TABLE 1.
Representative observational studies and interventional clinical studies regarding statins use in cancer.
| Large-scale observational studies | |||||||
|---|---|---|---|---|---|---|---|
| Statins | Cancer type | Study type/patient number | Findings | ||||
| Statins | Prostate cancer | Prospective cohort study/44,126 | Current statin use was associated with lower risk of PTEN-null and lethal prostate cancer (HR, 0.40; 95% CI, 0.19–0.87; and HR, 0.76; 95% CI, 0.60–0.96; respectively). Allott et al. (2020) | ||||
| Statins | Prostate cancer | Case-control study/42,480 | The use of statins was associated with a risk reduction of overall prostate cancer (adjusted OR, 0.94; 95% CI, 0.91–0.97) and specifically with advanced prostate cancer (adjusted OR, 0.90; 95% CI, 0.85–0.96). Jespersen et al. (2014) | ||||
| Statins (before cancer diagnosis) | Non-Hodgkin lymphoma | Case-control study/18,657 | Previous statin administration was associated with a reduced risk of subsequent non-Hodgkin lymphoma (adjusted OR, 0.52; 95% CI, 0.43–0.62). Cho et al. (2015) | ||||
| Statins | HCC | Meta-analysis/59,703 | Statin use was associated with a reduced risk of HCC development (risk ratio, 0.54; 95% CI, 0.47–0.61) compared with nonusers, supporting the beneficial inhibitory effect of statins on HCC incidence. Islam et al. (2020b) | ||||
| Statins | HCC | Meta-analysis/1,774,476 | Statin use was associated with reduced HCC risk (HR: 0.52; 95% CI, 0.37–0.72). Zeng et al. (2023) | ||||
| Statins (before cancer diagnosis) | Glioblastoma | Prospective cohort study/280,455 | Ever statin use (HR, 1.43, 95% CI, 1.10–1.86) was significantly associated with increased glioma risk. Cote et al. (2019) | ||||
| Statins (before cancer diagnosis) | Endometrial cancer | Case-control study/77,509 | The use of statins was not associated with the risk of endometrial cancer (OR, 1.03; 95% CI, 0.94–1.14). In addition, endometrial cancer risk did not vary substantially with duration or intensity of statin use. Sperling et al. (2017) | ||||
| Statins | Colorectal cancer | Meta-analysis/387,518 | The use of statins was significantly associated with a decrease in overall mortality (HR, 0.81; 95% CI, 0.76–0.86) and cancer-specific mortality (HR, 0.78; 95% CI, 0.72–0.85) of colorectal cancer. Li et al. (2021) | ||||
| Statins (simvastatin being the mostly prescribed lipophilic statin) | Breast cancer | Prospective cohort study/18,769 | Simvastatin was associated with a reduced risk of breast cancer recurrence among Danish women diagnosed with stage I–III breast carcinoma (adjusted 10-year risk difference = −0.10, 95% CI, −0.11 to −0.08) Ahern et al. (2011) | ||||
| Statins (after cancer diagnosis) | Breast cancer | Retrospective cohort study/17,880 | Statin use after a diagnosis of breast cancer reduced mortality due to breast cancer (adjusted HR, 0.84; 95% CI, 0.68–1.04). Cardwell et al. (2015) | ||||
| Statins | Gastric cancer | Retrospective cohort study/80,271 | Statin use was associated with a reduction of gastric cancer mortality in the general population but not with gastric cancer incidence. Cho et al. (2021) | ||||
| Atorvastatin, simvastatin, lovastatin, pravastatin, and rosuvastatin (both pre- and post- cancer diagnosis) | Lung cancer | Retrospective cohort study/19,974 | Overall baseline statin exposure was associated with a decrease in mortality risk for squamous-cell carcinoma patients (HR, 0.89; 95% CI, 0.82–0.96) and adenocarcinoma patients (HR, 0.87; 95% CI, 0.82–0.94), but not among those with SCLC. Post-diagnostic statin exposure was associated with prolonged survival in squamous-cell carcinoma patients (HR, 0.68; 95% CI, 0.59–0.79) and adenocarcinoma patients (HR, 0.78; 95% CI, 0.68–0.89). Baseline or post-diagnostic exposure to simvastatin and atorvastatin was associated with extended survival in NSCLC cancer subtypes. Ung et al. (2018) | ||||
| Statins | Kidney cancer | Meta-analysis/18,105 | Statin use was not significantly associated with PFS (pooled HR 0.92, 95% CI, 0.51–1.65); however, statin use was associated with marked improvements in cancer-specific survival (pooled HR 0.67, 95% CI, 0.47–0.94) and overall survival (pooled HR 0.74, 95% CI, 0.63–0.88) in patients with kidney cancer. Nayan et al. (2017) | ||||
