The closer the better with cTACE⁽¹⁾

Standardized mixture and super-selective catheterization approach
Lipiodol^® Ultra-Fluid (Iodinated ethyl esters of fatty acids of poppy seed oil)

Today INSPIRE, tomorrow immunotherapies combos

Liver cancer, of which hepatocellular carcinoma (HCC), is the most common type, is the third-leading cause of cancer death with an estimated 900,000 people worldwide diagnosed in 2020.¹Transarterial chemoembolization with Lipiodol^® Ultra-Fluid (Iodinated ethyl esters of fatty acids of poppy seed oil), also called conventional TACE (cTACE), was developed in the early 1980s and is nowadays widely adopted worldwide ²and and TACE established as the standard of care for HCC BCLC stage A and B , with preserved liver function, no cancer-related symptoms (PS 0) and no vascular invasion or extrahepatic spread. ^{3 4}

More recently, immunotherapies have been shown to increase survival in patients with HCC and have changed the landscape for advanced disease. Trials on the role of systemic immunotherapy have not just been limited to advanced disease but are now extending towards patients with early or intermediate-stage disease who are suitable for existing treatments including TACE.⁵

Can we still further refine cTACE clinical outcomes?

Recent recommendations coming from the European Association for the Study of the Liver (EASL) and European Society of Medical Oncology (ESMO) highlighted that TACE must be used in Hepatocellular Carcinoma (HCC) "selectively targetable" and "accessible to supraselective catheterization." ⁶

Watch Professor
Maxime Ronot at the
ILCA 2023 conference

In his presentation at the ILCA 2023 conference, Professor Maxime Ronot (Beaujon Hospital -Clichy, France) illustrates how to improve the definition of HCC patients eligiblity to a superselective cTACE, and to standardize the procedure, with the aim of maximizing the anti-tumoral effect while minimizing the collateral damages of the surrounding liver parenchyma.⁶Prof. Ronot also shares his expectations as an interventional radiologist, regarding immunotherapies combined with TACE.

Sign-up to watch Pr. Maxime Ronot

References

¹ WHO. Liver Cancer Fact Sheet. Available at: https://gco.iarc.fr/today/data/factsheets/cancers/11-Liver-fact-sheet.pdf. Accessed November 2023
² T. de Baere et all Treatment of Liver Tumors with Lipiodol TACE: Technical Recommendations from Experts Opinion. Cardiovasc Intervent Radiol (2016) 39:334–343. DOI 10.1007/s00270-015-1208-y
³ Maria Reig et all. BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update. Journal of Hepatology. VOLUME 76, ISSUE 3, P681-693, MARCH 2022. DOI:https://doi.org/10.1016/j.jhep.2021.11.018
⁴ A. Vogel et all. Hepatocellular carcinoma. ESMO Clinical Practices guidelinesfor diagnostic, treatment and follow up. © 2021 ESMO. esmo.org/Guidelines/Gastrointestinal-Cancers/Hepatocellular-Carcinoma
⁵ Jonathan Tibballs et all. Immunotherapy and Transarterial therapy of HCC: What the interventional radiologist needs to know about the changing landsc. J Med Imaging Radiat Oncol. 2022 Jun; 66(4): 478–482. doi: 10.1111/1754-9485.13405
⁶ T. de Baere et all. Initiative on Superselective Conventional Transarterial Chemoembolization Results (INSPIRE). Cardiovasc Intervent Radiol. 2022 Oct;45(10):1430-1440. doi: 10.1007/s00270-022-03233-9. Epub 2022 Aug 17

Unleash the potential of Lipiodol^® in HCC

For decades, you’ve trusted Guerbet for interventional oncology treatments using anticancer drug-Lipiodol^{^®} emulsion in cTACE for hepatocellular carcinoma (HCC, or liver cancer). Indeed, conventional TACE with Lipiodol^{^®} demonstrates a median Overal Survival of 25/30 months on patients suffering from HCC⁽¹⁾.
Treatments continue to evolve thanks to close collaboration with physicians around the world.
Two recent studies document the power of super-selective cTACE catheterization approach and procedure standardization using Lipiodol^{^®} to help treat HCC patients^{(1, 2)}.

