ANTICANCER RESEARCH 34: 1563-1572 (2014)

Review

New Possibilities in Hepatocellular Carcinoma Treatment

MAHMOOD RASOOL1, SANA RASHID2, MAHWISH AROOJ3, SHAKEEL AHMED ANSARI1,
KHALID MAHMUD KHAN4, ARIF MALIK2, MUHAMMAD IMRAN NASEER1, SARA ZAHID2,
ABDUL MANAN2, MUHAMMAD ASIF5, ZARISH RAZZAQ2, SADIA ASHRAF2, MAHMOOD HUSAIN QAZI3,
ZAFAR IQBAL6, SIEW HUA GAN7, MOHAMMAD AMJAD KAMAL8 and ISHFAQ AHMED SHEIKH8
1Center

of Excellence in Genomic Medicine Research (CEGMR), King Abdulaziz University, Jeddah, Saudi Arabia;
of Molecular Biology and Biotechnology (IMBB), the University of Lahore, Lahore, Pakistan;
3Center for Research in Molecular Medicine (CRIMM), the University of Lahore, Lahore, Pakistan;
4Fatima Jinnah Medical College, Sir Gangaram Hospital, Lahore, Pakistan;
5Department of Biotechnology and Informatics, (BUITEMS), Quetta, Pakistan;
6College of Applied Medical Sciences, King Saud Bin Abdulaziz University of Health Sciences,
National Guards Health Affairs, Riyadh, Saudi Arabia;
7Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia,
Kubang Kerian, Kelantan, Malaysia;
8King Fahd Medical Research Center (KFMRC), King Abdulaziz University, Jeddah, Saudi Arabia

2Institute

Abstract. Hepatocellular carcinoma diagnosis and

treatment has witnessed many major changes and challenges
in the past two decades. Increasing incidence of HCC has
introduced new monitoring systems and increased the
efficacy of screening tests, as well as prognosis of the
disease, including the staging system, serological testing and
diagnostic imaging. Moreover, surgical resection, liver
transplantation and herbal therapy have improved treatment.
The most encouraging specific serological marker for HCC
is alpha fetoprotein (AFP), which, along with
ultrasonography, has improved earlier detection of HCC.
Most recently, circulating tumor cell measurement has
emerged as a promising tool for the prognosis of HCC.
Herbal drugs and herbal composite formula drugs are
promising towards the prevention of invasion and

This article is freely accessible online.

Correspondence to: Dr. Ishfaq Ahmed Sheikh, King Fahd Medical
Research Center, King Abdulaziz University, P. O. Box 80216,
Jeddah 21589, Saudi Arabia. E-mail: [email protected],
[email protected] and Mohammad Amjad Kamal, King
Fahd Medical Research Center, King Abdulaziz University, P. O.
Box 80216, Jeddah 21589, Saudi Arabia. E-mail:
[email protected]
Key Words: Hepatocellular carcinoma, alpha fetoprotein, surgical
resection, herbal drugs, chemo and radiotherapy for HCC, review.

0250-7005/2014 $2.00+.40

proliferation of tumor cells. Chemotherapeutic agents, such

as sorafenib, bevacizumab and erlotinib, which target growth
factor receptors in signaling pathways, are also used as
HCC treatments. Furthermore, radiotherapy is employed in
the treatment of unresectable tumors. The present report
provides an analysis of the above parameters in the
management of HCC.
Hepatocellular carcinoma (HCC) is unique among cancers
because 90% of HCCs develop in the context of chronic liver
disease and cirrhosis. HCC is thought to account for more
than 5% of all cancers and for 80-90% of primary liver
cancers. It is the third most common cause of death globally,
fifth for men and eighth for women (1). Since most HCC
patients are diagnosed at the end-stage of liver dysfunction,
the mortality rate is approximately the same as the incidence
rate (2). Therefore, early detection of HCC is of paramount
importance to improve the survival of affected patients (3).
Among various major risk factors in the progression of HCC
are the following: hepatitis B or hepatitis C, metabolic
disorders such as diabetes, non-alcoholic fatty liver disease
or galactosemia and exposure to toxins, including alcohol,
cigarette smoke, androgenic steroids and aflatoxins (4-7).
The course of malignant cancer transformation involves
the accumulation of mutations and aberrations among the
genes that govern proliferation and apoptosis in cells, leading
to apoptotic avoidance, neo-angiogenesis and metastatic
potential (8). During this multi-step process in the

