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Despite improvements in radiation techniques, pelvic radiotherapy is responsible for acute and delayed bladder adverse events, defined as radiation cystitis. The initial symptoms of bladder injury secondary to pelvic irradiation are likely to occur during treatment or within 3 months of radiotherapy in approximately 50% of irradiated patients, and have a significant impact on their quality of life. The pathophysiology of radiation cystitis is not well understood, particularly because of the risk of complications associated with access to bladder tissue after irradiation, which limits our ability to study this process and develop treatments.
It is an original study combining digital data collection to monitor patients’ symptoms and biological markers during irradiation. The main objective of our study is to evaluate the correlation of biological biomarkers with the intensity of acute radiation cystitis and the quality of life of patients, assessed with the digital telemonitoring platform Cureety.
Patients with intermediate-risk localized prostate cancer who are eligible for localized radiotherapy will be included. Inflammatory biomarkers will be analyzed in urine and blood samples before the start of radiotherapy and at weeks 4, 12, and 48 of irradiation, through quantitative methods such as a multiplex Luminex assay, flow cytometry, and enzyme-linked immunosorbent assay. We will also characterize the patients’ gut and urine microbiota composition using 16S ribosomal RNA sequencing technology. Between sample collection visits, patients will complete various questionnaires related to radiation cystitis symptoms (using the International Prostate Symptom Score), adverse events, and quality of life (using the Functional Assessment of Cancer Therapy–Prostate questionnaire), using the Cureety digital remote monitoring platform. Upon receipt of the questionnaires, an algorithm will process the information and classify patients in accordance with the severity of symptoms and adverse events reported on the basis of Common Terminology Criteria for Adverse Events and International Prostate Symptom Score standards. This will allow us to correlate levels of urinary, blood, and fecal biomarkers with the severity of acute radiation cystitis symptoms and patient-reported quality of life.
The study started in March 2022. We estimate a recruitment period of approximately 18 months, and the final results are expected in 2024.
This prospective study is the first to explore the overexpression of inflammatory proteins in fluid biopsies from patients with symptoms of acute radiation cystitis. In addition, the 1-year follow-up after treatment will allow us to predict which patients are at risk of late radiation cystitis and to refer them for radioprotective treatment. The results of this study will allow us to develop strategies to limit radiation damage to the bladder and improve the quality of life of patients.
ClinicalTrials.gov NCT05246774; https://clinicaltrials.gov/ct2/show/NCT05246774?term=NCT05246774
DERR1-10.2196/38362
Prostate cancer is the leading cancer diagnosed in men in France, with 50,400 new cases and 8100 deaths in 2018. Improved diagnostic strategies and therapeutic management have led to a 3.7% reduction in mortality between 2010 and 2018, and the survival rate is 93% at 5 years and 80% at 10 years [
Radiation therapy (including conventional radiation therapy, stereotactic body radiation therapy, and brachytherapy) is an important therapeutic technique in the management of pelvic cancers, including prostate cancer [
Early symptoms of radiation cystitis may occur during treatment and up to 3 months after the end of radiotherapy, with an estimated all grade incidence of nearly 50% after pelvic irradiation [
Although some factors have been identified, such as the dose received, fractionation and, comorbidities (eg, diabetes and tobacco smoking), the pathophysiology of radiation cystitis remains poorly studied, particularly because of the risks of complications arising from access to the bladder tissue post irradiation, thus limiting our knowledge of and therapies targeting this process
Immunity plays an important role in the mechanism of radiation-induced toxicity or inflammation [
The interstitial cystitis model is similar to the radiation cystitis model in terms of not only collagen accumulation but also symptoms. Patients with interstitial cystitis have very severe genitourinary pain, and many are diagnosed with depression and anxiety. A positive correlation between elevated urinary proinflammatory cytokines (interleukin [IL] 4 and macrophage-derived chemokines) and the severity of interstitial cystitis has been reported [
Evidence of the protection of microbial communities, especially in the gastrointestinal tract, has led to investigations of the role of the human microbiota in patient health and well-being [
Radiation therapy to the prostate causes a disruption in the composition of the microbiota, which may promote gastrointestinal toxicities through altered gut barrier function and inflammation [
Biomarkers based on the urinary microbiota may represent new diagnostic, prognostic, and therapeutic tools for functional disorders of the lower urinary tract. It has been shown that the urinary microbiota of patients with interstitial cystitis is less diverse than that of patients without these symptoms [
To date, no study has evaluated the modification of the urinary microbiota in patients with radiation cystitis. A better understanding of the impact of the urinary microbiota on the etiopathogenesis of urological disorders may help optimize medical management.
