Hypofractionated Radiation Therapy for Localized Prostate Cancer: Executive Summary of an ASTRO, ASCO and AUA Evidence-Based Guideline

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1 Hypofrationated Radiation Therapy for Loalized Prostate Caner: Exeutive Summary of an ASTRO, ASCO and AUA Evidene-Based Guideline Sott C. Morgan, Karen Hoffman, D. Andrew Loblaw, Mark K. Buyyounouski, Caroline Patton, Daniel Baroas, Soren Bentzen, Mihael Chang, Jason Efstathiou, Patrik Greany, Per Halvorsen, Bridget F. Koontz, Colleen Lawton, C. Mar Leyrer, Daniel Lin, Mihael Ray and Howard Sandler* From the Amerian Soiety for Radiation Onology, Arlington, Virginia; Amerian Soiety of Clinial Onology, Shamburg, Illinois, and Amerian Urologial Assoiation Eduation and Researh, In., Linthium, Maryland Aepted for publiation August 1, Funded by the Amerian Soiety for Radiation Onology. This guideline was developed ollaboratively by the Amerian Soiety of Clinial Onology (ASCO), Amerian Urologial Assoiation (AUA) and the Amerian Soiety for Radiation Onology (ASTRO), and is published in print and eletroni format in Pratial Radiation Onology, Journal of Clinial Onology and The Journal of UrologyÒ. This doument is being published as submitted independent of editorial or peer review by the editors of The Journal of UrologyÒ. The omplete unabridged version of the guideline is available as supplementary material at * Correspondene. Cedars-Sinai Medial Center, 8700 Beverly Blvd, Los Angeles, California ( howard.sandler@shs.org). Purpose: The aim of this guideline is to present reommendations regarding moderately hypofrationated ( Gy per fration) and ultrahypofrationated (500 Gy or more per fration) radiation therapy for loalized prostate aner. Methods and Materials: The Amerian Soiety for Radiation Onology onvened a task fore to address 8 key questions on appropriate indiations and dosefrationation for moderately and ultrahypofrationated radiation therapy, as well as tehnial issues, inluding normal tissue dose onstraints, treatment volumes, and use of image guided and intensity modulated radiation therapy. Reommendations were based on a systemati literature review and reated using a predefined onsensus-building methodology and Soiety-approved tools for grading evidene quality and reommendation strength. Results: Based on high-quality evidene, strong onsensus was reahed for offering moderate hypofrationation aross risk groups to patients hoosing external beam radiation therapy. The task fore onditionally reommends ultrahypofrationated radiation may be offered for low- and intermediate-risk prostate aner but strongly enourages treatment of intermediate-risk patients on a linial trial or multi-institutional registry. For high-risk patients, the task fore onditionally reommends against routine use of ultrahypofrationated external beam radiation therapy. With any hypofrationated approah, the task fore strongly reommends image guided radiation therapy and avoidane of nonmodulated 3-dimensional onformal tehniques. Conlusions: Hypofrationated radiation therapy provides important potential advantages in ost and onveniene for patients, and these reommendations are intended to provide guidane on moderate hypofrationation and ultrahypofrationation for loalized prostate aner. The limits in the urrent evidentiary basedespeially for ultrahypofrationationdhighlight the imperative to support large-sale randomized linial trials and undersore the importane of shared deision making between liniians and patients. INTRODUCTION External beam radiation therapy (EBRT) is a standard definitive treatment for men with loalized prostate aner. 1 The probability of ell survival after a dose of ionizing radiation is governed by the linear-quadrati model, in whih urves of ell survival as a funtion of dose have an initial linear omponent followed by a steeper quadrati omponent. The relative weighting of eah omponent, 528 j /19/ /0 THE JOURNAL OF UROLOGY Ó 2019 byamerican UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH,INC. Vol. 201, , Marh 2019 Printed in U.S.A.