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ANTICANCER RESEARCH 34: 1563-1572 (2014)

development of HCC, mature hepatocytes undergo genetic
alterations in the hepatocytic microenvironment that lead to
necrosis, inflammation and re-generation, driving the
selection of monoclonal populations to become dysplastic
nodules that finally evolve into HCC (9). In approximately
40% of HCC cases, the undifferentiated cells expressing
biomarkers of liver progenitor cells are associated with
poorer prognosis (10).
Experimental studies have shown that hepatitis C virus
(HCV) operates via different routes to aggravate the
transformation of hepatocytes into malignant cells. Many
viral proteins (structural and non-structural), especially the
core protein and NS5A of HCV, are involved in the
advancement of HCC (11). Moreover, alcohol consumption
can worsen the situation because hepatocytes are the primary
site of alcohol metabolism through three main pathways that
include alcohol dehydrogenase in the cytoplasm, ethanol
oxidation in microsomes in the endoplasmic reticulum and
catalase in the peroxisomes (12).

Prognosis Staging System and Development

Cirrhosis, tumor characteristics (including multicentricity,
pathology, size, extrahepatic metastasis and either the
absence or the presence of vascular invasion), patient status
and treatment efficacy define the natural history of HCC.
There are two staging components of HCC: intrahepatic and
extrahepatic. Intrahepatic staging is performed to elucidate
the size and number of lesions and to ascertain whether
vascularization is present. Extrahepatic staging is required to
assess whether metastasis is present outside the liver. There
are seven classification schemes for the prognosis of HCC
(13): i. Okuda classification; ii. TNM (tumor, node,
metastasis) classification; iii. CLIP (Cancer of the Liver
Italian Program) classification; iv. BCLC (Barcelona Clinic
Liver Center) classification; v. French classification; vi.
CUPI (Chinese University Prognostic Index); vii. JIS (Japan
Integrated Staging) Score.
Okuda classification is one of the most common
classifications for HCC and is based on two parameters
tumor stage and functional status, such as bilirubin, ascites
and albumin but does not include prognostic measures, such
as the presence of thrombosis, distant vein metastasis and
alpha fetoprotein (AFP). This classification is generally used
for the stratification of patients with HCC and is not favorable
for prognosis (14, 15).
TNM classification is considered to be the best staging
system for assessing patients undergoing surgical resection;
it is based on tumor size, number, vascularization, node
status and metastasis to distant regions (16).
CLIP classification is based on survival, the severity of
liver damage and tumor characteristics, such as morphology,
AFP levels and thrombosis of the portal vein. CLIP has

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improved prognostic accuracy compared to the Okuda and

TNM classifications. Its only limitations are with early-stage
HCC patients (14, 17).
The BCLC classification of patients is based on the
evolutionary course of tumor progression and liver disease.
Thus, it allows for prediction of life expectancy and choice
of treatment modality for patients. According to this
classification, patients are classified into the following four
stages: early-stage, intermediate-stage, advanced-stage and
end-stage disease (18). It is the only stratification system that
correlates with the specific mode of treatment.
The French classification accounts for five prognostic
factors, including serum bilirubin, serum alkaline
phosphatase, serum alpha-fetoprotein, tumor spreading and
ultrasonographically-detected portal obstruction. According
to this classification, patients are classified into the three
groups: A, B and C. This classification has limited
prognostic capacity due to not taking into account the tumor
extension variables (14).
CUPI has been investigated in Hong Kong and divides
patients into three groups according to five prognostic
factors; total bilirubin, ascites, alkaline phosphatase, serum
alpha fetoprotein and tumor characteristics. The JIS score is
a modern staging system in Japan and is based on both the
TNM staging classification and the CLIP classification and
has been proposed for the classification of patients in the
early stages of HCC who require curative treatment. Its
prognostic power is equivalent to CLIP and is better than the
BCLC staging classification (19).

