Tolerability, safety and feasibility of metformin combined with chemoradiotherapy in patients with locally advanced cervical cancer: A phase II, randomized study
DOI:
https://doi.org/10.2340/1651-226X.2025.43045Keywords:
cervical cancer, multimodal imaging, hypoxia biomarkers, hypoxia modification, metformin, randomized phase II trialAbstract
Background and purpose: Locally advanced cervical cancer is treated with chemoradiotherapy. The treatment-related morbidity is high. Tumor hypoxia has prognostic impact and represents a valid, interventional target. This phase II study investigated efficacy of the antidiabetic drug metformin to modify hypoxia according to established biomarkers. Preliminary results including tolerability, safety and feasibility are reported here.
Patients and methods: Patients were included in a 1:1 randomized, open-label design, comparing standard chemoradiotherapy ± metformin. Metformin 850 mg twice daily was administered 1 week before and during chemoradiotherapy. Magnetic resonance images (MRI) and tumor biopsies were collected at baseline, after 1 week of metformin treatment, and at brachytherapy for biomarker assessments. Tolerability and safety were determined by treatment completion rates and frequency of adverse events (AEs). Safety was further evaluated by possible increase in MRI-based hypoxia during the first week of metformin. Feasibility was determined by proportion of completed study interventions and imaging and biopsy procedures.
Results: In total, 18 and 23 patients were allocated to the intervention and control arm, respectively. Eighteen and 15 patients completed metformin treatment for 1 and 5 weeks. Frequency of AEs ≥ grade 3 was not significantly different between study arms. Most AEs were gastrointestinal toxicities. Tumors with increase in hypoxia during the first week were all below the defined safety limit. A total of 98% of scheduled MR series and biopsies were collected with satisfactory quality.
Interpretation: Addition of metformin to chemoradiotherapy is tolerable and safe. Serial sampling of MRI and tumor biopsies for hypoxia biomarker assessment is feasible.
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References
Pötter R, Tanderup K, Schmid MP, Jürgenliemk-Schulz I, Haie-Meder C, Fokdal LU, et al. MRI-guided adaptive brachytherapy in locally advanced cervical cancer (EMBRACE-I): a multicentre prospective cohort study. Lancet Oncol. 2021;22(4):538–47.
https://doi.org/10.1016/S1470-2045(20)30753-1 DOI: https://doi.org/10.1016/S1470-2045(20)30753-1
Pötter R, Tanderup K, Kirisits C, de Leeuw A, Kirchheiner K, Nout R, et al. The EMBRACE II study: the outcome and prospect of two decades of evolution within the GEC-ESTRO GYN working group and the EMBRACE studies. Clin Transl Radiat Oncol. 2018;9:48–60.
https://doi.org/10.1016/j.ctro.2018.01.001 DOI: https://doi.org/10.1016/j.ctro.2018.01.001
Sundfor K, Lyng H, Trope CG, Rofstad EK. Treatment outcome in advanced squamous cell carcinoma of the uterine cervix: relationships to pretreatment tumor oxygenation and vascularization. Radiother Oncol. 2000;54(2):101–7.
https://doi.org/10.1016/S0167-8140(99)00175-9 DOI: https://doi.org/10.1016/S0167-8140(99)00175-9
Fjeldbo CS, Julin CH, Lando M, Forsberg MF, Aarnes EK, Alsner J, et al. Integrative analysis of DCE-MRI and gene expression profiles in construction of a gene classifier for assessment of hypoxia-related risk of chemoradiotherapy failure in cervical cancer. Clin Cancer Res. 2016;22(16):4067–76.
https://doi.org/10.1158/1078-0432.CCR-15-2322 DOI: https://doi.org/10.1158/1078-0432.CCR-15-2322
Overgaard J. Hypoxic radiosensitization: adored and ignored. J Clin Oncol. 2007;25(26):4066–74.
https://doi.org/10.1200/JCO.2007.12.7878 DOI: https://doi.org/10.1200/JCO.2007.12.7878
Pollak MN. Investigating metformin for cancer prevention and treatment: the end of the beginning. Cancer Discov. 2012;2(9):778–90.
