Abstract
Background/Aim: Non-small cell lung cancer (NSCLC) is increasingly detected in early stages and there is interest in improving outcomes with stereotactic body radiotherapy (SBRT). As metformin affects NSCLC signaling pathways, it might alter the metabolism of NSCLC treated with SBRT. This study investigated the long-term outcomes of a phase II clinical trial evaluating metformin in conjunction with SBRT for early-stage NSCLC. Patients and Methods: The trial evaluated patients with American Joint Commission on Cancer (AJCC) 7th edition Stage I-II, cT1-T2N0M0 NSCLC who were randomized 6:1 to receive metformin versus placebo in conjunction with SBRT. The outcomes analyzed included local failure (LF), progression-free survival (PFS), overall survival (OS), and Common Terminology Criteria for Adverse Events (CTCAE) version 4 toxicities. Results: There were 14 patients randomized to the metformin arm and one to the placebo. Median follow-up was four years. In the metformin group, the median PFS was 4.65 years [95% confidence interval (CI)=0.31-5.93] and median survival was 4.97 years (95%CI=3.05-4.61). Five year PFS was 27.8% (95%CI=5.3-57.3%) and OS was 46.0% (95%CI=16.0-71.9%). The one patient randomized to placebo was alive and without progression at five years. There were no LFs in the primary SBRT treatment volumes and no CTCAE version 4 Grade ≥3 adverse events. Conclusion: Outcomes of SBRT and metformin for early-stage NSCLC were similar to historic controls. These findings along with the results of the NRG-LU001 and OCOG randomized trials do not support the therapeutic use of metformin for NSCLC.
Lung cancer remains the leading cause of cancer-related mortality in the United States (1). With the implementation of low-dose computed tomography (CT) (2), non-small cell lung cancer (NSCLC) has been increasingly diagnosed in early stages (3, 4), providing new opportunities to improve tumor control and survival. While stereotactic body radiotherapy (SBRT) yields high rates of local tumor control for inoperable early-stage NSCLC, roughly 30-40% of patients develop locoregional or distant progression outside of their radiation treatment volumes (5, 6). As such, there has been great interest in exploring systemic strategies to reduce distant progression of early-stage NSCLC based on an understanding of tumor biology. Because of the dysregulation of 5′ adenosine monophosphate-activated protein (AMP) kinases frequently observed in NSCLC (7, 8), metformin has been prospectively studied as a potential systemic therapy for NSCLC (9-11). Previously, we reported initial primary 6-month outcomes of a phase II trial showing that metformin significantly increased glucose uptake as seen by positron emission tomography (PET)-scan when used in conjunction with SBRT for early-stage NSCLC (10). To characterize the potential long-term outcomes of metformin with SBRT for early-stage NSCLC, we report the 5-year results of that randomized phase II clinical trial (10).
Patients and Methods
This study was approved and monitored by the University of Texas, M.D. Anderson Cancer Center Institutional Review Board (2014-0255). The trial was registered at clinicaltrials.gov (NCT02285855). Written informed consent was obtained from all participants. Patients were enrolled from August, 2015 to August, 2017. In this single-blinded randomized phase II trial (Figure 1), patients with inoperable American Joint Commission on Cancer (AJCC) 7th edition Stage I-II, cT1-T2N0M0 NSCLC, were randomly assigned to receive SBRT +/− metformin in a 6:1 ratio with stratification based on tumor size (≥4 cm vs. <4 cm) as previously reported (10). Metformin was administered according to the parameters previously reported at a dose of 2,000 mg daily during the week of SBRT and up to two weeks following SBRT (10). Toxicity was monitored and graded per the Common Terminology Criteria for Adverse Events (CTCAE) version 4. Descriptive statistics were used to summarize all study characteristics. Continuous variables were described using means, standard deviations, medians, and range and categorical variables were described using frequencies and percentages. Local control (LF) was defined as time to clinical or radiographic progression by Response Evaluation Criteria in Solid Tumor (RECIST) within the primary SBRT treatment volume/field. Progression-free survival (PFS) was defined from the date of randomization to the date of local relapse, distant metastases, or death, which ever occurred first. Patients who did not experience an event were censored at their last follow-up date. Overall survival (OS) was defined from the date of randomization to the date of death with censoring patients alive at their last contact date. Median and 5-year PFS and OS estimates were provided using the Kaplan–Meier method. All statistical analyses were conducted using Stata version 16 (StataCorp, LLC, College Station, TX, USA).
Phase II clinical trial timeline. SBRT: Stereotactic body radiotherapy; PET: positron emission tomography; CT: computed tomography.
