Intestinal Microbiota in Prostate Cancer Patients as a Biomarker for Radiation-INduced Toxicity (IMPRINT)

Study Overview
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Brief Summary
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Radiotherapy (RT) of the abdomen and/or pelvis is known to cause acute and late gastrointestinal (GI) toxicities. While radiation dose and volume are known risk factors for developing such side effects, recent evidence suggests patterns of disturbance in the composition of the GI microbiota - so called dysbiosis - may also promote the host's susceptibility to GI toxicities through impaired intestinal barrier function and inflammation. The IMPRINT-study aims to expand the current knowledge on the role of intestinal bacteria and their metabolites involved in the pathophysiology of radiation-induced GI toxicities by longitudinally examining the microbiota composition (feces), the associated metabolome (blood, feces and urine) and bacterial extracellular vesicles (BEVs) (blood and feces).

Detailed Description
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The IMPRINT-study is a prospective biomarker study assessing the impact of different treatment field sizes and associated radiation doses on the patient's microbiome and metabolome, whereby the link with radiation-induced GI toxicities will be emphasized. Blood, urine and fecal samples will be longitudinally collected at 4 different time points: (1) shortly before, (2) during and (3) shortly after RT treatment, as well as (4) one-month post-RT. To our knowledge, this is the first clinical research project relating the impact of multiple radiation parameters on fecal-, urine- and blood-based biomarkers to risk of GI toxicities in a homogeneously defined study population.

Official Title
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Intestinal Microbiota in Prostate Cancer Patients as a Biomarker for Radiation-INduced Toxicity (IMPRINT): A Prospective Biomarker Study

Conditions
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Prostate Cancer, Prostate Adenocarcinoma, Prostatic Neoplasms

Intervention / Treatment
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* Other: Collection of human biofluids
* Other: Patient reported outcome measures


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically proven (initial) adenocarcinoma of the prostate Localized (confined to primary site) and/or regional (spread to regional pelvic lymph nodes) disease stage at diagnosis Age ≥ 18 years RT is an integral part of the treatment - primary, adjuvant or salvage WHO performance status 0-2 Administration of androgen deprivation therapy (ADT) before RT Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule Signed informed consent form (ICF) according to ICH/GCP and national/regional regulations Exclusion Criteria: Other primary tumor (except for non-melanoma skin cancer) diagnosed < 5 years before enrollment Diagnosis of inflammatory bowel disease (e.g. Crohn's disease or ulcerative colitis) Administration of systemic therapy during RT other that ADT Subjected to antibiotic treatment or medically imposed dietary restrictions < 1 month prior to enrollment Body mass index (BMI) > 35 Administration of pelvic RT < 1 year

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Prostate (Bed) only RadioTherapy (PBRT)<br>Primary, adjuvant or salvage RT of the prostate (bed) without RT of the pelvic nodal regions in the small pelvis, according to local hospital guidelines and protocols. | Other: Collection of human biofluids<br>* Feces, blood and urine: (1) shortly before, (2) during and (3) shortly after RT treatment, as well as (4) one-month post-RT<br>Other: Patient reported outcome measures<br>* EORTC QLQ-C30, PR25: (1) shortly before and (2) shortly after RT treatment, as well as (3) one-month post-RT<br>|
| Active Comparator: Whole Pelvis RadioTherapy (WPRT)<br>Primary, adjuvant or salvage RT of the pelvic nodal regions in the small pelvis with possible additional RT of the prostate (bed), according to local hospital guidelines and protocols. | Other: Collection of human biofluids<br>* Feces, blood and urine: (1) shortly before, (2) during and (3) shortly after RT treatment, as well as (4) one-month post-RT<br>Other: Patient reported outcome measures<br>* EORTC QLQ-C30, PR25: (1) shortly before and (2) shortly after RT treatment, as well as (3) one-month post-RT<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Microbiome profiles as assessed by fecal samples | Characterization of dynamic changes in the intestinal microbiota composition using 16S rRNA sequencing technology | Up to 3.5 months after inclusion | 
| Metabolome profiles as assessed by fecal, blood and urine samples | Characterization of dynamic changes in the concentration of all small molecules (metabolites) in feces, blood and urine using ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) | Up to 3.5 months after inclusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Discovery of potential predictive biomarkers for the development of RT-induced GI toxicities | The identified microbiota and metabolite signatures will be investigated for association with incidence and severity of GI toxicities | Up to 3.5 months after inclusion | 
| Incidence of GI and Genitourinary (GU) toxicities | GI and GU toxicities as per Common Terminology for Adverse Events (CTCAE) v4.0 | Up to 3.5 months after inclusion | 
| Patient reported QOL as per EORTC-QLQ C30 | Validated questionnaire assessing different health-related parameters (psychological, physical and social well-being) in cancer patients | Up to 3.5 months after inclusion | 
| Patient reported QOL as per EORTC-QLQ PR25 | Validated questionnaire assessing the health-related QOL of prostate cancer patients | Up to 3.5 months after inclusion | 
| Concentration of BEVs in fecal and blood samples | BEVs in fecal and blood samples will be separated and analyzed through the orthogonal implementation of ultrafiltration, size-exclusion chromatography (SEC) and density-gradient centrifugation, followed by biochemical characterization | Up to 3.5 months after inclusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radiotherapy, Microbiome, Metabolome