PROton Versus Photon Therapy for Esophageal Cancer - a Trimodality Strategy

Study Overview
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Brief Summary
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The PROTECT trial will test the hypothesis that proton (PT) -enabled radiation dose reductions to sensitive, normal tissues will result in lower rates of treatment-related pulmonary complications in esophageal cancer compared to standard photon therapy (XT).

Detailed Description
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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)

Official Title
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PROton Versus Photon Therapy for Esophageal Cancer - a Trimodality Strategy (PROTECT) A Multicenter International Randomized Phase III Study of Neoadjuvant Proton Versus Photon Chemoradiotherapy in Locally Advanced Esophageal Cancer

Conditions
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Esophageal Cancer, Radiotherapy, Side Effect, Proton Therapy

Intervention / Treatment
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* Radiation: Photon Radiotherapy
* Radiation: Proton Radiotherapy


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: open-label, non-blinded, international multicenter, randomized phase III study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Photon Arm<br>Standard arm with neoadjuvant chemoradiotherapy (nCXT) with photons | Radiation: Photon Radiotherapy<br>* nCXT consists of weekly carboplatin and paclitaxel for 5 weeks, following the CROSS trial. The radiation dose will be either 41.4 Gy in 23 fractions or 50.4 Gy in 28 fractions<br>|
| Experimental: Proton Arm<br>Experimental arm with neoadjuvant chemoradiotherapy (nCPT) with protons | Radiation: Proton Radiotherapy<br>* nCPT consists of weekly carboplatin and paclitaxel for 5 weeks, following the CROSS trial. The radiation dose will be either 41.4 Gy in 23 fractions or 50.4 Gy in 28 fractions<br>* Other names: Proton Therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pulmonary complications | Incidence of pulmonary complications during and following nCPT or nCXT and surgery | from randomization until 90 days after surgery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Early toxicity | Predefined items ≥ grade 2 scored by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | from start of nCPT or nCXT until surgery | 
| Late toxicity | Predefined items ≥ grade 2 scored by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 | up to 5 years | 
| Postoperative complications | Predefined items scored by Clavien-Dindo and Comprehensive Complications Index (CCI) | from surgery until 90 days after surgery | 
| Major cardiovascular events (MACE) | Predefined cardiovascular events scored by MACE | up to 5 years | 
| Patient-reported outcome measures | EORTC quality of life questionnaire | up to 5 years | 
| Compliance with trimodality treatment | The proportion of patients complying with trimodality treatment in each arm | 3 months | 
| Pathological response | tumor regression grade for the primary tumor scored according to Mandard score. | immediately after surgery | 
| Cumulative incidence of loco-regional failure | Locoregional failure evaluated according to RECIST with all failures within the irradiated volume counting as events. | from date of randomization up to 5 years | 
| Pattern of failure | First site of failure will be divided in loco-regional lymph node failures, loco-regional failures in anastomosis, and distant extra-cranial and intra-cranial failures. All loco-regional failures will be divided in failures inside and outside the treatment volume, which is defined to be within the specified treatment dose. | up to 5 years | 
| Disease-free survival (DFS) | Disease control evaluated according to RECIST with any recurrence (locoregional or distant) as well as death from any cause, whatever occurs first, will be considered as events. | up to 5 years | 
| Overall survival (OS) | Death from all causes will considered as events | up to 5 years |