Skip to main content
Download PDF

Statin use is associated with a lower risk of recurrence after curative resection in BCLC stage 0-A hepatocellular carcinoma

BMC Cancer volume 21, Article number: 70 (2021) Cite this article

Abstract

Background

Use of statins is associated with a reduced risk of hepatocellular carcinoma (HCC). However, the effect of statin use on HCC recurrence is unclear. This study aimed to evaluate the effect of statin use on recurrence after curative resection among patients with HCC.

Methods

We retrospectively assessed 820 patients with Barcelona Clinic Liver Cancer (BCLC) stage 0 or A HCC who underwent primary resection between January 2001 and June 2016 at Kaohsiung Chang Gung Memorial Hospital. Exposure to statins was defined as use of a statin for at least 3 months before HCC recurrence. Factors that influenced overall survival (OS) and recurrence-free survival (RFS) were analyzed using Cox proportional hazards models.

Results

Of the 820 patients, 46 (5.6%) used statins (statin group) and 774 (94.4%) did not (non-statin group). During the mean follow-up of 76.5 months, 440 (53.7%) patients experienced recurrence and 146 (17.8%) patients died. The cumulative incidence of HCC recurrence was significantly lower in the statin group than the non-statin group (p = 0.001); OS was not significantly different between groups. In multivariate analysis, age (hazard ratio [HR]: 1.291; p = 0.010), liver cirrhosis (HR: 1.743; p < 0.001), diabetes (HR:1.418; p = 0.001), number of tumors (HR: 1.750; p < 0.001), tumor size (HR: 1.406; p = 0.004) and vascular invasion (HR: 1.659; p < 0.001) were independent risk factors for HCC recurrence, whereas statin use (HR: 0.354; p < 0.001) and antiviral therapy (HR: 0.613; p < 0.001) significantly reduced the risk of HCC recurrence. The statin group still had lower RFS than the non-statin group after one-to-four propensity score matching.

Conclusion

Statins may exert a chemo-preventive effect on HCC recurrence after curative resection.

Peer Review reports

Background

Hepatocellular carcinoma (HCC), the most common primary malignancy of the liver, is the second leading cause of cancer-related deaths in many regions of the world [1]. Approximately 850,000 new cases of HCC are diagnosed worldwide per year [2]. The main risk factors for HCC are chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), consumption of aflatoxin-contaminated foodstuffs, heavy alcohol intake, obesity, smoking and type 2 diabetes [3]. The current management strategies for HCC depend on the tumor stage and include surgical resection, liver transplantation, radiofrequency ablation (RFA), transarterial chemoembolization, radiation therapy and systemic therapy [4, 5]. The ideal candidates for resection are patients with early stage (BCLC stage 0 or A) who do not have extrahepatic metastasis, macrovascular invasion or clinically significant portal hypertension [6].

Surgical resection is a potentially curative treatment for HCC, though cumulative recurrence rates remain high (50–60%) [7,8,9,10]. Known risk factors for HCC recurrence after hepatectomy are tumor size, serum α-fetoprotein, tumor differentiation, microvascular invasion, cirrhosis, surgical margin, serum HBV viral load and metabolic syndrome [7, 9, 11,12,13]. Nucleos(t)ide analogue (NA) therapy may reduce the risk of HCC recurrence after hepatic resection among patients with HBV-related HCC [14]. The adjuvant therapy sorafenib, a targeted therapy for advanced HCC, has been proven not to prevent HCC recurrence after complete resection or ablation of primary HCC [15]. However, using NA therapy alone is not enough to prevent HCC recurrence. To decrease the risk of HCC recurrence after curative resection, other effective chemopreventive agents need to be identified.

Statins, cholesterol-lowering 3-hydroxy-3-methyglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are the most common medications used for primary and secondary prevention of cardiovascular disease and mortality [16]. In addition to their effect on cholesterol biosynthesis, numerous previous studies have indicated statins can exert chemopreventive effects and reduce the risk of HCC in individuals with HBV [17, 18] or HCV [19, 20] infection. In vitro studies and animal models have explored the mechanisms underlying the anticancer effects of statins in HCC [21, 22]. Although these studies demonstrate statins reduce the risk of developing HCC, few studies have explored the impact of statins on the outcome of patients with HCC after curative resection. Thus, we aimed to evaluate the effect of statin use on the risk of recurrence after curative resection in patients with HCC.

Methods

Study design

The data used in this study were extracted from the Kaohsiung Chang Gung Memorial Hospital HCC registry database. A total of 2137 patients diagnosed with HCC who underwent surgical resection between January 2001 and June 2016 at Kaohsiung Chang Gung Memorial Hospital were retrospectively enrolled. We excluded 918 patients with Barcelona Clinic Liver Cancer (BCLC) stage B or C, 234 patients who underwent prior treatment for HCC and 67 patients who developed recurrence within less than 3 months after resection. In well-selected patients, liver transplantation is generally considered to cure the tumor and underlying cirrhosis at the same time, thus strongly influences survival and recurrence [23]. Therefore, 98 patients who underwent salvage liver transplantation were also excluded. Finally, a total of 820 patients with BCLC stage 0 or A HCC who underwent primary curative resection (Fig. 1) were included in this study.

