20 BioScience Trends. 2022; 16(1):20-30.

Review DOI: 10.5582/bst.2022.01061

The clinical management of hepatocellular carcinoma worldwide:

A concise review and comparison of current guidelines: 2022
update
Ningyuan Wen1, , Yulong Cai1, , Fuyu Li1, Hui Ye1, Wei Tang1,2, Peipei Song3,*,
§ §

Nansheng Cheng1,*
1
Department of Biliary Surgery, West China Hospital of Sichuan University, Chengdu, Sichuan, China;
2
International Health Care Center, National Center for Global Health and Medicine, Tokyo, Japan;
3
Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan.

SUMMARY Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the second leading
cause of cancer-related mortality worldwide. This review is an updated version that summarizes
comprehensive guidelines published from January 2001 to January 2022 worldwide with a focus on
the clinical management of HCC. The electronic databases MEDLINE, the Chinese SinoMed, and
the Japanese CiNii were systematically searched. A total of 22 characteristic guidelines for HCC
management were ultimately included, including 1 international guideline, 11 guidelines from Asia,
5 from Europe, 4 from the America, and 1 from Australia. If guidelines were published in multiple
versions, the most recent update was included, and surveillance, diagnosis, and treatment were
compared. The composition of and recommendations in current guidelines on HCC varied, so these
guidelines were regrouped and diagnostic and treatment algorithms were summarized graphically to
provide the latest information to clinicians. The diagnostic criteria were grouped into 2 categories:
a "Size-based pathway" and a "Non-size-based pathway". The treatment criteria were summarized
according to different treatment algorithms, and mainstream treatment options were reviewed. Findings
from comparison of current guidelines might help target and concentrate efforts to improve the clinical
management of HCC. However, further studies are needed to improve the management and outcomes
of HCC. More straightforward or refined guidelines would help guide doctors to make better decisions
in the treatment of HCC in the future.

Keywords hepatocellular carcinoma, clinical guideline, surveillance, diagnosis, treatment

1. Introduction and patients' outcomes, and assist regional and national

authorities in allocating resources (3).
As the most common primary malignancy of the liver, Since 2001, when the European Association for the
hepatocellular carcinoma (HCC) is the fifth most Study of the Liver (EASL) issued their HCC guideline,
common malignancy worldwide, with an increasing at least 20 comprehensive clinical guidelines for HCC
incidence of approximately > 500,000 new cases per have been published or updated, and each has its own
year (1,2). Over the past 2 decades, various studies have advantages. That said, gaps in knowledge and areas
examined the clinical management of HCC, markedly of controversy regarding certain aspects of HCC
improving treatment options, which include new drug management are still evident and cannot be ignored.
combinations. Despite the considerable advancement that I n a p r e v i o u s r e v i e w, w e s u m m a r i z e d 1 8
has occurred, the overall outcomes of HCC are still far comprehensive guidelines published worldwide from
from satisfactory. For better treatment of HCC, various 2001 to 2017 with a focus on the clinical treatment of
types of guidelines and expert consensus opinions have HCC; those guidelines have been significantly revised
been issued in multiple regions and subspecialties. since (4). To provide the latest information for clinicians,
If adequate guidelines are devised, they could serve the current review has summarized the current editions of
as roadmaps for clinicians to develop individualized those guidelines up to 2022. Twenty-two characteristic
decision-making algorithms, improve the quality of care guidelines were selected, including 1 international

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 BioScience Trends. 2022; 16(1):20-30. 21

