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

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.107 Multiple 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,111 which 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.131 Fortunately, 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,132 as 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.138,139 The 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.149 Although 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.

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)

Patients managed with active surveillance need to be counseled regarding the importance of continued follow-up as part of this management strategy. Indeed, active surveillance is distinct as a management strategy from watchful waiting, or passive surveillance, by the incorporation of follow-up cancer testing, including prostate biopsy. While the intensity of monitoring has varied among the various reported large active surveillance cohorts to date,112,114,118,150,151 critical components include following PSA values, which the Panel advises be in general obtained no more frequently than every six months and updating a symptom assessment and physical examination with DRE every one to two years.

Notably, the monitoring regimen for patients managed with active surveillance may be individualized. For example, among patients at low risk of progression or with a more limited life expectancy, a less intense follow-up schedule may be implemented.152 With regard to the use of genomic testing, as previously noted, while biopsy-based genomic testing may impact the decision of surveillance versus treatment, robust data are currently lacking for meaningful long-term outcomes among contemporary patients managed with active surveillance. In addition, serial genomic testing among patients on active surveillance should be discouraged.

An increase in PSA in a patient being managed with active surveillance should initially prompt re-testing of PSA as transient PSA elevations are common and PSA kinetics have variably been associated with pathology among patients on surveillance.153,154 Serial PSA increases, new DRE abnormalities, or other concerns for clinical progression should prompt re-evaluation with MRI and possible prostate biopsy; less frequently, direct conversion to treatment may be considered. Detection of significantly higher-volume or higher-grade disease on surveillance biopsy should then prompt discussion of definitive therapy. The decision to continue surveillance versus proceed with treatment should incorporate the principles of SDM and include the factors of age, comorbidity status, estimated life expectancy, cancer characteristics, and patient preference, balancing the relative risks of impacting quality-of-life with treatment and disease progression.

In patients selecting active surveillance, clinicians should utilize mpMRI to augment risk stratification, but this should not replace periodic surveillance biopsy. (Expert Opinion)

The purpose of active surveillance for suitable patients is to maintain patients’ QOL by deferring or delaying definitive treatment when prostate cancer is unlikely to cause mortality or significant morbidity, while simultaneously ensuring the appropriate potential to implement definitive treatment with curative intent should this become necessary. As such, a critical component of management with active surveillance for patients with newly diagnosed prostate cancer is an assessment of the patient’s risk for harboring more aggressive disease in the prostate than was detected on biopsy, which would thereby render the patient at increased risk for experiencing subsequent disease progression. mpMRI has been utilized as one such tool for risk assessment in this setting,155,156 particularly among patients whose initial prostate biopsy was performed without prior mpMRI guidance. The purported rationale here has been to obtain complete gland imaging, potentially allowing detection of more aggressive disease in the prostate in regions not sampled on the patient’s diagnostic biopsy. Patients with positive mpMRI findings have been found to be more likely to contain clinically significant disease (typically, higher Grade Group).157

A role for mpMRI prior to confirmatory biopsy among patients on active surveillance for low-risk prostate cancer was investigated in the prospective, randomized ASIST trial.158 Although the initial report of the trial did not find a statistically significant difference in the rate of biopsy upgrading among patients with versus without a pre-confirmatory biopsy mpMRI, a follow-up report from the trial found that patients who underwent mpMRI had fewer active surveillance failures and less grade progression at two years follow-up post biopsy.159 Thus, the Panel believes that an mpMRI should be obtained if the initial (diagnostic) prostate biopsy was performed without mpMRI guidance. If the mpMRI demonstrates findings suspicious for clinically-significant prostate cancer (PIRADS 4 or 5), then timely repeat (confirmatory) targeted biopsy is recommended, with disease risk re-established based on these biopsy results. Conversely, if the mpMRI is assessed as PIRADS 1, 2, or 3, then repeat biopsy may be performed within approximately 12 months after diagnosis. Thereafter, serial surveillance biopsies are recommended every one to four years depending on patient age, health, risk of progression, and preference.160-162

Evidence for the utility of serial prostate mpMRI to evaluate for changes in disease risk among patients on surveillance remains mixed; as such, mpMRI cannot be recommended as a stand-alone replacement for periodic repeat biopsy.163 For example, a recent cohort study demonstrated that a surveillance strategy using mpMRI or clinical changes as the sole indicator for repeat biopsy would have missed upgrading to Grade Group 2 or higher in 169 of every 1,000 patients on surveillance, leading to the conclusion by the authors that periodic biopsy should remain a component of the management of patients on surveillance.164 A subsequent meta-analysis found a pooled sensitivity and specificity for detecting Grade Group of 2 or more of 0.59 (95% CI 0.44 to 0.73) and 0.75 (95% CI 0.66 to 0.84), respectively.165 It should be noted that interobserver variability in interpreting mpMRI may be a limitation. Therefore, while the Panel recognizes that mpMRI may be utilized in patients electing active surveillance, further study is warranted to determine the optimal timing and incorporation of continued imaging for patient management.