Fig. 1
figure 1

Patient selection flow diagram

Full size image

This study was conducted in accordance with the standards of the Declaration of Helsinki and current ethics guidelines; approval was obtained from the Ethics Committee of Chang Gung Memorial Hospital (IRB number: 201901103B0). The requirement for informed consent was waived by the IRB; all data were analyzed anonymously.

Exposure to chemopreventive agents

To define the statins group and non-statins group, we calculated the defined daily dose (DDD) recommended by the World Health Organization to measure the amount of drugs prescribed [24]. Cumulative DDD (cDDD) was estimated as the sum of the dispensed DDDs for any statin (namely Atorvastatin, Fluvastatin, Pitavastatin and Rosuvastatin) before HCC recurrence. Patients taking a statin cDDD of more than 90 were enrolled in the statins group; patients with statin cDDD of less than 90 were enrolled in the non-statins group. The cDDD for other chemopreventive agents including aspirin, NSAIDs (namely diclofenac, ibuprofen, indomethacin, mefenamic acid, aceclofenac, sulindac, celecoxib, etoricoxib and naproxen), and metformin were also recorded.

Study assessments and follow-up evaluation

Medical records were reviewed to obtain data on patient demographics and clinical characteristics, including serum biochemistry, albumin, alpha-fetoprotein (AFP), Child-Pugh classification, viral hepatitis status, duration of follow-up and outcomes. The diagnosis of cirrhosis was confirmed using the histopathology reports for surgically resected non-tumor tissues. HCC stage was defined according to the BCLC guidelines [25]. Tumor differentiation was assessed using the Edmondson grading system.

Patients were followed-up 1 month after surgery, every 3 months in the first year, and every 3–6 months in subsequent years. Serum AFP levels, serum biochemistry and abdominal ultrasonography were performed at every follow-up. Dynamic computed tomography or magnetic resonance studies were performed 1 month after resection and every 12 months thereafter, or if HCC recurrence was clinically suspected. Last follow-up was April 30, 2020. Recurrence-free survival (RFS) was defined as the interval between surgery and the date of diagnosis of the first recurrence; overall survival (OS), as the interval between surgery and death or last follow-up.

Statistical analysis

Propensity score matching (PSM) was applied to reduce selection bias between the study groups. Age, sex, diabetes mellitus, hepatitis B, hepatitis C, liver cirrhosis, Child-Pugh grade, tumor size, tumor number and microvascular invasion were selected as independent variables. The greedy method of NCSS 10 Statistical Software (LLC, Kaysville, UT, USA) was used for matching the study groups in a 1:4 ratio; the caliper width was 0.2 of the standard deviation of the propensity score between study groups. The standardized mean difference (SMD) was used to evaluate covariate balance after PSM.

Demographic data were compared between groups using Fisher’s exact test or the chi-square test, as appropriate. Continuous variables are expressed as the median ± interquartile range (IQR). The Kaplan-Meier method was used to plot the RFS and OS curves stratified by chemopreventive agent use and the curves were compared using the log-rank test. Factors that were significant in the univariate analysis (p < 0.05) were included in multivariate analyses of OS and RFS using a Cox forward stepwise variable selection process. Hazard ratios (HR) and 95% confidence intervals (CI) were also calculated for each factor. Statistical analyses were performed using SPSS 22.0 software (SPSS Inc., Chicago, IL, USA). All statistical tests were two-sided; p-values < 0.05 were considered significant.

Results

Comparison of the clinical characteristics of patients with and without statin use

Table 1 summarizes the characteristics of the study cohort, which included 639 males and 181 females, with an age range of 52–66-years-old and median age of 59. Overall, 222 patients (27.1%) had diabetes before surgery and 378 (46.1%) were diagnosed with cirrhosis. Cirrhosis was defined as METAVIR stage 4 fibrosis based on histopathological evaluation of resected non-tumor liver tissues [26].

Table 1 Comparison of clinical and pathological characteristics before hepatectomy for patients with or without statin use
Full size table

Of the 820 patients, 46 (5.6%) were taking statins (statin group) and 774 (94.4%) were not taking statins (non-statin group). Compared to the non-statin group, the patients in the statin group were significantly older (p = 0.037) and had a higher frequency of diabetes mellitus (DM; p < 0.001) and larger tumors (p = 0.008), but a lower frequency of cirrhosis (p = 0.005). Overall, the statin group had a lower rate of recurrence (p = 0.003), though overall survival was not significant different between the statin and non-statin groups (p = 0.667).

