HCC

HCC

Primary liver cancer – a deadly disease

  • 782,000 new cancer cases worldwide occurred in 2012(1)
  •  5th most common cancer in men (554,000 cases) and the 9th in women (228,000 cases)(1)
  • 2nd most common cause of death from cancer worldwide, 746,000 deaths in 2012(1)
  • HCC represents more than 90% of primary liver cancers(2)
  • Very poor prognosis

Lipiodol® – Indicated to fight HCC

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

HCC etiology

  • 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
  • Complementary embolization with gelatin sponge or particules

Mechanism of Action

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.
  • 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
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®-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

Clinical Data

Clinical Data

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®’s efficiency is recognized and endorsed by guidelines worldwide

EASL-EORTC Clinical Practice Guidelines Management of Hepatocellular Carcinoma. J. Hepatol. 2012; 56: 908-943

  • Chemoembolization (Lipiodol®) is recommended for patients with BCLC stage B, multinodular asymptomatic tumors without vascular invasion or extra hepatic spread (evidence 1iiA; recommendation 1A)
  • Representation of EASL–EORTC recommendations for treatment according to levels of evidence (NCI classification [2]) and strength of recommendation (GRADE system). RF, radiofrequency ablation; PEI, percutaneous ethanol injection; OLT, orthotopic liver transplantation; LDLT, living donor liver transplantation.

Llovet J.M. et al. Hepathology 2003; 37: 429-442
EASL-EORTC Clinical Practice Guidelines Management of Hepatocellular Carcinoma. J. Hepatol. 2012; 56: 908-943

  • Barcelona-Clinic Liver Cancer (BCLC) staging system and treatment strategy
  • Staging systems are key to predict the prognosis of patients with cancer, to stratify the patients according to prognostic variables in the setting of clinical trials, to allow the exchange of information among researchers, and finally to guide the therapeutic approach.
    The BCLC staging classification links the stage of the disease to a specific treatment strategy
  • « 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 stage B HCC patient overall survival(2, 12)

Procedure Protocol

Procedure Protocol

Procedure protocol for an efficient and successful cTACE.

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

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

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

Mixture preparation with anticancer drug

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

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)
  • 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)