Unabridged version of this guideline [pdf]

To cite this guideline:

Morgan TM, Boorjian SA, Buyyounouski MK, et al. Salvage therapy for prostate cancer: AUA/ASTRO/SUO guideline part I: introduction and treatment decision-making at the time of suspected biochemical recurrence after radical prostatectomy. J Urol. 2024;211(4):509-517. https://www.auajournals.org/doi/10.1097/JU.0000000000003892

Morgan TM, Boorjian SA, Buyyounouski MK, et al. Salvage therapy for prostate cancer: AUA/ASTRO/SUO guideline part II: treatment delivery for non-metastatic biochemical recurrence after primary radical prostatectomy. J Urol. 2024;211(4):518-525. https://www.auajournals.org/doi/10.1097/JU.0000000000003891

Morgan TM, Boorjian SA, Buyyounouski MK, et al. Salvage therapy for prostate cancer: AUA/ASTRO/SUO guideline part III: salvage therapy after radiotherapy or focal therapy, pelvic nodal recurrence and oligometastasis, and future directions. J Urol. 2024;211(4):526-532. https://www.auajournals.org/doi/10.1097/JU.0000000000003890

Todd M. Morgan, MD; Stephen A. Boorjian, MD; Mark K. Buyyounouski, MD, MS; Brian F. Chapin, MD; David Y.T. Chen, MD; Heather H. Cheng, MD, PhD; Heather A. Jacene, MD; Sophia C. Kamran, MD; Amy N. Luckenbaugh, MD; Ben J. Nathanson; Yaw A. Nyame, MD, MS, MBA; Edwin M. Posadas, MD; Phuoc T. Tran, MD, PhD; Ronald C. Chen, MD, MPH

Sennett K. Kim; Erin Kirkby, MS; Roger Chou, MD

Purpose

This Guideline on salvage therapy for recurrent prostate cancer is intended to facilitate care decisions and aid clinicians in caring for patients who have experienced a recurrence following prior treatment with curative intent.

Methodology

The systematic review that informs this Guideline was based on searches in Ovid MEDLINE (1946 to July 21, 2022), Cochrane Central Register of Controlled Trials (through August 2022), and Cochrane Database of Systematic Reviews (through August 2022). Update searches were conducted on July 26, 2023. Searches were supplemented by reviewing electronic database 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 population of interest was patients with prostate cancer recurrence following primary curative treatment for prostate cancer.

GUIDELINE STATEMENTS

Treatment Decision-Making at the Time of Suspected Biochemical Recurrence After Primary Radical Prostatectomy (RP)

1. Clinicians should inform patients that salvage radiation for a detectable prostate-specific antigen (PSA) after RP is more effective when given at lower levels of PSA. (Strong Recommendation; Evidence Level: Grade B)
2. For patients with a detectable PSA after RP in whom salvage radiation therapy (RT) is being considered, clinicians should provide salvage radiation when the PSA is ≤0.5 ng/mL. (Moderate Recommendation; Evidence Level: Grade B) 
3. For patients with a detectable PSA after RP who are at high risk for clinical progression, clinicians may offer salvage radiation when PSA values are <0.2 ng/mL. (Conditional Recommendation; Evidence Level: Grade C) 
4. Clinicians should inform patients that salvage radiation after RP poses inherent risks to urinary control, erectile function, and bowel function. These risks must be considered in the context of the risks posed by recurrent cancer along with patient life expectancy, comorbidities, and preferences to facilitate a shared decision-making (SDM) approach to management. (Clinical Principle)
5. Clinicians should use prognostic factors (e.g., PSA doubling time [PSADT], Gleason Grade Group, pathologic stage, surgical margin status, validated post-prostatectomy genomic classifier and/or positron emission tomography (PET) imaging results) to counsel patients with a detectable PSA about their risk of clinical progression. (Moderate Recommendation; Evidence Level: Grade B)
6. Clinicians may obtain ultrasensitive PSA following RP in patients who are at high risk of recurrence and in whom salvage RT would be considered. (Expert Opinion) 
7. For patients who do not meet the AUA definition of biochemical recurrence (BCR) after RP (PSA ≥0.2 ng/mL) yet have a detectable ultrasensitive PSA, clinicians should confirm a rising trend in PSA before proceeding with therapy. (Expert Opinion) 
8. In patients with a BCR after local therapy, clinicians may obtain a prostate-specific membrane antigen (PSMA)-PET in lieu of conventional imaging or after negative conventional imaging for further evaluation of clinical recurrence. (Conditional Recommendation; Evidence Level: Grade C)
9. For patients with BCR following RP in whom salvage radiation is being considered, the clinician should perform next generation molecular PET imaging. (Moderate Recommendation; Evidence Level: Grade C)
10. In patients with BCR following RP with PET/computed tomography (CT) positive pelvic nodal disease, the clinician should incorporate treatment of these positive findings in the radiation plan. (Moderate Recommendation; Evidence Level: Grade C)
11. In patients with BCR, clinicians may obtain a pelvic magnetic resonance imaging (MRI) in addition to a PET/CT for evaluation of local recurrence. (Conditional Recommendation; Evidence Level: Grade C)
12. In a patient with a BCR following RP, clinicians should not withhold salvage prostate bed RT in the setting of a negative PET/CT. (Expert Opinion)

