Locoregional Treatment of Hepatocellular Carcinoma. Cory Johnston and Sung Cho HPB Surgery Fellows Providence Portland, Oregon

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1 Locoregional Treatment of Hepatocellular Carcinoma Cory Johnston and Sung Cho HPB Surgery Fellows Providence Portland, Oregon

2 Hepatocellular Carcinoma The 3 rd most common cause of cancer- related death worldwide Liver cirrhosis HepaCCs B,C Alcohol Chronic hepaccs B Non- alcoholic fafy liver disease Hereditary Rodriguez et al J Hepatology 2012

3 Diagnosis: AASLD guideline Bruix and Sherman Hepatology 2011

4 Staging and Treatment of HCC Barcelona Clinic Liver Cancer (BCLC) Staging : 3 consideracons Tumor Single tumor <2cm Single tumor <5cm or 3 tumors <3cm MulCnodular Portal vein invasion or extrahepacc spread Liver funccon Performance status

5 Assessment of Liver FuncCon Lencioni et al. Radiology 2012

6 ECOG score Performance Status Score Findings 0 AsymptomaCc 1 SymptomaCc but completely ambulatory 2 Ambulatory, capable of self- care, unable to do any work accvices, <50% in bed during the day 3 Limited to self- care only, >50% in bed 4 Unable to perform any self- care, bedbound 5 dead Oken et al. Am J Clin Oncol 1982

7 ECOG score Performance Status Score Findings 0 AsymptomaCc 1 SymptomaCc but completely ambulatory 2 Ambulatory, capable of self- care, unable to do any work accvices, <50% in bed during the day 3 Limited to self- care only, >50% in bed 4 Unable to perform any self- care, bedbound 5 dead Oken et al. Am J Clin Oncol 1982

8 Assessing Tumor Response * * Or no contrast enhancement on arterial phase of CT/MRI scan

9 BCLC guideline EASL- EORTC guideline. J Hepatology 2012

10 BCLC guideline EASL- EORTC guideline. J Hepatology 2012

11 Types of locoregional therapy AblaCve therapy (RFA, microwave, EtOH etc) TACE Bland hepacc artery embolizacon (HAE) ConvenConal (ctace) Drug elucng beads (DEB) YFrium 90

12 ConvenConal TACE Doxorubicin or cisplacn most used Lipiodol: iodized poppy seed oil HCC arterial blood supply Remaining liver dual blood supply

13 Drug- EluCng Beads ChemotherapeuCc ionic reaccon with bead Poly- vinyl alcohol N- fil hydrogel beads Slow elucon of drug from bead

14 SelecCng candidates for ctace/deb In most studies HCC confined to the liver and no extrahepacc- spread Portal vein thrombosis (relacve contraindicacon) Child- Pugh A, B Repeated uncl failure or untreatable progression However, in praccce, treatment is individualized

15 Case 58 yo M hepaccs C cirrhosis s/p TIPS bilirubin cm HCC seg 6/7

16 DEBs with Doxorubicin 3 months 18 months

17 EVIDENCE FOR CONVENTIONAL TACE

18 Llovet et al. Lancet 2002 A randomized trial comparing bland arterial embolizacon, ctace with doxorubicin or best supporcve care PaCents with untreated HCC, not suitable for curacve treatment

19 Llovet et al. Lancet 2002 Excluded pacents age>75 Child Pugh class C refractory ascites encephalopathy extrahepacc disease PS >2

20 Trial Design Llovet et al. Lancet 2002

21 Results TACE is associated with lower probability of developing PVT at 2 yrs (17% vs. 58%; p=0.005) Survival befer with TACE BeFer survival associated with treatment response (p=0.0007)

22 Mean Survival (in months) HAE ctace Suppor5ve care Trial stopped early P=0.009

23 TACE vs. control ctace SupporCve care Llovet et al. Lancet 2002

24 Lo et al. Hepatology 2002 A Randomized trial: TACE with cisplacn and gelacn sponge parccles vs. best supporcve care Treatment repeated every 2-3 months uncl progressive disease, poor hepacc funccon or PVT

25 Lo et al. Hepatology 2002 Excluded pacents refractory ascites encephalopathy extra- hepacc disease bilirubin >2.9mg/dL albumin<2.8g/l PT>4 sec over control PS>3

26 Results: TACE vs. supporcve care Median # treatments: 4.5 courses ObjecCve tumor response: 39% vs. 6% (p=0.014) RelaCve risk of death: 0.49 (95% CI: ; p=0.006) Lo et al. Hepatology 2002

27 ctace vs. SupporCve Care ctace SupporCve care Lo et al. Hepatology 2002

28 Issues with ctace Needs 1-2 days in hospital for pain control ComplicaCons post- embolizacon syndrome Nausea/vomiCng, abdominal pain, fever Difficult to standardize Dose of chemotherapeucc drugs Embolizing agents Portal vein thrombosis relacve contraindicacon

