Abstract
Background
Metformin, an oral drug used to treat patients with diabetes, has been associated with prolonged survival in patients with various visceral carcinomas. Although the exact mechanisms are unknown, preclinical translational studies demonstrate that metformin may impair tumor cellular metabolism, alter matrix turnover, and suppress oncogenic signaling pathways. Currently used chemotherapeutic agents have not been very successful in the adjuvant setting or for treating patients with metastatic sarcomas. We wanted to know whether metformin might be associated with improved survival in patients with a soft tissue sarcoma.
Questions/purposes
In patients treated for a soft tissue sarcoma, we asked: (1) Is there an association between metformin use and longer survival? (2) How does this association differ, if at all, among patients with and without the diagnosis of diabetes?
Methods
The Surveillance, Epidemiology, and End Results-Medicare (SEER-Medicare) database was used to identify patients with a diagnosis of soft tissue sarcoma from 2007 to 2016. Concomitant medication use was identified using National Drug Codes using the Medicare Part D event files. This database was chosen because of the large number of captured sarcoma patients, availability of tumor characteristics, and longitudinal linkage of Medicare data. A total of 14,650 patients were screened for inclusion. Patients with multiple malignancies, diagnosis at autopsy, or discrepant linkage to the Medicare database were excluded. Overall, 4606 patients were eligible for the study: 598 patients taking metformin and 4008 patients not taking metformin. A hazard of mortality (hazard ratio) was analyzed comparing patients taking metformin with those patient groups not taking metformin and expressed in terms of a 95% confidence interval. Cox regression analysis was used to control for patient-specific, disease-specific, and treatment-specific covariates.
Results
Having adjusted for disease-, treatment-, and patient-specific characteristics, patients taking metformin experienced prolonged survival compared with all patients not taking metformin (HR 0.76 [95% CI 0.66 to 0.87]). Associated prolonged survival was also seen when patients taking metformin were compared with those patients not on metformin irrespective of a diabetes diagnosis (HR 0.79 [95% CI 0.66 to 0.94] compared with patients with a diagnosis of diabetes and HR 0.77 [95% CI 0.67 to 0.89] compared with patients who did not have a diagnosis of diabetes).
Conclusion
Without suggesting causation, we found that even after controlling for confounding variables such as Charlson comorbidity index, tumor grade, size, stage, and surgical/radiation treatment modalities, there was an association between metformin use and increased survival in patients with soft tissue sarcoma. When considered separately, this association persisted in patients not on metformin with and without a diabetes diagnosis. Although metformin is not normally prescribed to patients who do not have a diabetes diagnosis, these data support further study, and if these findings are substantiated, it might lead to the performance of multicenter, prospective clinical trials about the use of metformin as an adjuvant therapy for the treatment of soft tissue sarcoma in patients with and without a preexisting diabetes diagnosis.
Level of Evidence
Level III, therapeutic study.
