VOLUME 23 䡠 NUMBER 13 䡠 MAY 1 2005

JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES

Hepatocellular Carcinoma: The Need for Progress

Melanie B. Thomas, The University of Texas M.D. Anderson Cancer Center, Houston, TX
Andrew X. Zhu, Massachusetts General Hospital, Dana-Farber/Partners Cancer Care, Harvard Medical School, Boston, MA

Hepatocellular carcinoma (HCC) is a malignancy
of worldwide significance and has become increasingly impor-
tant in the United States. HCC is currently the fifth most
common solid tumor worldwide and the fourth leading cause
of cancer-related death.1 Eighty percent of new cases occur in
developing countries, but the incidence is increasing in eco-
nomically developed regions, including Japan, Western Eu-
rope, and the United States.2,3 The worldwide distribution of
HCC and its associated etiologies is summarized in Table 1.
Liver cirrhosis is the seventh leading cause of death in the world
and the 10th most common cause of death in the United
States, and is acknowledged as a premalignant condition for
developing HCC.4,5 In the United States, hepatitis C virus
(HCV), alcohol use, and nonalcoholic fatty liver disease are the
most common causes of cirrhosis.4,6-8 Approximately 18,000
new cases of HCC are projected to occur in the United States in
2005,9 however, the incidence of HCC has doubled during the
period from 1975 to 1995 and continued to rise through
1998.10 This trend is expected to continue because of the esti-
mated 4,000,000 hepatitis C–seropositive individuals in the
United States and the known latency of HCC development
from the initial HCV infection, which may take two to three
decades.11 It is also known that nonalcoholic fatty liver dis-
ease–associated cirrhosis is increasing in the United States.12-14
Clearly, HCC represents a looming epidemic for which the
medical oncology community is largely unprepared.
Many excellent reviews summarize the status of treat-
ment options for this disease.15-20 Table 2 lists the principal
treatment modalities available. Despite the many treatment
options, the prognosis of HCC remains dismal. A majority
(70% to 85%) of patients present with advanced or unresect-
able disease. Even for those patients who undergo resection,
the recurrence rates can be as high as 50% at 2 years.49-51 In
1997, a meta-analysis evaluated the results of 37 randomized
clinical trials of systemic and regional chemotherapy in 2,803
HCC patients and concluded that nonsurgical therapies were
ineffective or minimally effective at best.48 Most published
studies of systemic chemotherapy report response rates of 0%
to 25%, and systemic chemotherapy has never been shown to
prolong survival in patients with HCC.
The majority of HCC occurs in patients with liver
cirrhosis and consequent hepatic dysfunction, which com-
plicates safe administration of systemic therapy and poses a
challenge to conducting clinical trials in this patient popu-
lation. Hepatocellular carcinoma is a heterogeneous disease
in terms of etiology and underlying associations as well as
biologic and clinical behavior. The underlying liver dys-
function, aggressive nature of the disease, lack of general
consensus regarding treatment, and lower incidence in the
United States contribute to the challenges of studying and
developing effective systemic therapies for HCC.
In an effort to identify the perceived obstacles to more
productive clinical research in HCC, a planning meeting was
held in San Francisco in January 2004, concurrent with the
first annual American Society of Clinical Oncology (ASCO)
gastrointestinal (GI) Cancers Symposium, jointly sponsored
with the American Gastroenterological Association, American
Society for Therapeutic Radiology and Oncology, and Society
for Surgical Oncology. The outcome of this session was iden-
tification by the participants (including medical and surgical
oncologists, diagnostic and interventional radiologists, and
gastroenterologists from throughout the United States, Asia,
Canada, and Europe) of what were believed to be the key
impediments to productive HCC research. This review briefly
summarizes the biology of HCC as it relates to the develop-
ment of new treatment options, and lists the key challenges
identified by the participants at the ASCO GI Cancers Sympo-
sium HCC Meeting that must be met to advance clinical re-
search in this important malignancy.
HCC BIOLOGY: KEY MOLECULAR AND
GENETIC ABERRATIONS
HCC develops commonly, but not exclusively, in a setting
of liver cell injury, which leads to inflammation, hepatocyte

2892 Journal of Clinical Oncology, Vol 23, No 13 (May 1), 2005: pp 2892-2899
DOI: 10.1200/JCO.2005.03.196

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 Comments and Controversies

Table 1. Epidemiology of HCC

HCC Incidence HCC Incidence
(occurrences/100,000 (occurrences/100,000
Region population) Males17 population) Females17 No. of HCC Cases Principal Associations

Asia, Sub-Saharan Africa 30-120 9-30 ⬎ 500,000 cases per year1,5 HBV, aflatoxin exposure
Japan 10-30 3-9 HCV
Southern Europe, Argentina, Switzerland 5-10 2-5 HCV
Western Europe ⬍5 ⬍3 HCV
United States ⬍5 ⬍3 18,000 predicted for 20059 HCV, alcohol

Abbreviations: HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus.

regeneration, liver matrix remodeling, fibrosis, and ulti-
mately, cirrhosis. The vast majority of HCC worldwide (80%)
is attributed to hepatitis B virus (HBV) and HCV, but other
risk factors include alcohol abuse, hemochromatosis, fatty
liver disease, androgenic steroid use, and other metabolic dis-
orders. The mechanisms by which these varied etiologies lead
to cirrhosis and HCC are not well understood. Hepatic carci-
nogenesis is likely due to both direct effects of the underlying
liver insult, and indirectly to hepatocyte inflammation and
regeneration. An estimated 60% to 80% of HCC arises in the
setting of cirrhosis, but a moderate number of patients do not
have cirrhosis in the background.
Nearly every carcinogenic pathway is altered to some
degree in HCC. Changes in hepatocyte growth factor
expression, somatic mutations, protease and matrix metal-
loproteinase overexpression, and oncogene expression are

