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 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 BHepatitis B-increase risk 100 -200 fold

- 90% of HCC are positive for (HBs Ag)

• Hepatitis CHepatitis C• CirrhosisCirrhosis

- 70% of HCC arise on top of cirrhosis- 70% of HCC arise on top of cirrhosis• Toxins Toxins --Alcohol -Tobacco Alcohol -Tobacco -- AflatoxinsAflatoxins

• Autoimmune hepatitisAutoimmune hepatitis• States of insulin resistance- Overweight in males States of insulin resistance- Overweight in males

Diabetes mellitusDiabetes mellitus

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.

Signs & symptoms

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

Physical findingsPhysical 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

- 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 1–3%.

Biopsy of potentially operable lesions should be avoided where possible

seeding

DiagnosisCirrhosis +

Mass > 2 cm

Raised AFP

Normal AFP

Confirmrd diagnosis

CT, MRI

DiagnosisCirrhosis + Mass < 2 cm

Raised AFP

Normal AFP

Assess for surgery

CT, MRI

lesion by exam

FNAC 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 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

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 didn’t response but

survival– should only be offered in the context of clinical trials

6) Hormonal therapy- Nolvadex, stilbestrol and flutamide

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

Targeted therapy for HCC

Selection of agents for targeted therapy in HCC

Name TargetGefitinibErlotinibLapatanibCetuximabBevacizumabSorafenib (Nexavar) Sunitinib VatalanibCediranibRapamycinEverolimusBortezomib (Velcade)

EGFREGFREGFREGFRVEGFRaf1, B-Raf, VEGFR , PDGFRPDGFR, VEGFR, c-KIT, FLT-3VEGFR, PDGFR, c-KITVEGFRmTOR (mammalian target of rapamycin)

mTORProteasome

Targeting angiogenesis for HCC

HCC is one of the most vascular tumorHCC is one of the most vascular tumor

Major driver of angiogenesis is vascular endothelial growth Major driver of angiogenesis is vascular endothelial growth

factor (VEGF)factor (VEGF)

Sorafenib and bevacezumab target VEGF in HCCSorafenib and bevacezumab target VEGF in HCC

• Bevacizumzb: Median OS of approximately 12 monthsBevacizumzb: Median OS of approximately 12 months

• Bevacizumab + erlotinib: Medain OS 15-17 monthsBevacizumab + erlotinib: Medain OS 15-17 months

Investigational combination therapies in HCC

Combinations under investigationsCombinations under investigations– Bevacizumzb + erlotinib– Sorafenib +erlotinib

Combination therapy will likely be used to treat Combination therapy will likely be used to treat

HCC in the futureHCC in the future

HCC (Whats ahead?)

Combinations therapy

• Bevacizumzb or Sorafenib + Erlotinib• Sorafenib + mTOR inhibitor

Early sequential therapies