The Role of Interventional Radiology (Locoregional … · Richard Owen MB, MRCP, FRCR ... o The...

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The Role of Interventional Radiology (Locoregional

therapies) in HCC

The Role of Interventional Radiology (Locoregional

therapies) in HCC

Richard Owen MB, MRCP, FRCRInterventional Radiology,

Associate Professor University of Alberta

Aldo Montana-Loza MD, FRCPCHepatology

Assistant Professor University of Alberta

Richard Owen MB, MRCP, FRCRInterventional Radiology,

Associate Professor University of Alberta

Aldo Montana-Loza MD, FRCPCHepatology

Assistant Professor University of Alberta

Western Canadian Gastrointestinal Cancer Consensus Conference - Winnipeg

DisclosureDisclosure

Received honorarium, research support, summer student support, consulted forCook Inc, Covidian, Gore Inc, Boston

Scientific,

Site PI for a MDT ‘STOP HCC trial’ of Sorafanib +/- Therasphere

Received honorarium, research support, summer student support, consulted forCook Inc, Covidian, Gore Inc, Boston

Scientific,

Site PI for a MDT ‘STOP HCC trial’ of Sorafanib +/- Therasphere

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What are the Locoregional therapies?What are the Locoregional therapies?

Radio Frequency Ablation (RFA)Percutaneous Ethanol Injection (PEI)

Cryotherapy (Similar Principles to RFA)

Trans Arterial Chemo Embolization (TACE)Drug eluting bead/traditional

Selective Internal Radiation Treatment (SIRT)Therasphere

Radio Frequency Ablation (RFA)Percutaneous Ethanol Injection (PEI)

Cryotherapy (Similar Principles to RFA)

Trans Arterial Chemo Embolization (TACE)Drug eluting bead/traditional

Selective Internal Radiation Treatment (SIRT)Therasphere

Where do Locoregional treatments fit in?

Where do Locoregional treatments fit in?

SIRT

RFA TACE

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The problem with the Liver in HCCThe problem with the Liver in HCC

Advanced tumours at presentationLife expectancy 7.9mths (Sorafanib trial – Control arm)

Advanced liver disease at presentationMajority have underlying Cirrhosis

Adverse tumor characteristics (portal vein invasion)Non sensitive to traditional external beam radiationPoor response to systemic chemotherapySorafanib

Max 3/12 improvementUp to 50% cannot tolerate Rx

Advanced tumours at presentationLife expectancy 7.9mths (Sorafanib trial – Control arm)

Advanced liver disease at presentationMajority have underlying Cirrhosis

Adverse tumor characteristics (portal vein invasion)Non sensitive to traditional external beam radiationPoor response to systemic chemotherapySorafanib

Max 3/12 improvementUp to 50% cannot tolerate Rx

Measures of CLDMeasures of CLD

MELD ScoreDeveloped in 1994 to asses risk for patients undergoing TIPPS

procedures 3.8 x log (e) (bilirubin mg/dL) + 11.2 x log (e) (INR) + 9.6 log (e)

(creatinine mg/dL)

Actually is ‘What is the risk of dying with liver disease in the next 3 months’

Child Pugh score2 year survival

A = 85%B = 57%C = 35%

MELD ScoreDeveloped in 1994 to asses risk for patients undergoing TIPPS

procedures 3.8 x log (e) (bilirubin mg/dL) + 11.2 x log (e) (INR) + 9.6 log (e)

(creatinine mg/dL)

Actually is ‘What is the risk of dying with liver disease in the next 3 months’

Child Pugh score2 year survival

A = 85%B = 57%C = 35%

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Radio Frequency ablation (RFA)Radio Frequency ablation (RFA) A radio frequency generator provides a source of

radiofrequency An active electrode (needle) is inserted into the body (liver), the

dispersive electrode is on the skin surface (grounding pad) An electric field is produced around the electrodes, the needle

has a much higher field around it than the grounding electrode The RF causes charged ions to oscillate and friction causes the

tissues to heat. Temperatures above 45c cause irreversible cell damage and

apoptosis Needle tip temperatures are recorded as a reflection of the tissue

temperatures

A radio frequency generator provides a source of radiofrequency

An active electrode (needle) is inserted into the body (liver), the dispersive electrode is on the skin surface (grounding pad)

An electric field is produced around the electrodes, the needle has a much higher field around it than the grounding electrode

The RF causes charged ions to oscillate and friction causes the tissues to heat.

