1. Treating HCC: TACE and RFA
Janette Durham, MD
University of Colorado
May 2013
No disclosures

2. Learning objectives
1. Stratify HCC by Barcelona criteria to organize treatment options.
2. Discuss the clinical features that predict a favorable treatment response.
3. Discuss the recent developments in the field of percutaneous therapies for HCC.
4. Understand the role or percutaneous therapy in relation to transplantation.
5. Understand the decision to treat with RFA vs. intra- arterial therapy.

3. Prognostic factors in treatment of HCC
Tumor status (number and size, portal invasion, extrahepatic disease)
Performance status-ECOG
Liver function – CP

4. UNOS TNM staging
T1 1 nodule < 1.9cm
T2 1 nodule 2.0-5.0 cm; 2-3 nodules all < 3.0 cm
T3 1 nodule > 5 cm; 2-3 nodules at least one > 3.0 cm
T4a 4 or more nodules
T4b T2,T3,T4a plus vascular involvement
N1 Regional nodes involved
M1 Metastatic disease including extrahepatic portal or hepatic vein involvement

5. Performance Status
ECOG
0 Fully active, able to carry on all pre-disease performance without restriction
1 Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature
2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more then 50% of waking hours.
3 Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4 Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5 Dead

6. BCLC Classification of HCC
Stage 0
PS 0; CP A
Single < 2 cm
Stage A-C
Early stage (A)
PS 0; CP A or B
Single < 5 cm or 3 nodules < 3 cm
Intermediate stage (B)
PS 0; CP A or B
Multinodular
Advanced (C) PS 1 -2;CP A or B Portal invasion, N1,M1
Stage D
PS > 2;CP C

7. Types of percutaneous therapy
Arterial therapy
cTACE-conventional transarterial chemoembolization Administration of chemotherapeutic agent mixed with ethiodal prior to arterial obstruction with embolic beads. Ethiodal is selectively retained within the tumor and prolongs chemotherapy dwell time.
DEB-TACE- drug eluting beads A bead loaded with chemotherapy that is trapped in the capillary bead of tumors slowly releasing chemotherapeutic agent into the tumor over days and decreasing systemic drug toxicity
TARE-transarterial radioembolization Radioembolization using beads loaded with yttrium that produce internal radiation centered within the tumor

8. Types of percutaneous therapy
Ablative therapy
PEI-percutaneous ethanol injection
RFA-radiofrequency ablation
Microwave- microwave ablation
IRE – Irreversible electroporation - non thermal ablation with electric current

9. Intermediate disease
Stage B
Multinodular (T3,T4a), PS 0, CP A and B No macrovascular invasion No extrahepatic disease
Survival without treatment is about 1.5 years
Therapies geared toward > 2 year survival
cTACE, DEB, TARE

10. cTACE
Chemotherapy-cytotoxic agent
CAM
Cisplatin
Doxorubicin
Mitomycin
Single agent
Cisplatin
Doxorubicin
Ebirubicin
Ethiodol (Lipiodol)
Embolization

11. Mechanism of cTACE
HCC exhibits intense new-angiogenic activity with blood supply progressing from the portal vein to the hepatic artery
Chemotherapy delivered in high concentration enhances coagulative tumor necrosis
Arterial obstruction results in ischemic tumor necrosis with a high rate of objective response
Perfusion to uninvolved liver is maintained by the portal vein permitting selective targeting of tumor

16. Author
Patients
% Survival 1,2, 3Y
Lo. Hepatology 2002;35:1164
Cisplatin
TACE
Palliative care
80 eligible patients
Hepatitis B-80%
40
40
57, 31,26
32, 11,3 (p=.02)
Llovet. Lancet 2002;359:1734 Doxorubicin
Embolization
TACE
Palliative care
112 RCT
Hepatitis C -80-90%
CP A or B;Okuda I, II
75,50
82, 63
63, 27 (p=.009)
Systemic review of randomized trials (7) Llovet.Hepatology 2003:37;429 TACE recommended as standard of care for Intermediate disease

17. Patient selection
Careful selection required due to concomitant ESLD
Bilirubin < 3.0
INR < 2.0
Platelet count > 50,000
Good performance status – ECOG 0 or 1
Limited embolization in ESLD

