Metronidazole for Rectal Cancer

Overseen By Michael G White, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Disulfiram

Disqualifiers: Chemotherapy, Radiotherapy, Brain metastases, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 2 weeks

60 Participants Needed

Trial Summary

Do I need to stop taking my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. However, if you are on disulfiram or have had recent chemotherapy or radiotherapy, you may not be eligible to participate.

What evidence supports the effectiveness of the drug Metronidazole for rectal cancer?

A Phase II study investigated the safety and effectiveness of using Metronidazole in combination with other treatments like chemoradiotherapy and local hyperthermia for advanced rectal cancer, suggesting it may have potential benefits when used as part of a combined treatment approach. ^{1 2 3 4 5}

Is metronidazole safe for human use?

Metronidazole is generally well-tolerated in humans, with some potential side effects like reversible nerve issues and reactions with alcohol. While animal studies have shown some cancer risks at high doses, long-term human studies have not shown an increased cancer risk, suggesting it is safe for both short-term and long-term use. ^{6 7 8 9 10}

How is the drug Metronidazole unique in treating rectal cancer?

Metronidazole is unique in treating rectal cancer because it is used as part of a combination therapy with chemoradiotherapy and local hyperthermia, which is not a standard treatment strategy for this condition. This approach aims to improve the effectiveness of treatment for locally advanced rectal cancer, which typically has a poor prognosis. ^{4 11 12 13 14}

What is the purpose of this trial?

To learn if adding metronidazole to standard therapy can decrease populations of Fusobacterium nucleatum (F. nucleatum) and other anaerobes (small organisms that cause infections) in participants with rectal cancer receiving neoadjuvant therapy, compared to neoadjuvant therapy alone.

Research Team

Michael White, MD

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

This trial is for individuals with rectal adenocarcinoma who are about to receive neoadjuvant therapy. Participants should not have taken antibiotics recently and must be able to undergo standard cancer treatments.

Inclusion Criteria

I haven't had chemotherapy for my current cancer.

I have another cancer, but it won't affect this trial's treatment.

My hepatitis B virus load is undetectable with treatment.

Exclusion Criteria

I have Cockayne syndrome.

I do not have any uncontrolled illnesses.

Participants who are receiving any other investigational agents

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive standard neoadjuvant therapy with or without metronidazole for 2 weeks

2 weeks

Regular visits as per standard care

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 year

Periodic visits for safety and tumor response assessment

Long-term follow-up

Overall survival and recurrence-free survival assessed over two years following study completion

2 years

Treatment Details

Interventions

• Metronidazole

Trial Overview The study tests if metronidazole, an antibiotic, can reduce harmful bacteria in the gut when added to usual pre-surgery cancer treatment compared to the standard treatment alone.

Participant Groups

Group I: Standard of Care Neoadjuvant Therapy + Metronidazole Experimental Treatment 1 Intervention

Participants found to be eligible to take part in this study, will be randomly assigned (as in the flip of a coin) to receive standard therapy alone or standard therapy plus metronidazole. Participants are assigned to the metronidazole group, will also take 1 tablet of metronidazole by mouth every 8 hours for 2 weeks.

Group II: Standard of Care Neoadjuvant Therapy Active Control 1 Intervention

Participants found to be eligible to take part in this study, will be randomly assigned (as in the flip of a coin) to receive standard therapy alone or standard therapy plus metronidazole. Participants in both study groups will receive their standard of care treatment, as assigned by their treating doctor outside of the research study.

Metronidazole is already approved in United States, European Union, India, Canada for the following indications:

Approved in United States as Flagyl for:

• Pelvic inflammatory disease
• Endocarditis
• Bacterial vaginosis
• Dracunculiasis
• Giardiasis
• Trichomoniasis
• Amebiasis
• Clostridioides difficile colitis

Approved in European Union as Flagyl for:

• Pelvic inflammatory disease
• Endocarditis
• Bacterial vaginosis
• Dracunculiasis
• Giardiasis
• Trichomoniasis
• Amebiasis
• Clostridioides difficile colitis

Approved in India as Metrogyl for:

• Pelvic inflammatory disease
• Endocarditis
• Bacterial vaginosis
• Dracunculiasis
• Giardiasis
• Trichomoniasis
• Amebiasis
• Clostridioides difficile colitis

Approved in Canada as Flagyl for:

• Pelvic inflammatory disease
• Endocarditis
• Bacterial vaginosis
• Dracunculiasis
• Giardiasis
• Trichomoniasis
• Amebiasis
• Clostridioides difficile colitis

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

Adjuvant radiochemotherapy significantly improves overall survival and reduces local failure rates in patients with stage II and III rectal cancer compared to surgery alone, making it the standard treatment for these patients.

