1. GENERAL INFORMATION
1.1.1 Incidence and mortality
Primary malignancies of the liver (ICD 9, 155.0,155.1) (ICD-O 2000) are a major health problem in developing countries, where more than 80% of the total world hepatic carcinomas occur. The highest incidence has been recorded in China (55% of the world total), Japan, South East Asia and sub-Saharan Africa (Stewart 2003). Liver cancer is uncommon in Europe. The age-standardised incidence in Europe is 7 per 100,000/year in men and 2 per 100,000/year in women, accounting for about 2% of total cancers (Ferlay 1999). In 2000, the incidence of hepatic cancer was estimated to be about 50,000 new cases a year (Ferlay 2001).
There is a noticeable geographical variation in the incidence of liver cancer throughout Europe (see Figure 1) (Ferlay 2001): in men, the highest incidence has been reported for Southern Europe, whilest the lowest was in the North of Europe; by contrast, in women the incidence was highest in the Northern part of the continent and lowest in the Eastern Europe.
Figure 1. Incidence of liver cancer by age in large European regions, in men and women (from Globocan) (Ferlay 2001).
About 71% of patients with liver cancer are over 65 years of age. In men, the incidence by age rises rapidly from 3 per 100,000/year in patients aged less than 45 to 32 per 100,000/year in the age group 60-64 and 62 per 100,000/year for those older than 75 years of age (Ferlay 1999).
The incidence of liver cancers has been increasing in the UK, particularly in older men (Taylor-Robinson 1997). Also in Japan, the US and France the incidence has increased over the past two decades and liver cancer has become progressively associated with younger age groups (Bergsland 2000; El-Serag 2004). In Italy, the incidence of liver cancer has increased overall during the period 1986-97, for both men and women. Mortality has shown a limited decrease during this period, however, this did reach statistical significance in women (Crocetti 2004). The trend in incidence is influenced to a major extent by the occurrence of disease in elderly people (>65 to >75 years).
Mortality rates have increased in several European regions, but some of these increases may be the results of improved detection (Stewart 2003).
About 80% of all primary cancers of the liver are hepatocellular carcinoma, (a tumour that arises from hepatocytes). Other tumour types, which include intrahepatic cholangiocarcinoma (tumour of that part of the bile duct epithelium located within the liver), hepatoblastoma (a malignant embryonal tumour of childhood) and angiosarcoma (arising from blood vessels) are relatively rare.
Patients with liver cancer have an extremely poor prognosis. The relative survival for adults diagnosed in Europe during the period 1990-94 (Berrino 2003) was 24% at one year and just 7% at five years, with no differences between the genders. Five-year survival was slightly higher in people under 45 years (20%).
During the period 1983-94, the 5-year survival for hepatic carcinomas significantly increased from 4% to 9 % for both sexes (Roazzi 2003). The small improvement in overall survival of patients with liver cancers in population based studies is most likely due to the small numbers of patient who received effective therapy.
The survival data reported here are derived from information collected by population-based cancer registries. They provide the means by which we can measure progress against cancer.
1.1.3 Aetiology and risk factors
Hepatitis virus types B and C and liver cirrhosis, either subsequent to hepatitis or alcohol- related, are the classic risk factors for hepatocarcinoma, but associations with smoking, aflatoxin and oral contraceptives have also been identified.
Primary liver cancer frequently occurs in association with chronic viral liver infections. Infection with hepatitis B virus is the predominant cause of liver cancer, with more than 80% of cases being a consequence of such an infection (Bergsland 2000). In developed countries liver cancer occurs in older patients with cirrhosis of the liver related to hepatitis C virus infection. The presence of occult persistent hepatitis B virus infection further increases the oncogenic potential of this virus. Chronic hepatitis B virus carriers have a 100-fold relative increase in risk of developing liver cancer compared with non-carriers, which decreases if the infection was acquired in adulthood (Bergsland 2000). Cirrhotic patients have a higher risk of hepatic cancer; the annual liver cancer incidence being 2-6.6 %, whereas it is 0.4% in non-cirrhotic patients (Llovet 2003). Hepaptitis B infection results from acquired infection at birth or early in life, and involves individuals aged 40 years or younger. This situation can be prevented by vaccination. Prevention of infection by hepatitis C virus relies on preventing transmission by transfusion of blood products. Vaccination is not available, therefore prevention of nosocomial infections and infections among at risk populations is paramount (Llovet 2003). Heavy (>50-70 g/d) and persistent alcohol consumption, leading to cirrhosis and alcoholic hepatitis, increases the risk of primary liver cancer (El-Serag 2002). The risk of cirrhosis and hepatocellular carcinoma are further increased in heavy drinkers who have concomitant chronic hepatitis C or B viral infections or diabetes (El-Serag 2002).