Principles of Surgery

In patients electing radical prostatectomy, nerve-sparing, when oncologically appropriate, should be performed. (Moderate Recommendation; Evidence Level: Grade B)

Preservation of the neurovascular bundles during radical prostatectomy has consistently been associated with a lower likelihood of postoperative erectile dysfunction, has variously but favorably been associated with improved urinary continence after surgery, and has not been found to significantly compromise the rates of positive surgical margins or biochemical recurrence.166-169 The Panel does acknowledge, however, that the systematic review did not identify RCTs of nerve-sparing versus non-nerve sparing radical prostatectomy. The Panel also recognizes the balance between nerve preservation and optimizing cancer control. Indeed, the decision to perform nerve-sparing is frequently multifactorial, and may include PSA, DRE, biopsy findings (grade, tumor volume, and location), MRI findings, as well as the patient’s baseline erectile function and stated prioritization of sexual function. The Panel further asserts that MRI should not be used in isolation to determine nerve-sparing, as the ability of MRI to predict extracapsular extension, particularly when microscopic, is suboptimal.170 Importantly, the Panel notes that nerve-sparing does not necessarily entail an “all or none” decision, and both partial nerve preservation and unilateral nerve-sparing may be utilized.

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)

The systematic review supporting this guideline identified 44 studies (N=244,889 patients) detailing the outcomes of patients who variously did or did not undergo pelvic lymph node dissection (PLND) at the time of radical prostatectomy for clinically localized prostate cancer. Of note, the absence of robust prospective clinical trials comparing the results of patients undergoing PLND versus not, as well as significant methodological issues (e.g., heterogeneity in risk of harboring lymph node positive disease among the populations studied, lack of standardized dissection templates) and bias limit the level of evidence from the reported outcome data. That said, from the existing literature, no consistent benefit to PLND can be derived with regard to oncologic outcomes such as biochemical recurrence, metastasis-free, cancer-specific, and overall survival.171-176 Two recent prospective trials randomized patients undergoing radical prostatectomy to limited versus extended PLND.177,178 In both trials, no statistically significant difference in subsequent biochemical recurrence-free survival was identified between the treatment arms, although one of the trials did note improved biochemical recurrence-free survival with extended lymph node dissection in an exploratory subgroup analysis of patients with Grade Group 3 to 5 tumors.177 At the same time, the systematic review did demonstrate a higher risk of adverse perioperative outcomes in patients undergoing PLND (operating time, blood loss, length of stay) and post-operative complications – most notably lymphocele.179

Nevertheless, as PLND (specifically, an extended PLND) does facilitate identification of positive nodes, 177,180 the Panel concluded that patients should be counseled regarding the staging benefit of PLND. Identifying positive nodes not only contributes to refined risk stratification/patient counseling, but may further be used to guide the selective application of secondary therapies.181,182 Given the uncertain oncologic benefit and noted – albeit small – increased risk of complications with PLND, the Panel believes that PLND should be advised according to a risk stratified approach, using nomograms for risk assessment. Several nomograms exist to facilitate selection of patients for PLND.183-185 When selecting a model, it is important that clinicians consider the risk profile of the patients included in model development (e.g., percentage of high-risk patients) as well as the reference standard (e.g., extended versus limited PLND) utilized to establish the model’s predictive capacity. Existing national and organizational guidelines have proposed various thresholds of nomogram-predicted probability of lymph node positive disease for clinicians to perform a PLND at the time of radical prostatectomy. Recognizing varying individual risk tolerance, the Panel believes that the patient’s calculated risk of harboring positive nodes should be discussed along with the utility of establishing the presence of positive nodes to inform future management and the risks associated with PLND and to facilitate the SDM approach to performing lymph node dissection.

Clinicians performing pelvic lymphadenectomy should perform an extended dissection, which improves staging accuracy compared to a limited dissection. (Moderate Recommendation; Evidence Level: Grade: B)

Using anatomic landmarks, PLND templates may be considered as follows:171

Limited = obturator fossa

Standard = limited plus external iliac lymph nodes

Extended = Standard plus internal iliac lymph nodes

Super-extended = Extended plus common iliac, presacral and/or other nodes

Extended PLND results in higher lymph node counts as well as a greater positive lymph node yield.177,179,180,186 While a more extensive lymph node dissection increases operative time as well as the risk of lymphocele,179 the Panel believes that the demonstrated staging benefit supports that extended dissection should be performed for appropriately risk-selected patients undergoing PLND.

