NCCN Guidelines® Insights: Prostate Cancer Early Detection, Version 1.2023

Featured Updates to the NCCN Guidelines

Authors:
Kelvin A. Moses Vanderbilt-Ingram Cancer Center

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Preston C. Sprenkle Yale Cancer Center/Smilow Cancer Hospital

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Clinton Bahler Indiana University Melvin and Bren Simon Comprehensive Cancer Center

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Geoffrey Box The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

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Sigrid V. Carlsson Memorial Sloan Kettering Cancer Center

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William J. Catalona Robert H. Lurie Comprehensive Cancer Center of Northwestern University

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Douglas M. Dahl Massachusetts General Hospital Cancer Center

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Marc Dall’Era UC Davis Comprehensive Cancer Center

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John W. Davis The University of Texas MD Anderson Cancer Center

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Bettina F. Drake Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

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Jonathan I. Epstein The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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Ruth B. Etzioni Fred Hutchinson Cancer Center

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Thomas A. Farrington Prostate Health Education Network

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Isla P. Garraway UCLA Jonsson Comprehensive Cancer Center

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David Jarrard University of Wisconsin Carbone Cancer Center

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Eric Kauffman Roswell Park Comprehensive Cancer Center

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Deborah Kaye Duke Cancer Institute

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Adam S. Kibel Dana-Farber/Brigham and Women’s Cancer Center

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Chad A. LaGrange Fred & Pamela Buffett Cancer Center

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Paul Maroni University of Colorado Cancer Center

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Lee Ponsky Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute

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Brian Reys UT Southwestern Simmons Comprehensive Cancer Center

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Simpa S. Salami University of Michigan Rogel Cancer Center

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Alejandro Sanchez Huntsman Cancer Institute at the University of Utah

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Tyler M. Seibert UC San Diego Moores Cancer Center

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Terrence M. Shaneyfelt O’Neal Comprehensive Cancer Center at UAB

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Marc C. Smaldone Fox Chase Cancer Center

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Geoffrey Sonn Stanford Cancer Institute

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Mark D. Tyson Mayo Clinic Cancer Center

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Neha Vapiwala Abramson Cancer Center at the University of Pennsylvania

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Robert Wake St. Jude Children’s Research Hospital/The University of Tennessee Health Science Center

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Samuel Washington UCSF Helen Diller Family Comprehensive Cancer Center

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Alice Yu Moffitt Cancer Center

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Bertram Yuh City of Hope National Medical Center

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Ryan A. Berardi National Comprehensive Cancer Network

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Deborah A. Freedman-Cass National Comprehensive Cancer Network

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Full access

The NCCN Guidelines for Prostate Cancer Early Detection provide recommendations for individuals with a prostate who opt to participate in an early detection program after receiving the appropriate counseling on the pros and cons. These NCCN Guidelines Insights provide a summary of recent updates to the NCCN Guidelines with regard to the testing protocol, use of multiparametric MRI, and management of negative biopsy results to optimize the detection of clinically significant prostate cancer and minimize the detection of indolent disease.

NCCN Continuing Education

Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.

Accreditation Statements

In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

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Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-23-003-H01-P

PAs: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until March 10, 2024. PAs should only claim credit commensurate with the extent of their participation.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/92899; and (3) view/print certificate.

Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email education@nccn.org.

Release date: March 10, 2023; Expiration date: March 10, 2024

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • • Integrate into professional practice the updates to the NCCN Guidelines for Prostate Cancer Early Detection

  • • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Prostate Cancer Early Detection

Disclosure of Relevant Financial Relationships

None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

Individuals Who Provided Content Development and/or Authorship Assistance:

The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.

Kelvin A. Moses, MD, PhD, Panel Chair

Marc Dall’Era, MD, Panel Member

Eric Kauffman, MD, Panel Member

Ryan A. Berardi, MSc, Guidelines Layout Specialist, NCCN

Deborah A. Freedman-Cass, PhD, Manager, Guidelines Processes, NCCN

The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships listed for these individuals have been mitigated.

Preston C. Sprenkle, MD, Panel Vice-Chair, has disclosed serving as a scientific advisor for Profound Medical Corp.

Sigrid V. Carlsson, MD, PhD, MPH, Panel Member, has disclosed receiving consulting fees from Ipsen.

Jonathan I. Epstein, MD, Panel Member, has disclosed serving as a scientific advisor for Biogensis, Inc.; receiving consulting fees from Dianon Systems, Inc.; having equity interest/stock options in PathAI; and receiving non-royalty payments from UroGen Pharma.

David Jarrard, MD, Panel Member, has disclosed serving as a scientific advisor for Gregor Diagnostics Inc.

Adam S. Kibel, MD, Panel Member, has disclosed serving as a scientific advisor for Bayer HealthCare, Cellvax Therapeutics, Exelixis, Inc., Janssen Pharmaceutica Products, LP, Myovant Sciences, ProFound Therapeutics, and Roche Laboratories, Inc.; and serving on a data safety monitoring board for Bristol-Myers Squibb Company and Candel Therapeutics.

Tyler M. Seibert, MD, PhD, Panel Member, has disclosed receiving grant/research support from General Electric; serving as a scientific advisor for CorTechs Labs; having equity interest/stock options in CorTechs Labs; and receiving honoraria from Varian Medical Systems, Inc.

Geoffrey Sonn, MD, Panel Member, has disclosed receiving consulting fees from Auris Health, Inc.; and serving as a scientific advisor for miR Scientific.

To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/guidelines/guidelines-panels-and-disclosure/disclosure-panels

This activity is supported by educational grants from AstraZeneca; Exact Sciences; Novartis; and Taiho Oncology, Inc. This activity is supported by an independent educational grant from Daiichi Sankyo. This activity is supported by independent medical education grants from Illumina, Inc. and Regeneron Pharmaceuticals, Inc.

Overview

Prostate cancer represents a spectrum of disease that ranges from nonaggressive, slow-growing disease that may not require treatment to aggressive, fast-growing disease that does. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Prostate Cancer Early Detection provide a set of sequential recommendations detailing an early detection and evaluation strategy for maximizing the detection of prostate cancer that is effectively treatable and that, if left undetected, represents a risk to the individual. At the same time, the guidelines focus on minimizing unnecessary procedures and limiting the detection of indolent disease.

The panel unanimously agrees that the goal of these guidelines is to reduce suffering and death from prostate cancer while at the same time limiting morbidity from unnecessary biopsies, overdiagnosis, and overtreatment. The guidelines use several methods to strike a balance between these goals: optimizing the early detection protocol, including the age at which to start and stop prostate-specific antigen (PSA) testing and the testing intervals; recommending other biomarker testing and multiparametric MRI (mpMRI) before initial or repeat prostate biopsy to improve the specificity of screening and help avoid unnecessary biopsies; using MRI-guided targeted biopsies to increase the detection of clinically significant prostate cancer; and optimizing follow-up of individuals with negative biopsies. The panel agrees that the NCCN Guidelines for Prostate Cancer Early Detection should be used in conjunction with the NCCN Guidelines for Prostate Cancer (available at NCCN.org), which explicitly recommend active surveillance or observation for appropriate candidates to minimize overtreatment.

