Effects of Metformin and Vitamin D on Clinical Outcome in Cholangiocarcinoma Patients

Casadei-Gardini, Andrea; Filippi, Roberto; Rimini, Margherita; Rapposelli, Ilario Giovanni; Fornaro, Lorenzo; Silvestris, Nicola; Aldrighetti, Luca; Aimar, Giacomo; Rovesti, Giulia; Bartolini, Giulia; Vivaldi, Caterina; Brunetti, Oronzo; Sperti, Elisa; Face, Rosa La; Ratti, Francesca; Andrikou, Kalliopi; Valgiusti, Martina; Bernardini, Laura; Argentiero, Antonella; Fenocchio, Elisabetta; Frassineti, Giovanni Luca; Cesario, S.; Giovannelli, Francesco; Quarà, Virginia; Leone, Francesco; Cascinu, Stefano

doi:10.1159/000512796

Cited by 10 publications

(17 citation statements)

References 39 publications

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“…Ling et al studies showed that metformin exhibited a timedependent and dose-dependent antiproliferation effect on intrahepatic cell lines, by mechanisms containing apoptosis induction and cell cycle arrest [9]. Metformin intake after starting chemotherapy can improve the clinical outcome in advanced cholangiocarcinomas [24]. Metformin could change the metabolic status of cancer cells and reverse the Warburg effect via the inhibition of lactate dehydrogenase A(LDHA), which was overexpressed in CCA tissues and indicated a shorter survival time [11].…”

Section: Discussionmentioning

confidence: 99%

Metformin Use and Survival in Patients with Advanced Extrahepatic Cholangiocarcinoma: A Single-Center Cohort Study in Fuyang, China

Zhou

Wang

2021

Gastroenterology Research and Practice

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Aims. Metformin is an oral antidiabetic agent that has been widely prescribed for the treatment of type II diabetes. In recent years, anticancer properties of metformin have been revealed for numerous human malignancies. However, there are few indications available regarding the feasibility and safety of these studies in an advanced extrahepatic cholangiocarcinoma (EHCC) population. This study is aimed at evaluating the feasibility, safety, and value of metformin use and survival in patients with advanced EHCC. Methods. All patients with advanced EHCC observed at Fuyang People’s Hospital between January 2015 and November 2020 were included in the study. Case data, clinical information, and imaging results were abstracted from the self-administered questionnaire and electronic medical record. All patients were divided into study subjects and control subjects, and the study subjects were given metformin, 0.5 g, three times a day, while control subjects were without metformin. The metformin use and survival time of the subjects were asked by telephone, out-patient, or door-to-door visit, after they left the hospital. Results. One hundred and thirty-three study cases and 589 controls were included in the analysis. This study showed that metformin use cannot improve the overall survival rate of patients with advanced EHCC ([95% CI]: -17.05-0.375, t = − 1.889 , P value = 0.061), but the survival time of patients with drainage treatment from control group ( n = 496 ) was significantly shorter than that of patients with drainage treatment from the study group ( n = 113 ), and the difference was statistically significant ( z = − 2.230 , P value = 0.026). There were significant differences between metformin used before or after the diagnosis of advanced EHCC (OR[95% CI], 3.432[2.617-4.502]; P value = 0.001) in survival time. And there was significant difference between the duration of metformin use and survival prognosis (OR[95% CI], 2.967[1.383-6.368]; P = 0.005 ). Conclusion. Metformin can improve the survival of advanced EHCC patients who underwent drainage treatment, especially for metformin use after diagnosis of advanced EHCC and long duration of metformin.

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Section: Discussionmentioning

confidence: 99%

Metformin Use and Survival in Patients with Advanced Extrahepatic Cholangiocarcinoma: A Single-Center Cohort Study in Fuyang, China

Zhou

Wang

2021

Gastroenterology Research and Practice

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“…The remaining 34 studies were read in full, among which 13 studies did not investigate the efficacy of metformin on BTC, 4 studies did not explore risks or prognostic endpoints for BTC, 3 studies were cellular or animal studies, and 3 studies were duplicate reports of the same study. Finally, a total of 11 studies were included in the meta-analysis [ 21 , 22 , 23 , 24 , 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. The detailed process of study selection is presented in Figure 1 .…”

Section: Resultsmentioning

confidence: 99%

“…A total of 11 studies involving 24,788,738 participants were finally included: two studies from each of the following countries: Italy, China, and the USA; and one study from each of the following countries: Thailand, Korea, Netherlands, Canada, and Sweden. Seven studies explored the effect of metformin on the risk of BTC [ 21 , 22 , 23 , 31 , 32 , 33 , 34 ], five explored its effect on OS [ 21 , 24 , 29 , 30 , 35 ], and two explored its effect on DFS [ 30 , 35 ]. The studies that reported median/mean age all ranged from 60 to 70.…”

