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Urinary Biomarkers for Cancer Screening, Diagnosis, and Surveillance

Policy Number: MP-433

Latest Review Date: January 2019

Category: Medicine

Policy Grade: B

POLICY:

Initial diagnosis

The following urinary bladder tumor markers may be considered medically necessary as an adjunct in the diagnosis of bladder cancer only in conjunction with current standard diagnostic procedures (urine cytology or cystoscopy, with or without biopsy):

  • BTA-STAT*, BTA-TRAK*;
  • NMP22*, NMP22 BLADDER CHEK*;
  • UROVYSION*;

The following urinary bladder tumor marker is considered not medically necessary and investigational in the diagnosis of bladder cancer:

  • IMMUNOCYT

Bladder cancer monitoring

The following urinary bladder cancer tumor markers may be considered medically necessary as an adjunct in the monitoring of bladder cancer only in conjunction with current standard diagnostic procedures (urine cytology or cystoscopy, with or without biopsy):

  • BTA-STAT*, BTA-TRAK*;
  • IMMUNOCYT*;
  • NMP22*, NMP22 BLADDER CHEK*;
  • UROVYSION*;

The use of all other bladder cancer tumor markers (including but not limited to, CertNDx, Cxbladder) are considered not medically necessary and investigational in the diagnosis, monitoring, or screening for bladder cancer.

The use of urinary tumor markers are considered not medically necessary and investigational for screening for cancer including but not limited to bladder cancer and precancerous colonic polyps.

* FDA Approved indications

DESCRIPTION OF PROCEDURE OR SERVICE:

The diagnosis of bladder cancer is generally made by cystoscopy and biopsy. Bladder cancer has a very high frequency of recurrence and therefore follow-up cystoscopy, along with urine cytology, is done periodically to identify recurrence early. Urine biomarkers that might be used to supplement or supplant these tests have been actively investigated.

Urinary Bladder Cancer

Urinary bladder cancer, a relatively common form of cancer in the United States, results in significant morbidity and mortality. Bladder cancer (urothelial carcinoma), typically presents as a tumor confined to the superficial mucosa of the bladder. The most frequent symptom of early bladder cancer is hematuria; however, urinary tract symptoms (i.e., urinary frequency, urgency, and dysuria) may also occur. Cigarette smoking is an important risk factor for urothelial carcinoma.

Diagnosis

The criterion standard for a confirmatory diagnosis of bladder cancer is cystoscopic examination with biopsy. At initial diagnosis, approximately 70% of patients have cancers confined to the epithelium or subepithelial connective tissue. Non-muscle-invasive disease is usually treated with transurethral resection, with or without intravesical therapy, depending on the depth of invasion and tumor grade. However, a 50% to 75% incidence of recurrence has been noted in these patients, with 10% to 15% progressing to muscle invasion over a 5-year period. Current follow-up protocols include flexible cystoscopy and urine cytology every 3 months for 1 to 3 years, every 6 months for an additional 2 to 3 years, and then annually thereafter, assuming no recurrence.

While urine cytology is a specific test (from 90% to 100%), its sensitivity is lower, ranging from 50% to 60% overall, and it is considered even lower for low-grade tumors. Therefore, interest has been reported in identifying tumor markers in voided urine that would provide a more sensitive and objective test for tumor recurrence.

Adjunctive testing to urine cytology has used a variety of nuclear and cytoplasmic targets, and a range of molecular pathology and traditional (e.g., immunohistochemistry) methods.

Commercially available tests approved or cleared by the U.S. Food and Drug Administration (FDA) as well as laboratory-developed tests are summarized in the Approved by Governing Bodies section.

KEY POINTS:

The most recent literature update was performed through October 4, 2018.