Factors associated with HCC recurrence

A total of 440 (53.7%) patients developed recurrence during the mean follow-up period of 76.5 months. The Kaplan-Meier curves shown in Fig. 2 indicated statin use (p = 0.001) was associated with a significantly lower risk of HCC recurrence. In contrast, aspirin, NSAIDs and metformin were not significantly associated with HCC recurrence. In subgroup analysis based on various clinical characteristics (Fig. 3), RFS was significantly higher in the statin group than non-statin group in the subgroups of patients with BCLC stage A (p = 0.001), AFP < 200 ng/mL (p = 0.004), without cirrhosis (p = 0.02), CHB (p = 0.051), without DM (p = 0.018) and with DM (p = 0.001).

Fig. 2
figure 2

Kaplan-Meier cumulative recurrence-free survival curves for patients stratified by a statin use, b aspirin use, c NSAID use and d metformin use

Full size image
Fig. 3
figure 3

Kaplan-Meier cumulative recurrence-free survival curves for patients with or without statin use stratified by a BCLC stage, b liver cirrhosis, c hepatitis, d serum AFP, e diabetes mellitus and f microvascular invasion

Full size image

In the stepwise Cox proportional hazard model (Table 2), age (HR:1.291; CI: 1.064–1.566; p = 0.010), liver cirrhosis (HR: 1.743; CI: 1.437–2.113; p < 0.001), diabetes (HR:1.418; CI: 1.147–1.755; p = 0.001), multiple tumors (HR: 1.750; CI: 1.304–2.348; p < 0.001), tumor size > 2 cm (HR: 1.406; CI: 1.113–1.774; p = 0.004) and vascular invasion (HR: 1.659; CI: 1.364–2.018; p < 0.001) were independent risk factors for HCC recurrence. Moreover, statin use (HR: 0.354; CI: 0.210–0.599; p < 0.001) and antiviral therapy (HR: 0.613; CI: 0.503–0.748; p < 0.001) were associated with a significantly lower risk of HCC recurrence.

Table 2 Multivariate analysis of recurrence after curative hepatectomy for patients with BCLC 0/A stage HCC
Full size table

We further analyzed RFS in subgroup among CHB and CHC patients. Among CHB patients (n = 458), liver cirrhosis, diabetes, tumor number, tumor size and vascular invasion were independent risk factors for HCC recurrence. Statin and nucleos(t)ide analogues (NA) therapy were found to decrease HCC recurrence. Among CHC patients (n = 284), liver cirrhosis, tumor number and vascular invasion were significantly associated with HCC recurrence. HCV therapy was associated with a significantly lower risk of recurrence.

Factors associated with overall survival

A total of 146 (17.8%) patients died during follow-up. Overall, 91 (62.3%) patients died of liver-related causes: 82 of HCC and nine of complications associated with cirrhosis. Of the 55 patients who died of non-liver-related causes, 36 died of sepsis, 10 of malignancies other than HCC, three of out-of-hospital cardiac arrest, three of heart failure, one of intracranial hemorrhage, one of in-hospital cardiac arrest and one of acute respiratory distress syndrome. The Kaplan-Meier curves in Fig. 4 suggested that statin, aspirin, NSAID and metformin use were not associated with OS.

Fig. 4
figure 4

Kaplan-Meier cumulative overall survival curves for patients stratified by a statin use, b aspirin use, c NSAID use and d metformin use

Full size image

In the stepwise Cox proportional hazard model (Table 3), liver cirrhosis (HR: 1.644; CI: 1.180–2.290; p = 0.003), diabetes (HR: 2.064; CI: 1.478–2.881; p < 0.001), Child-Pugh grade (HR: 1.915; CI: 1.185–3.096; p = 0.008) and vascular invasion (HR: 2.339; CI: 1.670–3.276; p < 0.001) were related to poorer OS, whereas antiviral therapy (HR: 0.350; CI: 0.241–0.509; p < 0.001) were associated with better OS.

Table 3 Multivariate analysis of overall survival after curative hepatectomy for patients with BCLC 0/A stage HCC
Full size table

In subgroup analysis, DM, Child-Pugh grade and vascular invasion were significantly associated with poor OS among CHB patients. Whereas, NA therapy was related to better OS. Among CHC patients, liver cirrhosis, diabetes and vascular invasion were related to poor OS, while HCV therapy was associated with better OS.

Patient RFS and OS evaluation using propensity score-matching analysis

After 1:4 case propensity score matching, 46 patients in the stain group and 174 patients in the non-statin group were analyzed. The baseline characteristics were balanced between the matched groups (SMD < 0.2 and p > 0.05 for all variables). The patient characteristics before and after matching are presented in Table 4. The RFS rate was significantly higher in the statin than non-statin group (p < 0.001, Fig. 5a). Moreover, statin use remained significantly associated with a reduced risk of HCC recurrence after PSM (HR: 0.328; CI: 0.190–0.566; p < 0.001; Table 5). The OS rate was not significantly different between the groups after PSM (Fig. 5b and Table 6).

