Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline (2017)

Published 2017 These guidelines for the management of localized prostate cancer are structured first, to provide a clinical framework stratified by cancer severity to facilitate care decisions and second, to guide the specifics of implementing the selected management options, including active surveillance, observation/watchful waiting, prostatectomy, radiotherapy, cryosurgery, high intensity focused ultrasound (HIFU) and focal therapy. Unabridged version of this Guideline [pdf]

Mandarin translated guideline courtesy of Chinese Urological Association (CUA) [pdf] Presentations from the 2017 AUA Annual Meeting: High-Risk Disease [pdf]

Intermediate-Risk Disease [pdf]

Low-Risk Disease [pdf]

ASCO endorsement

Panel Members

Martin G. Sanda, MD; Ronald C. Chen, MD; Tony Crispino; Stephen Freedland, MD; Kirsten Greene, MD; Laurence H. Klotz, MD; Danil V. Makarov, MD; Joel B. Nelson, MD; James Reston, PhD; George Rodrigues, MD; Howard M. Sandler, MD; Mary Ellen Taplin, MD; Jeffrey A. Cadeddu, MD

Executive Summary

Following a prostate cancer diagnosis, patients are faced with a multitude of care options, the advisability of which is influenced by patient factors and by cancer severity or aggressiveness. The ability to categorize patients based on cancer aggressiveness is invaluable for facilitating care decisions. Accordingly, these guidelines for the management of localized prostate cancer are structured first, to provide a clinical framework stratified by cancer severity (or risk group) to facilitate care decisions and second, to guide the specifics of implementing the selected management options, including active surveillance, observation/watchful waiting, prostatectomy, radiotherapy, cryosurgery, high intensity focused ultrasound (HIFU) and focal therapy. Secondary or salvage treatment for localized prostate cancer that persists or recurs after primary definitive intervention, and primary treatment of locally advanced/metastatic disease, are outside the scope of these guidelines. The content of these guidelines is formatted as shown in Table 1. Table 1. Localized Prostate Cancer Guidelines Content Section Subtopic Guideline Statements I. Introduction NA A. Guideline Statements B. Methodology C. Risk Stratification II. Shared Decision Making 1-5 III. Care Options by Cancer Severity/Risk Group 6-27 A. Very Low / Low Risk 6-14 B. Intermediate Risk 15-21 C. High Risk 22-27 IV. Recommended Approaches/Details of Specific Care Options 28-60 A. Active Surveillance 28-33 B. Radical Prostatectomy 34-41 C. Radiotherapy 42-49 D. Cryosurgery 50-56 E. HIFU/Focal therapy 57-60 V. Outcome Expectations and Management A. Side effects and HRQOL 61-65 B. Post-treatment follow-up 66-68 VI. Future Directions NA Guideline Statements Shared Decision Making (SDM) Counseling of patients to select a management strategy for localized prostate cancer should incorporate shared decision making and explicitly consider cancer severity (risk category), patient values and preferences, life expectancy, pre-treatment general functional and genitourinary symptoms, expected post-treatment functional status, and potential for salvage treatment. (Strong Recommendation; Evidence Level: Grade A) Prostate cancer patients should be counseled regarding the importance of modifiable health-related behaviors or risk factors, such as smoking and obesity. (Expert Opinion) Clinicians should encourage patients to meet with different prostate cancer care specialists (e.g., urology and either radiation oncology or medical oncology or both), when possible to promote informed decision making. (Moderate Recommendation; Evidence Level: Grade B) Effective shared decision making in prostate cancer care requires clinicians to inform patients about immediate and long-term morbidity or side effects of proposed treatment or care options. (Clinical Principle) Clinicians should inform patients about suitable clinical trials and encourage patients to consider participation in such trials based on eligibility and access. (Expert Opinion) Care Options by Cancer Severity/Risk Group Very Low-/Low-Risk Disease Clinicians should not perform abdomino-pelvic CT or routine bone scans in the staging of asymptomatic very low- or low-risk localized prostate cancer patients. (Strong Recommendation; Evidence Level: Grade C) Clinicians should recommend active surveillance as the best available care option for very low-risk localized prostate cancer patients. (Strong Recommendation; Evidence Level: Grade A) Clinicians should recommend active surveillance as the preferable care option for most low-risk localized prostate cancer patients. (Moderate Recommendation; Evidence Level: Grade B) Clinicians may offer definitive treatment (i.e. radical prostatectomy or radiotherapy) to select low-risk localized prostate cancer patients who may have a high probability of progression on active surveillance. (Conditional Recommendation; Evidence Level: Grade B) Clinicians should not add ADT along with radiotherapy for low-risk localized prostate cancer with the exception of reducing the size of the prostate for brachytherapy. (Strong Recommendation; Evidence Level: Grade B) Clinicians should inform low-risk prostate cancer patients considering whole gland cryosurgery that consequent side effects are considerable and survival benefit has not been shown in comparison to active surveillance. (Conditional Recommendation; Evidence Level: Grade C) Clinicians should inform low-risk prostate cancer patients who are considering focal therapy or high intensity focused ultrasound (HIFU) that these interventions are not standard care options because comparative outcome evidence is lacking. (Expert Opinion) Clinicians should recommend observation or watchful waiting for men with a life expectancy ≤5 years with low-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade B) Among most low-risk localized prostate cancer patients, tissue based genomic biomarkers have not shown a clear role in the selection of candidates for active surveillance. (Expert Opinion) Intermediate-Risk Disease Clinicians should consider staging unfavorable intermediate-risk localized prostate cancer patients with cross sectional imaging (CT or MRI) and bone scan. (Expert Opinion) Clinicians should recommend radical prostatectomy or radiotherapy plus androgen deprivation therapy (ADT) as standard treatment options for patients with intermediate-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade A) Clinicians should inform patients that favorable intermediate-risk prostate cancer can be treated with radiation alone, but that the evidence basis is less robust than for combining radiotherapy with ADT. (Moderate Recommendation; Evidence Level: Grade B) In select patients with intermediate-risk localized prostate cancer, clinicians may consider other treatment options such as cryosurgery. (Conditional Recommendation; Evidence Level: Grade C) Active surveillance may be offered to select patients with favorable intermediate-risk localized prostate cancer; however, patients should be informed that this comes with a higher risk of developing metastases compared to definitive treatment. (Conditional Recommendation; Evidence Level: Grade C) Clinicians should recommend observation or watchful waiting for men with a life expectancy ≤5 years with intermediate-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade A) Clinicians should inform intermediate-risk prostate cancer patients who are considering focal therapy or HIFU that these interventions are not standard care options because comparative outcome evidence is lacking. (Expert Opinion) High-Risk Disease Clinicians should stage high-risk localized prostate cancer patients with cross sectional imaging (CT or MRI) and bone scan. (Clinical Principle) Clinicians should recommend radical prostatectomy or radiotherapy plus ADT as standard treatment options for patients with high-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade A) Clinicians should not recommend active surveillance for patients with high-risk localized prostate cancer. Watchful waiting should only be considered in asymptomatic men with limited life expectancy (≤5 years). (Moderate Recommendation; Evidence Level: Grade C) Cryosurgery, focal therapy and HIFU treatments are not recommended for men with high-risk localized prostate cancer outside of a clinical trial. (Expert Opinion) Clinicians should not recommend primary ADT for patients with high-risk localized prostate cancer unless the patient has both limited life expectancy and local symptoms. (Strong Recommendation; Evidence Level: Grade Clinicians may consider referral for genetic counseling for patients (and their families) with high-risk localized prostate cancer and a strong family history of specific cancers (e.g., breast, ovarian, pancreatic, other gastrointestinal tumors, lymphoma). (Expert Opinion) Recommended Approaches and Details of Specific Care Options Active Surveillance Localized prostate cancer patients who elect active surveillance should have accurate disease staging including systematic biopsy with ultrasound or MRI-guided imaging. (Clinical Principle) Localized prostate cancer patients undergoing active surveillance should have routine surveillance PSA testing and digital rectal exams. (Strong Recommendation; Evidence Level: Grade B) Localized prostate cancer patients undergoing active surveillance should be encouraged to have a confirmatory biopsy within the initial two years and surveillance biopsies thereafter. (Clinical Principle) Clinicians may consider multiparametric prostate MRI as a component of active surveillance for localized prostate cancer patients. (Expert Opinion) Tissue based genomic biomarkers have not shown a clear role in active surveillance for localized prostate cancer and are not necessary for follow up. (Expert Opinion) Clinicians should offer definitive treatment to localized prostate cancer patients undergoing active surveillance who develop adverse reclassification. (Moderate Recommendation; Evidence Level: Grade B) Prostatectomy Clinicians should inform localized prostate cancer patients that younger or healthier men (e.g., <65 years of age or >10 year life expectancy) are more likely to experience cancer control benefits from prostatectomy than older men. (Strong Recommendation; Evidence Level: Grade B) Clinicians should inform localized prostate cancer patients that open and robot-assisted radical prostatectomy offer similar cancer control, continence recovery, and sexual recovery outcomes. (Moderate Recommendation; Evidence Level: Grade C) Clinicians should inform localized prostate cancer patients that robotic/laparoscopic or perineal techniques are associated with less blood loss than retropupic prostatectomy. (Strong Recommendation; Evidence Level: Grade B) Clinicians should counsel localized prostate cancer patients that nerve-sparing is associated with better erectile function recovery than non-nerve sparing. (Strong Recommendation; Evidence Level: Grade A) Clinicians should not treat localized prostate cancer patients who have elected to undergo radical prostatectomy with neoadjuvant ADT or other systemic therapy outside of clinical trials. (Strong Recommendation; Evidence Level: Grade A) Clinicians should inform localized prostate cancer patients considering prostatectomy, that older men experience higher rates of permanent erectile dysfunction and urinary incontinence after prostatectomy compared to younger men. (Strong Recommendation; Evidence Level: Grade B) Pelvic lymphadenectomy can be considered for any localized prostate cancer patients undergoing radical prostatectomy and is recommended for those with unfavorable intermediate-risk or high-risk disease. Patients should be counseled regarding the common complications of lymphadenectomy, including lymphocele development and its treatment. (Expert Opinion) Clinicians should inform localized prostate cancer patients with unfavorable intermediate-risk or high-risk prostate cancer about benefits and risks related to the potential option of adjuvant radiotherapy when locally extensive prostate cancer is found at prostatectomy. (Moderate Recommendation; Evidence Level: Grade B) Radiotherapy Clinicians may offer single modality external beam radiotherapy or brachytherapy for patients who elect radiotherapy for low-risk localized prostate cancer. (Clinical Principle) Clinicians may offer external beam radiotherapy or brachytherapy alone or in combination for favorable intermediate-risk localized prostate cancer. (Clinical Principle) Clinicians should offer 24-36 months of ADT as an adjunct to either external beam radiotherapy alone or external beam radiotherapy combined with brachytherapy to patients electing radiotherapy for high-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade A) Clinicians should inform localized prostate cancer patients that use of ADT with radiation increases the likelihood and severity of adverse treatment-related events on sexual function in most men and can cause other systemic side effects. (Strong Recommendation; Evidence Level: Grade B) Clinicians should consider moderate hypofractionation when the localized prostate cancer patient (of any risk category) and clinician decide on external beam radiotherapy to the prostate (without nodal radiotherapy). (Moderate Recommendation; Evidence Level: Grade B) For localized prostate cancer patients with obstructive, non-cancer-related lower urinary function, surgical approaches may be preferred. If radiotherapy is used for these patients or those with previous significant transurethral resection of the prostate, low-dose rate brachytherapy should be discouraged. (Moderate Recommendation; Evidence Level: Grade C) Clinicians should inform localized prostate cancer patients who are considering proton beam therapy that it offers no clinical advantage over other forms of definitive treatment. (Moderate Recommendation; Evidence Level: Grade C) Clinicians should inform localized prostate cancer patients considering brachytherapy that it has similar effects as external beam radiotherapy with regard to erectile dysfunction and proctitis but can also exacerbate urinary obstructive symptoms. (Expert Opinion) Whole Gland Cryosurgery Clinicians may consider whole gland cryosurgery in low- and intermediate-risk localized prostate cancer patients who are not suitable for either radical prostatectomy or radiotherapy due to comorbidities yet have >10 year life expectancy. (Expert Opinion) Clinicians should inform localized prostate cancer patients considering whole gland cryosurgery that cryosurgery has similar progression-free survival as did non-dose escalated external beam radiation (also given with neoadjuvant hormonal therapy) in low- and intermediate-risk disease, but conclusive comparison of cancer mortality is lacking. (Conditional Recommendation; Evidence Level: Grade C) Defects from prior transurethral resection of the prostate are a relative contraindication for whole gland cryosurgery due to the increased risk of urethral sloughing. (Clinical Principle) For whole gland cryosurgery treatment, clinicians should utilize a third or higher generation, argon-based cryosurgical system for whole gland cryosurgery treatment. (Clinical Principle) Clinicians should inform localized prostate cancer patients considering cryosurgery that it is unclear whether or not concurrent ADT improves cancer control, though it can reduce prostate size to facilitate treatment. (Clinical Principle) Clinicians should inform localized prostate cancer patients considering whole gland cryosurgery that erectile dysfunction is an expected outcome. (Clinical Principle) Clinicians should inform localized prostate cancer patients considering whole gland cryosurgery about the adverse events of urinary incontinence, irritative and obstructive urinary problems. (Strong Recommendation; Evidence Level: Grade B) HIFU and Focal Therapy Clinicians should inform those localized prostate cancer patients considering focal therapy or HIFU that these treatment options lack robust evidence of efficacy. (Expert Opinion) Clinicians should inform localized prostate cancer patients who are considering HIFU that even though HIFU is approved by the FDA for the destruction of prostate tissue, it is not approved explicitly for the treatment of prostate cancer (Expert Opinion). Clinicians should advise localized prostate cancer patients considering HIFU that tumor location may influence oncologic outcome. Limiting apical treatment to minimize morbidity increases the risk of cancer persistence. (Moderate Recommendation; Evidence Level: Grade C) As prostate cancer is often multifocal, clinicians should inform localized prostate cancer patients considering focal therapy that focal therapy may not be curative and that further treatment for prostate cancer may be necessary. (Expert Opinion) Outcome Expectations and Management Treatment Side Effects and Health Related Quality of Life Clinicians should inform localized prostate cancer patients that erectile dysfunction occurs in many patients following prostatectomy or radiation, and that ejaculate will be lacking despite preserved ability to attain orgasm, whereas observation does not cause such sexual dysfunction. (Strong Recommendation; Evidence Level: Grade B) Clinicians should inform localized prostate cancer patients that long-term obstructive or irritative urinary problems occur in a subset of patients following observation or active surveillance or following radiation, whereas prostatectomy can relieve pre-existing urinary obstruction. (Strong Recommendation; Evidence Level: Grade B) Clinicians should inform localized prostate cancer patients that whole-gland cryosurgery is associated with worse sexual side effects and similar urinary and bowel/rectal side effects as those after radiotherapy. (Strong Recommendation; Evidence Level: Grade B) Clinicians should inform localized prostate cancer patients that temporary urinary incontinence occurs in most patients after prostatectomy and persists long-term in a small but significant subset, more than during observation or active surveillance or after radiation. (Strong Recommendation; Evidence Level: Grade A) Clinicians should inform localized prostate cancer patients that temporary proctitis following radiation persists in some patients long-term in a small but significant subset and is rare during observation or active surveillance or after prostatectomy. (Strong Recommendation; Evidence Level: Grade A) Post-Treatment Follow Up Clinicians should monitor localized prostate cancer patients post therapy with PSA, even though not all PSA recurrences are associated with metastatic disease and prostate cancer specific death. (Clinical Principle) Clinicians should inform localized prostate cancer patients of their individualized risk-based estimates of post-treatment prostate cancer recurrence. (Clinical Principle) Clinicians should support localized prostate cancer patients who have survivorship or outcomes concerns by facilitating symptom management and encouraging engagement with professional or community-based resources. (Clinical Principle)