Conventional Methods of Screening

The rationale behind the screening of HCC is that the early
detection of HCC amenable to aggressive intervention can
improve the survival of affected individuals. HCC patients
have poor life expectancy and a mortality ratio of
approximately 1, with a mean survival of 6-20 months. Thus,
early detection of individuals suffering from chronic liver
disease and cirrhosis is key to improving HCC survival. To
improve patient selection, several strategies have been
employed that evaluate the status of the patient and the stage
of the cancer. The diagnostic evaluation includes serological
testing, proteomic approaches, imaging and liver biopsy.

Serological testing
The increasing incidence of HCC has improved the prospects
for screening the at-risk population, and the basic tools for
this evaluation are serological markers.
Alpha-fetoprotein (AFP). The most widely used onco-marker
for detecting HCC is serum AFP. In the American
population, AFP shows an accuracy of 82% and 16 ng/ml is

Rasool et al: New Possibilities in Hepatocellular Carcinoma Treatment (Review)

considered the best cut-off value to differentiate HCC from

chronic liver disease (CLD) (20). AFP is an oncoglycoprotein of unknown function that is more prevalent in
cirrhotic and HCC patients. AFP was first discovered by
Abelev et al. in 1963 (21). The surveillance of patients with
HCC varies with the specificity and sensitivity of the AFP.
Due to the performance characteristics, some experts
question the surveillance-based study of AFP and consider it
an obsolete tool for screening purposes. Despite these
pitfalls, AFP is still the gold standard for early prognosis of
HCC. Attempts are being made to enhance the specificity of
AFP by studying the glycoforms of the proteins, as
determined by reactivity with Lens Culinaris agglutinin
(AFP-L3) and concanavalin A. AFP-L3 is thought to be a
superior HCC marker and was recently awarded FDA
approval as a risk assessment test based on a 7-fold
increase correlating with the increased risk of HCC
development (21).
Des--carboxy prothrombin. Des--carboxy prothrombin
(DCP) is an abnormal form of prothrombin (coagulation
factor II), present in the sera of HCC-affected patients. The
specificity and sensitivity of DCP are disappointing
compared to AFP. However, recent trends studied by Wang
et al. in Taiwanese patients with HBV- and HCV-associated
liver disease suggest that DCP may compete with AFP as a
prognostic factor for HCC (22). As a result, DCP was added
to the HCC candidate marker list.
-L-Fucosidase. - L-Fucosidase is a ubiquitous lysosomal
enzyme with elevated levels in HCC patients. It has been
demonstrated that the measurement of - L-fucosidase
together with AFP is useful as a complementary assay (23).
Glypican-3 (GPC-3). GPC-3, a cell surface glycoprotein,
is highly expressed in HCC patients but is absent in normal
healthy controls. GPC-3 regulates the proliferation and
survival of cells and acts as a tumor suppressor. Increased
GPC-3 has been reported in several studies. The serum
levels of its C-terminal and N-terminal fragments have
been measured in different studies. Hippo et al., suggested
that the N-terminal GPC-3 fragment is more predominant
in the serum than the C-terminal fragment (24). GPC-3
specificity is comparable with AFP and its expression is
also increased in malignant melanoma patients.
Transforming growth factor-1 (TGF-1). Plasma levels of
TGF-1, a multi-functional cytokine, are also increased in
HCC patients (25). TGF-1 levels are measured by ELISA.
The authors hypothesize that increased levels of TGF-1
may be due to the decreased hepatic clearance in cirrhotic
patients, which would limit its usefulness in individuals
having advanced liver disease. Additionally, TGF-1 is

expressed or up-regulated in wound healing, fibrosis,

angiogenesis and extra-hepatic tumors (21).
Golgi protein 73 (GP73). GP73 is localized in the
membranes of the cis-Golgi complex, and is up-regulated in
the hepatocytes of patients with cirrhosis or HBV- or HCVrelated HCC. GP73 is analyzed by western blotting, and its
specificity for detecting HCC is superior to AFP. The release
and function of GP73 in HCC patients remains to be
elucidated (21).
Hepatocyte growth factor (HGF). HGF, a multi-functional
cytokine, affects mitogenesis, cell motility, cell invasion
and carcinogenesis and elevated serum levels are observed
in HCV-infected patients. Yamagamim et al. in 2002
studied HGF levels in cirrhotic, HCC and chronic hepatitis
patients and observed high levels in newly-diagnosed HCC
patients (26), which suggested that high levels of HGF
directly correlate with HCC. Additional studies are
necessary to study the inflammatory changes in hepatic
carcinogenesis (21).