Table 4 Patient Characteristics in the Propensity Model
Full size table
Fig. 5
figure 5

Kaplan-Meier cumulative recurrence-free survival a and overall survival b curves for propensity score-matched patients stratified by statin use

Full size image
Table 5 Univariate and multivariate analysis for recurrence after curative hepatectomy for propensity score-matched patients with BCLC 0/A stage HCC
Full size table
Table 6 Univariate and multivariate analysis for overall survival after curative hepatectomy for propensity score-matched patients with BCLC 0/A stage HCC
Full size table

Discussion

Liver resection remains the mainstay of curative treatment for early-stage HCC with preserved liver function; however, the 5-year cumulative recurrence rates after resection are higher than 50% [9]. Certain medications, including statins, aspirin, NSAIDs and metformin, have been reported to alter the risk of developing HCC [14, 17, 26,27,28]. However, the effects of these medications on HCC recurrence have not yet been examined. In this population-based, propensity score-matched study, we confirmed that statin use may lower the risk of HCC recurrence in patients with HCC after curative resection. This association remained consistent regardless of age, sex, cause of hepatitis, diabetic status or the presence or absence of cirrhosis, which suggests statins could be beneficially employed as a chemopreventive agent to reduce the risk of recurrence after resection in patients with HCC. These results emphasize the need for large-scale RCTs to validate the potential chemopreventive effect of statins on the recurrence of HCC.

Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are used worldwide as a treatment for dyslipidemia and can prevent cardiovascular events and mortality [16, 29]. In addition to their cholesterol-lowering capability, increasing evidence indicates statins also exert anti-oncogenic effects. Kim et al. reported that statin use decreased the risk of developing HCC among patients with new-onset type 2 diabetes mellitus in a nested case-control, longitudinal study [30]. Tsan et al. demonstrated that statins may dose-dependently reduce the risk of HCC among individuals with HBV or HCV infection [17, 19]. Furthermore, a recent meta-analysis of 25 studies that included 1,925,964 patients concluded statins exert a beneficial chemopreventive effect against the development of HCC [31].

However, most of these studies focused on the ability of statins to protect against the development of HCC; only a few studies have assessed the potential of statins to protect against recurrence after curative resection. A retrospective study in Japan by Kawaguchi et al. showed that statins may protect against HCC recurrence [32]. Similarly, we found statin use was associated with a significantly lower risk of recurrence after resection (HR: 0.34; p = 0.005). However, OS, including liver- and non-liver-related mortality, were not significantly different between the statin and non-statin groups in this study (Supplementary Figure 2). The differences between the study by Kawaguchi et al. and our findings may be related to the varied proportions of patients with HBV and HCV infection. In the study by Kawaguchi et al., significantly fewer patients in the statin group had hepatitis B surface antigen (HBsAg) positivity and hepatitis C virus antibody (HCVAb) positivity compared to the non-statin group (HBsAg: 6.5% vs. 22.8%, p = 0.032; HCVAb: 19.4% vs. 45.0%, p = 0.005). In the present study, there was no difference in the proportions of HBV- and HCV-positive patients between the statin and non-statin groups. More importantly, we also compared various potential chemopreventive agents, including statins, aspirin, metformin and NSAIDs. To the best of our knowledge, this study represents the largest analysis of the relationship between chemopreventive agents and HCC recurrence in a country where HBV and HCV are endemic.

The mechanisms underlying the ability of statins to protect against HCC development are not well understood; some potential mechanisms have been suggested. First, statin-mediated reduction of downstream metabolites of the mevalonate pathway—including geranyl pyrophosphate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate—interferes with cancer cell proliferation and differentiation, which promotes apoptosis [33, 34]. Secondly, statins can suppress proteasomal degradation, which limits breakdown of the cyclin-dependent kinase (CDK) inhibitors p21 and p27 and reduces CDK2 expression, and thus disrupts mitosis in malignant cells [35, 36]. Third, statins may inhibit tumor cell migration and invasion by attenuating angiogenesis via downregulating VEGF production [37]. Fourth, statins exert anti-inflammatory and immunomodulatory effects by decreasing TNF-α and IL-6 expression, downregulating the activity of metalloproteinases, and inducing a shift towards the TH2 cytokine anti-inflammatory response, which may reduce hepatic inflammation [38, 39]. Chronic hepatic inflammation plays an important role in hepatocarcinogenesis [40]. Moreover, statins activate AMP-activated protein kinase, which enhances p21 expression and the endoplasmic reticulum stress response, and thus induces higher levels of autophagy [41].

