Han Kathy, Fyles Anthony, Shek Tina, Croke Jennifer, Dhani Neesha, D'Souza David, Lee Ting-Yim, Chaudary Naz, Bruce Jeffrey, Pintilie Melania, Cairns Rob, Vines Douglass, Pakbaz Sara, Jaffray David, Metser Ur, Rouzbahman Marjan, Milosevic Michael, Koritzinsky Marianne
Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
Clin Cancer Res. 2022 Dec 15;28(24):5263-5271. doi: 10.1158/1078-0432.CCR-22-1665.
Tumor hypoxia is associated with poor response to radiation (RT). We previously discovered a novel mechanism of metformin: enhancing tumor RT response by decreasing tumor hypoxia. We hypothesized that metformin would decrease tumor hypoxia and improve cervical cancer response to RT.
A window-of-opportunity, phase II randomized trial was performed in stage IB-IVA cervical cancer. Patients underwent screening positron emission tomography (PET) imaging with hypoxia tracer fluoroazomycin arabinoside (FAZA). Only patients with FAZA uptake (hypoxic tumor) were included and randomized 2:1 to receive metformin in combination with chemoRT or chemoRT alone. A second FAZA-PET/CT scan was performed after 1 week of metformin or no intervention (control). The primary endpoint was a change in fractional hypoxic volume (FHV) between FAZA-PET scans, compared using the Wilcoxon signed-rank test. The study was closed early due to FAZA availability and the COVID-19 pandemic.
Of the 20 consented patients, 6 were excluded due to no FAZA uptake and 1 withdrew. FHV of 10 patients in the metformin arm decreased by an average of 10.2% (44.4%-34.2%) ± SD 16.9% after 1 week of metformin, compared with an average increase of 4.7% (29.1%-33.8%) ± 11.5% for the 3 controls (P = 0.027). Those with FHV reduction after metformin had significantly lower MATE2 expression. With a median follow-up of 2.8 years, the 2-year disease-free survival was 67% for the metformin arm versus 33% for controls (P = 0.09).
Metformin decreased cervical tumor hypoxia in this trial that selected for patients with hypoxic tumor. See related commentary by Lyng et al., p. 5233.
肿瘤缺氧与放疗（RT）反应不佳相关。我们之前发现了二甲双胍的一种新机制：通过降低肿瘤缺氧来增强肿瘤放疗反应。我们假设二甲双胍会降低肿瘤缺氧并改善宫颈癌对放疗的反应。
对IB-IVA期宫颈癌患者进行了一项机会性II期随机试验。患者接受了使用缺氧示踪剂氟阿糖胞苷（FAZA）的正电子发射断层扫描（PET）成像筛查。仅纳入有FAZA摄取（缺氧肿瘤）的患者，并按2:1随机分组，分别接受二甲双胍联合放化疗或单纯放化疗。在给予二甲双胍或不进行干预（对照）1周后，进行第二次FAZA-PET/CT扫描。主要终点是通过Wilcoxon符号秩检验比较FAZA-PET扫描之间缺氧体积分数（FHV）的变化。由于FAZA的可用性和新冠疫情，该研究提前结束。
在20名同意参与的患者中，6名因无FAZA摄取被排除，1名退出。二甲双胍组10名患者在服用二甲双胍1周后，FHV平均下降了10.2%（44.4%-34.2%）±标准差16.9%，而3名对照组患者的FHV平均增加了4.7%（29.1%-33.8%）±11.5%（P = 0.027）。服用二甲双胍后FHV降低的患者MATE2表达显著较低。中位随访2.8年，二甲双胍组的2年无病生存率为67%，而对照组为33%（P = 0.09）。
在这项针对缺氧肿瘤患者的试验中，二甲双胍降低了宫颈肿瘤缺氧。见Lyng等人的相关评论，第5233页。
