Page 1 of 52

[Type text] Page 1

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
Page 2 of 52

[Type text] Page 2

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
Page 3 of 52

[Type text] Page 3

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.






Page 4 of 52

[Type text] Page 4

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 the Barcelona
group.
The main prognostic factors of this staging 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
Page 5 of 52

[Type text] Page 5

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 [resection, LT,
or local ablation via percutaneous ethanol injection (PEI)
or radiofrequency (RF) ablation]. Patients with intermediate
HCC (stage B) have been found to benefit from
transarterial chemoembolization (TACE). Patients with
advanced HCC, defined as the presence 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.







Page 6 of 52

[Type text] Page 6

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 such 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 healthy 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 liver. 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
Page 7 of 52

[Type text] Page 7

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 controversial. Uncontrolled
tumour progression as a result of the proliferation
of malignant cells stimulated by this method and
the risk of variceal bleeding resulting from acute portal
hypertension should be carefully considered 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 hepatic
veins and either the caval vein or the retrohepatic 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
Page 8 of 52

[Type text] Page 8

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 been 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 hepatectomy.
Page 9 of 52

[Type text] Page 9

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 incidentally
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 preoperative
prognosis is still based on the number and size
of tumour nodes demonstrated, due to the evidence 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 patients
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).
Page 10 of 52

[Type text] Page 10

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 diameter in all tumour nodes.
The 1-year and 5-year survival 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 to 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 by
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
Page 11 of 52

[Type text] Page 11

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 patients 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)
Page 12 of 52

[Type text] Page 12

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].
3212 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol July 14,
2009 Volume 15 Number 26
www.wjgnet.com
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
Page 13 of 52

[Type text] Page 13

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 year[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 Model for End-Stage
Liver Disease score[57]. This change gives 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
Page 14 of 52

[Type text] Page 14

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 extended criteria has
been described[53], transplantation would offer a better
chance of survival than would all other therapeutic options.
Page 15 of 52

[Type text] Page 15

However, evidence-based universal guidelines for
this important issue have not been established. Primary
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]. Meticulous
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 transplant
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.
Page 16 of 52

[Type text] Page 16

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 survival advantage. The principle of
ablation is based on the destruction of tumour cells by
the application of chemical substances, such as ethanol,
or by using RF or laser to modify the temperature in the
tumour via the delivery of heat. Of all those techniques,
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 survival
rate as high as 72% if the accurate selection of patients
is performed[68,69]. The low rate of procedure-related
complications and the low cost of PEI are 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.
Page 17 of 52

[Type text] Page 17

In that regard, RF ablation has been 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 damage 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 bridge
to LT while awaiting organ availability, or as a palliative
treatment, and it may offer patients with preserved liver
function and no evidence of ascites a survival 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
Page 18 of 52

[Type text] Page 18

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 hepatic 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 liver 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 single agent
or combination of agents given systemically leads to reproducible
response rates that show beneficial effect 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
Page 19 of 52

[Type text] Page 19

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 been 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).










Page 20 of 52

[Type text] Page 20

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 therapies,
used in combination with surgical or locoregional
therapies.
LT still remains an important treatment approach for
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 development of
novel agents to prevent progression of HCC in patients
awaiting LT are needed. Promotion of organ donation
is necessary, the role of new systemic therapy 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.




Page 21 of 52

[Type text] Page 21

REFERENCES
1 Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world
cancer burden: Globocan 2000. Int J Cancer 2001; 94: 153-156
2 Befeler AS, Di Bisceglie AM. Hepatocellular carcinoma:
diagnosis and treatment. Gastroenterology 2002; 122:
1609-1619
3 Liu JH, Chen PW, Asch SM, Busuttil RW, Ko CY. Surgery
for hepatocellular carcinoma: does it improve survival? Ann
Surg Oncol 2004; 11: 298-303
4 Fong TL, Kanel GC, Conrad A, Valinluck B, Charboneau F,
Adkins RH. Clinical significance of concomitant hepatitis C
infection in patients with alcoholic liver disease. Hepatology
1994; 19: 554-557
5 Ming L, Thorgeirsson SS, Gail MH, Lu P, Harris CC,
Wang N, Shao Y, Wu Z, Liu G, Wang X, Sun Z. Dominant
role of hepatitis B virus and cofactor role of aflatoxin in
hepatocarcinogenesis in Qidong, China. Hepatology 2002; 36:
1214-1220
6 Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D,
Abbruzzese JL, Beasley P, Patt YZ. Risk factors for
hepatocellular carcinoma: synergism of alcohol with
viral hepatitis and diabetes mellitus. Hepatology 2002; 36:
1206-1213
7 Ohata K, Hamasaki K, Toriyama K, Matsumoto K, Saeki
A, Yanagi K, Abiru S, Nakagawa Y, Shigeno M, Miyazoe
S, Ichikawa T, Ishikawa H, Nakao K, Eguchi K. Hepatic
steatosis is a risk factor for hepatocellular carcinoma in
patients with chronic hepatitis C virus infection. Cancer
2003; 97: 3036-3043
8 El-Serag HB, Richardson PA, Everhart JE. The role of
diabetes in hepatocellular carcinoma: a case-control study
among United States Veterans. Am J Gastroenterol 2001; 96:
Page 22 of 52

[Type text] Page 22

2462-2467
9 Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag
HB. Diabetes increases the risk of hepatocellular carcinoma
in the United States: a population based case control study.
Gut 2005; 54: 533-539
10 Chokshi MM, Marrero JA. Hepatocellular carcinoma. Curr
Opin Gastroenterol 2001; 17: 276-280
11 Kew MC. The development of hepatocellular cancer in
humans. Cancer Surv 1986; 5: 719-739
12 Di Bisceglie AM. Hepatitis C and hepatocellular carcinoma.
Semin Liver Dis 1995; 15: 64-69
13 El-Serag HB. Hepatocellular carcinoma and hepatitis C in
the United States. Hepatology 2002; 36: S74-S83
14 Beasley RP. Hepatitis B virus. The major etiology of
hepatocellular carcinoma. Cancer 1988; 61: 1942-1956
15 Wingo PA, Tong T, Bolden S. Cancer statistics, 1995. CA
Cancer J Clin 1995; 45: 8-30
16 El-Serag HB, Mason AC. Rising incidence of hepatocellular
carcinoma in the United States. N Engl J Med 1999; 340:
745-750
17 Allen J, Venook A. Hepatocellular carcinoma: epidemic and
treatment. Curr Oncol Rep 2004; 6: 177-183
18 Tanaka Y, Hanada K, Mizokami M, Yeo AE, Shih JW,
Gojobori T, Alter HJ. Inaugural Article: A comparison of the
molecular clock of hepatitis C virus in the United States and
Japan predicts that hepatocellular carcinoma incidence in
the United States will increase over the next two decades.
Proc Natl Acad Sci USA 2002; 99: 15584-15589
19 Bolondi L, Sofia S, Siringo S, Gaiani S, Casali A, Zironi
G, Piscaglia F, Gramantieri L, Zanetti M, Sherman M.
Surveillance programme of cirrhotic patients for early
diagnosis and treatment of hepatocellular carcinoma: a cost
Page 23 of 52