A gold standard, super-selective cTACE consists of positioning the catheter as distal as possible and close to the tumor, delivering at a subsegmental level using a microcatheter and reaching the tumor feeders through terminal and intersegmental collaterals while sparing the surrounding healthy liver parenchyma. Procedure standardization includes proper and consistent preparation before administration using a water-in-oil emulsion with Lipiodol^{^®}/drug ratio of 2 or 3 to 1 prepared at the time of administration⁽¹⁾.

The combination of super-selective catheterization and standardized cTACE delivers improved results, including:

Patient overall survival increased from some months to more than 3 years⁽³⁾ or far more in some cases, 6 years⁽⁴⁾ or even 10 years⁽⁵⁾
More effective than selective DEB-TACE for local tumor control in HCC patients⁽⁶⁾
Most Adverse Events (Aes) observed as grade 1 or 2, mainly related to post embolization syndrome. Serious Adverse Events were reduced⁽⁷⁾.

References

1. Ikeda M. et al., Prospective Study of Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: An Asian Cooperative Study between Japan and Korea J. Vasc. Interv. Radiol. 2013; 24: 490-500

2. Lo C.M. et al. Randomized Controlled Trial of Transarterial Lipiodol Chemoembolization for Unresectable Hepatocellular Carcinoma Hepatology 2002; 35: 1164-1171

3. Llovet J.M. et al. arterial embolization or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial The Lancet 2002; 359: 1734-1739

4. Llovet J.M. et al . Systematic Review of Randomized Trials for Unresectable Hepatocellular Carcinoma: Chemoembolization Improves Survival Hepathology 2003; 37: 429-442

5. EASL-EORTC Clinical Practice Guidelines for the Management of Hepatocellular Carcinoma. J. Hepatol. 2018

6. Chen M. et al., High Dose Iodized Oil Transcatheter Arterial Chemoembolization for Patients with Large Hepatocellular Carcinoma World. gastroenterol. 2002; 8: 74-78.

7. Takayasu K. et al., Comparison of CT Findings with Resected Specimens After Chemoembolization with Iodized Oil for Hepatocellular Carcinoma AJR. 2000;175:699–704.

8. De Baere t. et al., Circulatory alterations induced by intra-arterial injection of iodized oil emulsions of iodized oil and doxorubicin: experimental study, Radiology.1995; 194: 165-170.

9. Europe: EASL-EORTC / Clinical Pratice Guidelines / Journal of Hepatology 2012 vol. 56; 908–943.

10. US Guidelines: Bruix J. AASLD Practice Guidelines; American Association for Study of the Liver Diseases;Hepatology 2011; Vol. 53, No. 3.

11. Chinese guidelines 2011 edition, Chin. Clin. Oncol. 2012; 1:10.

12. Japanese Guidelines: Hepatology Research 2010; 40 (Suppl. 1): 96–112.

13. Terayama N. et al., Accumulation of Iodized Oil Within the Non-Neoplastic Liver Adjacent to Hepatocellular Carcinoma via the Drainage Routes of the Tumor After Transcatheter Arterial Embolization CVIR. 2001; 24:383-387.

14. Georgiades C. et al. Lack of response after initial chemoembolization for hepatocellular carcinoma: Does it predict of subsequent treatment, Radiology. 2012; 265(1): 115-123.

15. Kan Z. et al. Liver anatomy: microcirculation of the liver, Sem. Intervent. Radiology 2008; 25: 77-85.

16. Thierry de Baere et al., Treatment of Liver Tumors with Lipiodol TACE: Technical Recommendations from Experts Opinion. Cardiovasc Intervent Radiol,2016;39:334–343.

17. Kudo M. et al., Orantinib versus placebo combined with transcatheter arterial chemoembolisation in patients with unresectable hepatocellular carcinoma (ORIENTAL): a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Lancet gastroenterol Hepatol.2018; (3) 37-46.

18. Ikeda M. et al.,Transarterial chemoembolization with miriplatin vs. epirubicin for unresectable hepatocellular carcinoma: a phase III randomized trial. J Gastroenterol.2018; 53:281–290.