| Statins (before cancer diagnosis) | 13 cancer types | Retrospective cohort study/295,925 | Statin use in patients with cancer was associated with reduced cancer-related mortality. Multivariable-adjusted HR for statin users, as compared with patients who had never used statins, were 0.85 (95% CI, 0.83–0.87) for death from any cause and 0.85 (95% CI, 0.82–0.87) for death from cancer. Nielsen et al. (2012) | ||||
| Statins | Not specified | Meta-analysis/1,111,407 | Statin use was significantly associated with decreased risk of all-cause mortality (HR, 0.70; 95% CI, 0.66–0.74) compared with nonusers. The observed pooled estimates were retained for cancer-specific mortality (HR, 0.60; 95% CI, 0.47–0.77), PFS (HR, 0.67; 95% CI, 0.56–0.81), recurrence-free survial (HR, 0.74; 95% CI, 0.65–0.83) and disease-free survival (HR, 0.53; 95% Cl, 0.40–0.72). Mei et al. (2017) | ||||
| Statins | Not specified | Prospective cohort study/146,326 | In a cohort of postmenopausal women, regular use of statins or other lipid-lowering medications was associated with decreased cancer death (HR, 0.78; 95% CI, 0.71–0.86), regardless of the type, duration, or potency of statin medications used. Wang et al. (2016) | ||||
| Statins | Not specified | Meta-analysis/175,000 | A median of 5 years of statin therapy had no effect on the incidence of, or mortality from, any type of cancer (or the aggregate of all cancer). Cholesterol Treatment Trialists et al. (2012) | ||||
| Interventional clinical studies | |||||||
| Intervention | Cancer type | Mechanisms | Study type/patient number | Findings | |||
| Lipophilic statins | |||||||
| Atorvastatin (80 mg/day before surgery) | Breast cancer | Inhibiting tumor cell growth by downregulation of cyclin D1 and p27 | Phase II, non-randomized, window of opportunity trial/50 | Atorvastatin treatment in patients with primary invasive breast cancer led to increased protein expression of the tumor suppressor p27, lower cyclin D1 expression, and a decrease in proliferation although not significantly (p = 0.08). (NCT00816244) Feldt et al. (2015) | |||
| Atorvastatin (10 mg/day) | HCC | NR | Phase IV, double-blind, randomized PC trial/recruiting | No results posted. The aims is to evaluate the effect of atorvastatin for preventing HCC recurrence after curative treatment. The primary endpoint is to compare the 3-year cumulative incidence of recurrent HCC between the intervention group and control counterpart. (NCT03024684) | |||
| Atorvastatin (20 mg/day) plus zoledronate | Kidney cancer | Bisphosphonates and statins target different steps in the mevalonate pathway, providing a synergistic effect | Phase II, single-arm, pilot trial/11 | The combination use of zoledronate and atorvastatin (or fluvastatin) were well tolerated, affected certain bone biomarkers and provided bone response. (NCT00490698) Manoukian et al. (2011) | |||
| Atorvastatin (Before surgery) plus metformin | Breast cancer | Inhibiting signaling pathways including PI3K/Akt/mTOR and AMPK | Phase I, window of opportunity trial/23 | No results posted. The aim is to assess whether tumor proliferation is reduced following ∼2 weeks of treatment with metformin plus atorvastatin in patients with newly diagnosed breast cancer. (NCT01980823) | |||
| Atorvastatin (40 mg/day) plus radiotherapy and temozolomide | Glioblastoma | NR | Phase II, single-arm trial/36 | 80% of patients discontinued because of disease progression. High LDL level was an important independent predictor of poor cancer-related outcome. (NCT02029573) Altwairgi FA et al. (2019) | |||
| Simvastatin (40 mg/day) | Ovarian cancer | NR | Phase I, single-arm, pilot trial/recruiting | No results posted. The aim is to evaluate the feasibility and effects of simvastatin to reduce cancer progression among patients with platinum-sensitive ovarian cancer treated with carboplatin and liposomal doxorubicin. (NCT04457089) | |||
| Simvastatin (40 mg/day) plus fluorouracil, adriamycin, and cyclophosphamide (FAC) | Locally advanced breast cancer | Inducing apoptosis and inhibiting tumor cell growth | Phase II, double-blind, randomized PC trial/70 | Simvastatin combined with FAC showed improvements in ORR and pathological response in patients with locally advanced breast cancer. Although no statistically significant difference was documented, there was a trend for better activity and tolerability. (NCT04418089) Yulian et al. (2021) | |||
