Hepatocellular Carcinoma Detection and Treatment

1. Hepatocellular Carcinoma Detection and Treatment Scott Cotler, MD Associate Professor of MedicineChief, Section of Hepatology University of Illinois at Chicago

2. Annual Report to the Nation on the Status of Cancer 1975-2002 Annual Percent Change Liver Cancer in Men J Natl Cancer Institute 2005;97:1407-27

3. Impact of Surveillance for HCC On Survival: China n=86 n=67 P<0.01 Zhang B-H, et al. J Cancer Res Clin Oncol 2004;130:417-22

4. Impact of Surveillance for HCCOn Survival: US • Surveillance associated with stage at diagnosis • Stage is key determinant of access to transplantation • Long term survival dependent on receiving a liver transplant Stravitz RT, et al. Am J Med 2008;121:119-126

5. Surveillance 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;42:1208-36

6. Surveillance Recommendations • Ultrasonography • 6-12 month interval • Nodule >1 cm warrants further evaluation Bruix J & Sherman M. Hepatology 2005;42:1208-36

7. Biomarkers 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;31:35-44

8. Further 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;42:1208-36

9. Noninvasive Criteria forDiagnosis 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;42:1208-36

10. CT: Arterial Phase

11. CT: Portal Venous Phase

12. Metastatic Workup • Physical examination • CT chest, abdomen, pelvis • Bone scan • Head CT (selected cases)

13. 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;72:104-110

14. Therapy: 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;35:519-24

15. Ablative 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

16. Therapy: Chemoembolization

17. TACE + 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;299:1669-1677

18. Radiation 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)

19. Liver 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;8:765-74

20. Systemic Chemotherapy: Sorafenib • 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:LBA1

21. Summary • 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