Annals of Oncology 20 (Supplement 4): iv41iv45, 2009

doi:10.1093/annonc/mdp124
clinical recommendations
Hepatocellular carcinoma: ESMO Clinical
Recommendations for diagnosis, treatment and
follow-up
S. Jelic
On behalf of the ESMO Guidelines Working Group*
Internal Medicine Service, Institute of Oncology and Radiology, Belgrade, Serbia
incidence
Hepatocellular carcinoma (HCC) is the fth most common
cancer in men and eighth most common cancer in women
worldwide. Its crude incidence in the European Union is 8.29/
100 000. Areas such as Asia and sub-Saharan Africa with
high rates of infectious hepatitis have incidences as high as
120 cases per 100 000. It is 48 times more common in
men and usually associated with chronic liver injury
(hepatitis B, hepatitis C and alcoholic cirrhosis). Chronic
infection with hepatitis B virus in the setting of cirrhosis
increases the risk of hepatocellular carcinoma 1000-fold. Some
530% of individuals with HCV infection develop chronic
liver disease, about 30% progress to cirrhosis, and in these,
12% per year develop hepatocellular carcinoma. Co-
infection with HBV further increases the risk. Alcohol
abuse in the setting of chronic HCV infection doubles the
risk of hepatocellular carcinoma compared with HCV
infection alone. Median age at diagnosis is between 50 and
60 years. In Africa and Asia, age at diagnosis is substantially
younger, occurring in the fourth and fth decades of life,
respectively.
surveillance
Patients with high risk for hepatocellular carcinoma can be
considered for, and offered to be entered into surveillance
programs. These include all cirrhotic hepatitis B carriers; non-
cirrhotic patients with high hepatitis B DNA concentration;
patients with hepatitis C related or alcoholic cirrhosis, as well as
patients with several more rare disorders. Surveillance should
be performed using ultrasonography at 612 months interval,
associated or not with AFP determination, in order to
detect early hepatocellular carcinoma amenable to surgical
treatment with curative intent (II, B). Despite correct
surveillance, there are, however, still no data conrming
that these advantages in detection of earlier lesions produce
an improvement in long-term survival, and cirrhotic
patients may have rather limited options for curative
treatment.
diagnosis
Tumors are multifocal in the liver in 75% of cases at diagnosis.
Diagnosis is usually made by history, physical examination,
imaging (ultrasound, MRI or CT scan showing a liver mass
consistent with HCC) and optionally elevated serum alpha-feto
protein (AFP higher than 400 ng/ml), because AFP is
elevated in only 5075% cases. A suspicious lesion on the
sonogram generally requires additional imaging studies to
conrm the stage of the tumor and sensitivity for detection of
small nodules may be low. The addition of arterial phase
imaging to conventional CT scanning increases the number of
tumor nodules detected, but in nodular cirrhotic livers the
sensitivity for detecting hepatocellular carcinoma is low. The
overall sensitivity of MRI is similar to that of triphasic CT scan,
but in patients with nodular cirrhotic livers MRI has
better sensitivity and specicity. Conrmation of diagnosis is
made by ne needle aspiration or biopsy. Elevation of
AFP over 400 ng/ml can be used instead of ne
needle cytology for diagnosis of HCC in patients with liver
cirrhosis and a focal hypervascular liver lesion (>2 cm) in at
least one imaging technique. Patients with potentially
resectable liver mass and AFP >400 ng/ml should undergo
surgery without pre-operative FNAC or biopsy. Any
deterioration in liver function in a patient with known liver
cirrhosis of any etiology should raise a suspicion for
hepatocellular carcinoma.
The size of lesions and the presence or not of cirrhosis may
inuence the sequence of tests used to diagnose hepatocellular
*Correspondence to: ESMO Guidelines Working Group, ESMO Head Ofce, Via L.
Taddei 4, CH-6962 Viganello-Lugano, Switzerland;
E-mail: clinicalrecommendations@esmo.org
Approved by the ESMO Guidelines Working Group: November 2007, last update
December 2008. This publication supercedes the previously published versionAnn
Oncol 2008; 19 (Suppl 2): ii27ii28.
Conict of interest: Dr Jelic has reported no conicts of interest
The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org

