Prostate Cancer Screening


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. Data from the National Cancer Institute indicates that an average American male has an 11 percent 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, with 75% of prostate cancer-specific deaths occurring in those above 75 years. The lifetime risk of dying from prostate cancer also varies in different ethnic groups, with African American men having the highest risk of 4.2%. 

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

Issues of Concern

Prostate-Specific Antigen (PSA) 

Prostate-specific antigen 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 large proteins found in the semen into smaller molecules over time. The result of this function is to decrease seminal viscosity, which improves sperm motility and ultimately facilitates fertility.[4]

A small amount normally leaks into the blood. In case of any trauma, prostatic disease, or any condition which disrupts the microarchitecture of the gland, PSA diffuses into the extracellular space at an increased rate. Extracellular PSA is drained by the lymphatics and enters the bloodstream, raising its serum level. The actual amount of PSA produced on a per-cell basis by malignant cells is less than normal or benign hyperplastic prostatic cells. PSA level increases in malignant as well as benign conditions of the prostate, like benign prostatic hyperplasia, prostatic inflammation or infection (prostatitis), perineal trauma, and ejaculation or sexual activity.

A raised PSA level has long been associated with prostatic malignancy, although high titers are not specific to prostate cancer.[5] In fact, the majority of men with an elevated PSA level will not have prostate cancer as PSA elevation is a sensitive but not very specific marker for malignancy. Conversely, a normal PSA value does not rule out prostate cancer.

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. These age-specific ranges are as follows: [6]

  • 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 affect (lower) the value of PSA levels. A few of these are statins, thiazide diuretics, NSAIDs, and particularly 5-alpha-reductase inhibitors.[7] 5-alpha-reductase medications will typically lower PSA levels by 50% after six months of use.[8] 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 also be screened for prostate cancer before starting these medications. 

For most patients who are eligible for PSA testing, a yearly screening test is recommended. Patients who are not of African descent, who 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.[9][10][11]

In addition to PSA, a digital rectal exam (DRE) is also used to aid screening, but it has low sensitivity and specificity when used alone. A digital rectal exam checks for the prostate gland's consistency, size, and texture. An abnormal digital rectal exam would likely indicate a nodularity, induration, change in tissue consistency, or asymmetry of the prostate. Digital rectal examinations alone, especially when utilized in a primary care setting, have a sensitivity and specificity of less than 60%, most likely due to inexperience and insufficient training, which is why DRE is not recommended to screen for prostate cancer without PSA testing.[12] 

PSA Testing [13][14]

Disadvantages of PSA Screenings

  • Overall survival is not changed for at least the first ten years after initial diagnosis for the vast majority of patients.
  • Most patients with 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 tend to 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 substantial patient anxiety.
  • Those foreign countries that do not perform extensive PSA testing but generally have good healthcare systems have noted similar reductions in prostate cancer-specific death rates compared to the US, which conducts extensive PSA screenings. 
  • Large-scale studies have shown little or no survival benefit to screenings.
  • In one study, PSA testing prevented one prostate cancer-related mortality for every 1,000 men screened for over ten years.[15]
  • Another demonstrated that PSA screenings might help prevent three cases of metastatic for every 1,000 men tested.[1] 
  • Finally, most current screening trials show no significant change in overall mortality.[16]
  • 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.
  • It is undeniable that PSA screening finds more prostate cancer than doing nothing and waiting for incurable, metastatic disease complications.
  • Just because the PSA test is imperfect is no reason to abandon it.
  • PSA remains a very sensitive and inexpensive but non-specific test for prostate cancer.
  • Stopping PSA screenings will not reduce prostate cancer mortality or morbidity.
  • 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.
  • The 2012 USPSTF report recommended the elimination of routine PSA screenings. This caused a significant (30%) drop in prostate cancer diagnosis and an increase in 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.[17] 
  • 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.
  • 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 US (1992), prostate cancer-specific mortality has decreased by over 44%, according to the NIH. 
  • Other countries that don't do extensive PSA testing reported a significantly smaller decrease in prostate cancer-specific mortality over the same period. (Typically about half of the US rate.)
  • 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. (Higher even than lung cancer!)
  • 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, the NIH has estimated that after ten years, an additional 25,000 to 30,000 men would die annually in the US from prostate cancer that would otherwise have been cured.
  • Currently, only 9% of all new prostate cancer cases involve advanced disease compared to 32% prior to the introduction of PSA testing, a 72% reduction.
  • There has been an 80% reduction in the rate of initial detection of metastatic prostate cancer since the introduction of PSA testing. (4% now vs. 21% before PSA.) There is no other reasonable explanation for this benefit other than PSA screening. 
  • 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 be too far advanced. 

Expert Recommendations for Prostate Cancer Screening

There are different recommendations regarding when and whom to screen for prostate cancer—all of these measures 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 the patient's 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 who consider undergoing periodic PSA testing should indulge in collaborative decision-making regarding the risks and benefits of screening.
  • It recommends against screening for prostate cancer in men 70+ years.[18]

The American Cancer Society

  • 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 50 years. 
  • Men at high risk (e.g., those with a family history of prostate cancer, in particular, a first-degree relative diagnosed before 65 yrs of age or black men) should receive this information before 50 yrs.[19]

American Urological Association (AUA)

  • Recommends against PSA screening for men less than 40 years of age.
  • It does not recommend routine PSA screening for men 40 to 54 Yrs at average risk (for those under 55 Yrs of age having high risk, the decision regarding screening is on an individual basis).
  • For men aged 55 to 69 years, the decision to undergo screening must involve weighing the risk against the benefits. Hence, in this age group, there must be shared decision making taking into consideration the patient's values and preferences.
  • For men who have made a shared decision with the provider and have agreed to go ahead, the routine screening interval must be of 2 years or more to reduce the harms of screening.
  • It recommends against PSA screening in men +70 yrs or any men with a life expectancy of less than 10 to 15 years.[20]

The Canadian Task Force on Preventive Health Care

  • Recommends against PSA-based screening for Prostate cancer.[21]

The European Association of Urology (EAU)

  • Men considering PSA testing should have a life expectancy of at least 10 to 15 years and be counseled on the potential risks and benefits.
  • Men at low risk (negative family history, PSA <1 ng/mL at 40 years or <2 ng/mL at 60 years of age can be safely screened every two years.
  • Men at average risk should consider screening starting 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]
  • They recommend against routine PSA screening in men 70 years and above 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 single consensus guideline, each physician must decide which protocol to follow. Some facts to consider:[13]

  • 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 not reasonable to perform screenings in patients who are unlikely to accept any therapy even if a treatable cancer were found.
  • It is not reasonable to perform screenings in men over age 75 or who have a reasonable life expectancy of <10 years based on age or comorbidities.
  • If a patient requests 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.
  • 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 life expectancy is still about 11 years.
    • Prostate cancer is relatively rare in individuals younger than 50 years, as it only accounts for about 1% to 3% of all such malignancies, but it tends to be aggressive when it occurs.
  • Taken together, these facts suggest it is reasonable to recommend PSA screening for informed, selected individuals with general good health starting at age 45 up to age 75.
  • It is reasonable to encourage even earlier screenings (at ages 40 to 45) in high-risk individuals:
    • Men of African descent
    • Men with a family history of prostate cancer
    • Men with a family history of multiple cancers
    • Men with a known high-risk genomic mutation (BRCA1, BRCA2)

The Role of Other Adjunctive Screening Tests [13]

Free and Total PSA: If the total PSA is <10 ng/mL, a low free % PSA can suggest cancer. 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 about 50% if the free % PSA is <10%, while the risk of malignancy will be <10% if the free % PSA is >25%. 

PSA Density: This refers to the calculated value of the total PSA in ng/mL divided by the volume of the prostate in cc's. The volume of the prostate can be determined objectively by MRI or ultrasound. The formula for calculating this is: Prostatic Volume = Width x Length x Height x 0.52. A value >0.15 is considered suspicious for prostatic cancer.[22] 

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

When To Do a Biopsy

After shared decision-making, a biopsy is usually indicated/justified when the patient has a reasonable life expectancy (based on age and comorbidities) of at least ten years and two abnormal PSA values (more than the normal age-specific range plus any of the following: [13]

  • A PSA increase >0.75 ng/ml over one year
  • A PSA increase of >25% over one year
  • A palpable abnormality on DRE suggestive of cancer
  • A known high-risk germline mutation such as BRCA2
  • A family history of prostate cancer, especially starting at a younger age or resulting in a mortality
  • A family history of multiple cancers, especially starting at a younger age
  • African descent

For some older men or those with other co-morbidities with a raised PSA level, not pursuing a biopsy may be the appropriate decision when the patient's preference aligns 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, even if they meet the other criteria. 

MRI imaging of the prostate can reliably indicate high-risk or suspicious areas in the prostate for focused biopsies. However, an MRI is expensive, takes time, and is not considered a screening test. While useful, it is not definitive or absolute.[23]

Bioassay testing may also be performed. These blood and/or urine tests (like Prostate Health Index (PHI), 4K score, PCA3, SelectMDx, and EPI Exosome testing) are very useful in deciding on pursuing a biopsy.[24] They are primarily designed to identify patients with a low risk of significant cancer so they can safely avoid biopsies. The 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. (See our companion StatPearls reference article on Prostate Cancer.)[13]

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.[25] 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.[26][27][28] Many of the screening-detected PCa are likely to have early-stage, low-grade cancer, which probably wouldn't have caused any clinical problems in the patient's lifetime. But this initial screening can lead the patient to undergo further confirmatory testing and potentially unnecessary aggressive treatment. Just the diagnosis of 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 as long as precautions are taken to avoid treating patients who would not benefit. Some patients with an initial low-stage, low-grade prostatic malignancy will progress to a higher stage or grade cancer for which treatment is indicated. Such patients would not be identified without 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

The goal of screening is to reduce prostate cancer-specific morbidity and mortality by early detection of localized, high-risk cancers which 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 yrs, PSA-based screening can prevent one prostate cancer-related death when screened for over ten years per 1,000 men screened.[15] Screening programs may prevent 3 cases of metastatic PCa per 1,000 men screened.[1] Current results from some screening trials show no reduction in all-cause mortality.[16] 

Other studies have refuted these findings that show persistent reductions of 50% in prostate cancer-specific mortality from PSA-screened populations followed for ten years or more.[13][29]

Nursing, Allied Health, and Interprofessional Team Interventions

To enhance prostate cancer screening outcomes, an interprofessional team of specialty-trained nurses, general practitioners, physician assistants, 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 include:

  • Individualizing the evaluation of a single, elevated PSA level
  • Use of other tests to complement PSA in improving diagnostic and prognostic accuracy
  • Various uncertainties regarding when and how to use the newly available genomic and bioassay tests at each stage of evaluation
  • The current controversy regarding prostate cancer screening
  • Conflicting recommendation guidelines of different professional organizations for prostate cancer screening

This result 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 major concerns regarding prostate cancer screening is overdiagnosis, which can lead to overtreatment of low-grade prostate cancer, decreasing the patient's quality of life by adding treatment-associated side effects and psychological harm when in reality, the cancer would not have caused any clinical harm. 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 are under close monitoring and followed through their disease course with the expectation to intervene only if the cancer progresses or advances.[30] This approach leads to the avoidance of treatment-associated side effects in such patients. Only about 25% of patients on active surveillance progress and require further treatment meaning that 75% of patients can safely avoid definitive therapy and its complications. This monitoring is only achievable by cumulative efforts and care coordination amongst the interdisciplinary team members.[31]


Article Details

Article Author

Manisha A. Jain

Article Author

Stephen W. Leslie

Article Editor:

Amit Sapra

Updated:

11/7/2022 11:53:46 AM

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