Chemoradiation With or Without Metformin in Locally Advanced Cervical Cancer: Phase II Randomized Trial

Abstract

Tumor hypoxia is associated with poor response to radiation (RT) and chemotherapy, and worse treatment outcome. We previously discovered a novel mechanism of metformin in a xenograft model: enhancing tumor RT response by inhibiting tumor cell oxygen consumption. Our population-based study showed that cumulative dose of metformin after cervical cancer diagnosis was independently associated with a decreased risk of cervical cancer-specific mortality in diabetic women. Based on the pre-clinical and retrospective data, we hypothesized that metformin would decrease tumor hypoxia and improve tumor response to RT in locally advanced cervical cancer.A window-of-opportunity, phase II randomized trial was performed in women with stage IB-IVA cervical adenocarcinoma, squamous cell or adenosquamous carcinoma. Patients underwent screening positron emission tomography (PET) imaging with hypoxia tracer fluoroazomycin arabinoside (FAZA). Those with non-hypoxic tumor (no FAZA uptake) were excluded. Patients with FAZA uptake were randomized centrally in a 2:1 ratio (in favor of metformin) to receive either metformin in combination with standard chemoRT or standard chemoRT alone. Metformin was started at 850mg once daily x 3 days, followed by 850mg twice daily throughout the entire duration of external radiotherapy. A second FAZA-PET/CT scan was performed after 1 week of metformin or no intervention in control group, just before start of chemoRT. The hypoxic volume was defined as all voxels within a tumor with standardized uptake values (SUVs) greater than 3 standard deviations (SD) from the mean gluteus maximus muscle SUV value. The hypoxic fraction (HF) was defined as the ratio of the number of hypoxic voxels to the total number of tumor voxels. The primary endpoint was absolute mean change in HF between the two FAZA-PET scans, compared using the Wilcoxon sign rank test. Disease-free survival (DFS) was defined as the duration of time from randomization to the time of relapse or death and compared using the log-rank test. Target accrual was 48 patients; the study was closed early to accrual due to FAZA availability and the COVID-19 pandemic.Of the twenty patients who consented, 6 were excluded due to no FAZA uptake and 1 withdrew. The median age of the 13 enrolled patients was 52; 8 (62%) had squamous cell carcinoma and 8 had stage IIB disease. HF of the 10 patients in the metformin arm decreased by an average of 10.2% (from 44.4% to 34.2%) ± SD 16.9% after 1 week of metformin, compared to an average increase of 4.7% (from 29.1% to 33.8%) ± 11.5% for the 3 patients in the control arm (P = 0.027). With a median follow-up of 2.8 years, the 2-year DFS was 67% for the metformin arm vs 33% for control (P = 0.09).Metformin decreases cervical tumor hypoxia with a trend towards improved DFS in this trial. A larger confirmatory trial is warranted.