Medical Policy: 02.04.25
Original Effective Date: October 2009
Reviewed: June 2021
Revised: June 2021
This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Prostate cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths in American men. In 2021, it is estimated that 248,530 men will be diagnosed with prostate cancer and 34,130 will die of this disease. During the same period, geno-typical men in the United States will be confronted with important decisions regarding early detection for prostate cancer. Geno-typical men born in the United States have about 1 chance in 9 of eventually being diagnosed with this malignancy and about 1 chance in 41 of eventually dying of it.
Prostate cancer represents a spectrum of disease that ranges from non-aggressive, slow growing disease that may not require treatment to aggressive, fast growing disease that does. The goal of screening for prostate cancer is to identify high-risk, localized prostate cancer that can be successfully treated, thereby preventing the morbidity associated with advanced or metastatic prostate cancer. Screening asymptomatic geno-typical men for prostate cancer has become a widespread practice in the United States. Tests used for prostate cancer screening include digital rectal examination (DRE) and serum prostate specific antigen (PSA).
Prostate cancer risk calculators have been developed to estimate an individual’s risk for prostate cancer from multiple factors. Common calculators are the Sunnybrook, ERSPC and PCPT based risk calculators. These online tools combine clinical variables including but not limited to age, family history, race, DRE and PSA, to estimate both the risk for biopsy detectable prostate cancer and the risk for biopsy detectable high grade prostate cancer. Such information potentially allows for more informed decision-making. However, such calculators have not been assessed in randomized controlled trials (RCTs) and cut-points of risk associated with reductions in prostate cancer mortality remain unknown. Such calculators have as much value in determining who might not need biopsy as in identifying those at higher risk. The use of risk calculators alone to determine whether a biopsy is indicated is not recommended.
Best evidence supports the use of serum PSA for the early detection of prostate cancer. Still, many experts continue to recommend DRE for screening, as some clinically significant prostate cancer may potentially be missed using serum PSA cutpoint alone. Studies have consistently shown that prostate cancer cases detected through PSA testing are more often confined to the prostate than those detected solely by DRE. Currently, 81% of prostate cancers are pathologically organ-confined at time of diagnosis.
The value of DRE as a stand-alone test for prostate detection is limited, even though DRE picks up some cases of advanced cancer that would otherwise be missed. DRE is recommended to be used as a complementary test with serum PSA in asymptomatic geno-typical men who had a risk/benefit discussion and decided to pursue screening for prostate cancer. Those individuals with a very suspicious DRE should be considered for biopsy referral regardless of PSA results, because it may identify high-grade cancers in such situations. DRE should be considered in all geno-typical men with an abnormal serum PSA to aid in decisions regarding biopsy.
Although PSA was originally introduced as a tumor marker to detect cancer recurrence or disease progression following treatment, it became widely adopted for cancer screening. PSA is a glycoprotein produced by the prostate epithelial cells. PSA enters the circulation through unknown mechanisms. PSA levels may be elevated in geno typical men with prostate cancer because PSA production is increased and because tissue barriers between the prostate gland lumen and the capillary are disrupted, releasing more PSA into the serum. Elevations of serum PSA may also be associated with other prostatic diseases including benign prostatic hypertrophy (BPH) which is a major clinical problem with PSA screening. It is recommended that the interpretation of PSA values should always take into account the following: age, the presence of urinary tract infection or prostate disease, recent diagnostic prostate procedures and prostate directed treatments.
Serum total PSA was the only PSA based test available in early detection programs for prostate cancer. Since then, several PSA derivatives have been developed and proposed to improve the performance of the PSA measurement, thus possibly increasing specificity and decreasing unnecessary biopsies. These PSA derivatives include:
Even though some guidelines (i.e., USPSTF) may not recommend the routine use of screening tests for prostate cancer which the benefits do not outweigh the harms in the target population, they do recognize the common use of PSA screening in practice today and that some physicians will continue to offer it. The decision to initiate or continue PSA screening should reflect an understanding of the possible benefits and harms and respect the patient’s preferences. Physicians should not offer or order PSA screening unless they are prepared to engage in shared decision making that enables an informed choice by the patient. Similarly, patients requesting PSA screening should be provided with the opportunity to make informed choices to be screened that reflect their values about specific benefits and harms.