Clinicians should complete a radical prostatectomy if suspicious regional nodes are encountered intraoperatively. (Moderate Recommendation; Evidence Level: Grade C)

The Panel acknowledges the absence of prospective trial testing in this setting. Numerous retrospective series – largely in historic cohorts of patients from an era during which frozen section analysis of pelvic lymph nodes at the time of prostatectomy was routine – have reported a benefit to completion of radical prostatectomy among patients found to have positive nodes versus patients whose surgery was aborted and who were then treated with ADT alone.187-190 Recognizing the design/methodologic limitations of these studies, the Panel believes that completion of surgery remains warranted among patients for whom lymph nodes suspicious for harboring malignancy are encountered during surgery, particularly given the overall demonstrated safety of radical prostatectomy in contemporary series.191

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)

Importantly, the documented postoperative natural history of patients with lymph node positive disease at radical prostatectomy is relatively heterogeneous. In fact, up to 30% of patients with positive lymph nodes may remain free of disease long-term following surgery without further therapy.192-194 As such, assessment of the risk for subsequent disease progression among patients with positive lymph nodes is warranted to guide the judicious use of secondary therapy. Various clinicopathologic features have been associated with oncologic outcomes in this setting, particularly the number of positive nodes identified.195

Further, while salvage therapy would be appropriate for such patients with a persistently detectable PSA after radical prostatectomy, the Panel believes that patients with an undetectable PSA may be offered adjuvant treatment versus continued PSA surveillance. Of note, a randomized trial in 98 patients assessed the use of immediate, indefinite ADT after radical prostatectomy for patients with lymph node positive disease versus delayed treatment with ADT (largely at the time of systemic progression).181 At the median 11.9 year follow-up, immediate ADT was associated with improved PFS (HR 3.42, 95% CI 1.96 to 5.98), prostate cancer-specific survival (HR 4.09, 95% CI 1.76 to 9.49), and overall survival (HR 1.84, 95% CI 1.01 to 3.35). However, relevant to contemporary management, the trial did not assess the comparative outcomes of adjuvant ADT versus ADT initiated at the time of biochemical recurrence, thus the optimal timing to initiate postoperative ADT for patients with lymph node positive disease remains to be determined. Interestingly, six cohort studies investigating this topic have reported mixed findings.196-201 Three studies found no significant association between treatment with adjuvant ADT 196-198 and oncologic outcomes including biochemical recurrence-free survival, metastasis-free survival, prostate cancer-specific survival, and overall survival, while three studies found improvement in various cancer-specific outcomes in certain populations.199-201

The role of postoperative radiation for patients with lymph node positive disease has not to date been addressed in the prospective clinical trial setting. Rather, a number of cohort studies have reviewed the outcomes of patients with lymph node positive disease treated with adjuvant ADT with or without adjuvant radiation as well.197,200-206 Five of those studies demonstrated improvements in a variety of oncologic outcomes, including overall and cause-specific survival when adjuvant radiation therapy was added to ADT.197,200,203-205 In addition, a retrospective analysis noted superior metastases-free survival among patients with lymph node positive disease treated with adjuvant radiation versus a cohort who received no treatment/salvage radiation.197 Nevertheless, the absence of prospective data preclude definitive recommendations regarding the optimal timing of radiation in patients with lymph node involvement at surgery.

Therefore, the Panel believes that both adjuvant therapies (e.g., ADT, radiation) as well as surveillance with the option for early salvage therapy should the patient experience PSA relapse may be utilized for patients with positive lymph nodes at radical prostatectomy and an undetectable postoperative PSA. The approach taken should be based on SDM, including an assessment of disease risk stratification (e.g., number of positive nodes, primary tumor features) as well as the potential toxicities of additional therapies.

Clinicians should not routinely recommend adjuvant radiation therapy after radical prostatectomy. (Strong Recommendation; Evidence Level: Grade A)

Three recent randomized trials (GETUG-AFU 17, RAVES, RADICALS) evaluated adjuvant radiation therapy versus surveillance with early salvage radiation therapy for PSA increase in patients with high-risk localized prostate cancer following radical prostatectomy.207-209 The criteria for early salvage therapy was a PSA >0.1 ng/mL or >0.2 ng/mL depending on the trial; the proportion of patients in the early salvage therapy groups that received radiation therapy ranged from one third to one half. All three trials demonstrated no significant difference in oncological outcomes between patients who received adjuvant radiation therapy versus patients managed with surveillance and early salvage therapy. Moreover, a prospectively planned systematic review of these trials found no evidence of improvement in event-free survival (pooled HR 0.95, 95% CI 0.75 to 1.21) with receipt of adjuvant therapy and noted that adjuvant radiation was associated with increased risk of genitourinary toxicity.210 Given these findings, together with the observation that between one third and one half of the patients in the surveillance arm of the trials did not require salvage therapy, the Panel concluded adjuvant radiation therapy should not be routinely recommended, and patients should be initially managed with PSA surveillance after radical prostatectomy. The Panel does recognize the relatively limited number of patients included in the aforementioned trials with particularly high-risk features (e.g., Gleason 8 to 10 disease with extraprostatic extension, positive lymph nodes) and thereby acknowledges a potential role for adjuvant radiation in such select patients.211

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)

As is common with other tumor systems in which radiation therapy is delivered for therapeutic benefit, an overarching paradigm in prostate cancer radiation therapy is the application of appropriate evidence-based dosages to the cancer target while simultaneously avoiding sensitive adjacent normal tissues. In this way, the therapeutic ratio between tumor control and normal tissue injury is established to maximize therapeutic benefit while minimizing toxicity, morbidity, and potentially treatment-related mortality. Over the past few decades, the specialty of radiation oncology has leveraged various technologies to achieve this goal of improved cancer outcomes with equal or improved toxicity profiles.