Methodology

Systematic Review. The systematic review utilized in the creation of this guideline was completed in part through the Agency for Healthcare Research and Quality (AHRQ) and through additional supplementation that further addressed additional key questions and more recently published literature. A research librarian experienced in conducting literature searches for comparative effectiveness reviews searched in MEDLINE®, PreMEDLINE, Embase®, the Cochrane Library, the Database of Abstracts of Reviews of Effects, the Health Technology Assessment Database, and the UK National Health Service Economic Evaluation database to capture literature published from January 1, 2007 through March 7, 2014. Additional supplemental searches were conducted adding additional literature in August 2015 and August 2016. Assessment of Risk-of-Bias of Individual Studies. Two researchers assessed methodologic risk of bias for each study and resolved discrepancies by consensus. When consensus could not be reached, a third researcher adjudicated. Researchers assessed the risk of bias by following the guidelines in the chapter “Assessing the Risk of Bias of Individual Studies When Comparing Medical Interventions” in the “Methods Guide for Effectiveness and Comparative Effectiveness Reviews.”1 This involved evaluating several items, such as randomization, allocation concealment, intention-to-treat-analysis, and completeness of follow-up. Additionally, researchers assessed fidelity to the protocol to address performance bias and blinding of outcome assessors to address detection bias when outcomes were subjective. To be considered as having low risk of bias, the study must have met all the following conditions: randomization or pseudo-randomization (e.g., using instrumental variable analysis) of study participants to treatment groups, concealment of allocation, data analysis based on the intention-to-treat-principle, an outcome that was objective if outcome assessors were not blinded or blinding of outcome assessors was not reported, a difference of 15% or less in the length of follow-up for the comparison groups, data for more than 85% of enrolled patients provided at the time point of interest, and no clear indication of lack of fidelity to the protocol. To be considered as having high risk of bias, the study must have met at least one of the following criteria: trial did not randomly or pseudo-randomly (i.e., using instrumental variables) assign patients to study groups and did not blind outcome assessors, trial had a difference of 15% or more in the length of follow-up for comparison groups, or trial stated that there was not good fidelity to the protocol. To be considered as having medium risk of bias, the study met neither the criteria for low risk of bias nor the criteria for high risk of bias. Determination of Evidence Strength. The categorization of evidence strength is conceptually distinct from the quality of individual studies. Evidence strength refers to the body of evidence available for a particular question and includes not only individual study quality but consideration of study design, consistency of findings across studies, adequacy of sample sizes, and generalizability of samples, settings, and treatments for the purposes of the guideline. 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). 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.2 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 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. Body of evidence strength Grade C is only rarely used in support of a Strong Recommendation. 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 Opinion with consensus achieved using a modified Delphi technique if differences of opinion emerged.3 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 is no evidence. TABLE 2: AUA Nomenclature Linking Statement Type to Level of Certainty, Magnitude of Benefit or Risk/Burden, and Body of Evidence Strength Evidence Strength A (High Certainty) Evidence Strength B (Moderate Certainty) Evidence Strength C (Low Certainty) Strong Recommendation (Net benefit or harm substantial) Benefits > Risks/Burdens (or vice versa) Net benefit (or net harm) is substantial Applies to most patients in most circumstances and future research is unlikely to change confidence Benefits > Risks/Burdens (or vice versa) Net benefit (or net harm) is substantial Applies to most patients in most circumstances but better evidence could change confidence Benefits > Risks/Burdens (or vice versa) Net benefit (or net harm) appears substantial Applies to most patients in most circumstances but better evidence is likely to change confidence (rarely used to support a Strong Recommendation) Moderate Recommendation (Net benefit or harm moderate) Benefits > Risks/Burdens (or vice versa) Net benefit (or net harm) is moderate Applies to most patients in most circumstances and future research is unlikely to change confidence Benefits > Risks/Burdens (or vice versa) Net benefit (or net harm) is moderate Applies to most patients in most circumstances but better evidence could change confidence Benefits > Risks/Burdens (or vice versa) Net benefit (or net harm) appears moderate Applies to most patients in most circumstances but better evidence is likely to change confidence Conditional Recommendation (No apparent net benefit or harm) Benefits = Risks/Burdens Best action depends on individual patient circumstances Future research unlikely to change confidence Benefits = Risks/Burdens Best action appears to depend on individual patient circumstances Better evidence could change confidence Balance between Benefits & Risks/Burdens unclear Alternative strategies may be equally reasonable Better evidence likely to change confidence Clinical Principle 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 A statement, achieved by consensus of the Panel, that is based on members' clinical training, experience, knowledge, and judgment for which there is no evidence Process. The Localized Prostate Cancer Panel was created in 2012 by the American Urological Association Education and Research, Inc. (AUA). The Practice Guidelines Committee (PGC) of the AUA selected the Panel Chair who in turn appointed the Vice Chair. In a collaborative process, additional Panel members, including members of the American Society for Radiation Oncology (ASTRO), the American Society of Clinical Oncology (ASCO), and Society of Urologic Oncology (SUO), with specific expertise in this area were then nominated and approved by the PGC. The AUA conducted a thorough peer review process. The draft guideline document was distributed to peer reviewers. The Panel reviewed and discussed all submitted comments and revised the draft as needed. Once finalized, the guideline was submitted for approval to the PGC and Science and Quality Council (S&Q). Then it was submitted to the AUA, ASTRO, and SUO Board of Directors for final approval. Panel members received no remuneration for their work.