Summary of Evidence

For individuals who have signs and/or symptoms of bladder cancer who receive urinary tumor marker tests in addition to cytology, the evidence includes a number of diagnostic accuracy studies and meta-analyses of these studies. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and resource utilization. A meta-analysis of diagnostic accuracy studies determined that urinary tumor marker tests have sensitivity ranging from 47% to 85% and specificity ranging from 53% to 95%. This analysis found that combining urinary tumor markers with cytology improves diagnostic accuracy, but about 10% of cancers would still be missed. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have a history of bladder cancer who receive urinary tumor marker tests in addition to cytology, the evidence includes a number of diagnostic accuracy studies, meta-analyses, as well as a decision curve analysis and a retrospective study examining the clinical utility of urinary tumor marker tests. Relevant outcomes are overall survival, disease-specific survival, test accuracy and validity, and resource utilization. The diagnostic accuracy studies found that urinary tumor marker tests have pooled sensitivity ranging from 46% to 84% and pooled specificity ranging from 71% to 91%. The decision analysis found only a small clinical benefit for use of a urinary tumor marker test and the retrospective study found that a urinary tumor marker test was not significantly associated with findings of the subsequent surveillance cystoscopy. No studies using the preferred trial design to evaluate clinical utility were identified; i.e., controlled studies prospectively evaluating health outcomes in patients managed with and without the use of urinary tests or prospective studies comparing different cystoscopy protocols used in conjunction with urinary tumor markers. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who are asymptomatic and at a population-level risk of bladder cancer who receive urinary tumor marker tests, the evidence includes a systematic review and several uncontrolled prospective and retrospective studies. Relevant outcomes are overall survival, disease-specific survival, and test accuracy and validity. A 2010 systematic review (conducted for the U.S. Preventive Services Task Force) did not identify any RCTs, the preferred trial design to evaluate the impact of population-based screening and found only one prospective study that the Task Force rated as poor quality. A more recent retrospective study, assessing a population-based screening program in the Netherlands, reported low diagnostic yield. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who are asymptomatic and at a population-level risk of colon cancer who receive urinary tests for precancerous polyps, evidence includes a validation study. Relevant outcomes are overall survival, disease-specific survival, and test accuracy and validity. A urine metabolite assay for adenomatous polyps is at a very early stage of development, with a report of a training and validation set published in 2017. Current evidence does not support the diagnostic accuracy of urinary tumor markers to screen asymptomatic individuals for precancerous polyps. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

National Comprehensive Cancer Network

National Comprehensive Cancer Network (NCCN) v.5.2018 bladder cancer guidelines include consideration for urinary urothelial tumor markers every three months along with urine cytology for the first two years of follow-up for high-risk patients with non-muscle invasive bladder cancer (category 2B recommendation).

American Urological Association et al

The 2016 guidelines from the American Urological Association and Society of Urologic Oncology addressed the diagnosis and treatment of non-muscle-invasive bladder cancer, based on a systematic review completed by the Agency for Health Care Research and Quality. The table below summarizes statements on the use of urine markers after the diagnosis of bladder cancer.

Table 1. Guidelines for Urine Tumor Markers after the Diagnosis of Bladder Cancer

Guidance Statement

SOR

LOE

“In surveillance of NMIBC, a clinician should not use urinary biomarkers in place of cystoscopic evaluation.”

Strong

B

“In a patient with a history of low-risk cancer and a normal cystoscopy, a clinician should not routinely use a urinary biomarker or cytology during surveillance.”

 

Expert opinion

“In a patient with NMIBC, a clinician may use biomarkers to assess response to intravesical BCG (UroVysion® FISH) and adjudicate equivocal cytology (UroVysion® FISH and ImmunoCyt™).”

 

Expert opinion

BCG: bacillus Calmette-Guérin; LOE: level of evidence; NMIBC: non-muscle-invasive bladder cancer; SOR: strength of recommendation.

The 2012 guidelines from the American Urological Association (reviewed and affirmed in 2016) on the evaluation of microscopic hematuria recommended cystoscopic evaluation for the following individuals:

Older than age 40 with microscopic hematuria; and

Younger than age 40 with microscopic hematuria and risk factors for developing bladder cancer.