A variety of approaches exist to optimize the therapeutic ratio in radiation oncology. A non-exhaustive list of these approaches include the following:

Simulation procedures: Bladder/rectum filling instructions, patient immobilization, placement of fiducial markers, and use of rectal spacers

Imaging procedures: CT simulations, integrations of fusion imaging (e.g., MRI prostate), image-guided radiation therapy approaches (e.g., cone-beam CT)

Planning procedures: Use of highly conformal radiation therapy such as intensity-modulated radiation therapy (IMRT), volumetric modulated arc therapy (VMAT), and stereotactic body radiation therapy (SBRT), combined with published target and normal tissue dose objectives to optimize planning

Most of these approaches have not been subject to prospective randomized phase III trial testing. One exception is the use of rectal spacers, which was evaluated in a trial that randomized 222 patients 2:1 to either a rectal spacer or control group prior to 79.2 Gy in 1.8 Gy fractions to the prostate ± seminal vesicles.212,213 With a median follow-up of three years, improvements in low-grade (one and two) rectal toxicity, no difference in urinary toxicity, and improvements in bowel health-related QOL were identified.213 Device-related toxicity events were not detected in this trial.212 Of note, the utility of this technology in conjunction with hypofractionated or ultra hypofractionated radiation therapy has not been reported in prospective randomized clinical trials to date.

Clinicians should utilize dose escalation when EBRT is the primary treatment for patients with prostate cancer. (Strong Recommendation; Evidence Level: Grade A)

With the introduction of modern treatment planning software and CT scans in the late 1980s and early 1990s, radiation oncology techniques evolved from basic conventional techniques using simple 2-dimensional planning. Prior to the implementation of sophisticated treatment planning software and CT scans, radiation doses used in the treatment of prostate cancer were limited to between 65-70 Gy.

Advances in radiation treatment planning software and imaging technology have allowed delivery of higher doses to the prostate while limiting doses to the surrounding normal tissues such as rectum and bladder, thus improving the therapeutic ratio.214,215 The current standard technique of external beam radiation therapy (EBRT) is IMRT, which allows dose escalation to greater than 80 Gy safely.

Since the 1990s, multiple phase III randomized prospective studies have compared dose-escalated EBRT (DE-EBRT) using both 3-D conformal radiation therapy (3DCRT) and IMRT with standard dose EBRT and have consistently demonstrated improved biochemical PFS with dose escalation. Multiple randomized trials (sample sizes 126 to 1,499) compared escalated versus conventional dose radiation therapy in patients with localized prostate cancer.216-230 The trials enrolled a mix of low-, intermediate-, and high-risk patients. Escalated doses ranged from 74 to 79.2 Gy, while conventional doses ranged from 64 to 70.2 Gy. The trials consistently demonstrated that escalated dose radiation therapy was associated with decreased rates of biochemical failure or recurrence. Of note, the Panel acknowledges that estimates from these trials for the endpoints of metastatic-disease free survival, prostate cancer-specific survival, and overall survival were imprecise and did not indicate a benefit to dose escalation, with the exception of one trial224,225,227 that did report reduced risks of distant metastatic failure (HR 0.33, 95% CI 0.13 to 0.82) and prostate cancer mortality (HR 0.52, 95% CI 0.27 to 0.98). The largest of the trials was NRG-RTOG 0126 (n=1,499) which looked at standard versus dose-escalated radiation therapy in patients with intermediate-risk prostate cancer.230, This trial demonstrated improvements in biochemical failure and distant metastases; however, the dose-escalated radiation therapy arm was not associated with improvements in overall survival. Furthermore, higher radiation doses were also associated with lower rates of post-radiation salvage at the expense of higher rates of late toxicity. Importantly, this trial has provided clinicians valuable information about radiation dose constraints for the safe planning of dose-escalated radiation therapy for intermediate-risk prostate cancer.231

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)

To date, no prospective study has demonstrated improved disease control or side effects with proton beam radiation therapy (PBRT) compared to IMRT. Proponents of PBRT have offered that it has dosimetric advantages compared to IMRT. That is, while the target volume for both techniques includes the prostate and a margin of normal tissue (bladder and rectum) that is irradiated to the prescribed dose, proton beam delivers lower integral doses and mean doses to normal tissues than IMRT.232 However, this dosimetric difference has not been shown to result in fewer side effects or better patient reported QOL. Indeed, the existing peer-reviewed literature suggests that clinical outcomes (e.g., complications, patient reported QOL) are similar.233