Table 2. Summary of Treatment Options for HCC

Treatment Option Comments References

Liver transplantation Historically low survival rates (20%-36%) recent improvement (61.1%; 1996- 21,22
2001), likely related to adoption of Milan criteria at US transplantation
centers
Currently HCC represents 20⫹% of liver transplantations performed annually
in the United States
Surgical resection Historical 5-year survival rates 30%-40% 22-26
Recent series indicates 5-year PFS as high as 48%; majority of patients
develop recurrence or second primary tumors
Resection in cirrhotic patients carries high morbidity and mortality
TACE Multiple trials show objective tumor responses and slowed tumor 27-30
progression but questionable survival benefit compared to supportive
care; greatest benefit seen in patients with preserved liver function,
absence of vascular invasion, and smallest tumors
Modest survival benefit demonstrated for repeated TACE (82% 1-year
survival) v supportive care (63%) in patients with preserved liver function,
PS 0, and small tumor burden; improvement in 1-year survival from 32%
in controls (supportive care) to 57% for TACE shown in randomized study
of 279 primarily HBV-positive patients with tumors ⬍ 7 cm
Intra-arterial iodine-131–lipiodol Efficacy demonstrated in unresectable patients, those with portal vein 31-33
administration thrombus, and as adjuvant therapy in resected patients
Percutaneous treatments PEI well tolerated, high RR in small (⬍ 3 cm) solitary tumors; no randomized 34-37
(ethanol injection, trial comparing resection to percutaneous treatments; recurrence rates
radiofrequency ablation) similar to those for postresection
Hormonal therapy Antiestrogen therapy with tamoxifen studied in several trials, mixed results 38-42
across studies, but generally considered ineffective
Octreotide (somatostatin analogue) showed 13-month MS v 4-month MS in 43
untreated patients in a small randomized study; results not reproduced
Chemotherapy Adjuvant: No randomized trials showing benefit of neoadjuvant or adjuvant 44-46
systemic therapy in HCC; single trial showed decrease in new tumors in 47
patients receiving oral synthetic retinoid for 12 months after resection/
ablation; results not reproduced
Palliative: Regimens that included doxorubicin, cisplatin, fluorouracil, 48
interferon, epirubicin, or taxol, as single agents or in combination, have
not shown any survival benefit (RR, 0%-25%); a few isolated major
responses allowed patients to undergo partial hepatectomy; no published
results from any randomized trial of systemic chemotherapy

Abbreviations: HCC, hepatocellular carcinoma; TACE, transarterial embolization/chemoembolization; PFS, progression-free survival; PS, performance status;
HBV, hepatitis B virus; PEI, percutaneous ethanol injection; RR, response rate; MS, median survival.

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 Thomas and Zhu

seen in hepatic inflammation and chronic hepatitis and, in
general, become more extensive as liver injury progresses
through fibrosis, cirrhosis, and dysplastic foci and nodules
to overt HCC. Because of the heterogeneity of the underly-
ing etiologies, it is a challenge to provide a clear and consis-
tent portrait of the principal molecular abnormalities in this
disease. There are several excellent reviews (Table 3) of the
most common and important molecular aberrations in
hepatocellular carcinoma. Identification of key molecular
targets and pathways involved in hepatocarcinogenesis has
significant therapeutic implications: the arrival of many
molecularly targeted agents in the clinic provides the ratio-
nale and opportunity for study of these agents in HCC.
CURRENT TRENDS IN MANAGEMENT OF HCC
At present, liver transplantation is considered the only cur-
ative treatment option for HCC. The current 1- and 5-year
survival rates for HCC patients undergoing orthotopic liver
transplantation are 77.0% and 61.1%, respectively. The
5-year survival rate has steadily improved from 25.3% in
1987 to 61.1% during the most recent period studied (1996
to 2001).108 These authors attribute this improvement to
the incorporation of the Milan criteria as guidelines for
patient selection at most United States liver transplantation
centers. These criteria, as published by Mazzaferro et al,109
suggest that the long-term survival after HCC liver trans-
plantation is highest in HCC patients with either a single
lesion ⱕ 5 cm or three lesions ⱕ 3 cm each and no evidence
of gross vascular invasion. Recent data from the United
Network for Organ Sharing indicate that 335 (7.9%) of the
3,893 liver transplantations performed in the United States
in 2003 were for malignant neoplasms.110 This number
represents a small proportion of the nearly 19,000 new HCC
patients expected in the United States in 2004. A much
larger number of liver transplantation candidates remain
on the waiting list until they die from tumor progression or
cirrhosis-related complications. Patients with cirrhosis gen-
erally are not considered good candidates for surgical resec-
tion because of high morbidity and mortality rates
associated with cirrhosis and its complications. For those
who do undergo resection, recurrence rates are among the
highest of any solid tumor, and approach 75% to 100% at 5
years.111 Estimated 5-year survival rates are in the range of
26% to 50%, and disease-free survival is 13% to 29%.112
Liver-directed therapies include a variety of techniques
to ablate individual tumors and are common practice in
many centers. A significant body of literature has developed
as a result of the extensive use of radiofrequency ablation,
percutaneous ethanol injection, cryoablation, intrahepatic

Table 3. Summary of Principal Molecular and Genetic Aberrations in HCC

Molecular Event Comment References

Growth factors and receptors:

EGFR Overexpression common in chronic hepatitis, fibrosis, cirrhosis, and HCC; known 52-58
EGFR ligands (EGF, HGF, TGF-␤, IGF) mitogenic for hepatocytes and implicated in
hepatocarcinogenesis; upregulated HCC cell lines, DN, HCC lesions
ErbB2 Variable (11%-80%) expression in HCC 58-62
VEGF HCC highly vascular tumors; VEGF overexpression in HCC cell lines, DN, tumors; may 63-74
correlate with tumor invasion and metastases
Intracellular signaling pathways MAPK/MEK signaling pathway activated in HCC in vivo model 75
Evidence for role of PKC in HCC is conflicting 76-81
Cell cycle control Cyclin D1 overexpression low to moderate in HCC; cyclin E overexpressed in majority 82-87
of HCCs and associated with large tumors, poor differentiation, and invasion; may
be correlated with p53 mutations
Abnormalities in p16/cyclin D1/pRB pathway common in HCC specimens 88-90
Of the positive cell-cycle regulators, cyclin D1, cyclin A and B1 significantly linked to
biologic character of HCC
Oncogenes No single oncogene preferentially required for human HCC development; activating 91-93
mutations seen in ras, Myc, Met, c-fos genes; Ras overexpression in HCC animal
model, less so in sporadic HCC
Tumor suppressor genes A variety of p53 aberrations common in HCC (30%-60%); aflatoxin-B–related HCC 94-97
commonly have consistent codon 249 changes
Altered expression of p16, p21, p27 common
Rb gene abnormalities seen in 25% HCC
Apoptosis FAS-Fas-L complex principal component of apoptotic signaling in normal liver; strongly 98-100
upregulated in chronic hepatitis, cirrhosis; Fas strongly downregulated in HCC
ECM Genes for ECM and cytoskeleton upregulated early in preneoplastic process; 101-107
integrins, MMP-14 important

Abbreviations: HCC, hepatocellular carcinoma; EGFR, epidermal growth factor receptor; VEGF, vascular endothelial growth factor; EGF, epidermal growth factor;
HGF, hepatocyte growth factor; TGF-␤, transforming growth factor beta; insulin-like growth factor; DN, dysplastic nodule; MAPK, mitogen-activate protein kinase;
MEK, MAPK-extracellular receptor kinase; PKC, protein kinase C; FAS, fascilin; Fas-L, Fas ligand; ECM, extracellular matrix; MMP-14, matrix metalloproteinase-14.

