4Kscore Test Algorithm

This local coverage determination (LCD) supplements but does not replace, modify or supersede existing Medicare applicable National Coverage Determinations (NCDs) or payment policy rules and regulations for 4Kscore Test Algorithm. Federal statute and subsequent Medicare regulations regarding provision and payment for medical services are lengthy. They are not repeated in this LCD. Neither Medicare payment policy rules nor this LCD replace, modify or supersede applicable state statutes regarding medical practice or other health practice professions acts, definitions and/or scopes of practice. All providers who report services for Medicare payment must fully understand and follow all existing laws, regulations and rules for Medicare payment for 4Kscore Test Algorithm and must properly submit only valid claims for them. Please review and understand them and apply the medical necessity provisions in the policy within the context of the manual rules. Relevant Centers for Medicare & Medicaid Services (CMS) manual instructions and policies may be found in the following Internet-Only Manuals (IOMs) published on the CMS Web site.

Internet Only Manual (IOM) Citations

• CMS IOM Publication 100-02, Medicare Benefit Policy Manual,
  • Chapter 15, Section 80 Requirements for Diagnostic X-Ray, Diagnostic Laboratory, and Other Diagnostic Tests
• CMS IOM Publication 100-03, Medicare National Coverage Determinations (NCD) Manual,
  • Chapter 1, Part 3, Section 190.31 Prostate Specific Antigen
  • Chapter 1, Part 4, Section 210.1 Prostate Cancer Screening Tests
• CMS IOM Publication 100-04, Medicare Claims Processing Manual,
  • Chapter 16 Laboratory Services
• CMS IOM Publication 100-08, Medicare Program Integrity Manual,
  • Chapter 13, Section 13.5.4 Reasonable and necessary Provision in an LCD

Social Security Act (Title XVIII) Standard References:

• Title XVIII of the Social Security Act, Section 1862(a)(1)(A) states that no Medicare payment shall be made for items or services which are not reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member.
• Title XVIII of the Social Security Act, Section 1862(a)(7). This section excludes routine physical examinations.
• Title XVIII of the Social Security Act, Section 1833(e) states that no payment shall be made to any provider for any claim that lacks the necessary information to process the claim.

Federal Register References:

• Code of Federal Regulations (CFR), Title 42, Chapter IV, Subchapter B, Part 410, Subpart B, Section 410.32 Diagnostic x-ray tests, diagnostic laboratory tests, and other diagnostic tests: Conditions.

History/Background and/or General Information

The 4Kscore test measures blood levels of four Kallikreins protein biomarkers (total prostate-specific antigen [tPSA], free PSA [fPSA], intact PSA [iPSA], and human Kallikrein-related peptidase 2 [hK2]) in addition to other clinical information, including age, digital rectal examination (DRE) and prior biopsy history. All of these components are placed into a proprietary algorithm to provide a percent risk for a high-grade Gleason score greater than or equal to 7 cancer on biopsy.¹ The 4Kscore test algorithm's goal is to refine patient selection for biopsies to reduce unnecessary biopsies in men being considered for biopsy of the prostate for potential cancer. The clinical features of this group of men are poorly defined.

NOTE: If any of the above components and protein elements are not present in the test, the test is not a true 4Kscore test and will not be considered for payment.

Covered Indications

The 4Kscore test will be considered medically reasonable and necessary when all the following are met:

1. When all of the components of the algorithm are present.
2. Testing of men 45 years of age and older, prior to an initial biopsy or following a negative biopsy, who have a confirmed* moderately elevated PSA (greater than 3 and less than 10 ng/mL; greater than or equal to 4 and less than 10 ng/mL in men greater than 75 years of age) when BOTH of the following are present:
   • No other relative indication** for prostate biopsy including ANY of the following: (this may not be an all inclusive list)
     • DRE suspicious for cancer should be encouraged to undergo biopsy
     • Persistent and significant increase in PSA should be encouraged to undergo biopsy
     • Positive multiparametric magnetic resonance imaging (MRI) (if done)
     • Other major risk factor for prostate cancer including: (this may not be an all inclusive list)
       • Ethnicity at higher risk for prostate cancer
       • First-degree relative with prostate cancer
       • High-penetrance prostate cancer risk gene(s) per the National Comprehensive Cancer Network (NCCN) (if known)
   • No other relative contraindication** for prostate biopsy including ANY of the following:
     • Less than a 10 year life expectancy
     • Benign disease not ruled out.

