This study summary is an excerpt from 2 Minute Medicine’s book The Classics in Medicine: Summaries of the Landmark Trials
1. In patients with unresectable hepatocellular carcinoma (HCC), arterial chemoembolization with doxorubicin showed a significant survival advantage 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
Study overview: HCC is the most common primary liver cancer and the second leading cause of cancer death worldwide. Although the mainstay of treatment is surgical resection, many patients do not meet the eligibility criteria for curative resection due to the high burden of disease. Alternative treatment modalities have been developed for patients with unresectable HCC, such as arterial chemoembolization of the feeding hepatic artery; however, early trials evaluating the use of arterial chemoembolization showed conflicting evidence about 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 study randomized more than 100 patients with unresectable HCC to chemoembolization with doxorubicin or symptomatic control. The study excluded all patients with advanced disease (Child-Pugh Score C), extra-hepatic disease or portal vein thrombosis. The study was discontinued early due to the significant survival benefit observed in the patient group randomized to arterial chemoembolization. In addition, the use of chemoembolization was associated with a significantly lower portal vein tumor invasion at two years of follow-up. The results of this study demonstrated a significant survival benefit of arterial chemoembolization in a rigorously selected patient population with unresectable HCC.
Click to read the study in The Lancet
in-depth [randomized controlled trial]† This was a single-blind, multicenter randomized controlled trial evaluating the survival benefit of arterial chemoembolization in patients with unresectable HCC. All adult patients (n = 903) with a biopsy or imaging confirmed diagnosis of HCC were screened sequentially for enrollment over four years at three centers in Barcelona, Spain. The inclusion criteria were patients with HCC who were not considered suitable for curative treatment. The main exclusion criteria were 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 patients with unresectable unresectable treatment were recruited and randomized to either chemoembolization with gelatin sponge and doxorubicin, 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. Treatment was discontinued if the patient developed any of the exclusion criteria. Response to treatment was monitored 6 months after recruitment by contrast enhanced spiral computed tomography. The primary endpoint was overall survival with the secondary endpoint being treatment response.
A total of 40 patients were randomized to chemoembolization, 37 patients were randomized to arterial embolization only and 35 patients were randomized to symptomatic treatment. There were no significant differences in baseline characteristics between each group, with the exception of serum bilirubin, which was significantly higher in the control group. The study was discontinued early due to a significant survival benefit in the chemoembolization group compared to the control group (HR: 0.47; 95%CI 0.25-0.91; p = 0.025). At the end of the study, the mean survival for the chemoembolization group was significantly longer compared to the control group (25.3 months vs 17.9 months; p < 0.009). There were no direct survival comparisons between the chemoembolization group and the embolization group; however, chemoembolization alone was associated with a reduced risk of portal vein thrombosis compared to control at two years of follow-up (17% vs 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 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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