Risk Stratification

After diagnostic biopsy and appropriate initial staging has demonstrated localized prostate cancer (clinical stage T1-T2, N0 or NX, M0 or MX), risk stratification of prostate cancer severity or aggressiveness should include PSA, clinical stage digital rectal exam (DRE), Grade Group, and amount of cancer on biopsy (i.e. number of cores involved, maximum involvement of any single core) PSA density, and imaging. The Panel agreed that segregating patients into a limited number of risk groups based upon these factors, are simple and easy to use and form the basis for decision making has clinical and practical value. The core of the Panel’s risk-grouping is the original low-, intermediate-, and high-risk grouping as proposed by D’Amico et al. in 19984 and that has been subsequently adopted by the National Comprehensive Cancer Network (NCCN).5 We have further augmented the D’Amico criteria by subcategorizing the low-risk group into very low- and low-risk based on criteria analogous to that first proposed by Epstein that have been adapted by the NCCN, and the intermediate-risk group is subcategorized into favorable and unfavorable intermediate risk, based on the contemporary distinction between Grade Group 2 (Gleason score = 3+4) versus Grade Group 3 (Gleason score 4+3), as recently adopted by the World Health Organization, combined with consideration of the criterion of PSA being less than or higher than 10 ng/ml, a criterion that has been validated in discerning outcome differences in numerous clinical trials (Table 3). A practical rationale for care stratification by these core risk groups is that they are broadly used in contemporary practice, and they are based on criteria (PSA, DRE, Gleason score or Grade Group) that have been the cornerstone of eligibility or risk stratification in randomized clinical trials and prospective multicenter studies that constitute the basis of guideline recommendations. The very low-risk group was adopted based upon the initial identification by Epstein et al.6 that men at the lowest risk of having significant cancer (defined as 0.2 cm3 or larger) were those with 2 or fewer cores positive, no core with >50% involved, Gleason 3+3/Grade Group 1, and a PSA density <0.15 ng/ml/cc. Multiple studies have since used this definition showing that these men have a very favorable outcome with a low probability of adverse pathology at surgery and low rate of metastatic disease when managed with active surveillance.7,8 Understanding that these data were derived largely from sextant biopsies, whereas extended core biopsies represent the vast majority of biopsies in clinical practice today, the Panel adopted the concept of no more than two of six cores positive to represent no more than one-third of cores should be positive. This aligns with the Cancer of the Prostate Risk Assessment (CAPRA) score, where patients with 34% or more positive cores are at increased risk.9 In regards to number of cores, there has been an increased adoption of targeted biopsies in recent years, often using MRI technology. As such, it is not uncommon to have an extended core systematic biopsy plus two or more targeted biopsies. The Panel strongly agreed that the targeted biopsies should not be included in the total percent of cores positive when defining risk group. In other words, if a man undergoes a 12-core systematic biopsy that finds 4 cores positive (1/3 of cores), and a targeted biopsy with 3 cores all of which are positive, the patient should be considered very-low risk (4/12 cores positive, not 7/15 cores positive), assuming he meets all other low-risk criteria and assuming the targeted biopsy was in the same location as one of the systematic biopsies. If the targeted biopsy was outside the location of a systematic biopsy, then it should count as one additional core. In this scenario, the patient would have 5/13 cores positive and be considered low-risk, but not very low-risk. Of note, while the very low-risk grouping was originally designed to detect men with high likelihood of insignificant tumors, defined as <0.2 cc3, the Panel acknowledges that the definition of an insignificant tumor is difficult to define. As such, an image detected lesion >0.2 cc3 does not in and of itself mean a patient cannot be very low-risk if the patient otherwise meets very low-risk criteria. As this is a rapidly evolving area, the Panel acknowledges that the definition of very low-risk in the era of highly accurate imaging may need to be revisited in the future. The intermediate-risk group is defined by the well-established D’Amico criteria for grade and PSA (i.e. Gleason 6 if PSA 10-20; or Gleason 7 if PSA <20), with updating of DRE wherein, consistent with NCCN recommendations, cT2c is categorized as intermediate-risk not high-risk (unless high risk Gleason score is present or PSA is over 20).10 The Panel determined that to facilitate care decisions, it would be prudent to incorporate contemporary “Grade Group” categorizations (Gleason 6 = Grade Group 1; Gleason 3+4 = Grade Group 2; Gleason 4+3 = Grade Group 3; Gleason score 4+4 = Grade Group 4, and Gleason score 4+5 = Grade Group 5) that were recently validated and endorsed by USCAP and WHO, as a cornerstone of subcategorizing the intermediate-risk group into “favorable” and “unfavorable” intermediate-risk group categories (Table 3).11-13 Accordingly, the Panel has defined favorable intermediate-risk as those patients having Grade Group 2 cancers and PSA < 10 ng/ml, whereas unfavorable intermediate-risk is comprised of men with either Grade Group 2 cancer with PSA = 10-20, or any Grade Group 3 with PSA <20 (Table 3). Alternatively, it has been proposed that men with more than one unfavorable risk feature (Grade Group 2, cT2b-c, PSA 10-20 ng/ml, or >50% positive cores) should be considered unfavorable.10 Evidence that >50% positive cores has consistent prognostic validity is less robust than evidence supporting the distinction between Grade Group 2 and 3, or the evidence of differential outcomes based on PSA less than or greater than 10ng/ml; therefore, the Panel opted not to include percentage positive biopsy core in the subcategorization of intermediate-risk cancers. Similarly, there was concern that in the unusual scenario of a man with cT2b or cT2c and a PSA between 10 and 20 ng/ml, but Grade Group 1, this may not represent unfavorable risk either, though this also requires formal validation in future studies. As such, unfavorable intermediate-risk was defined as Grade Group 3 or Grade Group 2 and either a PSA between 10 and 20 ng/ml and clinical stage cT2b or cT2c. TABLE 3: Risk Stratification for Localized Prostate Cancer Very Low Risk PSA <10 ng/ml AND Grade Group 1 AND clinical stage T1-T2a AND <34% of biopsy cores positive AND no core with >50% involved, AND PSA density <0.15 ng/ml/cc Low Risk PSA <10 ng/ml AND Grade Group 1 AND clinical stage T1-T2a Intermediate Risk PSA 10-<20 ng/ml OR Grade Group 2-3 OR clinical stage T2b-c · Favorable: Grade Group 1 (with PSA 10-<20) OR Grade Group 2 (with PSA<10) · Unfavorable: Grade Group 2 (with either PSA 10-<20 or clinical stage T2b-c) OR Grade Group 3 (with PSA < 20) High Risk PSA >20 ng/ml OR Grade Group 4-5 OR clinical stage >T3* *Clinical stage T3 cancer is considered locally advanced and, therefore, outside the scope of this guideline. The Panel did not substratify high-risk patients into high-risk and very high-risk (as has been proposed by the NCCN). The rationale to not further substratify high-risk men is not based upon differences in outcome, but rather the lack of clinical utility as a context for decisions about treatment options is generally similar between high-risk and very high-risk men. However, the Panel did keep the distinction between very low- and low-risk as this does have clinical utility in terms of the optimal management for these men. Finally, the panel acknowledges that multivariable nomograms can also be used to predict the risk of many clinically relevant outcomes. Of these, the CAPRA score has emerged as a well-validated and often used risk scoring system, though it has yet to be widely incorporated into clinical trial design.9,14 While the Panel acknowledges that nomograms have advantages in terms of accuracy, there is lack of consensus regarding the best nomogram and what outcome should be measured.

