Subject:
Tumor Markers Other Than Prostate Specific Antigen (PSA)
Description:
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IMPORTANT NOTE:
The purpose of this policy is to provide general information applicable to the administration of health benefits that Horizon Blue Cross Blue Shield of New Jersey and Horizon Healthcare of New Jersey, Inc. (collectively “Horizon BCBSNJ”) insures or administers. If the member’s contract benefits differ from the medical policy, the contract prevails. Although a service, supply or procedure may be medically necessary, it may be subject to limitations and/or exclusions under a member’s benefit plan. If a service, supply or procedure is not covered and the member proceeds to obtain the service, supply or procedure, the member may be responsible for the cost. Decisions regarding treatment and treatment plans are the responsibility of the physician. This policy is not intended to direct the course of clinical care a physician provides to a member, and it does not replace a physician’s independent professional clinical judgment or duty to exercise special knowledge and skill in the treatment of Horizon BCBSNJ members. Horizon BCBSNJ is not responsible for, does not provide, and does not hold itself out as a provider of medical care. The physician remains responsible for the quality and type of health care services provided to a Horizon BCBSNJ member.
Horizon BCBSNJ medical policies do not constitute medical advice, authorization, certification, approval, explanation of benefits, offer of coverage, contract or guarantee of payment.
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Tumor markers are glycoprotein/carbohydrate antigens circulated in serum or expressed on cell surfaces. Tumor markers are products of normal cells that are expressed in greater concentrations by malignant progeny of the root cell line or by cells involved in benign disease states. Marker concentrations are measured using monoclonal antibodies raised against individual antigens or by immunohistochemical analysis. Tumor markers may be specific to one tissue type and its diseases, or may be expressed by a group of organs made up of related tissue types.
Policy:
(NOTE: Alpha-fetoprotein (AFP) and carcinoembryonic antigen (CEA) are commonly used markers which have been developed and put into practice prior to the enactment of the 1976 Food, Drug and Cosmetic Act. Both CEA and AFP are purposely excluded from this policy.
For Medicare Advantage, Medicaid and FIDE-SNP, please refer to the Coverage Sections below for coverage guidance.)
1. Measurement of serum tumor markers or tumor antigens including, but not limited to, CA-125, CA 15-3 or CA27.29, CA19-9, Bladder Tumor Antigen (BTA), Nuclear Matrix Protein 22 (NMP22), Fibrinogen Degradation Products, ImmunoCyt, or detection of aneuploidy for chromosomes 3, 7, 17, and loss of the 9p21 locus (by UroVysion fluorescent in situ hybridization test) is considered medically necessary as a technique for:
- assessment or monitoring of response to cancer therapy;
- detection of cancer recurrence; or
- surveillance of members with an established diagnosis of cancer.
2. Measurements of the following specific serum tumor markers or tumor antigens are also considered medically necessary for the corresponding indications:
A. CA-125:
- for screening asymptomatic high-risk women with family history of ovarian cancer, or women with known BRCA1 or BRCA2 mutation;
- as an adjunct in evaluating members with pelvic mass or symptoms suggestive of ovarian cancer.
[Please refer to Policy #012 in the Pathology Section on 'Genetic Testing for Hereditary Breast and/or Ovarian Cancer Syndrome (BRCA1/BRCA2)'.
NOTE: On 09/07/2016, the FDA issued a Safety Communication on 'Ovarian Cancer Screening Tests'. The FDA is alerting women about the risks associated with the use of tests being marketed as ovarian cancer screening tests. The Agency is especially concerned about delaying effective preventive treatments for women who show no symptoms, but who are still at increased risk for developing ovarian cancer. Based on currently available information, the FDA recommends against using currently offered tests to screen for ovarian cancer.
Despite extensive research and published studies, there are currently no screening tests for ovarian cancer that are sensitive enough to reliably screen for ovarian cancer without a high number of inaccurate results. However, over the years, numerous companies have marketed tests that claim to screen for and detect ovarian cancer.
For more information, please refer to the FDA Safety Communication which is available at:http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm519540.htm]
B. Bladder Tumor Antigen (BTA Stat Test), Nuclear Matrix Protein (NMP22 Test), Fibrinogen Degradation Products (Aura-Tek FDP Test), or aneuploidy for chromosomes 3, 7, 17, and loss of the 9p21 locus (UroVysion fluorescent in situ hybridization test) :
- in the diagnostic work-up of members who are symptomatic (e.g., presenting with hematuria) and who are at increased risk for bladder cancer.