Dietary ingestion of aflatoxins (produced by the mould Aspergillus flavus, which, under hot and humid conditions, contaminates stored grain) is causally associated with the development of hepatic cancer, and exposure to aflatoxins may be synergistic with HBV infection (Stewart 2003).
Iron overload due to untreated haemochromatosis has been associated in some patient series with a risk of death from hepatocellular carcinoma as high as 45% (Schafer 1999). Hepatocellular carcinoma has been reported to occur in 37% of patients with tyrosinaemia and may occur in patients who have successfully undergone liver transplantion. Other predisposing conditions are: alpha-1-trypsin deficiency, hypercitrullinaemia and glycogen storage disease (Stewart 2003). All of these conditions are uncommon causes of liver cancer and, therefore, are not likely to play an important role in the epidemiology.
The World Cancer Research Fund (WCRF) and Association for International Cancer Research (AICR) panel of experts notes that diets high in vegetables possibly decrease the risk of liver cancer (WCRF&AICR 1997).
The insulin resistance syndrome, manifesting as obesity and diabetes, is emerging as a risk factor for hepatocellular carcinoma in the United States (El-Serag 2004).
Cigarette smoking has been implicated in host immune response variations, which is a cofactor for the development of liver cancers. The effect of tobacco may be enhanced by cytocrome p450 1A1 genetic polymorphisms, which modulate the biotransformation of tobacco-derived polycyclic aromatic hydrocarbons into carcinogenic metabolites (Yu 1999).
Other minor risk factor of HCC includes use of oral contraceptive steroids and use of anabolic androgenic steroids (De Maria 2002).
1.1.4 Early diagnosis
Screening programmes by ultrasound examination (US) with or without pre-selection on the basis of raised levels of alpha-fetoprotein (AFP) have not proved effective in reducing mortality (Stewart 2003).
Recent observations indicate that free DNA originating from tumour cells is detectable in the plasma of liver cancer patients at an early stage (Stewart 2003). The availability of simple, genetic tests would be an important contribution to screening programmes (Stewart 2003). In developed countries, although there is no evidence for the efficacy of hepatocellular carcinoma screening in high risk group, patients with chronic liver disease are routinely surveyed with US and AFP by referring hepatologists at time intervals ranging from 3 to 12 months. In a survey in the United States 84% of the respondents to a questionnaire mailed to American Association for the Study of Liver Diseases members were routinely screening patients with cirrhosis by AFP and US, in 99.7% and 93% of cases, respectively. Screening for liver cancer has been implemented in current clinical practice, despite the absence of randomised trials; a situation similar to that which occurred for cervical cancer screening in the past (Bolondi 2003).
2. PATHOLOGY AND BIOLOGY
2.1.1 General data
From the pathological point of view, hepatocellular carcinoma is composed of two separate entities. The neoplastic component and the degenerative one, i.e. cirrhosis. Between 50 and 85% of all HCCs arise in cirrhotic livers, and most HBV-related HCCs and almost all HCV-related HCCs coexist with chronic necroinflammatory disease (Kew 1989).
The pathology of hepatocellular carcinoma is, thus, important in order to define both tumour size, degree of hepatic cirrhosis and presence or absence of metastatic disease in regional lymphnodes.2.1.2 Macroscopic pathology
Gross anatomy at diagnosis shows that in 60% of cases of HCC the neoplasm is formed by multiple nodules, in 30% of cases by a single large lesion and in the remaining cases the liver is diffusely infiltrated. In the small percentage of patients without cirrhosis, the neoplasm is associated with collagen strands to forms cords, the so called fibro-lamellar variant. HCCs arising in normal liver tend to be a single massive cancer, sometime infiltrating whole lobes. In cirrhotic liver HCCs are small, usually well demarcated and surrounded by a fibrous capsule. Advanced cancer presents as expansive multinodular tumour, frequently accompanied by intrahepatic metastases (Lauwers 1998).