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 Comments and Controversies
iodine-131–lipiodol administration, and transarterial he-
patic artery embolization or chemoembolization in treating
individual HCC lesions. Statistically significant evidence of
improvement in survival as a result of liver-directed thera-
pies, as demonstrated in prospective controlled trials, is
scarce. However, two recently published studies in which
HCC patients were randomly assigned to receive repeated
transarterial hepatic artery embolization versus supportive
care demonstrated modest survival improvement seen in
patient groups who had small tumor burdens, good perfor-
mance status, and preserved liver function.113,114
A majority (⬎ 80%) of patients diagnosed with HCC
have advanced disease at presentation, and based on the
number, size, and location of lesions, and the severity of
underlying cirrhosis, are not candidates for transplantation,
surgical resection, or liver-directed therapies. At present,
systemic chemotherapy is quite ineffective in HCC, as evi-
denced by low response rates and no demonstrated survival
benefit (Table 2). Hepatocellular carcinomas are inherently
chemotherapy-resistant tumors115 and are known to express
the multidrug-resistant gene MDR-1.116,117 Few well-
controlled randomized chemotherapy trials have been pub-
lished in HCC. The ability to conduct controlled clinical trials
of systemic regimens in HCC patients has been hampered by
many factors, including the multiple comorbidities of cirrho-
sis, the advanced nature of HCC at presentation, rapid disease
progression in many instances, and the distribution of patients
primarily in developing nations, where multidisciplinary treat-
ment of HCC may not be available.
CHALLENGES TO PROGRESS IN THE DEVELOPMENT OF
EFFECTIVE THERAPEUTICS FOR HCC
The biologic heterogeneity and multiple etiologies of HCC
result in an incomplete understanding of the key molecular
changes that lead to HCC development. Developing a
clearer picture of the most prominent and relevant molec-
ular abnormalities is fundamental to developing effective
therapeutic options, and should be a priority of those in-
volved in basic and translational research.
Few patients with HCC qualify for traditional clinical
trials because of their compromised hepatic function. Liver
cirrhosis that leads to portal hypertension may result in
hypersplenism with platelet sequestration, thrombocytope-
nia, esophagogastric varices and GI bleeding, hepatic en-
cephalopathy, hypotension, and hypoalbuminemia that
may result in differential drug binding and altered pharma-
cokinetics. In patients with chronic HBV infection, their
disease can be reactivated when treated with immunosup-
pressive chemotherapy, further complicating their medical
management and clinical trial participation.
The vast majority of HCC patients live in developing
nations in Asia and Africa, where providing basic health care
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remains a challenge, and sophisticated, multidisciplinary can-
cer treatment is uncommon. In the United States, a compara-
tively small number of patients are spread among numerous
institutions. Collaboration among interested institutions is es-
sential, although it is recognized that collaboration can be
cumbersome, time consuming, and costly.
Many patients undergo surgical resection, tumor abla-
tion, and regional therapies, yet these approaches have high
tumor recurrence rates. Few large, controlled trials of adju-
vant systemic therapy have been performed to determine
whether adjuvant therapy is of benefit to these patients.
There is an acute need for randomized trials, particularly in
cirrhotic patients whose entire liver is at risk of recurrent as
well as second primary tumors.
Although liver transplantation offers a small number of
patients a relatively high likelihood of long-term cure, is it
the best and highest use of available medical resources? This
option is costly and medical resource intensive, and siphons
off the best HCC patients from a pool of patients with good
performance status and low tumor burden who would oth-
erwise be candidates for systemic therapy clinical trials. The
patients on the waiting list tend to be the star athletes (ie,
those with the smallest volume of disease at the time of
listing), yet a majority of them will never receive a new liver.
These patients represent a potential and important source
of patients for clinical trials. Conversely, the ethical ques-
tion remains: when liver transplantation offers patients the
only chance for cure, would participation in some other
therapy jeopardize their waiting list status and potential
long-term outcome?
The variety of disease etiologies and broad range of
liver dysfunction seen in HCC patients confound designing
and interpreting results from standard phase I, II, and III
clinical trials. In typical phase II trial designs, with response
rate as the primary end point, it is difficult to identify the
significant interpatient variability that exists in HCC pa-
tients due to the heterogeneous nature of the disease.
Few malignancies are cured by chemotherapy. More
realistic goals for clinical trials in HCC patients may include
prolonged survival, symptom palliation, and improved or
maintained quality of life. Assessment of clinical benefit re-
sponse should be incorporated into HCC clinical trial design.
PRIORITIES FOR HCC RESEARCH
Numerous challenges must be met in developing effective
therapeutic options for HCC patients. First and foremost,
HCC is a disease that requires multidisciplinary care, and pa-
tients will benefit from clinical care that integrates the expertise
of surgical oncology, diagnostic and interventional radiology,
gastroenterology, hepatology, radiation oncology, and medi-
cal oncology. Collaboration among the various medical disci-
plines remains essential in the care of complicated HCC
2895
 Thomas and Zhu
patients. Substantial worldwide research efforts have fo-
cused on liver-directed treatment options. Data from a num-
ber of trials are beginning to emerge and show that these
therapies can improve survival in HCC, but generally in highly
selected patients with preserved liver function and small tumor
burdens. Although progress in these areas is encouraging, it
must be remembered that the vast majority of HCC patients
present with unresectable disease and are not candidates for
liver-directed therapies. Given the preponderance of HCC pa-
tients present with advanced disease, and because the inci-