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carcinoma. Suspect nodules smaller than 1 cm should be
followed with ultrasound at intervals of 36 months; nodules
between 12 cm in a cirrhotic liver should be investigated with
at least two dynamic studies (triphasic CT scan, ultrasound, or
MRI with contrast). If two techniques show a typical
appearance of hepatocellular carcinoma, the nodule should be
Table 1. TNM staging criteria
TNM staging criteria for HCC
T1 Solitary tumor without vascular invasion
T2 Solitary tumor with vascular invasion or multiple tumors none more
than 5 cm
T3 Multiple tumors more than 5 cm or tumor involving a major branch
of the portal or hepatic vein(s)
T4 Tumor(s) with direct invasion of adjacent organs other than the gall
bladder or with perforation of visceral peritoneum
N0 Indicates no nodal involvement
N1 Indicates regional nodal involvement
M0 Indicates no distant metastasis
M1 Indicates metastasis present beyond the liver
Stage grouping
Stage I = T1 + N0 + M0
Stage II = T2 + N0 + M0
Stage IIIA = T3 + N0 + M0
Stage IIIB = T4 + N0 + M0
Stage IIIC = TX + N1 + M0
Stage IVB = TX + NX + M1
Staging systems such as CLIP or BCLC that include staging of liver cirrhosis
may improve prediction of the ultimate prognosis of HCC patients.
Specically, Barcelona clinic liver cancer (BCLC) staging system (that
includes also the Okuda staging) may prove more useful than the TNM for
planning future patient management since it takes into account tumor
stage, liver function and physical status.
Table 2. CLIP classication
Parameter Score
Child-Pugh
A 0
B 1
C 2
Tumor morphology
Uninodular and extension
<50% of tumor
0
Multinodular and
extension <50% of tumor
1
Massive or extension 50%
of tumor
2
Alpha fetoprotein
<400 ng/ml 0
>400 ng/ml 1
Macro vascular invasion
No 0
Yes 1
Risk assessment is based on Pughs modication of Childs grading of liver
function
CLIP scores range from 0 to 6 (CLIP 0 = 0 points, CLIP 1 = 1 point .
etc)
Table 3. Child-Pugh classication of severity of liver disease
Parameter Points assigned
1 2 3
Ascites Absent Slight Moderate
Bilirubin, mg/dl </= 2 23 >3
Albumin, g/dl >3.5 2.83.5 <2.8
Prothrombin time
* Seconds over control 13 46 >6
* INR <1.8 1.82.3 >2.3
Encephalopathy None Grade 12 Grade 34
A total score of 56 is considered grade A (well-compensated disease); 79
is grade B (signicant functional compromise); and 1015 is grade C
(decompensated disease).
Table 4. Denition of the Barcelona Clinic Liver Cancer (BCLC) staging
for hepatocellular carcinoma
BCLC stage PST Tumor
status
Liver
function status
Tumor stage Okuda
stage
Stage A:
early HCC
0
A1 0 Single, <5 cm I No portal
hypertension
and normal
bilirubin
A2 0 Single, <5 cm I Portal hypertension
and normal
bilirubin
A3 0 Single, <5 cm I Portal hypertension
and abnormal
bilirubin
A4 0 3 tumors
<3 cm
III Child-Pugh AB
Stage B:
intermediate
HCC
0 Large
multinodular
III Child-Pugh AB
Stage C:
advanced
HCC
12* Vascular
invasion or
extrahepatic
spread*
III Child-Pugh AB
Stage D:
end stage
HCC
34 Any III Child-Pugh C
Stages A and B: all criteria should be fullled.
Stage C: at least one criterion; *PST 12 or vascular invasion/extrahepatic
spread.
Stage D: at least one criterion; PST 34 or Okuda stage III/Child-
Pugh C.
clinical recommendations
Annals of Oncology
iv42 | Jelic Volume 20 | Supplement 4 | May 2009