Treatment Delivery for Non-Metastatic Biochemical Recurrence After Primary Radical Prostatectomy

13. Clinicians should offer androgen deprivation therapy (ADT) in addition to salvage RT for patients with BCR following RP and any high-risk features (e.g., higher post-prostatectomy PSA such as PSA ≥0.7ng/mL, Gleason Grade Group 4 to 5, PSADT ≤6months, persistently detectable post-operative PSA, seminal vesicle involvement). (Moderate Recommendation; Evidence Level: Grade B) 
14. For patients with BCR following RP without any high-risk features, clinicians may offer radiation alone. (Conditional Recommendation; Evidence Level: Grade C)
15. Clinicians should discuss treatment side effects and the impact of medical comorbidities when patients are being considered for ADT (as well as duration) with salvage RT, utilizing an SDM approach. (Clinical Principle)
16. For patients with pN1 disease being treated with post-operative RT, clinicians should include ADT rather than treating with RT alone. (Clinical Principle)
17. When providing ADT to patients undergoing salvage RT, clinicians should provide a minimum of four to six months of hormonal therapy. (Clinical Principle)
18. For patients with high-risk features, clinicians may extend ADT to 18 to 24 months. (Expert Opinion)
19. In patients with BCR following RP undergoing salvage RT with ADT, clinicians may use expanded radiation fields that include the regional lymph nodes. (Conditional Recommendation; Evidence Level: Grade B)
20. Clinicians should discuss with patients that including treatment of regional lymph nodes with salvage RT may increase the risk of side effects, particularly in the short term, compared to prostate bed RT alone. (Moderate Recommendation; Evidence Level: Grade A)
21. Clinicians should not recommend the addition of docetaxel in patients undergoing salvage RT and ADT. (Strong Recommendation; Evidence Level: Grade B)
22. For pN0 patients, clinicians should recommend the use of intensified androgen receptor (AR) suppression with salvage RT only within a clinical trial setting. (Clinical Principle)

Evaluation and Management of Suspected Non-Metastatic Recurrence After Radiation Therapy

23. For patients with BCR following primary RT or ablative therapy who have no evidence of metastatic disease and are candidates for local salvage therapy, clinicians should perform a prostate biopsy to evaluate for local recurrence. (Clinical Principle)
24. In patients with a biopsy-documented prostate cancer recurrence after primary RT who are candidates for salvage local therapy, clinicians should offer RP, cryoablation, high-intensity focused ultrasound (HIFU), or reirradiation as part of an SDM approach. (Moderate Recommendation; Evidence Level: Grade C)

Evaluation and Management of Suspected Non-Metastatic Recurrence After Focal Therapy