The panel meets annually to discuss the latest evidence emerging in the field and to decide about requested changes to the guidelines that come from panel members or other health professionals at NCCN Member Institutions or from outside individuals or groups. These NCCN Guidelines Insights describe some of the panel discussions for the 2023 update of the NCCN Guidelines for Prostate Cancer Early Detection. The panel also had involved discussions regarding biomarker testing that will be the topic of future publications.

Early Detection Protocols

Optimizing the early detection protocol is important for the balance between maximizing aggressive prostate cancer detection and minimizing overtesting, overdiagnosis, and overtreatment. However, the panel lacks consensus on how to find the best balance between these goals. Several aspects of the protocol were discussed by the panel during the 2023 update of the guidelines, as described in the following sections.

Digital Rectal Examination

Among patients with an elevated serum PSA level, individuals with an abnormal digital rectal examination (DRE) are more likely to have prostate cancer, and DRE used with PSA testing improves the positive predictive value (PPV) for the detection of clinically significant prostate cancer over that of PSA testing alone.1,2 DRE has its largest effect on the PPV for clinically significant prostate cancer in people with a PSA level >3 ng/mL.2 Thus, the panel agrees that DRE should be performed for anyone with an elevated PSA to aid in decisions regarding biopsy.

The panel also agrees that DRE should not be used as a standalone method for the early detection of prostate cancer, because DRE alone misses a substantial number of clinically significant cancers.3 In addition, prostate cancers detected solely by DRE are less likely to be confined to the prostate than those detected through PSA testing, and the PPV for DRE alone is poor.48

The role of a baseline DRE in all persons participating in a PSA-based early detection program is more controversial. An internal request questioned whether the guidelines should continue to recommend that a baseline DRE be “strongly considered” during risk assessment for individuals who decide to pursue an early detection program for prostate cancer.

In the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial, DRE was used in conjunction with PSA testing in 35,350 participants.9 Among those with an abnormal DRE, only 15.4% also had an elevated PSA level, and abnormal DRE was independently associated with detection of clinically significant prostate cancer and prostate cancer–specific mortality. This and other trials have shown that the cancer detection rate is higher when both tests are used than when PSA testing is used alone.6

However, panel members discussed that the risk of finding clinically significant disease is low when the PSA level is low. In a trial of approximately 36,000 participants, 3,568 prostate cancer cases were diagnosed and 2,233 participants underwent radical prostatectomy.10 Of these 2,233 patients, 303 (14%) were diagnosed by DRE alone, including 60 (3%) with non–organ-confined disease and 56 (3%) with clinical Grade Group ≥2. Thus, the number of clinically significant prostate cancers found by DRE in individuals with a PSA level <3 ng/mL is small, possibly around 0.2% of all individuals screened.

Some panel members expressed that the feasibility of DRE should also be considered. A quality DRE requires assessment of nodularity, induration, fixation, and asymmetry, and interexaminer variability is a known issue. Panel members also noted that not all clinicians are trained to perform a DRE as well as those conducting the trials, meaning that the benefit in a community physician’s office may be lower than in the cited studies. Furthermore, a DRE can be uncomfortable for patients, and there can be a poor correlation with tumor location in the prostate. Some panel members believe that DRE should not become a barrier to prostate cancer early detection.

Other panel members noted that the evidence described earlier comes from an era prior to the current MRI-directed pathway for prostate cancer diagnosis. Some therefore believe that there is little evidence regarding the added value of DRE if an MRI will be obtained regardless of DRE findings.

Considering these points, a minority of the panel wanted to remove the recommendation for a baseline DRE to be used with initial PSA testing from the guidelines completely. However, several panel members strongly opposed this option, stating that it would be unthinkable to eliminate a baseline DRE. In an analysis of the SEER database, 1% of patients with prostate cancer had PSA level ≤2.5 ng/mL and Grade Group 4–5 disease.11 These patients had a higher prostate cancer–specific mortality than those with a PSA level 4.1 to 10 ng/mL and Grade Group 4–5 disease. Results of an analysis of the National Cancer Database also showed that Grade Group 4–5 prostate cancer can be more aggressive in patients with lower PSA levels.12 These data suggest that some high-grade, aggressive lesions that do not produce a lot of PSA might be found by DRE. These panel members also argued that DRE is inexpensive and without significant risks.

Most panel members believe that PSA testing and DRE should be included in the guidelines as the optimal evaluation for individuals opting to participate in a prostate cancer early detection program, but that it should not be required for all patients. The panel voted to remove the word “strongly” from “strongly consider baseline DRE” to read “consider baseline DRE” (see PROSD-2, page 238). Further evaluation for possible biopsy is indicated if DRE is very suspicious for the presence of cancer at any PSA level.

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Age at Which to Stop PSA Testing

The panel uniformly agrees that people should undergo follow-up for a known elevated PSA level (PSA surveillance) or symptoms (case finding) regardless of age. In these cases, PSA as part of diagnostic testing is critical. However, the panel consensus is weaker for the use of PSA testing for early detection of prostate cancer in asymptomatic septuagenarians. Overall, the panel understands that a balance is needed between limiting unnecessary biopsies/overdiagnosis and maximizing the detection of aggressive disease that could threaten the lives of older individuals.

An internal request suggested that PSA testing should only be recommended in individuals aged 71 to 75 years based on shared decision-making and should be discontinued thereafter. Panel members were divided on this issue. Some agreed with the proposal, whereas others believed that the current guidelines recommendation was fine: PSA testing in select individuals aged >75 years (category 2B). A third group supported the middle ground, suggesting that the guidelines state that the preferred option is to discontinue PSA testing at age 75 years, but testing would still be an option in this group.

Panel members in support of the first proposal noted that a considerable proportion of individuals aged >70 years may have cancer that would be unlikely to diminish their life expectancy, and that screening in this population would substantially increase rates of overdiagnosis. However, one panel member challenged the notion that all Grade Group ≤1 cancers are, by definition, overdiagnosed and/or overtreated clinically insignificant cancers. Reasons given in support included the possibility of biopsy sampling errors and that some lower-grade tumors progress over time. Active surveillance studies have shown that 22% to 33% of patients with low-risk prostate cancer are upgraded while on active surveillance and a small number of patients on active surveillance ultimately die of prostate cancer (see the NCCN Guidelines for Prostate Cancer at NCCN.org). Some panel members argued that the population aged >70 years is actually at risk for underdiagnosis. They believe that PSA testing should continue in individuals aged >70 years, with consideration of more conservative management: higher PSA thresholds for further evaluation, using mpMRI and/or other biomarker testing to limit unnecessary biopsies, and active surveillance or observation for appropriate candidates.