Continuous infusion of 5-fluorouracil in adjuvant therapy leads to better long-term survival than bolus application, but adding leucovorin or levamisole increases toxicity without improving outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Principles of postoperative therapy in rectal carcinoma]. Folprecht, G., Köhne, CH.[2018]

In a study of 41 patients with lower rectal cancer, four courses of mFOLFOX6 chemotherapy before surgery resulted in a 3-year recurrence-free survival rate of 72.8% and a local recurrence rate of 8.5%, indicating a promising long-term oncological benefit.

Patients with clinical Stage III cancer who received adjuvant chemotherapy after the initial mFOLFOX6 treatment had a significantly higher 3-year recurrence-free survival rate (76.6%) compared to those who did not receive adjuvant therapy (40.0%), suggesting the importance of additional treatment for this group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The survival impact of preoperative FOLFOX for resectable locally advanced rectal cancer: the R-NAC-01 study. Ichikawa, N., Homma, S., Funakoshi, T., et al.[2022]

In a study of 3096 patients with locally advanced rectal cancer, elderly patients (over 75 years) had a significantly lower 3-year overall survival rate (77.2%) compared to younger patients (88.9%), indicating age is a critical factor in treatment outcomes.

Despite the age difference, elderly patients in good health can achieve similar cancer-specific survival and disease-free survival rates as younger patients when treated with neoadjuvant chemotherapy combined with chemoradiotherapy and total mesorectal excision.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oncologic and survival outcomes in elderly patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy and total mesorectal excision. He, F., Chen, M., Xiao, WW., et al.[2021]

In a study of 64 patients with locally advanced fixed T4 rectal cancer, neoadjuvant chemoradiotherapy combined with local hyperthermia achieved a high R0 resection rate of 92.2%, indicating effective tumor removal.

The treatment resulted in a 2-year overall survival rate of 91% and a disease-free survival rate of 83%, with manageable toxicity levels similar to standard treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II study of concomitant chemoradiotherapy with local hyperthermia and metronidazole for locally advanced fixed rectal cancer. Barsukov, YA., Gordeyev, SS., Tkachev, SI., et al.[2020]

Irinotecan has been established as a standard treatment for advanced/metastatic colorectal cancer, showing survival benefits over best supportive care and 5-fluorouracil (5-FU) without negatively affecting patients' quality of life.

Combining irinotecan with oral capecitabine has shown promising results in terms of efficacy and safety, offering a more convenient treatment option compared to traditional infused 5-FU, and represents a potential new standard for first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimizing the use of irinotecan in colorectal cancer. Cunningham, D., Maroun, J., Vanhoefer, U., et al.[2019]

A total of 2,309 cases of neurological adverse events associated with metronidazole were reported from 2011 to 2020, indicating a rising trend in these incidents.

Risk factors for developing metronidazole-associated neurological issues include liver cirrhosis, chronic kidney disease, intravenous administration of the drug, and lower body weight, suggesting that patients with these conditions should be monitored closely during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Frequency and Risk Factor Analysis for Metronidazole-Associated Neurologic Adverse Events. Lee, SJ., Kim, J., Lee, KH., et al.[2023]

Metronidazole is an effective treatment for various infections, including Trichomonas, amebiasis, and anaerobic infections, and is well tolerated with minimal impact on colonic flora.

While there are some concerns about potential mutagenicity and carcinogenicity in animals, the overall risk is considered low, and no increased cancer incidence has been observed in treated patients, highlighting the importance of weighing benefits against risks in treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metronidazole. Finegold, SM.[2019]

While metronidazole is generally considered safe for short-term use in treating conditions like trichomoniasis, concerns about its long-term safety have arisen due to three cases of young individuals developing malignancies after receiving high doses for Crohn's disease.

The authors emphasize the need for further prospective and long-term studies to investigate the potential risks of malignancy associated with prolonged metronidazole treatment, especially at higher dosages.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Occurrence of three cases of carcinoma in individuals with Crohn's disease treated with metronidazole. Krause, JR., Ayuyang, HQ., Ellis, LD.[2013]

Flagyl (metronidazole) is an effective anti-infective medication primarily used to treat infections caused by anaerobic bacteria and protozoa, particularly in gastrointestinal conditions like giardiasis.

It is also commonly used as a preoperative treatment to reduce the risk of bacterial contamination in patients undergoing colorectal surgery or emergency abdominal procedures, highlighting its importance in surgical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Flagyl (metronidazole hydrochloride). Claussen, DW.[2019]

Nitroimidazoles, including metronidazole, tinidazole, and ornidazole, are generally well-tolerated with low toxicity, and any adverse effects are usually transient and resolve after stopping treatment.

