Results of the Phase II randomized French trial PRODIGE 21 comparing sorafenib vs pravastatin vs sorafenib and pravastatin vs best supportive care for the palliative treatment of HCC in CHILD B cirrhotic patients

Blanc, J.-F.; Khemissa, Faïza; Bronowicki, Jean Pierre; Montérymard, Carole; Perarnau, Jean–Marc; Bourgeois, Vincent; Obled, Stéphane; Abdelghani, Méher Ben; Mabile-Archambeaud, Isabelle; Faroux, Roger; Seitz, J.-F.; Locher, C.; Senellart, Hélène; Villing, Anne-Laure; Audemar, Franck; Costentin, Charlotte; Delplanque, G.; Manfredi, S.; Edeline, Julien

doi:10.1016/s0168-8278(18)30601-9

Cited by 7 publications

(7 citation statements)

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“…There was a total of 157 participants in a RCT and 1221 participants in two observational studies (Additional file 1 : Table S2). Blanc et al reported similar occurrences of grade 3/4 toxicities in patients taking either pravastatin, sorafenib, both medications or none of the medications in a study involving mostly Child–Pugh B (96.8%) [ 43 ]. Munoz et al studied simvastatin in 30 patients with decompensated cirrhosis and reported 23% myalgia, 13% myalgia plus creatine kinase increase, 3% new onset diabetes, 63% digestive symptoms, and 13% headache [ 44 ] (after the search date of this review, the full article has now been published without changes in these figures [ 45 ]).…”

Section: Resultsmentioning

confidence: 99%

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%

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

et al. 2021

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“…Only 1 out of 155 patients in the pravastatin group showed an increase in creatine kinase. An additional trial in patients with Child-Pugh B with advanced HCC, reported only in abstract form,82 showed a numerically shorter median survival with pravastatin 40 mg OD alone (3.1 months), as compared with either sorafenib alone (3.8 months), sorafenib+pravastatin (4 months) and standard of care (3.5 months). The safety profile of pravastatin in patients with Child-Pugh B was similar to patients with Child-Pugh A.…”

Section: Human Studiesmentioning

confidence: 99%

“…This is likely due to the fact that the BLEPS study included patients with less advanced liver disease, and further suggests that patients with decompensated cirrhosis should not be treated with >20 mg OD of simvastatin. Additionally, in a randomised trial (presented in abstract form) in 77 patients with cirrhosis Child-Pugh B and advanced liver cancer82 treated with pravastatin 40 mg OD, no episodes of rhabdomyolysis were observed. Table 1 summarises the currently available efficacy, safety and pharmacokinetics data for different statins in patients with cirrhosis.…”

Section: Problems With Statin Use In Patients With Advanced Liver Dismentioning

confidence: 99%

Cirrhosis as new indication for statins

Bosch

Gracia‐Sancho

Abraldes

2020

Gut

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In the recent years, there have been an increasing number of reports on favourable effects of statins in patients with advanced chronic liver disease. These include reduction in portal pressure, improved liver sinusoidal endothelial and hepatic microvascular dysfunction, decreased fibrogenesis, protection against ischaemia/reperfusion injury, safe prolongation of ex vivo liver graft preservation, reduced sensitivity to endotoxin-mediated liver damage, protection from acute-on-chronic liver failure, prevention of liver injury following hypovolaemic shock and preventing/delaying progression of cirrhosis of any aetiology. Moreover, statins have been shown to have potential beneficial effects in the progression of other liver diseases, such as chronic sclerosing cholangitis and in preventing hepatocellular carcinoma. Because of these many theoretically favourable effects, statins have evolved from being considered a risk to kind of wonder drugs for patients with chronic liver diseases. The present article reviews the current knowledge on the potential applications of statins in chronic liver diseases, from its mechanistic background to objective evidence from clinical studies.

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“…Indeed, simultaneous targeted inhibition of RAF/MEK/ERK with the combination of sorafenib and statins are known to induce potentiated effects in different tumor cell lines, inducing cell cycle arrest and apoptosis [25]. It is important to highlight that no differences regarding TTP were observed in previous studies with pravastatin and sorafenib [23,26]. The fact that in our study the combination of sorafenib + pravastatin increased the TTP in three months compared to a previous Phase III clinical trial including Child-Pugh A patients with advanced HCC [23] could be related to characteristics of the patients of our cohort, since our study population was five years younger (median age).…”

Section: Discussionmentioning

confidence: 99%

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

Riaño

Martin

Varela

et al. 2020

Cancers

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Pravastatin has demonstrated anti-tumor activity in preclinical and clinical studies. This multicentric randomized double-blind placebo-controlled phase II study (NCT01418729) investigated the efficacy and safety of sorafenib + pravastatin combination on the overall survival (OS) and time to progression (TTP) of patients with advanced hepatocellular carcinoma (aHCC). A total of 31 patients were randomized. Median OS did not differ between both groups (12.4 months for the sorafenib + pravastatin group vs. 11.6 months for the control group). Of note, however, the radiological TTP was higher in patients treated with sorafenib + pravastatin than in the control group (9.9 months vs. 3.2 months; p = 0.008). Considering all the study population, the presence of portal vein thrombosis (PVT) was associated with worse OS, being lower in patients with PVT compared to patients without PVT (6.3 months vs. 14.8 months; p = 0.026). Data also showed a decrease in OS in patients with vascular invasion (VI) compared to patients who did not present it (6.3 months vs. 14.8 months; p = 0.041). The group of patients without dermatological events (DE) showed lower OS (6.9 months vs. 14.5 months; p = 0.049). In conclusion, combination of sorafenib + pravastatin was safe and well-tolerated, prolonging the TTP of patients with aHCC but not improving the OS compared to sorafenib + placebo. The absence of PVT and VI and the development of DE are positive prognostic factors of sorafenib response.

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Results of the Phase II randomized French trial PRODIGE 21 comparing sorafenib vs pravastatin vs sorafenib and pravastatin vs best supportive care for the palliative treatment of HCC in CHILD B cirrhotic patients

Cited by 7 publications

References 0 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

Cirrhosis as new indication for statins

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

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