U.S. Preventive Services Task Force Recommendations

The U.S. Preventive Services Task Force concluded in 2011 that there was insufficient evidence to assess the benefits and harms of screening for bladder cancer in asymptomatic adults. The recommendation was based on insufficient evidence (Grade I).

KEY WORDS:

Bladder Tumor Antigen, BTA Test, FISH, Bladder Cancer Testing, ImmunoCyt, NMP-22, Tumor Marker, Bladder Cancer, UroVysion, BTA Stat, CertNDx, FGFR3, Cxbladder, PolyDx, colonic polyp, colorectal, therascreen, FGFR3, urothelial carcinoma

APPROVED BY GOVERNING BODIES:

Table 6 lists urinary tumor marker tests approved or cleared for marketing by FDA. The FDA-approved or cleared tests are indicated as adjuncts to standard procedures for use in the initial diagnosis of bladder cancer or surveillance of bladder cancer patients.

Table 2. FDA-Approved or -Cleared Urinary Tumor Marker Tests     

Test

Manufacturer

Type

Detection

Indication

BTA stat®

Polymedco

Point of care immunoassay

Human complement factor H-related protein

Qualitative detection of bladder tumor- associated antigen in the urine of persons diagnosed with bladder cancer

BTA TRAK®

Polymedco

Reference laboratory immunoassay

Human complement factor H-related protein

Quantitative detection of bladder tumor- associated antigen in the urine of persons diagnosed with bladder cancer

Alere NMP22®

Alere

Immunoassay

NMP22 protein

in vitro quantitative determination of the nuclear mitotic apparatus protein (NuMA) in stabilized voided urine. Used as adjunct to cystoscopy

Bladder Chek®

Alere

Point of care immunoassay

NMP22 protein

Adjunct to cystoscopy in patients at risk for bladder cancer

UroVysion®

Abbott Molecular

FISH

Cell-based chromosomal abnormalities

Aid in the initial diagnosis of bladder cancer (P030052) and monitoring patients with previously diagnosed bladder cancer (K033982)

FISH: fluorescence in situ hybridization; IHC: immunohistochemistry; NMP: nuclear matrix protein

FISH is a molecular cytogenetic technology that can be used with either DNA or RNA probes to detect chromosomal abnormalities. DNA FISH probe technology involves the creation of short sequences of fluorescently labeled, single-strand DNA probes that match target sequences. The probes bind to complementary strands of DNA, allowing for identification of the location of the chromosomes targeted.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. Urine-based tests are available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing. To date, FDA has chosen not to require any regulatory review of these tests. Laboratory-developed tests include:

Cxbladder Monitor (Pacific Edge) measures the expression of 5 genes (MDK, HOXA13, CDC2, IGFBP5, CXCR2). Pacific Edge also has Cxbladder Detect and Cxbladder Triage tests.

Xpert Bladder Cancer Monitor (Cepheid) measures mRNA (ABL1, CRH, IGF2, UPK1B, ANXA10) in voided urine by rtPCR.

PolypDx™ (Metabolomic Technologies) is a urine metabolite assay that uses liquid chromatography–mass spectrometry. An algorithm compares urine metabolite concentrations to determine the likelihood of colonic adenomatous polyps.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply

FEP:  Special benefit consideration may apply.  Refer to member’s benefit plan.  FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING: 

CPT Codes:

86294

Immunoassay for tumor antigen; qualitative or semiquantitative (e.g., bladder tumor antigen)

86316

Immunoassay for tumor antigen; other antigen, quantitative, each

86386

Nuclear Matrix Protein 22 (NMP22), qualitative

88120

Cytopathology, in situ hybridization (e.g., FISH), urinary tract specimen with morphometric analysis, 3-5 molecular probes, each specimen; manual

88121

Cytopathology in situ hybridization (e.g., FISH), urinary tract specimen with morphometric analysis, 3-5 molecular probes, each specimen; using computer-assisted technology