Proteomic Approaches
Serum proteomics. Serum proteomics are based on the twodimensional gel electrophoresis technique, which is not
sensitive enough to detect low-abundance proteins. Recently,
surface-enhanced laser desorption/ionization-time of flight
(SELDI-TOF) mass spectrometry has become a superior
method for identifying unique serum fragments. Wang et al.
in 2005 studied two sets of SELDI peaks that allowed for
differentiation between Chinese HCC patients and normal
healthy subjects. A SELDI-based study in French patients
identified six peaks that were changed in 90% of HCC and
non-HCC patients. The informative peak is a C-terminal
fragment (27). A drawback of this method is the limited
range of measurable protein fragments (22).
Serum glycoproteomics. The identification of a new
generation of HCC glycoprotein markers draws attention to
the glycoproteomics approach for the detection of HCC. The
detection of -L-fucosidase serum proteins by ELISA is
currently being studied. Fucosylated differences are being
studied along with the overall abundance of protein markers
in cancer and control patients. Similarly, AFP is being
studied along with GPC-3 (28).

Diagnostic Imaging
Recent advances in imaging techniques play a pivotal role in
the early detection of HCC and have contributed to the
diagnosis of hepatic lesions. Several methods are being used
to diagnose hepatic abnormalities in HCC patients.

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ANTICANCER RESEARCH 34: 1563-1572 (2014)

Ultrasound. Ultrasonography is the oldest technique used in
imaging thanks to its high sensitivity and positive predictive
value. Advances in ultrasound have made it a better tool for
the early diagnosis of cirrhosis and HCC. Color Doppler
ultrasound and Duplex can be used for the intra-hepatic
assessment and vascular flow. HCC lesions show a fine
branching system with high-grade vascularization. The
Doppler evaluation of portal veins helps differentiate
thrombus from tumor invasion. The power Doppler should
be more sensitive in detecting tumor vascularization than
color Doppler (21, 29).
CT Scan. Evaluation of HCC CT scans is performed using
multi-phase contrast imaging of the liver. The intravenous
infusion of a contrast agent is given to the patient and
imaging is then performed at regular intervals. A tri-phase
scan is conducted prior to infusion and during the venous
and arterial phases. In HCC tumors, blood flow through the
hepatic artery is enhanced 2-40 sec after the contrast agent
is infused, and it is enhanced through the portal vein during
the portal phase 50-90 seconds after infusion. The arterial
phase enhances the detection of HCC by 10%. The presence
of lesion nodules is also characteristic of HCC. CT
arteriography is more invasive but also more effective in
increasing the rate and accuracy of detection (21).
MRI. Magnetic Resonance Imaging (MRI) is based on the
same procedure used in CT when evaluating hepatic lesions
for HCC. A time frame of one held breath is now used with
the recently advanced MRI technology. The specificity and
sensitivity of MRI is similar to that of a multiphase CT scan.
The super-paramagnetic iron oxide contrast agent, which
associates with Kupffer cells in the liver, is used to improve
the accuracy of MRI. The combination of superparamagnetic iron oxide and gadolinium chelate gives results
that are comparable to CT scan hepatic arteriography (30).
Angiography. The best diagnostic tool for HCC is
angiography, due to the extensive vascularization of HCC.
However, its ability to detect tumors less than 2 cm in
diameter is disappointing. Thus, the hepatic anatomy is often
detected by angiography prior to resection (21).