The presence of a capsule is an important characteristic because it is associated with lower nuclear grades, improved survival, lower intrahepatic recurrence rate and low incidence of local venous invasion (Nzeako 1996). Other significant gross features of hepatocellular carcinoma are multicentricity and intravascular and biliary tract growth.
Multicentricity is predictive of intra-hepatic recurrence after surgery, it is noted in 16% to 74% of resected HCCs. The development of multicentricity could be metachronous with multicentric carcinogenesis or with the spread of intra-hepatic metastases via the portal system (Sakamoto 1989; Toyosaka 1996). Major portal vein thrombosis portends a poor prognosis because the presence of tumour thrombi is the source of intra-hepatic metastases and such patients experience recurrence within one year and death within two years after surgery (Ikai 1998). Cancer invasion into the bile duct or the hepatic duct is relative rare, however the prognosis is worse than that for other patients (Kojiro 1982).2.1.3 Histologic type and grade
The histological classification of liver tumours is as follows:
- Hepatocellular carcinoma (including the fibrolamellar variant)
- Cholangiocarcinoma (intrahepatic bile duct carcinoma)
- Mixed types
The classification does not apply to primary sarcomas, extranodal lymphomas or metastatic tumours.The histologic grading system recommended is the scheme of Edmonson and Steiner (Edmonson 1954) which employs four grades:
- G1: well differentiated
- G2: moderately differentiated
- G3: poorly differentiated
- G4: undifferentiated
On the other hand it must be noted that in HCC, no firm correlation of prognosis to histological grade has been established.The different types of growth patterns of HCCs have been associated with a variable risk of intrahepatic and extrahepatic spread (Yuki 1990). Several classifications system are present in the literature.The first classification of HCC growth pattern is the Eggel’s classification (Eggel 1901):a) nodular type – tumour nodules scattered within the cirrhotic parenchymab) massive type – circumscribed nodule occupying most of or a whole hepatic lobec) diffuse type – innumerable indistinct small tumour nodules in cirrhotic liverThe Liver Cancer Study Group of Japan proposed to change the nodular type into three sub-categories (LCSGJ 1997):a) single nodular typeb) single nodular type with perinodular tumour growthc) confluent multinodular type.Other classifications included different subtypes.The WHO classification recognizes five major histological patterns (Ishak 1994):a) trabecularb) pseudoglandular (acinar)c) compact
The significance of this last pattern is that it is indicative of prognosis, because this carcinoma is more amenable to surgical resection with favourable outcomes. It occurs in young patients who lack underlying cirrhosis, it is firm, sharply demarcated and lacks a fibrous capsule. Clinical data shows that overall five years survival is estimated to be between 35% and 56% for patients undergoing cancer resection.
3.1 Clinical features
The classical clinical presentation of liver cancer includes right upper quadrant abdominal pain (>90%), presence of mass, and weight loss (35%) (Befeler 2002).
HCC is generally a slow-growing tumour, the majority of cases presenting at an advanced stage because tumours must reach a substantial size before they are palpable. Small cancers are most often asymptomatic and are usually discovered during screening programs or incidentally, during imaging performed for other reasons.
For most patients, the presentation of HCC will also be a simultaneous manifestation of the underlying cirrhosis, with the presence of other symptoms and signs who are dependent on the degree of functional liver impairment: anorexia, weakness, jaundice, ascites, hepatomegaly, splenomegaly, bleeding from oesophageal varices, encephalopathy. Portal hypertension may be due to cirrhosis or to intraportal neoplastic thrombi. Fever may be present due to central necrosis of the tumour. Intra-abdominal bleeding may result from both rupture of the tumour either from vascular invasion and intravascular growth.
