Pravastatin combination with sorafenib does not improve survival in advanced hepatocellular carcinoma

Jouve, Jean-Louis; Lecomte, Thierry; Bouché, Olivier; Barbier, E.; Akouz, F. Khemissa; Riachi, Ghassan; Khac, Eric Nguyen; Ollivier-Hourmand, Isabelle; Debette‐Gratien, Maryline; Faroux, Roger; Villing, Anne-Laure; Vergniol, Julien; Ramée, Jean-François; Bronowicki, Jean–Pierre; Seitz, Jean‐François; Legoux, Jean-Louis; Denis, Jacques; Manfrédi, Sylvain; Phélip, Jean-Marc; Investigators, Prodige

doi:10.1016/j.jhep.2019.04.021

Cited by 81 publications

(73 citation statements)

References 20 publications

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“…In addition, there were no serious AEs related to the treatment under study, and the incidence of AEs recorded in the total population was higher in the control group (63.2%) than in the experimental group (36.8%). These data suggest that patients with aHCC do not have increased susceptibility to hepatotoxicity from statins and these results are consistent with a recent clinical trial in patients with aHCC treated with pravastatin 40 mg [23]. Further, recent observations have shown that patients with liver disease do not have a higher risk of statin-induced liver toxicity when compared to the general population [16,28].…”

Section: Discussionsupporting

confidence: 90%

“…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). In fact, higher age was previously associated with shorter TTP for regorafenib treatment in aHCC [27], although it should be noted that neither Child B patients nor those with extrahepatic metastases were included in this trial, as were included in our study.…”

Section: Discussioncontrasting

confidence: 53%

“…In our Phase II study, the OS associated to sorafenib (mean 11.5 and median 12.4) was comparable to previously published Phase III clinical trials for aHCC [10,24], indicating that our study population behaves as expected when it comes to the response to sorafenib. However, similar to a recent Phase III clinical trial [23], the combination of sorafenib with pravastatin did not increase the OS of patients with aHCC, thus limiting its clinical impact. OS still represents the gold standard endpoint for trials in first-line treatment for aHCC; however, OS does not capture the full extent of anti-tumor effects.…”

Section: Discussionsupporting

confidence: 51%

“…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: 98%

“…Of note, the combination of pravastatin and sorafenib was more effective than sorafenib alone in experimental models of HCC, decreasing tumor cell proliferation in vitro and in vivo [18], thus pinpointing the potential of sorafenib + pravastatin for the adjuvant treatment of HCC. In this regard, the hepatic safety profile of pravastatin and the limited risks of drug interactions with sorafenib [23] make this combination even more attractive.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 90%

Section: Discussioncontrasting

confidence: 53%

Section: Discussionsupporting

confidence: 51%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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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Association of Quality-of-Life Outcomes in Cancer Drug Trials With Survival Outcomes and Drug Class

et al. 2022

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IMPORTANCEAlthough quality of life (QOL) is an important clinical end point, cancer drugs are often approved based on overall survival (OS) or putative surrogate end points such as progression-free survival (PFS) without QOL data.OBJECTIVE To ascertain whether cancer drug trials that show improvement in OS or PFS also improve global QOL of patients with cancer compared with the control treatment, as well as to assess how unchanged or detrimental QOL outcomes are reported in trial publications. DESIGN, SETTING, AND PARTICIPANTSThis retrospective cohort study included all patients with cancer in the advanced setting who were enrolled into phase 3 randomized clinical trials (RCTs) of cancer drugs reporting QOL data and published in English language in a PubMed-indexed journal in the calendar year 2019. The systematic search of PubMed was conducted in July 2020.MAIN OUTCOMES AND MEASURES Association of QOL outcomes with OS and PFS, framing of unchanged QOL outcomes in trial publications, and the association of favorable framing with industry funding of the trials.RESULTS A total of 45 phase 3 RCTs enrolling 24 806 participants (13 368 in the experimental arm and 11 438 in the control arm) met the inclusion criteria and were included in the study analyses. Improvement in global QOL with the experimental agent was reported in 11 (24%) RCTs. The RCTs with improved QOL were more likely to also show improved OS vs trials with unimproved QOL (7 of 11 [64%] trials vs 10 of 34 [29%] trials; χ 2 = 4.13; P = .04); there was no such association observed for PFS (6 of 11 [55%] trials vs 17 of 34 [50%] trials, χ 2 = 0.03; P = .87). Six trials reported worsening QOL, of which 3 (50%) were trials of targeted drugs, and 11 trials reported improvement in QOL, of which 6 (55%) were trials of immunotherapy drugs. Of the 34 trials in which QOL was not improved compared with controls, 16 (47%) reported these results in a positive frame, an observation statistically significantly associated with industry funding (χ 2 = 6.35; P = .01). CONCLUSIONS AND RELEVANCEIn this cohort study, a small proportion of RCTs of cancer drugs showed benefit in global QOL with the experimental agent. These results showed an association between QOL benefit and OS benefit but no such association with PFS benefit. Trials that failed to show improved QOL often reported their QOL outcomes more favorably. Non-immunotherapy-targeted drugs led to worse QOL more often than did cytotoxic agents.

