122
Hepatocellular Carcinoma Dr. Amina Abdul Rahman Junior Resident Dept. of Radiotherapy

Hepatocellular carcinomas

Embed Size (px)

DESCRIPTION

epidemiology, etiology, staging, management of hepatocellular carcinoma including radioablation, TACE

Citation preview

Page 1: Hepatocellular carcinomas

Hepatocellular Carcinoma

Dr. Amina Abdul RahmanJunior Resident

Dept. of Radiotherapy

Page 2: Hepatocellular carcinomas

Hepatocellular Carcinoma

• Anatomy• Epidemiology• Screening• Diagnosis • Staging• Management

Page 3: Hepatocellular carcinomas

ANATOMY

Page 4: Hepatocellular carcinomas
Page 5: Hepatocellular carcinomas

EPIDEMIOLOGY

Page 6: Hepatocellular carcinomas

EPIDEMIOLOGY

• Sixth most common cancer• Third most common cause of cancer death• M:F = 2.4 : 1• Common in areas endemic to viral hepatitis

Page 7: Hepatocellular carcinomas

Etiology

• Cirrhosis Viral hepatitis B, CAlcohol Autoimmune chronic active hepatitisNAFLDPrimary Biliary CirrhosisHemochromatosisAlpha 1 Anti trypsin Def

Page 8: Hepatocellular carcinomas

Etiology

• Without CirrhosisHereditary TyrosinemiaGlycogen storage diseaseGalactosemia Alagille syndrome

Page 9: Hepatocellular carcinomas

Hepatitis B

• Less than 1 yr 80-90% become chronic• 1 – 6 yrs 30 -50 % become chronic• Adults ˂ 5 % become chronic• Annual risk of HCC in c/c Hep B is 0.5%

Page 10: Hepatocellular carcinomas

Hepatitis C

• Chronic hepatitis in 75-85% of pts with Hep C• 17 fold increase in risk of HCC• Annual risk of 3-5%

Page 11: Hepatocellular carcinomas

Risk Factors for HCC in Viral Hepatitis

• Male sex• ˃ 50 yrs• Family history• Cirrhosis• Obesity• Larger HBV DNA load• Co infection with HIV, HCV, HDV • DM and liver Fe stores for Hep C

Page 12: Hepatocellular carcinomas

Prevention of HCC in viral hepatitis

• Use vaccines• Early treatment with nucleoside analogues

Page 13: Hepatocellular carcinomas

Clinical featuresHepatitis B Hepatitis C

Larger Lesions Smaller lesions

Bilobar disease More liver dysfunction

Doesn’t meet Milan criteria Meets Milan’s criteria

Younger age Older age

Better response to Sorafenib

Better response to TACE

Better response to surgery

Page 14: Hepatocellular carcinomas

SCREENING

Page 15: Hepatocellular carcinomas

Screening

• AASLD Guidelines• Recommend enrolling patients at high risk for

HCC for screening programs• Based on a study conducted in China which

screened 18,800 people with Hep B with AFP and USG every 6 months

Page 16: Hepatocellular carcinomas

Candidates for screening

• Cirrhosis induced by viral hep B,C• Cirrhosis due to alcohol, GH, NASH, Stage IV

PBC, • Hep B without cirrhosis• Less risk: Wilson’s disease, Sclerosing

Cholangitis, Type IV Glycogen Storage Disease, chronic right heart failure, TR

Page 17: Hepatocellular carcinomas
Page 18: Hepatocellular carcinomas

PATHOLOGY

Page 19: Hepatocellular carcinomas

Pathology

• Epithelial tumors

• Mesenchymal tumors

Page 20: Hepatocellular carcinomas

Tumors of the liver

Epithelial tumors

Hepatocellular Carcinoma childhood fibrolamellar Combined Spindle cell Clear cell Giant cell Carcinosarcoma Sclerosing HCC

Cholangiocarcinoma Hepatoblastoma Biliary cystadenocarcinoma

Page 21: Hepatocellular carcinomas

Tumors of the liver

Mesenchymal Tumors

Angiomyosarcoma

Leiomyosarcoma

Embryonal Sarcoma

Lymphoma

Schwannoma

Page 22: Hepatocellular carcinomas

DIAGNOSIS

Page 23: Hepatocellular carcinomas

Diagnosis

• Imaging

• Serum Markers

• Biopsy

Page 24: Hepatocellular carcinomas

Imaging

• Ultrasound

• CT

• MRI

Page 25: Hepatocellular carcinomas

USG

• Useful screening tool

• Expansive HCC : discrete nodules with a hypoechoeic rim

• Infiltrative HCC: heterogeneous echogenicity, may be missed

Page 26: Hepatocellular carcinomas

Computed Tomography

• Multi Slice , Multi Phase contrast enhanced CT• Phases: unenhanced arterial venous delayed