[Type text] Page 23

effectiveness analysis. Gut 2001; 48: 251-259
20 Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma.
Lancet 2003; 362: 1907-1917
21 Makuuchi M, Sano K. The surgical approach to HCC: our
progress and results in Japan. Liver Transpl 2004; 10: S46-S52
22 Shimozawa N, Hanazaki K. Longterm prognosis after
3214 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol July 14, 2009 Volume 15 Number 26
www.wjgnet.com
hepatic resection for small hepatocellular carcinoma. J Am
Coll Surg 2004; 198: 356-365
23 Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti
A, Bozzetti F, Montalto F, Ammatuna M, Morabito A,
Gennari L. Liver transplantation for the treatment of small
hepatocellular carcinomas in patients with cirrhosis. N Engl
J Med 1996; 334: 693-699
24 Bruix J, Sherman M. Management of hepatocellular
carcinoma. Hepatology 2005; 42: 1208-1236
25 Tang ZY. Hepatocellular carcinoma--cause, treatment and
metastasis. World J Gastroenterol 2001; 7: 445-454
26 Tang ZY. Hepatocellular carcinoma. J Gastroenterol Hepatol
2000; 15 Suppl: G1-G7
27 Llovet JM, Di Bisceglie AM, Bruix J, Kramer BS, Lencioni
R, Zhu AX, Sherman M, Schwartz M, Lotze M, Talwalkar
J, Gores GJ. Design and endpoints of clinical trials in
hepatocellular carcinoma. J Natl Cancer Inst 2008; 100: 698-711
28 Bruix J, Sherman M, Llovet JM, Beaugrand M, Lencioni
R, Burroughs AK, Christensen E, Pagliaro L, Colombo M,
Rods J. Clinical management of hepatocellular carcinoma.
Conclusions of the Barcelona-2000 EASL conference.
European Association for the Study of the Liver. J Hepatol
2001; 35: 421-430
29 Marrero JA, Fontana RJ, Barrat A, Askari F, Conjeevaram
Page 24 of 52

[Type text] Page 24

HS, Su GL, Lok AS. Prognosis of hepatocellular carcinoma:
comparison of 7 staging systems in an American cohort.
Hepatology 2005; 41: 707-716
30 Cillo U, Vitale A, Grigoletto F, Farinati F, Brolese A, Zanus
G, Neri D, Boccagni P, Srsen N, D'Amico F, Ciarleglio
FA, Bridda A, D'Amico DF. Prospective validation of the
Barcelona Clinic Liver Cancer staging system. J Hepatol 2006;
44: 723-731
31 Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc
JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz
M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz
JF, Borbath I, Hussinger D, Giannaris T, Shan M, Moscovici
M, Voliotis D, Bruix J. Sorafenib in advanced hepatocellular
carcinoma. N Engl J Med 2008; 359: 378-390
32 Llovet JM, Bruix J. Molecular targeted therapies in
hepatocellular carcinoma. Hepatology 2008; 48: 1312-1327
33 Buell JF, Rosen S, Yoshida A, Labow D, Limsrichamrern
S, Cronin DC, Bruce DS, Wen M, Michelassi F, Millis JM,
Posner MC. Hepatic resection: effective treatment for
primary and secondary tumors. Surgery 2000; 128: 686-693
34 De Carlis L, Giacomoni A, Pirotta V, Lauterio A, Slim AO,
Sammartino C, Cardillo M, Forti D. Surgical treatment of
hepatocellular cancer in the era of hepatic transplantation. J
Am Coll Surg 2003; 196: 887-897
35 Vauthe y JN, Cha oui A, Do KA, Bi l imo r i a MM,
Fenstermacher MJ, Charnsangavej C, Hicks M, Alsfasser
G, Lauwers G, Hawkins IF, Caridi J. Standardized
measurement of the future liver remnant prior to extended
liver resection: methodology and clinical associations.
Surgery 2000; 127: 512-519
36 Farges O, Belghiti J, Kianmanesh R, Regimbeau JM,
Santoro R, Vilgrain V, Denys A, Sauvanet A. Portal vein
Page 25 of 52

[Type text] Page 25

embolization before right hepatectomy: prospective clinical
trial. Ann Surg 2003; 237: 208-217
37 Oldhafer KJ, Lang H, Malag M, Testa G, Broelsch CE. [Ex
situ resection and resection of the in situ perfused liver: are
there still indications?] Chirurg 2001; 72: 131-137
38 Tsuzuki T, Sugioka A, Ueda M, Iida S, Kanai T, Yoshii H,
Nakayasu K. Hepatic resection for hepatocellular carcinoma.
Surgery 1990; 107: 511-520
39 Yamanaka N, Okamoto E, Toyosaka A, Mitunobu M,
Fujihara S, Kato T, Fujimoto J, Oriyama T, Furukawa K,
Kawamura E. Prognostic factors after hepatectomy for
hepatocellular carcinomas. A univariate and multivariate
analysis. Cancer 1990; 65: 1104-1110
40 Bismuth H, Chiche L, Castaing D. Surgical treatment of
hepatocellular carcinomas in noncirrhotic liver: experience
with 68 liver resections. World J Surg 1995; 19: 35-41
41 Fong Y, Sun RL, Jarnagin W, Blumgart LH. An analysis of
412 cases of hepatocellular carcinoma at a Western center.
Ann Surg 1999; 229: 790-799; discussion 799-800
42 Marn-Hargreaves G, Azoulay D, Bismuth H. Hepatocellular
carcinoma: surgical indications and results. Crit Rev Oncol
Hematol 2003; 47: 13-27
43 Ringe B, Weimann A, Tusch G, Pichlmayr R. Resection
versus transplantation for malignancy of liver and bile
duct. In: Wanebo HJ, ed. Surgery for gastrointestinal cancer.
Philadelphia: Lippincott-Raven, 1997: 513-524
44 Pawlik TM, Delman KA, Vauthey JN, Nagorney DM, Ng IO,
Ikai I, Yamaoka Y, Belghiti J, Lauwers GY, Poon RT, Abdalla
EK. Tumor size predicts vascular invasion and histologic
grade: Implications for selection of surgical treatment for
hepatocellular carcinoma. Liver Transpl 2005; 11: 1086-1092
45 Bismuth H, Chiche L, Adam R, Castaing D, Diamond T,
Page 26 of 52

[Type text] Page 26

Dennison A. Liver resection versus transplantation for
hepatocellular carcinoma in cirrhotic patients. Ann Surg
1993; 218: 145-151
46 Achkar JP, Araya V, Baron RL, Marsh JW, Dvorchik I,
Rakela J. Undetected hepatocellular carcinoma: clinical
features and outcome after liver transplantation. Liver
Transpl Surg 1998; 4: 477-482
47 Ojogho ON, So SK, Keeffe EB, Berquist W, Concepcion W,
Garcia-Kennedy R, Imperial J, Esquivel CO. Orthotopic
liver transplantation for hepatocellular carcinoma. Factors
affecting long-term patient survival. Arch Surg 1996; 131:
935-939; discussion 939-941
48 Molmenti EP, Klintmalm GB. Liver transplantation in
association with hepatocellular carcinoma: an update of the
International Tumor Registry. Liver Transpl 2002; 8: 736-748
49 Plessier A, Codes L, Consigny Y, Sommacale D, Dondero F,
Cortes A, Degos F, Brillet PY, Vilgrain V, Paradis V, Belghiti
J, Durand F. Underestimation of the influence of satellite
nodules as a risk factor for post-transplantation recurrence
in patients with small hepatocellular carcinoma. Liver
Transpl 2004; 10: S86-S90
50 Jonas S, Bechstein WO, Steinmller T, Herrmann M, Radke
C, Berg T, Settmacher U, Neuhaus P. Vascular invasion
and histopathologic grading determine outcome after liver
transplantation for hepatocellular carcinoma in cirrhosis.
Hepatology 2001; 33: 1080-1086
51 Bruix J, Fuster J, Llovet JM. Liver transplantation for
hepatocellular carcinoma: Foucault pendulum versus
evidence-based decision. Liver Transpl 2003; 9: 700-702
52 Yao FY, Ferrell L, Bass NM, Watson JJ, Bacchetti P, Venook
A, Ascher NL, Roberts JP. Liver transplantation for
hepatocellular carcinoma: expansion of the tumor size limits
Page 27 of 52