Panel members in support of the proposed change pointed to the results of the major randomized controlled early detection trials (ERSPC, PLCO, and Göteborg), which observed benefits to testing only in participants aged ≤70 years.1315 In addition, they pointed to a longitudinal cohort study that included 122 individuals with prostate cancer and 727 without prostate cancer in the Baltimore Longitudinal Study of Aging (BLSA), in which no individuals aged 75 to 80 years with a PSA level <3.0 ng/mL died of prostate cancer.16 Moreover, the time to death or diagnosis of aggressive prostate cancer was longer in those with a PSA level <3.0 ng/mL compared with those with PSA level >3.0 ng/mL, suggesting that individuals aged ≥75 years with a PSA level <3.0 ng/mL are unlikely to die or experience aggressive prostate cancer in their lifetime, and most may safely discontinue screening. However, other panel members countered that there has been little in the way of prospective, randomized prostate cancer early detection trials in populations aged >70 years, so a benefit of continued versus discontinued PSA testing in this population cannot be ascertained. Some of the only data are from an exploratory analysis of the ERSPC trial suggesting that improvements in death from prostate cancer after 9 years of follow-up may be similarly absent between patients aged 70 to 74 years and those aged 50 to 54 years, with wide confidence intervals.15

Panel members who support continued PSA testing in those aged >70 years pointed to an increased prevalence of higher-risk cases in this age group that could benefit from earlier detection. A study of 4,561 patients who underwent radical prostatectomy found that those aged >70 years were more likely to have higher grade and stage of disease and worse survival compared with those aged <70 years.17 Others have published similar findings.18 In addition, an analysis of the SEER database showed that patients who were diagnosed with prostate cancer at age >70 years were more likely to die of their disease than those diagnosed at age <70 years (21% vs 17%, respectively).19 A separate analysis of the SEER database showed that patients whose prostate cancer was diagnosed at age ≥75 years were more likely to have advanced disease and had a higher risk of death from prostate cancer despite greater death rates from competing causes than those diagnosed before age 75 years.20 Another cohort study in Sweden showed similar results, but also showed that older patients may not receive sufficient diagnostic workup and curative treatment, thus confounding the interpretation of the results.21 Another possible issue with the interpretation of these studies is that fewer of the patients aged >70 years may have undergone PSA-based early detection than those aged <70 years, explaining the higher prevalence of advanced disease at diagnosis.

After discussing the data and considerations presented earlier, the panel voted on 3 options for PSA testing in asymptomatic older individuals. In one option, “shared decision-making based on past PSA levels and general health” was recommended for those aged 71 to 75 years. For those aged ≥76 years who are asymptomatic, PSA-based early detection was not recommended. In the second option, PSA-based early detection would continue to be an option for select individuals aged >75 years (category 2B), but the preferred option would be “no screening.” As the final option, PSA-based early detection would continue to be recommended for those aged 40 to 75 years depending on risk, and for select individuals aged >75 years (category 2B).

The panel selected the third option, so there was no change to the upper age for PSA testing (see PROSD-2, page 238). Despite a lack of consensus on this issue, the panel uniformly agrees that screening beyond the age of 75 years should be limited to very healthy people with little to no comorbidity and thus lower competing causes of death, especially if they have never undergone PSA testing or have increasing PSA levels, to detect the small number of aggressive cancers that pose a significant risk if left undetected until signs or symptoms develop. Overall, most panel members believe that widespread testing in this population would substantially increase rates of overdiagnosis. The panel also points out that individuals aged >75 years with a PSA level <3 ng/mL have a very low risk of prostate cancer metastases in their lifetime. Widespread testing in individuals aged >75 years is therefore not recommended.

Testing Intervals

The ideal screening interval for individuals with PSA levels below the threshold for further evaluation to maximize morbidity and mortality reduction while minimizing overdiagnosis remains uncertain. Some panel members proposed that the testing intervals be modified. A proposal was to use different testing intervals depending on both the age of the individual and the PSA level, with the idea that screening intervals can be safely lengthened for many people. Such a change, it was argued, has the potential to decrease overdiagnosis and unnecessary testing with minimal effect on the lives saved.

Panel members in support of this proposal presented data showing that an 8-year interval was safe for those aged ≥55 years with PSA level <1 ng/mL.22 They also cited the Malmö Preventive Project in Sweden, in which the risk of a prostate cancer diagnosis, prostate cancer metastases, and death from prostate cancer before age 85 years correlated with PSA level at age 60 years.23 Those in the 80th percentile at age 60 years (PSA level 2.12 ng/mL) had a 17% risk of clinically diagnosed prostate cancer, a 6.6% risk of prostate cancer metastases, and a 5.7% risk of death from prostate cancer at age 85 years. The corresponding risks in an individual at the 50th percentile (PSA level of 1.06 ng/mL) were 7.2%, 1.6%, and 0.9%, respectively, and at the 25th percentile (PSA level of 0.65 ng/mL) were 4.3%, 0.53%, and 0.28%, respectively. Other analyses, some with racially and ethnically diverse cohorts, show a similar correlation with a very low risk of prostate cancer diagnoses, metastases, and death for those with PSA levels in the lower percentiles for their age.2429 Overall, the available data clearly show that individuals who have a PSA level above the median for their age group are at a higher risk for prostate cancer and aggressive prostate cancer. The higher above the median, the greater the risk.

Panel members also discussed a study in which people who were not screened for prostate cancer were compared with those who were regularly screened.30 The authors concluded that the harms of testing outweigh the benefits for those with PSA level <1 ng/mL at age 60 years (approximately 50% of the population). PSA testing in this population did not decrease prostate cancer mortality compared with the unscreened population, although diagnoses were increased. Furthermore, panel members noted that a microsimulation model demonstrated that an approach of lengthening screening intervals for those with lower PSA levels might significantly reduce overtesting, while having smaller effects on reducing overdiagnosis and lives saved.31 A panel member also pointed to a study that compared a cohort tested every 2 years versus the unscreened Malmö cohort.30 The authors estimated that PSA testing every 2 years in individuals with a PSA level <1 ng/mL would result in 171 additional diagnoses per 10,000 individuals in 15 years without a concomitant reduction in prostate cancer mortality.

Some panel members argued against the proposed change. First, they noted that it is not fully clear how many overdiagnoses would be prevented by lengthening the PSA testing interval for those with lower PSA levels. Second, they argued that even if the numbers are low, potentially curable cases of otherwise lethal disease would be missed. Third, they noted that risks of overdiagnosis and overtreatment could be lowered by limiting who is biopsied and treated rather than by limiting PSA testing. Furthermore, others noted that death is not the only endpoint that matters. For instance, identifying prostate cancer earlier can decrease the need for androgen deprivation therapy. Another argument against the change was that it was overly complicated and would be difficult for clinicians to follow, potentially adding barriers to prostate cancer early detection.

Panel members countered that healthcare resources are limited, and the focus should be on getting baseline PSA values for younger individuals with higher risk and closely following those with higher PSA levels for their age. Carefully following individuals with a lower risk of developing prostate cancer, they argued, would not be a good use of resources.

A panel member questioned whether a shorter retesting interval should be recommended for Black individuals, because data shows that they are more like to have aggressive prostate cancer.3235 A modeling study looked at the effects of different PSA intervals in Black individuals.36 Although the data are not as clear as they are for starting earlier in Black people, a shorter interval does not appear to increase the risk of overdiagnosis.

Although there was disagreement on optimal PSA testing intervals, most of the panel voted for intervals that would maximize the ability to identify cancers at early stages in which treatment for cure is possible (see PROSD-2, page 238). The previous recommendations, based on the ERSPC trial, included repeat testing at 2- to 4-year intervals for those with a PSA level <1 ng/mL. This recommendation now only applies to people at average risk of developing prostate cancer. For those at high risk (ie, Black/African American individuals, those with germline mutations that increase the risk for prostate cancer, and those with suspicious family history), repeat testing is recommended at 1- to 2-year intervals if PSA is ≤3 ng/mL. This same recommendation also applies to individuals with average risk and PSA 1 to 3 ng/mL. In addition, the testing interval for those aged >75 years with a PSA level <4 ng/mL was changed from “1 to 4 years” to “1 to 2 years.” The panel agrees that clinical judgment and shared decision-making should be used to determine the testing interval within these ranges for each individual.