Prostate cancer screening has been a controversial issue. There is evidence that PSA based screening leads to substantial over-diagnosis of prostate tumors and there is a high incidence for physicians and patients to elect to treat most cases of screen detected cancer, given the current inability to distinguish tumors that will remain indolent from those destined to be lethal. Thus, many geno-typical men are being subjected to the harms of treatment of prostate cancer that will never become symptomatic. Even for geno-typical men whose screen-detected cancer would otherwise have been later identified without screening, most experience the same outcome and are, therefore, subjected to the harms of treatment for much longer period. There is convincing evidence that PSA based screening for prostate cancer results in considerable overtreatment and its associated harms.
Despite its limitations, recent population-based prostate cancer screening studies have demonstrated survival benefits using PSA, sometimes in combination with digital rectal examination (DRE).
PSA-based screening for prostate cancer has been studied in 3 very large RCTs, each with at least a decade of median follow-up: the US-based Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, the European Randomized Study of Screening for Prostate Cancer (ERSPC), and the Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP). These trials used varying screening intervals (from 1-time screening to every 1 to 4 years) and PSA thresholds (2.5 to 10.0 ng/mL) for diagnostic biopsy.
In 2018, de Koning et. al. reported on the efficacy of prostate-specific antigen screening and the impact of the key components in the European Randomized Study for Prostate Cancer (ERSPC) and the U.S. Prostate, Lung, Colorectal and Ovarian (PLCO) trials. The European Randomized Study of Screening for Prostate Cancer (ERSPC) demonstrated that prostate-specific antigen (PSA) screening significantly reduced prostate cancer mortality (rate ratio, 0.79; 95% confidence interval, 0.69-0.91). The U.S. Prostate, Lung, Colorectal, and Ovarian (PLCO) trial indicated no such reduction but had a wide 95% CI (rate ratio for prostate cancer mortality, 1.09; 95% CI, 0.87-1.36). Standard meta-analyses are unable to account for key differences between the trials that can impact the estimated effects of screening and the trials' point estimates. The authors calibrated 2 microsimulation models to individual-level incidence and mortality data from 238,936 men participating in the ERSPC and PLCO trials. A cure parameter for the underlying efficacy of screening was estimated by the models separately for each trial. The authors changed step-by-step major known differences in trial settings, including enrollment and attendance patterns, screening intervals, PSA thresholds, biopsy receipt, control arm contamination, and primary treatment, to reflect a more ideal protocol situation and differences between the trials. Using the cure parameter estimated for the ERSPC, the models projected 19% to 21% and 6% to 8%, respectively, prostate cancer mortality reductions in the ERSPC and PLCO settings. Using this cure parameter, the models projected a reduction of 37% to 43% under annual screening with 100% attendance and biopsy compliance and no contamination. The cure parameter estimated for the PLCO trial was 0. The authors concluded, the observed cancer mortality reduction in screening trials appears to be highly sensitive to trial protocol and practice settings. Accounting for these differences, the efficacy of PSA screening in the PLCO setting is not necessarily inconsistent with ERSPC results.
The potential benefit of screening for prostate cancer is because of treatment. It is important for geno-typical men to consider both the potential benefits and harms of treatment (including surveillance) as they consider whether to be screened. Geno typical men not able or willing to tolerate treatment should not be screened for prostate cancer. Most cases of prostate cancer advance very slowly, if at all, the 10- year survival rate for screen-detected, localized prostate cancer is very high. In recent major trial that enrolled more than 1500 men randomized to receive either active treatment or active surveillance, the 10-year survival rate in all groups was 99%. The good prognosis for early-stage prostate cancer makes it difficult to study the effectiveness of treatment.
