Hepatocellular carcinoma (HCC) is the sixth most common malignant tumor and the fastest-growing fatal cancer in the United States, with its mortality rate rising rapidly worldwide. Determining the optimal treatment strategy for HCC is challenging and depends on the tumor stage at diagnosis. Surgical or interventional therapies such as local ablation, surgical resection, and liver transplantation are the preferred treatments for tumors diagnosed at an early stage. However, in many cases, detecting early-stage tumors is not feasible, and only 13% of HCC cases are diagnosed early enough to receive curative treatment. Although the cure rates for surgical interventions like tumor resection or liver transplantation are acceptable, the recurrence rates are also high, with over 50% of patients experiencing recurrence within five years post-surgery. Despite the use of new predictive models, post-transplant recurrence rates range between 8% and 21%.

Both animal and human studies have demonstrated an independent relationship between cholesterol levels and HCC progression. HCC cell lines utilize cholesterol for their cell membrane and organelle division, and high-density lipoprotein cholesterol levels are associated with tumor aggressiveness. Statins, which are inhibitors of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, are commonly used to reduce blood cholesterol levels. Additionally, statins possess immunomodulatory effects, contributing to their anticancer properties. Several studies have attempted to investigate the potential role of statins in preventing HCC recurrence. Early research indicates that statins influence molecular pathways in HCC cell lines to prevent excessive proliferation in vivo. These anticancer effects make statins an intriguing candidate for HCC prevention.

Recent studies suggest that statins can improve survival rates in liver cancer patients and reduce the recurrence rate of HCC after curative treatment. In this systematic review and meta-analysis, we examined the role of statins in preventing HCC recurrence post-liver surgery.

A literature search identified 1,362 studies, excluding duplicates. Qualitative analysis included nine retrospective studies involving 44,219 patients (2,243 in the statin group and 41,976 in the non-statin group). All studies were published between 2012 and 2021. The quality of evidence for the outcomes, assessed using the GRADE method, was moderate.

Qualitative report

Among the 9 included studies (Table 1), only the research by Yang and Young [26, 27] classified patients according to the Barcelona Clinic Liver Cancer (BCLC) staging system. In this younger study, out of 430 participants, approximately 59% were in stage A, 36 in stage B, and the remainder in stage C. Only patients at stage 0 or A were included in Yang's study. Four studies [20, 23, 26, 28] provided sufficient information on recurrence-free survival between statin and non-statin groups. Based on available data from the included studies, we conducted two separate meta-analyses for HRs and ORs. The Wu LL study [22] was excluded from the HR meta-analysis because statin use was not separately reported among patients who underwent surgery.

The quality assessment of the included studies is presented in Table 2. The overall MINORS scores for all included studies were below 20, indicating a considerable risk of bias. All incorporated studies carried a high risk of biased evaluation for study endpoints as they were non-randomized and non-blinded. Additionally, all included studies were retrospective, so sample sizes were not prospectively calculated.

Quantitative analysis

Among the 8 studies involving a total of 25,327 participants, the association between statin use and HCC recurrence was reported as HRs. After pooling the HRs for hepatocellular carcinoma recurrence using a random-effects model, patients who received statins preoperatively showed a significantly reduced recurrence rate (HR: 0.53; 95% CI: 0.44–0.63; p < 0.001; Figure 2). In this regard, no significant heterogeneity was observed among the studies (I² = 34%; P = 0.16).

A total of 2,544 patients from four studies (232 patients in the statin group and 2,312 patients in the non-statin group) reported postoperative HCC recurrence. In the statin group, 16 patients (6.89%) experienced HCC recurrence within 1 year after surgery, compared with 663 patients (28.67%) in the non-statin group. Meta-analysis using a random-effects model showed that statin use reduced the risk of HCC recurrence at 1 year postoperatively (OR: 0.27; 95% CI: 0.16–0.47; p < 0.001; Figure 3). No significant heterogeneity was observed among these studies (I² = 0%; p = 0.39).

HCC recurrence at 3 years post-operation was reported in 31 patients (13.3%) in the statin group and 1,159 patients (50.1%) in the non-statin group. Meta-analysis using a random-effects model showed that statin use reduced HCC recurrence at 3 years post-operation (OR: 0.22; 95% CI: 0.15–0.33; p < 0.001; Figure 4). No significant heterogeneity was observed among the studies (I² = 0%; p = 0.56).

HCC recurrence at 5 years post-operation was reported in 49 patients (20.9%) in the statin group and 1,360 patients (58.8%) in the non-statin group. Meta-analysis using a random-effects model showed that statin use reduced the 5-year HCC recurrence rate after surgery (OR: 0.28; 95% CI: 0.19–0.42; p < 0.001; Figure 5). No significant heterogeneity was observed among these studies (I² = 18%; p = 0.30).

In summary, this meta-analysis involving 44,219 patients (2,243 in the statin group and 41,976 in the non-statin group) demonstrated that patients receiving statin therapy had a lower recurrence rate after liver surgery (HR: 0.53; 95% CI: 0.44–0.63; p < 0.001). Additionally, statins reduced recurrence at 1 year post-operation (OR: 0.27; 95% CI: 0.16–0.47; p < 0.001), 3 years post-operation (OR: 0.22; 95% CI: 0.15–0.33; p < 0.001), and 5 years post-operation (OR: 0.28; 95% CI: 0.19–0.42; p < 0.001). The quality of evidence for these outcomes was moderate.

In summary, statins increase the disease-free survival rate of liver cancer patients after hepatic surgery. These drugs appear to have a chemopreventive effect, reducing the likelihood of HCC recurrence following liver transplantation or resection. Unfortunately, current evidence remains too limited (small study populations, retrospective study designs, and single-center research) to confirm the role of statins in reducing disease recurrence in HCC patients. Further randomized clinical trials should verify the effectiveness of statins in preventing post-surgical HCC recurrence and should determine the significance of different surgical types and statin varieties.