DETECT: Target Volume for Rectal Endoluminal Radiation Boosting

Study Overview
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Brief Summary
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The aim of the study is to provide prospective data regarding microscopic tumor spread in all directions from the macroscopic tumor in pathology specimens, as seen by eye, and on imaging to define the target volume for endoluminal radiation boosting in rectal cancer patients.

Detailed Description
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This study is a prospective multicentre cohort trial in ≥50 patients with a residual ycT1-3N0 tumor after neoadjuvant chemoradiotherapy or radiotherapy for rectal adenocarcinoma at least 6 weeks after the neoadjuvant treatment. In addition to standard workup and treatment (e.g. a flexible endoscopy and an MRI scan at 6-8 weeks post-neoadjuvant therapy), patients will undergo pre-operatively, after induction of general anaesthesia, an endorectal ultrasound and rigid rectoscopy as study procedures if these procedures are not already part of standard workup. Furthermore, the pathological specimens of some patients will be scanned using MR imaging during certain parts of the pathological process. Objectives include determining the maximum distance of microscopic tumor spread per patient in all directions, creating a tissue deformation model to account for changes due to e.g. fixation and pathological processing, using this tissue deformation model to translate the microscopic tumor spread back to the in vivo situation (e.g. back to in vivo MRI scans, 3D endo-ultrasounds), and evaluating/determining risk factors for the presence and/or extent of microscopic tumor spread. This data will be used for target volume definition in rectal endoluminal radiation boosting.

Official Title
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DETECT: Defining the Target Volume for Endoluminal Radiation Boosting in Patients With Rectal Cancer