• Intense arterial uptake with washout in venous and delayed phase

Page 27: Hepatocellular carcinomas

Two classical enhancements

• Liver supplied by the portal vein (75%) and the hepatic artery (25%)

• The HCC is supplied solely by the hepatic artery

• Arterial Phase: contrast in the hepatic artery“intense arterial uptake”• Venous Phase: contrast in the portal vein,

“wash out”

Page 28: Hepatocellular carcinomas

MRI

• Best for detecting intrahepatic lesions

• If one is inconclusive, the other may be used

Page 29: Hepatocellular carcinomas
Page 30: Hepatocellular carcinomas
Page 31: Hepatocellular carcinomas

AASLD Diagnosis Guidelines

• Is only for cirrhotic liver or those with liver disease

• Radiological diagnosis not sufficient for a liver nodule picked up on routine scanning in an otherwise healthy liver

Page 32: Hepatocellular carcinomas

Differential Diagnosis

• Early HCC ‘hypovascular’

• Metastatic liver lesions Peripheral, multiple, cause umblication of liver surface

• Dysplastic nodules

Page 33: Hepatocellular carcinomas

Serum Markers

• Serum AFP

• PIVKA II

Page 34: Hepatocellular carcinomas

Serum AFP

• Not specific : can be normal in some HCC

• Not sensitive: maybe elevated in colorectal metastases, IHCC

• Not recommended for screening

• Not used for diagnosis

Page 35: Hepatocellular carcinomas

Serum AFP

‘Plays an important role in the regulation of tumor growth and cell differentiation and can stimulate proliferation of human hepatoma cells, probably through AFP receptors’

Page 36: Hepatocellular carcinomas

Serum AFP

• Prognostic indicator

• Higher levels correlates with larger size higher grade more of vascular invasion early tumor recurrence

Page 37: Hepatocellular carcinomas

Serum AFP

Higher AFP Lower AFP

Younger Age Elderly

HBsAg positive Hep C positive

P53 mutation Beta catenin mutation

Page 38: Hepatocellular carcinomas

Serum AFP

• Normal level < 6.0 ng/ml

• Low levels 20- 400 ng/ml

• High levels > 400 ng/ml

Page 39: Hepatocellular carcinomas

PIVKA 2

• des-γ-carboxy Prothrombin protein Induced by Vitamin K abnormality

• Not useful for screening or diagnosis

• May have a prognostic role

Page 40: Hepatocellular carcinomas

Biopsy

• Fine needle aspiration : deep seated tumors, near blood vessels rapid staining

• Core biopsy: Tissue architecture IHC tests can be done

• Caution : bleeding, tumor seeding

Page 41: Hepatocellular carcinomas

Histological features

• Stromal invasion : invasion of fibrous septa and portal tract

• tumor vessels is quantified by the inflow vessels

1. Hepatic artery2. Portal vein3. Unpaired artery

Page 42: Hepatocellular carcinomas

Hepatocarcinogenesis

• High Grade Dysplastic NoduleNo stromal invasion

• Very Early HCC Ill-defined, hypovascularStromal invasion, No vascular invasion

• Small/progressed HCCWell-defined, hypervascularStromal and vascular invasion, unpaired artery

Page 43: Hepatocellular carcinomas

Stromal invasion : Invasion of fibrous septa

Page 44: Hepatocellular carcinomas

Vascular invasion

Page 45: Hepatocellular carcinomas
Page 46: Hepatocellular carcinomas

Immunohistochemistry

• Markers for HCC Glypican 3, HSP 70, glutamine synthetase

• Vascular epith CD 34 +ve

• Biliary epith stains CK 7, CK 19 negative

Page 47: Hepatocellular carcinomas

Work Up

• Viral MarkersHep B : HBsAg +ve HBeAg, HBeAb, HBV DNAHep C : HCV Ab, HCV RNA• LFT• Look for comorbidities• Chest imaging : MC site of mets• Bone Scan : if bone pain

Page 48: Hepatocellular carcinomas

Tumor Burden

• CE CT/ MRISite size, number of lesionsNodal diseaseVascular invasionPortal hypertensionExtent of CLDEstimate future liver remnant (FLR)

Page 49: Hepatocellular carcinomas

Child-Pugh Score

Page 50: Hepatocellular carcinomas

Portal Hypertension

• Esophageal varices• Splenomegaly• Abdominal collaterals• Thrombocytopenia• CT/MRI • Measure the Hepatic Venous Pressure