Introduction
Soft tissue sarcomas represent approximately 50% to 70% of all extremity malignant tumors. They are expected to affect the lives of 13,460 patients (7720 males and 5740 females) and result in 5350 deaths in 2020 in the United States [28]. There is a limited role of and consensus for the routine use of current cytotoxic chemotherapy regimens unless patients have advanced disease [32]. Repurposed common, safe, nontoxic medications have been evaluated with increasing frequency in current limited systemic treatment regimens in other cancers [7]. To date, noncytotoxic medical adjuvants have not been routinely used to treat patients with soft tissue sarcomas. Metformin has shown some very preliminary promise as a candidate molecule emanating from retrospective database studies where patients taking metformin appeared to experience prolonged survival from various visceral carcinomas [23]. Metformin is a biguanide medication commonly used to treat diabetes mellitus because of its favorable profile regarding cost, side effects, and minimal interaction with other medications for diabetes [27]. The exact mechanisms of action of metformin to treat hyperglycemia remain to be fully elucidated; certainly, the interaction of any hypoglycemic effect on tumor growth and spread remains speculative and poorly understood [9]. As we learn more about the molecular basis of these rare cancers, targeted and immunotherapies may become more common with personalized oncologic care. The antineoplastic effects of metformin include alterations in distinct molecular mechanisms (activation of liver kinase B1 and adenosine monophosphate–activated kinase) as well as inhibition of mechanistic target of rapamycin (mTOR), cellular behavior (inhibiting protein synthesis, inhibiting the unfolding protein response, stopping the cell cycle, and triggering apoptosis or autophagy by p53 and p21), tissue response (preventing angiogenesis), and systemic effects including decreasing blood insulin levels, activating the immune system, destructing cancer stem cells, and reducing hyperlipidemia [27]. Of particular interest in soft tissue sarcoma treatment, metformin has been extensively investigated as a radiosensitizing agent. Preclinical models have suggested that multiple mechanisms are attributable to its radiosensitivity effect including mitochondrial complex one inhibition (with resultant increased reactive oxygen species) and protein kinase activation [6, 26]. In addition, radiation and metformin can activate p53 with subsequent activation of the p21 gene, which may act by reducing tumor cell proliferation and inducing cell senescence [24, 27]. Overall, these characteristics have prompted numerous translational and clinical studies across a broad spectrum of malignancies.
A preexisting diagnosis of diabetes has been shown to have a negative effect on long-term all-cause mortality in patients who have cancer [2]. However, a survival advantage has been observed in a distinct group of patients with diabetes taking metformin at the time of diagnosis for various visceral carcinomas [1, 15, 21, 29]. In addition, patients taking metformin experience a decreased risk of developing carcinoma compared with similarly matched patients over the same time in large-population studies [8, 10]. Collectively, these findings have supported the study of metformin as a noncytotoxic adjunct in the treatment of various carcinomas in candidate populations, including patients with and without a preexisting diagnosis of diabetes [3, 12, 14, 25].
To date, investigation into the antineoplastic effects of metformin in musculoskeletal malignancies has been confined to the preclinical stage, and clinical data remain lacking [12, 14, 25].We therefore asked, in patients treated for a soft tissue sarcoma: (1) Is there an association between metformin use and longer survival? (2) How does this association differ, if at all, among patients with and without the diagnosis of diabetes?
Patients and Methods
Overview
The study was performed by accessing the Surveillance, Epidemiology, and End Results registry (SEER), linked to Medicare claims [13]. A specific dataset of all patients with a diagnosis of soft tissue sarcoma from 2007 to 2016 in the registry provided the basis of the analysis. We chose the SEER-Medicare database for this analysis because of the large number of captured cancer patients, the availability of tumor characteristics, and longitudinal linkage of Medicare data were consistent with similar studies [1, 13, 15, 21, 29]. Beginning in 2006, Medicare initiated the optional Part D drug benefit to cover outpatient prescription drugs and supplement traditional Medicare and Medicare Advantage plans; Part D claims were filed for each event in which a prescription of metformin was filled. Soft tissue sarcomas emanating from the connective, nervous, and soft tissues were selected, and their location was limited to the trunk and extremities. Kaposi sarcoma and visceral and retroperitoneal sarcomas were not included. Patients with multiple malignancies were also excluded. ICD-9, primary site codes, and Healthcare Common Procedure Coding System codes were used to identify cancer treatment, comorbidities, and procedures in the Medicare claims files. Diabetes medications were identified with National Drug Codes using the Medicare Part D event files as performed elsewhere for a similar purpose [21, 29]. Patients with a diagnosis at autopsy or by death certificate were excluded from the analysis (Fig. 1).
Fig. 1.
This flowchart shows patient selection/exclusion before analysis.
