hepatocelular carcinoma

8/8/2019 Hepatocelular Carcinoma

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Hepatocelular carcinoma

Introduction:

Hepatocellular carcinoma (HCC) is the third leading

cause of cancer-related death and accounts for as many

as 500 000 deaths annually being a considerable challenge

for surgeons[1]. The incidence of HCC varies by geographic

location from a relatively rare tumor, like those

found in North America and Europe, to a very common

and highly malignant tumor as occurs in sub-Saharan

Africa and Southeast Asia. HCC has been found to account

for 80% of all primary liver cancers, being the

fifth most common cancer worldwide[1,2]. Most patients

with HCC also suffer from coexisting cirrhosis, which

is the major clinical risk factor for hepatic cancer and is

correlated to hepatitis B virus or hepatitis C virus (HCV)

infection[3]. However, cirrhosis from non-viral causes

such as alcoholism, hemochromatosis and primary biliary

cirrhosis are also associated with an elevated risk

of HCC. Furthermore, concomitant risk factors such as

HCV infection in addition to alcoholism, tobacco use,

diabetes or obesity increase the relative risk of HCC development,

as numerous studies in humans and animal

models have shown[4-10]. The incidence of HCC varies

by geographic area worldwide. Research has shown that



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Southeast Asia and sub-Saharan Africa have an incidence

rate of HCC that ranges from 150 to 500 per 100 000

population, primarily because of the endemic nature of

hepatitis B and C in those regions[11-13].

HCV accounts for almost 90% of all cases of HCC

in Japan, and in China, hepatitis B infection is diagnosed

in about 80% of patients with HCC[12-14]. In Europe and

North America, however, despite a significantly lower incidence

rate of 3 to 4 per 100 000 population, a distinct

increase in cases of HCC has been reported as a result

of intravenous drug use, unsafe sexual practices, and

other causes[15-17]. Because of a lack of effective HCV

vaccination, underlying HCV infection is largely responsible

for that increase. As a result of the interval between

the onset of infection and the development of liver cirrhosis,

the incidence of HCV-related HCC will continue

to increase over the next few years[18]. In contrast to

Asian populations, the percentage of Western patients

with HCC but without underlying cirrhosis is considerable,

and the development of HCC in cirrhotic individuals

in the West is associated with a wider spectrum

of underlying diseases. In the West, the percentage of

virally engendered cirrhosis is lower than that in Asian

regions, but alcohol-toxic or cryptogenic hepatic dam-

age is observed more frequently in Western countries[14].

Thus, the etiologic pattern of HCC in Western regions



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of low risk for that disease differs appreciably from that

in Southeast Asia and sub-Saharan Africa.

Surgery, including liver transplantation (LT), still

remains the most important therapeutic approach for

patients with HCC. Over the past few decades, considerable

progress has been made in the diagnosis and surgical

treatment of HCC. In fact, tumors are now often identified

at an early stage[19,20], surgery is safer with an acceptable

overall mortality rate (in cirrhotic patients < 5%),

being characterized by a good long-term survival[21,22] and

results of LT have steadily improved because of careful

patient selection[23].

However, HCC is still associated with a high rate

of mortality and prognosis of this tumor is poor even

when treatment has been considered potentially curative[

24,25].

This brief report summarizes the current status of

the management of this disease and includes a short

description of a new pharmacological approach in HCC

treatment.



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STAGING:

Various classification systems are available for HCC. The

Barcelona Clinic Liver Cancer (BCLC) classification has

emerged during recent years as the standard classification

that is used for trial design and clinical management

of patients with HCC[26,27]. This classification has been

approved by EASL and the AASLD [24,28] and has subsequently

been corroborated in clinical studies [29,30]. The

BCLC staging system was constructed on the basis of

the results obtained in the setting of several cohort studies

and randomized controlled trials by th e Barcelona

group.

The main prognostic factors of this s taging system

are related to tumor status (defined by the number and

size of nodules, the presence or absence of vascular

invasion, and the presence or absence of extrahepatic

spread), liver function (defined by the Child-Pugh score

system, serum bilirubin and albumin levels, and portal

hypertension), and general health status [defined by

the Eastern Cooperative Oncology Group (ECOG),

classification and presence of symptoms]. On the other

hand, aetiology is not an independent prognostic factor.

The BCLC classification links stage stratification with a

recommended treatment strategy and defines standard



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of care for each tumor stage (Figure 1).

Patients with very early HCC (stage 0) are optimal

candidates for resection. Patients with early HCC (stage A)

should be considered for radical therapy [rese ction, LT,

or local ablation via percutaneous ethanol injection (PEI)

or radiofrequency (RF) ablation]. Patients with intermed iate

HCC (stage B) have been found to benefit from

transarterial chemoembolization (TACE). Patients with

advanced HCC, defined as the prese nce of macroscopic

vascular invasion, extrahepatic spread, or cancer-related

symptoms (ECOG performance status 1 or 2) (stage

C), have recently been found to benefit from Sorafenib

treatment[31,32]. Patients with end-stage disease (stage D)

will receive symptomatic treatment.