[Type text] Page 27

does not adversely impact survival. Hepatology 2001; 33:
1394-1403
53 Yao FY, Bass NM, Nikolai B, Davern TJ, Kerlan R, Wu
V, Ascher NL, Roberts JP. Liver transplantation for
hepatocellular carcinoma: analysis of survival according
to the intention-to-treat principle and dropout from the
waiting list. Liver Transpl 2002; 8: 873-883
54 Roayaie S, Haim MB, Emre S, Fishbein TM, Sheiner PA,
Miller CM, Schwartz ME. Comparison of surgical outcomes
for hepatocellular carcinoma in patients with hepatitis B
versus hepatitis C: a western experience. Ann Surg Oncol
2000; 7: 764-770
55 Mazzaferro V, Llovet JM, Miceli R, Bhoori S, Schiavo M,
Mariani L, Camerini T, Roayaie S, Schwartz ME, Grazi GL,
Adam R, Neuhaus P, Salizzoni M, Bruix J, Forner A, De
Carlis L, Cillo U, Burroughs AK, Troisi R, Rossi M, Gerunda
GE, Lerut J, Belghiti J, Boin I, Gugenheim J, Rochling
F, Van Hoek B, Majno P. Predicting survival after liver
transplantation in patients with hepatocellular carcinoma
beyond the Milan criteria: a retrospective, exploratory
analysis. Lancet Oncol 2009; 10: 35-43
56 Sarasin FP, Giostra E, Mentha G, Hadengue A. Partial
hepatectomy or orthotopic liver transplantation for the
treatment of resectable hepatocellular carcinoma? A cost-
Rampone B et al . Hepatocellular carcinoma 3215
www.wjgnet.com
effectiveness perspective. Hepatology 1998; 28: 436-442
57 Saab S, Wang V, Ibrahim AB, Durazo F, Han S, Farmer DG,
Yersiz H, Morrisey M, Goldstein LI, Ghobrial RM, Busuttil
RW. MELD score predicts 1-year patient survival postorthotopic
liver transplantation. Liver Transpl 2003; 9: 473-476
58 Yao FY, Bass NM, Ascher NL, Roberts JP. Liver transplantation
Page 28 of 52

[Type text] Page 28

for hepatocellular carcinoma: lessons from the first year
under the Model of End-Stage Liver Disease (MELD) organ
allocation policy. Liver Transpl 2004; 10: 621-630
59 Helton WS, Di Bisceglie A, Chari R, Schwartz M, Bruix
J. Treatment strategies for hepatocellular carcinoma in
cirrhosis. J Gastrointest Surg 2003; 7: 401-411
60 Bruix J, Llovet JM. Prognostic prediction and treatment
strategy in hepatocellular carcinoma. Hepatology 2002; 35:
519-524
61 Van Kleek EJ, Schwartz JM, Rayhill SC, Rosen HR, Cotler
SJ. Liver transplantation for hepatocellular carcinoma: a
survey of practices. J Clin Gastroenterol 2006; 40: 643-647
62 Pomfret EA. Early and late complications in the right-lobe
adult living donor. Liver Transpl 2003; 9: S45-S49
63 Cuomo O, Perrella A, Pisaniello D, Marino G, Di Costanzo
G. Evidence of liver histological alterations in apparently
healthy individuals evaluated for living donor liver
transplantation. Transplant Proc 2008; 40: 1823-1826
64 Broering DC, Wilms C, Bok P, Fischer L, Mueller L, Hillert
C, Lenk C, Kim JS, Sterneck M, Schulz KH, Krupski G,
Nierhaus A, Ameis D, Burdelski M, Rogiers X. Evolution
of donor morbidity in living related liver transplantation:
a single-center analysis of 165 cases. Ann Surg 2004; 240:
1013-1024; discussions 1024-1026
65 Trotter JF, Wachs M, Everson GT, Kam I. Adult-to-adult
transplantation of the right hepatic lobe from a living donor.
N Engl J Med 2002; 346: 1074-1082
66 Umeshita K, Fujiwara K, Kiyosawa K, Makuuchi M, Satomi
S, Sugimachi K, Tanaka K, Monden M. Operative morbidity
of living liver donors in Japan. Lancet 2003; 362: 687-690
67 Livraghi T, Giorgio A, Marin G, Salmi A, de Sio I,
Bolondi L, Pompili M, Brunello F, Lazzaroni S, Torzilli G.
Page 29 of 52

[Type text] Page 29

Hepatocellular carcinoma and cirrhosis in 746 patients:
long-term results of percutaneous ethanol injection.
Radiology 1995; 197: 101-108
68 Ryu M, Shimamura Y, Kinoshita T, Konishi M, Kawano
N, Iwasaki M, Furuse J, Yoshino M, Moriyama N, Sugita
M. Therapeutic results of resection, transcatheter arterial
embolization and percutaneous transhepatic ethanol
injection in 3225 patients with hepatocellular carcinoma: a
retrospective multicenter study. Jpn J Clin Oncol 1997; 27:
251-257
69 Lau H, Fan ST, Ng IO, Wong J. Long term prognosis after
hepatectomy for hepatocellular carcinoma: a survival analysis
of 204 consecutive patients. Cancer 1998; 83: 2302-2311
70 Lin SM, Lin CJ, Lin CC, Hsu CW, Chen YC. Radiofrequency
ablation improves prognosis compared with ethanol
injection for hepatocellular carcinoma < or =4 cm.
Gastroenterology 2004; 127: 1714-1723
71 Livraghi T, Goldberg SN, Lazzaroni S, Meloni F, Solbiati L,
Gazelle GS. Small hepatocellular carcinoma: treatment with
radio-frequency ablation versus ethanol injection. Radiology
1999; 210: 655-661
72 Livraghi T, Solbiati L, Meloni MF, Gazelle GS, Halpern
EF, Goldberg SN. Treatment of focal liver tumors with
percutaneous radio-frequency ablation: complications
encountered in a multicenter study. Radiology 2003; 226:
441-451
73 Llovet JM, Real MI, Montaa X, Planas R, Coll S, Aponte J,
Ayuso C, Sala M, Muchart J, Sol R, Rods J, Bruix J. Arterial
embolisation or chemoembolisation versus symptomatic
treatment in patients with unresectable hepatocellular
carcinoma: a randomised controlled trial. Lancet 2002; 359:
1734-1739
Page 30 of 52