Temperatures above 45c cause irreversible cell damage and apoptosis

Needle tip temperatures are recorded as a reflection of the tissue temperatures

RFARFA

Impedance may also be used to measure tissue dessication and indirectly temperature

Temperature of >90 are undesirable as charring and gas formation occur and inhibit needle function

Impedance may also be used to measure tissue dessication and indirectly temperature

Temperature of >90 are undesirable as charring and gas formation occur and inhibit needle function

Day case procedure, usually under sedation onlyUltrasound usual guidance modalityMay use CT

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Principles of TreatmentPrinciples of Treatment

Zone of ablation exceeds diameter of lesion (ie ‘surgical’ margin)

Adjacent tissues (both inside and outside liver) must be considered when zone of ablation is planned

RFA is non specific (ie will kill all tissues –including the ones you want to preserve within the heat radius of 45 degrees)

Zone of ablation exceeds diameter of lesion (ie ‘surgical’ margin)

Adjacent tissues (both inside and outside liver) must be considered when zone of ablation is planned

RFA is non specific (ie will kill all tissues –including the ones you want to preserve within the heat radius of 45 degrees)


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Different tissues and materials conduct heat differently

Heat ‘sink’ effect of flowing blood may preserve tissue viability within the ‘kill zone’ (ie adjacent to IVC)

Different tissues and materials conduct heat differently

Heat ‘sink’ effect of flowing blood may preserve tissue viability within the ‘kill zone’ (ie adjacent to IVC)

RFA Pre and PostRFA Pre and Post

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ContraindicationsContraindications

Uncorrectable coagulopathyInability to image the lesion (position)Subcapsular and ExophyticHilarAdjacent to large vessels (IVC/Major Portal

vein)Immediately adjacent to the gall bladder>5cm diameter

Uncorrectable coagulopathyInability to image the lesion (position)Subcapsular and ExophyticHilarAdjacent to large vessels (IVC/Major Portal

vein)Immediately adjacent to the gall bladder>5cm diameter

Complications of RFAComplications of RFA3554 lesions in 2320 patients

Procedure related mortality (0.3%)

Major complications (2.2%)Bleeding, tract seeding, infection

Minor Complications (4.7%)Burns, biloma, gallbladder injury

3554 lesions in 2320 patients

Procedure related mortality (0.3%)

Major complications (2.2%)Bleeding, tract seeding, infection

Minor Complications (4.7%)Burns, biloma, gallbladder injury

Livraghi et al – Radiology – Treatment of Focal Liver Tumors with Percutaneous Radio-Frequency Ablation: Complications in a MultiCenter study.

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Trans Arterial Embolization +/-Chemo

Trans Arterial Embolization +/-Chemo

o The occlusion of tumor blood supply to induce infarction, with or without the addition of chemotherapy

o Embolization induces ischaemia and may increase the effectiveness of some chemo drugs and increase the inter tumoral concentrations

o Liver has dual blood supply protecting against infarction and severe liver injury

o Tumor blood supply primarily from hepatic artery, there may be a solitary feeder

o Tumor hypervascular c/w background parenchyma

o The occlusion of tumor blood supply to induce infarction, with or without the addition of chemotherapy

o Embolization induces ischaemia and may increase the effectiveness of some chemo drugs and increase the inter tumoral concentrations

o Liver has dual blood supply protecting against infarction and severe liver injury

o Tumor blood supply primarily from hepatic artery, there may be a solitary feeder

o Tumor hypervascular c/w background parenchyma

Trans Arterial Embolization +/_ Chemo (TACE)

Trans Arterial Embolization +/_ Chemo (TACE)

Bland EmbolizationParticulate embolics

Polyvinyl alcohol (contour© etc)PLGAAcrylic co polymer (Embospheres©

Conventional TACE (lipiodol emulsion)Introduced intra arterially via catheterFeeding vessels occluded with particulate emboli50 mg Doxyrubricin (Cisplatin/Mitomycin)

Drug Eluting Bead technology (DEB TACE)

Bland EmbolizationParticulate embolics

Polyvinyl alcohol (contour© etc)PLGAAcrylic co polymer (Embospheres©

Conventional TACE (lipiodol emulsion)Introduced intra arterially via catheterFeeding vessels occluded with particulate emboli50 mg Doxyrubricin (Cisplatin/Mitomycin)

Drug Eluting Bead technology (DEB TACE)

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Exclusion Criteria for TACEExclusion Criteria for TACE

Age > 80 years

Advanced liver disease (Childs C) Bili >34 µmol/l*

Main portal vein occlusion*

Extrahepatic spread or Metastatic disease

Renal failure (Creatinine >250 µmol/l)*

Age > 80 years

Advanced liver disease (Childs C) Bili >34 µmol/l*

Main portal vein occlusion*

Extrahepatic spread or Metastatic disease

Renal failure (Creatinine >250 µmol/l)*

* Absolute Contra-indication

DEB (Drug Eluting Beads)DEB (Drug Eluting Beads)

DC Beads/Hepaspheres

Chemo Drug (Doxorubricin or Irinotecan) contained within polymer beads

Drug added few hours prior to Rx Diffuses into bead (diffuses out)

DC Beads/Hepaspheres

Chemo Drug (Doxorubricin or Irinotecan) contained within polymer beads

Drug added few hours prior to Rx Diffuses into bead (diffuses out)

