This document discusses treatment options for hepatocellular carcinoma (HCC), focusing on transarterial chemoembolization (TACE) and radiofrequency ablation (RFA). It stratifies HCC using the Barcelona criteria and examines prognostic factors. For intermediate stage HCC, TACE is the standard treatment and can provide 1, 2, and 3 year survival rates of 57%, 31%, and 26% respectively. Newer techniques like drug-eluting bead TACE may have fewer side effects than conventional TACE. RFA provides the best results for tumors under 3cm, with a 5 year survival of 40-70% for eligible patients. The document compares various locoregional therapies and their roles based on

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