[INFORMATIONAL NOTE: Risk factors for bladder cancer include:
a) chronic bladder inflammation
b) men and women between the ages of 50 and 70 (men are four times more likely to develop bladder cancer than women)
c) occupational exposure to aromatic amines or carcinogens
d) smoking has been identified as the greatest risk factor.]
C. CA19-9:
- to aid in the detection of cholangiocarcinoma in members with primary sclerosing cholangitis
3. Cxbladder test is consider investigational for all indications, including but not limited to, its use in screening asymptomatic members for bladder cancer, in the diagnostic work-up of members who are symptomatic and at increased risk for bladder cancer, and in surveillance of members with bladder cancer for recurrence, either as an alternative or adjunct to conventional tests.
[INFORMATIONAL NOTE: Cxbladder is a family of non-invasive urinary biomarker tests manufactured by Pacific Edge Diagnostics. Cxbladder was developed as an alternative or adjunct to conventional tests for the initial diagnosis of bladder cancer or for later disease recurrence.
Bladder cancer is typically diagnosed using a combination of cytologic evaluation of urine, imaging tests, and cystoscopy. However, patients have reported that cystoscopy is uncomfortable and expensive, and as a result, investigators are exploring alternative methods of to detect bladder cancer.
The following tests are included in the Cxbladder family:
o Cxbladder Triage
Used to rule out bladder cancer at an early stage.
o Cxbladder Detect
Used to assess the probability of bladder cancer.
o Cxbladder Monitor
Used to assess the probability of disease recurrence.
o Cxbladder Resolve
Used to identify patients with high grade or late stage bladder cancer.
Test Information
According to the manufacturer, levels of messenger RNA (mRNA) of five biomarker genes, including MDK, HOXA13, CDC2, IGFBP5, CXCR2, are believed to be in higher concentrations in urine samples of patients with bladder cancer.
The Cxbladder test involves the extraction, purification, and quantification of mRNA of the 5 biomarkers by reverse transcription (RT) quantification polymerase chain reaction (RT-qPRC).
o Cxbladder Triage
Combines bladder cancer risk factors as well as urinary biomarkers to rule out the presence of bladder cancer.
o Cxbladder Detect
Analyzes five urinary biomarkers to identify bladder cancer.
o Cxbladder Monitor
Combines clinical information and urinary biomarkers to assess the chance that bladder cancer has recurred.
o Cxbladder Resolve
Used to identify high grade or late stage bladder cancer in patients with haematuria.
Guidelines and Evidence
The National Comprehensive Cancer Network (NCCN , 2018) Clinical Practice Guidelines do not specifically comment on the Cxbladder tests. However, the guidelines states the following regarding the use of other available urinary biomarkers:
o “Management of bladder cancer is based on the pathologic findings of the biopsy specimen, with attention to histology, grade, and depth of invasion. These factors are used to estimate the probability of recurrence and progression to a more advanced stage. Consideration may be given to FDA-approved urinary biomarker testing by fluorescence in situ hybridization or nuclear matrix protein 22 in monitoring for recurrence.”
In 2011, the U.S. Preventive Services Task Forcehttps://www.uspreventiveservicestaskforce.org/Page/Document/evidencesummary14/bladder-cancer-in-adults-screening updated its 2004 evidence review with regard to bladder cancer screening, and reported the following:
o “no study evaluated the sensitivity or specificity of tests for hematuria, urinary cytology, or other urinary biomarkers for bladder cancer in asymptomatic persons without a history of bladder cancer. The positive predictive value of screening is less than 10% in asymptomatic persons, including higher-risk populations. No study evaluated harms associated with treatment of screendetected bladder cancer compared with no treatment.”
o “screening tests that might be feasible for primary care include tests for hematuria, urinary cytology, and other urinary biomarkers. The U.S. Preventive Services Task Force (USPSTF) last reviewed the evidence on bladder cancer screening in 2004 but found insufficient evidence to guide a recommendation.”
