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. nCRT has led to pathological complete response (pCR) rate in squamous cell EC of almost 50%. Patients with a pCR have a favorable prognosis with 5-year OS >50%. In addition, patients who will achieve a pCR might be candidates for an organ preserving treatment strategy. Current standard nCRT consists of a relatively low dose of radiation compared to other tumors in the same area. The investigators hypothesize that increasing the dose of radiation will lead to increased local tumor control and pCR rates.

Objective: The main objective of this study is to determine the maximum tolerated dose (MTD) of 2-fraction boost MRI-guided radiotherapy (MRgRT) for patients with SCC following CROSS 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 3 radiotherapy dose levels. Study population: Patients with a resectable squamous cell esophageal carcinoma who are eligible for nCRT, surgery and MRgRT.

Intervention: 2 sequential, homogenous boost fractions of 4-7 Gy on the gross tumor volume (GTV) in the week following CROSS using MR-guided online adaptive radiotherapy on the MR-linac. Start in dose level 0, of 2 x 5Gy boost per patient, and if safe this is increased step-wise to a maximum dose level 2 of 2 x 7Gy 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 4 toxicity according to Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0 occurring within 14 weeks after the start of radiotherapy and before surgery or the postponing of surgery > 14 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 pathological response that initially leads to increased survival and could eventually result in organ-sparing treatment programs. Compared to standard treatment, the CROSS regimen including the sequential boost will take 2 days extra in the final week of CROSS. Possible risks include higher radiation toxicity and surgical complication rates. However, it is expected this increase to be minor, for the investigators will use dose constraints on organs at risk, which are associated with low radiation-induced toxicity, and they will not be exceeded.

Inclusion criteria

In order to be eligible for this study, a subject must meet all of the following criteria:

• Histologically confirmed squamous cell carcinoma of the esophagus or GE- junction (Siewert I/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
• Scheduled to receive neoadjuvant chemoradiotherapy according to CROSS-regimen: weekly administration of carboplatin and paclitaxel for 5 weeks and concurrent radiotherapy (41.4Gy in 23 fractions, 5 days per week), followed by esophagectomy (as judged by the multidisciplinary tumor board)
• 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)
• Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule before patient registration/randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.

Exclusion criteria

A subject who meets any of the following criteria will be excluded from participation in this study:

• Adenocarcinoma of the esophagus
• Non-resectable, inoperable or metastatic squamous cell carcinoma of the esophagus or GE-junction
• Siewert type III
• Squamous cell carcinoma of the cervical esophagus
• 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
• Patients who meet exclusion criteria for MRI
• Irradical endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) of primary tumor prior to start of neoadjuvant chemoradiotherapy
• Pregnant or breast-feeding patients
• Patients in whom it is not in their best interest to participate (in the judgment of the PI)

Undecided. Plans for individual participant data (IPD) sharing have not been finalized at this time. Any future data sharing will depend on institutional policies, ethical approvals, and participant consent.