1. HEPATOCELLULAR CARCINOMA Manal Abdel Hamid Associate Prof. Of medical oncology

2. Epidemiology Hepatocellular carcinoma is the 5 th most common malignancy worldwide & the 3 rd 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 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 Toxins - Alcohol -Tobacco - AflatoxinsToxins - Alcohol -Tobacco - Aflatoxins Autoimmune hepatitisAutoimmune hepatitis States of insulin resistance- Overweight in males Diabetes mellitus 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 Nonspecific symptoms – abdominal pain – Fever, chills – anorexia, weight loss – jaundice Physical findings 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 NameTarget Gefitinib Erlotinib Lapatanib Cetuximab Bevacizumab Sorafenib ( Nexavar) Sunitinib Vatalanib Cediranib Rapamycin Everolimus Bortezomib (Velcade) 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 HCC is one of the most vascular tumor Major driver of angiogenesis is vascular endothelial growth factor (VEGF) Major driver of angiogenesis is vascular endothelial growth factor (VEGF) Sorafenib and bevacezumab target VEGF in HCC Sorafenib 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

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