Management of HCC, an update

Management of Hepatocellular
Carcinoma
“An Update”
Mohammed A. Suwaid, SHO, Internal Medicine
Ahmed Heshmat Gado, MD, Internal Medicine

INTRODUCTION
Hepatocellular carcinoma (HCC) is the most common
primary cancer of the liver, accounting for more than 90%
of primary liver cancers. Worldwide, HCC is the fifth most
common cancer and the third most common cause of
cancer related deaths.

INTRODUCTION
In the past decade HCC has gone from being an almost universal
death sentence to a cancer that can be prevented, detected at an
early stage, and effectively treated.
Physicians caring for patients at risk need to provide a high-quality
screening, proper management of screen-detected lesions, and
provision of therapy that is most appropriate for the stage of
disease.

INTRODUCTION
Care of the patient with HCC involves multidisciplinary teams
(Tumor Boards), including hepatologists, pathologists, medical
oncologists, surgeons, liver transplant specialists, interventional
radiologists, and to some extent radiation oncologists.
In this setting, the hepatologist plays a central role in directing the
treatment plan because he is responsible for assessing the degree
of liver function impairment and suitability of various therapies. He
must ensure that only treatments of proven value are
administered. This specific expertise is important since HCC usually
appears on a background of liver disease.
► Jordi Bruix, and Morris Sherman; Management of Hepatocellular Carcinoma: An Update; AASLD Practice Guidelines 2011.

RISK FACTORS
Patients at risk of developing HCC can be divided into two
categories:
1- With cirrhosis: hapatitis B & C, alcohol, genetic
hemochromatosis, autoimmune hepatitis, non-alcoholic
steatohepatitis, primary biliary cirrhosis, and α1-antitrypsin
deficiency.
2- Without cirrhosis: hepatitis B carriers, family history of
HCC, Asian males ≥ 40 y, Asian females ≥ 50 y, and Africans ≥ 20 y.
► NCCN Clinical Practice Guidelines in Oncology; Hepatobiliary Cancers, Version 1, 2010.

SURVEILLANCE OF HCC IN HIGH RISK GROUPS
The guiding principle of surveillance should be that the best
available screening test should be chosen, and it should be applied
regularly. Combined use of α-fetoprotein (AFP) and
ultrasonography (U/S) increases detection rates, but also increases
costs and false-positive rates.
● AFP-only surveillance had a 69% detection rate & 5% false
positive rate.
● U/S alone had an 84% detection rate & 2.9% false positive rate.
● The combination has a 92% detection rate & 7.5% false positive
rate.
In the Unites States, U/S alone costs about $2000 per tumor
found, whereas the combination costs about $3000 per tumor
found.► Jordi Bruix, and Morris Sherman; Management of Hepatocellular Carcinoma: An Update; AASLD Practice Guidelines 2011.

So, the AASLD (American Association for the Study of Liver
Diseases) guidelines 2010 recommends that:
1. Surveillance for HCC should be performed using U/S.
2. Patients should be screened at 6 month intervals.
3. The surveillance interval does not need to be shortened for
patients at a higher risk of HCC.
While the NCCN (National Comprehensive Cancer Network)
Practice Guidelines 2010 recommends the addition of AFP to
increase the likelihood of detecting HCC in the screening setting as
U/S is highly operator dependent.

In Egypt (75 million), 20% (15 million) of people are HCV
positive, 50% of them (7.5 million) will develop cirrhosis, and of
those cirrhotic patients, 14% (1.05 million) will develop HCC late in
the course of the disease.
Surveillance increases the chance of early detection of HCC and
doubles the chances for curative options, including locoregional
ablation therapy and liver transplantation. Furthermore, to
improve the chances of curative options. So, implementation of
HCC surveillance program should be recommended in Egypt.
► A. R. El-Zayadi, H. M. Badran, S. Shawky, S. Emara, and M. Sobhi. Effect of surveillance for hepatocellular carcinoma on tumor staging
and treatment decisions in Egyptian patients; Asian Pacific Association for the Study of the Liver 2010.

DIAGNOSIS OF HCC
It depends on:
● Classic radiological appearance.
● Biopsy which is interpreted by an expert pathologist.
● Diagnostic AFP level (in the not-at-risk patients).