Treatment strategy will transition from one stage to

another on treatment failure or contraindications for the

procedures.



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HCC TREATMENT OPTIONS:

Liver resection:

Pre-treatment imaging studies such as computed tomography

and magnetic resonance imaging, either with

or without angiography, can be used to match patients

with their most appropriate treatment. Positron emission

tomography is also useful in the identification of

extrahepatic metastases which considerably influence

clinical decision-making. These types of studies aid in

detecting intrahepatic and extrahepatic disease as well

as vascular invasion. Knowledge about the relation of

the tumour to regional anatomic structures su ch as large

vessels is crucial because it provides valuable information

about resectability. Furthermore, volumetric studies

can be used to define the residual parenchyma exactly.

The determination of hepatic reserve is also significant

when resection is considered. The he althy liver has a

great capacity for regeneration and adjusts to the metabolic

requirements of the host after liver resection due

to hypertrophy of the residual live r. Partial hepatectomy

usually ensures a safety margin of at least one centimeter

and is associated with an operative mortality rate of less

than 5%[33,34]. For patients with inadequate or borderline

remnant parenchyma, hypertrophy of the prospective



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liver remnant can be induced by preoperative portal

vein embolization[35]. However, the use of portal vein

embolization to induce compensatory hypertrophy of

healthy liver before major resection is controve rsial. Uncontrolled

tumour progression as a result of the proliferation

of malignant cells stimulated by this me thod and

the risk of variceal bleeding resulting from acute portal

hypertension should be carefully considere d and for that

reason this procedure raises some concerns[36]. In certain

circumstances, an unfavourable location of the tumour

and involvement of the confluence of the three he patic

veins and either the caval vein or the re trohepatic caval

vein can render resection by conventional techniques impossible.

In these rare cases, special techniques such as

in situ or ante situm resection can be used[37].

The overall long-term results after resection are favourable.

However, only 20% to 30% of patients with

HCC are eligible for resection because of advanced or

multifocal disease or inadequate functional hepatic reserve[

38]. In patients with solitary lesions of less than 5 cm,

no vascular invasion, and a negative surgical margin of

at least 1 cm, the 5-year survival rate after resection has

been reported to be greater than 70%[39]. In a series consisting

of 68 patients with HCC and non-cirrhotic liver,

an overall 5-year survival rate of 40% was achieved even



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when extensive resection had been performed[40]. Similar

results were observed in a large series in which patients

with HCC and non-cirrhotic liver demonstrated a survival

rate of 58% after 3 years and 42% after 5 years[41].

Despite earlier detection, safer surgical procedures

and more aggressive treatment of HCC, recurrence, as a

result of multicentric carcinogenesis or intrahepatic metastases

from the primary tumour may occur. In selected

patients, repeat resection provides good long-term benefits

and is an option for those with solitary peripheral

tumors that can be treated with segmental or atypical

resection. In patients with adequate functional reserve

capacity and no extrahepatic tumour growth, the 5-year

survival rate after repeat resection has be en reported to

be as high as 86%[42].

Liver Transplant:

LT is one of the best treatment approaches for HCC

in patients who fulfil the selection criteria (solitary tumors

of less than 5 cm and up to three tumour nodules,

each of which is smaller than 3 cm)[23]. First, it removes

the tumour with the widest margin together with any

intrahepatic metastasis. Second, it cures the underlying

cirrhosis that is responsible for both hepatic decompensation

and metachronous tumour after partial he patectomy.



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Finally, it allows the histologic examination of

the entire liver explant for the most accurate pathologic

staging.

Study results have generally shown a significantly

higher probability of survival in patients with incide ntally

discovered tumors, no vascular invasion, a negative

nodal status, a tumour size of less than 5 cm, and a tumour

of lower histologic grade[43-48]. The 5-year reported

survival rate is around 26% after resection and 69% after

transplantation in cirrhotic patients with HCC[43]. The

decisive prognostic factor for patients with HCC is vascular

invasion, which no system of medical imaging can

accurately demonstrate at this time[49]. Therefore, the preoperativ e

prognosis is still based on the number and size

of tumour nodes demonstrated, due to the evide nce that

vascular invasion has been found to be correlated to tumour

size and number[44]. Because of the present lack of

organs available, an accurate estimation of the patie nts

prognosis is important and not every patient with HCC

and cirrhosis can be treated with LT. Thus the need to

obtain the optimal benefit from the limited number of

organs available has prompted adherence to strict selection

criteria, so that only those patients with early HCC

and the highest likelihood of survival after transplantation

are listed to undergo that procedure (Figure 1).