2 HYPOFRACTIONATED RADIATION THERAPY FOR LOCALIZED PROSTATE CANCER 529 and thus the sensitivity of the irradiated tissue to frationation, is haraterized by the alpha-beta ratio. The alpha-beta ratio of prostate adenoarinoma is onsidered low ompared with most neoplasms, 2 whereas that of adjaent dose-limiting normal strutures has been estimated to be greater than that of prostate aner. 3,4 An impliation of this relationship is that hypofrationation, daily delivery with fration sizes >200 Gy, may improve the therapeuti ratio of EBRT in loalized prostate aner. In this guideline, hypofrationation is subdivided into moderate hypofrationation (fration size Gy) and ultrahypofrationation (fration size 500 Gy). These are pragmati definitions refleting 2 distint approahes to hypofrationation that have emerged in linial pratie. The fration size gap reated by these definitions (ie, >340 Gy but <500 Gy) represents a little-studied range that is outside of the sope of this doument. Conventional frationation is defined as a fration size of 180 to 200 Gy. These reommendations apply to men who require or prefer treatment instead of ative surveillane and who have opted for EBRT instead of other treatment options. This Exeutive Summary introdues the guideline and its reommendations. See the full-text guideline in the Supplementary Materials (available online at for disussion of the evidene underpinning the reommendations. This guideline is endorsed by the Soiety of Urologi Onology, the European Soiety for Radiotherapy & Onology (ESTRO), and the Royal Australian and New Zealand College of Radiologists. METHODS AND MATERIALS Proess The Amerian Soiety for Radiation Onology (ASTRO), Amerian Soiety of Clinial Onology (ASCO), and Amerian Urologial Assoiation proposed an evidenebased guideline on hypofrationated EBRT in loalized prostate aner, whih was approved by the ASTRO Board of Diretors in Otober A task fore of radiation onologists, medial physiists, and urologi surgeons/onologists from aademi settings, ommunity pratie, and the Veterans Affairs system was reruited. A radiation onology resident and a patient representative were also inluded. Through onferene alls and s, the task fore and ASTRO staff refined the key questions (KQs), ompleted the literature review, and formulated reommendation statements and narratives. The draft was reviewed by 6 expert reviewers (see the Aknowledgments) and ASTRO legal ounsel and was plaed online for publi omment in Otober and November The final guideline was approved by the 3 soieties. The ASTRO Guidelines Subommittee will monitor this guideline for updating beause additional data have been published and presented sine the end of the literature review, and an update in the near term is antiipated. Literature Review The guideline was based on a systemati literature review in MEDLINE PubMed of English-language studies published between Deember 1, 2001 and Marh 31, Both Medial Subjet Headings terms and text words were used, and hand searhes supplemented the eletroni searhes. Inluded studies evaluated men with loalized prostate aner reeiving hypofrationated EBRT to the prostate with or without the seminal vesiles. Outomes of interest were prostate aner ontrol (biohemial and linial reurrene-free survival, disease-speifi survival, and overall survival), aute and late toxiity, and quality of life. Studies onerning radiation to the pelvi lymph nodes were outside the sope. For moderate hypofrationation, only randomized ontrolled trials (RCTs) or meta-analyses of RCTs were inluded. For ultrahypofrationation, RCTs, meta-analyses, and prospetive observational studies with 50 patients were aepted. In total, 480 abstrats were sreened; 419 were eliminated, and 61 were inluded and abstrated. Abstrats from ASTRO, ASCO, ESTRO, and European Caner Organisation meetings between January 2014 and January 2017 fulfilling the inlusion riteria were also identified. They ould be disussed in the narrative but were not used to support reommendations. Grading of Evidene, Reommendations and Consensus Methodology Reommendation statements were developed using a modified Grading of Reommendations Assessment, Development, and Evaluation method 5,6 and were based on high-quality data supplemented by expert opinion when neessary. Reommendations were lassified as strong or onditional. A strong reommendation indiates the task fore was onfident the benefits of the intervention learly outweighed the harms, or vie versa, and all or almost all informed people would make the reommended hoie. Conditional reommendations were made when risks and benefits were even or unertain and most informed people would hoose the reommended ourse of ation, but a substantial number would not, suggesting a strong role for shared deision-making. 