25. In patients for whom salvage local therapy is being considered following focal ablation, clinicians should offer whole gland treatment by RP or RT. (Expert Opinion)

Evaluation and Management of Regional Recurrence

26. In patients with pelvic nodal recurrence following primary RP, clinicians should offer ADT plus salvage RT to the prostate bed and pelvic lymph nodes. (Expert Opinion)
27. In patients with pelvic nodal recurrence following primary RT who did not receive prior pelvic nodal RT, clinicians should offer salvage pelvic nodal RT plus ADT. (Expert Opinion)
28. Clinicians may offer salvage pelvic lymphadenectomy for patients with evidence of pelvic lymph node recurrence after RP or RT; however, these patients should be counseled regarding the uncertain oncologic benefit from surgery in this setting. (Conditional Recommendation; Evidence Level: Grade C)

Management for Molecular Imaging Metastatic Recurrence

29. In patients with evidence of regional or metastatic oligorecurrence following primary therapy (RP or RT), clinicians may perform stereotactic ablative radiotherapy (SABR) metastasis-directed therapy (MDT) but should consider the risk of toxicity versus benefits. (Conditional Recommendation; Evidence Level: Grade C)
30. In patients with BCR who have non-regional disease seen on PET/CT but no visible disease on conventional imaging, clinicians may omit salvage RT to the prostate bed and should discuss the uncertain role of systemic therapy in this setting. (Expert Opinion)

Methodology

The systematic review utilized to inform this Guideline was conducted by an independent methodological consultant. Determination of the Guideline scope and assessment of the final systematic review to inform Guideline statements was conducted in conjunction with the Salvage Therapy for Prostate Cancer Guideline Panel. This Guideline was developed in collaboration with the American Society for Radiation Oncology (ASTRO) and the Society of Urologic Oncology (SUO). Primary methodology was provided by the Pacific Northwest Evidence-based Practice Center of Oregon Health & Science University (OHSU).

Panel Formation

The Panel was created in 2022 by the American Urological Association Education and Research, Inc. (AUAER). The Practice Guidelines Committee (PGC) of the American Urological Association (AUA) selected the Panel Chairs who in turn appointed the additional panel members following an open nomination process to identify members with specific expertise in this area. This is a multidisciplinary panel that includes representation from urology/urologic oncology, radiation oncology, nuclear medicine, and medical oncology in addition to patient representation. Funding for the Panel was provided by the AUA, ASTRO, and SUO; panel members received no remuneration for their work.

Searches and Article Selection

The systematic review that informs the Guideline statements was based on searches in Ovid MEDLINE (1946 to July 21, 2022), Cochrane Central Register of Controlled Trials (through August 2022), and Cochrane Database of Systematic Reviews (through August 2022). Update searches were conducted on July 26, 2023. Searches were supplemented by reviewing electronic databases reference lists of relevant articles. Criteria for inclusion and exclusion of studies were based on the Key Questions and the PICOTS of interest. The population of interest was patients with prostate cancer recurrence following primary curative treatment for prostate cancer.

Several Key Questions were developed to focus on patients with BCR. BCR is defined as a detectable or rising PSA level ≥0.2 ng/mL on 2 separate determinations after undergoing RP with curative intent for prostate cancer (nadir PSA <0.2 ng/mL),¹ or meeting the Phoenix criteria (≥2 ng/mL rise in PSA over nadir)² for BCR following RT³ and no evidence of metastatic disease on conventional imaging. However, salvage treatment before these conventional thresholds for BCR was also carefully evaluated in this Guideline. Patients with a persistent detectable PSA after RP were included as well. The Key Questions included the timing of salvage RT, salvage ADT, duration of ADT, risk markers, next generation imaging, and use of prophylactic pelvic nodal RT versus omission of pelvic lymph node RT. There were additional Key Questions developed to focus on intensified systemic therapy which addressed all patients undergoing salvage RT plus ADT (including patients with nodal metastases), metastasis-directed stereotactic body RT (SBRT), salvage lymphadenectomy, recurrence after focal therapy, and pelvic lymph node RT which addressed patients with regional (nodal) recurrence. Salvage brachytherapy, cryotherapy, HIFU, RP, or systematic therapy and RP, repeat ablation, and prostate RT were covered as well to focus on patients with local recurrences. For patients at high risk of recurrence following RP (based on Gleason Grade Group 4 to 5, tumor stages pT3 and pT4, presence of positive surgical margins, and/or node-positive disease), a Key Question was developed for ultrasensitive PSA. OHSU did not exclude randomized controlled trials (RCTs) that included mixed populations of patients with BCR or PSA persistence after primary treatment given the limited numbers of RCTs. However, observational studies were restricted to patients with recurrence. Primary treatments (RP, RT, and either RP or RT) were identified based on the Key Questions. The outcomes included various oncologic outcomes (e.g., overall mortality, prostate cancer specific mortality, biochemical progression, local progression, and metastasis), quality of life (QOL), and harms.