Shared Decision Making

Guideline Statement 1

Counseling of patients to select a management strategy for localized prostate cancer should incorporate shared decision making and explicitly consider cancer severity (risk category), patient values and preferences, life expectancy, pre-treatment general functional and genitourinary symptoms, expected post-treatment functional status, and potential for salvage treatment. (Strong Recommendation; Evidence Level: Grade A)

Discussion

× Discussion Prostate cancer treatment is a complex medical decision. In almost all cases, there is not a single best treatment choice with regard to oncologic outcomes or side effects. Treatment selection should consider patient, tumor, and treatment-related factors. However, men undergoing treatment for prostate cancer are often not presented with a complete description of all treatment options and treatment-related side effects; up to a quarter of men are not asked about their treatment preferences.15 It is the consensus of the Panel that clinicians should fully engage in shared decision making (SDM), allowing patient values to drive this decision. SDM is a collaborative decision making process between patients and their clinicians. SDM is especially relevant in discussion of prostate cancer treatment because such decisions involve multiple clinically accepted options, and the ratio of benefits to harms is uncertain, equivalent, or “preference sensitive” (i.e. dependent on the value that an individual patient may place on them).16,17 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.18-21 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.17,18 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.22,23

Guideline Statement 2

Prostate cancer patients should be counseled regarding the importance of modifiable health-related behaviors or risk factors, such as smoking and obesity. (Expert Opinion)

Discussion

× Discussion While age is a well-established risk factor for prostate cancer, there are now clear data showing that other patient-related factors such as smoking and excess body weight, typically assessed as a high body mass index (BMI), are correlated with prostate cancer death.24,25 Moreover, these factors are also risk factors for death from any cause. As such, clinicians are strongly encouraged to use the time of prostate cancer diagnosis as a “teachable moment” to counsel patients about weight loss and smoking cessation. In regards to surgically treated patients, in general, smoking, older age, and obesity increase the risk of perioperative complications, including bleeding, infections, and deep venous thromboses in non-prostate surgeries.26-28 As similar results have been seen elsewhere in the urological literature, there is no reason to believe these factors do not contribute to perioperative morbidity from prostate cancer.29 Another factor linked with poor outcomes is frailty. Two recent studies using patients undergoing urological surgery both found that higher frailty index was associated with a significantly higher risk of complications.29,30 Similarly, another study found lower functional status (i.e. partially or totally dependent versus independent) was associated with increased risk of complications, particularly Clavien Grade IV or V complications.31 Therefore, life-expectancy should be assessed on all men prior to deciding on appropriate treatment for prostate cancer. However, while these factors increase the risk of general surgical complications, the degree to which these factors impact prostate cancer treatment-related morbidity is less clear. A prospective multicenter study of 1,201 prostate cancer survivors treated with radical prostatectomy or radiotherapy reported an independent association of obesity with reduced vitality or androgen function but not other aspects of health-related quality of life (QoL), such as urinary or sexual function.32 As obesity is correlated with more aggressive prostate cancer, whether this worse androgen function is related independently to obesity or mediated by a greater need for hormonal therapy in obese men due to their more aggressive disease is not known. Similarly, another prospective study found obesity was associated with worse pretreatment vitality,33 which had a negative impact on posttreatment health-related QoL. In regards to smoking, there are limited data linking smoking with treatment-specific outcomes. However, as smoking is in general associated with poor erectile function and urinary problems, it stands to reason that smoking may make recovery of these factors post-treatment more problematic. In summary, there is strong circumstantial evidence that smoking and obesity may adversely impact treatment outcomes in men undergoing treatment for prostate cancer. Given these concerns, the Panel felt that patients should be informed of the risks. Moreover, the Panel agreed that most patients should be offered the opportunity to delay therapy for a few months to allow them time to lose weight or stop smoking to reduce these perioperative risks as long as doing so does not significantly impair cancer control.

Guideline Statement 3

Clinicians should encourage patients to meet with different prostate cancer care specialists (e.g., urology and either radiation oncology or medical oncology or both), when possible to promote informed decision making. (Moderate Recommendation; Evidence Level: Grade B)

Discussion

× Discussion A patient deciding on treatment for localized prostate cancer often has many options. Even choosing among common treatment options can be overwhelming for a newly diagnosed patient. The various and evolving options also make it less likely that any individual clinician will have personal experience and current knowledge of all therapeutic modalities. Moreover, studies suggest that practitioners may have biases (conscious and subconscious, financial and non-financial) for and against certain management strategies.34Both urologists and radiation oncologists have been observed to recommend whichever therapy they deliver in their practice.35,36 Such observations are troubling, since prostate cancer treatment decisions should be concordant with patients’ preferences. Providers can combat the effects of such biases on treatment selection by engaging the patient in SDM. Additionally, patients may better understand the available treatment options by consulting with multiple practitioners skilled in the specific treatment modalities relevant to the patient’s particular case. Consultation with multiple providers, especially in teams including a medical oncologist, in one location on the same day, may benefit the patient by encouraging SDM and mitigating the possible effects of physician bias.37-39Additionally, including primary care providers in the treatment discussion may help patients make a preference-concordant decision.40

Guideline Statement 4

Effective shared decision making in prostate cancer care requires clinicians to inform patients about immediate and long-term morbidity or side effects of proposed treatment or care options. (Clinical Principle)

Discussion

× Discussion Each of the initial localized prostate cancer management strategies has a typical pattern of side effects, frequently different from those of other treatments. For properly counseled patient, these side effect profiles may determine treatment selection. However, patients are often not informed of these side effects in sufficient detail, which precludes effective SDM and may lead to a preference-discordant treatment choice.23 Active surveillance has no immediate effect on urinary, bowel, or sexual function. Indeed, over time, active surveillance preserves QoL compared to surgical and radiation treatments until such time as one of those treatments may become necessary. 41 However, patients who elect active surveillance as an initial management strategy may expect to see declines in urinary, bowel, and sexual function over time, and select men may experience anxiety over deferring definitive management.42-44 Changes in urinary and sexual function come as a normal part of aging in these men. Conflicting data exist regarding the possibility that serial biopsies may be associated with accelerated declines in these domains.45,46 However, prediagnosis obstructive urinary symptoms are known to be worse in active surveillance patients in comparison to those who elect surgery.47 All in all, between 50-73% of men who elect active surveillance as an initial management strategy have discontinued it by year 10.7,48,49 Patients electing definitive therapy are more likely to have immediate side effects. Surgery patients may experience bleeding, infection, and pain in the immediate term and then experience erectile dysfunction, urinary incontinence, urethral stricture and (very rarely) bowel problems. The risk of perioperative death from prostate cancer surgery is <0.1% in most series.32,50,51 The same side effects observed after surgery are possible with radiotherapy approaches, though bowel problems are more common, and sexual and continence side effects take much longer to develop. In general, radical prostatectomy causes more early erectile dysfunction (nerve-sparing better than non-nerve sparing) and urinary incontinence than radiation treatment,32,52 though erectile dysfunction and urinary bother beyond two to five years may be similar between surgery and radiation.43,44,53 Radiation treatment causes more urinary irritation (brachytherapy more than external beam radiation)32 and modestly more gastrointestinal side effects than radical prostatectomy.44,52 Radiation treatment may be associated with a very small but increased risk for secondary cancer, specifically bladder cancer and rectal cancer. The suspected incidence of radiation-induced second primary cancers is reported to affect between 1-3% of patients in the years following treatment.54,55 However, the absolute increase in risk is likely small, and published studies are difficult to interpret due to uncontrolled confounders. External beam radiotherapy is associated with secondary rectal cancers (30 cases per 100,000 person-years of follow-up; or 0.03% of patients followed for 10 years). Brachytherapy may have a slightly lower risk of secondary rectal cancers than external beam radiation (6 cases per 100,000 person-years).

Guideline Statement 5

Clinicians should inform patients about suitable clinical trials and encourage patients to consider participation in such trials based on eligibility and access. (Expert Opinion)

Discussion

× Discussion Treatment options can be characterized as standard and as investigational (clinical trial). In general standard therapies have proven efficacy and risks determined by prospective trials. There are many types of clinical trials including trials evaluating novel systemic, surgical or radiation therapies, new approaches to approved therapies, device trials and trials focusing on QoL and other patient outcomes. All clinical trials include specified aim(s) with a predetermined statistical plan. Institutional Review Boards (IRB) approve all clinical trials and patient consent forms, and all patients must sign consent for trial participation. In appropriate patients (i.e., good performance status, no active medical issues), clinical trial options should be considered, and trial options should be discussed with patients as part of the SDM process. Clinical trials are listed by diagnosis and stage on the Clinicaltrials.gov website.

Care Options by Cancer Severity/Risk Group

Management options for localized prostate cancer stratified by cancer severity risk group, are summarized in Table 4 based on level of evidence and strength of recommendation. Table 4. Care Options for Localized Prostate Cancer by Level of Evidence and Strength of Recommendation1 Evidence Level/ Recommendation Strength Prostate Cancer Severity/Aggressiveness Low Risk Intermediate Risk High Risk Very Low Risk Low Risk Favorable Unfavorable A / Strong Active Surveillance NA Radical Prostatectomy OR Radiotherapy2 with Androgen Deprivation Therapy Radical Prostatectomy OR Radiotherapy2 with Androgen Deprivation Therapy Radical Prostatectomy OR Radiotherapy2 with Androgen Deprivation Therapy B / Moderate NA Active Surveillance Radiotherapy2 without Androgen Deprivation Therapy NA NA B / Conditional NA Radical Prostatectomy OR Radiotherapy2 NA NA NA C / Conditional NA Cryosurgery (whole gland) Active Surveillance OR Cryosurgery (whole gland) Cryosurgery (whole gland) NA No evidence / clinical principle or expert opinion NA Focal Ablative Therapy OR High Intensity Focused Ultrasound Focal Ablative Therapy OR High Intensity Focused Ultrasound Focal Ablative Therapy OR High Intensity Focused Ultrasound NA 1Multicenter Randomized Clinical Trials that constitute the basis for evidence: EORTC-Bolla (XRT+ADT vs XRT): Evidence supporting XRT+ADT (intermediate-risk, high-risk) SPCG4 (RP vs WW): Evidence supporting RP (intermediate-risk, high-risk) RTOG 9408 (XRT+ADT vs XRT): Evidence supporting XRT+ADT (intermediate risk) PIVOT (RP vs WW): Evidence supporting AS (very low-risk, low-risk); RP (intermediate-risk, high-risk) EORTC (Widmark XRT+ADT vs ADT alone): Evidence supporting XRT+ADT (intermediate-risk, high-risk) PROTECT (AS vs RP vs XRT+ADT): Evidence supporting AS (very low-risk, low-risk, favorable intermediate-risk); RP or XRT+ADT (low-risk, favorable intermediate-risk) Single-center RCT: Donnelly et al. (Cryo+ADT vs XRT+ADT): Evidence supporting whole gland cryotherapy (low-risk, intermediate-risk) 2Radiotherapy includes a range of various forms of radiotherapy delivery (e.g., IMRT, brachytherapy, other) for which details of evidence and recommendation strength are presented in statements 42-49 of the guideline text Specific guidelines for selecting management options for each localized prostate cancer risk group and the evidence basis for these recommendations follow:

Very Low-/Low-Risk Disease

Very Low Risk: PSA <10 ng/ml AND Grade Group 1 AND clinical stage T1-T2a AND <34% of biopsy cores positive AND no core with >50% involved, AND PSA density <0.15 ng/ml/cc Low Risk: PSA <10 ng/ml AND Grade Group 1 AND clinical stage T1-T2a

Guideline Statement 6

Clinicians should not perform abdomino-pelvic CT or routine bone scans in the staging of asymptomatic very low- or low-risk localized prostate cancer patients. (Strong Recommendation; Evidence Level: Grade C)

Discussion

× Discussion Evidence does not support the use of these scans for staging of newly diagnosed very low- and low-risk prostate cancer. CT scan is very unlikely to provide actionable information in men with very low/low-risk prostate cancer. Likewise, bone scans are generally unnecessary in patients with favorable risk, newly diagnosed prostate cancer (PSA <20.0 ng/mL and a Grade Group =1; or PSA<10ng/ml and Grade Group 2, Table 3); unless the patient’s history or clinical examination suggests bony involvement.56,57

Guideline Statement 7

Clinicians should recommend active surveillance as the best available care option for very low-risk localized prostate cancer patients. (Strong Recommendation; Evidence Level: Grade A)

Discussion

× Discussion Multiple studies have shown that overall and prostate specific mortality appears higher for men with higher baseline Gleason scores.58-61 While Gleason 6 disease may have genetic and genomic abnormalities of disease with metastatic potential (though unclear if clinically significant), substantial evidence indicates that the majority of Gleason 6 prostate cancer has limited or no metastatic potential and does not pose a threat to the patient’s life.62,63 Most Gleason pattern 3 cancers lack the characteristic genetic aberrations associated with malignancy. Very low-risk patients have a lower risk of harboring occult high-grade cancer than those with higher volume Gleason 6. Low PSA density and low number of cores involved are all associated with a lower risk of contemporaneous high-risk disease. Long-term follow up studies of very low-risk patients initially managed with active surveillance have shown a metastatic progression rate of <1% at 15 years.7,64,65 Studies indicate that the QoL of men managed with surveillance is superior to those who are treated with surgery or radiotherapy.52 Continence and erectile function is better in men on surveillance compared to those who undergo treatment, though both decline as a natural part of aging. Aside from disease progression, a major risk of active surveillance is that entailed by serial biopsies. These are recommended at between three and five year intervals after the initial confirmatory biopsy.7,66 Biopsies are associated with risks of infection and bleeding as well as increased rates of erectile dysfunction. The risks of serial prostate biopsies on health and QoL, particularly if performed at infrequent intervals, are considerably less than the long-term risks of surgery and radiotherapy. There is a small subset of men who find the prospect of living with untreated prostate cancer severely anxiety-provoking and are unwilling to remain on surveillance.42 Thus patients with very low-risk prostate cancer in most cases require no treatment and should have active surveillance as their recommended care option.

Guideline Statement 8

Clinicians should recommend active surveillance as the preferable care option for most low-risk localized prostate cancer patients. (Moderate Recommendation; Evidence Level: Grade B)

Discussion

× Discussion There is now sufficient evidence that the majority of men with low-risk localized prostate cancer should initially be managed by active surveillance regardless of life expectancy. Such men with lower-risk disease have a lower risk of both overall mortality and disease progression.58-61 While the natural history of active surveillance is uncertain and continues to be better defined, there is evidence that the risk of ultimate death from prostate cancer for low-risk men managed with active surveillance is low. Likewise, the risk of metastases is low, though the very long-term outcomes of active surveillance are not yet known. Moreover, while it is unlikely that active surveillance can lead to better oncological outcomes versus active treatment, it is clear that all treatments for prostate cancer have potential side effects. This is in sharp contrast with active surveillance, wherein the risks are related to repeat biopsies and missed occult higher-risk disease, not the treatment itself. Thus, given the low risk of progression to metastatic disease on surveillance coupled with QoL benefits, active surveillance is the preferred management for most low-risk men. The natural history of active surveillance for low-risk men (as opposed to very low-risk men) is less clear in part due to inherent limitations in biopsy sampling and current imaging approaches, though still appears quite favorable. The Panel acknowledges that men with higher volume disease (i.e. greater >50% of cores positive or those larger lesions seen on imaging), albeit still low-risk, may be better served with active treatment. However, as with all treatment decisions in prostate cancer, SDM is paramount.

Guideline Statement 9

Clinicians may offer definitive treatment (i.e. radical prostatectomy or radiotherapy) to select low-risk localized prostate cancer patients who may have a high probability of progression on active surveillance. (Conditional Recommendation; Evidence Level: Grade B)

Discussion

× Discussion Active surveillance for low-risk disease reduces over-treatment in prostate cancer. However, some men with low-risk disease may have a higher risk of clinical progression on active surveillance and may benefit from definitive treatment at the time of diagnosis. Definitive treatment may be in the form of radical prostatectomy or radiotherapy with equivalent outcomes as discussed elsewhere in this guideline. Surgical and radiation treatments do not improve survival within 10 years of follow-up compared to active surveillance for patients with early disease, but has been found to reduce disease progression and development of metastatic disease as shown in the Prostate Cancer Intervention Versus Observation Trial (PIVOT) (10% versus 5%) and the Prostate Testing for Cancer Treatment trial (ProtecT) (6% versus 2%).50,51 The rationale for electing definitive treatment in low-risk men is based on the fact that even men with low-risk disease face a small chance of metastasis or prostate cancer specific mortality on active surveillance with data from long term studies finding this occurrence to be roughly 3%.66 While this number is based on a combination of low- and intermediate-risk patients, it should be noted that metastasis occurs even in low-risk patients, as evidenced by the data from the PIVOT and ProtecT trials, although at a low rate. Patients should be informed of the potential tradeoffs between immediate treatment versus active surveillance. In the PIVOT and ProtecT studies, 20% and 50%, respectively, of patients who started on active surveillance received treatment within 10 years.50,51 These patients likely harbored higher grade disease at the time of diagnosis, and identifying variables associated with progression may decrease the likelihood of these men missing their window for cure. Clinical predictors for an increased risk of higher grade disease or reclassification of subsequent biopsy include PSA density > 0.15, obesity as measured by BMI, African American race, and extensive Gleason 6 cancer on systematic biopsy cores.67-72 Men with a family history of aggressive prostate cancer characterized by early metastasis may not be ideal candidates for active surveillance even when presenting with low-risk disease and should be counseled carefully regarding the diagnostic uncertainty of biopsy and progression. A recent analysis of the Canary Prostate Cancer Active Surveillance cohort identified patients with BMI>35kg/m as having a three-fold increased risk of reclassification to higher risk disease on first surveillance biopsy. Men with PSA density >0.15ng/ml have a two-fold risk of reclassification on first biopsy.67 African American men have a higher rate of reclassification than Caucasian men on active surveillance as well as a higher rate of adverse pathology on radical prostatectomy when this is chosen as definitive treatment.73,74 This is true among low-risk patients, and this unique risk should be carefully weighed when deciding among treatment options. While reclassification does not always indicate that definitive treatment is required, the likelihood of short term progression must be discussed with all men considering active surveillance. The use of multiparametric MRI (mpMRI) has increased diagnostic specificity and should be considered at some point in the evaluation of men considering active surveillance.

Guideline Statement 10

Clinicians should not add ADT along with radiotherapy for low-risk localized prostate cancer with the exception of reducing the size of the prostate for brachytherapy. (Strong Recommendation; Evidence Level: Grade B)

Discussion

× Discussion In RTOG 9408, which randomized 1,979 patients to EBRT with four months of ADT versus without ADT and had 9.1 years of median follow-up, overall survival was not improved with ADT in subgroup analysis of 685 low-risk patients.75 There is no randomized trial supporting a survival benefit from adding ADT to radiotherapy for low-risk cancer. ADT can be used to reduce the size of the prostate to allow for improved dosimetry brachytherapy, but can cause short-term sexual dysfunction and other associated side effects.

Guideline Statement 11

Clinicians should inform low-risk prostate cancer patients considering whole gland cryosurgery that consequent side effects are considerable and survival benefit has not been shown in comparison to active surveillance. (Conditional Recommendation; Evidence Level: Grade C)

Discussion

× Discussion As most men with low-risk disease have favorable outcomes with active surveillance, it is unclear whether cryosurgery improves survival outcomes. One randomized trial of EBRT versus cryosurgery with primarily intermediate- and high-risk prostate cancer patients reported similar actuarial five-year overall and disease–specific survival.76 Both utilized six months of perioperative ADT for both treatment arms. Prospective randomized or comparative trials of cryosurgery with active surveillance in a low-risk cohort are lacking. It is unlikely that whole gland cryosurgery can provide comparable QoL as the preferred management for most low-risk men. Erectile dysfunction should be an expected outcome for potent patients. A 2009 review of the literature concluded that most patients (80-90%) should expect erectile dysfunction after whole gland cryosurgery and that it should not be offered to patients who desire preservation of potency.77 As with all treatments, patients considering cryosurgery should also be informed about the risks of adverse urinary and bowel function outcomes. Urinary retention after cryosurgery can persist for a few weeks and is best managed with a urethral or suprapubic catheter. Urethral sloughing at the verumontanum where the urethral warming catheter may not fully contact the mucosa apposition can result in temporary bothersome irritative symptoms in the early recovery period.