Section: Resultsmentioning

confidence: 99%

Effects of Metformin on Risk and Prognosis of Biliary Tract Cancer: A Systematic Review and Meta-Analysis

et al. 2023

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Background and Objectives: Metformin has been found to potentially reduce the risk and improve the prognosis of a variety of tumors, but these findings remain controversial in biliary tract cancer (BTC). Therefore, this systematic review and meta-analysis was conducted to investigate the association between metformin and BTC. Materials and Methods: Two independent researchers comprehensively searched PubMed, Embase, the Cochrane Library, and Web of Science for eligible studies published from their inception to 31 March 2022. Comparisons of risk, overall survival (OS), and disease-free survival (DFS) for patients with BTC were selected as the endpoints of interest and pooled by random or fixed-effects models. Results: Eleven studies with a total of 24,788,738 participants were eligible for this analysis. The overall pooled effects showed no significant differences in biliary tract cancer risk (hazard ratio (HR) = 0.82, 95% confidence interval (CI): 0.50–1.35, p = 0.436), OS (HR = 0.88, 95% CI: 0.74–1.04, p = 0.135), or DFS (HR = 1.03, 95% CI: 0.79–1.34, p = 0.829) between metformin users and non-users. When restricting participants to those with diabetes, a similar negative result was found, demonstrating that metformin use was not significantly associated with a lower risk of developing BTC compared with a lack of metformin use (HR = 0.65, 95% CI: 0.39–1.07, p = 0.089); notably, the included studies exhibited significant heterogeneity in the selection of participants and the definition of metformin users. Conclusions: Metformin may not be able to reduce the risk of BTC and improve prognosis in certain populations. Based on the limited quantity and quality of the included studies, the present results should be interpreted within their limitations, and further studies are warranted to determine the optimal timing, dose, duration, and scenario of metformin administration.

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“…Although the results of observational studies regarding the association between vitamin D status and liver cancer development are promising, they are still inadequate [ 31 ]. In a retrospective study of cholangiocarcinoma patients, vitamin D intake was associated with shorter disease-free survival in patients who underwent surgery [ 32 ]. This demonstrates the necessity for future prospective studies with a larger number of patients to investigate the association between vitamin D status and intake with hepatobiliary malignancy in patients with PSC.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Significance of Severe Vitamin D Deficiency in Patients with Primary Sclerosing Cholangitis

et al. 2023

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Vitamin D deficiency has been linked with adverse events in various liver diseases. The present study aimed to recognize the association between severe vitamin D deficiency and disease progression, hepatobiliary malignancies, liver-related mortality, and the need for liver transplantation in primary sclerosing cholangitis (PSC). Patients with a diagnosis of PSC (n = 354), followed by the autoimmune liver disease clinic at the University of Alberta, were included. Patients with vitamin D levels < 25 nmol/L were defined as severely deficient. Univariate and multivariate analyses were conducted using the Cox proportional hazards regression models. The mean vitamin D level was 59 ± 2 nmol/L, and 63 patients (18%) had a severe vitamin D deficiency. Patients with a severe vitamin D deficiency were 2.5 times more likely to experience hepatobiliary malignancies (HR 2.55, 95% CI, 1.02–6.40, p = 0.046). A severe vitamin D deficiency at diagnosis (HR 1.82, 95% CI, 1.05–3.15, p = 0.03) and persistent deficiencies over time (HR 2.26, 95% CI, 1.17–4.37, p = 0.02) were independently associated with a higher risk of poor clinical liver outcomes. A severe vitamin D deficiency at diagnosis and persistent deficiency at longitudinal assessments were associated with liver-related mortality or the need for liver transplantation.

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Effects of Metformin and Vitamin D on Clinical Outcome in Cholangiocarcinoma Patients

Cited by 10 publications

References 39 publications

Metformin Use and Survival in Patients with Advanced Extrahepatic Cholangiocarcinoma: A Single-Center Cohort Study in Fuyang, China

Metformin Use and Survival in Patients with Advanced Extrahepatic Cholangiocarcinoma: A Single-Center Cohort Study in Fuyang, China

Effects of Metformin on Risk and Prognosis of Biliary Tract Cancer: A Systematic Review and Meta-Analysis

Prognostic Significance of Severe Vitamin D Deficiency in Patients with Primary Sclerosing Cholangitis

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