Medical Policy: 02.04.25
Original Effective Date: October 2009
Reviewed: February 2015
Revised: February 2015
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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 non-skin cancer in men in the United States, with a lifetime risk for diagnosis currently estimated at 15.9%. Most cases of prostate cancer have a good prognosis even without treatment, but some cases are aggressive; the lifetime risk for dying of prostate cancer is 2.8%. Prostate cancer is rare before age 50 years, and very few men die of prostate cancer before age 60 years. Seventy percent of deaths due to prostate cancer occur after age 75 years.
The primary goal of prostate cancer screening is to reduce deaths due to prostate cancer, therefore, increasing length of life. An additional important outcome would be a reduction in the development of symptomatic metastatic disease. Screening asymptomatic men for prostate cancer has become a widespread practice in the United States. Test procedures used for prostate cancer screening include digital rectal examination (DRE) and prostate specific antigen (PSA).
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 levels may be elevated in 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 age, the presence of urinary tract infection or prostate disease, recent diagnostic procedures and prostate directed treatments.
Prostate cancer screening has been a controversial issue. There is evidence that PSA based screening leads to substantial overdiagnosis 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 men are being subjected to the harms of treatment of prostate cancer that will never become symptomatic. Even for 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.
Even though some guidelines (i.e. USPSTF) discourage the use of screening tests for 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.
Gene Based Biomarkers
There are a variety of gene based biomarkers that have been associated with prostate cancer. These tests have the potential to improve the accuracy of risk prediction, diagnosis, staging or prognosis of prostate cancer.
In response to the need for better biomarkers for risk assessment, diagnosis and prognosis, a variety of exploratory research is ongoing. Some products of this work have already been translated or are in the process of being translated into commercially available tests, including:
- Single nucleotide polymorphisms (SNPs) for risk assessment
- Prostate cancer antigen 3 (PCA3) for disease diagnosis and prognosis
- Transmembrane serine protease (TMPRSS) fusion genes for diagnosis and prognosis
- Multiple gene tests (gene panels) for prostate cancer diagnosis
- Gene hypermethylation for diagnosis and prognosis
While studies using these tests generate much information that may help understand the biologic mechanisms of prostate cancer and eventually help design treatments, the above mentioned tests are in the developmental phase.
Evidence on the clinical validity of genetic tests related to prostate cancer screening, detection, and management is variable and incomplete, leaving considerable uncertainty regarding clinical performance characteristics such as sensitivity, specificity and predictive value. Some tests show evidence for predictive ability in the diagnosis or prognosis of prostate cancer; however, incremental accuracy in comparison with currently available tests has not been consistently demonstrated. In addition, the data does not demonstrate clinical utility, i.e. that using a test will change treatment decisions and improve patient outcomes. Therefore, the use of gene based testing for risk assessment, diagnosis, prognosis and management of prostate cancer is considered investigational.
Practice Guidelines and Position Statements
American Urological Association (AUA)
The AUA updated its guidelines in 2013 regarding Early Detection of Prostate Cancer:
The Panel recommends against PSA screening men under age 40 years. (Recommendation; Evidence Strength Grade C). In this age group there is a low prevalence of clinically detectable prostate cancer, no evidence demonstrating benefit of screening and likely the same harms of screening as in other age groups.
The Panel does not recommend routine screening in me between ages 40 to 54 years at average risk. (Recommendation; Evidence Strength Grade C). For men younger than age 55 years at higher risk (e.g. positive family history or African American race), decisions regarding prostate cancer screening should be individualized.
For men ages 55 to 69 years the Panel recognizes that the decision to undergo PSA screening involves weighing the benefits of prostate cancer mortality in 1 man for every 1,000 men screened over a decade against the known potential harms associated with screening and treatment. For this reason, the Panel strongly recommends shared decision making for men age 55 to 69 years that are considering PSA screening, and proceeding based on a man’s values and preferences. (Standard; Evidence Strength Grade B). The greatest benefit of screening appears to be in men ages 55 to 69 years.
To reduce the harms of screening, a routine screening interval of two years or more may be preferred over annual screening in those men who have participated in shared decision making and decided on screening. As compared to annual screening, it is expected that screening intervals of two years preserve the majority of the benefits and reduce overdiagnosis and false positives. (Option; Evidence Strength Grade C). Additionally, intervals for rescreening can be individualized by a baseline PSA level.
