Prostate cancer diagnosis and treatment rates have increased significantly since the introduction of prostate-specific antigen (PSA) screening. Although it was initially thought that most prostate cancers would lead to death or significant morbidity, recent randomized trials have demonstrated that many patients with screening-detected cancer will not die of their disease. Modifications to PSA screening, screening guideline statements, and novel screening markers have been developed to minimize the risk and morbidity associated with overdiagnosis and overtreatment. Less aggressive management strategies such as active surveillance may lead to lower treatment rates in men who are unlikely to benefit while maintaining cure rates.
Key points
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Prostate cancer diagnosis and treatment rates have increased significantly since the introduction of prostate-specific antigen (PSA) screening.
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Although it was initially thought that most prostate cancers would lead to death or significant morbidity, recent randomized trials have demonstrated that many patients with screening-detected prostate cancer will not die of their disease.
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Modifications to PSA screening, screening guideline statements, and novel screening markers have been developed to minimize the risk and morbidity associated with this overdiagnosis and overtreatment.
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Active surveillance protocols, in which patients with localized, low-risk prostate cancer are systematically monitored with the goal of deferring treatment until signs of disease progression arise, may also lead to lower treatment rates in men who are unlikely to benefit.
Introduction
Prostate cancer is the most commonly diagnosed cancer in men with an expected 238 600 new cases and 28 000 deaths in 2013 accounting for the second leading cause of cancer death in US men. Over the past 20 years, a clinical focus has been on early detection using prostate-specific antigen (PSA) screening to find cancer before it becomes incurable. The result has been a dramatic increase in diagnosis accompanied by a decrease in mortality of almost 3.7% per year since 1994. Recently, however, the utility of PSA screening has come into question because of an increase in diagnosis of cancers that are unlikely to cause significant harm to patients during their lifetime. Although controversy exists as to the effect of PSA screening on mortality, what is unquestioned is that a relatively large number of patients must be screened in order to prevent one cancer-related death. As a result, efforts are focused on screening men most likely to benefit, development of new tests designed to aid in screening, and limiting treatment in men at low risk for dying of cancer. Herein, the authors review recent data on PSA screening, the rationale for new recommendations, novel screening tests, and the role of active surveillance in the management of this disease.
Introduction
Prostate cancer is the most commonly diagnosed cancer in men with an expected 238 600 new cases and 28 000 deaths in 2013 accounting for the second leading cause of cancer death in US men. Over the past 20 years, a clinical focus has been on early detection using prostate-specific antigen (PSA) screening to find cancer before it becomes incurable. The result has been a dramatic increase in diagnosis accompanied by a decrease in mortality of almost 3.7% per year since 1994. Recently, however, the utility of PSA screening has come into question because of an increase in diagnosis of cancers that are unlikely to cause significant harm to patients during their lifetime. Although controversy exists as to the effect of PSA screening on mortality, what is unquestioned is that a relatively large number of patients must be screened in order to prevent one cancer-related death. As a result, efforts are focused on screening men most likely to benefit, development of new tests designed to aid in screening, and limiting treatment in men at low risk for dying of cancer. Herein, the authors review recent data on PSA screening, the rationale for new recommendations, novel screening tests, and the role of active surveillance in the management of this disease.
PSA screening
PSA was introduced in the late 1980s as a screening tool for prostate cancer. The initial recommendations were that all men older than 50 years undergo yearly screening with PSA and digital rectal examination (DRE), and screening should begin at 40 years of age for men at a higher risk. This screening paradigm led to a dramatic increase in the number of cases from about 100 per 100 000 US men in the pre-PSA era to approximately 160 per 100 000 US men subsequently. In addition, a dramatic stage migration has been noted. Currently, 85% of prostate cancers diagnosed in the United States are clinically localized. Before PSA testing, as many as two-thirds of patients with apparently clinically localized disease were found to have pathologically advanced disease at the time of prostatectomy and approximately one-third were found to have lymph node metastatic disease. The number of patients presenting with locally advanced disease (stage T3 or T4) has decreased from 19.2% in the pre-PSA era to only 4.4% a decade later. The rate of metastatic disease at presentation has also been greatly affected by PSA screening. Scosyrev and colleagues performed an analysis of Surveillance Epidemiology and End Results (SEER) data and demonstrated a 3-fold decrease in the age-specific and race-specific observed annual incidence rates of metastatic prostate cancer at diagnosis in 2008 compared with the expected rates based on the incidence between 1983 and 1985.
