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Treating Hepatocellular Carcinoma: Deciphering the Clinical Data
Derek DuBay, MDAssociate Professor of Surgery
Director of Liver TransplantLiver Transplant and Hepatobiliary Surgery
UAB Department of Surgery
Liver RegenerationWorldwide Incidence of HCC per 100,000
El-Serag, New England Journal of Medicine 2011
Liver RegenerationIncidence of HCC in the US
El-Serag, New England Journal of Medicine 2011
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tion Liver Cancer has the Fastest Growing Death Rate in the US
http://statecancerprofiles.cancer.gov
iveeneration5-Year Rate Change-INCIDENCE Alabama HCC Both Sexes, All Races
http://statecancerprofiles.cancer.gov
iveeneration5-Year Rate Change - MORTALITY Alabama HCC Both Sexes, All Races
http://statecancerprofiles.cancer.gov
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ation5-Year Rate Change - MORTALITY Alabama HCC Both Sexes, All Races
http://statecancerprofiles.cancer.gov
ation5-Year Rate Change - MORTALITY Alabama CRC Both Sexes, All Races
http://statecancerprofiles.cancer.gov
1. Natural History of Treated HCC 2. HCC Treatment Algorithm3. Multimodal HCC Treatment4. Active Clinical Trials
HCC Treatment Decision Tree
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0-2 factors
3-4 factors
P
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HCC Clinical Staging Schemes
Pons F et al. HPB 2005; 7:35
Llovet JM et al. Lancet 2003; 362:1907
25% 75%
Treatment Algorithm• Transplant• Surgical Resection = Ablation• Other Locoregional Approaches• Chemotherapy
HCC Treatment Decision Tree
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Llovet JM et al. Lancet 2003; 362:1907
Non-Resectable Patients
Milan Criteria:• 1 tumor 2-5cm• Up to 3 tumors less than 3cm • No vascular invasion• No extrahepatic disease
Hepatocellular CarcinomaLiver Transplantation
NEJM 1996;334(11):693-99
0-2 factors
3-4 factors
P
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• 33/99 Liver Tx at UAB in 2014• ~72% 5 year survival1• Who Should/not be offered Liver
Transplantation for HCC?
Hepatocellular CarcinomaLiver Transplantation
1. Am J Trans 2008;8(2):958-976
Treatment Algorithm• Transplant• Surgical Resection = Ablation• Other Locoregional Approaches• Chemotherapy
HBP Surgeon Role for HCC
Llovet JM et al. Lancet 2003; 362:1907
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0-2 factors
3-4 factors
P
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Treatment Algorithm• Transplant• Surgical Resection = Ablation• Other Locoregional Approaches• Chemotherapy
HCC Treatment Decision Tree
Llovet JM et al. Lancet 2003; 362:1907
Rational• Tumor Treated in situ• Percutaneous or Operative Approaches• Tumor Coagulative NecrosisChemical Ablation Fallen out of FavorRadiofrequency vs. Microwave AblationAASLD: Front Line Therapy for Small HCC1
1Hepatology 2005 42(5): 1208
Hepatocellular CarcinomaAblation
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Liver Regeneration
Pre-AblationMicrowave Ablation Post- Ablation
Hepatocellular CarcinomaPercutaneous Ablation
Treatment Algorithm• Transplant• Surgical Resection = Ablation• Other Locoregional Approaches• Chemotherapy
HCC Treatment Decision Tree
Llovet JM et al. Lancet 2003; 362:1907
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Rational• Obliteration of Arterial Tumor Blood Flow• Intra-Tumoral Chemotherapy Administration
AASLD: Treatment for Non-Transplantable, Non-Resectable HCC>3cm1
1Hepatology 2005 42(5): 1208
Hepatocellular CarcinomaTACE (TransArterial ChemoEmbolization)
Liver RegenerationHepatocellular CarcinomaTACE
2 Year Risk of Death HR 0.53 (95% CI 0.32 – 0.89)
Llovet JM et al. Hepatology 2003;37:429-42
Hepatocellular CarcinomaTACE
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Bryant MK et al. HPB Journal 2013
TACE Predictors of >90% Tumor Necrosis
Haywood, N et al. AHPBA 2015
Median Survival as a Function ofTACE-Induced Tumor Necrosis
Child Pugh Class A Patients
Dorn D et al. HPB Journal 2013
Hepatocellular CarcinomaTACE
Child’s A 21.9 mo vs. Childs B/C 13.7mo, p=0.03
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Survival Predictors• Child-Pugh Class• Functional Status• Tumor Volume• Response to TACE
Hepatocellular CarcinomaBCLC Class B & C Patients
Rational• Tumor Treated in situ• 90Yttruim Microspheres Trapped in Tumor• Preferential in case of portal vein thrombosis• Multifocal Disease?AASLD: No recommendations$$$$$$$$$Approved as Device (not drug)--No Efficacy data.