18. Complications
Common
Post embolization syndrome from arterial obstruction– fever, abdominal pain, nausea, ileus
Hepatic dysfunction
Bilirubin toxicity (Grade 3 or 4) in 20% at 1 year
Progressive deterioration with multiple treatments
Severe and uncommon
Systemic
Bone marrow depression
Alopecia
Liver failure
Worsening encephalopathy
Death
Gastrointestinal bleeding
Hepatic abscess
Cholecystitis

19. Challenges
Drug shortages
Ethiodol/Lipiodol
Powder Cisplatin
Powder Doxorubicin

20. DEB TACE LC Bead/DC Bead
Drug delivery system comprising biocompatible, non resorable hydrogel beads loaded with anthracyclin derivatives
Higher tumor concentrations and lower systemic concentrations of doxorubicin compared to cTACE
Better tolerated permitting repeat procedures in shorter intervals.

23. PRECISION V
212 patients with intermediate stage HCC not suitable for curative treatments and naive to chemotherapy or radiotherapy
Randomized to cTACE or DEB
Primary end point was MRI tumor response (EASL) at 6 months
Lammer.Cardiovasc Intervent Radiol 2010;33:41

24. Technique
cTACE
Selective injection of 50-75 mg/m2 doxorubicin – lipiodol emulsion
Embolization to stasis with gelatin sponge
DC Bead
Selective injection of 2 vials of DC Beads loaded with 150 mg Doxorubicin.
1 vial of 300-500 um beads
1 vial of 500-700 um beads
Embolization to stasis
Treatment at 2 month intervals for up to 3 sessions with follow up at 3 months
Lammer.Cardiovasc Intervent Radiol 2010;33:41

25. 6 Month response
DC Bead cTACE
% CR 27 22
% Objective response 52 44
% Disease control 63 52
Superiority was not found
Significant advantage in OR in advanced liver disease (CP B, ECOG 1, bilobar disease, recurrent disease patients).
Significant reduction in liver toxicity and lower rate of doxorubicin related side effects
Lammer.Cardiovasc Intervent Radiol 2010;33:41

26. TARE
Yttrium 90 is a β particle emitter as it decays to stable zirconium-90
Maximum penetration < 10mm (mean < 2.5 mm)
Half life of 64 hrs, mean life of 3.85 days
94% of radiation delivered in 11 days
Tumor to non-tumor uptake may triple the absorbed dose in tumor

27. 35 Gy
70-90 Gy
Curative Doses: Adenocarcinoma
Radiation hepatitis
Whole liver XRT
TARE
150 Gy
Andrews. J Nucl Med 1994;35:1637-1644 Herba. Semin Oncol 2002;29:152-159
Radiation pneumonitis
30 Gy
43 Gy
Focused XRT

28. Yittrium 90 Microspheres - Products
SIR-Spheres ® (Sirtex Medical Limited-Sydney, Australia
•20-30 μm resin spheres
•30-60 million spheres per dose
•50 Bq per sphere
•2002 FDA approval for colorectal liver metastases
TheraSphere ® (MDS Nordion-Ottawa ON, Canada)
•20-30 μm glass spheres
•3-8 million spheres per dose
• 2500 Bq per sphere
•2000 FDA approval (HDE) for HCC

29. Response
Imaging more difficult to interpret
Less embolization effect so enhancement not eliminated
Looking for changes in lesion size
Treatment response slow (6m)
Changes in liver morphology common

30. Y90 Results
Retrospective review of 245 B/C patients treated with cTACE vs 123 treated with y90 at a single institution
Abdominal pain and increased transaminase more frequent after cTACE
RR 49 vs 36% favored y90 (NS)
TTP 13.3 vs 8.4m favored y90 (p = .046)
Median survival 20.5 vs 17.4m (NS)
Intermediate disease survival 17.5 vs 17.2 (NS)
Salem. Gastroenterolgoy 2012;140:497

31. Cost
cTACE: < $1000
DEB: $1,500 per vial
Y90: $15-20,000 per vial
Sorafenib $5,400 /month

32. Advanced disease
Stage C
Portal invasion, N1,M1,PS 1-2, CP A and B
Survival without treatment .5 y
Therapies geared toward > 3 month survival benefit
Sorafenib advanced disease - increased survival from 7.9 - 10.7m
N Engl J MED 2008;359:378

