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

November 1, 2022 updated by: University of Aarhus

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).

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Anticipated)

396

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Toke Hansen, PhD
  • Phone Number: +45 78456442
  • Email: tokeha@rm.dk

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Photon Arm
Standard arm with neoadjuvant chemoradiotherapy (nCXT) with photons
Radiation: Photon 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
Experimental: Proton Arm
Experimental arm with neoadjuvant chemoradiotherapy (nCPT) with protons
Radiation: Proton 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
Other Names:
  • Proton Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Pulmonary complications
Time Frame: from randomization until 90 days after surgery
Incidence of pulmonary complications during and following nCPT or nCXT and surgery
from randomization until 90 days after surgery

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Total toxicity burden (TTB)
Time Frame: from randomization until 90 days after surgery
The combined toxicity scale TTB used in the trial by Lin et al (Lin 2020)
from randomization until 90 days after surgery
Concordance of observed pulmonary complications with predicted complications from NTCP models
Time Frame: up to 5 years
Comparison of observed and predicted toxicity rates
up to 5 years
Blood biomarkers as predictors for treatment failure
Time Frame: up to 5 years
circulating tumor DNA
up to 5 years
Proportion of patients receiving adjuvant immunotherapy
Time Frame: up to 5 years
The actual number of patients starting adjuvant immunotherapy will be recorded
up to 5 years
Cost-effectiveness of proton therapy relative to photon therapy
Time Frame: 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.
up to 5 years
FDG/PET CT as predictors for treatment failure
Time Frame: 12 months
Correlation between diagnostic PET, planning PET-CT and PET at 12 months
12 months
Concordance of observed cardiac complications with predicted
Time Frame: Up to 5 years
Comparison of observed and predicted toxicity rates
Up to 5 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of Aarhus

Collaborators

Centre Leon Berard
University College London Hospitals
Aarhus University Hospital
KU Leuven
University College, London
University of Leeds
Technische Universität Dresden
CNAO National Center of Oncological Hadrontherapy
HollandPTC
The Christie NHS Foundation Trust
Centre Antoine Lacassagne
Institut Curie
Academisch Ziekenhuis Groningen
Agenzia Nazionale per i Servizi Sanitari Regionali
Maastro Clinic, The Netherlands
Paul Scherrer Institut, Center for Proton Therapy
IBA worldwide
Varian- A Siemens Healthineer Company

Investigators

  • Study Director: Marianne Nordsmark, Dr., University of Aarhus
  • Study Chair: Karin Haustermans, Dr., UKleuven

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

May 1, 2022

Primary Completion (Anticipated)

May 1, 2025

Study Completion (Anticipated)

May 1, 2030

Study Registration Dates

First Submitted

August 26, 2021

First Submitted That Met QC Criteria

September 14, 2021

First Posted (Actual)

September 24, 2021

Study Record Updates

Last Update Posted (Actual)

November 2, 2022

Last Update Submitted That Met QC Criteria

November 1, 2022

Last Verified

October 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • DCPT101008134

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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