*PSA elevation should be verified after a few weeks under standardized conditions (e.g. no ejaculation, manipulations, and urinary tract infections, no medications such as 5α-reductase) in the same laboratory or other CLIA approved laboratory before considering a biopsy.

**The relative indications and contraindications are not absolute. When it is determined that the 4Kscore test is medically reasonable and necessary in a beneficiary with one of the relative indications or contraindications for prostate biopsy the medical record must support the medical necessity for the test and there must be documented evidence of shared decision making between the patient and provider. This supporting documentation must be provided to the laboratory at the time of ordering the test.

3.  Presence of shared decision making between the ordering provider and the beneficiary concerning the 4Kscore testing.

Limitations 

The following are not considered reasonable and necessary:

1. Any test that does not contain all of the following components:
   • 4 Kallikreins proteins (Total PSA [tPSA], Free PSA [fPSA], Intact PSA [iPSA] and human Kallikrein-2 [hK2])
   • Clinical information including age
   • DRE
   • Prior biopsy history
2. Tests performed without evidence of shared decision making between the ordering provider and the beneficiary.

As published in the CMS IOM Publication 100-08, Medicare Program Integrity Manual, Chapter 13, Section 13.5.4, an item or service may be covered by a contractor LCD if it is reasonable and necessary under the Social Security Act Section 1862 (a)(1)(A). Contractors shall determine and describe the circumstances under which the item or service is considered reasonable and necessary.

In response to 4Kscore data being criticized suggesting that patients were not part of the intended population or that the results of a specific PSA range were not cited, Vickers et al² reanalyzed data from a recent meta-analysis using a Gleason grade group (GGG) of greater than or equal to 2. The base model that was used consisted of age, total PSA and DRE (if available). Initially, 1,792 different analyses reflecting the most common age, PSA and DRE were performed. The results of these analyses did not vary substantially. An analysis across all possible subgroups of age, PSA, DRE and cohorts was then performed. Out of 180,224 analyses 159,847 had meaningful data. Clinical validity was assessed by calculating the net benefit for the panel and base model at threshold probabilities of 6%, 9%, 12% and 15%. While sometimes at low threshold probabilities, if the PSA or age range was restricted or unusual, the authors were unable to find any reasonable combination of age or PSA in contemporary cohorts for which the decision curve did not support clinical utility of the panel.

Limitations of this analysis include no validation of this format being noted and no clinical outcomes noted. Several terms and definitions such as “results did not vary importantly” and “net benefit” were not defined.

In their guidelines, the American Urological Association (AUA)³ recognizes that the decision to undergo PSA screening in men ages 55 to 69 involves weighing the benefits of reducing the rate of metastatic prostate cancer and prevention of prostate cancer death against the known potential harms associated with screening and treatment. For this reason, the Panel strongly recommends shared decision-making for men 55 to 69 years of age that are considering PSA screening, and proceeding based on a man's values and preferences.

The Panel does not recommend routine PSA screening in men 70 years of age or older or for any man with less than a 10 to 15 year life expectancy.

It is important to note that the guideline statements listed in this document target men at average risk, defined as a man without risk factors, such as a family history of prostate cancer in multiple generations and/or family history of early onset below age 55, or African American race.

The greatest benefit of screening appears to be in men 55 to 69 years of age. Multiple approaches subsequent to a PSA test (e.g., urinary and serum biomarkers, imaging, risk calculators) are available for identifying men more likely to harbor a prostate cancer and/or one with an aggressive phenotype. The use of such tools can be considered in men with a suspicious PSA level to inform prostate biopsy decisions.³

The NCCN updated guidelines⁴ states that the 4Kscore test may be considered prior to biopsy for those with prior negative biopsy who are thought to be at risk for clinically significant prostate cancer. The NCCN notes that it is important for patients and their urologists to understand that no optimal cutoff threshold has been established for the 4Kscore test. The panel recommends that the 4Kscore test may be considered before biopsy in men with serum PSA levels greater than 3ng/ml who desires more specificity.

With a recommendation for specific clinical scenarios, coupled with documented shared decision making the AUA and NCCN organizations both state that biomarkers specifically 4Kscore “can be considered in men with a suspicious PSA level to inform prostate biopsy decisions.” ^3,4 Shared decision making is given evidence strength of Grade A for the use of this tool by AUA. The quality of evidence is graded a B by the same organization.³

NCCN grades this tool for testing to improve specificity a 2A recommendation.

