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An Approach Using PSA Levels of 1.5 ng/mL as the Cutoff for Prostate Cancer Screening in Primary Care

      Historical Perspective on Prostate-specific Antigen (PSA) Screening

      Prostate Cancer (PCa) Epidemiology

      PCa is the most commonly diagnosed malignancy in males, but has 1 of the lowest percentage mortality compared to other cancers. An estimated 180,890 new cases are expected to be diagnosed in 2016 and 26,120 men are expected to die from the disease. A significant dichotomy exists between lifetime risk of being diagnosed vs dying from the disease. Seventeen percent of US males are diagnosed with PCa within their lifetime, whereas only 3% die from the disease.
      • Siegel R.L.
      • Miller K.D.
      • Jemal A.
      Cancer statistics, 2015.
      The prevalence is highest in African American men, who also have a higher risk of mortality from PCa. Caucasian males have the next highest risk, whereas incidence is lower among those of Asian descent.

      Historical Perspective on PSA Screening

      Historically, there have been 2 ways to screen for PCa: the digital rectal examination (DRE) and PSA blood test. In 1986, the Food and Drug Administration approved PSA for use in monitoring PCa recurrence. In 1994, PSA was approved for screening, and was historically used in conjunction with DRE.
      Screening with PSA has several limitations. Many men who do not have PCa will screen positive and require a biopsy to rule out cancer, whereas a few with aggressive disease have low PSA. Because many PCa grow so slowly that they never threaten a patient's life, there is a danger of overtreatment if these cancers are detected. This is a particularly important issue because treatment for PCa is often associated with significant side effects. Our emphasis going forward should be finding the more aggressive cancers, while avoiding biopsy in those at low risk or those with indolent disease.

      Current Screening Recommendations and the Evidence

      PCa Screening

      Screening is defined as the process of identifying apparently healthy people who may be at increased risk of a disease or condition. Current strategies for managing PCa are mainly aimed at early detection. The potential risks incurred by screening, diagnosis, and the resulting overtreatment of PCa have been well documented within the literature.
      • Loeb S.
      • Bjurlin M.A.
      • Nicholson J.
      • et al.
      Overdiagnosis and overtreatment of prostate cancer.
      These include erectile dysfunction, incontinence, and complications from biopsies, surgery, radiation, or androgen deprivation therapy. The majority of harms associated with overtreatment occur in men in whom PCa would not have been detected in their lifetime had it not been for screening.
      • Andriole G.L.
      • Crawford E.D.
      • Grubb 3rd, R.L.
      • et al.
      Mortality results from a randomized prostate-cancer screening trial.
      Rates of active surveillance are rising rapidly across the globe.
      • Cooperberg M.R.
      • Carroll P.R.
      Trends in management for patients with localized prostate cancer, 1990-2013.
      • Womble P.R.
      • Montie J.E.
      • Ye Z.
      • et al.
      Contemporary use of initial active surveillance among men in Michigan with low-risk prostate cancer.
      Conversely, discontinuing screening altogether has been projected to increase the rates of metastatic disease
      • Gulati R.
      • Tsodikov A.
      • Etzioni R.
      • et al.
      Expected population impacts of discontinued prostate-specific antigen screening.
      and will preclude the opportunity for many men to receive life-saving intervention. Given the substantial advantages and disadvantages associated with historical screening and management paradigms, many providers have been left without a clear roadmap.

