PROton Versus Photon Therapy for Esophageal Cancer - a Trimodality Strategy

PROTECT is a unblinded international multicenter randomized phase III study for patients with operable EC or EGC receiving nCXT (standard of care) or nCPT (intervention). The study will be open-label for the patient and the treating physician.

The radiation dose is either 41.4 Gy in 23 fractions, five fractions per week or 50.4 Gy in 28 fractions, five fractions per week. Prior to trial opening, each proton center will determine a single dose regimen for all patients treated in that specific proton center and its assigned photon centers.

The protocol prescribes that all referring centers will use the same chemotherapy regimen, which is weekly carboplatin (AUC 2), and paclitaxel (50 mg/m2), five cycles, irrespective of choice of dose regimen. Chemotherapy is a non-investigational drug.

Prior to referral to any proton therapy center, patients will be randomed (1:1) to either nCXT or nCPT. Only patients randomized to the PT arm will be referred to a PT center. Randomization will be performed centrally using an online 24-hour web-based system maintained by the Clinical Trial Office at Aarhus University Hospital, ensuring allocation concealment to the clinical investigators. The method of randomization will be stratified permuted blocks of size 4 and 6 (selected randomly) with the following strata:

• Histopathology (non-squamous vs squamous cell carcinoma)
• Planned surgical technique (open versus minimal invasive/robotic or hybrid)
• Proton center and sites assigned to this center (which will deliver the nCXT)

Inclusion criteria

• Patients with histologically verified squamous cell carcinoma or adenocarcinoma (including signet cell carcinoma and large cell carcinoma, not further specified) of the 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, absolute neutrophil 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 x ULN, GFR (may be calculated) > 30 ml/min
• MDT decision on suitability to undergo curatively intended nCXT or nCPT followed by surgery.
• Planned transthoracic esophagectomy or gastrectomy being open, minimally invasive 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. low risk prostate cancer) are allowed in the study. Adequately treated diagnoses such as cervix uteri carcinoma in situ, in situ urothelial carcinoma or localized non-melanoma skin cancer are allowed, regardless of time of diagnosis.
• Patients of childbearing potential: pregnancy prevention according to the standards of each country. Patients of childbearing potential must present a negative pregnancy test. Patients and their partners must use effective contraception. Patients of childbearing potential included in the study must use oral contraceptives, intrauterine devices, depot injection of progestin subdermal implantation, a hormonal vaginal ring, or transdermal patch during the 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 the esophageal/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 remission or complete resection was achieved at least 5 years prior to study entry.
• Any unstable systemic disease (including clinically significant lung and cardiovascular disease, unstable angina, New York Heart Association (NYHA) grade III-IV congestive heart, severe hepatic, renal or metabolic disease or active inflammatory bowel disease).
• Symptomatic peripheral neuropathy greater than grade 1 (scored according to CTCAE v5.0).
• Any other serious or uncontrolled illness, which, in the opinion of the investigator, makes it undesirable for the patient to enter the trial.
• Unable to understand and digest study patient information or comply with study treatment and safety instructions.
• Gastro-esophageal stent within the irradiated volume.