Gradient

Page 51: Hepatocellular carcinomas

STAGING

Page 52: Hepatocellular carcinomas

Staging

• AJCC

• Okuda

• CLIP

• BCLC

Page 53: Hepatocellular carcinomas

AJCC STAGING

Page 54: Hepatocellular carcinomas

TNM Staging

• Can only be used after surgical resection

• Does not take PS and liver function into account

• Does not have adequate prognostic accuracy

Page 55: Hepatocellular carcinomas
Page 56: Hepatocellular carcinomas

Okuda Staging

• Used for identifying advanced disease

• Not useful for stratifying early or intermediate disease

Page 57: Hepatocellular carcinomas

CLIP Staging

Page 58: Hepatocellular carcinomas
Page 59: Hepatocellular carcinomas

BCLC Staging

• Child-Pugh score• Performance status• Size and number of lesion• Portal hypertension• Comorbidities

Page 60: Hepatocellular carcinomas

BCLC Staging

• Stage 0 & A : 5 yr survival 50-75%• Stage B : 3 yr survival 50%• Stage C : 1 yr survival 50%• Stage D : Mean survival < 3 months

Page 61: Hepatocellular carcinomas

MANAGEMENT

Page 62: Hepatocellular carcinomas

Management of HCC

• Few RCTs

• The use of “disease free survival” is discouraged

• Use “survival”

Page 63: Hepatocellular carcinomas

Management

• CurativeSurgical ResectionLiver TransplantRadiofrequency Ablation• PalliativeTACE/TAESorafenib

Page 64: Hepatocellular carcinomas

Surgical Resection

Page 65: Hepatocellular carcinomas

Surgical Resection

˃70% survival at 5 yrs after resectionSelection criteria• Normal bilirubin• Normal hepatic venous pressure• Single lesion, size ≤ 5 cm• 3 or less tumors of size ≤3 cm• No evidence of gross vascular invasion

Page 66: Hepatocellular carcinomas

Surgical Resection

• Margin of 1 cm recommended• Non anatomic wedge resection for surface

tumors• Anatomic resection (couinaud segments) for

deeper tumors

Page 67: Hepatocellular carcinomas

Prevent post op Liver Failure

• Indocyanine clearance testRetention rate ˂10% all resections can be done10-20% 2 segments may be removed20-29% single segment may be removed ˃30 % resection cannot be done

Page 68: Hepatocellular carcinomas

Prevent post op Liver Failure

• Assess putative Functional Liver Remnant (FLR)

• Functional liver remnant Total Liver Volume• This ratio should be 20% without cirrhosis and

30-40% with cirrhosis

Page 69: Hepatocellular carcinomas

Preop Portal V. Embolization

• Pre op PV embolization of the lobe hosting the tumor

1. Atrophy of the affected lobe2. Induces hypertrophy of the non affected lobeCaution!!• Malignant cells may respond to the

proliferative stimulus• Increase in portal pressure

Page 70: Hepatocellular carcinomas

Recurrence after resection

• ˃ 70% risk of recurrence at 5 yrs

Factors :1. Microvascular invasion2. Additional tumor sites

Page 71: Hepatocellular carcinomas

Treatment of recurrence

• Solitary recurrence my benefit from repeat resection

• Liver transplantation may be attempted

• No role for pre-op chemoembolization to increase resectability

• No role for adjuvant treatment after resection to prevent recurrence

Page 72: Hepatocellular carcinomas

Liver Transplant

Page 73: Hepatocellular carcinomas

Liver Transplant

• For lesions meeting the UNOS criteria1. Size ˂ 5 cm, ≤ 3 nodules with size ˂ 3 cm2. No gross vascular invasion3. No extra hepatic disease• With moderate to severe cirrhosis, Child-Pugh

score B or C• No cancer symptoms, no comorbid disease

Page 74: Hepatocellular carcinomas

Advantage of Transplant

• Removing both the detectable and the undetectable disease

• Treating cirrhosis• Avoiding problems due to inadequate FLR• 4 yr OS of 85% in patients who have

undergone transplant, strictly acc to Milan criteria

Page 75: Hepatocellular carcinomas

Expanded Milan criteria(UCSF)

