Paul Martin MD FACG. University of Miami

Transcription

1 Paul Martin MD FACG University of Miami 1

2 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 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% HCV alone: 28% Yang JD, et al. Mayo Clin Proc. 212;87:

3 .8 Cirrhosis Cumulative rate.6.4 Fibrosis Years after randomization Lok AS Gastroenterology. 29 3

4 1. Surviv al Std-of-Care.4 Substandard.2 Unknown Cx 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

5 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:

6 Arterial Phase Portal Venous Phase 6

7 Mass on surveillance < 1 cm 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 > 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: 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:

8 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 MELD Score =.957 x Loge(creatinine mg/dl) x INR)) Loge(bilirubin mg/dl) x Loge(INR 8

9 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:

10 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

11 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 A %.5 N = NS A1 = No portal hypertension A2 = Portal hypertension, normal bilirubin A3 = Portal hypertension, abnormal bilirubin Test for trend of survivor functions: P = Pts at Risk, n A1 16 A2 37 A % 46% Mos Santambrogio R, et al. HPB (Oxford). 213;15:

12 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

13 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

14 Author Child-Pugh Cl Class N 1 Yr 3 Yrs 5 Yrs Lencioni[1] A B Tateishi[2] A B/C A B NA NA Choi[3] Survival 1. Lencioni R, et al. Radiology. 25;234: Tateishi R, et al. Cancer. 25;13: Choi D, et al. Eur Radiol. 27;17: N = 168 HCC < 4 cm and up to 2 nodules 85% positive for viral hepatitis (77% with HBV) OS Pro obability of Survival Resection group Radiofrequency ablation group Censored.4.2 Pts at Risk, n RES group 84 RFA group Mos Feng K, et al. J Hepatol. 212;57:

15 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 Mos After Transplantation Pts at Risk, n Following liver transplantation, Actuarial survival at 4 yrs: 75% Mazzaferro V, et al N Engl J Med. 1996;334: Recurrence-free survival at 4 yrs: 83% 15

16 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

17 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

18 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

19 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: Wilhelm SM, et al. Mol Cancer Ther. 28;7:

20 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 P < 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 OS 1. Sorafenib Placebo P < Llovet NEJM 27 Pts at Risk. n Sorafenib Placebo Mos Since Randomization

21 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: Screen cirrhotic and HBV patients with twice yearly ultrasound, AFP limited utility Diagnosis is radiological Curative options include RFA, resection and transplant Multidisclipinary approach Treating the cause of liver disease (HBV, HCV) reduces risk 21