Original StudyMetformin Use and Outcome of Sunitinib Treatment in Patients With Diabetes and Metastatic Renal Cell Carcinoma
Introduction
Renal cell carcinoma is the most common cancer of the kidney.1 Of patients with the disease, 20% to 30% are diagnosed with metastatic disease, and 70% to 80% of patients present with localized or locally advanced disease at diagnosis, which is potentially curable by radical surgical resection alone.2 Among patients who undergo radical resection for localized disease, future metastatic disease develops in 20% to 40%.3
An understanding of the pathogenesis of renal cell carcinoma at the molecular level, and randomized clinical trials, have established the standard role of the orally administered vascular endothelial growth factor receptor and platelet derived growth factor receptor inhibitor sunitinib for the treatment of advanced renal cell carcinoma.4
The oral hypoglycemic agent metformin is widely used in the treatment of diabetes.
Data suggest that metformin might have antineoplastic properties. It might affect cancer cells indirectly by decreasing insulin levels or directly by inhibiting cancer cell proliferation and apoptosis.5 Metformin is a potent adenosine monophosphate–activated protein kinase (AMPK) activator.6 When activated, AMPK inactivates enzymes involved in adenosine triphosphate consumption such as fatty acid and protein synthesis.6 Furthermore, AMPK activation inhibits the mammalian target of rapamycin (mTOR) complex 1 pathway and S6K1 phosphorylation implicated in the tumorigenesis process.7 Metformin might also induce autophagy and apoptosis mechanisms.8 Although some data suggest that metformin inhibits renal cell carcinoma cell proliferation in vitro,9 its effect on the outcome of targeted therapies in metastatic renal cell carcinoma is poorly defined.
In the present study we sought to determine the effect of concomitant metformin use on the outcome of diabetic patients with metastatic renal cell carcinoma who are treated with sunitinib.
Section snippets
Study Group
We reviewed the records of patients (unselected cohort, international multicenter database) with evidence of metastatic renal cell carcinoma, who were treated with sunitinib, between February 1, 2004 and December 31, 2014, in 8 centers across 2 different countries: the United States (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD) and Israel (Institutes of Oncology at Meir Medical Center, Kfar Saba; Asaf Harofe Medical Center, Zerifin; Rambam Medical Center, Haifa;
Patient Characteristics
Between February 1, 2004 and December 31, 2014, 108 diabetic patients with metastatic renal cell carcinoma were treated with sunitinib. There were 52 metformin users (group 1) and 56 nonusers (group 2). The median daily dose of metformin was 850 mg (mean, 1200 ± 500 mg; range 500-2350 mg). The distribution of clinicopathologic and prognostic factors is shown in Table 1. The groups were balanced regarding the following clinicopathologic factors: age, sex, Heng risk, past nephrectomy, metastatic
Discussion
Results of the present study suggest that concomitant use of metformin might improve the outcome of sunitinib treatment in diabetic patients with metastatic renal cell carcinoma. In this retrospective study, diabetic patients who received metformin, had a significant (HR, 0.42; P = .001) 11-month increase of OS, after adjustment for other known risk factors for poorer outcome. Patients using metformin also had an increase in clinical benefit (96% vs. 84%; 12% vs. 0% complete response), a
Conclusion
Concomitant use of metformin might improve the outcome of sunitinib therapy in metastatic renal cell carcinoma.
Disclosure
The authors have stated that they have no conflicts of interest.
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Cited by (20)
Mechanism and application of metformin in kidney diseases: An update
2021, Biomedicine and PharmacotherapyCitation Excerpt :In a retrospective analysis of patients with mRCC in phase II and III clinical trials, Hamieh et al. concluded that a survival benefit for metformin treatment in mRCC patients with sunitinib [145]. Keizman et al. also displayed that metformin might improve the overall survival (OS) of diabetic patients with mRCC treated with sunitinib [146]. Despite the lack of potent evidence, the promising retrospective data have shed a light on the potential role of metformin in RCC therapy.
Diabetes and kidney cancer survival in patients undergoing nephrectomy: A Canadian multi-center, propensity score analysis
2019, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :Therefore, if metformin were to confer a survival advantage in kidney cancer, the direction bias in this study would be towards improved survival in diabetics since only they would be exposed to the medication. However, studies demonstrating an association between metformin and improved survival in kidney cancer [27–29] have been prone to several important limitations [30] and it is difficult to interpret their findings. Conversely, other studies have shown no protective benefit of metformin in kidney cancer [31,32], including a recent population-based study that evaluated cumulative use metformin [33].
Comment on: Bono P, Oudard S, Bodrogi I, et al. Outcomes in Patients With Metastatic Renal Cell Carcinoma Who Develop Everolimus-Related Hyperglycemia and Hypercholesterolemia: Combined Subgroup Analyses of the RECORD-1 and REACT Trials. Clin Genitourin Cancer 2016
2017, Clinical Genitourinary CancerMeta-Analysis of Metformin on Recurrence Risk and Long-Term Survival in Patients with Diabetes and Renal Cell Carcinoma
2023, Alternative Therapies in Health and Medicine
Daniel Keizman and Maya Ish-Shalom contributed equally to this study.
Raanan Berger and Michael A. Carducci contributed equally to this study.