Elsevier

The Lancet

Volume 359, Issue 9319, 18 May 2002, Pages 1734-1739
The Lancet

Articles
Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial

https://doi.org/10.1016/S0140-6736(02)08649-XGet rights and content

Summary

Background

There is no standard treatment for unresectable hepatocellular carcinoma. Arterial embolisation is widely used, but evidence of survival benefits is lacking.

Methods

We did a randomised controlled trial in patients with unresectable hepatocellular carcinoma not suitable for curative treatment, of Child-Pugh class A or B and Okuda stage I or II, to assess the survival benefits of regularly repeated arterial embolisation (gelatin sponge) or chemoembolisation (gelatin sponge plus doxorubicin) compared with conservative treatment. 903 patients were assessed, and 112 (12%) patients were finally included in the study. The primary endpoint was survival. Analyses were by intention to treat.

Findings

The trial was stopped when the ninth sequential inspection showed that chemoembolisation had survival benefits compared with conservative treatment (hazard ratio of death 0·47 [95% CI 0·25–0·91], p=0·025). 25 of 37 patients assigned embolisation, 21 of 40 assigned chemoembolisation, and 25 of 35 assigned conservative treatment died. Survival probabilities at 1 year and 2 years were 75% and 50% for embolisation; 82% and 63% for chemoembolisation, and 63% and 27% for control (chemoembolisation vs control p=0·009). Chemoembolisation induced objective responses sustained for at least 6 months in 35% (14) of cases, and was associated with a significantly lower rate of portal-vein invasion than conservative treatment. Treatment allocation was the only variable independently related to survival (odds ratio 0·45 [95% CI 0·25–0·81], p=0·02).

Interpretation

Chemoembolisation improved survival of stringently selected patients with unresectable hepatocellular carcinoma.

Introduction

The incidence of hepatocellular carcinoma is increasing worldwide.1 Curative therapies, such as resection, liver transplantation, or percutaneous treatments, benefit only 25% of patients and are the only chance to improve life expectancy.2, 3, 4, 5 Despite the implementation of surveillance programmes for early hepatocellular carcinoma, most tumours are diagnosed at advanced stages, for which no standard therapy has been established.2, 3, 4, 5 Arterial embolisation induces objective responses in 16–55% of patients and lowers the rate of tumour progression. However, six randomised trials have found no survival benefits in comparisons of this therapy with or without chemotherapy (doxorubicin, cisplatin) versus conservative management or suboptimum treatments.6, 7, 8, 9, 10, 11 Similarly, two systematic reviews of some of these trials showed discrepant results.12, 13 The lack of survival benefits could be due to two factors. First, prognosis is related not only to the hepatocellular carcinoma itself, but also to the functional status of the underlying cirrhosis. Second, objective responses are not maintained with time. Accordingly, we hypothesised that very strict selection of candidates and a more aggresive retreatment schedule, aiming to prolong the initial antitumoral effect, might allow the identification of a treatment-related survival benefit and clarify the uncertainty about the usefulness of this therapy.

This sequential, multicentre, randomised controlled trial assessed the survival benefits of arterial embolisation or chemoembolisation in patients with unresectable hepatocellular carcinoma in comparison with conservative management. The three-group design would allow us to identify potential advantages from the type of embolisation applied.

Section snippets

Patients

The study included consecutive white patients who met the entry criteria and agreed to participate in the trial, recruited during a 4-year period in three centres in the area of Barcelona. Hepatocellular carcinoma was diagnosed, staged, and treated according to a previously reported schedule.2 Patients with early tumours (single tumours measuring less than 5 cm or three nodules measuring less than 3 cm) are considered for radical therapies. Resection is indicated for patients with single

Results

The study began on July 1, 1996, and was stopped on July 28, 2000, when the ninth sequential inspection detected significant differences in favour of chemoembolisation. 112 (12·4%) of the 903 patients diagnosed with hepatocellular carcinoma during this time met the entry criteria and agreed to take part (figure 1). Of the 791 excluded, 310 had early hepatocellular carcinoma and underwent curative therapy (resection or liver transplantation in 154, and percutaneous treatments in 156), 68 were

Discussion

There is no standard therapy for patients with unresectable hepatocellular carcinoma.2, 3, 4, 5 Six randomised trials of arterial embolisation, with or without chemotherapy, have shown a strong antitumoral effect, but none detected survival benefits in comparison with conservative management or suboptimum treatments.6, 7, 8, 9, 10, 11 Two systematic reviews justified additional studies to define the efficacy of this technique unequivocally,12, 13 and our study offers relevant data by showing

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