It is also important to note that the microbiota of different organs are linked. It is known that the gut microbiota is capable of changing its microbial composition, and these changes can affect the urinary microbiota [
The main objective of this study is to determine inflammatory and remodeling markers involved in the occurrence of early (<3 months) radiation cystitis in patients with localized prostate cancer.
Our secondary objectives are to determine biological markers of the severity of early radiation cystitis and to describe changes in urinary and fecal microbiota in accordance with the severity of early radiation cystitis.
Our exploratory objectives are to describe the biological markers of severity of late radiation cystitis (>6 months) and to describe the lipidome and metabolome changes in accordance with the precocity of radiation cystitis.
The Radiotoxicity Bladder Biomarkers (RABBIO) study is an interventional, prospective, single-arm, exploratory study aimed to identify factors potentially related to radiation-induced bladder toxicity in patients with localized prostate cancer treated with radiotherapy. This study will be conducted at the Bégin Military Teaching Hospital (Saint-Mandé, France).
The study has been validated by national ethics committees (unique protocol ID number 2021-A03196-35; favorable opinion of the South Mediterranean Committee for the Protection of Persons I 03/02/2022) and the French Data Protection Agency. The study is registered on ClinicalTrials.gov (NCT05246774). The survey complies with the tenets of the Declaration of Helsinki. All patients will be informed that the data collected may be used for research purposes, and will be asked to provide their written consent.
The eligibility criteria for the RABBIO study are listed in
Collection of signed informed consent forms prior to participation in the study
Patients are aged ≥18 years at the time of selection
Histologically confirmed adenocarcinoma of the prostate is present
Localized adenocarcinoma of the prostate according to the D'Amico classification is present
Patients are eligible for external radiotherapy or brachytherapy
Patients are affiliated to a social security scheme
Patients are able to communicate well, understand, and comply with the requirements of the study according to the physician investigator
Patient has a smartphone or computer to use the Cureety platform
Patients have advanced or metastatic prostate cancer
Patients are receiving preirradiation hormone therapy
Patients have bladder or urethral cancer or a history of cancer
Previous urinary tract surgery (bladder augmentation or cystectomy)
Patients are participating in an interventional clinical study
Patients have a history of pelvic irradiation
Early symptoms of radiation cystitis are likely to occur during treatment or within 3 months of radiotherapy in approximately half of the patients [
Late manifestations of bladder damage secondary to pelvic irradiation may occur after a minimum of 3 months or even several years after the end of irradiation [
The design of RABBIO study is shown in
Study design.
Demographic data and cancer characteristics (localized or biologically relapsed prostate cancer, stage of disease, radiation regimen, concomitant treatments, and comorbidities) of the patients will be collected.
Clinical examination at each visit will include performance index (performance status), weight, blood pressure, heart rate, and oxygen saturation.
The Cureety platform will allow remote monitoring of urinary symptoms reported by patients in accordance with the CTCAE (Common Terminology Criteria for Adverse Events) guidelines [
Patients will complete the Pelvic Radiation Adverse Events Questionnaire at the inclusion visit, then once a week for 3 months (weeks 1 to 12), and then at the end-of-study visit (week 52). The questionnaire includes the following items: fatigue, nausea or vomiting, pain, hematuria, frequency of urination (pollakiuria), urinary burning, diarrhea, fecal incontinence, urinary leakage, blood in the stool (rectorrhagia), constipation, weight loss, and dysuria.