https://doi.org/10.1158/2159-8290.CD-12-0263 DOI: https://doi.org/10.1158/2159-8290.CD-12-0263
Coyle C, Cafferty FH, Vale C, Langley RE. Metformin as an adjuvant treatment for cancer: a systematic review and meta-analysis. Ann Oncol. 2016;27(12):2184–95.
https://doi.org/10.1093/annonc/mdw410 DOI: https://doi.org/10.1093/annonc/mdw410
Koritzinsky M. Metformin: a novel biological modifier of tumor response to radiation therapy. Int J Radiat Oncol Biol Phys. 2015;93(2):454–64.
https://doi.org/10.1016/j.ijrobp.2015.06.003 DOI: https://doi.org/10.1016/j.ijrobp.2015.06.003
Chevalier B, Pasquier D, Lartigau EF, Chargari C, Schernberg A, Jannin A, et al. Metformin: (future) best friend of the radiation oncologist? Radiother Oncol. 2020;151:95–105.
https://doi.org/10.1016/j.radonc.2020.06.030 DOI: https://doi.org/10.1016/j.radonc.2020.06.030
Zannella VE, Dal Pra A, Muaddi H, McKee TD, Stapleton S, Sykes J, et al. Reprogramming metabolism with metformin improves tumor oxygenation and radiotherapy response. Clin Cancer Res. 2013;19(24):6741–50.
https://doi.org/10.1158/1078-0432.CCR-13-1787 DOI: https://doi.org/10.1158/1078-0432.CCR-13-1787
Conza D, Mirra P, Calì G, Insabato L, Fiory F, Beguinot F, et al. Metformin dysregulates the unfolded protein response and the WNT/β-catenin pathway in endometrial cancer cells through an AMPK-independent mechanism. Cells. 2021;10(5):1067.
https://doi.org/10.3390/cells10051067 DOI: https://doi.org/10.3390/cells10051067
Chen YH, Yang SF, Yang CK, Tsai HD, Chen TH, Chou MC, et al. Metformin induces apoptosis and inhibits migration by activating the AMPK/p53 axis and suppressing PI3K/AKT signaling in human cervical cancer cells. Mol Med Rep. 2021;23(1):88.
https://doi.org/10.3892/mmr.2020.11725 DOI: https://doi.org/10.3892/mmr.2020.11725
American Diabetes Association. Introduction: standards of medical care in diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S1–2.
https://doi.org/10.2337/dc22-Sint DOI: https://doi.org/10.2337/dc22-Sint
Kim JO, McDonald MO, Ong A, Koul R, Dubey A, Hunter W, et al. Gastrointestinal and genitourinary toxicity profiles of metformin versus placebo in men with prostate cancer receiving prostate radiotherapy: interim toxicity results of a double-blinded, multicenter, phase II randomized controlled trial. Radiat Oncol. 2021;16(1):212.
https://doi.org/10.1186/s13014-021-01935-x DOI: https://doi.org/10.1186/s13014-021-01935-x
Skinner H, Hu C, Tsakiridis T, Santana-Davila R, Lu B, Erasmus JJ, et al. Addition of metformin to concurrent chemoradiation in patients with locally advanced non-small cell lung cancer: the NRG-LU001 phase 2 randomized clinical trial. JAMA Oncol. 2021;7(9):1324–32.
https://doi.org/10.1001/jamaoncol.2021.2318 DOI: https://doi.org/10.1001/jamaoncol.2021.2318
Han K, Fyles A, Shek T, Croke J, Dhani N, D’Souza D, et al. A phase II randomized trial of chemoradiation with or without metformin in locally advanced cervical cancer. Clin Cancer Res. 2022;28(24):5263–71.
https://doi.org/10.1158/1078-0432.CCR-22-1665 DOI: https://doi.org/10.1158/1078-0432.CCR-22-1665
Thiruthaneeswaran N, Bibby BAS, Yang L, Hoskin PJ, Bristow RG, Choudhury A, et al. Lost in application: measuring hypoxia for radiotherapy optimisation. Eur J Cancer. 2021;148:260–76.