29 DRUG ELUTING BEADS

30 Drug- EluCng Beads Burrel et al. J Hepatology 2012

31 DEBs vs ctace: Precision V study: A Randomized Trial Doxorubicin: DEBs vs ctace 212 pacents Large and/or mulcnodular, unresectable HCC Child Pugh A or B ECOG PS 0-1

32 DEBs vs ctace: Precision V study: A Randomized Trial Lammer et al. Cardiovasc Intervent Radiol 2010

33 Liver toxicity Lammer et al. Cardiovasc Intervent Radiol 2010

34 TACE vs. DEBs Similar efficacy DEBs: less liver toxicity and less systemic leak DEBs: dose release more readily standardized

35 Case 85 year old male 7cm typical HCC appearance on CT Compensated liver cirrhosis, Child A PS>1: CAD, AICD Not a surgical or transplant candidate

36 YFrium 90 Treatment 3 mo amer YFrium 90 3 yrs amerwards

37 YFrium 90 β emiong radio- isotope Maximum 11mm penetracon Half- life 64 hours Two types Glass spheres (Theraspheres) Resin spheres (SIR- spheres) Murthy et al. Radiographics 2005

38 YFrium 90 Murthy et al. Radiographics 2005

39 YFrium 90 Advantages An outpacent procedure Portal vein thrombosis NOT a contra- indicacon Induces compensatory hypertrophy of contra- lateral lobe radiacon hepatectomy

40 YFrium 90 Main complicacons Pulmonary shunts GI toxicity Fibrosis Planning Angiography 99 Tc- MAA scan RadiaCon GastriCs Murthy et al. Radiographics 2005

41 Planning angiogram Lem HA Right HA GDA GDA coil embolized Denecke et al. Eur Radiol 2008

42 99 Tc MMA scan Calculate lung shuncng fraccon Y90 not used if lungs are exposed to >20% injected dose >30 Gy radiacon Murthy et al. Radiographics 2005

43 YFrium 90 Kulik et al. Hepatology 2008

44 Survival amer Y90 according to BCLC Salem et al. Gastroenterology 2010

45 ctace vs. Y90 No RCTs exist RetrospecCve cohort studies Salem et al. Gastroenterology 2011 ctace with adriamycin and cisplacn (n=122) vs. YFrium 90 (n=123) Similar tumor size, number, liver funccon and PS

46 Study design Salem et al. Gastroenterology 2011

47 Results: ctace vs. Y90 Median no of treatment: 2 vs 1(p=0.09) Median hospital stay: 3.4 vs. 0 days (p<0.001) Abd pain (p<0.001) and elevated ALT (29% vs. 11%) more common with TACE Time to progression: longer with Y90 (8.4 vs months p=0.046) Similar survival: 17.4 vs months (p=0.232) Salem et al. Gastroenterology 2011

48 Survival Curve ctace vs. Y90 Salem et al. Gastroenterology 2011

49 YFrium 90 Pre- treatment high risk factors Bulky disease (tumor volume >70% of the target liver volume) Bilirubin >2mg/dL AST or ALT > 5 Cme normal Tumor volume>50% + albumin <3g/dL

50 Y90 or DEBs: Which one is befer? Providence Portland Cancer Center Data A retrospeccve study of 149 pacents who received Y90 or DEB or both Y90 (n=59) n=18 treated with addiconal modality 11 DEB 4 DEB + RFA 1 TACE 1 RFA 1 reseccon DEBs (n=80) n=12 treated with addiconal modality 3 Y90 9 RFA Hammill et al. not yet published

51 Survival: Y90 vs. DEBs Y90 DEB

52 IniCal Response Response Median Survival (months) 95% CI Complete (24%) Not reached n/a ParCal (50%) Stable (5%) Progression (21%) Overall (100%) Hammill et al. not yet published

53 Best Response amer mulc- modality Rx Response Median Survival (months) 95% CI Complete (38%) ParCal (40%) Stable (3%) Progression (19%) Overall(100%) Hammill et al. not yet published

54 MulCvariate analysis Two variables were associated with survival Best response (HR = 0.144; p<0.001) MELD score (HR = 1.142; p=0.01 Hammill et al. not yet published

55 Conclusion from Our Study 38% can achieve complete response with median survival of 70 months IniCal treatment modality (DEBs or Y90) did not influence survival Response to treatment and lower MELD score improved survival Hammill et al. not yet published

56 Rescue treatment amer progression on TACE/DEBs (revised) Y 90 Y 90 Bruix et al. Hepatology 2012

57 In Summary In treacng pacents with HCC, consider Tumor characterisccs Size, number, portal vein thrombosis, metastasis Liver funccon Child- Pugh Class MELD Performance Status

58 What would you do? 62 yo M, hemochromatosis, alcohol abuse Child Pugh A Bilirubin normal PS=0

59 Portal vein thrombosis Angiogram showing seg 4 and 8 HCC

60 YFrium 90 4 mo amerwards 22 mo amerwards

61 Special Thanks Chet Hammill MD Tyler Thiesing MD Paul Hansen MD Ron Wolf MD Pippa Newell MD Maria Cassera BA