EPRIMM: Effect of Pelvic Radiotherapy on the Intestinal Microbiome and Metabolome

Sponsor

The Christie NHS Foundation Trust (Other)

Overall Status

Recruiting

CT.gov ID

NCT04995809

Collaborator

University of Liverpool (Other), University of Manchester (Other), Wythenshawe Hospital (Other)

Enrollment

Location

23.6

Anticipated Duration (Months)

1.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Eight in ten patients will develop bowel problems during radiotherapy, eg diarrhoea, pain and incontinence, half will develop difficult long-term bowel problems. It is not known why some people get bowel problems and others do not and there is no test to predict who will develop bowel problems following their treatment.

There is a link between the changes in the number and type of gut bacteria (the microbiome) in some bowel conditions and it is possible to test for these different bacteria in a simple stool sample using genetic testing. Also gut bacteria produce different gases in the stool called "volatile organic compounds" (VOCs), which can be measured in stool samples. Specific VOC patterns have been seen in other bowel conditions and small studies suggesting that there are specific VOC and gut bacteria patterns in the stool of those undergoing pelvic radiotherapy which may help to identify people who will get difficult bowel problems. Diet can change the microbiome/VOCs so diet change could improve bowel symptoms after radiotherapy.

The investigators would like to test stool samples of patients with womb, cervix or bladder cancer having pelvic radiotherapy to see if there are differences in the number/type of gut bacteria and VOCs between those who get severe bowel symptoms compared to those with mild bowel symptoms. They also want to see whether these differences in VOCs or gut bacteria can tell who will develop severe bowel symptoms during or after radiotherapy and determine the effect of diet.

The first step is to run the study on a small scale to confirm that a larger study would work. This will make sure the investigators can recruit and consent people safely and will test the best ways of measuring bowels symptoms using several questionnaire options. They will collect the information needed to work out how many people would be needed in a large trial to fully test the theory. Ultimately, the investigators would like to use differences in the number/type of gut bacteria and VOCs to find ways to better prevent and treat bowel problems after pelvic radiotherapy.

Condition or Disease	Intervention/Treatment	Phase
Urinary Bladder Neoplasms Uterine Cervical Neoplasms Endometrial Neoplasms

Detailed Description

Background 80% of patients develop GI-toxicity during pelvic radiotherapy and half develop chronic GI-toxicity. This manifests as diarrhoea, pain, bleeding and incontinence. Unlike many diseases, the triggering event, i.e. radiotherapy, is known, enabling the identification of specific pathophysiological changes. The metabolomic and microbiomic profile of patients undergoing pelvic radiotherapy and the link with GI-toxicity has not been fully explored. Studies suggest radiation alters the gut microbiome, altering microbial diversity. Higher pre-radiotherapy diversity has been seen in those with no GI symptoms with reducing diversity as GI-toxicity increases and an association between low microbial diversity and severity of chronic GI-toxicity. Dietary change can alter microbial composition. Faecal VOCs are chemicals that exist in the gaseous phase at ambient temperature and form the faecal metabolome, the result of the interaction between the gut microbiota and cell metabolism. VOCs can be identified using established techniques and unique VOCs patterns have been identified in specific GI diseases. Early data suggest differences in VOCs between patients with high vs low levels of GI-toxicity. Metabolomic and microbiomic profiling and manipulation has the potential to advance understanding of disease-related pathways to predict, prevent and treat GI-toxicity.

Rationale GI-toxicity is a significant cause of morbidity both during and after pelvic radiotherapy to the extent that it adversely affects quality of life. There is a paucity of research into this condition. The metabolomic and microbiomic profile of patients undergoing pelvic radiotherapy and the link with GI-toxicity has not been fully explored. Studies suggest radiation alters the gut microbiome, altering microbial diversity. Higher pre-radiotherapy diversity has been seen in those with no GI symptoms with reducing diversity as GI-toxicity increases and an association between low microbial diversity and severity of chronic GI-toxicity. Dietary change can alter microbial composition. Unique VOCs patterns have been identified in specific GI diseases. Early data suggest differences in VOCs between patients with high vs low levels of GI-toxicity. Metabolomic and microbiomic profiling and manipulation has the potential to advance understanding of disease-related pathways to predict, prevent and treat GI-toxicity.

By comparing samples collected pre and post radiotherapy the investigators aim to identify potential biomarkers. They are going to integrate metadata indicating a negative GI response to the therapy, i.e. GI toxicity symptoms from validated questionnaires, with microbial community data and VOCs data in order to identify markers (VOCs or bacteria) that increase with symptoms. They will also identify which species make patients more susceptible to negative outcomes by analysing the community pre-treatment.

