Multicentre randomised phase III trial comparing Tamoxifen alone or with Transarterial Lipiodol Chemoembolisation for unresectable hepatocellular carcinoma in cirrhotic patients (Fédération Francophone de Cancérologie Digestive 9402)

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Abstract

The FFCD 9402 multicentre phase III trial was designed to compare the effects of the combination of Transarterial Lipiodol Chemoembolisation (TACE) and tamoxifen with tamoxifen alone on overall survival and quality of life in the palliative treatment of hepatocellular carcinoma with cirrhosis. From 1995 to 2002, 138 patients were randomised between the two groups. One hundred and twenty three patients were eligible including 61 in the Tamoxifen group and 62 in the TACE group. Baseline characteristics were similar: Child-Pugh class A: 70%, alcoholic cirrhosis: 76%, Okuda stage I: 71%, multinodular tumour: 70% and segmental portal vein thrombosis: 10%. At 2 years, the overall survival was 22% and 25% in the Tamoxifen and TACE groups (P = .68), respectively. Multivariate analysis identified four independent prognostic factors for survival: α-fetoprotein (AFP) > 400 ng/mL (P = .008), abdominal pain (P = .011), hepatomegaly (P = .023) and Child-Pugh score (P = .032). The Spitzer Index level assessing the quality of life during follow-up did not differ between the two groups (P = .70). Amongst patients with stage Okuda I, the 2-year overall survival was 28% in the Tamoxifen group and 32% in the TACE group (P = .58). In this subgroup, two prognostic factors were statistically significant for survival: AFP > 400 ng/mL (P = .004) and Spitzer Index (P = .013) as shown by multivariable analysis.

In conclusion, this study suggests that TACE improves neither the survival nor the quality of life in patients with HCC and cirrhosis.

Introduction

The prognosis of hepatocellular carcinoma (HCC) is poor because curative therapies are dedicated to a small proportion of patients with early stage of the disease.1 At intermediate or advanced stages there is no standard treatment.1, 2 Transarterial Lipiodol Chemoembolisation (TACE) is a controversial intervention with still uncertain efficacy,3, 4, 5, 6, 7, 8, 9 even if the two most recent randomised controlled clinical trials (RCT) identified overall survival (OS) benefit.8, 9 Two meta-analyses 10, 11 showed that chemoembolisation significantly improved OS although a third meta-analysis12 failed to demonstrate a significant advantage. The efficacy of antiestrogen therapy in advanced HCC is also controversial. In the early 1990s, a positive effect was attributed to tamoxifen.13, 14 However, the recent meta-analyses of Llovet and colleagues11 and Nowak and colleagues15 and a large RCT,16 concluded that tamoxifen therapy did not provide any significant survival benefit.

Thus, we conducted a French multicentre randomised controlled phase III trial to compare the effect of the TACE-tamoxifen with tamoxifen alone on OS and quality of life (QoL) in patients with unresectable HCC.

Section snippets

Selection of patients

Inclusion criteria were patients with liver cirrhosis (diagnosis of cirrhosis was obtained by histopathology, clinical presentation or laboratory findings) and unresectable HCC based on biopsy, or persistently elevated serum α-fetoprotein (AFP) levels (>500 ng/mL) with one typical imaging finding (ultrasonography, CT scan or magnetic resonance imaging). These criteria were near from the Barcelona criteria.1 A signed informed consent was required.

Exclusion criteria were age older than 75 years,

Results

From May 1995 to June 2002, 138 patients in 15 French centres were randomly assigned to the TACE group (70 patients) or the Tamoxifen group (68 patients). Eligible patients were 62 in the TACE group and 61 in the Tamoxifen group (Fig. 1). The two groups were well balanced with respect to demographic, clinical or biological characteristics (Table 1). The majority of patients (76%) had alcoholic cirrhosis with well-compensated liver function (Child-Pugh class A: 70%) and Okuda stage I (71%) with

Intent-to-treat analyses

By 1 August 2004, 58 and 56 had, respectively, died in the TACE and the Tamoxifen groups. The median follow-up was 12.4 months in the TACE group and 11.0 months in the Tamoxifen group. OS (Fig. 2) did not differ according to treatment arm (P = .68, log-rank test). At 1 and 2 years, the survival rates were 51% (95% CI, 38–63%), and 25% (15–37%) in the TACE group and 46% (33–58%) and 22% (12–33%) in the Tamoxifen group (P = .68). The median OS was 13.8 months (95% CI, 7.6–16.8) in the TACE group and

Discussion

This study suggests that TACE improves neither survival nor QoL in patients with well-preserved liver function and Okuda stages I and II.

Our results were not in agreement with the two most recent RCT8, 9 and two meta-analysis.10, 11 However, they are consistent with two French trials.5, 7 The French studies were characterised by a large number of patients with alcohol-induced cirrhosis, whereas the Hong Kong and Barcelona trials included patients with hepatitis B or C virus-induced cirrhosis (

Conflict of interest statement

None declared.

Acknowledgements

We thank the following physicians for their participation to this study: S. Agostini (Marseille), F. Audemar (Strasbourg), G. Bommelaer (Clermont-Ferrand), C. Bonny (Clermont-Ferrand), F. Boudghene (Paris), B. Bour (Le Mans), J.P. Cercueil (Dijon), W. Chbeir (Le Mans), S. Dohin (Le Mans), G. Debillon (Orléans), B. Gollentz (Belfort), M. Grand (Reims), M. Guillot (Bourgoin-Jallieu), P. Hillon (Dijon), J.L. Jouve (Dijon), D. Krause (Dijon), J.L. Legoux (Orléans), C. Legrand (Nantes), G. Lepeu

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