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PROton Versus Photon Therapy for Esophageal Cancer - a Trimodality Strategy (PROTECT)

Primary Purpose

Esophageal Cancer, Radiotherapy, Side Effect

Status
Recruiting
Phase
Not Applicable
Locations
International
Study Type
Interventional
Intervention
Photon Radiotherapy
Proton Radiotherapy
Sponsored by
University of Aarhus
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Esophageal Cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Catholic University of Leuven
  • Aarhus University Hospital (AUH)Recruiting
  • Centre Léon Bérard (CLB)
  • Centre Antoine Lacassagne (CAL)
  • Institut Curie
  • Technische Universität Dresden (TUD)
  • Centro Nazionale di Adroterapia Oncologica (CNAO)
  • Azienda Provinciale Per I Servizi Sanitari (APSS)
  • Academisch Ziekenhuis Groningen (UMCG)
  • Stichting Maastricht Radiation Oncology (MAASTRO)
  • Paul Scherrer Institute (PSI)
  • University College London Hospital (UCLH)
  • The Christie NHS foundation trust

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Photon Arm

Proton Arm

Arm Description

Standard arm with neoadjuvant chemoradiotherapy (nCXT) with photons

Experimental arm with neoadjuvant chemoradiotherapy (nCPT) with protons

Outcomes

Primary Outcome Measures

Pulmonary complications
Incidence of pulmonary complications during and following nCPT or nCXT and surgery

Secondary Outcome Measures

Early toxicity
Predefined items ≥ grade 2 scored by Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Late toxicity
Predefined items ≥ grade 2 scored by Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Postoperative complications
Predefined items scored by Clavien-Dindo and Comprehensive Complications Index (CCI)
Major cardiovascular events (MACE)
Predefined cardiovascular events scored by MACE
Patient-reported outcome measures
EORTC quality of life questionnaire
Compliance with trimodality treatment
The proportion of patients complying with trimodality treatment in each arm
Pathological response
tumor regression grade for the primary tumor scored according to Mandard score.
Cumulative incidence of loco-regional failure
Locoregional failure evaluated according to RECIST with all failures within the irradiated volume counting as events.
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.
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.
Overall survival (OS)
Death from all causes will considered as events

Full Information

First Posted
August 26, 2021
Last Updated
November 1, 2022
Sponsor
University of Aarhus
Collaborators
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
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1. Study Identification

Unique Protocol Identification Number
NCT05055648
Brief Title
PROton Versus Photon Therapy for Esophageal Cancer - a Trimodality Strategy
Acronym
PROTECT
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

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Recruiting
Study Start Date
May 1, 2022 (Actual)
Primary Completion Date
May 1, 2025 (Anticipated)
Study Completion Date
May 1, 2030 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Aarhus
Collaborators
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

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

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)

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Esophageal Cancer, Radiotherapy, Side Effect, Proton Therapy

