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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