Taking into consideration the AUA guidelines and the 2019 NCCN guidelines, limited coverage will be considered medically reasonable and necessary when performed within the covered indications and limitations of this LCD.

Documentation Requirements

Please refer to the Local Coverage Article: Billing and Coding: 4Kscore Test Algorithm (A56287) for documentation requirements that apply to the reasonable and necessary provisions outlined in this LCD.

Utilization Guidelines

Please refer to the Local Coverage Article: Billing and Coding: 4Kscore Test Algorithm (A56287) for utilization guidelines that apply to the reasonable and necessary provisions outlined in this LCD.

Other Contractors’ Policies

Novitas, L37792 4K Score Test Algorithm

1. Punnen S, Pavan N, Parekh DJ. Finding the Wolf in Sheep's Clothing: The 4Kscore Is a Novel Blood Test That Can Accurately Identify the Risk of Aggressive Prostate Cancer. Rev Urol. 2015;17(1):3-13.
2. Vickers AJ, Vertosick EA, Sjoberg DD. Value of a Statistical Model Based on Four Kallikrein Markers in Blood, commercially available as 4Kscore, in all reasonable prostate biopsy subgroups. Eur Urol. 2018 May 17; 74:535-536.
3. Carter HB, Albertsen PC, Barry MJ, et al. American Urological Association (AUA). Early Detection of Prostate Cancer. 2013. Accessed August 29, 2018.
4. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines) Prostate Cancer Early Detection. Version 1.2019. January 31, 2019.
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7. Bhindi B, Mamdani M, Kulkarni GS, et al. Impact of the U.S. Preventive Services Task Force recommendations against prostate specific antigen screening on prostate biopsy and cancer detection rates. J Urol. 2015 May;193(5):1519-24.
8. Bratt O, Lilja H. Serum markers in prostate cancer detection. Curr Opin Urol. 2015 Jan;25(1):59-64.
9. Braun K, Sjoberg DD, Vickers AJ, Lilja H, Bjartell AS. A Four-kallikrein Panel Predicts High-grade Cancer on Biopsy: Independent Validation in a Community Cohort. Eur Urol. 2016 Mar;69(3):505-11.
10. Bryant RJ, Sjoberg DD, Vickers AJ, et al. Predicting high-grade cancer at ten-core prostate biopsy using four kallikrein markers measured in blood in the ProtecT study. J Natl Cancer Inst. 2015 Apr 11;107(7).
11. Carroll PH, Mohler JL. NCCN Guidelines Updates: Prostate Cancer and Prostate Cancer Early Detection. J Natl Compr Canc Netw. 2018 May;16(5S):620-623.
12. Crawford ED, Moul JW, Rove KO, Pettaway CA, Lamerato LE, Hughes A. Prostate-specific antigen 1.5-4.0 ng/mL: a diagnostic challenge and danger zone. BJU Int. 2011 Dec;108(11):1743-9.
13. Crawford ED, Rosenberg MT, Partin AW, et al. An approach using PSA Levels of 1.5 ng/mL as the cutoff for prostate cancer screening in primary care. Urology. 2016 Oct;96:116-120.
14. Eggener SE, Badani K, Barocas DA, et al. Gleason 6 Prostate Cancer: Translating Biology into Population Health. J Urol. 2015 Sep;194(3):626-34.
15. Higgins CE, Neybold P, Holdridge MB, et al. Performance of the 4Kscore Test in Plasma and Serum and Stability of the Component Analytes in Clinical Samples. JALM. 2018:1-15.
16. Jalloh M, Myers F, Cowan JE, Carroll PR, Cooperberg MR. Racial variation in prostate cancer upgrading and upstaging among men with low-risk clinical characteristics. Eur Urol. 2015 Mar;67(3):451-7.
17. Konety B, Zappala SM, Parekh DJ, et al. The 4Kscore® Test Reduces Prostate Biopsy Rates in Community and Academic Urology Practices. Rev Urol. 2015;17(4):231-40.
18. Lin DW, Newcomb LF, Brown MD, et al. Evaluating the Four Kallikrein Panel of the 4Kscore for Prediction of High-grade Prostate Cancer in Men in the Canary Prostate Active Surveillance Study. Eur Urol. 2017 Sep;72(3):448-454.
19. Loeb S, Carter HB, Berndt SI, Ricker W, Schaeffer EM. Complications after prostate biopsy: data from SEER- Medicare. J Urol. 2011 Nov;186(5):1830-4.
