ANZCTR
ERUPT Trial: External Beam Radiotherapy and Urinary Toxicities After Prostate Cancer TreatmentInvestigatorsPrincipal Investigator: Dr. Michelle Ong, Urology PHO Toowoomba Hospital QLD AustraliaEmail: mhmong8@Mobile: 04 3700 1888Principal Investigator: Dr. Devang Desai Urology Consultant Toowoomba Hospital QLD Australia, St. Andrew’s Toowoomba Hospital, Toowoomba QLD Australia Email:ddesai@.au Associate Investigator:Dr. Lekshmi NairRadiation Oncologist St. Andrew’s Toowoomba Hospital, 280 North Street Rockville, Toowoomba QLD 4350Study sitesToowoomba Hospital and St. Andrew’s Private Hospital will be the 2 sites utilized in this study. Patients will be recruited in the outpatient setting at the Toowoomba Hospital by the prostate cancer nurse. Data will also be collected by this nurse at Toowoomba Hospital through the pre- and post- radiotherapy surveys as well as the uroflow measurements.As all patients in Toowoomba have their radiation treatment at St. Andrew’s Private Hospital, another nurse will also collect data from this site i.e. radiation dosages used. Introduction & BackgroundExternal beam radiotherapy is a very common treatment modality for prostate cancer treatment It is sometimes utilized as adjuvant treatment, primary treatment, or in combination with hormone therapy (androgen-deprivation therapy). Several studies have looked at the long-term effects of prostate cancer treatment on the genitourinary and gastrointestinal systems. These studies have suggested that radiation therapy can contribute to urethral strictures when patients have undergone a combination of treatment modalities i.e. surgery + radiotherapy or brachytherapy + radiotherapy. However there have not been any prospective trials looking at external beam radiotherapy alone as a significant risk factor for developing urethral strictures. Rationale and purpose of the studyThe purpose of this study is to identify if there is a correlation between radiation therapy alone and the development of urethral strictures. The results from this study will benefit the community by providing urologists and radiation oncologists with a clearer idea of the risk of developing urethral strictures as a consequence of external beam radiotherapy. The early detection of urethral strictures may help to minimise the need for invasive procedures for repair and thus decrease the morbidity associated with these operations for patients. The results from this study will also help clinicians counsel patients on the risk of developing urethral strictures post radiotherapy for prostate cancer. By understanding the natural progression and course of radiation-related urethral stricture disease, clinicians will be able to detect strictures early and minimise the number of invasive procedures required for management of these in the future.Literature reviewExternal beam radiotherapy is a common therapeutic option for localized prostate cancer with high local control related to the delivered dose.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmFuc3NvbjwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+
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ADDIN EN.CITE.DATA 1 The development of urethral strictures are a potential side effect of external beam radiotherapy and has been documented in the literature to occur in 2-25% of patients who undergo this treatment in conjunction with surgery, brachytherapy or hormone therapy. PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FbGxpb3R0PC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48
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ADDIN EN.CITE.DATA 2To date, there have been no prospective trials looking at external beam radiotherapy alone and its correlation with the development of these strictures. Several studies have looked at the long term effect of prostate cancer treatment on the genitourinary and gastrointestinal systems. Elliott et al. examined the incidence of urethral strictures in patients who have had a variety of treatments for prostate cancer. A 1.7% risk of developing urethral strictures after EBRT alone was described but was not investigated further.2 Jarosek et al. also looked at urinary adverse events and found that patients who had EBRT alone or in combination with surgery tended to have higher rates of urethral strictures, however this was again not elaborated further in terms of treatment modalities, specific patient risk factors, or dosages of radiotherapy. PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KYXJvc2VrPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48
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ADDIN EN.CITE.DATA 3A study conducted by James et al. looked at the rates of minimally invasive urological procedures performed for urinary side effects secondary to radiation therapy. ADDIN EN.CITE <EndNote><Cite><Author>James</Author><Year>2018</Year><RecNum>551</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>551</rec-number><foreign-keys><key app="EN" db-id="at9xtv5r40sf2ne0s5fxf5s955rv500fwp0v" timestamp="1547941288">551</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>James, M.</author><author>McLean, G.</author><author>Williams, S.</author><author>Robinson, B.</author><author>Yi, M.</author></authors></contributors><auth-address>Canterbury Regional Cancer and Blood Service, Christchurch Hospital, Christchurch, New Zealand.