Patients with advanced stage HCC usually die of hepatic failure and cachexia, as a result of local growth and a consequent destruction of liver tissue and replacement, rather than because of extrahepatic metastatic disease.3.2 Diagnostic proceduresAppropriate diagnostic procedures should be employed when there is a suspicion of HCC. The diagnostic process should collect all data relevant to the ideal staging system:
1) verification of diagnosis: in particular, differentiation between small neoplastic lesions and regenerative, displastic nodules
2) determination of the extent of disease: defining the criteria for resectability of the HCC (how many neoplastic nodules and where they are located) and the presence of contraindications to surgery (presence of tumour thrombus)
3) determination of functional liver reserve
4) assessment of biological determinants that affect long-term prognosis.The major diagnostic criteria for diagnosing HCC are (Colombo 2002):
1) histological proof
2) cytological proof
3) non histological proof defined by the contemporaneous presence of:
i.established cirrhosis from ethanol, hepatitis B or C, or haemochromatosis
ii.focal lesion demonstrated by two morphological methods among US, CT or MR with imaging suggestive for HCC
iii.arterial hypervascularization demonstrated by spiral CT or dynamic MR
iv.alpha-FP value above 500 ng/mL
In the absence of a biological verification, the diagnosis of HCC can be made by:
i.coincidental findings from two imaging techniques (US, CT, MRI) showing a nodule greater then 2 cm with arterial hypervascularization
ii.a single positive imaging technique associated with a high alpha-FP serum level
A diagnostic biopsy is recommended for the following indications: in patients with potentially respectable disease, if alpha-FP is less than 400 ng/mL if the diagnosis is uncertain, or when the result may influence treatment. A biopsy is contraindicated if there is radiological evidence of vascular invasion. HCC biopsy presents a defined risk of complications including bleeding, seeding of tumour cell and also death. Finally a liver biopsy may not distinguish well-differentiated HCC from focal hyperplasia, macroregenerative nodules or adenoma (Colombo 2002).
Imaging studies play a central role in the diagnosis and staging of HCC (Coakley 2001). The sensitivity and specificity values of each procedure are listed in table 1.
a) Ultrasound (US) examination in the diagnostic setting of HCC has been replaced by CT. It represents an useful tool for screening of HCC because of its relatively high sensitivity and specificity and is recommended in this setting. However, US can be utilized to study some specific aspects of HCC: to detect the presence of a capsule; to distinguish neoplastic invasion of the portal vein, hepatic veins or inferior vena cava from non neoplastic thrombus by Colour Doppler (the presence of a flow indicates a neoplastic thrombus); to show arterioportal shunting. Finally, the advent of intraoperative ultrasonography has improved rates of tumour detection with the possibility of identifying nodules 1 cm in diameter during surgical intervention (Borzio 1997).
b) Computed Tomography (CT) scan replaced US in diagnosis of HCC. In particular, triphasic spiral CT multislices scan allows for a very rapid imaging of the liver after infusion of intravenous contrast agents. The term triphasic CT scan describes the 3-step process of vascularization, including the phase before contrast, the arterial phase and the portal phase. HCC which receives its blood supply predominantly from the hepatic artery, enhances early during the infusion of contrast, in the arterial phase, while the normal liver parenchyma enhances during the portal venous phase. In the past, CT scanning using lipiodol as contrast agent has been suggested to have a high sensitivity in differentiating dysplastic or regenerative nodules from small neoplastic nodules (that incorporates lipiodol). At present time, multiphase CT multislices should be considered the standard imaging modalityy for HCC.
c) MR imaging could become the diagnostic procedure of choice for HCC because the morphology of HCC is well demonstrated by MRI and tumour capsules and central scars are visualized better than on CT. However, the sensitivity of MRI is lower in tumours less then 2 cm in diameter. The introduction of Gadolinium-enhanced multiphase (dynamic) MRI represented a major improvement in the differential diagnosis of dysplastic or regenerative cirrhotic nodules (ipo- isovascular) and malignant nodules (hypervascular), because of the typical hypervascular pattern of enhancement in the arterial phase. Multiphase gadolinium-enhanced MRI depicts more HCC than multiphase contrast-enhanced CT but in practice often suffers from poor image quality in patients with advanced stage cirrhosis (Krinsky 2001).