The diagnostic accuracy of Cxbladder has been compared with standard diagnostic methods in individuals suspected of urothelial cancer due to gross hematuria in the urine.
o According to Chou et al. (2015), the diagnostic accuracy study carries a medium risk of bias and reported sensitivity of the Cxbladder text of 82% (95% CI, 70% to 90%) and specificity of 85% (95% CI, 81% to 88%).
There are available studies that evaluated the effects of on patient-relevant outcomes (survival, quality of life) of using the Cxbladder test (clinical utility).
o Additional research is needed to assess how Cxbladder testing will be used in the disease management of patients with cancer. Questions persist regarding if Cxbladder has sufficient clinical utility to replace invasive cystoscopy or if Cxbladder has the potential to augment or clarify uncertain results obtained using conventional diagnostic methods.
Ongoing clinical trials
o The Cxbladder Monitoring Study: A Clinical, Non-Intervention Study of the Cxbladder Urine Test for the Detection of Recurrent Urothelial Carcinoma (UC).
Primary Outcome Measures:
“Proportion of participants with bladder cancer who are correctly identified as having cancer (true positives) and no cancer (true negatives) by the Cxbladder test.”
“The Cxbladder test results will be compared to that of cystoscopy, which is the gold standard method for diagnosing urothelial cancer; the true positive and true negative rates will be measured, along with the false positive and false negative rates of the test. The results will be reported as sensitivity and specificity of the Cxbladder test for detecting urothelial cancer in patients with recurrent disease.”
“Probability that patients identified as having cancer and no cancer by the Cxbladder test truly have cancer (positive predictive value; PPV), and truly have no cancer (negative predictive value; NPV) respectively.”]
4. AssureMDX test is consider investigational for all indications, including but not limited to, its use in screening asymptomatic members for bladder cancer, in the diagnostic work-up of members who are symptomatic (e.g., hematuria) to assist in identifying who is at low risk for bladder cancer and possibly avoid cystoscopy, and in surveillance of members with bladder cancer for recurrence, either as an alternative or adjunct to conventional tests.
[INFORMATIONAL NOTE: AssureMDx is a non-invasive method to analyze tumor markers in the urine of patients with hematuria to identify patients at low risk and high risk for bladder cancer.
The test is intended to assist in deciding who is at low risk for bladder cancer and can avoid cystoscopy, and who may benefit from a cystoscopy.
AssureMDx is a urine assay that analyzes three mutation markers or chromosomal changes (FGFR3, TERT, and HRAS) and the genetic methylation status of three
biomarkers (OTX1, ONECUT2, AND TWIST1). These results, in conjunction with patient age, yield a patient’s risk of bladder cancer (risk profile) and guide the
recommendations for cystoscopy. Patients identified at low risk for bladder cancer can avoid an unnecessary cystoscopy. Patients at medium- to high-risk of bladder cancer will proceed with cytoscopy as the gold standard for the diagnosis of bladder cancer.
Guidelines
American Urological Association (AUA)
The current guidelines set forth by the American Urological Association (AUA) recommend cystoscopy for all adults age 35 and older presenting with asymptomatic
microhematuria (after ruling out benign causes), and any individual presenting with gross hematuria.
American College of Physicians (ACP)
Guidelines suggested by the American College of Physicians (ACP) posit that any patient presenting with gross hematuria should receive a referral to a urologist, and any patient presenting with asymptomatic microhematuria should be referred to a urologist, if benign causes are ruled out. Only 9%-25% of patients presenting with hematuria undergo cystoscopy within six months of their initial diagnosis, and this is observed across different patient populations (academic health practice, community health clinic, Medicare-eligible patients).
Literature Review
There is insufficient evidence to support the use of the AssureMDx to accurately predict the risk of bladder cancer in patients with hematuria, and thus identify patients for whom cystoscopy is necessary. Analytical validity studies are lacking. Clinical validity studies are limited by small study populations and the lack of long-term follow up regarding the development of bladder cancer at a later date. Although one prospective clinical utility study suggests that recurrence of bladder cancer can be
detected by follow-up urine assays, it is unclear if the use of AssureMDx versus conventional cystoscopy leads to changes in health care decision-making and
improvement in patient survival.
Additional Studies
Additional well-designed studies are needed to add to the evidence base, corroborate the early findings in larger patient populations, and include additional
clinical factors such as age, gender, smoking history, and presence of gross versus microscopic hematuria.