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Excellent 5-year post-transplant patient survival of

at least 70% has been reported from many centres[50,51].

In another study, excellent results were achieved in patients

with solitary lesions of a maximum diameter of 6.5

cm, patients with a maximum of three lesions (the largest

of which was no larger than 4.5 cm), and those who

had no more than 8 cm in diamete r in all tumour nodes.

The 1-year and 5-year survi val rates of these patients

were as high as 90% and 72%, respectively[52].

Even if the selection criteria for LT to treat HCC

could be expanded, the current shortage of liver grafts

and the lack of data defining the new limits for LT in

patients with HCC makes the attempt t o expand the

listing criteria a very controversial issue. As a result of

expanded listing criteria, the inclusion of patients with

more advanced cancer may result in a higher dropout

rate that in turn leads to poor survival rates in an intentto-

treat analysis[53,54].

In their recent publication, Mazzaferro and colleagues[

55] developed a new prognostic model that could

be used to expand the Milan criteria and help identify

patients whose odds of survival could be improved b y

having a liver transplant. Using the up-to-seven criteria,

where seven is the maximum number obtained by

adding the size of the largest tumour (in centimeter) to



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the total number of tumors, the report indicates that the

5-year survival in patients without microvascular invasion

was 71.2%, similar to patients who met the Milan

criteria. The researchers conclude: more patie nts with

HCC could be candidates for transplantation if the current

dual (yes/no) approach to candidacy, based on the

strict Milan criteria, was replaced with a more precise

estimation of survival contouring individual tumour

characteristics and use of the up-to-seven criteria.

Stage 0

PST 0, Child-Pugh A

Stage A-C

PST 0-2, Child-Pugh A-B

Stage D

PST > 2, Child-Pugh C

Early stage (A)

Single or 3 nodules < 3 cm, PS 0

Intermediate stage (B)

Multinodular, PST 0

Advanced stage (C)

Portal invasion, N1, M1, PST 1-2

Very early stage (0)

Single < 2 cm

Carcinoma in situ

End stage (D)



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HCC

Single

Portal pressure/bilirubin

Normal

Resection

Increased Associated diseases

3 nodules 3 cm

No Yes

Liver transplantation

(CLT/LDLT)

PEI/RF TACE Sorafenib

Curative treatments (30%)

5-yr survival: 40%-70%

Randomized controlled trials (50%)

Median survival 11-20 mo

Symptomatic treatment (20%)

Survival < 3 mo

Figure 1 Barcelona Clinic Liver Cancer staging classification and

treatment schedule[27].

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2009 Volume 15 Number 26

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Therefore, the ultimate therapeutic choice should

always result from the analysis of each individual case

and should be based on the experience and judgment of



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the transplant team and not just on the statistical results

derived from the literature.

The wait for a graft to become available still presents

the greatest challenge. Methods of neoadjuvant therapy

(PEI, RF, TACE) may be used to provide tumour

control in patients on a waiting list for LT.

Patients can reach a prognostically unfavourable

stage because of tumour progression with subsequent

deterioration of their clinical profile while waiting and

may no longer fulfil the criteria for LT[52]. As a result,

these patients should be removed from the waiting list,

indeed about 50% of HCC patients who were initially

candidates for LT will become ineligible for transplantation

if the median waiting period exceeds 1 ye ar[53,56].

Strategies to increase the donor pool and diminish

the tumour progression rate have become a priority in

many centres. In the United States, the United Network

for Organ Sharing proposed a new system to allocate patients

on the list according to the Mode l for End-Stage

Liver Disease score[57]. This change give s priority to patients

to minimize drop-out rates and has improved the

access to timely liver transplant for patients with HCC[58].

Recent advances in adult living-donor liver

transplantation (LDLT) may produce a drastic change

in the role of transplantation surgery for HCC. This



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option enables patients to avoid the long waiting time

before transplantation and consequently to reduce the

dropout rate. The keynote of living donation in patients

with HCC and cirrhosis is supported by these factors:

(1) Better graft function, because each graft is obtained

from a healthy person;

(2) Better clinical condition of the patient at the time of

transplantation;

(3) Optimal organ harvest, conservation, and reduced cold ischemia

time;

(4) A significantly reduced waiting time.

Whether LDLT is indicated in patients with HCC

that exceeds the Milan criteria remains controversial[59,60].

A recent survey of transplant surgeons from North

America, Europe, and Asia revealed that 41% of the respondents

favoured LDLT for use in patients with HCC

that exceeds the Milan criteria[61]. Patients who no longer

fulfil the criteria because of tumour size or the number

of tumour nodes may still retain the option of LDLT.

Because a potential 5-year survival rate of around 50%

in patients whose LT is justified by exte nded criteria has

been described[53], transplantation would offer a better

chance of survival than would all other therapeutic options.