Previous literature using culture based methods showed an increase in E. coli and Staphylococcus spp. and the investigators will determine whether they can confirm this. In terms of VOCs, they will look for markers of inflammation, e.g. aldehydes. It has been proposed that there are similarities between radiation-induced GI-toxicity and IBD, particularly Crohn's disease, therefore it would be interesting to see whether there is a similar dysbiosis of the microbial community and VOCs profile to that observed in Crohn's disease, i.e. whether decreased species diversity, increased Bacteroides species and Enterobacteriaceae coupled with a decrease in Faecal bacterium are also observed in patients with severe GI toxicity symptoms.

Potential interventions to modify the gut microbiome, e.g. diet, pre/probiotics, synthetic faecal microbiota transplantation, are in wide clinical research use currently in other related clinical areas, e.g. inflammatory bowel disease, and would be the types of interventions that may be indicated by information from this work and the subsequent definitive study.

The objectives of the subsequent definitive study are as follows:

Determine the differences in VOC profile/microbiome in patients with the most severe vs least severe GI-toxicity at 4 weeks and 6 months.
Determine the differences in VOC profile/microbiome at baseline in patients who develop the most severe vs least severe GI-toxicity at 4 weeks and 6 months.
Characterise disease-related pathways for GI-toxicity to identify potential therapeutic targets, including dietary.

Study Design

Study Type:

Observational

Anticipated Enrollment :

40 participants

Observational Model:

Other

Time Perspective:

Prospective

Official Title:

Investigating the Effect of Pelvic Radiotherapy on the Intestinal Microbiome and Metabolome to Improve the Detection and Management of Gastrointestinal (GI) Toxicity.

Actual Study Start Date :

Jun 25, 2021

Anticipated Primary Completion Date :

Dec 13, 2022

Anticipated Study Completion Date :

Jun 13, 2023

Arms and Interventions

Arm	Intervention/Treatment
EPRIMM study participants No intervention: Questionnaires, food diaries and stool sample.

Outcome Measures

Primary Outcome Measures

Rate of recruitment [12 months]
Recruitment rates: can we achieve sufficient recruitment to the study? Are patients willing to participate?
Acceptability of recruitment [12 months]
Acceptability of recruitment process to patient cohort measured using internally generated non-validated questionnaire led by the research nurse
Patient experience of study [6 months]
Experience of the study process by patient cohort measured using internally generated non-validated questionnaire led by the research nurse
Stool sample collection [6 months]
Practicality and acceptability of obtaining stool samples for patient cohort measured using internally generated non-validated questionnaire led by the research nurse
Attrition rates [18 months]
Rate of patient leaving the study before completing
Reason for attrition [18 months]
Reason for patient leaving the study before completing

Secondary Outcome Measures

Acceptability of questionnaires/food diaries [6 months]
Acceptability of questionnaires and food diaries to patient cohort measured using internally generated non-validated questionnaire led by the research nurse
Completion of information [6 months]
Proportion of patients who complete the study eg rate of attrition of patients and rate of missing data items
The number of participants required to take part in a larger multicentre trial which will identify microbiome/VOC profiles which confer risk of GI toxicity [24 months]
To identify microbiome (diversity or composition) or VOCs profile that confers risk of GI-toxicity and that is associated with participants greater severity of GI-toxicity in response in response to radiotherapy in the acute and chronic phases
The number of participants required to take part in a larger multicentre trial which will identify potential therapeutic targets from metabolomic and microbiomic profiling [24 months]
To use metabolomic and microbiomic profiling to further understand the pathophysiology of GI-toxicity to identify potential therapeutic targets for treatment and/or prevention, including dietary targets

Other Outcome Measures

Microbiome data (DNA reads) [24 months]
Obtain initial data regarding microbiome (diversity or composition) associated with risk of GI-toxicity and that is associated with greater severity of GI-toxicity in response in response to radiotherapy in the acute and chronic phases
VOC profile by solid-phase microextraction followed by gas chromatography-mass spectrometry SPME-GC/MS [24 months]
Obtain initial data (peak area/metabolite(VOC)/sample) regarding VOCs profile associated with risk of GI-toxicity and that is associated with greater severity of GI-toxicity in response in response to radiotherapy in the acute and chronic phases.
Metabolomic profiling by SPME-GC/MS [24 months]
To use metabolomic profiling to further understand the pathophysiology of GI-toxicity to identify potential therapeutic targets for treatment and/or prevention, including dietary targets
Microbiomic profiling by bacterial 16S rRNA metabarcoding sequencing [24 months]
To use microbiomic profiling ( data table containing number of reads/species/sample) to further understand the pathophysiology of GI-toxicity to identify potential therapeutic targets for treatment and/or prevention, including dietary targets