88299

Unlisted cytogenetic study

81479

Unlisted molecular pathology procedure

0012M

Oncology (urothelial), mRNA, gene expression profiling by real-time quantitative PCR of five genes (MDK, HOXA13, CDC2 [CKD1], IGFBP5, and XCR2), utilizing urine, algorithm reported as a risk score for having urothelial carcinoma (Effective 04/01/2018)

0013M

Oncology (urothelial), mRNA, gene expression profiling by real-time quantitative PCR of five genes (MDK, HOXA13, CDC2 [CKD1], IGFBP5, and XCR2), utilizing urine, algorithm reported as a risk score for having recurrent urothelial carcinoma (Effective 04/01/2018)

0002U

Oncology (colorectal), quantitative assessment of three urine metabolites (ascorbic acid, succinic acid and carnitine) by liquid chromatography with tandem mass spectrometry (LC-MS/MS) using multiple reaction monitoring acquisition, algorithm reported as likelihood of adenomatous polyps (Effective 02/01/2017)

0154U

FGFR3 (fibroblast growth factor receptor 3) gene analysis (i.e., p.R248C [c.742C>T], p.S249C [c.746C>G], p.G370C [c.1108G>T], p.Y373C [c.1118A>G], FGFR3-TACC3v1, and FGFR3-TACC3v3) (Effective 1/1/2020)

REFERENCES:

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  21. Guo A, Wang X, Gao L, et al. Bladder tumour antigen (BTA stat) test compared to the urine cytology in the diagnosis of bladder cancer: A meta-analysis. Can Urol Assoc J. May 2014; 8(5-6):E347-352.
  22. Horstmann M, Patschan O, Hennenlotter J, et al.  Combinations of urine-based tumor markers in bladder cancer surveillance.  Scand J Urol Nephrol 2009; 43(6):461-6.
  23. Kamat AM, Karan JA, Grossman B et al. Prospective trial to identify optimal bladder cancer surveillance protocol: reducing costs while maximizing sensitivity. BJU Int 2011; 108(7):1119-24.
  24. Kim PH, Sukhu R, Cordon BH et al. Reflex fluorescence in situ hybridization assay for suspicious urinary cytology in bladder cancer patients with negative surveillance cystoscopy. BJU Int 2013.
  25. Ku JH, Godoy G, Amiel GE et al. Urine survivin as a diagnostic biomarker for bladder cancer: a systematic review. BJU Int 2012; 110(5):630-6.
  26. Lahme S, et al. Comparison of cytology and nuclear matrix protein 22 (NMP 22) for the detection and follow-up of bladder-cancer. Adv Exp Med Biol. 2003;539(PtA):111-9.
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  28. Li HX, Li M, Li CL et al. ImmunoCyt and cytokeratin 20 immunocytochemistry as adjunct markers for urine cytologic detection of bladder cancer. Ann Quant Cytol Histol 2010; 32(1):45-52.
  29. Lodde M, Mian C, Wiener H et al. Detection of upper urinary tract transitional cell carcinoma with ImmunoCyt: a preliminary report. Urology 2001; 58(3):362-6.
  30. Lotan Y, Elias K, Svatek RS, et al.  Bladder cancer screening in a high risk asymptomatic population using a point of care urine based protein tumor marker.  J Urol 2009; 182(1):52-8.
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  37. Pichler R, Fritz J, Tulchiner G, et al. Increased accuracy of a novel mRNA-based urine test for bladder cancer surveillance. BJU Int. Jan 2018;121(1):29-37.
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  39. Placer J, et al. Clinical utility of a multiprobe FISH assay in voided urine specimens for the detection of bladder cancer and its recurrences, compared with urinary cytology. Eur Urol 2002; 42(6):547-52.
  40. Ponsky LE, Sharma S, Pandrangi L et al. Screening and monitoring for bladder cancer: refining the use of NMP-22. J Urol 2001; 166(1): 75-8.
  41. Raitanen MP; FinnBladder Group. The role of BTA stat test in follow-up of patients with bladder cancer: Results from FinnBladder studies. World J Urol 2008; 26(1):45-50.
  42. Rieger-Christ KM, Mourtzinos A, Lee PJ et al. Identification of fibroblast growth factor receptor 3 mutations in urine sediment DNA samples complements cytology in bladder tumor detection. Cancer 2003; 98(4):737-44.
  43. Roobol MJ, Bangma CH, et al. Feasibility study of screening for bladder cancer with urinary molecular markers (the BLU-P project). Urol Oncol 2010 Nov-Dec, 28(6):686-90.
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  45. Schmitz-Drager BJ, Tirsar LA, Schmitz-Drager C et al. Immunocytology in the assessment of patients with asymptomatic hematuria. World J Urol 2008; 26(1):31-7.
  46. Shariat SF, Savage C, Chromecki TF et al. Assessing the clinical benefit of nuclear matrix protein 22 in the surveillance of patients with nonmuscle-invasive bladder cancer and negative cytology. Cancer 2011; 117(13):2893-7.
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  49. Sturgeon CM, Duffy MJ, Hofmann BR, et al. National Academy of Clinical Biochemistry Laboratory Medicine practice guidelines for use of tumor markers in liver, bladder, cervical and gastric cancers. Clin Chem 2010 Jun; 56(6):e1-48.
  50. Sullivan PS, Nooraie F, Sanchez H, et al. Comparison of ImmunoCyt, UroVysion and urine cytology in detection of recurrent urothelial carcinoma. Cancer Cytopathol 2009; 117(3):167-73.
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POLICY HISTORY:

Medical Policy Group, June 2010 (3)

Medical Policy Administration Committee, July 2010

Available for comment July 2-August 16, 2010

Medical Policy Group, December 2010 (1): 2 new CPT codes added effective 1/1/2011

Medical Policy Group, June 2011; Updated Description, Key Points, & References

Medical Policy Group, July 2011 (1): Added “prior to July 1, 2010” policy statements concerning bladder cancer from policy 195

Medical Policy Group, August 2011 (1): Added CertNDx tumor marker test to investigational portion of policy statement; Key Points, Key Words and References updated related to CertNDx

Medical Policy Administration Committee, August 2011

Medical Policy Group, November 2011 (1): Added CPT 86386

Medical Policy Group, March 2012 (1): Clarification to policy statement; standard diagnostic procedures include urine cytology or cystoscopy with or without biopsy

Medical Policy Group, September 2013 (1): 2013 Update to Description, Key Points and References; no change to policy statement

Medical Policy Panel, March 2014

Medical Policy Group, March 2014 (1): 2014 Update to Description, Key Points and References; no change to policy statement

Medical Policy Panel, March 2015

Medical Policy Group, March 2015 (3): 2015 Updates to Key Points and References; no change to policy statement.

Medical Policy Panel, December 2015

Medical Policy Group, January 2016 (3): 2016 Updates to Key Points, Key Words and References. Added “Cxbladder” to the investigational policy statement for all other bladder tumor markers.

Medical Policy Panel, June 2017

Medical Policy Group, July 2017 (3): 2017 Updates to Description, Key Points, Approved by Governing Bodies & References; no change in policy statements.

Medical Policy Group, March 2018: Quarterly Coding Update, April 2018; added new CPT codes 0012M and 0013M to Current Coding.

Medical Policy Panel, June 2018

Medical Policy Group, July 2018 (3): Updates to Title, Description, Key Points, Approved by Governing Bodies, and References. Policy section - added clarifying statement to include the screening for precancerous colonic polyps as investigational. Key words added – PolypDx and colonic polyp, colorectal; Current coding – added code 0002U.  Deleted Previous Coding section containing info prior to 2011.

Medical Policy Panel, December 2018

Medical Policy Group, January 2019 (9): 2018 Updates to Approved by Governing Bodies, Key Points, Description, References. No change to policy statement.

Medical Policy Group, November 2019: 2020 Annual Coding Update. Added CPT code 0154U to Current coding section. Added key words: therascreen, FGFR3, urothelial carcinoma. Updated Key Points.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.