PROton Versus Photon Therapy for Esophageal Cancer - a Trimodality Strategy

Phase 3

Recruiting

• Conditions: Side Effect; Proton Therapy; Esophageal Cancer; Radiotherapy
• Interventions: Radiation: Proton Radiotherapy; Radiation: Photon Radiotherapy

• Registration Number: NCT05055648
• Lead Sponsor: University of Aarhus

Brief Summary

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

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)

Study Timeline

• Study First Submitted: 2021-08-26
• Study First Submitted QC: 2021-09-14
• Study First Posted: 2021-09-24
• Study Start: 2022-05-01
• Status Verified: 2024-12
• Last Update Submitted: 2024-12-12
• Last Update Posted: 2024-12-17
• Primary Completion: 2027-12-01
• Study Completion: 2032-12-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 396

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Proton Arm	Proton Radiotherapy	Experimental arm with neoadjuvant chemoradiotherapy (nCPT) with protons
Photon Arm	Photon Radiotherapy	Standard arm with neoadjuvant chemoradiotherapy (nCXT) with photons

Primary Outcome Measures

Name	Time	Method
Pulmonary complications	from randomization until 90 days after surgery	Incidence of pulmonary complications during and following nCPT or nCXT and surgery

Secondary Outcome Measures

Name	Time	Method
Late toxicity	up to 5 years	Predefined items ≥ grade 2 scored by Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Patient-reported outcome measures	up to 5 years	EORTC quality of life questionnaire
Disease-free survival (DFS)	up to 5 years	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.
Overall survival (OS)	up to 5 years	Death from all causes will considered as events
Compliance with trimodality treatment	3 months	The proportion of patients complying with trimodality treatment in each arm
Early toxicity	from start of nCPT or nCXT until surgery	Predefined items ≥ grade 2 scored by Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Pathological response	immediately after surgery	tumor regression grade for the primary tumor scored according to Mandard score.
Pattern of failure	up to 5 years	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.
Postoperative complications	from surgery until 90 days after surgery	Predefined items scored by Clavien-Dindo and Comprehensive Complications Index (CCI)
Major cardiovascular events (MACE)	up to 5 years	Predefined cardiovascular events scored by MACE
Cumulative incidence of loco-regional failure	from date of randomization up to 5 years	Locoregional failure evaluated according to RECIST with all failures within the irradiated volume counting as events.

Trial Locations

Locations (15)

San Raffaele Hospital; 🇮🇹 Milan, Italy

University Hospital Zurich (USZ); 🇨🇭 Zürich, Switzerland

Catholic University of Leuven; 🇧🇪 Leuven, Belgium

Aarhus University Hospital (AUH); 🇩🇰 Aarhus, Denmark

Centre Léon Bérard (CLB); 🇫🇷 Lyon, France

Centre Antoine Lacassagne (CAL); 🇫🇷 Nice, France

Institut Curie; 🇫🇷 Paris, France

Technische Universität Dresden (TUD); 🇩🇪 Dresden, Germany

Centro Nazionale di Adroterapia Oncologica (CNAO); 🇮🇹 Pavia, Italy

Azienda Provinciale Per I Servizi Sanitari (APSS); 🇮🇹 Trento, Italy

Academisch Ziekenhuis Groningen (UMCG); 🇳🇱 Groningen, Netherlands

Stichting Maastricht Radiation Oncology (MAASTRO); 🇳🇱 Maastricht, Netherlands

Paul Scherrer Institute (PSI); 🇨🇭 Villigen, Switzerland

University College London Hospital (UCLH); 🇬🇧 London, United Kingdom

The Christie NHS foundation trust; 🇬🇧 Manchester, United Kingdom