Liver biopsy
For approximately half a century, liver biopsy has been safely
and effectively used as a diagnostic tool for hepatic liver
lesions. Fine-needle aspiration (FNA) and needle core biopsy
are used to obtain cytological and histological samples under
ultrasound or CT scan guidance. The combination of these
techniques increases the diagnostic power of liver biopsy. The
microscopic features of HCC include peripheral endothelial
wrapping, atypical naked nuclei and an elevated nuclear-to-

1566

cytoplasmic ratio. The most malignant identifiable

histological feature is dysplasia. Thus, liver biopsy
confirmation of HCC plays a wider role than any other
emerging technique (31). The diagnosis of lesions less than 2
cm in diameter by biopsy has an accuracy of 95.6% (32).

Current Strategies to Treat HCC

Surgical treatment
Currently, surgical resection is the most suitable option for the
treatment of HCC, and its safety has been repeatedly
demonstrated over the last few decades. Resection decreases the
mortality rate to less than 5%. Therefore, surgical resection is
the only option for the resectable tumor and is potentially
satisfactory. Several criteria have been developed for deciding
whether a tumor is resectable, depending on the surgeons skills.
In the majority of Western countries, the most important
criterion for resection is portal hypertension with various
biochemical and imaging findings, including splenomegaly and
esophagogastric varices. BCLC, one of the classic staging
systems for HCC tumors, uses the same criteria along with
solitary HCC and the absence of portal hypertension. In
contrast, indocyanin green retention at 15 min (ICG-R15) is
currently being used for patient selection. This method is used
as a pre-operative tool for assessing liver damage with the
presence or absence of ascites, bilirubin, albumin and
prothrombin (33). For more advanced HCC tumors, greater than
10 cm in diameter, surgical resection is the best treatment. Local
ablation, chemotherapy or liver transplantation, previously
proposed as a strategy to treat hepatic failure, are not
appropriate treatments for these large tumors. The resection of
large HCC tumors can only be achieved when liver functions
are maintained within satisfactory limits. HCC that has invaded
the venous territories has an increased risk of intra-hepatic and
extra-hepatic metastases (34). The resection of HCC with
vascular invasion is dismal because it is technically challenging
to treat such tumors; surgical resection still has better outcomes
than non-surgical treatment of HCC (35). Two procedures have
been reported for resection of the portal vein thrombus. One is
the resection of the involved segment; the second is the peelingoff technique, in which the portal vein is removed and replaced,
and the thrombus is detached from the portal vein and removed
(36). Poon et al. found little benefit for extrahepatic metastatic
resection. The lungs are the primary site of HCC metastasis,
with a metastasis rate of 50-60%. There are different techniques
for tumor resection; the most commonly used methods are
explained by Poon et al. (37).
Anatomic resection. This type of hepatectomy makes use of
ultrasonography to locate the position of the tumor by
injecting a tumor-accumulating dye (indigo carmine) into the
portal vein. The area containing the tumor is demarcated by

Rasool et al: New Possibilities in Hepatocellular Carcinoma Treatment (Review)

electrocautery and resection is performed parenchymally. This

portion of the liver is resected according to the location and
size of the tumor and the liver function background. The postoperative prognosis has been evaluated and its influence by
anatomic resection has been studied recently (38). Anatomic
resection is superior to other methods for prolonging overall
survival, especially in solitary small HCC patients.
Pre-operative and adjuvant treatments. At present, no
approved and established pre-operative adjuvant strategy for
HCC exists, unlike the case for colorectal liver metastasis.
Most studies, including randomized control trials (RCTs),
have not shown any marked benefit for HCC (39). In
contrast, transarterial chemoembolization (TACE) patients
show a good prognosis after hepatic resection. Several
studies emphasize that pre-operative TACE can improve
survival of HCC patients with macroscopic portal vein
invasion or end-stage tumor and/or liver dysfunction.
Additionally, some multi-functional drugs, such as sorafenib,
which possesses anti-proliferative and anti-angiogenic
properties, show survival benefits in HCC patients (40).
Laparoscopic hepatectomy. In the 1990s, the first
laparoscopic liver resection was reported and its use
increased dramatically afterwards, especially during the last
five years. Some surgeons still have difficulty in evaluating
the curative potential of laparoscopic surgery in patients with
HCC and prognosis is still required to justify this minimallyinvasive approach (41). In a conference held in October
2008, surgeons proposed that solitary lesions with diameters
5 cm or less are suitable for laparoscopic hepatectomy (42).
Laparoscopic hepatectomy has been recommended by many
surgeons, especially for patients with a cirrhotic liver,
because there is less intravenous fluid, less fluid loss and less
liver mobilization. However, the downside is that the
morbidity and mortality rates are high compared to open
hepatectomy. Thus, the suitability of laparoscopic
hepatectomy should be determined based on the size, type
and condition of the tumor.
Liver transplantation for HCC. Liver transplantation is based
on the Milan criteria proposed in 1996, which suggested the
best selection criteria for HCC. Subsequent studies have shown
that HCC patients that fulfill the Milan criteria and undergo
transplants have better outcomes than patients that do not fulfill
the criteria. Hepatitis C virus is the most common cause of HCC
globally and it inevitably recurs despite liver transplantation;
cirrhosis is more rapid because of immunosuppression. Thus,
cyclosporine-based
immunosuppressants
should
be
administered. Anti-viral therapy with ribavirin and interferon
before transplantation reduces the risk of fibrosis in implanted
grafts (43). Due to the shortage of donors, liver transplantation
has limited opportunities.

