Determination of Microbiological Factors Associated With Poor Response to Neoadjuvant Treatment in Rectal Cancers

Rectal Cancer Clinical Trial

— MICARE  

Official title:

Determination of Microbiological Factors Associated With Poor Response to Neoadjuvant Therapy in Rectal Cancers: Focus on Cyclomodulin-producing Escherichia Coli

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04103567
• Other study ID #: PROICM 2019-14-MIR
• Status: Recruiting
• Phase: N/A
• Start date: January 14, 2020
• Est. completion date: January 30, 2030

Study information

• Verified date: September 2023
• Source: Institut du Cancer de Montpellier - Val d'Aurelle
• Contact: Aurore MOUSSION, MD
• Phone: 0467612446
• Email: Aurore.Moussion[@]icm.unicancer.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The objective of this project is to determine in a non-invasive manner (fecal samples) the predictive value of the intestinal microbiota and the presence of genotoxin-producing bacteria on the response to neoadjuvant treatment in rectal cancer. This could lead to a better understanding and selection of patients for personalized treatment in rectal cancer.

Description:

Rectal cancer is the 8th leading cause of cancer in the world with more than 300,000 deaths in 2018. In addition to surgery, neoadjuvant treatment has proven its value in reducing local recurrences. Evaluation of the response to neoadjuvant treatment (essential for the subsequent therapeutic decision but also for the oncological prognosis. It is based on rectal magnetic resonance imaging, completed after surgery by anatomopathology. A personalised treatment with therapeutic de-escalation or intensification for aggressive tumours can be decided depending on the response to Neoadjuvant treatment. Thus, knowledge of the predictive factors of response to neoadjuvant treatment would permit to anticipate and adapt care.

The intestinal microbiota is a true microbial organ, playing a major role in maintaining intestinal homeostasis. Some bacterial species have been identified and suspected of playing a role in colorectal carcinogenesis. Among these species, genotoxin-producing Escherichia coli (CPEC) strains such as colibactin (cyclomodulin encoded by the genomic islet pks) are preferentially detected in patients with colorectal cancer (CRC), especially the most aggressive forms. Recent studies show that the intestinal microbiota is a prognostic factor in the response to certain chemotherapies or immunotherapies, but little work has been done on its potential influence on the effectiveness of radiotherapy. This suggests the possibility of using these biomarkers associated with response to neoadjuvant treatment.

The objective of this project is to determine in a non-invasive manner (fecal samples) the predictive value of the intestinal microbiota and the presence of genotoxin-producing bacteria on the response to neoadjuvant treatment in rectal cancer. This could lead to a better understanding and selection of patients for tailored treatment in rectal cancer.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 220
• Est. completion date: January 30, 2030
• Est. primary completion date: January 30, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Histologically proven lower and mid-rectal adenocarcinoma at clinical stage II and III

2. Patient is to receive neoadjuvant treatment (radiochemotherapy or chemotherapy or radiotherapy). Induction chemotherapy such as folfox or folfirinox is allowed

3. Patient who has signed the informed consent of the study

4. Male or female = 18 years old

5. Appropriate contraceptive measures should be used by both men and non-menopausal women before entering the trial until at least 8 weeks after the last course of radiochemotherapy. The investigator should inform the patient about the contraceptive measures to be used.

Exclusion Criteria:

1. Antibiotic treatment at the time or in the month preceding stool sampling

2. Presence of an ostomy

3. Previous treatment for rectal cancer

4. Patient not affiliated to a French social protection system

5. Patient not in favour of good compliance with treatment for psychological, family, social or geographical reasons

6. Legal incapacity (Patient under curatorship or guardianship)

7. Prior radiation therapy or pelvic curia in the year prior to inclusion

8. History of other cancers in the last 5 years (except for in-situ cervical carcinomas and non-melanoma skin carcinomas treated optimally)

9. Pregnant or breastfeeding woman

Related Conditions & MeSH terms

• Rectal Cancer
• Rectal Neoplasms

Intervention

Other:
• Biological collection
Fecal samples collected at different times : during inclusion consultation with surgeon, after neoadjuvant treatment and before surgery.