For assessment of treatments, imaging, and risk stratification tools, inclusion was restricted to randomized trials and cohort studies. OHSU excluded studies published only as conference abstracts, case reports, narrative reviews, and non-English language articles. In vitro and animal studies were excluded as well.

Using the pre-specified criteria, two investigators independently reviewed the titles and abstracts of all citations. Two investigators independently screened full-text articles identified during the review of titles and abstracts. OHSU identified relevant, high-quality systematic reviews, 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 (e.g., age, race, tumor stage), results, and source of funding. 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, OHSU adapted criteria for assessing risk of bias from the U.S. Preventive Services Task Force (USPSTF).⁴ Criteria for randomized trials included the 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 factors. OHSU assessed systematic reviews using Assessing the Methodological Quality of Systematic Reviews (AMSTAR 2) criteria.⁵ Criteria included the use of pre-specified systematic review methods, appropriate search methods, assessment of risk of bias, and appropriate synthesis methods. 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” were generally considered valid. “Low risk of bias” randomized trials included 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” were susceptible to some bias, though not necessarily enough to invalidate the results. These studies did not meet all the criteria for a rating of low risk of bias but had no flaw likely to cause major bias. Studies may have been missing information, making it difficult to assess limitations and potential problems. The “medium risk of bias” category is broad, and studies with this rating varied in their strengths and weaknesses. Therefore, the results of some medium risk of bias studies were likely to be valid, while others may only be possibly valid.

Studies rated “high risk of bias” had significant flaws that may have invalidated the results. They had 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 to be less reliable than low or medium risk of bias studies.

Data Synthesis

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. Pooled estimates and other results from systematic reviews were reported and examined whether the findings of new studies were consistent with the reviews.

The strength of evidence for management interventions evaluated in this report were graded in accordance with AUA Guideline development methods as discussed in the following section.

Determination of Evidence Strength

The Grading of Recommendations Assessment, Development, and Evaluation (GRADE)⁶ system was used to determine the aggregate evidence quality for each outcome or group of related outcomes informing Key Questions. GRADE defines a body of evidence in relation to how confident guideline developers can be that the estimate of effects as reported by that body of evidence, is correct. Evidence is categorized as high, moderate, low, and very low, and assessment is based on the aggregate risk of bias for the evidence base, plus limitations introduced as a consequence of inconsistency, indirectness, imprecision, and publication bias across the studies.⁷ Additionally, certainty of evidence can be downgraded if confounding across the studies has resulted in the potential for the evidence base to overestimate the effect. Upgrading of evidence is possible if the body of evidence indicates a large effect or if confounding would suggest either spurious effects or would reduce the demonstrated effect.

The AUA employs a 3-tiered strength of evidence system to underpin evidence-based guideline statements. Table 1 summarizes the GRADE categories, definitions, and how these categories translate to the AUA strength of evidence categories. In short, high certainty by GRADE translates to AUA A-category strength of evidence, moderate to B, and both low and very low to C.