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interpreted as such; if it is not the case, the lesion should be
either biopsied whenever possible or extirpated at the discretion
of the physician. Nodules larger than 2 cm with a typical feature
of hepatocellular carcinoma on a dynamic imaging technique,
as well as any nodule associated with an AFP level higher than
400 ng/ml or a rising AFP on sequential determinations need
not be biopsied but should be considered as proven
hepatocellular carcinoma.
staging and risk assessment
Staging should include X-ray of chest (alternatively CT scan),
and CT scan (alternatively MRI) of the abdomen. Imaging
studies for eventual other tumor localizations should be
performed as needed according to the clinical context. Tumors
should be staged according to AJCC staging criteria/TNM
system, although it appears to be of less predictory value than
the CLIP (Cancer of the Liver Italian Program) and the BCLC
staging. The brolamellar variant is not associated with
cirrhosis of any etiology and, if resectable, has a more favorable
prognosis.
For patients being considered for liver transplantation, the
MELD score is also useful.
Child-Pugh grade C patients should be offered only
supportive care. Child-Pugh grade A and favorable grade B
should be evaluated for specic treatment options. For the
brolamellar variant, local treatment modalities should only be
considered as there is no documented chemotherapy regimen
or biological agent that has shown any activity.
treatment plan
This should be based on extent of disease, growth pattern of
tumor, hepatic functional reserve and patients performance
status.
localized resectable tumors (T1, T2, T3 and
selected T4; N0; M0)
Optimal treatment should be surgical resection (partial
hepatectomy) with no adjuvant therapy, for patients without
liver cirrhosis [II, A]. However resection is possible in only 5%
of all diagnosed patients with hepatocellular carcinoma, and
with the absence of strict criteria concerning tumor size, the
cutoff tends to be xed at 5 cm.
For patients with liver cirrhosis, surgical resection or liver
transplantation may be considered depending on hepatic
functional reserve, and whether donor-related supply is
adequate to demand. Only about 5% of hepatocellular
carcinoma patients are suitable for transplantation; these
patients may have a 5-year survival greater than 75%. Liver
transplantation should be performed according to standard
Milan criteria and at the moment no denite recommendations
can be made regarding extension of the original criteria, a topic
that is being currently assessed.
localized unresectable tumors (selected T2, T3 and
T4; N0; M0)
Total hepatectomy with liver transplantation should be
considered [II, A]. Local ablation as further cited can be used as
a separate treatment modality by itself, or as a bridge to
transplantation.
Local ablation options include:

Trans-arterial chemoembolization (TACE) for patients with

adequate hepatic functional reserve andmultifocal HCCthat does
not present vascular invasion or extrahepatic spread. TACE
principle is intra-arterial injection of cytotoxic drug
combinations like Doxorubicin and/or Cisplatin and/or
Mitomycin into the hepatic artery, followed by Lipiodol
injection, gelfoam for vessel occlusion and degradable
microspheres (II, A).

Percutaneous ethanol injection (PEI) for patients with less

than 34 tumor nodules, maximum 5 cm in size (III, B).

Radiofrequency ablation also for tumors less than 5 cm in size

and/or less than 4 in number, its efcacy being clearly
superior to PEI in larger tumors (II, B).
Other options include.

Sorafenib that in a phase II study induced response in 8% and

disease control in 41% of patients. In a further phase III study
with patients with Child-Pugh grade A liver disease, it
extended survival for 2,8 months as compared to placebo (II,
A), and may be a rst line option for systemic treatment.

Inclusion in clinical trials.

Best supportive care.

