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Embolization of HCC: Embolization of HCC: Cocktails, Beads, Hot, or Cocktails, Beads, Hot, or Bland- Bland- Does it make any difference? Does it make any difference? vs. vs. Doxy Bead Man

HCC EMBOLIZATION

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Embolization of HCC:Embolization of HCC:Cocktails, Beads, Hot, or Bland-Cocktails, Beads, Hot, or Bland-Does it make any difference?Does it make any difference?

vs.vs.

Doxy Bead Man

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DisclosuresDisclosures

• Guerbet LLC, BTG – consultant, Guerbet LLC, BTG – consultant, researchresearch

• MERIT Medical– medical monitor, MERIT Medical– medical monitor, HiQUALITY trialHiQUALITY trial

• Sirtex – speaker, proctorSirtex – speaker, proctor• Cambridge University Press - royaltiesCambridge University Press - royalties

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Monday...

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www.io-central.org

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LipiodolLipiodol®® History HistoryDiscovered in 1901 by Guerbet and LafayDiscovered in 1901 by Guerbet and LafayUsed as a vector of Iodine for tuberculosis, syphilis, Used as a vector of Iodine for tuberculosis, syphilis,

rheumatoid arthritis, and goiterrheumatoid arthritis, and goiterIn 1926 LipiodolIn 1926 Lipiodol®® becomes the first iodinated contrast becomes the first iodinated contrast

medium used in radiologymedium used in radiology

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LipiodolLipiodol®® History History1951, development of Lipiodol1951, development of Lipiodol®® UltraFluid (ethyl esters of Lipiodol UltraFluid (ethyl esters of Lipiodol®®))1957, used in endemic goiter (IM injection) and for lymphography1957, used in endemic goiter (IM injection) and for lymphography1986, oral Lipiodol for goiter1986, oral Lipiodol for goiter

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Lipiodol in the LiverLipiodol in the LiverPortal Vein Portal Vein Idezuki Y, Sugiura M, Hatano S, Kimoto S. Hepatography for

detection of small tumor masses in the liver; experiences with oily contrast medium. Surgery 1966;60:572

Intraoperative injection of Lipiodol into SMV tributary in 37 patients, followed by xrays +/- tomography on Day 0, 3, 7, and 14. “Hepatograms were succcessfully used in the diagnosis of space-occupying lesions in the liver.”

Hepatic ArteryLaval-Jeantet M, Tristant H, Guerbet M, et al. Une nouvelle méthode d'hépatographie lipiodolée par voie intra-artérielle. J Radiol Electrol 1972; 53:29-34.“Twelve clinical cases let appear the value of the method in the detection of intra-hepatic tumoral masses.”

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Lipiodol in the LiverLipiodol in the Liver• First use of Lipiodol for chemoembolizationFirst use of Lipiodol for chemoembolization• ““In 1981, Prof. Konno who used for the first time In 1981, Prof. Konno who used for the first time

lipiodol, said that if we injected Lipiodol directly into lipiodol, said that if we injected Lipiodol directly into the hepatic artery of patients with hepatocellular the hepatic artery of patients with hepatocellular carcinoma, it  binds selectively to the tumor and carcinoma, it  binds selectively to the tumor and accumulates for prolonged periods up to several accumulates for prolonged periods up to several months.”months.”Bonnemai B, Guerbet M. Histoire du Lipiodol (1901-1994) ou Bonnemai B, Guerbet M. Histoire du Lipiodol (1901-1994) ou Comment un médicament peut évoluer avec son tempsComment un médicament peut évoluer avec son temps. . In: Revue In: Revue d'histoire de la pharmacie, 83e année, N. 305, 1995. pp. 159-170.d'histoire de la pharmacie, 83e année, N. 305, 1995. pp. 159-170.

• 1983 1983 - First publications of diagnostic and therapeutic - First publications of diagnostic and therapeutic Lipiodol via the hepatic artery for HCC.Lipiodol via the hepatic artery for HCC.

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Tumor Necrosis: Oil +/- Tumor Necrosis: Oil +/- ParticleParticle

Rate of complete tumor necrosis on Rate of complete tumor necrosis on explant:explant:

Main TumorMain Tumor Daughter Daughter NodulesNodules

DoxDox//LipiodolLipiodol//GelfoamGelfoam

83%83% 53%53%

DoxDox//LipiodolLipiodol 13%13% 6%6%

LipiodolLipiodol only only 0%0% 0%0%

Takayasu K, RAD 1987;163:345-51

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Survival: Particle +/- OilSurvival: Particle +/- OilSurvivalSurvival DoxDox/Gelfoam//Gelfoam/

LipiodolLipiodolDoxDox/Gelfoam/Gelfoam

N = 100N = 100 N = 104N = 104

1 year1 year 54%54% 45%45%

2 year2 year 33%33% 16%16%

3 year3 year 18%18% 4%4%

Nakamura H, RAD 1989;170:783-86

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Hydrophilic vs. Lipophilic DrugsHydrophilic vs. Lipophilic Drugs

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Water-in-Oil Emulsion• Specific gravity of contrast adjusted to match Lipiodol Ultra-Fluide

• 8.5ml Conray 43 + 1.5ml sterile water• Mix at oil:chemo ratio of 1-2:1

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Lipiodol as a Drug Carrier

OilW/OO/W

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Copyright © 2011 by the American Roentgen Ray Society

Takayasu, K. et al. Am. J. Roentgenol. 2000;175:699-704

Lipiodol is - Tumor selective- A drug carrier- An imaging biomarker for response...

