Esophageal Cancer, Radiotherapy, Side Effect, Proton Therapy
Conditions
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)
Interventions
RADIATIONPhoton Radiotherapy
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
RADIATIONProton Radiotherapy
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
Sponsors
University of Leeds
KU Leuven
University College, London
Aarhus University Hospital
Technische Universität Dresden
Academisch Ziekenhuis Groningen
CNAO National Center of Oncological Hadrontherapy
Agenzia Nazionale per i Servizi Sanitari Regionali
Centre Antoine Lacassagne
Centre Leon Berard
Institut Curie
Maastro Clinic, The Netherlands
University College London Hospitals
The Christie NHS Foundation Trust
Paul Scherrer Institut, Center for Proton Therapy
HollandPTC
IBA worldwide
Varian- A Siemens Healthineer Company
University of Aarhus
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
open-label, non-blinded, international multicenter, randomized phase III study
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pulmonary complications | from randomization until 90 days after surgery | Incidence of pulmonary complications during and following nCPT or nCXT and surgery |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Postoperative complications | from surgery until 90 days after surgery | Predefined items scored by Clavien-Dindo and Comprehensive Complications Index (CCI) |
| Patient-reported outcome measures | up to 5 years | EORTC quality of life questionnaire |
| Compliance with trimodality treatment | 3 months | The proportion of patients complying with trimodality treatment in each arm |
| Pathological response | immediately after surgery | tumor regression grade for the primary tumor scored according to Mandard score. |
| 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. |
| 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. |
| 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 |
| 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 |
| Late toxicity | up to 5 years | Predefined items ≥ grade 2 scored by Common Terminology Criteria for Adverse Events (CTCAE) v5.0 |
| Major cardiovascular events (MACE) | up to 5 years | Predefined cardiovascular events scored by MACE |
Other
| Measure | Time frame | Description |
|---|---|---|
| Blood biomarkers as predictors for treatment failure | up to 5 years | circulating tumor DNA |
| Proportion of patients receiving adjuvant immunotherapy | up to 5 years | The actual number of patients starting adjuvant immunotherapy will be recorded |
| Cost-effectiveness of proton therapy relative to photon therapy | up to 5 years | Incremental cost effectiveness ratios (ICERs), cost per QALY gained, cost per complication avoided, and cost per total toxicity burden avoided will be reported. |
| FDG/PET CT as predictors for treatment failure | 12 months | Correlation between diagnostic PET, planning PET-CT and PET at 12 months |
| Concordance of observed cardiac complications with predicted | Up to 5 years | Comparison of observed and predicted toxicity rates |
| Total toxicity burden (TTB) | from randomization until 90 days after surgery | The combined toxicity scale TTB used in the trial by Lin et al (Lin 2020) |
| Concordance of observed pulmonary complications with predicted complications from NTCP models | up to 5 years | Comparison of observed and predicted toxicity rates |
Countries
Belgium, Denmark, France, Germany, Italy, Netherlands, Switzerland, United Kingdom
Contacts
Primary ContactDorte Winter
Backup ContactToke Hansen, PhD
Outcome results
None listed