      Screening Guidelines

      Screening recommendations from various organizations differ widely. The U.S. Preventive Services Task Force and Canadian Task Force on Preventive Health Care have recommended against any screening for men of all ages, whereas most other organizations recommend some variation of shared decision-making. The American Urological Association does not recommend routine screening for men aged 50-55, but recommends shared decision-making for men aged 55-69. The American Urological Association further mentions that 2-year intervals can be considered to reduce harm.
      Prostate-specific antigen (PSA) best practice policy. American Urological Association (AUA).
      The National Comprehensive Cancer Network (NCCN) recommends a risk-based screening algorithm, including the patient's age (consider screening at age 45; in the later 40s, 1.0 ng/mL is recommended by the NCCN as a cutoff for screening within 2 years). Notably, DRE is no longer the first line in the 2015 NCCN guidelines.
      Separate European and American randomized screening trials demonstrated divergent results. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial did not show convincing evidence that PSA screening reduces PCa mortality. However, a large majority of men in the control group received PSA testing before and/or during the study so it was not comparison of screening vs no screening, but rather organized vs opportunistic screening. Furthermore, recent data from the PLCO trial indicate that contamination substantially limited the ability of the PLCO to identify a clinically significant screening benefit.
      • Gulati R.
      • Tsodikov A.
      • Wever E.M.
      • et al.
      The impact of PLCO control arm contamination on perceived PSA screening efficacy.
      The European Randomized Study of Screening for Prostate Cancer found that screening reduces metastasis and PCa death, but also leads to overdiagnosis. In both trials, biopsy was recommended based on a fixed PSA threshold. An alternate approach to a fixed screening protocol is a risk-adapted approach. For example, Gelfond et al suggested that optimal PSA screening frequency for men with PSA 0.1 to 1.0 ng/mL might be up to every 10 years. This approach has the potential to dramatically reduce the cost of screening, decrease overdetection of inconsequential tumors, and maintain detection of tumors for which treatment has been proven to reduce PCa mortality.
      • Gelfond J.
      • Choate K.
      • Ankerst D.P.
      • Hernandez J.
      • Leach R.J.
      • Thompson Jr, I.M.
      Intermediate-term risk of prostate cancer is directly related to baseline prostate specific antigen: implications for reducing the burden of prostate specific antigen screening.

      Screening in the Primary Care Setting

      Today, after nearly 3 decades since PSA was first used as a tool for early detection of PCa, substantial uncertainty surrounds its use. Primary care physicians (PCPs), including internists, order approximately 90% of all PSA screening tests.
      • Aslani A.
      • Minnillo B.J.
      • Johnson B.
      • Cherullo E.E.
      • Ponsky L.E.
      • Abouassaly R.
      The impact of recent screening recommendations on prostate cancer screening in a large health care system.
      Shared decision-making is ideal but may be difficult to implement in the primary care setting due to several factors, including the following: the limited time and availability that PCPs have for in-depth discussions about the pros and cons of PSA testing (given the numerous other issues typically covered in a visit); the wide range of information and data that could be discussed during each visit; and the complex tradeoff between immediate harms and long-term benefits.
      • Vickers A.J.
      • Edwards K.
      • Cooperberg M.R.
      • Mushlin A.I.
      A simple schema for informed decision making about prostate cancer screening.
      Furthermore, shared decision-making rarely occurs with many tests performed by PCPs—often times, it only occurs after an abnormality is detected.
      In some cases, spending considerable amounts of time discussing PSA may be seen as an inherent bias toward screening and could result in reduced time spent on other preventive services, thereby resulting in an opportunity cost. Studies have found that only approximately half of PCPs are compliant with recommendations to discuss screening with eligible patients, with a large proportion adopting a default “screen all” or “screen none” approach.
      • Vickers A.J.
      • Edwards K.
      • Cooperberg M.R.
      • et al.
      Supplement. Recommendations on shared decision making for prostate cancer screening: review of the literature.
      The value of a “detailed discussion” about PSA depends critically on the PCPs' knowledge. Less than 1 in 5 PCPs report confidence in their knowledge about PSA, with a low correlation between confidence and actual knowledge.
      • Tasian G.E.
      • Cooperberg M.R.
      • Cowan J.E.
      • et al.
      Prostate specific antigen screening for prostate cancer: knowledge of, attitudes towards, and utilization among primary care physicians.
      • Tasian G.E.
      • Cooperberg M.R.
      • Potter M.B.
      • et al.
      PSA screening: determinants of primary-care physician practice patterns.
      A recent article in JAMA by Eggener et al acknowledged that a novel approach to PCa screening is needed because of the workflow limitations in “discussing this complex decision” in the PCP office.
      • Vickers A.J.
      • Edwards K.
      • Cooperberg M.R.
      • Mushlin A.I.
      A simple schema for informed decision making about prostate cancer screening.
      • Eggener S.E.
      • Cifu A.S.
      • Nabhan C.
      Prostate Cancer Screening.
      Assuming that some element of screening is embraced, there is a need to develop a simple and easy algorithm regarding the role of PSA in PCa screening and to assess when further diagnostic tests are needed.

