Hepatocellular carcinoma (HCC) is the 5th most common cancer worldwide and the 3rd leading cause of cancer death. Risk factors include hepatitis B, hepatitis C, and cirrhosis. Definitive diagnosis requires imaging showing a liver mass in the setting of cirrhosis plus elevated AFP or biopsy. The only potentially curative treatments are surgical resection or liver transplantation for small, early-stage tumors. For unresectable HCC, locoregional therapies include ablation or chemoembolization. The targeted drug sorafenib improves survival and is the standard first-line systemic therapy. Combination therapies and sequential targeted agents are under investigation.

1. HEPATOCELLULAR
CARCINOMA

2. Epidemiology
• Hepatocellular carcinoma is the 5th most common malignancy
worldwide & the 3rd cause of cancer related death with male-to-female
ratio
– 5:1 in Asia
– 2:1 in the United States
• Tumor incidence varies significantly, depending on geographical
location.
• HCC with age.
• 53 years in Asia
• 67 years in the United States.

3. Incidence of HCC

4. Etiology
• Hepatitis B
-increase risk 100 -200 fold
- 90% of HCC are positive for (HBs Ag)
• Hepatitis C
• Cirrhosis
- 70% of HCC arise on top of cirrhosis
• Toxins -Alcohol -Tobacco - Aflatoxins
• Autoimmune hepatitis
• States of insulin resistance- Overweight in males
Diabetes mellitus

5. Incidence according to etiology
Abbreviations: WD, Wilson′s disease; PBC, primary biliary cirrhosis, HH, hereditary
hemochromatosis; HBV, hepatitis B virus infection; HCV, hepatitis C virus infection.

6. Signs & symptoms
• Nonspecific symptoms
• abdominal pain
• Fever, chills
• anorexia, weight loss
• jaundice
• Physical findings
• abdominal mass in one third
• splenomegaly
• ascites
• abdominal tenderness

7. 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.

8. 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

9. 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

10. Diagnosis
3) Biopsy is rarely required for diagnosis
in 1–3%.
Biopsy of potentially operable lesions should be
avoided where possible
seeding

11. Diagnosis
Cirrhosis +
Mass > 2 cm
Raised
AFP
Normal
AFP
Confirmrd
diagnosis
CT, MRI

12. Diagnosis
Cirrhosis + Mass < 2 cm
Raised
AFP
Normal AFP
Assess for
surgery
CT, MRI
lesion by exam
FNAC or biopsy
Confirmed
diagnosis

13. 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.

14. 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.

15. Treatment (Surgery)
• Recurrence rates of 50–60% 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

16. 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

17. 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)

18. 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 didn’t 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)

19. Targeted therapy for HCC

20. 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

21. 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

22. Investigational combination
therapies in HCC
• Combinations under investigations
• Bevacizumzb + erlotinib
• Sorafenib +erlotinib
• Combination therapy will likely be used to treat HCC in the
future

23. HCC (Whats ahead?)
• Combinations therapy
• Bevacizumzb or Sorafenib + Erlotinib
• Sorafenib + mTOR inhibitor
• Early sequential therapies