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Drug Eluting Beads c/w Conventional TACE

Drug Eluting Beads c/w Conventional TACE

AdvantagesDecreased systemic and hepatic toxicity (Day case

procedure)Improved Tumor response*Embolic agent combinedMore predictable endpointEasier to detect recurrence, easier to RF

DisadvantagesExpensive ($1495/vial)Different complications and endpointVisualization of Rx zones more difficult

AdvantagesDecreased systemic and hepatic toxicity (Day case

procedure)Improved Tumor response*Embolic agent combinedMore predictable endpointEasier to detect recurrence, easier to RF

DisadvantagesExpensive ($1495/vial)Different complications and endpointVisualization of Rx zones more difficult

*Level 2

Safety Profile of DEBSafety Profile of DEB

237 Patients

37.5 mg/ml

30 day mortality 1.26%

Grade 4 complications 5.48%

PES 86.5%

Cholecystitis 5.48%

Grade 2 liver function deterioration 4.2%

237 Patients

37.5 mg/ml

30 day mortality 1.26%

Grade 4 complications 5.48%

PES 86.5%

Cholecystitis 5.48%

Grade 2 liver function deterioration 4.2%

Athens – Dec 2010 - CVIR

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11 Jan 10AFP NormalCreat NormBili 25-531 vial DC Beads

2nd and 3rd Bead RxFeb 9, Mar 24, Jun 25 20105 Vials Total (100-300 x3,300-5– x 2)No Bilirubin change

CT’s after 1st and 2nd Rx

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• Radioembolization with Yttrium-90 is a novel form of liver-directed brachytherapy

• Radiolabeled glass beads 30-50µm in diameter are injected into the hepatic artery, become trapped at the precapillary level, and emit lethal internal radiation (Beta emitter T1/2 64.6 hours .9367 MeV); limiting exposure to the surrounding normal parenchyma, and allowing higher dose delivery than with an external beam

Tumor cells sensitive to radiation doses of >100 Gy,Material made by placing Yttrium 89 in a nuclear reactorand adding a Neutron, decays to stable Zirconium 90

• Radioembolization with Yttrium-90 is a novel form of liver-directed brachytherapy

• Radiolabeled glass beads 30-50µm in diameter are injected into the hepatic artery, become trapped at the precapillary level, and emit lethal internal radiation (Beta emitter T1/2 64.6 hours .9367 MeV); limiting exposure to the surrounding normal parenchyma, and allowing higher dose delivery than with an external beam

Tumor cells sensitive to radiation doses of >100 Gy,Material made by placing Yttrium 89 in a nuclear reactorand adding a Neutron, decays to stable Zirconium 90

Selective Internal Radiation Therapy (SIRT) with Y90 (Therasphere)

Appropriate PatientsAppropriate Patients

• Advanced HCC not amenable to other treatments

Bridge to transplantationDownstaging to resection, transplant or RFALarge or multifocal tumoursPortal vein involvement

• Advanced HCC not amenable to other treatments

Bridge to transplantationDownstaging to resection, transplant or RFALarge or multifocal tumoursPortal vein involvement

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Advantages of Therasphere over TACE (and other palliative

treatments)

Advantages of Therasphere over TACE (and other palliative

treatments)Outpatient procedure

Better tolerated than TACE (Esp in elderly)

Wider indicationsLarge tumours (up to 70% liver volume)

Portal vein thrombus

Can be used in patients with worse synthetic function (bilirubin up to 50 µm/L)

Single treatment per lobe (c/w multiple TACE procedures)

Outpatient procedure

Better tolerated than TACE (Esp in elderly)

Wider indicationsLarge tumours (up to 70% liver volume)

Portal vein thrombus

Can be used in patients with worse synthetic function (bilirubin up to 50 µm/L)

Single treatment per lobe (c/w multiple TACE procedures)

Follow up CT’s at 4,7 and 10 months

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Adverse Events (121Rx)Adverse Events (121Rx)

Transient Elevation in Bilirubin (23%)Severe (7%)

GI tract Ulceration (4.1%)

Cholecystitis (1.7%)

Hepatic Failure (1.7%)

Hepatic Abscess (<1%)

Transient Elevation in Bilirubin (23%)Severe (7%)

GI tract Ulceration (4.1%)

Cholecystitis (1.7%)

Hepatic Failure (1.7%)

Hepatic Abscess (<1%)

Barcelona Clinic Liver CancerStaging Classification (BCLC)Barcelona Clinic Liver CancerStaging Classification (BCLC)

Liver transplantation(CLT/LDLT)Liver transplantation(CLT/LDLT) PEI/RFAPEI/RFA SorafenibSorafenib

Curative treatmentsTarget: 30-40% Median OS >60 months; 5 years survival 40-70%

Curative treatmentsTarget: 30-40% Median OS >60 months; 5 years survival 40-70%

Target: 20%OS: 20 months (SD 14-45)