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However, evidence-based universal guidelines for

this important issue have not been established. Pri mary

graft failure and the risk to the donor present ethical

concerns that cannot be disregarded. Donor deaths and

other complications, such as insufficiency of the donors

remaining liver (which required subsequent transplantation),

have been reported[62]. Furthermore, some data

also suggest the need to have a better evaluation of the

donor, including liver histology[63]. The complication rate

for LT in North America and Europe ranges between

9.2% and 40% for the donor, and the mortality risk in

donors is still 0.3% to 0.61%[64,65 ]. In contrast, data

in Japan showed a complication rate of 12% with no

perioperative deaths in living liver donors[66]. Meticu lous

surgical techniques and perioperative management, lean

body mass in individual Japanese donors, and genetic

factors were given as possible explanations for the zero

transplant-related mortality rate in Japan. In general,

however, morbidity after living liver donation strongly

correlates with the expertise of the staff of the transp lant

centre. Therefore, a combination of surgical expertise

and thorough, individualized medical and psychological

evaluations is vital to ensure the lowest morbidity

rate and best outcome, not only in the recipient, but also

in the donor.



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Locoregional procedures and

chemotherapy:

Percutaneous ablation:

For patients who are not candidates

for liver resection or transplantation, percutaneous

ablation offers the best treatment option. However,

to our knowledge, there are no randomized controlled

clinical trials that have compared the results of this treatment

option with those of surgical therapy for HCC,

and none of the ablation techniques have been shown

to offer a definitive surviv al advantage. The principle of

ablation is based on the destru ction of tumour cells by

the application of chemical substances, su ch as ethanol,

or by using RF or laser to modify the temperature in the

tumour via the delivery of heat. Of all those technique s,

PEI has been the most investigated[67]. In individuals

who do not fit the optimal surgical profile, PEI is as effective

as surgery and is associated with a 5-year surviv al

rate as high as 72% if the accurate selection of patients

is performed[68,69]. The low rate of procedure-re lated

complications and the low cost of PEI a re additional

advantages. The main drawback of this technique is the

need for repeated injections in separate sessions and the

inability to achieve complete necrosis in larger tumors.



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In that regard, RF ablation has be en shown to be more

effective in achieving complete necrosis in tumors larger

than 2 cm and to require fewer treatment sessions[70]. RF

ablation involves the delivery of energy created by RF

waves to tumors to induce thermal da mage and coagulative

necrosis. Study results have shown that RF ablation

is superior to PEI in terms of causing complete tumour

necrosis (90% vs 80%) and in the number of required

treatments (1.2 vs 4.8)[71]. However, RF ablation causes

more complications such as pleural effusion, bleeding,

and tumour seeding than does PEI[71,72]. In addition, the

effectiveness of RFA decreases as the tumour size exceeds

3 cm.

Chemoembolization:

This approach can be used before

liver resection to improve resectability, as a bri dge

to LT while awaiting organ availability, or as a palliative

treatment, and it may offer patients with preserved liv er

function and no evidence of ascites a surviv al advantage[

73]. Chemoembolization is based on the principle of

arterial obstruction (obstruction of the hepatic artery

during angiography via the use of agents such as an absorbable

gelatin sponge, alcohol, etc, to induce ischemic

tumour necrosis). This technique is effective because the

growth of HCC depends primarily on the hepatic artery



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blood supply, but the healthy hepatic parenchyma has a

dual blood supply (85% is supplied by the portal vein,

and the remainder is supplied by the he patic artery). The

injection of a chemotherapeutic agent [usually cisplatin,

doxorubicin hydrochloride (Adriamycin), or mitomycin

C] before arterial obstruction (transcatheter arterial embolization)

results in TACE, a method by which regionally

elevated levels of these agents in the live r can be

achieved while concomitant systemic toxicity is avoided.

When compared with controls, patients treated with

TACE exhibited a decrease in tumour size of 16% to

61% and a 1-year survival advantage as high as 82%[74-77].

Systemic treatment:

A number of systemic chemotherapies have been evaluated

in many clinical trials. Unfortunately, no sing le agent

or combination of agents given systemically leads to reproducible

response rates that show beneficial effe ct of

systemic chemotherapy on survival rates[78]. Tamoxifen,

octreotide, interferon, and interleukin-2 have not been

shown to be effective in treating HCC in randomized

controlled clinical trials[79,80]. The increasing knowledge in

the molecular structure of HCC as well as the introduction

of molecular targeted therapies in oncology have

created an encouraging trend in the management of this



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disease[81]. These targeted molecular therapies are aimed

at growth factors and their receptors, intracellular signal

transduction and cell cycle control. Recent positive results

from a preliminary study of the receptor tyrosine

kinase inhibitor, sorafenib, have bee n reported in the

treatment of HCC[31,32]. This oral multikinase inhibitor

action of several kinases (VEGF, PDGF, c-kit receptor,

Raf) involved in both tumour cell proliferation (tumour

growth) and angiogenesis (tumour blood supply).



