Association of Metformin With the Growth of Vestibular Schwannomas Otolaryngology–Head and Neck Surgery
Sophia Tran1, Daniel E. Killeen, MD2, Shafeen Qazi1, Sanjana Balachandra1, and Jacob B. Hunter, MD2
Abstract
Objective. To assess whether medication use, specifically statin, metformin, and aspirin, affects the growth of vestibular schwannomas (VSs).
Study Design. Retrospective case series.
Setting. Single tertiary care academic hospital.
Subjects and Methods. Patients were enrolled if they were diagnosed with sporadic VS and had at least 2 magnetic resonance imaging (MRI) studies at a minimum of 6 months apart prior to any intervention. Electronic medical records were reviewed for demographic and medication data. Tumor volumes on MRI studies were assessed via BrainLab iPlan. The primary endpoint was VS tumor growth, defined as a 20% increase in tumor volume, between consecutive MRI studies or between the first and last available MRI study. Predictors of volumetric growth, specifically statin, aspirin, or metformin use, were analyzed with t tests, chi-square test, univariate logistic regression, and multivariate logistic regression.
Results. A total of 387 patients met inclusion criteria, 53.5% of whom were women. For all patients, the mean age was 60.6 years (range, 18.2-89.2 years); the mean axial tumor diameter, 11.9 mm (range, 1.7-32.0 mm); and the mean tumor volume, 0.85 cm3 (range, 0.01-13.1 cm3). In review of the electronic medical record, 46 patients (11.9%) were taking metformin; 145 (37.5%), a statin; and 117 (30.2%), aspirin. Among patients taking metformin, 39.1% (18/46) exhibited volumetric growth, as opposed to 58.2% (198/340) of nonusers (P = .014). Metformin (odds ratio, 0.497; P = .036) is significantly associated with reduced VS growth when controlling for aspirin, statin, and tumor size on multivariate logistic regression.
Conclusion. Metformin use is associated with reduced volumetric VS growth.
Keywords
vestibular schwannoma, metformin, acoustic neuroma Received March 4, 2020; accepted June 7, 2020.
Introduction
Vestibular schwannomas (VSs) are benign tumors of the vestibulocochlear nerve. The majority of patients present with unilateral hearing loss, unilateral tinnitus, or vertigo. While these tumors are the most common tumor of the cerebellopontine angle and the internal auditory canal, historical epidemiologic studies indicate that VSs have an incidence rate between 1 and 20 cases per million persons, with recent studies suggesting higher incidence rates.1 VSs can be managed conservatively with observation or actively with either stereotactic radiosurgery or microsurgical resection. But VS growth patterns are heavily varied, with many VSs showing no significant increase in axial length or volume, while many others have rapid increases interspersed with quiescent periods.2 Thus, identifying tumors that are at higher risk of growth is valuable in determining treatment and counseling patients.3
With an increase in patients pursuing observation at the time of diagnosis, there has been an increasing interest in determining predictive factors for tumor growth. Prior studies suggested that tumor diameter, patient disequilibrium, and extrameatal location at presentation are associated with tumor growth.4-6 Previous studies also suggested that aspirin may be associated with reduced tumor growth, though additional studies have failed to note this relationship.7-9
There has been recent evidence that metformin may reduce growth of VSs.10 With metformin being a first-line antidiabetic drug that allows glycemic control by downregulating the cyclic AMP pathway, decreasing hepatic gluconeogenesis, there is evidence showing that diabetic patients on metformin therapy have decreased rates of cancer than do their counterparts who are not on the drug.11,12 Statins are a first-line class of lipid-lowering medications that target HMG-CoA reductase enzyme and decrease mevalonate, a cholesterol precursor.13 Although primarily used in the setting of atherosclerosis and heart disease, there is increased interest in its use as an anticancer therapy, as mevalonate is implicated in tumor proliferation and growth.14-16 This study sought to investigate the relationship between these commonly used medications and VS tumor growth.