Guideline Statement 12

Clinicians should inform low-risk prostate cancer patients who are considering focal therapy or high intensity focused ultrasound (HIFU) that these interventions are not standard care options because comparative outcome evidence is lacking. (Expert Opinion)

Discussion

× Discussion As most men with low-risk disease have favorable outcomes with active surveillance, it is unclear whether focal therapy or HIFU improve survival outcomes or provide comparable QoL as the preferred management for most low-risk men. Prospective randomized or comparative trials of HIFU with active surveillance or other treatment modalities are lacking. Published five year oncologic outcomes are variable and attributable to the lack of consensus on objective response criteria.78 The Panel awaits the results of well-designed comparative clinical trials in order to define the appropriate role of this technology in the management of low-risk prostate cancer. The Panel also recognizes there is a growing interested in partial prostate treatment (i.e. focal therapy) by both patients and clinicians. Theoretical advantages include less morbidity versus whole gland treatment. However, this is at the potential expense of leaving undetected and untreated cancer. In a group of men at high risk for overtreatment and coupled with the lack of long-term oncological data of focal therapy, the Panel felt it was premature at this point to consider partial prostate treatment outside of a clinical trial.

Guideline Statement 13

Clinicians should recommend observation or watchful waiting for men with a life expectancy ≤5 years with low-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade B)

Discussion

× Discussion Men with a life expectancy of ≤5 years do not benefit from prostate cancer screening,79 diagnosis, or treatment. Prostate cancer treatment does not improve survival within five years of follow-up.51 Patients diagnosed with low-risk disease and a limited life expectancy should pursue watchful waiting. Unlike active surveillance, watchful waiting carries a palliative, non-aggressive intent, and does not involve routine cancer monitoring including biopsies. With watchful waiting, patients who develop symptomatic progression from prostate cancer are offered treatments to palliate these symptoms. An accurate determination of a man’s life expectancy based on age and comorbidities is difficult.80 Methods available to determine life expectancy include clinician prediction, model prediction and publicly available calculators. Life expectancy may be assessed in conjunction with a man’s primary care physician to determine a shared decision regarding surveillance. Clinicians should include the life expectancy estimate in a discussion with patient and family to develop rational individual patient treatment plans.

Guideline Statement 14

Among most low-risk localized prostate cancer patients, tissue based genomic biomarkers have not shown a clear role in the selection of candidates for active surveillance. (Expert Opinion)

Discussion

× Discussion Prospective active surveillance cohorts now comprise >10,000 patients, thousands of whom have been followed for >10 years. Clinical parameters (e.g., PSA, PSA density, extent of disease on biopsy, race, T-stage) allow for stratification for risk of co-existent higher-grade disease. Monitoring low-risk patients on surveillance is associated with a low risk of prostate cancer-specific mortality. Therefore, the benefit to most patients of a biomarker to further stratify patients according to the risk of progression is modest. However, selected patients, particularly those whose risk factors suggest they are at above average risk for higher-grade disease, may benefit from genomic testing. There are two potential benefits: reassurance for those patients with a favorable genomic risk score that conservative management is likely to be safe, and earlier identification of those at risk for disease progression on active surveillance who could benefit from treatment. As of the publication of this document, the three genetic tissue assays summarized below have been approved by the FDA for men with prostate cancer. None of these tests have yet been validated as providing substantial benefit in the active surveillance population. Genomic Classifier (GC) This is a 22-marker genomic classifier (GC), based on RNA expression. GC had independent predictive value on multivariable analysis for predicting metastasis following prostatectomy, with a hazard ration (HR) of 1.5 for each 10 percent increase in score,81 and these results were validated in two separate prostatectomy cohorts.82,83 A high score on biopsy is associated with an increased risk of metastasis (HR 1.7 for each 10% increase in score).84,85 Genomic Prostate Score (GPS): This assay incorporates 12 cancer genes that represent four biological pathways of prostate cancer oncogenesis: the androgen receptor pathway, cellular organization, stromal response, and proliferation. A 20-point increase in the genomic prostate score (GPS) is associated with a statistically significantly increased risk of high-grade and/or non-organ-confined disease (odds ratio [OR] 1.9, 95% CI 1.3-2.9).86-88 Cell Cycle Progression (CCP): This analyzes 31 cell cycle related genes and 15 housekeeping genes by quantitative RT-PCR. The Transatlantic Prostate Group examined cell cycle progression (CCP) scores using needle biopsies of a conservatively managed prostate cancer cohort from Great Britain.89 In this cohort, of 349 men managed without primary treatment, the cumulative incidence of death was increased among those with CCP scores >2 (19% of the population) compared with those with lower CCP scores. Patient outcomes could not be differentiated in those with lower CCP scores. The HR of prostate cancer death was 1.7 per unit increase in CCP score to 10 or CAPRA high-risk disease.90

Intermediate Risk Disease

Intermediate Risk: PSA 10-<20 ng/ml OR Grade Group 2-3 OR clinical stage T2b-c Favorable: Grade Group 1 (with PSA 10-<20) OR Grade Group 2 (with PSA<10)

Unfavorable: Grade Group 2 (with either PSA 10-<20 or clinical stage T2b-c) OR Grade Group 3 (with PSA < 20)

Guideline Statement 15

Clinicians should consider staging unfavorable intermediate-risk localized prostate cancer patients with cross sectional imaging (CT or MRI) and bone scan. (Expert Opinion)

Discussion

× Discussion The probability for metastasis at diagnosis of localized prostate cancer associates with risk classification.91 The presence of metastasis increases with tumor stage and influences treatment options. Baseline staging recommendations are guides with the goal of reducing or eliminating routine imaging in men at low risk for metastasis and performing imaging of common metastatic sites in men at most risk for metastasis. The most common sites are pelvic/retroperitoneal lymph nodes and bones. Less common metastatic sites include lung and liver; however, metastasis to lung and liver are often seen at late disease stage or with uncommon variants, such as small cell. For men with intermediate-risk prostate cancer, the Panel does not recommend routine imaging at diagnosis in all patients. The Panel recommends metastasis staging for men with two or more of the following features – palpable nodule on DRE (stage T2b/c), Gleason 7 (3+4 or 4+3) or PSA >10. The type of imaging performed may vary by physician preference and availability, but testing should evaluate the pelvic/retroperitoneal lymph nodes by cross sectional imaging and bones by bone scintigraphy (99mTc-MDP).92 The recommended cross sectional imaging is either MRI of the prostate or pelvis or CT scan of the abdomen/pelvis. There are relative advantages and disadvantages associated with MRI and CT. Prostate MRI provides more accurate imaging of the prostate gland and has no associated radiation exposure compared to CT; however, high-quality prostate MRI may not be available at all sites.93 Technetium bone scans have been a longstanding assessment tool in prostate cancer. More sensitive bone imaging is becoming available, including 18F-sodium fluoride PET/CT bone scans, PSMA-PET imaging, and whole body MRI.94,95 Currently, only 18F-sodium fluoride PET/CT is FDA approved. While these next generation scans are routinely used outside the United States, because of development and reimbursement issues, they are not routinely available in the United States and are not routinely recommended for staging at this time herein. For intermediate-risk prostate cancer, the Panel’s recommendations for baseline imaging vary somewhat from NCCN and American College of Radiology (ACR) recommendations. NCCN qualifies staging recommendations for men with life expectancy > 5 years or symptomatic disease and recommends bone scan for T2 and PSA >10 and CT if T2 and have a nomogram probability for nodal involvement >10%. ACR uses descriptive language, and for intermediate-risk prostate cancer recommends that pelvic MRI “usually” be done and CT and bone scan “may” be done.92 This Panel’s recommendation, based on expert opinion, is that imaging be considered if two or more risk factors are present and does not include nomogram calculations.

Guideline Statement 16

Clinicians should recommend radical prostatectomy or radiotherapy plus androgen deprivation therapy (ADT) as standard treatment options for patients with intermediate-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade A)