Magnetic Resonance Imaging

mpMRI has been increasingly used to guide needle placement during biopsy. The benefits of mpMRI-targeting include reducing the detection of clinically insignificant prostate cancer and fewer significant upgrades at radical prostatectomy. Furthermore, adding MRI-targeted biopsy to systematic biopsy increases the yield of clinically significant prostate cancer over systematic biopsy alone. See the full NCCN Guidelines for a detailed discussion and references on targeted biopsies.

Using mpMRI to select patients for biopsy has the potential to reduce unnecessary biopsies and overdiagnosis and to improve the detection of clinically significant disease. More recently, there is interest in the role mpMRI can have in management decisions regarding certain biopsy results.

mpMRI Before Biopsy

An internal request questioned whether, in modern times, anyone with an elevated PSA should go straight to biopsy without a mpMRI evaluation. In the current version of these guidelines, mpMRI was included in this setting as “if available.”

Data supporting the use of mpMRI before proceeding to biopsy comes from several prospective trials in Europe and North America.3740 Results of these trials and other studies suggest that a significant proportion of biopsy-naïve people with elevated PSA level can avoid biopsy based on a PI-RADS ≤2 result on mpMRI (21%–49%), but some of these people have clinically significant disease that would be missed (2%–14% of the study populations).3742 Panel members noted that a similar or possibly higher proportion of clinically significant disease is missed with a traditional approach of proceeding to a systematic biopsy without an mpMRI, with higher detection of indolent disease.38,43 Furthermore, numerous other studies support the role of mpMRI before biopsy for reducing unnecessary biopsies and the detection of indolent disease, in both the initial and the repeat biopsy settings.4448

The panel discussed what mpMRI result should be considered high-risk for the presence of prostate cancer. Panel members generally agreed that PI-RADS 4 and 5 results should prompt a biopsy. There was some question, however, as to how to approach PI-RADS 3 results. Some panel members noted that they identify clinically significant cancer in approximately 50% of PI-RADS 3 cases. Others stated that the rates in their institutions are as low as 15% to 20%. Others pointed out that variation in radiologist skill in interpreting prostate MRI contributes to high rates of false-positives in PI-RADS 3 and 4 lesions and that biopsy may therefore be safely omitted in select individuals with PI-RADS 3 lesions and even some with PI-RADS 4 lesions if they are deemed to be at low risk. The panel discussed whether to add specific recommendations in the guidelines based on the PI-RADS level, but decided against this option to leave room for clinical judgment. Things that should be considered in the context of the mpMRI result include the pretest probability of cancer (eg, determined by PSA, PSA density, prior biopsy results), the life expectancy of the individual, and the quality of the mpMRI and reading.

The panel also discussed that most centers have mpMRI available now, but quality can be lacking, especially in the training of radiologists for the interpretation of scans. Some panel members wondered if the situation would continue to improve if NCCN strengthened the recommendation for high-quality mpMRI, thereby increasing the demand for this training.

The panel consensus was to strengthen their recommendation for a mpMRI evaluation before the initial biopsy to inform biopsy decisions and to help identify regions of the prostate that may harbor cancer (see PROSD-3, page 239). The panel continues to caution that false-negative mpMRI results can occur even with the best equipment and readers due to the negative predictive value (NPV) for clinically significant prostate cancer (approximately 86%–98%3742). Therefore, proceeding to transrectal ultrasound (TRUS)–guided systematic biopsy following a negative MRI should still be considered, particularly in situations where the individual is considered to be at high risk for cancer based on PSA density or other biomarkers.45,49,50 The PPV of mpMRI for clinically significant prostate cancer was around 54% in one study, so false-positives can be common.42 In light of evidence showing considerable interobserver variability in the interpretation of prostate MRI, the panel emphasizes the need for high-quality mpMRI and radiologic expertise for optimal reading of scans.5153

F2

Management of Biopsy Results

Most prostate biopsy results are benign. Even in the absence of invasive cancer, however, some notable pathologic features may be present. Approximately 10% of patients undergoing biopsy will be found to have high-grade prostatic intraepithelial neoplasia (HGPIN).54 Cytologically, the nuclear features of HGPIN resemble those of malignant tumors; however, the presence of a basal layer on the acini distinguishes this entity from cancer. Approximately 5% of patients receive a biopsy result of atypia, which is characterized by glands that either architecturally or cytologically in some ways resemble prostatic adenocarcinoma but lack full criteria for malignancy. These cases are either diagnosed with descriptive terminology or synonymously designated as atypical small acinar proliferation (ASAP).55,56 Unlike HGPIN, ASAP is not a distinct pathologic diagnosis; rather it represents either benign mimickers of prostate cancer or cancer that lacks sufficient architectural or cytologic atypia to warrant a definitive malignant diagnosis.

A negative prostate biopsy does not preclude the presence of cancer. Thus, patients with benign results, as well as those with HGPIN or ASAP, may have prostate cancer and require follow-up. However, a balance is needed between maximizing the identification of clinically significant cancer and minimizing overtesting and overdiagnosis. Studies have shown that 4% to 9% of patients with ASAP, HGPIN, or benign biopsy results receive a diagnosis of Grade Group ≥2 prostate cancer on repeat biopsy, with no significant difference between these groups.55,5760 The rates of Grade Group 1 prostate cancer on repeat biopsy are 24% to 30%.55,5860 Furthermore, the prostate cancer–specific mortality rate in individuals with initially negative biopsy results is low. In a Danish study, the 15-year prostate cancer-specific mortality rate of patients with an initially negative biopsy was 1.3% for those with PSA level <10 ng/mL and 4.6% for PSA level >20 ng/mL.61

The 2022 version of the NCCN Guidelines included consideration of biomarker testing and mpMRI evaluation for patients with benign, HGPIN, and atypia biopsy results to better understand their risk. For atypia, consideration of a repeat biopsy with a relative increased sampling of the atypical site was also recommended. For those with HGPIN and benign results, PSA and DRE were recommended at 6- to 24-month intervals, with repeat biopsy using refined biopsy techniques based on risk.

An internal request noted that the recommendations for follow-up of atypia, HGPIN, and benign biopsy results seem to assume that the biopsy was performed without MRI targeting and mpMRI imaging and asked if it would be appropriate to note that a repeat biopsy is not necessarily needed when mpMRI was performed before the biopsy. A related request noted that, because most cancers found on repeat biopsy for atypia are often of low clinical risk, the guidelines should consider adding short-interval PSA monitoring without additional testing if a prebiopsy mpMRI was negative. Although a single core with HGPIN has been recognized as not warranting a repeat biopsy, multifocal HGPIN has been considered to place patients at the same risk of subsequent cancer as an initial biopsy showing ASAP. However, a recent study demonstrated that in approximately 25% of individuals with multifocal HGPIN, serum PSA levels and/or DRE findings normalize after a negative prostate biopsy.62 The risk of clinically significant prostate cancer detection in repeat biopsies in such individuals appears to be identical to that reported in those with low PSA values. In those with persistent prostate cancer suspicion based on DRE and/or PSA results, the risk of clinically significant prostate cancer detection in repeat prostate biopsies is independent of the previous finding of HGPIN and is driven by the clinical findings (PSA, DRE). However, the risk of insignificant prostate cancer detection increases with repeat biopsy following HGPIN.

