Effects of metformin on clinical outcome in diabetic patients with advanced HCC receiving sorafenib

Casadei-Gardini, Andrea; Marisi, Giorgia; Scarpi, Emanuela; Scartozzi, Mario; Faloppi, Luca; Silvestris, Nicola; Masi, Gianluca; Vivaldi, Caterina; Brunetti, Oronzo; Tamberi, Stefano; Foschi, Francesco Giuseppe; Tamburini, Emiliano; Tenti, Elena; Rosellini, Salvatore Ricca; Ulivi, Paola; Cascinu, Stefano; Nanni, Oriana; Frassineti, Giovanni Luca

doi:10.1517/14656566.2015.1102887

Cited by 68 publications

(59 citation statements)

References 32 publications

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“…The concomitant use of sorafenib and metformin was associated with a median progression-free survival of 2.6 months, compared to 5.0 months for patients receiving sorafenib alone ( p =0.029). The median overall survival of patients treated with the combination was 10.4 months, compared to 15.1 months for those who were not given metformin ( p =0.014) 20. These findings indicated increased tumor aggressiveness and resistance to sorafenib in metformin-treated patients, which is in direct contrast to the results of our in vitro study.…”

Section: Discussioncontrasting

confidence: 82%

Synergistic effect of metformin on sorafenib in in vitro study using hepatocellular carcinoma cell lines

Chung

Tak

Hwang

et al. 2018

Ann Hepatobiliary Pancreat Surg

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Backgrounds/AimsHepatocellular carcinoma (HCC) recurrence remains a great concern following hepatic resection and liver transplantation. We investigated the metformin-induced cytotoxic effects on sorafenib in an in vitro study using HCC cell lines.MethodsThis research was conducted through an in vitro study using one HepG2.2.15 liver tumor and two patient-derived graft HCC cell lines.ResultsAn in vitro study revealed noticeable cytotoxic effects of metformin as well as noticeable synergistic cytotoxic effects of metformin and sorafenib on cell viability. Assays for the mechanisms of action of antitumor effects revealed that alpha-fetoprotein expression was suppressed by both metformin and sorafenib, but no synergistic effect was observed. LC3-I and LC3-II assays revealed the synergistic upregulation of autophagy and assays for IL-1β, IL-6, p53, and TNF-α revealed the synergistic upregulation of cell damage and apoptosis. In contrast, metformin did not affect HBx expression, thus no noticeable synergistic effect was considered to be present.ConclusionsOur in vitro study demonstrated cytotoxic effects of metformin and synergistic antitumor effects of sorafenib. These results should be verified in further clinical studies with patients of advanced HCC.

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Section: Discussioncontrasting

confidence: 82%

Synergistic effect of metformin on sorafenib in in vitro study using hepatocellular carcinoma cell lines

Chung

Tak

Hwang

et al. 2018

Ann Hepatobiliary Pancreat Surg

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“…Specifically, deactivation of sirtuin‐1 and ‐3 (SIRT1, SIRT3) – proteins involved in metabolic diseases and known tumour suppressors in HCC – has been suggested as key players in the potential metformin‐related anti‐HCC mechanisms . In contrast to these antitumour effects, there are studies suggesting that metformin may confer resistance to sorafenib treatment in patients with advanced HCC potentially leading to a worse outcome …”

Section: Introductionmentioning

confidence: 99%

Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma

Schulte

Scheiner

Voigtländer

et al. 2019

Liver International

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Background Hepatocellular carcinoma (HCC) is one of the most lethal cancers. Nutrition‐ and life style‐associated risk factors are increasingly prevalent. Metformin, the mainstay of type 2 diabetes mellitus (T2DM)‐treatment, reduces the risk of hepatocarcinogenesis. However, its influence on the prognosis of patients with HCC has not been investigated on a large scale, yet. Methods Five thousand and ninety‐three patients treated for HCC between 2000 and 2016 at three referral centres were included in this retrospective multicentre study. The aim of this study was to assess whether treatment with metformin for T2DM is associated with a prolonged overall survival (OS) in patients diagnosed with HCC. Results Among 5093 patients with HCC, 1917 patients (37.6%) were diagnosed with T2DM, of which 338 (17.6%) received treatment with metformin. Compared to diabetic patients not treated with metformin, patients on metformin had a significantly better hepatic function (Child‐Pugh‐Score A: 69.2% vs 47.4%, P < 0.001) and underwent significantly more often tumour resection (22.1% vs 16.5%, P = 0.024). Patients on metformin had a significantly longer median OS (mOS) compared to diabetic patients not treated with metformin (22 vs 15 months, P = 0.019). The prolongation of survival was most significant in patients treated with surgery. Using a propensity score match (PSM), patients were adjusted for hepatic function and initial therapy. In the matched cohorts, mOS remained significantly longer in metformin‐treated patients (22 vs 16 months, P = 0.021). Co‐treatment of metformin and sorafenib was associated with a survival disadvantage. Conclusion Treatment with metformin was associated with an improved survival in patients with T2DM and HCC. This effect was most pronounced in patients at potentially curative tumour stages.

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“…Hepatocellular carcinoma (HCC) represents the most common primary liver cancer with an increasing incidence [1]. …”

Section: Introductionmentioning

confidence: 99%

Immune inflammation indicators and implication for immune modulation strategies in advanced hepatocellular carcinoma patients receiving sorafenib

et al. 2016

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We evalueted a systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) with the aim to explored their prognostic value in patients with advanced hepatocellular carcinoma (HCC) treated with sorafenib. 56 advanced HCC patients receiving sorafenib were available for our analysis. Lymphocyte, neutrophil and platelet were measured before beginning of treatment and after one month. Patient with SII ≥ 360 showed lower median PFS (2.6 vs. 3.9 months, P < 0.026) and OS (5.6 vs. 13.9 months, P = 0.027) with respect to patients with SII < 360.NLR ≥ 3 had a lower median PFS (2.6 vs. 3.3 months, P < 0.049) but not OS (5.6 vs. 13.9 months, P = 0.062) than those with NLR < 3. After adjusting for clinical covariates SII and NLR remained an independent prognostic factor for OS. The SII and NLR represent potential prognostic indicator in patients with advanced HCC treated with sorafenib.

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Effects of metformin on clinical outcome in diabetic patients with advanced HCC receiving sorafenib

Abstract: Our findings could be the result of increased tumor aggressiveness and resistance to sorafenib in metformin-treated patients.

Cited by 68 publications

References 32 publications

Synergistic effect of metformin on sorafenib in in vitro study using hepatocellular carcinoma cell lines

Synergistic effect of metformin on sorafenib in in vitro study using hepatocellular carcinoma cell lines

Treatment with metformin is associated with a prolonged survival in patients with hepatocellular carcinoma

Immune inflammation indicators and implication for immune modulation strategies in advanced hepatocellular carcinoma patients receiving sorafenib

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