HEPATOCELLULAR CARCINOMA

Epidemiology
Hepatocellular carcinoma adalah kelainan malignan sel terbesar
ke 5 di dunia & dan ke 3 terbesar kanker yang dapat
menyebabkan kematian
5:1 di Asia

Variasi terjadinya tumor sangat berbeda tergantung dari lokasi
geografi

HCC terhadap umur
53 tahun di Asia
67 tahun di Amerika


Incidence of HCC
Etiology
Hepatitis B
- Meningkatkan resiko 100 sampai 200 kali
- 90% dari HBs Ag reactive akan mengalami HCC
Hepatitis C
Cirrhosis
- 70% HCC terjadi setelah sirosis
Toxins -Alcohol -rokok - Aflatoxins
Autoimmune hepatitis
Penderita diabetes yang insulin resistance- laki-laki
Overweight pada penderita Diabetes mellitus

Incidence according to etiology
Abbreviations: WD, Wilsons disease; PBC, primary biliary cirrhosis, HH, hereditary
hemochromatosis; HBV, hepatitis B virus infection; HCV, hepatitis C virus infection.
Signs & symptoms
Nonspecific symptoms
Nyeri perut
Demam, menggigil
malas makan, penurunan berat badan
ikterus

Physical findings
adanya massa di salah satu regio abdomen
splenomegaly
ascites
rasa kembung/penuh pada perut


Guidlines
(a) which patients are at high risk for the development
of HCC and should be offered surveillance
(b) what investigations are required to make a definite
diagnosis
(c) which treatment modality is most appropriate in a
given clinical context.



Guidlines

- M &F with established cirrhosis due to HBV and/ or HCV, particularly
those with ongoing viral replication

- M &F with established cirrhosis due to genetic haemochromatosis

- M with alcohol related cirrhosis who are abstinent from alcohol or likely to
comply with treatment

- M with primary biliary cirrhosis


Abdominal US and AFP/ 6 months
(a) which patients are at high risk for the development of HCC &
should be offered surveillance
Diagnosis
(b) what investigations are required to make a
definite diagnosis

1) AFP produced by 70% of HCC
> 400ng/ml
AFP over time


2) Imaging
- focal lesion in the liver of a patient with cirrhosis is highly likely to
be HCC

- Spiral CT of the liver

- MRI with contrast enhancement
Diagnosis

3) Biopsy is rarely required for diagnosis
in 13%.
Biopsy of potentially operable lesions should
be avoided where possible
seeding
Diagnosis
Cirrhosis +
Mass > 2 cm
Raised
AFP
Normal
AFP
Confirmrd
diagnosis
CT, MRI
Diagnosis
Cirrhosis + Mass < 2 cm
Raised
AFP
Normal AFP
Assess for
surgery
CT, MRI
lesion by exam
FNAC or biopsy
Confirmed
diagnosis
Treatment (Surgery)
The only proven potentially curative therapy for HCC

Hepatic resection or liver transplantation


Patients with single small HCC (5 cm) or up to three lesions 3
cm

Involvement of large vessels (portal vein, Inferior vena cava)
doesnt automatically mitigate against a resection; especially in
fibrolamellar histology

No randomised controlled trials comparing the outcome of
surgical resection and liver transplantation for HCC.

Treatment (Surgery)
Hepatic resection should be considered in HCC and a non-
cirrhotic liver (including fibrolamellar variant)

Resection can be carried out in highly selected patients with
cirrhosis and well preserved hepatic function (Child-Pugh A) who
are unsuitable for liver transplantation. It carries a high risk of
postoperative 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.

The majority of early mortality is due to liver failure.

Treatment (Surgery)
Recurrence rates of 5060% after 5 years after resection are
usual (intrahepatic)

Liver transplantation should be considered in any patient with
cirrhosis

Patients with replicating HBV/ HCV had a worse outlook due to
recurrence and were previously not considered candidates for
transplantation.

Effective antiviral therapy is now available and patients with small
HCC, should be assessed for transplantation


Treatment (non-Surgical)
should only be used where surgical therapy is not
possible.

1) Percutaneous ethanol injection (PEI)
has been shown to produce necrosis of small HCC.
It is best suited to peripheral lesions, less than 3 cm in
diameter

2) Radiofrequency ablation (RFA)
High frequency ultrasound to generate heat
good alternative ablative therapy
No survival advantage
Useful for tumor control in patients awaiting liver transplant

Treatment (non-Surgical)

3) Cryotherapy
intraoperatively to ablate small solitary tumors outside a
planned resection in patients with bilobar disease

4) Chemoembolisation
Concurrent administration of hepatic arterial chemotherapy
(doxirubicin) with embolization of hepatic artery
Produce tumour necrosis in 50% of patients
Effective therapy for pain or bleeding from HCC
Affect survival in highly selected patients with good liver
reserve
Complications: (pain, fever and hepatic decompensation)
Treatment (non-Surgical)
5) Systemic chemotherapy
very limited role in the treatment of HCC with poor esponse
rate
Best single agent is doxorubicin (RR: 10- 20%)
Combination chemotherapy didnt response but
survival
should only be offered in the context of clinical trials

6) Hormonal therapy
- Nolvadex, stilbestrol and flutamide

7) Interferon-alfa
8) retinoids and adaptive immunotherapy (adjuvant)


Targeted therapy for HCC
Selection of agents for targeted therapy
in HCC
Name Target
Gefitinib
Erlotinib
Lapatanib
Cetuximab
Bevacizumab
Sorafenib (Nexavar)
Sunitinib
Vatalanib
Cediranib
Rapamycin
Everolimus
Bortezomib (Velcade)
EGFR
EGFR
EGFR
EGFR
VEGF
Raf1, B-Raf, VEGFR , PDGFR
PDGFR, VEGFR, c-KIT, FLT-3
VEGFR, PDGFR, c-KIT
VEGFR
mTOR (mammalian target of rapamycin)
mTOR
Proteasome
Targeting angiogenesis for HCC
HCC is one of the most vascular tumor
Major driver of angiogenesis is vascular endothelial growth
factor (VEGF)
Sorafenib and bevacezumab target VEGF in HCC

Bevacizumzb: Median OS of approximately 12 months
Bevacizumab + erlotinib: Medain OS 15-17 months

Investigational combination therapies in
HCC
Combinations under investigations
Bevacizumzb + erlotinib
Sorafenib +erlotinib


Combination therapy will likely be used to treat
HCC in the future


HCC (Whats ahead?)

Combinations therapy

Bevacizumzb or Sorafenib + Erlotinib
Sorafenib + mTOR inhibitor



Early sequential therapies