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 TRENDS AND PRACTICES IN
DIAGNOSIS AND TREATMENT OF
HEPATOCELLULAR CARCINOMA
 The following States are Members of the International Atomic Energy Agency:

AFGHANISTAN GHANA NORWAY

ALBANIA GREECE OMAN
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 IAEA HUMAN HEALTH SERIES No. 10

TRENDS AND PRACTICES IN

DIAGNOSIS AND TREATMENT OF
HEPATOCELLULAR CARCINOMA

INTERNATIONAL ATOMIC ENERGY AGENCY

VIENNA, 2010
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STI/PUB/1446

IAEA Library Cataloguing in Publication Data

Trends and practices in diagnosis and treatment of hepatocellular carcinoma. —

Vienna : International Atomic Energy Agency, 2010.
p. ; 24 cm. — (IAEA human health series, ISSN 2075–3772 ; no. 10)
STI/PUB/1446
ISBN 978–92–0–102710–8
Includes bibliographical references.

1. Developing countries — Liver — Cancer — Diagnosis. 2. Developing

countries — Liver — Cancer — Therapeutics. 3. Radiotherapy.
I. International Atomic Energy Agency. II. Series.

IAEAL 10–00644
 FOREWORD

Hepatocellular carcinoma (HCC), or primary liver cancer, is one of the

most common causes of cancer and cancer death globally, and has an increasing
incidence. It is currently the fifth most common cancer among men and eighth
among women. In some Asian and African countries, its incidence is similar to
that of lung cancer. It carries a very poor prognosis; the majority of patients die
within a year, making it the third most common cause of cancer death. Currently,
the main treatments offering the chance of cure are surgical resection and liver
transplantation. However, owing to late presentation and underlying liver
cirrhosis, these are suitable only for a small minority of patients. Therefore, new
investigative protocols in radiotherapy using the most advanced technologies
have been developed with some promise of cure and effective palliation.
However, no uniform recommendations exist and the use of radiotherapy is
limited by pre-existing liver disease.
The IAEA has extensive projects in radiation oncology in low and middle
income countries, including areas in Asia and Africa where HCC is a common
problem. Since there has been a reported significant increase in the use of
radiotherapy in HCC, an expert review was considered timely to assess the role of
radiotherapy within the entire framework of HCC management. This publication
developed from the need to address this issue.
A meeting on the current knowledge of HCC epidemiology and
management protocols was convened in October 2008. The given task was to
define the current role of radiotherapy in the management of HCC. The greatest
number of patients requiring optimal management protocols for HCC lives in
Asia and sub-Saharan Africa, where in many countries access to radiotherapy and
cancer care in general is limited and resources for research and access to the most
advanced technologies are not available.
This review is intended for use in training courses and as a source of
information on treatment decisions. It may also help guide the use of limited
resources towards the most appropriate indications and help to differentiate
approaches used for cure or palliation. An international registry of radiation
treatment applications in HCC would facilitate conclusions regarding clinical
applications.
The contributions leading to this publication are gratefully acknowledged.
Special thanks are due to G. Stevens, consultant radiation oncologist at Auckland
City Hospital and associate professor at the University of Auckland (New
Zealand), for his work in producing the final report and updating the text and
references. The IAEA officer responsible for this publication was E. Salminen of
the Division of Human Health.
 EDITORIAL NOTE

Although great care has been taken to maintain the accuracy of information contained in
this publication, neither the IAEA nor its Member States assume any responsibility for
consequences which may arise from its use.
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on such web sites is, or will remain, accurate or appropriate.
 CONTENTS

1. EPIDEMIOLOGY, AETIOLOGY, PATHOLOGY . . . . . . . . . . . . . . 1

1.1. Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2. Aetiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2.1. Liver cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2.2. Chronic viral hepatitis . . . . . . . . . . . . . . . . . . . . . . . . . . 2
1.2.3. Aflatoxin B1 (AFB1) exposure . . . . . . . . . . . . . . . . . . . . 3
1.2.4. Alcohol consumption . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.2.5. Inherited metabolic diseases . . . . . . . . . . . . . . . . . . . . . 4
1.2.6. Other risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.3. Pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.3.1. Appearance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1.3.2. Tumour biology and behaviour . . . . . . . . . . . . . . . . . . . 5
1.3.3. Carcinogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.3.4. Advances in molecular pathology . . . . . . . . . . . . . . . . . 6

2. CLINICAL FEATURES AND DIAGNOSIS OF HCC . . . . . . . . . . . 7

2.1. Clinical features . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7

2.1.1. Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.1.2. Child–Pugh score . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
2.2. Laboratory investigations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
2.2.1. Alpha-fetoprotein (AFP) . . . . . . . . . . . . . . . . . . . . . . . . 8
2.2.2. Alkaline phosphatase and carcinoembryonic antigen . . 9
2.2.3. Desgamma-carboxyprothrombin (DCP) . . . . . . . . . . . . 9
2.2.4. GP-73 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.3. Radiological detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.3.1. Ultrasonography (US) . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
2.3.2. Computed tomography (CT) . . . . . . . . . . . . . . . . . . . . . 10
2.3.3. MRI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
2.3.4. Summary of imaging . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.4. Liver biopsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
2.5. Algorithm for diagnosis of HCC . . . . . . . . . . . . . . . . . . . . . . . . 12
2.5.1. Pre-existing cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
2.5.2. No cirrhosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.6. Screening for HCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
2.7. Staging systems and prognosis . . . . . . . . . . . . . . . . . . . . . . . . . 15
3. TREATMENT OF HCC . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

3.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.2. Surgery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
3.2.1. Resection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
3.2.2. OLT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
3.2.3. Transplantation or resection for HCC in cirrhosis . . . . . 24
3.2.4. Other, less common surgical situations . . . . . . . . . . . . . 24
3.3. Non-surgical treatment of HCC . . . . . . . . . . . . . . . . . . . . . . . . . 25
3.3.1. Ablative therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
3.4. Systemic therapies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
3.4.1. Cytotoxic chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . 30
3.4.2. Molecular targeted therapy . . . . . . . . . . . . . . . . . . . . . . 30
3.4.3. Hormonal therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
3.4.4. Immunotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

4. RADIOTHERAPY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

4.1. Rationale for radiation therapy . . . . . . . . . . . . . . . . . . . . . . . . . 33

4.2. Indications for radiation therapy . . . . . . . . . . . . . . . . . . . . . . . . 33
4.2.1. Definitive, high dose radiotherapy . . . . . . . . . . . . . . . . . 33
4.2.2. Palliation with radiotherapy . . . . . . . . . . . . . . . . . . . . . . 35
4.2.3. Radiotherapy combined with other therapies . . . . . . . . . 36
4.2.4. Bridge to transplantation . . . . . . . . . . . . . . . . . . . . . . . . 37
4.3. Types of radiation therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
4.3.1. Brachytherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
4.3.2. Radioisotopes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
4.3.3. Photons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
4.4. Technical aspects of high dose external beam radiotherapy . . . 43
4.5. Radiotherapy toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
4.5.1. Hepatic toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
4.6. Gastrointestinal mucosal toxicity . . . . . . . . . . . . . . . . . . . . . . . . 47
4.6.1. Biliary toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
4.6.2. Other radiotherapy related toxicities . . . . . . . . . . . . . . . 49

5. FUTURE DIRECTIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50

5.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
5.2. Existing treatment guidelines for HCC . . . . . . . . . . . . . . . . . . . 50
5.3. Treatment of HCC: The radiation oncologist’s perspective . . . . 52
 5.4. Unresolved issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
5.4.1. Dose escalation studies using radiotherapy
as a single modality . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
5.4.2. Development of combination strategies . . . . . . . . . . . . . 53
5.4.3. New radiotherapy technologies . . . . . . . . . . . . . . . . . . . 54
5.4.4. Redefinition of liver toxicity . . . . . . . . . . . . . . . . . . . . . 54
5.5. Recommendation for future studies . . . . . . . . . . . . . . . . . . . . . . 54
5.5.1. Clinical trials of HCC incorporating radiotherapy . . . . . 54
5.5.2. Stem cell recovery of liver function . . . . . . . . . . . . . . . . 55
5.5.3. Redefinition of staging . . . . . . . . . . . . . . . . . . . . . . . . . . 55
5.5.4. Measurement of end points in palliation . . . . . . . . . . . . 55

6. CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56

REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57

ANNEX I: MOLECULAR PATHOLOGY OF HEPATOCELLULAR

CARCINOMA (HCC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
ANNEX II: TECHNICAL CONSIDERATIONS IN RADIOTHERAPY
OF HEPATOCELLULAR CARCINOMA (HCC) . . . . . . . . . 79

ABBREVIATIONS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 87
CONTRIBUTORS TO DRAFTING AND REVIEW . . . . . . . . . . . . . . . . . 89
 1. EPIDEMIOLOGY, AETIOLOGY, PATHOLOGY

1.1. EPIDEMIOLOGY

Heptocellular carcinoma (HCC) is the fifth most common cancer globally,

with an estimate of more than 500 000 new cases annually, and it is the third
leading cause of cancer deaths [1, 2]. A striking geographical difference in the
incidence of HCC exists, with 80% of new cases occurring in developing
countries. High incidence regions include sub-Saharan Africa and East and
Southeast Asia, whereas low incidence regions include Northern and Western
Europe and North America.
Better control of the risk factors has resulted in a recent decline in HCC in
some places such as Taiwan, China and mainland China. In Taiwan, China, for
example, mortality from HCC in male and female children younger than 15 years
of age has decreased by up to 70% and 62%, respectively, as a result of
vaccination against hepatitis B virus (HBV) [3]. However, there is a recent trend
of increasing incidence of HCC in Europe and North America due to changes in
lifestyle and an increase in HBV and the hepatitis C virus (HCV). In the United
States of America, the age adjusted incidence has doubled over the past two
decades [4]. There is a marked male predominance, with a male to female ratio of
24:1 [5].

1.2. AETIOLOGY

The key risk factors of HCC are well established and include chronic HBV
and HCV infections [6, 7], cirrhosis [8], aflatoxin B1 [9] and inherited metabolic
disorders.

1.2.1. Liver cirrhosis

The association of HCC with cirrhosis has been documented widely.

Although cirrhosis and HCC development share some common risk factors, such
as viral hepatitis and excessive alcohol consumption, cirrhosis itself is an
independent risk factor for HCC [10, 11].

1
1.2.2. Chronic viral hepatitis

1.2.2.1. HBV

HBV is an enveloped DNA virus containing a partially double stranded,

circular DNA genome, classified into the Hepadnaviridae family. The 3.2 kb
HBV genome consists of four major open reading frames, P, S, C and X,
encoding the reverse transcriptase essential for viral replication, the viral
envelope proteins, the nucleocapsid (core) protein and the X protein, respectively.
There are at least 300 million HBV carriers in the world and 8–20% of the
population in endemic areas, including China, are carriers [12]. HBV
transmission in adults occurs primarily by blood exchange and sexual contact,
while children often acquire infection from their infected mothers at the time of
birth [13, 14].
HBV is the dominant risk factor for HCC, causing up to 80% of HCCs
worldwide. HBV acts as a pro-oncogenic agent indirectly and directly [15, 16].
The indirect mechanism involves the ability of HBV infection to induce
hepatocellular necrosis, chronic inflammation and regeneration of the liver,
eventually leading to cirrhosis and predisposition to HCC [17–19]. The direct
carcinogenic mechanisms have been related to the integration of HBV DNA into
the host genome. As HBV DNA insertions are frequently associated with
deletions, amplifications or chromosomal translocations, HBV DNA integration
may result in chromosomal instability [20]. When the expressions of tumour
suppressor genes and proto-oncogenes responsible for regulating cell growth,
differentiation and apoptosis are altered, selective growth advantage of infected
cells may trigger the onset of tumour and cancer progression [21]. One such
molecule is the HBx protein, which is a multifunctional regulator for a number of
host processes by interacting with the virus and host factors [22]. For example,
the HBx protein plays a role in modulating gene expression by interacting with
promoters of oncogenes, cytokines and growth factors [23]. HBx also interacts
with transcription activators such as the leucine zipper family, p53, and Smad4.
The abnormal activation of the signal transduction in the hepatocytes may result
in oncogenic alterations and outgrowth of genetically damaged cells.

1.2.2.2. HCV

HCV is an enveloped single stranded ribonucleic acid virus with a 9.6 kb

genome, classified into the Flaviviridae family. There are six major genotypes
with several subtypes based on the genomic sequence heterogeneity [24, 25].
Types 1a and 1b are the most common, contributing to up to 60% of global
infections. HCV is usually spread by sharing infected needles and sexual contact

2
[26]. HCV has a worldwide distribution, but predominates in Italy, Japan and
Egypt [27]. An estimated 3% of the world’s population is infected by HCV, with
more than 170 million chronic carriers at risk of liver cirrhosis or HCC [28]. HCV
infected individuals have a seventeenfold increased risk of developing HCC,
compared with HCV negative individuals [29].
Unlike the HBV infection, the HCV genome does not integrate into the host
genome [30], and almost all HCC patients infected by HCV suffer from cirrhosis,
suggesting that cirrhosis is the major risk factor of HCC development in
individuals with HCV [31]. The polymerase enzyme of ribonucleic acid viruses
such as HCV lacks efficient ‘proofreading’ ability, resulting in constant mutation
and escape from the host immune response. Although the underlying mechanism
of HCV-induced HCC development remains unclear, the core protein of HCV has
been reported to have a significant role in HCC development in chronic hepatitis
C [32]. The proposed mechanism suggests that the core protein binds with p53
and modulates cellular regulatory functions by regulating the expression of the
cyclin-dependent inhibitor p21WAF1, which promotes either cell proliferation or
apoptosis [33, 34].

1.2.3. Aflatoxin B1 (AFB1) exposure

Extensive studies suggest that HCC risk is increased with high dietary
intake of AFB1 in Western Africa and China [35]. Aflatoxins are naturally
produced mycotoxins, being secondary metabolites of Aspergillus flavus and
Aspergillus parasiticus fungi. Warmth and moisture favour fungal contamination
of staple crops such as rice, corn and nuts in developing countries, leading to
increased dietary intake [36]. AFB1 is the predominant form among known
aflatoxins with the highest toxicity, classified as a category I human carcinogen
and a potent genotoxic agent (International Agency for Research on Cancer [37]).
Studies report that the synergistic effect of aflatoxin and HBV increases the risk
of HCC by twenty-five- to thirtyfold [38].

1.2.4. Alcohol consumption

Although alcohol is not a carcinogen, the association between heavy

alcohol intake and risk of HCC has been broadly reported in many epidemiologic
studies [39–41]. Alcohol abuse leading to cirrhosis increases HCC risk appreciably
by promoting liver cirrhosis. However, only severe, but not moderate, alcohol
consumption is related to HCC [42, 43].

3
1.2.5. Inherited metabolic diseases

Other risk factors for HCC include inherited metabolic diseases such as
hereditary hemochromatosis [44], alpha-1-antitrypsin deficiency and hereditary
tyrosinemia. Hemochromatosis is an iron overload hereditary disease which
involves a predominant mutation C282Y on the HFE gene [45]. The incidence of
C282Y homozygosity is 1 in 250 persons in the general population and higher
prevalence has been observed in individuals with northern European ancestry
[46]. When hepatic production of the essential hormone hepcidin is aberrantly
regulated, enterocyte iron absorption is disrupted [47]. Since iron cannot be
removed from the human body, a chronic iron overload occurs, leading to severe
organ damage and development of HCC [48].

1.2.6. Other risk factors

The role of tobacco smoking in the causation of HCC is controversial.

Although the association is supported by some epidemiological studies [49, 50],
the mechanism remains incompletely understood. However, cigarette smoke
contains many hepatic carcinogens such as 3-aminobiphenyl [9].
Obesity and diabetes can lead to non-alcoholic steatohepatitis, which is an
established risk factor for HCC, probably via progression of the steatohepatitic
disease to cirrhosis and HCC [51]. Obesity and diabetes have been reported as
risk factors for HCC in some case studies. In particular, the synergistic effect of
diabetes, viral hepatitis and heavy alcohol consumption in the development of
HCC has been emphasized [9].
Other factors have also been implicated. For example, oral contraceptives
consisting of estrogens and progestogens may act as inducers and promoters for
liver tumours. The high level of inorganic arsenic metal in the drinking water of
Japan and Taiwan, China, has been linked to HCC, possibly due to induction of
oxidative stress by arsenic [9].

1.3. PATHOLOGY

1.3.1. Appearance

1.3.1.1. Macroscopic appearance

HCC is predominantly a soft light brown or tan coloured mass with very
little stroma. Hemorrhagic areas are usually present and often extensive, because
the tumour is highly vascular, deriving most of its support from very thin-walled

4
sinusoids. The rich blood supply comes chiefly from branches of the hepatic
artery which grow with the tumour. Some areas of the tumour may be better
differentiated to produce bile which gives the tumour a green discolouration.
Production of bile is a diagnostic feature of HCC.

1.3.1.2. Microscopic appearance

Microscopically, the tumour cells commonly retain the recognizable

features of hepatocytes, arranged in a trabecular (80%) or pseudoglandular
pattern. Other histological changes may include acinar necroinflammation,
steatosis or liver cell dysplasia [52].
HCC has been divided into several histological subtypes, which have some
clinicopathological correlations:

• Combined hepatocellular-cholangiocarcinoma (HCC-CC) is a rare tumour

in which dual differentiation towards both hepatocytes and bile duct
epithelia coexists in the same tumour or the same liver. HCC-CC frequently
exhibits an invasive character with frequent venous permeation and tumour
microsatellite formation, which are more frequently seen in ordinary HCC
than CC. This tumour has been reported to be more aggressive than HCC,
with widespread metastases and regional lymph node involvement.
• Sclerosing HCC [53].
• Fibrolamellar HCC [54] occurs in young patients and has an equal sex
distribution. It is not associated with HBV infection and has a better
prognosis when completely resected.