Although initially it was thought that most of the tumors diagnosed by PSA screening had the potential to cause harm, there has been a realization over time that many of these tumors were similar to those detected in autopsy series and thought to be clinically insignificant. Incidental tumors were first appreciated in autopsy studies that demonstrated histologic evidence of prostate cancer in 1 in 3 men older than 50 years, with up to 80% of these tumors being clinically insignificant because of their limited size and grade. These studies illustrated the high latent disease prevalence, thus, allowing for potential overdiagnosis by screening tests.
Selecting a threshold for normal PSA has also proven difficult because significant cancer has been shown to occur even with low PSA values. The Prostate Cancer Prevention Trial (PCPT) randomized men with PSA of less than 4 ng/mL to receiving finasteride or placebo to investigate whether finasteride prevented prostate cancer. The study incorporated an end-of-study biopsy for all patients, including men on placebo, which allowed a more full understanding of prostate cancer risk in men with a normal PSA. Cancer was identified at the end-of-study biopsy in 15.2% of men with normal annual PSA and DRE over a 7-year interval. These tumors were not all clinically indolent because Gleason 7 or higher cancer was found in 2.3% of these patients. In men with a PSA between 2.1 and 4.0 ng/mL, 24.7% had prostate cancer and 5.2% had Gleason 7 or higher cancer. Even a PSA cutoff of 1.1 ng/mL would miss cancers because 25% of all cancers and 18% of Gleason 7 to 10 cancers were found in patients with PSA of less than this value. It is clear from this data that there is no level of PSA that can be thought of as truly normal or abnormal.
Clinical trial data on the utility of PSA screening also have mixed results. Despite the decreases in prostate cancer mortality and rates of advanced disease at presentation during the era of PSA screening and aggressive therapy, data emerged demonstrating that patients with localized prostate cancer at diagnosis had high non–prostate cancer–specific mortality if left untreated, raising the possibility that treatment in these patients would not have provided a benefit. These seemingly contradictory findings highlighted the clear need for prospective, randomized controlled trials investigating the utility of PSA screening.
Randomized controlled trials of PSA screening
Although the debate on PSA screening has continued for a decade or more, the recent publication of randomized trials has brought this discussion into the public eye. The Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial enrolled 76 693 men between 55 and 74 years of age and randomized them to annual PSA screening for 6 years and DRE for 4 years or usual care as the control group. The study demonstrated no significant difference in prostate cancer mortality between the intervention cohort (screened) and the control cohort (usual care) at the 13-year follow-up. There were 4250 cancers detected it the screening group compared with 3815 cancers in the control group, resulting in a relative increase of 12% (relative risk [RR] 1.12, 95% confidence interval [CI] 1.07–1.17). A total of 158 prostate cancer deaths occurred in the screened arm and 145 deaths in the control arm, corresponding to a statistically insignificant difference in cumulative prostate cancer mortality rates of 3.7 and 3.4 deaths per 10 000 person-years, respectively (RR 1.09, 95% CI 0.87–1.36). There were some flaws in the PLCO trial. There was significant screening before randomization, with 45% of the total control cohort having a PSA before enrollment. Contamination was also a significant problem, with 52% in the control group undergoing at least one PSA test during the study. In addition, 15% of men in the screening group did not undergo PSA testing during the trial. As a result, the study lost power. Lastly, the study was designed to test PSA screening in the community. PSA was obtained; the results were sent to the primary care physician; and recommendations were made. However, neither biopsy nor treatment was mandated. As a consequence, an elevated PSA did not uniformly lead to biopsy and the diagnosis of cancer did not lead to treatment, which further decreased the ability of the study to detect a difference.
