Hepatocellular Carcinoma Detection and Treatment Scott Cotler, MD Associate Professor of Medicine Chief, Section of Hepatology University of Illinois at.

Hepatocellular Carcinoma Hepatocellular Carcinoma Detection and TreatmentDetection and Treatment

Scott Cotler, MDAssociate Professor of Medicine

Chief, Section of Hepatology University of Illinois at Chicago

Annual Report to the Nation on the Annual Report to the Nation on the Status of Cancer 1975-2002Status of Cancer 1975-2002

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J Natl Cancer Institute 2005;97:1407-27J Natl Cancer Institute 2005;97:1407-27

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Zhang B-H, et al. J Cancer Res Clin Oncol 2004;130:417-22Zhang B-H, et al. J Cancer Res Clin Oncol 2004;130:417-22

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Stage I or II OLT Surveillance associated Surveillance associated with stage at diagnosiswith stage at diagnosis

Stage is key determinant Stage is key determinant of access to of access to transplantationtransplantation

Long term survival Long term survival dependent on receiving dependent on receiving a liver transplanta liver transplant

Stravitz RT, et al. Am J Med 2008;121:119-126Stravitz RT, et al. Am J Med 2008;121:119-126

Surveillance RecommendationsSurveillance Recommendations

Hepatitis B carriers– Asian males > 40– Asian females > 50– Africans > 20– All cirrhotics with hepatitis B– Family history of HCC

Non-hepatitis B cirrhosis

Bruix J & Sherman M. Hepatology 2005;42:1208-36Bruix J & Sherman M. Hepatology 2005;42:1208-36

Surveillance RecommendationsSurveillance Recommendations

Ultrasonography

6-12 month interval

Nodule >1 cm warrants further evaluation

Bruix J & Sherman M. Hepatology 2005;42:1208-36Bruix J & Sherman M. Hepatology 2005;42:1208-36

Biomarkers for HCCBiomarkers for HCC

AFP: sensitivity 60-80%, specificity 70-90%

AFP-L3 isoform– AFP-L3 >10% total AFP associated with an

increased risk of HCC development

Golgi protein 73 (GP73)– More sensitive than AFP in detecting HCC in

preliminary studies

Des-gamma-carboxy-prothrombin (DCP)– Limited sensitivity in some studies for HCC < 3 cm

HCC-specific autoantibodies

Wright LM, et al. Cancer Detect Prevent 2007;31:35-44Wright LM, et al. Cancer Detect Prevent 2007;31:35-44

Further Evaluation of Liver NodulesFurther Evaluation of Liver Nodules

<1 cm – Low likelihood of HCC– US every 3-6 months, revert to routine

surveillance if no growth over 2 years

>1 cm and < 2 cm– Treat as HCC if characteristic features on 2

dynamic studies (CT & MRI)– Biopsy if radiologic features are atypical

• Difficult to identify lesions < 2 cm by US• False negative rate >10%• Small risk of bleeding (<5%), rare tumor

seeding

Bruix J & Sherman M. Hepatology 2005;42:1208-36Bruix J & Sherman M. Hepatology 2005;42:1208-36

Noninvasive Criteria forNoninvasive Criteria forDiagnosis of HCC in CirrhosisDiagnosis of HCC in Cirrhosis

Focal lesion >2 cm with arterial hypervascularity and venous washout on 1 dynamic imaging technique (CT or MRI)

Focal lesion >2 cm with arterial hypervascularity + AFP >200

Bruix J & Sherman M. Hepatology 2005;42:1208-36Bruix J & Sherman M. Hepatology 2005;42:1208-36

CT: Arterial PhaseCT: Arterial Phase

CT: Portal Venous PhaseCT: Portal Venous Phase

Metastatic WorkupMetastatic Workup

Physical examination

CT chest, abdomen, pelvis

Bone scan

Head CT (selected cases)