Conditions
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Rectal Cancer

Intervention / Treatment
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* Diagnostic Test: Ultrasound
* Diagnostic Test: Rectoscopy
* Other: Scan, e.g. CT (resection specimen)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ≥18 years of age and capable of giving informed consent. ycT1-3N0(*) residual(**) histology confirmed rectal adenocarcinoma after neoadjuvant radiotherapy or long-course chemoradiotherapy for which patients will undergo TME surgery. Minimal interval between end of neoadjuvant chemoradiotherapy or radiotherapy: 6 weeks. (*)= as determined by clinical assessment (digital rectal examination, endoscopy with or without biopsy) and/or MRI. Biopsy/histology around the time of diagnosis is adequate; no biopsy/histology is needed after neoadjuvant therapy. (**)= including tumor regrowths/local recurrence after an initial clinical complete response and a watch and wait approach. These patients will also be included after the local recurrence has been determined using endoscopy and/or MRI. Exclusion Criteria: Patient has received brachytherapy as part of neoadjuvant treatment. <18 years of age or incapable of giving informed consent. Patient has not been treated with neoadjuvant radiotherapy or long-course chemoradiotherapy. Patient will not undergo TME surgery for a ycT1-3N0 residual histology confirmed rectal adenocarcinoma. Interval between end of neoadjuvant therapy and surgery is <6 weeks.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Observational<br>In addition to standard workup and treatment, patients will undergo pre-operatively, after induction of general anaesthesia, an endorectal ultrasound and rigid rectoscopy as study procedures if these are not part of standard workup yet. | Diagnostic Test: Ultrasound<br>* 3D endorectal ultrasound.<br>Diagnostic Test: Rectoscopy<br>* Rigid rectoscopy.<br>Other: Scan, e.g. CT (resection specimen)<br>* For some patients, images of the resection specimen (note: NOT of the patients) during the pathological process will be acquired.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum distance of microscopic tumor spread per patient in all directions from the macroscopic tumor remnant in the pathology specimen | The maximum distance of microscopic tumor spread in all directions from the macroscopic remnant in the specimen will be measured per patient in millimeters by the pathology department in the pathologic resection specimens. | During post-resection pathological analysis (i.e. approximately 14 days post-resection) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum distance of microscopic tumor spread per patient from the macroscopic tumor remnant in the pathology specimen, reported separately for MTS perpendicular to the bowel wall and for MTS parallel to the bowel wall | Measured per patient in millimeters by the pathology department in the pathologic resection specimens. Microscopic tumor spread perpendicular to the bowel wall and parallel to the bowel wall will be reported separately. | During post-resection pathological analysis (i.e. approximately 14 days post-resection) | 
| Maximum distance of microscopic tumor spread per patient in all directions from the macroscopic tumor remnant in the pathology specimen excluding ypT0 patients | Measured per patient in millimeters by the pathology department in the pathologic resection specimens. For this secondary outcome, this will be reported excluding all ypT0 patients. | During post-resection pathological analysis (i.e. approximately 14 days post-resection) | 
| Maximum distance of microscopic tumor spread per patient in all directions from the macroscopic tumor remnant in the pathology specimen only including patients with microscopic tumor spread | Measured per patient in millimeters by the pathology department in the pathologic resection specimens. For this secondary outcome, this will be reported only for patients with microscopic tumor spread. | During post-resection pathological analysis (i.e. approximately 14 days post-resection) | 
| Maximum distance of microscopic tumor spread per patient in all directions from the macroscopic tumor remnant in the pathology specimen only for patients with regrowths | Measured per patient in millimeters by the pathology department in the pathologic resection specimens. For this secondary outcome, this will be reported only for patients with regrowths. | During post-resection pathological analysis (i.e. approximately 14 days post-resection) | 
| Tissue deformation factor/model to compensate for tissue deformation due to removal of the specimen from the body, formalin fixation and tissue processing at the pathology department | The deidentified images of the flexible endoscopy and in vivo MRI scan will be collected for the study. During the certain parts of the pathologic process, e.g. before and after fixation, MRIs of the pathological specimens of some of the patients will be made. These deidentified images of the specimens, together with e.g. the deidentified endoscopic, rectoscopic, ultrasound and in vivo MR images and possibly with optical images taken during pathological analysis, will be used to develop the deformation model. The flexible endoscopy and in vivo MRI scan are both taken approximately 6-8 weeks post-neoadjuvant treatment. The images of the rigid rectoscopy and 3D endorectal ultrasound are taken directly before TME surgery. | The tissue deformation model will be created once all required data (e.g. MRI scans, rectoscopy images, endorectal ultrasound images) is available (approximately 14 days post-surgery for the final included patient). | 
| Maximum distance of microscopic tumor spread per patient in all directions from the macroscopic tumor remnant as seen by eye and/or on imaging | The tissue deformation factor/model and the location of the microscopic tumor spread in relation to the macroscopic remnant determined during pathological analysis, will be used to determine the maximum distance of microscopic tumor spread in relation to the macroscopic tumor as seen by eye (rectoscopically/endoscopically) and/or on imaging (endo-ultrasound, MRI) per patient in all directions. The flexible endoscopy and in vivo MRI scan are both taken approximately 6-8 weeks post-neoadjuvant treatment. The images of the rigid rectoscopy and 3D endorectal ultrasound are taken directly before TME surgery. | When the tissue deformation model is finished (approximately 3 months after all data for every patient is available). For the imaging time frames: please refer to the description. | 
| Treatment margin (in the various directions) relative to the macroscopic tumor to cover 90% and 95% of all microscopic tumor spread | Distance that covers the microscopic tumor spread in all directions in millimeters for 90 and 95% of patients, including 95% confidence intervals, both reported including and excluding ypT0 patients. Reported both by eye and on imaging, for which among others the tissue deformation model will be used. | Once the microscopic tumor spread is determined for all patients (approximately 14 days post-surgery for the final included patient), the treatment margins will be calculated. | 
| Evaluation of risk factors for the presence and/or the extent of microscopic tumor spread identified by the meta-analysis we performed | These risk factors include pathological T stage after chemoradiation (ypT stage) and time interval between neoadjuvant chemoradiotherapy and surgery. | ypT stage is determined during post-resection pathological analysis (i.e. approximately 14 days post-resection). The time interval is determined at the day of surgery. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rectal Cancer, Microscopic Tumor Spread, Target Volume Definition, Endoluminal Radiation Boosting