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

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

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.

Guideline Statements

Shared Decision Making (SDM)

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)
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)
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)
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)
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)

Care Options by Cancer Severity/Risk Group

Very Low-/Low-Risk Disease

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)
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)
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)
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)
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)
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)
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)
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)
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)

Intermediate-Risk Disease

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

High-Risk Disease

22. Clinicians should stage high-risk localized prostate cancer patients with cross sectional imaging (CT or MRI) and bone scan. (Clinical Principle)
23. 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)
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)
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)
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
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)

Recommended Approaches and Details of Specific Care Options

Active Surveillance

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)
29. Localized prostate cancer patients undergoing active surveillance should have routine surveillance PSA testing and digital rectal exams. (Strong Recommendation; Evidence Level: Grade B)
30. 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)
31. Clinicians may consider multiparametric prostate MRI as a component of active surveillance for localized prostate cancer patients. (Expert Opinion)
32. 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)
33. Clinicians should offer definitive treatment to localized prostate cancer patients undergoing active surveillance who develop adverse reclassification. (Moderate Recommendation; Evidence Level: Grade B)

Prostatectomy

34. 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)
35. 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)
36. 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)
37. 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)
38. 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)
39. 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)
40. 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)
41. 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

42. Clinicians may offer single modality external beam radiotherapy or brachytherapy for patients who elect radiotherapy for low-risk localized prostate cancer. (Clinical Principle)
43. Clinicians may offer external beam radiotherapy or brachytherapy alone or in combination for favorable intermediate-risk localized prostate cancer. (Clinical Principle)
44. 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)
45. 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)
46. 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)
47. 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)
48. 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)
49. 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

50. 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)
51. 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)
52. 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)
53. For whole gland cryosurgery treatment, clinicians should utilize a third or higher generation, argon-based cryosurgical system for whole gland cryosurgery treatment. (Clinical Principle)
54. 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)
55. Clinicians should inform localized prostate cancer patients considering whole gland cryosurgery that erectile dysfunction is an expected outcome. (Clinical Principle)
56. 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

57. Clinicians should inform those localized prostate cancer patients considering focal therapy or HIFU that these treatment options lack robust evidence of efficacy. (Expert Opinion)
58. 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).
59. 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)
60. 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

61. 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)
62. 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)
63. 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)
64. 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)
65. 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

66. 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)
67. Clinicians should inform localized prostate cancer patients of their individualized risk-based estimates of post-treatment prostate cancer recurrence. (Clinical Principle)
68. 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)

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.

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.

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.

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.

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)

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.

Specific guidelines for selecting management options for each localized prostate cancer risk group and the evidence basis for these recommendations follow:

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

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: 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)

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

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 androgen deprivation therapy 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 A)

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)

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)

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)

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)

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)

The Panel recommends that if HIFU is offered as an alternative treatment modality for localized prostate cancer, it should be done within the context of a clinical trial. Prospective randomized or comparative trials with other treatment modalities are lacking. Published five year oncologic outcomes are variable and attributable to the lack of consensus on objective response criteria.⁷⁸ However, it has been recognized that the PSA nadir level after whole gland HIFU is predictive of biochemical recurrence.²⁶¹ 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 localized prostate cancer. Whole prostate ablation utilizing HIFU with or without short term neoadjuvant ADT has been associated with a comparable incidence of post-treatment incontinence, bladder neck/urethral stricture, and rectourethral fistulae.²⁶²

Focal therapy is based on the concept that, although prostate cancer can present as multifocal disease within the prostate gland, some patients may have a significant single index intraprostatic lesion. This index lesion may be associated with the most aggressive nidus of cancer within the gland and may be the most appropriate target for treatment. A prerequisite for focal therapy involves advanced mapping of lesions within the prostate. This can be done with a saturation biopsy or, more commonly, with MRI imaging with focused biopsy or a 3-dimensional transperineal mapping biopsy to identify appropriate patients with clinically significant disease, to provide an appropriate index target, and to provide an appropriate target for follow-up scanning and biopsies.^118,125

Focal therapy involves subtotal or zonal destruction of the prostate with cryosurgery, HIFU or other focally ablative techniques with the aim to minimize treatment toxicity. The Panel acknowledges that focal ablative therapy is of significant interest to patients and clinicians as it may offer benefits in terms of QoL for selected patients with a solitary well-defined index lesion. However, the Panel recommends that if focal therapy is offered as an alternative treatment modality for localized prostate cancer, it should only be done within the context of a clinical trial. Initial studies with short term follow up suggest that effective disease eradication in the treated volume can be attained.^118,124 A systematic review of focal therapy has been published to provide some information regarding the clinical outcomes that can be expected with the application of focal therapy.¹²⁴ However, it should be noted that long-term follow up data is lacking. The Panel recognizes that concern exists about the potential for undetected and, therefore, occult untreated clinically-significant multifocal disease. Confirmation of oncologic effectiveness is currently lacking and will require prospective studies with long-term follow up.