Panel members agreed that an immediate second biopsy in these patients after a targeted biopsy or after a negative, high-quality mpMRI would increase the risk of overdiagnosis with a low likelihood of identifying clinically significant prostate cancer. In addition, many panel members noted that, in the absence of prebiopsy MRI, they routinely recommend a mpMRI evaluation before proceeding to a second biopsy. Therefore, it was proposed that the follow-up recommendations for patients with atypia, HGPIN, or benign results be split into 2 pathways: one for individuals who received prior high-quality mpMRI and one for those who did not. Those with a prior mpMRI should not receive a repeat mpMRI and the recommended PSA/DRE testing intervals could be lengthened. The recommendation to consider biomarker testing for these individuals would remain. For those without prior high-quality mpMRI, mpMRI and/or biomarker testing could be considered. For atypia, consideration of a repeat biopsy in 12 to 24 months with a relative increased sampling of the atypical site would remain if there was no prior mpMRI. For all patients, a repeat prostate biopsy with refined biopsy techniques would continue to be recommended for a high suspicion of cancer.

The panel noted that characteristics that increase the suspicion of cancer after a negative biopsy are a positive mpMRI, a persistently high PSA level, a shorter PSA doubling time, a high PSA density, and/or an abnormal DRE.6264

One panel member questioned whether many cancers might be missed if fewer patients with a negative mpMRI undergo a repeat biopsy. However, most of the panel agreed that, because the NPV of mpMRI is high,42 a large number of unnecessary biopsies can be avoided while only a small number of Grade Group ≥2 tumors might be missed.

A few panel members suggested that patients with atypia may need more careful follow-up than those with HGPIN and benign results, because they might be more likely to develop clinically significant cancer. Several panel members noted, however, that they treat atypia as benign if there was a negative, high-quality mpMRI before the biopsy. They argued that the detection rates of clinically significant cancer on repeat biopsy in patients who had a negative mpMRI are similarly low for patients with atypia and benign initial biopsy results in their experience. Published data also support these observations.57

All panel members agreed that the quality of the mpMRI matters greatly. This is mainly based on the quality of the hardware and of the reading by the radiologist. In general, the panel members think that high-quality hardware is becoming more readily available, and the quality of the readings should improve over time.

Overall, the panel consensus was to define separate follow-up recommendations based on whether a high-quality mpMRI was performed before the biopsy, as proposed (see PROSD-4, page 240).

F3

Conclusions

Prostate cancer early detection can identify cancer at early stages when morbidity and mortality can be reduced. However, a balance is needed between maximizing the detection of aggressive prostate cancer and minimizing overtesting, overdiagnosis, and overtreatment. The NCCN Guidelines for Prostate Cancer include active surveillance and observation as ways to reduce overtreatment. The NCCN Guidelines for Prostate Cancer Early Detection include several ways to minimize overtesting and overdiagnosis while minimizing missed cases of clinically significant disease. These approaches include optimizing the interval of PSA testing depending on risk, stopping PSA testing in older individuals, using mpMRI and/or biomarker testing to determine the initial and repeat biopsy, performing targeted biopsies, and optimizing follow-up for patients with atypia, HGPIN, and benign initial biopsy results.

References

  • 1.

    Gosselaar C, Roobol MJ, Roemeling S, et al. The role of the digital rectal examination in subsequent screening visits in the European randomized study of screening for prostate cancer (ERSPC), Rotterdam. Eur Urol 2008;54:581588.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Halpern JA, Oromendia C, Shoag JE, et al. Use of digital rectal examination as an adjunct to prostate specific antigen in the detection of clinically significant prostate cancer. J Urol 2018;199:947953.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Gosselaar C, Roobol MJ, Roemeling S, et al. Screening for prostate cancer at low PSA range: the impact of digital rectal examination on tumor incidence and tumor characteristics. Prostate 2007;67:154161.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. J Urol 1994;151:12831290.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Catalona WJ, Smith DS, Ratliff TL, et al. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993;270:948954.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. J Urol 2017;197(Suppl 2):S200207.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Flanigan RC, Catalona WJ, Richie JP, et al. Accuracy of digital rectal examination and transrectal ultrasonography in localizing prostate cancer. J Urol 1994;152:15061509.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Schröder FH, van der Maas P, Beemsterboer P, et al. Evaluation of the digital rectal examination as a screening test for prostate cancer. J Natl Cancer Inst 1998;90:18171823.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Halpern JA, Shoag JE, Mittal S, et al. Prognostic significance of digital rectal examination and prostate specific antigen in the prostate, lung, colorectal and ovarian (PLCO) cancer screening arm. J Urol 2017;197:363368.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Okotie OT, Roehl KA, Han M, et al. Characteristics of prostate cancer detected by digital rectal examination only. Urology 2007;70:11171120.

  • 11.

    Mahal BA, Aizer AA, Efstathiou JA, et al. Association of very low prostate-specific antigen levels with increased cancer-specific death in men with high-grade prostate cancer. Cancer 2016;122:7883.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Falchook AD, Martin NE, Basak R, et al. Stage at presentation and survival outcomes of patients with Gleason 8–10 prostate cancer and low prostate-specific antigen. Urol Oncol 2016;34:119.e1926.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Göteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 2010;11:725732.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Andriole GL, Crawford ED, Grubb RL III, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst 2012;104:125132.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate- cancer mortality in a randomized European study. N Engl J Med 2009;360:13201328.

  • 16.

    Schaeffer EM, Carter HB, Kettermann A, et al. Prostate specific antigen testing among the elderly—when to stop? J Urol 2009;181:16061614.

  • 17.

    Sun L, Caire AA, Robertson CN, et al. Men older than 70 years have higher risk prostate cancer and poorer survival in the early and late prostate specific antigen eras. J Urol 2009;182:22422248.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Bechis SK, Carroll PR, Cooperberg MR. Impact of age at diagnosis on prostate cancer treatment and survival. J Clin Oncol 2011;29:235241.

  • 19.

    Clark R, Vesprini D, Narod SA. The effect of age on prostate cancer survival. Cancers 2022;14:4149.

  • 20.

