Combination of Chemotherapy and Adaptive MR-Guided Radiotherapy to Improve Outcomes in Patients With Esophageal Adenocarcinoma

NCT07359443 | Recruiting Phase 1 DMC

• 1 other identifier: NL87824.041.24
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 1

Brief Summary

Rationale: Esophageal cancer (EC) is the seventh most frequently diagnosed cancer and the sixth leading cause of cancer-related death worldwide. As a result of the late onset of symptoms, most patients with EC present in an advanced stage with a corresponding poor prognosis. Poor disease outcome after surgery alone (5-yr overall survival between 25-40%) prompted many researchers to explore neoadjuvant chemoradiotherapy (nCRT) or neoadjuvant or perioperative chemotherapy (nCT/pCT) approaches. In the Netherlands, neoadjuvant chemoradiation has become standard of care for esophageal cancer since publication of the CROSS trial showing a benefit of nCRT over surgery alone for both adenocarcinoma (AC) and squamous cell carcinoma (SCC) (van Hagen et al., 2012). However, the benefit of nCRT was less pronounced in AC, which was also reflected by pathologic complete response (pCR) rates: 23% in AC vs. 49% in SCC. Furthermore, SCC and AC differ in patterns of recurrence after nCRT or chemotherapy. AC is more likely to develop distant metastases while SCC has a predisposition for locoregional recurrences. This difference in response to nCRT and in recurrence pattern indicates that histology-tailored treatment strategies should be explored. In the modern multidisciplinary discussion on the optimal approach to locally advanced adenocarcinoma of the esophagus and junction, both a trimodiality approach or perioperative chemotherapy are acceptable and evidence based. Therefore both are viable options within current guidelines. As mentioned above, patients with an AC of the esophagus are especially prone to develop distant recurrences. In addition, response to nCRT is only moderate in AC. Therefore, the investigators hypothesize that the ideal neoadjuvant treatment should consist of adding MR-guided radiotherapy to standard pCT in order to achieve maximum systemic control and achieve maximum local control. Objective: The main objective of this study is to determine the maximum tolerated dose (MTD) of 5 fractions MRgRT for patients with AC following FLOT therapy. The secondary objectives are feasibility, non-dose limiting toxicity, oncological outcomes and to explore variables for early response evaluation. Study design: 6+3 dose-escalation design with 4 radiotherapy dose levels. Study population: Patients with a resectable esophageal adenocarcinoma who are eligible for nCRT and surgery and who are eligible for MRgRT. Intervention: 5 sequential, homogenous fractions of 4-8 Gy within 2 weeks on the gross tumor volume (GTV) following preoperative FLOT (as part of standard perioperative chemotherapy) using MR-guided online adaptive radiotherapy on the MR-linac. Start in dose level 0, of 5 x 5Gy per patient, and if safe this is increased step-wise to a maximum dose level 3 of 5 x 8Gy per patient. Main study parameters/endpoints: The primary endpoint is the incidence of a dose limiting toxicity (DLT). Early DLT is defined as radiation induced esophageal fistula/ perforation/ hemorrhage/ necrosis or tracheal, bronchial or bronchopleural fistula/tracheal or bronchopulmonary hemorrhage grade ≥ 3 or any non-hematological grade ≥ toxicity, assessed clinically significant and related to the radiotherapy, according to Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0 occurring within 16 weeks after the start of radiotherapy and before surgery or postponing of surgery \> 16 weeks after the end of radiotherapy due to any grade of treatment-related toxicity. Subacute DLT is defined as peri- and/or postoperative complications occurring within 30 days after surgery, defined as postoperative anastomotic leakage or pneumonitis ≥ 3b according to Clavien-Dindo. Secondary endpoints are non-DLT toxicity, the technical feasibility of dose delivery, perioperative complications. and oncological outcomes including R0 resection rate, histopathological tumor response, local and regional recurrence and death from any cause. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The benefits for the patients may include higher probability of complete primary tumor and lymph node metastases response that initially lead to increased survival and could eventually result in organ-sparing treatment programs. Possible risks are mainly esophageal fistula/perforation and broncho-esophageal fistula or hemorrhage.

Conditions

Esophageal Adenocarcinoma; Esophageal Adenocarcinoma (EAC); Adenocarcinoma - Gastroesophageal Junction (GEJ)

Keywords

MR-Guided Radiotherapy; Adaptive Radiotherapy; MR-Linac; Dose Escalation; Phase 1 Trial

Outcome Measures

Primary Outcomes (1)

• Number of Participants Experiencing Dose-Limiting Toxicity (DLT)

  Number of participants who experience a dose-limiting toxicity (DLT) after MR-guided radiotherapy, as defined in the study protocol. The maximum tolerated dose (MTD) will be determined as the highest radiotherapy dose level at which fewer than a predefined number of participants experience a DLT using a 6+3 dose-escalation design.