Statins are generally classified into hydrophilic and lipophilic groups based on tissue selectivity. Lipophilic statins, including atorvastatin, simvastatin, lovastatin, fluvastatin and pitavastatin, distribute widely throughout various tissues. Hydrophilic statins, such as pravastatin and rosuvastatin, have lower levels of tissue absorption—except in the liver—and exert fewer side effects as they are not metabolized by cytochrome P450 enzymes [42]. Although a previous meta-analysis showed lipophilic statins, but not hydrophilic statins, were associated with a lower risk of developing HCC, we did not observe a significant difference in RFS between the subgroups of patients taking lipophilic and hydrophilic statins (Supplementary Figure 1). However, this analysis may be affected by the limited number of patients. Furthermore, the mechanisms that explain the varied anticancer efficacies of lipophilic and hydrophilic statins remain to be determined.

A recent cohort study by Young et al. indicated aspirin use—but, interestingly, not statin use—reduced the risk of HCC recurrence [43]. In contrast, aspirin use was not significantly associated with HCC recurrence in our cohort (p = 0.864). These discrepancies may be related to differences between the design of each study. Firstly, Young et al. only examined exposure to chemopreventive agents in the 30 days before tumor recurrence. However, we defined exposure as more than 90 days, as generally adopted by previous studies [32, 44]. Secondly, Young et al. enrolled patients with BCLC stage A/B/C HCC who underwent resection. In contrast, we only assessed patients with BCLC stage 0/A, so called early-stage HCC, for which surgical resection is the widely accepted standard treatment. Moreover, Young et al. focused on HBV-related HCC, while we investigated all etiologies. Since no RCTs have been published in this field, our results further emphasize the need for large-scale RCTs to validate the potential chemopreventive effect of statins on HCC recurrence.

We found that age, liver cirrhosis, diabetes, number of tumors, tumor size and vascular invasion represented the major risk factors for HCC recurrence, and antiviral therapy may reduce the risk of HCC recurrence. These results are consistent with previous reports [7, 9, 11,12,13,14, 45].

Increasing evidence indicates that gut microbiota alterations promote the development of HCC by inducing a leaky gut and gut dysbiosis; both of which are prominent features of all stages of chronic liver disease, and promote the stepwise progression from fibrosis to cirrhosis and HCC [46]. In addition to dysbiosis, gut microbiota-derived metabolites may also promote hepatocarcinogenesis via a variety of metabolic pathways [47]. Although there is no evidence to prove statin use affects HCC development and recurrence by altering the human gut microbiome, several studies have indicated statin therapy lowers the prevalence of gut microbiota dysbiosis [48] and also affects the virulence and growth of bacterial pathogens in microbial infections [49, 50]. Therefore, we hypothesize that statin use may affect the human gut microbiome, and in turn directly or indirectly reduce hepatocarcinogenesis via the gut-liver axis. Further animal experiments are required to delineate the effects of statins on the development and recurrence of HCC through the gut-microbiota-liver axis.

There are some limitations to this study. First, this was a retrospective study of patients from a single institution and the data were collected from medical records. Despite the use of multivariable analysis and propensity score-matching analysis, not all confounding factors can be completely adjusted for. Secondly, the number of patients was relatively low. There were 46 (5.6%) patients in the statin group; however, this is comparable to the study in Japan (31/734, 4.2%) and may reflect the real-world situation. Finally, we could not obtain information on tobacco use and alcohol consumption, which may also be risk factors in survival analysis. Ultimately, a large randomized trial of a suitable regimen in well-selected patients treated using standard approaches is required to obtain this important information.

Conclusions

In summary, statin use may exert a chemopreventive effect on HCC recurrence after curative resection. Further prospective randomized controlled studies are needed to confirm these observations.

Availability of data and materials

The original data are available upon reasonable request to the corresponding author.

Abbreviations

HCC:

Hepatocellular carcinoma

BCLC:

Barcelona Clinic Liver Cancer

OS:

Overall survival

RFS:

Recurrence-free survival

HR:

Hazard ratio

HBV:

Hepatitis B virus

HCV:

Hepatitis C virus

RFA:

Radiofrequency ablation

NA:

Nucleos(t)ide analogue

HMG-CoA:

3-hydroxy-3-methyglutaryl-coenzyme A

DDD:

Defined daily dose

AFP:

Alpha-fetoprotein

HBsAg:

Hepatitis B surface antigen

HCVAb:

Hepatitis C virus antibody

CDK:

Cyclin-dependent kinase

SMD:

Standardized mean difference

NSAIDs:

Nonsteroidal anti-inflammatory drugs

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

    Article  PubMed  Google Scholar 

  2. Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, Gores G. Hepatocellular carcinoma. Nat Rev Dis Primers. 2016;2:16018.

    Article  PubMed  Google Scholar 

  3. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol. 2019;16(10):589–604.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Omata M, Cheng AL, Kokudo N, Kudo M, Lee JM, Jia J, Tateishi R, Han KH, Chawla YK, Shiina S, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma: a 2017 update. Hepatol Int. 2017;11(4):317–70.

    Article  PubMed  Google Scholar 

  5. Heimbach JK, Kulik LM, Finn RS, Sirlin CB, Abecassis MM, Roberts LR, Zhu AX, Murad MH, Marrero JA. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology. 2018;67(1):358–80.

