Hepatocellular Carcinoma: Transplantation, Resection or Ablation?

Transcription

1 Hepatocellular Carcinoma: Transplantation, Resection or Ablation? Roberto Gedaly MD Chief, Abdominal Transplantation Transplant Service Line University of Kentucky

2 Nothing to disclose Disclosure

3 Objective Discuss basic principles in Hepatocellular Carcinoma treatment

4 Hepatocellular Carcinoma Represents the fourth most common cause of cancer-related deaths worldwide Risk Factors: HCV, HBV Incidence: from 1970 to 1990, 1.4 to 3.0 per , in 2010 is 6 per HCC in HCV infection will continue to rise and will peak in 2019 Men has 3-fold increased risk El-Serag H, Hepatology, Feb 2015

5 Hepatocellular Carcinoma Treatment Size Number of Lesions Function (Child s) Vascular Invasion Extrahepatic Disease

6 Hepatocellular Carcinoma Treatment Liver Transplantation Resection Ablation (MWA, RFA) TACE Radio-embolization Chemotherapy and Radiotherapy Molecular Targeted Therapies

7 Resection Only 20% Liver Function (Child s A) No portal hypertension (splenomegaly or low platelet count) No extrahepatic disease Bruix J et al,, Hepatology 1997

8 Resection

9 Solitary lesions No vascular invasion Size <5cm Margin 1cm 5-year survival 78%

10 Incurable by Resection Invasion of a major portal or hepatic vein Direct invasion of organs other than the gallbladder Nodal or distant metastases

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12 Liver Transplantation One Tumor <5cm Less than 3 lesions <3cm No extrahepatic disease 5 year survival rate 60-70% Mezzaferro et al, N Eng J Med 1996

13 Liver Transplantation: Allocation Initially listed with their fuctional MELD MELD 28 at 6 months Capped at MELD 34

14 Liver Transplantation: Bridging therapy AASLD guidelines UNOS T2 To decrease dropout Waiting more than 6 months TACE, Ablation, Y90 AASLD does not recommend one specific form of therapy over another Benefits remain unclear

15 Liver Transplantation: Downstaging TACE, Y90, Ablation Sistematic review showed 48% success rate Downstage within Milan AASLD guidelines: Patients beyond the Milan criteria after downstaging into the Milan criteria AFP levels Parikh ND et al, Liver Transpl. 2015

16 RISING INCIDENCE OF NONALCOHOLIC STEATOHEPATITIS AMONG PATIENTS TRANSPLANTED FOR HEPATOCELLULAR CARCINOMA IN THE UNITED STATES 1 Roberto Gedaly, MD; 1 Davenport DL, PhD; 1 Michael F. Daily, MD; 1 M Shah, MD; 1 Jonathan C. Hundley, MD; 1 Lucy Dagher MD; 2 Paul Angulo, MD ASSLD

17 101 patients Predictors of survival and tumor recurrence Predictors of microvascular invasion HBP, 2010

18 Liver Transplant Median Size 2.6 ±1.5 cm (range cm) Perioperative mortality 4% Recurrence 11% Gedaly R et al HBP, 2010

19 Liver Transplant Predictors of survival Microvascular Invasion OR 4.70 Lymph nodes OR 6.05 Predictors of recurrence Microvascular Invasion Predictors of Microvascular Invasion Size (OR 4.1) AFP>100 (OR 5.0) Gedaly R et al HBP, 2010

20 No Microvascular Invasion 92%, 78% and 72% Gedaly R et al HBP, 2010

21 Conclusion Excellent results can be obtained in selected patients with survival rates above 70% at 5 years AFP and tumor size are strongly associated with microvascular invasion Microvascular invasion is independently associated with poor outcomes

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24 AIMS To determine the correlation of expression of CD133 and CD44 with AFP levels and tumor differentiation To study the association of LCSC marker expression (CD133 and CD44) in conjunction with MVI with patients outcomes

25 TUMORS CHARACTERISTICS

26 PREDICTORS OF AFP LEVELS >100mg/dl Independent Variables Odds Ratio p-value AGE GENDER CD CD133 + tumors were independently associated with levels of AFP > 100 mg/dl

27 PREDICTORS OF TUMOR DIFFERENTIATION Independent Variables Odds Ratio p-value AGE GENDER CD133+/CD AFP > 100mg/dl CD133 + /CD44 + tumors and AFP levels were significantly associated with moderate to poorly differentiated HCC

28 OVERALL SURVIVAL WITH MVI AND CD44 CD44 + expression and MVI in the explanted tumors was an independent predictor of recurrence and survival (recurrence p<0.003, OR= 8.05 survival p<0.001, HR 3.7)

29 OVERALL SURVIVAL WITH MVI AND CD133 CD133 + expression and MVI in the explanted tumors was an independent predictor of recurrence and survival (recurrence p<0.001, OR= 9.5 survival p<0.004, HR 3.2)

30 CONCLUSIONS CD133 + tumors were significantly associated with elevated levels of AFP (10 fold) CD133 + /CD44 + tumors and AFP levels were independently associated with moderate to poorly differentiated HCC Patients with MVI and positive expression of CD44 or CD133 had 5-year survival rates lower than those with MVI alone

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32 LT FOR PRIMARY LIVER MALIGNANCY UNOS Database 4,049 patients have been transplanted for primary liver malignancy 94 HCC-CC - 3,515 HCC CC

33 Tumor Type 1 year 3 year 5 year 10 year HCC-CC (n=94) HCC (n=3515) CC (n=440)

34 Ablation Therapy Radiofrequency Less than 3-4cms Not surgical candidates Bridge to OLT 4-Year Survival Rates of 45%

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36 Molecular Targeted Therapies Advanced disease Improved Survival 7.8 a 10.7 months, placebo vs. Sorafenib p<0.05 Tumor progression Llovet et al N Engl J Med Jul 24;359(4):378-90

37 In-Vitro PI103 + Sorafenib Combination significantly inhibit EGF stimulated HCC proliferation by Blocking Ras/Raf/MAPK and PI3K/AKT/mTOR pathways OD (570nm) Sorafenib and PI-103 on Inhibition of EGF Stimulated Huh7 Proliferation in 1%FBS (MTT Assay) P<0.001 P<0.001 P<0.001 P=0.037 P<0.001 Control (DMSO) EGF (2.5 nm) EGF + Sora (2.5μM) EGF+PI-103 ( 2 μm) EGF+ Sora + PI-103 0

38 In-Vivo PI103 + Sorafenib Combination significantly inhibit tumor progression Increased apoptosis Normalized Band Dencity (Arbitrary Units) Drug Induced Apoptosis in Tumors (Assayed by Cleaved PARP) Control Sorafenib PI-103 Sorafenib + PI-103

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40 Signaling pathways in HCC Seminars in Oncology. 2012; 39(4):

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42 New Wnt/B-catenin inhibitors

43 Cancer Immunotherapy HEP3B HUH7 PLC PDL1 PDL2

44 Conclusions Surgery should be considered in patients without significant PH, small lesions and good functional reserve Transplantation is probably the best option in patients within Milan criteria and those that can be down-staged

45 Conclusions Ablation should be considered in patients with less than 3-4 lesion less than 3-4cms each if surgery is contraindicated Bridging Therapy indicated in T2 HCC Downstaging is useful in selected cases