d) The role of angiography as an imaging technique for the study of vascular anatomy of HCC and its relationships with hepatic parenchyma has been mostly replaced by triphasic spiral CT scan and by MRI. Its role is now more therapeutic because it is limited to the administration of drugs such as those used in chemoembolization (Befeler 2002).
e) Serum level of alpha-FP is elevated above 20 ng/mL in 70% of patients with HCC. alpha-FP serum level between 10 to 500 ng/mL may be seen in patients with only necroinflammatory activity such as chronic viral hepatitis. Thus, alpha-FP may play a role in the diagnosis of HCC together with appropriate imaging analysis and it also represents a good marker for monitoring response to treatment and detecting relapse. The serum dosage of alpha-FP should be recommended in HCC patients (Johnson 2001; Collier 1998).
Table 1: sensitivity values of different diagnostic procedures for HCC.
|Triphasic spiral CT||76%|
|Triphasic multislice CT||78%|
3.3 Diagnostic algorithm
An integrated and practical approach to the imaging of HCC is based on the pathological and radiological features of the disease. The approach depends on whether the patient has cirrhosis (including chronic viral hepatitis) or not. In cirrhotic patients, any dominant solid nodule that is not clearly a haemangioma should be considered a HCC until proven otherwise. If the lesion is hypervascular, if it demonstrates venous invasion, or is of increased T2 signal intensity and is associated with an elevated serum alpha-FP, the diagnosis of HCC is almost certain. In uncertain cases, repetition of imaging in 4 months is recommended. However stable nodules, especially in cirrhotic livers, must be kept under surveillance because they are at high risk of developing into HCC in the future.
Diagnostic algorithm and workup for HCC
|Diagnostic algorithm and workup for HCC|
|Clinical suspect of HCC
(elevated alpha-FP, liver mass)
|Liver imaging studies & lab tests
(US + spiral CT or MRI, Chest x-ray, liver function, CBC, PT, INR, Hepatitis B, C)
|Diagnosis of HCC uncertain
|Diagnosis of HCC
|Cyto- histological proof +Cyto- histological proof –
||Staging & prognostic score
(additional imaging: chest CT scan, bone scan, assessment of liver function & comorbities)
|Screening after 4 months with alpha-FP and liver imaging|
4.1 General data
The ideal staging system for a given neoplasm should give information about the natural history of the tumour (local tumour growth, spread to regional lymphnodes and metastasis) and provide information with prognostic significance that can inform the decisional process to allow appropriate management of a group of patients who may have the same characteristics.
In the case of HCC, the official staging system is the AJCC TNM classification that accurately describes the tumour load (considering vascular invasion, number of neoplastic nodules, size of tumour) but does not provide information regarding the function of the liver. When advanced underlying liver disease (cirrhosis) dominates the prognosis, primary tumour factors (T stage) may become irrelevant in terms of prognosis. In these cases, other staging systems (Child-Pugh, Okuda staging, Cancer of the Liver Italian Program Investigators [CLIP], Barcelona-Clinic Liver Cancer [BCLC] or the Simplified Staging System for HCC) may provide more useful information (Vauthey 2002). However, to date, the TNM classification should be considered the standard option for staging on a type C basis. The TNM classification according to the last version of the UICC/AJCC Cancer Staging Manual (UICC 2002) and the other staging systems are reported.
4.2 TNM Classification
Primary tumor (T)
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Solitary tumour without vascular invasion
T2 Solitary tumour with vascular invasion or multiple tumors none more than 5 cm
T3 Multiple tumours more than 5 cm or tumours involving a major branch of the portal vein(s)
T4 Tumour(s) with direct invasion of adjacent organs other than gallbladder or with perforations of visceral peritoneum.
Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph nodes metastasis
N1 Regional lymph nodes metastasis
Distant Metastasis (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1 Distant metastasis
Stage I T1; N0; M0
Stage II T2; N0; M0
Stage IIIA T3; N0; M0
Stage IIIB T4; N0; M0
Stage IIIC Any T; N1; M0
Stage IV Any T; Any N; M1
4.3 Other staging systems
It is important to note that none of the following staging systems is clearly superior to the others and that no general consensus exists to recommend one system over another. So they can be used as an option individualized for a specific patient or within a specific trial on a type 2 level of evidence.