The AUA categorizes body of evidence strength as Grade A (e.g., well-conducted and highly-generalizable RCTs or exceptionally strong observational studies with consistent findings), Grade B (e.g., RCTs with some weaknesses of procedure or generalizability or moderately strong observational studies with consistent findings), or Grade C (e.g., 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). By definition, 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.⁸

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, 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 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 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 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, 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 in opinion emerged.⁹ 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.

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 who were knowledgeable in the area of salvage therapy for 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 external content experts. Additionally, a call for reviewers was placed on the AUA website from July 21^st to August 3^rd, 2023 to allow any additional interested parties to request a copy of the document for review. Additional notifications were sent through various AUA membership and patient advocacy channels to further promote the availability of the document for review. The draft Guideline was distributed to 153 peer reviewers. All peer review comments were blinded and sent to the Panel for review. In total, 97 reviewers provided comments, including 77 external reviewers. At the end of the peer review process, a total of 568 comments were received. Following comment discussion, the Panel revised the draft as needed. Once finalized, the Guideline was submitted to the AUA PGC, SQC, and BOD for final approval in addition to the approval bodies of collaborators ASTRO and SUO.

While definitive standard of care therapies cure most patients with clinically localized prostate cancer, the risk of recurrence, and even subsequent metastasis, is over 50% in patients with the highest disease risk features.¹⁰ Understanding the evaluation and appropriate use of salvage therapies for patients with BCR is a critical area of prostate cancer care. In fact, a cure is still possible for many of these patients. Novel PET/ CT and MRI are now identifying regional and distant recurrences that were previously undetectable. Balancing undertreatment with overtreatment, utilizing new therapeutic agents and imaging modalities, and optimizing patient selection through use of evidence-driven prognostic markers are all critical to improving oncologic outcomes and maintaining QOL for these patients.

Terminology and Definitions

This Guideline intends to inform the care of patients who experience BCR after initial definitive local therapy for clinically localized disease. As such, this Guideline bridges the gap between the AUA/ASTRO Localized Prostate Cancer Guideline and the AUA/SUO Advanced Prostate Cancer Guideline.^{11, 12} For instance, while the Localized Prostate Cancer Guideline includes discussion of adjuvant therapy, it does not extend to the setting of PSA recurrence following local therapy. Conversely, the Advanced Prostate Cancer Guideline specifically starts with the assumption that patients have exhausted all local therapy options. Given the early, maturing results regarding PET/CT scans at the time of BCR and with an awareness of the nuanced nature of stage migration in this context, metastatic disease detected only on PET/CT scans has been included in this Guideline rather than the current Advanced Prostate Cancer Guideline.

The prostate cancer field has made substantial advancements since the original AUA/ASTRO Guideline on Adjuvant and Salvage Radiotherapy published in 2013.¹³ The introduction of PET/CT imaging is just one of the major developments that have begun to shape the care of patients with BCR. New data providing clinical and molecular parameters for risk stratification and decision-making, use of ADT, and approaches to lymphadenectomy or nodal irradiation in the absence of regional disease have collectively transformed the management landscape in this critically important prostate cancer disease state.

It is important to note the resources available to those who are undergoing prostate cancer treatment to address concerns outside of direct disease management. As discussed within AUA/ASTRO’s Localized Prostate Cancer Guideline, there are multiple resources that exist for patients with prostate cancer and their loved ones. These resources may be engaged at any time in the patient's clinical course, including at the time of diagnosis (pre-treatment) as well as following definitive local therapy. Important psychosocial support can be provided through social work services and local virtual and in-person prostate cancer support groups, as well as through national patient advocacy organizations (e.g., Active Surveillance Patients International [aspatients.org], AnCan Foundation [ancan.org], Prostate Cancer Foundation [pcf.org], Prostate Cancer Research Institute [PCRI.org], Prostate Cancer Supportive Care Program [pcscprogram.ca], the Prostate Health Education Network [prostatehealthed.org], the Urology Care Foundation [urologyhealth.org], ZERO/UsTOO – the End of Prostate Cancer [zerocancer.org]). Additional physical and lifestyle survivorship support may be provided through referrals to dietary and nutrition services, physical therapists, pelvic floor rehabilitation specialists, and psychosexual therapists. The array of survivorship needs for an individual patient and caregiver may be broad and should be explored by the clinician and team to ensure that appropriate support, especially peer support, is offered.¹¹

The Panel also notes that this Guideline is intended for all patient populations with a prostate gland. For consistency purposes, this Guideline refers to these individuals as “people” or “patients” throughout this document.

