HEPATOCELLULAR CARCINOMA

Manal Abdel Hamid Associate Prof. Of medical oncology

Epidemiology
Hepatocellular carcinoma is the 5th most common malignancy

worldwide & the 3rd cause of cancer related death with male-tofemale 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.

Incidence of HCC

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

Incidence according to etiology

Abbreviations: WD, Wilsons disease; PBC, primary biliary cirrhosis, HH, hemochromatosis; HBV, hepatitis B virus infection; HCV, hepatitis C virus infection.

hereditary

Signs & symptoms

Nonspecific symptoms abdominal pain Fever, chills anorexia, weight loss jaundice

Physical findings abdominal mass in one third splenomegaly ascites abdominal tenderness

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
(a) which patients are at high risk for the development of HCC & should be offered surveillance

- 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

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

seeding

in 13%.

Biopsy of potentially operable lesions should be avoided where possible

Diagnosis
Cirrhosis + Mass > 2 cm

Raised AFP

Normal AFP

Confirmrd diagnosis

CT, MRI

Diagnosis
Cirrhosis + Mass < 2 cm

Raised AFP

Normal AFP

CT, MRI

Assess for surgery

lesion by exam

Confirmed diagnosis

FNAC or biopsy

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