PROton Versus Photon Therapy for Esophageal Cancer - a Trimodality Strategy

Inclusion Criteria:

• Patients with histologically verified squamous cell carcinoma or adenocarcinoma (including signet cell carcinoma and large cell carcinoma, not further specified) ofthe esophagus (E) or gastro-esophageal junction (GEJ).

• FDG PET/CT performed.

• Tumor stage according to TNM (8th edition): cT1-4a and/or cN+, cM0.

• Age ≥18 years.

• Performance status WHO ≤2.

• Adequate laboratory findings: hematological: hemoglobin > 90 g/L, absoluteneutrophil count (ANC) ≥ 1,5 x 109/L, platelets ≥ 75 x 109/L hepatic: bilirubin ≤ 1.5 x upper limit of normal (ULN), ALAT ≤ 3 x ULN renal: creatinine ≤ 1.5 xULN, GFR (may be calculated) > 30 ml/min

• MDT decision on suitability to undergo curatively intended nCXT or nCPTfollowed by surgery.

• Planned transthoracic esophagectomy or gastrectomy being open, minimallyinvasive of combination of both.

• Ability to adhere to procedures for study and follow-up.

• Patients with low risk cancers with a life expectancy above 5 years (e.g. lowrisk prostate cancer) are allowed in the study. Adequately treated diagnosessuch as cervix uteri carcinoma in situ, in situ urothelial carcinoma orlocalized non-melanoma skin cancer are allowed, regardless of time ofdiagnosis.

• Patients of childbearing potential: pregnancy prevention according to thestandards of each country. Patients of childbearing potential must present anegative pregnancy test. Patients and their partners must use effectivecontraception. Patients of childbearing potential included in the study mustuse oral contraceptives, intrauterine devices, depot injection of progestinsubdermal implantation, a hormonal vaginal ring, or transdermal patch duringthe study treatment and one month after.

Exclusion Criteria:

Patients who meet one or more of the following exclusion criteria cannot be included in the study:

• Prior thoracic XT or PT, chemotherapy or surgical resection in theesophageal/gastric region (previous EMR or ESD is allowed).

• Tumor < 3 cm from oropharyngeal sphincter.

• Planned transhiatal resection

• Patients with other previous malignancies are excluded unless a complete remissionor complete resection was achieved at least 5 years prior to study entry.

• Any unstable systemic disease (including clinically significant lung andcardiovascular disease, unstable angina, New York Heart Association (NYHA) gradeIII-IV congestive heart, severe hepatic, renal or metabolic disease or activeinflammatory bowel disease).

• Symptomatic peripheral neuropathy greater than grade 1 (scored according to CTCAEv5.0).

• Any other serious or uncontrolled illness, which, in the opinion of theinvestigator, makes it undesirable for the patient to enter the trial.

• Unable to understand and digest study patient information or comply with studytreatment and safety instructions.

• Gastro-esophageal stent within the irradiated volume.