guideline, 11 from Asia, 5 from Europe, 4 from the of appropriate methods for surveillance of the high-risk
America, and 1 from Australia. These characteristic population are crucial to early diagnosis and a better
guidelines have been compared and summarized in order outcome. This process is usually divided into 3 parts: i)
to describe new aspects of the surveillance, diagnosis, determining risk factors, ii) screening the population with
and treatment of HCC. risk factors for individuals who need to be monitored,
and iii) devising the form of surveillance that yields the
2. An update to characteristic guidelines for the most benefit.
clinical management of HCC The current review found that 17 of the 22 guidelines
clearly described risk factors and surveillance. The
Like the previous review, the current review involved a guidelines contained a lot of similar information on those
systematic search of mainstream databases in English, topics, but there were discrepancies among guidelines
Chinese, and Japanese, including MEDLINE, the due to regional differences in disease and other variables.
Chinese SinoMed (http://www.sinomed.ac.cn/zh/), and HCC has been proven to be linked to liver disease
the Japanese CiNii (http://ci.nii.ac.jp/), for applicable independently, and its major risk factors can be divided
results from January 2001 to January 2022. No language into those that are cirrhosis-related and those that are
restriction was applied. Search terms (medical subject non-cirrhosis-related. The former includes hepatitis
headings or keywords) included: "hepatocellular B virus (HBV) or hepatitis C virus (HCV) infection,
carcinoma", "guidelines/practice guidelines", "consensus", alcoholic cirrhosis, genetic causes (hemochromatosis
"strategy", "liver cancer", and "liver carcinoma". and tyrosinosis), nonalcoholic fatty liver disease
Inclusion criteria were as follows: i) credibility, (NAFLD), stage IV primary biliary cholangitis, alpha
as measured by whether the guidelines were widely one antitrypsin deficiency, and other causes of cirrhosis;
cited by subsequent guidelines or other publications the latter includes being an HBV carrier with a family
regarding the management of HCC after the original history of HCC, being Asian and elderly (males ≥ 40
guidelines were published; ii) influence, an indication years and females ≥ 50 years), and being an African/
that the guidelines were created with the support of North American black infected with hepatitis B (1,21).
government or academic/medical societies and that the Among these risk factors, cirrhosis caused by various
guidelines attracted nationwide attention with respect etiologies is the strongest predictor of HCC, with an
to their implementation and the standard care for HCC; associated annual incidence of HCC of 1-8% (26,27).
and iii) multifaceted, meaning that the guidelines Hepatitis B is the leading cause of HCC in East Asia and
included aspects of the diagnosis and treatment of HCC Africa while hepatitis C is the leading cause in Western
at a minimum. Hence, many specialized guidelines, countries (28). In recent years, NAFLD-related HCC
though credible and influential, did not make the list has attracted more attention since a growing population
of 22 guidelines but they are still discussed in specific worldwide is estimated to have NAFLD (29,30).
subsections. If the guidelines were published in HCC surveillance is cost-effective, especially for
multiple versions, the most recent update was analyzed. high-risk groups. Ultrasound (US) is the most widely
Moreover, references listed in guidelines were manually recommended method of HCC detection (1,7,22,31,32).
searched for other potential sources. The title and However, whether alpha-fetoprotein (AFP ) should serve
abstract of retrieved studies were evaluated for relevance as a routine screening test for HCC is still being debated.
and compliance. If compliance was not clearly defined The NCCN/AASLD recommendations suggested US
by the abstract, the full text was reviewed for further surveillance with or without AFP (22,31). The EASL
assessment. guideline described AFP as "suboptimal" as a serological
In line with the criteria above, 22 comprehensive test for surveillance since its levels were interfered with
guidelines published between 2001 and 2022 were by viral replication and underlying liver disease, so they
identified for analysis, including 1 international often do not appear abnormal in the early stages of HCC
guideline, 11 guidelines from Asia, 5 from Europe, 4 (1). Several studies indicated that AFP alone has limited
from the America, and 1 from Australia (Table 1) (1,5- and inconsistent sensitivity and specificity as a screening
25). Among the 18 guidelines included in our previous biomarker and that elevated levels of AFP may be found
review, 10 of them have been updated within the last in < 20% of patients with early-stage HCC (33-35).
5 years. Besides, 5 new guidelines were included for In contrast, some expert panels consider AFP to be
the first time. These 22 characteristic guidelines were a good surveillance marker due to its wide utility in
examined with a focus on the clinical management of diagnostic settings, where it has been studied extensively
HCC, and surveillance, diagnosis, and treatment in those (36), and its role in combination with US, which can
guidelines were compared. significantly maximize early detection of HCC, despite
the lack of evidence concerning improvement in survival
3. High-risk population and surveillance of HCC (37,38). In the 22 guidelines that were reviewed here, 6
recommended US for screening with AFP, 6 suggested
Identification of the risk factors for HCC and devising US alone, and the others considered AFP to be optional.

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 Table 1. Twenty-two characteristic guidelines for the clinical management of HCC
22

Year
No. Area Guidelines Drafted by Aspects covered Ref.
(latest update)

International
1 2010 WGO Guideline • World Gastroenterology Organization D&T+E+P+S (5)
Asia
2 2020 Pan-Asian adapted ESMO Guideline • ESMO Asia Meeting D&T+E+P+S+F (6)
3 2017 APASL Guideline • Asian-Pacific Association for the Study of the Liver D&T+E+P+S (7)
4 2009 AOS Guideline • Asian Oncology Summit 2009 D&T+P+S (8)
5 China 2020 CSCO Guideline • Chinese Society of Clinical Oncology D&T+S+F (9)
6 Japan 2021 JSH Consensus Statements and Recommendations • Japan Society of Hepatology D&T+S (10)
7 2021 J-HCC Guideline • Group formed to establish "Guidelines for evidence-based clinical practice
for the treatment of liver cancer"
8 2019 JSH Guideline • Japan Society of Hepatology D&T+S (11)
9 Korea 2014 Korean Guideline • Korean Liver Cancer Study Group and National Cancer Center D&T+E+P (12)
10 Saudi Arabia 2020 Saudi Guideline • Saudi Association for the Study of Liver diseases and Transplantation D&T+E+P+S (13)
11 India 2019 INASL Guideline • The Indian National Association for Study of the Liver D&T+E+P+S (14)
12 2019 ICMR Consensus • Indian Council of Medical Research D&T+E+P+S+F (15)
Europe (16)
13 2021 ESMO Guideline • European Society for Medical Oncology D&T+E+P+S+F (17)
14 2018 EASL Guideline • European Association for Study of the Liver, European Organization for D&T+E+P+S (1)
Research and Treatment of Cancer
15 Belgium 2004 BASL Guideline • Belgian Association for the Study of the Liver D&T+E+P+S (18)
16 Britain 2003 BSG Guideline • British Society of Gastroenterology D&T+E+S (19)
17 Italy 2009 GOIM Guideline • Italian Southern Oncological Group D&T+E (20)
America
18 2021 NCCN • National Comprehensive Cancer Network D&T+E+S (21)

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19 2018 AASLD • American Association for the Study of Liver Disease D&T+S (22)
20 2010 NCI Guideline • United States National Cancer Institute D&T+E (23)
21 2007 ACS Guideline • American College of Surgeons* D&T (24)
BioScience Trends. 2022; 16(1):20-30.

Oceania
22 Australia 2020 GESA Guideline • Gastroenterological Society of Australia D&T+E+P+S+F (25)

Abbreviations: D&T: diagnosis and treatment, E: epidemiology, P: prevention, S: surveillance, F: follow-up. *A review article published on J Am Coll Surg by the American College of Surgeons.
 BioScience Trends. 2022; 16(1):20-30. 23

