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| Name | Class |
|---|---|
| Maastricht University Medical Center | OTHER |
| Catharina Ziekenhuis Eindhoven | OTHER |
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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Observational | 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. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ultrasound | Diagnostic Test | 3D endorectal ultrasound. |
| |
| 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) |
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Identification of potential risk factors for the presence and the extent of microscopic tumor spread not yet identified by our meta-analysis | Potential risk factors include among others ycT stage, regrowths/local recurrence, diameter, predominant histologic grade, tumor regression score/grade (pathologically), vascular invasion, lymphatic invasion, perineural invasion, microsatellite instability (MSI) and parameters related to in vivo MR imaging. |
Inclusion Criteria:
(*)= 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:
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Patients with a limited (ycT1-3N0) residual tumor after neoadjuvant radiotherapy or long-course chemoradiotherapy for rectal adenocarcinoma.
| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Maaike Berbée, MD, PhD | Contact | 0031884455600 | maaike.berbee@maastro.nl | |
| Evert Van Limbergen, MD, PhD | Contact | 0031884455600 | evert.vanlimbergen@maastro.nl |
| Name | Affiliation | Role |
|---|---|---|
| Maaike Berbée, MD, PhD | Maastro | Principal Investigator |
| Evert Van Limbergen, MD, PhD | Maastro | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Maastro | Recruiting | Maastricht | Limburg | 6229 ET | Netherlands |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21596621 | Background | van Gijn W, Marijnen CA, Nagtegaal ID, Kranenbarg EM, Putter H, Wiggers T, Rutten HJ, Pahlman L, Glimelius B, van de Velde CJ; Dutch Colorectal Cancer Group. Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer: 12-year follow-up of the multicentre, randomised controlled TME trial. Lancet Oncol. 2011 Jun;12(6):575-82. doi: 10.1016/S1470-2045(11)70097-3. Epub 2011 May 17. | |
| 19269519 |
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The data will not be shared with other researchers, however the following applies if patients have given specific, additional consent:
If patients have consented to the use of leftover body material and/or data in further studies, the deidentified images (endoscopy, rectoscopy, ultrasound, in vivo MRIs and specimen MRIs) and pathological specimens/samples including (re)biopsies, and the accompanying data can be used for further scientific research related to rectal cancer by the investigators, including investigators from collaborating institutions, without requiring additional informed consent.
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| ID | Term |
|---|---|
| D012004 | Rectal Neoplasms |
| ID | Term |
|---|---|
| D015179 | Colorectal Neoplasms |
| D007414 | Intestinal Neoplasms |
| D005770 | Gastrointestinal Neoplasms |
| D004067 | Digestive System Neoplasms |
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| ID | Term |
|---|---|
| D014463 | Ultrasonography |
| D011351 | Proctoscopy |
| ID | Term |
|---|---|
| D003952 | Diagnostic Imaging |
| D019937 | Diagnostic Techniques and Procedures |
| D003933 | Diagnosis |
| D016099 | Endoscopy, Gastrointestinal |
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Both are part of standard clinical care.
| Rectoscopy |
| Diagnostic Test |
Rigid rectoscopy. |
|
| Scan, e.g. CT (resection specimen) | Other | For some patients, images of the resection specimen (note: NOT of the patients) during the pathological process will be acquired. |
|
| 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. |
| Most are determined during post-resection path. analysis (approx. 14 days post-resection). ycT stage is determined approx. 6-10 weeks post-neoadjuvant treatment (multidisciplinary team), in vivo imaging is done approx 6-8 weeks post-neoadjuvant treatment |
| Analysis of (re)biopsy material | This includes the biopsy material at time of diagnosis, and also the rebiopsy material for patients with tumor regrowths/local recurrence after an initial clinical complete response and a "watch and wait" approach. These (re)biopsies are a part of the standard diagnostic work-up. Part of this analysis will be performed during this study by reassessment of the histology of the biopsy material and/or if applicable the rebiopsy material. | Biopsy material is obtained at time of diagnosis. |
| Maastricht University Medical Center | Recruiting | Maastricht | Limburg | 6229 HX | Netherlands |
|
| Catharina Hospital | Recruiting | Eindhoven | North Brabant | 5623 EJ | Netherlands |
|
| Background |
| Sebag-Montefiore D, Stephens RJ, Steele R, Monson J, Grieve R, Khanna S, Quirke P, Couture J, de Metz C, Myint AS, Bessell E, Griffiths G, Thompson LC, Parmar M. Preoperative radiotherapy versus selective postoperative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet. 2009 Mar 7;373(9666):811-20. doi: 10.1016/S0140-6736(09)60484-0. |
