Statin and aspirin for chemoprevention of hepatocellular carcinoma: Time to use or wait further?
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SUBMITTER: Goh MJ
PROVIDER: S-EPMC9293618 | biostudies-literature | 2022 Jul
REPOSITORIES: biostudies-literature
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Statin and aspirin for chemoprevention of hepatocellular carcinoma: Time to use or wait further?
Goh Myung Ji MJ Sinn Dong Hyun DH
Clinical and molecular hepatology 20220113 3
Preclinical studies highlighted potential therapeutic applications of aspirin and statins as anticancer agents based on their pleiotropic effects. Epidemiologic studies suggested the role of aspirin and statins in the chemoprevention of hepatocellular carcinoma (HCC). However, observational data is prone to bias, and no prospective randomized trials are currently available to assess the risks and benefits of statin or aspirin therapy for chemoprevention of HCC. It is therefore important for clin ...[more]
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Project description:BackgroundEmerging data suggest that statins, aspirin and metformin may protect against hepatocellular carcinoma (HCC) development. However, prior meta-analyses were limited by heterogeneity and inclusion of studies without adequate adjustment for baseline risks.AimTo examine by an updated meta-analysis the association between these medications and HCC risk.MethodsMedline and Embase databases were searched from inception to March 2022 for studies that balanced baseline risks between study groups via propensity score matching or inverse probability of treatment weighting, that reported the impact of statins, aspirin or metformin on HCC risk. Multivariable-adjusted hazard ratios (HRs) for HCC were pooled using a random effects model.ResultsStatin use was associated with reduced HCC risk overall (HR: 0.52; 95% CI: 0.37-0.72) (10 studies, 1,774,476), and in subgroup analyses for cirrhosis, hepatitis B/C, non-alcoholic fatty liver disease, studies accounting for concurrent aspirin and metformin consumption and lipophilic statins. Aspirin use was associated with reduced HCC risk overall (HR: 0.48; 95% CI: 0.27-0.87) (11 studies, 2,190,285 patients) but not in studies accounting for concurrent statin and metformin use. Metformin use was not associated with reduced HCC risk overall (HR: 0.57; 95% CI: 0.31-1.06) (3 studies, 125,458 patients). Most analyses had moderate/substantial heterogeneity, except in follow-up <60 months for aspirin (I2 = 0%).ConclusionAlthough statin and aspirin use were associated with reduced HCC risk, only statin use was significant in subgroup analyses accounting for concurrent medications. Metformin use was not associated with reduced HCC risk. These data have implications for future clinical trial design.
| S-EPMC10792521 | biostudies-literature
Project description:ImportanceProspective data on the risk of hepatocellular carcinoma (HCC) according to dose and duration of aspirin therapy are limited.ObjectiveTo examine the potential benefits of aspirin use for primary HCC prevention at a range of doses and durations of use within 2 prospective, nationwide populations.Design, setting, and participantsPooled analysis of 2 prospective US cohort studies: the Nurses' Health Study and the Health Professionals Follow-up Study. Data were accessed from November 1, 2017, through March 7, 2018. A total of 133 371 health care professionals who reported data on aspirin use, frequency, dosage, and duration of use biennially since 1980 in women and 1986 in men were included. Individuals with a cancer diagnosis at baseline (except nonmelanoma skin cancer) were excluded.Main outcomes and measuresCox proportional hazards regression models were used to calculate multivariable adjusted hazard ratios (HRs) and 95% CIs for HCC.ResultsOf the 133 371 participants, 87 507 were women and 45 864 were men; in 1996, the median time of follow-up, the mean (SD) age was 62 (8) years for women and 64 (8) years for men. Over more than 26 years of follow-up encompassing 4 232 188 person-years, 108 incident HCC cases (65 women, 43 men) were documented. Compared with nonregular use, regular aspirin use (≥2 standard-dose [325-mg] tablets per week) was associated with reduced HCC risk (adjusted HR, 0.51; 95% CI, 0.34-0.77). This benefit appeared to be dose related: compared with nonuse, the multivariable-adjusted HR for HCC was 0.87 (95% CI, 0.51-1.48) for up to 1.5 standard-dose tablets per week, 0.51 (95% CI, 0.30-0.86) for more than 1.5 to 5 tablets per week, and 0.49 (95% CI, 0.28-0.96) for more than 5 tablets per week (P for trend = .006). Significantly lower HCC risk was observed with increasing duration (P for trend = .03); this decrease was apparent with use of 1.5 or more standard-dose aspirin tablets per week for 5 or more years (adjusted HR, 0.41; 95% CI, 0.21-0.77). In contrast, use of nonaspirin nonsteroidal anti-inflammatory drugs was not significantly associated with HCC risk (adjusted HR, 1.09; 95% CI, 0.78-1.51).Conclusions and relevanceThis study suggests that regular, long-term aspirin use is associated with a dose-dependent reduction in HCC risk, which is apparent after 5 or more years of use. Similar associations were not found with nonaspirin NSAIDs. Further research appears to be needed to clarify whether aspirin use represents a feasible strategy for primary prevention against HCC.
