HCC

This page is intended to provide information where cTACE indication is registered. It is not intended for use in USA, France and UK.
In USA, Lipiodol® is indicated for Imaging of HCC during interventional radiological procedures. Please refer to your local SPC.
HCC Treatment

Localisation | Vectorization | Visualization
Chemo-Embolization

HCC Treatment

Localisation | Vectorization | Visualization
Chemo-Embolization

HCC (Hepatocellular carcinoma)

Primary liver cancer – a deadly disease

  • 841,080 new cancer cases worldwide occurred in 2018(1)
  •  6th most common cancer and 4th most common cause of death from cancer worldwide (1)
  • HCC represents more than 90% of primary liver cancers(2)
  • Very poor prognosis

Lipiodol® – Indication in HCC

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

HCC etiology 2

  • 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

Mechanism of Action

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

Lipiodol® in cTACE: mechanism of action

  • Lipiodol® droplets are heterogeneous in size.
  • 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.

Lipiodol®-Drug droplets deformability & size diversity for optimal drug delivery & dual embolization

Lipiodol®-drug droplets are deformable & heterogeneous in size(3-4)

10 & 20µm Microscopic image

Lipiodol® + doxorubicin droplets

Droplet deformability

Extract of in vivo video microscopy of rat cremastervessels perfused with Lipiodol® - Courtesy of Prof. Th. de Baère

Droplet division

Extract of in vivo video microscopy of rat cremastervessels perfused with Lipiodol® - Courtesy of Prof. Th. de Baère

10 & 20µm Microscopic image

Lipiodol® + doxorubicin droplets

Droplet deformability

Extract of in vivo video microscopy of rat cremastervessels perfused with Lipiodol® - Courtesy of Prof. Th. de Baère

Droplet division

Extract of in vivo video microscopy of rat cremastervessels perfused with Lipiodol® - Courtesy of Prof. Th. de Baère

10 & 20µm Microscopic image

Lipiodol® + doxorubicin droplets
Source: Guerbet Group

Droplet deformability

Extract of in vivo video microscopy of rat cremastervessels perfused with Lipiodol® - Courtesy of Prof. Th. de Baère

Droplet division

Extract of in vivo video microscopy of rat cremastervessels perfused with Lipiodol® - Courtesy of Prof. Th. de Baère

Lipiodol®-drug droplets allow both proximal & distal anticancer drug delivery(3)

Lipiodol® + anticancer agent
Droplet deformability
Lipiodol® + anticancer agent
Droplet deformability
Lipiodol® + anticancer agent

Droplet deformability

Lipiodol®-drug droplets achieve transient dual embolization (arterial & portal vessels)(5)

PV = Portal Venule
HA = Hepatic Arteriole
BD = Bile Duct
HV = Hepatic Venule
HC = Hepatocytes

Peribiliary plexa allow Lipiodol®-Drug droplets shunting from hepatic artery to portal vein(6)

Radiological evidence of dual vascularization of HCC

GRADE 0

Arterial enhancement of the tumor

GRADE 1

Early venous enhancement thanks to the peribiliary vascular plexa

GRADE 2

Full visualization of the arterioportal vascular bed

GRADE 0
GRADE 1
GRADE 2

Arterial enhancement of the tumor

Early venous enhancement thanks to the peribiliary vascular plexa

Full visualization of the arterioportal vascular bed

GRADE 0

Arterial enhancement of the tumor

GRADE 1

Early venous enhancement thanks to the peribiliary vascular plexa

GRADE 3

Full visualization of the arterioportal vascular bed

Lipiodol clinical data in HCC

Llovet J.M. et al. (2002)(8)

  • Multicenter, randomized, controlled clinical trial
  • 112 patients with unresectable HCC (Child-Pugh class A or B)
    • Arterial embolization group (TAE without cytotoxic drug): 37 patients
    • Chemoembolization group  (cTACE with Lipiodol® + doxorubicin): 40 patients
    • Control group (conservative treatment): 35 patients
  • 1ary endpoint = survival

Objective

«… assessed the efficacy of transarterial Lipiodol (Lipiodol® Ultrafluide, Laboratoire Guerbet, Aulnay-Sous-Bois, France) chemoembolization in patients with unresectable hepatocellular carcinoma. »

Result

«…chemoembolization with gelfoam and doxorubicin improves survival in selected candidates with unresectable hepatocellular carcinoma.»

