Esophageal CancerPhase 3PROTECTNCT05055648
PROton Versus Photon Therapy for Esophageal Cancer - a Trimodality Strategy
A Phase 3 study testing Photon Radiotherapy and Proton Radiotherapy in people with Esophageal Cancer and Radiotherapy, run by University of Aarhus at 15 sites in 8 countries.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Esophageal Cancer, Radiotherapy, Side Effect
- What is being tested?
- Photon Radiotherapy and Proton Radiotherapy
- Type of treatment
- Surgery or procedure
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 396 participants
- Where
- 15 sitesin 8 countries
- Study dates
- 1 May 2022to 1 Dec 2032
- Phase
- Phase 3
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
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- 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.
Who cannot join
- 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).
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- 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.
Trial locations and contacts
15 sites in 8 countries. Contact the study team or a site near you to ask about taking part.
15 sites in 8 countries
France3 sites, 3 recruiting
- Not yet recruiting
Centre Léon Bérard (CLB)
Lyon
Laurie Bissuel, laurie.bissuel@lyon.unicancer.fr
Jessica Serrand
- Not yet recruiting
Centre Antoine Lacassagne (CAL)
Nice
Jérôme Doyen, Jerome.DOYEN@nice.unicancer.fr
- Not yet recruiting
Institut Curie
Paris
Gilles Crehange, gilles.crehange@curie.fr
Italy3 sites, 3 recruiting
- Recruiting
San Raffaele Hospital
Milan
Elena Mazza, mazza.elena@hsr.it
Nadia Di Muzio
- Recruiting
Centro Nazionale di Adroterapia Oncologica (CNAO)
Pavia
Cristina Bono, cristina.bono@cnao.it
Ester Orlandi
- Recruiting
Azienda Provinciale Per I Servizi Sanitari (APSS)
Trento
Daniele Scartoni, daniele.scartoni@apss.tn.it
Netherlands2 sites
- Withdrawn
Academisch Ziekenhuis Groningen (UMCG)
Groningen
- Withdrawn
Stichting Maastricht Radiation Oncology (MAASTRO)
Maastricht
Switzerland2 sites, 2 recruiting
- Recruiting
Paul Scherrer Institute (PSI)
Villigen
Ulrike Kliebsch
Damien Weber
- Recruiting
University Hospital Zurich (USZ)
Zurich, 8091
Antonia Schiess
Panagiotis Balermpas
United Kingdom2 sites, 1 recruiting
- Withdrawn
University College London Hospital (UCLH)
London
- Not yet recruiting
The Christie NHS foundation trust
Manchester
Ganesh Radhakrishna, g.radhakrishna@nhs.net
Belgium1 site, 1 recruiting
- Recruiting
Catholic University of Leuven
Leuven
Pieter Populaire, pieter.populaire@uzleuven.be
Karin Haustermans
Denmark1 site, 1 recruiting
- Recruiting
Aarhus University Hospital (AUH)
Aarhus, 8000
Dorte Winther, Dr.
Marianne Nordsmark
Germany1 site, 1 recruiting
- Recruiting
Technische Universität Dresden (TUD)
Dresden
Esther Troost, Esther.Troost@uniklinikum-dresden.de
About this study
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
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).
Read the 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)
- Conditions
- Esophageal Cancer, Radiotherapy, Side Effect, Proton Therapy
- Being tested
- Photon Radiotherapy, Proton Radiotherapy
- Medical subject headings
- Esophageal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Photon RadiotherapyRadiation
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
Proton RadiotherapyRadiation
Also called Proton Therapy
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
| Study group | Role | What they receive |
|---|---|---|
| Photon Arm | Active comparator | Standard arm with neoadjuvant chemoradiotherapy (nCXT) with photons Receives: Radiation: Photon Radiotherapy |
| Proton Arm | Experimental | Experimental arm with neoadjuvant chemoradiotherapy (nCPT) with protons Receives: Radiation: Proton Radiotherapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Pulmonary complications
Incidence of pulmonary complications during and following nCPT or nCXT and surgery
Measured: from randomization until 90 days after surgery
Secondary outcomes (11)
Early toxicity
Predefined items ≥ grade 2 scored by Common Terminology Criteria for Adverse Events (CTCAE) v5.0
Measured: 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
Measured: up to 5 years
Postoperative complications
Predefined items scored by Clavien-Dindo and Comprehensive Complications Index (CCI)
Measured: from surgery until 90 days after surgery
Major cardiovascular events (MACE)
Predefined cardiovascular events scored by MACE
Measured: up to 5 years
Patient-reported outcome measures
EORTC quality of life questionnaire
Measured: up to 5 years
Compliance with trimodality treatment
The proportion of patients complying with trimodality treatment in each arm
Measured: 3 months
Pathological response
tumor regression grade for the primary tumor scored according to Mandard score.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: up to 5 years
Overall survival (OS)
Death from all causes will considered as events
Measured: up to 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Sep 2021
- Study start1 May 2022
- Primary completion1 Dec 2027 (estimated)
- Study completion1 Dec 2032 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Esophageal CancerStudies of the same condition, open and under way.