1.3.2. Tumour biology and behaviour

HCC has a marked tendency to spread into portal vein branches within the
liver and also the main portal vein, resulting in intrahepatic metastasis, which
dominates the clinical picture. Similarly, invasion into the hepatic venous system
and main hepatic veins may lead to systemic metastases to lung, bone and
elsewhere. Lymphatic spread may lead to porta hepatic lymphadenopathy.
However, in many cases, death occurs before metastases are extensive. Invasion
of intra- or extra-hepatic bile ducts occurs less commonly, but can result in biliary
obstruction.
Successful treatment of HCC poses particular challenges because in the
majority of cases two diseases need to be considered: the aggressive HCC with a
propensity for multiple foci and invasion, and a cirrhotic liver that may
decompensate with minimal insult and is at risk of developing more tumours.

5
1.3.3. Carcinogenesis

Hepatocarcinogenesis is understood to be a multistep process with

transition from normal liver through chronic liver diseases (chronic hepatitis and
cirrhosis), liver dysplasia, dysplastic nodule and, finally, HCC. In the majority of
the cases, HCC arises with a background disease of either chronic hepatitis or
cirrhosis, although HCC can arise in an apparently normal liver.
The multistep process involves accumulation of chromosomal, genetic and
epigenetic abnormalities. Recent evidence suggests that chromosomal instability
emerges at an early stage during hepatocarcinogenesis and is an inherent property
of tumour cells, ultimately resulting in acquisition of the malignant phenotype
[55].

1.3.4. Advances in molecular pathology

Hepatocarcinogenesis is strongly linked to increases in allelic losses,

chromosomal changes, gene mutations, epigenetic alterations and alterations in
signalling pathways. These genetic changes are undoubtedly of fundamental
importance to an understanding of the process of hepatocarcinogenesis and they
have started to impact current treatments and treatment guidelines. Therefore, a
discussion of these genetic and molecular issues is included in Annex I.
Compared with other cancers such as colon and breast cancers, gene
mutations in HCC are relatively infrequent: p53 and β-catenin probably are the
most frequently mutated genes in HCC. Interestingly, recent data suggest that
HCC harbouring p53 and β-catenin mutation may arise from two independent
pathways. In one, p53 mutation is associated with a high level of chromosomal
instability, whereas in the other, β-catenin mutation is associated with frequent
epigenetic alterations [56].

6
 2. CLINICAL FEATURES AND DIAGNOSIS OF HCC

2.1. CLINICAL FEATURES

2.1.1. Presentation

The presentation of HCC varies according to the size of the mass or masses.
With greater use of imaging, particularly ultrasound (US), small asymptomatic
lesions are increasingly being diagnosed [57]. In many cases, the clinical
manifestations are masked by features of underlying cirrhosis or chronic
hepatitis. Large tumours may cause pressure effects and present with ill-defined
upper abdominal pain, malaise, weight loss, fatigue and sometimes an awareness
of an abdominal mass or fullness. Jaundice may result from compression of the
common bile duct, or hepatic decompensation; ascites suggests advanced disease
or co-existing cirrhosis. Other presentations include the paraneoplastic syndrome,
hypercalcaemia, hormonal imbalance, gastrointestinal (GI) or oesophageal
variceal bleeding and tumour-necrosis induced fever [58].
HCCs develop mainly as slow growing nodules which may be
asymptomatic for many years. Estimated doubling times of HCCs vary between 1
and 19 months [59], with a median of six months [60].
It has been suggested that tumours with certain defined aetiologies may
have more aggressive behaviour, but there are no conclusive data to support this.
Data from untreated HCC show that the major factors influencing overall survival
are severity of underlying liver dysfunction and tumour size at initial detection.
Small HCCs at presentation have relatively long tumour doubling times, and
overall survival with tumours of less than 5 cm was 81–100% at one year and
17–21% at three years without therapy [61]. These results suggest that if
diagnosis can be made during the asymptomatic phase when the tumour is small,
the opportunity for cure may be greater.

2.1.2. Child–Pugh score

As indicated above, the management of HCC for most patients is

complicated by the presence of cirrhosis. The degree of cirrhosis is prognostic for
survival of the patient in the absence of HCC and also for treatment of the HCC,
as sufficient functioning liver must be retained. The Child–Pugh scoring system
(Table 1) uses clinical examination and liver function tests to stratify patients for
prediction of surgical mortality among cirrhotic patients [59].

7
TABLE 1. CHILD–PUGH SCORING OF SEVERITY OF LIVER DISEASE
[59]

Variable 1 point 2 points 3 points

1. Encephalopathy None Moderate Severe

2. Ascites None Slight Moderate
3. Albumin (mg/dL) >3.5 2.8–3.5 <2.8
a
4. PT prolongation <4 s 4–6 s >6 s
(INRa) (<1.7) (1.7–2.3) (>2.3)
5. Bilirubin (mg/dL) <2 2.1–3 >3
a
PT: prothrombin time, INR: international normalized ratio.

The scores from Table 1 are summed to group patients into three classes, as
follows:

• Child–Pugh A = 5–6 points, indicates good liver function; ~100% 1 year

survival.
• Child–Pugh B = 7–9 points, indicates intermediate liver function; ~80%
1 year survival.
• Child–Pugh C = 10–15 points, indicates poor liver function; ~45% 1 year
survival.

2.2. LABORATORY INVESTIGATIONS

2.2.1. Alpha-fetoprotein (AFP)

AFP, a serum protein synthesized normally by fetal liver cells and yolk sac
cells, is the most widely studied tumour marker for HCC. AFP is produced by
over 80% of HCCs. The normal range for AFP is 10–20 ng/mL and a level
>400 ng/mL is usually regarded as diagnostic for HCC. However, two thirds of
HCCs of <4 cm have AFP levels less than 200 ng/mL and up to 20% of HCC do
not produce AFP, even when very large [62].
Modifications of AFP with differing carbohydrate structures may occur in
HCC and can be detected by altered patterns of lectin binding. These altered
profiles have led to the development of alternative diagnostic tests [63], but none
are widely available or have been shown to enhance markedly diagnostic ability
over AFP. False positive results occur, with AFP levels of 20–250 ng/mL seen
with regenerating nodules in viral cirrhosis [64], testicular teratoma, benign liver

8
disease, normal pregnancy and obstetric abnormalities. Low human chorionic
gonadotropin levels help to exclude these possibilities [63]. AFP levels are
particularly helpful in monitoring HCC activity after treatment and in screening
cirrhotic patients at risk of developing HCC [63].

2.2.2. Alkaline phosphatase and carcinoembryonic antigen

These serum markers may be elevated but are not useful diagnostically, as
they are non-specific. Carcinoembryonic antigen levels are often raised with
hepatic metastases from colorectal cancer [63].

2.2.3. Desgamma-carboxyprothrombin (DCP)

DCP is a prothrombin precursor resulting from failure to carboxylate

glutamic acid residues and may be detected in the serum of HCC patients [65].
DCP has been used as an alternative tumour marker for HCC; 67% of HCCs have
elevated levels, but as only 8% of small (<2 cm) HCCs have abnormal levels
[66], DCP has not gained wide acceptance as a marker for HCC [63].

2.2.4. GP-73

GP-73 is a recently discovered Golgi protein that is increased in cirrhosis

and HCC. DCP and GP-73 are purported to have superior positive and negative
predictive values for early HCC compared with AFP. These findings suggest that
these markers may eventually replace AFP as a screening assay for HCC [67].

2.3. RADIOLOGICAL DETECTION

2.3.1. Ultrasonography (US)

Imaging of the lesion usually begins with US (if not already performed),
which provides information on the shape, echogenicity, growth pattern and
vascular involvement of the tumour [68]. US can detect large tumours with high
sensitivity and specificity, but has limitations in identifying smaller lesions,
which is an essential requirement for improved outcomes in this disease.
Expertise of the operator and use of dedicated equipment seem important to
optimize results; where these are available, US detects 85% of tumours <3 cm,
85–95% of tumours 3–5 cm in diameter and can achieve 60–80% sensitivity in
the detection of tumours measuring 1 cm [61].

9
 The combination of AFP and US improves detection rates. Screening with
US has been suggested at six monthly intervals on the basis of tumour doubling
times. However, there is evidence that more frequent examinations may enhance
sensitivity, but at the expense of a higher false positive rate [69]. Patients with a
negative US and an elevated, but not diagnostic, AFP appear to be at higher risk
and more frequent US, probably three monthly, may be appropriate in this group
[70].

2.3.2. Computed tomography (CT)

CT is used for detection and evaluation of the extent of HCC [71]. Many
combinations of techniques and contrast agents have been proposed to improve
imaging [72]. Examples include:

• Lipiodol CT (CT following intra-arterial injection of lipiodol). Lipiodol

was shown to detect a greater proportion of small HCCs in 22 patients who
were subsequently surgically treated (86% for lipiodol CT versus 70% for
US, 65% for CT, 62% for magnetic resonance imaging (MRI) and 73% for
digital subtraction angiography; p<0.05) [73].
• Helical CT hepatic arteriography combined with CT performed during
arterial portography. This technique has shown promise as a more accurate
diagnostic tool than several forms of MRI (spin echo, phase shift gradient
recalled echo and triple phasic dynamic) in the pre-operative detection of
HCC in 37 patients with cirrhosis [74]. Multiphase imaging is important to
characterize the vascular features of a hepatic lesion which may be useful in
distinguishing HCC from other liver cancers. HCC typically enhances in
the arterial phase of imaging and washes out (more than the adjacent liver)
in delayed phase imaging.

2.3.3. MRI

MRI techniques are extremely useful in the identification and

characterization of regenerating nodules, dysplastic nodules and HCC. Arterial
phase dynamic MRI has been reported to allow greater detection of HCC than
arterial-phase CT (but not for the delayed phase) [75] and MRI during arterial
portography has been suggested to have greater value than CT during arterial
portography, to distinguish benign lesions and pseudolesions [76].

10
2.3.4. Summary of imaging

Despite numerous approaches, no single investigation has been shown to be

clearly superior and both MRI and CT scanning yield similar detection rates for
HCC [77]. Radiological imaging with US, CT and angiography usually
understages HCC [78–80]. The development of US contrast agents and the
improving technology of MRI, using iron or gadolinium contrast agents, may
enhance the ability to detect satellite or second distant lesions within the liver
[81]. The exact role of these contrast agents in treatment planning is uncertain and
while these may produce major changes in the diagnostic radiology of HCC in the
near future, at present their role should be regarded as experimental [82].
Accurate diagnosis is important for localized treatments such as resection
and radiotherapy, as the precise size of the tumour and any associated satellites,
or of second primary HCC, will influence the extent of resection (or the
radiotherapy treatment volume), but the presence of cirrhosis may limit the
tolerance of treatment. Conversely, understaging the extent of intrahepatic
tumour has little significance in the selection of patients for transplantation, as
prognosis relates to the pre-operative radiological assessment of the tumour
rather than to the actual stage at pathological examination of the removed organ
[80].

2.4. LIVER BIOPSY

When aggressive treatment of HCC is possible but the diagnosis remains

uncertain, a percutaneous liver biopsy or fine needle aspirate under US or CT
guidance may aid diagnosis [83]. In a study of 121 patients with suspected HCC
<3 cm using US, 118 were finally diagnosed as HCC by percutaneous biopsy, CT
and angiography. Retrospective analysis of results produced a correct diagnosis
of HCC in 87.3% by histology, 55.1% by CT and 52.5% by angiography.
However, for tumours <1.5 cm, the specificity of the imaging techniques fell
markedly and the correct diagnosis was obtained in 88.5% (biopsy), 34.6% (CT)
and 23.1% (angiography). On the basis of these findings, it has been suggested
that percutaneous biopsy with histological examination is the most reliable
method of making a definitive diagnosis of small HCC [84].
The requirement for histological confirmation of all HCC is controversial,
owing to the added risks of biopsy (haemorrhage, inadequate sampling and
needle track metastases) versus the higher false positive results from imaging
alone. Some authors have suggested that percutaneous biopsy of potentially
resectable tumours may not be appropriate, as patients with resectable HCC
occasionally develop post-resection recurrence along the needle track [85]. The

11
risk of needle track recurrence may be reduced if the length of interposing liver
parenchyma exceeds 1 cm, as shown in a study of 139 liver biopsies in which two
cases of bleeding occurred following the procedure, both cases having
interposing tracks of <1 cm [86]. The risk of seeding of HCC does not appear to
be related to tumour size [79]; therefore, if curative treatment is considered,
biopsy should be avoided if possible, even for small lesions [87].

2.5. ALGORITHM FOR DIAGNOSIS OF HCC

When a patient presents with a liver mass, there is a requirement to make

a diagnosis and to stage the disease. The commonest clinical scenario is a
patient with cirrhosis and a mass discovered on US where AFP may or may not
be raised.

2.5.1. Pre-existing cirrhosis

2.5.1.1. Liver mass >2 cm in diameter

• Of these lesions, >95% are HCC [88].

• If AFP is raised, this confirms the diagnosis and further investigation is
only required to establish the most appropriate therapy.
• If AFP is normal, further radiological imaging (CT, MRI, or lipiodol
angiography with follow-up CT) will usually allow a confident diagnosis to
be made and proceed to assessment of treatment without the need for biopsy
[73, 89, 90]. In the few cases where diagnostic doubt persists and would
affect management, biopsy is indicated [87].

2.5.1.2. Liver mass <2 cm in diameter

• Approximately 75% are HCC [91].

• Using CT and/or MRI, a firm diagnosis of HCC is still difficult to reach
when the nodule is <1 cm in diameter and short term follow-up is suitable in
this setting.
• Nodules 1–2 cm in diameter should be further studied by the determination
of serum AFP and additional imaging, either CT and/or MRI, even though
diagnosis should rely on histology [92].

12
2.5.1.3. Non-invasive criteria

Criteria for the diagnosis of HCC in cirrhotic patients without the

requirement for biopsy have been proposed. The basis for considering this
approach is that:

• The incidence of HCC is high in cirrhotic patients.

• Any focal lesion growing in a cirrhotic liver has a high probability of being
neoplastic; either a pre-malignant dysplastic nodule or an HCC.
• Most HCCs are hypervascular during the arterial phase of contrast
enhancement, with absence of discrete hypervascularity in other lesions.

The diagnosis of HCC has been proposed by the findings of either:

• Two imaging techniques showing a nodule of >2 cm with arterial

hypervascularity; or
• A single positive imaging technique and AFP of >400 ng/mL.

These criteria are simple, specific and easy to use, even by a non-specialist
[93]. These non-invasive criteria have yet to be validated in large scale studies.
New criteria are required for tumours <2 cm in diameter [94].
These recommendations for the diagnosis of HCC in a patient with cirrhosis
are summarized in Table 2.

2.5.2. No cirrhosis

With a liver mass as the presenting problem, the initial investigation is AFP:

• If the AFP is raised, in the absence of a germ cell tumour (particularly

testicular), the diagnosis of HCC is confirmed.
• If AFP is normal, a search for other causes (non-liver primary) and further
radiological assessment are required.
• Radiological imaging can exclude benign liver lesions (e.g. cysts,
haemangiomas) with a high degree of sensitivity and specificity. In situations
where considerable doubt exists, biopsy of the lesion is required [91].

2.6. SCREENING FOR HCC

A number of series demonstrate the value of AFP, either alone or in

combination with US, in screening for HCC [93]. The largest screening study is

13
TABLE 2. DIAGNOSTIC PROCESS FOR A LIVER NODULE NEWLY
DISCOVERED BY ULTRASOUND IN PATIENTS WITH CIRRHOSIS [94]

Nodule size
(diameter) Likelihood of HCC Recommended diagnostic procedure
(cm)

<1 Improbable Repeat US at 3 months; if progression,

proceed to step below
(<50% are finally HCC)
1–2 Probable Serum AFP, CT and/or MRI
Biopsy required for diagnosis, but 40%
are false negatives
2–3 Highly probable Apply non-invasive criteria (AFP, CT
and/or MRI)
Biopsy is indicated in the absence of
arterial hypervascularity
>3 Apply non-invasive criteria (AFP, CT
and/or MRI), biopsy rarely indicated

in the Alaskan population with a high HBV carrier rate. Screening was
undertaken in the total population with hepatitis B surface antigen (HBsAg)
positivity, irrespective of viral replication. The results of this study showed that
from 1982 to 1998 there were 18 299 AFP estimations undertaken in
2230 HBsAg positive individuals. Twenty cases developed HCC. Of these, five
were inoperable at presentation and 14 had resections, six of which recurred [95].
A similar study of patients with HBV, only 4% of whom had proven cirrhosis,
detected 14 cancers in 1069 cases screened [96]. Prospective studies of patients
with viral cirrhosis have been carried out using US and AFP measurements and
showed that 64–87% of detected tumours were single and 43–75% were <3 cm in
diameter [97].
A New Zealand study compared the outcomes of chronic hepatitis B
carriers with HCC who were identified in a new HCC screening programme,
using 6 monthly AFP and US. There was a marked improvement in identifying
treatable, early stage cancers among this population with endemic HBV infection,
as well as overall improved survival in the screened group compared with
unscreened patients. Even with a 3 year lead time bias correction, screened cases
had a superior outcome. However, as this was not a randomized study, this result
could be due to selection bias [98].

14
 Marrero et al. assessed the utility of DCP, GP-73 and AFP as markers for
identifying patients with early stage HCC. DCP and GP-73 had superior positive
and negative predictive values for early HCC compared with AFP. These findings
suggest that these markers may eventually replace AFP as a screening study for
HCC. However, results of a planned, multicentre trial of markers for early HCC
and an easier assay for measuring serum GP-73 are needed before these tools can
be adapted for routine screening [67].