5 The quality of evidene underlying eah reommendation was ategorized as follows: High: We are very onfident that the true effet lies lose to that of the estimate of the effet, Moderate: We are moderately onfident in the effet estimate: The true effet is likely to be lose to the estimate of the effet, but there is a possibility that it is substantially different, Low: Our onfidene in the effet estimate is limited: The true effet may be substantially different from the estimate of the effet, Very Low: We have very little onfidene in the effet estimate: The true effet is likely to be substantially different from the estimate. 6

3 530 HYPOFRACTIONATED RADIATION THERAPY FOR LOCALIZED PROSTATE CANCER Task fore onsensus on the reommendations was evaluated through a modified Delphi approah adapted from the ASCO proess. 7 In an online survey, task fore members rated their agreement with eah reommendation on a 5-point Likert sale, ranging from strongly disagree to strongly agree. A prespeified threshold of 75% of raters seleting agree or strongly agree indiated onsensus. If a reommendation did not meet this threshold, it was edited and resurveyed. Reommendations that ahieved onsensus that were modified after the first round were also resurveyed. RESULTS KQ 1: In patients with loalized prostate aner who are andidates for EBRT, how does moderately hypofrationated EBRT ( Gy per fration) ompare to onventionally frationated EBRT ( Gy per fration) in terms of prostate aner ontrol, toxiity, and quality of life, based on Prostate aner risk stratifiation group? Patient age, omorbidity, anatomy (eg, prostate gland volume), and baseline urinary funtion? Prostate Caner Control Outomes: Impat of Risk Stratifiation Group Statement KQ1A: Inmenwithlow-riskprostate aner who deline ative surveillane and reeive EBRT to the prostate with or withoutradiationto the seminal vesiles, moderate hypofrationation should be offered. Reommendation strength: Strong Quality of evidene: High Consensus: 100% Statement KQ1B: In men with intermediate-risk prostate aner reeiving EBRT to the prostate with or without radiation to the seminal vesiles, moderate hypofrationation should be offered. Reommendation strength: Strong Quality of evidene: High Consensus: 100% Statement KQ1C: In men with high-risk prostate aner reeiving EBRT to the prostate, but not inluding pelvi lymph nodes, moderate hypofrationation should be offered. Reommendation strength: Strong Quality of evidene: High Consensus: 94% Four large, prospetive, RCTs with over 6000 patients, as well as additional single-institution randomized trials, demonstrate that EBRT to the prostate using moderate hypofrationation provides prostate aner ontrol similar to that of EBRT delivered using onventional frationation. Prostate Caner Control Outomes: Impat of Patient Age, Comorbidity, Anatomy, and Urinary Funtion Statement KQ1D: In patients who are andidates for EBRT, moderate hypofrationation should be offered regardless of patient age, omorbidity, anatomy, or urinary funtion. However, physiians should disuss the limited follow-up beyond 5 years for most existing RCTs evaluating moderate hypofrationation. Reommendation strength: Strong Quality of evidene: High Consensus: 94% Toxiity and Quality of Life Statement KQ1E: Men should be ounseled about the small inreased risk of aute gastrointestinal (GI) toxiity with moderate hypofrationation. Moderately hypofrationated EBRT has a similar risk of aute and late genitourinary and late GI toxiity ompared with onventionally frationated EBRT. However, physiians should disuss the limited follow-up beyond 5 years for most existing RCTs evaluating moderate hypofrationation. Reommendation strength: Strong Quality of evidene: High Consensus: 100% KQ 2: In patients with loalized prostate aner who are andidates for EBRT, how do moderately hypofrationated EBRT regimens used in linial trials ompare in terms of prostate aner ontrol, toxiity, and quality of life, and an partiular regimens be reommended based on prostate aner risk stratifiation group, age, omorbidity, anatomy (eg, prostate gland volume), and baseline urinary funtion? Statement KQ2A: Regimens of 6000 Gy delivered in 20 frations of 300 Gy and 7000 Gy delivered in 28 frations of 250 Gy are suggested sine they are supported by the largest evidentiary base. One optimal regimen annot be determined beause most of the multiple frationation shemes evaluated in linial trials have not been omparedheadtohead. Reommendation strength: Conditional Quality of evidene: Moderate Consensus: 100% Statement KQ2B: One moderately hypofrationated regimen is not suggested over another for aner ontrol for speifi risk groups, and the effiay of moderately hypofrationated EBRT