Discussion

× Discussion Two RCTs have evaluated overall survival and prostate cancer-specific survival among men undergoing radical prostatectomy compared to watchful waiting or observation: the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4)96 and PIVOT.51 The SPCG-4 trial provided evidence supporting the setting of intermediate-risk disease, because even though subset analyses focusing on the intermediate-risk subgroup defined for the guidelines herein were not pre-specified, most trial participants had intermediate-risk cancer as evidenced by a) Gleason score 7 on biopsy, or b) clinical stage of T2, or c) PSA >10ng/ml at enrollment. SPCG-4 showed higher overall survival and prostate cancer-specific survival among patients randomized to radical prostatectomy at 10 year’s follow-up. In the trial, the relative risk of dying after surgery was observed to be reduced at 0.62 (95% CI 0.44 to 0.87, p=0.01) with a reduction of cumulative incidence of death from prostate cancer from 20.7% to 14.6% at fifteen years. The PIVOT trial is the only RCT to have included pre-specified analyses for evaluating survival differences stratified by prostate cancer risk categories and by PSA at initial diagnosis. Subject participants in PIVOT had predominantly low-risk disease, and the trial was underpowered to conclusively demonstrate non-inferiority. Accordingly, there was no difference in overall survival among the entire trial cohort (including low- and intermediate-risk subjects combined). However, pre-specified subset analyses showed reduction in prostate cancer mortality among PIVOT participants who had either intermediate-risk cancer or baseline PSA greater than 10ng/ml and underwent radical prostatectomy. In the trial, men who were randomized to surgery were found to have a lower risk of death from prostate cancer or treatment (hazard ratio 0.63, 95% CI 0.36 to 1.09, p=0.09) with an absolute risk reduction estimated at 2.6%. Surgery was associated with an improvement in all-cause mortality primarily in patients with PSA levels greater than 10 ng/ml (p=0.04) and possibly with intermediate- and high-risk cancers (p=0.07). Notably, the watchful waiting and observation arms of SPCG-4 and PIVOT, respectively, did not include monitoring or surveillance with intent to use delayed definitive intervention for specific progression criteria, as is the fundamental principle that discerns contemporary active surveillance/management (in contrast to watchful waiting or observation). Such active surveillance/management was compared to radical prostatectomy in the ProtecT trial, which randomized subjects to surveillance, external beam radiotherapy combined with hormonal therapy, or radical prostatectomy.50 However, ProtecT had an even greater preponderance of low-risk prostate cancer among participants than was present in PIVOT. Among patients randomized to surveillance, nearly half underwent definitive intervention at some point during the first 10 years of follow-up. A non-significant difference in overall survival or prostate cancer specific survival was seen at 10 years follow-up in ProtecT, but subset analysis of intermediate-risk patients was not performed, limiting the relevance of ProtecT with regard to possible survival benefit of radical prostatectomy in intermediate-risk cancer. Of interest, despite the preponderance of low-risk disease in ProtecT, prostate cancer clinical progression and metastases were significantly lower among subjects randomized to either prostatectomy or radiation with hormonal therapy compared to those randomized to surveillance. Additionally, an early underpowered RCT enrolling 97 men compared radical prostatectomy to radiotherapy but found no difference in death or metastatic rate after five years of follow-up.97 A series of comparative outcome results based on retrospective information using propensity adjustment or instrumental analysis comparing radical prostatectomy versus external beam radiotherapy, and radical prostatectomy versus prostate brachytherapy, have suggested a mortality reduction in patients treated with surgery compared to external beam radiation and brachytherapy.59,60,98-107 In follow-up to these individual investigations, Wallis et al. have published a meta-analysis of nineteen pooled studies with 118,830 patients.108 This study reported that overall survival and prostate cancer specific survival were higher for the surgical patients. In particular, the observed benefit was seen irrespective of risk category, radiation regimen, time period, and follow-up length. This study, although large, utilizes retrospective data and can be subject to significant bias. The magnitude of this potential clinical benefit, if any, has not been prospectively validated or demonstrated in any large RCT, including the ProtecT study.

Guideline Statement 17

Clinicians should inform patients that favorable intermediate-risk prostate cancer can be treated with radiation alone, but that the evidence basis is less robust than for combining radiotherapy with ADT. (Moderate Recommendation; Evidence Level: Grade B)

Discussion

× Discussion Two randomized trials support the addition of ADT to EBRT for intermediate-risk prostate cancer. RTOG 9408 randomized 1,979 patients to EBRT (66.6 Gy) with versus without four months of ADT and had 9.1 years of median follow-up.75 Ten year overall survival improved with ADT for the intermediate-risk subgroup of 1,068 patients from 54% to 61% (p=.03). A smaller trial randomized 206 patients to 70 Gy of radiation with versus without 6 months of ADT.109 In patients with little or no comorbidity, 15-year overall survival was improved with ADT (31% versus 44%, p=.04). A caveat to these trials was the use of lower radiation doses no longer considered standard today. At least four randomized trials have compared lower radiation doses (68-70 Gy) to modern higher radiation doses (74-80 Gy), and all demonstrated improved cancer control with higher radiation doses.110-113 These trials have led to the adoption of higher radiation doses as the modern standard of care, and the benefit of adding ADT to modern higher doses of radiation is the subject of continued investigation. EORTC 22991 randomized 819 patients (75% intermediate risk) to RT (doses ranged from 70 to 78 Gy) versus RT with ADT;114 ADT improved clinical progression-free survival even among patients who received 78 Gy of RT, but overall survival data are not yet mature. There are no randomized trials demonstrating a survival benefit from adding ADT to low-dose rate or high-dose rate brachytherapy monotherapy, so ADT should not be added to brachytherapy except to reduce the size of the prostate to allow the dosimetry to be optimized. There is emerging recognition that intermediate-risk prostate cancer represents a broad group of patients with varying prognoses, and a new classification system separates intermediate-risk into unfavorable and favorable groups (as defined in the Introduction).11Patients with unfavorable intermediate risk disease should be especially considered for the addition of ADT to EBRT.

Guideline Statement 18

In select patients with intermediate-risk localized prostate cancer, clinicians may consider other treatment options such as cryosurgery. (Conditional Recommendation; Evidence Level: Grade C)

Discussion

× Discussion Treatment options routinely employed for the treatment of intermediate-risk prostate cancer include radical prostatectomy, and external-beam radiotherapy. However, cryosurgery, may be appropriate depending on patient-specific factors, including preferences, comorbidities, and life expectancy. Comparative effectiveness research evaluating cryosurgery for localized prostate cancer has been limited to one RCT and several non-randomized prospective or comparative studies.115-117 Whole gland ablative therapies such as cryosurgery may be appropriate for patients with contraindications to more traditional therapies, such as prostatectomy or radiotherapy (e.g. medically inoperable patients with either previous pelvic radiotherapy or autoimmune disorders). All of these management approaches (observation/watchful waiting, active surveillance, cryosurgery) do not currently have sufficient published prospective comparative evidence for their routine application for the management of intermediate-risk prostate cancer, and patients should be informed of this lack of comparative evidence during SDM discussions.

Guideline Statement 19

Active surveillance may be offered to select patients with favorable intermediate-risk localized prostate cancer; however, patients should be informed that this comes with a higher risk of developing metastases compared to definitive treatment. (Conditional Recommendation; Evidence Level: Grade C)

Discussion

× Discussion Active surveillance may be appropriate in selected patients with intermediate-risk disease who have selected deferred primary treatment to delay treatment-related toxicities until tumor progression. Patients who are considering surveillance may benefit from an MRI and targeted biopsy. If the MRI is negative, or targeted biopsy shows only Gleason 6 disease, they are likely to have a favorable prognosis, and surveillance is a reasonable strategy. However, patients who elect active surveillance should be informed that this comes with a risk of developing metastases as shown in the PIVOT and ProtecT trials.50,51 There are, several groups of Gleason 7 patients who may be favorable candidates.118 Patients with small volume cancer on biopsy who have < 10% Gleason pattern 4 may reflect artifactual upgrading due to tangential cut of a Gleason 3 acinus, in which case the lumen is not seen and the pathologist’s impression is of a solid clump of cells (i.e. higher grade).119,120

Guideline Statement 20

Clinicians should recommend observation or watchful waiting for men with a life expectancy ≤5 years with intermediate-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade A)

Discussion

× Discussion Observation/watchful waiting is an approach to prostate cancer that does not include active surveillance with PSA/MRI/repeat prostate biopsy and by definition also does not include prostate cancer therapies such as surgery/radiation/androgen deprivation. Randomized trials have been done comparing prostatectomy to observation.51,52,96 The SPCG-4 trial was composed of non-screen detected tumors and demonstrated benefit for prostatectomy; the survival benefit was primarily in men < 65 years of age.96 The PIVOT trial (40% low-, 34% intermediate-, 25% high-risk) did not show a benefit for prostatectomy for the total group; however, a subset analysis of the intermediate-risk patients did show benefit (HR 0.69).51 At four years the mortality was identical in both cohorts. Thus patients with life expectancy <5 years are unlikely to derive survival benefit from prostatectomy. When choosing an initial therapy for localized prostate cancer, it is important to consider the patients psychological state (competency, anxiety, depression). A SEER-Medicare analysis demonstrated that men with depression were less likely to have definitive therapy (surgery or radiation) and that depressed men also had worse overall (not prostate cancer specific) mortality across prostate cancer risk classifications.121 Clinicians should be aware of mental health issues as a possible cause of treatment disparity and seek multidisciplinary input when appropriate.

Guideline Statement 21

Clinicians should inform intermediate-risk prostate cancer patients who are considering focal therapy or HIFU that these interventions are not standard care options because comparative outcome evidence is lacking. (Expert Opinion)

Discussion

× Discussion The Panel recognizes that novel therapies including HIFU and focal prostate ablation may provide QoL advantages for patients in comparison to surgery and radiotherapy. However, there are no prospective randomized or comparative effectiveness data versus traditional treatments available. Published five year oncologic outcomes for HIFU are variable and attributable to the lack of consensus on objective response criteria.78 The Panel awaits the results of well-designed comparative clinical trials of HIFU in order to define the appropriate role of this technology in the management of intermediate risk prostate cancer. The Panel also recognizes there is a growing interested in partial prostate treatment (i.e. focal therapy) by both patients and clinicians. Theoretical advantages include less morbidity versus whole gland treatment though this is at the potential expense of leaving undetected and untreated cancer. Initial focal therapy reports with short term follow-up suggest effective disease eradication in the treated area of appropriately selected patients. Studies where TRUS biopsy of the treated volume or side was performed per protocol, clinically significant cancer was identified in a minority (<14%) of patients.122-124 However, comparative data comparing focal therapy to other treatment approaches, such as prostatectomy, radiotherapy, observation, or active surveillance, are lacking in the literature.118,125 The Panel recommends that if focal therapy or HIFU is offered as an alternative treatment modality for intermediate risk prostate cancer, it should preferably be offered within the context of a clinical trial.