2.7. STAGING SYSTEMS AND PROGNOSIS

Although surgery (resection or transplantation) is the preferred option for

curative treatment in localized HCC, recurrence rates remain high and long term
survival is poor. Recurrence in the liver is the main cause of poor prognosis in
patients with resectable HCC and the type of hepatectomy has little influence on
recurrence or long term survival. Consequently, there is an urgent need to identify
factors that can predict tumour recurrence and prognosis in order to stratify patients
into risk groups that warrant consideration of more intensive monitoring and/or
clinical trials assessing adjuvant treatment.
Pathological prognostic factors are useful not only in predicting survival
but also to stratify patients into risk groups for relapse. Tumour grade, size of
tumour, microvascular invasion, portal vein tumour thrombus and the presence of
tumour microsatellite lesions have all been found to predict survival [99, 100].
With advances in understanding of tumour biology, molecular biomarkers of
carcinogenesis have been investigated with regard to both their prognostic
significance and their potential as therapeutic targets [101].
Cancer staging is used to predict prognosis, to stratify patients for clinical
trials and to guide management [102–104]. However, as previously stated, there
is an added dimension in HCC due to the presence of cirrhosis as an independent
prognostic factor.
There is no consensus regarding the preferred HCC staging system, which
remains controversial. To date, several HCC staging systems have been
developed. These include:

• TNM: The TNM staging system, developed by the International Union

Against Cancer (UICC), is less predictive of prognosis than the Okuda
system in HCC patients undergoing hepatic resection [105].
• Okuda: The Okuda staging system [106], which is based on variables
including liver function and tumour size, was proposed to be discriminatory
for patients with unifocal HCC who underwent surgery in Western
countries [107].

15
 • CLIP: The Cancer of the Liver Italian Program staging system uses the
following parameters: the Child–Pugh score, tumour morphology and
extent, AFP and the presence of portal vein thrombosis [108]. One study
found that the CLIP system had a greater predictive power for survival than
the Okuda system [109].
• JIS: Aside from the CLIP scoring system, Kudo et al. reported that the
Japan Integrated Staging (JIS) score is a better staging system for HCC,
which includes the TNM stage according to the criteria set by the liver
cancer study group of Japan as well as the Child–Pugh score [110]. For
treatment with radiation therapy (radiotherapy), the TNM staging approach
appeared to be the best predictor of prognosis. Staging systems that reflect
liver disease status (Okuda stage, CLIP, and JIS score) showed limitations
in stratifying patients undergoing radiotherapy into different prognostic
groups [111]. However, these systems are based on tumour status with or
without liver function. Treatment factors were not considered.
• BCLC: The Barcelona Clinic Liver Cancer staging system [112, 113] was
based on data from several independent studies representing different
disease stages and/or treatment modalities. It includes variables related to
tumour stage, liver functional status, physical status and cancer related
symptoms [114–116]. The main advantage of the BCLC staging system is
that it links staging with treatment modalities and with an estimation of life
expectancy that is based on published response rates to the various
treatments [112, 117].
• AASLD: For the best assessment of prognosis, the American Association
for the Study of Liver Disease recommended that the staging system should
take into account tumour extent, liver function and physical status. The
impact of treatment should also be considered when estimating life
expectancy. Currently, the BCLC system is the only system that takes into
consideration the treatment options available for patients [118].

16
 3. TREATMENT OF HCC

3.1. INTRODUCTION

The treatment of HCC is a therapeutic challenge. Many different medical

disciplines need to be involved and a high degree of clinical expertise is needed to
achieve the best outcomes for patients. HCC is a slowly growing malignancy
with a 50% two year survival of untreated patients diagnosed with small tumours.
Once patients become symptomatic, however, the mean survival is approximately
6 months.
The factors which dominate treatment decisions include patient age, the
number, size and location of intrahepatic lesions, and the degree of cirrhosis.
Although many modalities of treatment may be utilized, curative treatment
predominantly involves surgery. However, a range of other modalities is available
for treatment to prolong disease control, potentially with curative intent. These
include high dose external beam radiotherapy, either alone or in combination with
other modalities, such as injected radioisotopes, alcohol injection, radio
frequency ablation, cryotherapy and regional chemotherapy. Many of these
modalities are also suitable for palliative treatment, which, unfortunately, is the
situation for most patients with HCC. This section will deal with all treatments
except those involving radiotherapy, which is covered in Section 4.

3.2. SURGERY

As stated above, the only proven curative therapy for HCC remains
surgical, being either hepatic resection or orthotopic liver transplantation (OLT).
Therefore, patients with single, small (<5 cm) HCC, or with no more than three
lesions, each <3 cm in diameter, should be referred for surgical assessment [119].
However, only a small proportion of patients with HCC will be suitable for either
of these potentially curative treatments. There are no randomized clinical trials
(RCTs) comparing the outcome of surgical resection and OLT for HCC. The
decision as to which therapy is appropriate will depend on availability of
resources and individual tumour characteristics. Early results of OLT for HCC
were poor [120], with 5 year survival figures of <50%, mainly due to tumour
recurrence. It is now clear that this was the result of poor selection of patients for
transplantation [87].

17
3.2.1. Resection

Hepatic resection should be considered as primary therapy in any patient

with HCC and a non-cirrhotic liver (including the fibrolamellar variant discussed
below). Resection can also be carried out in highly selected patients with hepatic
cirrhosis and well-preserved hepatic function (Child–Pugh A) who are unsuitable
for OLT. Such surgery carries a high risk of post-operative decompensation and
should be undertaken in units with expertise in hepatic resection and management
of liver failure [119]. Less than 25% of HCC patients are suitable for surgical
resection due to several factors, including the presence of cirrhosis, anatomically
unresectable disease, extrahepatic spread and vascular spread [87]. The results of
surgical treatment of HCC are inferior to the results of treating hepatic metastases
from colorectal cancer, although the same general surgical principles apply in
both conditions.
Resection remains the treatment of choice for lesions confined to one lobe.
The aim of resection is to remove the entire portal territory of the tumour
containing segment(s) with a 1 cm clear margin, while preserving maximum liver
parenchyma to avoid hepatic failure. In non-cirrhotic HCC patients, greater
resection is tolerated as the capacity for liver regeneration is not compromised
[121]. Over the past decade, the use of parenchymal-sparing segmental resections
has increased significantly. The number of hepatic segments resected, and
operative blood loss, were the only predictors of both perioperative morbidity and
mortality. Reduction of both these factors is largely responsible for the overall
decrease in perioperative mortality [122].
Complications associated with surgical resection include haemorrhage, bile
leakage, stress ulceration complicated with bleeding, transient haemobilia,
atelectasis and inflammatory changes in the right lung [123]. Hospital mortality
rates for resection alone vary from 5 to 24% [121]. Mortality was mainly due to
hepatorenal or cardiorespiratory failure and also occasionally to myocardial
infarction or disseminated intravascular coagulation [123].

3.2.1.1. Non-cirrhotic liver

Surgical resection in the non-cirrhotic patient is the ‘gold standard’ for the
treatment of HCC. The indications for resection are lesions limited to one lobe,
mild hepatic dysfunction and absence of extrahepatic spread of the cancer. The
1 year survival rate post-resection varies between 50 and 80%, with a 5 year
maximum survival of 50%. There is a 68% recurrence rate. In non-cirrhotic HCC
patients, partial hepatectomy is associated with a 5 year survival of 30–68%
[124, 125].

18
 Prognosis following resection is improved for tumours with the
characteristics shown in Table 3.

3.2.1.2. Cirrhotic liver

In the presence of cirrhosis, the risks from surgery are increased. Cirrhosis
affects post-operative survival in several debilitating ways and remains the major
determinant of post-operative survival for the following reasons:

• Liver regeneration cannot occur in the cirrhotic remnant.

• Recurrent HCC may develop in the hepatic remnant [126].
• Pre-operative clotting is abnormal in cirrhosis.
• Hepatic reserve is poor [127].

The pre-operative Child–Pugh score, hepatic reserve [128] and indocyanine

green 15 min retention rate [120] may also correlate with post-operative prognosis.
With cirrhosis, operative mortality is higher, and of those who survive the surgery,
a 5 year survival of 25–30% has been recorded [129]. Wu et al. suggested that the
size of the tumour is also a significant determining factor in survival. Of
2051 cases, ‘small’ (<5 cm in diameter) and ‘very small’ (<3 cm in diameter)
tumours had post-resection 5 year survivals of 79.8% and 85.3%, respectively
[130]. Incidence of HCC recurrence, however, has been reported to vary between
20 and 70%, with almost all relapses occurring within two years of surgery [124].

3.2.2. OLT

In the early days of OLT, HCC was a frequent indication for transplantation.
The results were inferior to those for benign disease, owing to the high recurrence
rate. Thereafter, HCC accounted for <5% of all liver transplants. However,
increasing data in the literature suggest that, with selection of appropriate
candidates, the results of OLT for HCC may be as good as for benign disease
[126].

TABLE 3. TUMOUR CHARACTERISTICS WITH IMPROVED SURVIVAL

FOLLOWING RESECTION

<5 cm diameter No vascular invasion

Tumour margins >5 mm Lower tumour grade or stage

Single nodule (compared with multiple) No lymph node involvement

19
 OLT is indicated for patients with HCC who have centrally located tumours
not amenable to resection, large tumours, bilobar lesions, cirrhosis and for
patients who have no evidence of extrahepatic involvement. Early outcomes in a
collective series of 654 patients from the United States Registry, Pittsburgh,
Boston and Europe were 40–80% 1 year survivals, 18–65% 5 year survivals, and
21–67% recurrence rates [126].
Three non-randomized studies comparing liver resection (n = 261) and OLT
(n = 225), conducted across several centres (Pittsburgh, France and Hanover)
showed similar 1 and 5 year survivals. However, for cirrhotic patients with HCC,
mean survival time was improved following transplantation compared with
resection [126].
Management of HCC by OLT remains contentious, owing to the restricted
availability of organ donors and the high rate of recurrence, due to circulating
HCC cells implanting in donor hepatic tissue and/or due to unrecognized
micrometastatic disease [131]. In addition to the standard investigations used to
diagnose HCC, patients should undergo chest and abdominal CT scans to exclude
metastases or nodal disease [121].
The 3 and 5 year survival rates following OLT were 16–82% [132] and
19.6–36% [133], respectively. These wide ranges are not unexpected, as two
subgroups with quite different prognoses have been enrolled into OLT trials:
those with large and unresectable HCCs and those with small incidentally
discovered HCCs with concomitant cirrhosis. Recurrence in the grafted liver,
lungs or bone occurred in >80% of the large and unresectable tumour group at
2 years but in <5% in the group with small tumours [134]. Survival following
OLT was not influenced by patient age, gender, extent of human leukocyte
antigen matching, rejection, immunosuppressive regimen or surgical technique
used [132].
In addition to tumour recurrence, cytomegalovirus infection, acute
rejection, atelectasis, pleural effusion, pneumonia, hepatic encephalopathy,
invasive fungal infection and neurological disease have all been observed after
OLT [131]. Chronic liver rejection is also a major problem [135], as are intra- and
post-operative mortality rates, which approach 10–20% [136].
To date, OLT has provided the best chance of a cure for most patients with
HCC. The surgical procedure for this group of patients is generally simpler than
for patients transplanted for end stage liver disease. Unlike patients with end
stage liver disease, most patients with HCC are in relatively good physical
condition, with well-compensated cirrhosis, absent or mild portal hypertension
and without the peripheral stigmata of advanced liver disease. OLT is effective
and indicated for patients with stage I and stage II tumours [87].
Adult living related liver transplantation using the right lobe is an
alternative to cadaveric donor liver transplantation. However, the recurrence rate

20
of cancer in the transplanted liver is high. In addition, in patients who have
chronic hepatitis B or C infection, the virus reinfection rate within the
transplanted liver is also high. Previously, the outlook for patients with
replicating HBV was worse due to HBV recurrence and consequently these
patients were not considered candidates for transplantation. However, effective
antiviral therapy is now available [87]. Undoubtedly, if donor liver grafts were
readily available, many patients with locally advanced HCC might benefit from
transplantation. However, living related liver transplantation for patients with
locally advanced HCC poses the ethical problem of potentially fatal risk to the
healthy donor, coupled with the heightened risk of early post-transplant
recurrence and death of the recipient. Another possibility for patients with
advanced, intrahepatic HCC is the use of livers from deceased donors as a means
to expand the pool of available donors [137].

3.2.2.1. Milan criteria

Mazzafero et al. reported from a prospective study in 1996 that small HCCs
(1 nodule <5 cm or 3 nodules <3 cm) had an excellent chance of recurrence free
long term survival after OLT [132]. These ‘Milan criteria’ are now widely
accepted. Therefore, OLT represents the best available treatment for a small HCC
in the patient with cirrhosis (even Child–Pugh A) and should be performed as
soon as possible after diagnosis to improve survival. Resection for Child–Pugh A
cases should be limited to patients with contraindications to OLT, such as
psychiatric problems, advanced age, high grade tumour, extrahepatic spread of
the tumour, or non-availability of transplantation [138]. Using the Milan criteria,
3 year post-transplant survival was 83% with an 8% recurrence rate. The
recurrence rate of HCC found incidentally at the time of OLT for non-malignant
indications is very low [139].

3.2.2.2. Expanded Milan criteria

Patients with nodule(s) in excess of the Milan criteria (University of

California, San Francisco expansion criteria) have a significantly lower chance of
cure after OLT and should not routinely be considered for transplantation.
However, cure remains possible if there is no extrahepatic spread.
In 2001, Yao et al. proposed that the Milan criteria for transplantation
eligibility could potentially be expanded to either a unifocal tumour mass
<6.5 cm in diameter or multifocal tumours, fewer than four in number, each
<4.5 cm in diameter with total tumour diameter <8 cm (now designated stage
T3A) and demonstrated a 75% 5 year survival. This proposal is problematic
because it was based on tumour size and number identified by histopathological

21
review of the removed liver, rather than the clinically available pre-operative
radiological evaluation [140].
Recently, these authors reported a new analysis, comparing the outcomes
after transplant of 17 T3A patients versus 53 T1,2 patients, all staged by
radiological evaluation before transplantation. They found similar 3 year survival
between the groups. Preoperative understaging occurred in 17% of T1,2 patients
and in 35% of T3A patients. However, 23% of pre-operatively staged T3A
patients were overstaged, having T2 tumours on histopathology [141].
A French group also assessed the expanded Milan criteria for OLT in
patients with HCC and confirmed the original findings of Yao et al. of good
5 year survival based on tumour explant data [142]. However, longer term
assessment is required, as early and aggressive recurrence occurred in patients
with good prognosis according to the Milan criteria, and conversely, some
patients with high grade tumours remained recurrence free [138].
Overall, these studies indicate the pressing need for a large multicentre trial
to determine whether the current tumour size criteria for transplantation can be
modestly expanded. These studies also caution that many patients will be under-
and overstaged by current radiological evaluation [143].

3.2.2.3. Model for ESLD score

As many patients with HCC become ‘untransplantable’ whilst waiting for

liver transplantation owing to progressive tumour that exceeds the Milan criteria,
efforts were made to change organ allocation policy in the USA. In February
2002, allocation of organs for OLT in the USA changed to the model for end stage
liver disease (MELD) system and special exception points were granted to
patients with HCC. T1 lesions (solitary HCC <2 cm) received 24 MELD points,
which is equivalent to a 15% 3 month waiting list mortality, and T2 (solitary
lesion 2–5 cm or 2–3 lesions each <3 cm) received 29 MELD points, equivalent
to a 30% 3 month mortality. A priority MELD weight of 24–29 points is given to
patients with HCC who meet the Milan criteria while awaiting transplantation.
Under this system, transplantation in patients with HCC increased 350% over a
corresponding time interval from the previous year. It was found that 86–91% of
patients with HCC received a transplant within 3 months of being issued a
priority MELD score [144]. The end result was that HCC became a major
indication for OLT, representing 22% of all adult deceased donor liver
transplants. This system may have disproportionally favoured HCC patients,
because <7% of potential candidates with HCC were removed from the waiting
list for tumour progression or other causes [143].

22
3.2.2.4. Reduced MELD exception point

A review of the explant pathology reports from this first period of MELD
transplant allocation showed that at least 23% of the patients transplanted for
HCC had no evidence of HCC on further evaluation, including 31% of all patients
with a T1 lesion. Additionally, during this period, withdrawal of patients with T1
tumours from the transplant waiting list due to death, deterioration in
performance status, or progressive HCC was only 4% [144].
Subsequently, the United Network for Organ Sharing changed the organ
allocation policy, with patients with T1 lesions receiving 20 points and those with
T2 lesions receiving 24 points, i.e. reduction in the MELD exception points. HCC
now represents about 14% of all adult OLT in the USA [144].
Sharma et al. assessed the impact of the reduction in the MELD exception
points for HCC. They showed no differences in the 12 month dropout rate on the
transplant waiting list, no differences in survival while waiting for OLT and no
differences in post-OLT survival. Thus, reducing the MELD score for HCC
candidates did not adversely affect patient outcomes. More recently, exception
points were eliminated for patients with T1 lesions because of their excellent
short term survival [144].
Analysis of the Milan criteria and other systems will continue in an effort to
refine criteria for entry of patients with HCC into the United Network for Organ
Sharing liver transplant waiting list [139]. Continued assessment and refinement
of this allocation policy is ongoing and, clearly, the changes are a great
improvement on the former scoring systems [144].

3.2.2.5. Transplantation following resection of HCC in cirrhotic patients

Owing to the chronic shortage of organ donors, many clinicians have

suggested that OLT cannot be advocated as the primary treatment modality for
HCC without overwhelming the transplant system. A group from Clichy, France,
reported the outcome of patients who had undergone hepatic resection for HCC
prior to transplantation. They found no differences in survival between the
patients with prior resection and those without, after a median follow-up period
of 32 months [145].
In 2004, another group assessed 47 patients with HCV-associated HCC who
conformed to the Milan criteria and underwent resection. They found a low 5 year
survival of 49% compared with an expected survival of 74% with OLT.
Additionally, 61% of the tumour recurrences were more advanced than the Milan
criteria, thus contraindicating ‘rescue OLT’. These authors suggested that using
resection as a bridge to transplant was a better strategy than resection with
salvage transplant [146]. In reality, however, salvage transplantation after

23
resection is rarely possible. While surgery may serve as a better bridge to
transplantation, local ablative therapies discussed below are utilized more often
in this setting [143].