ChemoembolizationChemoembolization

SingleSingle

IncreasedIncreased Associated diseasesAssociated diseases

NormalNormal NoNo YesYes

Terminalstage (D)Terminalstage (D)

Best Supportive Care

Stage A-CStage A-CPST 0-2, Child-Pugh A-BPST 0-2, Child-Pugh A-B

Multinodular, PST 0 Multinodular, PST 0

Portal invasion,N1, M1Portal invasion,N1, M1

Portal pressure / bilirubinPortal pressure / bilirubin

3 nodules <3 cm3 nodules <3 cm

Intermediate stage (B)Intermediate stage (B)

PST >2,Child-Pugh CPST >2,Child-Pugh C

Stage DStage D

Very early stage (0)Very early stage (0)Single <2 cmCarcinoma in situSingle <2 cmCarcinoma in situ

Early stage (A)Early stage (A)Single or 3 nodules<3 cm, PST 0Single or 3 nodules<3 cm, PST 0

Advanced stage (C)Advanced stage (C)Portal invasion,N1, M1, PST 1–2Portal invasion,N1, M1, PST 1–2

PST 0, Child-Pugh APST 0, Child-Pugh A

Stage 0Stage 0

ResectionResection

CLT/LDLT = cadaveric liver transplantation/living donor liver transplantation; PST = Performance Status Test CLT/LDLT = cadaveric liver transplantation/living donor liver transplantation; PST = Performance Status Test

Bruix J, et al. Hepatology 2011;51:1020Llovet JM et al. Nat Rev Gastroenterol Hepatol 2013;10:34

Bruix J, et al. Hepatology 2011;51:1020Llovet JM et al. Nat Rev Gastroenterol Hepatol 2013;10:34



Target: 10%OS: <3 months Target: 10%OS: <3 months

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BCLC Staging System BCLC Staging System

Marrero JA, et al. Hepatology 2005;41:707Marrero JA, et al. Hepatology 2005;41:707

100100

Sur

viva

l Pro

babi

lity

Sur

viva

l Pro

babi

lity

8080

6060

4040

2020

0000 1010 2020 3030 4040 5050 6060 7070

No at Risk:Stage A 64 51 25 8Stage B 60 22 11 4Stage C 76 10 3 1Stage D 39 7 1 0

No at Risk:Stage A 64 51 25 8Stage B 60 22 11 4Stage C 76 10 3 1Stage D 39 7 1 0

Log RankA vs. B P < .0001B vs. C P = .04C vs. D P = .01

Log RankA vs. B P < .0001B vs. C P = .04C vs. D P = .01

AA

BB

CCDD

Time (Months)Time (Months)

Locoregional Therapies for Hepatocellular CarcinomaLocoregional Therapies for Hepatocellular Carcinoma

Barcelona Clinic Liver CancerStaging Classification (BCLC)Barcelona Clinic Liver CancerStaging Classification (BCLC)

PEI/RFAPEI/RFA

Curative treatments50%-75% at 5 yearsCurative treatments50%-75% at 5 years

Randomized controlled trials 40%-50% at 3 years vs 10% at 3 yearsRandomized controlled trials 40%-50% at 3 years vs 10% at 3 years

Chemoembolization TACE/DEB/TAREChemoembolization TACE/DEB/TARE

Associated diseasesAssociated diseases

YesYes

Stage A-CStage A-CPST 0-2, Child-Pugh A-BPST 0-2, Child-Pugh A-B

Multinodular, PST 0 Multinodular, PST 0

3 nodules <3 cm3 nodules <3 cm

Intermediate stage (B)Intermediate stage (B)Early stage (A)Early stage (A)Single or 3 nodules<3 cm, PST 0Single or 3 nodules<3 cm, PST 0

CLT/LDLT = cadaveric liver transplantation/living donor liver transplantation; PST = Performance Status Test CLT/LDLT = cadaveric liver transplantation/living donor liver transplantation; PST = Performance Status Test

Bruix J, et al. Hepatology 2011;51:1020Bruix J, et al. Hepatology 2011;51:1020

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Author Treatment (n)

OverallSurvival

LocalRecurrence

CompleteResponse

Prognostic Factors

Lencioni RA, et al. Radiology 2003

PEI: 50RFA: 52

88%98%

At 2 yearsP=0.13

62%96%

At 2 yearsP=0.001

82%91%

For recurrence:Treatment (RFA vs. PEI)Tumor size (≥3 vs. <3cm)Bilirubin level ≥34.2 vs. <34.2 μmol/L

Lin SM, et al. Gastroenterology 2004

PEI:52PEI-HD: 53RFA: 52

50%55%74%

At 3 years**P<0.02

45%33%18%

At 3 years**P<0.03

88%92%96%

For survival and recurrence:Tumor size (≥3 vs. <3cm)Tumor differentiation (I vs. II-III)Treatment (RFA vs. PEI/PEI-HD)