20. Mottet N, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part 1: Screening, Diagnosis, and Local Treatment with Curative Intent. Eur Urol. 2017 Apr;71(4):618-629.
21. Mottet N, Bellmunt J, Briers E, et al. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. 2016.
22. Nam RK, Saskin R, Lee Y, et al. Increasing hospital admission rates for urological complications after transrectal ultrasound guided prostate biopsy. J Urol. 2013 Jan;189(1 Suppl):S12-18.
23. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines) Prostate Cancer Early Detection. Version 2.2018 – April 5, 2018.
24. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines) Prostate Cancer Early Detection. Version 1.2018 - March 12, 2018.
25. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines) Prostate Cancer Early Detection. Version 2.2017-September 15, 2017.
26. Nordström T, Vickers A, Assel M, Lilja H, Grönberg H, Eklund M. Comparison Between the Four-kallikrein Panel and Prostate Health Index for Predicting Prostate Cancer. Eur Urol. 2015 Jul;68(1):139-46.
27. Parekh DJ, Punnen S, Sjoberg DD, et al. A multi-institutional prospective trial in the USA confirms that the 4Kscore accurately identifies men with high-grade prostate cancer. Eur Urol. 2015 Sep;68(3):464-70
28. Punnen S, Freedland SJ, Polascik TJ, et al. A Multi-Institutional Prospective Trial Confirms Noninvasive Blood Test Maintains Predictive Value in African American Men. J Urol. 2018 Jun;199(6):1459-1463.
29. Punnen S, Nahar B, Prakash NS, Sjoberg DD, Zappala SM, Parekh DJ. The 4Kscore Predicts the Grade and Stage of Prostate Cancer in the Radical Prostatectomy Specimen: Results from a Multi-institutional Prospective Trial. Eur Urol Focus. 2017 Feb;3(1):94-99.
30. Sanda MG, Chen RC, Crispino T, et al. Clinically Localized Prostate Cancer: AUA/ASTRO/SUO Guideline. 2017.
31. Sjoberg DD, Vickers AJ, Assel M, et al. Twenty-year Risk of Prostate Cancer Death by Midlife Prostate-specific Antigen and a Panel of Four Kallikrein Markers in a Large Population-based Cohort of Healthy Men. Eur Urol. 2018 Jun;73(6):941-948.
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34. U.S. Preventative Services Task Force (USPSTF) Prostate Cancer Screening Final Recommendation (2018). Accessed August 21, 2018.
35. Vickers A, Vertosick EA, Sjoberg DD, et al. Value of Intact Prostate Specific Antigen and Human Kallikrein 2 in the 4 Kallikrein Predictive Model: An Individual Patient Data Meta-Analysis. J Urol. 2018 Jun;199(6):1470- 1474.
36. Vickers AJ, Cronin AM, Aus G, et al. A panel of kallikrein markers can reduce unnecessary biopsy for prostate cancer: data from the European Randomized Study of Prostate Cancer Screening in Göteborg, Sweden. BMC Med. 2008 Jul 8;6:19.
37. Vickers AJ, Cronin AM, Björk T, et al. Prostate specific antigen concentration at age 60 and death or metastasis from prostate cancer: case-control study. BMJ. 2010 Sep 14;341:c4521.
38. Vickers AJ, Cronin AM, Roobol M, et al. Reducing unnecessary biopsy during prostate cancer screening using a four-kallikrein panel: an independent replication. J Clin Oncol. 2010 May 20;28(15):2493-8.
39. Vickers AJ, Gupta A, Savage CJ, et al. A panel of kallikrein marker predicts prostate cancer in a large, population-based cohort followed for 15 years without screening. Cancer Epidemiol Biomarkers Prev. 2011 Feb;20(2):255-61.
40. Zappala SM, Dong Y, Linder V, et al. The 4Kscore blood test accurately identifies men with aggressive prostate cancer prior to prostate biopsy with or without DRE information. Int J Clin Pract. 2017 Jun;71(6).
41. Zappala SM, Scardino PT, Okrongly D, Linder V, Dong Y. Clinical Performance of the 4Kscore Test to Predict High-Grade Prostate Cancer at Biopsy: A Meta-Analysis of US and European Clinical Validation Study Results. Rev Urol. 2017;19(3):149-155.
42. Zhu X, Albertsen PC, Andriole GL, Roobol MJ, Schröder FH, Vickers AJ. Risk-based prostate cancer screening. Eur Urol. 2012 Apr;61(4):652-61.