https://doi.org/10.1016/j.ejca.2021.01.039 DOI: https://doi.org/10.1016/j.ejca.2021.01.039
Hillestad T, Hompland T, Fjeldbo CS, Skingen VE, Salberg UB, Aarnes EK, et al. MRI distinguishes tumor hypoxia levels of different prognostic and biological significance in cervical cancer. Cancer Res. 2020;80(18):3993–4003.
https://doi.org/10.1158/0008-5472.CAN-20-0950 DOI: https://doi.org/10.1158/0008-5472.CAN-20-0950
Fjeldbo CS, Hompland T, Hillestad T, Aarnes EK, Günther CC, Kristensen GB, et al. Combining imaging- and gene-based hypoxia biomarkers in cervical cancer improves prediction of chemoradiotherapy failure independent of intratumour heterogeneity. EBioMedicine. 2020;57:102841.
https://doi.org/10.1016/j.ebiom.2020.102841 DOI: https://doi.org/10.1016/j.ebiom.2020.102841
Skipar K, Hompland T, Lund KV, Løndalen A, Malinen E, Kristensen GB, et al. Risk of recurrence after chemoradiotherapy identified by multimodal MRI and 18F-FDG-PET/CT in locally advanced cervical cancer. Radiother Oncol. 2022;176:17–24.
https://doi.org/10.1016/j.radonc.2022.09.002 DOI: https://doi.org/10.1016/j.radonc.2022.09.002
Milosevic MF, Townsley CA, Chaudary N, Clarke B, Pintilie M, Fan S, et al. Sorafenib increases tumor hypoxia in cervical cancer patients treated with radiation therapy: results of a phase 1 clinical study. Int J Radiat Oncol Biol Phys. 2016;94(1):111–17.
https://doi.org/10.1016/j.ijrobp.2015.09.009 DOI: https://doi.org/10.1016/j.ijrobp.2015.09.009
Hompland T, Hole KH, Ragnum HB, Aarnes EK, Vlatkovic L, Lie AK, et al. Combined MR imaging of oxygen consumption and supply reveals tumor hypoxia and aggressiveness in prostate cancer patients. Cancer Res. 2018;78(16):4774–85.
https://doi.org/10.1158/0008-5472.CAN-17-3806 DOI: https://doi.org/10.1158/0008-5472.CAN-17-3806
Skipar K, Hompland T, Lund KV, Lindemann K, Hellebust TP, Bruheim K, et al. MRI-guided dynamic risk assessment in cervical cancer based on tumor hypoxia at diagnosis and volume response at brachytherapy. Radiother Oncol. 2024;195:110263.
https://doi.org/10.1016/j.radonc.2024.110263 DOI: https://doi.org/10.1016/j.radonc.2024.110263
He J, Wang K, Zheng N, Qiu Y, Xie G, Su M, et al. Metformin suppressed the proliferation of LoVo cells and induced a time-dependent metabolic and transcriptional alteration. Sci Rep. 2015;5:17423.
https://doi.org/10.1038/srep17423 DOI: https://doi.org/10.1038/srep17423
Horsman MR, Mortensen LS, Petersen JB, Busk M, Overgaard J. Imaging hypoxia to improve radiotherapy outcome. Nat Rev Clin Oncol. 2012;9(12):674–87.
https://doi.org/10.1038/nrclinonc.2012.171 DOI: https://doi.org/10.1038/nrclinonc.2012.171
Prescribing, recording, and reporting brachytherapy for cancer of the cervix. J ICRU. 2013;13(1–2):NP.
https://doi.org/10.1093/jicru/ndw027 DOI: https://doi.org/10.1093/jicru/ndw027
Gaustad JV, Hauge A, Wegner CS, Simonsen TG, Lund KV, Hansem LMK, et al. DCE-MRI of tumor hypoxia and hypoxia-associated aggressiveness. Cancers (Basel). 2020;12(7):1979.