University of Otago Christchurch, Christchurch Hospital, Christchurch, New Zealand.
Canterbury District Health Board, Christchurch Hospital, Christchurch, New Zealand.</auth-address><titles><title>Complications of curative radiation treatment for early prostate cancer</title><secondary-title>Asia Pac J Clin Oncol</secondary-title><alt-title>Asia-Pacific journal of clinical oncology</alt-title></titles><periodical><full-title>Asia Pac J Clin Oncol</full-title><abbr-1>Asia-Pacific journal of clinical oncology</abbr-1></periodical><alt-periodical><full-title>Asia Pac J Clin Oncol</full-title><abbr-1>Asia-Pacific journal of clinical oncology</abbr-1></alt-periodical><dates><year>2018</year><pub-dates><date>Jan 16</date></pub-dates></dates><isbn>1743-7563 (Electronic)
1743-7555 (Linking)</isbn><accession-num>29336525</accession-num><urls><related-urls><url> They found that 12% of patients required a procedure, thus indicating a reassuringly low rate of interventions and hospital admissions after radiation therapy. 4 However, this study again did not look specifically at the development of urethral strictures or the relation of radiation dosages to the degree of urinary side effects. This study will aim to refine the identification, surveillance and treatment of urethral strictures in patients who have undergone EBRT for prostate cancer. In this way, we can contribute to the literature and fill the gap to guide future treatment options and regimes. The gap in current knowledge:This study is justified because there is evidence to suggest that EBRT can cause urethral strictures however no study has been performed to measure the exact incidence of urethral strictures and its correlation with external beam radiotherapy. Surveillance and treatment protocols have also not been formulated. This study will aim to shed light how external beam radiotherapy alone contributes to the development of urethral strictures and the dosages at which urethral strictures can be expected. Thus, future practice can be guided and patients can also be counselled on what to expect when undergoing treatment for prostate cancer. Aims & Objectives Aim/s: Our primary aim is to measure the incidence of urethral strictures in patients who have undergone radiation therapy for prostate cancer to see if there is a direct correlation between the two.The secondary aim is to identify what risk factors predispose patients to developing urethral strictures and at what radiation doses urethral strictures become more prevalent.Objectives: Primary objective: To identify if there is a correlation between radiation therapy and the development of urethral strictures. Secondary objectives:To ascertain if certain radiation dosages can increase the incidence of urethral strictures/To identify any other risk factors i.e. medical co-morbidities that also contribute to the development of urethral strictures in this patient settingResearch Question:Is there a correlation between radiation therapy and the development of urethral strictures in patients who undergo this treatment for prostate cancer? Hypothesis: External beam radiotherapy alone can cause urethral strictures in patients who receive this treatment for prostate cancer. Method: This study will be conducted as a prospective, observational trial. The target population includes all patients who undergo external beam radiotherapy as treatment for prostate cancer between 2019-2020, at the Toowoomba Base Hospital and St. Andrew's Private Hospital. Patients will be recruited in the outpatient setting with the help of a prostate cancer nurse. All patients who will undergo radiotherapy as part of their prostate cancer treatment will be invited to participate. Patients who will be included in the study include: All patients who prostate cancer who undergo radiation therapy between years 2019 – 2020. Patients who will be excluded will be those who have had congenital urethral strictures, previously known strictural disease, previous treatment for stricture disease, or patients who have previously undergone pelvic radiotherapy for other malignancies i.e. colorectal, gynaecological or urological. After the recruitment phase, patients will be stratified into 3 groups depending on the treatment modalities patients end up receiving i.e. EBRT alone, receiving androgen deprivation therapy and EBRT, or those receiving salvage EBRT which is usually dependent on the severity of the disease. The decision on what therapy patients receive will be left to clinical decision as per the treating team. After their radiation therapy, they will be followed up 3 monthly for the first year, 6 monthly for the next 2 years, then yearly thereafter for 2 years. At each follow-up, patients will be asked to perform a uroflow measurement where the speed and flow of urine will be measured and they will be asked to complete an AUA survey which will identify if patients are experiencing any obstructive voiding symptoms which will prompt us to investigate further for urethral strictures. Patients will then be followed up post radiotherapy with uroflow measurements and AUA surveys at regular intervals so as to detect