Indication

Lipiodol^® - Indication in HCC

Visualization, Localization and Vectorization during Trans-Arterial Chemoembolization (TACE) of hepatocellular carcinoma (HCC) at intermediate stage, in adults

HCC etiology ⁽⁵⁾

Hepatitis B & C
Prolonged alcohol abuse
Non alcoholic steato hepatitis (NASH)

Conventional Trans Arterial Chemoembolization (cTACE)

cTACE = Lipiodol^{^®} TACE
Intratumor injection of Lipiodol^{^®} + anticancer agent (such as Cisplatin, Doxorubicin, Epirubicin and Mitomycin)
Complementary embolization with gelatin sponge or particules

Lipiodol^{^®} in HCC management

Features	Benefits
Tumor, visualizer & localizer	- Immediate timer visualization & localization for real time procedure guiding⁽⁶⁾ - Per-procedure complete tumor filling visual confirmation for patient prognosis⁽⁷⁾
Chemotherapeutic drug vectorizer	- Proximal & distal drug delivery thanks to droplets defomability & size diversity⁽⁸⁾ - Improved patient Overall Survival up to 45 months⁽⁹⁾ - Endorsed by international guidelines as Standard-of-Care^{(5, 10, 11, 12)}
Transient dual embolizer	- Index & daughter nodules necrosis thanks to dual arterioportal embolization⁽¹³⁾ - Transient occlusion authorizing repeated treatment⁽¹⁴⁾

Overall Survival Data

Significant improvement of overall survival ⁽⁹⁾ for HCC patient at intermediate stage

Mechanism of Action

Thanks to its great physico-chemical & pharmacokinetic properties, Lipiodol^{^®} improves the efficiency of diversified indications.

Lipiodol^{^®} in cTACE: mechanism of action

Lipiodol^{^®} droplets are heterogeneous in size.⁽^{8, 15)}
Large & small droplets allow proximal & distal drug delivery into the tumor vascular system.
Lipiodol^{^®}-drug droplets have access to the tumor through the arterial vessels (red) and then to the portal venous system (blue).
Thanks to this dual vascularization, the drug is delivered in the whole tumor and can potentially reach the daughter ones.
At the end of Lipiodol^{^®}-drug administration, a complementary embolization is realized with gelatin foam.

More information about mechanism of action

Procedure Protocol

Procedure protocol for an efficient and successful cTACE.

Step1: Withdrawing

Lipiodol^{^®} Ultra Fluid – anticancer drug mixture preparation

Step 2: Mixing ⁽¹⁶⁾

Lipiodol^{^®} Ultra Fluid – anticancer drug mixture preparation

Step 3: Injecting

Lipiodol^® Ultra Fluid – anticancer drug mixture preparation

Learn more

Lipiodol^{^®} clinical data in HCC

Kudo M et al. (2018) (17)

Randomised, double-blind, phase 3 study was done at 75 sites in Japan, South Korea, and Taiwan.

Patients with unresectable HCC, no extra-hepatic tumour spread, and Child-Pugh score of 6 or less were randomly assigned (1:1) by interactive web response system using a computer-generated sequence to receive orantinib or placebo, within 28 days of cTACE.
Orantinib + cTACE group : 445 patients
Placebo+cTACE group:444 patients

1ary endpoint = Overall survival

Objective

Orantinib is an oral multi-kinase inhibitor.

This study was done to evaluate the efficacy of orantinib combined with conventional

transcatheter arterial chemoembolisation (cTACE) in patients with unresectable HCC

Results

…889 patients were randomly assigned to receive either orantinib (n=445) or placebo (n=444) at 41 sites in Japan, 21 sites in South Korea, and 13 sites in Taiwan.”

“The number of cTACE procedures after randomization including first TACE was 3.2 (SD 2.4) in the orantinib group and 3.7 (2.4) in the placebo group.”

“In the present study, orantinib combined with cTACE did not prolong overall survival in patients with unresectable hepatocellular carcinoma compared with placebo.

There was no improvement in overall survival with orantinib compared with placebo (median 31.1 months [95% CI 26·5–34·5] vs 32.3 months [28·4–not reached].

Ikeda M et al. (2018) (18)

Prospective, multicenter, open-label, randomized phase III trial

Objective : Compared TACE with miriplatin vs. TACE with epirubicin in patients with unresectable HCC.

257 patients with unresectable HCC.

cTACE (miriplatin) group: 129 patients
cTACE(epirubicin) group :128 patients

1ary endpoint = Overall survival

Results

…Median OS times were 1111 days for miriplatin and 1127 days for epirubicin .

Conclusions: OS after TACE with miriplatin was not superior to that after TACE with epirubicin; however, hepatic AEs were less frequent with miriplatin