Ongoing Clinical Trials
A study with the identifier: NCT03122964 is still in progress and is currently undergoing patient recruitment (updated August 17, 2018). The primary objective of this study is to evaluate the performance of AssureMDx for the detection of bladder cancer in patients with gross or microscopic hematuria. The secondary objective is to compare the predictive accuracy of a risk model including clinical factors (age, gender, smoking history, gross versus microscopic hematuria) with and without AssureMDx testing.]
5. Measurements of tumor markers or tumor antigens primarily for any of the following indications are considered investigational (except as noted in above policy statement #2A):
- screening asymptomatic members with or without risk factors;
- establishing or narrowing the differential diagnosis.
These include, but are not limited to, the following tumor markers:
- a2-PAG -pregnancy-associated alpha-2 glycoprotein
- BCM -breast cancer mucin
- CA50 -cancer antigen 50
- CA72-4 -cancer antigen 72-4
- CA195 -cancer antigen 195
- CA242 -cancer antigen 242
- CA549 -carbohydrate antigen/cancer antigen 549
- CA-SCC -squamous cell carcinoma antigen
- CAM17-1 -monoclonal antimucin antibody 17-1
- CAM-26 -monoclonal antimucin antibody 26
- CAM-29 -monoclonal antimucin antibody 29
- CAR-3 -antigenic determinant recognized by monoclonal antibody AR-3
- DU-PAN-2 -sialylated carbohydrate antigen DU-PAN-2
- MCA -mucin-like carcinoma-associated antigen
- MSA -mammary serum antigen
- NSE -neuron-specific enolase
- P-LAP -placental alkaline phosphatase
- PNA/ELLA -peanut lectin bonding assay
- SLEX -sialylated Lewis X-I antigen
- SLX -sialylated SSEA-1 antigen
- SPAN-1 -sialylated carbohydrate antigen SPAN-1
- ST-439 -sialylated carbohydrate antigen ST-439
- TAG12 -tumor-associated glycoprotein 12
- TAG72 -tumor-associated glycoprotein 72
- TAG72.3 -tumor-associated glycoprotein 72.3
- TATI -tumor-associated trypsin inhibitor
- TNF-a -tumor necrosis factor alpha
- TPA -tissue polypeptic antigen
Medicare Coverage:
Medicare Advantage Products differ from the Horizon BCBSNJ Medical Policy. There are several National Coverage Determinations applicable to this policy. For services represented by CPT codes 86300, 86301 and 86304, CMS has determined that limited coverage is available. Please refer to the NCDs listed below for coverage details.
National Coverage Determination (NCD) for Tumor Antigen by Immunoassay - CA 125 (190.28). Available to be accessed at CMS National Coverage Determinations (NCDs) Alphabetical Index search page: https://www.cms.gov/medicare-coverage-database/indexes/ncd-alphabetical-index.aspx.
National Coverage Determination (NCD) for Tumor Antigen by Immunoassay - CA 15-3/CA 27.29 (190.29). Available to be accessed at CMS National Coverage Determinations (NCDs) Alphabetical Index search page: https://www.cms.gov/medicare-coverage-database/indexes/ncd-alphabetical-index.aspx.
National Coverage Determination (NCD) for Tumor Antigen by Immunoassay - CA 19-9 (190.30). Available to be accessed at CMS National Coverage Determinations (NCDs) Alphabetical Index search page: https://www.cms.gov/medicare-coverage-database/indexes/ncd-alphabetical-index.aspx.
For services represented by CPT codes 86294, 86316, and 86386, there is no National Coverage Determination (NCD) or Local Coverage Determination (LCD) for jurisdiction JL for these services. Therefore, Medicare Advantage will follow the Horizon BCBSNJ Medical Policy for these codes.
The UroVysion Bladder Cancer Kit (UroVysion™ Kit) is covered when performed according to the FDA label (Summary of Safety and Effectiveness Data, Food and Drug Administration, January 24, 2005) as follows:
· In persons with hematuria suspected of having bladder cancer when results from the UroVysion Kit are intended for use, in conjunction with and not in lieu of current standard diagnostic procedures, as an aid for initial diagnosis of bladder carcinoma in patients with hematuria
· In persons with hematuria suspected of having bladder cancer when results from the UroVysion Kit are intended for use, in conjunction with and not in lieu of current standard diagnostic procedures and subsequent monitoring for tumor recurrence in patients previously diagnosed with bladder cancer.