3.2.3. Transplantation or resection for HCC in cirrhosis

It is well established that patients with the Milan criteria have an almost
zero recurrence rate for HCC following OLT and have a prognosis the same as
that for a similar underlying liver disease without HCC [132]. Relaxation of these
criteria to include the expanded Milan criteria carries a higher risk of HCC
recurrence and poorer overall prognosis. Resection of HCC is a viable option,
with short term survival figures very similar to transplantation. After three years
of follow-up, however, there is a clear advantage for transplantation in terms of
tumour free survival [147].
Resection is only suitable for patients with excellent liver function
(Child–Pugh A), because of the high risk of hepatic decompensation.
Perioperative mortality in experienced centres remains between 6 and 20%,
depending on the extent of the resection and the severity of preoperative liver
impairment [148]. The majority of this early mortality is due to liver failure. The
residual liver after resection continues to have a malignant potential. Recurrence
rates of 50–60% after five years of follow-up after resection are usual [149] and
the majority of this recurrence is intrahepatic, representing either satellite nodules
or de novo second tumour development. Small satellite nodules are not usually
detected by preoperative imaging, although the increasing use of intraoperative
US may allow detection and better resection margins [150].
In patients with cirrhosis, both resection and transplantation probably have
a role. In areas of the world where organ donation rates cannot supply existing
demand, resection is likely to be widely used. Transplantation probably offers the
best chance of cure for patients with small tumours and cirrhosis and is therefore
the treatment of choice, even in patients with Child–Pugh A cirrhosis. Any
patient with a single tumour <5 cm in diameter should be assessed for surgery in
a centre where resection or transplantation is available [87].

3.2.4. Other, less common surgical situations

3.2.4.1. Liver transplantation or resection in fibrolamellar HCC

Fibrolamellar HCC has a very different biology and arises in non-cirrhotic

liver. Surgical resection for this tumour is, therefore, less likely to produce liver
failure. The overall survival for fibrolamellar HCC at 5 years is 25–36% [151].
As it arises without pre-existing liver disease, fibrolamellar HCC usually presents

24
with symptoms of locally advanced disease and vascular or diaphragmatic
involvement. Reported outcomes following resection are poor, with 12–65%
5 year survival rates [152]. OLT has been performed for fibrolamellar HCC with
5 year survival rates of 28–49% [153]. However, as tumour recurrence remains
common, resection remains the main surgical procedure for this rare tumour,
where donor organ shortages exist [87].

3.2.4.2. Incidental HCC

Small HCCs are not infrequently found in liver pathology specimens. These
are known as ‘incidental HCCs’. They have a very good prognosis, e.g. 91%
survival at 33 months for a cohort of 12 such tumours[154, 155].

3.3. NON-SURGICAL TREATMENT OF HCC

3.3.1. Ablative therapies

A number of non-surgical therapies are in clinical use for HCC.

Percutaneous ablative therapies are well described, most commonly using ethanol
injection. Radiofrequency ablation (RFA) and cryotherapy are more recent
techniques to produce tumour necrosis with low morbidity and mortality. As
there are no RCTs of alcohol injection versus RFA and cryotherapy, or of these
techniques versus resection, assessment of the literature relies on comparisons of
prospective series of patients treated by the different techniques.
Chemoembolization can also produce tumour necrosis and has been shown to
improve survival in highly selected patients with good liver reserve.
Chemoembolization using lipiodol is effective therapy for pain or bleeding from
HCC [87].

3.3.1.1. Percutaneous ethanol injection (PEI)

PEI may induce 70–100% coagulation necrosis of the tumour via protein
degeneration and thrombotic effects [156, 157]. Using local anaesthetic for the
skin, abdominal wall and liver capsule, a 22 gauge Chiba needle is introduced
percutaneously into the liver tumour under US or other guidance system.
Absolute alcohol (99.5%) is slowly injected, with frequent adjustment of the
needle tip to achieve distribution within the whole tumour. PEI can be repeated
several times a week according to tumour size and patient compliance.
Contraindications to its use are gross ascites, severe clotting abnormalities and
obstructive jaundice. Good survival rates following PEI have been achieved, such

25
as 5 year figures of 44% in Child–Pugh A patients, 34% in Child–Pugh B patients
[158] and 3 year figures of 63% in patients with single lesions and 31% in those
with multiple lesions [157].
The selection criteria for PEI are:

• HCC <3 cm in diameter;

• No more than three lesions;
• No severe hepatic dysfunction;
• Child–Pugh A or B cirrhosis [131].

These encouraging survivals have been derived from uncontrolled studies.

In a cohort of PEI (n = 30) compared with resection (n = 33), there was no
difference in 1–4 year survivals between the two treatments, although recurrence
at 2 years was higher in the PEI group (66% versus 45%) [159]. Combination
treatment with transarterial chemoembolization (TACE) and PEI would be of
interest [160], but a controlled trial of PEI/TACE versus resection may be
unethical, as resection would be denied to patients with resectable tumours [131].
Although PEI has not been subjected to RCTs, there is a considerable
literature on its use in HCC. In large series, complete response rates of 75% in
tumours <3 cm in diameter have been reported, with 5 year survival rates of
35–75% [27]. These studies have generally been restricted to patients with good
underlying liver function. The largest series with 746 patients showed 79% and
47% survivals at 3 and 5 years, respectively, in patients with Child–Pugh A
cirrhosis (239 patients) and 63% and 29%, respectively, in Child–Pugh B
cirrhosis (149 patients) [161].
The results of series from Asia and Europe report similar survival rates.
One problem in the interpretation of these series is that a histopathological
diagnosis of HCC was not obtained in all series. This could introduce bias into
series with a substantial number of lesions <2 cm in diameter, where the
diagnosis may be uncertain. Treatment of larger and multiple lesions is possible,
often requiring repeated sessions and general anaesthesia, but recurrence occurs
in more than 50% at one year and only 10% of 3–4 cm lesions were completely
ablated [162].
Treatment is technically very difficult in lesions affecting the posterior
segments of the liver [108]. Complications associated with PEI include pain,
fever and transient drunkenness. Haemorrhage, needle track seeding [163] and
hepatic failure are more serious adverse effects [164]. Complications are
uncommon, but seeding in the needle tract occurs in 3% and serious bile duct
injury in 1% [164, 165].
The largest series to report complications included 1066 patients, for whom
the mean number of sessions needed to ablate a HCC nodule was 6.7. There was

26
one death (0.09%) and 34 complications (3.2%), including eight episodes of
bleeding and seven cases of tumour seeding. Pain following injection required
cessation of therapy in 3.2% [164].
Comparison with other techniques is difficult. However, historical
comparison suggests little difference in survival rates between resection,
transplantation and PEI for tumours <3 cm in diameter. A study of 260 tumours
<5 cm in diameter in Child–Pugh A cirrhosis showed a 3 year survival of 79% for
surgery and 71% for PEI, compared with 26% for no treatment [161]. Similar
results have been reported from other centres [159]. Most experts regard surgery
as the therapy providing the best chance of cure and PEI as the best therapy for
patients with small inoperable HCCs [164].
Experimental studies have been undertaken injecting agents other than
ethanol, e.g. cisplatin and cold acetic acid. Local injection of acetic acid, in one
RCT of 60 patients with tumours <3 cm in diameter demonstrated a higher
survival rate when compared with PEI (92% versus 63% at 2 years) and a lower
recurrence rate (8% versus 37% at 2 years) [166]. These interesting results
require confirmation in other studies.

3.3.1.2. RFA

RFA of HCC is a relatively newly described technique using a probe placed

into the tumour mass, usually percutaneously [167–169]. It uses high frequency
US to generate heat at the probe tip, which can destroy tissue. A single probe can
destroy lesions <3 cm in diameter and a multiple tipped probe has been used to
target lesions <6 cm in diameter. Larger tumours can be treated by RFA.
However, local control reduces significantly when tumour size exceeds 3–4 cm.
In a series of 126 HCCs >3 cm in diameter, complete necrosis occurred in 47%
[170].
In a single series of 149 tumour nodules with an average tumour diameter of
3.5 cm treated either percutaneously or at open operation, the local recurrence
rate at 19 months was 3.6%, with all nodules showing initial complete resolution
[171]. However, distant metastasis or a second tumour developed in 46%.
A comparison of 112 patients treated by PEI or RFA showed that 47 of 52
treated by RFA had complete tumour necrosis, with a median of 1.2 treatment
sessions, versus 48 of 60 having complete ablation by PEI, with 4.8 sessions
required [172]. The authors suggested that RFA was more effective but also had a
higher complication rate. Unpublished data suggest a possible higher rate of
tumour seeding. Clearly, RCTs of PEI versus RFA are required for further
evaluation [87].

27
3.3.1.3. Cryotherapy

This technique involves freezing the tumour and a 1 cm surrounding margin

of healthy tissue [173] using liquid nitrogen delivered by a vacuum insulated
cryoprobe, inserted under US guidance or during a laparoscopy or laparotomy.
There are limited data available on the efficacy of this therapy; Zhou and Tang
reported a 37.9% 5 year survival in 191 treated patients and a 53.1% rate in
56 patients with tumours smaller than 5 cm in diameter [174]. Follow-up
treatment with alcohol ablation after cryotherapy may be a useful adjunct in
treating residual tumour and controlling recurrences. The major complication is
damage to adjacent structures, particularly the portal and hepatic veins. Other
reported adverse effects are temperature rise, liver failure, pleural effusion and
basal atelectasis [175].

3.3.1.4. TACE

Chemoembolization has been widely used as the primary therapy for

inoperable HCC. The literature is difficult to interpret and compare, as the
techniques used differ substantially and the patient groups treated are frequently
those with advanced disease where the risk of therapy may be greatest. Initial
interest in radiological techniques producing tumour devascularization developed
in the 1970s [176], with good evidence of their efficacy in reducing tumour size
[177], pain and bleeding [178].
Of the six initial RCTs of chemoembolization as primary treatment for HCC
[179–184], none showed any increase in survival, although tumour shrinkage was
observed. All of these trials predominantly included patients with large tumours
and severe underlying liver disease, which may have masked any beneficial
effect.
TACE combines intra-arterial chemotherapy with intermittent occlusion of
the hepatic artery by embolic material, in order to prolong the contact time
between drug and tumour, and to induce massive tumour necrosis by ischaemia.
Normal liver tissue is permitted a degree of ‘ischaemic escape’ via portal vein
blood flow. Therefore, main portal vein thrombosis is a contraindication to TACE
therapy, as are insufficient hepatic reserve, severe clotting abnormalities and
significant arteriovenous shunting to the portal/hepatic vein. The use of CO2
microbubble enhanced sonographic angiography may help reveal tumour
vascularity before embarking upon treatment [185, 186].
The embolic material used is often gelatin foam powder or particles.
Lipiodol is now less commonly used. These compounds have been used alone in
TACE, but the results are limited by tumour type, size and extension. Most trials
have combined these embolic materials with chemotherapeutic agents, but as

28
there is no standard protocol, a large number of combinations have been used. For
example, Ryder et al. studied the effect of doxorubicin and lipiodol in
67 unresectable HCCs and reported a 50% reduction in tumour size in 10 of
18 patients with small tumours (<4 cm); 5 of 49 patients with large or multifocal
tumours also showed a response to treatment. Survival ranged between 3 days
and 4 years, with a median survival of 36 weeks. This study concluded that
TACE has promising effects on small tumours but that large tumours show a poor
response and a high rate of complications [177].
Despite encouraging figures for small tumours, several RCTs have failed to
show a marked improvement in survival with TACE, e.g. 24% 1 year survival for
TACE versus 31% with no treatment [180] and 62% for TACE versus 43.5% with
no treatment [182]. However, two RCTs have recently confirmed the superiority
of repeated TACE or transarterial embolization over supportive or symptomatic
care in patients with small tumours and good liver function [186, 187]. These
studies established the role of chemoembolization in the palliative treatment of
HCC. However, this will only be applicable to a relatively small group of patients
(Child–Pugh A without portal vein involvement, ideally with small volume
disease, e.g. <10 cm) and results in <10% 5 year survival.
Side effects of chemoembolization are those of the chemotherapeutic agent
used (usually doxorubicin), in addition to the complications of arterial
embolization, namely pain, fever, hepatic decompensation and, rarely, infarction
of organs other than the liver [188]. Serious complications occur in 3–5% of
treated patients. In addition, the use of TACE is associated with a ‘post-
embolization syndrome’ of fever, pain and vomiting in over 60% of patients
[188]. These complications are thought to be secondary to stretching of the liver
capsule, pancreatitis, gall bladder infarction, peptic ulceration and necrosis. This
is a transient side effect and in most cases can be controlled by non-steroidal anti-
inflammatory drugs or hydrocortisone. Less common complications include
hepatic failure, liver abscess, arteritis [189] and ruptured HCC [190]. A small
number of studies have combined ethanol injection with chemoembolization
[191–193].

3.3.1.5. Regional chemotherapy

This technique delivers a chemotherapeutic agent through the hepatic artery

via a catheter inserted by laparotomy or angiography. The drug can be given as a
single injection [194], a pump driven continuous drip, or using a ‘portacath’ for
repeated long term injection. Transarterial chemotherapy is based on the
principles that normal hepatic tissue is supplied by both the hepatic artery and
portal vein, whereas HCC tumours derive most of their blood supply from the
hepatic artery [195].

29
 Compared with systemic chemotherapy, transarterial chemotherapy permits
a higher concentration of drug in the tumour tissues using a lower drug dose and
lower toxicity [196]. Fluorouracil and anthracyclines (mainly doxorubicin) have
been used intra-arterially, the latter producing response rates of up to 42% [197].
Patt et al. reported a 64% response rate using doxorubicin in combination with
floxuridine, leucovorin and cisplatin, but with significant toxicity, including
deaths [198]. Other drugs used include mitomycin, cisplatin and mitoxantrone,
which yielded 50%, 55% and 25% response rates, respectively [199].

3.4. SYSTEMIC THERAPIES

3.4.1. Cytotoxic chemotherapy

Systemic chemotherapy has not been used widely for patients with
advanced HCC because HCC has generally been regarded as chemoresistant.
This may be due to the high rate of expression of drug resistant genes [200] and
underlying liver cirrhosis which reduces the tolerability of systemic
chemotherapy.
The efficacy of systemic cytotoxic chemotherapy is modest in HCC, with
low response rates and short response durations. Doxorubicin has been the most
widely studied cytotoxic, both as a single agent and in combination with other
drugs. It has a 10–15% response rate with a high frequency of severe neutropenia
[201, 202]. Other chemotherapeutic agents such as epirubicin, cisplatin, 5-FU,
and etoposide have also been studied, but with disappointing results [203–205].
Multiple combination regimens have been investigated in the treatment of
advanced HCC. However, these have not demonstrated a survival advantage in
RCTs. The combination of cisplatin, interferon-α-2b, doxorubicin and
fluorouracil showed a significantly higher response rate but no survival benefit
compared with doxorubicin alone [206].
Newer chemotherapeutic agents such as gemcitabine, irinotecan, and
oxaliplatin have been tested [207–209]. Recent phase II studies using a
combination of gemcitabine and oxaliplatin demonstrated modest efficacy and
promising toxicity profiles and require further validation [209]. Overall,
conventional cytotoxic chemotherapy has not been accepted as standard
treatment because of its failure to improve survival in advanced HCC.

3.4.2. Molecular targeted therapy

In recent years, advances in the knowledge of hepatocarcinogenesis have

provided an opportunity to treat this chemoresistant tumour with newly

30
developed molecular targeted agents. Sorafenib is an oral multikinase inhibitor
with antiproliferative and antiangiogenic effects that target the Raf/MAPK/ERK
signaling pathway and the tyrosine kinase VEGFR-2 and -3 and PDGF receptors
[210].
Two pivotal RCTs established sorafenib monotherapy as the new standard
systemic therapy for advanced HCC. The multicentre, double blind, European
SHARP trial randomly assigned 602 patients with locally advanced HCC,
unsuitable for local therapies, to receive sorafenib or placebo. Most patients
(82%) were BCLC C; 97% were Child–Pugh A; 38% had macrovascular invasion
and 51% had extrahepatic disease [211]. The results showed a significant
improvement in both overall survival (median 10.7 months versus 7.9 months)
and time to progression (median 5.5 months versus 2.8 months) in the sorafenib
arm compared with the placebo arm. Sorafenib was well tolerated with
acceptable side effects (8% grade 3/4 diarrhoea, 8% hand–foot syndrome). This
represents the first RCT to demonstrate an overall survival benefit of systemic
treatment in patients with advanced HCC. A similar sorafenib study of advanced
stage HCC patients was conducted in Asia, where there is a high prevalence of
HBV [212]. The median overall survival in the sorafenib arm was 6.2 months,
which was significantly better than the 4.1 months in the placebo arm. The
median time to progression was 2.8 months in the sorafenib group compared with
1.4 months in the placebo group.
In addition to sorafenib, other targeting agents have shown encouraging
activity. However, in order to improve survival substantially, more effective
combination of local, regional and/or systemic therapies will be needed in
patients with advanced HCC.

3.4.3. Hormonal therapy

There is a rationale for the use of hormonal agents such as tamoxifen, as

HCC (and cirrhotic liver) tissue contains oestrogen and androgen receptors [131].
Reports on the efficacy of tamoxifen have been conflicting; some studies
demonstrated improved survival [213], particularly in females [214], whereas
others have shown no impact on survival [215] and no benefit in females [216].
Initial data suggesting a positive effect on survival in patients with inoperable
HCC [217] were not confirmed in larger RCTs [218]. In addition to tamoxifen,
other agents that have been assessed include flutamide [219], ketoconazole [220]
and buserelin [221]. None have impacted significantly on survival. Overall,
hormonal therapy currently has no role in the treatment of HCC.