Comparative effectiveness studies have been published in an attempt to evaluate relative toxicity and oncologic outcomes between proton and photon therapies. Two such studies comparing patients treated with proton therapy or photon therapy reported similar toxicity rates. For one, a prospective comparison of patients treated with IMRT (n=204) and patients treated with proton therapy (n=1,234) with regard to patient-reported outcomes measured using the EPIC instrument concluded that “no differences were observed in summary score changes for bowel, urinary incontinence, urinary irritative/obstructive, and sexual domains between the 2 cohorts” after up to 2 years of follow-up.234 Meanwhile, a retrospective analysis of Medicare data from 421 patients treated with proton therapy and a matched cohort of 842 patients treated with IMRT showed less genitourinary toxicity at 6 months with proton therapy, although the difference disappeared after 1 year.235 No other significant differences were seen between the groups. Randomized trials are ongoing comparing IMRT and PBRT using long-term side effects and QOL as the primary endpoints (e.g., PARTIQoL, which has a primary endpoint of bowel function at 24 months).

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)

Using fewer (but larger dose) radiation treatments (i.e., hypofractionation) may be more convenient for patients with prostate cancer electing radiation therapy.236 Nevertheless, demonstrating equivalent cancer control and toxicity profiles with such an approach is paramount.

A systematic review compared hypofractionated (>2 Gy per fraction, range 2.35 to 3.4 Gy) versus conventionally fractionated (1.8 to 2 Gy) EBRT in patients with localized prostate cancer.236 This review included 10 randomized trials (N=8,278); seven trials used highly conformal radiation therapy, six used image-guided radiation therapy (IGRT), and two trials reported some form of motion management. In pooled analyses, no differences were noted between hypofractionation versus conventional fractionation with regard to biochemical recurrence-free survival (HR 0.88, 95% CI 0.68 to 1.13, 5 trials), metastasis-free survival (HR 1.07, 95% CI 0.65 to 1.76, 5 trials), prostate cancer-specific survival (HR 1.00, 95% CI 0.72 to 1.39, 8 trials), or overall survival (HR 0.94, 95% CI 0.83 to 1.07, 10 trials). There were also no differences identified with regard to acute genitourinary radiation therapy toxicity (Relative Risk [RR] 1.03, 95% CI 0.95 to 1.11, 4 trials), late genitourinary radiation therapy toxicity (RR 1.05, 95% CI 0.93 to 1.18), or late gastrointestinal radiation therapy toxicity (RR 1.10, 95% CI 0.68 to 1.78). Findings were consistent in stratified analyses based on radiation therapy dose (≥74 Gy or <74 Gy), difference in radiation therapy doses between hypofractionation and conventional fractionation, radiation therapy technique (highly conformal versus 3DCRT), and use of ADT (≤50% of >50%). Moreover, three trials (n=92, 139, and 303) published subsequent to the systematic review likewise found no clear differences between moderate hypofractionation (fraction size 2.25 to 2.7 Gy, total 70 to 72 Gy) versus conventional fractionation (fraction size 2.0 Gy, total 74 to 80 Gy) in oncological outcomes, QOL, or adverse events, though some estimates were imprecise.237-240

One randomized trial (HYPO-RT, n=1,200) compared ultra hypofractionation (42.7 Gy in 7 fractions, fraction size 6.1 Gy) versus conventional fractionation (78.0 Gy in 39 fractions, fraction size 2 Gy) in patients undergoing radiation therapy with image-guided 3DCRT, IMRT, or VMAT for intermediate- or high-risk localized prostate cancer.241,242 Ultra fractionation was found to be non-inferior to conventional fractionation with regard to failure-free survival (HR 1.00, 95% CI 0.76 to 1.32), prostate cancer mortality (incidence at 5 years 2% versus 1%, p=0.46), and overall survival (HR 1.11, 95% CI 0.73 to 1.69). In addition, although ultra hypofractionation was associated with increased incidence of acute urinary and bowel symptoms, no differences were found in late symptoms or QOL.

Currently, data on long-term control with ultra hypofractionated compared to moderate hypofractionation is less well documented; however, data to date support the use of hypofractionated EBRT. Of note, the recommendations herein are consistent with existing guidance provided by ASTRO/ASCO/AUA.243

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)

Trial data support the use of dose-escalated hypofractionated EBRT or brachytherapy including temporary high-dose rate (HDR) or permanent low-dose rate (LDR) prostate implants as appropriate treatment options for patients with low- or favorable intermediate-risk prostate cancer.244

Importantly, the systematic review undertaken for guideline development identified no randomized trials comparing EBRT to brachytherapy. Of note, a recent retrospective analysis among patients with intermediate-risk prostate cancer (n=684) found no difference between EBRT (75.3 Gy) versus brachytherapy (radioactive iodine seeds at minimum peripheral dose of 145 Gy), with or without neoadjuvant ADT, in propensity score adjusted 10-year metastasis-free survival (91% versus 94%), prostate cancer-specific survival (96% versus 95%), or overall survival (76% versus 78%).245 EBRT was associated with decreased likelihood of freedom from biochemical failure (57% versus 80%).