Herbal medication
Based on tradition, herbal medicine makes use of herbs and
extracts made from plants and plant sources to heal and treat
diseases. However, it is important to recognize the difference
between herbal medicine and herbal production, which are
both plant-based remedies. Herbal production is the use of
plant-based medicine of defined quantities required for
efficacy, whereas herbal medicine is devoid of such scientific
information and is used in a crude form to cure a particular
disease. Disease is an imbalanced state of the body and
herbalists believe that herbs can neutralize these imbalances
depending on the basis or the nature of a particular disease.
Generally, herbal medicine is only effective in combination
with other herbal ingredients in a herbal composite
formula. The latest biomolecular studies have shown that
herbal medicines have pleiotropic effects, such as anti-viral,
anti-inflammatory and anti-cancer activities. Some herbal
drugs are also designed to cure HCC (44). Three curative
strategies have been applied to treat HCC: liver
transplantation, surgical resection and local destruction.
Despite these strategies, the rate of HCC recurrence is still
very high; adjuvant treatments, such as TACE, anti-viral
treatments and immunotherapeutics, are given either before
or after treatment. Currently, some medicines are in clinical
trials for HCC, but no single-drug has been approved by the
medical community.
Herbal compounds. Many herbal compounds have been
studied for their curative properties and some have been
proven to be effective against HCC by targeting various
drivers of HCC. These drugs are called targeted-biological
response modifiers. Some of these drugs are listed in Table I.
Herbal Composite Formula. Along with the above-mentioned
compounds derived from herbs, there are many herbal
complex formulas prescribed by herbalists. Because state-ofthe-art technology is now being used, herbal extraction and
purification techniques have dramatically improved. More
refined forms of drugs, such as capsules, tablets and
injections, have replaced the traditional powders, pills and
decoctions. Many composite formulas have been devised and
clinical trials are being conducted to assess the curative
potential of these agents in HCC (44). Some of these are
listed in Table II.

Chemotherapy
Chemotherapy is not routinely administered in the treatment
of HCC for a variety of reasons, including the presence of
the multi-drug resistant gene (MDR1), which limits systemic
chemotherapy efficacy. However, several trials are being
conducted to develop a drug for HCC treatment. For this

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ANTICANCER RESEARCH 34: 1563-1572 (2014)

Table I. Targeted-biological response modifier drugs used against HCC.
Compounds
Curcumin
Resveratrol
Silibinin
Tanshinone IIA

Anti-HCC mechanisms proposed

References

Inhibits proliferation, induces apoptosis and inhibits oncogenic factors, such as nuclear factor B,
p21 (Ras) and histone deacetylases. It also increases the mitochondrial membrane potential.
Inhibits proliferation by down-regulating Bcl-2 and up-regulating Bax.
It also reduces ROS production and modulates NO and NOS.
Causes G1 cell cycle arrest and decreases cyclin D1, cyclin dependent kinase-2 (CDK-2) and CDK4.
It also inhibits cell proliferation, NO production and the ERK cascade.
Induces apoptosis by down regulating Bcl-2. It up regulates Fas, Bax and p53.
It can also inhibit DNA synthesis.