      A New Perspective on PSA Screening in the Primary Care Setting

      Rather than the fixed one-size-fits all approach used for screening in the past, there may be ways to use PSA more intelligently for more personalized decisions. We need to avoid PSA tests in men who would have little to no gain by focusing on age and health. Several authors have targeted the relative risks of a baseline PSA and subsequent risk of an abnormal level of greater than 4 in 5 years.
      • Loeb S.
      • Carter H.B.
      • Catalona W.J.
      • Moul J.W.
      • Schroder F.H.
      Baseline prostate-specific antigen testing at a young age.
      • Crawford E.D.
      • Pinsky P.F.
      • Chia D.
      • et al.
      Prostate specific antigen changes as related to the initial prostate specific antigen: data from the prostate, lung, colorectal and ovarian cancer screening trial.
      In a 2011 article, Crawford et al found that a PSA of <1.5 ng/mL constitutes a very low risk category for developing PCa (particularly high-risk disease) within 4-5 years.
      • Crawford E.D.
      • Moul J.W.
      • Rove K.O.
      • Pettaway C.A.
      • Lamerato L.E.
      • Hughes A.
      Prostate-specific antigen 1.5-4.0 ng/mL: a diagnostic challenge and danger zone.
      In a follow-up piece, they suggested embracing the 1.5 ng/mL level and only having further discussions or workup with those above that threshold. An elevated PSA (>1.5 ng/mL) becomes case finding (with a focus on identifying men who have a higher risk of having clinically significant disease). In such a case where there is increased suspicion of clinically significant disease, informed decision-making should be employed, as several options are available as next steps. These options include following up with the patient in 6 months or 1 year, referral to a urologist, or using new techniques, such as ,magnetic resonance imaging or biomarkers to determine whether the patient is at risk of harboring clinically significant disease. For those below the level, recommendations were made to screen again in 5 years. Potential benefits of this approach include reducing the cost of screening, decreasing overdetection of inconsequential tumors, and maintaining detection of tumors for which treatment has been proven to reduce PCa mortality.
      • Gelfond J.
      • Choate K.
      • Ankerst D.P.
      • Hernandez J.
      • Leach R.J.
      • Thompson Jr, I.M.
      Intermediate-term risk of prostate cancer is directly related to baseline prostate specific antigen: implications for reducing the burden of prostate specific antigen screening.
      Table 1 outlines PSA measurements on approximately 500,000 men from a reference laboratory outlining PSA levels by age. Approximately 70% of men aged 45 to 70 years have a PSA of less than 1.5 ng/mL. Some suggest that a change in screening that leads to the biggest health gain is to stop screening older men. This applies to the majority of men over 70 and those over 60 with low PSA (eg, <1.5 ng/mL).
      • 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.
      • van Leeuwen P.J.
      • Connolly D.
      • Tammela T.L.
      • et al.
      Balancing the harms and benefits of early detection of prostate cancer.
      Indeed, Lilja et al found that a single PSA measured in white men between 44 and 50 years was highly correlated with any cancer, palpable disease, and advanced cancer. At a PSA threshold of 1.5 ng/mL, theses values were approximately 20%, <15%, and 5%, respectively, 20-25 years after blood was drawn when they were aged 44-50 years. Similarly, Vickers et al showed that white men with a PSA in the highest 10th grouping (ie, 1.6 ng/mL or greater) at age 45-49 contributed to nearly half of all PCa deaths over the next 25-30 years. They further postulated that low-risk men based on baseline PSA might only need 3 PSA measurements in their lifetime (ie, 40s, 50, and age 60). Little is known, however, whether these long-term data apply to men of other racial and ethnic groups.
      • Lilja H.
      • Cronin A.M.
      • Dahlin A.
      • et al.
      Prediction of significant prostate cancer diagnosed 20 to 30 years later with a single measure of prostate-specific antigen at or before age 50.
      • Vickers A.J.
      • Ulmert D.
      • Sjoberg D.D.
      • 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.
      Crawford et al showed that at least over a 4-year period both Caucasian and African American men were at low risk for any cancer diagnosis (0.51% and 0.54% respectively) when their baseline serum PSA level was <1.5 ng/mL.
      • Crawford E.D.
      • Moul J.W.
      • Rove K.O.
      • Pettaway C.A.
      • Lamerato L.E.
      • Hughes A.
      Prostate-specific antigen 1.5-4.0 ng/mL: a diagnostic challenge and danger zone.
      Of note, among both African American and Caucasian men, a substantial majority of PSA values were <1.5 ng/mL (79% and 80% ,respectively).
      • Crawford E.D.
      • Moul J.W.
      • Rove K.O.
      • Pettaway C.A.
      • Lamerato L.E.
      • Hughes A.
      Prostate-specific antigen 1.5-4.0 ng/mL: a diagnostic challenge and danger zone.
      Table 1PSA measurements of less than 1.5 ng/mL (provided with permission of Charles T. Todd Jr., BioReference Laboratories, Inc.)
      Age GroupNo. of Men With PSA < 1.5 ng/mL% of Men by Age Group with PSA < 1.5 ng/mLTotal No. of Results
      41-4536,12189.640,306
      46-5054,61684.164,920
      51-5569,85376.890,949
      56-6059,19567.288,034
      61-6545,38658.178,072
      66-7034,93151.667,675
      71-7523,74248.349,185
      76-8016,25547.134,506
      81-85957246.420,616
      86-90456244.910,154
      91-96126640.13154
      Grand total355,49964.9547,571
      PSA, prostate-specific antigen.