High-Risk Disease

High Risk: PSA >20 ng/ml OR Grade Group 4-5 OR clinical stage >T3

Guideline Statement 22

Clinicians should stage high-risk localized prostate cancer patients with cross sectional imaging (CT or MRI) and bone scan. (Clinical Principle)

Discussion

× Discussion Before widespread adoption of PSA screening, most incident prostate cancers were only diagnosed at an advanced stage. Treatment options such as surgery or radiation were believed only to benefit patients with localized disease, which necessitated an imaging evaluation to stage almost every patient prior to treatment. In the modern era, however, over 90% of prostate cancers are localized, making the need for routine imaging to detect metastases with CT, MRI, or bone scan obsolete.126 Prior studies demonstrate that PSA <10 ng/ml has a negative predictive value of 99.5% for significant findings on bone scan, and <1% of patients with PSA < 20ng/ml have positive bone scans or CTs.127-131 In spite of these data and longstanding guidelines to curb imaging overuse, many patients still undergo improper imaging.126 Data is limited for other tests to detect distant metastases such as fluciclovine PET, total body MRI, NaF PET, choline/acetate PET, PSMA PET.132 Further research may establish the utility of these modalities, but likely only for high-risk patients. Standard FDG-PET is generally not a useful test in this setting.133

Guideline Statement 23

Clinicians should recommend radical prostatectomy or radiotherapy plus androgen deprivation therapy as standard treatment options for patients with high-risk localized prostate cancer. (Strong Recommendation; Evidence Level: Grade A)

Discussion

× Discussion Men with high-risk disease are most likely to develop metastases and die from prostate cancer. There are two randomized prospective studies that support radical prostatectomy as treatment of high-risk disease. The SPCG-4 trial compared radical prostatectomy and watchful waiting.96 At 15 years, all-cause mortality favored radical prostatectomy (46.1% versus 52.7%, RR, 0.75; 95% CI, 0.61 to 0.92), and prostate cancer-specific mortality favored radical prostatectomy (14.6% versus 20.7%, RR, 0.62; 95% CI, 0.44 to 0.87). Although the PIVOT trial did not demonstrate an overall survival advantage with surgery, there was a significant difference in the rate of bone metastases at both the 10-year and 12-year follow-up favoring radical prostatectomy treated patients.51 Furthermore, in men with high-risk disease undergoing surgery, the rates of prostate cancer-specific death was significantly lower, 9.1% compared to 17.5% for the observation arm. For radiotherapy and ADT, there are two types of studies that show efficacy. First, ADT and radiotherapy are superior to radiotherapy alone, and long term ADT is superior to short term ADT although the duration of long term ADT remains under investigation.134-136 Second, ADT and radiotherapy are superior to ADT alone and thus suggest that local therapy is important even among patients at high risk for subclinical metastatic disease.137,138 For high-risk prostate cancer patients receiving external beam radiotherapy and ADT, brachytherapy boost (low-dose rate or high-dose rate) should be offered to eligible patients.

Guideline Statement 24

Clinicians should not recommend active surveillance for patients with high-risk localized prostate cancer. Watchful waiting should only be considered in asymptomatic men with limited life expectancy (≤5 years). (Moderate Recommendation; Evidence Level: Grade C)

Discussion

× Discussion Localized high-risk prostate cancer should be considered a life threatening disease. Albertsen et al. analyzed Connecticut Tumor Registry data of men with localized prostate cancer who were either not treated or treated with delayed ADT.139 Men with Gleason 8-10 tumors had a 60-87% chance of dying from prostate cancer within 15 years of diagnosis (age dependent). Thus watchful waiting for high-risk prostate cancer should only be considered for asymptomatic men with limited life expectancy (<5 years). RCTs are of high quality, but results differ likely based on baseline patient characteristics.51,52,96 The PIVOT trial randomly assigned men with localized prostate cancer to prostatectomy or observation (21% were high-risk).51 For the total cohort at four years, there was no difference in death from prostate cancer. Prostate cancer mortality was lower for high-risk patients in the prostatectomy cohort compared to observation (9.1% versus 17.5%, p=0.04). In the SPCG-4 trial (25% high-risk) prostatectomy was associated with reduced mortality in all groups with the most benefit in the younger men (<65 years, relative risk 0.38). While randomized data is lacking comparing radiation to observation, in a population based cohort, prostate cancer specific mortality was higher with observation compared to radiation in the subset of men with high-risk disease.140 Available data supports active intervention (rather than surveillance) in men with high-risk disease unless a patient is expected to die from competing causes within five years.

Guideline Statement 25

Cryosurgery, focal therapy and HIFU treatments are not recommended for men with high-risk localized prostate cancer outside of a clinical trial. (Expert Opinion)

Discussion

× Discussion A randomized clinical trial evaluating the efficacy of cryosurgery in comparison to radiotherapy or radical prostatectomy for high-risk localized prostate cancer is lacking. One randomized clinical trial demonstrating similar short-term oncologic outcomes for EBRT versus cryosurgery has been reported for primarily intermediate- risk disease patients.76 A small percentage had high-risk features (9% Gleason score ≥8, 18% ≥ T3a, none with PSA > 20) but a subset analysis was not provided to support cryosurgery for high-risk localized prostate cancer patients. Another randomized trial comparing outcomes of EBRT versus cryosurgery for primarily high-risk or locally advance disease patients terminated early for lack of accrual and demonstrated inferior 8-year biochemical disease-free recurrence rate for the cryosurgery (17% versus 59%).141 Long-term prospective randomized data of cryosurgery for men with high-risk localized prostate cancer is lacking. There are no prospective randomized or comparative effectiveness data for HIFU versus traditional treatments available. Published five year oncologic outcomes for HIFU are variable and attributable to the lack of consensus on objective response criteria.78 The Panel awaits the results of well-designed comparative clinical trials of HIFU in order to define the appropriate role of this technology in the management of high-risk prostate cancer. There is no agreement defining the ideal patient for focal therapy. Consensus statements identify patients with low-risk prostate cancer and an unequivocal solitary primary tumor who desire intervention as the ideal candidate for this investigational approach.118,124Some investigators have expanded criteria to patients with intermediate-risk disease and rarely high- risk. However, comparative data comparing focal therapy to other treatment approaches for high-risk prostate cancer, such as prostatectomy or radiotherapy, are lacking in the literature. The Panel recommends that if cryosurgery, focal therapy or HIFU is offered as an alternative treatment modality for high-risk prostate cancer, it should only be done within the context of a clinical trial.

Guideline Statement 26

Clinicians should not recommend primary ADT for patients with high-risk localized prostate cancer unless the patient has both limited life expectancy and local symptoms. (Strong Recommendation; Evidence Level: Grade A)

Discussion

× Discussion A randomized prospective study comparing the androgen receptor inhibitor bicalutamide 150 mg to placebo found no significant difference in overall survival or prostate cancer specific survival in men with localized prostate cancer.142 Several large retrospective studies comparing primary ADT to no ADT failed to demonstrate improved long-term overall or disease-specific survival for men with localized prostate cancer.143-145 In one study, there was a slightly reduced risk of all-cause mortality in a high-risk subgroup treated with primary ADT,143 but in another study the small benefit was limited to prostate cancer-specific survival and not overall survival in men with poorly differentiated cancer.144 The risks of serious adverse events associated with ADT and the high costs associated with its use outweigh the limited benefits, if any. Therefore, primary ADT should be used only to palliate symptoms of disease or prevent imminent symptoms associated with disease progression.

Guideline Statement 27

Clinicians may consider referral for genetic counseling for patients (and their families) with high-risk localized prostate cancer and a strong family history of specific cancers (e.g., breast, ovarian, pancreatic, other gastrointestinal tumors, lymphoma). (Expert Opinion)

Discussion

× Discussion The incidence of germline mutation in DNA repair genes in localized prostate cancer is low with estimates of BRCA2 in 1-2%,146,147 and there have not been standard recommendations for genetic screening/counseling for prostate cancer patients. Recently it was reported that the incidence of somatic mutation of DNA repair genes (e.g., BRCA2, ATM) in metastatic castration-resistant prostate cancer (mCRPC) is 25%.148 The incidence of germ-line mutation of DNA repair genes in men with mCRPC is approximately 10%.149The mutations seen were BRCA2 (44%), ATM (13%), CHEK2 (12%), BRCA1 (7%) and others (1-4%). High Gleason score (8-10) and family history of cancer (breast, ovarian, pancreatic, other gastrointestinal, lymphoma) in first-degree relatives was associated with germline DNA repair mutations in mCRPC patients. Young age and family history of prostate cancer was not associated with germline DNA repair mutations in the seven cohorts analyzed. Patients with localized prostate cancer who are at highest risk for developing mCRPC, may have a higher incidence of germline DNA repair mutations than expected from published reports: the incidence is to be determined but may approach 5-8%. The presence of germline DNA repair gene mutations has important implications for the prostate cancer patient in terms of general cancer screening and possible future prostate cancer treatment decisions. Additionally the presence of germline DNA repair mutations is of utmost relevance to the patient’s first-degree family members due to increased cancer risk and screening implications. The Panel recommends that clinicians take detailed family history of cancers and give consideration to patient referral for genetic screening and counseling for men with localized high-risk prostate cancer, particularly in the setting of family history of first degree relatives with cancers of breast, ovary, pancreas, other gastrointestinal cancers, and lymphoma.

Recommended Approaches and Details of Specific Care Options

Active Surveillance

Guideline Statement 28

Localized prostate cancer patients who elect active surveillance should have accurate disease staging including systematic biopsy with ultrasound or MRI-guided imaging. (Clinical Principle)

Discussion

× Discussion The accuracy of initial prostate biopsy schemes depends on several factors. Sampling accuracy decreases progressively with increasing prostate volume.150 Furthermore, PSA, free/total PSA ratio (%fPSA), and DRE influence the detection rate. Substantial modifications from the original sextant approach have resulted in an extended biopsy scheme (defined as the traditional sextant template plus at least four and up to eight laterally directed samplings from the peripheral zone) as an initial diagnostic biopsy strategy.150-152 The 12-core biopsy scheme (sextant template plus laterally directed sampling from each sextant template) has become the most widely accepted method. Some practitioners also take a core from the anterior transition zone on each side since this is a common site for missed cancers.153 Extended biopsy has a significantly superior detection rate compared to sextant biopsy.154,155 The Vienna nomogram suggested a minimum number of cores (range: 8–18) based on patient age and gland volume in the PSA 2–10 ng/ml range to ensure 90% certainty of cancer detection.156 Most initial biopsy studies have shown that more than 12-15 cores is not beneficial.157,158 Current consensus supports a 10- to 12-core ex