    Article  PubMed  Google Scholar 

  6. Roayaie S, Jibara G, Tabrizian P, Park JW, Yang J, Yan L, Schwartz M, Han G, Izzo F, Chen M, et al. The role of hepatic resection in the treatment of hepatocellular cancer. Hepatology. 2015;62(2):440–51.

    Article  CAS  PubMed  Google Scholar 

  7. Tabrizian P, Jibara G, Shrager B, Schwartz M, Roayaie S. Recurrence of hepatocellular cancer after resection: patterns, treatments, and prognosis. Ann Surg. 2015;261(5):947–55.

    Article  PubMed  Google Scholar 

  8. Ercolani G, Grazi GL, Ravaioli M, Del Gaudio M, Gardini A, Cescon M, Varotti G, Cetta F, Cavallari A. Liver resection for hepatocellular carcinoma on cirrhosis: univariate and multivariate analysis of risk factors for intrahepatic recurrence. Ann Surg. 2003;237(4):536–43.

    PubMed  PubMed Central  Google Scholar 

  9. Forner A, Llovet JM, Bruix J. Hepatocellular carcinoma. Lancet. 2012;379(9822):1245–55.

    Article  PubMed  Google Scholar 

  10. Huang YH, Wu JC, Chen CH, Chang TT, Lee PC, Chau GY, Lui WY, Chang FY, Lee SD. Comparison of recurrence after hepatic resection in patients with hepatitis B vs. hepatitis C-related small hepatocellular carcinoma in hepatitis B virus endemic area. Liver Int. 2005;25(2):236–41.

    Article  PubMed  Google Scholar 

  11. Wu JC, Huang YH, Chau GY, Su CW, Lai CR, Lee PC, Huo TI, Sheen IJ, Lee SD, Lui WY. Risk factors for early and late recurrence in hepatitis B-related hepatocellular carcinoma. J Hepatol. 2009;51(5):890–7.

    Article  PubMed  Google Scholar 

  12. Hirokawa F, Hayashi M, Asakuma M, Shimizu T, Inoue Y, Uchiyama K. Risk factors and patterns of early recurrence after curative hepatectomy for hepatocellular carcinoma. Surg Oncol. 2016;25(1):24–9.

    Article  PubMed  Google Scholar 

  13. Zheng J, Kuk D, Gonen M, Balachandran VP, Kingham TP, Allen PJ, D'Angelica MI, Jarnagin WR, DeMatteo RP. Actual 10-year survivors after resection of hepatocellular carcinoma. Ann Surg Oncol. 2017;24(5):1358–66.

    Article  PubMed  Google Scholar 

  14. Wu CY, Chen YJ, Ho HJ, Hsu YC, Kuo KN, Wu MS, Lin JT. Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection. JAMA. 2012;308(18):1906–14.

    Article  CAS  PubMed  Google Scholar 

  15. Bruix J, Takayama T, Mazzaferro V, Chau GY, Yang J, Kudo M, Cai J, Poon RT, Han KH, Tak WY, et al. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2015;16(13):1344–54.

    Article  CAS  PubMed  Google Scholar 

  16. Cholesterol Treatment Trialists C, Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670–81.

    Article  CAS  Google Scholar 

  17. Tsan YT, Lee CH, Wang JD, Chen PC. Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection. J Clin Oncol. 2012;30(6):623–30.

    Article  PubMed  Google Scholar 

  18. Hsiang JC, Wong GL, Tse YK, Wong VW, Yip TC, Chan HL. Statin and the risk of hepatocellular carcinoma and death in a hospital-based hepatitis B-infected population: a propensity score landmark analysis. J Hepatol. 2015;63(5):1190–7.

    Article  CAS  PubMed  Google Scholar 

  19. Tsan YT, Lee CH, Ho WC, Lin MH, Wang JD, Chen PC. Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection. J Clin Oncol. 2013;31(12):1514–21.

    Article  PubMed  Google Scholar 

  20. Butt AA, Yan P, Bonilla H, Abou-Samra AB, Shaikh OS, Simon TG, Chung RT, Rogal SS, Team ES. Effect of addition of statins to antiviral therapy in hepatitis C virus-infected persons: results from ERCHIVES. Hepatology. 2015;62(2):365–74.

    Article  CAS  PubMed  Google Scholar 

  21. Demierre MF, Higgins PD, Gruber SB, Hawk E, Lippman SM. Statins and cancer prevention. Nat Rev Cancer. 2005;5(12):930–42.

    Article  CAS  PubMed  Google Scholar 

  22. Urbich C, Dernbach E, Zeiher AM, Dimmeler S. Double-edged role of statins in angiogenesis signaling. Circ Res. 2002;90(6):737–44.