Health Equity and Disparities

Given that novel and expensive technologies are repeatedly highlighted in this Guideline, it is imperative to first consider the ubiquitous nature of health inequities that prevent many patients from receiving guideline-concordant care. The Cancer Equity working group published recommendations for Elevating Equitable Cancer Care, which include suggestions for clinical practice guideline development.¹⁴ These suggestions may help to reduce disparities in guideline-adherent cancer care and include the following relevant to this Guideline: (1) review guidelines for disparity issues that could eliminate or reduce disparity, (2) incorporate language recognizing existence of bias in care, (3) incorporate a framework to account for health disparities into panel processes, and (4) consider adding a health equity expert representative. The Panel has sought to be attentive to these recommendations in the process of developing the present Guideline.

Relevant to this Guideline, Black individuals with prostates in the United States (U.S.) are known to have the highest incidence and more than double the death rate of prostate cancer compared to all other race/ethnic groups.^15-17 Health inequities have been documented at every stage of prostate cancer care, from screening to work-up, treatment, and follow-up as well as clinical trial enrollment. It is known that, despite PSA as a known biomarker for early detection of prostate cancer, Black individuals with prostates continue to be screened at a lower rate than non-Hispanic White counterparts.¹⁸ Separately, it has been found that inequities exist with respect to access to prostate cancer imaging, and these inequities also exist with respect to novel molecular imaging.^19-21 An analysis of a single U.S. tertiary medical center found that when it comes to molecular imaging scans, Black people were more likely than White people to undergo PET scans with ¹⁸F-fluciclovine versus ⁶⁸Ga-PSMA-11, with no other significant differences documented among any other demographic characteristics.¹⁹ We must be mindful of these potential inequities and disparities surrounding new technologies, particularly as novel molecular imaging is further incorporated into clinical guidelines such as this. In addition, it has been found that Black patients are underrepresented in prostate cancer clinical trials compared to their known prostate cancer incidence.^{22, 23} Many older studies did not include information surrounding racial composition of participants, thus treatment recommendations or clinical outcomes may not be broadly applicable to all diverse populations with prostate cancer. Prior evaluations of patients with prostate cancer in the Veterans Health Administration have 1) included a relative enrichment of Black patients (compared to standard trials or analyses of registries) and 2) found that, within an equal-access healthcare setting, many of the disparities associated with treatment response and outcomes among Black patients disappeared.^24-27 These findings must be validated further but suggest that it is critical that trials and studies going forward capture and report on race/ethnicity as well as other social determinants of health so that all outcomes are fully understood and all diverse individuals benefit from prostate cancer research breakthroughs.

As practitioners and stakeholders invested in treatment of people with prostate cancer, it is critical to recognize and address health disparities to achieve improved health equity for all minoritized populations.²⁸ At the congressional level, the PSA Screening for HIM Act was introduced in the 116th, 117th and now 118th Congress. The Act requires private insurance plans to cover preventive prostate cancer screenings for Black men and men with a familial history of prostate cancer, not already covered under the recommendations of the U.S. Preventive Services Task Force, without imposing any cost-sharing requirement. This act proposes to address health inequities related to PSA screening and can be read in full: https://www.congress.gov/bill/118th-congress/house-bill/1826). All prostate cancer care providers and healthcare organizations should be aware of the well-documented inequities that exist and pursue strategies that mitigate biases and barriers to care. This is particularly imperative for the care related to the present Guideline—although some of the recommendations here incorporate novel techniques or technology that may not be accessible to all prostate cancer patients at this time, the Panel believes these recommendations represent the best evidence to date for prostate cancer management. All stakeholders should strive to ensure equal access for quality care for all people with prostate cancer.

