Radiotherapy and Oncology xxx (2016) xxx–xxx
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Letter to editor Metformin for chemo-radio-sensitization of NSCLC
To the Editor We would like to congratulate the team of Wink et al. (2016)  for their retrospective study suggesting that metformin is associated with improved progression free survival (PFS) and distant metastasis free survival (DMFS) in diabetic patients with locally advanced (LA) non-small cell lung cancer (NSCLC). Many retrospective analyses have examined the potential benefits of metformin in cancer [2–7] but very few studies focused on patients with LA-NSCLC receiving curative concurrent chemo-radiotherapy (CCRT). The results of this study are consistent with observations made by our group and others that metformin inhibits proliferation and radio-sensitizes NSCLC through activation of AMPK , a heterotrimeric enzyme that acts as a sensor of metabolic and genotoxic stress . Metformin blocks complex I of mitochondria oxidative phosphorylation chain. This is believed to raise cellular AMP/ADP levels leading to direct activation of AMPK through its energy sensing c-subunit . However, we and others observed that metformin also activates the genotoxic stress sensor Ataxia Telangiectasia Mutated (ATM) [8,11,12]. While the mechanism of this activation remains unclear, it may involve generation of Reactive Oxygen Species (ROS), secondary to the metabolic stress induced by metformin, which would lead to activation of DNA repair pathways . Collectively, the available pre-clinical data suggest that metformin chronically activates in cells and tumors an ATM-AMPK-p53/p21cip1 axis and suppresses Akt-mTOR activity [8,9]. Apart from inhibition of cell cycle, survival and growth, this activity may also include improved genomic stability  that could contribute to improved clinical outcomes. By default, retrospective studies on metformin investigate diabetic patients. As such, cancer control results of the agent in this setting are confounded by the metabolic benefits of the drug in improving glycemia. Similarly, in the study by Wink et al., it is not possible to distinguish the activity in diabetics not treated with metformin from non-diabetics, as diabetics not on metformin appear to have been included in the control group. Hence, to fully understand the anti-tumor activity of metformin, the drug must be investigated in prospective studies with non-diabetic patients. In the past 2 years, two randomized phase II studies opened to investigate metformin in LA-NSCLC treated with CCRT: (i) NRG-LU001 (NCT02186847) investigates the chemo-radiosensitizing action of metformin in stage III NSCLC in patients receiving CCRT followed by consolidation chemotherapy, with metformin administered only concurrent with cytotoxic therapy; and (ii) the Ontario-Clinical-Oncology-Group (OCOG)–ALMERA
http://dx.doi.org/10.1016/j.radonc.2016.06.018 0167-8140/Ó 2016 Elsevier Ireland Ltd. All rights reserved.
(NCT02115464) trial which examines the ability of metformin to offer both chemo-radio-sensitization as well as consolidative therapy in stage III patients, with metformin delivered through cisplatin-based CCRT and beyond for a total of 12 months. The primary outcome in both trials is improvement in twelve month PFS. An additional randomized placebo-controlled phase II study at M.D. Anderson Cancer Center (NCT02285855), investigates metformin in combination with stereotactic radiotherapy in early stage NSCLC patients. These studies will provide much anticipated results on the concept of targeting metabolism to improve clinical outcomes in NSCLC patients treated with cytotoxic therapy. If positive, the results of NRG-LU001 and OCOG-ALMERA will help determine the design of subsequent phase III trials with metformin in NSCLC. References  Wink KC, Belderbos JS, Dieleman EM, et al. Improved progression free survival for patients with diabetes and locally advanced non-small cell lung cancer (NSCLC) using metformin during concurrent chemoradiotherapy. Radiother Oncol 2016;118:453–9.  Currie CJ, Poole CD, Jenkins-Jones S, et al. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care 2012;35:299–304.  Dowling RJ, Goodwin PJ, Stambolic V. Understanding the benefit of metformin use in cancer treatment. BMC Med 2011;9:33.  Evans JM, Donnelly LA, Emslie-Smith AM, et al. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005;330:1304–5.  Goodwin PJ, Ligibel JA, Stambolic V. Metformin in breast cancer: time for action. J Clin Oncol 2009;27:3271–3.  Jiralerspong S, Palla SL, Giordano SH, et al. Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 2009;27:3297–302.  Skinner HD, McCurdy MR, Echeverria AE, et al. Metformin use and improved response to therapy in esophageal adenocarcinoma. Acta Oncol 2012.  Storozhuk Y, Hopmans SN, Sanli T, et al. Metformin inhibits growth and enhances radiation response of non-small cell lung cancer (NSCLC) through ATM and AMPK. Br J Cancer 2013;108:2021–32.  Sanli T, Steinberg GR, Singh G, et al. AMP-activated protein kinase (AMPK) beyond metabolism: a novel genomic stress sensor participating in the DNA damage response pathway. Cancer Biol Ther 2014;15:156–69.  Steinberg GR, Kemp BE. AMPK in health and disease. Physiol Rev 2009;89:1025–78.  Alexander A, Cai SL, Kim J, et al. ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci USA 2010;107:4153–8.  Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, et al. Metformin activates an ataxia telangiectasia mutated (ATM)/Chk2-regulated DNA damage-like response. Cell Cycle 2011;10:1499–501.  Menendez JA, Cufi S, Oliveras-Ferraros C, et al. Metformin and the ATM DNA damage response (DDR): accelerating the onset of stress-induced senescence to boost protection against cancer. Aging (Albany NY) 2011;3:1063–77.
Theodoros Tsakiridis Radiation Oncology, Juravinski Cancer Center, Hamilton, Ontario, Canada
Letter to editor / Radiotherapy and Oncology xxx (2016) xxx–xxx
Department of Oncology, McMaster University, Hamilton, Ontario, Canada ⇑ Address: Department of Oncology, McMaster University, Hamilton, Ontario, Canada. Heath Skinner Department of Radiation Oncology, M.D. Anderson Cancer Center, Houston, TX, USA Gregory Pond Department of Oncology, McMaster University, Hamilton, Ontario, Canada
Anand Swaminath James Wright Radiation Oncology, Juravinski Cancer Center, Hamilton, Ontario, Canada Department of Oncology, McMaster University, Hamilton, Ontario, Canada Received 23 April 2016 Accepted 29 June 2016