    Article  CAS  PubMed  Google Scholar 

  23. Villanueva A. Hepatocellular Carcinoma. N Engl J Med. 2019;380(15):1450–62.

    Article  CAS  PubMed  Google Scholar 

  24. WHO. Collaborating Centre for Drug Statistics Methodology, Guidelines for ATC classification and DDD assignment 2020. Oslo; 2019. https://www.whocc.no/filearchive/publications/2020_guidelines_web.pdf

  25. Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19(3):329–38.

    Article  CAS  PubMed  Google Scholar 

  26. Asselah T, Marcellin P, Bedossa P. Improving performance of liver biopsy in fibrosis assessment. J Hepatol. 2014;61(2):193–5.

    Article  PubMed  Google Scholar 

  27. Fujiwara N, Friedman SL, Goossens N, Hoshida Y. Risk factors and prevention of hepatocellular carcinoma in the era of precision medicine. J Hepatol. 2018;68(3):526–49.

    Article  PubMed  Google Scholar 

  28. Singh S, Singh PP, Roberts LR, Sanchez W. Chemopreventive strategies in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol. 2014;11(1):45–54.

    Article  CAS  PubMed  Google Scholar 

  29. Blaha MJ, Martin SS. How do statins work?: changing paradigms with implications for statin allocation. J Am Coll Cardiol. 2013;62(25):2392–4.

    Article  PubMed  Google Scholar 

  30. Kim G, Jang SY, Han E, Lee YH, Park SY, Nam CM, Kang ES. Effect of statin on hepatocellular carcinoma in patients with type 2 diabetes: a nationwide nested case-control study. Int J Cancer. 2017;140(4):798–806.

    Article  CAS  PubMed  Google Scholar 

  31. Facciorusso A, Abd El Aziz MA, Singh S, Pusceddu S, Milione M, Giacomelli L, Sacco R. Statin Use Decreases the Incidence of Hepatocellular Carcinoma: An Updated Meta-Analysis. Cancers (Basel). 2020;12(4):874.

    Article  CAS  Google Scholar 

  32. Kawaguchi Y, Sakamoto Y, Ito D, Ito K, Arita J, Akamatsu N, Kaneko J, Hasegawa K, Moriya K, Kokudo N. Statin use is associated with a reduced risk of hepatocellular carcinoma recurrence after initial liver resection. Biosci Trends. 2017;11(5):574–80.

    Article  CAS  PubMed  Google Scholar 

  33. Gazzerro P, Proto MC, Gangemi G, Malfitano AM, Ciaglia E, Pisanti S, Santoro A, Laezza C, Bifulco M. Pharmacological actions of statins: a critical appraisal in the management of cancer. Pharmacol Rev. 2012;64(1):102–46.

    Article  CAS  PubMed  Google Scholar 

  34. Wong WW, Dimitroulakos J, Minden MD, Penn LZ. HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis. Leukemia. 2002;16(4):508–19.

    Article  CAS  PubMed  Google Scholar 

  35. Rao S, Porter DC, Chen X, Herliczek T, Lowe M, Keyomarsi K. Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase. Proc Natl Acad Sci U S A. 1999;96(14):7797–802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Shibata MA, Kavanaugh C, Shibata E, Abe H, Nguyen P, Otsuki Y, Trepel JB, Green JE. Comparative effects of lovastatin on mammary and prostate oncogenesis in transgenic mouse models. Carcinogenesis. 2003;24(3):453–9.

    Article  CAS  PubMed  Google Scholar 

  37. Dulak J, Jozkowicz A. Anti-angiogenic and anti-inflammatory effects of statins: relevance to anti-cancer therapy. Curr Cancer Drug Targets. 2005;5(8):579–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med. 2000;6(12):1399–402.

    Article  CAS  PubMed  Google Scholar 

  39. Chong LW, Hsu YC, Lee TF, Lin Y, Chiu YT, Yang KC, Wu JC, Huang YT. Fluvastatin attenuates hepatic steatosis-induced fibrogenesis in rats through inhibiting paracrine effect of hepatocyte on hepatic stellate cells. BMC Gastroenterol. 2015;15:22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Hoshida Y, Fuchs BC, Tanabe KK. Prevention of hepatocellular carcinoma: potential targets, experimental models, and clinical challenges. Curr Cancer Drug Targets. 2012;12(9):1129–59.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Yang PM, Liu YL, Lin YC, Shun CT, Wu MS, Chen CC. Inhibition of autophagy enhances anticancer effects of atorvastatin in digestive malignancies. Cancer Res. 2010;70(19):7699–709.

    Article  CAS  PubMed  Google Scholar 

  42. McKenney JM. Pharmacologic characteristics of statins. Clin Cardiol. 2003;26(4 Suppl 3):III32–8.

    Article  PubMed  Google Scholar 

  43. Young SH, Chau GY, Lee IC, Yeh YC, Chao Y, Huo TI, Su CW, Lin HC, Hou MC, Lee MH, et al. Aspirin is associated with low recurrent risk in hepatitis B virus-related hepatocellular carcinoma patients after curative resection. J Formos Med Assoc. 2020;119(1 Pt 2):218–29.