To delineate the study groups, we used Part D enrollment (in addition to Part A and B and no healthcare maintenance organizations) to identify metformin use [20]. Patients with a diabetes diagnosis were identified using published methods for Medicare claims-based data requiring the presence of ICD-9 code 250.xx, including inpatient/outpatient claims and antihyperglycemic medication use [19]. Accordingly, to determine whether a patient had a diabetes diagnosis for the purpose of including them in our groups, we required them have one hospital claim or one outpatient claim within 1 year of their soft tissue sarcoma diagnosis using the Patient Entitlement and Diagnosis Summary (PEDSF), Outpatient and National Claims History. The use of other antihyperglycemic medication including insulin, sulfonylurea, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, meglitinides, and alpha glucosidase inhibitors was also scrutinized and supported a diabetes diagnosis. Patients were considered to have used a specific diabetes medication if the pharmacy claim was submitted 6 months before the sarcoma diagnosis.
Patients and Disease-specific Characteristics
Patient demographic information (age at diagnosis, diagnosis year, and sex) and disease-specific characteristics (tumor grade, stage, size, and pulmonary metastasis) are provided in the SEER PDESF dataset and were collected (Table 1). Regarding stage, summary stage 2000 (SEER database) was used because of its ease of accessibility and because there are some concerns about the completeness of the American Joint Committee on Cancer staging data in the SEER dataset [4]. Tumor size and pulmonary metastasis were considered independently because of their independent prognostic effects [17, 22]. Medicare inpatient and outpatient data from the year of diagnosis were used to characterize comorbidities based on the Deyo modification of the Charlson comorbidity index [11].
Table 1.
Specific characteristics of the covariates for the patients on metformin and all patients who did not take metformin
| Factor | Patients not taking metformin (n = 4008) | Patients taking metformin (n = 598) | p value |
| Age at diagnosis in years | 76 (69-83) | 74 (68-79) | < 0.001 |
| % Female (n) | 47 (1887) | 43 (258) | 0.07 |
| Charlson comorbidity index | < 0.001 | ||
| 0 | 55 (2209) | 11 (65) | |
| 1-2 | 23 (925) | 53 (315) | |
| > 2 | 22 (874) | 36 (218) | |
| Tumor grade | 0.99 | ||
| Grade 1: well-differentiated | 13 (517) | 13 (75) | |
| Grade 2: moderately differentiated; intermediate differentiation | 11 (430) | 11 (66) | |
| Grade 3: poorly differentiated; differentiated | 18 (708) | 17 (103) | |
| Grade 4: undifferentiated; anaplastic | 31 (1224) | 30 (181) | |
| Unknown | 28 (1129) | 29 (173) | |
| Tumor size in cm | 8 (4.3-13.1) | 8 (4.5-13.2) | 0.73 |
| % with pulmonary metastases (n) | 6 (231) | 5 (31) | 0.57 |
| Tumor stage (derived from summary stage 2000) | 0.49 | ||
| In situ | 59 (2355) | 61 (366) | |
| Localized | 18 (720) | 19 (111) | |
| Regional, direct extension | 1 (59) | 1 (6) | |
| Regional, lymph nodes only | 1 (33) | 1 (7) | |
| Distant | 14 (576) | 13 (76) | |
| Unknown/unstaged | 7 (265) | 5 (32) | |
| Radiation modality | 0.20 | ||
| No radiation | 57 (2294) | 56 (335) | |
| Beam radiation | 38 (1529) | 41 (246) | |
| Radiation (method or source not specified) | 0.57 (23) | a | |
| Other | 0.97 (39) | a | |
| Refused | 2 66 | a | |
| Recommended (unknown if administered) | 1 (45) | a | |
| Unknown | 1.12 (45) | a | |
| Radation sequence with surgery | 0.07 | ||
| No radiation and/or cancer-directed surgery | 68 (2714) | 63 (378) | |
| Radiation before surgery | 6 (255) | 8 (46) | |
| Radiation after surgery | 24 (979) | 28 (167) | |
| Radiation before and after surgery | 0.7 (27) | a | |
| Intraoperative radiation with radiation before or after | 0.3 (14) | a | |
| Surgery both before and after radiation | 0.3 (12) | a |
Data presented as mean (range) or % (n); p values reflect comparisons between patients not taking metformin and patients taking metformin for combined subgroups in each section.
