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