31
3.4.4. Immunotherapy

Immunologically active agents are theoretically of use in HCC treatment, as

interferons are known to play a role in viral reproduction, i.e. hepatitis B/C, and
as the activity of lymphokine activated killer cells is often reduced in HCC
patients [222]. Immunotherapy has not, however, been demonstrated to achieve
any significant impact on patient survival and high incidences of severe
complications have been reported. Agents studied include interferon alone [223]
and in combination with doxorubicin [224] or fluorouracil [225].
Interferon may have a role in the prevention of HCC in hepatitis C cirrhosis.
There is a scientific rationale for this therapy as interferon alpha has a broad
range of antitumour activity and is known to be effective therapy for some
haematological malignancies. Initial data from both Japan and Europe showed a
lower risk of HCC in cohorts of patients with hepatitis C cirrhosis who were
given interferon therapy compared with those who were not treated [226]. This
effect was irrespective of the antiviral effects of interferon alpha and was
observed with a treatment duration of only three months.
However, these studies were not RCTs and had inherent selection bias. As
other evidence indicates no effect of interferon on tumour development rates
[227], such tumour preventative therapy in patients with cirrhosis should remain
investigational within clinical trials. Interferon has been used as treatment for
HCC rather than for the underlying viral infection. An RCT using high doses of
interferon alpha showed an improved survival [228], but a more recent RCT
using more conventional doses of interferon alpha showed no improvement in
survival and a high incidence of side effects [229].
Other approaches to prevent tumour development have included retinoids
and adaptive immunotherapy. Both of these approaches have been used in the
context of prevention of second tumour development after initial tumour
resection or ablation. Adaptive immunotherapy, using primed peripheral
lymphocytes, showed a significant increase in tumour free survival [230].
Retinoids and compounds involved in the vitamin A metabolic pathway are
known to be differentiation inducing agents with hypoproliferative effects. A
single study using retinol showed a 20% reduction in second tumour development
in patients who had been treated with PEI [231]. Further studies of
immunotherapy in HCC are required to validate these interesting results in
different patient cohorts.

32
 4. RADIOTHERAPY

4.1. RATIONALE FOR RADIATION THERAPY

The management options for the majority of patients with HCC are limited,
using the treatment options discussed in Section 3. The standard local therapies,
including resection, transplantation, PEI and RFA, are applicable to <30% of
patients with HCC. Similarly, hepatic arterial embolization, either
chemoembolization or bland embolization, is suitable for the minority of patients
with Child–Pugh A, without major vessel or extrahepatic involvement. Further,
the benefits of systemic agents (chemotherapy and biological agents) are modest,
with high recurrence rates.
By contrast, the anatomical barriers that may make resection, ablation or
embolization less effective do not exist for radiotherapy. Although HCC is a
radiosensitive tumour, the relatively low radiation tolerance dose of radiotherapy
to the whole liver, as used historically, has promoted the concept that
radiotherapy has no role in HCC. However, low doses of radiation can certainly
lead to palliation of symptoms from HCC, and there is a substantial and growing
body of clinical data supporting the view that radiotherapy can lead to sustained
local control, extended survival and pathological complete responses in patients
with early and locally advanced HCC.
There are technical challenges in delivering conformal high dose
radiotherapy safely to HCC and there is a lack of RCTs of radiotherapy in HCC.
As such, radiotherapy has not been recognized as a valuable treatment option for
HCC. Thus, there is a pressing need for further studies, including RCTs of
radiotherapy in HCC, to demonstrate its value.

4.2. INDICATIONS FOR RADIATION THERAPY

4.2.1. Definitive, high dose radiotherapy

Radiotherapy with curative intent may be used to treat HCC confined to the
liver when other treatment options are either unavailable, contraindicated or
considered ineffective due to co-morbidities or the size and location of the tumour.
A resurgence of interest in the definitive management of HCC with radiotherapy
has been generated by a number of factors, including improvements in:

• The ability to deliver tumouricidal doses of radiation;

• Diagnostic imaging and visualization of the tumour;

33
 • Radiotherapy treatment planning software;
• The ability to account for tumour and organ motion at the time of radiation
planning and delivery.

The specific indications for high dose radiotherapy include confirmed

HCCs confined to the liver, including the presence of satellite nodules. Although
there is no absolute limit on the maximum number of intrahepatic tumours that
can be treated, the ability to deliver tumourcidal doses decreases and the chance
of extensive subclinical disease increases as the number of tumours increases. A
maximum of 5 intrahepatic tumour nodules is an arbitrary recommendation for
treatment with curative intent.
Tumours fulfilling these criteria generally fall into two categories:

(1) Smaller tumours of <8 cm in diameter without portal vein thrombosis in

patients with medical co-morbidities that preclude surgery, transplantation
or ablative therapies. Tumouricidal doses of radiotherapy are indicated,
subject to normal tissue tolerances. Dose schedules vary widely and include
hyperfractionated (e.g. 70–90 Gy at 1.5 Gy bid), conventionally
fractionated (e.g. 66–70 Gy in 33–35 fractions) and hypofractionated
regimens (e.g. 50–65 Gy in 20 fractions, 50–66 Gy in 10 fractions,
42–54 Gy in 6 fractions, 50 Gy in 5 fractions and 48 Gy in 4 fractions).
Hypofractionated schedules should be used with caution, especially for
tumours centrally placed within the liver or in proximity to mucosal
structures. The ideal fractionation is not well established. The best results
for tumour control are reported with hypofractionation, with the risk of
increased toxicity.
(2) Larger tumours of >8 cm in diameter, which may include portal vein
thrombosis, which are ‘focal’ in distribution (such that portions of the liver
can be spared from radiation) and are not amenable to surgery or other
regional treatments. Typical treatment schedules using photons include
50–60 Gy in 25–30 fractions and 30–42 Gy in 6 fractions, depending on
normal tissue tolerance. With larger tumours, hypofractionation is less
favoured, again because of the risk of increased bowel and liver toxicity.
More aggressive schedules may be feasible with proton or carbon ion
therapy.

In addition to these tumour specific and anatomical features, a number of

patient specific factors also influence the decision to offer radiotherapy with
curative intent. Absolute and relative contraindications are listed in Table 4.

34
TABLE 4. CONTRAINDICATIONS TO CURATIVE RADIOTHERAPY FOR
HCC: PATIENT FACTORS

A Absolute contraindications:
Child–Pugh C
Portal hypertension with gross ascites
Variceal bleeding
Thrombocytopenia (<30 000/mm3)
Reduced volume of tumour free liver (<800 cm3)
Poor performance status (>Eastern Cooperative Oncology Group 3)
Substantial prior abdominal irradiation
Poor liver function (bilirubin >2 × normal, transaminases >5 × normal)

B Relative contraindications:
Platelets 30 000–70 000/mm3
Performance status Eastern Cooperative Oncology Group 2
Child–Pugh B cirrhosis
Close proximity of gastrointestinal mucosa (<1 cm separating the tumour from the nearest
mucosa)
Lack of response to prior non-radiation treatment

4.2.2. Palliation with radiotherapy

Simple, low dose radiation therapy may be delivered to any patient with
HCC (including Child–Pugh B or C) if they are unsuitable for any other therapy
and they have local symptoms from their HCC requiring palliation. Radiotherapy
may be used to improve liver related symptoms that may occur due to HCC
involving the liver capsule or diffusely infiltrating the liver. Symptoms of pain,
discomfort, fever, anorexia or bleeding can be reduced in the majority of HCC
patients. Local palliative radiotherapy may also be used following rupture of an
HCC nodule (into the peritoneal cavity) to reduce the chance of further rupture
and for symptoms of biliary obstruction (although biliary stenting is preferable
for palliation if possible).
The ability of radiotherapy to reduce symptoms from liver metastases has
been documented, but not specifically for symptomatic, locally advanced HCC.
In a trial of symptomatic liver metastases, Leibel et al. prospectively studied
187 patients treated with whole liver radiotherapy to a dose of 21 Gy in
7 fractions; abdominal pain was improved in 80% of patients [232]. There is a

35
paucity of literature on the palliative benefits of whole liver radiation, so the most
appropriate fractionation is not well defined. Possible palliative dose
fractionations include 8 Gy in 1 fraction, 10 Gy in 2 fractions, 16 Gy in
4 fractions and 21 Gy in 7 fractions. In a prospective Trans-Tasman Radiation
Oncology Group study using 10 Gy in 2 fractions to the whole liver, symptoms
were reduced in 54% of cases [233]. Simple beam arrangements (parallel
opposed fields) are appropriate for whole liver radiotherapy, with pre-medication
with steroids and antiemetics.
In the presence of portal vein thrombosis, a variety of fractionation
schedules have been used (up to 50 Gy in 20 fractions), with or without
chemotherapy. Inclusion of the tumour thrombus and the primary HCC in the
treatment volume is recommended if possible. However, if the main symptoms or
life threatening problem is due to the portal vein thrombus and inclusion of the
primary HCC is not possible, treatment of the portal vein thrombus only is
indicated. Recanalization occurs in approximately 50% of cases over 3–6 months
(though the time to maximum recanalization and response may exceed a year).
Symptoms due to HCC metastases to bone [234, 235], brain [236], lymph
nodes [237, 238] and other sites [237] can also be alleviated by palliative
radiotherapy. Pain relief from bone metastases was observed in 73–83% of
patients in two of the largest series [234, 235]. A variety of palliative schedules
can be used, depending on the volume of normal tissue to be treated and life
expectancy.

4.2.3. Radiotherapy combined with other therapies

Radiotherapy alone can be an effective modality for small tumours.

However, in treating locally advanced tumours, radiation doses are limited by
liver tolerance, particularly for patients with cirrhosis. In Asia, where TACE has
been a major non-surgical option, radiotherapy has been introduced to improve
the high rates of progression after TACE. In fact, the characteristic features of
HCC, which involve vascular shunting, recanalization around the tumour capsule
and development of multiple feeding vessels, have limited the efficacy of TACE
[239, 240].
Previously, only the patients referred for consideration of radiotherapy were
those with poor liver function contraindicating resection, tumours unresponsive
to TACE and locally advanced disease not suitable for TACE.
Seong et al. used radiotherapy following incomplete responses to TACE,
with response rates greater than 60% [241]. Of 73 patients with HCC and an
incomplete response to TACE, 38 were treated with radiotherapy and 35 with
repeat TACE. A statistically significant improvement in survival was observed in
patients treated with radiotherapy (2 year survival rate 37% with radiotherapy

36
versus 14% with repeated TACE, p = 0.001). The survival difference was greatest
for larger tumours, with 2 year survival rates of 63% versus 42% in 5–7 cm
tumours, 50% versus 0% in 8–10 cm tumours and 17% versus 0% in tumours
larger than 10 cm, for treatment with radiotherapy and TACE, respectively [241].
A similar range of response rates with TACE followed by radiotherapy has been
reported by other investigators [242–245]. While this strategy improves local
control within the irradiated volume, the pattern of recurrence continues to be
intrahepatic (outside the treatment volume) and/or extrahepatic metastasis.
Following chemotherapy, a washout period of at least two weeks is customary
prior to starting radiotherapy. It remains unclear whether there is any benefit to
concurrent chemoradiation; nevertheless, the use of fluoropyrimidines may be
considered.
Radiotherapy has also been combined with concurrent transarterial
chemotherapy. This combination has improved survival in patients with main
portal vein tumour thrombosis. Han et al. [246] reported promising survival
results of conformal radiotherapy combined with hepatic arterial chemotherapy
in 40 patients with locally advanced HCC with portal vein tumour thrombosis.
The 3 year overall survival rate was 24.1% and the median survival time was 13.1
months, which was a marked improvement compared with the previously
reported survivals of 4–6 months [211]. The same group updated the treatment
outcomes in 101 patients who had a median survival of 16.7 months [247].
Since 1987, investigators at the University of Michigan have dose escalated
conformal hyperfractionated radiotherapy (1.5 Gy twice daily over 6–8 weeks),
with concurrent hepatic arterial floxuridine in serial phase I/II studies of
unresectable HCC. In this approach, the prescribed dose was based on the volume
of liver irradiated, with no upper limit on size of HCC that may be irradiated. In
1997, the outcomes of 20 patients with HCC treated with this approach were
reported; the median survival was 16 months and the 4 year survival rate was
20% [248]. In the latest phase II study, a median survival of 15.2 months was
observed in 25 HCC patients treated with doses as high as 90 Gy [249].
In a Japanese series of 121 patients with HCC treated with
hyperfractionated radiotherapy (1.5 Gy bid, total dose 45–75 Gy) combined with
thalidomide, the 1 and 2 year survivals were 60% and 45%, respectively.
Multivariate analysis found that portal vein thrombosis and the AFP level were
significantly associated with survival [250].

4.2.4. Bridge to transplantation

There is limited experience in using radiotherapy as a bridge to liver

transplantation [251]. Since the waiting list for transplantation is long and many
standard therapies are not suitable in patients with poor liver function,

37
radiotherapy may have a role in this patient group. Pathological complete
responses have been reported and the safety of radiation in this setting is
becoming established. Most often, the majority of the liver (which is usually
Child–Pugh B or C) is spared from the high radiation dose. The majority of
experience with radiotherapy as a bridge to transplantation is with protons [251],
but photon therapy using conformal radiotherapy or intensity-modulated
radiation therapy (delivered in 6 fractions) has also been used without significant
toxicity in this setting (unpublished, L. Dawson, Princess Margaret Hospital,
Toronto, March 2009). It is recommended that the local standard radiotherapy
protocol be used as a bridge to transplantation, ideally in the context of a clinical
study, since experience is scarce. Centres without a local standard radiation
fractionation schedule or a policy for HCC should consider offering radiotherapy
only within a clinical trial, owing to the risk of radiotherapy induced liver
toxicity.

4.3. TYPES OF RADIATION THERAPY

There is a range of strategies that may be used to deliver radiotherapy to

HCCs. Although several strategies are reviewed in this section, the emphasis will
be on external beam photon treatment.

4.3.1. Brachytherapy

Interstitial and intraluminal brachytherapy have been used to treat liver

metastases and cholangiocarcinoma [252]. However, there is far less experience
in HCC, possibly due to the potential for tumour seeding and the increased risk of
intrahepatic haemorrhage in patients with underlying cirrhosis. Intraluminal 192Ir
has been used occasionally for intraductal HCC and following incomplete
resection [253, 254]. Overall, the role of brachytherapy in HCC is very limited.

4.3.2. Radioisotopes

Regional radionuclide therapeutic options are increasingly available for

HCC patients, with encouraging results. However, these methods have not
displaced external beam radiotherapy as the main radiotherapeutic technique. The
three ways by which radioisotopes are delivered to HCC are 90Y, 131I–lipiodol and
labelled antibodies.

38
 90
4.3.2.1. Y

Yttrium-90 is a pure  emitter that decays with a physical half life of 2.7 d.
The  rays from 90Y embedded in glass microspheres have an average penetration
of 2.5 mm and a maximum penetration of 11 mm in tissue. Intratumoural
injection of 90Y glass microspheres under US guidance was used by Tian et al. as
a means to administer local radiotherapy [255]. Yttrium-90 may be delivered to
HCCs by segmental, subsegmental, regional, or global hepatic arterial infusion
via an appropriately placed hepatic arterial catheter.
Safety trials in HCC have demonstrated that doses of up to 100 Gy can be
safely administered focally [256–259]. A subsequent phase II trial with a planned
dose of 100 Gy suggested a dose–response relationship and a survival benefit
among patients receiving a dose >104 Gy [260]. Not unexpectedly, the survival
durations are longer in patients with better liver function and earlier stages of
disease [261]. In a recent analysis of toxicity, Goin et al. documented an 18%
90 d mortality following this procedure [262, 263]. Patients were stratified into
high and low risk cohorts based on the presence or absence of seven pretreatment
and treatment variables. The significantly higher 90 d mortality (49% versus 7%)
and significantly lower median survival (108 d versus 466 d) in high risk
compared with low risk patients led the authors to conclude that the use of 90Y
microspheres should be limited to low risk patients [263].
Yttrium-90 has also been tagged to resin microspheres. Most of the clinical
experience in unresectable HCC comes from Hong Kong where the microspheres
were delivered intraoperatively [264]. Patients receiving <120 Gy had fewer
responses and a lower median survival (26 versus 56 weeks). A larger trial of
71 patients who were administered an estimated median tumour dose of 225 Gy
confirmed a 27% partial response rate and complete pathological response in 2 of
4 patients who underwent subsequent resection [265]. Treatment was well
tolerated and the median survival was 9.4 months. To date, this procedure is not
Federal Drug Administration approved for treatment of HCC.

131
4.3.2.2. I–lipiodol

Another form of administering regional radiotherapy is injection of

131
I–lipiodol via the hepatic artery. Similar to TACE, the lipiodol is selectively
retained and concentrated within the tumour and the 131I delivers internal
radiation. Iodine-131 decays with a half-life of 8 d by  emission, but also
produces  rays which can be used for scintigraphy. However, accurate dosimetry
remains a challenge with these treatments [266].
Two RCTs have been conducted in France by Raoul et al. In the first,
27 patients ineligible for TACE due to presence of a portal venous tumour

39
thrombus were randomized to intrahepatic artery injection of 131I–lipiodol versus
supportive care [267]. Treatment was tolerated well and a significant
improvement in 6 month overall survival was noted for the 131I–lipiodol group
(48% versus 0%, p < 0.01). In the subsequent trial, 129 unresectable HCC
patients were randomized to TACE versus 131I–lipiodol [268]. There was no
significant difference in overall survival and 131I–lipiodol therapy was better
tolerated clinically.

4.3.2.3. Labelled antibodies

The final mode of administering radionuclides is systemic infusion of

radiolabelled antibodies. Early attempts at using monoclonal 131I–anti-ferritin
antibody were not successful, as outcomes were no better than with
chemotherapy [269]. More recently, monoclonal antibodies against putative HCC
specific antigens have been conjugated to 131I (including Hepama-1, isoferritin,
AFP and carcinoembryonic antigen) [270]. However, tumour specificity and
tumour retention remain ongoing challenges in radioimmunotherapy.