Long-term studies, including a follow-up of 771 women treated with metronidazole, indicate no significant cancer risk associated with these medications, suggesting they are safe for both short-term and long-term use in treating anaerobic infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of nitroimidazoles. Roe, FJ.[2013]

In a study of 490 patients with stage IV A rectal carcinoma, a combined treatment approach involving preoperative large-fraction radiotherapy and local SHF-hyperthermia was recommended, followed by surgery 24-48 hours later, to effectively manage locally spread tumors.

For tumors that are difficult to resect, a two-stage treatment plan is suggested, starting with a relieving colostoma and administering distance gammatherapy alongside metronidazole and local SHF-therapy, with the addition of intraarterial chemotherapy using 5-fluorouracil to enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Definition, classification and combined treatment of locally invasive rectal neoplasms]. Knysh, VI., Kim, FP., Goldobenko, GV., et al.[2013]

Neoadjuvant chemoradiation significantly improves surgical and long-term outcomes for patients with locally advanced rectal cancer, with 5-fluorouracil (or capecitabine) being the most effective and tolerable radiosensitizing chemotherapy option.

There is a pressing need for new radiosensitizing agents and predictive biomarkers, as current options like oxaliplatin and irinotecan show increased toxicity without substantial benefits, and further research is needed on topoisomerase I and EGFR as potential predictors of treatment response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current status of radiosensitizing agents for the management of rectal cancer. Illum, H.[2019]

Raltitrexed is a selective thymidylate synthase inhibitor that offers a more convenient 3-weekly administration schedule compared to the prolonged infusion of 5-fluorouracil, which can cause discomfort for patients.

Raltitrexed may be particularly beneficial for colorectal cancer patients who have experienced cardiotoxicity from fluoropyrimidines or have a significant history of cardiac disease, suggesting it could be a safer alternative in these cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Targeting thymidylate synthase in colorectal cancer: critical re-evaluation and emerging therapeutic role of raltitrexed. Avallone, A., Di Gennaro, E., Silvestro, L., et al.[2014]

In a study of 106 patients with locally advanced rectal cancer, neoadjuvant modified FOLFOXIRI chemotherapy combined with selective radiotherapy resulted in a 3-year disease-free survival rate of 78.9%, which is significantly better than historical controls receiving chemoradiotherapy.

Patients treated with mFOLFOXIRI experienced a lower incidence of anastomotic fistula (5.5%) compared to those receiving chemoradiotherapy (17.8%), indicating a potential safety advantage of this treatment approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant Modified FOLFOXIRI With Selective Radiotherapy in Locally Advanced Rectal Cancer: Long-term Outcomes of Phase II Study and Propensity-Score-Matched Comparison With Chemoradiotherapy. Zhang, J., Li, J., Huang, M., et al.[2023]

References

1. Germany pubmed.ncbi.nlm.nih.gov

[Principles of postoperative therapy in rectal carcinoma]. [2018]

2. Japan pubmed.ncbi.nlm.nih.gov

The survival impact of preoperative FOLFOX for resectable locally advanced rectal cancer: the R-NAC-01 study. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Oncologic and survival outcomes in elderly patients with locally advanced rectal cancer receiving neoadjuvant chemoradiotherapy and total mesorectal excision. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Phase II study of concomitant chemoradiotherapy with local hyperthermia and metronidazole for locally advanced fixed rectal cancer. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Optimizing the use of irinotecan in colorectal cancer. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Frequency and Risk Factor Analysis for Metronidazole-Associated Neurologic Adverse Events. [2023]

7. United States pubmed.ncbi.nlm.nih.gov

Metronidazole. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

Occurrence of three cases of carcinoma in individuals with Crohn's disease treated with metronidazole. [2013]

9. United States pubmed.ncbi.nlm.nih.gov

Flagyl (metronidazole hydrochloride). [2019]

10. England pubmed.ncbi.nlm.nih.gov

Safety of nitroimidazoles. [2013]

11. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Definition, classification and combined treatment of locally invasive rectal neoplasms]. [2013]

12. United States pubmed.ncbi.nlm.nih.gov

Current status of radiosensitizing agents for the management of rectal cancer. [2019]

13. England pubmed.ncbi.nlm.nih.gov

Targeting thymidylate synthase in colorectal cancer: critical re-evaluation and emerging therapeutic role of raltitrexed. [2014]

14. United States pubmed.ncbi.nlm.nih.gov

Neoadjuvant Modified FOLFOXIRI With Selective Radiotherapy in Locally Advanced Rectal Cancer: Long-term Outcomes of Phase II Study and Propensity-Score-Matched Comparison With Chemoradiotherapy. [2023]