Hepatocellular carcinoma
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Comprehensive overview of Hepatocellular carcinoma: etiology, staging, diagnosis and treatment

Comprehensive overview of Hepatocellular carcinoma: etiology, staging, diagnosis and treatment

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  • 1. Hepatocellular Carcinoma Ahmed ZeeneldinAssociate Professor of Medical Oncology/Hematology NCI, Egypt
  • 2. Risk factors — Hepatitis B and/or C , — External sources: — alcohol , aflatoxin, — Particular comorbidities or conditions: — inherited errors of metabolism: hereditary hemochromatosis, porphyria cutanea tarda, α1-antitrypsin deficiency, and Wilson’s disease, — autoimmune hepatitis and primary biliary cirrhosis. — non-alcoholic fatty liver disease and steatohepatitis [NASH]2 Ahmed Zeeneldin
  • 3. 3 Ahmed Zeeneldin
  • 4. 4 Ahmed Zeeneldin
  • 5. HCC and Cirrhosis — Risk factors for HCC are also risk factors for liver cirrhosis. — 60%-80% of HCC have cirrhosis — Cirrhosis is a prerequisite for HCC in inherited metabolic diseases and autoimmune D. — annual incidence rate of HCC in hepatitis C-related cirrhosis: 2-8%.5 Ahmed Zeeneldin
  • 6. 6 Ahmed Zeeneldin
  • 7. 7 Ahmed Zeeneldin
  • 8. Screening for HCC — Aim: Early asymptomatic curable — China: — Hepatitis B or history of chronic hepatitis — Screening: AFP and US q 6m — <60% completed the screening program (5-10 times). — biannual screening reduced HCC mortality by 37% — Zhang et al, J Cancer Res Clin Oncol. 2004;130:417-422. Screening Control N 9,373 9,443 Total HCC n 86 67 Subclinical HCC n 52 (60%) 0 Small HCC 39 (45%) 0 Resection 40 (47%) 5 OS at 1,3,5y 66, 53, 46% 31,7,0% (S) Death 32 54 (S)8 Ahmed Zeeneldin
  • 9. Screening methods — AFP and US — US > AFP but operator dependednt — Both are better HCC No-HCC test + True + False + PPV=TP/TP+FP AFP: 5% AFP: 3% US : 3% US : 7% Both: 7% Both: 3% - False – True – NPP= TN/TN+FN Sensitivity: TP/TP+FN Specificity: TN/TN+FP AFP: 70% US : 85% Both: 92%9 Ahmed Zeeneldin
  • 10. Indications for screening — Patients at risk for HCC: — Cirrhosis — Hepatitis B, C — Alcohol — Genetic hemochromatosis — Auto immune hepatitis — Non-alcoholic steatohepatitis — Primary biliary cirrhosis — Alpha1-antitrypsin deficiency — Without cirrhosis — Hepatitis B carriers — Non-alcoholic steatohepatitis10 Ahmed Zeeneldin
  • 11. Screening11 Ahmed Zeeneldin
  • 12. Clinical picture — Symptoms — Signs — Paraneoplastic syndromes — hypercholesterolemia, — erythrocytosis, — hypercalcemia, and — hypoglycemia.12 Ahmed Zeeneldin
  • 13. Blood supply of the liver — Normal: — 1-portal vein — 2 Hepatic artery — 3 hepatic vein — Malignant: — 1-Hepatic artery — 2-portal vein — 3- hepatic vein13 Ahmed Zeeneldin
  • 14. Imaging of hepatic tumors — Triphasic CT, MRI, US* — 1-arterial phase (malignancy) — 2-portal venous phase (normal) — 3-venous phase after a delay — How classic HCC look in triphasic imaging — Arterial phase: intense arterial uptake or enhancement (White) — Delayed veous phase: washout or hypointensity (Grey)14 Ahmed Zeeneldin
  • 15. CT normal liver A eraly arterial, Hepatic artery opacified B late arterial, portal vein opacified C potal venous phase: middle hepatic vein opacified15 Ahmed Zeeneldin
  • 16. HCC CT CT evaluation of the liver during the early arterial (2a), late arterial (2b), and portal venous (2c) phases of enhancement. The mass in segment III (white arrow) demonstrates the classic pattern of enhancement for HCC.16 Ahmed Zeeneldin
  • 17. HCC US (a) RT hepatic lobe hypoechoic FL (b) Dynamic contrast enhanced US with SonoVue. The early arterial phase : peripheral tumoural vessels (arrows) with enhancement filling from the periphery. (c) The arterial phase : homogeneous tumoural enhancement with a small hypoechoic area (arrow). (d) In the portal phase, the HCC (arrows) became relatively hypoechoic to the surrounding enhanced liver parenchyma.17 Ahmed Zeeneldin
  • 18. HCC MRI (A) shows the arterial phase of the MRI, indicating an arterially enhancing mass in the right lobe of the liver near the dome (arrow), with an enhancing rim around the mass.18 Ahmed Zeeneldin
  • 19. HCC MRI (B) shows the 3-minute delayed image of the hepatic mass. The mass appears hypointense compared with the rest of the liver (arrow), consistent with a marked decrease in arterial blood supply to the mass. This process is called “washout of contrast.”19 Ahmed Zeeneldin
  • 20. HFL in US — Size >2cm — One imaging modality (triphasic CT, MRI, US) — Classic = HCC — None classic: Bx — Size 1-2 cm — 2 imaging modalities: — Both classic = HCC — One classic: biopsy — None classic: Bx — Size <1cm — One imaging modality q3-4 m — Stable for 18 m: imaging q 6-12 — Enlarging as before20 Ahmed Zeeneldin
  • 21. Needle biopsy — Sampling error, particularly 1-2 cm. — Negative biopsy : follow up closely21 Ahmed Zeeneldin
  • 22. HCC staging — M1: Distant metastasis — N1: Regional lymph node metastasis — T1: Solitary tumor without vascular invasion — T2: Solitary tumor with vascular invasion OR multiple tumors none more than 5 cm — T3: Multiple tumors more than 5 cm OR tumor involving a major branch of the portal or hepatic vein(s) — T4: direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum — F0: Fibrosis score 0-4 (none to moderate fibrosis) — F1: Fibrosis score 5-6 (severe fibrosis or cirrhosis)22 Ahmed Zeeneldin
  • 23. Serum biomarkers — AFP: not a sensitive or specific. — Diagnosis of HCC should not be based solely on the AFP level, regardless of how high it may be. — AFP in conjunction with other tests. — Additional imaging studies (ie, CT/MRI) with a rising serum AFP level in the absence of a liver mass23 Ahmed Zeeneldin
  • 24. Serum biomarkers — AFP: not a sensitive or specific. — Diagnosis of HCC should not be based solely on the AFP level, regardless of how high it may be. — AFP in conjunction with other tests. — Rising serum AFP level in the absence of a liver mass suggests additional imaging studies (ie, CT/MRI) — If still no masses: more frequent AFP and Imaging q 3 m — Mass > 2 cm with classic imaging , AFP > 200 ng/ml: is diagnostic of HCC24 Ahmed Zeeneldin
  • 25. workup — HP — Hepatic function? — Portal ypertension? — Is there hepatitis B/C? — Comorbidities? — Is there metastasis? — lung, abdominal lymph nodes and the bone.25 Ahmed Zeeneldin
  • 26. Assessments — liver function tests: — Bilirubin — Aspartate transaminase (AST), — alanine transaminase (ALT), — Alkaline phosphatase, lactate dehydrogenase (LDH), — albumin, and protein. — kidney function tests: BUN and creatinine — Others: PT/PC or INR and CBCD26 Ahmed Zeeneldin
  • 27. Child-Pugh classification Measure 1 point 2 points 3 points units Bilirubin (total) <34 (<2) 34-50 (2-3) >50 (>3) μmol/l (mg/dl) Serum albumin >35 28-35 <28 g/l INR <1.7 1.71-2.20 > 2.20 no unit Ascites None Mild Severe no unit Grade I-II (or Hepatic Grade III-IV (or None suppressed with no unit encephalopathy refractory) medication) One year Two year Points Class survival survival 5-6 A 100% 85% 7-9 B 81% 57% 10-15 C 45% 35%27 Ahmed Zeeneldin
  • 28. Child-Pugh classification — Advantages — Simple — Includes clinical parameters (ascites, encephalopathy) — Disadvatages — Lacks data on portal hypertension (esophagogastric varices, splenomegaly, abdominal collaterals) — Clinical data are subjective — Interpretation — Class A: compensated cirrhosis — Class B and C: decompensated cirrhosis28 Ahmed Zeeneldin
  • 29. Model for End-Stage Liver Disease (MELD) — MELD = 3.78[Ln serum bilirubin (mg/dL)] + 11.2[Ln INR] + 9.57[Ln serum creatinine (mg/dL)] + 6.43 — Predict death within 3 months after (TIPS) surgery transjugular intrahepatic portosystemic shunt — 40 or more — 100% mortality — 30–39 — 83% mortality — 20–29 — 76% mortality — 10–19 — 27% mortality — <10 — 4% mortality — Advantage: — Includes renal function — No subjectivity — Prioritize liver transplant29 Ahmed Zeeneldin
  • 30. Pathology of HCC — Gross — Nodular (Cirrohsis): well circumscribed nodules. — Massive (noncirrhotic): large area with or without satellite nodules — Diffuse: small indistinct tumor nodules throughout the liver.30 Ahmed Zeeneldin
  • 31. 31 Ahmed Zeeneldin
  • 32. Histology Cirrhotic nodules in upper left and Hepatocellular carcinoma lower right areas, separated by a fibrous band,32 Ahmed Zeeneldin
  • 33. 33 Ahmed Zeeneldin
  • 34. Prognostic Factors in HCC: — Tumor: stage, aggressiveness and growth rate: — AJCC TNM staging — Patient: general health — ECOG PS — Karnofsky PS — Liver: functions — Child-Pugh, MELD — Treatments34 Ahmed Zeeneldin
  • 35. Other systems — Okuda system: — based on tumor size, ascites, jaundice and serum albumin — The French classification (GRETCH) system — Karnofsky performance , measurements of liver function and serum AFP — Cancer of the Liver Italian Program (CLIP) — Child-Pugh stage, tumor morphology, alpha-fetoprotein (AFP), and portal vein thrombosis. — Barcelona Clinic Liver Cancer (BCLC),35 Ahmed Zeeneldin
  • 36. Management of HCC =MULTIDICIPLINARY36 Ahmed Zeeneldin
  • 37. HCC management — Patient, liver, tumor — Multidiscplinary — hepatologists, — pathologists — cross-sectional radiologists, — Interventional radiologists, — transplant surgeons, — surgical oncologists, — medical oncologists,37 Ahmed Zeeneldin
  • 38. Modalities — Surgery — Local Regional Therapy — Bland embolization and chemoembolization — Conformal or stereotactic radiation therapy — Systemic therapy — Best supportive care38 Ahmed Zeeneldin
  • 39. Surgery — Partial Hepatectomy — Early-stage HCC who are eligible to undergo the procedure. — solitary tumors without major vascular invasion. — 3 or fewer tumors of 3 cm or less (debateable) — Child-Pugh A, No portal HT, adequate reserve — Low operative morbidity and mortality (5% or less). — 5 year OS: ~ 50% — 5 year recurrences: ~70% — Hepatic reserve (HR) — Future liver remnant (FLR) — HR=FLR/total liver volume-Tu — =>20 % if no cirrhosis — =>30-40 % if cirrhosis39 Ahmed Zeeneldin
  • 40. Surgery — Liver Transplantation — Potentially curative for early HCC. — 4 y OS: 85% and 4-y RFS: 92% — Removes detectable and undetectable lesions, — treats underlying cirrhosis — Avoids complications of small FLR. — United Network for Organ Sharing (UNOS)/Milan criteria — Patient has a tumor 5 cm in diameter or 2-3 tumors 3 cm each — No macrovascular involvement — No extrahepatic disease — Child-Pugh B and C — These patients may be resected if transplantation not feasible Mazzaferro et al , N Engl J Med 1996;334(11):693-700.40 Ahmed Zeeneldin
  • 41. Surgery — Bridge therapy — Locoregional treatment of HCC as a bridge to liver transplantation in eligible patients waiting for the procedure. — radiofrequency ablation (RFA), — Chemoembolization — radioembolization41 Ahmed Zeeneldin