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Project description:Chronic fibrotic liver disease caused by viral or metabolic etiologies is a high-risk condition for developing hepatocellular carcinoma (HCC). Even after curative treatment of early-stage HCC tumor, the carcinogenic microenvironment persists in the remnant diseased liver and supports the development of de novo HCC tumors (de novo HCC recurrence). Therefore, prevention of HCC development in patients at risk of not only first-primary but also second-primary HCC tumors is theoretically the most impactful strategy to improve patient prognosis. However, no such therapy has been established to date. One major challenge is the identification of clinically relevant targets that can be achieved by utilizing the reverse-engineering strategy of chemoprevention discovery, which integrates omics information from clinical cohorts with completed follow-up for cancer development. Clinical and experimental studies have suggested etiology-specific and generic candidate HCC chemoprevention strategies, including statins, antidiabetic drugs, selective molecular targeted agents, and dietary and nutritional substances. Clinical testing of the candidate compounds can be cost-effectively performed by combining it with HCC risk biomarker evaluation to specify the target patient population most likely to benefit from the therapy. Nontoxic, generic agents will have broad clinical applicability across the diverse HCC etiologies and clinical contexts and are expected to substantially improve the still dismal prognosis of HCC.
| S-EPMC6420365 | biostudies-literature
Project description:Liver cancer, mainly hepatocellular carcinoma (HCC), remains a major cause of cancer-related death worldwide. With the global epidemic of obesity, the major HCC etiologies have been dynamically shifting from viral to metabolic liver diseases. This change has made HCC prevention difficult with increasingly elusive at-risk populations as rational target for preventive interventions. Besides ongoing efforts to reduce obesity and metabolic disorders, chemoprevention in patients who already have metabolic liver diseases may have a significant impact on the poor HCC prognosis. Hepatitis B- and hepatitis C-related HCC incidences have been substantially reduced by the new antivirals, but HCC risk can persist over a decade even after successful viral treatment, highlighting the need for HCC-preventive measures also in these patients. Experimental and retrospective studies have suggested potential utility of generic agents such as lipophilic statins and aspirin for HCC chemoprevention given their well-characterized safety profile, although anticipated efficacy may be modest. In this review, we overview recent clinical and translational studies of generic agents in the context of HCC chemoprevention under the contemporary HCC etiologies. We also discuss newly emerging approaches to overcome the challenges in clinical testing of the agents to facilitate their clinical translation.
