GEMOXIAL: Chemotherapy or Not, Following Complete Treatment of Hepatic Cancer in Cirrhotic Patients

Sponsor

Assistance Publique - Hôpitaux de Paris (Other)

Overall Status

Terminated

CT.gov ID

NCT00470340

Collaborator

(none)

263

Enrollment

Location

Arms

17.1

Duration (Months)

15.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Besides liver transplantation, the curative treatment of primary hepatic cancer with cirrhosis remains the surgical resection. Radiofrequency or cryotherapy currently allow local ablation of small cancer, with very good results. However, all these treatments are followed by high rates of recurrence (50 - 70% at 5 years). Then, it seems essential to associate to the surgical resection or to the local ablation as "adjuvant" treatment, in order to prevent or to decrease the rate of recurrence. However, no evidence supports this attitude. Therefore, following curative treatment of primary hepatic cancer with cirrhosis, we propose to compare treated to untreated patients. Postoperative treatment means either intra-arterial chemotherapy or systemic chemotherapy. The main criterion of the study is time of survival without recurrence. The main secondary objective is the safety.

Condition or Disease	Intervention/Treatment	Phase
Liver Neoplasms Liver Cirrhosis Carcinoma, Hepatocellular Recurrence Neoplasm Recurrence, Local	Drug: Oxaliplatin, gemcitabine, cisplatin, lipiodol	Phase 3

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

263 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Prevention

Official Title:

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

Study Start Date :

Jun 1, 2007

Actual Primary Completion Date :

Nov 1, 2008

Actual Study Completion Date :

Nov 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Oxaliplatin, gemcitabine, cisplatin, lipiodol	Drug: Oxaliplatin, gemcitabine, cisplatin, lipiodol Oxaliplatin, gemcitabine, cisplatin, lipiodol
Experimental: 2 Oxaliplatin, gemcitabine, cisplatin, lipiodol	Drug: Oxaliplatin, gemcitabine, cisplatin, lipiodol Oxaliplatin, gemcitabine, cisplatin, lipiodol

Arm

Intervention/Treatment

Experimental: 1

Oxaliplatin, gemcitabine, cisplatin, lipiodol

Drug: Oxaliplatin, gemcitabine, cisplatin, lipiodol

Oxaliplatin, gemcitabine, cisplatin, lipiodol

Experimental: 2

Oxaliplatin, gemcitabine, cisplatin, lipiodol

Drug: Oxaliplatin, gemcitabine, cisplatin, lipiodol

Oxaliplatin, gemcitabine, cisplatin, lipiodol

Outcome Measures

Primary Outcome Measures

Survival without recurrence at 2 years [2 years]

Secondary Outcome Measures

Morbidity and mortality following adjuvant treatment [at 6 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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 criteria)
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 treatment
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