[Type text] Page 30

74 Llovet JM, Bruix J. Systematic review of randomized trials for
unresectable hepatocellular carcinoma: Chemoembolization
improves survival. Hepatology 2003; 37: 429-442
75 Poon RT, Fan ST, Tsang FH, Wong J. Locoregional therapies
for hepatocellular carcinoma: a critical review from the
surgeon's perspective. Ann Surg 2002; 235: 466-486
76 Lo CM, Ngan H, Tso WK, Liu CL, Lam CM, Poon RT, Fan
ST, Wong J. Randomized controlled trial of transarterial
lipiodol chemoembolization for unresectable hepatocellular
carcinoma. Hepatology 2002; 35: 1164-1171
77 Ferrari FS, Stella A, Pasquinucci P, Vigni F, Civeli L,
Pieraccini M, Magnolfi F. Treatment of small hepatocellular
carcinoma: a comparison of techniques and long-term
results. Eur J Gastroenterol Hepatol 2006; 18: 659-672
78 Schwartz JD, Schwartz M, Mandeli J, Sung M. Neoadjuvant
and adjuvant therapy for resectable hepatocellular
carcinoma: review of the randomised clinical trials. Lancet
Oncol 2002; 3: 593-603
79 Chow PK, Tai BC, Tan CK, Machin D, Win KM, Johnson PJ,
Soo KC. High-dose tamoxifen in the treatment of inoperable
hepatocellular carcinoma: A multicenter randomized
controlled trial. Hepatology 2002; 36: 1221-1226
80 Yuen MF, Poon RT, Lai CL, Fan ST, Lo CM, Wong KW,
Wong WM, Wong BC. A randomized placebo-controlled
study of long-acting octreotide for the treatment of
advanced hepatocellular carcinoma. Hepatology 2002; 36:
687-691
81 Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet
JM. Genomics and signaling pathways in hepatocellular
carcinoma. Semin Liver Dis 2007; 27: 55-76
S- Editor Cheng JX L- Editor Webster JR E- Editor Zheng XM

Page 31 of 52

[Type text] Page 31

J Gastroenterol 2009; 44[Suppl XIX]:136141
DOI 10.1007/s00535-008-2252-z
Molecular targeted therapy for
hepatocellular carcinoma
MELANIE THOMAS
Di vi s i on of Hematol ogy/Oncol ogy Hol l i ngs Cancer Center, Medi cal Uni vers i t y of South Carol i na,
Charl es ton, SC 29425, USA
A majority of patients with HCC present with advanced
disease and are not candidates for li ver transplantation,
surgical resection, or regional therapy. Systemic
cytotoxic chemotherapy agents are mi nimally eff ective,
can have signif icant toxicity, and have not been
shown to improve patient survi val. Hepatocell ular carci nomas
are inherently chemotherapy-resistant tumors
and are known to overexpress the multidrug resistance
genes. Hepatocell ular carci noma is a very heterogeneous
disease in terms of its etiol ogy, molecular carcinogenic
mechanisms, and biol ogical behavior, which
complicate our abil ity to identify rational molecul ar
therapeutic targets. Nearl y every pathway invol ved
in carcinogenesis i s altered to some degree in HCC.
Changes in hepatocyte growth factor expression, i ntracellul ar
signali ng, protease and matrix metalloproteinase
expression, and oncogene expression are seen in
HCC. The recent demonstration, in randomized cli nical
trials, of survival benefit f or HCC patients treated with
the oral agent sorafenib is encouraging progress i n the
development of molecularly targeted anticancer agents in HCC.
Page 32 of 52

[Type text] Page 32

Key words: hepatocellular carcinoma, HCC, chemotherapy,
targeted therapy
Introduction
Hepatocellular carcinoma (HCC) is potentiall y curable
by surgical resection and l iver transplantation. However,
the majority of patients present with advanced-st age
disease, which is most commonly accompanied by severe
background l iver disease. Hence, surgery i s feasibl e for
only a small fraction of pati ents with localized disease,
and li ver transplantation is severel y l imited by the availability
of li ver donors. Systemic cytotoxic therapies
have demonstrated a very l imited impact on the natural
history of advanced HCC (Table 1). A 1997 metaanalysis
evaluati ng the results of 37 randomized cl inical
trials of systemic and regional chemotherapy in 2803
HCC patients concl uded that nonsurgi cal therapies
were inef fective or mi nimally effective at best. 1
Chemotherapy resistance in HCC
Cancer cel ls, includi ng HCC cells, often have i ntrinsic
drug resistance mediated via enhanced cel lular drug
effl ux of several cytotoxic agents. This phenomenon is
associated with i ncrease in a drug transporter f amily,
the adenosi ne triphosphate-bindi ng cassette proteins
that include MDR1, p-glycoprotei n (p-gp), and the
multidrug resistance protei n (MRP). 2, 3 Both these are
upregulated in HCC. 2, 4 Upregulation of MDR1 accompanied
by a decrease i n doxorubicin accumulation levels
has been reported i n certain HCC cel l li nes. 5 The H19
Page 33 of 52

[Type text] Page 33

gene is thought to i nduce p-gp expressi on and MDR1-
associated drug resistance i n HCC cells through
regulating MDR1 promoter methylation. 5 Also, coexpression
of p53 and p-gp may contribute to HCC chemoresi stance
in HCC cell li nes. 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 i n
doxorubicin-resistant HCC cell li nes, and its expression
is associated with an aggressive tumor phenotype. 10
Finall y, large HCCs commonly develop areas of central
necrosis, whi ch may i nterfere with drug delivery t o the
growing tumor.
Recei ved: J une 24, 2008 / Accepted: Jul y 3, 2008
Repri nt request s t o: M. Thomas
M. Thomas: Mol ecul ar targeted therapy for HCC 137
Thus, to improve the outcome f or patients with
advanced HCC, alternatives to traditi onal cytotoxi c
chemotherapy agents are clearly needed. Recently,
molecular characterization of HCC has led to the
recogniti on of defined aberrant signal ing pathways,
which helped i n subsequent development of targeted
agents as potential choices for the treatment of this
disease.

Page 34 of 52

[Type text] Page 34

Molecular therapeutic targets in
hepatocellular carcinoma
In HCC, several crucial intracell ular 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-deri ved growth f actor
receptor (PDGFR), fibroblast growth factor recept or
(FGFR), and vascular endothel ial growth factor receptor
(VEGFR), have been recognized. Subsequently,
targeted agents have entered cl ini cal trials i n HCC
patients, and this is of particular signif i cance for HCC
in l ight of the lack of existing effective systemic therapy
for this cancer.
The growth of HCC depends on stimulatory effects
of various growth factors, whi ch bi nd to tyrosine kinase
receptors and hence activate various intracell ular signal ing
pathways that subsequently l ead to tumor cel l
prolif eration, survival, migration, and metastasis. Both
the extracellular growth factors and the i ntracell ular
signali ng pathways represent potential molecular targets
for therapy of HCC. However, the antiangiogenic
pathway looks promisi ng i n HCC.

Targeting growth factors in hepatocellular carcinoma
The epidermal growth factor receptor (EGFR) is frequently
expressed i n human hepatoma cell s, and EGF
may be one of the mitogens needed for the growth of
Page 35 of 52

[Type text] Page 35

hepatoma cells. 11, 12 Several strategies have been tested
in HCC: one is through usi ng a neutralizing monoclonal
antibody such as cetuximab, and another is usi ng a small
molecule tyrosine kinase i nhibitor such as gefi ti nib
and erloti nib, as demonstrated i n HCC cell cultures. 13, 14
Erlotinib is an oral ly acti ve and selecti ve 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 erl otinib. 15 In two phase II studies
Tabl e 1. Summary of sel ected cl inical t rial s in patients with advanced hepatocel l ul ar carcinoma
(HCC)
Study Regi men Phase Sampl e size
Response rate
(%)
Median survi val
(months)
Cyt ot oxi c chemot herapy
Yeo et al . 59 PIAF vs. adriamycin 3 94/94 20. 9 vs. 10. 5 8. 6 vs. 6. 83
Mok et al . 60 Nol atrexed 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 Nol atrexed vs.
doxorubicin
3 444 1. 4 vs. 4. 0 5. 5 vs. 8 (P ! 0. 0068)
Patt et al . 30 Thal idomide 2 37 6% 6. 8
Pastorel l i et al . 63 Pegyl ated doxorubicin
gemcitabine
2 35 23% 8. 8
Page 36 of 52