The Panel does not recommend routine PSA screening in men age 70+ years or any man with less than a 10 to 15 year life expectancy. (Recommendation; Evidence Strength Grade C). Some men age 70+ years who are in excellent health may benefit from prostate cancer screening.
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).
Testing Frequency: There is evidence to suggest that annual screening is not likely to produce significant incremental benefits when compared with an inter-screening interval of two years. The PCLO trial compared annual screening with opportunistic screening in the US population, which corresponded to screening on average every two years. Prostate cancer mortality rates were similar in the two groups through 13 years of follow up.
Modeling studies have projected that screening intervals of two years will preserve most of the benefits of screening and reduce the harms (i.e. false positive tests and overdiagnosis) when compared with screening every year.
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.
Secondary Screening Tools
While the benefits of PSA-based prostate cancer screening have been evaluated in randomized controlled trials, the literature supporting the efficacy of DRE, PSA derivatives and isoforms (e.g. free PSA, 2proPSA, prostate health index, hK2, PSA velocity or PSA doubling time) and novel urinary markers and biomarkers (.e.g. PCA3) for screening with the goal of reducing prostate cancer mortality provide limited evidence to draw conclusions. While some data suggests use of these secondary screening tools may reduce unnecessary biopsies (i.e. reduce harms) while maintaining the ability to detect aggressive prostate cancer (i.e. maintain the benefits of PSA screening), more research is needed to confirm this.
National Comprehensive Cancer Network (NCCN), Prostate Cancer Early Detection 1.2014
The Panel recommends that baseline PSA testing should be offered to healthy, well-informed men aged 50 to 70 years based on the results of randomized clinical trials. The majority of panelists believed that baseline testing should be offered to men aged 45 to 49 years. Baseline testing may be complemented by DRE.
The Panel recommends that consideration may be given to biomarkers that improve specificity such as %fPSA, PHI and PCA3, although these biomarkers are indicated more strongly in the consideration of repeat biopsy after an initially benign result.
The American Cancer Society (ACS)
The American Cancer Society recommends that men have a chance to make an informed decision with their health care provider about whether to be screened for prostate cancer.
The discussion about screening should take place at age 50 for men who are at average risk of prostate cancer and are expected to live at least 10 more years.
The discussion should take place starting at 45 for men at high risk of developing prostate cancer. This includes African Americans and men who have first degree relative (father, brother or son) diagnosed with prostate cancer at an early age (younger than age 65).
This discussion should take place at age 40 for men at even high risk (those with more than one first degree relative who had prostate cancer at an early age).
After this discussion, those 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 patient’s general health preferences and values.
Assuming no prostate cancer is found as a result of screening, the time between future screenings depends on the results of the PSA blood test.
- Men who choose to be tested who have PSA of less than 2.5 ng/ml, may only need to be retested every 2 years.
- Screening should be done yearly for men who PSA level is 2.5 ng/ml or higher.
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.
U.S. Preventative Services Task Force (USPSTF)
The USPSTF recommends against prostate specific antigen (PSA) based screening for prostate cancer. The USPSTF assigned a Grade D recommendation to this statement since there is moderate or high certainty that the service has no net benefit or that harms outweigh the benefits.
Although the USPSTF discourages the use of screening tests for which the benefits do not outweigh the harms in the target population, it recognizes the common use of PSA screening in practice today and understands that some men will continue to request screening and some physicians will continue to offer it. The decision to initiate or continue PSA screening should reflect an explicit understanding of the possible benefits and harms and respect the patients’ 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 patients. 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 using prostate specific antigen (PSA) may be considered medically necessary for any of the following indications after informed decision with a health care provider:
- Asymptomatic men 40-49 years of age who are at high risk of prostate cancer due to any of the following factors:
- African-American race
- More than one first degree relative (father, brother, or son) diagnosed with prostate cancer at an early age (younger than age 65).
- Asymptomatic men age 50 and over with a life expectancy of at least 10 years.
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:
- < 2.5 ng/ml retesting may be performed every 2 years
- > 2.5 ng/ml retesting may be performed yearly
Prostate cancer risk using prostate specific antigen (PSA) in men > 40 years of age being considered for testosterone therapy may be considered medically necessary prior to initiation of therapy. If baseline PSA is greater than 0.6 ng/ml, additional PSA testing after 3 and 6 months of testosterone therapy may be considered medically necessary.
All other screening indications are considered not medically necessary.