      Next Generation of Clinical Decision-making Tools

      Under the proposed paradigm (Fig. 1), PSA can be performed as part of a regular blood panel and only men with a PSA ≥ 1.5 ng/mL require shared decision-making about further testing and diagnostic evaluation. This will greatly limit the number of men requiring such a discussion and can be performed either by the PCP or by referral to a urologist. Men with elevated PSA should be evaluated for benign causes. Repeat testing of PSA and secondary molecular tests such as PCA3, SelectMDx, 4KScore, and PHI can be used to refine the specificity of screening to detect high-risk disease (Table 2). However, sampling error is an inherent and well-documented issue with false-negative rates of prostate biopsy procedures reported as high as 25%-35%.
      • de la Calle C.
      • Patil D.
      • Wei J.T.
      • et al.
      Multicenter evaluation of the prostate health index to detect aggressive prostate cancer in biopsy naive men.
      • Stewart G.D.
      • Van Neste L.
      • Delvenne P.
      • et al.
      Clinical utility of an epigenetic assay to detect occult prostate cancer in histopathologically negative biopsies: results of the MATLOC study.
      This results in repeat biopsies, which are associated with additional risks of infection and hospitalization, and with significant costs.
      Figure 1
      Figure 1Approach to shared care in PCa diagnosis. The patient presents to the family practitioner for a routine visit. PSA is obtained with other routine laboratory tests. If PSA is less than 1.5 ng/mL, the patient enters the follow-up pool and has a repeat PSA in 5 years. If PSA is greater than 1.5 ng/mL, informed decision is obtained and referral to urologist is considered. Urologists will evaluate for possible causes including BPH, prostatitis, and PCa. If there is concern for PCa, then a genomic test such as PHI, SelectMDx, 4KScore, or PCA3 is performed to identify men who are at risk of a significant cancer. If the disease is considered low risk, a return to the family practitioner for a repeat in 1 year is made. If the disease is considered high-risk, consider a TRUS biopsy. BPH, benign prostatic hyperplasia; PCa, prostate cancer; PSA, prostate-specific antigen; TRUS, transrectal ultrasound.
      Table 2Molecular tests to identify Gleason sum equal to or greater than 7
      AssayPHI4KScorePCA3SelectMDx
      CompanyBeckman CoulterOpkoHologicMDxHealth
      SpecimenBloodSerum
      After digital rectal examination.
      Urine
      After digital rectal examination.
      Urine
      MethodologyImmunoassay, 3 protein biomarkers: tPSA and fPSA, proPSAImmunoassay, 4 kallikreins biomarkers,: PSA, fPSA, intact PSA, HK-2qPCR, mRNA test, 1 biomarker: PCA3qPCR, 2 mRNA biomarkers: DLX1, HOXC6
      RegulatoryFDA/CELDT/CLIA/CEFD/CELDT/CLIA/CE
      List Price ($)4991900500500
      Assay PerformanceAUC 0.73AUC 0.82AUC 0.68AUC 0.89
      Secondary molecular tests that may be used to refine the specificity of screening to detect high-risk prostate cancer.
      * After digital rectal examination.

