Skipar Kjersti, Hompland Tord, Lund Kjersti V, Fjeldbo Christina S, Lindemann Kristina, Hellebust Taran P, Lyng Heidi, Bruheim Kjersti
Department of Oncology, Telemark Hospital Trust, Skien, Norway; Department of Radiation Biology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Department of Radiation Biology, Oslo University Hospital, Oslo, Norway.
Acta Oncol. 2025 Mar 19;64:439-447. doi: 10.2340/1651-226X.2025.43045.
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 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.
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.
Addition of metformin to chemoradiotherapy is tolerable and safe. Serial sampling of MRI and tumor biopsies for hypoxia biomarker assessment is feasible.
局部晚期宫颈癌采用放化疗进行治疗。治疗相关的发病率较高。肿瘤缺氧具有预后影响，是一个有效的干预靶点。这项II期研究根据既定的生物标志物，调查了抗糖尿病药物二甲双胍改善缺氧的疗效。本文报告了包括耐受性、安全性和可行性在内的初步结果。
患者按1:1随机、开放标签设计分组，比较标准放化疗±二甲双胍。在放化疗前1周及放化疗期间，每日两次服用850mg二甲双胍。在基线、二甲双胍治疗1周后及近距离放疗时采集磁共振成像（MRI）和肿瘤活检样本，用于生物标志物评估。通过治疗完成率和不良事件（AE）发生率确定耐受性和安全性。通过二甲双胍治疗第一周基于MRI的缺氧情况可能增加，进一步评估安全性。通过完成研究干预措施以及成像和活检程序的比例确定可行性。
分别有18例和23例患者被分配至干预组和对照组。18例和15例患者分别完成了1周和5周的二甲双胍治疗。研究组之间≥3级AE的发生率无显著差异。大多数AE为胃肠道毒性。第一周缺氧增加的肿瘤均低于规定的安全限度。共采集了98%计划的MR系列和活检样本，质量令人满意。
放化疗联合二甲双胍是可耐受且安全的。对MRI和肿瘤活检进行系列采样以评估缺氧生物标志物是可行的。
