Esophageal and gastroesophageal junction cancers are serious diseases with limited cure rates, even when patients receive chemotherapy and surgery. New ways to improve treatment are urgently needed.

This study will test whether adding a commonly used cholesterol-lowering medication, simvastatin, to standard cancer treatment can improve outcomes. Simvastatin is widely used, safe, and inexpensive. Research suggests that it may also slow cancer growth by blocking pathways that cancer cells rely on for survival.

In this trial, patients will receive standard chemotherapy (with or without immunotherapy) before surgery. Half of the patients will also take simvastatin daily for up to two years. Researchers will compare how well tumors respond to treatment and whether patients remain cancer-free longer.

If successful, this approach could offer a simple and accessible way to improve survival for patients with these cancers without adding significant side effects or cost.

Inclusion Criteria:

1. Signed, informed consent.
2. Age, 18 years or older.
3. Histological diagnosis of adenocarcinoma or poorly differentiated carcinoma of the esophagus or EGJ.
4. The tumour must be deemed potentially resectable by the surgical team. This assessment is based on complete staging imaging studies (detailed below) - clinical staging of the tumor and ruling out metastatic disease.
5. Locally advanced disease as defined per AJCC/UICC 8th edition37: stage IIA, IIB, III, IVA (T1-4a N2-3).
6. Eligibility for standard-of-care perioperative systemic therapy with FLOT+/-D.
7. Life expectancy greater than 3 months.
8. ECOG performance status < 2.

Exclusion Criteria:

1. Prior esophageal or gastric malignancy.
2. History of allergic reactions to simvastatin or atorvastatin or similar chemical or biological compounds.
3. Ongoing cholesterol-lowering therapy (statins, fibrates, ezetimibe, PCSK9 inhibitors), in which case the patient is offered enrollment in the observational arm.
4. Hepatic dysfunction (alanine aminotransferase level more than three times the upper limit of the normal range) or renal dysfunction (creatinine level more than three times the upper limit of the normal range).
5. Predisposing factors for rhabdomyolysis: hypothyroidism, reduced renal function, muscle disease, or excessive alcohol consumption AND creatine kinase up to less than five times the upper limit (measured in the presence of predisposing factors).
6. Concurrent medication with potent CYP3A4-inhibitors, e.g. ketokonazole, erythromycin, gemfibrozil, cyclosporine, or danazol.
7. Pre-existing medical conditions precluding treatment, including any contraindication systemic chemotherapy or major surgery.
8. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule, discussed before registration in the trial.
9. Pregnant and breastfeeding women.
10. Unwillingness to undergo per-protocol investigations or treatments.