The usefulness of other biomarkers, including the lens stated that there was insufficient evidence to advise
culinaris agglutinin-reactive fraction of AFP (AFP-L3) surveillance for patients with chronic hepatitis C but
and des-gamma-carboxy prothrombin (DCP), has been without cirrhosis. The WGO Guideline divided the
studied (39,40). Concomitant use of these biomarkers criteria for HCC screening into 3 parts: hepatitis B
is recommended as a regular screening method by the carriers, cirrhosis not due to hepatitis B, and general
2019 updated JSH Guideline (12). In contrast, the 2018 patients. General patients referred to patients who were
EASL guideline described AFP, AFP-L3 and DCP as previously eligible for HCC screening and included
"suboptimal in terms of cost-effectiveness for routine cirrhotic patients who were successfully treated for
surveillance of early HCC". The debate goes on. chronic viral hepatitis. The AASLD guideline grouped
The ideal surveillance interval should be evaluated together patients who would benefit from surveillance
from the perspective of cost-effectiveness by considering and patients in whom there was no evidence of a benefit
the clinical status and available resources. Generally, from surveillance. The remaining guidelines did not
the surveillance interval is 6 to 12 months for the high- divide the population who needed to be surveilled into
risk population according to guidelines. A prospective smaller groups.
cohort study found that patients with HBV had a better Obviously, there are regional differences in
survival with a surveillance interval of 6 months than epidemiology that might change with time. For example,
with 12 months (41). However, other studies have found the importance of HBV as a cause of HCC is declining,
no significant differences in survival or the rate of HCC but the importance of NAFLD and nonalcoholic
detection with intervals of 6 and 12 months (42,43). Of steatohepatitis (NASH) as risk factors for HCC is on the
the 22 guidelines that were reviewed here, 8 tended to rise (29,30). Future guidelines should pay close attention
recommend a surveillance interval of 6 months and 2 to these changes, and each country could devise its
recommended an interval of 6 to 12 months. own method of HCC surveillance depending on local
The definition and description of the high-risk epidemiology. The current comparison of guidelines
population varied according to the guidelines. According could help organizations devise a meaningful and easily
to the 2019 update of the JSH Guideline, individuals with understood form of surveillance.
a high risk of developing HCC who need to be surveilled
are classified as the high-risk population and the very- 4. Diagnostic criteria for HCC according to
high-risk population (12). The high-risk population characteristic guidelines worldwide
includes: i) individuals with chronic hepatitis B, ii)
individuals with chronic hepatitis C, and iii) individuals The diagnosis of HCC is generally based on a
with liver cirrhosis (due to causes other than HBV or combination of clinical and laboratory features as well
HCV). The recommended form of surveillance is US as radiographic and histopathologic presentation. The
and tumor marker measurement (AFP/DCP/AFP-L3) diagnostic algorithms in the 22 guidelines that were
every 6 months. The very-high-risk population includes: reviewed here have been summarized in a flowchart
i) individuals with hepatitis B-related liver cirrhosis and (Figure 1). Although there were differences among
ii) individuals with hepatitis C-related liver cirrhosis. these guidelines, the final diagnosis of HCC was based
The surveillance protocol for those individuals is US and on imaging techniques or biopsy. With the recent
tumor marker measurement (AFP/DCP/AFP-L3) every advancement of various types of imaging techniques
3-4 months, with alternative dynamic CT/MRI especially even for "indeterminate lesions" as described by the
for those who cannot readily undergo US due to liver AASLD guideline, biopsy is only suggested in selected
atrophy, severe obesity, or post-operative deformity. cases.
The NCCN Guideline, INASL Guideline, and EASL In general, if US reveals a nodule or mass in an at-
Guideline classified patients who are at risk of developing risk individual, there are mainly 2 pathways for diagnosis
HCC into a group with cirrhosis and a group without of HCC according to current guidelines. For simplicity,
cirrhosis (1,15,31). The EASL/INASL/Saudi Guideline these 2 categories have been designated as the "Size-
also took liver function (Child-Pugh) into consideration based pathway" and the "Non-size-based pathway".
for the group with cirrhosis. Those 2 guidelines stressed
that patients on the waiting list for liver transplantation 4.1. Size-based pathway for HCC diagnosis
(LT), regardless of their liver function status, should be
screened for HCC in order to detect tumor progression The "Size-based pathway" for diagnosis of HCC starts
(whether it exceeds conventional criteria) and to help with tumor size (generally larger or smaller than 1 cm.
prioritize transplantation. The NCCN Guideline did In the latest CSCO guideline, this was subdivided into
not recommend surveilling the group without cirrhosis < 1 cm, 1-2 cm, and > 2 cm). HCC nodules with a
for chronic HCV with advanced fibrosis, but the small diameter are difficult to distinguish from cirrhotic
INASL Guideline and EASL Guideline do recommend nodules, and previous studies found that small nodules,
surveilling that group. Similarly, the Saudi Guideline and especially those with a diameter < 1 cm, were
suggests surveillance of all cirrhotic patients, but it also unlikely to be HCC nodules (44,45). This is the main

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24 BioScience Trends. 2022; 16(1):20-30.

Figure 1. The diagnostic algorithm for hepatocellular carcinoma in current guidelines. The diagnostic criteria were grouped into 2 categories
of a "Size-based pathway" and a "Non-size-based pathway". Abbreviations: EASL: European Association for the Study of the Liver; NCCN:
National Comprehensive Cancer Network; JSH: Japan Society of Hepatology; APASL: Asian-Pacific Association for the Study of the Liver; US:
ultrasonography; AFP: alpha-fetoprotein; Gd-EOB-DTPA: gadolinium ethoxybenzyl-diethylenetriaminepentaacetic acid.