    Scosyrev E, Messing EM, Mohile S, et al. Prostate cancer in the elderly: frequency of advanced disease at presentation and disease-specific mortality. Cancer 2012;118:30623070.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Pettersson A, Robinson D, Garmo H, et al. Age at diagnosis and prostate cancer treatment and prognosis: a population-based cohort study. Ann Oncol 2018;29:377385.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Roobol MJ, Roobol DW, Schröder FH. Is additional testing necessary in men with prostate-specific antigen levels of 1.0 ng/mL or less in a population-based screening setting? (ERSPC, section Rotterdam). Urology 2005;65:343346.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Vickers AJ, Cronin AM, Björk T, et al. Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study. BMJ 2010;341:c4521.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Vertosick EA, Häggström C, Sjoberg DD, et al. Prespecified 4-kallikrein marker model at age 50 or 60 for early detection of lethal prostate cancer in a large population based cohort of asymptomatic men followed for 20 years. J Urol 2020;204:281288.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Vickers AJ, Ulmert D, Sjoberg DD, et al. Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40-55 and long term risk of metastasis: case-control study. BMJ 2013;346:f2023.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Preston MA, Batista JL, Wilson KM, et al. Baseline prostate-specific antigen levels in midlife predict lethal prostate cancer. J Clin Oncol 2016;34:27052711.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Preston MA, Gerke T, Carlsson SV, et al. Baseline prostate-specific antigen level in midlife and aggressive prostate cancer in black men. Eur Urol 2019;75:399407.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Kovac E, Carlsson SV, Lilja H, et al. Association of baseline prostate- specific antigen level with long-term diagnosis of clinically significant prostate cancer among patients aged 55 to 60 years: a secondary analysis of a cohort in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. JAMA Netw Open 2020;3:e1919284.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Ulmert D, Cronin AM, Björk T, et al. Prostate-specific antigen at or before age 50 as a predictor of advanced prostate cancer diagnosed up to 25 years later: a case-control study. BMC Med 2008;6:6.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Carlsson S, Assel M, Sjoberg D, et al. Influence of blood prostate specific antigen levels at age 60 on benefits and harms of prostate cancer screening: population based cohort study. BMJ 2014;348:g2296.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Heijnsdijk EAM, Gulati R, Tsodikov A, et al. Lifetime benefits and harms of prostate-specific antigen-based risk-stratified screening for prostate cancer. J Natl Cancer Inst 2020;112:10131020.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Lillard JW Jr, Moses KA, Mahal BA, et al. Racial disparities in Black men with prostate cancer: a literature review. Cancer 2022;128:37873795.

  • 33.

    Wang M, Chi G, Bodovski Y, et al. Temporal and spatial trends and determinants of aggressive prostate cancer among Black and White men with prostate cancer. Cancer Causes Control 2020;31:6371.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Mahal BA, Berman RA, Taplin ME, et al. Prostate cancer-specific mortality across Gleason scores in Black vs nonblack men. JAMA 2018;320:24792481.

  • 35.

    Tsodikov A, Gulati R, de Carvalho TM, et al. Is prostate cancer different in black men? Answers from 3 natural history models. Cancer 2017;123:23122319.

  • 36.

    Nyame YA, Gulati R, Heijnsdijk EA, et al. The impact of intensifying prostate cancer screening in Black men: a model-based analysis. J Natl Cancer Inst 2021;113:13361342.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-targeted or standard biopsy for prostate-cancer diagnosis. N Engl J Med 2018;378:17671777.

  • 38.

    Rouvière O, Puech P, Renard-Penna R, et al. Use of prostate systematic and targeted biopsy on the basis of multiparametric MRI in biopsy-naive patients (MRI-FIRST): a prospective, multicentre, paired diagnostic study. Lancet Oncol 2019;20:100109.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    van der Leest M, Cornel E, Israël B, et al. Head-to-head comparison of transrectal ultrasound-guided prostate biopsy versus multiparametric prostate resonance imaging with subsequent magnetic resonance-guided biopsy in biopsy-naïve men with elevated prostate-specific antigen: a large prospective multicenter clinical study. Eur Urol 2019;75:570578.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Klotz L, Chin J, Black PC, et al. Comparison of multiparametric magnetic resonance imaging-targeted biopsy with systematic transrectal ultrasonography biopsy for biopsy-naive men at risk for prostate cancer: a phase 3 randomized clinical trial. JAMA Oncol 2021;7:534542.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Sathianathen NJ, Omer A, Harriss E, et al. Negative predictive value of multiparametric magnetic resonance imaging in the detection of clinically significant prostate cancer in the prostate imaging reporting and data system era: a systematic review and meta-analysis. Eur Urol 2020;78:402414.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Lo G, Burton KR, Haider MA, et al. Negative predictive value of prostate multiparametric magnetic resonance imaging among men with negative prostate biopsy and elevated prostate specific antigen: a clinical outcome retrospective cohort study. J Urol 2019;202:11591165.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Richenberg J, Løgager V, Panebianco V, et al. The primacy of multiparametric MRI in men with suspected prostate cancer. Eur Radiol 2019;29:69406952.

  • 44.

    Boesen L, Nørgaard N, Løgager V, et al. Clinical outcome following low suspicion multiparametric prostate magnetic resonance imaging or benign magnetic resonance imaging guided biopsy to detect prostate cancer. J Urol 2017;198:310315.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Hansen NL, Barrett T, Kesch C, et al. Multicentre evaluation of magnetic resonance imaging supported transperineal prostate biopsy in biopsy-naïve men with suspicion of prostate cancer. BJU Int 2018;122:4049.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Lu AJ, Syed JS, Nguyen KA, et al. Negative multiparametric magnetic resonance imaging of the prostate predicts absence of clinically significant prostate cancer on 12-core template prostate biopsy. Urology 2017;105:118122.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Simmons LA, Kanthabalan A, Arya M, et al. The PICTURE study: diagnostic accuracy of multiparametric MRI in men requiring a repeat prostate biopsy. Br J Cancer 2017;116:11591165.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    van Leeuwen PJ, Hayen A, Thompson JE, et al. A multiparametric magnetic resonance imaging-based risk model to determine the risk of significant prostate cancer prior to biopsy. BJU Int 2017;120:774781.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    Borofsky S, George AK, Gaur S, et al. What are we missing? False- negative cancers at multiparametric MR imaging of the prostate. Radiology 2018;286:186195.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Pagniez MA, Kasivisvanathan V, Puech P, et al. Predictive factors of missed clinically significant prostate cancers in men with negative magnetic resonance imaging: a systematic review and meta-analysis. J Urol 2020;204:2432.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Westphalen AC, McCulloch CE, Anaokar JM, et al. Variability of the positive predictive value of PI-RADS for prostate MRI across 26 centers: experience of the society of abdominal radiology prostate cancer disease-focused panel. Radiology 2020;296:7684.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52.

    Rosenkrantz AB, Ginocchio LA, Cornfeld D, et al. Interobserver reproducibility of the PI-RADS version 2 lexicon: a multicenter study of six experienced prostate radiologists. Radiology 2016;280:793804.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Sonn GA, Fan RE, Ghanouni P, et al. Prostate magnetic resonance imaging interpretation varies substantially across radiologists. Eur Urol Focus. Published online December 7, 2017. doi:j.euf.2017.11.010

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54.

    Bostwick DG, Cheng L. Precursors of prostate cancer. Histopathology 2012;60:427.

  • 55.

    Ericson KJ, Wenger HC, Rosen AM, et al. Prostate cancer detection following diagnosis of atypical small acinar proliferation. Can J Urol 2017;24:87148720.

  • 56.

    Dorin RP, Wiener S, Harris CD, et al. Prostate atypia: does repeat biopsy detect clinically significant prostate cancer? Prostate 2015;75:673678.

  • 57.

    Wiener S, Haddock P, Cusano J, et al. Incidence of clinically significant prostate cancer after a diagnosis of atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia, or benign tissue. Urology 2017;110:161165.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58.

    Taneja SS, Morton R, Barnette G, et al. Prostate cancer diagnosis among men with isolated high-grade intraepithelial neoplasia enrolled onto a 3-year prospective phase III clinical trial of oral toremifene. J Clin Oncol 2013;31:523529.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59.