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)

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)

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)

The extended time course between prostate cancer diagnosis and its eventual outcome poses challenges to the timeliness of ascertaining the efficacy of newer approaches to cancer risk ascertainment or therapeutic intervention. The maturation of evidence to provide robust guidance for optimizing care consequently lags the development of new technology. Nevertheless, emerging evidence is anticipated in several key areas, while well-designed, multi-center studies are urgently needed in others.

Emerging evidence is anticipated from follow up analyses of the ProtecT randomized trial comparing active surveillance, prostatectomy, and radiotherapy. Data maturation may elucidate longer term outcomes (i.e. whether or not differences seen in clinical metastases between arms at 10 years will lead to differences in subsequent mortality). Subsequent analyses of ProtecT also have the potential to further clarify the role of surveillance versus treatment between low and intermediate risk cancers. Emerging evidence is also anticipated from clinical trials evaluating the risk benefit of brachytherapy compared to external radiotherapy (RTOG 0232), and the relative risk/benefit of extended compared to standard lymphadenectomy during radical prostatectomy for patients with intermediate and high risk disease.

Well-designed prospective studies are needed to optimize the utility of new imaging modalities (e.g., multiparametric MRI or PET with prostate-specific radiotracers), to evaluate risk/benefit of ablative techniques (e.g., HIFU or focal ablative treatment), and to characterize the impact  that even limited intervals of androgen-deprivation may have on long-term HRQOL.  The need to better characterize long-term HRQOL effects of ADT warrants special emphasis, as this treatment modality is part of the standard recommended radiotherapy care options for intermediate and high risk disease and is already broadly utilized. We need better evidence to council patients regarding the impact of adjuvant androgen deprivation on long-term HRQOL, despite recognition that effects on vitality, libido, and cognitive status can be substantial among patients undergoing ADT monotherapy.

To enable progress in prostate cancer care that is informed by the best evidence we must continue to prospectively evaluate new technologies as they are developed.

Related Content:

• AQUA 29: Prostate Cancer: Patient report of urinary function after treatment [pdf]
• AQUA 30: Prostate Cancer: Patient report of sexual function after treatment  [pdf]

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This document was written by the Clinically Localized Prostate Cancer Guideline Panel of the American Urological Association Education and Research, Inc., which was created in 2014. The Practice Guidelines Committee (PGC) of the AUA selected the committee chair. Panel members were selected by the chair. Membership of the Panel included specialists in urology/ medical oncology/radiation oncology with specific expertise on this disorder. The mission of the Panel was to develop recommendations that are analysis-based or consensus-based, depending on Panel processes and available data, for optimal clinical practices in the treatment of clinically localized prostate cancer. Funding of the Panel was provided by the AUA. Panel members received no remuneration for their work. Each member of the Panel provides an ongoing conflict of interest disclosure to the AUA. While these guidelines do not necessarily establish the standard of care, AUA seeks to recommend and to encourage compliance by practitioners with current best practices related to the condition being treated. As medical knowledge expands and technology advances, the guidelines will change. Today these evidence-based guidelines statements represent not absolute mandates but provisional proposals for treatment under the specific conditions described in each document. For all these reasons, the guidelines do not pre-empt physician judgment in individual cases. Treating physicians must take into account variations in resources, and patient tolerances, needs, and preferences. Conformance with any clinical guideline does not guarantee a successful outcome. The guideline text may include information or recommendations about certain drug uses ('off label') that are not approved by the Food and Drug Administration (FDA), or about medications or substances not subject to the FDA approval process. AUA urges strict compliance with all government regulations and protocols for prescription and use of these substances. The physician is encouraged to carefully follow all available prescribing information about indications, contraindications, precautions and warnings. These guidelines and best practice statements are not in-tended to provide legal advice about use and misuse of these substances. Although guidelines are intended to encourage best practices and potentially encompass available technologies with sufficient data as of close of the literature review, they are necessarily time-limited. Guidelines cannot include evaluation of all data on emerging technologies or management, including those that are FDA-approved, which may immediately come to represent accepted clinical practices. For this reason, the AUA does not regard technologies or management which are too new to be addressed by this guideline as necessarily experimental or investigational.