Systemic chemotherapy should not be included in standards

of care but may be discussed with and offered to selected
candidates for systemic treatment if no other options are
locally available. Systemic chemotherapy containing
anthracyclines was reported to have a prospect of a 10%
response rate and no survival benet (if bilirubin normal and
hepatic reserve adequate). Cisplatin based combinations were
reported to improve response rate but again with no
survival benet as compared to supportive care alone (III, C).
In the PIAF regimen (cisplatin, interferonalpha, doxorubicin
and infusional 5FU) treatment-related toxicity was
signicant. Anthracycline/cisplatin based combination will
probably become obsolete with the wide availability of
Sorafenib.
Table 5. Denition of the Okuda staging system for hepatocellular
carcinoma
Points
0 1
Tumor size <50% of liver >50% of liver
Ascites No Yes
Albumin (g/dl) 3 <3
Bilirubin (mg/dl) <3 3
Okuda stage I, 0 points; Okuda stage II, 1 or 2 points; Okuda stage III, 3 or
4 points.
Annals of Oncology
clinical recommendations
Volume 20 | Supplement 4 | May 2009 doi:10.1093/annonc/mdp124 | iv43

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Thyrosine kinase inhibitors such as Sunitinib and Erlotinib (the
latter either alone or in combination with Bevacizumab) have
shown activity in hepatocellular carcinoma but at the moment
their use is limited to prospective clinical trials. Avoiding use of
investigational agents for hepatocellular carcinoma outside
clinical trials is strongly recommended.
advanced tumors (any T; N+; M1)
There is no established standard of care, and therapeutic
possibilities should be decided on an individual basis.
Sorafenib, inclusion in clinical trials, systemic chemotherapy
(this by default only), and best supportive care could be
considered. Best supportive care is the only option for patients
with Child B/C liver cirrhosis.
response assessment
Due to frequent multifocality of the tumor at presentation,
measuring the effect of systemic treatment in individual
patients may prove difcult. Clear-cut responses according to
RECIST criteria are rare. Published responses of chemotherapy
regimens should be interpreted with great caution. Endpoints
like progression-free survival and overall survival can only be
assessed in randomized trials. The assessment of response to
locoregional treatments is still a matter of debate. Tumor
control is an option that should be assessed both radiologically
and by estimating achieved clinical benet.
prevention
Recent studies suggest that antiviral treatment of chronic HCV
infections may reduce signicantly the risk of hepatocellular
carcinoma. It is anticipated that with implementation of
worldwide vaccination, the incidence of hepatitis B-related
hepatocelluar carcinoma will decrease.
follow-up
Patients undergoing curative resection should be followed up
36 monthly with AFP determination and liver imaging (for 2
years), since curative therapy can still be offered at relapse, to
a minority. The indications for antiviral/IFN therapy for
patients positive for hepatitis C and hepatitis B virus should
depend on degree of hepatitis and/or liver cirrhosis and viral
replicative status. For other patients, follow up aims to prevent
and/or treat hepatic decompensation.
Transplanted patients should be followed only in specialized
transplant centers. Post transplantation treatment includes
corticosteroids, cyclosporine and tacrolimus. Follow-ups
should be scheduled once monthly up to 6 months, then once
every 3 months up to 1 year, than twice a year up to 2 years and
once a year every year thereafter. Imaging studies should be
performed as needed. The follow-up is aimed at drug dosage
adjustment, early diagnosis of eventual immunosupression-
related infection, early detection of rejection or transplant
dysfunction, and later also at detection of immunosupression-
related neoplasia. Antiviral therapy should be continued if
previously started.
note
Levels of evidence [IV] and grades of recommendation [AD]
as used by the American Society of Clinical Oncology are given
in square brackets. Statements without grading were considered
justied standard clinical practice by the experts and the ESMO
faculty.
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clinical recommendations
Annals of Oncology
iv44 | Jelic Volume 20 | Supplement 4 | May 2009

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Annals of Oncology
clinical recommendations
Volume 20 | Supplement 4 | May 2009 doi:10.1093/annonc/mdp124 | iv45

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