4 HYPOFRACTIONATED RADIATION THERAPY FOR LOCALIZED PROSTATE CANCER 531 regimens does not appear to be affeted by patient age, omorbidity, anatomy, or urinary funtion. Reommendation strength: Conditional Quality of evidene: Moderate Consensus: 100% Multiple moderately hypofrationated regimens have been evaluated in RCTs, inluding 6000 Gy in 20 frations of 300 Gy and 7000 Gy in 28 frations of 250 Gy. Signifiant differenes in the populations enrolled in the trials, endpoint definitions, and use of onomitant androgen deprivation therapy prelude aross-trial omparisons of the effiay of the various regimens. KQ 3: In patients with loalized prostate aner who are andidates for EBRT, how does ultrahypofrationated EBRT ( 500 Gy per fration) ompare to onventionally frationated EBRT ( Gy per fration) in terms of prostate aner ontrol, toxiity, and quality of life? Statement KQ3A: In men with low-risk prostate aner who deline ative surveillane and hoose ative treatment with EBRT, ultrahypofrationation may be offered as an alternative to onventional frationation. Strength of reommendation: Conditional Quality of evidene: Moderate Consensus: 88% Statement KQ3B: In men with intermediate-risk prostate aner reeiving EBRT, ultrahypofrationation may be offered as an alternative to onventional frationation. The task fore strongly enourages that these patients be treated as part of a linial trial or multi-institutional registry. Strength of reommendation: Conditional Quality of evidene: Low Consensus: 94% Statement KQ3C: In men with high-risk prostate aner reeiving EBRT, the task fore does not suggest offering ultrahypofrationation outside of a linial trial or multi-institutional registry due to insuffiient omparative evidene. Strength of reommendation: Conditional Quality of evidene: Low Consensus: 94% Several prospetive, nonrandomized studies have doumented the safe delivery of ultrahypofrationation for patients with loalized prostate aner. No prospetive studies omparing ultrahypofrationated and onventionally frationated EBRT in intermediate- and high-risk prostate aner with published effiay data were identified. KQ 4: In patients with loalized prostate aner who are andidates for EBRT, how do ultrahypofrationated EBRT regimens used in linial trials ompare in terms of prostate aner ontrol, toxiity, and quality of life? Statement KQ4A: Ultrahypofrationated prostate EBRT of 3500 to 3625 Gy in 5 frations of 700 to 725 Gy to the planning target volume may be offered to low- and intermediate-risk patients with prostate sizes less than 100 m 3. The key dose onstraints in KQ5B should be followed. Strength of reommendation: Conditional Quality of evidene: Moderate Consensus: 88% Statement KQ4B: Five-fration prostate ultrahypofrationation at doses above 3625 Gy to the planning target volume is not suggested outside the setting of a linial trial or multi-institutional registry due to risk of late toxiity. Strength of reommendation: Conditional Quality of evidene: Moderate Consensus: 100% Statement KQ4C: Five-fration prostate ultrahypofrationation using onseutive daily treatments is not suggested due to potential inreased risk of late urinary and retal toxiity. Strength of reommendation: Conditional Quality of evidene: Very low Consensus: 100% The evidentiary base is largest for regimens of 3500 Gy in 5 frations of 700 Gy or 3625 Gy in 5 frations of 725 Gy, and these regimens have been shown to be well tolerated with aeptable rates of biohemial ontrol. KQ 5: In patients with loalized prostate aner who are reeiving moderately hypofrationated or ultrahypofrationated EBRT, how do normal tissue onstraints used in linial trials ompare in terms of toxiity and quality of life? Statement KQ5A: At least 2 dose-volume onstraint points for retum and bladder should be used for moderately or ultrahypofrationated EBRT: one at the high-dose end (near the total dose presribed) and one in the mid-dose range (near the midpoint of the total dose). Strength of reommendation: Strong Quality of evidene: Moderate Consensus: 100% Statement KQ5B: Use of normal tissue onstraints for moderately or ultrahypofrationated EBRT that