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Cardiovascular/anti‐inflammatory drugs repurposed for treating or preventing cancer: A systematic review and meta‐analysis of randomized trials

Benjamin,

Haslam,

Prasad

2024

Cancer Medicine

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BackgroundDue to encouraging pre‐clinical data and supportive observational studies, there has been growing interest in applying cardiovascular drugs (including aspirin, angiotensin‐converting enzyme [ACE] inhibitors, statins, and metformin) approved to treat diseases such as hypertension, hyperlipidemia, and diabetes mellitus to the field of oncology. Moreover, given growing costs with cancer care, these medications have offered a potentially more affordable avenue to treat or prevent recurrence of cancer.We sought to investigate the anti‐cancer effects of drugs repurposed from cardiology or anti‐inflammatories to treat cancer. We specifically evaluated the following drug classes: HMG‐CoA reductase inhibitors (statins), cyclo‐oxygenase inhibitors, aspirin, metformin, and both angiotensin receptor blockers (ARBs) and angiotensin‐converting enzyme inhibitors. We also included non‐steroidal anti‐inflammatory drugs (NSAIDs) because they exert a similar mechanism to aspirin by blocking prostaglandins and reducing inflammation that is thought to promote the development of cancer.MethodsWe performed a systematic literature review using PubMed and Web of Science with search terms including “aspirin,” “NSAID,” “statin” (including specific statin drug names), “metformin,” “ACE inhibitors,” and “ARBs” (including specific anti‐hypertensive drug names) in combination with “cancer.” Searches were limited to human studies published between 2000 and 2023.Main Outcomes and MeasuresThe number and percentage of studies reported positive results and pooled estimates of overall survival, progression‐free survival, response, and disease‐free survival.ResultsWe reviewed 3094 titles and included 67 randomized clinical trials. The most common drugs that were tested were metformin (n = 21; 30.9%), celecoxib (n = 20; 29.4%), and simvastatin (n = 8; 11.8%). There was only one study that tested cardiac glycosides and none that studied ACE inhibitors. The most common tumor types were non‐small‐cell lung cancer (n = 19; 27.9%); breast (n = 8; 20.6%), colorectal (n = 7; 10.3%), and hepatocellular (n = 6; 8.8%). Most studies were conducted in a phase II trial (n = 38; 55.9%). Most studies were tested in metastatic cancers (n = 49; 72.1%) and in the first‐line setting (n = 36; 521.9%). Four studies (5.9%) were stopped early because of difficulty with accrual. The majority of studies did not demonstrate an improvement in either progression‐free survival (86.1% of studies testing progression‐free survival) or in overall survival (94.3% of studies testing overall survival). Progression‐free survival was improved in five studies (7.4%), and overall survival was improved in three studies (4.4%). Overall survival was significantly worse in two studies (3.8% of studies testing overall survival), and progression‐free survival was worse in one study (2.8% of studies testing progression‐free survival).Conclusions and RelevanceDespite promising pre‐clinical and population‐based data, cardiovascular drugs and anti‐inflammatory medications have overall not demonstrated benefit in the treatment or preventing recurrence of cancer. These findings may help guide future potential clinical trials involving these medications when applied in oncology.

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Pravastatin combination with sorafenib does not improve survival in advanced hepatocellular carcinoma

Cited by 81 publications

References 20 publications

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

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

Association of Quality-of-Life Outcomes in Cancer Drug Trials With Survival Outcomes and Drug Class

Cardiovascular/anti‐inflammatory drugs repurposed for treating or preventing cancer: A systematic review and meta‐analysis of randomized trials

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