Non-selective Beta-Blockers May Reduce Risk of HCC
Background & Aims: Non-selective beta-blockers (NSBB) are used in patients with cirrhosis and oesophageal varices. Experimental data suggest that NSBB inhibit angiogenesis and reduce bacterial translocation, which may prevent hepatocellular carcinoma (HCC). We therefore assessed the effect of NSBB on HCC by performing a systematic review with meta-analyses of randomized trials.
Methods: Electronic and manual searches were combined. Authors were contacted for unpublished data. Included trials assessed NSBB for patients with cirrhosis; the control group could receive any other intervention than NSBB. Fixed and random effects meta-analyses were performed with I as a measure of heterogeneity. Subgroup, sensitivity, regression and sequential analyses were performed to evaluate heterogeneity, bias and the robustness of the results after adjusting for multiple testing.
Results: Twenty-three randomized trials on 2618 patients with cirrhosis were included, of which 12 reported HCC incidence and 23 reported HCC mortality. The mean duration of follow-up was 26 months (range 8–82). In total, 47 of 694 patients randomized to NSBB developed HCC vs 65 of 697 controls (risk difference −0.026; 95% CI−0.052 to −0.001; number needed to treat 38 patients). There was no heterogeneity (I = 7%) or evidence of small study effects (Eggers P = 0.402). The result was not confirmed in sequential analysis, which suggested that 3719 patients were needed to achieve the required information size. NSBB did not reduce HCC-related mortality (RD −0.011; 95% CI −0.040 to 0.017).
Conclusions: Non-selective beta-blockers may prevent HCC in patients with cirrhosis.
Hepatocellular carcinoma (HCC) is the main liver-related cause of death in patients with compensated cirrhosis and the third most common cause of cancer-related death worldwide. The early phases are asymptomatic and the prognosis in advanced stages is poor, which makes prevention essential.
Non-selective beta-blockers (NSBB) are recommended as bleeding prophylaxis in patients with cirrhosis and oesophageal varices. A recent meta-analysis showed that NSBB decrease mortality in patients with cirrhosis beyond what can be explained by a reduced rate of gastrointestinal bleeding. Observational and experimental studies suggest that the beneficial effect of NSBB may partly reflect a reduced risk of hepatocellular carcinoma. In animal and in vitro studies, NSBB inhibit catecholamine driven cancer cell migration, tumour angiogenesis, invasiveness and proliferation. As the concentration of catecholamines increases with the severity of cirrhosis, NSBB may be especially potent as an anticarcinogenic drug in cirrhosis. Furthermore, hepatic inflammation promotes carcinogenesis and NSBB reduce bacterial translocation and thus the load of proinflammatory cytokines from the gut to the liver. NSBB is anti-angiogenic, which may inhibit HCC growth.
A retrospective study found that the NSBB propranolol reduced the incidence of HCC in 291 patients with compensated cirrhosis due to hepatitis C. In a retrospective study on cirrhosis of mixed aetiologies, the risk of HCC did not differ between 135 patients on low dose NSBB compared with 135 untreated controls. In a network meta-analysis on antihypertensive drugs, a subgroup analysis found that beta-blockers reduced the risk of cancer. Performing a meta-analysis on NSBB for HCC based on observational studies may be misleading because patients who are not treated will differ from patients who receive NSBB. There are no randomized controlled trials on the effect of NSBB for prevention of HCC. However, the number of patients who develop HCC is registered in several randomized controlled trials on NSBB for prevention of variceal bleeding. Although the HCC data are not always reported, the information may be retrieved through unpublished data. We therefore performed a meta-analysis of randomized controlled trials on NSBB for HCC in patients with cirrhosis.
Abstract and Introduction
Abstract
Background & Aims: Non-selective beta-blockers (NSBB) are used in patients with cirrhosis and oesophageal varices. Experimental data suggest that NSBB inhibit angiogenesis and reduce bacterial translocation, which may prevent hepatocellular carcinoma (HCC). We therefore assessed the effect of NSBB on HCC by performing a systematic review with meta-analyses of randomized trials.
Methods: Electronic and manual searches were combined. Authors were contacted for unpublished data. Included trials assessed NSBB for patients with cirrhosis; the control group could receive any other intervention than NSBB. Fixed and random effects meta-analyses were performed with I as a measure of heterogeneity. Subgroup, sensitivity, regression and sequential analyses were performed to evaluate heterogeneity, bias and the robustness of the results after adjusting for multiple testing.
Results: Twenty-three randomized trials on 2618 patients with cirrhosis were included, of which 12 reported HCC incidence and 23 reported HCC mortality. The mean duration of follow-up was 26 months (range 8–82). In total, 47 of 694 patients randomized to NSBB developed HCC vs 65 of 697 controls (risk difference −0.026; 95% CI−0.052 to −0.001; number needed to treat 38 patients). There was no heterogeneity (I = 7%) or evidence of small study effects (Eggers P = 0.402). The result was not confirmed in sequential analysis, which suggested that 3719 patients were needed to achieve the required information size. NSBB did not reduce HCC-related mortality (RD −0.011; 95% CI −0.040 to 0.017).
Conclusions: Non-selective beta-blockers may prevent HCC in patients with cirrhosis.
Introduction
Hepatocellular carcinoma (HCC) is the main liver-related cause of death in patients with compensated cirrhosis and the third most common cause of cancer-related death worldwide. The early phases are asymptomatic and the prognosis in advanced stages is poor, which makes prevention essential.
Non-selective beta-blockers (NSBB) are recommended as bleeding prophylaxis in patients with cirrhosis and oesophageal varices. A recent meta-analysis showed that NSBB decrease mortality in patients with cirrhosis beyond what can be explained by a reduced rate of gastrointestinal bleeding. Observational and experimental studies suggest that the beneficial effect of NSBB may partly reflect a reduced risk of hepatocellular carcinoma. In animal and in vitro studies, NSBB inhibit catecholamine driven cancer cell migration, tumour angiogenesis, invasiveness and proliferation. As the concentration of catecholamines increases with the severity of cirrhosis, NSBB may be especially potent as an anticarcinogenic drug in cirrhosis. Furthermore, hepatic inflammation promotes carcinogenesis and NSBB reduce bacterial translocation and thus the load of proinflammatory cytokines from the gut to the liver. NSBB is anti-angiogenic, which may inhibit HCC growth.
A retrospective study found that the NSBB propranolol reduced the incidence of HCC in 291 patients with compensated cirrhosis due to hepatitis C. In a retrospective study on cirrhosis of mixed aetiologies, the risk of HCC did not differ between 135 patients on low dose NSBB compared with 135 untreated controls. In a network meta-analysis on antihypertensive drugs, a subgroup analysis found that beta-blockers reduced the risk of cancer. Performing a meta-analysis on NSBB for HCC based on observational studies may be misleading because patients who are not treated will differ from patients who receive NSBB. There are no randomized controlled trials on the effect of NSBB for prevention of HCC. However, the number of patients who develop HCC is registered in several randomized controlled trials on NSBB for prevention of variceal bleeding. Although the HCC data are not always reported, the information may be retrieved through unpublished data. We therefore performed a meta-analysis of randomized controlled trials on NSBB for HCC in patients with cirrhosis.
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