5 532 HYPOFRACTIONATED RADIATION THERAPY FOR LOCALIZED PROSTATE CANCER differ from those of a published referene study is not reommended due to the risk of both aute and late toxiity. Strength of reommendation: Strong Quality of evidene: Low Consensus: 100% KQ 6: In patients with loalized prostate aner who are reeiving moderately hypofrationated or ultrahypofrationated EBRT, how do treatment volumes used in linial trials ompare in terms of prostate aner ontrol and toxiity? Statement KQ6A: Use of target volume and assoiated margin definitions for hypofrationated EBRT that deviate from those of a published referene study is not reommended, espeially for ultrahypofrationated regimens. Strength of reommendation: Strong Quality of evidene: Low Consensus: 100% Given substantial variation in target volume and margin definitions among reports of moderately hypofrationated or ultrahypofrationated EBRT, data are laking to ompare their impat on prostate aner ontrol and toxiity. KQ 7: In patients with loalized prostate aner who are reeiving moderately hypofrationated or ultrahypofrationated EBRT, how does treatment using image guided radiation therapy (IGRT) ompare to treatment not using IGRT in terms of prostate aner ontrol, toxiity, and quality of life? Statement KQ7A: IGRT is universally reommended when delivering moderately or ultrahypofrationated EBRT. Strength of reommendation: Strong Quality of evidene: Moderate Consensus: 100% The vast majority of moderately hypofrationated and ultrahypofrationated EBRT reports have used IGRT, and it is onsidered entral to the safe and effetive delivery of hypofrationated regimens. KQ 8: In patients with loalized prostate aner who are reeiving moderately hypofrationated or ultrahypofrationated EBRT, how does treatment using IMRT ompare to treatment with 3- dimensional onformal radiation therapy (3-D CRT) in terms of prostate aner ontrol, toxiity, and quality of life? Statement KQ8A: Nonmodulated 3-D CRT tehniques are not reommended when delivering moderately frationated or ultrahypofrationated prostate EBRT. Strength of reommendation: Strong Quality of evidene: Moderate Consensus: 100% CONCLUSION This evidene-based guideline was developed to make reommendations on moderately and ultrahypofrationated EBRT for loalized prostate aner. Several large-sale RCTs demonstrate that moderate hypofrationation onfers prostate aner ontrol outomes and rates of late toxiity similar to those of onventional frationation. Moderate hypofrationation holds important potential advantages for patient onveniene and resoure utilization. Based on this high-quality evidene, task fore onsensus was reahed that moderately hypofrationated radiation therapy should be offered to patients who hoose EBRT for treatment of prostate aner. Although there is limited follow-up beyond 5 years in ompleted trials, the task fore nonetheless onluded that the existing evidentiary base is suffiiently robust to justify routine use of moderate hypofrationation. Future updates to this guideline will disuss longer-term results from ompleted trials of moderate hypofrationation. The task fore reahed a weaker onsensus for ultrahypofrationated radiation therapy. To date, the evidentiary base onsists largely of prospetive, single-arm trials in low-risk and, to a lesser extent, intermediate-risk loalized disease and with limited follow-up. No published effiay data from RCTs are urrently available. The reommendation for ultrahypofrationation in low-risk loalized prostate aner was graded as onditional, refleting only moderate-quality evidene and the remaining unertainty in the balane between benefit and risk for this treatment strategy. The reommendation for ultrahypofrationated EBRT in intermediate-risk prostate aner is also graded as onditional. However, beause the evidentiary base is weaker than that in low-risk disease, support of linial trials and multi-institutional registries in this population is strongly enouraged. The task fore onditionally reommended against the routine use of ultrahypofrationated radiation in high-risk loalized prostate aner and esalation in dose beyond 3625 Gy with 5-fration regimens outside of linial trials. When either moderately or ultrahypofrationated EBRT is undertaken, metiulous attention to the tehnial aspets of treatment planning and delivery are important, and the task fore strongly reommends use of IGRT and avoidane of nonmodulated 3-D CRT tehniques. The task fore