Lo C.M. et al. (2002)(7)

  • Single center, open-label, randomized, controlled clinical trial
  • 79 Asian patients with unresectable HCC (Okuda I/II stage)
    • Chemoembolization group (cTACE with Lipiodol® + cisplatin repeated every 2-3 months): 40 patients
    • Control group (symptomatic treatment): 39 patients
  • 1ary endpoint = survival

Objective

«… assessed the efficacy of transarterial Lipiodol (Lipiodol® Ultrafluide, Laboratoire Guerbet, Aulnay-Sous-Bois, France) chemoembolization in patients with unresectable hepatocellular carcinoma. »

 

Result

«… transarterial Lipiodol® chemoembolization […] prolongs the survival of a selected group of Asian patients with unresectable hepatocellular carcinoma and is an effective palliative treatment option. »

 

Llovet J.M. et al. (2003)(13)

  • Systematic review of RCTs identifying survival benefits of medical interventions (arterial embolization/chemoembolization) for unresectable HCC in comparison with conservative management or suboptimal therapies
  • Meta-analysis of 7 RCTs: 6 studies reporting 2-year death rates (503 patients) + 1 study reporting 1 year survival* (42 patients)

Objective

« …Meta-analysis of RCTs comparing 2-year survival with chemoembolization/embolization versus conservative management or suboptimal therapies for unresectable HCC (core group). Random effects model (OR, 0.53; 95% CI, 0.32-0.89; P = .017)… »

Result

« …chemoembolization improves survival of patients with unresectable HCC and may become the standard treatment. »

 

Mabed M. et al. (2009)(14)

  • Single center, prospective, randomized, controlled clinical trial
  • 100 patients with HCC not eligible for ablation
    • cTACE with Lipiodol® + doxorubicin + cisplatin: 50 patients
    • Systemic chemotherapy with doxorubicin: 50 patients
  • 1ary endpoint = tumor response, 2ary endpoints = progression-free survival & overall survival

Hypothesis

« …to find a significant difference between both treatment arms as regard the tumour response. »

Result

« Patients treated with TACE achieved a significantly higher response rate, with partial response achieved in 16 patients (32%) versus five patients (10%) in the chemotherapy arm (P = 0.007). »


« The median progression free survival for patients treated with TACE was 32 weeks (range, 16-70 weeks) and for patients treated with systemic chemotherapy was 26 weeks (range, 14-54 weeks) (log-rank test, P = 0.03). »

 


« The median overall survival in the chemoembolization arm was 38 weeks (range, 22-72 weeks) and for patients who received systemic chemotherapy was 32 weeks (range, 26-68 weeks) (log-rank test, P = 0.08). »


« The median overall survival in the TACE arm was significantly longer than in the systemic chemotherapy arm in cases with serum albumin > 3.3 g/dL (60 vs 36 weeks, P = 0.003). »

Conclusion

« Higher response rate was achieved with TACE versus systemic chemotherapy. In addition, this response was better maintained as evidenced by the significantly longer time to disease progression and was associated with significantly longer survival in patients who responded. However, the study failed to prove a significant impact on overall survival. »

 
 
 

Shi M. et al. (2013)

  • Multicenter, single blind, randomized, controlled clinical trial
  • 365 patients with HCC stage B/C with ~good performance status & liver function
    • Arm 1 = “Triple drug – cTACE” (lobaplatin + epirubicin + mitomycin C) with sponge embolization: 122 patients
    • Arm 2 = “Triple drug – TAC” (lobaplatin + epirubicin + mitomycin C) without embolization: 121 patients
    • Arm 3 = “Single drug – cTACE” (epirubicin) with sponge embolization: 122 patients
  • 1ary endpoint = overall survival

Objective

« …to compare the efficacy and safety of: 1) transarterial chemolipiodolization with gelatin sponge embolization vs chemolipiodolization without embolization, and 2) chemolipiodolization with triple chemotherapeutic agents vs epirubicin alone. »

Result

« Chemolipiodolization played an important role in transarterial chemoembolization, and the choice of chemotherapy regimen may largely affect survival outcomes… »

Guidelines

Lipiodol® use in TACE efficacy is recognized and endorsed by guidelines worldwide

EASL -Modified BCLC staging system and treatment strategy (2)

Overall Survival
« … Recently, a systematic review on conventional TACE has included 101 articles, with a total of 10,108 patients. The objective response rate was 52.5% (95% CI 43.6–61.5), and the overall survival (OS) was 70.3% at one year, 51.8% at two years,40.4% at three years, and 32.4% at five years with a median OS of 19.4 months (95% CI 16.2–22.6) …» Lencioni et al. 2016

Safety
« … a retrospective study has show that biliary injuries, intrahepatic biloma, and global hepatic damage were significantly higher following TACE-DEB than with conventional TACE, especially in patients with advanced cirrhosis (Monier et al. 2017)… » Monier et al. 2017