Cell size suppression per the data user agreement for values (1-10 patients).
We identified 14,650 patients with soft tissue sarcoma that was diagnosed from 2007 to 2016. A total of 4844 patients were immediately excluded based on the presence of multiple malignancies. Further exclusion of patients with multiple sarcomas or diagnosis at autopsy left 9000 patients (Fig. 1). Of these, 4780 patients had complete, linked datasets (Medicare) to enable analysis. Among the patients with complete datasets, 31% (4606 of 14,650) of patients had medication claims data and diagnosis codes to identify the presence or absence of a diagnosis of diabetes comparing favorably to similar SEER database studies investigating the effects of metformin use in patients with head/neck cancer (13.3%) and lung cancer (12.6%) [21, 29]. Of the 4606 patients chosen for the final analysis, 13% (598 of 4606) took metformin in the 6 months before their sarcoma diagnosis and were held as the key group (metformin) to answer the study questions. Comparison groups comprised all patients not taking metformin (87% [4008 of 4606]), patients with diabetes who did not take metformin (14% [648 of 4606]), and patients without a diagnosis of diabetes who were not taking metformin (73% [3360 of 4606]).
Overall, the follow-up period was longer for patients taking metformin (50 ± 40 months) than for patients not taking metformin (45 ± 39 months; p < 0.001). In addition, patients taking metformin (73 ± 11 years) were younger than those not taking this drug (76 ± 11 years; p < 0.001). Patients in the metformin group had more comorbidities, as measured by the Charlson comorbidity index score, than in the other groups. Otherwise, we observed no differences in disease-specific and treatment-specific covariates.
Treatment Modalities
We used Medicare Provider Analysis and Review, carrier, and outpatient claims to identify neoadjuvant and adjuvant radiotherapy beginning within 9 months of soft tissue sarcoma diagnosis, as defined by ICD-9 diagnosis codes. We considered a single claim for radiotherapy sufficient to reflect that an individual had radiotherapy, with a distinction made between neoadjuvant and adjuvant radiotherapy. We extracted surgery and the timing of surgery relative to radiation therapy from the PEDSF. The accurate identification and extraction of subsequent reexcision of positive margins or recurrence was not possible in these datasets.
Data Synthesis and Subgroup Analysis
To optimize our patient resolution, we performed the data analysis only for patients with complete dataset linkages with respect to the carefully chosen covariates that are known to affect outcome related to sarcoma survival [16]. For patients not taking metformin, subgroups were created and analyzed regarding diabetes status. A diabetes diagnosis was only satisfied if a patient had diagnostic codes and dispensed medication (insulin, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 inhibitors, meglitinides, and alpha glucosidase inhibitors) consistent with diabetic status, as reported [1]. Overall, patients taking metformin were compared with the following: all patients not taking metformin, patients with diabetes who did not take metformin, and patients without a diabetes diagnosis who did not take metformin (Fig. 2).
Fig. 2.
This flowchart shows an overview of the study groups and analyzed covariates.
Primary and Secondary Study Outcomes
Our primary outcome was to explore the association between metformin use and survival in all patients with soft tissue sarcoma. To achieve this, we petitioned the SEER-Medicare database and compared the hazard of mortality expressed as a hazard ratio in soft tissue sarcoma patients taking metformin with those who were not taking it. We adjusted the analysis for both patient- and disease-specific covariates between the groups.
Our secondary study goal was to investigate whether survival in patients taking metformin differed when compared with patients with and without a diabetes diagnosis. These data would further delineate the specific candidate patient populations, such as those patients not on metformin at the time of diagnosis with soft tissue sarcoma with or without a diabetes diagnosis.
Ethical Approval
This study was approved by our institutional review board at Albany Medical Center, Albany, NY, USA.