[Type text] Page 36

Target ed bi ol ogi cal t herapy
Ll ovet et al . 53 Sorafenib vs. pl acebo 3 602 2. 3% 10. 7 vs. 7. 9 (P ! 0. 00058)
Abou-Al fa et al . 36 Sorafenib 2 137 2. 2 9. 3
Phil ip et al . 16 Erl otonib 2 38 9% 13
Thomas et al . 15 Erl otonib 2 40 0% 10. 75
Thomas et al . 64 Bevacizumab erl otonib 2 40 25% 15. 65 (CI48-78)
Ramanathan et al . 65 Lapatinib 2 30 5% 6. 2
Gruenwal d et al . 66 Cetuximab 2 32 0% NR
Zhu et al . 67 Cetuximab 2 30 0% PFS 6 weeks; OS 22
weeks
O Dwyer et al . 68 Gef i ti nib 2 31 3% PFS 2. 8; OS 6. 5
Combi nati on cyt ot oxi c bi ol ogi cal t herapy
Sun et al . 69 Capecitabine, oxal ipl atin,
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
PI AF, ci s pl ati num, i nt erf eron, doxorubi ci n, and 5- f l uorour aci l ; OS, overal l s ur vi val ; GEMOX, gemci tabi ne,
oxal i pl ati n; PFS, progres s i on- f ree
s urvi val ; TTTF, ti me to t reatment f ai l ure; NR, not report ed
138 M. Thomas: Mol ecul ar target ed 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, respectivel y. 15, 16 Other
studies of anti-EGFR agents in HCC are summarized
in Table 2.
Rationale for antiangiogenic therapy of
hepatocellular carcinoma
The cancer cell has been the only target of anticancer
Page 37 of 52

[Type text] Page 37

therapy for more than 50 years. However, the cancer
cell is geneti cally unstable, and mutations accumulate.
On the other hand, antiangiogenic therapy targets
endothelial cel ls that are geneticall y stable. The genetic
stability of endothel ial cells may make them less
susceptible to acquired drug resistance. As a resul t,
angiogenesis inhibitors are emerging as a new class of
therapeutic agents.
The role of angi ogenesis i n 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 study
reported VEGF tissue expression i n HCC of 88. 8%. 20
Notably, studies have suggested a correlati on bet ween
the degree of tissue VEGF expression and the i ntensity
of both the magnetic resonance signal and the computed
tomographic enhancement of the hepati c artery,
which represent radiologic vascular signals. 2123 Hence,
the hypervascular nature of HCC has led to increasing
interest in exploring the potential of antiangi ogenic
therapy i n this disease.
Tabl e 2. Ongoing cl inical t rial s of systemic ant iangiogenic therapy in HCC
Page 38 of 52

[Type text] Page 38

Regimen
Study
phase Patient popul ation Trial #/sponsor
AZD2171 II Unresectabl e or metastatic HCC NCT00238394
NCI
AZD-2171 II Unresectabl e l ocal l y advanced or
metastatic HCC
NCT00427973a
Massachusetts General Hospital /NCI
Bevacizumab II Unresectabl e or metastatic HCC NCT00162669
Institute Gusatve Roussy
Bevacizumab Erl otinib II Unresectabl e HCC NCT00242502
M. D. Anderson Cancer Cent er
Bevacizumab Erl otinib II Unresectabl e or metastatic HCC NCT00287222
University of Arkansas/Genentech
Bevacizumab Erl otinib II Advanced unresectabl e HCC NCT00365391
Mayo Cl inic/NCI
Bevacizumab Sirol imus I Unresectabl e l ocal l y advanced or
metastatic HCC
NCT00467194
NCI
BMS-582664 vs. Doxorubicin II Unresectabl e, l ocal l y advanced or
metastatic HCC
NCT00355238
Bristol -Myers Squibb
BMS-582664 I Advanced HCC with varying
l evel s of hepatic impairment
NCT00437424a
Bristol -Myers Squibb
Page 39 of 52

[Type text] Page 39

Sorafenib tegafur/uracil
(UFUR)
II Unresectabl e l ocal l y advanced or
metastatic HCC
NCT00464919
National Taiwan University Hospital
Doxorubicin s sorafenib II Unresectabl e or metastatic HCC NCT00108953b
Bayer
Pazopanib I HCC NCT00370513
Gl axoSmithKl ine
Sunitinib II Unresectabl e l ocal l y advanced or
metastatic HCC
NCT00361309
Massachusetts General Hospital
Sunitinib II Unresectabl e HCC NCT00247676
Pfi zer
Thal idomide III Local l y advanced or metastatic
HCC
NCT00225290
TTY Biopharm
Thal idomide tegafur/uracil
(UFUR)
II Unresectabl e l ocal l y advanced or
metastatic HCC
NCT00384800
Far Eastern Memorial Hospital
a Not open yet
b No l onger recrui ti ng pati ents
M. Thomas: Mol ecul ar targeted therapy for HCC 139
Page 40 of 52

[Type text] Page 40

Clinical trials of antiangiogenic agents in
hepatocellular carcinoma
Several vascular targeted agents, includi ng thalidomide,
suniti nib, 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 antiangi ogenic effects. 2426 Nevertheless,
several cli nical trials of thal idomide alone or i n
combination with epirubici n or interf eron showed rare
responses rangi ng from 0% to 6. 3%. 2733 A recent report
in abstract form of 19 pati ents treated with oral t halidomide
200 mg/day continuously showed a 6-month
progression-free survi val of 41%. 34
Suniti nib, an oral multikinase inhibitor, exerts an
antiangiogenic ef fect by targeting VEGFR and plateletderived
growth factor receptor (PDGFR) tyrosine
kinases. A phase II study of suniti nib al one in 19 patients
with unresectable or metastatic HCC reported a partial
response in 1 patient. 35
Sorafenib, an oral multiki nase inhibitor, exerts an
antiangiogenic ef fect by targeting VEGFR and PDGFR
tyrosine kinases. It exerts its ef fect through targeting
Raf/MEK/ERK signaling at the level of Raf ki nase and
exerts an antiangiogenic eff ect by targeting VEGFR-2/
-3. A phase II study of Soraf enib alone i n 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-
Page 41 of 52

[Type text] Page 41

month improvement in median overal l survival [hazard
ratio (HR), 0. 69; 95% confi dence i nterval (CI), 0. 55
0. 87; P ! 0. 0006] along with increased time to progression
and disease control rate. 37
Bevacizumab is a recombinant, humanized monocl onal
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 reporti ng a partial response
rate of 12. 5% with a di sease control rate (PR SD) of
67%. 40, 41 Bevacizumab was also combined with gemcitabine
and oxali platin 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-l ine
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 overal l survival of
10. 7 months (95% CI, 5. 314. 7) and median progression-
free survi val (PFS) of 4. 1 months. 43 In addition, a
phase II study of advanced or unresectable metastatic
HCC treating 30 patients with bevacizumab, oxal i platin,
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 erl otinib in 29
Page 42 of 52

[Type text] Page 42

patients with unresectable HCC recently showed a 22%
response rate. 45
There is a number of ongoing cli nical trials of diff erent
vascular targeted agents in HCC (see Table 2). Preclinical
studies of agents that target other foci which
interact with VEGF, such as hypoxia-inducibl e fact or
(HIF)-1 alpha and APRIL (a proli feration-i nducing
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-acti vated protein kinase (MAPK) pathway
incl udes a cascade of phosphorylation of four maj or
cellular ki nases, ras, raf, mitogen-activated protei n
kinase (MAP), and extracell ular signal -regulated kinase
(ERK), which is responsible mainly for cellular di f ferentiation
and prol iferati on signal transduction. These
intermediates are f ound 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 inhi bitors
of farnesyl transferase has been developed to prevent
prenylation of Ras proteins: ABT-100, whi ch has
been shown to prevent the development of chemically
induced HCC in rats. 52 Raf ki nase inhibitor Bay-439006
Page 43 of 52