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CONCLUSION:

Novel treatment options based on an improved understanding

of the molecular pathogenesis of HCC have

been proposed. Nonetheless a substantial improvement

in the outcomes of intermediate and advanced stage

HCC is expected with the advent of these targeted the rapies,

used in combination with surgical or locoregional

therapies.

LT still remains an important treatment approach f or

HCC and is a well-documented and proven treatment

modality for this disease. However, early unsatisfactory

results have emphasized that only a highly selected

patient population would benefit from transplantation.

Pretransplantation therapies and the deve lopment of

novel agents to prevent progression of HCC in patients

awaiting LT are neede d. Promotion of organ donation

is necessary, the role of new systemic therap y is now

becoming a new and interesting option in the treatment

of patients with HCC, but LDLT as the dominant

strategy will continue to escalate.



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S- Editor Cheng JX L- Editor Webster JR E- Editor Zheng XM



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J Gastroenterol 2009; 44[Suppl XIX]:136±141DOI 10.1007/s00535-008-2252-z

Molecular targeted therapy f or

hepat o

cell

ul

ar carcinom

aM ELANIE T HOMAS

Di vi s i on of Hematology/ O n cology Hol l i n gs Can cer Cen ter , Medi cal Un i vers i ty of S ou th Carol i n a ,

Charleston , S C 29425, US A

A majority of patients with HCC present with advanced

disease and are not candidates for liver transplantation,

surgical resection, or regional therapy. Systemic

cytotoxic chemotherapy agents are minimally effective,

can have significant toxicity, and have not been

shown to improve patient survival. Hepatocellular carcinomas

are inherently chemotherapy-resistant tumors

and are known to overexpress the multidrug resistance

genes. Hepatocellular carcinoma is a very heterogeneous

disease in terms of its etiology, molecular carcinogenic

mechanisms, and biological behavior, which

complicate our ability to identify rational molecular

therapeutic targets. Nearly every pathway involved

in carcinogenesis is altered to some degree in HCC.

Changes in hepatocyte growth factor expression, intracellular

signaling, protease and matrix metalloproteinase

expression, and oncogene expression are seen in

HCC. The recent demonstration, in randomized clinical

trials, of survival benefit for HCC patients treated with

the oral agent sorafenib is encouraging progress in the

development of molecularly targeted anticancer agents in HCC.



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[Type text] Page 32

Key words: hepatocellular carcinoma, HCC, chemotherapy,

targeted therapy

Introduction

Hepatocellular carcinoma (HCC) is potentially curable

by surgical resection and liver transplantation. However,

the majority of patients present with advanced-stage

disease, which is most commonly accompanied by severe

background liver disease. Hence, surgery is feasible for

only a small fraction of patients with localized disease,

and liver transplantation is severely limited by the availability

of liver donors. Systemic cytotoxic therapies

have demonstrated a very limited impact on the natural

history of advanced HCC (Table 1). A 1997 metaanalysis

evaluating the results of 37 randomized clinical

trials of systemic and regional chemotherapy in 2803

HCC patients concluded that nonsurgical therapies

were ineffective or minimally effective at best.1

Chemotherapy resistance in HCC

Cancer cells, including HCC cells, often have intrinsic

drug resistance mediated via enhanced cellular drug

effl ux of several cytotoxic agents. This phenomenon is

associated with increase in a drug transporter family,

the adenosine triphosphate-binding cassette proteins

that include MDR1, p-glycoprotein (p-gp), and the

multidrug resistance protein (MRP). 2,3 Both these are

upregulated in HCC. 2,4 Upregulation of MDR1 accompanied

by a decrease in doxorubicin accumulation levels

has been reported in certain HCC cell lines. 5 Th e H19



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gene is thought to induce p-gp expression and MDR1-

associated drug resistance in HCC cells through

regulating MDR1 promoter methylation.5 Also, coexpression

of p53 and p-gp may contribute to HCC chemoresistance

in HCC cell lines. 6 In addition, recent

evidence suggests that hypoxia, MDR1 expression, and

an angiogenic HCC phenotype may be interacting. 7, 8

Topoisomerase IIa encodes an enzyme that is the

target for anticancer chemotherapeutic agents such as

doxorubicin, and mutations are associated with resistance.

9 There is upregulation of topoisomerase IIa in

doxorubicin-resistant HCC cell lines, and its expression

is associated with an aggressive tumor phenotype. 10

Finally, large HCCs commonly develop areas of central

necrosis, which may interfere with drug delivery to the

growing tumor.

Received: June 24, 2008 / Accepted: July 3 , 2008

Reprint requests to: M. Thomas

M. Thomas: Molecular targeted therapy for HCC 137

Thus, to improve the outcome for patients with

advanced HCC, alternatives to traditional cytotoxic

chemotherapy agents are clearly needed. Recently,

molecular characterization of HCC has led to the

recognition of defined aberrant signaling pathways,

which helped in subsequent development of targeted

agents as potential choices for the treatment of this

disease.