4.3.3. Photons

4.3.3.1. Conformal radiotherapy

As the external beam dose that may be delivered safely to the whole liver is
less than 30 Gy over three weeks, the benefits of whole liver irradiation are
palliative, predominantly to reduce symptoms such as pain. Advances in CT
based radiation planning have permitted high doses of radiation to conform to the
HCC target volume tightly, allowing the volume of uninvolved liver spared from
radiotherapy to be quantified, providing improved understanding of partial
volume tolerance.
In the French radiotherapy F1 prospective phase II trial of conformal
radiotherapy, a response rate of 92% was observed in 27 cirrhotic patients with
small HCCs (single nodule ≤5 cm, or 2 nodules ≤3 cm) treated with 66 Gy in
33 fractions [271]. Two grade 4 toxicities occurred in 11 Child–Pugh B patients
with pre-existing grade 3 abnormalities. Others have observed similar outcomes
following conformal radiation, with increased local control and survival
associated with higher doses [272].
The greatest experience with radiotherapy for HCC is from Asia, where a
variety of fractionation schemes with conformal radiation techniques have been
used. Seong et al. from the Republic of Korea reviewed their data for 1992–2003
to evaluate which staging system was most appropriate for Child–Pugh A patients
with HCC treated with radiotherapy. They found that the TNM staging system

40
was the best predictor of treatment outcomes in patients with Child–Pugh A liver
cirrhosis and HCC [111]. They also reported the largest series of radiotherapy
outcomes [273]. Using a multicentre retrospective cohort study, they analysed
398 HCC patients treated with conformal radiotherapy (326 patients) or
radiosurgery (72 patients) from 10 major cancer referral centres. The 2 year
overall survival and the median survival time were 27.7% and 12 months,
respectively. In multivariate analysis, tumour size of <5 cm, absence of lymph
mode metastasis and a radiation dose of >53.1 Gy10 (biologically equivalent
dose) were independent factors predicting improved outcome.
In summary, following a variety of dose and fractionation schedules, 1 year
survival rates range from 50–95% and 5 year survival rates range from 9 to 25%
following 40–60 Gy delivered over 1–5 weeks [274–278]. The reasons for the
large range of outcomes include substantial heterogeneity in patient selection
(Child–Pugh A and B), treatment intent and treatment delivered. Some series
report on outcomes for liver confined disease, whilst others report on tumours
with portal vein thrombus or regional metastases treated with palliative intent.

4.3.3.2. Stereotactic body radiation therapy (SBRT)

SBRT refers to the use of high dose radiotherapy delivered in far fewer
radiation fractions (e.g. 1–10 fractions) compared with conventional
radiotherapy. The use of improved imaging for tumour delineation, CT based
conformal planning, breathing motion management and image guided radiation
therapy allow high radiation doses to be delivered to focal HCCs with relative
safety. As dose gradients are steeper and doses are higher with SBRT than
conventional radiotherapy, the consequences of error in tumour delineation,
errors introduced by dosimetry and geometric uncertainties may be more serious
than following conventional radiotherapy. Thus, all aspects of treatment planning
that are important in conformal radiation planning are even more crucial in SBRT,
especially for tumours in close proximity to critical normal tissues, where a
systematic error could lead to permanent serious toxicity if sensitive normal
tissue is unexpectedly subjected to the high doses planned for the tumour. Special
quality assurance procedures are required prior to SBRT and it has been
recommended that radiation delivery equipment should have mechanical
tolerances accurate to +/–2 mm.
Blomgren et al. first reported on the use of SBRT for HCC in 1995 [279].
Patients with HCC and hepatic metastases were treated with 15–45 Gy in
1–5 fractions, with frequent objective responses. Wulf et al. treated 5 patients
with HCC and 39 patients with liver metastases using SBRT, with no limit on
tumour size if no more than 50% and 30% of the liver received 5 Gy and 7 Gy
respectively. No local recurrences or toxicity were seen in the 5 HCC patients

41
[280]. Mendez Romero et al. treated 8 Child–Pugh A or B patients with 11 HCCs
with 25 Gy in 5 fractions, 30 Gy in 3 fractions or 37.5 Gy in 3 fractions over
5–10 d. The maximum tumour diameter was 7 cm. Two HCC patients treated
with 25 Gy in 5 fractions recurred locally at 4 and 7 months and were re-treated
with 24 Gy in 3 fractions. The crude local control rate for HCC was 82% and the
1 and 2 year actuarial survival rates were 75% and 40%, respectively. One patient
(Child–Pugh B) developed grade 5 toxicity due to liver failure and infection
[281].
One series of hypofractionated conformal radiotherapy (similar to SBRT)
has been reported in which 98 patients with HCC received 48–63 Gy in
6–9 fractions over 12–18 d. Most (94%) showed tumour remission 6 months
post-treatment. From 48 patients with malignant portal vein thrombosis, there
was reduction in the size of the thrombus in 31 (65.6%) and significant reduction
in AFP levels (p = 0.015). Among the stage III patients, the 1 year survival rate
was 68% and the 2 and 3 year survival rates were 41% and 35%, respectively
[282].
In Toronto, a phase I study of a 6 fraction SBRT schedule in 31 HCC
patients (52% with portal vein thrombosis) refractory to, or unsuitable for,
standard therapies was reported. The median tumour volume was 173 cm3
(9–1913 cm3). The median dose was 36 Gy in 6 fractions (24–54 Gy). No classic
radiation induced liver disease (RILD) was observed, but five patients had a
decline in Child–Pugh score 3 months following radiotherapy (3 with progressive
disease). The 12 month local control rate was 65%. The overall median survival
was 11.7 months and the median survival of patients without portal vein
thrombosis was 17.2 months [283].

4.3.3.3. Proton and heavy ion therapy

Proton and heavy ion therapy exploits the unique characteristics of charged
particle beams to deposit most of their energy at the end of their range (the Bragg
peak effect), with steep dose gradients after the fall-off. In addition, charged
particle radiotherapy has sharp lateral margins and a slightly greater biologically
effective dose than photons. A modulated (spread out) Bragg peak is used to
encompass the target volume completely.
Most experience gained with proton radiotherapy for HCC is from Tsukuba,
Japan, where Chiba et al. treated 162 patients (192 HCCs) with proton beam
therapy with or without transarterial chemotherapy or PEI [284]. The median
dose of 72 Gy in 16 fractions over 29 d was well tolerated. The 5 year local
control rate was 87% and the 5 year overall survival was 23.5%. Among a subset
of 50 patients with solitary tumours and Child–Pugh A, the 5 year survival rate

42
was 53.5%. Outcomes were also good in patients with portal venous thrombosis
[285] and impaired liver function [286, 287].
Further prospective studies from Tsukuba have confirmed these impressive
outcomes [288]. Most recently, in a prospective study of 51 patients (20%
Child–Pugh B), proton therapy was used to deliver 66 Gy equivalent in
10 fractions to patients with 1–3 tumour nodules (10 cm). Five year local
control and survival rates were 88% and 39%, respectively. In Child–Pugh A
patients with solitary tumours, 5 year survival was 46%, similar to the results of
surgery. Liver function remained stable or improved in 84%, with no RILD. Late
rib fractures were seen in 3 patients, indicating that ribs may be a novel sensitive
tissue for late radiation damage. No other serious late toxicities were observed.
Patients with tumours near the gastrointestinal tract or porta hepatis were
ineligible for this hypofractionated protocol, which is used to reduce the risk of
mucosal and biliary toxicities that may occur following high doses per fraction.
This paper adds to the growing literature demonstrating the efficacy of
radiotherapy in HCC.
Bush et al. reported the results of a phase II trial of 34 patients treated with
63 cobalt Gray equivalent in 15 fractions over 3 weeks. Two year local control
and overall survival rates were 75% and 55%, respectively [251]. Gastrointestinal
bleeding occurred in 9% owing to the proximity of the tumour to the bowel. More
recently, Kawashima et al. reported a 66% overall 2 year survival in 30 patients
treated on a phase II protocol with 72 cobalt Gray equivalent in 20 fractions over
5 weeks, without gastrointestinal or pulmonary toxicity greater than grade 1 [289].
Kato et al. treated 24 patients in the first phase I/II protocol of carbon ions.
The treatment dose was 49.5–79.5 Gray equivalent in 15 fractions over 5 weeks
with step-wise escalation of dose per fraction. The 5 year local control was 81%
and 5 year overall survival was 25%. The only reported grade 3 toxicity was
radiation dermatitis [290].

4.4. TECHNICAL ASPECTS OF HIGH DOSE EXTERNAL BEAM

RADIOTHERAPY

As stated above, the ability to deliver high dose radiotherapy, using any of
the advanced technologies already discussed, is dependent on modern imaging,
planning and treatment methods. These include methods that reduce, or account
for, the considerable normal movement of the liver and other normal dose
limiting structures. As most of these advanced radiotherapy technologies are
applied in the treatment of many disease sites, including the liver, a brief
description has been included in Annex II.

43
4.5. RADIOTHERAPY TOXICITY

4.5.1. Hepatic toxicity

4.5.1.1. RILD

Early studies of whole abdominal irradiation demonstrated that irradiation

of the liver produced signs and symptoms of liver disease within three months of
treatment in approximately one third of patients [291–293]. This form of
subacute liver injury has been termed RILD [294]. Irradiated patients recorded
rapid weight gain, increase in abdominal girth, enlargement of the liver (often
with tenderness) and occasionally jaundice [292]. This clinical picture resembled
veno-occlusive disease (as observed in the Budd–Chiari syndrome or after
conditioning regimens used for bone marrow transplantation) and the typical
laboratory abnormality was a marked elevation in ALP, with less frequent
transaminitis [292]. While most patients recovered, deaths were recorded. The
pathological hallmarks of this injury included marked congestion, hyperemia,
haemorrhage of the central portion of the lobules and atrophy of the hepatocytes
surrounding the central vein with minimal congestion of the portal triad [293].
The central venous congestion extended to the sublobular veins (between the
central vein and the hepatic vein) but not the hepatic vein [294, 295]. Later in the
subacute course of RILD, small portal vein branches became obstructed due to
collagen deposition [295]. The lack of a predominantly inflammatory component
to this injury led to the choice of nomenclature as ‘RILD’ rather than ‘radiation
hepatitis’.
To confirm RILD rather than disease progression, it is usual to obtain a CT
scan and to perform a paracentesis. The CT scan may demonstrate a band of
decreased density of liver parenchyma corresponding to the radiation portals,
especially following proton therapy, but may be less apparent with the use of
multiple beams or intensity-modulated radiation therapy [294, 296, 297]. The low
attenuation area on non-contrast CT scans may show enhancement with dynamic
contrast studies [297].
There are no established therapies for subacute RILD. Over the course of
1–2 months, most patients respond to conservative measures such as diuretics
(spironolactone), vitamin K for coagulopathy, and repeated paracenteses. A
minority of patients develop jaundice (markedly elevated bilirubin, alkaline
phosphatase and prothrombin time with moderately elevated transaminases),
progressive ascites refractory to paracentesis and diuretics, and coagulopathies.
Although some of these patients may recover, a substantial proportion will die of
liver failure [294].

44
 At radiation doses inadequate for tumour eradication, whole liver radiation
with doses as low as 28 Gy delivered over 3 weeks carry a risk of RILD of >5%.
With conventional fractionation, the mean liver (minus gross tumour volume)
dose should be <18 Gy to minimize toxicity. A summary of liver radiotherapy
tolerances from the literature is shown in Table 5. Partial liver irradiation permits
dose escalation to tumours while sparing surrounding normal liver; this concept
has been responsible for resurgence in the role of radiotherapy in unresectable
HCC.
Liver tolerance depends on the radiation dose, the proportion of liver that is
irradiated, the pretreatment functional capacity of the liver and the use of
concurrent chemotherapy. Also, hepatic toxicity following radiotherapy
combined with chemotherapy is influenced by the organ distribution of the
chemotherapeutic drugs [298]. Pre-irradiation estimates of liver radiation
tolerance are difficult when liver function is damaged or when the total liver
volume has been reduced by cancer, chemotherapy, or previous disease. No
accurate assessment of liver reserve exists, although liver function tests coupled
with CT or isotope scanning, angiography and US are helpful. One method that
has been employed by surgical groups, mostly in Japan, has been to determine the
functional capacity of the liver using an indocyanine-green retention test [299,
300]. Another method that provides functional and anatomical data is
99m
Tc galactosyl serum albumin scintigraphy, which gives volumetric data as well
as kinetic distribution curves [301].
Table 6 shows the recommended radiation dose–volume to normal liver and
total liver. All dose limits are kept as low as possible, especially if hepatitis B
carrier or Child–Pugh B.

4.5.1.2. Non-RILD hepatic toxicity

Another liver related acute toxicity observed in HCC patients treated with
focal radiotherapy is reactivation of viral hepatitis and precipitation of underlying
liver disease [302, 303]. Treatment of active hepatitis B is always recommended
before irradiation, if possible. The radiation tolerance of the liver in hepatitis B
patients in Taiwan, China, with HCC is lower than for hepatitis B HCC patients in
North America. In patients from Taiwan, China, the risk of liver toxicity is very
low if the mean liver dose is kept <18 Gy in 20–35 fractions [304].
A common complication in patients with portal hypertension and
splenomegaly, or baseline liver dysfunction, is the increased risk of coagulopathies
due to decreased platelet count or function and/or elevated prothrombin time. As
these patients are at risk of bleeding (often from stomach and duodenal mucosae
within the treatment field), prophylactic treatment with proton pump inhibitors and
discontinuing radiotherapy at platelet counts <50 000/mm3 is advised.

45
 TABLE 5. SUMMARY OF LIVER RADIOTHERAPY TOLERANCES FROM LITERATURE REVIEW

Baseline Radiotherapy dose MDTNL in patients with Factors associated

Study group N Diagnosis Crude % RILD
Child–Pugh score per fraction and (without) RILD with RILD

Michigan 203a PLC+LM 203 A 1.5 Gy bid 9.4% (19/203) 37 Gy (31.3 Gy) PLC versus LM
(Dawson) mean liver dose
Taipei (Cheng) 89b HCC 68 A 1.8–3.0 Gy 19% (17/89) 23 Gy (19 Gy) HBV, cirrhosis
21 B
Shanghai (Liang) 109b PLC 93 A 4–6 Gy 15.6% (17/109) 24.9 Gy (19.9 Gy) Cirrhosis
16 B
Guangdong 94b HCC 43 A 4–8 Gy 17% (16/94) Not stated Cirrhosis
(Wu, Xu) 51 B (4 fatal)
Republic of Korea 158b HCC 117 A 1.8 Gy 7% (11/158) Not stated Dose
(Seong, Park) 41 B
Republic of Korea 105b HCC 85 A 2.0 Gy 12.3% (13/105) 25.4 Gy (19.1 Gy) Total liver volume
(Kim) 20 B >30 Gy exceeds 60%
a
Patients also received Fluorouracil deoxyribose or bromouracil deoxyribose. The MDTNL was calculated as corrected for 1.5 Gy bid equivalent
dose. Comparison of patients with versus without RILD refers to the median value of the MDTNL, whereas for other series the comparison is
between the averages (mean) of the MDTNL in each group.
b
At least 77% of patients in these series also received TACE.
PLC: primary liver cancer (including HCC and intrahepatic cholangiocarcinoma); LM: liver metastases; MDTNL: mean dose to normal liver.

46
TABLE 6. RECOMMENDED RADIATION DOSE–VOLUMES TO NORMAL
LIVER AND TOTAL LIVER

Organs at risk Constraint

1. V50% (50% of the isocentre dose) [271, 305, 306])

V50% (%) Total dose (Gy)
Normal liver University of <33 Up to 93a
Michigan 33–66 Up to 47a
guideline >66 Up to 32a
Yonsei <25 59.4 or more
University 25–49 45–54
guideline 50–75 30.6–45
>75 No treatment
2. Normal tissue complication probability model [294, 307–309]
5% risk of RILD (TD5)
1/3 liver 2/3 liver Whole liver
43–93a Gy 34–47 Gy 30–35 Gy
50% risk of RILD (TD50)
39.8–49.4
Child–Pugh A: 40.5–48.9 Gy
Child–Pugh B: 23–38.7 Gy
3. MDTNL [309–311]
MDTNL for whole patients:
<28 Gy in conventional 2 Gy per fraction
<18 Gy in 6 fractions
Child–Pugh A: 21 Gy; Child–Pugh B: 6 Gy
4. Non-tumour liver volume >800 cm3
Total liver including No more than 60% of normal liver receives over 30 Gy
target volume (V30 <40–60%) [312]
All dose limits are kept as low as possible, especially if hepatitis B carrier or Child–Pugh B
a
1.5 Gy twice daily.

4.6. GASTROINTESTINAL MUCOSAL TOXICITY

Other critical structures that may be included in high dose treatment

volumes for HCC include the oesophagus, stomach, duodenum, small intestine
and large intestine. If portions of these tissues are irradiated beyond threshold
doses (approximately 45 Gy in 1.8 Gy per fraction or 30 Gy in 6 fractions), acute
oesophagitis, gastritis, duodenitis, or colitis may occur 1–3 months following

47
irradiation. The discomfort from these self-limited, acute reactions is generally a
response to antacids, topical analgesics (e.g. viscous lidocaine) or proton pump
inhibitors. Other acute reactions may include nausea (if the stomach is irradiated),
anorexia, diarrhoea or abdominal cramps.
Acute variceal bleeding may occur in cirrhotic patients and is more
common in patients with prior variceal bleeds, baseline portal hypertension and
treatment with higher doses per fraction. Optimization of liver function and
banding of varices prior to irradiation may reduce the risk.
Late gastronintestinal mucosal complications may occur if doses exceeding
50 Gy in 1.8 Gy per fraction (or 30 Gy in 6 fractions) are delivered to portions of
the gastrointestinal tract. These late toxicities include bleeding, ulcer formation,
chronic gastritis, bowel obstruction and fistula formation. Although not proven to
reduce bleeding or ulcer formation, H2 receptor blockers or proton pump
inhibitor medications are often used in patients if high doses are delivered to the
gastrointestinal tract.
Late gastrointestinal bleeding occurred in 5% of patients treated with
conformal radiotherapy for HCC or hepatic metastases with 1.2 Gy twice daily
[249]. When external beam radiation is combined with intraluminal 192Ir
brachytherapy, focal regions of the duodenum may receive high doses and the
risk of gastrointestinal bleeding is increased. Bleeding has been reported to occur
in 25–30% of patients with biliary malignancies treated with external irradiation
plus intraluminal 192Ir. Mogavero et al. reported gastric and duodenal obstruction
in 7 of 63 patients who underwent radiotherapy for hilar cholangiocarcinoma,
although some of these symptoms may have been due to the tumour in addition to
radiation fibrosis [313].