the development of urethral strictures. Other information that will be obtained for the study will include patient demographics, age, body mass index and medical co-morbidities. This information will be obtained from patient charts and history taking. Patients will then be stratified into 3 outcome groups: no strictures, short-term strictures (1-2 years) and long-term strictures (3-5 years).In patients who develop urethral strictures, we will then note the location and severity of the stricture as well as the treatment required i.e. operative versus non-operative management. Study designThis study will be conducted as prospective observational trial. The data collection points will be at baseline, 3 months, 6 months, 1 year, then yearly up to 5 years post radiation therapy completion.Participants Sample size: We estimate that we see approximately 350 patients with prostate cancer who receive radiation therapy in a year.Inclusion/Exclusion: Inclusion criteria: All patients who have prostate cancer who undergo radiation therapy between years 2019 – 2020. Exclusion criteria: Patients who have had congenital urethral strictures, previously known strictural disease or previous treatment for stricture disease. These patients are excluded because they are already inherently at higher risk for urethral stricture development and can skew the results. Potential participants who meet the inclusion criteria will be identified through clinic appointments and GP referrals by the principal investigators and the prostate cancer nurse.Participant Information: We have constructed patient information and consent forms that will be handed out to potential participants identified according to the inclusion and exclusion criteria detailed above. Participants will be encouraged to read these forms and decide on if they would like to participate or not. They will sign a patient consent form, which will be filed. Interventions and/or Participant Activities Patients will undergo a more intensive follow up process compared to other patients where they will be followed up are regular intervals in the first year then yearly up to 5 years. This is currently different to current practice.At each follow up, patients will be asked to complete an AUA survey as well as a uroflow measurement which can be done in the outpatient setting. These assessments will only take approximately 10 minutes to complete in total. If there are any changes in these measurements from previous then the patient will be flagged for a review by a urology doctor who will organise any further imaging/testing that is required. This will aid in the early detection of urethral strictures. Recruitment and Consenting: Patients will be flagged for recruitment in the outpatient setting by the medical team. The prostate cancer nurse will provide the patient with the patient information sheets and the consent form for the patient to sign. Patient questions will be addressed by the prostate cancer nurse. Patients will be allowed to consider the requirements of their participation and be recruited at a subsequent appointment, however there is not a considerable time commitment associated with this study so we do not think that this will be a difficult decision to make. Data collection At time of recruitment, patient data that will be collected will include medical co-morbidities, age, body mas index, gender, severity of prostate cancer, history of previous radiation treatment. A baseline AUA survey will be completed and a baseline uroflow measurement as well. After external beam radiation treatment, patients will be followed up once again in urology/radiation oncology OPD and asked to complete an AUA survey (see attached) and perform uroflometry to detect any sign of lower urinary tract symptoms or difficulty in urination, which may reflect signs of early urethral stricture disease. Other signs of urinary toxicities or side effects from the radiation therapy will also be noted. This follow up will be performed at 3 monthly intervals for the first year, then 6 monthly intervals for 2 years, then yearly thereafter. Patients will then be stratified into 3 outcome groups: no strictures, short term strictures (1-2 years), and long-term strictures (3-5 years). Data will be collected in patients who proceed to have treatment for these strictures. This will include the type of treatment i.e. operative versus non-operative and the varying degrees of treatment (dilations + intermittent self-catheterisation, laser therapy, urethroplasty) All data will be de-identified and entered into an online database (currently we are looking at using the RedCaps database which is widely used by various other health services. This will need approval by the hospital executives and is currently being looked at) which is password protected and confidential. Tools: The tools that will be utilised include the AUA surveys and uroflow measurements. The AUA surveys will be handed out by the prostate cancer nurses in urology outpatient clinic and the uroflow measurements will be performed by the urology clinic nurses. The uroflow is a very standard urological test that is