A Phase II Randomized Trial of Chemoradiation with or without Metformin in Locally Advanced Cervical Cancer

Mené sur 20 patientes atteintes d'un cancer du col de l'utérus localement avancé, cet essai de phase II évalue l'efficacité, du point de vue de la réduction de l'hypoxie tumorale, de l'ajout de metformine à une chimioradiothérapie

Résumé en anglais

Purpose: 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.

Experimental Design: 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 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.

Results: 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% to 34.2%) ± SD 16.9% after 1 week of metformin, compared to an average increase of 4.7% (29.1% to 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 (DFS) was 67% for the metformin arm vs 33% for controls (p=0.09).

Conclusions: Metformin decreased cervical tumor hypoxia in this trial that selected for patients with hypoxic tumor.