      Conclusion

      Although many organizations now recommend shared decision-making when it comes to PSA testing, this can present many logistical challenges in daily clinical practice and is not always realistic. Furthermore, we acknowledge that several groups recommend that informed decision-making take place before the PSA test is ordered. However, our aim is to draw a parallel to what happens in the real world for PCPs—that is, informed decision-making typically comes after the test results (be it blood sugar, blood pressure, cholesterol, or in this case PSA) are known. PCPs are confused about the messages we try to deliver regarding PSA: PSA velocity, age-specific PSA, percent free PSA, PSA density, PSA cutoffs of 1 ng/mL, 1.5 ng/mL, 2.5 ng/mL, and 4 ng/mL. We believe that a simple message using a PSA cutoff of 1.5 ng/mL is reflective of what PCPs often experience with conditions such as mild hypertension and prediabetes. In this paper, we have presented an alternative approach in which screening is performed for men with at least a 10-year life expectancy. If the PSA is less than 1.5 ng/mL (approximately 70% of men who have a screening PSA), consider a 5-year rescreening interval. If the PSA is ≥ 1.5 ng/mL, or the PCP identifies an abnormality on DRE, refer to a specialist or consider a biomarker to assess risk more precisely. This algorithm is similar to that utilized for an elevated blood sugar, where an abnormal result triggers another test such as an A1C hemoglobin. In our algorithm, we recommend that a biopsy should not be performed unless the risk of an aggressive tumor is significant, and following a thorough discussion of benefits and risks with the patient. These discussions should emphasize that the purpose of screening is the early identification of potentially lethal disease, and that in most cases low-risk tumors, if identified, do not require immediate treatment. A potential benefit of this approach is that it could greatly reduce the number of men requiring shared decision-making and further testing to those at greater risk of significant PCa.

      Acknowledgment

      The authors thank Karen Ventii, PhD, for editorial support.