    Leone A, Rotker K, Butler C, et al. Atypical small acinar proliferation: repeat biopsy and detection of high grade prostate cancer. Prostate Cancer 2015;2015:810159.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60.

    Ynalvez LA, Kosarek CD, Kerr PS, et al. Atypical small acinar proliferation at index prostate biopsy: rethinking the re-biopsy paradigm. Int Urol Nephrol 2018;50:16.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61.

    Kawa SM, Stroomberg HV, Larsen SB, et al. A nationwide analysis of risk of prostate cancer diagnosis and mortality following an initial negative transrectal ultrasound biopsy with long-term followup. J Urol 2022;208:100108.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62.

    Morote J, Schwartzmann I, Celma A, et al. The current recommendation for the management of isolated high-grade prostatic intraepithelial neoplasia. BJU Int 2022;129:627633.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63.

    Grivas N, Lardas M, Espinós EL, et al. Prostate cancer detection percentages of repeat biopsy in patients with positive multiparametric magnetic resonance imaging (Prostate Imaging Reporting and Data System/Likert 3-5) and negative initial biopsy. A mini systematic review. Eur Urol 2022;82:452457.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 64.

    Kotb AF, Spaner S, Crump T, et al. The role of mpMRI and PSA density in patients with an initial negative prostatic biopsy. World J Urol 2018;36:20212025.

NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel’s discussion, including the literature reviewed.

The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.

The complete and most recent version of these NCCN Guidelines is available free of charge at NCCN.org.

© 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.

  • Collapse
  • Expand
  • 1.

    Gosselaar C, Roobol MJ, Roemeling S, et al. The role of the digital rectal examination in subsequent screening visits in the European randomized study of screening for prostate cancer (ERSPC), Rotterdam. Eur Urol 2008;54:581588.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Halpern JA, Oromendia C, Shoag JE, et al. Use of digital rectal examination as an adjunct to prostate specific antigen in the detection of clinically significant prostate cancer. J Urol 2018;199:947953.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Gosselaar C, Roobol MJ, Roemeling S, et al. Screening for prostate cancer at low PSA range: the impact of digital rectal examination on tumor incidence and tumor characteristics. Prostate 2007;67:154161.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. J Urol 1994;151:12831290.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Catalona WJ, Smith DS, Ratliff TL, et al. Detection of organ-confined prostate cancer is increased through prostate-specific antigen-based screening. JAMA 1993;270:948954.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Catalona WJ, Richie JP, Ahmann FR, et al. Comparison of digital rectal examination and serum prostate specific antigen in the early detection of prostate cancer: results of a multicenter clinical trial of 6,630 men. J Urol 2017;197(Suppl 2):S200207.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Flanigan RC, Catalona WJ, Richie JP, et al. Accuracy of digital rectal examination and transrectal ultrasonography in localizing prostate cancer. J Urol 1994;152:15061509.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Schröder FH, van der Maas P, Beemsterboer P, et al. Evaluation of the digital rectal examination as a screening test for prostate cancer. J Natl Cancer Inst 1998;90:18171823.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Halpern JA, Shoag JE, Mittal S, et al. Prognostic significance of digital rectal examination and prostate specific antigen in the prostate, lung, colorectal and ovarian (PLCO) cancer screening arm. J Urol 2017;197:363368.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Okotie OT, Roehl KA, Han M, et al. Characteristics of prostate cancer detected by digital rectal examination only. Urology 2007;70:11171120.

  • 11.

    Mahal BA, Aizer AA, Efstathiou JA, et al. Association of very low prostate-specific antigen levels with increased cancer-specific death in men with high-grade prostate cancer. Cancer 2016;122:7883.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Falchook AD, Martin NE, Basak R, et al. Stage at presentation and survival outcomes of patients with Gleason 8–10 prostate cancer and low prostate-specific antigen. Urol Oncol 2016;34:119.e1926.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Hugosson J, Carlsson S, Aus G, et al. Mortality results from the Göteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 2010;11:725732.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Andriole GL, Crawford ED, Grubb RL III, et al. Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up. J Natl Cancer Inst 2012;104:125132.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate- cancer mortality in a randomized European study. N Engl J Med 2009;360:13201328.

  • 16.

    Schaeffer EM, Carter HB, Kettermann A, et al. Prostate specific antigen testing among the elderly—when to stop? J Urol 2009;181:16061614.

  • 17.

    Sun L, Caire AA, Robertson CN, et al. Men older than 70 years have higher risk prostate cancer and poorer survival in the early and late prostate specific antigen eras. J Urol 2009;182:22422248.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Bechis SK, Carroll PR, Cooperberg MR. Impact of age at diagnosis on prostate cancer treatment and survival. J Clin Oncol 2011;29:235241.

  • 19.

    Clark R, Vesprini D, Narod SA. The effect of age on prostate cancer survival. Cancers 2022;14:4149.

  • 20.

    Scosyrev E, Messing EM, Mohile S, et al. Prostate cancer in the elderly: frequency of advanced disease at presentation and disease-specific mortality. Cancer 2012;118:30623070.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Pettersson A, Robinson D, Garmo H, et al. Age at diagnosis and prostate cancer treatment and prognosis: a population-based cohort study. Ann Oncol 2018;29:377385.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Roobol MJ, Roobol DW, Schröder FH. Is additional testing necessary in men with prostate-specific antigen levels of 1.0 ng/mL or less in a population-based screening setting? (ERSPC, section Rotterdam). Urology 2005;65:343346.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Vickers AJ, Cronin AM, Björk T, et al. Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study. BMJ 2010;341:c4521.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Vertosick EA, Häggström C, Sjoberg DD, et al. Prespecified 4-kallikrein marker model at age 50 or 60 for early detection of lethal prostate cancer in a large population based cohort of asymptomatic men followed for 20 years. J Urol 2020;204:281288.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Vickers AJ, Ulmert D, Sjoberg DD, et al. Strategy for detection of prostate cancer based on relation between prostate specific antigen at age 40-55 and long term risk of metastasis: case-control study. BMJ 2013;346:f2023.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Preston MA, Batista JL, Wilson KM, et al. Baseline prostate-specific antigen levels in midlife predict lethal prostate cancer. J Clin Oncol 2016;34:27052711.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Preston MA, Gerke T, Carlsson SV, et al. Baseline prostate-specific antigen level in midlife and aggressive prostate cancer in black men. Eur Urol 2019;75:399407.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Kovac E, Carlsson SV, Lilja H, et al. Association of baseline prostate- specific antigen level with long-term diagnosis of clinically significant prostate cancer among patients aged 55 to 60 years: a secondary analysis of a cohort in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. JAMA Netw Open 2020;3:e1919284.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Ulmert D, Cronin AM, Björk T, et al. Prostate-specific antigen at or before age 50 as a predictor of advanced prostate cancer diagnosed up to 25 years later: a case-control study. BMC Med 2008;6:6.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Carlsson S, Assel M, Sjoberg D, et al. Influence of blood prostate specific antigen levels at age 60 on benefits and harms of prostate cancer screening: population based cohort study. BMJ 2014;348:g2296.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Heijnsdijk EAM, Gulati R, Tsodikov A, et al. Lifetime benefits and harms of prostate-specific antigen-based risk-stratified screening for prostate cancer. J Natl Cancer Inst 2020;112:10131020.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Lillard JW Jr, Moses KA, Mahal BA, et al. Racial disparities in Black men with prostate cancer: a literature review. Cancer 2022;128:37873795.