| Simvastatin (80 mg/day) plus XELOX and bevacizumab | Metastatic colorectal cancer | Inducing tumor cell senescence and apoptosis, and showing anti-angiogenesis effect | Phase II, single-arm trial/60 | Addition of simvastatin to XELOX and bevacizumab showed comparable clinical efficacy in patients with metastatic colorectal cancer as first-line chemotherapy and did not increase toxicity. The median PFS was 10.4 months, the disease-control rate and overall RR was 88.3% and 58.3%. (NCT02026583) Kim et al. (2019) | |||
| Simvastatin (40 mg/day) plus gefitinib | NSCLC | Impairment of protein prenylation and interference with lipid rafts both affect the function of EGFR and EGFR signaling | Phase II, randomized trial/106 | The combination of simvastatin and gefitinib resulted in higher RR (40% vs. 0%, p = 0.043) and longer PFS (3.6 months vs. 1.7 months, p = 0.027) compared with gefitinib alone in subgroup of patients with wildtype EGFR non-adenocarcinomas. (NCT00452244) Han et al. (2011) | |||
| Simvastatin (40 mg/day) plus afatinib | NSCLC | Inhibition of RAS activation and downstream signaling cascades | Phase II, randomized trial/68 | Combination of simvastatin plus afatinib was well-tolerated, but did not improve RR and PFS compared with afatinib alone in patients with advanced non-adenocarcinomas who progressed after chemotherapy regimens. (NCT01156545) Lee et al. (2017) | |||
| Simvastatin (40 mg/day) plus capecitabine and cisplatin | Gastric cancer | Regulating modifications of Ras and RhoA, inducing apoptosis, and lowering VEGF serum levels | Phase III, double-blind, randomized PC trial/244 | Addition of simvastatin to capecitabine-cisplatin did not increase PFS in patients with previously untreated advanced gastric cancer, although it did not increase toxicity. (NCT01099085) Kim et al. (2014) | |||
| Simvastatin (40 mg/day) plus gemcitabine | Pancreatic cancer | Impairment of protein prenylation and interference with lipid rafts both affect the function of EGFR and EGFR signaling | Phase II, double-blind, randomized PC trial/114 | Addition of simvastatin to gemcitabine in advanced pancreatic cancer did not provide clinical benefit, although it did not result in increased toxicity. The median time to progression was not significantly different between the two arms (2.4 months vs. 3.6 months, p = 0.903). (NCT00944463) Hong et al. (2014) | |||
| Simvastatin (40 mg/day) plus FOLFIRI/XELIRI chemotherapy regimens | Metastatic colorectal cancer | Impairment of protein prenylation and intracellular signal transduction | Phase III, double-blind, randomized PC trial/269 | Addition of simvastatin to the regimens did not improve median PFS (5.9 months vs. 7.0 months, p = 0.826) in patients with previously treated metastatic colorectal cancer nor did it increase toxicity. (NCT01238094) Lim et al. (2015) | |||
| Simvastatin (40 mg/day) plus chemotherapy/radiation | Rectal cancer | NR | Phase II, double-blind, randomized PC trial/222 | No results posted. The primary objective is rates of favorable MRI-based tumor regression grading. Patients receive simvastatin or placebo daily for 90 days starting 1 week prior to standard preoperative chemoradiotherapy. (ACTRN 12617001087347) Jameson et al. (2019) | |||
| Simvastatin (80 mg/day) plus capecitabine | Locally advanced rectal cancer | NR | Phase II, single-arm trial/60 | No results posted. The aim is to investigate the synergistic effect of simvastatin combined with capecitabine and radiotherapy in locally advanced rectal cancer patients. The primary outcome is pathologic complete response rate. (NCT02161822) | |||
| Simvastatin (20 mg/day before surgery) plus metformin | Bladder cancer | Inhibiting signaling pathways including PI3K/Akt/mTOR and AMPK | Phase II, single-arm, window of opportunity trial/44 | No results posted. The aim is to evaluate the effect and feasibility of using a combination of metformin and simvastatin as a neoadjuvant treatment for patients with invasive bladder cancer who are to undergo cystectomy. (NCT02360618) | |||
| Lovastatin (0.5–2 mg/kg) plus thalidomide and dexamethasone | Multiple myeoloma | Anti-neoplasmatic property and inducing apoptosis | Randomized trial/91 | Lovastatin plus thalidomide–dexamethasone prolonged OS and PFS compared with thalidomide–dexamethasone alone in patients with relapsed or refractory multiple myeloma. Hus et al. (2011) | |||