The European Randomized Study of Screening for Prostate Cancer (ERSPC) was a larger study that randomized 182 160 men between 50 and 74 years of age to PSA screening every 4 years or a control group that did not undergo screening. Importantly, an elevated PSA (defined as 3.0 ng/mL or more) uniformly led to biopsy and treatment was strongly encouraged. At a median 11-year follow-up, the incidence of prostate cancer in the screening group was 9.6% compared with 6.0% in the control group. There were 299 prostate cancer deaths in the screening group and 462 prostate cancer deaths in the control group, with death rates of 0.39 and 0.50 per 1000 person-years, respectively. This finding corresponded to an overall RR reduction of 21% in the screened group (RR 0.79, 95% CI 0.68–0.91) but an absolute difference in overall mortality of only 1.07 deaths per 1000 men randomized. When looking at prostate cancer deaths occurring in years 10 and 11 of the follow-up, an even more pronounced RR reduction of 38% was detected (RR 0.62, 95% CI 0.45–0.85). Although this study did demonstrate a clear advantage, it is important to point out that the number needed to screen was 1055 men to detect 37 cancers to prevent one prostate cancer death.
A third cohort reported was a subgroup of the ERSPC trial. It was reported separately because the trial predates the larger ERSPC trial and, as a result, was considered a separate study. This study randomized 19 904 men aged 50 to 64 years to PSA screening at 2-year intervals or no screening. Although the study population was smaller, the follow-up was longer. At the 14-year follow-up, 1138 cancers were detected in the screening group and 718 in the control group, resulting in a cumulative incidence of 12.7% versus 8.2% (hazard ratio [HR] 1.64, 95% CI 1.50–1.80). There were 78 prostate cancer deaths in the screening group and 44 in the control group, for an absolute risk reduction of 0.4%. This finding corresponded to a 44% reduction in death rate (RR 0.56, 95% CI 0.39–0.82). In this trial, the number needed to be screened was much more reasonable; 293 men would need to be screened to diagnose 12 prostate cancers and to prevent one prostate death.
These trials demonstrate that PSA screening invariably leads to a higher rate of detection of prostate cancer with some of the trials demonstrating a reduction in prostate cancer mortality.
PSA screening modifications to improve detection
PSA is a glycoprotein produced by the epithelial cells that line the acini and ducts of the prostate gland. Any disruption of the normal prostatic architecture allows greater amounts of PSA to enter the general circulation. Therefore, many prostatic diseases, including benign prostatic hyperplasia, prostatitis, urinary tract infection, and urinary retention, have been shown to persistently elevate the PSA and should be treated before screening. In addition, DRE and ejaculation may also lead to small, transient increases in serum PSA that persist for approximately 2 days. Lastly, major manipulations of the genitourinary tract, such as prostate biopsy, transurethral resection of the prostate, and cystoscopy, have been shown to cause more dramatic elevations of PSA in the range of 6 to 8 ng/mL and result in persistently elevated levels for up to 4 weeks. For this reason, PSA testing should be postponed until an adequate time period has elapsed. Because of these confounders, it is not surprising that modifications are needed to improve its ability to detect cancer.
Because of the known shortcomings of PSA testing, efforts have been underway for the past decades to improve PSA-based screening. These efforts can be placed into 4 broad categories: (1) PSA refinements, (2) novel tests, (3) prediction tools, and (4) risk-based screening. All of these modifications have been shown to improve the detection of cancer; but, unfortunately, most of them have a limited ability to detect aggressive disease.
PSA refinements
PSA Velocity
Because PSA increases more rapidly in the setting of prostate cancer, PSA velocity has been proposed as an adjunct to improve PSA performance. This method involves obtaining at least 3 serial readings over an 18-month period to calculate the rate of increase in PSA. Carter and colleagues were the first to demonstrate this relationship. They found that a PSA velocity greater than 0.75 ng/mL/y was associated with an increased risk of cancer diagnosis and had a specificity of 90% compared with 60% if a PSA cutoff of 4.0 ng/mL alone was used. PSA velocity has been investigated in multiple settings since. The most pertinent to screening is a second article by Carter and colleagues, which examined PSA levels and the rate of risk decades before diagnosis in the Baltimore Longitudinal Study. They found that a PSA velocity greater than 0.35 ng/mL/y tested 10 to 15 years before the diagnosis of prostate cancer was associated with significantly worse cancer-specific survival and a higher RR of prostate cancer death (RR 4.7, 95% CI 1.3–16.5, P = .02). Not all studies have demonstrated a benefit to the use of PSA velocity. Pinsky and colleagues examined PSA velocity as a predictor of aggressive disease in the PLCO trial. They failed to find an association with an advanced pathologic stage and, therefore, concluded that PSA velocity added little to the accuracy of PSA alone. In the ERSPC trial, subgroup analysis demonstrated that PSA velocity was not a predictor of positive biopsy when adjusting for PSA. Similarly in the PCPT, the PSA velocity did not add clinically important information to PSA testing alone in men. However, this trial showed that for men with PSA less than 4.0 ng/mL and normal DRE, a PSA velocity of 0.35 ng/mL/y was a predictor of cancer but would lead to a higher number of unnecessary biopsies, with nearly 1 in 7 men being biopsied. It is important to note that, with the exception of the data from Carter and colleagues, all PSA values were obtained relatively close to the diagnosis of prostate cancer. Therefore, it is possible that PSA velocity decades before diagnosis may be of clinical utility; but short-term fluctuations do not provide additional information.