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Model Description
open-label, non-blinded, international multicenter, randomized phase III study
Masking
None (Open Label)
Allocation
Randomized
Enrollment
396 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Photon Arm
Arm Type
Active Comparator
Arm Description
Standard arm with neoadjuvant chemoradiotherapy (nCXT) with photons
Arm Title
Proton Arm
Arm Type
Experimental
Arm Description
Experimental arm with neoadjuvant chemoradiotherapy (nCPT) with protons
Intervention Type
Radiation
Intervention Name(s)
Photon Radiotherapy
Intervention Description
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
Intervention Type
Radiation
Intervention Name(s)
Proton Radiotherapy
Other Intervention Name(s)
Proton Therapy
Intervention Description
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
Primary Outcome Measure Information:
Title
Pulmonary complications
Description
Incidence of pulmonary complications during and following nCPT or nCXT and surgery
Time Frame
from randomization until 90 days after surgery
Secondary Outcome Measure Information:
Title
Early toxicity
Description
Predefined items ≥ grade 2 scored by Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Time Frame
from start of nCPT or nCXT until surgery
Title
Late toxicity
Description
Predefined items ≥ grade 2 scored by Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Time Frame
up to 5 years
Title
Postoperative complications
Description
Predefined items scored by Clavien-Dindo and Comprehensive Complications Index (CCI)
Time Frame
from surgery until 90 days after surgery
Title
Major cardiovascular events (MACE)
Description
Predefined cardiovascular events scored by MACE
Time Frame
up to 5 years
Title
Patient-reported outcome measures
Description
EORTC quality of life questionnaire
Time Frame
up to 5 years
Title
Compliance with trimodality treatment
Description
The proportion of patients complying with trimodality treatment in each arm
Time Frame
3 months
Title
Pathological response
Description
tumor regression grade for the primary tumor scored according to Mandard score.
Time Frame
immediately after surgery
Title
Cumulative incidence of loco-regional failure
Description
Locoregional failure evaluated according to RECIST with all failures within the irradiated volume counting as events.
Time Frame
from date of randomization up to 5 years
Title
Pattern of failure
Description
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.
Time Frame
up to 5 years
Title
Disease-free survival (DFS)
Description
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.
Time Frame
up to 5 years
Title
Overall survival (OS)
Description
Death from all causes will considered as events
Time Frame
up to 5 years
Other Pre-specified Outcome Measures:
Title
Total toxicity burden (TTB)
Description
The combined toxicity scale TTB used in the trial by Lin et al (Lin 2020)
Time Frame
from randomization until 90 days after surgery
Title
Concordance of observed pulmonary complications with predicted complications from NTCP models
Description
Comparison of observed and predicted toxicity rates
Time Frame
up to 5 years
Title
Blood biomarkers as predictors for treatment failure
Description
circulating tumor DNA
Time Frame
up to 5 years
Title
Proportion of patients receiving adjuvant immunotherapy
Description
The actual number of patients starting adjuvant immunotherapy will be recorded
Time Frame
up to 5 years
Title
Cost-effectiveness of proton therapy relative to photon therapy
Description
Incremental cost effectiveness ratios (ICERs), cost per QALY gained, cost per complication avoided, and cost per total toxicity burden avoided will be reported.
Time Frame
up to 5 years
Title
FDG/PET CT as predictors for treatment failure
Description
Correlation between diagnostic PET, planning PET-CT and PET at 12 months
Time Frame
12 months
Title
Concordance of observed cardiac complications with predicted
Description
Comparison of observed and predicted toxicity rates
Time Frame
Up to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Dorte Winter
Phone
+45 78456442
Email
dorte.skriver.winther@auh.rm.dk
First Name & Middle Initial & Last Name or Official Title & Degree
Toke Hansen, PhD
Phone
+45 78456442
Email
tokeha@rm.dk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Marianne Nordsmark, Dr.
Organizational Affiliation
University of Aarhus
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Karin Haustermans, Dr.
Organizational Affiliation
UKleuven
Official's Role
Study Chair
Facility Information:
Facility Name
Catholic University of Leuven
City
Leuven
Country
Belgium
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Karin Haustermans
Email
karin.haustermans@uzleuven.be
Facility Name
Aarhus University Hospital (AUH)
City
Aarhus
ZIP/Postal Code
8000
Country
Denmark
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Marianne Nordsmark, Dr.
Email
marianne.nordsmark@rm.dk
First Name & Middle Initial & Last Name & Degree
Hanna Mortensen, Dr.
Email
Hanna.Mortensen@auh.rm.dk
Facility Name
Centre Léon Bérard (CLB)
City
Lyon
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Vincent Grégoire
Email
Vincent.GREGOIRE@lyon.unicancer.fr
Facility Name
Centre Antoine Lacassagne (CAL)
City
Nice
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jérôme Doyen
Email
Jerome.DOYEN@nice.unicancer.fr
Facility Name
Institut Curie
City
Paris
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Gilles Crehange
Email
gilles.crehange@curie.fr
Facility Name
Technische Universität Dresden (TUD)
City
Dresden
Country
Germany
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Esther Troost
Email
Esther.Troost@uniklinikum-dresden.de
Facility Name
Centro Nazionale di Adroterapia Oncologica (CNAO)
City
Pavia
Country
Italy
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ester Orlandi
Email
ester.orlandi@cnao.it
Facility Name
Azienda Provinciale Per I Servizi Sanitari (APSS)
City
Trento
Country
Italy
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Daniele Scartoni
Email
daniele.scartoni@apss.tn.it
Facility Name
Academisch Ziekenhuis Groningen (UMCG)
City
Groningen
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Kristel Muijs
Email
c.t.muijs@umcg.nl
Facility Name
Stichting Maastricht Radiation Oncology (MAASTRO)
City
Maastricht
Country
Netherlands
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maaike Berbee
Email
maaike.berbee@maastro.nl
Facility Name
Paul Scherrer Institute (PSI)
City
Villigen
Country
Switzerland
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Damien Weber
Email
damien.weber@psi.ch
Facility Name
University College London Hospital (UCLH)
City
London
Country
United Kingdom
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Maria Hawkins
Email
m.hawkins@ucl.ac.uk
Facility Name
The Christie NHS foundation trust
City
Manchester
Country
United Kingdom
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Ganesh Radhakrishna
Email
g.radhakrishna@nhs.net

12. IPD Sharing Statement

Plan to Share IPD
No

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PROton Versus Photon Therapy for Esophageal Cancer - a Trimodality Strategy

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