  • 33.

    Wang M, Chi G, Bodovski Y, et al. Temporal and spatial trends and determinants of aggressive prostate cancer among Black and White men with prostate cancer. Cancer Causes Control 2020;31:6371.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Mahal BA, Berman RA, Taplin ME, et al. Prostate cancer-specific mortality across Gleason scores in Black vs nonblack men. JAMA 2018;320:24792481.

  • 35.

    Tsodikov A, Gulati R, de Carvalho TM, et al. Is prostate cancer different in black men? Answers from 3 natural history models. Cancer 2017;123:23122319.

  • 36.

    Nyame YA, Gulati R, Heijnsdijk EA, et al. The impact of intensifying prostate cancer screening in Black men: a model-based analysis. J Natl Cancer Inst 2021;113:13361342.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-targeted or standard biopsy for prostate-cancer diagnosis. N Engl J Med 2018;378:17671777.

  • 38.

    Rouvière O, Puech P, Renard-Penna R, et al. Use of prostate systematic and targeted biopsy on the basis of multiparametric MRI in biopsy-naive patients (MRI-FIRST): a prospective, multicentre, paired diagnostic study. Lancet Oncol 2019;20:100109.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    van der Leest M, Cornel E, Israël B, et al. Head-to-head comparison of transrectal ultrasound-guided prostate biopsy versus multiparametric prostate resonance imaging with subsequent magnetic resonance-guided biopsy in biopsy-naïve men with elevated prostate-specific antigen: a large prospective multicenter clinical study. Eur Urol 2019;75:570578.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Klotz L, Chin J, Black PC, et al. Comparison of multiparametric magnetic resonance imaging-targeted biopsy with systematic transrectal ultrasonography biopsy for biopsy-naive men at risk for prostate cancer: a phase 3 randomized clinical trial. JAMA Oncol 2021;7:534542.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Sathianathen NJ, Omer A, Harriss E, et al. Negative predictive value of multiparametric magnetic resonance imaging in the detection of clinically significant prostate cancer in the prostate imaging reporting and data system era: a systematic review and meta-analysis. Eur Urol 2020;78:402414.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Lo G, Burton KR, Haider MA, et al. Negative predictive value of prostate multiparametric magnetic resonance imaging among men with negative prostate biopsy and elevated prostate specific antigen: a clinical outcome retrospective cohort study. J Urol 2019;202:11591165.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Richenberg J, Løgager V, Panebianco V, et al. The primacy of multiparametric MRI in men with suspected prostate cancer. Eur Radiol 2019;29:69406952.

  • 44.

    Boesen L, Nørgaard N, Løgager V, et al. Clinical outcome following low suspicion multiparametric prostate magnetic resonance imaging or benign magnetic resonance imaging guided biopsy to detect prostate cancer. J Urol 2017;198:310315.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Hansen NL, Barrett T, Kesch C, et al. Multicentre evaluation of magnetic resonance imaging supported transperineal prostate biopsy in biopsy-naïve men with suspicion of prostate cancer. BJU Int 2018;122:4049.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Lu AJ, Syed JS, Nguyen KA, et al. Negative multiparametric magnetic resonance imaging of the prostate predicts absence of clinically significant prostate cancer on 12-core template prostate biopsy. Urology 2017;105:118122.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Simmons LA, Kanthabalan A, Arya M, et al. The PICTURE study: diagnostic accuracy of multiparametric MRI in men requiring a repeat prostate biopsy. Br J Cancer 2017;116:11591165.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    van Leeuwen PJ, Hayen A, Thompson JE, et al. A multiparametric magnetic resonance imaging-based risk model to determine the risk of significant prostate cancer prior to biopsy. BJU Int 2017;120:774781.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    Borofsky S, George AK, Gaur S, et al. What are we missing? False- negative cancers at multiparametric MR imaging of the prostate. Radiology 2018;286:186195.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Pagniez MA, Kasivisvanathan V, Puech P, et al. Predictive factors of missed clinically significant prostate cancers in men with negative magnetic resonance imaging: a systematic review and meta-analysis. J Urol 2020;204:2432.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Westphalen AC, McCulloch CE, Anaokar JM, et al. Variability of the positive predictive value of PI-RADS for prostate MRI across 26 centers: experience of the society of abdominal radiology prostate cancer disease-focused panel. Radiology 2020;296:7684.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52.

    Rosenkrantz AB, Ginocchio LA, Cornfeld D, et al. Interobserver reproducibility of the PI-RADS version 2 lexicon: a multicenter study of six experienced prostate radiologists. Radiology 2016;280:793804.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Sonn GA, Fan RE, Ghanouni P, et al. Prostate magnetic resonance imaging interpretation varies substantially across radiologists. Eur Urol Focus. Published online December 7, 2017. doi:j.euf.2017.11.010

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54.

    Bostwick DG, Cheng L. Precursors of prostate cancer. Histopathology 2012;60:427.

  • 55.

    Ericson KJ, Wenger HC, Rosen AM, et al. Prostate cancer detection following diagnosis of atypical small acinar proliferation. Can J Urol 2017;24:87148720.

  • 56.

    Dorin RP, Wiener S, Harris CD, et al. Prostate atypia: does repeat biopsy detect clinically significant prostate cancer? Prostate 2015;75:673678.

  • 57.

    Wiener S, Haddock P, Cusano J, et al. Incidence of clinically significant prostate cancer after a diagnosis of atypical small acinar proliferation, high-grade prostatic intraepithelial neoplasia, or benign tissue. Urology 2017;110:161165.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 58.

    Taneja SS, Morton R, Barnette G, et al. Prostate cancer diagnosis among men with isolated high-grade intraepithelial neoplasia enrolled onto a 3-year prospective phase III clinical trial of oral toremifene. J Clin Oncol 2013;31:523529.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59.

    Leone A, Rotker K, Butler C, et al. Atypical small acinar proliferation: repeat biopsy and detection of high grade prostate cancer. Prostate Cancer 2015;2015:810159.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60.

    Ynalvez LA, Kosarek CD, Kerr PS, et al. Atypical small acinar proliferation at index prostate biopsy: rethinking the re-biopsy paradigm. Int Urol Nephrol 2018;50:16.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61.

    Kawa SM, Stroomberg HV, Larsen SB, et al. A nationwide analysis of risk of prostate cancer diagnosis and mortality following an initial negative transrectal ultrasound biopsy with long-term followup. J Urol 2022;208:100108.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 62.

    Morote J, Schwartzmann I, Celma A, et al. The current recommendation for the management of isolated high-grade prostatic intraepithelial neoplasia. BJU Int 2022;129:627633.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63.

    Grivas N, Lardas M, Espinós EL, et al. Prostate cancer detection percentages of repeat biopsy in patients with positive multiparametric magnetic resonance imaging (Prostate Imaging Reporting and Data System/Likert 3-5) and negative initial biopsy. A mini systematic review. Eur Urol 2022;82:452457.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 64.

    Kotb AF, Spaner S, Crump T, et al. The role of mpMRI and PSA density in patients with an initial negative prostatic biopsy. World J Urol 2018;36:20212025.

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