| 17968156 | Background | Peeters KC, Marijnen CA, Nagtegaal ID, Kranenbarg EK, Putter H, Wiggers T, Rutten H, Pahlman L, Glimelius B, Leer JW, van de Velde CJ; Dutch Colorectal Cancer Group. The TME trial after a median follow-up of 6 years: increased local control but no survival benefit in irradiated patients with resectable rectal carcinoma. Ann Surg. 2007 Nov;246(5):693-701. doi: 10.1097/01.sla.0000257358.56863.ce. |
| 22067400 | Background | Maas M, Beets-Tan RG, Lambregts DM, Lammering G, Nelemans PJ, Engelen SM, van Dam RM, Jansen RL, Sosef M, Leijtens JW, Hulsewe KW, Buijsen J, Beets GL. Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer. J Clin Oncol. 2011 Dec 10;29(35):4633-40. doi: 10.1200/JCO.2011.37.7176. Epub 2011 Nov 7. |
| 20692872 | Background | Maas M, Nelemans PJ, Valentini V, Das P, Rodel C, Kuo LJ, Calvo FA, Garcia-Aguilar J, Glynne-Jones R, Haustermans K, Mohiuddin M, Pucciarelli S, Small W Jr, Suarez J, Theodoropoulos G, Biondo S, Beets-Tan RG, Beets GL. Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data. Lancet Oncol. 2010 Sep;11(9):835-44. doi: 10.1016/S1470-2045(10)70172-8. Epub 2010 Aug 6. |
| 28366579 | Background | Rijkmans EC, Cats A, Nout RA, van den Bongard DHJG, Ketelaars M, Buijsen J, Rozema T, Franssen JH, Velema LA, van Triest B, Marijnen CAM. Endorectal Brachytherapy Boost After External Beam Radiation Therapy in Elderly or Medically Inoperable Patients With Rectal Cancer: Primary Outcomes of the Phase 1 HERBERT Study. Int J Radiat Oncol Biol Phys. 2017 Jul 15;98(4):908-917. doi: 10.1016/j.ijrobp.2017.01.033. Epub 2017 Jan 20. |
| 29229327 | Background | Sun Myint A, Smith FM, Gollins S, Wong H, Rao C, Whitmarsh K, Sripadam R, Rooney P, Hershman M, Pritchard DM. Dose Escalation Using Contact X-ray Brachytherapy After External Beam Radiotherapy as Nonsurgical Treatment Option for Rectal Cancer: Outcomes From a Single-Center Experience. Int J Radiat Oncol Biol Phys. 2018 Mar 1;100(3):565-573. doi: 10.1016/j.ijrobp.2017.10.022. Epub 2017 Oct 20. |
| 26156652 | Background | Appelt AL, Ploen J, Harling H, Jensen FS, Jensen LH, Jorgensen JC, Lindebjerg J, Rafaelsen SR, Jakobsen A. High-dose chemoradiotherapy and watchful waiting for distal rectal cancer: a prospective observational study. Lancet Oncol. 2015 Aug;16(8):919-27. doi: 10.1016/S1470-2045(15)00120-5. Epub 2015 Jul 5. |
| 31476417 | Background | Garant A, Magnan S, Devic S, Martin AG, Boutros M, Vasilevsky CA, Ferland S, Bujold A, DesGroseilliers S, Sebajang H, Richard C, Vuong T. Image Guided Adaptive Endorectal Brachytherapy in the Nonoperative Management of Patients With Rectal Cancer. Int J Radiat Oncol Biol Phys. 2019 Dec 1;105(5):1005-1011. doi: 10.1016/j.ijrobp.2019.08.042. Epub 2019 Aug 30. |
| 30396854 | Background | Verrijssen AS, Opbroek T, Bellezzo M, Fonseca GP, Verhaegen F, Gerard JP, Sun Myint A, Van Limbergen EJ, Berbee M. A systematic review comparing radiation toxicity after various endorectal techniques. Brachytherapy. 2019 Jan-Feb;18(1):71-86.e5. doi: 10.1016/j.brachy.2018.10.001. Epub 2018 Nov 3. |
| 25585073 | Background | Smith FM, Rao C, Oliva Perez R, Bujko K, Athanasiou T, Habr-Gama A, Faiz O. Avoiding radical surgery improves early survival in elderly patients with rectal cancer, demonstrating complete clinical response after neoadjuvant therapy: results of a decision-analytic model. Dis Colon Rectum. 2015 Feb;58(2):159-71. doi: 10.1097/DCR.0000000000000281. |
| 31710942 | Background | Verrijssen AS, Guillem J, Perez R, Bujko K, Guedj N, Habr-Gama A, Houben R, Goudkade D, Melenhorst J, Buijsen J, Vanneste B, Grabsch HI, Bellezzo M, Paiva Fonseca G, Verhaegen F, Berbee M, Van Limbergen EJ. Microscopic intramural extension of rectal cancer after neoadjuvant chemoradiation: A meta-analysis based on individual patient data. Radiother Oncol. 2020 Mar;144:37-45. doi: 10.1016/j.radonc.2019.10.003. Epub 2019 Nov 9. |
| 26198074 | Background | Maas M, Lambregts DM, Nelemans PJ, Heijnen LA, Martens MH, Leijtens JW, Sosef M, Hulsewe KW, Hoff C, Breukink SO, Stassen L, Beets-Tan RG, Beets GL. Assessment of Clinical Complete Response After Chemoradiation for Rectal Cancer with Digital Rectal Examination, Endoscopy, and MRI: Selection for Organ-Saving Treatment. Ann Surg Oncol. 2015 Nov;22(12):3873-80. doi: 10.1245/s10434-015-4687-9. Epub 2015 Jul 22. |
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| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D004066 | Digestive System Diseases |
| D005767 | Gastrointestinal Diseases |
| D007410 | Intestinal Diseases |
| D012002 | Rectal Diseases |
| D016145 | Endoscopy, Digestive System |
| D003938 | Diagnostic Techniques, Digestive System |
| D004724 | Endoscopy |
| D003949 | Diagnostic Techniques, Surgical |
| D013505 | Digestive System Surgical Procedures |
| D013514 | Surgical Procedures, Operative |
| D019060 | Minimally Invasive Surgical Procedures |