Altered Tumor Oxygenation by Metformin, a Potential Step in Overcoming Radiotherapy Resistance in LACC

Inclusion criteria

• Histologically confirmed cervical cancer (squamous cell carcinoma, adenocarcinoma and adenosquamous carcinoma)

• Planned for radical chemoradiotherapy
• Over 18 years
• Speaks and understands Norwegian
• ECOG 0-1
• Cervical tumor available for biopsy by gynecological examination
• Hemoglobin ≥ 9 g/dL (blood transfusions are allowed)
• Leukocytes ≥ 3,5 x 10^9/L 18
• Absolute neutrophil count ≥ 1,5 x 10^9/L
• Platelets ≥ 100 x 10^9/L
• Total bilirubin ≤ 25 umol/L
• AST/ALT ≤ 2,5 x institutional upper limit
• Creatinine ≤ 90 or creatinine clearance ≥ 60 ml/min/1.73m2 Patients with elevated creatinine secondary to hydronephrosis may be eligible if renal function returns to normal after inserting an internal stent or nephrostomy
• Women of childbearing potential (WOCBP) should have a negative highly sensitive serum pregnancy test within 72 hours prior to receiving the first dose of study medication.

Exclusion criteria

• Evidence of distant metastasis. Suspicious paraaortic lymph nodes below the renal vessel are allowed if they are covered by the radiation field
• Patients who have received other cancer treatments for their cervical cancer
• Patients who receive other experimental drugs
• Known diabetes mellitus
• Currently taking Metformin or any other antidiabetic drugs (sulfonylureas, thiazolidinediones, insulin)
• History of allergic reaction attributed to compounds of similar chemical or biologic composition to metformin
• Contraindications such as

• Hypersensitivity to the active substance or to any of the excipients listed Section 6.1.
• Severe renal failure (GFR <30 ml / min).
• Acute conditions leading to the risk of renal impairment, eg: dehydration, severe infectious conditions, shock.
• Disease that can cause tissue hypoxia (especially acute illness or exacerbation of chronic illness), such as: acute decompensated heart failure, lung failure, recent heart attack, shock.
• Liver failure, acute alcohol intoxication, alcoholism.
• Any condition associated with increased risk of metformin- induced lactic acidosis (congestive heart failure defined as New York Heart Association (NYHA) class III or IV functional status, history of acidosis of any kind)
• Uncontrolled intercurrent somatic illness including, but not limited to, ongoing or active serious infections, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, myocardial infarction within 6 months and cerebrovascular disease with previous stroke
• Already on medication with increased risk of lactic acidosis
• Patients who are pregnant or breastfeeding are excluded due to risk of teratogenic and abortifacient effects of radiotherapy and cisplatin, and the potential risk of adverse effect of nursing infants