GUIDELINE STATEMENTS

Clinicians should inform patients that salvage radiation for a detectable PSA after RP is more effective when given at lower levels of PSA. (Strong Recommendation; Evidence Level: Grade B)

For patients with a detectable PSA after RP in whom salvage RT is being considered, clinicians should provide salvage radiation when the PSA is ≤0.5 ng/mL. (Moderate Recommendation; Evidence Level: Grade B)

For patients with a detectable PSA after RP who are at high risk for clinical progression, clinicians may offer salvage radiation when PSA values are <0.2 ng/mL. (Conditional Recommendation; Evidence Level: Grade C)

Clinicians should inform patients that salvage radiation after RP poses inherent risks to urinary control, erectile function, and bowel function. These risks must be considered in the context of the risks posed by recurrent cancer along with patient life expectancy, comorbidities, and preferences to facilitate an SDM approach to management. (Clinical Principle)

Clinicians should use prognostic factors (e.g., PSADT, Gleason Grade Group, pathologic stage, surgical margin status, validated post-prostatectomy genomic classifier and/or PET imaging results) to counsel patients with a detectable PSA about their risk of clinical progression. (Moderate Recommendation; Evidence Level: Grade B)

Clinicians may obtain ultrasensitive PSA following RP in patients who are at high risk of recurrence and in whom salvage RT would be considered. (Expert Opinion) 

For patients who do not meet the AUA definition of BCR after RP (PSA ≥0.2 ng/mL) yet have a detectable ultrasensitive PSA, clinicians should confirm a rising trend in PSA before proceeding with therapy. (Expert Opinion) 

In patients with a BCR after local therapy, clinicians may obtain a PSMA-PET in lieu of conventional imaging or after negative conventional imaging for further evaluation of clinical recurrence. (Conditional Recommendation; Evidence Level: Grade C)

For patients with BCR following RP in whom salvage radiation is being considered, the clinician should perform next generation molecular PET imaging. (Moderate Recommendation; Evidence Level: Grade C)

In patients with BCR following RP with PET/CT positive pelvic nodal disease, the clinician should incorporate treatment of these positive findings in the radiation plan. (Moderate Recommendation; Evidence Level: Grade C)

In patients with BCR, clinicians may obtain a pelvic MRI in addition to a PET/CT for evaluation of local recurrence. (Conditional Recommendation; Evidence Level: Grade C)

In a patient with a BCR following RP, clinicians should not withhold salvage prostate bed RT in the setting of a negative PET/CT. (Expert Opinion)

Clinicians should offer ADT in addition to salvage RT for patients with BCR following RP and any high-risk features (e.g., higher post-prostatectomy PSA such as PSA ≥7ng/mL, Gleason Grade Group 4 to 5, PSADT ≤6 months, persistently detectable post-operative PSA, seminal vesicle involvement). (Moderate Recommendation; Evidence Level: Grade B) 

For patients with BCR following RP without any high-risk features, clinicians may offer radiation alone. (Conditional Recommendation; Evidence Level: Grade C)

Clinicians should discuss treatment side effects and the impact of medical comorbidities when patients are being considered for ADT (as well as duration) with salvage RT, utilizing an SDM approach. (Clinical Principle)

For patients with pN1 disease being treated with post-operative RT, clinicians should include ADT rather than treating with RT alone. (Clinical Principle)

When providing ADT to patients undergoing salvage RT, clinicians should provide a minimum of four to six months of hormonal therapy. (Clinical Principle)

For patients with high-risk features, clinicians may extend ADT to 18 to 24 months. (Expert Opinion)

In patients with BCR following RP undergoing salvage RT with ADT, clinicians may use expanded radiation fields that include the regional lymph nodes. (Conditional Recommendation; Evidence Level: Grade B)

Clinicians should discuss with patients that including treatment of regional lymph nodes with salvage RT may increase the risk of side effects, particularly in the short term, compared to prostate bed RT alone. (Moderate Recommendation; Evidence Level: Grade A)