Multiple treatment options exist for prostate cancer, the three most common treatment options for men with screen-detected localized prostate cancer are surgical removal of prostate gland (radical prostatectomy), radiation therapy, and active surveillance. Available evidence on treatment evaluating the effectiveness of screening found that current evidence suggests that treatment of early-stage, screen-detected prostate cancer with radical prostatectomy or radiation therapy likely reduces the risk of clinical progression and metastatic disease and may reduce prostate cancer mortality.
Active surveillance is a treatment approach that seeks to limit the harms of treatment by allowing men with apparent low-risk prostate cancer to forego surgery or radiation in favor of ongoing monitoring of their cancer. Although protocols vary, active surveillance usually includes regular, repeated PSA testing and often repeated digital rectal examination (DRE) and prostate biopsy, with the potential for exposure to repeated harms from biopsies. Geno typical men whose cancer is found to be changing are offered definitive treatment with surgery or radiation therapy. Active surveillance has become a more common treatment choice in the United States over the past several years. Active treatment of prostate cancer can result in major adverse effects.
There are a number of clinical studies identified in the peer-reviewed medical literature that address the impact of PSA screening on the stage of cancer detection and on disease-specific survival rates, as well as studies that evaluate the relative sensitivities and specificities of derivative types of PSA testing. Although PSA testing is widely used there is controversy regarding the question of whether PSA-based screening reduces prostate cancer mortality. In addition, PSA-based screening is associated with risks of overdiagnosis and overtreatment. The 2019 National Comprehensive Cancer Network Guideline (NCCN) on Prostate Cancer Early Detection states in the NCCN recommendations that factors to consider in the early detection of prostate cancer include the patient’s age, life expectancy, race, presence of inherited mutations, family history, and previous results from early detection tests. The NCCN Panel recommends that baseline testing should be offered to healthy, well-informed men aged 45 to 75 years based on the results of randomized controlled trials (RCTs). Baseline testing may be complemented by DRE. The panel recommends frequency of repeat testing be 2 to 4 years for men aged 45 to 75 years with serum PSA values below 1 ng/mL. For men with PSA of 1 to 3 ng/mL, repeat testing should occur at 1- to 2- year intervals. The panel recommends that PSA testing be considered only in very select patients after the age of 75 years (category 2B [Based on lower-level evidence, there is NCCN consensus that the intervention is appropriate]) and that indication for biopsy be carefully evaluated. The NCCN recommendation also states African ancestry men have a higher incidence of prostate cancer, increased prostate cancer mortality, and earlier age of diagnosis compared to Caucasian-American men. This is attributable to a greater risk of developing preclinical prostate cancer and a higher likelihood that a preclinical tumor will spread. Consequently, it is reasonable for African ancestry men to consider shared decision making about PSA screening at age 40 and to consider screening at annual intervals rather than every other year. Panel members uniformly discourage PSA testing in men unlikely to benefit from prostate cancer diagnosis based on age and/or comorbidity. The primary goal of PSA based screening is to find men from whom treatment would reduce morbidity and mortality.
In 2013, the American Urological Association (AUA) published guidelines for the early detection of prostate cancer, this guideline was reviewed and validated 2018:
The panel concluded that PSA based screening should not be performed in the absence of shared decision making. Thus, they recommend against organized screening in settings where shared decision making is not part of routine practice (e.g., including but not limited to health fairs, health system promotions, community organizations).
The Panel believes that annual PSA screening as a routine should be discouraged for those who choose to be screened, that two year PSA intervals are reasonable approach and will be unlikely to miss a curable prostate cancer in most men, and that for men over 60 with PSA levels below 1.0ng/ml, longer PSA screening intervals (e.g. of four years) could be considered. Men with PSA below 3 ng/mL at age 70 to 75 years, PSA screening could be safely discontinued if a man at this age is still being screened.
