Efficacy and Safety of the Combination of Pravastatin and Sorafenib for the Treatment of Advanced Hepatocellular Carcinoma (ESTAHEP Clinical Trial)

Riaño, Ioana; Martin, Louis L.; Varela, Marı́a; Serrano, Trinidad; Núñez, Óscar; Mínguez, Beatriz; Rodrigues, Pedro M.; Arenas, Juan

doi:10.3390/cancers12071900

Cited by 19 publications

(14 citation statements)

References 38 publications

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“…Search in the reference list of one review article [ 8 ] identified four additional articles. One of the authors identified an additional article [ 31 ] that was published after initial search was completed. Two additional articles [ 32 , 33 ] that were not indexed in any of the databases were identified outside of the search strategy and included for the review.…”

Section: Resultsmentioning

confidence: 99%

“…Indeed, none of the studies reporting clinical outcomes or safety of statins in cirrhosis provided pharmacokinetic information. These RCTs focused on liver-specific efficacy outcomes including hepatic venous pressure gradient (HVPG] [ 42 , 48 – 50 ], mortality and survival [ 33 , 42 , 51 ], survival in hepatocellular carcinoma [ 31 , 52 ], variceal bleeding [ 33 , 42 , 51 ], and liver stiffness [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

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A systematic review on pharmacokinetics, cardiovascular outcomes and safety profiles of statins in cirrhosis

et al. 2021

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Background/Aims There is increased interest in the therapeutic use of statins in cirrhosis, but preferred statin and safety outcomes are still not well known. In this systematic review we aimed to address pharmacokinetics (PK), safety, and effects on cardiovascular (CV) outcomes of statins in cirrhosis. Methods Our systematic search in several electronic databases and repositories of two regulatory bodies up to 2020-06-11 yielded 22 articles and 2 drug monographs with relevant data. Results Rosuvastatin and pitavastatin showed minimal PK changes in Child–Pugh A cirrhosis. Only rosuvastatin was assessed in a repeated dosing PK study. Atorvastatin showed pronounced PK changes in cirrhosis. No PK data was found for simvastatin, the most commonly used statin in cirrhosis trials. There was insufficient data to assess CV effects of statins in cirrhosis. Clinical trials in cirrhosis were limited to simvastatin, atorvastatin, and pravastatin. In patients taking simvastatin 40 mg, pooled frequency of rhabdomyolysis was 2%, an incidence 40-fold higher than that reported in non-cirrhosis patients, while this was no rhabdomyolysis observed in patients on simvastatin 20 mg, atorvastatin 20 mg, or pravastatin 40 mg. Drug-induced liver injury was of difficult interpretation due to co-existence of muscle damage. No overt liver failure was reported. Conclusions Simvastatin 40 mg should be avoided in decompensated cirrhosis. Safety data on simvastatin 20 mg or other statins are based on small study sample size. This rarity of evidence combined with lack of data in dose adjustment methods in cirrhosis is a barrier for using statins for CV indications or for investigational use for liver indications.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A systematic review on pharmacokinetics, cardiovascular outcomes and safety profiles of statins in cirrhosis

et al. 2021

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“…There are several phase II or III RCTs that studied this effect. Sorafenib plus pravastatin did not improve time to progression (TTP), PFS, and OS compared with sorafenib alone [151,152], but improved TTP in another study [153]. In a study of transcatheter arterial embolization followed by fluorouracil, the addition of pravastatin prolonged OS compared with the standard therapy alone in advanced hepatocellular carcinoma [154].…”

Section: Hepatocellular Carcinomamentioning

confidence: 98%

Beyond Lipid-Lowering: Effects of Statins on Cardiovascular and Cerebrovascular Diseases and Cancer