Shiina S, et al. Gastroenterology 2005

PEI: 114RFA: 118

57%74%

At 4 yearsP=0.01

11%1.7%

At 4 years P=0.003

NR For survival: Treatment (RFA vs.PEI )For local recurrences: Treatment (RFA vs. PEI )Cirrhosis vs. chronic hepatitisProthrombin time (≤80 vs. >80)Tumor number (multiple vs. single)Tumor grade (I vs. II-III)

Lin SM, et al.Gut 2005

PEI: 62PAI: 63RFA: 62

51%53%74%

At 3 years *P=0.04

34%31%14%

At 3 years*P=0.01

88.1%92.4%96.1%

For survival and recurrence:Tumor size (≥2 vs. <2 cm)Differentiation grade (III-IV vs. I-II)Treatment (RFA vs. PEI/PAI)

Brunello F, et al. Scand J Gastroenterol 2008

PEI: 69RFA: 70

56.7%58.9%

At 3 yearsP=0.47

NR 36.2% 65.7%

At 1 yearP=0.0005

For survival:Child-Pugh BAge

Orlando A, et al. Am J Gastroenterol 2009

PEI: 347RFA: 354

OR=1.92 1.35 -2.74)

RFA vs. PEI

OR=0.29 (0.18- 0.47)RFA vs. PEI

OR=2.28(1.46-3.35)

RFA vs. PEI

NR

RCT and and Meta-Analyses Comparing RFA versus PEI

Summary for Ablation Therapy Summary for Ablation Therapy


• RFA standard percutaneous ablation treatment for pts with lesions ≤3cm (single or up to 3 lesions), and single lesion ≤5cm

• Not candidates for liver resection or liver transplant • Well preserved liver function (Child-Pugh A or B) and good

performance status (BCLC Stage A-C) • Recommendation grade A

• PEI should be reserved only when RFA is not available or not technically possible (pericholecystic and subcapsular lesions and lesions near the hilum)• Recommendation grade B

• RFA standard percutaneous ablation treatment for pts with lesions ≤3cm (single or up to 3 lesions), and single lesion ≤5cm

• Not candidates for liver resection or liver transplant • Well preserved liver function (Child-Pugh A or B) and good

performance status (BCLC Stage A-C) • Recommendation grade A

• PEI should be reserved only when RFA is not available or not technically possible (pericholecystic and subcapsular lesions and lesions near the hilum)• Recommendation grade B

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Randomized Control Trails and Meta-Analyses of TACERandomized Control Trails and Meta-Analyses of TACEAuthor Pts

(n)Treatment Mean (n)

SessionsOverall,

1 and 2 years survival

ResponseRates (%)

Prognostic Factors for Survival

Lin DY, et al. Gastroenterology 1988

212121

TAETAE+IV 5FUIV 5FU

2.11

42 and 25%20 and 20%13 and 13%

62489.5

NR

Pelletier G, et al. J Hepatol 1990

2121

TACE-Dox 50mgConservative tx

2 24%33%

330

NR

Trinchet JC, et al. N Engl J Med 1995

5046

TACE-Cis 70mgConservative treatment

2.9 62 and 38%43 and 26%

165

NR

Bruix J, et al Hepatology 1998

4040

TAEConservative treatment

1.4 70 and 49%72 and 50%

550

NR

Pelletier G, et al. J Hepatol 1998

3736

TACE-Cis 2mg/kg+TamTam

2.8 51 and 24%55 and 26%

245.5

NR

Lo CM, et al. Hepatology 2002

4039

TACE-Cis 30mgConservative treatment

4.5 57 and 31%32 and 11%

P=0.005

272.6

-TACE: RR of death: 0.49 (0.29-0.81); P =0.006-Portal vein obstruction RR of death 2.71 (1.38-5.32); P=0 .004

Llovet JM, et al. Lancet 2002

374035

TAETACE-Dox 25-75mg/m2Conservative treatment

3.12.8

75 and 50%82 and 63%63 and 27%

P=0.009

43350

-TACEOR: 0.45 (0.25-0.81), P=0.02-Treatment response OR: 0.59 (0.44-0.81), P=0.0007

Llovet JM, et al. Hepatology 2003

307238

Treatment groupControl group

1-4.5 41%27%

35 NR

Trans-Arterial ChemoembolizationTrans-Arterial Chemoembolization


Follow-up (mo)Follow-up (mo)

Sur

viva

l (%

)S

urvi

val (

%)

Pt followed (no.)

60 50 42 36 24 21 16 15 13 8 5 5 3

Pt followed (no.)