Hepatocellular Carcinoma90Yttruim Radiomicrosphere Therapy
Rational• Tumor Treated in situ• Unfractionated or Hyper-fractionated DosingExcellent adjunct to Ablation and TACE
(Control of Tumor Periphery)AASLD: No recommendationsLow Morbidity/ Well Tolerated
Hepatocellular CarcinomaExternal Beam Radiotherapy
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Llovet JM et al. Lancet 2003; 362:1907
Hawkin MA et al. Cancer 2006;106:1653-63
Hepatocellular CarcinomaExternal Beam Radiotherapy
Treatment Algorithm• Transplant• Surgical Resection = Ablation• Other Locoregional Approaches• Chemotherapy
HCC Treatment Decision Tree
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Llovet JM et al. Lancet 2003; 362:1907
Sorafenib is recommended by the NCCN for the following patients with unresectable HCC and have Child-Pugh A or B diseasea,b Not transplant candidates (category 1) Inoperable by performance status or comorbidity, local
disease only (category 1) Metastatic disease (category 1)
Adapted from: NCCN Clinical Practice Guidelines in Oncology. Hepatobiliary Cancer. V2.2009; Available at: www.nccn.org. Accessed 1 October 2009.
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.
Hepatocellular CarcinomaChemotherapy
100
0
75
50
25
Sur
viva
l Pro
babi
lity
(%)
Months
0 4 6 8 10 12 14 1621 3 5 7 9 11 13 15 17
Sorafenib (n=299)Median: 10.7 mo95% CI: 9.4-13.3
Placebo (n=303)Median: 7.9 mo95% CI: 6.8-9.1
HR (Sor/Pbo): 0.69 (95% CI: 0.55-0.87)P
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Median treatment duration 3.8 monthsA
Better outcomes 800mg/d vs. 400mg/dB
Most common side effects: fatigue, HFSR, HTN, wt loss, diarrheaA
Survival CP-A vs. CP-B 10.0 vs. 3.8 monthsC Drug should be stopped with evidence of tumor
progressionAHepatology 2011:54(6):2055-63BHepatology 2011:54:n2119CAnn Oncol 2013; 24(2):407-11
Hepatocellular CarcinomaSorafenib “Tidbits”
TAKEHOME POINT #2
Widespread Underutilization of Curative or (more Commonly)
Life Prolonging HCC Therapies
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 2011
Underutilization of Clinically Proven HCC Treatments
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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 EfficaciesFuture Direction for HCC Treatment
Liver Regeneration
Post-TACE, Pre-AblationPost-TACE, Post-Ablation
Hepatocellular CarcinomaTACE/ Ablation
Pre-TACE, Pre-Ablation
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Jacob R et al. HPB Journal 2014
Hepatocellular CarcinomaTACE-Alone vs. TACE/ SBRT
TACE-Alone 20mo vs. TACE/SBRT 33mo, p=0.02
A Prospective, Multicenter Comparison of Multiphase Contrast-Enhanced CT and Multiphase Contrast-Enhanced MRI for Diagnosis of Hepatocellular Carcinoma and Liver Transplant Allocation.
A Pilot Study of Trans Arterial Chemoembolisation (TACE), Followed by Stereotactic Radiation Therapy (SBRT) for Patients with Hepatocellular Carcinoma (HCC)
Phase 3 Prospective, Randomized, Blinded and Controlled Investigation of Hepasphere/ QuadrasphereMicrospheres for Delivery of Doxorubicin for the Treatment of Hepatocellular Carcinoma
Active HCC Clinical Trials
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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 invasion3. AFP less than 4004. No constitutional symptoms5. 6 months observation between bridging
intervention and transplant listing
1. Yao FY et al. Am J Trans 2007;7:2587-96
Liver RegenerationHCC Downstaging Protocol
Evaluation: 2 HCC (4.1 and 2.1 cm) June 2009First TACE July 2009Hypofractionated Radiotherapy
October-November 2009Second TACE September 2009
Liver Transplant July 2010Path: No Viable Tumor Detected
Special Thanks to the UAB Liver Tumor Clinic
Physician Extenders:Beth Comeaux, CRNPSarah Slaughter, CRNPEmily Broeseker, CRNP
Support Staff:Linda GuyLesley Miller
Locoregional Interventional Experts:Souheil Saddekni, MDRojymon Jacob, MDDavid Bolus, MDKevin Smith, MD
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UAB Liver Tumor Clinic
Referrals: 205 996 5970 (phone)205 996 9037 (fax)800 UAB MIST