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Arterial LIPIODOLISED Chemotherapy Versus Systemic Chemotherapy With Gemcitabine Plus Oxaliplatin (GEMOX) Versus no Treatment Following Surgical Resection or Local Ablation of Hepatocellular Carcinoma in Cirrhotic Patients

Phase 3
18 Years
75 Years
Not Enrolling
Liver Neoplasms, Liver Cirrhosis, Carcinoma, Hepatocellular, Recurrence, Neoplasm Recurrence, Local

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Trial Information

Arterial LIPIODOLISED Chemotherapy Versus Systemic Chemotherapy With Gemcitabine Plus Oxaliplatin (GEMOX) Versus no Treatment Following Surgical Resection or Local Ablation of Hepatocellular Carcinoma in Cirrhotic Patients

The best treatment for hepatocellular carcinoma (HCC) with cirrhosis, currently is liver
transplantation because treating the cancer and the causal disease. For the majority of
patients, transplantation is not proposed, and the curative treatment remains the surgical
resection. Radiofrequency or cryotherapy currently allows local destruction (or ablation) of
the small HCC, with results that seem equivalent to the surgical resection. These last
techniques increase the therapeutic possibilities in the presence of hepatic insufficiency.
However, all these treatments are followed by high rates of recurrence (50 - 70% at 5 years
and close to 100% at 10 years). The development of tumoral nodules, undetected at the time
of the curative treatment, or the occurrence of new HCC, under the effects of the cirrhotic
process or viral genomic modifications explain these disappointing results. Therefore, it
seems essential to associate an adjuvant treatment to the surgical resection or the local
destruction. Intra-arterial chemotherapy with or without embolisation is a largely evaluated
therapeutic approach whose results are contradictory. Several retrospective studies, seem
nevertheless to show a benefit of this treatment in adjuvant situation. Systemic
chemotherapy for a long time regarded as ineffective, currently has a renewed interest due
to the use of new drugs like gemcitabine and oxaliplatin (GEMOX regimen). This regimen
showed a certain effect in a phase II study in advanced forms of HCC with cirrhosis. We
propose to test by a prospective randomized multicentric phase III study, the effectiveness
of an adjuvant treatment by systemic chemotherapy or intra-arterial LIPIODOLISED
chemotherapy (CIAL), after surgery or complete local destruction of HCC. Three groups will
be compared: a group of untreated patients (n=109), a group of patients treated by
intra-arterial chemotherapy (CIAL = cisplatin 75 mg + lipiodol 10 ml; 3 courses every 6
weeks)(n=77) and a group of patients treated by systemic chemotherapy (GEMOX= day 1:
gemcitabine 1000 mg/m² iv within 100 min; day 2: oxaliplatin 100 mg/m² iv within 2h; 8
courses every 2 weeks, d1 = d14)(n=77). Selection and randomisation are planned 4-8 weeks
following complete treatment of the HCC. Identical follow up for the 3 groups includes
clinical, biological, morphological exams every 3 months for 2 years, then every 6 months
for 3 years. The main criterion of the study is survival without recurrence. The secondary
objectives are the global survival, the safety and an estimate of the costs of the various
treatments. The awaited results are 1) to demonstrate the effectiveness of at least one of
these adjuvant treatment following complete treatment of HCC in cirrhotic patients and 2) to
determine the best adjuvant treatment. Estimated inclusion time is 2 years, with an analysis
of the principal criterion at 3 years. Follow-up of 5 years is envisaged for each patient,
leading to a 7 years duration study.

Inclusion Criteria:

- Hepatocellular carcinoma (histology or Barcelona criteria) curatively treated by
surgical resection or by radiofrequency or by cryotherapy

- Evidence of liver cirrhosis (clinical, biological, endoscopic or histological

- Morphological evaluation 4 to 6 weeks following curative treatment

- No evidence of local or distant disease on the morphological evaluation

- Absence of peritoneal or lymph node metastasis

- Absence of pre- or per-operative macroscopic tumoral thrombus

- Minimal free margin of 5 mm following pathological exam

- ALPHAAFOETOPROTEINE level of less than 4 normal values or decreased by 50%, 4 to 6
weeks following curative treatment

- Biological criteria, 2 weeks before treatment as follow:

- neutrophilic polymorphonuclear > 1500/mm3,

- platelets > 100 000/mm3,

- total bilirubin < 25 mmol/l (1.46 mg/dl),

- creatinin < 1.5 x normal value

- Eastern Cooperative Oncology Group (ECOG) equal to 0 or 1

- Life expectancy > 12 weeks

- Absence of sensitive neuropathy at inclusion time

- Health insurance coverage

- Efficient contraceptive method if applicable

- Signed informed consent

Exclusion Criteria:

- Curative treatment performed 10 weeks or more before the beginning of adjuvant

- Contraindication to an angiography or hepatic artery thrombosis or portal thrombosis.

- Pregnant or breastfeeding woman

- Concomitant involvement to any clinical trial

- Decompensate cirrhosis and Child-Pugh score ≥ 8 or clinical ascitis.

- Cancer of the Liver Italian Program (C.L.I.P.) score ≥ 2

- Heart or lung insufficiency

- Other cancer not considered as definitively cured

- Creatinin clearance < 30 ml/min

- Recurrence of HCC less than 12 months following any last treatment

- Any radiotherapy during the 4 weeks before inclusion

- Known sensitivity to any drug of this protocol

- Immunodeficiency (HIV+, transplanted patient)

- Inability of follow up

- Impossibility of clear understanding of the protocol for no french speaking patient

- Patient under legal protection

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Outcome Measure:

Survival without recurrence at 2 years

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

Eric Savier, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Assistance Publique - Hôpitaux de Paris


France: Ministry of Health

Study ID:




Start Date:

June 2007

Completion Date:

November 2008

Related Keywords:

  • Liver Neoplasms
  • Liver Cirrhosis
  • Carcinoma, Hepatocellular
  • Recurrence
  • Neoplasm Recurrence, Local
  • Recurrence
  • Neoplasm Recurrence, Local
  • Liver
  • Liver Neoplasms
  • Liver Cirrhosis
  • Carcinoma, Hepatocellular
  • Iodized Oil
  • gemcitabine [Substance Name]
  • oxaliplatin [Substance Name]
  • gemcitabine-oxaliplatin regimen [Substance Name]
  • Randomized Controlled Trials
  • Multicenter Studies
  • Cisplatin
  • Injections, Intra-Arterial
  • Injections, Intravenous
  • Chemotherapy, Adjuvant
  • Neoplasms
  • Carcinoma
  • Liver Cirrhosis
  • Fibrosis
  • Liver Neoplasms
  • Neoplasm Recurrence, Local
  • Recurrence
  • Carcinoma, Hepatocellular