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

Annual Report to the Nation on the Status of Cancer 1975-2002 Annual Percent Change NCI SEER registries Based on 10% of US population Rates calculated based on 2000 census data Incidence projected to increase another 80% by 2020 Liver Cancer in Men J Natl Cancer Institute 2005;97:1407-27

Impact of Surveillance for HCC On Survival: China n=86 n=67 P<0.01 Prospective study in an Urban Chinese population HBV or history of HBV Age 35-59 Screening—AFP and US on 6 months basis Screening group completed on 58% of screening offered Screening led to detection of HCC at an earlier stage 37% reduction in mortality Therapy consisted of surgery or ablative therapy, but not liver transplantation Zhang B-H, et al. J Cancer Res Clin Oncol 2004;130:417-22

Impact of Surveillance for HCC On 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 Retrospective analysis of 269 patients SOC: suriveillance within 1 year of diagnosis Substandard—no surveillance within 1 year of diagnosis, but recognized cirrhosis Absence of surveillance—not know to be cirrhotic A: proportion diagnosed within the Milan criteria B: LRT is locoregional therapy—TACE or RFA Of 60 patients who had OLT for HCC, only 8% recurrence rate at median f/u of 39 mos Stravitz RT, et al. Am J Med 2008;121:119-126

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 AASLD Practice Guideline Groups in which risk of HCC exceeds 0.2%/year Want to screen at risk patients who have potential treatment options Bruix J & Sherman M. Hepatology 2005;42:1208-36

Surveillance Recommendations Ultrasonography 6-12 month interval Nodule >1 cm warrants further evaluation AFP was deemed an inadequate screening test Sensitivity of US is 65-80% Advanced cirrhosis with small lesion 20-30% 4-12 mos for tumor to go from undetectable to 2 cm. If want to detect small tumors, screen q6 mos. CT if AFP > 20 Bruix J & Sherman M. Hepatology 2005;42:1208-36

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 AFP should not be used alone for screening DCP: data are mixed Golgi protein 73 (GP73) Preliminary studies used Western blotting Need a quantitative ELISA Combinations of tumor associated antibodies appear promising Wright LM, et al. Cancer Detect Prevent 2007;31:35-44

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 Typical—hypervascular with washout in portal-venous phase US, CT, and MRI miss 30-40% of lesions < 1 cm US minimum lesion size detected under ideal situation is 0.5 cm US sensitivity for 2-3 cm lesions is 82-93% Middle category: more likely to be HCC Limitations 30-40% false negative rate for FNA Risk of tumor seeding Further strategies need to be developed for this group Recent data suggesting MR angiography may have increased sensitivity for this group (84%) Contrast-enhanced sonography increases sensitivity and specificity Bruix J & Sherman M. Hepatology 2005;42:1208-36

Noninvasive Criteria for Diagnosis 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 Biopsy if atypical vascular pattern or non-cirrhotic liver Advantages of noninvasive criteria for lesions >2 cm Avoidance of 10-20% false negative rate with biopsy Avoid small risk of tumor seeding Limitations: misclassification of vascular dysplastic nodules and primary hepatic lymphomas Bruix J & Sherman M. Hepatology 2005;42:1208-36

CT: Arterial Phase CT arteriography Capsule, mosaic pattern Necrosis and fibrous elements Majority of blood flow to liver is from portal venous supply, so liver does not enhance substantially during the arterial phase In a patient with cirrhosis, arterial enhancement followed by portal venous washout has a sensitivity of 80% and specificity of 95% for HCC

CT: Portal Venous Phase CT arterial portography Portal perfusion defect Tumor washout with enhancement of liver parenchyma during portal venous phase

Metastatic Workup Physical examination CT chest, abdomen, pelvis Bone scan Head CT (selected cases) Brain mets rare

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 18 flourodeoxyglucose In one study, sensitivity of PET was 55% False positives did occur with PET assessment for extrahepatic disease Could consider in patients with lesion > 5 cm, who have greater risk for mets PET might be particularly good at identifying involved lymph nodes Rahbin N, et al. Acta Radiologica 2008;49:251-257; Yoon KT, et al. Oncology 2007;72:104-110

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 Tumor size is not a clear cut limiting factor Location is more important No benefit from chemoembolization prior to resection Recurrence includes dissemination and de novo tumors Most powerful predictors are microvascular invasion and satellite lesions Bruix J, Hepatology 2002;35:519-24

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 RFA Use energy to achieve coagulative necrosis of tumor tissue CR=complete ablation RFA is a thermoablative therapy Effective up to 3 cm, want to achieve a 1 cm rim Larger probes available but efficacy questionable TACE Tumor is dependent on arterial blood flow Drug eluting beads available, don’t use lipiodol with beads Often used as a bridge to transplant Post-emboliztion syndrome—occurs to some extent in nearly all patients For both RFA and TACE, liver failure is rare Most frequently use adriamycin and cisplatin

Therapy: Chemoembolization Chemoembo being delivered through a 3-Fr coaxial micro catheter positioned as close as possible to the feeding arterial branches. The ethiodal is very radiodense allowing the operator to identify any nontarget embolization and access how well the tumor is taking up the chemotherapeutic agents. Mix chemo agent with ethiodol, serves as a delivery vehicle and is radioopaque

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 Childs A, B < 3 lesions, < 7.5 cm RFA within 2 weeks of TACE Rx 0, 2, 4 mos, mean 3-4 rx 5 cm probe Cheng B-Q et al. JAMA 2008;299:1669-1677

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) Yttrium—treatment of advanced HCC Radiation therapy Whole liver has low tolerance for RT, particularly in cirrhotics RILD--VOD like pathology Image guided therapy—localize tumor at time of treatment

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 Milan Median f/u 26 mos (9-54) Including CT every 6 mos, AFP Most tumors recur within 2 years 45 (94%) patients with HCV or HBV Correct Pre-op staging (n=35) significantly better than incorrect staging (n=13) for patient and recurrence free survival Milan Criteria Adopted by UNOS Understaging in about 10% to 15% in general Rate of exclusion on waiting list is as high as 25% HCC—24 points, increase by 10% every three months on waiting list Decision analysis suggest that LDLT is cost-effect if waiting time exceeds 7 months A number of studies show that 5 year survival >70% UCSF: Retrospective study of 70 patients —Included 14 who met the UCSF criteria but exceeded the Milan criteria (overall, only 10% exceed Milan but meet UCSF) 2 year survival Evidence not entirely conclusive due to the wide confidence interval Based on this study would make OLT available to 10% of patients who would have been excluded by Milan criteria In other studies, size correlates with microvascular invasion and histologic grade Study from Colorado showed improved tumor free survival. Other studies inconsistent Mazzafero V, N Engl J Med 1996;334:693-99, Yao FY, Liver Transpl 2002;8:765-74

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 Oral multikinase inhibitor also used to treat renal cell carcinoma Blocks tumor cell proliferation Targets RAF kinase Antiangiogenic Hand-foot: rash/desquamation First systemic chemotherapeutic agent to show a survival benefit in patients with advanced HCC. Benefit is modest Llovet J, et al. J Clin Oncol 2007;25:LBA1

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 Median survival: 7-8 mos US data, 1974-1996 <1% had surgical resection of OLT <8% local therapy