  From start of radiotherapy through 16 weeks after start of radiotherapy and up to 30 days after surgery

Secondary Outcomes (3)

• Proportion of Participants Completing All Planned MR-Guided Radiotherapy Fractions

  From start of radiotherapy through the end of the planned radiotherapy course (approximately 2 weeks)

• Pathological Tumor Response on Surgical Resection Specimen

  At time of surgery

• Disease-Free Survival

  Up to 12 months after surgery

Study Arms (1)

MRI guided radiotherapy

EXPERIMENTAL

5 sequential, homogenous fractions of 4-8 Gy within 2 weeks on the gross tumor volume (GTV) following preoperative FLOT (as part of standard perioperative chemotherapy) using MR-guided online adaptive radiotherapy on the MR-linac. Start in dose level 0, of 5 x 5Gy per patient, and if safe this is increased step-wise to a maximum dose level 3 of 5 x 8Gy per patient.

Radiation: MRI guided radiotherapy

Interventions

MRI guided radiotherapy RADIATION

MRI guided radiotherapy

Also known as: MRgRT, MR Linac

MRI guided radiotherapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed adenocarcinoma of the esophagus or GE- junction (Siewert I or II)
• Potentially resectable, locally advanced esophageal tumor (cT1bN+, cT2-3, N0-3, M0) based on standard primary staging by EUS and 18F-FDG PET-CT
• Eligible for neoadjuvant treatment: followed by esophagectomy (as judged by the multidisciplinary tumor board)
• Eligible for pCT FLOT
• Tumor length ≤ 10 cm
• Age ≥ 18 years
• WHO performance status 0-2
• Signed informed consent
• Tumor volume that can be defined on MRI at baseline (T2w and DW-MRI)
• Written informed consent must be given according to ICH/GCP, and national/local regulations.

You may not qualify if:

• Squamous cell carcinoma
• Non-resectable, inoperable or metastatic adenocarcinoma of the esophagus or GE junction
• Siewert type III tumors
• Prior (chemo)radiotherapy to the mediastinum
• Prior esophageal surgery that impedes the ability to perform an esophagectomy
• Patients with multiple primary carcinomas of the esophagus
• \* Irradical endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) of primary tumor prior to start of neoadjuvant chemoradiotherapy
• Pregnant or breast-feeding patients
• Presence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule before patient registration. Patients in whom it is not in their best interest to participate (in the judgment of the PI)

Sponsors & Collaborators

• UMC Utrecht: lead
• Julius Centre for Health Sciences and Primary Care, UMC Utrecht: collaborator

Study Sites (1)

University Medical Center Utrecht

Utrecht, Utrecht, 3582CX, Netherlands

RECRUITING

Related Publications (2)

• van Hagen P, Hulshof MC, van Lanschot JJ, Steyerberg EW, van Berge Henegouwen MI, Wijnhoven BP, Richel DJ, Nieuwenhuijzen GA, Hospers GA, Bonenkamp JJ, Cuesta MA, Blaisse RJ, Busch OR, ten Kate FJ, Creemers GJ, Punt CJ, Plukker JT, Verheul HM, Spillenaar Bilgen EJ, van Dekken H, van der Sangen MJ, Rozema T, Biermann K, Beukema JC, Piet AH, van Rij CM, Reinders JG, Tilanus HW, van der Gaast A; CROSS Group. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012 May 31;366(22):2074-84. doi: 10.1056/NEJMoa1112088.

  PMID: 22646630 BACKGROUND

• Hoeppner J, Brunner T, Schmoor C, Bronsert P, Kulemann B, Claus R, Utzolino S, Izbicki JR, Gockel I, Gerdes B, Ghadimi M, Reichert B, Lock JF, Bruns C, Reitsamer E, Schmeding M, Benedix F, Keck T, Folprecht G, Thuss-Patience P, Neumann UP, Pascher A, Imhof D, Daum S, Strieder T, Krautz C, Zimmermann S, Werner J, Mahlberg R, Illerhaus G, Grimminger P, Lordick F. Perioperative Chemotherapy or Preoperative Chemoradiotherapy in Esophageal Cancer. N Engl J Med. 2025 Jan 23;392(4):323-335. doi: 10.1056/NEJMoa2409408.

  PMID: 39842010 BACKGROUND

MeSH Terms

Conditions

Adenocarcinoma Of Esophagus

Central Study Contacts

drs. Sanders, MD

CONTACT

+31 (0)88-755-5555; MRGuidedRTSlokdarm@umcutrecht.nl

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: This is a phase 1 single-arm dose-escalation study using a 6+3 design with sequential patient cohorts treated at increasing radiotherapy dose levels.

Study Record Dates

• First Submitted: December 31, 2025
• First Posted: January 22, 2026
• Study Start: May 21, 2025
• Primary Completion (Estimated): May 1, 2028
• Study Completion (Estimated): May 1, 2028
• Last Updated: January 22, 2026

Record last verified: 2025-12

Locations

NL (1)