60 50 42 36 24 21 16 15 13 8 5 5 3

00

2020

4040

6060

8080

100100

00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424

Median survival after first TACE 19.4±3.8 mo (95% CI, 11.8-26.8)Probability of survival at 6-mo and 1-yr was 77%, and 69%

Median survival after first TACE 19.4±3.8 mo (95% CI, 11.8-26.8)Probability of survival at 6-mo and 1-yr was 77%, and 69%

Sawhney S, et al. Can J Gastroenterol 2011;25:426Sawhney S, et al. Can J Gastroenterol 2011;25:426

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Author Patients (n)

Studyphase

Treatments / Dose

Overall Survival

Objective Response**

PrognosticFactors

Varela M, et al. J Hepatol 2007

27 II 2 / 150mg At 1 year: 92.5%At 2 year: 88.9%

66.6% (EASL) NR

Poon RT, et al. Clin Gastroenterol Hepatol 2007

30 II 2 / 150mg NR 42.9% (RECIST+necrosis)

NR

Malagari K, et al. Cardiovasc Intervent Radiol 2008

62 II 3 / 150mg NR 70.8% (EASL) NR

Sadick M, et al. Onkologie 2010

24 II 2-3 / 160mg At 30months: 42%

NR NR

Lammer J, et al. Cardiovasc Intervent Radiol 2010

10893

III 3 / TACE 50-75mg/m2

3 / DC Bead 150mg NR43.5%51.6%(EASL) P=0.11

Better tumor response:Child-Pugh B Bilobar or recurrent diseaseP=0.02

Dhanasekaran R, et al. J Surg Oncol 2010

2645

III 1.46/ TACE 50 mg/m2

1.27/ DC Bead 75 mg284 days (4-563)610 days (351-868) P=0.03

NR Grade 5 clinical toxicity was similar

TACE with Drug-Eluting Bead

*Maximum doxorubicin dose per treatment. **Objective response: complete + partial response

Summary for TACE and DC Bead Summary for TACE and DC Bead


• Conventional TACE standard treatment for solitary lesions <8 cm or multinodular tumors (>3 lesions), with no evidence of extrahepatic disease (visceral or lymph node metastasis),

• Well preserved liver function (Child-Pugh A and early B) and performance status (BCLC A-C) • Recommendation grade A

• TACE with drug eluting-beads may be an option, particularly in pts with more advanced liver disease (Child Pugh B, BCLC C, bilobar or recurrent disease) or pts with mild-moderate cardiac failure • Recommendation grade B

• Conventional TACE standard treatment for solitary lesions <8 cm or multinodular tumors (>3 lesions), with no evidence of extrahepatic disease (visceral or lymph node metastasis),

• Well preserved liver function (Child-Pugh A and early B) and performance status (BCLC A-C) • Recommendation grade A

• TACE with drug eluting-beads may be an option, particularly in pts with more advanced liver disease (Child Pugh B, BCLC C, bilobar or recurrent disease) or pts with mild-moderate cardiac failure • Recommendation grade B

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Author N #Treatments/ dose*

Overall Survival Response rates

Prognostic factors

Kulik LK, et al. Hepatology 2008

108 68% had 1 tx31% had 2 tx PVT: 139.7 GyNo PVT: 131.9 Gy

No PVT: 15.6 moBranch PVT: 10 mo Main PVT: 4.5 mo P=0.0052

PR: 70% (EASL)PR: 42% (WHO)SD: 35% (WHO)

NR

Vente MA, et al. Eur Radiol 2009

425 NR 9.4-24 months PR: 16-72%SD: 29-65

NR

Salem R, et al. Gastroenterology 2010

291 No tx 1.8 / 103 Gy Child-Pugh A: 17.2 moChild-Pugh B: 7.7 moP =0.002

PR: 57% (EASL)PR: 42% (WHO)

Age <65, PS 0Absence of PHTSolitary lesionsBilirubin <2mg/dLAlbumin >3.5mg/LAFP <200ng/mlTumor response

Salem R, et al. Gastroenterology 2011

TACE 245TARE 123

2 (IQR 1–3) 1 (IQR 1–2)

Median survival times not statistically different (20.5 vs 17.4 mo, P = .232

Time-to-progression longer following TARE (13.3 vs 8.4 mo, P = .046)

Post hoc analyses of sample size indicated that randomized study with > 1000 pts would be required to establish equivalence of survival times between pts treated with these two therapies

Phase II Trials Using SIRT for Unresectable HCC

Author N #Treatments/ dose*

Overall Survival Response rates

Prognostic factors

Sangro S, et al. J Clin Oncol 2010

250 1.7 GBq 14.1 months NR Extrahepatic diseaseBilirubin level# nodulesCLIP classification

Mazzaferro V, et al. Hepatology 2013

52 120 Gy median OS was 15 months (95% confidence interval [CI], 12-18 months)

Five complete responses occurred (9.6%), Objective response was 40.4

tumor response was the sole variable affecting TTP (P < 0.001) and the second affecting survival (after Child-Pugh class)

Moreno-Luna LE, et al. Cardiovasc Intervent Radiol 2013

61 TAREmatched 55 TACE

120 Gy 15.0 mo TARE 14.4 mo TACE(P = 0.47)

Complete tumor response more common after TARE (12 %) TACE (4 %) (p = 0.17)