reason why the AASLD/EASL Guideline recommend of tumors 1-2 cm in diameter. The 2018 EASL guideline
that those patients be closely followed-up with US every also stated that non-invasive criteria can apply to nodules
3 or 4 months. The NCCN Guideline recommends repeat over 1 cm in diameter. This indicates that, as imaging
US plus AFP every 3 to 6 months. Kim et al. argued techniques such as gadolinium-based MRI advance,
that hyper-intensity on both T2 and diffusion-weighted smaller nodules are diagnosed more accurately through
images is helpful in the diagnosis of hypervascular HCC non-invasive approaches.
nodules smaller than 1 cm in diameter (46). The Korean Needle biopsy of a suspicious liver lesion could
Guideline established stricter criteria for diagnosis of guide management for patients who do not exhibit a
HCC nodules < 1 cm. Nodule size according to 2 or classic imaging presentation and serology, although it is
more imaging modalities is a typical hallmark of HCC not recommended generally because of the possibility
in combination with elevated serum AFP and absence of of tumor dissemination outside the liver. The overall
hepatitis activity (13). The technique that first detected incidence of needle-tract tumor seeding following biopsy
nodules should be performed again 3 to 6 months later. of HCC is 0.9-2.7% per year (48). Moreover, the NCCN
If the nodules remain the same size, a close follow-up Guideline stresses that a negative biopsy result does not
should be performed. Otherwise, special attention should rule out HCC if a nodule or mass has increased in size.
be paid to the growing nodule size.
Liver nodules larger than 1 cm in size should be 4.2. Non-size-based pathway for HCC diagnosis
evaluated with dynamic contrast-enhanced CT/MRI
or Gd-EOB-DTPA MRI. Evidence of one or more In the "Non-size-based pathway", patients will be
radiological hallmarks of HCC, arterial hypervascularity, scheduled for dynamic imaging regardless of tumor
and venous/late-phase washout is considered indicative size. All of the guidelines indicate that HCC can be
of HCC. A non-biopsy diagnosis based on a nodule definitively diagnosed when dynamic CT/MRI reveals
size > 1 cm has been updated several times. According intense arterial uptake followed by a "washout" of
to the 2002 version of the EASL Guideline, a positive contrast. Moreover, ever since the 2014 JSH Guideline
imaging finding plus AFP levels > 400 ng/mL can lead included Gd-EOB-DTPA MRI (gadoxetic acid disodium,
to a diagnosis of HCC when nodules > 2 cm (47). In a liver-specific contrast agent) as a tool for first-line
2005, the AASLD Guideline excluded AFP from the surveillance and diagnosis of HCC, multiple guidelines
diagnostic algorithm and recommended radiological have cited gadoxetic acid-enhanced MRI as a first-line
hallmarks according to 2 imaging techniques to diagnose imaging technique. In principle, this contrast agent is
HCC nodules between 1 and 2 cm in size. For nodules > specifically absorbed by normal hepatocytes, resulting in
2 cm, a hallmark detected by 1 imaging technique would contrast enhancement. Therefore, HCC nodules lacking
be sufficient. The 2010 version of the AASLD Guideline normal hepatocytes are hypo-intense, and this difference
updated the criterion: an imaging technique revealing a can help distinguish tumors from non-tumorous
radiological hallmark of HCC is sufficient for diagnosis ("normal") nodules (49).

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 BioScience Trends. 2022; 16(1):20-30. 25

