This document discusses various methods of embolization for hepatocellular carcinoma (HCC), including the use of cocktails, beads, radioactive spheres, and bland embolization. It provides a brief history of the use of Lipiodol as a drug carrier and imaging biomarker. Randomized trials are summarized that compare chemoembolization using doxorubicin-eluting beads or Lipiodol to bland embolization or best supportive care, showing improved survival with the addition of chemotherapy. Adverse events are higher with doxorubicin-eluting beads compared to Lipiodol or bland embolization due to increased risk of hepatobiliary necrosis and non-target embolization.

1. 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

2. DisclosuresDisclosures
• Guerbet LLC, BTG – consultant, researchGuerbet LLC, BTG – consultant, research
• MERIT Medical– medical monitor,MERIT Medical– medical monitor,
HiQUALITY trialHiQUALITY trial
• Sirtex – speaker, proctorSirtex – speaker, proctor
• Cambridge University Press - royaltiesCambridge University Press - royalties

3. Monday...

4. www.io-central.org

5. LipiodolLipiodol®®
HistoryHistory
Discovered in 1901 by Guerbet and LafayDiscovered in 1901 by Guerbet and Lafay
Used as a vector of Iodine for tuberculosis, syphilis, rheumatoidUsed as a vector of Iodine for tuberculosis, syphilis, rheumatoid
arthritis, and goiterarthritis, and goiter
In 1926 LipiodolIn 1926 Lipiodol®®
becomes the first iodinated contrast medium usedbecomes the first iodinated contrast medium used
in radiologyin radiology

6. LipiodolLipiodol®®
HistoryHistory
1951, development of Lipiodol1951, development of Lipiodol®®
UltraFluid (ethyl esters of LipiodolUltraFluid (ethyl esters of Lipiodol®®
))
1957, used in endemic goiter (IM injection) and for lymphography1957, used in endemic goiter (IM injection) and for lymphography
1986, oral Lipiodol for goiter1986, oral Lipiodol for goiter

7. Lipiodol in the LiverLipiodol in the Liver
Portal VeinPortal 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 Artery
Laval-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.”

8. 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 lipiodol, saidIn 1981, Prof. Konno who used for the first time lipiodol, said
that if we injected Lipiodol directly into the hepatic artery ofthat if we injected Lipiodol directly into the hepatic artery of
patients with hepatocellular carcinoma, it binds selectively topatients with hepatocellular carcinoma, it binds selectively to
the tumor and accumulates for prolonged periods up tothe tumor and accumulates for prolonged periods up to
several months.”several months.”
Bonnemai B, Guerbet M. Histoire du Lipiodol (1901-1994) ou Comment unBonnemai B, Guerbet M. Histoire du Lipiodol (1901-1994) ou Comment un
médicament peut évoluer avec son tempsmédicament peut évoluer avec son temps.. In: Revue d'histoire de laIn: Revue d'histoire de la
pharmacie, 83e année, N. 305, 1995. pp. 159-170.pharmacie, 83e année, N. 305, 1995. pp. 159-170.
• 19831983 - 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.

12. Tumor Necrosis: Oil +/- ParticleTumor Necrosis: Oil +/- Particle
Rate of complete tumor necrosis on explant:Rate of complete tumor necrosis on explant:
Main TumorMain Tumor DaughterDaughter
NodulesNodules
DoxDox//LipiodolLipiodol/G/G
elfoamelfoam
83%83% 53%53%
DoxDox//LipiodolLipiodol 13%13% 6%6%
LipiodolLipiodol onlyonly 0%0% 0%0%
Takayasu K, RAD 1987;163:345-51

13. Survival: Particle +/- OilSurvival: Particle +/- Oil
SurvivalSurvival DoxDox/Gelfoam//Gelfoam/LipiLipi
odolodol
DoxDox/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

14. Hydrophilic vs. Lipophilic DrugsHydrophilic vs. Lipophilic Drugs

15. 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

16. Lipiodol as a Drug Carrier
Oil
W/O
O/W

17. 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

18. ...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.

19. Oil Retention vs. Survival
Kim, AP&T 2012;35:1343

20. Lipiodol Chemoembolization of HCC:Lipiodol Chemoembolization of HCC:
Randomized TrialsRandomized Trials
1)1) Lo et al., Hepatology 2002Lo et al., Hepatology 2002
80 Patients, 80% hep. B +, 7 cm tumors (60% multifocal)80 Patients, 80% hep. B +, 7 cm tumors (60% multifocal)
2)2) Llovet et al., Lancet 2002Llovet et al., Lancet 2002
112 Patients, 80% hep. C +, 5 cm tumors (70% multifocal)112 Patients, 80% hep. C +, 5 cm tumors (70% multifocal)
Survival 1 year 2 years 3 years
TACE 57% 31% 26%
BSC 32% 11% 3%
Survival 1 year 2 years
TACE 82% 63%
BSC 63% 27%

21. 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

22. Bland vs ChemoembolizationBland vs Chemoembolization
HCC all-comers US populationHCC all-comers US population
16
N=322
1 yr 66%
2 yr 46%
3 yr 33%
N = 206
1 yr 64%
2 yr 39%
3 yr 28%
Microspheres (MSKCC)
Maluccio, JVIR 2008;19:862
CAM/Lip/PVA (U Penn)
Weiss, WCIO 2008

23. GIDEON 2nd Interim Analysis
Geschwind et al, ASCO GI 2012
J Clin Oncol 30, 2012 (suppl 4; abstr 317)
J Clin Oncol 30, 2012 (suppl 4; abstr 317)
J Clin Oncol 30, 2012 (suppl 4; abstr 317)

24. 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

25. 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
BlandBland
N = 41N = 41
DEBDEB
N = 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

26. 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

27. 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

28. 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

29. 2626

30. DEB Adverse Events:DEB Adverse Events:
Hepatobiliary necrosis due to dox in normal tissueHepatobiliary necrosis due to dox in normal tissue
Non-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%

31. 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

32. Is anything better than cTACE?Is anything better than cTACE?
18
DEB Y90 sorafenib

33. 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 not
Caveats:Caveats:
Cardiac, hematologic, renal insufficiency- blandCardiac, hematologic, renal insufficiency- bland
Extrahepatic collaterals - blandExtrahepatic collaterals - bland
Limiting PES a priority (frail, caretaker) - Y-90Limiting PES a priority (frail, caretaker) - Y-90
Whipple/ biliary stent - Y-90Whipple/ biliary stent - Y-90

34. ‫شكرا‬