Preoperative Endoscopic Treatment With Fosfomycin and Metronidazole in Patients With Right-sided Colon Cancer and Colon Adenoma (MEFO-trial)

• Status: Recruiting
• Trial end date: 2023-03-01
• Target enrollment: 0
• Participant gender: All

Summary

Clinical studies have shown that patients with right-sided colon cancer have reduced progression-free and overall survival compared to patients with left-sided colon cancer. At the same time, patients with right-sided colon adenomas have a higher risk of developing interval cancers after endoscopic mucosal resection. Dysbiosis and known bacterial drivers play a significant role in the carcinogenesis of colorectal cancer, and may contribute to the growth of adenomas. Clinical studies have found biofilm formation and positive staining for Fusobacterium nucleatum (FN) in almost all right-sided colon cancers and adenomas. The composition of bacteria also in the normal mucosa in these two groups of patients has been found to be different from healthy controls.

Endoscopic preoperative antibiotic local treatment of the biofilm and tumors would theoretically result in decreased tumor mass, recovery of the mucosa, and a normalization of the immune response in the treated section of the colon. The oral administration of the antibiotic metronidazole in mice has shown to lower the tumor load (FN-positive xenograft tumors) and decrease in intratumoral abundance of the pro-carcinogenic bacteria, FN.

The aim of this study is to investigate the effect of local antibiotic treatment with fosfomycin and metronidazole on tumor characteristics and the colonic biofilm in patients with right-sided colon cancer or right-sided colon adenomas. This is a clinical proof-of-concept intervention study, and the investigators are to our knowledge the first group to look into local antibiotic treatment of biofilm in patients with colon cancer or colon adenoma. It is based on a non-randomized trial design with an open label single group assignment. There are two tracks depending on the pathology of the tumor: 1) patients with right-sided colon cancer; 2a) patients with right-sided colon adenoma. The intervention is a therapeutic endoscopy where the antibiotics fosfomycin and metronidazole are sprayed throughout the right colon section from caecum to the right colon flexure (100ml of gel contains 800mg of fosfomycin and 200mg of metronidazole). Patients will be included prospectively from the surgical department of Herlev University Hospital and Zealand University Hospital once having received oral and written information, followed by signing the consent. There will be a retrospective cohort of patients with colon adenoma from 2018 (track 2b). The investigators will retrieve the archived adenoma tissue as control tissue. In Clinical Trial, Track 1 and Track 2a will be registered as two different arms that use the same intervention, but the results from each arm later on is going to be reported in separate publications.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Zealand University Hospital
• Collaborators: Costerton Biofilm Center; Region Zealand; Reponex Pharmaceuticals A/S
• Treatments: Fosfomycin; Metronidazole

Criteria

Inclusion Criteria:

Inclusion criteria for track 1 and 2a:

• Male and female patients above 18 years of age with either:

right-sided colon cancer tumor with adenocarcinoma histologically verified scheduled for open or laparoscopic resection at the Department of Surgery, Herlev Hospital or Zealand University Hospital for track 1.

Right-sided adenomas ≥2cm in diameter endoscopically verified scheduled for endoscopic mucosal resection at the Department of Surgery, Herlev Hospital or Zealand University Hospital for track 2a.

• ASA I,II or III

• The caecum must be reached by the endoscope.

Inclusion criteria for retrospective controls (track 2b):

Male and female patients above 18 years of age who were operated for colon adenoma ≥2cm in diameter in the right hemicolon in 2018 at Department of Surgery, Zealand University Hospital. They will be matched 2:1 with the patients included in track 2a (cases) based on age and gender and pathology of the tumor.

Exclusion Criteria:

Exclusion criteria for track 1 and track 2a

1. Patients with previous allergic reaction to fosfomycin and/or metronidazole

2. Patients under current antibiotic treatment or patient who had the last dose of antibiotics 30 days prior to inclusion.

3. Patients with a non-passable tumor or patients where a part of the tumor is not visible during endoscopy (Track 1)

4. Patients with neoadjuvant chemotherapy or radiation 12 months prior to the resection.

5. Patients with a history of familial adenomatous polyposis (FAP) or hereditary nonpolyposis colorectal cancer (HNPCC)

6. Patients with a history of inflammatory bowel disease (IBD)

7. Patients under current treatment with warfarin (Marevan) and phenprocoumon (Marcoumar), or NOAK such as dabigatran (Pradaxa®), rivaroxiban (Xarelto®), edoxaban (Lixiana®) or apixaban (Eliquis®)

8. Patients under current treatment with Fenemal (Phenobarbital)

9. Patients who previously have received a fecal transplantation

10. Patients who have previously had colorectal cancer, and are now presenting with a secondary colon tumor.

11. Patients with a current alcohol use disorder (AUD): defined as a patient who are currently drinking 8 or more drinks/week for women and 15 or more drinks/week for men.

12. Predictable poor compliance (psychiatric disease, not speaking fluent Danish, mentally, impaired etc)

13. Patients with an American Society of Anaesthesiologists physical status

14. Classification (ASAscore) of IV.

15. Patients unable to be sedated

16. Pregnancy or lactation (fertile women must have a negative serum or urine pregnancy test to participate)

17. Fertile women who do not use safe contraception during the study period

18. Following contraceptive methods are acceptable when used consistently and in accordance, with both the product label and the instructions of the physician are:

• Oral contraceptive, either combined or progestogen alone

• Injectable progestogen

• Implants of levonorgestrel

• Estrogenic vaginal ring

• Percutaneous contraceptive patches

• Intrauterine device or intrauterine system with a documented failure rate < 1% per year

• Male partner sterilization (vasectomy with documented azoospermia) prior to female patient ́s entry into the study, and this male is the sole partner for that patient.

• Double barrier method: condom with spermicidal agent (foam/gel/film/cream/suppository), condom and occlusive cap (diaphragm or cervical/vault cap) with vaginal spermicidal agent (foam/gel/film/cream/suppository).

Exclusion criteria for retrospective controls (track 2b):

• Patients under the age of 18 years during the resection for colon adenoma

• Patients who were under antibiotic treatment during the EMR or patients who had the last dose of antibiotics 30 days prior to EMR

• Patients with neoadjuvant chemotherapy or radiation 12 months prior to the resection

• Patients with a history of familial adenomatous polyposis (FAP) or hereditary nonpolyposis colorectal cancer (HNPCC)

• Patients with a history of inflammatory bowel disease (IBD)

• Patients who previously have received a fecal transplantation

• Patients who have previously had colorectal cancer

• Patients registered in "Vævsanvendelsesregistret"

• Patients with insufficient tissue samples