ultra-high speed alternating electric field into the tumor tissue (99). Irreversible electroporation is another technique in which delivered electrical pulses at microseconds rate causes tumor necrosis through irreversible cell membrane damage (100). The major advantages of these ablation techniques are safety to adjacent vasculature and surrounding structure (100).
Cryoablation is a technique in which cryoprobe is used to apply alternating freeze-thaw cycles into the tumor directly. It has been most frequently applied in patients who are determined to have unresectable HCC intraoperatively. It may be preferred over RFA in peripheral lesion or when there is a high likelihood of collateral thermal damage.
TACE involves administration of chemotherapeutic and embolizing agents through hepatic artery selectively into the artery supplying the tumor to cause tumor necrosis. Most suitable patients are those with compensated underlying cirrhosis (bilirubin <2) without any vascular involvement or extrahepatic tumor spread. Studies comparing TACE with standard supportive care has reported significant survival benefit with TACE (101-103). In patients with Child–Pugh B or C class cirrhosis or HCC with portal vein thrombosis, TACE is contraindicated.
Currently, there are no consensus regarding number of sessions and treatment schedule (on demand with response or scheduled), choice of anticancer agents (e.g., mitomycin, cisplatin, and doxorubicin alone or in combination), embolizing agent (e.g., gelatin sponge particles or polyvinyl alcohol particles) or bland embolization (104,105). Reported side effects of TACE are intrahepatic biloma, acute hepatic failure, liver infarction, abscess formation, chemotherapy-related systemic toxicities and post embolization syndrome (106).
Doxorubicin-loaded drug eluting beads (DEB-TACE) is a new technique to increase predictable delivery of doxorubicin to HCC with reduced systemic side effects (107,108). Apart from release of drug, these beads also cause embolization of tumor vascular supply causing subsequent ischemia and necrosis (109). TACE combination with other ablation techniques (RFA, microwave etc.) have shown to have better outcome compared either of the technique alone (110).
Another treatment for intermediate stage HCC is selectively delivering radioactive isotope Yttrium 90 (Y-90) labeled microspheres to tumor via the hepatic artery (111). Yttrium 90 (Y-90) microspheres are smaller than DEB-TACE beads which allow them to be trapped in smaller tumor capillary bed to deliver Y-90 with beta radiation to tumor causing necrosis without surrounding liver tissue ischemia. Y-90 radioembolization has major advantage over TACE as can be used in patients with portal vein thrombosis (112). Y-90 toxicities have proven to be well tolerated (113,114). Results of radioembolization are comparable to TACE (115,116).
Stereotactic body radiation therapy (SBRT)
In SBRT multiple high-dose radiation fractions are delivered to a small, precisely defined tumor target with three-dimensional conformal radiation therapy techniques thus preventing radiation damage to surrounding normal liver tissue. However, it is available only in few centers and studies regarding its response are limited. Primarily it is seen as complementary treatment in localized HCC not amenable to ablative therapies due to vascular involvement with preserved underlying liver function.
Molecular targeted Systemic therapy
There is paradigm shift in the systemic therapy for advanced HCC with emergence of new molecularly targeted agents like multi-kinase inhibitors and immune check point inhibitors. Though these options are expensive, management of advanced HCC is now well beyond sorafenib.
Sorafenib (Nexavar), orally active small molecule tyrosine kinase inhibitor (TKI) which inhibits Raf kinase and the vascular endothelial growth factor receptor (VEGFR) intracellular kinase pathway (117). The landmark SHARP trial reported a modest but statistically significant survival benefit for sorafenib in patients with advanced HCC which lead to its approval as a new first line treatment for advanced HCC in 2008 (118).
Lenvatinib is multi-kinase inhibitor targeting VEGFR, fibroblast growth factor receptors (FGFR) and platelet-derived growth factor receptor (PDGFR). A randomized REFLECT study showed Lenvatinib was noninferior to sorafenib in patients with unresectable HCC (119). Lenvatinib was approved as first-line treatment of unresectable HCC in 2018.
Nivolumab and pembrolizumab
These are immune check-point inhibitor, targeting programmed cell death receptor (PD-1) and activating T cells against tumor, approved for treatment of HCC in patients previously treated with sorafenib. In Phase III CheckMate 459 trial in patients with advanced HCC, nivolumab was associated with a twofold higher objective response rate, but it failed to show significant benefit in overall survival (median 16.4 versus 14.7 months with sorafenib) (120). In phase II Keynote-224 trial in patients previously treated with sorafenib, pembrolizumab showed benefit (121).
Regorafenib is newly approved second line therapy for patient with advanced HCC showing progression on sorafenib. Regorafenib is again oral multi kinase inhibitor active against VEGFR, stromal and oncogenic receptor tyrosine kinases, with more activity in angiogenic and tumor growth-promoting pathways.
Cytotoxic conventional Systemic chemotherapy
Role of cytotoxic chemotherapy is limited and its use is only in patients with advanced HCC who cannot afford these new expensive agents. Though, there is no recommended protocol for conventional chemotherapy, in general most centers use oral capecitabine or leucovorin-modulated fluorouracil regimen.
HCC is becoming worldwide public health problem due to rising prevalence and high mortality in both developing and developed world. To fight this important global health care challenge, controlling the risk factors and detecting the cancer early is important. The demography and risk factors for HCC are well known and vary with geography. Hepatitis B vaccination and new effective anti HCV medications resulted in a decline in hepatitis B and elimination of HCV, but the incidence of NASH and alcohol related HCC is growing. Surveillance of HCC is critical since the clinical outcome depends on the ability to identify this cancer in early stages. At present, resection and LT still remain the main curative therapy for early stage HCC and advances in the locoregional techniques for intermediate stage HCC continue to expand. There is recent resurgence in molecular targeted drugs in advanced HCC.
Multidisciplinary team approach is critical for HCC management as newer advances continue to change landscape of this disease.
Dr. Bhakti Samant for collecting and assembling the data.
Provenance and Peer Review: This article was commissioned by the Guest Editors (John F. Gibbs and Quyen D. Chu) for the series “Global GI Malignancies” published in Journal of Gastrointestinal Oncology. The article has undergone external peer review.
Conflicts of Interest: The authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jgo.2020.02.08). The series “Global GI Malignancies” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
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