+ Dox in resected HCC @ 1-2 mo

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...and Survival!...and Survival!

• El Khaddari S, El Khaddari S, Gastroenterol Clin Biol. 2002;26:728-34.Gastroenterol Clin Biol. 2002;26:728-34.Figure 4. Courbe de survie selon la fixation lipiodolée.Survival curve according to lipiodol tumor uptake.

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Oil Retention vs. Survival

Kim, AP&T 2012;35:1343

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Lipiodol Chemoembolization of HCC: Lipiodol Chemoembolization of HCC: Randomized TrialsRandomized Trials

1)1)Lo et al., Hepatology 2002Lo et al., Hepatology 200280 Patients, 80% hep. B +, 7 cm tumors (60% 80 Patients, 80% hep. B +, 7 cm tumors (60% multifocal)multifocal)

2) 2) Llovet et al., Lancet 2002Llovet et al., Lancet 2002 112 Patients, 80% hep. C +, 5 cm tumors (70% 112 Patients, 80% hep. C +, 5 cm tumors (70%

multifocal)multifocal)

Survival 1 year 2 years 3 yearsTACE 57% 31% 26%BSC 32% 11% 3%

Survival 1 year 2 yearsTACE 82% 63%BSC 63% 27%

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15

What about bland?What about bland?

15

1-year 2-year 3-year HR

Control 63% 27% 17%

Chembo 82% 63% 29% 0.47 [0.25-0.91] p=0.02

Bland 75% 50% 29% 0.57 [0.31-1.04] p=0.07

Llovet, Lancet 2002

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Bland vs ChemoembolizationBland vs ChemoembolizationHCC all-comers US populationHCC all-comers US population

16

N=3221 yr 66%2 yr 46%3 yr 33%

N = 2061 yr 64%2 yr 39%3 yr 28%

Microspheres (MSKCC)Maluccio, JVIR 2008;19:862

CAM/Lip/PVA (U Penn)Weiss, WCIO 2008

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GIDEON 2nd Interim AnalysisGeschwind et al, ASCO GI 2012

J Clin Oncol 30, 2012 (suppl 4; abstr 317)

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9

DEB Chemoembolization of HCC:DEB Chemoembolization of HCC:Randomized Trials - Precision VRandomized Trials - Precision V

9

Lammer, CVIR 2010

p = 0.11

6-month Imaging Response

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DEB Chemoembolization of HCC:DEB Chemoembolization of HCC:Randomized Trials - DEB vs. BlandRandomized Trials - DEB vs. Bland

• Major hepatic complications: DEB 17% vs. bland 2%Major hepatic complications: DEB 17% vs. bland 2%• Relative risk of biloma/infarct DEB vs. oil 9.8:1Relative risk of biloma/infarct DEB vs. oil 9.8:1

BlandBlandN = 41N = 41

DEBDEBN = 43N = 43

6 mo6 mo 100%100% 100%100%

9 mo9 mo 95%95% 97.5%97.5%

12 mo12 mo 86%86% 85%85%

Malagari, CVIR 2010;33:541-51; Guiu, J Hepatol 2012;56:609

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MRI of Iron-labeled DEBs 300-500 micron

Source: Journal of Vascular and Interventional Radiology 2008; 19:1490-1496 (DOI:10.1016/j.jvir.2008.06.008 )

Copyright © 2008 SIR Terms and Conditions

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MRI of Iron-labeled DEBs 100-300 micron

Source: Journal of Vascular and Interventional Radiology 2008; 19:1490-1496 (DOI:10.1016/j.jvir.2008.06.008 )

Copyright © 2008 SIR Terms and Conditions

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Source: Journal of Vascular and Interventional Radiology 2010; 21:259-267 (DOI:10.1016/j.jvir.2009.10.026 )

Copyright © 2010 SIR Terms and Conditions

Fluorescence Imaging of Doxorubicin Eluting Bead

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DEB Adverse Events:DEB Adverse Events:Hepatobiliary necrosis due to dox in normal tissueHepatobiliary necrosis due to dox in normal tissueNon-target injuries due to lack of image guidanceNon-target injuries due to lack of image guidance

*Malagari CVIR 2011;34:774 ** Brown JVIR 2012;23:287

N = 267 DEB* SIR QI**Guidelines

grade 4-5 hepatobiliary injury 5.5% 4%cholecystitis 5.5% <1%skin injury 0.8%GI injury 0.8% <1%pancreatitis 0.5%

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Retrospective Cohort Analysis:Retrospective Cohort Analysis:Y-90 vs. CE of HCCY-90 vs. CE of HCC

Overall Survival, p=0.78

•AFP & Imaging response equivalent•No difference in morbidity•Median TTP:Y-90 13.3 mo vs. CE 8.4 mo

p=0.046

Salem, Gastro 2011;140:497

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Is anything better than cTACE?Is anything better than cTACE?

18

DEB Y90 sorafenib

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Hepatic Embolotherapy:Hepatic Embolotherapy:Cocktails, Beads, Hot, or Bland-Cocktails, Beads, Hot, or Bland-Does it make any difference?Does it make any difference?

Probably notProbably notCaveats:Caveats:Cardiac, hematologic, renal insufficiency- Cardiac, hematologic, renal insufficiency- blandblandExtrahepatic collaterals - blandExtrahepatic collaterals - blandLimiting PES a priority (frail, caretaker) - Y-Limiting PES a priority (frail, caretaker) - Y-9090Whipple/ biliary stent - Y-90Whipple/ biliary stent - Y-90

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