(45)
(46)
(47)
(48)

Table II. Herbal Composite Formulas used against HCC.

Herbal Composite Formula
Sho-saiko-to (TJ-9)
Shenqi mixture (SQM)
Shi-Quan-Da-Bu-Tang (TJ-48)

Possible anti-HCC mechanism

References

Increases TNF-, inhibits 8-OHdG formation, thus reducing DNA synthesis, has cytotoxic effects
Boosts immune system by increasing natural killer cells and CD3 and CD4 positive cells
Inhibits tumor growth and reduces oxidative DNA damage and cytokine expression

(49)
(50)
(51)

purpose, the molecular basis of the disease is routinely and

frequently taken into consideration. Cancer stem cells are a
key target for chemotherapy. The ability of these cells to
infinitely renew and proliferate makes them a target for
several laboratory trials toward the development of effective
chemotherapeutic drugs.
Molecular pathogenesis of HCC. Two predominant
mechanisms have been reported for the pathogenesis of HCC.
One is tissue damage leading to cirrhosis and the second
involves oncogene and tumor suppressor gene mutations. Both
are strongly associated with cell signaling pathway
abnormalities that result in extensive tumor vascularization.
Different tyrosine kinase receptors, such as vascular endothelial
growth factor (VEGF), platelet derived growth factor (PDGF),
epidermal growth factor (EGF), and insulin growth factor
(IGF), facilitate this process cell proliferation (52).
Tyrosine kinase receptors. Tyrosine kinase receptors (PDGF,
VEGF, EGF and IGF) activate the intracellular
RAF/MEK/ERK signaling pathway by activating Ras and are
related to HCC progression. Adult hepatocytes up-regulate
the production of these growth-promoting tyrosine kinase
receptors and this creates a problem when growth is
dysregulated in injured liver, causing sustained signaling
(53). VEGF is a mediator of angiogenesis in HCC and thus
anti-angiogenic drugs can be helpful in treating HCC.
Sorafenib, bevacizumab and other drugs target different
points along these signaling pathways (54).

1568

Sorafenib. Sorafenib is a humanized monoclonal antibody

and an oral multi-kinase inhibitor of VEGF, PDGF, EGF and
IGF. The activation of these receptors activates Ras. Ras
regulates the Raf/MAPK (mitogen activating protein kinase)
and ERK (extracellular signal-regulated kinase) cascades
(55). Tumors secrete different growth factors that bind these
receptors and regulate the cascade to induce angiogenesis
and vascularization. Sorafenib is the first agent to improve
the survival of patients (56). Thus, administration of the drug
can be a potent treatment for HCC.
Bevacizumab. Bevacizumab is a recombinant humanized
monoclonal antibody against VEGF. It is also used for the
treatment of other malignancies, such as colon, breast and
kidney cancers. It can be used alone or in combination with
other chemotherapeutic agents, such as erlotinib, for treating
HCC. Bevacizumab is also being studied by various
scientists in different combinations with gemcitabine,
oxalipitin and capecitabine (57).
Brivanib. Brivanib is a dual inhibitor of the vascular
endothelial growth factor receptor and fibroblast growth
factor receptor pathways and it has shown inhibitory effects
in xenograft mouse models of HCC. Raoul et al., 2009
studied brivanib in advanced metastatic HCC patients and
found that it has efficacy in the post-sorafenib treatment of
HCC (58). Trial results are being awaited for the first-line
setting of brivanib as a best supportive drug in comparison
to sorafenib in HCC (59).

Rasool et al: New Possibilities in Hepatocellular Carcinoma Treatment (Review)

Anti-growth factor receptor strategies. EGFR is overexpressed in 40-70% of patients and was shown to play a
role in the pathogenesis of HCC and tumor angiogenesis via
the activation of the Raf/MEK/ERK and mammalian target
of rapamycin (mTOR) pathways. These receptors can be
targeted to control the progression of HCC via antibodies,
such as cetuximab, erlotinib, bevacizumab, sorafenib and
sunitinib. Gefitinib is also thought to block the extracellular
domain of EGFR. As explained earlier, multiple pathways
are involved in the progression of HCC; thus, it is postulated
that blocking only one pathway may not be effective against
HCC. Multiple signaling pathways should be targeted via the
combination of different chemotherapeutic agents (57).

