This study summary is an excerpt from the book 2 Minute Medicine’s The Classics in Medicine: Summaries of Landmark Trials
1. In patients with unresectable hepatocellular carcinoma (HCC), arterial chemoembolization with doxorubicin has demonstrated a significant survival benefit compared to the control group.
2. The randomized controlled trial had strict inclusion criteria and included only Child-Pugh class A/B patients without evidence of end-stage tumor disease, portal vein obstruction, or encephalopathy.
Original publication date: May 2002
Summary of the study: HCC is the most common primary liver cancer and the second leading cause of cancer death worldwide. While the mainstay of treatment is surgical resection, many patients do not meet the eligibility criteria for curative resection due to the heavy disease burden. Alternative treatment modalities for patients with unresectable HCC such as arterial chemoembolization of the feeder hepatic artery have been developed; however, early trials evaluating the use of arterial chemoembolization demonstrated conflicting evidence on the survival benefit of these procedures. The purpose of this landmark randomized controlled trial was to determine the effectiveness of arterial chemoembolization in a study population most likely to benefit from this procedure. The trial randomized more than 100 patients with unresectable HCC to chemoembolization with doxorubicin or symptom control. The trial excluded all patients with advanced disease (Child-Pugh Score C), extrahepatic disease, or portal vein thrombosis. The trial was terminated prematurely due to the significant survival benefit observed in the group of patients randomized to receive arterial chemoembolization. In addition, the use of chemoembolization was associated with a significantly lower rate of portal vein tumor invasion at two years of follow-up. The results of this trial demonstrated a significant survival benefit of arterial chemoembolization in a population of carefully selected patients with unresectable HCC.
In depth [randomized controlled trial]: This was a multicenter, single-blind, randomized controlled trial evaluating the survival benefit of arterial chemoembolization in patients with unresectable HCC. All adult patients (n=903) with a diagnosis of HCC confirmed by biopsy or imaging were consecutively screened for enrollment over four years at three centers in Barcelona, Spain. The inclusion criteria were patients with HCC deemed ineligible for curative treatment. Primary exclusion criteria included patients with Child-Pugh Class C disease, evidence of extrahepatic disease, presence of vascular invasion, renal failure, or end-stage tumor disease. A total of 112 unresectable patients were recruited and randomized to receive either chemoembolization with gelatin sponge and doxorubicin, or arterial embolization alone, or symptomatic treatment. Arterial embolization with or without doxorubicin was performed at baseline, 2 months, 6 months, and every 6 months thereafter. The treatment was stopped if the patient developed one of the exclusion criteria. Response to treatment was monitored by spiral CT scan with contrast at 6 months after recruitment. The primary endpoint was overall survival with a secondary endpoint of response to treatment.
Overall, 40 patients were randomized for chemoembolization, 37 patients were randomized for arterial embolization only, and 35 patients were randomized for symptomatic treatment. There were no significant differences in baseline characteristics between each group except for serum bilirubin, which was significantly higher in the control group. The trial was stopped prematurely due to a significant survival benefit in the chemoembolization group compared to the control group (RR: 0.47; 95% CI: 0.25-0.91; p=0.025). At the end of the trial, the average survival of the chemoembolization group was significantly longer than that of the control group (25.3 months versus 17.9 months; p < 0.009). There were no direct survival comparisons between the chemoembolization group and the embolization group; however, only chemoembolization was associated with a reduced risk of portal vein thrombosis compared to control at two years of follow-up (17% versus 58%; p = 0.005). The mean number of chemoembolization treatment sessions was 3.08 (95% CI 2.4-3.5). Eleven patients had treatment-related complications and there was only one treatment-related death. Common complications included cholecystitis, leukopenia, and spontaneous bacterial peritonitis.
Llovet JM, Real MI, Montaña X, Planas R, Coll S, Aponte J, et al. Arterial embolization or chemoembolization versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomized controlled trial. The Lancet. 2002 May 18;359(9319):1734–9.
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