When an advanced imaging technique reveals by the NCCN (2021), AASLD (2018), CSCO (2020),
only hypervascularity with no washout, the diagnostic JSH (2019), INASL (2019), ESMO (2021), EASL (2018),
algorithms differ among the guidelines that were and Saudi Arabia (2020). New guidelines published
reviewed here. Recommendations in the J-HCC between 2017 and 2022 added to the current review are
Guideline depend on tumor size. If the tumor diameter the Pan-Asian adapted ESMO (2020), ICMR (2019),
is larger than 1 cm, other optional examinations should and GESA (2020) guidelines. The treatment algorithms
be performed, including Gd-EOB-DTPA-MRI, SPIO- in these updated guidelines and in other guidelines were
MRI, CEUS, CTA, and biopsy. A 3-month follow-up reviewed here and are discussed in terms of surgical and
is recommended for patients with a tumor < 1 cm in non-surgical approaches.
diameter and elevated levels of tumor markers while Different staging systems are used to select the
dynamic CT/MRI is recommended for a larger tumor. In best treatment option for patients, which is the main
the JSH Guideline, a tumor that is hypo-intense during difference between the guidelines. Typically, Japanese
the hepatobiliary phase of GD-EOB-DTPA-MRI can be guidelines (J-HCC/JSH guidelines) use the Child-Pugh
diagnosed as HCC provided that cavernous hemangioma score for the very first evaluation for treatment options,
is first ruled out by other modalities. A biopsy is while AASLD, ESMO, EASL, Saudi, and INASL
necessary if the tumor is iso-intense or hyper-intense guidelines involve an initial evaluation based on BCLC
in the hepatobiliary phase. According to the APASL staging system. A flowchart has been included here
Guideline, a lesion can be diagnosed as HCC when high to provide an overview of the diverse staging systems
SPIO-enhanced MRI signals or a defect in the Kupffer (Figure 2).
phase of Sonazoid-enhanced US is evident (7). However,
the APASL Guideline only recommends a close follow- 5.1. Surgical approaches
up instead of a biopsy for patients with intense uptake in
SPIO-MRI or CEUS. Basically, all of the staging systems focus on the
There is still a lack of a broad consensus on the most determination of tumor resectability, since surgery is still
appropriate diagnostic algorithm to use when initial recommended as the best treatment option for selected
dynamic CT/MRI reveals a hypo-vascular mass in the patients, with a 5-year survival rate as high as 80%
arterial phase. The updated J-HCC Guideline suggested (1). Initially, tumor resectability should be evaluated
that an optional examination should be undergone by based on parameters like liver function, the presence of
patients with a tumor larger than 1.5 cm and it suggested portal hypertension, tumor location, and the presence
a follow-up of 3 months for those with a tumor smaller of extrahepatic metastases. If a tumor is resectable,
than 1.5 cm. The JSH Guideline stresses presentation resection or radiofrequency ablation (RFA) (for a tumor
in the hepatobiliary phase of GD- EBO-DTPA- with a small diameter) is recommended. LT should also
MRI. If hypo-intensity is present, Sonazoid CEUS is be considered for patients with cancer that is Child-
recommended; otherwise, follow-up should be continued. Pugh class C. LT has become the first-line treatment for
The APASL Guideline tended to recommend SPIO- patients with unresectable tumors that nonetheless meet
enhanced MRI or Sonazoid CEUS for those patients. the Milan or United Network for Organ Sharing (UNOS)
A close follow-up was recommended in the event of a criteria. If those patients are not optimal candidates
negative imaging finding. for transplantation, the choice of locoregional therapy,
sorafenib, or supportive care depends on individual
5. Treatment criteria for HCC according to circumstances (including tumor location, liver function,
characteristic guidelines worldwide and institutional capabilities). Moreover, the NCCN
Guideline added that transplantation can be considered
The treatment algorithm for HCC is constantly changing or recommended for those patients who initially failed
as the criteria for hepatic resection expand, locoregional to meet the Milan criterion but who received successful
therapies advance, novel targeted systemic therapies are downstaging therapy.
introduced, techniques for internal and external radiation The BCLC staging system takes tumor stage, liver
therapy improve, and the possibility of receiving a function, and physical status into account, and this
transplant increases. However, long-term outcomes system had been widely adopted for HCC staging and
of HCC depend on both the medical complexity of treatment (50). Moreover, the BCLC staging system is
HCC (involving multiple confounding factors: tumor the only staging system that assigns treatment strategies
heterogeneity, liver function and performance status) as based on specific prognostic subclasses, an approach
well as the choice of an appropriate treatment, posing a that has proven effective (51). The spectrum of treatment
challenge for both patients and clinicians. options with curative intent may be a subject of some
An important aim of clinical guidelines is to feature controversy, but it generally consists of liver resection,
up-to-date, specific, quality evidence to help clinicians LT, and ablation. Patients with stage 0 or stage A liver
select the most appropriate treatment. Compared to our cancer may have a 5-year survival rate of 40-70% after
previous review (4), the updated guidelines include those treatment with curative intent. Liver resection still

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26 BioScience Trends. 2022; 16(1):20-30.

Figure 2. The treatment algorithm for hepatocellular carcinoma in current guidelines. Four clinical pathways based on different staging
systems are shown. Abbreviations: BCLC staging system: Barcelona Clinic Liver Cancer staging system; mUICC staging system: modified Union of
International Cancer Control staging system; EASL: European Association for the Study of the Liver; AASLD: American Association for the Study
of Liver Disease; ESMO: European Society for Medical Oncology; JSH: Japan Society of Hepatology; NCCN: National Comprehensive Cancer
Network; TACE: transarterial chemoembolization.