Clinicians should not recommend the addition of docetaxel in patients undergoing salvage RT and ADT. (Strong Recommendation; Evidence Level: Grade B)

For pN0 patients, clinicians should recommend the use of intensified AR suppression with salvage RT only within a clinical trial setting. (Clinical Principle)

For patients with BCR following primary RT or ablative therapy who have no evidence of metastatic disease and are candidates for local salvage therapy, clinicians should perform a prostate biopsy to evaluate for local recurrence. (Clinical Principle)

In patients with a biopsy-documented prostate cancer recurrence after primary RT who are candidates for salvage local therapy, clinicians should offer RP, cryoablation, HIFU, or reirradiation as part of an SDM approach. (Moderate Recommendation; Evidence Level: Grade C)

In patients for whom salvage local therapy is being considered following focal ablation, clinicians should offer whole gland treatment by RP or RT. (Expert Opinion)

In patients with pelvic nodal recurrence following primary RP, clinicians should offer ADT plus salvage RT to the prostate bed and pelvic lymph nodes. (Expert Opinion)

In patients with pelvic nodal recurrence following primary RT who did not receive prior pelvic nodal RT, clinicians should offer salvage pelvic nodal RT plus ADT. (Expert Opinion)

Clinicians may offer salvage pelvic lymphadenectomy for patients with evidence of pelvic lymph node recurrence after RP or RT; however, these patients should be counseled regarding the uncertain oncologic benefit from surgery in this setting. (Conditional Recommendation; Evidence Level: Grade C)

In patients with evidence of regional or metastatic oligorecurrence following primary therapy (RP or RT), clinicians may perform SABR MDT but should consider the risk of toxicity versus benefits. (Conditional Recommendation; Evidence Level: Grade C)

In patients with BCR who have non-regional disease seen on PET/CT but no visible disease on conventional imaging, clinicians may omit salvage RT to the prostate bed and should discuss the uncertain role of systemic therapy in this setting. (Expert Opinion)

Optimizing and personalizing the approach to salvage therapy remains an ongoing area of work in the field of genitourinary oncology and represents an area of research and clinical care that requires well-coordinated, multi-disciplinary care. Advancing work in the area of diagnostic tools (particularly imaging), biomarkers, radiation delivery, and biological manipulation with the evolving armamentarium of therapeutic agents will undoubtedly present new opportunities for patients to experience long-term control of their cancer while minimizing toxicity.

As examples of these opportunities, the field will soon see the completion of studies involving the use of PSMA-PET/CT both to optimize patient selection and radiation planning for managing locoregional recurrences. Nevertheless, as newer and more sensitive imaging agents and modalities become available, further studies will be needed to define appropriate utilization in patients being considered for salvage therapy. With continued investigation of molecular biomarkers, the field will also gain insight into the optimization of systemic therapies, particular suppression of AR activation, for example, in using genomic classifiers. Indeed, NRG-GU006 (BALANCE, NCT03371719), which evaluates the role of luminal-basal subtyping to personalize the use of hormonal manipulation in salvage RT, is due to mature.

In addition, there is renewed interest in balancing the harms and benefits of early AR suppression in prostate cancer, fueled by studies showing the benefits of treatment intensification for patients with metastatic disease. In addition to optimizing the duration of AR suppression, there is now interest in understanding the role of intensified AR suppression in the setting of salvage RT. Early results from the completed phase 2 studies point to potential benefit, but there is still need to develop trials in this space and to follow fully accrued studies as they mature. (NCT02319837, NCT03009981) Similarly, there is now evidence from the EMBARK study to support early intensified AR suppression for patients at particularly high risk of developing metastasis.¹⁶⁴ This topic will be addressed in a future update to the Advanced Prostate Cancer Guideline.

Continuous and deliberate efforts for multidisciplinary care in prostate cancer will be required to optimize and improve the oncologic and functional outcomes of patients treated with salvage therapies in the future.

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