dence of HCC is increasing, there will be an ever-increasing
demand for effective systemic therapies. Thus, the medical
oncology community needs to become more active in advo-
cating for broad, rational research into systemic chemotherapy
options for these patients.
Priorities for the future include the formation of a
group that focuses efforts, resources, and attention on
HCC, such as existing and highly productive working
groups for sarcoma, brain tumors, leukemia, and other
less-common tumors. The goals of such a group would
include the following points.
First, an HCC clinical research network should be estab-
lished that fosters national and international collaborations to
focus research effort and resources on HCC. An ASCO HCC
Working Group, which integrates all of the important medical
disciplines, could be a focal point for this effort.
Second, all of the medical disciplines involved in the
care of HCC patients must advocate for more basic, trans-
lational, and clinical research in both treatment and preven-
tion of HCC. Medical oncologists, in particular, need to
make HCC a research priority and actively develop clinical
trials of systemic therapies for these patients to expand their
treatment options. Working cooperatively with other med-
ical specialties, particularly liver transplantation programs,
offers a rich resource for both patients and for tissue for
research programs. There are numerous potential clinical
trial opportunities for HCC patients awaiting liver trans-
plantation; for example, a trial could evaluate whether re-
gional chemoembolization or other neoadjuvant therapy
changes the histologic response rate in the liver explant and
improves long-term survival.
Third, advocating for clinical trial designs that account
for variability in underlying HCC etiology and the wide
spectrum of liver dysfunction seen is essential. End points
such as time to progression and survival may be more
informative in this patient population. Clinical trial designs
should include stratification of patients according to one of
the many clinical prognostic scoring systems (eg, Childs
Pugh, Cancer of the Liver Italian Programme118) and strat-
ification by disease etiology (for example, HBV related,
HCV related, or other) to better identify those patients who
may truly benefit from systemic therapy.
Fourth, clinical trials in HCC should also include
quality-of-life assessments because improvement in quality
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of life, particularly for the many patients with advanced
disease in whom tumor response or prolonged survival may
not be achievable, is beneficial.
Fifth, response rates of traditional cytotoxic chemo-
therapy agents are low across all studies in HCC and there is
no consensus regarding the standard chemotherapy regi-
men for this disease. A thorough, critical review of existing
preclinical research on the efficacy of cytotoxic chemother-
apy in HCC should be performed to provide a rational basis
for identifying those agents that should be studied in future
trials. For example, doxorubicin is commonly used as a
control arm, yet it is a drug that is particularly susceptible to
cellular efflux pumps, which may account for the low re-
sponse rates seen with this agent. Clinical trial designs that
include a placebo-controlled arm should be considered the
gold standard in HCC, particularly in evaluating newer
targeted therapies; it is recognized that many clinicians may
object to such designs.
Sixth, because of the chemotherapy-resistant nature of
HCC, attention should shift to focus on translational work
that identifies the most important and relevant molecular
abnormalities, followed by clinical evaluation of existing
molecularly targeted agents in HCC.
Seventh, identifying the most appropriate imaging mo-
dality for assessing treatment response in HCC is challeng-
ing. HCC presents radiographically as a spectrum, from
large dominant hypervascular masses to diffuse, infiltrative,
poorly visualized lesions. Novel but practical imaging mo-
dalities for following HCC responses, particularly to novel
biologic therapies, must be developed. This is particularly
important in HCC, where the use of routine liver biopsy to
conduct correlative studies is risky and likely unethical.
Finally, it has been a challenge traditionally to interest the
pharmaceutical industry in supporting clinical trials in less
common diseases, and although HCC is extremely common
worldwide, it is considered an orphan disease in the United
States. Some of the most productive medical research in recent
years has been fueled by the efforts of organized patient advo-
cacy groups. Hepatocellular carcinoma offers a rich opportu-
nity for the oncology community to develop a working
partnership with advocacy groups such as The American Liver
Foundation. Such partnerships can leverage their influence
with pharmaceutical companies and cancer regulatory agen-
cies to call their attention to the acute need for progress in
developing effective therapies for our patients with HCC.
Note: The is original work by the authors that is based
on published literature and the consensus views of partici-
pants in a Hepatocellular Carcinoma (HCC) Meeting held
concurrently with the First Annual American Society of
Clinical Oncology GI Cancers Symposium, San Francisco,
CA, January 22-24, 2004.
■ ■ ■
JOURNAL OF CLINICAL ONCOLOGY
 Comments and Controversies
Authors’ Disclosures of Potential
Conflicts of Interest
The authors indicated no potential conflicts of interest.
© 2005 by American Society of Clinical Oncology
REFERENCES
1. Parkin DM, Pisani P, Ferlay J: Estimates of the worldwide incidence of
25 major cancers in 1990. Int J Cancer 80:827-841, 1999
2. Taylor-Robinson SD, Foster GR, Arora S, et al: Increase in primary liver
cancer in the UK, 1979-94. Lancet 350:1142-1143, 1997
3. Deuffic S, Poynard T, Buffat L, et al: Trends in primary liver cancer.
Lancet 351:214-215, 1998
4. Davis GL, Albright JE, Cook SF, et al: Projecting future complications of
chronic hepatitis C in the United States. Liver Transpl 9:331-338, 2003
5. Parkin DM, Bray FI, Devesa SS: Cancer burden in the year 2000: The
global picture. Eur J Cancer 37:S4-S66, 2001 (suppl 8)
6. Smart RG, Mann RE, Suurvali H: Changes in liver cirrhosis death rates
in different countries in relation to per capita alcohol consumption and
Alcoholics Anonymous membership. J Stud Alcohol 59:245-249, 1998
7. Wong JB, McQuillan GM, McHutchison JG, et al: Estimating future
hepatitis C morbidity, mortality, and costs in the United States. Am J Public
Health 90:1562-1569, 2000
8. National Vital Statistics Report 50:28-31, 2002
9. Jemal AT, Murray T, Ward E, et al: Cancer Statistics 2005. CA Cancer
J Clin 55:8-29, 2005
10. El-Serag HB, Davila JA, Petersen NJ, et al: The continuing increase in
the incidence of hepatocellular carcinoma in the United States: An update.
Ann Intern Med 139:817-823, 2003
11. El-Serag HB, Mason AC: Rising incidence of hepatocellular carcinoma
in the United States. N Engl J Med 340:745-750, 1999
12. Loguercio C, De Simone T, D’Auria MV, et al: Italian AISF Clinical
Group: Non-alcoholic fatty liver disease—A multicentre clinical study by the
Italian Association for the Study of the Liver. Dig Liver Dis 36:398-405, 2004
13. McCullough AJ: The clinical features, diagnosis and natural history of
nonalcoholic fatty liver disease. Clin Liver Dis 8:521-533, 2004
14. Ruhl CE, Everhart JE: Epidemiology of nonalcoholic fatty liver. Clin
Liver Dis 8:501-519, 2004
15. Johnson PJ: Systemic chemotherapy of liver tumors. Semin Surg
Oncol 19:116-124, 2000
16. Curley SA, Izzo F, Ellis LM, et al: Radiofrequency ablation of hepato-
cellular cancer in 110 patients with cirrhosis. Ann Surg 232:381-391, 2000
17. Akriviadis EA, Llovet JM, Efremidis SC, et al: Hepatocellular carci-
noma. Br J Surg 85:1319-1331, 1998
18. Nakakura EK, Choti MA: Management of hepatocellular carcinoma.
Oncology (Huntingt) 14:1085-1102, 2000
19. Nagasue N, Kohno H, Chang YC, et al: Liver resection for hepatocel-
lular carcinoma: Results of 229 consecutive patients during 11 years. Ann
Surg 217:375-378, 1993
20. Bergsland EK, Venook AP: Hepatocellular carcinoma. Curr Opin Oncol
12:357-361, 2000
21. Hemming AW, Cattral MS, Reed AI, et al: Liver transplantation for
hepatocellular carcinoma. Ann Surg 233:652-659, 2001
22. Iwatsuki S, Starzl TE, Sheahan DG, et al: Hepatic resection versus
transplantation for hepatocellular carcinoma. Ann Surg 214:221-229, 1991
23. Soreide O, Czerniak A, Blumgart LH: Large hepatocellular cancers:
Hepatic resection or liver transplantation? BMJ 291:853-857, 1985
24. Fong Y, Sun RL, Jarnagin W, et al: An analysis of 412 cases of
hepatocellular carcinoma at a Western center. Ann Surg 229:790-800, 1999
25. Poon RT, Fan ST, Lo CM, et al: Improving survival results after
resection of hepatocellular carcinoma: A prospective study of 377 patients
over 10 years. Ann Surg 234:63-70, 2001
26. Vauthey JN, Klimstra D, Franceschi D, et al: Factors affecting long-
term outcome after hepatic resection for hepatocellular carcinoma. Am J
Surg 169:28-35, 1995
27. Vogl TJ, Trapp M, Schroeder H, et al: Transarterial chemoembolization
for hepatocellular carcinoma: Volumetric and morphologic CT criteria for
assessment of prognosis and therapeutic success-results from a liver
transplantation center. Radiology 214:349-357, 2000
www.jco.org
Downloaded from ascopubs.org by 111.94.147.138 on October 1, 2017 from 111.094.147.138
Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
28. Poon RT, Ngan H, Lo CM, et al: Transarterial chemoembolization for
inoperable hepatocellular carcinoma and postresection intrahepatic recur-
rence. J Surg Oncol 73:109-114, 2000
29. Camma C, Schepis F, Orlando A, et al: Transarterial chemoemboliza-
tion for unresectable hepatocellular carcinoma: Meta-analysis of randomized
controlled trials. Radiology 224:47-54, 2002
30. Llovet JM, Bruix J: Systematic review of randomized trials for
unresectable hepatocellular carcinoma: Chemoembolization improves sur-
vival. Hepatology 37:429-442, 2003
31. Raoul Jl, Guyader D, Bretagne JF, et al: Prospective randomized trial
of chemoembolization versus intra-arterial injection of 131-I-labelled iodized
oilin the treatment of hepatocellular carcinoma. Hepatology 26:1156-1161,
1997
32. Raoul Jl, Guyader D, Bretagne JF, et al: Randomized controlled trial for
hepatocellular carcinoma with portal vein thrombosis: Intra-arterial iodine-
131-iodized oil versus medical support. J Nucl Med 35:1782-1787, 1994
33. Lau WY, Leung TWT, Ho SKW, et al: Adjuvant intra-arterial iodibe-
131-labelled Lipiodol for respectable hepatocellular carcinoma: A prospec-
tive randomized trial. Lancet 353:797-801, 1999
34. Livraghi T, Giorgio A, Marin G, et al: Hepatocellular carcinoma and
cirrhosis in 746 patients: Long-term results of percutaneous ethanol injec-
tion. Radiology 197:101-108, 1995
35. Vilana R, Bruix J, Bru C, et al: Tumor size determines the efficacy of
percutaneous ethanol injection for the treatment of small hepatocellular
carcinoma. Hepatology 16:353-357, 1992
36. Ishii H, Okada S, Nose H, et al: Local recurrence of hepatocellular
carcinoma after percutaneous ethanol injection. Cancer 77:1792-1796, 1996
37. Goldberg SN, Gazelle GS, Solbiati L, et al: Ablation of liver tumors
using percutaneous RF therapy. AJR Am J Roentgenol 170:1023-1028, 1998
38. Elba S, Giannuzzi V, Misciagna G, et al: Randomized controlled trial of
tamoxifen versus placebo in inoperable hepatocellular carcinoma. Ital J
Gastroenterol 26:66-68, 1994
39. Perrone F, Gallo C, Daniele B, et al: Tamoxifen in the treatment of
hepatocellular carcinoma: 5-year results of the CLIP-1 multicentre random-
ised controlled trial. Curr Pharm Des 8:1013-1019, 2002
40. CLIP Group (Cancer of the Liver Italian Programme): Tamoxifen in
treatment of hepatocellular carcinoma: A randomised controlled trial. Lancet
352:17-20, 1998
41. Pignata S, Daniele B, Gallo C, et al: Endocrine treatment of hepato-
cellular carcinoma: Any evidence of benefit? Eur J Cancer 34:25-32, 1998
42. Tan CK, Chow PK, Findlay M, et al: Use of tamoxifen in hepatocellular
carcinoma: A review and paradigm shift. J Gastroenterol Hepatol 15:725-
729, 2000
43. Kouroumalis E, Skordilis P, Thermos K, et al: Treatment of hepatocel-
lular carcinoma with octreotide: A randomised controlled study. Gut 42:442-
447, 1998
44. Lai EC, Lo CM, Fan ST, et al: Postoperative adjuvant chemotherapy
after curative resection of hepatocellular carcinoma: A randomized con-
trolled trial. Arch Surg 133:183-188, 1998
45. Yamamoto M, Arii S, Sugahara K, et al: Adjuvant oral chemotherapy to
prevent recurrence after curative resection for hepatocellular carcinoma.
Br J Surg 83:336-340, 1996
46. Llovet JM, Mas X, Aponte JJ, et al: Cost effectiveness of adjuvant
therapy for hepatocellular carcinoma during the waiting list for liver trans-
plantation. Gut 50:123-128, 2002
47. Muto Y, Moriwaki H, Ninomiya M, et al: Prevention of second primary
tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocel-
lular carcinoma: Hepatoma Prevention Study Group. N Engl J Med 334:
1561-1567, 1996
48. Simonetti RG, Liberati A, Angiolini C, et al: Treatment of hepatocellular
carcinoma: A systematic review of randomized controlled trials. Ann Oncol
8:117-136, 1997
49. Nagasue N, Uchida M, Makino Y, et al: Incidence and factors
associated with intrahepatic recurrence following resection of hepatocellular
carcinoma. Gastroenterology 105:488-494, 1993
50. Yamamoto J, Kosuge T, Takayama T, et al: Recurrence of hepatocel-
lular carcinoma after surgery. Br J Surg 83:1219-1222, 1996
51. Poon RT, Fan ST, Lo CM, et al: Intrahepatic recurrence after curative
resection of hepatocellular carcinoma: Long-term results of treatment and
prognostic factors. Ann Surg 229:216-222, 1999
2897
 Thomas and Zhu
52. Fausto N: Growth factors in liver development, regeneration and
carcinogenesis. Prog Growth Factor Res 3:219-234, 1991
53. Fausto N, Mead JE, Gruppuso PA, et al: Effects of TGF-beta s in the
liver: Cell proliferation and fibrogenesis. Ciba Found Symp 157:165-177,
1991
54. Fausto N, Webber EM: Control of liver growth. Crit Rev Eukaryot
Gene Expr 3:117-135, 1993
55. Fausto N, Laird AD, Webber EM: Liver regeneration: 2. Role of growth
factors and cytokines in hepatic regeneration. FASEB J 9:1527-1536, 1995
56. Inui Y, Higashiyama S, Kawata S, et al: Expression of heparin-binding
epidermal growth factor in human hepatocellular carcinoma. Gastroenterol-
ogy 107:1799-1804, 1994
57. Morimitsu Y, Hsia CC, Kojiro M, et al: Nodules of less-differentiated
tumor within or adjacent to hepatocellular carcinoma: Relative expression of
transforming growth factor-alpha and its receptor in the different areas of
tumor. Hum Pathol 26:1126-1132, 1995
58. Kiss A, Wang NJ, Xie JP, et al: Analysis of transforming growth factor
(TGF)-alpha/epidermal growth factor receptor, hepatocyte growth factor/
c-met, TGF-beta receptor type II, and p53 expression in human hepatocel-
lular carcinomas. Clin Cancer Res 3:1059-1066, 1997
59. Ito Y, Takeda T, Sakon M, et al: Expression and clinical significance of
erb-B receptor family in hepatocellular carcinoma. Br J Cancer 84:1377-
1383, 2001
60. Hsu C, Huang CL, Hsu HC, et al: HER-2/neu overexpression is rare in
hepatocellular carcinoma and not predictive of anti-HER-2/neu regulation of
cell growth and chemosensitivity. Cancer 94:415-420, 2002
61. Prange W, Schirmacher P: Absence of therapeutically relevant
c-erbB-2 expression in human hepatocellular carcinomas. Oncol Rep 8:727-
730, 2001
62. Su Q, Liu Y: Expression of c-erbB-2 protein and EGF receptor in
hepatitis B, cirrhosis and hepatocellular carcinoma. Zhonghua Bing Li Xue Za
Zhi 24:93-95, 1995 [in Chinese]
63. Mise M, Arii S, Higashituji H, et al: Clinical significance of vascular
endothelial growth factor and basic fibroblast growth factor gene expression
in liver tumor. Hepatology 23:455-464, 1996
64. Suzuki K, Hayashi N, Miyamoto Y, et al: Expression of vascular
permeability factor/vascular endothelial growth factor in human hepatocel-
lular carcinoma. Cancer Res 56:3004-3009, 1996
65. Yamaguchi R, Yano H, Iemura A, et al: Expression of vascular
endothelial growth factor in human hepatocellular carcinoma. Hepatology
28:68-77, 1998
66. Miura H, Miyazaki T, Kuroda M, et al: Increased expression of vascular
endothelial growth factor in human hepatocellular carcinoma. J Hepatol
27:854-861, 1997
67. An FQ, Matsuda M, Fujii H, et al: Expression of vascular endothelial
growth factor in surgical specimens of hepatocellular carcinoma. J Cancer
Res Clin Oncol 126:153-160, 2000
68. Park YN, Kim YB, Yang KM, et al: Increased expression of vascular
endothelial growth factor and angiogenesis in the early stage of multistep
hepatocarcinogenesis. Arch Pathol Lab Med 124:1061-1065, 2000
69. Chow NH, Hsu PI, Lin XZ, et al: Expression of vascular endothelial
growth factor in normal liver and hepatocellular carcinoma: An immunohis-
tochemical study. Hum Pathol 28:698-703, 1997
70. Yoshiji H, Kuriyama S, Yoshii J, et al: Vascular endothelial growth
factor tightly regulates in vivo development of murine hepatocellular carci-
noma cells. Hepatology 28:1489-1496, 1998
71. Li XM, Tang ZY, Zhou G, et al: Significance of vascular endothelial
growth factor mRNA expression in invasion and metastasis of hepatocellular
carcinoma. J Exp Clin Cancer Res 17:13-17, 1998
72. Li Y, Su JJ, Qin LL, et al: Synergistic effect of hepatitis B virus and
aflatoxin B1 in hepatocarcinogenesis in tree shrews. Ann Acad Med
Singapore 28:67-71, 1999
73. Torimura T, Sata M, Ueno T, et al: Increased expression of vascular
endothelial growth factor is associated with tumor progression in hepato-
cellular carcinoma. Hum Pathol 29:986-991, 1998
74. Mazzanti R, Messerini L, Monsacchi L, et al: Chronic viral hepatitis
induced by hepatitis C but not hepatitis B virus infection correlates with
increased liver angiogenesis. Hepatology 25:229-234, 1997
75. McKillop IH, Schmidt CM, Cahill PA, et al: Altered expression of
mitogen-activated protein kinases in a rat model of experimental hepatocel-
lular carcinoma. Hepatology 26:1484-1491, 1997
2898
Downloaded from ascopubs.org by 111.94.147.138 on October 1, 2017 from 111.094.147.138
Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
76. Kambe H, Kishima Y, Kuroda T, et al: Protein kinase C inhibitor, H-7
suppresses the growth activity of hepatoma-derived growth factor. Hepa-
togastroenterology 47:1645-1648, 2000
77. Okamoto Y, Nishimura K, Nakayama M, et al: Protein kinase C in the
regenerating rat liver. Biochem Biophys Res Commun 151:1144-1149, 1988
78. Perletti GP, Smeraldi C, Porro D, et al: Involvement of the alpha
isoenzyme of protein kinase C in the growth inhibition induced by phorbol
esters in MH1C1 hepatoma cells. Biochem Biophys Res Commun 205:
1589-1594, 1994
79. Lee YS, Hong SI, Lee MJ, et al: Differential expression of protein
kinase C isoforms in diethylnitrosamine-initiated rat liver. Cancer Lett
126:17-22, 1998
80. Ducher L, Croquet F, Gil S, et al: Differential expression of five protein
kinase C isoenzymes in FAO and HepG2 hepatoma cell lines compared with
normal rat hepatocytes. Biochem Biophys Res Commun 217:546-553, 1995
81. Chang KJ, Lin JK, Lee PH, et al: The altered activity of membrane-
bound protein kinase C in human liver cancer. Cancer Lett 105:211-215,
1996
82. Peng SY, Chou SP, Hsu HC: Association of downregulation of cyclin
D1 and of overexpression of cyclin E with p53 mutation, high tumor grade
and poor prognosis in hepatocellular carcinoma. J Hepatol 29:281-289, 1998
83. Jung YJ, Lee KH, Choi DW, et al: Reciprocal expressions of cyclin E
