6/16/2016. Treating Hepatocellular Carcinoma: Deciphering the Clinical Data. Liver Regeneration. Liver Regeneration

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1 Treating : Deciphering the Clinical Data Derek DuBay, MD Associate Professor of Surgery Director of Liver Transplant Liver Transplant and Hepatobiliary Surgery UAB Department of Surgery Liver Regeneration Worldwide Incidence of HCC per 100,000 El-Serag, New England Journal of Medicine 2011 Liver Regeneration Incidence of HCC in the US El-Serag, New England Journal of Medicine

2 tion Liver Cancer has the Fastest Growing Death Rate in the US iveeneration 5-Year Rate Change-INCIDENCE Alabama HCC Both Sexes, All Races iveeneration 5-Year Rate Change - MORTALITY Alabama HCC Both Sexes, All Races 2

3 ation 5-Year Rate Change - MORTALITY Alabama HCC Both Sexes, All Races ation 5-Year Rate Change - MORTALITY Alabama CRC Both Sexes, All Races HCC Treatment Decision Tree 1. Natural History of Treated HCC 2. HCC Treatment Algorithm 3. Multimodal HCC Treatment 4. Active Clinical Trials 3

4 85% of HCC pts developed a new HCC Median time to new tumor 22 months 3-4 factors 0-2 factors P< P< N=706pts with HCC <3.5cm Hepatology 2011;53: TAKEHOME POINT #1 Short of a Liver Transplant, HCC is a Chronic Recurring Terminal Malignancy for the 95% of HCC that Arise in Cirrhotic Patients (One exception is the 5% of HCC that arise spontaneously in a normal liver) HCC Treatment Decision Tree Treatment Algorithm Transplant All Other Therapies Palliative Therapy 4

5 HCC Clinical Staging Schemes Pons F et al. HPB 2005; 7:35 25% 75% Llovet JM et al. Lancet 2003; 362:1907 HCC Treatment Decision Tree Treatment Algorithm Transplant Surgical Resection = Ablation Other Locoregional Approaches Chemotherapy 5

6 Llovet JM et al. Lancet 2003; 362:1907 Liver Transplantation Non-Resectable Patients Milan Criteria: 1 tumor 2-5cm Up to 3 tumors less than 3cm No vascular invasion No extrahepatic disease NEJM 1996;334(11): Liver Transplantation 0-2 factors 3-4 factors P< P< NEJM 1996;334(11):

7 Liver Transplantation 33/99 Liver Tx at UAB in 2014 ~72% 5 year survival 1 Who Should/not be offered Liver Transplantation for HCC? 1. Am J Trans 2008;8(2): HBP Surgeon Role for HCC Treatment Algorithm Transplant Surgical Resection = Ablation Other Locoregional Approaches Chemotherapy Llovet JM et al. Lancet 2003; 362:1907 7

8 Hepatic Resection 0-2 factors 3-4 factors P< P< yo Female with 21.5cm HCC Hepatic Resection Traditionally considered Gold Standard Morbidity/ Mortality higher than for non-hcc Only 10-15% eligible for resection 1-3 Recurrence as high as 68% within 2 years 4 1. El-Serag HB. Gastroenterology. 2004;127:S27-S34; 2. Lau WY, et al. Ann Surg. 2009;249:20-25; 3. del Pozo AC, et al. Clin Liver Dis. 2007;11: ; 4. Yamamoto J, et al. Br J Surg. 1996;83: ; Hepatic Resection Author Period N Mortality 1 Year Survival 3 Year 5 Year Kawasaki, % 92% 79% NR Makuuchi, <1% 92% 73% 47% Fong, % 81% 54% 37% Poon, % 82% 62% 49% Belgheti, % 81% 57% 37% Cha, % 79% 51% 40% Totals % 85% 63% 39% 8

9 HCC Treatment Decision Tree Treatment Algorithm Transplant Surgical Resection = Ablation Other Locoregional Approaches Chemotherapy Llovet JM et al. Lancet 2003; 362:1907 Ablation Rational Tumor Treated in situ Percutaneous or Operative Approaches Tumor Coagulative Necrosis Chemical Ablation Fallen out of Favor Radiofrequency vs. Microwave Ablation AASLD: Front Line Therapy for Small HCC 1 1 Hepatology (5):

10 Liver Hepatocellular Regeneration Carcinoma Percutaneous Ablation Pre-AblationMicrowave Ablation Post- Ablation HCC Treatment Decision Tree Treatment Algorithm Transplant Surgical Resection = Ablation Other Locoregional Approaches Chemotherapy Llovet JM et al. Lancet 2003; 362:

11 TACE (TransArterial ChemoEmbolization) Rational Obliteration of Arterial Tumor Blood Flow Intra-Tumoral Chemotherapy Administration AASLD: Treatment for Non-Transplantable, Non-Resectable HCC>3cm 1 1 Hepatology (5): 1208 Liver Regeneration TACE TACE 2 Year Risk of Death HR 0.53 (95% CI ) Llovet JM et al. Hepatology 2003;37:

12 TACE Predictors of >90% Tumor Necrosis Bryant MK et al. HPB Journal 2013 Median Survival as a Function of TACE-Induced Tumor Necrosis Child Pugh Class A Patients Haywood, N et al. AHPBA 2015 TACE Child s A 21.9 mo vs. Childs B/C 13.7mo, p=0.03 Dorn D et al. HPB Journal