On receipt of the questionnaires on the adverse effects of radiation, an artificial intelligence algorithm will classify patients into 1 of 4 states: correct condition (green), fragile state (yellow), condition to monitor (orange), and critical condition (red;
Monitoring of radiotherapy adverse events and patient-reported quality of life using the Cureety app.
The International Prostate Symptom Score (IPSS) [
The Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaire [
The International Physical Activity Questionnaire (IPAQ) [
The IPSS, FACT-P and IPAQ questionnaires will be completed by the patient via the Cureety platform at inclusion and at the visits at weeks 4, 12, and 52.
Nearly 2 dozen studies have defined urinary biomarkers indicative of visceral disorders. Three main categories of markers have been studied: proteins involved in epithelial cell growth, mediators of inflammation, and neurotrophins. All marker levels were significantly altered in patients with interstitial cystitis, but antiproliferative factor, epidermal growth factor, and heparin-binding epidermal growth factor were the markers with the most promising results [
Biomarkers of urinary and intestinal microbiota may be prognostic of radiation-induced functional disorders [
Physical activity, as determined on the basis of muscle contraction and the oxygen consumption it generates, can induce changes in the gut microbiota profile, helping to explain the health benefits of exercise. Researchers have identified differences in the composition of the gut microbiota of elite athletes in comparison with those of sedentary individuals [
The collected samples will be analyzed for circulating biomarkers and microbiota composition.
Overall, 6 mL of blood and 5 mL of urine per patient per visit will be used for the analysis of the following 33 biomarkers: inflammatory biomarkers (including macrophage migration inhibitory factor; cytokines IL-1α, IL-1β, IL-4, IL-6, IL-7, IL-8, IL-10, IL-13, and IL-17α; macrophagic inflammatory protein 1α; TNF-α; vascular cell adhesion molecule 1; intercellular adhesion molecule 1; chemotactic cytokines including monocyte chemoattractant protein 1 and 3 and regulated on activation, normal T-expressed, and secreted; the C-X-C motif chemokine ligand 10; the M1:M2 macrophage ratio; CD4+ and CD8+ T cells; and CRP) and biomarkers of remodeling (including plasminogen activator inhibitor 1, metalloproteinases such as matrix metalloproteinase 9, matrix metalloproteinase inhibitors including tissue inhibitor of matrix metalloproteinase 1 and 2, hepatocyte growth factor, placental growth factor, VEGF, epidermal growth factor, heparin-binding epidermal growth factor, nerve tissue growth factor, and glycoprotein GP51).
The advent of molecular biology and high-throughput sequencing has revealed the diversity of urinary and fecal microbiota and led to a better understanding of these ecosystems. Over the past 2 decades, shotgun metagenomic and 16S ribosomal RNA sequencing approaches have been widely used to determine the composition of these microbiota.
This involves the analysis of metabolites (small molecules) and lipids in the blood and urine before, during, and after radiation therapy. The identity and quantity of the different metabolites and lipids depend on several factors such as available nutrients, environmental stimuli, or physiological state. Metabolome and lipidome analyses help elucidate the influence of radiotherapy on the expressed phenotype and metabolism of the patient. A GC 7890B gas chromatography system (Agilent) coupled to a MS 7010 triple quadrupole mass spectrometer will help identify lipid and metabolic proinflammatory mediator profiles in the serum and urine of patients.
As this is a pilot exploratory study, the sample size was not based on a statistical argument. As the variability and evolution of biomarkers over time and the history of the disease are not known, and in order to explore the links between biomarkers and the occurrence of radiation cystitis, based on the hypothesis that half of the patients initially included will develop cystitis, a sample size of 60 individuals—including 30 individuals with cystitis and 30 individuals without cystitis—seems acceptable. Statistical analysis will be carried out using SAS (version 9.4; SAS Institute Inc) and R (The R Foundation) [
Basic statistics will be used for continuous variables n, missing n (if applicable), mean, type of deviation, median, first and third quartiles, and minimum and maximum values, and for categorical variables, we will use frequency and percentage values.