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[Type text] Page 34

M olecular therapeutic targets in

hepatocellular carcinoma

In HCC, several crucial intracellular signaling pathways

such as the Ras/Raf/Mek/Erk pathway and PI3k/Akt/

mTOR pathway, in addition to several growth and

angiogenic factors/receptors such as epidermal growth

factor receptor (EGFR), platelet-derived growth factor

receptor (PDGFR), fibroblast growth factor receptor

(FGFR), and vascular endothelial growth factor receptor

(VEGFR), have been recognized. Subsequently,

targeted agents have entered clinical trials in HCC

patients, and this is of particular signifi cance for HCC

in light of the lack of existing effective systemic therapy

for this cancer.

The growth of HCC depends on stimulatory effects

of various growth factors, which bind to tyrosine kinase

receptors and hence activate various intracellular signaling

pathways that subsequently lead to tumor cell

proliferation, survival, migration, and metastasis. Both

the extracellular growth factors and the intracellular

signaling pathways represent potential molecular targets

for therapy of HCC. H owever, the antiangiogenic

pathway looks promising in HCC.

T argeting growth factors in hepatocellular carcinoma

The epidermal growth factor receptor (EGFR) is frequently

expressed in human hepatoma cells, and EGF

may be one of the mitogens needed for the growth of



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hepatoma cells.11,12 Several strategies have been tested

in HCC: one is through using a neutralizing monoclonal

antibody such as cetuximab, and another is using a small

molecule tyrosine kinase inhibitor such as gefi tinib

and erlotinib, as demonstrated in HCC cell cultures.13,14

Erlotinib is an orally active and selective inhibitor of the

EGFR/HER1-related tyrosine kinase enzyme. EGFR/

HER1 expression was detected in 88% of the patients

in a phase II study of erlotinib. 15 In two phase II studies

T able 1. Summary of selected cl inical trials in patients with advanced hepatocel lular carcinoma

(HCC)

Study Regimen Phase Sample size

Response rate

(% )

Median survival

(months)

Cytotoxic chemotherapy

Y eo et al . 59 PIAF vs. adriamycin 3 94/94 20.9 vs . 10.5 8 .6 vs . 6 .83

Mok et al . 60 Nolatrexed vs .

doxorubicin

2 37/17 0 4.9 vs . 3 . 7

Posey et al . 61 TI38067 vs. adriamycin 2/3 169/170 NA 5.7 vs . 5 .6

Gish et al . 62 Nolatrexed vs .

doxorubicin

3 444 1.4 vs . 4 .0 5 .5 vs . 8 ( P ! 0.0068)

Patt et al . 30 Thalidomide 2 37 6% 6.8

Pastorel l i et al . 63 Pegylated doxorubicin

gemcitabine

2 35 23% 8.8



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[Type text] Page 36

Targeted biological therapy

Llovet et al . 53 Sorafenib vs . placebo 3 602 2.3% 10.7 vs . 7 .9 ( P !0.00058)

Abou-Alfa et al . 36 Sorafenib 2 137 2.2 9 .3

Phil ip et al . 16 Erlotonib 2 38 9% 13

Thomas et al . 15 Erlotonib 2 40 0% 10.75

Thomas et al . 64 Bevacizumab erlotonib 2 40 25% 15.65 (CI48-78)

Ramanathan et al . 65 Lapatinib 2 30 5% 6.2

Gruenwald et al . 66 Cetuximab 2 32 0% NR

Zhu et al . 67 Cetuximab 2 30 0% PFS 6 weeks; OS 22

weeks

ODwyer et al . 68 Gefi t inib 2 31 3% PFS 2.8; OS 6.5

Combination cytotoxic biological therapy

Sun et al . 69 Capecitabine, oxal iplatin,

bevacizumab

2 30 11% PFS 5.4

Louafi et al . 70 GEMOX Cetuximab 2 43 23% 9.2

Zhu et al . 42 GEMOX bevacizumab 2 33 20 9.6

PIAF, c i splat i n u m, i n terferon , dox oru bi c i n , an d 5-f l u orou raci l ; O S , overal l su rvi val ; GE MO X, gemci tabi n e ,ox al i plat i n ; PFS , progress i on -free

su rvi val ; TTTF, t i me to treatmen t fai lu re; NR, n o t reported

138 M. Thomas: Molecular targeted therapy for HCC

of this agent, the response rates were 10%, but the

disease control rate was " 50%, and median survival

times were 10.75 and 13 months, respectively.15,16 Other

studies of anti-EGFR agents in HCC are summarized

in Table 2.