- More trials run by University of AarhusThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- open-label, non-blinded, international multicenter, randomized phase III study
- Masking
- None (open label)
- Enrolment
- 396 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Aarhus
- Sponsor type
- University, hospital or other
- 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 Healthineers Company
- Responsible party
- Sponsor
- Investigators
- Marianne Nordsmark, Dr., Study director, University of AarhusKarin Haustermans, Dr., Study chair, UKleuven
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05055648
- Sponsor's protocol ID
- DCPT101008134
- Acronym
- PROTECT
- Status last verified
- Dec 2024
- First submitted
- 26 Aug 2021
- Last updated
- 17 Dec 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Muijs CT, Klaver YLB, Nuyttens J, Lips IM, Muller K, Ebrahimi GM, Dankers FJWM, Verhoeven R, Schuit E, Berbee M. National indication protocol for proton radiotherapy in esophageal cancer patients in the Netherlands. Radiother Oncol. 2025 Dec;213:111164. doi: 10.1016/j.radonc.2025.111164. Epub 2025 Sep 24.
PubMed 41005671
Study at a glance
From the registry record, last updated by the sponsor on 17 Dec 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT05055648
- Acronym / sponsor ID
- PROTECT / DCPT101008134
- Conditions
- Esophageal Cancer, Radiotherapy, Side Effect, Proton Therapy
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 396 participants (estimated)
- Lead sponsor
- University of AarhusUniversity, hospital or other
- 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 Healthineers Company
- Study start
- 1 May 2022 (actual)
- Primary completion
- 1 Dec 2027 (estimated)
- Study completion
- 1 Dec 2032 (estimated)
- First posted
- 24 Sep 2021 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- open-label, non-blinded, international multicenter, randomized phase III study
| Arm | Type | Receives |
|---|---|---|
| Photon Arm | Active comparator | Radiation: Photon RadiotherapyStandard arm with neoadjuvant chemoradiotherapy (nCXT) with photons |
| Proton Arm | Experimental | Radiation: Proton RadiotherapyExperimental arm with neoadjuvant chemoradiotherapy (nCPT) with protons |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (11 listed)
- 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).
Key exclusion criteria (10 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Photon RadiotherapynCXT 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 | Radiation | Photon Arm |
| Proton RadiotherapyAlso: Proton TherapynCPT 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 | Radiation | Proton Arm |
Primary outcome
Pulmonary complications
Time frame: from randomization until 90 days after surgery
Incidence of pulmonary complications during and following nCPT or nCXT and surgery
11 secondary outcomes
Early toxicity
Time frame: from start of nCPT or nCXT until surgery
Late toxicity
Time frame: up to 5 years
Postoperative complications
Time frame: from surgery until 90 days after surgery
Major cardiovascular events (MACE)
Time frame: up to 5 years
Patient-reported outcome measures
Time frame: up to 5 years
Compliance with trimodality treatment
Time frame: 3 months
Pathological response
Time frame: immediately after surgery
Cumulative incidence of loco-regional failure
Time frame: from date of randomization up to 5 years
Pattern of failure
Time frame: up to 5 years
Disease-free survival (DFS)
Time frame: up to 5 years
Overall survival (OS)
Time frame: up to 5 years
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Dec 2024.
- Derived from this study: PubMed 41005671Muijs CT, Klaver YLB, Nuyttens J, Lips IM, Muller K, Ebrahimi GM, Dankers FJWM, Verhoeven R, Schuit E, Berbee M. National indication protocol for proton radiotherapy in esophageal cancer patients in the Netherlands. Radiother Oncol. 2025 Dec;213:111164. doi: 10.1016/j.radonc.2025.111164. Epub 2025 Sep 24.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Marianne Nordsmark, Dr. study director
University of Aarhus
Karin Haustermans, Dr. study chair
UKleuven
15 sites in 8 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Photon Radiotherapy and Proton Radiotherapy in people with Esophageal Cancer and Radiotherapy, run by University of Aarhus at 15 sites in 8 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 11 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 17 Dec 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 15 sites in France, Italy, Netherlands, Switzerland, United Kingdom and 3 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Dorte Winter (+45 78456442, dorte.skriver.winther@auh.rm.dk), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Pulmonary complications (time frame: from randomization until 90 days after surgery). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05055648, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Dec 2024.