and cyclin D1 in hepatocellular carcinoma. Cancer Lett 168:57-63, 2001
84. Azechi H, Nishida N, Fukuda Y, et al: Disruption of the p16/cyclin
D1/retinoblastoma protein pathway in the majority of human hepatocellular
carcinomas. Oncology 60:346-354, 2001
85. Ito Y, Matsuura N, Sakon M, et al: Both cell proliferation and apoptosis
significantly predict shortened disease-free survival in hepatocellular carci-
noma. Br J Cancer 81:747-751, 1999
86. Ito Y, Takeda T, Sakon M, et al: Expression and prognostic role of
cyclin-dependent kinase 1 (cdc2) in hepatocellular carcinoma. Oncology
59:68-74, 2000
87. Boivin-Angele S, Lefrancois L, Froment O, et al: Ras gene mutations
in vinyl chloride-induced liver tumours are carcinogen-specific but vary with
cell type and species. Int J Cancer 85:223-227, 2000
88. Pulling LC, Klinge DM, Belinsky SA: P16INK4a and beta-catenin
alterations in rat liver tumors induced by NNK. Carcinogenesis 22:461-466,
2001
89. Liew CT, Li HM, Lo KW, et al: High frequency of p16INK4A gene
alterations in hepatocellular carcinoma. Oncogene 18:789-795, 1999
90. Wagayama H, Shiraki K, Sugimoto K, et al: High expression of
p21WAF1/CIP1 is correlated with human hepatocellular carcinoma in pa-
tients with hepatitis C virus-associated chronic liver diseases. Hum Pathol
33:429-434, 2002
91. Chao HK, Tsai TF, Lin CS, et al: Evidence that mutational activation of
the ras genes may not be involved in aflatoxin B(1)-induced human hepato-
carcinogenesis, based on sequence analysis of the ras and p53 genes. Mol
Carcinog 26:69-73, 1999
92. Xia Q, Yi P, Zhan DJ, et al: Liver tumors induced in B6C3F1 mice by
7-chlorobenz[a]anthracene and 7-bromobenz[a]anthracene contain K-ras pro-
tooncogene mutations. Cancer Lett 123:21-25, 1998
93. Liew CT, Li HM, Lo KW, et al: Frequent allelic loss on chromosome 9
in hepatocellular carcinoma. Int J Cancer 81:319-324, 1999
94. Kazachkov Y, Khaoustov V, Yoffe B, et al: p53 abnormalities in
hepatocellular carcinoma from United States patients: Analysis of all 11
exons. Carcinogenesis 17:2207-2212, 1996
95. Vautier G, Bomford AB, Portmann BC, et al: p53 mutations in British
patients with hepatocellular carcinoma: Clustering in genetic hemochroma-
tosis. Gastroenterology 117:154-160, 1999
96. Piao Z, Kim H, Jeon BK, et al: Relationship between loss of heterozy-
gosity of tumor suppressor genes and histologic differentiation in hepato-
cellular carcinoma. Cancer 80:865-872, 1997
97. Honda K, Sbisa E, Tullo A, et al: p53 mutation is a poor prognostic
indicator for survival in patients with hepatocellular carcinoma undergoing
surgical tumour ablation. Br J Cancer 77:776-782, 1998
98. Sheu JC: Molecular mechanism of hepatocarcinogenesis. J Gastro-
enterol Hepatol 12:S309-S313, 1997
99. Thorgeirsson SS, Grisham JW: Molecular pathogenesis of human
hepatocellular carcinoma. Nat Genet 31:339-346, 2002
100. Grisham JW: Molecular Genetic Alterations in Primary Hepatocellular
Neoplasms. Towtowa, NJ, Humana Press, 2002
JOURNAL OF CLINICAL ONCOLOGY
 Comments and Controversies
101. Giannelli G, Bergamini C, Marinosci F, et al: Clinical role of MMP-2/
TIMP-2 imbalance in hepatocellular carcinoma. Int J Cancer 97:425-431,
2002
102. Masumoto A, Arao S, Otsuki M: Role of beta1 integrins in adhesion
and invasion of hepatocellular carcinoma cells. Hepatology 29:68-74, 1999
103. Jaskiewicz K, Chasen MR: Differential expression of transforming
growth factor alpha, adhesions molecules and integrins in primary, meta-
static liver tumors and in liver cirrhosis. Anticancer Res 15:559-562, 1995
104. Arii S, Mise M, Harada T, et al: Overexpression of matrix metallopro-
teinase 9 gene in hepatocellular carcinoma with invasive potential. Hepatol-
ogy 24:316-322, 1996
105. Harada T, Arii S, Mise M, et al: Membrane-type matrix metalloproteinase-
1(MT1-MTP) gene is overexpressed in highly invasive hepatocellular carcino-
mas. J Hepatol 28:231-239, 1998
106. Ozaki I, Yamamoto K, Mizuta T, et al: Differential expression of
laminin receptors in human hepatocellular carcinoma. Gut 43:837-842, 1998
107. Yamamoto H, Itoh F, Sakamoto H, et al: Association of reduced cell
adhesion regulator messenger RNA expression with tumor progression in
human hepatocellular carcinoma. Int J Cancer 74:251-254, 1997
108. Yoo HY, Patt CH, Geschwind JF, et al: The outcome of liver
transplantation in patients with hepatocellular carcinoma in the United
States between 1988 and 2001: 5-year survival has improved significantly
with time. J Clin Oncol 21:4329-4335, 2003
109. Mazzaferro V, Regalia E, Doci R, et al: Liver transplantation for the
treatment of small hepatocellular carcinomas in patients with cirrhosis.
N Engl J Med 334:693-699, 1996
110. Cha CH, Ruo L, Fong Y, et al: Resection of hepatocellular carcinoma in
patients otherwise eligible for transplantation. Ann Surg 238:315-323, 2003
www.jco.org
Downloaded from ascopubs.org by 111.94.147.138 on October 1, 2017 from 111.094.147.138
Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
111. Tung-Ping Poon R, Fan ST, Wong J: Risk factors, prevention, and
management of postoperative recurrence after resection of hepatocellular
carcinoma. Ann Surg 232:10-24, 2000
112. Poon RT, Ng IO, Fan ST, et al: Clinicopathologic features of
long-term survivors and disease-free survivors after resection of hepato-
cellular carcinoma: A study of a prospective cohort. J Clin Oncol
19:3037-3044, 2001
113. Llovet JM, Real MI, Montana X, et al: Arterial embolisation or
chemoembolisation versus symptomatic treatment in patients with unre-
sectable hepatocellular carcinoma: A randomised controlled trial. Lancet
359:1734-1739, 2002
114. Lo CM, Ngan H, Tso WK, et al: Randomized controlled trial of
transarterial lipiodol chemoembolization for unresectable hepatocellular car-
cinoma. Hepatology 35:1164-1171, 2002
115. Huang M, Liu G: The study of innate drug resistance of human
hepatocellular carcinoma Bel7402 cell line. Cancer Lett 135:97-105, 1999
116. Kato A, Miyazaki M, Ambiru S, et al: Multidrug resistance gene
(MDR-1) expression as a useful prognostic factor in patients with human
hepatocellular carcinoma after surgical resection. J Surg Oncol 78:110-115,
2001
117. Kuo MT, Zhao JY, Teeter LD, et al: Activation of multidrug resistance
(P-glycoprotein) mdr3/mdr1a gene during the development of hepatocellular
carcinoma in hepatitis B virus transgenic mice. Cell Growth Differ 3:531-540,
1992
118. The Cancer of the Liver Italian (CLIP) Investigators: A new prognostic
system for hepatocellular carcinoma: A retrospective study of 435 patients.
Hepatology 28:751-755, 1998
2899