4.3.1 Child-Pugh Score for hepatic function
The Child-Pugh score is not a staging system for HCC but a score system to detect different degrees of impairment of liver function in cirrhotic patients (Pugh 1973).
|Chemical and biochemical parameters||Scores (points) for increasing abnormality|
|Prothrombin time prolonged (sec)||1-4||4-6||>6|
|Class A: 5-6 points; Class B: 7-9 points; Class C: 10-15 points|
4.3.2 Okuda Staging Classification
The Okuda classification considers both tumour stage and also parameters of liver function and has an ability to identify patients with advanced stage cirrhosis (Okuda 1985).
Okuda Staging Classification
|(+)||(-)||< 3 g/gdl
|> 3 g/gdl
|> 3 mg/dl
|< 3 mg/dl
|II||1 or 2 (+)|
|III||3 or 4 (+)|
4.3.3 CLIP Staging Classification
The CLIP classification takes into account the Child-Pugh score for cirrhosis, tumour size and nodularity, portal thrombosis and alpha-fetoprotein serum level. It appears to be more effective at stratifying patients who are not candidates for resection or transplantation (CLIP 2000).
CLIP Staging Classification
|Tumor morphology||Single nodule and <50% area||Multiple nodules||Massive or >50% area|
|Alpha-Fetoprotein (ng/ml)||<400||>= 400|
|Portal vein thrombosis||No||Yes|
4.3.4 BCLC Staging Classification
The BCLC classification combines several parameters, retrospectively derived, such as tumour factors (size, nodularity), liver function and treatment modalities. This staging system is useful in selecting treatment options particularly for patients with early stage HCC (stage A). The major limitation of the BCLC staging system is the lack of an external validation (Llovet 1999a; Llovet 2002).
BCLC Staging Classification
|Stage||Performance status||Tumor stage||Liver function|
|Stage A: early HCC|
|A1||0||Single, < 5 cm||No portal HTN and normal bilirubin|
|A2||0||Single, < 5 cm||Portal HTN and normal bilirubin|
|A3||0||Single, < 5 cm||Portal HTN and elevated bilirubin|
|A4||0||3 tumors < 3 cm||Child-Pugh class A-B|
|Stage B: intermediate HCC||0||Large multinodular||Child-Pugh class A-B|
|Stage C: advanced HCC||1-2||Vascular invasion or extrahepatic spread||Child-Pugh class A-B|
|Stage D: end-stage HCC||3-4||Any||Child C|
Early HCC stage
Stage A1: Single tumours and absence of relevant portal hypertension and normal bilirubin.
Stage A2: Single tumours associated with relevant portal hypertension and normal bilirubin.
Stage A3: Single tumours with both relevant portal hypertension and abnormal bilirubin.
Stage A4: Three tumours smaller than 3 cm regardless of liver function.
Intermediate HCC Stage
Stage B: asymptomatic patients with multinodular tumours without vascular invasion or extra hepatic spread.
Advanced HCC stage (at least one criteria)
Stage C: symptomatic patients (PS 1-2) and /or those with invasive tumoral pattern reflected by vascular invasion or extrahepatic spread.
End stage HCC (at least one criterion)
Stage D: patents with severe cancer related symptoms (PS 3-4) or with tumours arising in heavily decompensated cirrhosis (Okuda stage III or Child-Pugh).
5.1 Prognostic factors
Four main factors affect the prognosis of the patient with HCC (Colombo 2002):
1) tumour characteristics: stage, aggressiveness, growth rate
2) general health of the patient
3) liver function of the patient
4) specific therapy which, in turn, is based on each of the previously mentioned factors.Prognostic categories of patients with HCC are defined by multivariate analyses which constitute the background of the staging systems cited in the previous chapter.
6.1 Treatment strategy and general data
At present, the only potentially curative treatment for HCC is represented by surgical resection of the tumour, with partial hepatectomy or with total hepatectomy followed by orthotopic liver transplantation (OLT). Unfortunately, the overall operability rate is only 10% to 25% since most patients present at diagnosis with unresectable disease because of poor liver reserve (75% of cases), bilobar disease or extrahepatic disease. However, even in patients who undergo surgical resection there is a continuous risk of recurrence up to 83% at 5 years (Johnson 2002). Non surgical treatments with palliative intention is indicated for all those patients with unresectable disease at presentation or with a relapsing disease.