      References

        • Siegel R.L.
        • Miller K.D.
        • Jemal A.
        Cancer statistics, 2015.
        CA Cancer J Clin. 2015; 65: 5-29
        • Loeb S.
        • Bjurlin M.A.
        • Nicholson J.
        • et al.
        Overdiagnosis and overtreatment of prostate cancer.
        Eur Urol. 2014; 65: 1046-1055
        • Andriole G.L.
        • Crawford E.D.
        • Grubb 3rd, R.L.
        • et al.
        Mortality results from a randomized prostate-cancer screening trial.
        N Engl J Med. 2009; 360: 1310-1319
        • Cooperberg M.R.
        • Carroll P.R.
        Trends in management for patients with localized prostate cancer, 1990-2013.
        JAMA. 2015; 314: 80-82
        • Womble P.R.
        • Montie J.E.
        • Ye Z.
        • et al.
        Contemporary use of initial active surveillance among men in Michigan with low-risk prostate cancer.
        Eur Urol. 2015; 67: 44-50
        • Gulati R.
        • Tsodikov A.
        • Etzioni R.
        • et al.
        Expected population impacts of discontinued prostate-specific antigen screening.
        Cancer. 2014; 120: 3519-3526
      1. Prostate-specific antigen (PSA) best practice policy. American Urological Association (AUA).
        Oncology (Williston Park). 2000; 14 (277-268, 280 passim): 267-272
        • Gulati R.
        • Tsodikov A.
        • Wever E.M.
        • et al.
        The impact of PLCO control arm contamination on perceived PSA screening efficacy.
        Cancer Causes Control. 2012; 23: 827-835
        • Gelfond J.
        • Choate K.
        • Ankerst D.P.
        • Hernandez J.
        • Leach R.J.
        • Thompson Jr, I.M.
        Intermediate-term risk of prostate cancer is directly related to baseline prostate specific antigen: implications for reducing the burden of prostate specific antigen screening.
        J Urol. 2015; 194: 46-51
        • Aslani A.
        • Minnillo B.J.
        • Johnson B.
        • Cherullo E.E.
        • Ponsky L.E.
        • Abouassaly R.
        The impact of recent screening recommendations on prostate cancer screening in a large health care system.
        J Urol. 2014; 191: 1737-1742
        • Vickers A.J.
        • Edwards K.
        • Cooperberg M.R.
        • Mushlin A.I.
        A simple schema for informed decision making about prostate cancer screening.
        Ann Intern Med. 2014; 161: 441-442
        • Vickers A.J.
        • Edwards K.
        • Cooperberg M.R.
        • et al.
        Supplement. Recommendations on shared decision making for prostate cancer screening: review of the literature.
        Ann Intern Med. 2014; 161: 3
        • Tasian G.E.
        • Cooperberg M.R.
        • Cowan J.E.
        • et al.
        Prostate specific antigen screening for prostate cancer: knowledge of, attitudes towards, and utilization among primary care physicians.
        Urol Oncol. 2012; 30: 155-160
        • Tasian G.E.
        • Cooperberg M.R.
        • Potter M.B.
        • et al.
        PSA screening: determinants of primary-care physician practice patterns.
        Prostate Cancer Prostatic Dis. 2012; 15: 189-194
        • Eggener S.E.
        • Cifu A.S.
        • Nabhan C.
        Prostate Cancer Screening.
        JAMA. 2015; 314: 825-826
        • Loeb S.
        • Carter H.B.
        • Catalona W.J.
        • Moul J.W.
        • Schroder F.H.
        Baseline prostate-specific antigen testing at a young age.
        Eur Urol. 2012; 61: 1-7
        • Crawford E.D.
        • Pinsky P.F.
        • Chia D.
        • et al.
        Prostate specific antigen changes as related to the initial prostate specific antigen: data from the prostate, lung, colorectal and ovarian cancer screening trial.
        J Urol. 2006; 175 (discussion 1290): 1286-1290
        • Crawford E.D.
        • Moul J.W.
        • Rove K.O.
        • Pettaway C.A.
        • Lamerato L.E.
        • Hughes A.
        Prostate-specific antigen 1.5-4.0 ng/mL: a diagnostic challenge and danger zone.
        BJU Int. 2011; 108: 1743-1749
        • 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
        • van Leeuwen P.J.
        • Connolly D.
        • Tammela T.L.
        • et al.
        Balancing the harms and benefits of early detection of prostate cancer.
        Cancer. 2010; 116: 4857-4865
        • Lilja H.
        • Cronin A.M.
        • Dahlin A.
        • et al.
        Prediction of significant prostate cancer diagnosed 20 to 30 years later with a single measure of prostate-specific antigen at or before age 50.
        Cancer. 2011; 117: 1210-1219
        • Vickers A.J.
        • Ulmert D.
        • Sjoberg D.D.
        • 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
        • de la Calle C.
        • Patil D.
        • Wei J.T.
        • et al.
        Multicenter evaluation of the prostate health index to detect aggressive prostate cancer in biopsy naive men.
        J Urol. 2015; 194: 65-72
        • Stewart G.D.
        • Van Neste L.
        • Delvenne P.
        • et al.
        Clinical utility of an epigenetic assay to detect occult prostate cancer in histopathologically negative biopsies: results of the MATLOC study.
        J Urol. 2013; 189: 1110-1116