[Type text] Page 43

(sorafenib), a therapeuti c 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 i n 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 f or at
least 4 months, with many showing central tumor necrosis.
36 On the basis of the encouraging overal l survival of
9. 2 months reported i n the phase II trial , a placebocontroll ed
international trial was completed i n HCC
patients with ChildsPugh A cirrhosis. 53 The results
concl uded that sorafenib offers a survi val advantage
compared with placebo (10. 7 months vs. 7. 9 mont hs,
HR 0. 69; 95% CI, 0. 55 to 0. 87). This may be comparable
to survi val observed with other biol ogical agents (see
Table 2).
140 M. Thomas: Mol ecul ar target ed therapy for HCC
PI3K/AKT/mTOR pathway (phosphoinositide-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 cell ul ar proli feration
Page 44 of 52

[Type text] Page 44

and apoptosis and is cl osely li nked 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 cell ular translational activities
through the eukaryotic initiation factor 4E-binding
protein-1 (4E-BP1) and the 40s ribosomal protein S6
kinase (p70s6k); these are l inked with the translation of
mRNAs of genes regulating cell proli feration and angiogenesis,
such as c-myc, cycl in D1, and HIF-1. 56 Rapamycin
is an antibiotic that inhibits mTOR and is cl ini call y
used as an immunosuppressive drug to prevent graft
rejection. It was shown to possess activity against HCC
cell l ines. 57, 58
References
1. Si monet ti RG, Li ber at i A, Angi ol i ni C, et al . Treat ment of hepatocel l ul ar
carci noma: a s ys temat i c r evi ew of randomi zed cont rol l ed
tri al s . Ann Oncol 1997; 8: 11736.
2. Ng I O, Li u CL, Fan ST, et al . Ex pres s i on of P- gl ycoprotei n
i n hepatocel l ul ar car ci noma. A det er mi nant of chemother apy
res pons e. Am J Cl i n Pathol 2000; 113: 355 63.
3. Endi cot t J A, Li ng V. The bi ochemi s t ry of P- gl yco protei nmedi ated
mul t i drug r es i s t ance. Annu Rev Bi ochem 1989; 58: 137
71.
4. Par k J G, Lee SK, Hong I G, et al . MDR1 gene ex pr es s i on: i ts
ef f ect on drug r es i s t ance to doxorubi ci n i n human hepatocel l ul ar
carci noma cel l l i nes . J Natl Cancer I ns t 1994; 86: 7005.
5. Ts ang WP, Kwok TT. Ri bor egul ator H19 i nducti on of MDR1-
as s oci at ed drug res i s tance i n human hepatocel l ul ar car ci noma
cel l s . Oncogene 2007; 26: 487781.
Page 45 of 52

[Type text] Page 45

6. Chan KT, Lung ML. Mutant p53 ex pres s i on enhances drug res i s tance
i n a hepatocel l ul ar car ci noma cel l l i ne. Cancer Chemother
Phar macol 2004; 53: 519 26.
7. Las agna N, Fant appi e O, Sol azzo M, et al . Hepatocyte growth
f actor and i nduci bl e ni t ri c oxi de s ynthas e are i nvol ved i n mul ti drug
res i s tance- i nduced angi ogenes i s i n hepatocel l ul ar c arci noma
cel l l i nes . Cancer Res 2006; 66: 2673 82.
8. Zhu H, Chen XP, Luo SF, et al . I nvol vement of hy poxi a- i nduci bl e
f actor- 1- al pha i n mul ti drug res i s tance i nduced by hypoxi a i n
HepG2 cel l s . J Ex p Cl i n Cancer Res 2005; 24: 565 74.
9. Okada Y, Tos aka A, Ni mur a Y, et al . At ypi cal mul ti drug res i s tance
may be as s oci ated wi th catal yt i cal l y acti ve mut ants of
human DNA topoi s omer as e I I al pha. Gene ( Ams t) 2001; 272:
141 8.
10. Wat anuki A, Ohwada S, Fukus ato T, et al . Prognos ti c s i gni f i cance
of DNA topoi s omer as e I I al pha ex pr es s i on i n human hepatocel l ul ar
carci noma. Anti cancer Res 2002; 22: 1113 9.
11. Hi s aka T, Yano H, Har amaki M, et al . Expres s i ons of epi der mal
growth f actor f ami l y and i ts r eceptor i n hepatocel l ul ar car ci noma
cel l l i nes : rel ati ons hi p to cel l prol i f er ati on. I nt J Oncol 1999; 14:
453 60.
12. Faus to N. Growth f actors i n l i ver devel opment, regener at i on and
carci nogenes i s . Prog Growth Factor Res 1991; 3: 219 34.
13. Hopf ner M, Sutt er AP, Huether A, et al . Tar geti ng the epi dermal
growth f actor receptor by gef i ti ni b f or t reatment of hepatocel l ul ar
carci noma. J Hepatol 41: 1008 16, 2004.
14. Huether A, Hopf ner M, Sut ter AP, et al . Erl oti ni b i nduces cel l
cycl e arr es t and apoptos i s i n hepatocel l ul ar cancer cel l s and
enhances chemos ens i ti vi ty towar ds cytos t ati cs . J He patol 2005; 43:
661 9.
15. Thomas MB, Chadha R, Gl over K, et al . Phas e 2 s tudy of erl ot i ni b
Page 46 of 52

[Type text] Page 46

i n pati ents wi th unres ectabl e hepatocel l ul ar car ci noma. Cancer
(Phi l a) 2007; 110: 1059 67.
16. Phi l i p PA, Mahoney MR, Al l mer C, et al . Phas e I I s tudy of
Erl ot i ni b (OSI - 774) i n pat i ents wi th advanced hepatocel l ul ar
cancer. J Cl i n Oncol 2005; 23: 665763.
17. Hanahan D, Fol kman J . Patt erns and emer gi ng mechani s ms of the
angi ogeni c s wi t ch dur i ng tumori genes i s . Cel l 1996; 86: 353
64.
18. Park YN, Ki m YB, Yang KM, et al . I ncr eas ed ex pres s i on of
vas cul ar endothel i al growth f actor and angi ogenes i s i n the earl y
s tage of mul ti s tep hepatocar ci nogenes i s . Arch Pathol Lab Med
2000; 124: 10615.
19. Zhao J , Hu J , Cai J , et al . Vas cul ar endothel i al growth f actor
expres s i on i n s erum of pat i ents wi th hepatocel l ul ar car ci noma.
Chi n Med J ( Engl ) 2003; 116: 7726.
20. Huang GW, Yang LY, Lu WQ. Ex pr es s i on of hypoxi a- i nduci bl e
f actor 1 al pha and vas cul ar endothel i al growth f actor i n hepatocel l ul ar
carci noma: i mpact on neovas cul ari z ati on and s urvi val .
Worl d J Gas t roenterol 2005; 11: 1705 8.
21. Kanemats u M, Os ada S, Amaoka N, et al . Expres s i on of vas cul ar
endothel i al growth f actor i n hepatocel l ul ar carci noma and t he
s urroundi ng l i ver: cor rel at i on wi th angi ogr aphi cal l y as s i s t ed CT.
AJ R Am J Roent genol 2004; 183: 1585 93.
22. Kanemats u M, Semel ka RC, Os ada S, et al . Magneti c res onance
i magi ng and ex pres s i on of vas cul ar endothel i al growth f actor i n
hepatocel l ul ar nodul es i n ci r rhos i s and hepatocel l ul ar car ci nomas .
Top Magn Res on I magi ng 2005; 16: 67 75.
23. Wang B, Gao ZQ, Yan X. Cor rel ati ve s tudy of angi ogenes i s and
dynami c contr as t- enhanced magneti c res onance i magi ng f eatur es
of hepatocel l ul ar car ci noma. Act a Radi ol 2005; 46: 353 8.
24. D Amato RJ , Loughnan MS, Fl ynn E, et al . Thal i domi de i s an
Page 47 of 52