To note as well, in a Phase II trial of 170 patients randomized to receive HDR as either a single (19 Gy) fraction or as two fractions (13.5 Gy), the 5-year biochemical disease-free survival and cumulative incidence of local failure was 73.5% and 29% in the single fraction arm and 95% (p = 0.001) and 3% (p < 0.001) in the 2-fraction arm, respectively.246 Toxicity results from this study were reported separately; in the single fraction arm, the 5-year cumulative incidence of Grade 2 or higher genitourinary and gastrointestinal toxicity was 62% and 12%, and was 47% and 9% in the two-fraction arm. Grade 3 genitourinary toxicity was only seen in the single fraction arm. No significant differences in mean urinary health related QOL were seen compared to baseline in the two-fraction arm, in contrast to the single-fraction arm, wherein a decline in urinary health-related QOL was seen at 4 and 5 years. The authors ultimately concluded that both single fraction and 2-fraction HDR monotherapy were well tolerated.247

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)

A prior trial (n=446) that compared whole pelvis (46 Gy with cone-down to prostate) to prostate only (66 to 70 Gy) radiation therapy among low-, intermediate-, and high-risk patients with clinical stage T1b-T3 localized prostate cancer found no difference in PFS (adjusted HR 0.96, 95% CI 0.64 to 1.43) or overall survival between the treatment arms.248,249 Similarly, the RTOG 9413 trial, which contained intermediate-risk patients and utilized a 2 x 2 factorial design, demonstrated no significant difference in biochemical failure when comparing whole pelvic radiation therapy to prostate only radiation.250-252 As these are the only prospective trials with sub-groups of intermediate-risk patients, and no benefit was found with nodal radiation, the Panel recommends against the routine use of elective pelvic nodal irradiation for low- and intermediate-risk patients electing radiation therapy.

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)

ADT is associated with well-recognized side effects and may significantly impact patients’ health-related QOL.253,254 These side effects commonly include (but are not limited to) decreased libido, erectile dysfunction, hot flashes, depression and other mood disturbances, fatigue, and weight gain. In addition, treatment with ADT may result in significant changes in metabolic function, including reduction in bone mineral density, increased insulin resistance, and changes in blood lipid profiles.255

Given the potential deleterious short- and long-term effects of ADT, its application in the treatment of localized prostate cancer must be based on an individualized risk-benefit balance. While a number of randomized trials have investigated the use of ADT in combination with radiation therapy versus radiation therapy alone,256-269 most of these studies have investigated intermediate- and high-risk cancer populations. However, in a large trial (n=2,028) that included patients in all risk strata, the use of ADT was not associated with improved overall survival outcome for low-risk patients (HR 0.93, 95% CI 0.72 to 1.20).264 Moreover, although trials have demonstrated a benefit to ADT with radiation for intermediate-risk patients, these trials have not consistently sub-stratified intermediate-risk patients into favorable and unfavorable risk for separate outcome reporting. In line with recommendations of other organizations,14 the Panel believes that routine use of ADT in favorable intermediate-risk patients is not recommended given the observed positive cancer outcomes of radiotherapeutic monotherapy for this patient population (acknowledging the exception of unique circumstances such as planned prostate gland volume reduction prior to definitive radiation therapy, in which ADT may be useful). At the same time, the Panel recognizes that the utility of ADT for favorable intermediate-risk localized prostate cancer is currently under investigation (e.g., NRG Oncology/RTOG 0815).

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)

Given the higher risk of local and distant relapse with unfavorable intermediate-risk disease, the use of ADT is recommended for this patient population. Eight randomized trials have evaluated the role of ADT with radiation therapy versus radiation therapy alone.256-269 All eight trials included intermediate-risk patients, with one trial including patients from all risk strata264 and one trial exclusive to intermediate-risk patients only.269 These trials were heterogeneous in terms of radiation therapy dosage (ranging from 65 to 78 Gy) and technique (3DCRT and IMRT), as well as ADT duration (three to six months in all trials except one trial, which treated for three years), ADT timing (neoadjuvant in five trials, concurrent in two trials, and unknown in one trial), and ADT type (luteinizing hormone-releasing hormone [LHRH] agonist plus antiandrogen in six trials, LHRH agonist alone in one trial, and antiandrogen in one trial). Regardless, these studies collectively demonstrated a consistent benefit with regard to oncologic outcomes among the patients who received ADT with radiation. In an analysis stratified by prostate cancer risk category from one of these trials (n= 2,028), radiation therapy plus short-term ADT was associated with improved overall survival among patients with intermediate-risk disease (HR 0.81, 95% CI 0.67 to 0.98).264 The benefit of hormonal therapy was also demonstrated in the recently published MARCAP meta-analysis, which demonstrated that the addition of ADT to radiotherapy significantly improved metastasis-free survival (HR 0.83, 95% CI 0.77 to 0.89, p<0·0001).270

Toxicity was assessed in seven of the trials indicated above.256-261,263-269 The use of ADT was associated with expected toxicities during ADT administration. These effects generally diminished or resolved after discontinuation of ADT treatment.269 Notably, late gastrointestinal and genitourinary effects were not impacted by the use of ADT with radiation therapy.258,265,269

With regard to the duration of ADT with radiation in unfavorable intermediate-risk disease, six clinical trials assessed very short course ADT (eight weeks to three months) versus standard short course ADT (six months) in intermediate-risk disease, five of which demonstrated that the six-month approach had superior cancer outcomes, including all-cause mortality and/or prostate cancer-specific mortality.259,262,271-280 Nevertheless, the Panel acknowledges that a four-month course of ADT is also commonly given to patients with radiation therapy for intermediate-risk disease in an effort to mitigate the deleterious effects of ADT while maintaining the benefit of combination therapy for cancer control.