Locations

Country	Name	City	State
France	CHU Clermont-Ferrand	Clermont-Ferrand	Puy De Dôme
France	Institut régional du Cancer de Montpellier	Montpellier	Hérault

Sponsors (1)

Lead Sponsor	Collaborator
Institut du Cancer de Montpellier - Val d'Aurelle

Country where clinical trial is conducted

France, 

References & Publications (16)

Bonnet M, Buc E, Sauvanet P, Darcha C, Dubois D, Pereira B, Dechelotte P, Bonnet R, Pezet D, Darfeuille-Michaud A. Colonization of the human gut by E. coli and colorectal cancer risk. Clin Cancer Res. 2014 Feb 15;20(4):859-67. doi: 10.1158/1078-0432.CCR-13-1343. Epub 2013 Dec 13. — View Citation

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12. Erratum In: CA Cancer J Clin. 2020 Jul;70(4):313. — View Citation

Buc E, Dubois D, Sauvanet P, Raisch J, Delmas J, Darfeuille-Michaud A, Pezet D, Bonnet R. High prevalence of mucosa-associated E. coli producing cyclomodulin and genotoxin in colon cancer. PLoS One. 2013;8(2):e56964. doi: 10.1371/journal.pone.0056964. Epub 2013 Feb 14. — View Citation

Dworak O, Keilholz L, Hoffmann A. Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis. 1997;12(1):19-23. doi: 10.1007/s003840050072. — View Citation

Gerard JP, Andre T, Bibeau F, Conroy T, Legoux JL, Portier G, Bosset JF, Cadiot G, Bouche O, Bedenne L; Societe Francaise de Chirurgie Digestive (SFCD), Societe Francaise d'Endoscopie Digestive (SFED0), Societe Francaise de Radiotherapie Oncologique (SFRO). Rectal cancer: French Intergroup clinical practice guidelines for diagnosis, treatments and follow-up (SNFGE, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO). Dig Liver Dis. 2017 Apr;49(4):359-367. doi: 10.1016/j.dld.2017.01.152. Epub 2017 Jan 20. — View Citation

Habr-Gama A, Perez RO, Nadalin W, Sabbaga J, Ribeiro U Jr, Silva e Sousa AH Jr, Campos FG, Kiss DR, Gama-Rodrigues J. Operative versus nonoperative treatment for stage 0 distal rectal cancer following chemoradiation therapy: long-term results. Ann Surg. 2004 Oct;240(4):711-7; discussion 717-8. doi: 10.1097/01.sla.0000141194.27992.32. — View Citation

Nougayrede JP, Homburg S, Taieb F, Boury M, Brzuszkiewicz E, Gottschalk G, Buchrieser C, Hacker J, Dobrindt U, Oswald E. Escherichia coli induces DNA double-strand breaks in eukaryotic cells. Science. 2006 Aug 11;313(5788):848-51. doi: 10.1126/science.1127059. — View Citation

Nougayrede JP, Taieb F, De Rycke J, Oswald E. Cyclomodulins: bacterial effectors that modulate the eukaryotic cell cycle. Trends Microbiol. 2005 Mar;13(3):103-10. doi: 10.1016/j.tim.2005.01.002. — View Citation

Renehan AG, Malcomson L, Emsley R, Gollins S, Maw A, Myint AS, Rooney PS, Susnerwala S, Blower A, Saunders MP, Wilson MS, Scott N, O'Dwyer ST. Watch-and-wait approach versus surgical resection after chemoradiotherapy for patients with rectal cancer (the OnCoRe project): a propensity-score matched cohort analysis. Lancet Oncol. 2016 Feb;17(2):174-183. doi: 10.1016/S1470-2045(15)00467-2. Epub 2015 Dec 17. — View Citation