The percent free PSA test (fPSA) when used in conjunction with the total PSA test to aid in distinguishing between malignant and benign prostate conditions, may be considered medically necessary if all of the following criteria are met:
- Have a total PSA level between 4 and 10 ng/mL
- Digital rectal exam is not suspicious for malignancy
Genetic tests for the screening, detection and management of prostate cancer are considered investigational. This includes, but not limited to the following:
- Single-nucleotide polymorphisms (SNPs) for risk assessment
- TMPRSS fusion genes for diagnosis and prognosis
- Multiple gene tests (gene panels) for prostate cancer diagnosis; or
- Gene hypermethylation for diagnosis and prognosis
The evidence on clinical utility of genetic tests related to prostate cancer screening, detection and management is variable and incomplete, leaving considerable uncertainty regarding the clinical performance characteristics such as sensitivity, specificity and predictive value. Some tests show evidence of predictive ability in the diagnosis or prognosis of prostate cancer; however, incremental accuracy in comparison to currently available tests has not been demonstrated. In addition, the data does not demonstrate clinical utility, i.e., that using a test will change treatment decisions and improve subsequent outcomes. Therefore, the use of gene based testing for risk assessment, diagnosis, prognosis and management of prostate cancer is considered investigational.
Procedure Codes and Billing Guidelines:
- To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
- 81313 PCA3/KLK3 (prostate cancer antigen 3 [non-protein coding]/kallikrein-related peptidase 3 [prostate specific antigen] ratio (eg, prostate cancer)
- 84152 Prostate-specific antigen (PSA); complexed (direct measurement)
- 84153 Prostate specific antigen (PSA); total
- 84154 Prostate-specific antigen (PSA); free
- G0103 Prostate cancer screening; prostate specific antigen test (PSA)
- S3721 Prostate cancer antigen 3 (PCA3) testing
- 81479 unlisted molecular pathology procedure
- Barry MJ. Clinical Practice. Prostate-specific-antigen testing for early diagnosis of prostate cancer. N Engl J Med. 2001 May 3; 344(18):1373-7.
- Wilson WG et al. Abelhoff’s Clinical Oncology, 4th ed. Churchill Livingstone Elsevier, Philadelphia, PA, 2008, Chap. 88, “Prostate Cancer”.
- Andriole GL, Crawford ED, Grubb 3rd RL et al. Mortality Results from a Randomized Prostate-Cancer Screening Trial. N Engl J Med 2009; 360(13): 1310-19.
- Brawley OW, Ankerst DP, Thompson IM. Screening for Prostate Cancer. CA Cancer J Clin 2009[Epub prior to print June 29, 2009].
- Schroder FH, Hugosson J, Roobol MJ et al. Screening and Prostate Cancer Mortality in a Randomized European Study. N Engl J Med 2009; 360(13): 1320-28.
- Miller MC, O’Dowd GJ, Partin AW et al. Contemporary use of complexed PSA and calculated percent free PSA for early detection of prostate cancer: Impact of changing disease demographics. Urology. 2001 Jun;57(6):1105-11.
- Catalona WJ, Partin AW, Slawin KM et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: A prospective multicenter clinical trial. JAMA. 1998 May 20; 279(19):1542-7.
- Lin K, Lipsitz R, Miller T et al. Benefits and Harms of Prostate-specific Antigen Screening for Prostate Cancer: An Evidence Update for the U.S. Preventive Services Task Force. Ann Intern Med. 2008;149(3):192-99.
- Lim LS, Sherin K, and the American College of Preventive Medicine (ACPM) Prevention Practice Committee. Screening for Prostate Cancer in U.S. Men: ACPM Position Statement on Preventive Practice. Am J Prev Med 2008;34(2):164-70.
- Wolf AM, Wender RC, Etzioni RB et al. American Cancer Society Prostate Cancer Advisory Committee. American Cancer Society guideline for the early detection of prostate cancer: update 2010. CA Cancer J Clin 2010 Mar-Apr;60(2):70-98
- Sandblom G, Varenhorst E, Rosell J et al. Randomised prostate cancer screening trial: 20 year follow up. BMJ 2011;342:d1539. doi:10.1136/bmj.d1539.
- Shao Y-H, Albertsen PC, Roberts CB et al. Risk profiles and treatment patterns among men diagnosed as having prostate cancer and a prostate-specific antigen level below 4.0 ng/mL. Arch Intern Med. 2010;170(14):1256-61.
