HCC comprises more than 80% of primary liver cancers (32) and is the third most deadly cancer worldwide. In Europe, it is the seventh leading cause of death (33, 34). OS is higher if the diagnosis is made early (9), but high HCC recurrence rates after surgical treatment still remain a big challenge (12, 35). New methods are urgently needed to reduce recurrence, thereby improving long-term surgical outcomes and reducing healthcare-related costs in the future.
Because of the virulent character of HCC, prevention plays a significant role in treatment (36). Different studies have investigated the protective effect of several drugs against HCC recurrence, including statins, aspirin, and anti-diabetic agents (37). Statins are classified into lipophilic and hydrophilic statins and have been used extensively to prevent and treat cardiovascular diseases (38, 39). Studies have recently demonstrated that statins can reduce the risk of many cancers, including liver cancers (38, 40). Furthermore, statins can inhibit progression of liver fibrosis and cirrhosis in HCC patients (41) and can reduce the risk of HCC in patients with Hepatitis C Virus (HCV) infection and also with nonalcoholic fatty liver disease (NAFLD) (42, 43). Lipophilic statins seem to be more effective at preventing HCC than hydrophilic statins are (38). Fluvastatin has been revealed as the most effective drug in reducing HCC risk (37).
In this systematic review and meta-analysis, we investigated whether statins can reduce HCC recurrence following liver surgery. We showed that the recurrence was lower at one, three, and five years after surgery in patients with HCC who underwent liver surgery in combination with statin treatment than in patients who underwent liver surgery without statin treatment. These results indicate that statins should be considered effective at reducing the recurrence of HCC tumors.
Statins may reduce the risk of cancer via several mechanisms, including inhibiting oncogenic pathways, promoting tumor-specific apoptosis, inhibiting the proteasome pathway, inhibiting hepatitis virus replication, and reducing cholesterol synthesis (44, 45). Statins can also decrease endothelial dysfunction, intrahepatic vasoconstriction, inflammation, and fibrosis (46–48). The anti-inflammatory and immunomodulatory effects of statins allow them to inhibit harmful inflammatory and immunologic responses that may promote cancer (46–48). The effect of statins on liver regeneration and ischemia-reperfusion injury after extensive hepatectomy has been investigated in animal models. These studies showed that these drugs can improve outcomes by facilitating regeneration and by inhibiting the harmful inflammatory response (49, 50). In a pilot clinical study, preoperative oral atorvastatin therapy for 3 days prior to liver resection reduced the harmful immunologic and inflammatory responses due to ischemia-reperfusion injury (51).
Patients who are not eligible for liver resection can be treated with more conservative options (22). Wu et al. (22) reported that combining statin treatment with these conservative methods improves the survival of patients with advanced HCC. In patients with a contraindication for these conservative therapies, especially those with HBV/HCV, palliative treatment with statins can reduce the mortality rate (22). It seems that combining statins and conservative therapies in patients who cannot undergo surgical therapies can improve the HCC prognosis (22, 52). According to Aaron et al., statins can improve the survival of HCC patients when administered both before or after HCC is diagnosed (53).
HCC recurrence is detected in half of patients three years after liver surgery (54). Recurrent disease is not easily treatable, so it is important to prevent recurrence after resection (20). Studies have shown that statins can reduce HCC recurrence rate by reducing viremia in patients with HBV and HCV. Possible mechanisms include reducing pro-inflammatory cytokines in serum (37, 55, 56), reducing the virulent potency of viral infections (20, 56), or inhibiting cirrhotic progression (56).
Preventing HCC recurrence after liver transplantation is also an important issue (57) but has not been well investigated. Statins have several side-effects (including myalgia and myotoxicity that may lead to rhabdomyolysis), especially when administered at high doses. These side-effects need to be properly investigated in post-transplant patients (58),(59). The prevalence of post-liver transplant dyslipidemia is 16–66% worldwide (46). Statins decrease lipidemia in patients after liver transplantation, thereby preventing cardiovascular events (58).
There are some limitations to the present systematic review and meta-analysis. We found no RCT that compared the clinical outcomes of liver surgery between statin and non-statin groups. Furthermore, the timing, dosage, and type of statin is important to evaluate the outcomes; however, this information was not provided in every study. Further well-designed, large-scale RCTs are needed to determine whether statin therapy prevents HCC recurrence after liver resection or transplantation.
In conclusion, statins increased disease-free survival of patients with HCC after liver surgery. They may reduce HCC recurrence after liver surgery by chemoprevention effects. Unfortunately, the existing evidence is still too limited (small study populations, retrospective study designs, and single-center studies) to confirm a role for statins in reducing disease recurrence in HCC patients. Further randomized clinical trials should confirm the effectiveness of statins in preventing HCC recurrence after liver surgery, and should determine the importance of different types of surgery and types of statins.