Methods Patient Selection
University of Texas Southwestern Institutional Review Board approval was obtained (STU 112016-040). Using the electronic medical record, we identified all adult patients diagnosed with a VS between 2009 and 2018. To be included in the study, patients required a minimum of 2 magnetic resonance imaging (MRI) scans within the last 10 years that were at least 6 months apart with no intervention between the studies. One patient was included whose followup MRI was days shy of the 6-month anniversary of the diagnostic MRI. Intervention was defined as receiving either stereotactic radiosurgery or surgical resection of the VS.
Exclusion criteria included patients with previously treated VSs and patients with \2 MRI studies available for review before undergoing treatment. Tumors were measured volumetrically and linearly, the latter with the greatest axial tumor diameter, with iPlan software (BrainLab). Two reviewers conducted the measurements, both of whom were blinded to medication use.
Each electronic medical record was reviewed to determine the patient’s age, sex, hemoglobin A1c (HbA1c), and metformin, statin, or aspirin usage based on the patient’s medication profile. Per several previous reports in the literature, VS tumor growth was defined as a 20% increase in tumor volume17-20 between consecutive MRI studies or between the first and last MRI study available, which was the primary endpoint. Tumor growth in patients who had evidence of having been prescribed any of the aforementioned medications were compared with medication nonusers.
Statistical Analyses
Results were summarized as means and ranges for continuous variables and percentages for categorical variables. Univariate analysis was completed with chi-square analyses and t tests. A binomial logistic regression model was created for volumetric growth. P values \.05 were considered statistically significant. All analyses were performed with SPSS 26.0 (IBM).
Results
A total of 387 patients were included in the study, with a mean age of 60.6 years (range, 18.2-89.2 years), and 53.5% were women. At diagnosis, the mean axial tumor diameter was 11.9 mm (range, 1.7-32.0 mm), while the mean tumor volume was 0.85 cm3 (range, 0.01-13.1 cm3). Overall, the average patient had 3.5 MRI studies (range, 2-13), with a mean follow-up period of 30.8 months (range, 5-111 months). Overall, 27.5% of tumors demonstrated 2 mm of growth via the greatest axial diameter, while 55.8% demonstrated tumor growth based on volumetric definitions (.20% volume expansion). Table 1 summarizes the demographic data of the sample.
When medications were assessed, 11.9% (46/387) of patients were taking metformin; 37.5% (145/387), a statin; and 30.2% (117/387), aspirin. Figure 1 summarizes the tumor growth profiles of these medications. When growth was defined as an increase in tumor volume of 20%, 39.1% (18/46) of patients on metformin exhibited growth, as opposed to 58.2% (198/340) not taking metformin (P = .014). In reference to statin usage, 51.0% (74/145) of patients on a statin demonstrated volumetric growth, as compared with 58.7% (142/242) of nonusers (P = .143). Finally, 52.1% (61/117) of patients taking aspirin exhibited volumetric growth versus 57.8% (156/270) of nonusers (P = .583).
Because metformin users demonstrated less VS growth, metformin users and nonusers were examined in more detail. Table 2 compares the demographics and tumor characteristics between patients who took metformin and nonusers. Initial tumor axial diameter, initial tumor volumes, and follow-up were similar between groups. Of note, significantly more men were taking metformin (67.4% vs 51%, P = .011). Additionally, the metformin group had higher rates of statin use (63.8% vs 33.8%, P \ .001) and aspirin use (42.6% vs 28.5% , P = .0497). The median metformin dosage was 500 mg twice a day, ranging from 250 mg twice a day to 1250 mg twice a day. Between patients who demonstrated volumetric VS growth and those who did not, the median metformin dosage was not different; however, the mean metformin dosage was 616 mg in those patients who exhibited growth versus 714 mg in those who demonstrated no VS growth (P = .271). We also examined if metformin had a different impact on larger tumors relative to smaller tumors by comparing tumors larger and smaller than the median volume of 0.85 cm3. In separating tumors 0.85 cm3, there was no difference in volumetric growth between those patients who took metformin (46.2%) and nonusers (54.3%, P = .584). However, for tumors \0.85 cm3, patients who took metformin demonstrated significantly less growth (36.4%) than nonusers (59.2%, P = .013).