• For providing marginally larger HCC a chance for transplant

• Tumors 6.5 cm or smaller• Max of 3 tumors, none ˃ 4.5 cm or cumulative

size ˂ 8 cm

Page 76: Hepatocellular carcinomas

MELD Score

• The Model for End-Stage Liver Disease (MELD)• from 6 (less ill) to 40 (gravely ill)• It gives each person a ‘score’ (number) based

on how urgently he or she needs a liver transplant within the next three months

Now used by UNOS for prioritizing allocation of liver transplant

Page 77: Hepatocellular carcinomas

MELD Score

Score depends on1. Serum bilirubin2. Serum Creatinine3. INR4. Etiology

Page 78: Hepatocellular carcinomas

MELD

MELD Score = 3.78 xln[S. Bilirubin]+11.2x ln[INR]+ 9.57x ln[S. Creatinine]+ 6.43 x aetiology

Page 79: Hepatocellular carcinomas

MELD Exception

Additional score for patients with cancer Solitary HCC ˂ 2 cm score is 0 HCC 2 to 5 cm, or 3 nodules each ˂ 3 cm score is 22

Page 80: Hepatocellular carcinomas

Post Transplant Management

• No adj treatment to prevent recurrence

• Treat the Hep B infection to prevent re infection of graft, not effective in Hep C

Page 81: Hepatocellular carcinomas

Bridge Therapy

• To decrease tumor progression while on waiting list

• Options include1. RFA2. TACE3. TARE4. Sorafenib

Page 82: Hepatocellular carcinomas

Downstaging Therapy

• Reduce tumor burden in patients with advanced HCC without mets

• Options include1. PEI2. TACE3. TARE

Page 83: Hepatocellular carcinomas

Locoregional Ablation

Page 84: Hepatocellular carcinomas

Percutaneous Ablation

• Chemical :Ethanol Acetic AcidBoiling Saline• Temperature Modulation :Radiofrequency MicrowaveLaserCryotherapy

Page 85: Hepatocellular carcinomas

Mechanism of action of RFA

• Induce temp change by utilising high freq AC of 400-500Hz

• Generate ionic agitation , causing localised friction heat of tissue surrounding electrode

• Coagulative necrosis• Energy level rapidly dissipates with increasing

distance from the electrode

Page 86: Hepatocellular carcinomas

RFA

• 7 cm zone of necrosis adequate for a 5 cm tumor

Caution!!Tumors close to vascular structuresTumors close to biliary ductPeripheral tumorsSubcapsular tumorsTumors with poor differentiation

Page 87: Hepatocellular carcinomas
Page 88: Hepatocellular carcinomas

Side Effects

• Pleural effusion• Peritoneal bleeding• Tumor seeding• Bile duct damage

Page 89: Hepatocellular carcinomas

Response to Treatment

• Assessed by doing CE CT/MRI• Absence of contrast uptake within tumor

reflects tumor necrosis• S. AFP

Page 90: Hepatocellular carcinomas

Percutaneous Ethanol Injection

• Direct destruction of cancer cells• May destroy normal tissue also• Useful for tumors upto 3 cm• Requires multiple injections• Easier to perform, cheaper

Page 91: Hepatocellular carcinomas

RFA Vs. PEI

• RFA is similar in efficacy to PEI for tumors less than 2 cm

• RFA is superior to PEI for tumors more than 2 cm

• RFA has lesser risk of recurrence, but more expensive

• 5 yr survival rate 70% Vs. 68% for RFA and PEI

Page 92: Hepatocellular carcinomas

Arterially Directed Therapy

Page 93: Hepatocellular carcinomas

Principle of Arterially Directed Therapy

• Tumor is solely supplied by the hepatic artery as a result of neovascularisation

• Selectively blocking the artery feeding the tumor will result in tumor ischemia followed by necrosis with no damage to the surrounding normal liver

Page 94: Hepatocellular carcinomas

Arterially Directed Therapy

• TAE• TACE• DEB-TACE• TARE

Page 95: Hepatocellular carcinomas

Embolization Agents

• Gel sponge cubes• Polyvinyl alcohol particles• Polyacrylamide microspheres• Steel coils• Autologous blood clot

Page 96: Hepatocellular carcinomas

TACE

• When embolization is preceded by injection of concentrated dose of chemotherapeutic agent

• Chemo agent is usually Doxorubicin or Cisplatin

• Chemo agent is suspended in Lipiodol

Page 97: Hepatocellular carcinomas

TAE/TACE Procedure

• Femoral artery is punctured in the right groin pass a catheter the abd aorta to the ceoliac trunk to the hepatic artery

• Then a selective angiogram is done to identify the vessel feeding the tumor

• Chemotherapy injected followed by embolization agent

Page 98: Hepatocellular carcinomas
Page 99: Hepatocellular carcinomas
Page 100: Hepatocellular carcinomas