6 HYPOFRACTIONATED RADIATION THERAPY FOR LOCALIZED PROSTATE CANCER 533 advoates the general priniple that to onfidently repliate the results of a published referene study, the approah used in that study should be followed to the extent possible. The onditional reommendations regarding ultrahypofrationation undersore the importane of shared deision-making between liniians and patients in this setting. The deision to use ultrahypofrationated radiation therapy should follow a detailed disussion of the unertainties in the risk-benefit balane for this treatment approah and should be informed at all stages by the patient s values and preferenes. ACKNOWLEDGMENTS The authors thank the expert reviewers: Brett Cox, MD, David Dearnaley, MA, MB, BCh, MD(Camb), Sott Eggener, MD, Himanshu Lukka, MD, Mihael Zelefsky, MD, and Anthony Zietman, MD. They also aknowledge Sokny Lim, MPH, Margaret Amankwa- Sakyi, MPH, and Shushan Rana, MD, for literature review assistane. Amerian Soiety for Radiation Onology (ASTRO) guidelines present sientifi, health, and safety information and may reflet sientifi or medial opinion. They are available to ASTRO members and the publi for eduational and informational purposes only. Commerial use of any ontent in this guideline without the prior written onsent of ASTRO is stritly prohibited. Adherene to this guideline will not ensure suessful treatment in every situation. This guideline should not be deemed inlusive of all proper methods of are or exlusive of other methods reasonably direted to obtaining the same results. The physiian must make the ultimate judgment regarding any speifi therapy in light of all irumstanes presented by the patient. ASTRO assumes no liability for the information, onlusions, and findings ontained in its guidelines. This guideline annot be assumed to apply to the use of these interventions performed in the ontext of linial trials. This guideline was prepared on the basis of information available at the time the panel was onduting its researh and disussions on this topi. There may be new developments that are not refleted in this guideline and that may, over time, be a basis for ASTRO to revisit and update the guideline. REFERENCES 1. Hamdy FC, Donovan JL, Lane JA et al: 10-Year outomes after monitoring, surgery, or radiotherapy for loalized prostate aner. N Engl J Med 2016; 375: Miralbell R, Roberts SA, Zubizarreta E et al: Dosefrationation sensitivity of prostate aner dedued from radiotherapy outomes of 5,969 patients in seven international institutional datasets: Alpha/beta [ 1.4 ( ) Gy. Int J Radiat Onol Biol Phys 2012; 82: e Brenner DJ: Frationation and late retal toxiity. Int J Radiat Onol Biol Phys 2004; 60: Tuker SL, Thames HD, Mihalski JM et al: Estimation of alpha/beta for late retal toxiity based on RTOG Int J Radiat Onol Biol Phys 2011; 81: Andrews J, Guyatt G, Oxman AD et al: GRADE guidelines: 14. Going from evidene to reommendations: the signifiane and presentation of reommendations. J Clin Epidemiol 2013; 66: Balshem H, Helfand M, Shunemann HJ et al: GRADE guidelines: 3. Rating the quality of evidene. J Clin Epidemiol 2011; 64: Loblaw DA, Prestrud AA, Somerfield MR et al: Amerian Soiety of Clinial Onology Clinial Pratie Guidelines: Formal systemati reviewbased onsensus methodology. J Clin Onol 2012; 30: AUTHOR AFFILIATIONS Division of Radiation Onology, The Ottawa Hospital and University of Ottawa, Ottawa, Ontario, Canada (SCM); Department of Radiation Onology, MD Anderson Caner Center, Houston, Texas (KH); Department of Radiation Onology, Odette Caner Centre, Sunnybrook Health Sienes Centre, Toronto, Ontario, Canada (DAL); Department of Radiation Onology, Stanford University, Stanford, California and Palo Alto Veterans Affairs Health System, Palo Alto, California (MKB); Amerian Soiety for Radiation Onology, Arlington, Virginia (CP); Department of Urologi Surgery, Vanderbilt University Medial Center, Nashville, Tennessee (DB); Division of Biostatistis and Bioinformatis, University of Maryland Shool of Mediine, Baltimore, Maryland (SB); Hunter Holmes MGuire Veterans Affairs Medial Center and Department of Radiation Onology, Virginia Commonwealth University, Rihmond, Virginia Rihmond, Virginia (MC); Department of Radiation Onology, Massahusetts General Hospital, Boston, Massahusetts (JE); Patient Representative, Tallahassee, Florida (PG); Department of Radiation Onology, Lahey Hospital and Medial Center, Burlington, Massahusetts (PH); Department of Radiation Onology, Duke University Medial Center, Durham, North Carolina (BFK); Department of Radiation Onology, Medial College of Wisonsin, Milwaukee, Wisonsin (CL); Department of Radiation Onology, Wake Forest University, Winston-Salem, North Carolina (CML); Department of Urology, University of Washington, Seattle, Washington (DL); Radiology Assoiates of Appleton, ThedaCare Regional Caner Center, Appleton, Wisonsin (MR); Department of Radiation Onology, Cedars-Sinai Medial Center, Los Angeles, California (HS).

7 534 HYPOFRACTIONATED RADIATION THERAPY FOR LOCALIZED PROSTATE CANCER CONFLICT OF INTEREST DISCLOSURES Before initiating work on this guideline, all task fore members ompleted dislosure statements and pertinent dislosures are published within this report. Where potential onflits are deteted, remedial measures to address them are taken and noted here. These dislosures were reviewed by the Guidelines Subommittee hairs (for task fore hairs), the task fore hairs (for task fore members) and the Conflit of Interest Review Committee. They were determined to be suffiiently managed by dislosure to the task fore and in this publiation and no other remedial measures were onsidered neessary. Daniel Baroas: AstraZenea (advisory board; ended during dislosure period for guideline), Tolmar (onsultant; ended during dislosure period for guideline), and Journal of Urology (editorial board); Soren Bentzen: University of Copenhagen (onsulting, travel expenses); Mark Buyyounouski: Wolters Kluwer and Elsevier (honoraria); Jason Efstathiou: Blue Earth Diagnostis (onsultant), Genenteh (advisory board; ended during dislosure period for guideline), and EMD Serona/Pfizer (advisory board; ended during dislosure period for guideline), Bayer (Joint Safety Review Committee; ended during dislosure period for guideline); Per Halvorsen: Amerian College of Radiology Radiation Onology Pratie Areditation program (honoraria, travel expenses); Karen Hoffman: Vanderbilt University (onsultant); Patrik Greany: Department of Defense Prostate Caner Researh Program (researh funding, honoraria, travel expenses); Bridget Koontz: Janssen (researh funding), Blue Earth Diagnostis (advisory board), Amerian Soiety for Radiation Onology (travel expenses), UpToDate (royalties; ended during dislosure period for guideline); Daniel Lin: Genomi Health, GenomeDx (ended during dislosure period for guideline) and Hologi (researh funding), Astellas (onsulting), and Dendreon and Bayer (advisory boards); D. Andrew Loblaw: Dr. Loblaw Mediine Professional Corporation (president), Astellas and Janssen (honoraria and advisory board), Abbvie (honoraria and onsulting), Bayer (honoraria), and Amgen and Ferring (advisory board; ended during dislosure period for guideline), patent with Sunnybrook Researh Institute (no fees reeived), and Prostate Cure Foundation (founder and hair); Sott Morgan: Janssen (honoraria and advisory board), Bayer and Astellas (honoraria and advisory board; ended during dislosure period for guideline), and Sanofi and Amgen (honoraria; ended during dislosure period for guideline); Howard Sandler: Amerian College of Radiology-Radiation Therapy Onology Group (researh funding), Janssen (leadership of linial trial and onsulting), Blue Earth Diagnostis (onsulting; ended during dislosure period for guideline) Sanofi (onsulting and honoraria; ended during dislosure period for guideline), Ferring, Dendreon, and NantHealth (advisory board; ended during dislosure period for guideline), Advaned Medial Isotope Corporation (stok and advisory board; ended during dislosure period for guideline).