HEPATOCELLULAR CARCINOMA

Manal Abdel HamidAssociate Prof. Of medical oncology

EpidemiologyHepatocellular carcinoma is the 5th most common malignancy worldwide & the 3rd cause of cancer related death with male-to-female ratio5:1 in Asia2:1 in the United States Tumor incidence varies significantly, depending on geographical location.

HCC with age. 53 years in Asia67 years in the United States.

Incidence of HCC

EtiologyHepatitis B-increase risk 100 -200 fold- 90% of HCC are positive for (HBs Ag)Hepatitis CCirrhosis- 70% of HCC arise on top of cirrhosisToxins -Alcohol -Tobacco - AflatoxinsAutoimmune hepatitisStates of insulin resistance- Overweight in males Diabetes mellitus

Incidence according to etiologyAbbreviations: WD, Wilsons disease; PBC, primary biliary cirrhosis, HH, hereditary hemochromatosis; HBV, hepatitis B virus infection; HCV, hepatitis C virus infection.

Signs & symptomsNonspecific 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 definitediagnosis (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

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 possibleseeding

DiagnosisCirrhosis +Mass > 2 cmRaised AFPNormal AFPConfirmrd diagnosisCT, MRI

DiagnosisCirrhosis + Mass < 2 cmRaised AFPNormal AFPAssess for surgeryCT, MRI lesion by examFNAC or biopsyConfirmed 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.

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

Radiofrequency ablation (RFA)High frequency ultrasound to generate heatgood alternative ablative therapy No survival advantageUseful for tumor control in patients awaiting liver transplant

Treatment (non-Surgical)

3) Cryotherapyintraoperatively 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 arteryProduce tumour necrosis in 50% of patientsEffective therapy for pain or bleeding from HCCAffect survival in highly selected patients with good liver reserveComplications: (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 survivalshould only be offered in the context of clinical trials

6) Hormonal therapyNolvadex, stilbestrol and flutamide

7) Interferon-alfa8) retinoids and adaptive immunotherapy (adjuvant)

Targeted therapy for HCC

Selection of agents for targeted therapy in HCC

Targeting angiogenesis for HCCHCC is one of the most vascular tumorMajor driver of angiogenesis is vascular endothelial growth factor (VEGF)Sorafenib and bevacezumab target VEGF in HCC

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

Investigational combination therapies in HCCCombinations 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 + ErlotinibSorafenib + mTOR inhibitor

Early sequential therapies

5-year survival less than 10%Maximum increase in obesity