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

Official title

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

Overview

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.

Detailed 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.

Interventions

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

Primary outcome measures

• 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) [Time frame: About 1 years]

Secondary outcome measures (12)

• Change of cyclomodulin-Producing Escherichia Coli colonization rate before and after neoadjuvant treatment [Time frame: About 1 years]
• Change of cyclomodulin-Producing Escherichia Coli prevalence before and after neoadjuvant treatment [Time frame: About 1 years]
• Change of prevalence forming the overall bacterial composition before and after neoadjuvant treatment [Time frame: About 1 years]
• Change of colonization rate (in addition to cyclomodulin-Producing Escherichia Coli) forming the overall bacterial composition before and after neoadjuvant treatment [Time frame: About 1 years]
• Relative risk of poor response to neoadjuvant treatment in colonized patients with other bacteria ("exposed") compared to non-colonized patients ("unexposed") [Time frame: About 1 years]
• Proportion of patients colonized according to the modality of the clinical variable age [Time frame: About 1 years]
• Proportion of patients colonized according to the modality of the clinical variable gender [Time frame: About 1 years]
• Proportion of patients colonized according to the modality of the clinical variable body mass index [Time frame: About 1 years]
• 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 [Time frame: About 1 years]
• 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 [Time frame: About 1 years]
• 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 [Time frame: About 1 years]
• Types of other bacteria forming the overall bacterial composition before neoadjuvant treatment [Time frame: About 1 years]

Eligibility criteria

Inclusion criteria

• Histologically proven lower and mid-rectal adenocarcinoma at clinical stage II and III
• Patient is to receive neoadjuvant treatment (radiochemotherapy or chemotherapy or radiotherapy). Induction chemotherapy such as folfox or folfirinox is allowed
• Patient who has signed the informed consent of the study
• Male or female ≥ 18 years old
• 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

• Antibiotic treatment at the time or in the month preceding stool sampling
• Presence of an ostomy
• Previous treatment for rectal cancer
• Patient not affiliated to a French social protection system
• Patient not in favour of good compliance with treatment for psychological, family, social or geographical reasons
• Legal incapacity (Patient under curatorship or guardianship)
• Prior radiation therapy or pelvic curia in the year prior to inclusion
• History of other cancers in the last 5 years (except for in-situ cervical carcinomas and non-melanoma skin carcinomas treated optimally)
• Pregnant or breastfeeding woman

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

N/A

Model

Single group

Masking

Open label

Primary purpose

Other

Study locations

France · 2 centers

• Institut régional du Cancer de Montpellier — Montpellier
• CHU Clermont-Ferrand — Clermont-Ferrand

Publications

• 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. PMID 30207593
• 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, S PMID 28179091
• 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. Ep PMID 21596621
• 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. PMID 15496622
• 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. PMID 9112145
• 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. PMID 15383798
• 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 D PMID 26705854
• 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/S014 PMID 28601342

Identifiers

NCT: NCT04103567 · PROICM 2019-14-MIR

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