Statistical Analysis
To achieve our study goals, HRs were calculated comparing patients taking metformin with (1) all patients not taking metformin, (2) patients with diabetes not taking metformin, and (3) patients without diabetes not taking metformin. We performed a Cox regression analysis to adjust for covariates including age at the time of diagnosis, sex, Charlson comorbidity index score, tumor grade, pulmonary metastasis, tumor size, tumor stage, surgical intervention, and radiation therapy, including modality and timing. All of the aforementioned covariates were used in the final analysis with the exception of pulmonary metastasis status, which was removed as it did not confer any effect in the model. The Surveillance Research Program, National Cancer Institute SEER*Stat software (seer.cancer.gov/seerstat) was used, along with an additional statistical software package (STATA version 9.2; STATA Corp). Significance was set at p < 0.05.
As part of the comprehensive assessment, overall survival was also assessed by comparing patients who took metformin and those who did not using a log-rank test for equality of survivor functions. These data are unadjusted (Supplementary Fig. 1; http://links.lww.com/CORR/A662).
Results
Association Between Metformin Use and Increased Survival
Patients who took metformin at the time of diagnosis with soft tissue sarcoma experienced prolonged survival compared with those who were not on metformin. The adjusted hazard of mortality in patients taking metformin was 0.76 (95% CI 0.66 to 0.87) compared with all of those patients not taking metformin (p < 0.001).
Does the Association Differ in Patients With and Without Diabetes?
This association of prolonged survival in patients taking metformin compared with those patients who were not taking metformin persisted irrespective of diabetes status. The adjusted hazard of mortality in soft tissue sarcoma patients taking metformin at their time of diagnosis was 0.79 (95% CI 0.66 to 0.94) when compared with patients who had diabetes but were not taking metformin (p < 0.01). Similarly, the hazard of mortality of patients already taking metformin was 0.77 (95% CI 0.67 to 0.89) when compared with those patients who were neither diabetic nor taking metformin (p < 0.001).
Discussion
The repurposing of noncytotoxic medications in the treatment of malignancy remains of intense interest. In this regard, metformin has appeared to be associated with prolonged survival for various visceral malignancies including non–small cell lung, breast, pancreas, colon, and head and neck cancer [5, 15, 21, 29]. Using a national database (SEER-Medicare), an association between metformin use and prolonged survival in patients with soft tissue sarcoma was observed. This association persisted when patients taking metformin were compared with both candidate populations: patients not taking metformin with and without a diabetes diagnosis.
Limitations
There are several limitations to this study. First, this study was observational and retrospective and used big data from a national registry. Unfortunately, because of the nature of registry data capture and logistics, a careful balance of maintaining patient numbers with requisite data resolution can be challenging. In this study, we determined that 31% (4606 of 14,650) were eligible for analysis; this number compared favorably with similar SEER database studies by Stokes et al. [29] (13.3%) and Lin et al. [21] (12.6%). To strengthen our investigation, we restricted eligibility to those patients with completed, linked datasets to account for patient-, disease-, and treatment-specific characteristics between the patient groups. Although we captured metformin use by analyzing pharmacy claims, we cannot infer patient adherence to the medication during the study period. Contextually, it is acknowledged that pharmacy claims data have been shown to have high concordance with pill counts and medication use in similarly aged patient groups [18]. We acknowledge that the 5-year survival across groups was lower than the reported 60% to 70%, and this may be due to the advanced age of this patient cohort. Finally, as a stated limitation of the SEER database, we were unable to determine disease recurrence (and treatment thereof). In this regard, it is acknowledged that local recurrence of soft tissue sarcoma has not been definitely shown to affect overall survival [31, 33].