59 (97 %) TARE pts received outpatient treatment53 (98 %) TACE pts were hospitalized for ≥1 day (P < 0.001)

Phase II Trials Using SIRT for Unresectable HCC

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Trans-arterial Chemoembolization for Hepatocellular CancerTrans-arterial Chemoembolization for Hepatocellular CancerLocoregional Therapies for Hepatocellular CarcinomaLocoregional Therapies for Hepatocellular Carcinoma

Pre-treatment Features n (%) or mean ± SE

Age (years) 62 ± 2Male: Female 64: 7

Etiology of HCCAlcohol HBVHCVNASHOthers*

10 (14)11 (16)23 (32)9 (13)18 (25)

Bilirubin (μmol/L) 28±7INR 1.2±0.07Child-Pugh Classification

ABC

39 (55)27 (38)

5 (7)Child-Pugh (Points) 7±0.2MELD Score 10±1BCLC Staging Classification

BCD

44 (62)22 (31)

5 (7)

Features at Accession in Patients Receiving SIRT

Montano-Loza AJ, et al. J Hepatol 2013;58:S112


Tumor Characteristics in Patients Receiving SIRT

Tumor Characteristics n (%) or mean ±

SE

Location of the Tumors

Right Lobe

Left Lobe

Both

34 (48)

12 (17)

25 (35)

Maximum Diameter (cm) 8±1

Tumor Largest Diameter >8 cm 28 (39)

Number of Tumors 3.1±0.5

Single Tumor 38 (54)

≥3 Tumors 19 (27)

Portal vein thrombosis 22 (31)

AFP (μg/L) 1280±480


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Tumor Response Assessment after SIRT in Patients with HCC

Type of Tumor

Response

WHO

Criteria

RECIST

Criteria

EASL

Criteria

Complete Response 0 0 7 (12)

Partial Response 4 (7) 7 (12) 25 (43)

Stable Disease 45 (78) 41 (71) 26 (45)

Progressive Disease 9 (15) 10 (17) 0

WHO = World Health Organization; RECIST = Response Evaluation Criteria in Solid Tumors; EASL = European Association for the Study of the Liver Criteria


Follow-up (mo)Follow-up (mo)Pt followed (no.)

71 70 58 53 46 35 26 21 19 15 15 13 13Pt followed (no.)

71 70 58 53 46 35 26 21 19 15 15 13 13

00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424

00

2020

4040

6060

8080

100100

Sur

viva

l (%

)S

urvi

val (

%)

Median survival 12±2 mo (95% CI, 9-15)Median survival 12±2 mo (95% CI, 9-15)



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Features Associated Death(n=43)

Alive(n=28)

HR 95% CI P-value

Age (years) 62±2 61±3 0.99 0.97-1.01 0.5

Gender (M: F) 37: 6 27: 1 1.29 0.54-3.09 0.6

Ascites 20 (47) 4 (14) 2.38 1.29-4.36 0.005

Encephalopathy 4 (9) 1 (4) 7.48 2.42-23.17 <0.001

Creatinine (nl, 50-115 μmol/L) 87±5 80±4 1.00 0.99-1.01 0.7

INR (nl, 0.8-1.2) 1.3±0.1 1.2±0.05 1.55 1.05-2.28 0.03

Albumin (nl, 35-50 g/L) 36±1 37±1 0.94 0.88-0.99 0.02

Bilirubin (nl, <20 μmol/L) 31±11 23±4 1.01 1.003-1.01 0.002

Sodium (nl, 133-146 mmol/L) 138±1 138±1 0.97 0.88-1.06 0.5

MELD Score 10±1 9±1 1.16 1.08-1.25 <0.001

MELD ≥13 points 11 (26) 2 (7) 3.24 1.59-6.62 0.001

Child-Pugh (A/B/C) 22/18/3 18/8/2 2.83 1.62-4.92 <0.001

Child-Pugh (points) 7±0.5 6±0.5 1.39 1.14-1.68 0.001

Child-Pugh ≥8 points 12 (28) 4 (14) 3.18 1.60-6.34 0.001

BCLC Classification (B/C/D) 26/14/3 18/8/2 2.21 1.24-3.93 0.007

Tumor Largest Dimension (cm) 7±1 8±1 0.96 0.90-1.03 0.3

Tumor Largest Diameter >8 cm 14 (33) 14 (50) 0.81 0.42-1.53 0.5

Number of Tumors 2.8±0.5 3.5±1 0.98 0.91-1.06 0.6

≥3 Tumors 13 (30) 6 (21) 0.88 0.49-1.84 0.9

Alpha fetoprotein (ng/L) 993±540 1656±863 1.0 1.0-1.0 0.6

Portal vein thrombosis 14 (33) 8 (29) 1.46 0.75-2.85 0.3

Features Associated with Mortality after TARE by Univariate Cox Analysis


First Model Death

(n=43)