Free PSA
PSA circulates in the blood in 2 fractions. Complexed PSA is bound to other plasma proteins and free PSA circulates unbound. Because benign prostatic tissue produces more free PSA than prostate cancer in the serum, patients with prostate cancer will have lower free/total PSA ratios. A large, multicenter prospective trial in men between 50 and 75 years of age with PSA levels of 4.0 to 10.0 ng/mL and normal DRE found that a free PSA of 25% or more reduced unnecessary biopsies by 20%. If the free PSA cutoff was set to 10%, the biopsy detection rate increased to 56%, more than doubling the reported positive biopsy rate. On multivariate analysis, the percentage of free PSA was an independent predictor of prostate cancer (odds ratio [OR] 3.2, 95% CI 2.5–4.1, P <.001) and had a stronger association than age (OR 1.2, 95% CI 0.92–1.55) or total PSA level (OR 1.0, 95% CI 0.92–1.11). However, the investigators also reported an 8% chance of prostate cancer among men with free PSA greater than 25%. A meta-analysis of 41 studies found that in men with PSA between 4.0 and 10.0 ng/mL, free PSA was of clinical value at the extremes of its range (less than 7%–10% or greater than 20%–25%). For free PSA less than 7% to 10%, sensitivity was approximately 40% and specificity ranged between 72% and 92%. If the threshold of 20% to 25% free PSA was used, sensitivity would be increased to 90% to 95%.
Complexed PSA
Complexed PSA has also been investigated as an adjunct to total PSA. Most trials have studied the performance of complexed PSA in men with intermediate PSA values (4.0–10.0 ng/mL). These studies have demonstrated an increase in specificity and, thus, a decrease in unnecessary biopsies. Partin and colleagues conducted a large, multi-institutional prospective trial and showed a complexed PSA specificity of 13.3% compared with only 8.6% for total PSA in men with total PSA between 4.0 and 10.0 ng/mL. This finding was less specific than the specificity of free PSA at 21.5%. When looking at patients with a total PSA between 2.0 and 6.0 ng/mL, complexed PSA was more specific than total or free PSA. However, the investigators concluded that complexed PSA offered little additional benefit to total PSA in the differentiation of benign and malignant disease.
PSA Density
Prostate cancer has been reported to produce up to 10 times more PSA per volume of tissue than benign conditions. For this reason, PSA density has been proposed as a way to improve PSA performance. A prospective multicenter clinical trial of nearly 5000 men demonstrated that using the accepted PSA density cutoff of 0.15 ng/mL/cm 3 had better specificity than PSA alone; however, this threshold missed 47% of the tumors detected by PSA alone in men with a PSA range of 4.0 to 10.0 ng/mL or abnormal DRE.
All of the aforementioned modifications to PSA seem to be able to improve the sensitivity or specificity of the standard PSA test but depend highly on the cutoff values used and the subsets of the populations in which they were evaluated.
Risk-based screening
Applying PSA screening to a higher-risk population is another way of improving the performance of PSA testing. African American ethnicity and a family history of prostate cancer have been shown to be significant risk factors for the development of prostate cancer. Race-specific incidence of prostate cancer has been shown to be significantly higher for African Americans as compared with Caucasians. African American men also have a younger age of diagnosis, higher-grade disease, and increased risk of death. Family history is also a strong risk factor. Data from 2 meta analyses demonstrated a RR risk of prostate cancer of 2.0 to 3.5 for men with a family history of prostate cancer, depending on the degree of relatedness and number of affected relatives. Brandt and colleagues used the Swedish Family Cancer Database to estimate the age-specific risk of prostate cancer according to the number of affected relatives. The investigators reported that HRs of prostate cancer diagnosis increased with the number of affected relatives and decreased with increasing age, with the highest hazard ratios in men younger than 65 years with 3 affected brothers (HR approximately 23) and lowest ratio in men aged 65 to 74 years with an affected father (HR approximately 1.8). For this reason, men at an increased risk for disease, particularly aggressive disease, should be a focus for prostate cancer screening.
