Clinical trial NCT05055648: PROton Versus Photon Therapy for Esophageal Cancer - a Trimodality Strategy
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Esophageal Cancer
Radiotherapy
Side Effect
Proton Therapy
Lead sponsor: University of Aarhus
Sponsor class: OTHER
Collaborators: name: University of Leeds
name: KU Leuven
name: University College, London
name: Aarhus University Hospital
name: Technische Universität Dresden
name: Academisch Ziekenhuis Groningen
name: CNAO National Center of Oncological Hadrontherapy
name: Agenzia Nazionale per i Servizi Sanitari Regionali
name: Centre Antoine Lacassagne
name: Centre Leon Berard
name: Institut Curie
name: Maastro Clinic, The Netherlands
name: University College London Hospitals
name: The Christie NHS Foundation Trust
name: Paul Scherrer Institut, Center for Proton Therapy
name: HollandPTC
name: IBA worldwide
name: Varian- A Siemens Healthineer Company
First posted: 2021-09-24
Enrollment: 396
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: open-label, non-blinded, international multicenter, randomized phase III study
Primary purpose: TREATMENT

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)

Eligibility criteria: 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.

Primary outcomes:
measure: Pulmonary complications
timeFrame: from randomization until 90 days after surgery
Secondary outcomes:
measure: Early toxicity
timeFrame: from start of nCPT or nCXT until surgery
measure: Late toxicity
timeFrame: up to 5 years
measure: Postoperative complications
timeFrame: from surgery until 90 days after surgery
measure: Major cardiovascular events (MACE)
timeFrame: up to 5 years
measure: Patient-reported outcome measures
timeFrame: up to 5 years
measure: Compliance with trimodality treatment
timeFrame: 3 months
measure: Pathological response
timeFrame: immediately after surgery
measure: Cumulative incidence of loco-regional failure
timeFrame: from date of randomization up to 5 years
measure: Pattern of failure
timeFrame: up to 5 years
measure: Disease-free survival (DFS)
timeFrame: up to 5 years
measure: Overall survival (OS)
timeFrame: up to 5 years
Other outcomes:
measure: Total toxicity burden (TTB)
timeFrame: from randomization until 90 days after surgery
measure: Concordance of observed pulmonary complications with predicted complications from NTCP models
timeFrame: up to 5 years
measure: Blood biomarkers as predictors for treatment failure
timeFrame: up to 5 years
measure: Proportion of patients receiving adjuvant immunotherapy
timeFrame: up to 5 years
measure: Cost-effectiveness of proton therapy relative to photon therapy
timeFrame: up to 5 years
measure: FDG/PET CT as predictors for treatment failure
timeFrame: 12 months
measure: Concordance of observed cardiac complications with predicted
timeFrame: Up to 5 years
Locations:
city: Leuven
country: Belgium
facility: Catholic University of Leuven
city: Aarhus
country: Denmark
facility: Aarhus University Hospital (AUH)
city: Lyon
country: France
facility: Centre Léon Bérard (CLB)
city: Nice
country: France
facility: Centre Antoine Lacassagne (CAL)
city: Paris
country: France
facility: Institut Curie
city: Dresden
country: Germany
facility: Technische Universität Dresden (TUD)
city: Milan
country: Italy
facility: San Raffaele Hospital
city: Pavia
country: Italy
facility: Centro Nazionale di Adroterapia Oncologica (CNAO)
city: Trento
country: Italy
facility: Azienda Provinciale Per I Servizi Sanitari (APSS)
city: Groningen
country: Netherlands
facility: Academisch Ziekenhuis Groningen (UMCG)
city: Maastricht
country: Netherlands
facility: Stichting Maastricht Radiation Oncology (MAASTRO)
city: Villigen
country: Switzerland
facility: Paul Scherrer Institute (PSI)
city: Zürich
country: Switzerland
facility: University Hospital Zurich (USZ)
city: London
country: United Kingdom
facility: University College London Hospital (UCLH)
city: Manchester
country: United Kingdom
facility: The Christie NHS foundation trust
Study officials:
affiliation: University of Aarhus
name: Marianne Nordsmark, Dr.
role: STUDY_DIRECTOR
affiliation: UKleuven
name: Karin Haustermans, Dr.
role: STUDY_CHAIR
References: