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Clinically Localized Prostate Cancer: AUA/ASTRO Guideline (2022)

Using AUA Guidelines

This AUA guideline is provided free of use to the general public for academic and research purposes. However, any person or company accessing AUA guidelines for promotional or commercial use must obtain a licensed copy. To obtain the licensable copy of this guideline, please contact Keith Price at kprice@auanet.org.

Endorsed by SUO

To cite this guideline:

Eastham JA, Auffenberg GB, Barocas DA, et al. Clinically localized prostate cancer: AUA/ASTRO guideline, part I: introduction, risk assessment, staging, and risk-based management. J Urol. 2022;208(1):10-18.
Eastham JA, Auffenberg GB, Barocas DA, et al. Clinically localized prostate cancer: AUA/ASTRO guideline, part II: principles of active surveillance, principles of surgery, and follow-up. J Urol. 2022;208(1):19-25.
Eastham JA, Auffenberg GB, Barocas DA, et al. Clinically localized prostate cancer: AUA/ASTRO guideline. Part III: principles of radiation and future directions. J Urol. 2022;208(1):26-33.

Guideline as it appears in The Journal of Urology® Part I [pdf]

Guideline as it appears in The Journal of Urology® Part II [pdf]

Guideline as it appears in The Journal of Urology® Part III [pdf]

Unabridged version of this guideline [pdf]

Panel Members

James A. Eastham, MD; Gregory B. Auffenberg, MD, MS; Daniel A. Barocas, MD, MPH; Roger Chou, MD; Tony Crispino; John W. Davis, MD, Scott Eggener, MD; Eric M. Horwitz, MD; Christopher J. Kane, MD; Daniel W. Lin, MD; Sean M. McBride, MD, MPH; Alicia K. Morgans, MD, MPH; Phillip M. Pierorazio, MD; George Rodrigues, MD; William W. Wong, MD; Stephen A. Boorjian, MD

Summary

Purpose

The recommendations discussed herein for the management of clinically localized prostate cancer provide a framework stratified by risk to facilitate care decisions and guide clinicians in the implementation of selected management options.

Methodology

The systematic review that informs this Guidelines was based on searches in Ovid MEDLINE (September 2021), Cochrane Central Register of Controlled Trials (August 2021), and Cochrane Database of Systematic Reviews (September 2021). Searches were supplemented by reviewing reference lists of relevant articles. Criteria for inclusion and exclusion of studies were based on the Key Questions and the populations, interventions, comparators, outcomes, timing, types of studies and settings (PICOTS) of interest. The target population was patients with clinically localized prostate cancer, defined as up to clinical stage T3 (by digital rectal examination [DRE]) prostate cancer without nodal or distant metastasis (N0M0) on conventional imaging.

Guideline Statements

Risk Assessment

Clinicians should use clinical T stage, serum prostate-specific antigen (PSA), Grade Group (Gleason score), and tumor volume on biopsy to risk stratify patients with newly diagnosed prostate cancer. (Strong Recommendation; Evidence Level: Grade A)
Clinicians may selectively use tissue-based genomic biomarkers when added risk stratification may alter clinical decision-making. (Expert Opinion)
Clinicians should not routinely use tissue-based genomic biomarkers for risk stratification or clinical decision-making. (Moderate Recommendation; Evidence Level: Grade B)
Clinicians should perform an assessment of patient and tumor risk factors to guide the decision to offer germline testing that includes mutations known to be associated with aggressive prostate cancer and/or known to have implications for treatment. (Expert Opinion)

Staging

Clinicians should not routinely perform abdomino-pelvic computed tomography (CT) scan or bone scan in asymptomatic patients with low- or intermediate-risk prostate cancer. (Expert Opinion)
Clinicians should obtain a bone scan and either pelvic multi-parametric magnetic resonance imaging (mpMRI) or CT scan for patients with high-risk prostate cancer. (Strong Recommendation; Evidence Level: Grade B)
In patients with prostate cancer at high risk for metastatic disease with negative conventional imaging, clinicians may obtain molecular imaging to evaluate for metastases. (Expert Opinion)

Risk-Based Management

Clinicians should inform patients that all prostate cancer treatments carry risk. The risks of treatment, in particular to patients’ urinary, sexual, and bowel function, must be incorporated with the risk posed by the cancer, patient life expectancy, comorbidities, pre-existing medical conditions, and patient preferences to facilitate a shared decision-making approach to management. (Clinical Principle)
Clinicians should provide an individualized risk estimate of post-treatment prostate cancer recurrence to patients with prostate cancer. (Clinical Principle)
For patients with low-risk prostate cancer, clinicians should recommend active surveillance as the preferred management option. (Strong Recommendation; Evidence Level: Grade A)
In asymptomatic patients with prostate cancer and limited life expectancy (determined on a patient-specific basis), clinicians should recommend watchful waiting. (Strong Recommendation; Evidence Level: Grade A)
For patients with favorable intermediate-risk prostate cancer, clinicians should discuss active surveillance, radiation therapy, and radical prostatectomy. (Strong Recommendation; Evidence Level: Grade A)
Clinicians should inform patients with intermediate-risk prostate cancer considering whole gland or focal ablation that there are a lack of high-quality data comparing ablation outcomes to radiation therapy, surgery, and active surveillance. (Expert Opinion)
For patients with unfavorable intermediate- or high-risk prostate cancer and estimated life expectancy greater than 10 years, clinicians should offer a choice between radical prostatectomy or radiation therapy plus androgen deprivation therapy (ADT). (Strong Recommendation; Evidence Level: Grade A)
Clinicians should not recommend whole gland or focal ablation for patients with high-risk prostate cancer outside of a clinical trial. (Expert Opinion)
Clinicians may recommend palliative ADT alone for patients with high-risk prostate cancer, local symptoms, and limited life expectancy. (Expert Opinion)

Principles of Management

Principles of Active Surveillance

Patients managed with active surveillance should be monitored with serial PSA values and repeat prostate biopsy. (Expert Opinion)
In patients selecting active surveillance, clinicians should utilize mpMRI to augment risk stratification, but this should not replace periodic surveillance biopsy. (Expert Opinion)

Principles of Surgery

In patients electing radical prostatectomy, nerve-sparing, when oncologically appropriate, should be performed. (Moderate Recommendation; Evidence Level: Grade B)
Clinicians should inform patients that pelvic lymphadenectomy provides staging information, which may guide future management, but does not have consistently documented improvement in metastasis-free, cancer-specific, or overall survival. (Moderate Recommendation; Evidence Level: Grade B)
Clinicians should use nomograms to select patients for lymphadenectomy. The potential benefit of identifying lymph node positive disease should be balanced with the risk of complications. (Clinical Principle)
Clinicians performing pelvic lymphadenectomy should perform an extended dissection, which improves staging accuracy compared to a limited dissection. (Moderate Recommendation; Evidence Level: Grade: B)
Clinicians should complete a radical prostatectomy if suspicious regional nodes are encountered intraoperatively. (Moderate Recommendation; Evidence Level: Grade C)
Clinicians should risk stratify patients with positive lymph nodes identified at radical prostatectomy based on pathologic variables and postoperative PSA. (Expert Opinion)
Clinicians may offer patients with positive lymph nodes identified at radical prostatectomy and an undetectable post-operative PSA adjuvant therapy or observation. (Conditional Recommendation; Evidence Level: Grade C)
Clinicians should not routinely recommend adjuvant radiation therapy after radical prostatectomy. (Strong Recommendation; Evidence Level: Grade A)

Principles of Radiation

Clinicians should utilize available target localization, normal tissue avoidance, simulation, advanced treatment planning/delivery, and image-guidance procedures to optimize the therapeutic ratio of external beam radiation therapy (EBRT) delivered for prostate cancer. (Clinical Principle)
Clinicians should utilize dose escalation when EBRT is the primary treatment for patients with prostate cancer. (Strong Recommendation; Evidence Level: Grade A)
Clinicians may counsel patients with prostate cancer that proton therapy is a treatment option, but it has not been shown to be superior to other radiation modalities in terms of toxicity profile and cancer outcomes. (Conditional Recommendation; Evidence Level: Grade C)
Clinicians should offer moderate hypofractionated EBRT for patients with low- or intermediate-risk prostate cancer who elect EBRT. (Strong Recommendation; Evidence Level: Grade A)
Clinicians may offer ultra hypofractionated EBRT for patients with low- or intermediate risk prostate cancer who elect EBRT. (Conditional Recommendation; Evidence Level: Grade B)
In patients with low- or favorable intermediate-risk prostate cancer electing radiation therapy, clinicians should offer dose-escalated hypofractionated EBRT (moderate or ultra), permanent low-dose rate (LDR) seed implant, or temporary high-dose rate (HDR) prostate implant as equivalent forms of treatment. (Strong Recommendation; Evidence Level: Grade B)
In patients with low- or intermediate-risk prostate cancer electing radiation therapy, clinicians should not electively radiate pelvic lymph nodes. (Strong Recommendation; Evidence Level: Grade B)
In patients with low- or favorable intermediate-risk prostate cancer electing radiation therapy, clinicians should not routinely use ADT. (Moderate Recommendation; Evidence Level: Grade B)
In patients with unfavorable intermediate-risk prostate cancer electing radiation therapy, clinicians should offer the addition of short-course (four to six months) ADT with radiation therapy. (Strong Recommendation; Evidence Level: Grade A)
Clinicians should offer moderate hypofractionated EBRT for patients with high-risk prostate cancer who are candidates for EBRT. (Moderate Recommendation; Evidence Level: Grade C)
In patients with unfavorable intermediate- or high-risk prostate cancer electing radiation therapy, clinicians should offer dose-escalated hypofractionated EBRT or combined EBRT + brachytherapy (LDR, HDR) along with a risk-appropriate course of ADT. (Strong Recommendation; Evidence Level: Grade A/B)
In patients with high-risk prostate cancer electing radiation therapy, clinicians may offer radiation to the pelvic lymph nodes. (Conditional Recommendation; Evidence Level: Grade B)
When treating the pelvic lymph nodes with radiation, clinicians should utilize intensity-modulated radiation therapy (IMRT) with doses between 45 Gy to 52 Gy. (Strong Recommendation; Evidence Level: Grade B)
In patients with high-risk prostate cancer electing radiation therapy, clinicians should recommend the addition of long-course (18 to 36 months) ADT with radiation therapy. (Strong Recommendation; Evidence Level: Grade A)
When combined ADT and radiation are used, ADT may be initiated neoadjuvantly, concurrently, or adjuvantly. (Conditional Recommendation; Evidence Level: Grade C)
When combining ADT with radiation therapy, clinicians may use combined androgen suppression (luteinizing hormone-releasing hormone [LHRH] agonist with an antiandrogen), an LHRH agonist alone, or an LHRH antagonist alone. (Expert Opinion)

Follow-up after Treatment

Clinicians should monitor patients with prostate cancer post therapy with PSA and symptom assessment. (Clinical Principle)
Clinicians should support patients with prostate cancer through continued symptom management and encouraging engagement with professional or community-based resources. (Clinical Principle)

Introduction

Methodology

The Localized Prostate Cancer Guideline Panel was created in 2019 by the American Urological Association (AUA). This guideline was developed in collaboration with the American Society for Radiation Oncology (ASTRO) with additional representation from the American Society of Clinical Oncology (ASCO) and Society of Urologic Oncology (SUO). The Practice Guidelines Committee (PGC) of the AUA selected the Panel Chair and Vice Chair who in turn appointed the additional panel members with specific expertise in this area in conjunction with ASTRO, ASCO, and SUO. Additionally, the Panel included patient representation. Funding of the Panel was provided by AUA and ASTRO; panel members received no remuneration for their work.

Primary methodology was provided by the Pacific Northwest Evidence-based Practice Center of Oregon Health & Science University (OHSU).¹ The Panel also utilized the systematic review developed by the Agency for Healthcare Research and Quality (AHRQ) on Therapies for Clinically Localized Prostate Cancer.^2,3

Data Sources and Searches

A research librarian conducted searches in Ovid MEDLINE (September 2021), Cochrane Central Register of Controlled Trials (August 2021), and Cochrane Database of Systematic Reviews (September 2021). Searches were supplemented by reviewing reference lists of relevant articles.

Study Selection

Criteria for inclusion and exclusion of studies were based on the Key Questions and the populations, interventions, comparators, outcomes, timing, types of studies and settings (PICOTS) of interest. The target population was patients with clinically localized prostate cancer, defined as up to clinical stage T3 (by digital rectal examination [DRE]) prostate cancer without nodal or distant metastasis (N0M0) on conventional imaging. Studies of patients with low-, intermediate-, or high-risk clinically localized prostate cancer were included.

For evaluation of prognostic factors, OHSU included primary studies and systematic reviews that reported risk estimates and controlled for potential confounders, evaluated patients that did not undergo curative treatment or who underwent radical prostatectomy or radiation therapy, and recruited patients in or after 1990. OHSU restricted inclusion to large (n>1,000) studies, unless no such studies were available. Such sample size criterion was only applied to studies of prognosis. For diagnosis, the methodology team included primary studies and systematic reviews that reported diagnostic accuracy or discrimination (e.g., the area under the receiver operating characteristic curve). For evaluation of treatments/management, OHSU focused on randomized trials; if no randomized trials were available, methodologists also included recent, large cohort studies that evaluated comparisons of interest and controlled for confounders. OHSU excluded uncontrolled studies of treatments, case reports, narrative reviews, and non-English language articles. In vitro and animal studies were also excluded. Articles must have been published in a peer-reviewed journal.

Using the pre-specified criteria, two investigators independently reviewed titles and abstracts of all citations. OHSU used a two-phase method for screening full-text articles identified during review of titles and abstracts. In the first phase, OHSU reviewed full-text articles to identify relevant systematic reviews for inclusion. When there were many primary studies or the primary studies were primarily observational, OHSU utilized systematic reviews that addressed Key Questions, were higher quality, and published within the last five years. The second phase reviewed full-text articles to identify primary studies for key questions not sufficiently answered by previously published systematic reviews, and new studies published after the systematic reviews.

Data Abstraction

For primary studies that met inclusion criteria, a single investigator abstracted information on study design, year, setting, country, sample size, eligibility criteria, dose and duration of the intervention, population characteristics (age, race, tumor stage, tumor grade, prostate-specific antigen [PSA] level, performance status, prostate cancer risk category), results, and source of funding. For systematic reviews, OHSU abstracted characteristics of the included studies (number, design, and sample sizes of included studies, study settings), population characteristics (inclusion and exclusion criteria), interventions, methods, and ratings for the risk of bias of included studies, synthesis methods, and results. For survival and progression-free survival (PFS), risk estimates were based on the number of deaths or cases of progression, so that estimates <1 indicate improved survival; if necessary, reported risk estimates were converted to this format. Data abstractions were reviewed by a second investigator for accuracy and discrepancies were resolved through discussion and consensus.

Risk of Bias Assessment

Two investigators independently assessed risk of bias using predefined criteria. Disagreements were resolved by consensus. For randomized trials and cohort studies, the methodology team adapted criteria for assessing risk of bias from the U.S. Preventive Services Task Force.⁴ Criteria for randomized trials included use of appropriate randomization and allocation concealment methods, baseline comparability of groups, blinding, attrition, and use of intention-to-treat analysis. For cohort studies on prognostic factors, criteria included methods for assembling cohorts, attrition, blinding assessment of outcomes, and adjustment for potential confounding. OHSU assessed systematic reviews using AMSTAR 2 (Assessing the Methodological Quality of Systematic Reviews) criteria.⁵ Criteria included use of pre-specified methods, appropriate search methods, assessment of risk of bias, and appropriate synthesis methods. For diagnostic accuracy studies, OHSU adapted criteria from QUADAS-2 to assess risk of bias related to patient selection, interpretation of the index test, selection and interpretation of the reference standard, and flow and timing (e.g., interval between index test and reference standard, receipt of the reference standard, and exclusion of patients from the analysis).⁶ Studies were rated as “low risk of bias,” “medium risk of bias,” or “high risk of bias” based on the presence and seriousness of methodological shortcomings.

Studies rated “low risk of bias” are generally considered valid. “Low risk of bias” randomized trials include clear descriptions of the population, setting, interventions, and comparison groups; a valid method for allocation of patients to treatment; low dropout rates and clear reporting of dropouts; blinding of patients, care providers, and outcome assessors; and appropriate analysis of outcomes.

Studies rated “medium risk of bias” are susceptible to some bias, though not necessarily enough to invalidate the results. These studies do not meet all the criteria for a rating of low risk of bias, but no flaw is likely to cause major bias. Studies may be missing information, making it difficult to assess limitations and potential problems. The “medium risk of bias” category is broad, and studies with this rating vary in their strengths and weaknesses. Therefore, the results of some medium risk of bias studies are likely to be valid, while others may be only possibly valid.

Studies rated “high risk of bias” have significant flaws that may invalidate the results. They have a serious or “fatal” flaw in design, analysis, or reporting; large amounts of missing information; discrepancies in reporting; or serious problems in the delivery of the intervention. The results of high risk of bias studies could be as likely to reflect flaws in study design and conduct as true difference between compared interventions. OHSU did not exclude studies rated high risk of bias a priori, but high risk of bias studies were considered less reliable than low or medium risk of bias studies.

Data Synthesis and Determination of Evidence Strength

OHSU constructed evidence tables with study characteristics, results, and risk of bias ratings for all included studies, and summary tables to highlight the main findings. OHSU reported pooled estimates and other results from systematic reviews and examined whether the findings of new studies were consistent with the reviews.

The AUA employs a three-tiered strength of evidence system to underpin evidence-based guideline statements. (Table 1) The AUA categorizes body of evidence strength as Grade A (well-conducted and highly-generalizable randomized controlled trials [RCTs] or exceptionally strong observational studies with consistent findings), Grade B (RCTs with some weaknesses of procedure or generalizability or moderately strong observational studies with consistent findings), or Grade C (RCTs with serious deficiencies of procedure or generalizability or extremely small sample sizes or observational studies that are inconsistent, have small sample sizes, or have other problems that potentially confound interpretation of data). Grade A evidence is evidence about which the Panel has a high level of certainty, Grade B evidence is evidence about which the Panel has a moderate level of certainty, and Grade C evidence is evidence about which the Panel has a low level of certainty.⁷

AUA Nomenclature: Linking Statement Type to Evidence Strength

The AUA nomenclature system explicitly links statement type to body of evidence strength, level of certainty, magnitude of benefit or risk/burdens, and the Panel’s judgment regarding the balance between benefits and risks/burdens. (Table 2) Strong Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is substantial. Moderate Recommendations are directive statements that an action should (benefits outweigh risks/burdens) or should not (risks/burdens outweigh benefits) be undertaken because net benefit or net harm is moderate. Conditional Recommendations are non-directive statements used when the evidence indicates that there is no apparent net benefit or harm, when benefits and harms are finely balanced, or when the balance between benefits and risks/burden is unclear. All three statement types may be supported by any body of evidence strength grade. Body of evidence strength Grade A in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances and that future research is unlikely to change confidence. Body of evidence strength Grade B in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances, but that better evidence could change confidence. Body of evidence strength Grade C in support of a Strong or Moderate Recommendation indicates that the statement can be applied to most patients in most circumstances, but that better evidence is likely to change confidence. Conditional Recommendations also can be supported by any evidence strength. When body of evidence strength is Grade A, the statement indicates that benefits and risks/burdens appear balanced, the best action depends on patient circumstances, and future research is unlikely to change confidence. When body of evidence strength Grade B is used, benefits and risks/burdens appear balanced, the best action also depends on individual patient circumstances and better evidence could change confidence. When body of evidence strength Grade C is used, there is uncertainty regarding the balance between benefits and risks/burdens; therefore, alternative strategies may be equally reasonable, and better evidence is likely to change confidence.

Where gaps in the evidence existed, the Panel provides guidance in the form of Clinical Principles or Expert Opinions with consensus achieved using a modified Delphi technique if differences of opinion emerged.⁸ A Clinical Principle is a statement about a component of clinical care that is widely agreed upon by urologists or other clinicians for which there may or may not be evidence in the medical literature. Expert Opinion refers to a statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there may or may not be evidence.

Peer Review and Document Approval

An integral part of the guideline development process at the AUA is external peer review. The AUA conducted a thorough peer review process to ensure that the document was reviewed by experts in the diagnosis and management of Clinically Localized Prostate Cancer. In addition to reviewers from the AUA PGC, Science and Quality Council (SQC), and Board of Directors (BOD), the document was reviewed by representatives from ASTRO, ASCO, and SUO as well as external content experts. Additionally, a call for reviewers was placed on the AUA website from December 3-17, 2021 to allow any additional interested parties to request a copy of the document for review. The guideline was also sent to the Urology Care Foundation and representation from prostate cancer patient and advocacy organizations to open the document further to the patient perspective. The draft guideline document was distributed to 115 peer reviewers. All peer review comments were blinded and sent to the Panel for review. In total, 78 reviewers provided comments, including 61 external reviewers. At the end of the peer review process, a total of 668 comments were received. Following comment discussion, the Panel revised the draft as needed. Once finalized, the guideline was submitted for approval to the AUA PGC, SQC, and BOD as well as the governing body of ASTRO for final approval.

Background

Prostate cancer remains the most common non-cutaneous cancer among US men, with an estimated 268,490 new cases and 34,500 deaths in 2022.⁹ As the vast majority of newly-diagnosed prostate cancer patients have clinically-localized disease,⁹ providing evidence-based guideline statements to support clinical decision-making represents an important component of facilitating the delivery of standardized, high-quality care.

Given the breadth of investigation into various aspects of the evaluation and management of clinically-localized disease that has occurred over the past several years, with the resultant emergence of data relevant to patient care delivery, the AUA, in collaboration with ASTRO, undertook to re-evaluate and update the organization’s prior prostate cancer guidelines.^10,11

An important component of the updated guidelines is the continued utilization of a risk stratification classification for patients with newly diagnosed clinically localized disease. The Panel believes that risk stratification facilitates patient counseling, should be used in shared decision-making (SDM) for treatment recommendations, and facilitates clinical trial enrollment. Recognizing that various risk classifications have been described,¹⁰^-14 the Panel elected to maintain a risk group model (Table 3). Of note, the Panel did combine the prior risk categories of “very low-risk” and “low-risk” disease together, as the recommended management for these patients is consistent. The Panel understands that risk assessment may be refined as new information becomes available. The intention of the risk groups is to provide a framework to discuss management options. The importance of SDM between patient and clinician is emphasized in the statements and supporting text. In addition to detailing the components of risk stratification, the Guideline is also intended to address indications for staging in the newly-diagnosed patient, provide risk-based treatment approaches to be reviewed by the clinician with the patient, and offer recommendations for post-treatment follow-up. Further, information is outlined regarding specifics of care delivery for various therapeutic modalities, such as pelvic lymph node management during radical prostatectomy, radiation dosage, fields, and concurrent androgen deprivation therapy (ADT) usage, as well as principles of conducting active surveillance. Further, the Panel identified several areas of ongoing study that are likely to be of significant relevance in the future for the care of patients with clinically localized disease, including genomic tumor tissue testing and advanced imaging.

Guideline Statements

Risk Assessment

Clinicians should use clinical T stage, serum PSA, Grade Group (Gleason score), and tumor volume on biopsy to risk stratify patients with newly diagnosed prostate cancer. (Strong Recommendation; Evidence Level: Grade B)

The risk of disease progression and adverse oncologic outcomes of prostate cancer varies widely based on clinicopathologic characteristics. Disease risk stratification is vital at the outset of patient counseling to align the aggressiveness of management to the severity of disease. Several risk stratification systems have been described and have been variously utilized, including risk groups, risk scores, and nomograms.¹⁰^-¹⁴ The Panel did conduct a systematic review of the literature to verify that the individual features of the risk groups remain associated with likelihood of adverse pathologic findings, biochemical recurrence, metastases, and death, and to evaluate whether mature data exist to support inclusion of additional parameters to enhance risk stratification. In total, 30 studies on prognostic factors in localized prostate cancer met inclusion criteria.^17-49 Sample sizes ranged from 1,062 to 19,684 patients.

Nineteen cohort studies evaluated baseline PSA level as a prognostic factor in patients with clinically localized prostate cancer who underwent curative treatment (typically radical prostatectomy or radiation therapy). Higher PSA level was associated with increased risks of biochemical recurrence,¹⁸^,²¹^-²³^,²⁵^,²⁷^-³¹^,³³^,³⁶^,³⁸^,⁴¹^,⁴⁴^,⁴⁵^,⁴⁷ prostate cancer-specific mortality,¹⁸^,²⁶^,³²^,³⁵^,⁴⁷ and all-cause mortality.³²^,³⁵^,⁴⁰ Similarly, a separate series evaluated baseline PSA level as a prognostic factor in patients with clinically localized prostate cancer who did not undergo curative treatment and noted an association between higher PSA level and increased risk of prostate cancer mortality.²⁴ Overall, PSA level was deemed to be an important risk factor that should be assessed, documented, and used to categorize patient risk.

Clinical T-stage is determined by DRE and is defined according to the American Joint Committee on Cancer (AJCC) system.¹⁶^,50 Higher clinical T-stage was found to be associated with increased risk of biochemical recurrence,¹⁸^,²¹^,²³^,³³^,³⁶^,³⁸^,⁴¹^,⁴⁶ prostate cancer-specific mortality,¹⁸^,²⁶^,³⁵^,⁴⁷ and all-cause mortality,³²^,³⁵ including among patients who did not undergo definitive treatment.¹⁷^,²⁴ Thus, clinical T-stage should be ascertained by DRE, documented in the chart, and used to categorize patient risk. Of note, prostate imaging (ultrasound or MRI) is not at this time used to assign clinical T-stage for risk classification. Nevertheless, the Panel acknowledges that imaging (e.g., MRI) findings may provide additional information regarding local tumor extent,⁵¹ and may be utilized in disease prognostication/treatment planning.

Cancer grade on biopsy is assigned using the World Health Organization/ International Society of Urologic Pathologists (WHO/ISUP) Grade Group system or the older Gleason score system. ISUP recommends that Gleason scores 6, 3 + 4 = 7, 4 + 3 = 7, 8 and 9-10, be reported as ISUP grades 1-5, respectively.⁵² Fourteen cohort studies evaluated baseline Gleason score as a prognostic factor in patients with clinically localized prostate cancer who underwent curative treatment. Higher Gleason score was associated with increased risks of biochemical recurrence,²¹^,²³^,³³^,³⁶^-³⁸^,⁴¹^,⁴⁶ metastatic disease,³⁹^,⁴²^,⁴³ prostate cancer-specific mortality,²⁶^,³²^,³⁵^,⁴²^,⁴³^,⁴⁷ and all-cause mortality.³²^,³⁵^,⁴⁰ Gleason score was also a strong predictor of prostate cancer mortality in patients who did not undergo curative treatment.¹⁷^,²⁴ As such, Grade Group is included in risk assessment. The Panel acknowledges that certain histologic features, such as intraductal and cribiform patterns, have likewise been associated with worse prognosis.^53-55 Such features, when available, should be considered when counseling an individual patient.

Of note, the Panel did not include PSA density (serum PSA [ng/mL] divided by imaging measured prostate volume [cc]) in the systematic literature review. However, an ad-hoc literature review demonstrated that a PSA density ≥ 0.15 ng/mL/cc has been associated with the risk of upgrading on subsequent biopsy among patients on active surveillance.⁵⁶ As such, the Panel believes that PSA density remains an important component of disease risk assessment. Of note, the Panel does recognize the continuous nature of risk associated with the spectrum of PSA density values and cautions against use of threshold values in isolation for management decision-making.

Clinicians may selectively use tissue-based genomic biomarkers when added risk stratification may alter clinical decision-making. (Expert Opinion)
Clinicians should not routinely use tissue-based genomic biomarkers for risk stratification or clinical decision-making. (Moderate Recommendation; Evidence Level: Grade B)

Regarding tissue-based genomic biomarkers, several currently available commercial tests, including Prolaris, Oncotype Dx, and Decipher, variously offer prediction of adverse pathology as well as the risks of biochemical recurrence, metastasis, and prostate cancer death. However, most of the reported studies to date that evaluated the prognostic ability of these genomic tests did not meet inclusion criteria for the systematic review as the studies used surgical (i.e., prostatectomy) rather than biopsy specimens. Notably, two studies using biopsy data have shown that a cell cycle progression panel (Prolaris) score was associated with the risks of biochemical recurrence, metastatic disease, and prostate cancer death; however, only one of those studies met inclusion criteria for the systematic review.¹⁹^,²⁰^,57 The Oncotype Dx assay has been validated on needle biopsy tissue and found to be associated with adverse pathology, biochemical recurrence, metastasis, and prostate cancer death; again, however, the studies did not meet inclusion criteria for the systematic review.^58-61Meanwhile, a multi-institutional evaluation of Decipher Biopsy testing found that a high-risk Decipher score was associated with conversion from active surveillance to definitive treatment.⁴⁸

Thus, based on the level of existing data, the Panel concluded that clinicians should not routinely use tissue-based genomic biomarkers for risk stratification or clinical decision-making; however, clinicians may use such tests selectively when added risk stratification may alter SDM. These recommendations are largely consistent with recent ASCO Guidelines as well.⁶²Examples of patients for whom tissue-based genomic markers may help clarify risk include patients with high-volume (multiple involved cores) Gleason score 6 cancer as well as select men with favorable intermediate-risk prostate cancer who are interested in active surveillance. Examples of patients for whom tissue-based genomic markers are not recommended including the majority of men with low-volume (few involved cores) Gleason score 6 cancer and men with favorable intermediate-risk prostate cancer who are interested in treatment.

The Panel recognizes that this is an active area of research. Most notably, prospective validation of the predictive capacity of genomic classifiers (GC) in localized disease will be important to support widespread use for treatment selection. Additional discussion on GCs may be found in Future Directions.

Clinicians should perform an assessment of patient and tumor risk factors to guide the decision to offer germline testing that includes mutations known to be associated with aggressive prostate cancer and/or known to have implications for treatment. (Expert Opinion)

Germline testing in patients with clinically localized prostate cancer has several potential goals, including enhanced risk stratification, identification of genes that may guide treatment decisions, and providing information to determine the need for personal and family member cancer screening. Identified prostate cancer associated genes to date include ATM, BRCA1, BRCA2, CHEK2, HOXB13, MLH1, MSH2, MSH6, NBN, PALB2, PMS2, and TP53. For example, studies have demonstrated that men with prostate cancer harboring BRCA2 genetic aberrations are more likely to have worse disease and a poorer prognosis.⁶³Testing is typically performed via a saliva or blood sample. Patient education, testing, and referral to a genetic counselor should be considered. Establishing specific indications for genetic testing is beyond the scope of this Guideline; indeed, such recommendations have recently been outlined by a large expert-panel consensus conference.⁶⁴ A number of the indications for germline testing are provided in Table 4. Importantly, patient and family history risk factors should be investigated by the clinician through careful history taking, while pathology from biopsy or radical prostatectomy should be reviewed in the consideration of germline testing.

Staging

Clinicians should not routinely perform abdomino-pelvic computed tomography (CT) scan or bone scan in asymptomatic patients with low- or intermediate-risk prostate cancer. (Expert Opinion)

Imaging studies are intended to define the local extent of disease as well as determine the presence of nodal and distant metastases, and thereby inform management. Clinicians should use a risk-based approach to staging patients with newly diagnosed prostate cancer, considering the probability of the patient harboring metastatic disease as well as the sensitivity and specificity of the imaging modality. For asymptomatic patients with low- or intermediate-risk prostate cancer, the probability of nodal or distant metastasis is low.^65-67 Therefore, abdomino-pelvic computed tomography (CT) scan and bone scan are unlikely to be helpful and should not be routinely obtained.

Clinicians should obtain a bone scan and either pelvic multi-parametric magnetic resonance imaging (mpMRI) or CT scan for patients with high-risk prostate cancer. (Strong Recommendation; Evidence Level: Grade B)

For patients with high-risk prostate cancer, CT scan or multi-parametric magnetic resonance imaging (mpMRI) scan should be obtained to evaluate the loco-regional extent of disease and presence of distant metastasis. For detection of extracapsular extension or seminal vesicle invasion, MRI scan has a low to moderate sensitivity (approximately 0.6) and high specificity (approximately 0.9).^51,68-78 mpMRI is preferred for local tumor staging, which may thereby inform therapy.^79-81 For both mpMRI scan and CT scan, the assessment of nodal metastasis is based on size criteria, and these modalities have similar accuracy. For example, in detection of nodal metastasis, MRI has been found to be associated with a low to moderate sensitivity (range 0.09 to 0.44) and high specificity (range 0.88 to 1.0).⁷¹^,⁷⁵^,⁷⁶^,82,83 To evaluate for the presence of bone metastasis, conventional bone scan should be obtained as the initial staging study. As robust evidence to support an imaging evaluation in unfavorable intermediate-risk disease remains lacking, the Panel offers that clinicians may consider obtaining staging imaging for patients within this risk classification.

In patients with prostate cancer at high risk for metastatic disease with negative conventional imaging, clinicians may obtain molecular imaging to evaluate for metastases. (Expert Opinion)

The role of molecular imaging, also referred to as next generation imaging (NGI), continues to evolve as new and more sensitive radiotracers become available. Recently, both the Gallium 68 prostate-specific membrane antigen (PSMA)-11 (Ga 68 PSMA-11) and piflufolastat F-18 PSMA (18F-DCFPyL) PET scanning have been FDA approved for initial staging for patients at high risk of metastasis (as well as for evaluation of biochemical relapse after treatment).^84,85 In a multicenter randomized trial, Ga-68 PSMA PET scan was compared with conventional imaging using CT scan and bone scan in patients with high-risk prostate cancer before definitive therapy. Ga-68 PSMA PET scan was found to have a 27% greater accuracy than conventional imaging, with better sensitivity and specificity, in the detection of nodal or distant metastasis.⁸⁶ While data to date supporting a clinical benefit to novel imaging modalities for patients with negative conventional imaging remain quite limited, the Panel did conclude that clinicians may offer molecular imaging in patients at high risk for metastatic disease based on the demonstrated enhanced staging accuracy. This recommendation is consistent with recent ASCO Guidelines as well.⁸⁷ The Panel recognizes that the identification of disease with molecular imaging may influence treatment (e.g., the addition of systemic therapy or metastases-directed therapy) and underscores the current uncertainty regarding an incremental oncologic benefit of altering treatment based on the identification of metastases with molecular imaging among patients with negative conventional imaging. The Panel further acknowledges that the role of NGI is an active area of investigation, availability remains inconsistent, and the impact on patient outcomes remains to be determined in order to guide its place in clinical decision making. Further discussion on this topic is provided in the Future Directions section.

Risk-Based Management

Clinicians should inform patients that all prostate cancer treatments carry risk. The risks of treatment, in particular to patients’ urinary, sexual, and bowel function, must be incorporated with the risk posed by the cancer, patient life expectancy, comorbidities, pre-existing medical conditions, and patient preferences to facilitate a shared decision-making approach to management. (Clinical Principle)

The selection of a management strategy for clinically localized prostate cancer is preference-sensitive and very often based on patients’ interpretation of the balance between treatment-specific risks and benefits.

With that in mind, clinicians must inform patients thoroughly regarding the risks and benefits of the various management options. Clinicians also must elicit from patients their values, preferences, and concerns about outcomes of treatment. This collaborative, SDM process is designed to yield a well-informed, high-quality decision that is consistent with patients’ preferences and values.

SDM aims to improve the quality of medical decisions by helping patients choose options consistent with their own values and in accordance with the best available scientific evidence.^88-91 RCTs of SDM versus routine care have demonstrated that patients engaged in SDM are more knowledgeable, have more realistic expectations, participate more actively in the care process, and more frequently arrive at decisions aligned with their personal preferences.^88,92 The Institute of Medicine and the AUA have both articulated strong support for the use of SDM for complex decisions such as treatment for localized prostate cancer.^93,94 Key components of SDM in selecting a management option for localized prostate cancer are provided in Table 5.

Clinicians should counsel patients regarding the severity of disease and documented natural history to provide perspective regarding the tradeoff between treatment-related side effects and the likelihood of disease progression. Furthermore, risk level dictates the intensity of the staging evaluation and the intensity of treatment, so a discussion of risk level sets the foundation for patient understanding of these decisions. Similarly, as the intensity of treatment is also tied to the patient’s life expectancy, an estimate of life expectancy should factor into the SDM discussion.

The expected harms of treatment include immediate risks (e.g., perioperative risks associated with surgery), short-term side effects, and long-term (typically quality of life [QOL]) implications. Local treatments are associated with differing profiles of urinary, sexual, and bowel side effects (variously termed ‘functional outcomes’), which may evolve or resolve over time.⁹⁵ Meanwhile, hormonal therapy, which is sometimes used in conjunction with radiation therapy, is associated with systemic side effects, some of which are symptomatic (e.g., hot flashes, fatigue, cognitive changes, sexual dysfunction) and some of which remain asymptomatic (e.g., changes in metabolic syndrome parameters). The patient must be informed about the expected risks and side effects of each management option in order to compare the options and to facilitate clear expectations. Specifying the likelihood of various outcome scenarios with each treatment can facilitate SDM, and there are tools available to estimate the likelihood of functional outcomes with each treatment.⁹⁶

Since baseline function is one of the strongest predictors of functional outcomes,⁹⁷ the clinician should ascertain the patient’s pre-treatment urinary, bowel, and sexual function (and hormone therapy-related domains if concurrent hormone therapy and radiation is being considered). These functional domains are best assessed using standardized instruments to minimize clinician bias and to facilitate longitudinal comparisons. The Expanded Prostate Cancer Index Composite (EPIC)-26 is one such validated instrument, and it has been selected by the International Consortium on Health Outcomes Measurement (ICHOM) as part of the ‘standard set’ of data that should be collected on each patient with clinically localized prostate cancer. A shorter instrument tailored to clinical care is the Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP).^98,99 The 5-item Sexual Health Inventory for Men (SHIM)¹⁰⁰ is an instrument designed to assess erectile function as is the longer 15-item International Index of Erectile Function (IIEF).¹⁰¹ Alternative questionnaires for assessment of urinary continence include the International Continence Society Male Short-Form (ICSmaleSF)¹⁰² and International Consultation on Incontinence Questionnaires (ICIQ).¹⁰³ The EORTC has developed and validated QOL instruments pertinent to a general oncology population (QLQ-C30) and has refined sets for specific cancers, including prostate cancer. The EORTC-QLQ-PR25 assesses urinary function, sexual function, bowel function, and hormone therapy symptoms.¹⁰⁴ Similarly, the Functional Assessment of Cancer Therapy (FACT) measurement system has developed a 12-item prostate cancer subscale (PCS), appended to the 35-item FACT-G for the general oncology population.¹⁰⁵ The Patient-Reported Outcomes Measurement Information System (PROMIS), initiated by the National Institutes of Health, curates a wide variety of QOL measures, and some have been used to assess symptoms after prostate cancer treatment.¹⁰⁶

Clinicians should provide an individualized risk estimate of post-treatment prostate cancer recurrence to patients with prostate cancer. (Clinical Principle)

Post-treatment cancer recurrence risk is dependent on a number of clinicopathologic factors, including most notably tumor grade and stage, as well as pretreatment PSA and, for patients undergoing radical prostatectomy, surgical margin status.¹⁰⁷Multiple predictive models and nomograms have been developed to estimate the risks of biochemical recurrence, metastases, and death from prostate cancer.¹²^,¹³^,108-110 These tools may be used to support discussions with patients regarding their personalized risk. In addition, competing risks of mortality from patient age and comorbidity status should be considered. Discussion of risk is a particularly important aspect of patient counseling and SDM.

For patients with low-risk prostate cancer, clinicians should recommend active surveillance as the preferred management option. (Strong Recommendation; Evidence Level: Grade A)

The intent of active surveillance is to maintain patients’ QOL by deferring or delaying definitive treatment when prostate cancer is unlikely to cause mortality or significant morbidity, while simultaneously maintaining the potential to implement definitive treatment with curative intent should this become necessary. Relevant data to inform management for patients with low-risk prostate cancer may be found in the ProtecT trial,¹¹¹which randomized 1,643 patients with clinically localized prostate cancer to surgery, radiation therapy, or active surveillance (referred to as active monitoring in the trial). In total, 77% of patients in the trial had a Gleason score of 6, 76% had clinical stage T1c (non-palpable) disease, and approximately two-thirds of patients had low-risk prostate cancer.¹⁸ The incidence of all-cause mortality for radical prostatectomy, radiation therapy, and active monitoring was 10.1, 10.3, and 10.9 per 1,000 person-years, respectively (P=0.87). Moreover, no significant differences were identified in prostate cancer-specific mortality. As such, the trial provides high-level evidence supporting the concept that selected patients with prostate cancer can delay or altogether avoid treatment. These results from ProtecT reinforced numerous cohort studies that have documented the outcomes of patients managed with active surveillance for low-risk prostate cancer and consistently demonstrated low rates of metastases (<1.5%) and prostate cancer related death (<1%) within 10 years after diagnosis.^112-118

Given the demonstrated relative safety of active surveillance, the Panel believes that the benefits of aggressive treatment do not outweigh the risk of treatment-related harms for most patients with low-risk disease. Indeed, the potential adverse events associated with prostate cancer treatment, predominantly urinary morbidity, bowel complications, and sexual dysfunction, have been well documented.^119-121 The Panel nevertheless acknowledges that select patients with low-risk disease may elect definitive local therapy after an informed discussion between clinician and patient. In particular, clinicians may offer immediate treatment to select patients who are fully informed as to all options and risks with low-risk prostate cancer such as those who have a high probability of disease risk reclassification on active surveillance (e.g., high-volume cancer, higher PSA density) or other risk factors for harboring higher-risk disease (e.g., family history of lethal prostate cancer, germline mutation associated with adverse pathology).¹²²

Patients electing to proceed with active surveillance should be informed of the importance of regular cancer surveillance to avoid missing the window of curability. Strategies for monitoring disease in patients electing active surveillance are detailed further in Principles of Active Surveillance.

In asymptomatic patients with prostate cancer and limited life expectancy (determined on a patient-specific basis), clinicians should recommend watchful waiting. (Strong Recommendation; Evidence Level: Grade A)

Patients with a life expectancy of ≤5 years do not benefit from prostate cancer screening, diagnosis, or treatment¹²³ as prostate cancer treatment does not improve survival within five years of follow-up.¹²⁴ The PIVOT and SPCG-4 randomized trials of radical prostatectomy versus observation/watchful waiting collectively demonstrate the relative importance of competing risks of mortality and of patient longevity (minimum estimated life expectancy of 8-10 years) in order for treatment to result in a reduction in the risk of death.^125,126

Watchful waiting does not involve routine cancer surveillance, but rather aims to deliver palliative therapy for relief of symptoms should they develop. The critical goal of watchful waiting is to maintain the patient’s QOL by avoiding treatment when prostate cancer is unlikely to cause mortality or significant morbidity. One of the principal aims of watchful waiting is avoidance of side effects from local treatment or ADT. Watchful waiting is appropriate for elderly patients or patients with significant comorbidities in whom competing risks of mortality are considerably greater than the risk of death from prostate cancer.

The Panel acknowledges that life expectancy is difficult to predict and notes the existence of several predictive tools to help with this assessment, such as the Kent model.¹²⁷

For patients with favorable intermediate-risk prostate cancer, clinicians should discuss active surveillance, radiation therapy, and radical prostatectomy. (Strong Recommendation; Evidence Level: Grade A)

The management of patients with intermediate-risk disease may likewise be informed in part by the ProtecT trial, as approximately one third of patients therein had intermediate- or high-risk disease.¹¹¹ Of note, in the trial, active monitoring was found to be associated with an increased risk of clinical progression compared to radical prostatectomy or radiotherapy (22.9 per 1,000 person-years versus 8.9 per 1,000 person-years for radical prostatectomy and 9.0 per 1,000 person-years for radiation therapy, P<0.001). Similarly, an increased risk of metastatic disease was seen for patients managed with active monitoring (6.3 per 1,000 person-years versus 2.4 per 1,000 person-years for radical prostatectomy and 3.0 per 1,000 person-years for radiation therapy, P=0.004). Nevertheless, all-cause mortality was low in each treatment arm, and no difference was noted in prostate cancer deaths. As such, the Panel believes that, with appropriate counseling, favorable intermediate-risk patients should be offered active surveillance, radical prostatectomy, and radiation therapy. Patients with favorable intermediate-risk disease who may be considered for active surveillance include those with a low PSA density, low tumor volume, as well as a low percentage of Gleason pattern 4 disease on biopsy. The Panel does recognize the noted increased risk of disease progression with active surveillance among intermediate-risk (versus low-risk) patients, particularly those with Grade Group 2 disease,¹¹⁴^,128 as well as the relatively limited data on very long-term follow-up of such patients, and thereby emphasizes the importance of informed SDM. Again, patients electing active surveillance should be informed of the importance of regular cancer surveillance to avoid missing the window of curability. Further, for favorable intermediate-risk patients electing treatment with radiation, at this time, ADT should not be used. The Panel recognizes the ongoing accumulation of evidence on this topic (e.g., NRG RTOG 08-15 trial, the results of which have been presented but not yet to date published). Thus, it remains unclear at this time what the benefit for these patients will be in adding ADT to their radiation treatment. Evolving evidence will inform future practice for these patients.

Clinicians should inform patients with intermediate-risk prostate cancer considering whole gland or focal ablation that there are a lack of high-quality data comparing ablation outcomes to radiation therapy, surgery, and active surveillance. (Expert Opinion)

Numerous ablative modalities, relying on differing energy sources/differing mechanisms of action, are currently available to patients with clinically localized prostate cancer.¹²⁹ Patient selection criteria in reported studies have varied widely as has treatment planning approach (e.g., lesion-based focal therapy, hemi-ablation, whole-gland). The only properly powered randomized trial reported to date on prostate ablation was restricted to patients with low-risk prostate cancer and demonstrated that focal photodynamic therapy (PDT) lowered the likelihood of cancer progression and rates of surgery/radiation compared to active surveillance, at an expense of an increased likelihood of mild urinary or erectile dysfunction.¹³⁰ However, PDT is not approved in the United States. Further, active surveillance is the preferred approach for patients with low-risk prostate cancer.

A number of institutional, multi-site, and population-based studies have reported outcomes of various ablative therapies; however, with absence of randomization, non-standardized protocols, and insufficient follow-up, the role of ablative therapy in the management of clinically localized prostate cancer remains to be defined.¹³¹Fortunately, randomized trials are ongoing and more are anticipated.

Currently, the Panel believes that ablation may be considered in select, appropriately informed patients (with clinical trial enrollment prioritized). Patients being considered for ablation should have intermediate-risk prostate cancer,¹³²as data supporting treatment of high-risk disease with ablation are lacking, while patients with low-risk cancers should be preferentially managed with active surveillance. Patients considering ablation should be counseled regarding side effects and recurrence risk and should be followed post-ablation with PSA, DRE, MRI, and biopsy tailored to their specific health and cancer characteristics.¹³³

For patients with unfavorable intermediate- or high-risk prostate cancer and estimated life expectancy greater than 10 years, clinicians should offer a choice between radical prostatectomy or radiation therapy plus androgen deprivation therapy (ADT). (Strong Recommendation; Evidence Level: Grade A)

For patients with unfavorable intermediate- or high-risk clinically localized prostate cancer, definitive local therapy is advised.^134-137 The optimal treatment for these patients remains a topic of active study, and prior published meta-analyses have reported relatively disparate findings as to comparative survival following each of these treatment approaches.^138,139The Panel supports offering patients with unfavorable intermediate- and high-risk disease either radical prostatectomy or radiation with ADT (see Principles of Surgery and Principles of Radiation). For patients with sufficiently high-risk disease (clinically node positive, or with 2 of 3 of the following criteria: clinical stage T3 or T4, PSA ≥ 40 ng/mL, or ≥ Gleason 8), treatment with radiation and ADT can include two years of concurrent abiraterone acetate plus prednisone as well.¹⁴⁰

Clinicians should not recommend whole gland or focal ablation for patients with high-risk prostate cancer outside of a clinical trial. (Expert Opinion)

As previously discussed, the only properly powered randomized trial reported to date on prostate ablation included only patients with low-risk prostate cancer. Currently, patients being considered for ablation should have intermediate-risk prostate cancer,¹³² as there is a lack of data supporting treatment of high-risk disease with ablation, while again, patients with low-risk cancers should be managed with surveillance.

Clinicians may recommend palliative ADT alone for patients with high-risk prostate cancer, local symptoms, and limited life expectancy. (Expert Opinion).

Due to the lack of evidence indicating a significant oncologic benefit to treatment with primary ADT for clinically localized prostate cancer, the Panel concluded primary ADT should only be recommended for palliation of local disease-related symptoms in select patients with a limited life expectancy for whom definitive local therapy is not advised. Indeed, among eight cohort studies evaluating survival outcomes between primary ADT and observation in prostate cancer populations of various risk categories - all of which were rated as having a moderate risk of bias - none demonstrated improvements in all-cause or prostate cancer-specific survival.^141-148 Moreover, in a cohort study of patients with unfavorable intermediate- or high-risk clinically localized prostate cancer, no significant differences were identified between immediate treatment with primary ADT versus observation with regard to all-cause (adjusted HR 0.69, 95% CI 0.45 to 1.07) or prostate cancer-specific mortality (adjusted HR 2.69, 95% CI 0.77 to 9.32).¹⁴² Likewise, in a population-based analysis of patients with poorly differentiated tumors using Surveillance, Epidemiology, and End Results Program (SEER)-Medicare data, no significant differences were noted between immediate treatment with primary ADT versus observation with regard to overall mortality (adjusted HR 1.04, 95% CI 0.97 to 1.13) or prostate cancer-specific mortality (adjusted HR 1.12, 95% CI 0.96 to 1.29).¹⁴⁴ Of note, in one trial, patients with clinically localized prostate cancer who were unfit for (or declined) local treatment were randomized to immediate versus delayed (at the time of symptomatic progression or metastatic disease) ADT.¹⁴⁹Although the trial did not report outcomes specifically for patients with high-risk prostate cancer, immediate treatment with ADT was associated with a decrease in overall mortality (HR 0.80, 95% CI 0.68 to 0.95), but not prostate cancer-specific mortality (10-year incidence 24.8% versus 26.0%, p=0.44) or disease progression. Further, the study was rated as having moderate risk of bias due to open-label design and unclear blinding of outcomes.

For such patients, the primary goals of care include symptom control/palliation and maintenance of QOL. As such, ADT may be used to manage urinary tract sequelae of local tumor growth through (albeit transient) cytoreduction.