Clinicians should offer moderate hypofractionated EBRT for patients with high-risk prostate cancer who are candidates for EBRT. (Moderate Recommendation; Evidence Level: Grade C)

As noted above, moderate hypofractionation holds important advantages in terms of patient convenience and resource utilization. Moreover, multiple large-scale randomized prospective clinical trials have been completed comparing moderately hypofractionated and conventionally fractionated EBRT.239,281-283 These studies have demonstrated that moderate hypofractionation confers similar prostate-cancer-control outcomes and similar rates of late toxicity compared to conventional fractionation. In one study, men with intermediate- to high-risk prostate adenocarcinoma were randomized to receive C-IMRT (76 Gy in 38 fractions; n=152) or H-IMRT (70.2 Gy in 26 fractions; n=151).239 High-risk patients were prescribed 24 months of ADT. Intermediate-risk patients were prescribed 4 months of ADT at the discretion of the treating physician. The primary end point was the cumulative incidence of biochemical and/or clinical disease failure. Median follow up was 130 months (range 7 to 181 months). Ten-year biochemical disease free survival was similar in both arms (25.9% in the C-IMRT arm and 30.6% in the H-IMRT arm; HR 1.31, 95% CI 0.82 to 2.11). The two treatment groups also had similar rates of 10-year freedom from metastatic disease, prostate cancer-specific, and overall survival. The authors concluded that H-IMRT demonstrated no difference in disease outcomes when compared to C-IMRT at 10 years.239

Of note, ultra hypofractionation in high-risk patients receiving EBRT with elective nodal coverage is not currently recommended outside a clinical trial or multi-institutional registry due to insufficient comparative evidence.243

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)

Trials have demonstrated a benefit in clinical control for unfavorable intermediate- or high-risk prostate cancer patients who receive either dose-escalated moderately hypofractionated IMRT or EBRT plus a brachytherapy boost (HDR temporary prostate implant or LDR permanent prostate implant).284-289 Combining EBRT and brachytherapy has demonstrated improved biochemical control over EBRT plus ADT alone in randomized trials.284-287

Interestingly, the phase III randomized ASCENDE-RT trial compared two methods of dose escalation in 398 patients with intermediate- or high-risk prostate cancer: dose-escalated EBRT boost to 78 Gy or LDR brachytherapy boost.287-289 All patients were initially treated with 12 months of ADT and pelvic EBRT to 46 Gy. The primary endpoint of control (biochemical, no evidence of disease) was 89% versus 84% at 5 years; 86% versus 75% at 7 years; and 83% versus 62% at 9 years for the LDR versus EBRT boost arms (log-rank P < .001). However, toxicity was higher in the brachytherapy arm, with a cumulative incidence of grade 3 genitourinary events at 5 years of 18.4% for brachytherapy boost and 5.2% for EBRT boost (P < .001). In addition, increased gastrointestinal toxicity among patients treated with a brachytherapy boost was also seen (cumulative incidence of grade 3 events at 5 years, 8.1% versus 3.2%; P = .12).

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)

The recently published POP-RT trial randomized patients (n=214) with NCCN high- (~50%) and very high-risk (~50%) prostate cancer290 to IMRT to the whole pelvis (68 Gy in 25 fractions to prostate with 50 Gy to pelvic lymph nodes) versus prostate-only (68 Gy). This currently represents the only trial of elective pelvic nodal irradiation that delivered both modern standard-of-care radiotherapy doses and ADT duration while looking exclusively at high-risk patients.

All patients received ADT (surgical or medical) starting eight weeks prior to radiation therapy; medical ADT was via an LHRH agonist and was administered for two years. The trial demonstrated improved 5-year biochemical failure-free survival (HR 0.23, 95% CI 0.10 to 0.52; trial’s primary endpoint), distant metastasis-free survival (HR 0.35, 95% CI 0.15 to 0.82), and disease-free survival (HR 0.40, 95% CI 0.22 to 0.73) with whole pelvis IMRT, although no difference was detected in overall survival (HR 0.92, 95% CI 0.41 to 2.05).