6.2 Treatment for resectable disease
Resectable HCC includes categories T1, T2 and some selected T3, N0, M0. For these categories of HCC, surgical resection is considered the first-line option. Partial hepatectomy ranges from single segment resection to trisegmental resection (80% hepatectomy). Partial hepatectomy is the treatment of choice, on a type C basis, for non-cirrhotic patients with localized disease, no evidence of vascular invasion or extrahepatic disease and for patients with the fibrolamellar variant of HCC (Befeler 2002). Surgical resection for cirrhotic patients should be limited to Child-Pugh class A patients as a standard option, on a type C basis. In recently published large series of patients the 5 year survival rate after surgical resection was around 50.5% (Ikai 2004; Song 2004; Liu 2004; Shimozawa 2004). However, the recurrence rate at 3 years is currently reported at 50%.
6.3 Treatment for unresectable disease
Ortothopic liver transplantation (OLT) is considered the standard treatment, on a type 1 level of evidence, for cirrhotic patients with small unresectable HCC, because the procedure can cure both the tumour and the underlying cirrhosis (Schwartz 2004). Current inclusion criteria for a transplantation program (United Network for Organ Sharing) comprise single HCC nodule smaller than 5 cm or 3 nodules smaller than 3 cm. OLT is contraindicated where extrahepatic spread or vascular invasion exist. With these criteria, the 5 year survival is 75% and the recurrence rate is 8% (Mazzaferro 1996). Unfortunately, the average waiting time for OLT is over 1 year and is usually responsible for HCC progression and increased death rate (Llovet 1999b). The use of interstitial radiofrequency and/or chemoembolization to attenuate tumour progression while waiting for a transplant is investigational on a type R basis (Colombo 2002).
More accurate analyses of prognostic factors in those patients who are candidates for liver transplantation are underway in order to identify those subjects who stand to gain the highest benefit from this procedure (Del Gaudio 2004; Wiesner 2004).
Other treatments for unresectable HCC include local ablative therapy (alcohol, cryotherapy, radiofrequency), chemoembolization, chemotherapy, and conformal radiotherapy. These will be described in the following chapter.
6.4 Treatment for unresectable and unoperable disease
Patients with inoperable disease are those with concomitant morbidities, poor performance status or bilateral tumours. For these patients the treatment of choice is local percutaneous ablative therapy. Tumour ablation may be achieved by chemical (e.g. ethanol) or physical (cryotherapy, radiofrequency) means. Percutaneous ethanol injection (PEI) is a well-tolerated treatment, with survival rates comparable to those of surgical resection but with a recurrence rate of 100% at 5 years (Livraghi 1995). There are no randomised trials comparing PEI with surgical treatment. Thus PEI can be considered a standard option on a type C basis for unoperable patients with cirrhotic liver. The best alternative to PEI is thermal radiofrequency ablation (RFA) (Head 2004). The major advantage is that it is a single-step treatment, but, on the other hand it presents a higher rate of side-effects (bleeding, fever, abdominal pain) and has an overall lower applicability because it is dependent on tumour location. Survival rates are similar to those of PEI. As for PEI, radiofrequency ablation may be considered as standard option for those patients with small unresectable tumors (Livraghi 1999). Both are also valid options for patients waiting for a liver transplant. Other local ablative techniques include injection of acetic acid or hot saline solution, laser therapy, microwave therapy and cryotherapy. No one of them has been proven to be superior to PEI or RFA (Bruix 1999). An alternative to percutaneous ablative therapy is trans-arterial chemoembolization (TACE) (Bruix 2004). The rationale of this treatment is based on the fact that HCC receives its blood supply from the hepatic artery while the normal liver parenchyma from the portal vein. Thus it is possible to administer chemotherapuetic agents to the tumor in a relatively selective way. TACE achieves objective responses without differences in survival rates when compared with conservative treatments (Simonetti 1997), but in recent trials it has been shown to achieve better results than symptomatic treatment (Llovet 2003; Llovet 2002). However, TACE is followed by the so-called post-embolization syndrome (fever, abdominal pain, vomiting) with a procedure-related mortality of 2%. The combination of TACE with PEI has been reported to be more effective than TACE alone. TACE can therefore be considered for patients with larger tumours or multifocal disease as suitable for individual clinical use on a type 1 level of evidence (Kuyvenhoven 2001).