Another strategy is to obtain a PSA early in life and allow that to determine risk and, therefore, subsequent need for additional testing. Although not a randomized controlled trial, a recent case-control study evaluating a total of 21 277 Swedish men aged 27 to 52 years who provided blood samples at baseline and 4922 men invited to provide a second sample 6 years later revealed that the measurement of the PSA concentration in early midlife can identify a small group of men at an increased risk of prostate cancer metastasis several decades later. At a median 27 years of follow-up, 44% of the deaths were noted to occur in men with PSA concentrations in the highest 10th percentile (PSA≥1.6 ng/mL) at 45 to 49 years of age, with a similar proportion for 51 to 55 years of age. For patients with PSA less than the median (0.68 ng/mL for 45–49 years of age and 0.85 ng/mL for 51–55 years of age), the 15-year risk of metastatic disease was 0.09% at 45 to 49 years of age and 0.28% at 51 to 55 years of age. These results supported the use of only 3 lifetime PSA tests (mid to late 40s, early 50s, and 60 years of age) for at least of half of the men who are less than the medians.
Prediction tools
Several multivariate prediction tools for assessing the individualized risk of prostate cancer have been developed. These tools provide individualized, evidence-based information with the aim of decreasing overdiagnosis through decreasing the number of unnecessary biopsies. One of the most commonly used tools is the PCPT risk calculator ( http://deb.uthscsa.edu/URORiskCalc/Pages/uroriskcalc.jsp ). It is based on serum PSA, family history, DRE, and prior biopsy data. The study reported an area under the curve (AUC) of 0.70 for the calculator compared with 0.68 for PSA alone. A postulated reason for the relatively small benefit of the calculator over PSA alone was the impact on the predictive value of PSA level on systematically biopsied patients as opposed to the use of a cutoff level. The PCPT risk calculator has been externally validated with accuracies between 0.57 and 0.74. It has also been shown to underestimate the risk of high-grade disease. The ERSPC risk calculator ( www.prostatecancer-riskcalculator.com ) is another commonly used assessment tool. It comprises 6 steps based on 6 different logistic regression models and estimates the risk of positive biopsy according to serum PSA, prostate volume, DRE, outcome of transrectal ultrasound, and previous biopsy results. External validation studies demonstrated AUCs between 0.71 and 0.80. Trottier and colleagues compared the PCPT with the ERSPC risk calculators and demonstrated that the ERSPC calculator was superior with an AUC of 0.71 compared with 0.63 for the PCPT calculator and 0.55 for PSA alone.
Novel screening tests
The controversy around PSA screening for prostate cancer has demonstrated the need for a more reliable prostate cancer screening marker. Many novel markers are currently under investigation, with prostate cancer antigen 3 (PCA3), Prostate Health Index, and TMPRSS2:ERG gene fusion among the most studied.