4.6.1. Biliary toxicity

Kopelson et al. reported asymptomatic, non-obstructing biliary fibrosis

after 60 Gy of external irradiation [314]. Biliary fibrosis is often amenable to
endoscopic or percutaneous transhepatic bile duct stenting. However, as bile duct
stenting combined with radiotherapy may increase the incidence of stent related
infection, prophylactic stenting is not recommended [315, 316].
Relevant to HCC are the reports of biliary toxicity in long term HCC
survivors treated with radiotherapy. Chiba et al. reported 5 late complications
following 185 proton treatment courses in 162 patients. These included one case
of common bile duct stenosis and two cases of infection bilomas [284].

48
4.6.2. Other radiotherapy related toxicities

The constitutional symptoms of fatigue, anorexia, fever and asymptomatic

bone marrow suppression are common, but usually mild and transient. Depending
on the fractionation used, grade 1–2 fatigue may start during therapy and usually
passes within a few months following radiotherapy. Occasionally, substantial
fatigue may last >2 months, sometimes associated with hypoalbuminemia or a
reduction in liver function.
Thrombocytopenia is the most common haematological toxicity and is
related to the presence of portal hypertension and splenomegaly in cirrhotic
patients. Thrombocytopenia is also more likely in patients who have been heavily
pretreated with chemotherapy or where TACE is used with radiotherapy.
Substantial declines in the platelet count are unusual following radiotherapy
alone.
Depending on the location of the HCC, other normal tissues, including the
kidneys, spinal cord, heart and lungs, should be considered at the time of
radiotherapy planning, to reduce the risk of toxicity. Similar to the liver, partial
organ radiographic changes may be seen following high dose radiotherapy to the
kidneys (on renal scans) and/or the base of the lungs (ground glass changes in the
lung parenchyma). These acute changes may develop into fibrosis, but would
constitute a clinically important decline in organ function only if a substantial
portion of the organ were irradiated.
Another less common subacute side effect from radiotherapy is pleuritic
pain that is usually transient, but which can mimic pulmonary embolus. This is
more common following SBRT. This usually resolves within 4 months following
radiotherapy and may be due to lower lung irradiation. Rib fractures are another
toxicity that may occur following high dose radiotherapy, more likely following
SBRT or hypofractionated proton therapy.

49
 5. FUTURE DIRECTIONS

5.1. INTRODUCTION

The tumour status and hepatic functional reserve are equally important as
major determinants of treatment selection and prognosis. Although potentially
curative therapies are well established for HCC, these are only applicable to
20–30% of patients. Also, resection is accompanied by high recurrence rates and
transplantation has limitations. TACE, the most common non-surgical
alternative, and other ablative therapies, including PEI and RFA, are effective
only in limited instances. HCC is also resistant to current systemic
chemotherapeutic regimens. Even sorafenib, the first systemic drug to show
statistically improved survival in a RCT may not find widespread use, owing to
the small absolute gain in survival and its high cost.
There is, therefore, an urgent need both to define other effective therapies
and to systematize the use of existing therapies, including radiotherapy. As
indicated in Chapter 4 and Annex II, there have been major advances in radiation
treatment planning and delivery during the past decade, providing a capability for
effective treatment of HCC. However, radiotherapy has not been incorporated
into many management guidelines, and the optimal fractionation for HCC has yet
to be determined.

5.2. EXISTING TREATMENT GUIDELINES FOR HCC

On the basis of the encouraging reports showing the efficacy of

radiotherapy, delivered in a variety of techniques, it is of interest to review the
extent to which radiotherapy is incorporated into existing guidelines for the
management of HCC (Table 7).
Table 7 indicates that radiotherapy is not included as a treatment option in
several guidelines. Some relevant aspects of these guidelines are:

• The NCCN practice guideline (version.2.2008, www.nccn.org) is a

consensus statement regarding current approaches to management. There is
level 2A evidence that radiotherapy is an alternative therapeutic option to
transplantation for patients with unresectable disease, or for those who
decline surgery. This is supported by the uniform NCCN consensus on the
appropriateness of this recommendation.

50
TABLE 7. PUBLISHED GUIDELINES FOR THE MANAGEMENT OF HCC

Radiotherapy
Year Guideline for HCC management
in guideline

2001 Barcelona–European Association for the Study of the No

Liver consensus

2003 Korean Liver Cancer Study Group (KLCSG) guideline Yes

2005 AASLD guideline Noa

2005 Japan guideline for evidence based clinical practice Nob

2007 Japan Society of Heptology guideline (consensus based No

clinical practice manual)

2008 United States National Comprehensive Cancer Network Yes

(NCCN) guideline
2009 Taiwan, China, national guideline Yes
a
Non-curative treatment. There are multiple other treatment modalities such as octreotide,
interferon, external radiation, tamoxifen, or anti-androgenic therapy, but none have been
shown to improve survival.
b
For Child–Pugh C cases with vascular invasion or an extrahepatic lesion, palliative care is the
basic treatment, including radiotherapy aimed at pain relief.

• In the KLCSG practice guideline for diagnosis and treatment of HCC [317],
radiotherapy is considered for surgically unresectable, locally advanced
tumours without extrahepatic metastasis, Child–Pugh A or B, and tumours
occupying less than two thirds of the liver. The KLCSG guideline describes
the use of radiotherapy as level III evidence (clinical experience,
descriptive studies, or expert committee reports) according to the AASLD
definition.
• The AASLD practice guideline for the management of HCC contains an
evidence-based treatment strategy for HCC patients based on fewer than
one hundred RCTs [118]. Patients are stratified by BCLC stage, with a
suggested treatment for each stage. Patients diagnosed at an early HCC
stage are optimal candidates for resection, liver transplantation or
percutaneous ablation. If these options are not feasible, patients are
considered for palliation.

51
5.3. TREATMENT OF HCC: THE RADIATION ONCOLOGIST’S
PERSPECTIVE

There has been increasing interest in the role of radiotherapy in the

treatment of HCC over the past few years, as indicated by the results of a PubMed
search (Fig. 1). This shows an exponential growth in the number of publications
over the past 15 years, in all aspects of radiotherapy for liver cancers. Therefore,
it is timely to reassess the role of radiotherapy in HCC.
From the radiation oncologist’s viewpoint, radiotherapy may be used as the
definitive therapy with curative intent in early stage tumours. The best outcomes
have been reported following proton or carbon therapy, but high dose photon
therapy is also potentially curative. Radiotherapy may also be used in
combination with TACE, or in patients not suitable for TACE for intermediate
stage tumours. In locally advanced tumours, radiotherapy may be used in
combination with systemic agents (on trials only), or alone in patients with portal
vein thrombosis not suitable for other therapies. Technical advances in the use of
radiotherapy allow more precise delivery of radiation, permitting higher doses to
the tumour and reduced doses to surrounding normal tissues. As HCC usually
arises in already compromised livers, these modern technologies are a
prerequisite for local control and possible cure.
Radioisotopes are also available as a treatment option. The selection of
patients for external beam radiotherapy versus radioisotope therapy is not well

RT result for intrahepatic tumour

16
RT toxicity
RT technique
14 Particle therapy
RT for extrahepatic tumour
Number of articles

12 Other

10

0
1975 1980 1985 1990 1995 2000 2005
Year

FIG. 1. Increasing frequency of publications on radiotherapy for liver cancer (source:

PubMed).

52
defined. In general, radioisotopes may be considered for multifocal diffuse
intrahepatic HCC, where conformal radiotherapy is not an option. However,
many questions remain unanswered and many of the comparative clinical trials
between different treatment methods and modalities have not been undertaken.
Patients with advanced stage and deteriorating condition should be
managed palliatively. For control of local or distant symptoms, short fractionation
schedules (e.g. 5–8 Gy in a single fraction, 20 Gy in 4 fractions) are
recommended, since survival is generally short.

5.4. UNRESOLVED ISSUES

5.4.1. Dose escalation studies using radiotherapy as a single modality

A number of studies demonstrate a radiation dose response relationship for

HCC. Higher doses improve tumour response at the expense of greater toxicity.
With better understanding of partial liver irradiation, delivery of very high doses
should be possible using conventional or hypofractionated radiotherapy if <25%
of the effective liver volume is irradiated. With this proviso, radiotherapy with
high doses can achieve substantial tumour response in selected patients.
However, the availability of dose/volume statistics from 3-D planning is required
for dose escalation to be undertaken safely.

5.4.2. Development of combination strategies

The natural progression of HCC involves early vascular invasion,

contributing to intrahepatic relapse and extrahepatic metastasis even after
substantial tumour regression by local treatments. This provides a rationale to
combine local and systemic modalities. Radiotherapy can be combined with
TACE, regional or systemic chemotherapy, or new targeting agents in an attempt
to reduce these recurrences. This approach has been proven to achieve substantial
tumour regression, even with portal vein invasion. Despite the impressive
outcomes reported from single institutions, these combined treatments have not
been tested in RCTs. Until RCTs are available, tumour boards may be unwilling
to incorporate these combinations into clinical guidelines.
An increased number of novel molecular targeting agents have been
developed and are awaiting assessment in clinical studies. Combinations of
radiotherapy and these novel molecular targeting agents may well lead to further
outcome improvement.

53
5.4.3. New radiotherapy technologies

A variety of newer precision technologies has been developed to improve

radiotherapy dose delivery and improve the therapeutic ratio. These include
intensity-modulated radiation therapy, image guided technology and particle
beam radiotherapy. Reports using these techniques are increasing and fusion of
these technologies and concepts are being trialled (e.g. the use of intensity
modulation technology with proton beams). However, the impact of these new
technologies on outcomes for HCC needs to be confirmed in further studies.

5.4.4. Redefinition of liver toxicity

Traditionally, radiation induced toxicity in the liver has been defined as

RILD, as discussed in Section 4. While applicable for radiotherapy alone,
different types of toxicity are frequently seen in combined modality strategies
[304]. With the development of novel targeting agents and their combination with
radiotherapy, the toxicity profile may change. In fact, any ‘hepatic dysfunction’
following therapy (including radiation therapy) should be included in future
reports and considered as possibly related to therapy. One measure to be
incorporated into a definition of hepatic dysfunction may be the Child–Pugh
score.

5.5. RECOMMENDATION FOR FUTURE STUDIES

A number of clinical trials are suggested for consideration, as it is

anticipated that the HCC community will be reluctant to accept radiotherapy
without positive results confirming the advantage of radiotherapy, either alone or
in various combinations. Suggested phase I, II and III trials are listed below.
Given the substantial patient and tumour heterogeneity associated with HCC,
some randomized phase II trials are recommended below (rather than single arm
phase II studies). The following studies are recommended.

5.5.1. Clinical trials of HCC incorporating radiotherapy

• Phase I trials:
— Radiotherapy combined with sorafenib or other molecular targeted agents.
• Phase II trials:
— Randomized phase II trial of radiotherapy combined with TACE;
— Randomized phase II trial of radiotherapy combined with molecular
targeted agents.

54
 • Phase III randomized trials:
— BCLC B: TACE +/- radiotherapy;
— BCLC C (portal vein thrombosis only): sorafenib +/- radiotherapy.

Symptomatic HCC is not suitable for other therapies: 8 Gy in one fraction versus
best supportive care.

5.5.2. Stem cell recovery of liver function

Other studies indirectly related to the role of radiotherapy in the treatment

of HCC include hematopoietic or hepatocyte stem cell transfer to rescue end
stage liver disease from HCC or from radiation induced toxicity.

5.5.3. Redefinition of staging

It is clear that the tumour stage alone or the status of liver function alone is
insufficient to categorize and select patients for optimal management. As stated in
Section 3, the BCLC system may be helpful in describing patient populations in
future studies, in addition to TNM staging. Furthermore, the Child–Pugh score
should always be reported for all patients in any future studies.

5.5.4. Measurement of end points in palliation

In contrast to curative trials, for which the end points are survival and time
to progression, the appropriate end points for palliative trials are short term
improvement using validated questionnaires for symptom control (e.g. McGill
pain tool) and quality of life (e.g. the European Organisation for Research and
Treatment of Cancer or FACT HCC module).

55
 6. CONCLUSIONS

HCC is a disease common to developing countries and one that usually

develops following a number of well defined insults (viral, toxins, etc.) that are
both hepatotoxic and carcinogenic. The anatomy of the liver, particularly the rich
network of intrahepatic vascular structures draining into the hepatic veins, allows
easy intrahepatic and extrahepatic tumour progression. The scenario of locally
advanced tumour development within a compromised yet vital organ has
implications for all aspects of management, including diagnosis, staging and
treatment.
The only treatments currently with a recognized role for curative
management are resection and liver transplantation. These are inapplicable for
most patients, owing to the inability to leave a functional remnant of liver
(resection) and the shortage of donor livers (transplantation). Unfortunately both
procedures are associated with high intrahepatic and/or extrahepatic relapses.
As a result, most patients are considered incurable at the time of diagnosis,
owing to a combination of tumour characteristics — predominantly size — and
compromised hepatic function. This combination limits the application of many
local treatments, including PEI, RFA and TACE, all of which are associated with
high intrahepatic relapse rates.
In an attempt to improve the poor results of non-surgical treatment, there is
currently a resurgence of interest in radiotherapy, either alone or in combination
with other modalities. The rapid developments in radiotherapy technology over
the past decade, together with promising early results of the treatment of HCC
with radiotherapy, suggest that radiotherapy should be viewed as a legitimate
treatment modality for HCC. High dose radiotherapy, delivered in a variety of
ways, may be superior to non-surgical treatments in improving survival and even
cure. The patterns of recurrence following high dose radiotherapy provide a
strong rationale for combining radiotherapy with regional therapies such as
TACE. Similarly, the feasibility and safety of combining radiotherapy with
biological targeted agents should be assessed in future studies. Radiotherapy also
retains a useful place in palliation of symptoms from advanced disease.
The lack of comparative data, especially RCTs, has impeded the inclusion of
radiotherapy in the routine management of HCC. Thus, the imperative is the
conduct of well designed RCTs, in parallel with phase I and II clinical trials using
developing radiotherapy technology and combination therapies with radiotherapy.
Ultimately, the aim must be earlier diagnosis, when the tumour is smaller,
reducing the risk of intra- or extrahepatic spread and facilitating curative
treatments that retain a sufficient functioning liver. In particular, diagnostic
imaging techniques with novel contrast enhancement are being explored.

56
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 Annex I

MOLECULAR PATHOLOGY OF HEPATOCELLULAR CARCINOMA

(HCC)

I–1. CHROMOSOMAL AND GENETIC ALTERATIONS IN

HEPATOCARCINOGENESIS

Allelic loss is uncommon in cirrhotic livers. For dysplastic nodules, an

analysis of chromosomal gains and losses using comparative genomic
hybridization (CGH) demonstrated that the frequency and pattern of genetic
alterations in dysplastic nodules greatly resembled those in HCCs. Gains of DNA
were found to cluster in chromosome arms 1p, 1q, 7q, 15q, 16p, 17q and 20q,
with losses of DNA at 3p, 4q, 9p and 11q [I–1]. Such frequency and pattern of
genetic alterations were not seen in other hepatocellular nodules such as focal
nodular hyperplasia and hepatocellular adenomas, implying that dysplastic
nodule is a precancerous lesion. Altogether, the genetic results indicate a stepwise
increase in the genetic abnormalities from cirrhosis through dysplastic nodule to
HCC, giving support to the notion of multistep hepatocarcinogenesis. Moreover,
low grade dysplastic nodules and macroregenerative nodules did not show
chromosomal imbalances of allelic losses on 8p and of gains of 1q, as in high
grade dysplastic nodule and HCC [I–2]. Recently, genome wide microarray
analysis has been employed to study the molecular expression profiles of the
different stages in hepatocarcinogenesis from cirrhosis through dysplastic
nodules to HCC [I–3 to I–5]. These have been useful in identifying a possible
‘molecular signature’ to distinguish dysplastic nodules from HCC.
In HCC, recurrent chromosome alterations are frequent and they include
loss of 1p, 4q, 8p, 16q and 17p, and gain of 1q, 8q and 20q [I–6 to I–8]. These
findings reflect a high degree of chromosomal instability in HCC, contributing to
hepatocarcinogenesis. Coupled with detailed clinicopathological correlation and
gene mutation analysis (e.g. p53 or β–catenin mutations), different genetic
pathways can be delineated [I–9, I–10]. HCC can be divided into two groups, one
having chromosome stability with β–catenin mutation and chromosome 8p losses
and the other demonstrating chromosomal instability, with frequent allelic losses
on chromosome 1p, 4q, 6q, 9p, 13q, 16p, 16q and 17p, and p53 and Axin1
mutations [I–10]. A recent study, using comprehensive genome wide allelotyping
with >400 markers coupled with detailed clinicopathological correlation and p53
mutation analysis, has shown that HCC can be stratified into low stage and
advanced stage tumours predicting different survivals. In addition, chromosomes
1p, 8p and 13q are among the most frequently affected chromosome arms in HCC

75
and other cancers [I–11]. Previous reports in HCC have shown that allelic losses
on these chromosomes range from 17.5 to 53% and they may harbour putative
tumour suppressor genes [I–12 to I–14].
With CGH analysis, HCC has been shown to harbour multiple
chromosomal abnormalities, predominantly losses, with increased chromosomal
instability. Recurrent aberrant gains have been found on 1q, 8q, 16p and 20q and
recurrent chromosomal losses on 1p, 4q, 8p, 13q, 16q and 17p to [I–15 to I–18].
Recently, array based CGH has been used to provide high resolution mapping of
chromosomal aberrations in HCC. Although the chromosomal abnormalities
reported are similar to those obtained with CGH, correlation with gene
expression data may identify novel oncogenes and tumour suppressor genes
[I–19].
Aberrations have also been found to differ in HCC with different etiological
backgrounds. Chromosomal aberrations were more frequent in HBV related
HCCs than in HCV associated tumours [I–20]. Another study showed that HBV
associated HCCs had significantly more frequent (40% on average) losses at 4q,
16q and 17p (including the p53 region) than in non-viral HCC samples,
suggesting that these abnormalities were associated with HBV infection [I–20].
With regard to other chromosomes, a gain of 10q (7/41, 17%) was detected
exclusively in cases with HCV infection, whereas amplification of 11q13 was
more frequently seen in HBV positive HCCs. However, in other studies, no
significant difference in chromosomal aberrations between HBV and HCV
associated HCCs were found [I–21].