| S-EPMC10870259 | biostudies-literature
Project description:Preclinical and clinical studies provide evidence for aspirin as a preventative agent for cancer. Compelling direct evidence supports a chemopreventive effect of aspirin in individuals at high risk of developing colorectal cancer due to Lynch syndrome, while indirect evidence indicates that aspirin may reduce the risk of and mortality from sporadic colorectal cancer. There is weaker evidence for a protective effect of aspirin against all cancers taken as a group. Nevertheless, the results of recent retrospective cohort studies consistently indicate a beneficial effect of aspirin as a chemopreventive or adjuvant chemotherapeutic agent in hepatocellular carcinoma (HCC). Epidemiologic studies conducted in the general population or in selected populations at higher risk for HCC reveal that regular aspirin use is associated with reduced HCC incidence. In addition, aspirin may act as an adjuvant to other therapies in reducing HCC recurrence. According to studies in animal models, the cancer-preventative effect of aspirin may be related to its antiplatelet and anti-inflammatory activities. Prospective studies are warranted to determine whether aspirin should be recommended to diverse populations of patients at risk for HCC.
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Project description:PurposeStatins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) are medications widely prescribed to reduce cholesterol levels. Observational studies in high-risk populations, mostly in Asia, have suggested that statins are associated with a reduced risk of hepatocellular carcinoma (HCC). The current study sought to evaluate the association of statin use and HCC in a U.S.-based, low-risk, general population.MethodsA nested case-control study was conducted among members of the Health Alliance Plan HMO of the Henry Ford Health System enrolled between 1999 and 2010. Electronic pharmacy records of statin use were compared among tumor registry-confirmed cases of HCC (n=94) and controls (n=468) matched on age, sex, diagnosis date, and length of HMO enrolment.ResultsIn multivariate analyses, ever-use of statins was significantly inversely associated with development of HCC (Odds ratio (OR): 0.32, 95%CI: 0.15-0.67). No clear dose-response relationship was evident as statin use for <2 years (OR=0.32, 95%CI=0.13-0.83) and >2 years (OR=0.31, 95CI%=0.12-9.81) resulted in very similar ORs.ConclusionsThe use of statins among populations in low-risk HCC areas may be associated with decreased risk of HCC.
| S-EPMC4188715 | biostudies-literature
Project description:Background & aimsStatin use is associated with a lower risk of developing hepatocellular carcinoma (HCC). However, it is unclear whether postdiagnosis statin use is associated with a reduced risk of death in patients with HCC.MethodsWe performed a retrospective analysis of data from 15,422 patients with HCC in the Veterans Administration Central Cancer Registry, diagnosed from 2002 through 2016. We identified statin prescriptions that were filled before and after the cancer diagnosis and used time-dependent Cox regression models to calculate adjusted hazard ratios (HRs) and 95% CIs for risk of death. We used a time-varying exposure to avoid immortal time bias, and a 3-month lag (following up patients from 3 months after the cancer diagnosis) to reduce reverse causation. A sensitivity analysis was conducted varying the lag duration between date of cancer diagnosis and start of follow-up evaluation.ResultsStatin use after diagnosis was recorded for 14.9% of patients with HCC. We found that postdiagnosis statin use was associated with a decreased risk of cancer-specific death (adjusted HR, 0.85; 95% CI, 0.77-0.93) and all-cause mortality (HR, 0.89; 95% CI, 0.83-0.95). The magnitudes of these inverse associations were consistent for patients who used high or low doses of statins, and the inverse associations remained across a range of lag periods (from 0 months to 12 months after HCC diagnosis). We found no evidence for effect modification by prediagnosis statin use, or by presentation- or treatment-related factors, and no independent association with prediagnosis statin use.ConclusionsIn a retrospective analysis of data from veterans with HCC, use of statins (high or low doses) after a diagnosis of HCC was associated with reduced mortality.