CLASSIC RADIOLOGICAL APPEARANCE
HCC can be diagnosed radiologically, without the need for biopsy if
the typical imaging features are present. This requires a contrast-
enhanced study (MDCT-scan or Dynamic MRI). In the arterial
phase, HCC enhances more intensely than the surrounding liver. In
the venous phase, the HCC enhances less than the surrounding
liver. This is known as ‘‘washout’’. In the delayed phase, the
presence of ‘‘washout’’ persists, and sometimes ‘‘washout’’ is only
present in the delayed phase. The presence of arterial uptake
followed by washout is highly specific for HCC.
Contrast enhanced U/S has been dropped off from the diagnostic
work up as it does not differentiate intrahepatic
cholangiocarcinoma (ICC) from HCC.

CLASSIC RADIOLOGICAL APPEARANCE
Since radiological diagnosis is so crucial, it is essential that imaging
be properly carried out in expert centers. There are established
protocols for the diagnosis of HCC that vary by the type of
equipment used, define the amount of contrast to be given, the
method of administering the agent, the timing of the studies after
administration of contrast, and the thickness of the slices to be
gathered. The physician ordering the tests should know whether
the studies have been conducted under these defined conditions.

BIOPSY
A biopsy is recommended in some cases when the diagnosis of
HCC is uncertain, e.g. when classic arterial enhancement is not
observed by any imaging method. Nevertheless, use of needle
biopsy is limited by a number of factors including risk of
hemorrhage, tumor rupture or seeding in the needle track and
sampling error, particularly when the lesions are between 1-2 cm.
Biopsies of small lesions should be evaluated by expert
pathologists to differentiate them from high grade dysplastic
nodules.
► Vincent T. Devita, Samuel Hellman, and Steven A. Rosenberg; Cancer: Principles and Practice of Oncology 6th edition (July 2001).

BIOPSY
Tissue that is not clearly HCC should be stained with all the
available markers including CD34, CK7, glypican 3, HSP-70, and
glutamine synthetase to improve diagnostic accuracy.
If the biopsy is negative for HCC, the lesion should be followed by
imaging at 3-6 monthly intervals until the nodule either
disappears, enlarges, or displays diagnostic characteristics of HCC.
If the lesion enlarges but remains atypical for HCC a repeat biopsy
is recommended.

α-Fetoprotein (AFP) Normal value: 0-20 ηg/mL
AFP has long been used for the diagnosis of HCC. It has also been a
part of surveillance algorithms. However, recent studies revealed
that AFP alone is insufficiently sensitive or specific for use as a
surveillance assay. They also suggest that its use as a diagnostic
test is less specific than was once thought because:
● AFP can be elevated in ICC and in some metastases from colon
cancer.
● In fibrolamellar carcinoma (a variant of HCC), AFP is not elevated
in 95% of cases.
● It is rare for the AFP to be elevated in lesions that are
smaller than 2 cm in diameter.
►Trevisani F, D’Intino PE, Morselli-Labate AM, Mazzella G, Accogli E, Caraceni P, Domenicali M, et al. Serum alpha-fetoprotein for diagnosis
of hepatocellular carcinoma in patients with chronic liver disease: influence of HBsAg and anti-HCV status. J Hepatol 2001;34:570-75.
► Vincent T. Devita, Samuel Hellman, and Steven A. Rosenberg; Cancer: Principles and Practice of Oncology 6th edition (July 2001).

α-Fetoprotein (AFP) Normal value: 0-20 ηg/mL
Therefore, the finding of a mass in the liver with a normal AFP does
not exclude HCC; furthermore, when elevated, it does not
automatically indicate HCC unless it exceeds a specific number (the
cutoff value). The cutoff value of AFP is variable among institutions
but it almost lies between 200-500 ηg/mL.
Now use of AFP is restricted to:
● Surveillance of HCC in conjunction with U/S.
● Follow up of treated patients in whom the AFP was greatly
elevated (above the cutoff value) prior to treatment.
● Help diagnosis of HCC in the not-at-risk patients.

Algorithm for investigating liver nodule found incidentally or during screening of
patients at high risk for HCC
< 1 cm
HEPATIC NODULE
> 1 cm
Repeat US at
3-month interval
MDCT or Dynamic
Contrast Enhanced MRI
StableGrowing or
Changing
Investigate
according to size
Classic radiological
appearance
Yes No
HCC
Other contrast enhanced
study (MDCT or MRI)
Classic radiological
appearance
Yes No
BiopsyPositive Negative
Followupevery3-6months

STAGING AND TREATMENT ALLOCATION
The prognosis of solid tumors is generally related to tumor stage at
presentation. Tumor stage also guides treatment decisions.
However, in HCC patients the prediction of prognosis is more
complex because the underlying liver function also affects
prognosis.
The BCLC (Barcelona Clinic for Liver Cancer) staging system has
been widely and efficiently used in several major trials to define
the patient population to be recruited and to stratify them into
separate prognostic categories.