easily done in an outpatient setting with minimal discomfort and time constraints. Patient information from charts will also be sought. A PHA approval will be obtained prior to obtaining this information as part of the routine ethics approval process. Outcome measures Primary Outcome: The primary outcome that we will measure will be the incidence of urethral strictures in patients who have had radiotherapy. This will be obtained from the results of the AUA surveys and uroflow measurements post radiotherapy as well as any other investigations that the patients would have undergone. The outcome will also be categorically measured. Patients will be divided into 3 outcome groups: no strictures, short term strictures (1-2 years), long term strictures (3-5 years). Secondary outcomes:Secondary outcomes include the detection of other medical co-morbidities that could also predispose patients to developing urethral strictures after radiotherapy. The database that will be used in this study may also lend itself to other potential research projects in the future. Currently, no such database exists in QLD for patients who have undergone external beam radiotherapy for prostate cancer. Data Analysis Patient AUA survey scores and uroflow measurements will be collated and compared against the dosages of radiotherapy to see if certain dosages predispose to the development of urethral strictures.Patients will then be stratified into 3 outcome groups: no strictures, short term strictures (1-2 years) and long term strictures (3-5 years).Confounding factors will be initially controlled for then multivariate analysis will be conducted to see if these factors can also predispose to urethral strictures.Data will be collated in the form of a research paper. Preliminary results will be available after 1 year and may be presented at international conferences. Target audience will be urologists, radiation oncologists, nurses, trainees, medical students and allied health professionals.Data will be of mixed categorical and continuous type. The AUA surveys ask that patients rate their symptoms on a score of 0-5 with each question. Scores of 0-7 are classified as mild, 8-19 indicates moderate symptom severity and 20-35 indicates severe symptoms. Uroflow measurements look at the voiding time, flow time, maximum flow rate and volume voided. These are continuous measurements. Data management: Storage, access, destruction and confidentialityStorage: Data will be stored on an online database, which is password protected and confidential. Patients will also be de-identified prior to having their information inputted into the database to maintain full patient confidentiality. We are currently looking at using the RedCaps database system for data storage. This is a system that is widely used amongst other health services for research. Its use will have to be approved by hospital executives and we are currently in talks with hospital administration to try and get this set up.Given that it is an online database, the information would be accessible via private PCs or laptops. However, online people who have the password will be able to have access to this database. As one of our secondary outcomes is for this database to be able to be widely used for future research, the password would be made available to those researchers who require it in the future, however for now, it is only those people who are directly involved in this trial that will have access to it. Access to data in the future will only be after further HREC approval.Digital documents: Digital documents will be stored on the DDH secure network drive Data 7 (W:), with access restricted to the researchers.Hard copy documents: Hard copy files will be stored in a designated research only locked filing cabinet in the DDH Library.Off site: N/APersonal PC or laptop: Data will not be directly stored on a personal computer but the online database will be able to be accessed on a personal computer. The database will still be password protected and access will be restricted to the people directly involved in the study only. Access & Confidentiality:Currently, only the people who are directly involved in the trial will have access to the data. Patient consent forms and completed AUA forms will be kept in the filing cabinet set aside for research in the DDH library and the data will be inputted manually onto the online database. The data will be de-identified and password protected and will not be accessible to persons other than the researchers who are directly involved in the trial. It is noted that after initial patient data collection at recruitment, patient data will have to be re-identified and subsequently de-identified again during the follow up process. For the digital documents, only researchers listed on the ethics document for this study will be able to access the sub-folder assigned to the research project. Access to drives and folders are part of each staff member’s Novell Login profile, which has numerous security measures in place to ensure the integrity of permissions to network drives.For hardcopy documents, the DDH Senior Librarian, Research Fellow