Alive

(n=28)

HR 95% CI P-value

MELD Score 10±1 9±1 1.11 1.02-1.21 0.02

Child-Pugh (A/B/C) 22/18/3 18/8/2 2.14 1.18-3.87 0.01

Second Model

Ascites 20 (47) 4 (14) 1.91 1.01-3.61 0.05

Encephalopathy 4 (9) 1 (4) 3.63 0.61-21.70 0.2

INR (nl, 0.8-1.2) 1.3±0.1 1.2±0.0

5

1.04 0.60-1.79 0.9

Albumin (nl, 35-50 g/L) 36±1 37±1 0.96 0.90-1.02 0.2

Bilirubin (nl, <20 μmol/L) 31±11 23±4 1.00 0.99-1.01 0.2

Features Associated with Mortality by Multivariate Cox Analysis


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Pt followed58 57 51 48 41 25 20 16 16 14 14 12 1213 12 7 5 5 5 2 2 2 1 1 1 1

Pt followed58 57 51 48 41 25 20 16 16 14 14 12 1213 12 7 5 5 5 2 2 2 1 1 1 1

00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424

00

2020

4040

6060

8080

100100

Sur

viva

l (%

)S

urvi

val (

%)

MELD ≤12MELD ≤12

MELD ≥13MELD ≥13

Log Rank, P=0.001 Log Rank, P=0.001




Pt followed (no.)55 54 50 47 42 32 25 20 18 14 14 12 12

16 15 8 6 4 3 1 1 1 1 1 1 1

Pt followed (no.)55 54 50 47 42 32 25 20 18 14 14 12 12

16 15 8 6 4 3 1 1 1 1 1 1 1

00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424

00

2020

4040

6060

8080

100100

Sur

viva

l (%

)S

urvi

val (

%)

Child-Pugh ≤7Child-Pugh ≤7

Child-Pugh ≥8Child-Pugh ≥8

Log Rank, P=0.001 Log Rank, P=0.001




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Summary for TARE Summary for TARE


• TARE promising results in phase II trials for locally advanced HCC

• RCT in comparison to conventional TACE/drug-eluting beads are needed

• TARE therapy appears to be safe in more advanced disease including portal vein invasion and larger tumors • Recommendation grade B

• TARE promising results in phase II trials for locally advanced HCC

• RCT in comparison to conventional TACE/drug-eluting beads are needed

• TARE therapy appears to be safe in more advanced disease including portal vein invasion and larger tumors • Recommendation grade B

Author Patients

(n)

Treatment Treatments(n)

Tumor Size

Overall Survival

TumorRecurrence

PrognosticFactors

Koda M, et al. Cancer 2001

2626

TACE+PEIPEI

3.85.3

<3cm<3cm

80.8 and 40.4%65.9 and 37.7%P=0.4

39.3 and 39.3%19.3 and 19.3%P=0.01

Tumors <2cm

Bartolozzi C, et al. Radiology 1995

2627

TACETACE+PEI

2-51

4.8cm5.1cm

69.7 and 43.4%86.7 and 72.2%P>0.1

64.1 and 70.1%35.6 and 48.4%P<0.05

NR

Becker G, et al. World J Gastroenterol 2005

2725

TACETACE+PEI

NRNR

>5cm: 63%>5cm: 68%

61.5 and 38.7%62.9 and 18%P=0.04

NR Okuda I

Akamatsu M, et al. Liver Int 2004

2220

TAE+PEI/RFAPEI / RFA

NRNR

100 and 82.4%95.5 and 82.2%P=0.6

0%25%P=0.04

NR

Marelli L, et al. Cancer Treat Rev 2006

10099

TACE+PEI/RFAvs. TACE or PEI/RFA

- - OR, 0.534(0.288-0.990)P=0.046

NR NR

Randomized Control Trials Comparing TACE versus TACE + Other Local Therapies

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Algorithm of Treatment for Patients with Hepatocellular Carcinoma Candidates for Locoregional Treatment

Meza-Junco J, et al. Cancer Treat Rev 2011;38:54Meza-Junco J, et al. Cancer Treat Rev 2011;38:54

Child-Pugh A or B,Single ≤3 cm, but up to ≤5 cm or3 nodules ≤3 cm

Locoregional Treatment for HCC

Percutaneous Ethanol Injection

Conventional Transarterial Chemoembolization

Portal Vein Thrombosis or Portal Vein invasion Larger Tumors

Child-Pugh A or B, Multinodular tumors (>3 lesions)Solitary Lesion >5 cm <8 cm

Radiofrequency Ablation

TACE with DC Bead

Transarterial Radioembolization

Pericholecystic, Subcapsular Lesions or Lesions Near the Hilum

Patients with more Advance Liver Disease or Heart Failure

The Role of Interventional Radiology (Locoregional … · Richard Owen MB, MRCP, FRCR ... o The...

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