remains the mainstay of HCC treatment in non-cirrhotic according to the INASL Guideline (54). On the whole,
patients or in selected cirrhotic patients with a single primary recommendations for LT have remained the
lesion. The AASLD Guideline repeatedly stresses the same.
usefulness of measuring portal pressure in predicting The 2014 Korean Guideline adopted the mUICC as
patient outcomes and optimizing patient selection for its primary staging system. Its recommendations for first-
liver resection; the usefulness of this index has also line treatment are based on mUICC staging system, but
been verified in Japan (52). The AASLD Guideline its algorithm only applied to patients with Child-Pugh
also indicated that patients with portal hypertension class A HCC, no portal hypertension, and an Eastern
or multiple lesions could receive a survival benefit Cooperative Oncology Group (ECOG) performance
from resection. The algorithm in the ESMO Guideline status of 0-1. The basic criteria of the mUICC staging
excluded hypertension and it expanded the criteria for system include: i) the number of tumors, ii) the diameter
clinical decision-making with regard to resection (17). of the largest tumor, and iii) vascular or bile duct
LT is indicated for patients with BCLC stage A invasion. The best treatment option for a stage I tumor
cancer meeting the Milan criterion (solitary HCC nodule (single/≤ 2 cm/VI-) is resection or RFA. There are 3
< 5 cm in size or fewer than 3 nodules, none larger than options for Stage II cancer: i) resection or RFA (tumor
3 cm in diameter). Patients with cancer meeting the size ≤ 3 cm) is recommended for treatment of stage IIa
Milan criterion had a 5-year overall survival rate of 65- cancer (single/> 2 cm/VI-); ii) LT (for cancer meeting
78% after LT, which is why this criterion was integrated the Milan criterion) is the first option for treatment of
into the BCLC staging system (53). This strict criterion stage IIb cancer (multiple/≤ 2 cm/VI-) and transarterial
also has certain limitations. According to the ESMO chemoembolization (TACE) or RFA is an alternative
Guideline, LT is ruled out for patients with cancer when there are more than 3 nodules; and iii) stage IIc
meeting the Milan criterion and poor liver function cancer (single/≤ 2 cm/VI+) is amenable to TACE. The
(Child-Pugh class C), who would be classed as BCLC mainstay for treatment of stage III cancer is TACE or
stage D. The University of California San Francisco sorafenib. However, LT must be taken into account when
(UCSF) criterion extends beyond the Milan criterion, cancer meets the Milan criterion. Sorafenib is better
and the UCSF criterion results in comparable outcomes suited to treatment of a stage IV tumor. The Korean

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 BioScience Trends. 2022; 16(1):20-30. 27

Guideline also added that external beam radiation option for BCLC stage B HCC in guidelines such as
therapy could be useful in alleviating symptoms caused those from the EASL, and that procedure is described as
by primary HCC or metastases. being supported by strong evidence (58,59). The current
An algorithm based on the Child-Pugh class of liver guidelines reviewed here recommend TACE at about
function is utilized in Japan. The class is based on 3 the same level as they did previously. Recent studies
factors: liver function, the number of tumors, and tumor have found transarterial radioembolization (TARE), also
size. Before a Child-Pugh class is assigned, whether called selective internal radiation therapy (SIRT), might
extrahepatic spread is present is first determined. If outperform TACE in terms of tumor downstaging, and its
extrahepatic spread is present, chemotherapy is the combined use with Yttrium-90 microspheres may result
treatment of choice for Child-Pugh class A cancer. in an encouraging outcome in terms of survival (60,61).
Palliative care is recommended for patients with Thus, TARE with Yttrium 90 could be considered as an
decreased liver function. Undoubtedly, liver resection has alternative to TACE, particularly in cases of HCC with
been the first option for a solitary tumor that is Child- portal vein thrombosis.
Pugh class A/B. According to the 2021 updated version
of the J-HCC guideline, RFA is also recommended for 5.2.3. Systemic therapy
a tumor < 3 cm. For patients with 2 to 3 tumor nodules,
resection or RFA/TACE is recommended depending Molecularly targeted therapy has made vast progress over
on their size (12). For patients with more than 4 tumor the past few years. Traditionally, sorafenib is indicated
nodules, TACE is first recommended, but the JSH when BCLC stage C HCC or BCLC stage B HCC
Guideline contends that resection can sometimes be progresses after TACE. Two widely cited RCTs have
performed, and ablation is sometimes performed in revealed that sorafenib can serve as a first-line treatment
combination with TACE. in patients with HCC who still have liver function but
LT is recommended for patients younger than 65 with who can no longer be treated with other more effective
cancer meeting the Milan criterion, even if they have therapies (62,63). Previous studies on sorafenib have
class C liver function according to the Child-Pugh score. reported its safety data and its efficacy in prolonging
survival (64-66). Another first-line drug recommended
5.2. Non-surgical approaches by recently updated guidelines is lenvatinib. In a
randomized phase 3 trial (about 2/3 of the included
5.2.1. Ablation patients were from the Asia-Pacific region), the efficacy
of lenvatinib was not inferior to that of sorafenib (67).
RFA and percutaneous ethanol injection (PEI) are the In the study in question, lenvatinib displayed superior
most widely used forms of ablative treatment. They efficacy in the Chinese subgroup, and the overall
are considered the standard treatment for HCC that is survival time was prolonged by 4.8 months. Lenvatinib
BCLC 0-A stages and that is not amenable to surgery. has a survival benefit for HBV-related HCC. According
Previous studies have found that RFA or PEI, as first- to the AASLD guideline, there is no evidence to support
line treatment, can yield similar outcomes to surgical whether second-line treatment options such as regofinib
resection when tumors are smaller than 2 cm in size or nivolumab can be used for patients with tumor
and BCLC stage 0 (55,56). A study in 2019, the SURF progression receiving lenvatinib, but sequential use of
trial, recommended RFA for patients with 1-3 tumors tyrosine kinase inhibitors with a similar mechanism of
smaller than 3 cm (57). In contrast, the INASL Guideline action can be considered.
only recommends that patients with stage 0 undergo In the latest NCCN guideline, however, the
ablation when they are not potential candidates for recommended dose of sorafenib was reduced and
LT (15). Substantial evidence is required to verify the the preferred regimen was changed to atzumab +
effectiveness of ablation as a first-line treatment for very bevacizumab (referred to as the T + A regimen, Child-
early HCC. Pugh class A only). Data presented at the 2019 ESMO
Patients in the terminal stage (BCLC stage D) should Asia Congress indicated that the T+A regimen was
receive the best supportive care. External beam radiation superior to sorafenib in patients with unresectable HCC
therapy has only been tested in non-controlled studies. (68). Nevertheless, the cost-effectiveness of the T+A
The INASL Guideline contends that radiation therapy regimen still needs to be optimized (69).
cannot be recommended for management of HCC until
its effectiveness is verified in clinical trials. 6. Conclusion