33. cTACE, DEB TACE
cTACE
Retrospective review of 172 patients treated with cTACE –CAM
Median survival Stage A/B/C: 40.0/17.4/6.6m
DEB-TACE
Consecutive treatment of 121 patients with Stage C disease with DEB- TACE
Median survival 13.5m ( 17.8 m CP A)
Survival worse with T4b disease – 18.8 vs 4.4m in CP A patients
Lewandowski.Radiology 2010;255:955 Prajapati.J Vasc Interv Radiol 2013;24:307

34. Comparison to medical therapy
Retrospective evaluation of 97 Stage C patients with TACE (34) at a single institution or Sorafenib (63) at multiple institutions.
Results
TTP similar
Median survival 9.2 vs 7.4m favoring TACE (NS)
Pinter.Radiology 2012;263:590

35. Y90 Results
Phase 2 – prospective study of 52 patients with Intermediate (17) and Advanced disease (35) all with PVT looking at safety and efficacy with a mean fup of 36 m
Results:
TTP 11m ( 7 vs 13 m if PVT present (NS))
TR CR 10%
OR 40%
DC 79%
OS 15m (13 vs 18m if PVT present (NS))
Safety
Various grades of liver decompensation in 35% at 6 m (TACE 20%)
Mortality 3.8% at 90 d
Mazzaferro.Hepatology 2013:57:1826

36. Y90 emerging role
PVT
Advanced disease with well preserved liver function
Intermediate disease
Large lesions
Multiple bi-lobar nodules

37. Early stage disease (A)
Stage A
Single tumors < 5 cm, 3 nodules < 3 cm
CP A-B, PS 0-2
Therapies geared toward minimum median survival of 5 years
Resection
Transplantation
Ablation Role of percutaneous therapy is brideging and downstaging for transplant.

40. Ablation therapy
Recurrence rates with RFA appear lower than PEI at the expense of higher complications and cost
Complete response in 80% of tumors less than 3 cm and 50% if 3-5 cm
Best results – 5 year survival of 40-70%
Predictors of best results– Child-Pugh A, single tumors, less than 2 cm, initial response
Gervais. J Vasc Inaterv Radiol 2009;20.

41. RFA Complications
Morbidity 7%; Mortality , 1%
Bleeding requiring transfusion 1%
Abscess 1% - highest when biliary enteric anastomosis
Tract seeding < 1% with tract coagulation-
Gervais. J Vasc Inaterv Radiol 2009;20.

42. Current Role of RFA
Indications
Primary treatment instead of partial hepetectomy for lesions < 3 cm
Unresectable small HCC
Recurrent small HCC
Bridging therapy before liver transplantation
Increasing role in 3-5 cm lesions
Chen: solitary HCC < 5 cm
4 year survival 68% (46% DF) vs. 64% (51%DF)
Lu: solitary HCC < 5 cm or < 3 nodules < 3 cm
3 year survival: 87% (51% DF) vs.86% (82% DF)
Lau.Ann Surg 2009;249:20 Chen Ann Surg 2006;243:321 Lu Zhonghua Yi Xuwe Za Zhi 2006;86:801

43. Microwave
Electromagnetic radiation
More efficient energy deposition
Desiccation and charring not limiting
Changes in design decrease skin burns or pain
Faster heating, higher temperatures, larger ablation volumes, shorter ablation zones
Less susceptibility to heat sink
Maybe safer around bile ducts
Easier to use – no grounding pads, easier to run machine

44. 80 patients with HCC 3- 8cm (mFUP 32m)
CP A and B
< UNOS T4
23 with recurrent disease
Lesion size
52 - 3-5 cm
28 - 5-8 cm
Results
Complete ablation – 87.5%
94% cw 75% depending on size
22% local recurrence
15% vs 41% depending on size
Location near bile duct
54% distant recurrence
More frequent in recurrent HCC
Complications – 7.5% without mortality
1 tract seeding
Liu 2012 Clin Radiol 2012: 68;21
Role for microwave in larger lesions

45. Survival 1 2 3 5 years 81% 68% 56% 34%
Liu 2012 Clin Radiol 2012: 68;21

46. Conclusions
Strong evidence:
cTACE for Stage B patients suggesting disease control and benefit over medical therapy
Equivalency of DC Bead cw cTACE in Stage B patients with lower toxicity ( and y90 is also equivalent with further reduction in toxicity)
DEB-TACE and y90 may provide better results in selected Stage C patients than Sorafenib
Similar survival outcomes with ablation cw resection for small Stage 0- A tumors
RFA best results in Stage A disease but microwave is increasing the success in Stage B disease