Association Between Metformin Use and Increased Survival
We observed an association between taking metformin and improved survival in patients who had were being treated for a soft tissue sarcoma. Disease-specific and treatment-specific covariates did not appear to vary between patients who took metformin and those who did not. This was not surprising since there is no clinical distinction of metformin use or diabetic status in the treatment of soft tissue sarcomas. Although statistically modest, the adjusted hazard of mortality observed in soft tissue sarcoma patients taking metformin for the candidate population groups (ranging from 0.76 to 0.79) taken together compare favorably with similar retrospective observational studies that have supported prospective study of metformin as a repurposed, noncytotoxic adjuvant in the treatment of various other carcinomas in the clinic and at the benchtop. Benchtop, prospective, and retrospective observational studies have all supported the prospective study of metformin as a noncytotoxic adjuvant that has been applied safely to patients with and without a preexisting diabetes diagnosis [3, 6, 24, 26, 27]. Coyle et al. [7] performed a meta-analysis of studies comparing patients who used metformin and those who did not for various cancer types, with all but one study being retrospective. They reported lower aggregated hazard of mortality (prolonged survival) of 0.69 for colorectal cancer, 0.82 for prostate cancer, 0.99 for breast cancer, and 0.94 for urothelial cancer for patients taking metformin. They also reported a series of single studies with hazard of mortality reported as 0.85 for lung cancer, 0.54 for pancreatic cancer, 0.43 for endometrial cancer, and 0.86 for gastric cancer. The National Cancer Institute (NCI) coordinates the United States National Cancer Program and is part of the National Institutes of Health. Currently, the NCI are supporting seven prospective clinical studies analyzing the effect of metformin as a noncytotoxic adjuvant treatment in diabetic and nondiabetic patients with various visceral malignancies including head and neck cancer, breast cancer, thyroid cancer, multiple myeloma, chronic lymphocytic leukemia, and ovarian cancer (Table 2).
Table 2.
Active clinical trials at the time of publication investigating metformin as a treatment adjunct for various visceral malignancies that are supported by the National Cancer Institute (https://www.cancer.gov/about-cancer/treatment/clinical-trials/intervention/metformin-hydrochloride)
| Study title (National Clinical Trial number) |
Trial phase/type | Intervention | Primary outcome measure | Study population relating to diabetes status |
| Chemotherapy with or without metformin hydrochloride in treating patients with HER2-positive breast cancer that can be removed by surgery (NCT03238495) | Phase 2 treatment | Two study arms: taxotere, carboplatin, herceptin + pertuzumab (TCH+P) with and without metformin; metformin 850 mg daily during the first cycle, then 850 mg twice daily for the remaining 5 cycles | pCR at surgery | Only patients already taking metformin were excluded, irrespective of diabetes status |
| Metformin hydrochloride, cisplatin, and external beam radiation therapy in treating participants with stage III-IV head and neck squamous cell cancer (NCT02949700) | Phase 1/2 treatment | Experimental study: Single arm, treatment beginning 14 days before external beam radiotherapy; participants receive metformin hydrochloride orally twice daily, then undergo radiation therapy daily and cisplatin intravenously on day 1; courses repeat every 7 days for up to 7 weeks in the absence of disease progression or unacceptable toxicity | Phase I: To define the MTD of metformin hydrochloride (metformin) with cisplatin and external beam radiotherapy Phase II: To measure the effect of metformin as an adjuvant treatment in combination with standard of care cisplatin and radiation on disease response, tissue response, and survival |
All patients with a diagnosis of diabetes were excluded |
| Metformin hydrochloride and levonorgestrel-releasing intrauterine system in treating patients with atypical endometrial hyperplasia or endometrial cancer (NCT02035787) | Phase 0 treatment | Metformin is added to the standard nonsurgical treatment with levonorgestrel-releasing intrauterine treatment after dilation and curettage; metformin hydrochloride orally (850 mg) once daily titrated to twice daily within 1 month for 12 months | The outcome is response rate at 6 months; response is defined as the percentage of individuals achieving complete disease regression as defined by no evidence of microscopic viable hyperplasia or carcinoma on endometrial biopsy compared with a base rate of 50% | Only patients already taking metformin were excluded, irrespective of diabetes status |