  • « TACE is recommended as first line non-curative therapy for non-surgical patients with large / multifocal HCC who do not have vascular invasion or extra hepatic spread (level I) »
  • « Chemotherapy has to be injected prior to arterial obstruction. It is usual to suspend chemotherapy in Lipiodol®, an oily contrast agent used for lymphographic studies. Lipiodol® is selectively retained within the tumor and this expands the exposure of the neoplastic cells to chemotherapy… »(9)
  • « Transcatheter arterial chemoembolization/TAE is recommended as treatment for advanced hepatocellular carcinoma with liver damage stages A and B (inoperable and not candidates for local ablation therapy)… (grade A) »(11)
  • « Lipiodol®-TACE taking account of hepatic functional reserve and the area of non-cancerous liver tissues to be chemoembolized is recommended for current TACE (grade B). […] The prognosis of advanced hepatocellular carcinoma or small hepatocellular carcinoma patients with good liver function is favorable after Lip-TACE… »(11)

« Superselective catheterization is preferred whenever possible, in combination with proper embolization agents. An emulsion mixture of super-liquid Lipiodol® and chemotherapeutic agents is commonly used for this therapy. The dosage of iodized oil should depend on the size, blood supply, and feeding arteries of the tumor. »(10)

Overall Survival Data

Significant improvement of overall survival (2, 12) for HCC patient at intermediate stage

Procedure Protocol

Procedure protocol for an efficient and successful cTACE.

Play Video

Lipiodol® Ultra Fluid – anticancer drug mixture preparation
Step1: Withdrawing

Play Video

Lipiodol® Ultra Fluid – anticancer drug mixture preparation
Step 2: Mixing 2

Play Video

Lipiodol® Ultra Fluid – anticancer drug mixture preparation
Step 3: Injecting

Mixture preparation with anticancer drug by Vectorio®

1

Prepare a syringe containing Lipiodol® Ultra Fluid & a syringe containing the anticancer agent

2

Connect both syringes to a three-way stopcock

3

Perform 20 back & forth movements through the three-way 4 ports stopcock between the two syringes to obtain a homogeneous mixture

4

Obtain a mixture of Lipiodol® Ultra Fluid + anticancer agent

1
2
3
4

Prepare a syringe containing Lipiodol® Ultra Fluid & a syringe containing the anticancer agent

Connect both syringes to a three-way stopcock

Perform 20 back & forth movements through the three-way 4 ports stopcock between the two syringes to obtain a homogeneous mixture

Obtain a mixture of Lipiodol® Ultra Fluid + anticancer agent

Mixture preparation recommendation

  • Anticancer drug should be first pushed towards the syringe containing Lipiodol® (14)
  • Volume of anticancer drug should be lower than the volume of Lipiodol®, ideally
    1 volume of drug to 2 volume of Lipiodol® (15)
  • Vigorous mixing of the anticancer drug and Lipiodol® through the three-way 4 ports stopcock(14)

Documentation

You are welcome to consult and read the following online version of our brochures, bibliography and CCDS