TACE VS TAE

• Both procedures have shown superiority over best supportive care

• But no reliable study to compare TACE with TAE

• At present, no evidence suggests that TACE is better than TAE

Page 101: Hepatocellular carcinomas

Contraindications to TACE

• Portal Vein Thrombosis• Advanced Liver Disease (Child-Pugh B to C)• Clinical symptoms of end stage cancer• Biliary obstruction (S. Bilirubin ˃ 3 mg/dl)

Page 102: Hepatocellular carcinomas

Complications of TAE/TACE

• Post embolization Syndrome• Non-target embolization• Liver Failure• Cholecystitis• Complications of chemo agent

Page 103: Hepatocellular carcinomas

DEB-TACE

• Chemo agent is eluted onto embolic beads for higher concentrated delivery of the chemo agent to the neoplastic cells

• Occlude feeding vessels while chemo agent is released gradually

Page 104: Hepatocellular carcinomas

TAE/TACE with VEGFR

• Embolization causes hypoxia which upregulates VEGFR which is associated with increased risk of recurrence

• TAE/TACE with Sorafenib

Page 105: Hepatocellular carcinomas

TARE

• Intra arterial administration of Yttrium 90 embolic microspheres

• β emitting isotope• Delivers internal radiation to the tumor

Page 106: Hepatocellular carcinomas

TARE Technique

• Work up session1. Angiographic map of the patient’s vascular

anatomy is obtained2. Technetium 99 labelled albumin is injected

and a SPECT CT taken to detect the extra hepatic deposition

Page 107: Hepatocellular carcinomas

TARE Technique

• Treatment Session1. Calculate dose to be delivered depending on

the liver mass2. A dose of 100 to 120 Gy is the target dose3. Hepatic artery will be catheterized and the

Yttrium 90 will be injected at the exact same position as where the Technetium labeled albumin was injected

Page 108: Hepatocellular carcinomas
Page 109: Hepatocellular carcinomas

SORAFENIB

Page 110: Hepatocellular carcinomas

Sorafenib

Mech of action:Blocks tyrosine kinase receptors in the tumor cells as well as the tumor vasculatureInhibits :Multi kinase inhibitorInhibits c-Raf, b-Raf, VEGFR, PDGFR-betaIndication in HCC:Locally advanced HCC and metastatic HCC but with preserved liver function

Page 111: Hepatocellular carcinomas

Sorafenib

• Dose : 400 mg PO twice daily one hour before or two hour after food

• Dosage need not be modified in mild to moderate renal and hepatic failure but to be avoided in severe renal/hepatic failure

Page 112: Hepatocellular carcinomas

Side Effects

• Hand-foot skin reaction• Diarrhoea • Haemorrhage (cerebral or GI)• Cardiac ischemia / hypertension• Fatigue• Weight loss

Page 113: Hepatocellular carcinomas

SHARP Trial

• 602 patients with advanced HCC (not eligible for TACE or failed with TACE) were randomized to Sorafenib and best supportive care

• Median survival was 10.7 months for Sorafenib Vs 7.9 months for placebo

• Stopped at interim analysis

Page 114: Hepatocellular carcinomas

Sorafenib

• Locally advanced or metastatic HCC• With preserved liver function (Child-Pugh

score of A • PS of 0-2

Page 115: Hepatocellular carcinomas

EXTERNAL BEAM RADIOTHERAPY

Page 116: Hepatocellular carcinomas

SBRT Stereotactic Body RT

• Advanced tech of EBRT to deliver large ablative doses of radiation

• Effective local therapy for patients unsuitable for locoregional therapy

• SBRT : shorter radiation schedule with very high conformal doses delivered at each fraction for focal HCC

• Image guided RT and enhanced management of breathing motion has allowed delivery of very high focal doses of RT

Page 117: Hepatocellular carcinomas
Page 118: Hepatocellular carcinomas

SBRT

• Most effective if size ˂ 6 cm with local control rates of 70-95% at 2 yrs

• Can sustain growth of HCC tumors of size ˃ 6 cm

• Toxicity increases with Child-Pugh score of B or C

• 15 to 45 Gy delivered over 1 to 5 fractions• 63 Gy in 15 fractions

Page 119: Hepatocellular carcinomas

Radiation induced Toxicity

• RILD : clinical syndrome of anicteric hepatomegaly, ascites, elevated liver enzymes 3mnths after RT

• Gastrointestinal ulceration, fistula or bleed• Chest pain, rib fracture• Biliary stenosis

Page 120: Hepatocellular carcinomas

Prevent RILD

• Keep the mean dose for uninvolved liver to less than 32 Gy in 2 Gy per fraction

• Or ensure that no greater than 30% of liver recieves 21 Gy in 3 fractions

Page 121: Hepatocellular carcinomas
Page 122: Hepatocellular carcinomas

The End