5.2.2. Embolization This work has reviewed updated information from

current comprehensive guidelines for HCC management
In recent years, HCC interventional therapy has made published worldwide between 2001 and 2022. Twenty-
huge advances, such that it has become an independent two characteristic guidelines were identified, including 1
subspecialty. TACE was listed as the primary treatment international guideline, 11 guidelines from Asia, 5 from

www.biosciencetrends.com
28 BioScience Trends. 2022; 16(1):20-30.

Europe, 4 from the US, and 1 from Australia. Those hepatocellular carcinoma: A 2017 update. Hepatol Int.
guidelines were compared in terms of surveillance, 2017; 11:317-370.
diagnosis, and treatment with a focus on the clinical 8. Poon D, Anderson BO, Chen LT, Tanaka K, Lau WY, Van
Cutsem E, Singh H, Chow WC, Ooi LL, Chow P, Khin
management of HCC. The composition of and
MW, Koo WH, Asian Oncology Summit. Management
recommendations in current guidelines on HCC varied, of hepatocellular carcinoma in Asia: Consensus statement
so these guidelines were regrouped and diagnostic and from the Asian Oncology Summit 2009. Lancet Oncol.
treatment algorithms were summarized graphically to 2009; 10:1111-1118.
provide the latest information for clinicians. 9. Zhou J, Sun HC, Wang Z, et al. Guidelines for Diagnosis
Over the past few decades, HCC has changed from and Treatment of Primary Liver Cancer in China (2017
an almost universal death sentence to a cancer that can Edition). Liver Cancer. 2018; 7:235-260.
10. Kudo M, Kawamura Y, Hasegawa K, et al. Management
be prevented, detected in an early stage, and effectively
of hepatocellular carcinoma in Japan: JSH consensus
treated, but HCC is still the second leading cause of statements and recommendations 2021 update. 2021;
cancer-related mortality worldwide, and the leading Liver Cancer. 2021; 10:181-223.10:181-223.
cause of death among patients with chronic liver disease 11. Group formed to establish "Guidelines for evidence-
(2). Findings from this comparison of current guidelines based clinical practice for the treatment of liver cancer";
may help target and concentrate efforts to improve the Japan Society of Hepatology. Clinical practice guidelines
clinical management of HCC. However, further studies for hepatocellular carcinoma (2021 version). Kanehara,
are needed to improve the management and outcomes Tokyo, Japan, 2021. (in Japanese)
12. Kokudo N, Takemura N, Hasegawa K, et al. Clinical
of HCC. More straightforward or refined guidelines
practice guidelines for hepatocellular carcinoma: The
would help guide doctors to make better decisions in the Japan Society of Hepatology 2017 (4th JSH-HCC
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1113.
Funding: None. 13. Korean Liver Cancer Study Group (KLCSG); National
Cancer Center, Korea (NCC). 2014 Korean Liver Cancer
Conflict of Interest: The authors have no conflicts of Study Group-National Cancer Center Korea practice
guideline for the management of hepatocellular carcinoma.
interest to disclose.
Korean J Radiol. 2015; 16:465-522.
14. Alqahtani SA, Sanai FM, Alolayan A, Abaalkhail F,
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§
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