Rationale for antiangiogenic therapy of


The cancer cell has been the only target of anticancer



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[Type text] Page 37

therapy for more than 50 years. However, the cancer

cell is genetically unstable, and mutations accumulate.

On the other hand, antiangiogenic therapy targets

endothelial cells that are genetically stable. The genetic

stability of endothelial cells may make them less

susceptible to acquired drug resistance. As a result,

angiogenesis inhibitors are emerging as a new class of

therapeutic agents.

The role of angiogenesis in the initial progression

from a premalignant tumor to a cancer prompted investigators

to study the role of VEGF in the natural history

of HCC.17 In 1999, a group of researchers suggested that

the degree of tissue VEGF expression increased according

to the stepwise development of HCC. 18 In addition,

studies have shown that VEGF was frequently expressed

in HCC. In a quantitative analysis study, VEGF expression

was demonstrated in 63.9% of encapsulated HCC

and 78.3% of nonencapsulated HCC. 19 Another stud y

reported VEGF tissue expression in HCC of 88.8%. 20

Notably, studies have suggested a correlation between

the degree of tissue VEGF expression and the intensity

of both the magnetic resonance signal and the computed

tomographic enhancement of the hepatic artery,

which represent radiologic vascular signals. 2123 Hence,

the hypervascular nature of HCC has led to increasing

interest in exploring the potential of antiangiogenic

therapy in this disease.

T able 2. Ongoing cl inical trials of systemic antiangiogenic therapy in HCC



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[Type text] Page 38

Regimen

Study

phase Patient population Trial #/s ponsor

AZD2171 II Unresectable or metastatic HCC NCT00238394

NC I

AZD-2171 II Unresectable local ly advanced or

metastatic HCC

NCT00427973a

Massachusetts General Hospital/NCI

Bevacizumab II Unresectable or m etastatic HCC NCT00162669

Institute Gusatve Roussy

Bevacizumab Erlotinib II Unresectable HCC N CT00242502

M.D. Anderson Cancer Center

Bevacizumab Erlotinib II Unresectable or metastatic HCC NCT00287222

University of Arkansas/Genentech

Bevacizumab Erlotinib II Advanced unresectable HCC NCT 00365391

Mayo Cl inic/NCI

Bevacizumab Sirol imus I Unresectable local ly advanced or

metastatic HCC

NCT00467194

NC I

BMS-582664 vs. Doxorubicin II Unresectable, local ly advanced or

metastatic HCC

NCT00355238

Bristol-Myers Squibb

BMS-582664 I Advanced HCC with varying

levels of hepatic impairment

NCT00437424a

Bristol-Myers Squibb



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[Type text] Page 39

Sorafenib tegafur/uracil

(UFUR)

II Unresectable local ly advanced or

metastatic HCC

NCT00464919

National Taiwan University Hospital

Doxorubicin ssorafenib II Unresectable or metastatic HCC NCT00108953b

Bayer

Pazopanib I HCC NCT00370513

GlaxoSmithKline

Sunitinib II Unresectable local ly advanced or

metastatic HCC

NCT00361309

Massachusetts General Hospital

Sunitinib II Unresectable HCC NCT00247676

Pfi zer

Thalidomide III Local ly advanced or metastatic

HC C

NCT00225290

TT Y Biopharm

Thalidomide tegafur/uracil

(UFUR)

II Unresectable local ly advanced or

metastatic HCC

NCT00384800

Far Eastern Memorial Hospital

a Not open yet

b No lon ger recru i t i n g pat i en ts




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[Type text] Page 40

Clinical trials of antiangiogenic agents in


Several vascular targeted agents, including thalidomide,

sunitinib, sorafenib, and bevacizumab, have been tested

in advanced HCC (see Tables 1, 2). The thalidomide

mechanism was not clearly known but was thought to

be partly based on its antiangiogenic effects. 2426 Nevertheless,

several clinical trials of thalidomide alone or in

combination with epirubicin or interferon showed rare

responses ranging from 0% to 6.3%. 2733 A recent report

in abstract form of 19 patients treated with oral thalidomide

200 mg/day continuously showed a 6-month

progression-free survival of 41%.34

Sunitinib, an oral multikinase inhibitor, exerts an

antiangiogenic effect by targeting VEGFR and plateletderived

growth factor receptor (PDGFR) tyrosine

kinases. A phase II study of sunitinib alone in 19 patients

with unresectable or metastatic HCC reported a partial

response in 1 patient.35

Sorafenib, an oral multikinase inhibitor, exerts an

antiangiogenic effect by targeting VEGFR and PDGFR

tyrosine kinases. It exerts its effect through targeting

Raf/MEK/ERK signaling at the level of Raf kinase and

exerts an antiangiogenic effect by targeting VEGFR-2/

-3. A phase II study of Sorafenib alone in advanced

HCC showed 2.2% partial and 5.8% minor response.36

Recently, a randomized, placebo-controlled phase III

trial of Sorafenib in advanced HCC reported a 2.8-



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month improvement in median overall survival [hazard