PCA3
The PCA3 gene was identified in 1999. PCA3 is a noncoding RNA whose expression is restricted to the prostate and noted to be highly overexpressed in prostate cancer tissue as compared with normal or hyperplastic prostate tissues. PCA3 mRNA can be detected in first-catch urine samples following attentive DRE. PCA3 mRNA and PSA mRNA in these samples are quantified and the ratio of PCA3/PSA is reported. Deras and colleagues demonstrated that an increasing PCA3 score correlated with an increased risk of positive biopsy and was independent of prostrate volume, serum PSA, and number of prior biopsies. A logistic regression algorithm using PCA3, serum PSA, prostate volume, and DRE resulted in an increased AUC from 0.69 for PCA3 alone to 0.75 ( P = .0002). Both of these were superior to serum PSA alone, which had an AUC of 0.58. Aubin and colleagues investigated the performance of PCA3 in the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial cohort. The REDUCE trial was a prostate cancer risk reduction study in men taking dutasteride. The study enrolled men with an increased risk of prostate cancer (aged 50–75 years, serum PSA 2.5–10.0 ng/mL [defined as intermediate PSA], and negative biopsy at baseline). Men were randomized to daily dutasteride or placebo, and biopsies were performed at 2 and 4 years. PCA3 scores were measured before year 2 and year 4 biopsies from 1072 and 1140 subjects in the placebo arm of the trial, respectively. PCA3 was found to be predictive of the biopsy outcome in patients with a previously negative biopsy, whereas PSA and free PSA were not. A meta-analysis of the utility of the PCA3 score from 11 clinical trials in men with PSA between 2.5 and 10.0 ng/mL or negative prior biopsy reported a sensitivity of 53% to 84% and a specificity of 71% to 80% for the intermediate PSA group and a sensitivity of 47% to 58% and a specificity of 71% to 72% for the negative biopsy group. PCA3 performance was superior to both PSA and free PSA. Based on this data, PCA3 has been approved by the Food and Drug Administration (FDA) for screening in men with clinical suspicion of prostate cancer and a previously negative prostate biopsy. The PCA3 assay involves the collection of whole urine following aggressive DRE. Using PCA3 and PSA mRNA levels, a PCA3 score is generated using the following formula: (PCA3 mRNA)/(PSA mRNA) × 1000. Based on the aforementioned data, a PCA3 score greater than 35 is considered abnormal.
Prostate Health Index
The prostate health index (PHI) is a composite number using PSA, free PSA, and [-2]proPSA. The [-2]proPSA is a precursor to PSA and has been noted to have a higher sensitivity and specificity for the detection of prostate cancer than PSA or free PSA alone. A study of 892 men with no history of prostate cancer, normal DRE, and PSA between 2.0 and 10.0 ng/mL demonstrated that the PHI had a higher sensitivity and specificity than PSA or free PSA. An increasing PHI was associated with a 4.7-fold increased risk of prostate cancer and a 1.61-fold increased risk of Gleason score greater than or equal to 4 + 3 = 7 disease on biopsy. The study concluded that the use of the PHI may be a useful screening tool and decrease unnecessary biopsies in men older than 50 years with normal DRE and intermediate PSA. The PHI has been FDA approved for this indication.
TMPRSS2:ERG Gene Fusion
The gene fusion of the TMPRSS2 prostate-specific gene to the ERG transcription factor on chromosome 21q forms an oncogenic rearrangement that has been identified in half of prostate cancers and more than 40% of lymph node metastases indicating that the TMPRSS2:ERG fusion is associated with clinical features for prostate cancer progression compared with tumors that lack the TMPRSS2:ERG rearrangement. A urine assay similar to PCA3 was developed and evaluated in a multicenter trial of 1312 men with elevated PSA. Urine TMPRSS2:ERG was associated with indicators of clinically significant cancer at biopsy and prostatectomy. Importantly, because upwards of 50% of tumors do not express a fusion, the absence of a fusion by assay does not mean that cancer is not present. As a result, the investigators have used an assay that also incorporates PCA3. Men in the highest and lowest of 3 TMPRSS2:ERG+PCA3 score groups had markedly different rates of cancer, clinically significant cancer by Epstein criteria, and high-grade cancer. The study concluded that the TMPRSS2:ERG+PCA3 score enhances the utility of serum PSA for predicting the presence of clinically significant cancer on biopsy.
Current screening guidelines
Various national organizations have developed guidelines to aid clinicians in the diagnosis of prostate cancer, particularly with regard to screening and the use of PSA. These results are summarized in Table 1 . Questions raised by the aforementioned large randomized trials have led to a national debate on the benefits of PSA screening and recommendations have been modified. Guideline panels develop analysis criteria a priori. The result is that similar data can be used to draw different conclusions and can lead to different recommendations.
| Screening Modality | Age to Commence Screening | Age to Terminate Screening | Screening Frequency | Triggers for Biopsy | |
|---|---|---|---|---|---|
| ACS | PSA ± DRE | 50 y a | Life expectancy <10 y | Annually if PSA ≥2.5 ng/mL, every 2 y otherwise | PSA ≥4.0 ng/mL b |
| NCCN | PSA and DRE | 40 y c | 75 y or significant comorbidities | Annually after 50 y d |
|
| AUA | PSA and DRE | 55 y f | 70 y g or life expectancy <10–15 y | Every 2 y or more | PSA ≥4.0 ng/mL h |
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