  • 42. Local Regional Therapy — Aim: selective tumor necrosis, — categories: ablation or embolization. — They are not comparable to that of liver resection or transplantation. — should not be used in place of resection or transplantation for eligible patients42 Ahmed Zeeneldin
  • 43. Local Regional Therapy — Ablation: inducing direct necrosis — Chemical : ethanol (PEI), acetic acid — Physical: radiofrequency ablation [RFA], microwave ablation, cryoablation — laparoscopic, percutaneous or open approaches. — Indications: local disease only completely amenable to ablative therapy according to the size and location of the tumor(s). — Major complications 5%, mortality 0% — Tumor necrosis is assessed by CT/MRI at intervals an no contrast uptake43 Ahmed Zeeneldin
  • 44. RFA: Needle and effect44 Ahmed Zeeneldin
  • 45. PEI vs RFA HCC <= 4cm RCT Complete tumor necrosis was defined as persistent hypoattenuation of the tumor on helical CT 4 months after the most recent ablation therapy Lim et al, Gastroenterology. 2004 Dec;127(6):1714-23. Conventional PEI Higher dose PEI RFA 52 (64 tumors) 53 (56 T) 52 (61T) Complete necrosis (NS) 88% 92% 96% Sessions More More Fewer (S) 1,2,3 OS (S) 85%, 61%, 50% 88%, 63%, 55% 90%, 82%, 74% 1,2,3 DFS (S) 61%, 42%, 17% 63%, 45%, 20% 78%, 59%, 37%45 Ahmed Zeeneldin
  • 46. PEI vs RFA Cirrhosis, child A/B, 1-3 Tumors, 1.5-3 cm RCT Brunello et al, Scand J Gastroenterol. 2008;43(6):727-35. Conventional PEI RFA 69 70 1-y CR (S) 36% 66% HR OS (NS) 1 0.8846 Ahmed Zeeneldin
  • 47. PEI Vs RFA Cirrhosis, child A/B, 1-3 Tumors, <= 3 cm RCT Shiina et al, Gastroenterology. 2005 Jul;129(1):122-30. Conventional PEI RFA 114 118 Sessions (S) 6.4 2.1 4-y OS (S) 57% 74% Recurrence/progression (S) higher Lower47 Ahmed Zeeneldin
  • 48. Resection Vs RFA Cirrhosis, child A/B, solitary Tumors, <= 5 cm RCT Chen et al, Ann Surg. 2006;243:321-328. Surgery resection RFA 90 71 (19 withdrew consent) complications () More and severer 1,2,3,4-y OS (NS) 93.3%, 82.3%, 73.4%, 95.8%, 82.1%, 71.4%, 64.0% 67.9% 1,2,3,4-y DFS(NS) 85.9%, 69.3%, 64.1%, 86.6%, 76.8%, 69%, 46.4% 51.6%48 Ahmed Zeeneldin
  • 49. Ablation limitations — Dome — Capsule — Near major blood vessel or bile duct or abdominal organ49 Ahmed Zeeneldin
  • 50. Embolization — Aim: selective catheter-based infusion of particles targeted to the arterial branch of the hepatic artery feeding the tumor leading to ischemia. T:HA, NL: PV — Types: — bland embolization, — chemoembolization — radioembolization) — Caution: — arterial anatomy outlined — embolization is limited to a segment, subsegment, or lobe — Indications: — All HCC tumors are embolizable if the arterial supply is isolated. — Used in unresectable/inoperable tumors not amenable to ablation (>5cm), alone or followed by ablation50 Ahmed Zeeneldin
  • 51. A celiac angiogram showing the blood vessels of the liver with multiple HCC tumors before (left) and after (right) treatment showing loss of vascularity and response to therapy.51 Ahmed Zeeneldin
  • 52. Bland embolization (TAE) chemoembolization (TACE) — Particles to block arterial flow. : — Gelatin sponge, — polyvinyl alcohol, and — polyacrylamide microspheres — Chemotherapeutic agents: — Doxorubicin and/or Cisplatin — Containdications to TACE: — Child C — Portal v thrombosis — Bilirubin > 3 mg/ml: liver abscess — Biliary enteric bypass: liver abscess52 Ahmed Zeeneldin
  • 53. Bland embolization (TAE) chemoembolization (TACE) — Complications: — acute portal vein thrombosis, — cholecystitis, and — bone marrow suppression, — post-embolization syndrome — fever, — abdominal pain, — and intestinal ileus — Mortality: <5 %53 Ahmed Zeeneldin
  • 54. TAE Vs TACE Vs BSC Unresectable HCC, Child A and B, Okuda I and II RCT HR of death for TACE vs BSC =0.47 (S) Terminated early TAE Vs TACE ?? Llovet et al, Lancet. 2002;359:1734-1739. BSC TAE TACE 35 37 40 1,2-y OS (S) 63% and 27% 75% and 50% 82% and 63%*S RR 34% PortalV inasion Less54 Ahmed Zeeneldin
  • 55. TACE Vs BSC Unresectable HCC, RCT TACE q 2-3 months HR of death for TACE vs BSC =0.49 (S) Lo et al, Hepatology. 2002;35:1164-1171. BSC TACE (Cisplatin) 40 40 1,2, 3-y OS (S) 32, 11, 3% 57, 31, 26% Death from liver failure more55 Ahmed Zeeneldin
  • 56. Radioembolization — Agents: — Microspheres embedded with yttrium-90 (beta radiation emitter) — tumor necrosis is more likely to be induced by radiation rather than ischemia. — PRR: 42% — Complications: — cholecystitis and — abscess formation.56 Ahmed Zeeneldin
  • 57. Combinations of local therapies TAE then RFA — Aim: focused heat delivery of RFA may be enhanced by vessel occlusion by TAE — Use 3-5 cm tumors who are not eligible for liver resection or transplantation57 Ahmed Zeeneldin
  • 58. TAE-> RFA Vs resection Retrospective 1-3 lesions, size ,<= 3 cm, or single tumor ,<= 5cm Child A, no vascular invasion, no mets, Yamakado et al, Radiology. 2008;247:260-266 TAE/RFA Resection 104 62 1,2, 5-y OS (NS) 98%, 94%, 75% 97%, 93%, 81% 1,2, 5-y DFS (NS) 92%, 64%, 27% 89%, 69%, 26%58 Ahmed Zeeneldin
  • 59. TAE-> RFA/PEI Vs resection Retrospective , single author experience single tumor ,<= 7cm Yamakado et al, Radiology. 2008;247:260-266 TAE/RFA/PEI Resection 33 40 1,2, 5-y OS (NS) 97%, 77%, 56% 81%, 70%, 58%59 Ahmed Zeeneldin
  • 60. Radiotherapy!! — Conformal or stereotactic — Focused, thus limiting the risk of radiation-induced liver damage — unresectable/inoperable due to performance status or comorbidity e.g. if PEI, RFA, TACE, TAE is not feasible60 Ahmed Zeeneldin
  • 61. Systemic therapy61 Ahmed Zeeneldin
  • 62. Doxorubicin: NO! Combination: NO! — Low RR — No OS advantage — Yeo et al, J Natl Cancer Inst. 2005;97:1532-1538. — Unresectable HCC doxo Cisp-INF-Doxo-FU PIAF MOS (NS) 6.8 m 8.7m RR 10% 20% Toxicity higher62 Ahmed Zeeneldin
  • 63. Tamoxifen!!! — ???63 Ahmed Zeeneldin
  • 64. Sorafinib (NEXAVAR)64 Ahmed Zeeneldin
  • 65. Sorafinib mechanism of action oral multikinase inhibitor which suppresses tumor cell proliferation and angiogenesis,65 Ahmed Zeeneldin
  • 66. SHARP trial — Llovet et al, N Engl J Med. 2008;359:378-390. — Patient inclusion criteria included — Histologically proven HCC — Advanced HCC — (ECOG PS) 0-2 — ≥1 measurable untreated lesions — Child-Pugh class A (mild hepatic impairment) — No prior systemic treatment66 Ahmed Zeeneldin
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  • 73. COST — One box(m)$ 5000 = 5000 x 5.5 = 27,500 LE — Duration of therapy — Until no longer clinically benefiting from therapy or until unacceptable toxicity occurs — For OS of 10.7 m: — 10.7 x 27, 500= 294, 250 — For PFS of 5.5 m — 5.5 x 27, 500= 151, 25073 Ahmed Zeeneldin
  • 74. Sharp trial summary Sorafinib BSC MOS (S) 10.7 m 7.9 m TTP (S) 5.5 m 2.8 m Toxicity Hand-foot diarrhea Cost 150-294, 000 LE Child A >90% * PS 0-1 >90%*74 Ahmed Zeeneldin
  • 75. Asia-Pacific Sorafinib trial Sorafinib BSC 150 76 MOS (S) 6.2 m 4.1 m MTTP (S) 2.8m 1.4 m Child A >97% * PS 0-1 >90%* Cheng et al., J Clin Oncol 26: 2008 (May 20 suppl; abstr 4509)75 Ahmed Zeeneldin
  • 76. Take home message — Risk factors for HCC — Screen high-risk subjects by US and AFP — Classic appearance in CT, MRI, tri-US: arterial uptake and venous washout — Liver function assessment and reserve — Patient, liver, tumor — Surgery: resection and transplant — Local regional therapy: ablation, emobolization — Systemic therapy = sorafinib76 Ahmed Zeeneldin