Paul Martin MD FACG. University of Miami

Paul Martin MD FACG University of Miami 1

Liver cirrhosis of any cause Chronic C o c hepatitis epat t s B Risk increases with Male gender Age Diabetes Smoking ~5% increase in HCV-related HCC between 1991-28 Others: 21% Others: 38% Others: 46% HBV: 4% NAFLD: 11% HBV:1% HBV: 4% NAFLD:7% Alcohol alone: 25% Alcohol alone: 45% Alcohol alone: 19% Alcohol and HCV: 17% Alcohol and HCV: 7% HCV alone: 18% 1976-199 1991-2 HCV alone: 28% 21-28 Yang JD, et al. Mayo Clin Proc. 212;87:9-16. 2

.8 Cirrhosis Cumulative rate.6.4 Fibrosis.2. 1 2 3 4 5 Years after randomization Lok AS Gastroenterology. 29 3

1. Surviv al 8.8.6 Std-of-Care.4 Substandard.2 Unknown Cx. 1 2 3 4 5 Year s P <.5 Stravitz Am J Med. 28 Ultrasound every 6 months in patients at risk Sensitivity 94% overall, decreases with smaller tumors AFP not recommended as adds only 6% to sensitivity butt adds 7.5% iti it b dd up tto 7 5% ffalse l positives iti 6 month interval optimal ( compared to 12 or 3 months) Bolondi 213 4

Ultrasound is the usual modality for HCC surveillance cheap safe, safe Advantages: cheap, supported by data Drawbacks: operator dependent, limited sensitivity, difficult in obese patients Masses detected by ultrasound typically require further characterization with other modalities (CT, MRI) Sonogram shows a small hypoechoic mass Wilson SR, et al. Radiology. 21;257:24-39. 5

Arterial Phase Portal Venous Phase 6

Mass on surveillance < 1 cm 1-2 1 2 cm > 2 cm Repeat US every 3-4 mos 1 dynamic imaging study 1 dynamic imaging technique Atypical vascular pattern with both techniques Typical vascular pattern Stable > 18-24 mos Typical vascular pattern on dynamic imaging Biopsy Enlarging Return to surveillance every 6-12 mos Atypical vascular pattern Diagnostic of HCC Nondiagnostic of HCC Other diagnosis Repeat biopsy or imaging follow-up Proceed according to lesion size Change in size/profile + Repeat imaging and/or biopsy - Treat as HCC Adapted from Bruix J, et al. Hepatology. 211;53:12-122. Yes Positive biopsy provides Diagnostic certainty if imaging is inconsistent with HCC Prognostic information Avoids inappropriate treatment and misleading cure cure May permit personalized therapy based on tumor gene expression No Not always feasible Not needed if high diagnostic certainty based on imaging Risk Hemorrhage Tumor seeding False negatives (up to 1/3 of biopsies) may delay treatment Heuman DM, et al. Eur J Intern Med. 212;23:37-39. 7

Prognosis for patient often dictated more by cirrhosis than by cancer Choice of therapy often depends more on cirrhosis and performance status than on cancer itself Metastatic disease rarely a cause of mortality Transplantation for cure an option in selected cases Assessment of Severity of Cirrhosis CTP S Score Ascites Encephalopathy Bilirubin Protime INR Protime Albumin MELD Score Creatinine Bilirubin Protime INR www unos org www.unos.org MELD Score =.957 x Loge(creatinine mg/dl) +.378 x INR)) +.643. Loge(bilirubin mg/dl) + 1.12 x Loge(INR 8

HCC PS, Child-Pugh A Very early stage () Early stage (A) Single or 3 nodules Single < 2 cm < 3 cm, PS Carcinoma in situ Single Resection Intermediate stage (B) Multinodular, PS Advanced stage (C) Portal invasion, N1, M1, PS 1-2 Terminal stage (D) 3 nodules 3 cm Portal pressure/bilirubin Increased Normal Okuda Ok d 3 3, PS > 2, 2 Child-Pugh C Okuda 1-2, PS -2, Child-Pugh A-B Associated diseases No Liver transplantation Yes RFA/PEI Curative treatments (3%); 5-yr survival: 4%-7% TACE Sorafenib RCTs (5%); 3-yr survival: 1%-4% Symptomatic (2%); survival < 3 mos Llovet JM, et al. Journal of the National Cancer Institute. 28;1:698-711. 9

Curative (stage I-II) Thermal ablation ((radiofrequency, q y microwave)) Resection (partial hepatectomy) Liver transplantation (total hepatectomy) Palliative (stage III-IV) Transarterial therapies Targeted therapy (sorafenib) 1

Well compensated cirrhosis Platelets > 1k, normal bilirubin, no varices Hepatic venous pressure gradient < 1 mmhg Size of tumor and extent of resection Proportion Alive 1 1. A1 A2 A3.75 65%.5 N = NS A1 = No portal hypertension A2 = Portal hypertension, normal bilirubin A3 = Portal hypertension, abnormal bilirubin Test for trend of survivor functions: P =.67.25 Pts at Risk, n A1 16 A2 37 A3 26 12 24 5% 46% 36 48 6 75 16 7 58 1 5 51 6 4 Mos 123 24 13 93 18 1 Santambrogio R, et al. HPB (Oxford). 213;15:78-84 11