Radiotherapy
Cellular signaling pathways are key factors of responce to
radiation therapy in normal and tumor cells. Because HCC
is often diagnosed at an advanced stage when tumors are
unresectable, radiotherapy can be safely administered to such
patients as high-dose focused radiation. A wide range of
strategies is being used for this purpose.
Internal radiotherapy. Internal radiotherapy uses regional
radionuclides and is very promising for treating HCC. Radiolabeled antibodies are being used for the radioimmunodetection
of tumors using radio-labeled iodine-131 (131I), which does not
have any destructive effects on the antibody and has promising
results in tumor remission. Currently, yttrium-99 (99Y) is
frequently used for a wide range of internal radiotherapy. It is
a powerful -emitter and is converted to physically-stable
zirconium-90, which has a half-life of 2.7 days. 99Y is typically
used for unresectable HCC tumors having branched/portal vein
thrombosis (PVT) (60).
External radiotherapy. Conformal liver radiotherapy (CRT) is
an emerging strategy for treating unresectable primary or
metastatic tumors of the liver. Three-dimensional CRT shapes
the radiation beam to fit the target; for this purpose, a CT
scan is used for focusing the treatment position via several
optical markers relative to the target in the CT simulator.
While treating with radiotherapy, radiosensitive organs are
taken into consideration and tumor movement during
respiration is also considered (61). The more advanced form
of 3D-CRT is intensity-modulated radiotherapy (IMRT),
which involves non-uniform beam intensity patterns with a
CT scan. This method allows for greater controlled
distribution of the beam and spares radiosensitive organs,
such as the kidney, stomach and spinal cord (62). Another
technique, stereotactic body radiotherapy (SBRT), has been
recently administered for more precise delivery of radiation
to tumors anywhere in the body. SBRT uses external-beam
radiation with pin-point accuracy, thus increasing the

likelihood of precisely killing cancer cells. SBRT involves

just three to five treatments, depending on the severity of the
tumor, over a one- to two-week time frame (63).
Proton therapy. Protons are positively charged particles that
transfer their energy as they slow down, thus exhibiting a
dose peak. This unique dose distribution makes protons
suitable for treatment of deep tumors surrounded by normal
cells anywhere in the body. This method has the advantage
that a lower dose of radiation enters the region in a single
treatment. Additionally, a radiation dose could be directed to
a critical angle and structure due to the finite range and sharp
distal fall-off of the proton particle. Thanks to these
advantages, several clinicians have reported promising
outcomes for HCC patients treated with proton therapy (64).

Future Directions
As reported, HCC is the most aggressive cancer and is often
detected at a terminal stage, with less than 1 year of survival.
The choice of treatment and prognosis depends upon the
severity of the cancer. Circulating tumor cells (CTCs) may be
useful in making these choices. CTCs are the circulating cells
found in the bloodstream or lymphatic system of patients and
are thought to be circulating tumoral microemboli (CTMs).
The aggressiveness of the solid tumors can be detected by the
CTCs and many attempts are underway to design a reliable
assay for their detection to improve the early prognosis of
HCC. CTC detection is usually used for breast cancer
detection, but there are also on-going trials using it as
diagnostic tool for HCC. CTCs can be used to evaluate the
metastasis and early recurrence of disease and are optimal for
the detection of patients eligible for liver transplantation. For
detecting CTCs in the blood, it is essential to identify
circulating hepatoma-specific biomarkers. As reported in the
literature, HCC can synthesize many tumor-related proteins
and isoenzymes, and it is essential to define tumor-specific
biomarkers for HCC detection. Tumors can release many
cytokines, such as VEGF, IL-8 and tumor-specific growth
factor (TSGF), and these could be quite helpful for HCC
prognosis. Additionally, AFP mRNA acts as a circulating
marker that corresponds to normal circulating cells and can
thus be used as a more reliable indicator of disease (65).

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Received January 23, 2014

Revised March 10, 2014
Accepted March 11, 2014

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