LIPIODOL® ULTRA-FLUID.
Composition
: Ethyl esters of iodized fatty acids of poppy seed oil 10 mL, corresponding to an iodine content of 480 mg/mL. Indications (**): In diagnostic radiology – Hysterosalpingography – Ascending urethrography – Lymphography – Sialography – Fistulography and exploration of abscesses – Exploration of frontal sinuses – Pre and post-operative cholangiography. In interventional radiology – Visualisation and localization (by selective intra-arterial use during CT) of liver  lesions in adults with known or suspected hepatocellular carcinoma – Visualisation, localisation and vectorisation during Trans-Arterial Chemo-Embolisation (TACE) of hepatocellular carcinoma at intermediate stage, in adults – Selective embolization in combination with Histoacryl glue (particularly for arteriovenous malformation or aneurysms) – Selective injections of LIPIODOL ULTRA-FLUID into the hepatic artery for diagnostic purposes where a spiral CT scan is not practical. In endocrinology – Prevention of severe cases of iodine deficiency. Posology and method of administration (*): have to be adapted according to the type of examination, the territories explored, the age and weight of the patient. The volume to be administered depends on the particular requirements of the technique and the size of the patient. Contraindications: Hypersensitivity to LIPIODOL ULTRA-FLUID – Confirmed hyperthyroidism – Patients with traumatic injuries, recent haemorrage or bleeding – Hysterosalpingography during pregnancy or acute pelvic inflammation – Bronchography. In interventional radiology (Trans-Arterial Chemo-Embolization), Administration in liver areas with dilated bile ducts unless drainage has been performed. Special warnings and special precautions for use (*): There is a risk of hypersensitivity regardless of the dose administered.  Lymphography:  Pulmonary embolism may occur immediately or after few hours to days from inadvertent systemic vascular injection or intravasation of LIPIODOL ULTRA-FLUID: Perform radiological monitoring during LIPIODOL ULTRA-FLUID injection and avoid use in patients with severely impaired lung function, cardiorespiratory failure or right-sided cardiac overload.  Hypersensitivity: all iodinated contrast agents can lead to minor or major hypersensitivity reactions, which can be life-threatening. These hypersensitivity reactions are of an allergic nature (known as anaphylactic reactions if they are serious) or a non-allergic nature. They can be immediate (occurring within 60 min) or delayed (not occurring until up to 7 days later). Anaphylactic reactions are immediate and can be fatal. They are dose-independent, can occur right from the first administration of the product, and are often unpredictable: avoid use in patients with a history of sensitivity to other iodinated contrast agents, bronchial asthma or allergic disorders because of an increased risk of a hypersensitivity reaction to LIPIODOL ULTRA-FLUID. Thyroid: can cause hyperthyroidism in predisposed patients. Lymphography saturates the thyroid with iodine for several months and thyroid exploration should be performed before radiological examination.  Chemo-Embolization: Trans-Arterial Chemo-Embolization is not recommended in patients with decompensated liver cirrhosis (ChildPugh ≥8), advanced liver dysfunction, macroscopic invasion and/or extra-hepatic spread of the tumour. Renal insufficiency must be prevented by correct rehydration before and after the procedure. Oesophageal varices must be carefully monitored. Hepatic intra-arterial treatment can progressively cause an irreversible liver insufficiency in patients with serious liver malfunction and/or undergoing close multiple sessions. The risk of superinfection in the treated area is normally prevented by administration of antibiotics. Embolization with glue: An early polymerisation reaction may exceptionally occur between LIPIODOL ULTRA-FLUID and certain surgical glues, or even certain batches of glue. Before using new batches of LIPIODOL ULTRA-FLUID or surgical glue, the compatibility of LIPIODOL ULTRA-FLUID and the glue must be tested in vitro. Interaction with other medicinal products and other forms of interaction (*): Metformin, Beta blockers, vasoactive substances, angiotensin-converting enzyme inhibitors, angiotensin-receptor antagonists, Diuretics, Interleukin II. Fertility, pregnancy and lactation (*): LIPIODOL ULTRA-FLUID must only be used in pregnant women if absolutely necessary and under strict medical supervision. Breastfeeding should be discontinued if LIPIODOL ULTRA-FLUID must be used – Effects on ability to drive and use machines: The effects on ability to drive and to use machines have not been investigated – Undesirable effects (*): Most adverse effects are dose-related and dosage should therefore be kept as low as possible :hypersensitivity, anaphylactic reaction, anaphylactoid reaction, vomiting, diarrhea, nausea, fever, pain, dyspnea, cough, hypothyroidism, hyperthyroidism, thyroiditis, pulmonary embolism, cerebral embolism, retinal vein thrombosis, lymphoedema aggravation, hepatic vein thrombosis, granuloma. Overdose (*): The total dose of LIPIODOL ULTRA-FLUID administered must not exceed 20 mL – Pharmacodynamic properties (*): Pharmacotherapeutic group: X-ray contrast media, iodinated; ATC code: V08A D01. Water-insoluble iodinated contrast medium. Presentation (**):
10 mL glass ampoule. Marketing authorization holder (*): Guerbet – BP 57400 – F-95943 Roissy CdG cedex – FRANCE. Information: tel: 33 (0) 1 45 91 50 00. Revision: April 24th, 2018.

(*) For complete information please refer to the local Summary of Product Characteristics
(**) Indications, volumes and presentations may differ from country to country.

Reporting of suspected adverse reactions is important as it helps to continuously assess the benefit-risk balance. Therefore, Guerbet encourages you to report any adverse reactions to your health authorities or to our local Guerbet representative.

Countries in which cTACE indication is registered: Austria, Argentina, Belgium, Brazil, Cambodia, Czech Republic, France, Japan, Hong Kong, Hungary, Ireland, India, Iran, Luxembourg, Mexico, Mongolia, New Zealand, Peru, Portugal, Philippines, South Korea, Turkey, The Netherlands, Thailand, Taiwan, Tunisia, Vietnam.
For a copy of the SPC, please contact a member of Guerbet.

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