    Article  CAS  PubMed  Google Scholar 

  44. Simon TG, Duberg AS, Aleman S, Chung RT, Chan AT, Ludvigsson JF. Association of Aspirin with hepatocellular carcinoma and liver-related mortality. N Engl J Med. 2020;382(11):1018–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Choi Y, Choi Y, Choi CS, Lee YH. Diabetes mellitus increases the risk of intrahepatic recurrence of hepatocellular carcinoma after surgical resection. Tumori. 2017;103(3):279–85.

    Article  CAS  PubMed  Google Scholar 

  46. Fukui H. Role of Gut Dysbiosis in Liver Diseases: What Have We Learned So Far? Diseases. 2019;7(4):58.

    Article  CAS  PubMed Central  Google Scholar 

  47. Chu H, Duan Y, Yang L, Schnabl B. Small metabolites, possible big changes: a microbiota-centered view of non-alcoholic fatty liver disease. Gut. 2019;68(2):359–70.

    Article  CAS  PubMed  Google Scholar 

  48. Vieira-Silva S, Falony G, Belda E, Nielsen T, Aron-Wisnewsky J, Chakaroun R, Forslund SK, Assmann K, Valles-Colomer M, Nguyen TTD, et al. Statin therapy is associated with lower prevalence of gut microbiota dysbiosis. Nature. 2020;581(7808):310–5.

    Article  CAS  PubMed  Google Scholar 

  49. Hennessy E, Adams C, Reen FJ, O'Gara F. Is there potential for repurposing statins as novel antimicrobials? Antimicrob Agents Chemother. 2016;60(9):5111–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Smit J, Lopez-Cortes LE, Thomsen RW, Schonheyder HC, Nielsen H, Froslev T, Rodriguez-Bano J, Sogaard M. Statin use and risk of community-acquired Staphylococcus aureus bacteremia: a population-based case-control study. Mayo Clin Proc. 2017;92(10):1469–78.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This study was supported by grants CMRPG8L0261 from Chang Gung Memorial Hospital, Taiwan. The authors would like to thank all of the patients and their providers who participated in this study. We also thank the Biostatistics Center, Kaohsiung Chang Gung Memorial Hospital, for statistical work.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Ta Pei Road, Kaohsiung, Taiwan

    Shih-Yu Yang, Yu-Chieh Tsai, Chih-Chien Yao, Yi-Hao Yen, Tsung-Hui Hu & Ming-Chao Tsai

  2. Liver Transplantation Center and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Chih-Chi Wang, Yueh-Wei Liu & Chih-Che Lin

  3. Center for Translational Research in Biomedical Sciences, Liver Transplantation Program and Department of Surgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Kuang-Den Chen

  4. Head Nurse, Department of Nursing, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan

    Ching-Hui Chuang

  5. Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan

    Chang-Chun Hsiao & Ming-Chao Tsai

  6. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

    Chang-Chun Hsiao

Authors
  1. Shih-Yu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chih-Chi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kuang-Den Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yueh-Wei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chih-Che Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ching-Hui Chuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu-Chieh Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chih-Chien Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yi-Hao Yen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chang-Chun Hsiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tsung-Hui Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ming-Chao Tsai
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, K.-D.C. and M.-C.T.; Data curation, C.-C.W., Y.-W.L., C.-C.L., Y.-C.T., C.-C.Y., Y.-H.Y. and T.-H.H.; Methodology, C.-H.C.; Supervision, M.-C.T and C.-C.H.; Writing—original draft, S.-Y.Y.; Writing—review & editing, M.-C.T and C.-C.H. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Ming-Chao Tsai.

Ethics declarations

Ethics approval and consent to participate

The clinical data was acquired with the approval and permission of the Institutional Review Board of the Kaohsiung Chang Gung Memorial Hospital. The study protocol was approved by the Institutional Review Board of the Kaohsiung Chang Gung Memorial Hospital. Informed consent was not required because this study was a retrospective report of cases, which is a retrospective analysis of clinical data with no relevant to human biological ethic problems.

Consent for publication

Not applicable.

Competing interests

The authors have no competing interests to declare.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1: Supplementary Figure 1.

Kaplan-Meier cumulative recurrence-free survival curves for patients with HCC using statins stratified by (A) lipophilic or hydrophilic statins and (B) individual statins.

Additional file 2: Supplementary Figure 2.

Kaplan-Meier (A) liver-related survival and (B) non-liver-related survival curves after curative resection for patients with HCC stratified by statin use.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and Permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, SY., Wang, CC., Chen, KD. et al. Statin use is associated with a lower risk of recurrence after curative resection in BCLC stage 0-A hepatocellular carcinoma. BMC Cancer 21, 70 (2021). https://doi.org/10.1186/s12885-021-07796-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12885-021-07796-7

Keywords

  • Hepatocellular carcinoma
  • Statin
  • Resection
  • Recurrence

BMC Cancer

ISSN: 1471-2407

Contact us