Per Local Coverage Determination (LCD): Biomarkers for Oncology (L35396), CxBladder (CPT codes 0012M, 0013M) is noncovered.
For additional information, refer to Local Coverage Determination (LCD): Biomarkers for Oncology (L35396). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/LcdSearch?_afrLoop=90769712476969#!%40%40%3F_afrLoop%3D90769712476969%26centerWidth%3D100%2525%26leftWidth%3D0%2525%26rightWidth%3D0%2525%26showFooter%3Dfalse%26showHeader%3Dfalse%26_adf.ctrl-state%3D63y7eftob_46
Local Coverage Article: Biomarkers for Oncology (A52986). Available to be accessed at Novitas Solutions, Inc., Medical Policy Search page: https://www.novitas-solutions.com/webcenter/portal/MedicareJL/LcdSearch?_afrLoop=90769712476969#!%40%40%3F_afrLoop%3D90769712476969%26centerWidth%3D100%2525%26leftWidth%3D0%2525%26rightWidth%3D0%2525%26showFooter%3Dfalse%26showHeader%3Dfalse%26_adf.ctrl-state%3D63y7eftob_46
PROPRIETARY LABS (Labs that are the sole source for the diagnostic lab test)
For labs which are proprietary (that is, the sole source for the diagnostic lab test involved), Medicare Advantage Products will follow the Medicare Local Coverage Determination of the State where the proprietary lab is located.
Medicaid Coverage:
For members enrolled in Medicaid and NJ FamilyCare plans, Horizon BCBSNJ applies the above medical policy.
FIDE SNP:
For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.
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Horizon BCBSNJ Medical Policy Development Process:
This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.
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Index:
Tumor Markers Other Than Prostate Specific Antigen (PSA)
Antigens, Cancer
Aura-Tek FDP Test
Bladder Tumor Antigen
BTA Test
CA15-3
CA19-9
CA-125
CA27.29
Cancer Antigens
Fibrinogen Degradation Products
NMP22 Test
Nuclear Matrix Protein
Ovarian Tumor-Associated Antigen
Truquant BR RIA
UroVysion
ImmunoCyt
Cxbladder
AssureMDx
References:
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2. Sawczuk IS, Bagiella E, Sawczuk AT, et al. Clinical application of NMP22 in the management of transitional cell carcinoma of the bladder. Cancer Detect Prev. 2000;24(4):364-368.
3. Pirtskalaishvili G, Konety BR, Getzenberg RH. Update on urine-based markers for bladder cancer. Postgraduate Medicine. 1999 November;106(6):85-94.
4. Sawczuk IS, Lee B. The mechanism and clinical applications of the NMP22 tumor marker immunoassay: A review. American Clinical Pathology. 1999 April.
5. Zippe C, Pandragi L, Agarwal A. NMP22 is a sensitive, cost-effective test in patients at risk for bladder cancer. The Journal of Urology. 1999 January;161:62-65.
6. Pirtskalaishvili G, Konety BR, Getzenberg RH. Update on urine-based markers for bladder cancer. Postgrad Medicine. 1999;106:85-94.
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52. Fritsche HA, Grossman HB, Lerner S, et al. National Academy of Clinical Biochemistry Guidelines for use of tumor markers in bladder cancer. Use of tumor markers in liver, bladder, cervical, and gastric cancers, Chapter 3. 2010. https://www.aacc.org/science-and-research/practice-guidelines/liver-tumor-markers. Accessed January 20, 2015.
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56. Breen V, Kasabov N, Kamat AM, et al. A holistic comparative analysis of diagnostic tests for urothelial carcinoma: a study of Cxbladder Detect, UroVysion(R) FISH, NMP22(R) and cytology based on imputation of multiple datasets. BMC Med Res Methodol. 2015;15:45. PMID 25962444.
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Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)
CPT*
81479
86294
86300
86301
86304
86316
88120
88121
88365
88367
88368
0012M
0013M
HCPCS
* CPT only copyright 2020 American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.
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