To limit selection bias given the retrospective nature of the study, a multivariate binomial logistic regression was performed for volumetric growth, defining growth as a binary variable. The model was statistically significant, x2(7) = 15.211, P = .033 (Table 3). Of the predictor variables, only follow-up (odds ratio, 1.009; P = .047) and metformin usage (odds ratio, 0.497; P = .036) were statistically significant when controlling for age, sex, initial tumor volume, statin usage, and aspirin usage.
In addition, an attempt was made to control for HbA1c values. Overall, 77 patients had recorded HbA1c values, 32.5% (25/77) of whom were taking metformin. The mean HbA1c for patients not taking metformin was 5.67 (range, 4.6-8.1), as opposed to 6.88 (range, 5.6-10.2) for those taking metformin, a statistically significant difference (P \ .001). When a binomial logistic regression model was created including HbA1c (Table 4), metformin usage was the only negative significant predictor variable (odds ratio, 0.18; P = .025) of volumetric growth, with follow-up and HbA1c values not statistically significant (P = .630 and P = .559, respectively).
Discussion
Metformin and statins both have a relationship with reduced cancer growth patterns. Previous studies have also suggested that metformin and aspirin use may be associated with reduced VS growth. We found that metformin use was significantly associated with reduced volumetric tumor growth on multivariate logistic regression analysis as compared with controls, while a longer follow-up period was significantly associated with tumor growth, when controlling for age, tumor volume, sex, statin, and aspirin use. The association between VS growth and longer follow-up period is intuitive. VS with longer follow-up periods have a greater period of time for an eventual expansion of 20% volume.
In this study, 387 VSs were reviewed that had at least 2 imaging studies prior to intervention. Per linear measurements, 27.5% demonstrated growth .2 mm in the greatest axial tumor diameter, which corresponds with the natural history of VSs reported by Stangerup et al, who found linear tumor growth in 17% and 28.9% of intra- and extrameatal VSs, respectively.5 In a larger cohort, Hunter et al reported linear VS growth in 40.8% of patients, not differentiating between intra- and extrameatal tumors.4 Additionally, VS volumetric measurements were consistent with previous reports. Within the current cohort, 55.8% demonstrated volumetric growth, comparable to data from Lees et al and Schnurman et al, who reported volumetric growth in 69% and 66% of VSs, respectively.19,20
As to the potential role that metformin plays in VS growth, it has shown a clear epidemiologic benefit in regard to cancer growth and the development of cancer, as evident from a large-scale meta-analysis indicating that diabetic patients taking metformin have a lower risk of colon, lung, and breast cancer than do those not taking the drug.21 Some data suggest that there is no correlation between metformin use and decreased cancer risk; however, these studies suffer from smaller sample sizes and restrictive criteria that focused on only 1 ethnic group or patient population.22,23
Several theories explain why metformin might inhibit tumor growth. Metformin is theorized to inhibit cell growth through activation of adenosine monophosphate–activated protein kinase (AMPK) and inhibition of oxidative phosphorylation in the mitochondria, creating reactive oxygen species, which in turn induce apoptosis in cells that use oxidative phosphorylation for ATP production.24-26 In addition, metformin-induced activation of AMPK inhibits mTOR, which simulates a starved state on the cell, promoting autophagy or apoptosis.27 Furthermore, metformin-induced activation of AMPK downregulates c-myc proto-oncogene, thereby reducing tumor growth while possessing antiinflammatory and antiangiogenic effects by decreasing production of TNFa, IL-6, IL-1B, NFkB, and HIF-1a.28 Metformin also inactivates Stat3 and Bcl-2, which in turn leads to autophagy and apoptosis in esophageal squamous cell carcinoma cells.29 Metformin has also been observed to inhibit the proliferation of cancer cells in vitro. At varying concentrations ranging 2 to 50 mM, metformin induced cell cycle arrest at G0/G1 and G2/M checkpoints in cell lines that include breast, kidney, pancreas, and prostate cancer.30 Thus, numerous possible etiologies can explain why metformin inhibits tumor growth.