- Screening for Prostate Cancer, Topic Page. August 2008. U.S. Preventive Services Task Force.
- Djulbegovic M, Beyth RJ, Neuberger MM et al. Screening for prostate cancer: systematic review and meta-analysis of randomised controlled trials. BMJ 2010;341:c4543. doi:10.1136/bmj.c4543.
- Crawford ED, Grubb III R, Black A et al. Comorbidity and mortality results from a randomized prostate cancer screening trial. J Clin Oncol Feb 1,2011;29(4):355-61.
- Loeb S, Vonesh EF, Metter J et al. What is the true number needed to screen and treat to save a life with prostate-specific antigen testing? J Clin Oncol Feb1, 2011;29(4):464-67.
- Hugosson J, Carlsson S, Aus G et al. Morality results from the Göteborg randomised population-based prostate-cancer screening trial. Lancet Oncol 11:725-32, 2010.
- Chou R, Croswell JM, Dana T et al. Screening for prostate cancer: a review of the evidence for the US Preventive Services Task Force. Ann Intern Med. 2011; 155(11):762-71.
- Cooperberg MR, Broering JM, Carroll PR. Time trends and local variations in primary treatment of localized prostate cancer. J Clin Oncol. 2010; 28(7):1117-1123.
- US Preventive Services Task Force Screening for Prostate Cancer; US Preventive Services Task Force recommendation statement: draft summary of recommendation and evidence. Accessed April 2012.
- American Cancer Society, Recommended Guidelines for Prostate Cancer Screening, Issued 2/27/12
- National Comprehensive Cancer Network (NCCN) Guidelines, Prostate Cancer Early Detection, Version 2.2012.
- American Urological Assocation (AUA) 2013 Guidelines, Early Detection of Prostate Cancer.
- American Society of Clinical Oncology. Screening for Prostate Cancer with Prostate Specific Antigen Testing: American Society of Clinical Oncology Provisional Clinical Opinion. Journal of Clinical Oncology. DOI:10.1200/JCO.2012.43.3441.
- UpToDate. Screening for Prostate Cancer. Richard M. Hoffman, M.D.,MPH. Topic Last Updated January 14, 2014.
- ECRI. Emerging Technology Evidence Report. PCA3 Assay (Progensa) for Aiding Repeat Biopsy Decision Making for Suspected Prostate Cancer. April 2013.
- Sam W. Chan, et al, Early Detection of Clinically Significant Prostate Cancer at Diagnosis: A Prospective Study using Novel Panel of TMPRSS2:ETS Fusion Gene Markers. Cancer Medicine. February 2013. doi: 10.1002/cam4.49
- Hui-Yi Lin, et al. SNP-SNP Interaction Network in Angiogenesis Genes Associated with Prostate Cancer Agressiveness. PLOS One April 2013, doi: 10.1371/journal.pone.0059688.
- PubMed. Phe V, et al, Methylated Genes a Potential Biomarkers in Prostate Cancer. BJU Int.2010 May; 105(10):1364-70, doi: 10.1111/j.1464-410X.2009.09167.x.Epub 2010 Jan 8
- PubMed. Chen Y, et al, APC Gene Hypermethylation and Prostate Cancer: A Systematic Review and Meta Analysis. Eur J Hum Genet. 2013 Sept 21 (9):929-35. Doi: 10.1038/ejhg.2012.281
- National Comprehensive Cancer Network (NCCN) Prostate Cancer Early Detection Version 1.2014. Also available at www.nccn.org
- ECRI. Product Brief. Progensa PCA3 Urine Test (Gen Probe, Inc) for Determining the Need for Repeat Biopsy of the Prostate. June 2014. Also available at www.ecri.org
- Agency for Healthcare Research and Quality (AHRQ), Comparative Effectiveness Review Number 98, PCA3 Testing for the Diagnosis and Management of Prostate Cancer, April 2013. Also available at www.ahrq.gov
- National Institute for Health and Clinical Excellence (NICE), NICE Issues Draft Diagnostics Guidance on Prostate Cancer Tests, Press Release, December 17, 2014. Also available at www.nice.org.uk
Date Reason Action
May 2011 Annual review Policy renewed
April 2012 Annual review Policy renewed
February 2013 Interim review Policy revised
April 2013 Annual review Policy revised
March 2014 Annual review Policy revised
February 2015 Annual review Policy revised
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*Current Procedural Terminology © 2012 American Medical Association. All Rights Reserved.