The type I error (α, 2-sided) will be 5%. The type II error (β) will be 20%; that is, a power (1-β) of 80% will be considered.
The primary end point will indicate variations in the expression of the 33 inflammatory and remodeling biomarkers assessed using the MILLIPLEX MAP technique for the analysis of circulating markers and flow cytometry for the analysis of the immune population at the 4th and 12th weeks after the start of irradiation.
The secondary endpoints will indicate symptoms and the severity of early radiation cystitis through electronic reporting of patient-reported outcomes–CTCAE self-assessment questionnaires at inclusion and once a week during weeks 1 to 12. We will also be interested in voiding disorders, quality of life, and physical activity assessed using the IPSS, FACT-P, and IPAQ self-assessment questionnaires at inclusion and at weeks 4 and 12. Furthermore, we will characterize the composition of the urinary and fecal microbiota via 16S ribosomal RNA sequencing at baseline and at weeks 4 and 12.
Finally, we shall explore the eligibility criteria, and then at week 52, the symptoms and severity of cystitis will be assessed through electronic reporting of patient-reported outcomes–CTCAE self-assessment questionnaires, and voiding disorders, quality of life, and physical activity will be assessed with the IPSS, FACT-P, and IPAQ self-assessment questionnaires, and then the composition of the urinary and fecal microbiota will be characterized through 16S ribosomal RNA sequencing. We will analyze serum and urine lipidome and metabolomes at weeks 4, 12, and 52.
The RAABIO study started in March 2022. It is an original study combining digital data collection to monitor patients' symptoms and biological markers during irradiation. We estimate a recruitment period of approximately 18 months. The final results are expected in 2024.
The quality of life of long-surviving patients is a goal of their care. Minimizing the impact of our treatments remains very challenging. This study is expected to improve our knowledge of the pathophysiology of radiation cystitis and its impact on the quality of life of our patients.
Radiation cystitis—which is characterized by hematuria, inflammation, and partly by fibrosis—has a strong impact on the daily life of our patients. Telemonitoring allows the recording of patients' experiences and the assessment of the impact of side effects on his quality of life. Collecting data from the patient (patient-reported outcomes) help to correct the discrepancy in the severity of the side effects when reported by the clinician or by the patient. Remote monitoring has been shown to provide high-quality care and has the potential to significantly improve patient care.
An increasing number of pathologies or their treatments, including radiation therapy of the prostate, now report alterations of the host-microbiome symbiosis [
This prospective study is the first to explore the overexpression of inflammatory proteins in fluid biopsies from patients with symptoms of acute radiation cystitis. In addition, the 1-year follow-up after treatment will allow us to predict which patients are at risk of late radiation cystitis and to guide them toward radioprotective treatment. The RABBIO study will provide a better understanding of the pathophysiology of radiation-induced cystitis, along with data on the kinetics of these biomarkers. The results of this study will allow us to develop strategies to limit radiation damage to the bladder and improve the quality of life of patients.
The Common Terminology Criteria for Adverse Events (version 5.0) questionnaire for classification of noninfectious cystitis and the International Prostate Symptom Score for the severity of prostate cancer symptoms.
Common Terminology Criteria for Adverse Events
Functional Assessment of Cancer Therapy–Prostate
interleukin
International Physical Activity Questionnaire
International Prostate Symptom Score
Radiotoxicity Bladder Biomarkers
The data sets generated or analyzed during this study are available from the corresponding author on reasonable request.
All authors contributed to the design of the work, the acquisition, analysis and interpretation of the data, and approved the submitted version. They have agreed to be personally responsible for their own contributions.
None declared.