DETECT: Target Volume for Rectal Endoluminal Radiation Boosting

Rectal Cancer Clinical Trial

— DETECT  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04927897
• Other study ID #: NL77886.068.21
• Status: Recruiting
• Start date: August 16, 2022
• Est. completion date: December 2024

Study information

• Verified date: October 2023
• Source: Maastricht Radiation Oncology
• Contact: Maaike Berbée, MD, PhD
• Phone: 0031884455600
• Email: maaike.berbee[@]maastro.nl
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 50
• Est. completion date: December 2024
• Est. primary completion date: December 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Rectal Cancer
• Rectal Neoplasms

Intervention

Diagnostic Test:
• Ultrasound
3D endorectal ultrasound.
• Rectoscopy
Rigid rectoscopy.

Other:
• Scan, e.g. CT (resection specimen)
For some patients, images of the resection specimen (note: NOT of the patients) during the pathological process will be acquired.

Locations

Country	Name	City	State
Netherlands	Catharina Hospital	Eindhoven	Noord-Brabant
Netherlands	Maastricht University Medical Center	Maastricht	Limburg
Netherlands	Maastro	Maastricht	Limburg

Sponsors (3)

Lead Sponsor	Collaborator
Maastricht Radiation Oncology	Catharina Ziekenhuis Eindhoven, Maastricht University Medical Center

Country where clinical trial is conducted

Netherlands, 

References & Publications (23)

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. — View Citation

Dayde D, Tanaka I, Jain R, Tai MC, Taguchi A. Predictive and Prognostic Molecular Biomarkers for Response to Neoadjuvant Chemoradiation in Rectal Cancer. Int J Mol Sci. 2017 Mar 7;18(3):573. doi: 10.3390/ijms18030573. — View Citation

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. — View Citation

Goldstein NS, Soman A, Sacksner J. Disparate surgical margin lengths of colorectal resection specimens between in vivo and in vitro measurements. The effects of surgical resection and formalin fixation on organ shrinkage. Am J Clin Pathol. 1999 Mar;111(3):349-51. doi: 10.1093/ajcp/111.3.349. — View Citation

Kapali AS, Chandramohan K, Jayasudha AV. A Prospective Study of Distal Microscopic Spread in Rectal Cancer After Neoadjuvant Chemoradiation in Pinned and Unpinned Specimen. Indian J Surg Oncol. 2017 Dec;8(4):469-473. doi: 10.1007/s13193-017-0637-2. Epub 2017 Mar 18. — View Citation

Lam D, Kaneko Y, Scarlett A, D'Souza B, Norris R, Woods R. The Effect of Formalin Fixation on Resection Margins in Colorectal Cancer. Int J Surg Pathol. 2019 Oct;27(7):700-705. doi: 10.1177/1066896919854159. Epub 2019 Jun 14. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Martens MH, Maas M, Heijnen LA, Lambregts DM, Leijtens JW, Stassen LP, Breukink SO, Hoff C, Belgers EJ, Melenhorst J, Jansen R, Buijsen J, Hoofwijk TG, Beets-Tan RG, Beets GL. Long-term Outcome of an Organ Preservation Program After Neoadjuvant Treatment for Rectal Cancer. J Natl Cancer Inst. 2016 Aug 10;108(12):djw171. doi: 10.1093/jnci/djw171. Print 2016 Dec. — View Citation

Nuernberg D, Saftoiu A, Barreiros AP, Burmester E, Ivan ET, Clevert DA, Dietrich CF, Gilja OH, Lorentzen T, Maconi G, Mihmanli I, Nolsoe CP, Pfeffer F, Rafaelsen SR, Sparchez Z, Vilmann P, Waage JER. EFSUMB Recommendations for Gastrointestinal Ultrasound Part 3: Endorectal, Endoanal and Perineal Ultrasound. Ultrasound Int Open. 2019 Jan;5(1):E34-E51. doi: 10.1055/a-0825-6708. Epub 2019 Feb 5. — View Citation

Park HS, Lee S, Haam S, Lee GD. Effect of formalin fixation and tumour size in small-sized non-small-cell lung cancer: a prospective, single-centre study. Histopathology. 2017 Sep;71(3):437-445. doi: 10.1111/his.13237. Epub 2017 Jun 16. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Simpson G, Hopley P, Wilson J, Day N, Haworth A, Montazeri A, Smith D, Titu L, Anderson J, Agbamu D, Walsh C. Long-term outcomes of real world 'watch and wait' data for rectal cancer after neoadjuvant chemoradiotherapy. Colorectal Dis. 2020 Nov;22(11):1568-1576. doi: 10.1111/codi.15177. Epub 2020 Jul 20. — View Citation

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. — View Citation

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. — View Citation

Thies S, Langer R. Tumor regression grading of gastrointestinal carcinomas after neoadjuvant treatment. Front Oncol. 2013 Oct 7;3:262. doi: 10.3389/fonc.2013.00262. — View Citation

Tran T, Sundaram CP, Bahler CD, Eble JN, Grignon DJ, Monn MF, Simper NB, Cheng L. Correcting the Shrinkage Effects of Formalin Fixation and Tissue Processing for Renal Tumors: toward Standardization of Pathological Reporting of Tumor Size. J Cancer. 2015 Jul 2;6(8):759-66. doi: 10.7150/jca.12094. eCollection 2015. — View Citation

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. — View Citation

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. — View Citation

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. Erratum In: Brachytherapy. 2019 May - Jun;18(3):427. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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.	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
Other	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.
Primary	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	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)
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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).
Secondary	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.
Secondary	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.
Secondary	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.