Metformin as a Metabolic Intervention in Oesophageal Adenocarcinomas to Improve Response to Neoadjuvant Chemoradiotherapy

Inclusion Criteria:

* Surgical resectable (\<T4b, N0 or N+, M0), and histologically proven adenocarcinoma of the oesophagus or gastro-oesophageal junction planning to undergo neoadjuvant chemoradiotherapy.
* Adult patients (age ≥ 18 years).
* ECOG performance status 0 or 1 (cf. Appendix A).
* Adequate hematological, renal and hepatic functions defined as:

  * Absolute Neutrophil Count ≥ 1.5 x 10\^9/L
  * Platelets ≥ 100 x 10\^9/L
  * Hemoglobin ≥ 5.6 mmol
  * Total bilirubin ≤ 1.5 x upper normal limit
  * Creatinine clearance (Cockroft) \> 30 ml/min
* Patients must be willing to undergo two endoscopies for investigational purposes.
* Written, voluntary informed consent.
* Patients must be accessible to follow up and management in the treatment center.

Exclusion Criteria:

* Patients diagnosed with diabetes mellitus type 1 or 2 receiving anti-diabetic drugs.
* Patients prescribed metformin or another anti-diabetic drug for any reason.
* Patients allergic or intolerant to metformin.
* Excessive alcohol consumption.
* Use of OCT1/OCT2 inhibitors (e.g. verapamil, cimetidine, dolutegravir, isavuonazol, trimethoprim, vandetanib, crizotinib and Olaparib).
* Use of OCT1/OCT2 inducers (e.g. rifampicine).
* Use of immunosuppressive medication (corticosteroids, cyclosporine, tacrolimus, sirolimus, everolimus, cyclophosphamide).
* Previous systemic therapy or radiotherapy on the oesophagus.
* Severe renal impairment (CLcr ≤ 30 ml/min).
* Past (within 5 years) or current history of malignancy other than entry diagnosis interfering with prognosis of oesophageal cancer.
* Previous systemic therapy for other forms of cancer within the last six months.
* Patients with prior allogeneic stem cell or solid organ transplantation
* Pregnancy (positive serum pregnancy test), planning to become pregnant, and lactation.
* Clinically significant cardiovascular disease (including myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia) precluding major surgery.
* Pulmonary fibrosis, active, non-infectious pneumonitis and/or severely impaired lung function precluding major surgery and/or radiation.
* Serious underlying medical condition which would impair the ability of the patient to receive the planned treatment, including prior allergic reactions to drugs containing Cremophor, such as teniposide or cyclosporine.
* Dementia or altered mental status that would prohibit the understanding and giving of informed consent.