and HREC Coordinator are gatekeepers to the research filing cabinet in the Library and access is dependent on their authorisation.DDH secure document storage: For the digital documents, only researchers listed on the ethics document for this study will be able to access the sub-folder assigned to the research project. Access to drives and folders are part of each staff member’s Novell Login profile, which has numerous security measures in place to ensure the integrity of permissions to network drives.Individual documents will be password-restricted within the sub-folders. For hardcopy documents, the DDH Senior Librarian, Research Fellow and HREC Coordinator are gatekeepers to the research filing cabinet in the Library and access is dependent on their authorisation.Secure transfer of confidential information:Data movement is necessary as this study spans across 2 disciplines, urology and radiation oncology. In Toowoomba, the bulk of radiation oncology occurs off site at a private hospital and as such, nurses and doctors at this site will also need to be able to access the data information and input data. Data will be transferred between sites and shared between collaborating researchers using Microsoft lync meeting and messaging platform. This will allow the transfer of large files internally and is accessible to all QH staff. Destruction: Data will at this stage be kept for long-term storage with mediated access for other researchers. The establishment of a database of patients who undergo radiation treatment for prostate cancer will aid in future research projects and a record of side effects and complications from radiation therapy. DDH secure document storage: The Library will maintain a register of when documents are deposited into the secure locations, and who is responsible for them. The library will use the register to create alerts for when documents need to be reviewed for destruction. Hard copy documents and electronic files will be destroyed according to DDH confidential document destruction protocols.Ethical and Safety ConsiderationsResearch related risks: None of the interventions or measurements used in this trial have been deemed to cause harm. The only tools used will be the AUA surveys as well as uroflow measurements. The latter is a very routine test that is performed in the outpatient setting which is non-invasive and associated with minimal to no risk to the patient.Duty of Care:Coincidental health concerns identified in the course of the research, that do not relate to the research, its procedures or goals, will be managed through standard referral pathways.Participants in non-intervention arms:N/ADissemination of resultsResults will be published in a research article and presented at a urological conference in the form of a slide show/poster presentation. This will be available to other urologists, radiation oncologists, trainees, residents, medical students, nurses and allied health professionals.Participant feedback will be provided at the conclusion of the study via email address. Participants will acknowledge their interest in finding out the outcomes of the study on the participant information sheets and consent forms. Translation to practice: The outcomes of the research will be able to guide future practice in the early identification of urethral strictures and the protocols used in radiation treatment for prostate cancer. Patients will also be able to be counselled on what to expect in regards to side effects and potential outcomes after radiation treatment. Duration of the project: The project will extend over a period of approximately 5 years in total. 1 year for data collection and database input + 5 year follow up. An extra 5 months is added to account for ethics approvals, collation of the data and dissemination of results. ActivityJan-Feb 2019Feb 2019 – Feb 2020Feb 2020 – Feb 2022Feb 2022-Feb 2024Mar 2024-Apr 2024Apr 2024-June 2024Obtain ethics approvalsRecruit Interval follow-upData entry Data analysisPreliminary results 1 yearPreliminary results 3 year5 year resultWrite manuscriptDisseminate resultsReferences: ADDIN EN.REFLIST 1.Fransson P. Patient-reported lower urinary tract symptoms, urinary incontinence, and quality of life after external beam radiotherapy for localized prostate cancer--15 years' follow-up. A comparison with age-matched controls. Acta Oncol. 2008;47(5):852-861.2.Elliott SP, Meng MV, Elkin EP, et al. Incidence of urethral stricture after primary treatment for prostate cancer: data From CaPSURE. J Urol. Aug 2007;178(2):529-534; discussion 534.3.Jarosek SL, Virnig BA, Chu H, Elliott SP. Propensity-weighted long-term risk of urinary adverse events after prostate cancer surgery, radiation, or both. Eur Urol. Feb 2015;67(2):273-280.4.James M, McLean G, Williams S, Robinson B, Yi M. Complications of curative radiation treatment for early prostate cancer. Asia Pac J Clin Oncol. Jan 16 2018.Appendices:Appendices included in this application include: CV of all researchers involvedAUA survey (data collection tool) Participant information and consent forms ................
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