I–2. EPIGENETIC ALTERATIONS IN HEPATOCARCINOGENESIS

In addition to genetic alterations, epigenetic alterations play an important

role in human carcinogenesis. ‘Epigenetic’ refers to changes in DNA methylation
and histone modifications that stably modify gene transcription but do not
involve changes of the DNA sequences. DNA methylation is the covalent
addition of a methyl group (–CH3) to the 5 position of cytosine and is the most
well-characterized epigenetic event. The dominant epigenetic alteration in
cancers is the aberrant hypermethylation of CpG islands in gene promoter
regions. Hypermethylated promoters are almost always transcriptionally silent.
Aberrant CpG island methylation may result in inactivation of tumour
suppressor genes. The tumour suppressor gene p16/INK4A, a cyclin dependent
kinase inhibitor regulating the phosphorylation status of the retinoblastoma gene
product, is frequently inactivated in HCC by promoter methylation [I–16 to
I–22]. Loss of p16 function may limit the tumour suppressor function of the wild
type retinoblastoma gene product and lead to unregulated cellular proliferation

76
[I–23]. Another tumour suppressor gene, deleted in liver cancer 1, a negative
regulator of Rho family GTPases, has been reported to be frequently silenced in
human HCCs via DNA hypermethylation [I–24]. Other well-characterized
tumour suppressor genes that regulate various cellular pathways in human HCC
include E–cadherin [I–25], RASSF1A [I–26], SFRP1 [I–27], GTSP1 [I–28],
SOSC–1 [I–29] and PTEN [I–30].

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78
 Annex II

TECHNICAL CONSIDERATIONS IN RADIOTHERAPY OF

HEPATOCELLULAR CARCINOMA (HCC)

II–1. RADIATION TREATMENT PLANNING

II–1.1. Imaging at simulation

At the time of simulation, patient positioning and the imaging modality

(computed tomography (CT), magnetic resonance imaging), resolution (e.g. CT
thickness), and phase of contrast (e.g. arterial IV contrast for HCC) must be
chosen. Breathing motion must be considered at this time, as breathing introduces
artifacts in planning CT and possibly in tumour definition, normal tissue
definition and resultant errors in tumour control probability and normal tissue
complication probability.
One method to account for motion is to eliminate it, for example, with a
breath hold scan. Diagnostic breath hold scans are often obtained in inhalation.
However, exhalation breath hold scans are often used for radiation planning of
HCC patients. An alternative to breath hold imaging is to obtain a 4-D imaging
data set. From this, any position could be used for planning and image guidance
[II–1]. Planning on the exhalation dataset with asymmetric planning target
volume (PTV) margins is an option [II–2], as is planning using the mean tumour
position.

II–1.2. Target volumes

The gross tumour volume (GTV) should consist of the arterial enhancing
parenchymal liver tumour and any enhancing portal vein thrombosis. The clinical
target volume (CTV) margin should include the GTV. The ideal CTV margin to
account for microscopic disease is unknown. CTV margins from 5 to 10 mm are
often used in conformal radiotherapy. With stereotactic body radiotherapy
(SBRT), it is usual to equate the CTV to the GTV, as some dose is delivered to
microscopic disease in the rim around the GTV, owing to dose fall-off outside the
target volume.
The PTV margins must consider set-up uncertainty and internal organ
motion. Individual institution set-up uncertainty data should be used if available.
Individual patient internal organ motion, for example, breathing motion, should
be used if this information is known. If unavailable, a PTV margin is used to
ensure coverage of 90% of the population for 90% of the time.

79
II–1.3. Radiotherapy planning

CT based conformal planning software is generally used for dose

calculations for a radical HCC radiotherapy plan. Inhomogeneities should be
considered and computer optimization of beam angles, beam weights or segments
within beam angles can help to optimize the shape and the dose distribution of
critical normal tissues.
For SBRT, many beams of low weight are used to develop a highly
conformal dose distribution. If required, non-coplanar beams or arcs are used to
reduce the dose to normal tissues. When sufficient beams are summed, the PTV
may be covered by a lower isodose, such as 60%, which often corresponds to the
steepest part of the dose gradient. Resultant high doses/hotspots occur in the
centre of the PTV, perhaps giving the highest dose to the central hypoxic volume
(although the potential benefit of this is unproven).

II–2. MOTION MANAGEMENT

Organ motion due to physiological functions during a radiation fraction can

be substantial. For example, the liver can move 3–5 cm in the caudal–cranial
direction during free breathing [II–3], causing motion of the upper abdominal and
lower thoracic cavity. As this motion can result in alterations in target and normal
organ volume definitions, PTV margins and the entire dose distribution and
interventions to reduce the impact of intratreatment organ motion are required.
Strategies to compensate for breathing motion include the use of abdominal
pressure, voluntary shallow breathing, voluntary deep inspiration, voluntary
breath holds at variable phases of the respiratory cycle, active breathing control,
gated radiotherapy and real time tumour tracking. Voluntary breath holding may
be beneficial for some patients, although there is potential for leaking air and
patient error. Active breathing control refers to organ immobilization with breath
holds that are controlled, triggered and monitored by a caregiver. In
approximately 60% of patients with HCC, active breathing control was able to be
used successfully. However, despite the use of breath holding to reduce the
amplitude of breathing motion, the mean liver position may vary from day to day
relative to the vertebral bodies, providing a rationale for daily image guidance.
Gated radiotherapy, in which the beam is triggered to be ‘on’ only during a
predetermined phase of the respiratory cycle, usually refers to the use of an
external surrogate for tumour position (as opposed to direct tumour imaging) to
gate the radiation. Ideally, gating should be based on imaging of the tumour rather
than external surrogates for the tumour. Gating can be used to reduce the volume

80
of normal tissue irradiated. Changes in baseline liver position can occur from
day-to-day [II–1] and thus image guidance is important.
Tumour tracking is another approach to reduce the adverse effects of organ
motion. Fluoroscopic X ray tubes in the treatment room allow visualization of
radio-opaque markers or the diaphragm, both surrogates for movement of the
HCC. The linear accelerator is triggered to irradiate only when the marker is
located within the planned treatment region [II–4]. As an alternative to turning
the radiation beam off when the tumour moves outside the treatment fields,
multileaf collimators, the couch position or the entire accelerator may move with
the tumour to ensure adequate tumour coverage at all times. An example of
mobility of all components is the Cyberknife image guided radiosurgery system
(Accuray, Sunnyvale, CA). The Cyberknife is a lightweight (150 kg) 6 MV linear
accelerator mounted on a robotic arm, with 5–60 mm collimators and providing a
dose rate of 300–400 MU/min.
There are advantages to gating, breath hold and tracking in the exhalation
phase of the respiratory breathing cycle versus the inhalation phase. Exhalation
tends to be more reproducible and is longer than inhalation, so that treatment
during exhalation reduces the treatment time.

II–3. IMAGE GUIDED RADIOTHERAPY (IGRT)

II–3.1. Introduction to IGRT

Imaging immediately before or during treatment delivery is used to

improve the precision and accuracy of radiotherapy. This frequent imaging is
referred to as image guided radiotherapy, or IGRT. Since IGRT improves set-up
accuracy and precision, it allows PTV margins to be reduced, reducing the
volume of normal tissue that is required to be irradiated.
Traditionally, surrogates for the target (e.g. skin marks) have been used to
guide the placement of radiation treatment beams. In most body tumours, the
internal structures cannot be accurately localized with such surrogates. The use of
bony anatomy with electronic portal imaging is another historical standard
practice in radiotherapy. However, for many clinical situations, the position of the
bones is not well correlated with the internal tumour position. Options for
locating internal anatomy include the use of implanted radio-opaque fiducial
markers as surrogates for the target, or localizing tissues adjacent to the tumour or
the tumour itself.
IGRT can be performed with conventional linear accelerators using the
megavoltage treatment beam. However, more specialized treatment units are now
available with the potential to allow soft tissue image guidance. Examples

81
include the Cyberknife and modified linear accelerators such as Novalis
(BrainLAB, Westchester, IL), Synergy (Elekta Oncology, Stockholm), Trilogy
(Varian Medical Systems, Palo Alto, CA), Artiste (Siemens, Concord, CA) and
Tomotherapy (Madison, WI).

II–3.2. Image guidance strategies

The two primary correction strategies that may be used to reduce setup error
are an on-line approach and an off-line approach. The on-line approach refers to
the use of daily imaging prior to every fraction with correction for off-sets when
the position is greater than a predefined threshold prior to daily treatment. An off-
line approach refers to the collection of imaging data with high frequency at the
beginning of therapy (e.g. first 5 fractions), followed by an off-line analysis to
determine the set-up errors. A correction is then made to counter the systematic
error, with possible replanning to individualize the PTV margins based on the
patient’s random set-up error as sampled at the beginning of therapy.
On-line correction strategies reduce both systematic and random set-up
errors, with a greater reduction in error compared with the off-line approach, but
at the expense of increased time and cost. On-line correction strategies are most
appropriate for hypofractionated radiotherapy or SBRT, as there are generally few
fractions to collect set-up data and there is a strong rationale for reducing set-up
error.

II–3.3. Two dimensional IGRT

Orthogonal MV portal films (replaced more recently by electronic portal

imaging devices) have been used for image guidance for decades. Although
mostly used to visualize bones to position the patient, if radio-opaque fiducial
markers are inserted in or near the tumour, the fiducial markers may be used for
guidance. Other alternatives for guidance include using surrogates that are in
close proximity to the tumour, for example, the diaphragm as a surrogate for liver
tumours.
Orthogonal kV radiographs and kV fluoroscopy have also been used for
image guidance of tumours and/or fiducial markers, either immediately prior to,
or throughout, each treatment fraction [II–5, II–6] or throughout radiation
delivery [II–4]. The kV X ray tubes may be ceiling or wall mounted or attached to
the linear accelerator. With both MV and kV orthogonal imaging, alignment tools
registering the images to reference images obtained at the time of planning can
improve the accuracy and efficiency of image matching to determine the off-sets
in position.

82
 Real time tumour tracking while the radiation beam is turned on is another
IGRT approach. A highly integrated tracking system consisting of four ceiling
mounted fluoroscopic X ray tubes and four floor mounted flat panel imagers in
the treatment room allowing visualization of radio-opaque markers in the
tumours was first described by Shirato et al. [II–4]. This system has a temporal
resolution is 30 frames/s and a precision of 1.5 mm. The linear accelerator is
triggered to irradiate only when the fiducial marker is located within a predefined
volume.
As an alternative to turning the radiation beam off when the tumour moves
outside the treatment region, multileaf collimators, the couch position or the
entire accelerator on a robotic arm may move with the tumour to ensure adequate
tumour coverage combined with dual orthogonal fluoroscopy tubes to track
radio-opaque markers in or near the tumour at a preset frequency. When the beam
is on, infrared external surrogates are continuously monitored, while the internal
anatomy is monitored periodically with kV imaging. Another system (Novalis)
also acquires kV orthogonal images and matches them to images obtained from
the planning CT. The imaging axes are not coincident with the isocentre, and a
translation of patient position is required between imaging and treatment.

II–3.4. Three dimensional IGRT

Technological advances allowing volumetric imaging permit image

guidance immediately prior to treatment using either the tumour or a soft tissue
organ in close proximity to the tumour for guidance, rather than the bony
anatomy. Volumetric imaging systems have the advantage that adjacent normal
organs can also be visualized for more accurate avoidance of critical structures.
Ultrasound (US) has also been used for image guidance of HCCs.
Significant reductions in residual set-up error were observed using US guidance,
with a mean 3-D residual set-up error vector of 4.6 mm (+/–3.4 mm) following
image guidance [II–7]. The advantages of US are that it is widely available and
relatively inexpensive; the disadvantages are that the accuracy of the system for
image guidance requires specialized training and is user dependent.
The placement of a diagnostic CT scanner in the treatment room with a
known geometric relationship to the linear accelerator is another volumetric
IGRT strategy. Uematsu et al. have used this approach to treat HCCs. With these
systems, the CT scanner is in close proximity to the linear accelerator, allowing
the couch to be moved from the imaging position to the treatment position. The
CT scanner gantry is often translated during acquisition to minimize couch
motion. An advantage of in-room CT is that state of the art diagnostic quality CT
can be used for optimal image quality and robustness. A disadvantage of this
system is that the imaging and treatment isocentres are not coincident. Accuracy

83
of motion from the CT scanner gantry, the accelerator couch and the coincidence
of the CT and linear accelerator isocentres need to be verified.
The concept of cone beam CT for image guided radiotherapy was
introduced in 1997 [II–8]. Cone beam CT refers to combined kV X ray imaging
and MV radiation delivery into one integrated gantry mounted system.
Advancements in large area flat panel detector technology facilitated volumetric
imaging to be acquired in a single rotation of the linear accelerator gantry. Planar
kV image projections are obtained as the gantry rotates about the patient on the
linear accelerator table, from 30 s to 4 min. Cone beam CT 3-D volume
reconstruction images may then be obtained for image guidance. In addition to
providing volumetric imaging for verification and guidance, these systems have
the ability to be used for real time kV tracking; the latter application has not been
used clinically.
CT imaging using MV beams has also been used for IGRT [II–9 to II–12].
The advantages of MV cone beam CT are that the treatment MV beam is used to
obtain the image, requiring less modification to the linear accelerator, the electron
density estimates for treatment planning are accurate and there is no high Z
artifact that is associated with kV imaging.
MV tomotherapy combines tomographic scanning capabilities, from a
conventional CT detector, with a linear accelerator mounted on a rotating gantry.
In the tomotherapy treatment platform, the MV treatment beam is used to obtain
images, with a lower energy (3.5 MV instead of 6 MV).

REFERENCES TO ANNEX II

[II–1] SONKE, J.J., et al., Respiratory correlated cone beam CT, Med. Phys. 32 (2005)
1176–1186.
[II–2] BALTER, J.M., et al., Improvement of CT-based treatment planning models of
abdominal targets using static exhale imaging, Int. J. Radiat. Oncol. Biol. Phys. 41
(1998) 939–943.
[II–3] BOOTH, J.T., ZAVGORODNI, S.F., Set-up error & organ motion uncertainty: A
review, Australas. Phys. Eng. Sci. Med. 22 (1999) 29–47.
[II–4] SHIRATO, H., et al., Four-dimensional treatment planning and fluoroscopic real-time
tumor tracking radiotherapy for moving tumor, Int. J. Radiat. Oncol. Biol. Phys. 48
(2000) 435–442.
[II–5] DAWSON, L.A., et al., Accuracy of daily image guidance for hypofractionated liver
radiotherapy with active breathing control, Int. J. Radiat. Oncol. Biol. Phys. 62 (2005)
1247–1252.
[II–6] BALTER, J.M., et al., Daily targeting of intrahepatic tumors for radiotherapy, Int. J.
Radiat. Oncol. Biol. Phys. 52 (2002) 266–271.

84
 [II–7] FUSS, M., et al., Daily ultrasound-based image-guided targeting for radiotherapy of
upper abdominal malignancies, Int. J. Radiat. Oncol. Biol. Phys. 59 (2004) 1245–1256.
[II–8] JAFFRAY, D.A., et al., A radiographic and tomographic imaging system integrated
into a medical linear accelerator for localization of bone and soft-tissue targets, Int. J.
Radiat. Oncol. Biol. Phys. 45 (1999) 773–789.
[II–9] SIMPSON, R.G., et al., A 4–MV CT scanner for radiation therapy: The prototype
system, Med. Phys. 9 (1982) 574–579.
[II–10] SWINDELL, W., et al., Computed tomography with a linear accelerator with
radiotherapy applications, Med. Phys. 10 (1983) 416–420.
[II–11] MACKIE, T.R., et al., Tomotherapy: a new concept for the delivery of dynamic
conformal radiotherapy, Med. Phys. 20 (1993) 1709–1719.
[II–12] MACKIE, T.R., et al., Image guidance for precise conformal radiotherapy, linear
accelerator for localization of bone and soft-tissue targets, Int. J. Radiat. Oncol. Biol.
Phys. 56 (2003) 89–105.

85
.
 ABBREVIATIONS

3-D Three dimensional

AASLD American Association for the Study of Liver Disease
AFP Alpha fetoprotein
BCLC Barcelona Clinic Liver Cancer
CGH Comparative genomic hybridization
CLIP Cancer of the Liver Italian Program
CT Computed tomography
CTV Clinical target volume
DCP Desgamma-carboxyprothrombin
DNA Deoxyribonucleic acid
Gy Gray
GyE Gray equivalent
HCV Hepatitis C virus
HBV Hepatitis B virus
HCC Hepatocellular carcinoma
HCC-CC Hepatocellular-cholangiocarcinoma
IGRT Image guided radiation therapy
JIS Japan integrated staging
KLCSG Korean Liver Cancer Study Group
MDTNL Mean dose to normal liver
MELD Model for end stage liver disease
MRI Magnetic resonance imaging
NCCN National Comprehensive Cancer Network
OLT Orthotopic liver transplantation
PEI Percutaneous ethanol injection
PLC Primary liver cancer
PTV Planning target volume
RCT Randomized clinical trial
RILD Radiation induced liver disease
RFA Radiofrequency ablation
SBRT Stereotactic body radiation therapy
TACE Transarterial chemoembolization
TCP Tumour control probability
UICC Union internationale contre le cancer
US Ultrasound

87
.
CONTRIBUTORS TO DRAFTING AND REVIEW

Alaa, I. Ain Shams University, Egypt

Dawson, L. Princess Margaret Hospital, Canada

Imai, R. International Atomic Energy Agency

Krishnan, S. M.D. Anderson Cancer Center,

United States of America

Ng, I. The University of Hong Kong, China

Salminen, E. International Atomic Energy Agency

Seong, J. Yonsei University, Republic of Korea

Stevens, G. Auckland Hospital, New Zealand

89
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