[Type text] Page 47

i nhi bi tor of angi ogenes i s . Proc Natl Acad Sci U S A 1994; 91:
40825.
25. Kenyon BM, Browne F, D Amato RJ . Ef f ects of thal i domi de and
rel at ed met abol i t es i n a mous e corneal model of neovas cul ar i zati on.
Exp Eye Res 1997; 64: 971 8.
26. Kumar S, Wi tzi g TE, Raj kumar SV. Thal i domi d: cur rent r ol e i n
the t reat ment of non- pl as ma cel l mal i gnanci es . J Cl i n Oncol
2004; 22: 247788.
27. Hs u C, Chen CN, Chen LT, et al . Low- dos e thal i domi de t reat ment
f or advanced hepatocel l ul ar car ci noma. Oncol ogy 2003; 65:
242 9.
28. Wang TE, Kao CR, Li n SC, et al . Sal vage ther apy f or hepatocel l ul ar
carci noma wi th thal i domi de. Worl d J Gas t roenterol 2004;
10: 649 53.
29. Li n AY, Brophy N, Fi s her GA, et al . Phas e I I s tudy of thal i domi de
i n pati ents wi th unres ectabl e hepatocel l ul ar car ci noma.
Cancer ( Phi l a) 2005; 103: 119 25.
30. Patt YZ, Has s an MM, Loz ano RD, et al . Thal i domi de i n the
tr eat ment of pat i ents wi th hepatocel l ul ar car ci noma: a phas e I I
tri al . Cancer (Phi l a) 2005; 103: 74955.
31. Schwar tz J D, Sung M, Schwar tz M, et al . Thal i do mi de i n advanced
hepatocel l ul ar carci noma wi th opti onal l ow- dos e i nt erf eronal pha2a
upon progres s i on. Oncol ogi s t 2005; 10: 718 27.
32. Zhu AX. Sys t emi c ther apy of advanced hepatocel l ul ar car ci noma:
how hopef ul s houl d we be? Oncol ogi s t 2006; 11: 790800.
33. Zhu AX, Fuchs CS, Cl ark J W, et al . A phas e I I s tudy of epi r ubi ci n
and thal i domi de i n unres ectabl e or metas tati c hepatocel l ul ar car ci noma.
Oncol ogi s t 2005; 10: 392 8.
34. Fazi o N, Pet ral i a G, Mancus o P, et al . Thal i domi de i n pat i ents wi th
advanced hepatocel l ul ar car ci noma: a cl i ni cal /bi ol ogi cal s t udy.
M. Thomas: Mol ecul ar targeted therapy for HCC 141
Page 48 of 52

[Type text] Page 48

ASCO Annual Meeti ng Proceedi ngs , Par t I . J Cl i n Oncol 2007; 25:
A15076.
35. Zhu AX, Sahani DV, di Tomas o E, et al . A phas e I I s tudy of s uni ti ni b
i n pati ents wi th advanced hepatocel l ul ar car ci noma. ASCO
Annual Meeti ng Proceedi ngs , Part I . J Cl i n Oncol 2007: 25:
A4637.
36. Abou- Al f a GK, Schwartz L, Ri cci S, et al . Phas e I I s tudy of
s oraf eni b i n pati ents wi th advanced hepatocel l ul ar carci noma.
J Cl i n Oncol 2006; 24: 4293300.
37. Ll ovet J , Ri cci S, et al . Soraf eni b i mproves s urvi val i n advanced
hepatocel l ul ar carci noma (HCC): res ul ts of a Phas e I I I randomi zed
pl acebo- control l ed t ri al (SHARP tr i al ). ASCO Annual
Meeti ng Proceedi ngs , Par t I . J Cl i n Oncol 25: ABA1.
38. J ai n RK. Nor mal i zi ng tumor vas cul atur e wi th anti - angi ogeni c
ther apy: a new paradi gm f or combi nati on ther apy. Nat Med
2001; 7: 987 9.
39. Wi l l ett CG, Boucher Y, di Tomas o E, et al . Di rect evi dence that
the VEGF- s peci f i c anti body bevaci zumab has anti vas cul ar ef f ects
i n human rect al cancer. Nat Med 2004; 10: 1457.
40. Schwar tz MS, Lehr er D, Cohen E, Sung M, Ki nkhabwal a M, Si egel
A, et al . Bevaci zumab i n unres ectabl e hepatocel l ul ar carci noma
(HCC) f or pati ents wi thout met as t as i s and wi thout i nvas i on of the
por t al vei n. ASCO Annual Meeti ng Proceedi ngs . J Cl i n Oncol
2006; 24(18 s uppl ): A4144.
41. Mal ka D, Dromai n C, Far ace F, et al . Bevaci zumab i n pati ents
(pts ) wi th advanced hepatocel l ul ar car ci noma ( HCC): prel i mi nar y
res ul ts of a phas e I I s tudy wi th ci rcul ati ng endoth el i al cel l
(CEC) moni tori ng. ASCO Annual Proceedi ngs , Part I . J Cl i n
Oncol 2007; 25: A4570.
42. Zhu AX, Bl as z kows ky LS, Ryan DP, et al . Phas e I I s tudy of gemci t abi ne
and oxal i pl ati n i n combi nati on wi th bevaci zumab i n
Page 49 of 52

[Type text] Page 49

pati ents wi th advanced hepatocel l ul ar carci noma. J Cl i n Oncol
2006; 24: 1898903.
43. Hs u C, Hs u C, Yang T, et al . Modi f i ed- dos e capeci t abi ne bevaci zumab
f or the t reat ment of advanced/met as t at i c hepatocel l ul ar
carci noma (HCC): a phas e I I , s i ngl e- ar m s tudy. ASCO Annual
Proceedi ngs , Par t I . J Cl i n Oncol 2007; 25: A15190.
44. Sun W, Hal l er DG, Mykul owycz K, et al . Combi nati on of
capeci tabi ne, oxal i pl ati n wi th bevaci zumab i n tr eat ment of
advanced hepatocel l ul ar car ci noma ( HCC): a phas e I I s tudy.
ASCO Annual Proceedi ngs , Par t I . J Cl i n Oncol 2007; 25: A4574.
45. Thomas MB, Chadha R, I was aki M, et al . The combi nati on of
bevaci zumab (B) and erl oti ni b (E) s hows s i gni f i cant bi ol ogi cal
acti vi t y i n pati ents wi th advanced hepatocel l ul ar c arci noma.
ASCO Annual Proceedi ngs , Par t I . J Cl i n Oncol 2007; 25: A4567.
46. Zhang Q, Tang X, Lu QY, et al . Res ver at rol i nhi bi ts hypox i ai nduced
accumul ati on of hypoxi a- i nduci bl e f actor- 1al pha and
VEGF expres s i on i n human tongue s quamous cel l car ci noma and
hepatoma cel l s . Mol Cancer Ther 2005; 4: 1465 74.
47. Okano H, Shi raki K, Yamanaka Y, et al . Functi onal expres s i on of
a pr ol i f erati on- r el ated l i gand i n hepatocel l ul ar car ci noma and i ts
i mpl i cati ons f or neovas cul ari zati on. Worl d J Gas t roenterol
2005; 11: 46504.
48. Toyoda M, Has hi moto N, Toki t a K, et al . I ncreas ed acti vi t y and
expres s i on of MAP ki nas e i n HCC model r ats i nduced by 3-
methyl - 4- di methyl ami no- azobenzene. J Hepatol 1999; 31: 72533.
49. McKi l l op I H, Schmi dt CM, Cahi l l PA, et al . Al t er ed ex pres s i on of
mi togen- acti vated prot ei n ki nas es i n a rat model of ex peri ment al
hepatocel l ul ar carci noma. Hepatol ogy 1997; 26: 1484 91.
50. I to Y, Sas aki Y, Hori moto M, et al . Acti vati on of mi togenacti vated
protei n ki nas es /ext r acel l ul ar s i gnal - regul ated ki nas es i n
human hepatocel l ul ar car ci noma. Hepatol ogy 1998; 27: 951 8.
Page 50 of 52