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Project description:Statins can decrease hepatocellular carcinoma (HCC) occurrence, but the magnitude and the predictors of these effects remain unclear. This meta-analysis provides a pooled estimate of the impact of statin use on HCC occurrence. Pooled effects were calculated using a random-effects model by means of the DerSimonian and Laird test. Primary endpoint was the time-dependent correlation between statin use and HCC incidence expressed as hazard ratio (HR), both crude and adjusted. The crude and adjusted odds ratios (OR) for HCC occurrence between statin users and non-users were analyzed. Twenty-five studies with 1,925,964 patients were included. Crude OR for HCC incidence was 0.59 (95% CI: 0.47-0.74), confirmed in adjusted analysis (OR: 0.74, 95% CI: 0.70-0.78). Adjusted HR was 0.73 (95% CI: 0.69-0.76). This effect was more pronounced in HBV patients (HR: 0.46, 95% CI: 0.36-0.60) and with a cumulative daily dose beyond 365 (HR: 0.27, 95% CI: 0.11-0.67). Lipophilic statins were associated with reduced HCC incidence (HR: 0.49, 95% CI: 0.39-0.62). Atorvastatin determined the greater magnitude of effect (HR: 0.43, 95% CI: 0.28-0.65). This meta-analysis demonstrates the beneficial chemopreventive effect of statins against HCC occurrence. This effect is dose-dependent and more pronounced with lipophilic statins.
| S-EPMC7225931 | biostudies-literature
Project description:ObjectiveTo evaluate the association of aspirin and other nonsteroidal anti-inflammatory drugs with the incidence of postmenopausal breast cancer for risk subgroups defined by selected nonmodifiable or difficult to modify breast cancer risk factors in order to better understand the potential risk-benefit ratio for targeted chemoprevention.Patients and methodsPostmenopausal women with no history of cancer on July 1, 1992 (N=26,580), were prospectively followed up through December 31, 2005, for breast cancer incidence (N=1581). Risk subgroups were defined on the basis of family history of breast cancer, age at menarche, age at menopause, parity/age at first live birth, personal history of benign breast disease, and body mass index. Hazard ratios (HRs) and 95% CIs adjusted for other breast cancer risk factors were estimated using Cox models.ResultsAspirin use was associated with a lower incidence of breast cancer for women with a family history of breast cancer (HR, 0.62 for 6 or more times per week vs never use; 95% CI, 0.41-0.93) and those with a personal history of benign breast disease (HR, 0.69; 95% CI, 0.50-0.95) but not for women in higher-risk subgroups for age at menarche, age at menopause, parity/age at first live birth, or body mass index. In contrast, inverse associations with aspirin use were observed in all lower-risk subgroups. Nonsteroidal anti-inflammatory drug use had no association with breast cancer incidence.ConclusionOn the basis of their increased risk of breast cancer, postmenopausal women with a family history of breast cancer or a personal history of benign breast disease could potentially be targeted for aspirin chemoprevention studies. Future studies are needed to confirm these findings.
| S-EPMC4807132 | biostudies-literature
Project description:BACKGROUND:Association between statin use and prognosis in patients with hepatocellular carcinoma (HCC) remains unknown. We performed a meta-analysis of follow-up studies to systematically evaluate the influence of statin use on clinical outcome in HCC patients. METHODS:Studies were obtained via systematic search of PubMed, Cochrane's Library, and Embase databases. A randomized-effect model was used to pool the results. Subgroup analyses were performed to evaluate the influence of study characteristics on the association. RESULTS:Nine retrospective cohort studies were included. Overall, statin use was associated with a reduced all-cause mortality in HCC patients (risk ratio [RR]: 0.81, 95% CI: 0.74-0.88, P < 0.001; I2 = 63%). Subgroup analyses showed similar results for patients with stage I-III HCC (RR: 0.83, 0.79, and 0.90 respectively, P all < 0.01) and patients after palliative therapy for HCC (RR: 0.80, P < 0.001), but not for patents with stage IV HCC (RR: 0.91, P = 0.28) or those after curative therapy (RR: 0.92, P = 0.20). However, the different between subgroups were not significant (both P > 0.05). Moreover, statin use was associated with reduced HCC-related mortality (RR: 0.78, P = 0.001) in overall patient population and HCC recurrence in patients after curative therapies (RR: 0.55, P < 0.001). CONCLUSIONS:Satin use is associated with reduced mortality and recurrence of HCC. These results should be validated in prospective cohort studies and randomized controlled trials.
| S-EPMC7133516 | biostudies-literature