Definition/Introduction

Globally, prostate cancer is the most frequently diagnosed cancer in 112 countries and the leading cause of cancer death in 48 countries.[1] It is the fifth leading cause of male cancer-related deaths worldwide, accounting for 1,414,000 newly diagnosed cases and 375,304 deaths annually.[2] 

According to the American Cancer Society, prostate cancer is the second leading cause of male cancer-related deaths in the United States, with about 268,490 new cases and 34,500 annual deaths estimated for 2022. In addition, data from the National Cancer Institute indicates that an average American male has an 11% risk of being diagnosed with prostate cancer over their lifetime (the incidence increasing with age) and a 2.5% overall risk (1 out of every 41) of dying from it.

The median age of death due to prostate cancer is 80 years, with 75% of prostate cancer-specific deaths occurring in those above 75 years. The lifetime risk of dying from prostate cancer varies in different ethnic groups, with Black men having the highest risk of 4.2%. 

Being the most commonly diagnosed cancer in men (other than skin cancer) does raise concerns for prostate cancer screening; however, most cases are slow-growing and may never become clinically evident. Data has suggested that many men die of other causes before prostate cancer becomes advanced. Definitive treatment is expensive and carries significant morbidity, thus making routine screening somewhat controversial.[3]

Issues of Concern

Prostate-specific Antigen (PSA) 

Prostate-specific antigen (PSA) is a glycoprotein enzyme secreted by prostatic secretory epithelium and seminal vesicles and is the most abundant protein in seminal plasma. The function of PSA is to chemically shorten over time large proteins found in the semen into smaller molecules. This results in decreased seminal viscosity, which improves sperm motility and ultimately facilitates fertility.[4]

A small amount of PSA normally leaks into the blood. In cases of trauma, prostatic disease, or any condition that disrupts prostatic microarchitecture, PSA diffuses into the extracellular space at an increased rate. Extracellular PSA is drained by the lymphatics and enters the bloodstream, raising the serum level. The amount of PSA produced per malignant prostatic cell is less than that of normal or benign hyperplastic prostatic cells. PSA levels increase in malignant and benign prostatic conditions, like benign prostatic hyperplasia, prostatic inflammation or infection (prostatitis), perineal trauma, and during or after ejaculation or sexual activity.

An elevated PSA level has long been associated with prostatic malignancy, although high titers are not specific to prostate cancer.[5] Most men with an elevated PSA level will not have prostate cancer, as PSA elevation is a sensitive but nonspecific marker for malignancy. Conversely, a normal PSA value does not rule out prostate cancer.

Diagnosing an elevated PSA requires two separate abnormal serum PSA levels, optimally done eight weeks apart. This is because 25% to 40% of men with an initial serum PSA elevation will demonstrate normal levels on a subsequent recheck and can be spared the expense, discomfort, and inconvenience of further investigations.[6] 

The Choosing Wisely American Urological Association (AUA) Initiative and current AUA Guidelines in the Early Detection of Prostate Cancer do not recommend empiric antibiotics as initial treatment for an elevated PSA.[7][8][9] However, several studies demonstrate the effectiveness of such empiric therapy in lowering PSA levels in patients with prostatitis but without cancer; many experts continue to utilize it selectively.[10][11][12][13][14] Given the controversy, it would seem reasonable to consider empiric antibiotic therapy, at least for patients with elevated PSA levels and signs or symptoms of prostatitis or a history of prostatitis, using a prostate-specific agent (sulfamethoxazole-trimethoprim, doxycycline, or a fluoroquinolone) for two to six weeks.  

Despite its significant lack of specificity, PSA remains the single most widely utilized screening test for the early detection of prostate cancer. The normal value of PSA is generally considered to be less than or equal to 4 ng/mL. However, serum PSA levels increase with age, and PSA levels rise faster in older men. Hence various age-specific ranges have been defined in an attempt to reduce the detection of less advanced tumors in the older age group and increase the detection of potentially curable tumors in the younger age group.[15] These age-specific ranges are as follows:

• 40 to 49 yrs: 0 to 2.5ng/mL
• 50 to 59 yrs: 0 to 3.5ng/mL
• 60 to 69 yrs: 0 to 4.5ng/mL 
• 70 to 79 yrs: 0 to 6.5ng/mL

Apart from age, studies have shown that certain medications also lower the value of PSA levels. A few of these are statins, thiazide diuretics, NSAIDs, and 5-alpha-reductase inhibitors; 5-alpha-reductase inhibitors will typically lower PSA levels by 50% after six months of use.[16][17] Hence any rise in PSA levels while a patient is on these medications should raise the suspicion of prostate cancer. For patients on 5-alpha-reductase inhibitors for six months or longer, the values should be doubled to compensate for the expected PSA-lowering effect of the medication. Patients should be screened for prostate cancer before starting these medications. 

A yearly screening test is recommended for most patients eligible for PSA testing. Patients who are not of African descent, who do not have a family history of prostate cancer, are 40 years of age with an initial PSA <1 ng/mL, and those with a PSA <2 ng/mL at 60 years of age are considered to be at low risk and a screening interval of every two years is suggested.[18][19][20]

In addition to PSA, a digital rectal exam (DRE) is also used to aid screening; the DRE has low sensitivity and specificity when used alone. A DRE evaluates the consistency, size, and texture of the prostate gland. An abnormal DRE would likely reveal nodularity, induration, tissue consistency change, or prostatic asymmetry. It may also detect unrelated pathologies, such as hemorrhoids and rectal cancer. DRE alone, particularly when utilized in a primary care setting, has a sensitivity and specificity for prostate cancer of less than 60%, most likely due to clinician inexperience and insufficient training. A DRE alone is not recommended to screen for prostate cancer without PSA testing.[21] 

Free and Total PSA

If the total PSA is <10 ng/mL, a low free % PSA can suggest a higher cancer risk. The higher the percentage of free PSA in the serum, the lower the estimated cancer risk. This varies by age, but in general, the cancer risk will be over 50% if the free % PSA is <10%, while the risk of malignancy will be <10% if the free % PSA is >25%.[22][23] 

Since a second confirmatory PSA level must be completed, it is suggested that this second laboratory study take advantage of the opportunity to perform a free and total PSA assay. 

Disadvantages of PSA Screenings

Overall survival is not changed for at least the first ten years after the initial diagnosis of prostate cancer for the vast majority of patients.[24][25] Most patients who undergo biopsies (about 70% to 75%) show no sign of cancer. As the vast majority of biopsies are negative, they can be considered "unnecessary" and only tend to cause increased patient anxiety, discomfort, higher medical costs, and possible complications (prostatitis, UTIs, and bleeding).

Patients who have low-risk disease may ultimately be overtreated. Screenings tend to find lower-risk, slower-growing cancers and miss the more aggressive, faster-growing malignancies that are the most dangerous. A finding of low-risk, low-grade prostate cancer, which ultimately will not affect survival, can cause considerable patient anxiety.

Those countries that do not perform extensive PSA testing but generally have sound healthcare systems have noted similar reductions in prostate cancer-specific death rates compared to the United States, which conducts extensive PSA screenings. However, several large-scale studies have shown little or no survival benefit to screenings.

Most patients with elevated PSA levels do not have cancer. Patients with prostatitis tend to have elevated PSA levels, and their prostate cancer evaluations will ultimately be unnecessary.

In one study, PSA testing prevented one prostate cancer-related mortality for every 1,000 men screened for over ten years.[26] Another demonstrated that PSA screenings might help prevent three cases of metastatic prostate cancer for every 1,000 men tested.[1] 

Finally, many current screening trials show no significant change in overall mortality.[27] The large-scale PIVOT trial (Prostate Cancer Intervention Versus Observation Trial), the European Randomized Study of Screening for Prostate Cancer (ERSPC) study and several others showed no benefit from early prostate cancer treatment, which would make screening unnecessary. 

Advantages of PSA Screenings

Prostate cancer remains the second leading cause of cancer death in men, and the worldwide incidence is increasing. Undeniably, PSA screening finds more prostate cancer than doing nothing and just waiting for incurable, metastatic disease to develop. Therefore, stopping PSA screenings will not reduce prostate cancer mortality or morbidity. However, PSA remains a very sensitive and inexpensive but nonspecific test for prostate cancer.

The 2012 USPSTF report recommended the elimination of routine PSA screenings. This caused a significant (30%) drop in overall prostate cancer diagnosis but increased the incidence of higher-stage disease. The Surveillance, Epidemiology, and End Results (SEER) program data showed a significant overall increase in metastatic prostate cancer detection starting after the USPSTF recommendations were released in 2012.[28] 

Most studies that suggested a lack of any survival benefit to PSA screenings have been shown to have significant statistical mistakes, used contaminated data, utilized poor methodology, or demonstrated a clear selection bias. However, properly done studies comparing PSA-screened with unscreened populations followed for at least ten years consistently demonstrate a clear 50% cancer-specific survival advantage in the screened groups.

Since PSA testing became widely available in the United States in 1992, prostate cancer-specific mortality has decreased by over 44%, according to the NIH. Other countries that do not extensively use PSA testing reported a significantly smaller decrease in prostate cancer-specific mortality over the same period, typically at half the rate in the United States. For example, PSA testing is minimal in Sweden, which has a modern health system but enjoys a prostate cancer-specific death rate more than double the rate in the US. Other long-term Scandinavian studies prove the value of definitive curative therapy for prostate cancer, although this may not be appreciated for ten years or more. If all PSA screenings were suspended in the United States, the NIH has estimated that after ten years, an additional 25,000 to 30,000 men would die annually from prostate cancer that would otherwise have been cured.

Currently, only 9% of all new prostate cancer cases involve advanced disease compared to 32% before the introduction of PSA testing, a 72% reduction. In addition, there has been an 80% reduction, from 21% to 4%, in the rate of initial detection of metastatic prostate cancer since the introduction of PSA testing. There is no other reasonable explanation for this benefit other than PSA screening. 

The optimal use of risk stratification bioassays in lower-risk patients and MRI scans in higher-risk individuals can eliminate many unnecessary biopsies while improving the retrieval rate of clinically significant disease. Overtreatment of prostate cancer has been significantly reduced due to the advent of active surveillance, MRI testing, MRI-TRUS fusion biopsies, and now genomic testing. Many new diagnostic aids and treatment options now have lower costs, minimal side effects, and improved outcomes. Without reasonable PSA screenings, these new minimally invasive therapies are useless as the disease presentation would otherwise be too far advanced. 

Expert Recommendations for Prostate Cancer Screening

There are different recommendations regarding when and whom to screen for prostate cancer; these measures all incorporate serum prostate-specific antigen (PSA) testing as the primary initial screening tool. Apart from subtle differences, the primary focus of all of these recommendations is to help the patient make an informed decision regarding whether or not to undergo screening after a careful review of the benefits and potential risks, as well as to take into consideration their values, age, general health, comorbidities, and preferences in this process. 

The American Academy of Family Physicians (AAFP)

• Recommends against routine PSA screening.
• Men aged 55 to 69 years considering periodic PSA testing should engage in collaborative decision-making regarding the risks and benefits of screening.
• Screening for prostate cancer in men aged greater than 70 years is not recommended.[29]

The American Cancer Society (ACS)

• Asymptomatic men with less than a 10-year life expectancy must receive information about risks, benefits, and uncertainties associated with prostate cancer screening before making an informed decision. 
• Average-risk men should receive this information beginning at the age of 50 years. 
• Men at high risk (e.g., Black men or those with a family history of prostate cancer, particularly a first-degree relative diagnosed before 65 years of age) should receive this information before the age of 50 years.[30]

American Urological Association (AUA)

• Recommends against PSA screening for men less than 40 years of age.
• Does not recommend routine PSA screening for men aged 40 to 54 years at average risk
• The decision regarding screening should be individualized for those under 55 years of age who are deemed at increased risk.
• For men aged 55 to 69 years, the decision to undergo screening must involve weighing the risks against the benefits; in this age group, shared decision-making must take into consideration the values and preferences of the patient.
• For men who have made a shared decision with the provider and agreed to proceed with screening, the routine screening interval may be two years or more to reduce the harm of screening.
• Recommends against PSA screening in men over 70 years of age and any men with a life expectancy of less than 10 to 15 years.[7]

The Canadian Task Force on Preventive Health Care

• Recommends against PSA-based screening for prostate cancer.[31]

The European Association of Urology (EAU)

• Patients considering PSA testing should have a life expectancy of at least 10 to 15 years and be counseled on the potential risks and benefits.
• Patients at low risk can be safely screened every two years. Low risk is defined as having a negative family history, a PSA <1 ng/mL at 40 years, or <2 ng/mL at 60 years of age.
• Patients at average risk should consider starting screening at 50 years of age.
• Men at higher risk (African descent, family history of prostate cancer) should start screening at age 45.
• Men with known BRCA2 mutations should start screening starting at the age of 40 years. 

The US Preventive Services Task Force (USPSTF)

• In men aged 55 to 69, the decision to undergo periodic PSA screening should be an individual one after a thorough upfront discussion between the physician and patient regarding the risks, benefits, and limitations of such screening incorporating the patient's values and values preferences.[1]
• Recommends against routine PSA screening in men age 70 years and older as treatment statistically offers minimal survival benefit, which does not outweigh the significant treatment side effects and morbidities for most men.[1] 

Which Guideline to Follow?

With no consensus guideline, each healthcare provider must decide which protocol to follow.[24] Topics of consideration include:

• It is recommended and good practice to have a meaningful, frank, and well-documented discussion of the pros and cons of PSA screenings with every male patient within the recommended age group of 45 to 75 years.
• It is unreasonable to perform screenings in patients who are unlikely to accept any therapy even if a treatable cancer were found.
• It is unreasonable to perform screenings in men over age 75 or with a reasonable life expectancy of <10 years based on age or comorbidities.
• For patients who request a PSA test after a comprehensive review of the risks and benefits, it is usually preferable to perform the examination even if the indications are questionable or outside of guidelines.
• It typically takes a small, localized, moderately aggressive (Gleason 4) untreated prostate cancer at least ten years to become symptomatic, possibly metastatic, and potentially harmful to the patient. This is why there is an age restriction on PSA screenings.
• According to the Social Security Administration, the typical 70-year-old American male with reasonable health enjoys an average life expectancy of 14 years and three months. 
• At age 75, the average male life expectancy is about 11 years. Life expectancy does not reach ten years until age 77.
• Prostate cancer is relatively rare in individuals younger than 50 years, as it only accounts for about 1% to 3% of all such malignancies; it tends to be aggressive when it occurs.

Considering these topics suggest that it may be reasonable to recommend PSA screening for informed, selected individuals with general good health starting at age 45 up to age 75. In addition, it is reasonable to encourage even earlier screenings (at ages 40 to 45) in high-risk individuals. High-risk individuals may include but not be limited to men of African descent or ethnicity, men with a family history of prostate cancer, men with a family history of multiple cancers or Lynch syndrome, and men with a known high-risk genomic mutation such as BRCA1 or BRCA2 mutations.

The Role of Other Adjunctive Screening Tests

PSA density refers to the calculated value of the total PSA in ng/mL divided by the volume of the prostate in milliliters. The volume of the prostate can be determined objectively by MRI or ultrasound. The formula for calculating prostatic volume is prostate width x length x height x 0.52. A value of greater than 0.15 is considered suspicious for prostatic cancer.[32][33][34][35] However, PSA velocity, a change in PSA values over time, is not considered a good or reliable indicator of possible malignancy.[36][37][38][39] 

Transrectal ultrasound can be used to measure the volume of the prostate and is helpful when performing prostatic biopsies. Unfortunately, it cannot reliably differentiate malignant prostatic tissue from benign and, therefore, cannot be used alone for diagnosis.[24]

Magnetic resonance imaging (MRI) of the prostate can reliably locate many high-risk or suspicious areas in the prostate for targeted (fusion) biopsies. Still, they may also miss 25% to 35% of the clinically significant malignancies.[40] An MRI is expensive, takes time, and is not considered a screening test. A positive MRI does not guarantee cancer, and a negative study cannot rule it out. While helpful, a prostatic MRI is not definitive or absolute and should not be used to indicate whether or not a biopsy should be done.[41] It is most useful once a decision has been made to perform a biopsy or if a repeat biopsy is needed and an MRI has not been recently done.

Prostate MRI scanning is best used in patients at increased risk for disease or if a repeat biopsy is indicated and a prostatic MRI was not previously or recently performed. In addition, prostatic MRI may be useful after the decision has been made to perform a biopsy by highlighting suspicious nodules inside the prostate for an MRI-guided fusion biopsy, examining the seminal vesicles and prostatic capsule for possible involvement or malignant extension, and visualizing surrounding structures for possible metastases or other abnormalities.

Bioassay risk stratification testing may also help determine the need for a prostatic biopsy in patients with moderately elevated PSA levels (<10 ng/mL). These blood or urine tests (My Prostate Score (MPS), the Prostate Health Index (PHI), 4K score, PCA3, SelectMDx, and EPI Exosome testing) are primarily designed to identify patients with a low risk of significant cancer, so they can safely avoid biopsies.[42][43][44][45][46][47][48] They are very useful in helping determine the need for performing a biopsy or even an MRI in low to medium-risk patients and in various borderline situations.[49] They are also useful in patients undergoing active surveillance, although their exact role remains unclear.

Bioassay risk stratification tests are designed to have a negative predictive value of 90% or more. If the test is negative, then a biopsy can be safely avoided. A risk stratification bioassay can also help make the final determination in selected cases of PIRADS 3 (borderline) findings on a prostatic MRI or a higher-risk patient with negative imaging who wishes to avoid a biopsy.[50] Shared decision-making discussions with the patient are critically important in such situations. 

Bioassay risk stratification testing should only be performed when the results will be used to help make clinical management decisions, generally to stop further investigations and return to routine surveillance if the test is negative. There is no point in doing the test if a biopsy is performed regardless of the outcome.[24]

In general, bioassay risk stratification testing should reasonably be performed first in evaluating elevated PSA levels in lower-risk patients. In contrast, MRI scans are typically preferred as the initial study in higher-risk individuals.[24][51] Overall, the optimal use of bioassay risk stratification testing could reduce the number of prostate biopsies performed by about 35% while delaying the detection of clinically significant cancers by only 5% to 10%.[42][24]

When To Perform a Biopsy

After shared decision-making, a biopsy is usually indicated or justified when the patient has a reasonable life expectancy of at least ten years and two abnormal PSA values. Any of the following, in addition to elevated PSA levels, would further increase the risk of cancer: [24]

• A PSA increase >0.75 ng/mL over one year.
• A PSA increase of >25% over one year.
• The PSA is >10 ng/mL on two separate laboratory evaluations.
• A palpable abnormality on DRE that is suggestive of cancer.
• A known high-risk germline mutation such as BRCA2.
• A family history of prostate cancer, especially at a younger age or resulting in mortality.
• A family history of multiple cancers, especially starting at a younger age.
• A family history of Lynch syndrome.
• Patients of African descent or ethnicity.

For some older men or those with other co-morbidities with a raised PSA level, not pursuing a biopsy may be appropriate when the patient preferences align with a less aggressive approach to further management. A patient who would not accept any treatment even if cancer were found is not a suitable candidate for PSA testing or prostate cancer screening, even if they meet the other criteria. 

Although the widespread availability of PSA screening in 1992 did lead to an increase in the number of prostate cancers detected and a 44% reduction in mortality as suggested by simulation models, calculations suggest that screening does not improve quality-adjusted life years (QALYs), even if there is an overall reduction in mortality.[52] For prostate cancer screening, there is a high potential for overdiagnosis. Overdiagnosis means screening for a condition that would not have been clinically evident in the patient's lifetime. The prevalence of prostate cancer detection at autopsies of men who died due to other causes is higher than the lifetime incidence of prostate cancer in the population.

It is estimated that 23% to 50% of prostate cancers are overdiagnosed.[53][54][55] Many screening-detected prostate cancers are likely to be early-stage, low-grade cancer. This initial screening can lead to further confirmatory testing and potentially unnecessary treatment. Just diagnosing cancer, no matter how harmless, can cause patients significant adverse effects from anxiety and cancer-related psychological effects.

It has been argued that overdiagnosis is not a real problem if patients are appropriately counseled, and precautions are taken to avoid treating patients who would not benefit. Approximately 25% of patients will initially have a low-stage, low-grade prostatic malignancy that will progress to a higher stage or grade for which treatment is indicated. Such patients would not have been identified without the initial screening and appropriate follow-up examinations.

The lack of a reasonable consensus guideline on prostate cancer screening has led to multiple recommendations from different sources and professional societies, leading to greater confusion on the issue.

Clinical Significance

Screening aims to reduce prostate cancer-specific morbidity and mortality by early detection of localized, high-risk cancers that can be successfully treated. Screening has been shown to potentially reduce the chance of dying from prostate cancer in some men.[1] 

Studies from randomized controlled trials have demonstrated that in men aged 55 to 69, PSA-based screening can prevent one prostate cancer-related death for over ten years per 1,000 men screened.[26] Screening programs may prevent three cases of metastatic prostate cancer per 1,000 men screened.[1] Current results from some screening trials show no reduction in all-cause mortality.[27] 

Other studies have refuted these findings. They show persistent reductions of about 50% in prostate cancer-specific mortality from PSA-screened groups followed for ten years or more compared to identical but unscreened populations.[24][56]

While the controversy continues, virtually all medical professional societies and organizations recommend prostate cancer screening or, at a minimum, discussing such screenings with men of suitable age and life expectancy. They also recommend shared decision-making with patients at each critical management point in the screening process.

Nursing, Allied Health, and Interprofessional Team Interventions

To enhance prostate cancer screening outcomes, an interprofessional team of specialty-trained nurses, general practitioners, advanced practice providers, urologists, and oncologists must coordinate to deal with various issues that continue to challenge them in dealing with uncertainties regarding prostate cancer screening outcomes. Some of these challenges include:

• Individualizing the evaluation of a single, elevated PSA level.
• Recognizing that a second, separate PSA test is required before confirming a diagnosis.
• Resolving the controversy regarding empiric antibiotic therapy.
• Using other tests to complement PSA in improving diagnostic and prognostic accuracy.
• Using prostatic MRIs and risk stratification bioassays.
• Implementing new prostate screening guidelines when available.
• Using the newly available genomic and bioassay tests at each stage of the evaluation.
• Negotiating conflicting recommendation guidelines.

Enhancing outcomes is achievable by being familiar with the new recommendations and information regarding screening for prostate cancer, as well as effective collaboration and communication amongst the interdisciplinary team members. The interprofessional team can individualize the appropriate evaluation of each patient through shared communication and care coordination. Specialty care nurses must work with the team to coordinate care and aid in educating patients. [Level 5]

Nursing, Allied Health, and Interprofessional Team Monitoring

One of the significant concerns regarding prostate cancer screening is overdiagnosis. Overtreatment of low-grade prostate cancer can decrease the quality of life by adding treatment-associated side effects and psychological harm. Such outcomes are particularly problematic when the malignancy would possibly not have caused clinical harm to the patient. This outcome can be overcome by greater utilization of active surveillance (monitoring) for low-grade prostate cancers.

Active surveillance is one of the management strategies in which a select group of low-grade cancer patients is under close observation and monitoring. They are followed throughout their disease course, expecting intervention only if their cancer progresses or advances.[57] This approach leads to avoiding treatment-associated side effects in most such patients. Only about 25% of patients on active surveillance experience disease progression and require further treatment; 75% can safely avoid definitive therapy and its associated complications. This monitoring is only achievable and successful by patient-centered care coordination amongst the interdisciplinary team members and their cumulative efforts.[58]