Feng et al recently conducted a retrospective analysis examining 149 patients with VSs, 42 of whom were taking metformin.10 They measured intra- and extracanalicular length and width, approximating the tumor surface area via a previously published formula adapted for VSs, defining tumor growth as a 25% increase in the sum of the perpendicular products. They reported that 28.6% of metformin users demonstrated growth, as compared with 49.5% of nonusers, a statistically significant difference. However, while using tumor size approximations, they were unable to control for diabetic patients, and they failed to account for medication adherence and dosage changes.
Our current study supports the findings of Feng et al10 and provides evidence of reduced tumor growth in a sample of 387 patients with tumors assessed volumetrically through BrainLab iPlan software. Furthermore, our study found that metformin was significantly associated with decreased tumor growth when controlling for age, tumor volume, sex, aspirin use, statin use, and follow-up time. We also attempted to examine the effect of glucose control, though data on HbA1c level were available for only 77 patients. When controlling for HbA1c levels, metformin was still significantly predictive of a reduction in tumor growth. This analysis suggests that the reduction in tumor growth is less related to the disease process of diabetes and potentially related to the action of metformin itself. Nevertheless, given the retrospective nature of this work and potential metabolic effects of metformin, we do not currently recommend the routine use of metformin for patients with VSs who are not diabetic. These data warrant further inquiry. However, a recent small placebo-controlled trial studied metformin in nondiabetic patients with endometrial cancer, with no significant increase in metabolic side effects in the metformin group as compared with placebo,31 suggesting that this medication could be a safe option if efficacy was more conclusively established.
This study has limitations, which most notably include its retrospective nature. Because this study is retrospective, there is a significant concern for selection bias between the metformin users and nonusers. An additional limitation is that this study did not examine metformin compliance. In addition, tumor growth was classified as a dichotomous variable. While this is most representative of clinical decision making, noting that tumor enlargement \20% generally does not change management, we can appreciate that growth is a continuous variable and that reclassifying it categorically results in a loss of information and power. Given these limitations, we are unable to determine the causality of this association between metformin use and reduced tumor growth. Further study, ideally with a randomized placebocontrolled trial, would be needed to assess if metformin prevents VS growth. An additional area to investigate would be the effect of metformin on hearing loss.
Conclusion
In a large retrospective study, metformin use was associated with reduced VS volumetric growth when controlling for age, sex, HbA1c, follow-up time, initial tumor volume, statin usage, and aspirin usage.
References
1. Marinelli JP, Grossardt BR, Lohse CM, Carlson ML. Prevalence of sporadic vestibular schwannoma: reconciling temporal bone, radiologic, and population-based studies. Otol Neurotol. 2019;40:384-390.
2. Schmidt RF, Boghani Z, Choudhry OJ, Eloy JA, Jyung RW,Liu JK. Incidental vestibular schwannomas: a review of prevalence, growth rate, and management challenges. Neurosurg Focus. 2012;33:E4.
3. Paldor I, Chen AS, Kaye AH. Growth rate of vestibularschwannoma. J Clin Neurosci. 2016;32:1-8.
4. Hunter JB, Francis DO, O’Connell BP, et al. Single institutional experience with observing 564 vestibular schwannomas: factors associated with tumor growth. Otol Neurotol. 2016; 37(10):1630-1636.
5. Stangerup SE, Caye-Thomasen P, Tos M, Thomsen J. The natural history of vestibular schwannoma. Otol Neurotol. 2006;27: 547-552.
6. Carlson ML, Habermann EB, Wagie AE, et al. The changinglandscape of vestibular schwannoma management in the United States—a shift toward conservatism. Otolaryngol Head Neck Surg. 2015;153:440-446.
7. Kandathil CK, Cunnane ME, McKenna MJ, Curtin HD,Stankovic KM. Correlation between aspirin intake and reduced growth of human vestibular schwannoma: volumetric analysis. Otol Neurotol. 2016;37:1428-1434.
8. Hunter JB, O’Connell BP, Wanna GB, et al. Vestibularschwannoma growth with aspirin and other nonsteroidal antiinflammatory drugs. Otol Neurotol. 2017;38:1158-1164.
9. Marinelli JP, Lees KA, Tombers NM, Lohse CM, Carlson ML.Impact of aspirin and other NSAID use on volumetric and linear growth in vestibular schwannoma. Otolaryngol Head Neck Surg. 2019;160:1081-1086.
