This study summary is an excerpt from the book 2 Minute Medicine’s The Classics in Medicine: Summaries of the Landmark Trials
1. In patients with unresectable hepatocellular carcinoma (HCC), arterial chemoembolization with doxorubicin demonstrated significant survival benefit compared to control group.
2. The randomized controlled trial had strict inclusion criteria and only included patients with Child-Pugh Class A/B with no evidence of end-stage tumoral disease, portal vein obstruction, or encephalopathy.
Original Date of Publication: May 2002
Study Rundown: HCC is the most common primary liver cancer and the second-leading cause of cancer mortality worldwide. While the mainstay of treatment is surgical resection, many patients do not meet the eligibility criteria for curative resection due to large disease burden. Alternative treatment modalities for patients with non-resectable HCC such as arterial chemoembolization of the feeding hepatic artery were 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 over 100 patients with non-resectable HCC to chemoembolization with doxorubicin or symptomatic control. The trial excluded all patients with advanced disease (Child-Pugh Score C), extra-hepatic disease, or portal vein thrombosis. The trial was stopped early due to the significant survival benefit observed in the patient group randomized to arterial chemoembolization. Additionally, the use of chemoembolization was associated with a significantly lower rate of tumor invasion of portal vein at two years of follow-up. The results of this trial demonstrated a significant survival benefit of arterial chemoembolization in a stringently selected patient population with non-resectable HCC.
In-Depth [randomized controlled trial]: This was a single-blind, multi-center randomized controlled trial evaluating the survival benefit of arterial chemoembolization in patients with non-resectable HCC. All adult patients (n = 903) with a biopsy- or imaging-confirmed diagnosis of HCC were consecutively screened for enrollment over four years across three centers in Barcelona, Spain. The inclusion criteria were patients with HCC that were deemed not suitable for curative treatment. Key exclusion criteria included patients with Child-Pugh class C disease, evidence of extra-hepatic disease, presence of vascular invasion, renal failure, or end-stage tumoral disease. Overall, 112 patients with non-resectable 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 halted if the patient developed any of the exclusion criteria. Treatment response was monitored by contrast-enhanced spiral computed tomography at 6 months post-recruitment. The primary end-point was overall survival with a secondary endpoint of treatment response.
Overall, 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 the baseline characteristics between each group with the exception of serum bilirubin, which was significant higher in the control group. The trial was stopped early due to significant survival benefit in the chemoembolization group compared to control (HR: 0.47; 95%CI 0.25-0.91; p = 0.025). At the conclusion of the trial, the mean survival for the chemoembolization group was significantly longer compared to 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 decreased risk of portal-vein thrombosis compared to control at two-year 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 embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. The Lancet. 2002 May 18;359(9319):1734–9.
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