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

Prior treatment

• Patients diagnosed with diabetes mellitus type 1 or 2 receiving anti-diabetic drugs.
• Patients prescribed metformin or another anti-diabetic drug for any reason.
• Use of OCT1/OCT2 inhibitors (e.g. verapamil, cimetidine, dolutegravir, isavuonazol, trimethoprim, vandetanib, crizotinib and Olaparib).
• Use of immunosuppressive medication (corticosteroids, cyclosporine, tacrolimus, sirolimus, everolimus, cyclophosphamide).
• Previous systemic therapy or radiotherapy on the oesophagus.
• Previous systemic therapy for other forms of cancer within the last six months.
• Patients with prior allogeneic stem cell or solid organ transplantation
• 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.

Other illness

• Patients allergic or intolerant to metformin.
• 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.
• 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.
• Dementia or altered mental status that would prohibit the understanding and giving of informed consent.

Lab values

• Pregnancy (positive serum pregnancy test), planning to become pregnant, and lactation.

Other

• Excessive alcohol consumption.
• Use of OCT1/OCT2 inducers (e.g. rifampicine).

• 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.