THE BCLC STAGING SYSTEM
It includes variables related to:
● Physical status
● Liver functional status
● Tumor stage
● Cancer related symptoms
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.
Currently, the BCLC system is the only staging system that offers
such a correlation.

PHYSICAL STATUS
This can be estimated by applying ECOG* Score, as follows:
0 → Fully active, able to carry on all predisease activities with
restriction.
1 → Restricted in physically strenuous activity but ambulatory
and able to carry out work of a light or sedentary nature.
2 → Ambulatory and capable of all self-care but unable to carry
out any work activities. Out of bed >50% of waking hours.
3 → Capable of a limited self-care, >50% of daytime
confined to bed or chair.
4 → Completely disabled, no self-care, totally confined to bed.
* Eastern Cooperative Oncology Group.

LIVER FUNCTION STATUS
This can be estimated by applying the Child’s-Pugh Score, as
follows:
A = 5 – 6 B = 7 – 9 C = 10 - 15
321Parameter
3-41-2NoneEncephalopathy grade
ModerateSlightNoneAscites
<2.82.8-3.5>3.5Albumin (g/dL)
>6
>2.3
4-6
1.8-2.3
1-4
<1.7
PT, prolonged (sec)
or INR
>3
>10
2-3
4-10
1-2
1-4
Bilirubin (mg/dL)
for primary biliary cirrhosis
► Kumar & Clark’s Clinical Medicine, Seventh Edition, 2009

PORTAL PRESSURE & BILIRUBIN LEVEL
For years the selection of candidates for resection has been based
on the Child’s-Pugh classification but this is known to have
inconsistent predictive value. Child’s-Pugh A patients may already
have significant liver functional impairment with increased
bilirubin, significant portal hypertension or even minor fluid
retention requiring diuretic therapy. These features indicate a
more advanced liver disease and preclude resection. So, bilirubin
level and portal pressure estimation are of a special value in
determining the treatment plan.

Stage 0: PS 0, Child-Pugh A, single lesion < 2cm.
(Very early stage → resection)
● In case of normal bilirubin level & absence of clinically significant
PH, more than 70% of patients will achieve 5 year survival after
resection.
● In clinically significant PH, patients will be more liable to
postoperative decompensation (mostly ascites, especially if the
right lobe is to be resected) with a 5 year survival of less than 50%.
● If both PH & hyperbilirubinemia are present &/or multifocal
disease, less than 30% will achieve 5 year survival regardless of
their Child’s-Pugh stage.

Stage A: PS 0, Child-Pugh A-B, single lesion < 5cm or 3 lesions ≤
3cm each.
(Early stage → liver transplantation or RFA)
● If there is a solitary HCC < 5cm or 3 nodules < 3cm each, liver
transplantation will achieve 5 year survival in more than 70% of
patients.
● Patients who are not eligible for transplantation will achieve 5
year survival after RFA or PEI in more than 50% of cases.

Stage B: PS 0, Child-Pugh A-B, large/multifocal lesions, no cancer
related symptoms, no macrovascular invasion or extrahepatic
spread.
(intermediate stage → TACE)
● By TACE-alone treatment, the 2 year survival rate was 63%, while
in combination with RFA the 1-, 3-, & 5 year survival rates were
97%, 77% & 56% respectively.

Stage C: PS 1-2, Child-Pugh A-B, presence of cancer related
symptoms and/or vascular invasion or extrahepatic spread (LN
and/or distant metastases).
(Advanced stage → Sorafenib)
● It increases median survival to 10.7 months & improves time to
progression (TTP) to 5.5 months.
Stage D: PS > 2, Child-Pugh C.
(Terminal stage→ Symptomatic treatment)
● Their median survival is < 3 months.

The BCLC staging system and treatment allocation of HCC, from AASLD practice
guidelines, Hepatology, Vol. 53, No. 3, 2011
Stage 0 Stage A Stage B Stage C Stage D
HEPATOCELLULAR CARCINOMA
Portal pressure/
bilirubin
Associated
diseases
Resection Liver Transp. RFA
Curative Treatment
TACE Sorafenib
Palliative Treatment
Symptomatic
Treatment
RFA: Radiofrequency ablation
TACE: Transarterial chemoembolization

Management of HCC, an update

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