13 BCLC Class B & C Patients Survival Predictors Child-Pugh Class Functional Status Tumor Volume Response to TACE 90 Yttruim Radiomicrosphere Therapy Rational Tumor Treated in situ 90 Yttruim Microspheres Trapped in Tumor Preferential in case of portal vein thrombosis Multifocal Disease? AASLD: No recommendations $$$$$$$$$ Approved as Device (not drug)--no Efficacy data. External Beam Radiotherapy Rational Tumor Treated in situ Unfractionated or Hyper-fractionated Dosing Excellent adjunct to Ablation and TACE (Control of Tumor Periphery) AASLD: No recommendations Low Morbidity/ Well Tolerated 13

14 Llovet JM et al. Lancet 2003; 362:1907 External Beam Radiotherapy Hawkin MA et al. Cancer 2006;106: HCC Treatment Decision Tree Treatment Algorithm Transplant Surgical Resection = Ablation Other Locoregional Approaches Chemotherapy 14

15 Llovet JM et al. Lancet 2003; 362:1907 Chemotherapy Sorafenib is recommended by the NCCN for the following patients with unresectable HCC and have Child-Pugh A or B disease a,b Not transplant candidates (category 1) Inoperable by performance status or comorbidity, local disease only (category 1) Metastatic disease (category 1) a The impact of sorafenib on patients eligible for transplant is unknown. Data are inadequate to define dosing for patients with abnormal liver function ( Child Pugh Class B or C) b Caution: There are limited safety data available for Child-Pugh B patients. Use with extreme caution in patients with elevated bilirubin levels. Adapted from: NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary Cancer. V2.2009; Available at: Accessed 1 October Survival Probability (%) Sorafenib Chemotherapy Overall Survival 25 HR (Sor/Pbo): 0.69 (95% CI: ) P<.001 a Months Sorafenib (n=299) Median: 10.7 mo 95% CI: Placebo (n=303) Median: 7.9 mo 95% CI: a O Brien-Fleming threshold for statistical significance was P= Progression-Free Probability (%) TTP Sorafenib Median: 5.5 months (95% CI, ) Placebo Median: 2.8 months (95% CI, ) 25 HR (Sor/Pbo): 0.58 (95% CI, ) P< Months From Randomization Adapted from: Llovet JM, et al. N Engl J Med. 2008;359:

16 Sorafenib Tidbits Median treatment duration 3.8 months A Better outcomes 800mg/d vs. 400mg/d B Most common side effects: fatigue, HFSR, HTN, wt loss, diarrhea A Survival CP-A vs. CP-B 10.0 vs. 3.8 months C Drug should be stopped with evidence of tumor progression A Hepatology 2011:54(6): B Hepatology 2011:54:n2119 C Ann Oncol 2013; 24(2): TAKEHOME POINT #2 Widespread Underutilization of Curative or (more Commonly) Life Prolonging HCC Therapies Underutilization of Clinically Proven HCC Treatments 8730 Medicare pts with HCC over 14 years: Resection: 8.7% Liver transplantation: 1.4% Ablation: 3.6% Transarterial chemoembolization: 16% NOTHING >60%!!! Shah, Smith, et al, Cancer

17 TAKEHOME POINT #3 75% of HCC Pts Only Candidates for Palliative Therapy Optimal HCC Therapy: 1. Starts with TACE 2. Darwinian Approach 3. Multimodal = Best Outcomes Multimodal Therapy Rational Tailor to Disease Pattern Tailor to Underlying Liver Function and Overall Patient Functional Status Tailor to Patient Response to Therapy Optimize Treatment Efficacies Future Direction for HCC Treatment Liver Hepatocellular Regeneration Carcinoma TACE/ Ablation Pre-TACE, Pre-Ablation Post-TACE, Pre-Ablation Post-TACE, Post-Ablation 17

18 TACE-Alone vs. TACE/ SBRT TACE-Alone 20mo vs. TACE/SBRT 33mo, p=0.02 Jacob R et al. HPB Journal 2014 Active HCC Clinical Trials A Prospective, Multicenter Comparison of Multiphase Contrast- Enhanced CT and Multiphase Contrast-Enhanced MRI for Diagnosis of and Liver Transplant Allocation. A Pilot Study of Trans Arterial Chemoembolisation (TACE), Followed by Stereotactic Radiation Therapy (SBRT) for Patients with (HCC) Phase 3 Prospective, Randomized, Blinded and Controlled Investigation of Hepasphere/ Quadrasphere Microspheres for Delivery of Doxorubicin for the Treatment of 18

19 UAB HCC Downstaging Protocol 1. UCSF Criteria: 1 1 tumor up to 6.5 cm Up to 3 tumors, each less than 4.5cm Total tumor diameter less than 8cm 2. NO vascular invasion 3. AFP less than No constitutional symptoms 5. 6 months observation between bridging intervention and transplant listing 1. Yao FY et al. Am J Trans 2007;7: Liver Regeneration HCC Downstaging Protocol First Evaluation: TACE July Hypofractionated 2009 Radiotherapy October-November Second 2 HCC (4.1 and TACE September cm) June Liver Transplant July 2010 Path: No Viable Tumor Detected Special Thanks to the UAB Liver Tumor Clinic Physician Extenders: Beth Comeaux, CRNP Sarah Slaughter, CRNP Emily Broeseker, CRNP Support Staff: Linda Guy Lesley Miller Locoregional Interventional Experts: Souheil Saddekni, MD Rojymon Jacob, MD David Bolus, MD Kevin Smith, MD 19

20 UAB Liver Tumor Clinic Referrals: (phone) (fax) 800 UAB MIST 20