Percutaneous Ethanol Ablation: effective for lesions up to 2 cm Radiofrequency Ablation (RFA): thermal technique, more consistent than alcohol for larger lesions Percutaneous Microwave Ablation: efficacy equivalent to RFA in early studies 12

Best: < 3 lesions < 3 cm Location: not subcapsular, not subdiaphragmatic, not near major vessels Visible by US/non-contrast US/non contrast CT Adequate clotting function B 13

Author Child-Pugh Cl Class N 1 Yr 3 Yrs 5 Yrs Lencioni[1] A B 144 43 1 89 76 46 51 31 Tateishi[2] A B/C 221 98 96 9 83 65 63 31 A B 359 16 NA NA 78 49 64 38 Choi[3] Survival 1. Lencioni R, et al. Radiology. 25;234:961-967. 2. Tateishi R, et al. Cancer. 25;13:121-129. 3. Choi D, et al. Eur Radiol. 27;17:684-692. N = 168 HCC < 4 cm and up to 2 nodules 85% positive for viral hepatitis (77% with HBV) OS Pro obability of Survival 1..8.6 Resection group Radiofrequency ablation group Censored.4.2 Pts at Risk, n RES group 84 RFA group 84 6 12 18 Mos 24 3 36 75 73 7 67 66 64 63 58 55 5 52 46 Feng K, et al. J Hepatol. 212;57:794-82. 14

Transplantation 1 Cures cancer 8 Feasibility demonstrated in a landmark study by Mazzaferro in 1996 Inclusion criteria (N = 48) Unresectable HCC Staging criteria Single lesion < 5 cm or < 3 lesions, each < 3 cm OS (%) Eliminates cirrhosis 6 4 2 6 12 18 24 3 36 42 48 Mos After Transplantation Pts at Risk, n 48 45 4 32 27 21 17 9 5 Following liver transplantation, Actuarial survival at 4 yrs: 75% Mazzaferro V, et al N Engl J Med. 1996;334:693-699. Recurrence-free survival at 4 yrs: 83% 15

Patients within Milan awarded MELD score of 22 ( 1 tumor < 5cm or if multiple 3 tumors 3 cms in diameter) Portal vein patent, normal CT Chest Increases every 3 months by 3 points until transplant or tumor progression Survival equivalent to cirrhotic patients without HCC Vitale Lancet 211 Subset of HCC patients with larger tumor burden than Milan with acceptable survival UCSF Criteria: solitary tumor 6.5 cm, or 3 nodules with largest 4.5 cm and total burden 8 cm. Not eligible for increased MELD points Yao 27 16

Tumor burden can be reduced by ablation or embolization Extra MELD points sought by appeal to UNOS once reduced to Milan Tumor burden be stable T b d needs d tto b t bl > 3 months th within Milan to qualify Yao 28 17

Transcather Arterial Chemoembolization (TACE):chemotx infused into arterial vessels feeding the tumor with subsequent arterial occlusion DEB-TACE: Drug eluting beads to reduce systemic toxicity. Transcatheter Arterial Radio-Embolization: newer technique with tumoricidal Yttrium-9 Pros Effective with large g and hard-to-reach tumors May delay progression and prolong survival May allow downstaging of tumors for transplantation candidacy Cons p Can p produce hepatic failure ((avoid in CTP class B-C or portal thrombosis) Rarely curative 18

Tumor cell Vascular cell Autocrine loop EGF/HGF Paracrine stimulation VEGFF PDGF-β PDGFR-β VEGFR-2 Apoptosis RAS RAS RAF RAF Mitochondria MEK HIF-2 ERK Nucleus EGF / HGF PDGF VEGF Proliferation Survival Mitochondria MEK Apoptosis ERK Nucleus Angiogenesis: Differentiation Proliferation Migration Tubule formation Wilhelm SM, et al. Cancer Res. 24;64:799-719. Wilhelm SM, et al. Mol Cancer Ther. 28;7:3129-314. 19

Considerable toxictiy Probability of Radiolog gic Progression Sorafenib delayed progression and prolonged survival from 7.9 to 1.7 mos Time to Radiologic Progression 1. Sorafenib Placebo.75.5.25 P <.1 1 2 3 4 5 6 7 8 9 1 11 12 Mos Since Randomization Pts at Risk, n Sorafenib Placebo Probability of Survival SHARP trial: CTP A patients with advanced HCC randomized to sorafenib 4 BID vs placebo 299 267 155 11 91 65 37 23 18 1 33 275 142 78 62 41 21 11 1 3 4 1 2 1 OS 1. Sorafenib Placebo.75.5.25 P <.1 1 2 3 4 5 6 7 8 9 1 11 12 1314 1516 17 Llovet NEJM 27 Pts at Risk. n Sorafenib Placebo Mos Since Randomization 299 29 27 249 234 213 2 172 14 111 89 68 48 37 24 7 1 33 295 272 243 217 189 174 143 18 83 69 47 31 23 14 6 3 2