Despite not showing an overall survival benefit, the Panel notes that elective nodal irradiation for high-risk patients may be offered given the reasonable morbidity (higher late grade II genitourinary toxicity with whole pelvis radiation but no difference in late gastrointestinal toxicity and no difference in grade III/IV genitourinary or gastrointestinal toxicity noted) as well as the reductions in biochemical failure and distant metastases. The Panel recognizes that neither the previous GETUG-01249 nor RTOG 9413251 trials demonstrated a benefit to elective nodal irradiation, but submits that those studies included variably-defined high-risk sub-groups (and lower risk than the POP-RT trial), used simpler radiation technologies with more limited pelvic fields, included a shorter duration of ADT, and delivered lower doses of radiation to the prostate; collectively, these differences may have blunted the impact of elective regional irradiation; as such, may be less relevant to inform contemporary practice.

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)

As the POP-RT trial290 outlined above utilized IMRT for the treatment of the pelvic lymph nodes, the Panel concludes that clinicians should utilize IMRT when treating the nodes electively in high-risk patients. Meanwhile, various reported trials that included pelvic nodal irradiation treated the nodes with doses from 45 Gy to 52 Gy (50 Gy in POP-RT);290 as such, the Panel supports this range when nodal radiation is utilized.

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)

Multiple prospective RCTs have informed the management of high-risk localized prostate cancer to include ADT with radiation based on improved cancer outcomes.256-269 In particular, the primary evidence for the use of ADT with radiation in high-risk disease comes from EORTC 22863, a trial that randomized 415 patients with locally advanced prostate cancer to 3 years of ADT plus 70 Gy of prostate radiation therapy versus radiation therapy alone.256-259 Benefits were noted in the combination treatment arm with regard to both prostate cancer-specific survival (HR 0.38, 95% CI 0.24 to 0.60) and overall survival (HR 0.60, 95% CI 0.45 to 0.80). From this study, three years of ADT was established as a reference standard ADT treatment for the duration of combined ADT with radiation therapy in the treatment of patients with high-risk prostate cancer. A subsequent RCT among high-risk patients tested 18 versus 36 months of ADT.280 This trial did not demonstrate differences in disease-free survival (HR 0.84, 95% CI 0.68 to 1.02), disease-specific survival (HR 0.95, 95% CI 0.58 to 1.55), or overall survival (HR 1.02, 95% CI 0.81 to 1.29) between the treatment durations, and has thereby introduced a minimum threshold duration of ADT when combined with radiation therapy for the management of high-risk disease. The recently published MARCAP meta-analysis further demonstrates the benefit of ADT in patients treated with radiation therapy.270

When combined ADT and radiation are used, ADT may be initiated neoadjuvantly, concurrently, or adjuvantly. (Conditional Recommendation; Evidence Level: Grade C)

The optimal sequencing of ADT and radiation has not been clearly defined. In the randomized Ottawa 0101 study, neoadjuvant and concurrent ADT for six months was compared with concurrent and adjuvant ADT for six months.291 No differences were detected in biochemical relapse-free survival or overall survival. Meanwhile, in NRG/RTOG 9413, a 2 x 2 factorial design was used whereby250,251 patients with prostate cancer were randomized to four months of neoadjuvant and concurrent ADT (starting two months before radiation) versus four months of adjuvant ADT, with a second randomization to prostate only versus whole pelvis irradiation. Interestingly, among patients who underwent prostate only radiation, adjuvant ADT was associated with improved PFS compared to neoadjuvant ADT. However, among patients who received whole pelvis radiation, adjuvant ADT was associated with worse PFS compared to neoadjuvant ADT. Meanwhile, in a meta-analysis including data from Ottawa 0101 and NRG/RTOG 9413, patients receiving neoadjuvant and concurrent ADT and prostate only radiation were combined into the neoadjuvant group, and patients receiving concurrent and adjuvant arm were combined into the adjuvant group.292 After a median follow-up of 14.9 years, the adjuvant group had significantly better biochemical control, PFS, and metastasis-free survival compared to the neoadjuvant group. Of note, patients receiving whole pelvic nodal radiation in NRG/RTOG 9413 were not included in the analysis. There were also systematic differences between the two trials (e.g., duration of ADT, inclusion of more aggressive disease in the NRG/RTOG 9413). As a result, the authors acknowledged that their ability to soundly perform comparative subset analyses was hindered. Thus, while this study suggested that adjuvant ADT is associated with improved disease control relative to neoadjuvant ADT in patients receiving (prostate only) radiation, the findings should not be considered definitive. Further, a separate, retrospective cohort study found no difference between neoadjuvant ADT and adjuvant ADT in biochemical recurrence-free survival or distant metastasis-free survival.293 Importantly, by initiating ADT concurrently or adjuvantly, radiation therapy can begin without delay and may thereby be more convenient for patients as compared to neoadjuvant ADT.

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)

Various compositions of ADT have been used in combination with radiation in the randomized trials to date. For example, a number of studies used combined androgen suppression for the entire course of treatment,258-260,275,277 while other series used an LHRH agonist for the duration of treatment with an initial a short course of antiandrogen at the early phase of treatment,278,280 and some trials used LHRH agonists alone.269,272 The Panel believes that clinicians may use any one of these options in combination with radiation.