Morofuji¹,

Nakagawa²,

Ujifuku³

et al. 2021

Preprint

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The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are administered as first-line therapy for hypercholesterolemia, both as primary and secondary prevention. Besides the lipid-lowering effect, statins have been suggested to inhibit the development of cardiovascular disease through anti-inflammatory, antioxidant, vascular endothelial function-improving, plaque-stabilizing, and platelet aggregation-inhibiting effects. The preventive effect of statins on atherothrombotic stroke has been well established, but statins can influence other cerebrovascular diseases. This suggests that statins have many neuroprotective effects in addition to lowering cholesterol. Furthermore, research suggests that statins cause pro-apoptotic, growth-inhibitory, and pro-differentiation effects in various malignancies. Preclinical and clinical evidence suggests that statins inhibit tumor growth and induce apoptosis in specific cancer cell types. The pleiotropic effects of statins on cardiovascular and cerebrovascular diseases have been well established; however, the effects of statins on cancer patients have not been fully elucidated and are still controversial. This review discusses the recent evidence on the effects of statins on cardiovascular and cerebrovascular diseases and cancer. Additionally, this study describes the pharmacological action of statins, focusing on the aspect of ‘beyond lipid-lowering.’

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“…Further, the treatment with simvastatin has improved sorafenib resistance via suppression of HIF-α1/PPAR-γ/PKM2 signaling [ 122 ]. In a phase II clinical trial, a combination of pravastatin with sorafenib was safe and well-tolerated with prolonged time to progression (TTP) in advanced hepatocellular carcinoma [ 123 ].…”

Section: Statins Possess Synergistic Action To Overcome the Resistance To Anti-cancer Therapiesmentioning

confidence: 99%

“…In a phase II clinical trial, a combination of pravastatin with sorafenib was safe and well-tolerated with prolonged time to progression (TTP) in advanced hepatocellular carcinoma [ 123 ]. A pooled analysis of metastatic renal cell carcinoma (mRCC) treated on phase II and phase III clinical trials by sunitinib, sorafenib, axitinib, temsirolimus, temsirolimus + interferon (IFN)-α, bevacizumab + temsirolimus, bevacizumab + IFN-α, or IFN-α, along with or without statin were evaluated with overall survival.…”

Section: A Clinical Trial Of Statin In Cancermentioning

confidence: 99%

Statin as a Potential Chemotherapeutic Agent: Current Updates as a Monotherapy, Combination Therapy, and Treatment for Anti-Cancer Drug Resistance

Pun

Jeong

2021

Pharmaceuticals

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Cancer is incurable because progressive phenotypic and genotypic changes in cancer cells lead to resistance and recurrence. This indicates the need for the development of new drugs or alternative therapeutic strategies. The impediments associated with new drug discovery have necessitated drug repurposing (i.e., the use of old drugs for new therapeutic indications), which is an economical, safe, and efficacious approach as it is emerged from clinical drug development or may even be marketed with a well-established safety profile and optimal dosing. Statins are inhibitors of HMG-CoA reductase in cholesterol biosynthesis and are used in the treatment of hypercholesterolemia, atherosclerosis, and obesity. As cholesterol is linked to the initiation and progression of cancer, statins have been extensively used in cancer therapy with a concept of drug repurposing. Many studies including in vitro and in vivo have shown that statin has been used as monotherapy to inhibit cancer cell proliferation and induce apoptosis. Moreover, it has been used as a combination therapy to mediate synergistic action to overcome anti-cancer drug resistance as well. In this review, the recent explorations are done in vitro, in vivo, and clinical trials to address the action of statin either single or in combination with anti-cancer drugs to improve the chemotherapy of the cancers were discussed. Here, we discussed the emergence of statin as a lipid-lowering drug; its use to inhibit cancer cell proliferation and induction of apoptosis as a monotherapy; and its use in combination with anti-cancer drugs for its synergistic action to overcome anti-cancer drug resistance. Furthermore, we discuss the clinical trials of statins and the current possibilities and limitations of preclinical and clinical investigations.

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Efficacy and Safety of the Combination of Pravastatin and Sorafenib for the Treatment of Advanced Hepatocellular Carcinoma (ESTAHEP Clinical Trial)

Cited by 19 publications

References 38 publications

A systematic review on pharmacokinetics, cardiovascular outcomes and safety profiles of statins in cirrhosis

A systematic review on pharmacokinetics, cardiovascular outcomes and safety profiles of statins in cirrhosis

Beyond Lipid-Lowering: Effects of Statins on Cardiovascular and Cerebrovascular Diseases and Cancer

Statin as a Potential Chemotherapeutic Agent: Current Updates as a Monotherapy, Combination Therapy, and Treatment for Anti-Cancer Drug Resistance

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