In 2019, the American Cancer Society reaffirmed their recommendations that men make an informed decision with their health care provider about whether to be screened for prostate cancer. The decision should be made after getting information about the uncertainties, risk, and potential benefits of prostate cancer screening. Men should not be screened unless they have received this information. The discussion about screening should take place at:
After this discussion men who want to be screened should be tested with the prostate specific antigen (PSA) blood test. The digital rectal exam (DRE) may also be done as part of screening.
If, after this discussion, a man is unable to decide if testing is right for him, the screening decision can be made by the health care provider, who should take into account the man’s general health preferences and values.
If no prostate cancer is found as a result of screening, the time between future screenings depends on the results of the PSA blood test:
Because prostate cancer often grows slowly, men without symptoms of prostate cancer who do not have a 10-year life expectancy should not be offered testing since they are not likely to benefit. Overall health status, and not age alone, is important when making decisions about screening.
Even after a decision about testing has been made, the discussion about the pros and cons of testing should be repeated as new information about the benefits and risks of testing becomes available. Further discussions are also needed to take into account changes in a man’s health, values, and preferences.
The guidelines for when to start and stop screening, at what intervals to conduct a screening, and when to biopsy were recommended by most panel members, but a consensus was not reached. The guidelines are continuously in a state of evolution, and the panel will incorporate changes based on new evidence and expert opinion and provide a rating of consensus for each recommendation.
History and physical including:
PSA < 1 ng/mL, DRE normal if done: repeat testing at 2-4 year intervals
PSA1-3 ng/mL, DRE normal if done: repeat testing at 1-2 year intervals
PSA > 3 ng/mL and/or very suspicious DRE: see indications for biopsy
Men of African ancestry have a higher incidence of prostate cancer, increased prostate cancer mortality, and earlier age of diagnoses compared to Caucasian-American men. This is attributable to a greater risk of developing preclinical prostate cancer and a higher likelihood that a preclinical tumor will spread. Although there are data suggesting a role for heritable genes linked to African ancestry, it is not known with certainty whether genetics rather than access to health care and other social determinants of health care the main drivers of increased risk in this patient population. Many support the recommendation for men of African ancestry to consider beginning shared decision making about PSA screening at age 40 and to consider screening at annual intervals rather than every other year. There is no current evidence to support that screening at an earlier age will result in decrease morbidity and mortality compared to testing at age 45.
In 2018, The USPSTF published updated recommendations regarding prostate cancer screening that states the following:
For men aged 55 to 69 years, the decision to undergo periodic prostate-specific antigen (PSA)–based screening for prostate cancer should be an individual one. Before deciding whether to be screened, men should have an opportunity to discuss the potential benefits and harms of screening with their clinician and to incorporate their values and preferences in the decision. Screening offers a small potential benefit of reducing the chance of death from prostate cancer in some men. However, many men will experience potential harms of screening, including false-positive results that require additional testing and possible prostate biopsy; overdiagnosis and overtreatment; and treatment complications, such as incontinence and erectile dysfunction. In determining whether this service is appropriate in individual cases, patients and clinicians should consider the balance of benefits and harms on the basis of family history, race/ethnicity, comorbid medical conditions, patient values about the benefits and harms of screening and treatment-specific outcomes, and other health needs. Clinicians should not screen men who do not express a preference for screening.
Grade C Recommendation
The USPSTF recommends against PSA-based screening for prostate cancer in men age 70 years and older.
Grade D Recommendation
This recommendation applies to adult men in the general U.S. population without symptoms or a previous diagnosis of prostate cancer. It also applies to men at increased risk of death from prostate cancer because of race/ethnicity or family history of prostate cancer.
See Related Medical Policies
Prostate cancer screening using prostate specific antigen (PSA) may be considered medically necessary for any of the following indications after informed decision with a health care provider:
After the initial PSA is determined, the time interval for repeat testing is dependent upon the PSA value. For those men with a PSA of:
All other screening indications in asymptomatic men are considered not medically necessary.
To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
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