Results
The trial was terminated early due to poor accrual with a total of 15 patients enrolled. There were 14 subjects randomized to the metformin arm and one patient randomized to the placebo arm. As previously reported (10), median age was 73 years in the metformin arm; the AJCC 7th edition stage was T1a in 71.4% (N=10) and T1b in 28.6% (N=4). The most prevalent histology was adenocarcinoma (N=8, 57.1%), followed by squamous carcinoma (N=5, 35.7%), and poorly-differentiated carcinoma (N=1, 7.1%). The median follow-up was four years. Among all patients enrolled (Figure 2), median PFS was 4.65 years and the median survival was 5.37 years, with a 5-year PFS of 34.9% and OS 50.8%. The metformin group had a median PFS of 4.65 years (95%CI=0.31-5.93) and median OS of 4.97 years (95%CI=3.05-6.41), as shown in Figure 3. For patients in the metformin group, the 5-year PFS was 27.8% (95%CI=5.3-57.3%), and the 5-year OS was 46.0% (95%CI=16.0-71.9%). The single patient randomized to placebo remained alive and without evidence of progression at 5 years. There were no LFs in the primary radiation treatment volume at any time point. No additional adverse events were reported since the initial report of the trial, and no CTCAE Grade ≥3 adverse events were deemed probably or definitely-related to protocol. Exploratory analysis was conducted to compare PFS among study variables of interest (Table I), but univariate analysis did not demonstrate factors significantly associated with prognosis.
Phase II clinical trial results for all participants. A) Kaplan–Meier analysis of progression-free survival (PFS). B) Kaplan–Meier analysis of overall survival (OS). NA: Not applicable; CI: confidence interval.
Phase II clinical trial results according to randomization arms (metformin versus placebo). A) Kaplan–Meier analysis of progression-free survival. B) Kaplan–Meier analysis of overall survival. CI: Confidence interval.
Univariate analysis of clinicopathologic factors associated with progression-free survival.
Discussion
The long-term follow-up of this small phase II clinical trial revealed no apparent improvement in outcomes when combining metformin with SBRT for medically-inoperable NSCLC. Long-term OS and PFS outcomes of this trial were comparable to those of RTOG 0236, RTOG 0813, and RTOG 0915 (5, 6, 12). Despite an abundance of pre-clinical and retrospective evidence suggesting that metformin may suppress metabolism and oncogenicity in NSCLC and other tumors like hepatocellular carcinoma (13, 14), our findings indicated that metformin actually increased tumor metabolism rather than having suppressed it (10). This might provide an explanation why the metformin arm had numerically worse PFS in NRG-LU001 (9), and worse outcomes in the Ontario Clinical Oncology Group (OCOG)-Advanced Lung Cancer Treatment With Metformin and Chemoradiotherapy trial (11). The findings of these three prospective trials taken together suggest that the off-target effects of metformin on NSCLC tumor metabolism and signaling remain poorly understood. Further study may be warranted in patients taking metformin for diabetes while undergoing treatment for NSCLC, as there are alternative anti-glycemic therapies available that do not perturb putative oncologic signaling pathways. Efforts to improve outcomes for early-stage NSCLC may depend on biomarker-driven strategies that target aberrations of specific tumor signaling pathways, such as the epidermal growth factor receptor (EGFR) (15), echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK) fusion protein (16), and Kirsten Rat Sarcoma Virus (KRAS) oncogene (17). Checkpoint immune therapy directed against programmed death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) is also being actively investigated in medically inoperable early-stage NSCLC (18). Going forward, targeted therapies using predictive biomarker strategies based on specific dysregulated oncogenes may be more fruitful than attempting to exploit off-target effects of drugs such as metformin.
Conclusion
In summary, while metformin was well tolerated in conjunction with metformin with no evidence of severe adverse effects, no clear efficacy was observed in this small prospective trial. Despite substantial preclinical data suggesting the utility of metformin for NSCLC, prospective trials to date have not corroborated a clinical benefit for patients. Our findings are consistent with the NRG-LU001 and OCOG trials, which similarly showed lack of efficacy of metformin for locally-advanced NSCLC (9, 11). More scrutiny into the outcomes of patients being treated for diabetes with metformin might be warranted to ensure that metformin is not associated with compromised oncologic outcomes. Recent improvements in the understanding of NSCLC disease biology and development of specific targeted biologics and PD-L1 directed immune therapy may yield new strategies to improve outcomes.
Acknowledgements
The Authors thank Mr. Gary Kott for generously supporting publication of this study through a philanthropic gift to the University of Texas M.D. Anderson Cancer Center.
Footnotes
Authors’ Contributions
Study conception and design: M.K.T, M.H., H.D.S, and S.G.C.; analysis and interpretation of results: M.K.T., M.H., J.Y.C., S.H.L., Z.L., S.M.K, H.D.S., and S.G.C.; draft manuscript preparation: M.K.T., M.H., and S.G.C. All Authors reviewed the results and approved the final version of the manuscript.
Conflicts of Interest
Dr. Chun reports consultant/travel fees from AstraZeneca, consultant fees/honorarium from Curio Science, consultant fees from Norton Healthcare, travel fees from ViewRay, honorarium from the Japanese Society for Radiation Oncology, honorarium from Henry Ford Health Systems, honorarium from the Hong Kong Precision Oncology Society, honorarium from the Binaytara Foundation, honorarium from Elsevier and travel fees from The American Board of Radiology.
Funding
Research reported in this publication was supported by the NIH/NCI under award numbers R50CA275822 and 5R21CA182964. The M.D. Anderson Biostatistics Resource Group is supported by National Institutes of Health/National Cancer Institute (NIH/NCI) grant P30CA016672. The content of this manuscript is solely the responsibility of the Authors and does not necessarily represent the official views of the NIH.
- Received November 11, 2023.
- Revision received November 30, 2023.
- Accepted December 1, 2023.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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