PROton Versus Photon Therapy for Esophageal Cancer - a Trimodality Strategy

Esophageal Cancer Clinical Trial

— 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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05055648
• Other study ID #: DCPT101008134
• Status: Recruiting
• Phase: N/A
• Start date: May 1, 2022
• Est. completion date: May 1, 2030

Study information

• Verified date: October 2022
• Source: University of Aarhus
• Contact: Dorte Winter
• Phone: +45 78456442
• Email: dorte.skriver.winther[@]auh.rm.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical 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).

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)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 396
• Est. completion date: May 1, 2030
• Est. primary completion date: May 1, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Esophageal Cancer
• Esophageal Neoplasms
• Proton Therapy
• Radiotherapy
• Side Effect

Intervention

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
• 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

Locations

Country	Name	City	State
Belgium	Catholic University of Leuven	Leuven
Denmark	Aarhus University Hospital (AUH)	Aarhus
France	Centre Léon Bérard (CLB)	Lyon
France	Centre Antoine Lacassagne (CAL)	Nice
France	Institut Curie	Paris
Germany	Technische Universität Dresden (TUD)	Dresden
Italy	Centro Nazionale di Adroterapia Oncologica (CNAO)	Pavia
Italy	Azienda Provinciale Per I Servizi Sanitari (APSS)	Trento
Netherlands	Academisch Ziekenhuis Groningen (UMCG)	Groningen
Netherlands	Stichting Maastricht Radiation Oncology (MAASTRO)	Maastricht
Switzerland	Paul Scherrer Institute (PSI)	Villigen
United Kingdom	University College London Hospital (UCLH)	London
United Kingdom	The Christie NHS foundation trust	Manchester

Sponsors (19)

Lead Sponsor

Collaborator

University of Aarhus

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

Countries where clinical trial is conducted

Belgium,  Denmark,  France,  Germany,  Italy,  Netherlands,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Total toxicity burden (TTB)	The combined toxicity scale TTB used in the trial by Lin et al (Lin 2020)	from randomization until 90 days after surgery
Other	Concordance of observed pulmonary complications with predicted complications from NTCP models	Comparison of observed and predicted toxicity rates	up to 5 years
Other	Blood biomarkers as predictors for treatment failure	circulating tumor DNA	up to 5 years
Other	Proportion of patients receiving adjuvant immunotherapy	The actual number of patients starting adjuvant immunotherapy will be recorded	up to 5 years
Other	Cost-effectiveness of proton therapy relative to photon therapy	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
Other	FDG/PET CT as predictors for treatment failure	Correlation between diagnostic PET, planning PET-CT and PET at 12 months	12 months
Other	Concordance of observed cardiac complications with predicted	Comparison of observed and predicted toxicity rates	Up to 5 years
Primary	Pulmonary complications	Incidence of pulmonary complications during and following nCPT or nCXT and surgery	from randomization until 90 days after surgery
Secondary	Early toxicity	Predefined items = grade 2 scored by Common Terminology Criteria for Adverse Events (CTCAE) v5.0	from start of nCPT or nCXT until surgery
Secondary	Late toxicity	Predefined items = grade 2 scored by Common Terminology Criteria for Adverse Events (CTCAE) v5.0	up to 5 years
Secondary	Postoperative complications	Predefined items scored by Clavien-Dindo and Comprehensive Complications Index (CCI)	from surgery until 90 days after surgery
Secondary	Major cardiovascular events (MACE)	Predefined cardiovascular events scored by MACE	up to 5 years
Secondary	Patient-reported outcome measures	EORTC quality of life questionnaire	up to 5 years
Secondary	Compliance with trimodality treatment	The proportion of patients complying with trimodality treatment in each arm	3 months
Secondary	Pathological response	tumor regression grade for the primary tumor scored according to Mandard score.	immediately after surgery
Secondary	Cumulative incidence of loco-regional failure	Locoregional failure evaluated according to RECIST with all failures within the irradiated volume counting as events.	from date of randomization up to 5 years
Secondary	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.	up to 5 years
Secondary	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.	up to 5 years
Secondary	Overall survival (OS)	Death from all causes will considered as events	up to 5 years