Rouanet P, Rullier E, Lelong B, Maingon P, Tuech JJ, Pezet D, Castan F, Nougaret S; and the GRECCAR Study Group. Tailored Treatment Strategy for Locally Advanced Rectal Carcinoma Based on the Tumor Response to Induction Chemotherapy: Preliminary Results of the French Phase II Multicenter GRECCAR4 Trial. Dis Colon Rectum. 2017 Jul;60(7):653-663. doi: 10.1097/DCR.0000000000000849. — View Citation

Roy S, Trinchieri G. Microbiota: a key orchestrator of cancer therapy. Nat Rev Cancer. 2017 May;17(5):271-285. doi: 10.1038/nrc.2017.13. Epub 2017 Mar 17. — View Citation

Rullier E, Rouanet P, Tuech JJ, Valverde A, Lelong B, Rivoire M, Faucheron JL, Jafari M, Portier G, Meunier B, Sileznieff I, Prudhomme M, Marchal F, Pocard M, Pezet D, Rullier A, Vendrely V, Denost Q, Asselineau J, Doussau A. Organ preservation for rectal cancer (GRECCAR 2): a prospective, randomised, open-label, multicentre, phase 3 trial. Lancet. 2017 Jul 29;390(10093):469-479. doi: 10.1016/S0140-6736(17)31056-5. Epub 2017 Jun 7. — View Citation

Sauer R, Becker H, Hohenberger W, Rodel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R; German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med. 2004 Oct 21;351(17):1731-40. doi: 10.1056/NEJMoa040694. — View Citation

Savage DC. Microbial ecology of the gastrointestinal tract. Annu Rev Microbiol. 1977;31:107-33. doi: 10.1146/annurev.mi.31.100177.000543. No abstract available. — 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

Villeger R, Lopes A, Veziant J, Gagniere J, Barnich N, Billard E, Boucher D, Bonnet M. Microbial markers in colorectal cancer detection and/or prognosis. World J Gastroenterol. 2018 Jun 14;24(22):2327-2347. doi: 10.3748/wjg.v24.i22.2327. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The ratio between the proportions of poor response to neoadjuvant treatment in populations so-called "exposed" (patients colonized by bacteria producing toxins (cyclomodulin) and unexposed (patients not colonized by bacteria producing toxins)		About 1 years
Secondary	Change of cyclomodulin-Producing Escherichia Coli colonization rate before and after neoadjuvant treatment		About 1 years
Secondary	Change of cyclomodulin-Producing Escherichia Coli prevalence before and after neoadjuvant treatment		About 1 years
Secondary	Change of prevalence forming the overall bacterial composition before and after neoadjuvant treatment		About 1 years
Secondary	Change of colonization rate (in addition to cyclomodulin-Producing Escherichia Coli) forming the overall bacterial composition before and after neoadjuvant treatment		About 1 years
Secondary	Relative risk of poor response to neoadjuvant treatment in colonized patients with other bacteria ("exposed") compared to non-colonized patients ("unexposed")		About 1 years
Secondary	Proportion of patients colonized according to the modality of the clinical variable age		About 1 years
Secondary	Proportion of patients colonized according to the modality of the clinical variable gender		About 1 years
Secondary	Proportion of patients colonized according to the modality of the clinical variable body mass index		About 1 years
Secondary	Overall survival in colonized people by the different types of bacteria that form the overall bacterial composition (including cyclomodulin-Producing Escherichia Coli) compared to non-colonized people		About 1 years
Secondary	Disease-free survival in colonized people by the different types of bacteria that form the overall bacterial composition (including cyclomodulin-Producing Escherichia Coli) compared to non-colonized people		About 1 years
Secondary	Specific survival in colonized people by the different types of bacteria that form the overall bacterial composition (including cyclomodulin-Producing Escherichia Coli) compared to non-colonized people		About 1 years
Secondary	Types of other bacteria forming the overall bacterial composition before neoadjuvant treatment		About 1 years