[Type text] Page 50

51. Feng DY, Zheng H, Tan Y, et al . Ef f ect of phos phoryl ati on of
MAPK and St at 3 and expres s i on of c- f os and c- j un protei ns on
hepatocar ci nogenes i s and thei r cl i ni cal s i gni f i cance. Worl d J Gas t roenterol
2001; 7: 336.
52. Carl oni V, Vi zzutti F, Pantal eo P. Farnes yl t r ans f er as e i nhi bi tor,
ABT- 100, i s a potent l i ver cancer chemoprevent i ve agent. Cl i n
Cancer Res 2005; 11: 4266 74.
53. Ll ovet J M, Ri cci S, Maz zaf er ro V, et al . Sor af eni b i n advanced
hepatocel l ul ar carci noma. N Engl J Med 2008; 359: 378 90.
54. Al exi a C, Br as M, Fal l ot G, et al . Pl ei ot ropi c ef f ects of PI - 3 ki nas e/
Akt s i gnal i ng i n human hepatoma cel l prol i f erati on and drugi nduced
apoptos i s . Ann N Y Acad Sci 2006; 1090: 1 17.
55. Saxena NK, Shar ma D, Di ng X, et al . Concomi t ant act i vati on of
the J AK/STAT, PI 3K/AKT, and ERK s i gnal i ng i s i nvol ved i n
l epti n- medi ated promoti on of i nvas i on and mi gr ati on of hepatocel l ul ar
carci noma cel l s . Cancer Res 2007; 67: 2497507.
56. Adj ei AA, Hi dal go M. Tr eati ng cancer by bl ocki ng cel l s i gnal s .
J Cl i n Oncol 2005; 23: 527980.
57. Sahi n F, Kannangai R, Adegbol a O, et al . mTOR and P70 S6
ki nas e expres s i on i n pri mary l i ver neopl as ms . Cl i n Cancer Res
2004; 10: 84215.
58. Si eghar t W, Fuereder T, Schmi d K, et al . Mammal i an t arget of
rapamyci n pathway acti vi ty i n hepatocel l ul ar car ci nomas of
pati ents undergoi ng l i ver t r ans pl ant ati on. Tr ans pl ant ati on 2007;
83: 425 32.
59. Yeo W, Mok TS, Zee B, et al . A r andomi zed phas e I I I s tudy of
doxorubi ci n vers us ci s pl ati n/i nterf eron al pha- 2b/doxorubi ci n/
f l uorouraci l ( PI AF) combi nati on chemotherapy f or unres ect abl e
hepatocel l ul ar carci noma. J Natl Cancer I ns t 2005; 97: 1532 8.
60. Mok TS, Leung TW, Lee SD, et al . A mul ti - cent re randomi zed
phas e I I s tudy of nol at rexed vers us doxorubi ci n i n t reat ment of
Page 51 of 52

[Type text] Page 51

Chi nes e pati ents wi th advanced hepatocel l ul ar carci noma. Cancer
Chemother Pharmacol 1999; 44: 307 11.
61. Pos ey J J P, Mok T, et al . Res ul ts of a phas e 2/3 open- l abel , r andomi z ed
tri al of T138067 vers us doxorubi ci n ( DOX) i n chemotherapy-
na ve, unr es ect abl e hepatocel l ul ar carci noma (HCC). J
Cl i n Oncol 2005; 23(s uppl ): 4035.
62. Gi s h RG, Port a C, Laz ar L, et al . Phas e I I I r andomi z ed control l ed
tri al compari ng the s urvi val of pati ents wi th unres ectabl e hepatocel l ul ar
carci noma t reat ed wi th nol atr exed or doxorubi ci n. J Cl i n
Oncol 2007; 25: 306975.
63. Pas tor el l i DCG, Zus tovi ch F, et al . A phas e I I s tudy of pegyl ated
l i pos omi al doxorubi ci n ( PLD) and gemci t abi ne ( G) i n the tr eat ment
of hepatocel l ul ar car ci noma ( HCC) not s ui t abl e f or l ocoregi onal
ther apy. J Cl i n Oncol 2007; 25(s uppl ): 4585.
64. Thomas MBCR, I was aki M, et al . The combi nati on of bevaci zumab
(B) and erl oti ni b (E) s hows s i gni f i cant bi ol ogi cal acti vi ty
i n pati ents wi th advanced hepatocel l ul ar car ci noma ( HCC). J Cl i n
Oncol 2007; 25(s uppl ): 4567.
65. Ramanathan CPB, Si ngh DA, et al . Phas e I I s tudy of l apat i ni b, a
dual i nhi bi tor of epi der mal gr owth f actor r eceptor (EGFR) t yros i ne
ki nas e 1 and 2 (Her 2/Neu) i n pati ents (pts ) wi th advanced
bi l i ar y tr ee cancer (BTC) or hepatocel l ul ar cancer ( HCC). A
Cal i f orni a Cons or ti um (CCC- P) Tr i al . J Cl i n Oncol 2006; 24( 18
s uppl ): 4010.
66. Gruenwal d LW, Gebel M, et al . A phas e I I open- l abel s tudy of
cetuxi mab i n unr es ect abl e hepatocel l ul ar carci noma. J Cl i n Oncol
2006; 24(18 s uppl ): 14079.
67. Zhu AXBL, Enzi nger PC, et al . Phas e I I s tudy of cetuxi mab i n
pati ents wi th unr es ect abl e or met as t at i c hepatocel l ul ar car ci noma.
J Cl i n Oncol 2006; 24(s uppl ): 14096.
68. O Dwyer PJ GB, Levy DE, et al . Gef i ti ni b i n advanced unres ect abl e
Page 52 of 52

[Type text] Page 52

hepatocel l ul ar carci noma: res ul ts f rom the Eas tern
Cooper ati ve Oncol ogy Group s Study E1203. J Cl i n Oncol 2006;
24(s uppl ): 4143.
69. Sun WHD, Mykul owycz K, et al . Combi nati on of capeci t abi ne,
oxal i pl ati n wi th bevaci zumab i n t reatment of advanced hepatocel l ul ar
carci noma (HCC): a phas e I I s tudy. J Cl i n Oncol 2007;
25(s uppl ): 4574.
70. Louaf i S, Boi ge V, Ducreux M, et al . Gemci tabi ne pl us ox al i pl ati n
(GEMOX) i n pat i ents wi th advanced hepatocel l ul ar car ci noma
(HCC): res ul ts of a phas e I I s tudy. Cancer ( Phi l a) 2007; 109:
138490.