10. Feng AY, Enriquez-Marulanda A, Kouhi A, Ali NE, MooreJM, Vaisbuch Y. Metformin potential impact on the growth of vestibular schwannomas. Otol Neurotol. 2020;41:403-410.
11. Rena G, Hardie DG, Pearson ER. The mechanisms of action ofmetformin. Diabetologia. 2017;60:1577-1585.
12. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, MorrisAD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330:1304-1305.
13. Brown MS, Goldstein JL. Multivalent feedback regulation ofHMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth. J Lipid Res. 1980;21:505517.
14. Bennis F, Favre G, Le Gaillard F, Soula G. Importance ofmevalonate-derived products in the control of HMG-CoA reductase activity and growth of human lung adenocarcinoma cell line A549. Int J Cancer. 1993;55:640-645.
15. Harwood HJ Jr, Alvarez IM, Noyes WD, Stacpoole PW. In vivo regulation of human leukocyte 3-hydroxy-3-methylglutaryl coenzyme A reductase: increased enzyme protein concentration and catalytic efficiency in human leukemia and lymphoma. J Lipid Res. 1991;32:1237-1252.
16. el-Sohemy A, Bruce WR, Archer MC. Inhibition of rat mammary tumorigenesis by dietary cholesterol. Carcinogenesis. 1996;17:159-162.
17. Van De Langenberg R, De Bondt BJ, Nelemans PJ, BaumertBG, Stokroos RJ. Follow-up assessment of vestibular schwannomas: volume quantification versus two-dimensional measurements. Neuroradiology. 2009;51(8):517-524.
18. Lawson McLean AC, McLean AL, Rosahl SK. Evaluating vestibular schwannoma size and volume on magnetic resonance imaging: an inter- and intra-rater agreement study. Clin Neurol Neurosurg. 2016;145:68-73.
19. Schnurman Z, Nakamura A, McQuinn MW, Golfinos JG,Roland JT, Kondziolka D. Volumetric growth rates of untreated vestibular schwannomas. J Neurosurg. Published online August 2, 2019. doi:10.3171/2019.5.JNS1923
20. Lees KA, Tombers NM, Link MJ, et al. Natural history ofsporadic vestibular schwannoma: a volumetric study of tumor growth. Otolaryngol Head Neck Surg. 2018;159(3):535-542.
21. Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD,Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care. 2009;32:1620-1625.
22. Saini N, Yang X. Metformin as an anti-cancer agent: actionsand mechanisms targeting cancer stem cells. Acta Biochim Biophys Sin (Shanghai). 2018;50:133-143.
23. Coperchini F, Leporati P, Rotondi M, Chiovato L. Expandingthe therapeutic spectrum of metformin: from diabetes to cancer. J Endocrinol Invest. 2015;38:1047-1055.
24. Owen MR, Doran E, Halestrap AP. Evidence that metforminexerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000;348(pt 3):607-614.
25. Wheaton WW, Weinberg SE, Hamanaka RB, et al. Metformininhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife. 2014;3:e02242.
26. Bridges HR, Jones AJ, Pollak MN, Hirst J. Effects of Guanidine metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J. 2014;462:475-487.
27. Wang Y, Xu W, Yan Z, et al. Metformin induces autophagyand G0/G1 phase cell cycle arrest in myeloma by targeting the AMPK/mTORC1 and mTORC2 pathways. J Exp Clin Cancer
28. Blandino G, Valerio M, Cioce M, et al. Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC. Nat Commun. 2012;3:865.
29. Feng Y, Ke C, Tang Q, et al. Metformin promotes autophagyand apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling. Cell Death Dis. 2014;5:e1088.
30. Takahashi A, Kimura F, Yamanaka A, et al. Metformin impairsgrowth of endometrial cancer cells via cell cycle arrest and concomitant autophagy and apoptosis. Cancer Cell Int. 2014;14:53.
31. Petchsila K, Prueksaritanond N, Insin P, Yanaranop M, Chotikawichean N. Effect of metformin for decreasing proliferative marker in women with endometrial cancer: a randomized double-blind placebo-controlled trial. Asian Pacific J Cancer Prev. 2020;21(3):733-741.