https://doi.org/10.3390/cancers12071979 DOI: https://doi.org/10.3390/cancers12071979
Bisgaard ALH, Keesman R, van Lier ALHMW, Coolens C, van Houdt PJ, Tree A, et al. Recommendations for improved reproducibility of ADC derivation on behalf of the Elekta MRI-linac consortium image analysis working group. Radiother Oncol. 2023;186:109803.
https://doi.org/10.1016/j.radonc.2023.109803 DOI: https://doi.org/10.1016/j.radonc.2023.109803
Manganaro L, Lakhman Y, Bharwani N, Gui B, Gigli S, Vinci V, et al. Staging, recurrence and follow-up of uterine cervical cancer using MRI: updated guidelines of the European Society of Urogenital Radiology after revised FIGO staging 2018. Eur Radiol. 2021;31(10):7802–16.
https://doi.org/10.1007/s00330-020-07632-9 DOI: https://doi.org/10.1007/s00330-020-07632-9
European Society of Urogenital Radiology. ESUR guidelines on contrast agents v 10.0 [Internet]. 2018. [Cited date: 26 Jan 2025] Available from: https://www.esur.org/wp-content/uploads/2022/03/ESUR-Guidelines-10_0-Final-Version.pdf
Skwarski M, McGowan DR, Belcher E, Di Chiara F, Stavroulias D, McCole M, et al. Mitochondrial inhibitor atovaquone increases tumor oxygenation and inhibits hypoxic gene expression in patients with non-small cell lung cancer. Clin Cancer Res. 2021;27(9):2459–69.
https://doi.org/10.1158/1078-0432.CCR-20-4128 DOI: https://doi.org/10.1158/1078-0432.CCR-20-4128
Welz S, Paulsen F, Pfannenberg C, Reimold M, Reischl G, Nikolaou K, et al. Dose escalation to hypoxic subvolumes in head and neck cancer: a randomized phase II study using dynamic [18F]FMISO PET/CT. Radiother Oncol. 2022;171:30–6.
https://doi.org/10.1016/j.radonc.2022.03.021 DOI: https://doi.org/10.1016/j.radonc.2022.03.021
Lyng H, Malinen E. Hypoxia in cervical cancer: from biology to imaging. Clin Transl Imaging. 2017;5(4):373–88.
https://doi.org/10.1007/s40336-017-0238-7 DOI: https://doi.org/10.1007/s40336-017-0238-7
Fleming IN, Manavaki R, Blower PJ, West C, Williams KJ, Harris AL, et al. Imaging tumour hypoxia with positron emission tomography. Br J Cancer. 2015;112(2):238–50.
https://doi.org/10.1038/bjc.2014.610 DOI: https://doi.org/10.1038/bjc.2014.610
Gottwald J, Han K, Milosevic M, Yeung I, Jaffray DA. Impact of PET scanner non-linearity on the estimation of hypoxic fraction in cervical cancer patients. Phys Med. 2022;93:1–7.
https://doi.org/10.1016/j.ejmp.2021.11.009 DOI: https://doi.org/10.1016/j.ejmp.2021.11.009
Lyng H, Skipar K, Hompland T. Targeted therapy on the screen: do we hit the target? Clin Cancer Res. 2022;28(24):5233–4.
https://doi.org/10.1158/1078-0432.CCR-22-2707 DOI: https://doi.org/10.1158/1078-0432.CCR-22-2707
Han K, Shek T, Vines D, Driscoll B, Fyles A, Jaffray D, et al. Measurement of tumor hypoxia in patients with locally advanced cervical cancer using positron emission tomography with (18)F-fluoroazomyin arabinoside. Int J Radiat Oncol Biol Phys. 2018;102(4):1202–9.
https://doi.org/10.1016/j.ijrobp.2018.02.030 DOI: https://doi.org/10.1016/j.ijrobp.2018.02.030
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Copyright (c) 2025 Kjersti Skipar, Tord Hompland, Kjersti V. Lund, Christina S. Fjeldbo, Kristina Lindemann, Taran P. Hellebust, Heidi Lyng, Kjersti Bruheim
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