6.5 Advanced and recurrent disease
Patients with advanced metastatic disease (any T, N1 or M1) or with recurrent disease are candidates for systemic treatment with palliative intent or for supportive care. Such treatment consists of systemic chemotherapy and hormonal therapy. HCC is generally considered to be chemotherapy resistant. Response rates for single agent chemotherapy are low and durable remission is rare. The most effective single agents against HCC are the anthracyclines that produce response rate of approximately 20% with a median survival of 4 months (Johnson 1978; Nerenstone 1988).
Combination chemotherapy produces higher response rates but the duration of remission remains short with no impact on survival and no significant differences compared with single agent chemotherapy (Simonetti 1997). Most combination chemotherapy includes doxorubicin and cisplatin. The PIAF regimen includes doxorubicin, cisplatin, 5-fluorouracil and alpha-interferon. In a phase II study this regimen achieved an objective response rate of 26% and rendered the disease operable in 9 of the 13 partial responders (Patt 1993). Systemic chemotherapy cannot be recommended as standard option outside a clinical trial and can be regarded as an individualized option for patients with advanced disease. Tamoxifen has not been confirmed as an active agent from a recent study based on a Cochrane review (Nowak 2005). Chemotherapy or hormonal therapy can be considered suitable for individual clinical use for patients with advanced disease, on a type 2 level of evidence and again controlled clinical trials should be considered in this setting. Best supportive care is a valid alternative.
7. LATE SEUQELAE
7.1 Surgery and other local techniques-related sequelae
In the non-cirrhotic liver up to two thirds of functional parenchyma can be removed safely with a good recovery expected. In this subset, patients can however experience biliary stasis and parenchymal ischemia. In cirrhotic patients there is an increased risk of haemorrhage from established varices, coagulation defects and thrombocytopenia while portal hypertension may result in unbalanced ascites. Together these factors account for a perioperative mortality rate of approximately 10%.
The current mortality rate for orthotopic liver transplantation (OLT) is 5%.
Chemoembolization is commonly associated with the occlusion of the hepatic artery thus producing ischemia in the remaining functional parenchyma. Moreover this technique is contraindicated in the presence of decompensated liver cirrhosis.
7.2 Radio- and chemotherapy-related sequelae
Radiotherapy is rarely used in the management of hepatocellular carcinoma. The radiation dose that should be used for killing of neoplastic cells is 50 Gy, but this dosage can induce hepatitis and liver failure if the whole liver is irradiated.
Early sequelae of chemotherapy are those of any chemotherapy regimen. However, systemic chemotherapy containing the most active drugs such as cisplatin and doxorubicin is unlikely to be tolerated in cirrhotic patients due to portal hypertension, hypoalbuminemia, third-space fluid retension, and hyperbilirubinemia.
Late sequelae do not represent a clinical problem because patients with advanced disease who undergo systemic chemotherapy have a median survival of only 3-5 months.
8.1 Suggested follow-up
Follow up for patients who have undergone surgical resection consists of diagnostic imaging examinations every 3-4 months for 2 years, then annually and of alpha-FP serum level every 3 months for 2 years then annually. Patients with evidence of hepatitis B or C at diagnosis should be monitored for viral replication activity (HBV-DNA, HCV-RNA) and interferon therapy and antiviral treatments should be considered.
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Dr. Giordano Beretta (Associate Editor)
Ospedale Sant’Orsola-Fatebenefratelli – Brescia, Italy.
Prof. Henri Bismuth (Reviewer)
Hopital Paul Brousse – Villejuif, France
Dr. Filippo de Braud (Editor)
START Clinical Editor – European Institute of Oncology – Milan, Italy
Dr. Vittorio Ferrari (Author)
Spedali Civili – Brescia, Italy
Dr. Gemma Gatta (Consultant)
Istituto Nazionale Tumori – Milan, Italy
Dr. Salvatore Grisanti (Author)
Spedali Civili – Brescia, Italy