Additional Imaging Techniques Additional Imaging Techniques

Contrast-enhanced ultrasonography (CEUS)– Uses microbubbles to detect hypervascularity

and characteristic washout of malignant lesions– Increases sensitivity and specificity of

conventional ultrasound

FDG-PET– Relatively low sensitivity for diagnosis of HCC,

particularly with well-differentiated tumors– May be useful for identifying extrahepatic

metastases including involvement of the lung, bone, and lymph nodes

Rahbin N, et al. Acta Radiologica 2008;49:251-257; Yoon KT, et al. Oncology 2007;72:104-110Rahbin N, et al. Acta Radiologica 2008;49:251-257; Yoon KT, et al. Oncology 2007;72:104-110

Therapy: Surgical ResectionTherapy: Surgical Resection

Solitary HCC– Normal bilirubin– Absence of significant portal hypertension

• HVPG <10 • (esophageal varices, ascites, or

splenomegaly with plt <100,000)

Perioperative mortality 1-3%

5 year survival: up to 70%

Recurrence: 50% at 3 years, 70% at 5 years

Bruix J, Hepatology 2002;35:519-24Bruix J, Hepatology 2002;35:519-24

Ablative TherapyAblative Therapy

Radiofrequency ablation (RFA)– 90% CR for lesions <3 cm– Not optimal for larger lesions or tumors near the

hilum or large vessels– AE: hemorrhage, infection/abscess, gallbladder

injury, liver failure

Transarterial chemoembolization (TACE)– Direct drug delivery + ischemic necrosis– Improves 2-year survival for unresectable HCC– AE: abdominal pain, nausea, fever,

infection/abscess, gallbladder injury, liver failure

Therapy: ChemoembolizationTherapy: Chemoembolization

TACE + RFA for Large HCCTACE + RFA for Large HCC

RCT of 291 patients with HCC >3 cm

Rationale: reducing tissue perfusion by TACE → ↓ heat loss, ↑efficacy of TACE

Survival benefit for TACE+RFA

– Overall, single, multiple lesions

Cheng B-Q et al. JAMA 2008;299:1669-1677Cheng B-Q et al. JAMA 2008;299:1669-1677

Radiation TherapyRadiation Therapy

Yttrium (90Y) radioembolization– Microscopic embolization with glass beads

– T1/2 65.4 hours, path length 5.3 mm

– Delivered selectively, segmentally, or diffusely– Safe with branch/lobar portal vein thrombosis– AE: radiation pneumonitis, GI bleeding, liver

failure

Focused high dose RT– Made possible by advances in RT planning, image

guided therapy, respiratory tracking– Radiation sensitizing agents– Particle therapy (protons or carbon ions)

Liver TransplantationLiver Transplantation

Milan: single tumor <5 cm or up to 3 tumors (none >3 cm), without vascular invasion or extrahepatic spread

– 5-yr post-transplant survival >70%

USCF: Single tumor < 6.5 cm or < 3 tumors, largest < 4.5 cm with total diameter < 8 cm

– 2-yr survival 86% (95% CI 54-96%)

Sirolimus might impact on recurrence

Mazzafero V, N Engl J Med 1996;334:693-99, Yao FY, Liver Transpl 2002;8:765-74Mazzafero V, N Engl J Med 1996;334:693-99, Yao FY, Liver Transpl 2002;8:765-74

Systemic Chemotherapy: Systemic Chemotherapy: SorafenibSorafenib

RCT of 602 patients– >95% Child-Pugh A cirrhosis– >80% with advanced HCC (BCLC stage C,

including portal vein thrombosis or extrahepatic spread)

Median survival– Sorafenib-10.7 mos– Placebo-7.9 mos

Adverse effects– Fatigue, diarrhea, hand-foot skin reaction

? Role as an adjuvant agent

Llovet J, et al. J Clin Oncol 2007;25:LBA1Llovet J, et al. J Clin Oncol 2007;25:LBA1

SummarySummary

The incidence of HCC is increasing in the US

Diagnosis and management require a multidisciplinary approach

Surveillance consists of ultrasound every 6-12 months in at risk patients

Diagnosis often made by noninvasive criteria

Ablative therapy improves survival and can serve as a bridge to transplant

Transplantation can be curative in selected cases