ratio (HR), 0.69; 95% confi dence interval (CI), 0.55

0.87; P !0.0006] along with increased time to progression

and disease control rate. 37

Bevacizumab is a recombinant, humanized monoclonal

antibody that targets VEGF and may augment chemotherapy

administration by making tumor vasculature

less permeable and decreasing the elevated tumor interstitial

pressure.38,39 Two recent phase II trials of bevacizumab

alone in advanced HCC suggested an improved

disease control, with one reporting a partial response

rate of 12.5% with a disease control rate (PR SD) of

67%.40,41 Bevacizumab was also combined with gemcitabine

and oxaliplatin in a phase II trial of advanced

HCC with an overall response rate of 20%. 42 A phase

II trial of bevacizumab capecitabine as a fi rst-line

treatment for advanced HCC recently reported a

response rate (CR PR) of 16% (95% CI, 4.5%36.1%)

and disease control rate (CR PR SD) of 60% (95%

CI, 38.7%78.9%), with a median overall survival of

10.7 months (95% CI, 5.314.7) and median progression-

free survival (PFS) o f 4.1 months. 43 In addition, a

phase II study of advanced or unresectable metastatic

HCC treating 30 patients with bevacizumab, oxaliplatin,

and capecitabine reported an 11% response rate with

mean PFS of 5.4 months.44 An ongoing phase II, singlearm,

open-label trial of bevacizumab and erlotinib in 29



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patients with unresectable HCC recently showed a 22%

response rate.45

There is a number of ongoing clinical trials of different

vascular targeted agents in HCC (see Table 2). Preclinical

studies of agents that target other foci which

interact with VEGF, such as hypoxia-inducible factor

(HIF)-1 alpha and APRIL (a proliferation-inducing

ligand), have shown promising results with reduced

VEGF expression in HCC cell cultures.46,47

Additional molecular pathways targeted in HCC

clinical trials

Mitogen-activated protein kinase pathway

The mitogen-activated protein kinase (MAPK) pathway

includes a cascade of phosphorylation of four major

cellular kinases, ras, raf, mitogen-activated protein

kinase (MAP), and extracellular signal-regulated kinase

(ERK), which is responsible mainly for cellular differentiation

and proliferation signal transduction. These

intermediates are found to be high in both HCC cell

lines and human specimens.4851 Notably, for Ras proteins

to be competent for signal transduction, posttranslational

modifi cation by incorporation of farnesyl and

geranylgeranyl groups is required. One of the inhibitors

of farnesyl transferase has been developed to prevent

prenylation of Ras proteins: ABT-100, which has

been shown to prevent the development of chemically

induced HCC in rats. 52 Raf kinase inhibitor Bay-439006



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[Type text] Page 43

(sorafenib), a therapeutic agent that targets this pathway,

is currently the most promising molecular targeting

drug for HCC that has undergone phase I, II, and III

trials. It targets both raf and vascular endothelial growth

factor receptor (VEGFR). A phase II trial of sorafenib

demonstrated antitumor activity in advanced HCC

patients. This study did not meet its primary endpoint

of response on the basis of World Health Organization

(WHO) criteria, with a response rate of 2.2%.

However, 33.6% of patients had stable disease for at

least 4 months, with many showing central tumor necrosis.

36 On the basis of the encouraging overall survival of

9.2 months reported in the phase II trial, a placebocontrolled

international trial was completed in HCC

patients with ChildsPugh A cirrhosis.53 The results

concluded that sorafenib offers a survival advantage

compared with placebo (10.7 months vs. 7.9 months,

HR 0.69; 95% CI, 0.55 to 0.87). This may be comparable

to survival observed with other biological agents (see

Table 2).

140 M. Thomas: Molecular targeted therapy for HCC

PI3K/AKT/mTOR pathway (phosphoinositid e-3 kinase/

protein kinase B/mammalian target

of rapamycin)

Activation of PI3K subsequently activates Akt kinase,

which phosphorylates and inactivates several proapoptotic

proteins. This activity in turn leads to a number of

downstream events that are responsible for cellular proliferation



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and apoptosis and is closely linked to the cell

cycle.54,55 This pathway is known to be upregulated in a

subset of HCC patients. Furthermore, mTOR is a downstream

of Akt that regulates cellular translational activities

through the eukaryotic initiation factor 4E-binding

protein-1 (4E-BP1) and the 40s ribosomal protein S6

kinase (p70s6k); these are linked with the translation of

mRNAs of genes regulating cell proliferation and angiogenesis,

such as c-my c , cyclin D1, a nd HIF-1£ .56 Rapamycin

is an antibiotic that inhibits mTOR and is clinically

used as an immunosuppressive drug to prevent graft

rejection. It was shown to possess activity against HCC

cell lines.57,58

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