Treating HCC: TACE and RFA

Janette Durham, MD

University of Colorado

May 2013

No disclosures

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.

Prognostic factors in treatment of HCC

Tumor status (number and size, portal

invasion, extrahepatic disease)

Performance status-ECOG

Liver function – CP

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

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

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

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

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

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

cTACE Chemotherapy-cytotoxic agent

CAM

Cisplatin

Doxorubicin

Mitomycin

Single agent

Cisplatin

Doxorubicin

Ebirubicin

Ethiodol (Lipiodol)

Embolization

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

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

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

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

Challenges

Drug shortages

Ethiodol/Lipiodol

Powder Cisplatin

Powder Doxorubicin

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.

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

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

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

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

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

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

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

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

Cost

cTACE: < $1000

DEB: $1,500 per vial

Y90: $15-20,000 per vial

Sorafenib $5,400 /month

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

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

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

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

Y90 emerging role

PVT

Advanced disease with well preserved liver

function

Intermediate disease

Large lesions

Multiple bi-lobar nodules

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.

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.

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.

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

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

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

Survival 1 2 3 5 years

81% 68% 56% 34%

Liu 2012 Clin Radiol 2012: 68;21

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