| Metformin for the treatment of smoldering multiple myeloma or smoldering Waldenstrom macroglobulinemia (NCT04850846) | Double-blind, randomized, placebo-controlled trial; patients are randomly assigned to receive a stepped dose escalation until target daily dose of 1500 mg metformin XR is reached over 6 months; the intervention duration will last 6 months | M protein concentrations/light chains change at 6 months as quantified using the serum-protein electrophoresis and serum-free light chain assays | Patients taking any medication for a diagnosis of diabetes were excluded | |
| Metformin, nelfinavir, and bortezomib in treating patients with relapsed and/or refractory multiple myeloma | Phase 1 treatment | Experimental study with a single arm; patients receive metformin hydrochloride orally on days 1-14, nelfinavir mesylate twice daily on days 1-14, and bortezomib subcutaneously on days 1, 8, and 15 | To define the MTD of administering metformin hydrochloride and nelfinavir mesylate in combination with bortezomib in patients with relapsed/refractory multiple myeloma; secondary objectives include hematological response and the assessment of biomarkers including signaling pathways and metabolomics-based profiling | All patients with a diagnosis of diabetes were excluded |
| Metformin hydrochloride in treating patients with relapsed chronic lymphocytic leukemia or untreated chronic lymphocytic leukemia with genomic deletion 11q (NCT01750567) | Phase 2 treatment | Experimental study with a single arm; the starting dose of metformin will be 500 mg daily orally for one week; the dose can be escalated to 500 mg twice a day after one week, and further escalated to the final dose of 1000 mg twice a day in week 3 | To evaluate whether metformin hydrochloride therapy has any clinical significance in retarding disease progression of chronic lymphocytic leukemia; this outcome was assessed using time to treatment failure, that is, until the patient meets failure criteria and stops metformin up to 6 months after start of metformin therapy and yearly thereafter; failure to be defined by clear clinical parameters | All patients with a diagnosis of diabetes including those taking metformin were excluded |
| Metformin hydrochloride and combination chemotherapy in treating patients with stage III-IV ovarian, fallopian tube, or primary peritoneal cancer (NCT02122185) | Phase 2 treatment | Randomized placebo-controlled Phase 2 trial with two treatment arms; patients receive a standard chemotherapy regimen at the discretion of the treating physician; patients are randomized to receiving metformin or a placebo in addition | Progression-free survival evaluated using the RECIST and GCIG criteria until disease progression or death from any cause, assessed up to 2 years | All patients with a diagnosis of diabetes, including those taking metformin, were excluded |
pCR = pathologic complete response; MTD = maximum tolerated dose; RECIST = Response Evaluation Criteria in Solid Tumors; GCIG = Gynecological Cancer Intergroup.
Does the Association Differ in Patients With and Without Diabetes?
Regarding patient-specific variables, patients taking metformin had higher levels of comorbidity than all patients not taking metformin and patients without diabetes who were not taking metformin. These findings are consistent with the result of a previous study in which patients with diabetes had more diabetes- and nondiabetes-related comorbidities than patients who did not [30]. In addition, patients with diabetes who did not take metformin had increased comorbidities compared with patients taking metformin; this finding was also unsurprising, given that metformin is more often used in patients with the earlier or less severe stages of diabetes and in the absence of renal failure [30].
Conclusion
Patients treated for soft tissue sarcoma while taking metformin had modestly prolonged survival compared with their counterparts who did not take metformin, irrespective of diabetes status. This finding supports the consideration of further studies assessing metformin as a noncytotoxic adjuvant agent in patients with soft tissue sarcomas. Ultimately, a well-designed, multi-institutional, randomized controlled trial of the effect of metformin on patients with soft tissue sarcomas may be considered.
Supplementary Material
Acknowledgments
We thank the staff at the SEER database for their participation in data disbursement and troubleshooting. We thank Dr. Wisnivesky’s lab at Mount Sinai, New York, NY, USA, for their collaborative gestures in navigating the comorbidity data.
Footnotes
Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members.
Research reported in this publication was supported financially by internal departmental research funds.
All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request.
Ethical approval for this study was obtained from Albany Medical Center, Albany, NY, USA.
Contributor Information
Ian D. Hutchinson, Email: i.hutch2012@gmail.com.
Ashar Ata, Email: ataa@amc.edu.
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