| Fluvastatin (80 mg/day) | Localized prostate cancer | Inducing tumor cell apoptosis | Phase II, single-arm, window of opportunity, pilot trial/33 | A median 2.7-fold increase in cleaved Caspase-3 positivity (95% CI: 1.9–5.0, p = 0.007) was observed in post-fluvastatin RP tissues compared with matched pre-treatment biopsy controls. Fluvastatin was associated with promising effects on tumor cell apoptosis. Longo et al. (2020) | |||
| Fluvastatin (80 or 20 mg/day) | Breast cancer | Inducing apoptosis and suppressing tumor cell proliferation | Randomized, peri-operative window trial/40 | Administration of fluvastatin for 3–6 weeks before surgery decreased proliferation of high-grade tumors by a median of 7.2% (p = 0.008), and increased apoptosis in 60% of high-grade tumors; for low-grade tumors, these effects were less evident. Garwood et al. (2010) | |||
| Fluvastatin (80 mg/day) | Breast cancer | NR | Single-arm, non-randomized, biomarker modulation trial/30 | Lovastatin was technically feasible and generally well-tolerated in women at increased risk of developing breast cancer, but no significant biomarker modulation was observed. The results did not exclude a favorable effect on breast cancer risk. (NCT00285857) Vinayak et al., (2013) | |||
| Hydrophilic statins | |||||||
| Rosuvastatin (40 mg/day) plus chemoradiation therapy | Rectal cancer | Sensitizing cancer tissues and protects normal tissues to the effects of radiation | Phase II, single-arm trial/45 | No results posted. The aim is to evaluate whether the addition of rosuvastatin to standard chemoradiation therapy for the treatment of locally advanced rectal cancer may improve the pathological response rate and survival compared to standard chemoradiation therapy alone. Rosuvastatin treatment starts 2 weeks prior to the initiation of radiation at week 1 and stops 4 weeks after the completion of radiation. (NCT02569645) | |||
| Pravastatin (40 mg/day) combined with etoposide plus cisplatin or carboplatin | SCLC | NR | Phase III, double-blind, randomized PC trial/846 | Pravastatin plus standard chemotherapy did not offer additional benefit compared with chemotherapy alone. The median PFS was 7.7 months vs. 7.3 months. The median OS (pravastatin v placebo) was 14.6 months in both groups for limited disease and 9.1 months versus 8.8 months, respectively, for extensive disease. (NCT00433498) Seckl et al. (2017) | |||
| Pravastatin (40 mg/day) plus chemotherapy | Gastric carcinoma | NR | Phase II, randomized trial/30 | Addition of pravastatin to epirubicin/cisplatin/capecitabine did not improve progression-free rate at 6 months, RR, PFS and OS. Konings et al. (2010) | |||
| Pravastatin (40 mg/day) plus TAE and 5-FU | HCC | NR | Randomized trial/91 | Pravastatin prolonged the survival of patients with advanced HCC (median survival, pravastatin group vs. controls, 18 months vs. 9 months, p = 0.006). Kawata et al. (2001) | |||
| Pravastatin (40 mg/day) plus sorafenib | HCC | Inhibiting Raf-Ras -MAPK pathway. The anti-invasive and anti-metastatic action of pravastatin is a complement to the anti-angiogenic action of sorafenib | Phase III, randomized trial/312 | Addition of pravastatin to sorafenib did not improve survival in patients with advanced HCC, with no difference in median OS between sorafenib-pravastatin and sorafenib groups (10.7 months vs. 10.5 months; HR = 1.00; p = 0.975). (NCT01075555) Jouve et al. (2019) | |||
| Pravastatin (40 mg/day) | Esophageal cancer and stomach cancer | NR | Phase IV, randomized trial/recruiting | No results posted. The objective is to evaluate the efficacy of treatment (increase in survival and recurrence-free period of the disease) with pravastatin in patients with advanced esophageal cancer and stomach cancer. The experimental group will receive pravastatin orally daily for 2 years. (NCT01038154) | |||
Abbreviations: HCC, hepatocellular carcinoma; HR, hazard ratio; LDL, low density lipoprotein; NR, not reported; NSCLC, non-small cell lung cancer; OR, odds ratio; ORR, objective response rate; OS, overall survival; PC, placebo-controlled; PFS, progression-free survival; RR, response rate; SCLC, small cell lung cancer; TAE, transcatheter arterial embolization.