| Coverage Policy Manual | |
| Policy #: | 1997185 |
| Category: | Laboratory |
| Initiated: | October 1996 |
| Last Review: | January 2024 |
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| Tumor Markers, Urinary Bladder Cancer | |
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| Description: |
URINARY BLADDER CANCER
Urinary bladder cancer, a relatively common form of cancer in the United States, results in significant morbidity and mortality (Comperat, 2022). 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, dysuria) may also occur.
Diagnosis
The criterion standard for a confirmatory diagnosis of bladder cancer is cystoscopic examination with biopsy (Comperat, 2022). At initial diagnosis, approximately 70% of patients have cancers confined to the epithelium or subepithelial connective tissue. The 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 (Comperat, 2022). 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 cleared by the U.S. Food and Drug Administration clearance as well as laboratory-developed tests are summarized in the Regulatory Status section.
REGULATORY STATUS
The following urinary tumor marker tests have been approved or cleared for marketing by the U.S. Food and Drug Administration (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.
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 (CLIA). Urine-based tests are available under the auspices of CLIA. Laboratories that offer laboratory-developed tests must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test. Laboratory-developed tests include:
Further, Predictive Laboratories (Lexington, MA) markets the CertNDx™ test; it assesses fibroblast growth factor receptor 3 (FGFR3) variants. The test is intended to be used in combination with cytology for identifying patients with hematuria at risk of bladder cancer. FGFR3 variants may be associated with lower grade bladder tumors that have a good prognosis.
CODING
The BTA (bladder tumor antigen) stat® and nuclear matrix protein 22 (NMP22) are immunoassay tests. When performed qualitatively in the physician’s office, CPT code 86294 Immunoassay for tumor antigen, qualitative and semiquantitative (e.g., bladder tumor antigen), may be used to describe the BTA stat test and CPT code 86386 (Nuclear Matrix Protein 22 [NMP22], qualitative) may be used to describe the NMP22 test.
For clinical laboratories performing a quantitative version of these tests, CPT code 86316 (Immunoassay for tumor antigen; other antigen, quantitative [e.g., CA 50, 72-4, 549], each) may be used to describe the test.
There are specific CPT codes for urinary fluorescence in situ hybridization (FISH) testing:
88120: Cytopathology, in situ hybridization (e.g., FISH), urinary tract specimen with morphometric analysis, 3-5 molecular probes, each specimen; manual
88121: using computer-assisted technology.
Effective April 01, 2018, there are specific codes for the Cxbladder ™ Detect (0012M) and the Cxbladder™ Monitor (0013M) tests:
0012M: Oncology (urothelial), mRNA, gene expression profiling by real-time quantitative PCR of five genes (MDK, HOXA13, CDC2 [CDK1], IGFBP5, and XCR2), utilizing urine, algorithm reported as a risk score for having urothelial carcinoma
0013M: Oncology (urothelial), mRNA, gene expression profiling by real-time quantitative PCR of five genes (MDK, HOXA13, CDC2 [CDK1], IGFBP5, and CXCR2), utilizing urine, algorithm reported as a risk score for having recurrent urothelial carcinoma
The CertNDx™ test is likely to be reported with the unlisted molecular pathology procedure code 81479.
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Policy/ Coverage: |
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
The use of bladder cancer tumor markers involving immunoassay tests NMP-22, NMP22 Bladder Chek, BTA stat ® or the BTA-TRAK, meets primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes as an adjunct in the diagnosis (in persons with hematuria suspected of having bladder cancer) and monitoring of bladder cancer only in conjunction with urine cytology and cystoscopy.
Fluorescence in situ hybridization (FISH) testing using the UroVysion test for urothelial carcinoma of the bladder is covered as an adjunct to detection and monitoring of bladder cancer only:
The use of the ImmunoCyt bladder cancer tumor markers meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness as an adjunct in the monitoring of bladder cancer only in conjunction with urine cytology and cystoscopy.
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
The use of the CxBladder™ Detect and the CxBladder™ Monitor tests and the CertNDx™ test do not meet member benefit certificate primary coverage criteria.
For members with contracts without primary coverage criteria, the use of the CxBladder™ Detect and the CxBladder™ Monitor tests and the CertNDx™ test is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Screening tests are exclusions in most member benefit certificates of coverage except for coverage based on the Patient Protection and Affordable Care Act (PPACA) screening recommendations for non-grandfathered plans and those contracts with wellness benefits (which like PPACA, covers specific screening procedures).
For contracts without this specific exclusion, the use of urinary bladder cancer tumor markers to screen for bladder cancer in asymptomatic patients does not meet member benefit primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes. For contracts without the specific exclusion or primary coverage criteria, the use of urinary bladder cancer tumor markers to screen for bladder cancer in asymptomatic patients is investigational.
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| Rationale: |
Urinary Tumor Markers in Individuals With a History of Bladder Cancer
No studies were identified that specifically address the diagnostic accuracy of urinary tumor markers for diagnosing UUT cancers in patients with a history of bladder cancer. Several studies have addressed the accuracy of urinary tumor markers for diagnosing upper urinary tract (UUT) diseases in mixed populations with suspected disease and a history of bladder cancer or UUT cancer. For example, Lodde et al (2001) in Austria evaluated the accuracy of ImmunoCyt for detecting UUT transitional cell carcinoma (UUTTCC) (Lodde, 2001). The study included 37 patients with signs or symptoms suggestive of UUT-TCC; 14 (38%) patients had a history of bladder cancer. Sixteen (43%) of 37 patients were found to have UUT-TCC. All patients also underwent cystoscopy, renal ultrasonography, and intravenous excretory urography. Using voided urine samples, ImmunoCyt had a 75% sensitivity and a 95% specificity for identifying UUT-TCC.
This compares to a sensitivity of 50% and specificity of 100% for cytology. Using ureteral urine samples, ImmunoCyt had a sensitivity of 91% and cytology had a sensitivity of 82%. Both tests had 100% specificity using ureteral urine. Combination ImmunoCyt plus cytology had a sensitivity of 88% in voided urine samples and a sensitivity of 100% in ureteral urine.
In 2011, Xu et al in China reported on the diagnostic accuracy of FISH (UroVysion) for detecting upper tract UC (Xu, 2011). The study included urine specimens from 85 patients suspected of having UUT disease. Patients underwent cystoscopy after urine collection. Seventeen (20%) patients had a history of urinary tract UC and 8 (9%) had a history of bladder cancer. The remaining patients had signs or symptoms of disease such as hematuria. The sensitivity of FISH for diagnosing urinary tract carcinoma was 79% and the sensitivity of cytology was 45%. Specificity was 98% for FISH and 100% for cytology. When findings from cytology and FISH were combined, the sensitivity was 86% and the specificity was 98%. Neither study separately reported findings for detection of recurrence in patients with a history of urinary tract cancer or for patients with a negative cystoscopy.
In 2012, Picozzi et al published a meta-analysis of studies that reported data on UUT recurrence following radical cystectomy for bladder cancer (Picozzi, 2012). Upper tract recurrence was defined as any documented recurrence in the renal collecting system or ureter. Reviewers identified 27 studies (total N=13,185 participants). The overall prevalence of urinary tract in the studies ranged from 0.75% to 6.4% and, among the cancers detected, 64.6% were advanced and 35.6% were metastatic. The Picozzi review also reported on the diagnostic yield of protocols used to follow patients after treatment for bladder cancer. As reported in the review, in 14 studies, 63 (38%) of 166 patients with UUT recurrence were identified by follow-up investigations and in the remaining 103 (62%) of patients, diagnosis was based on symptoms. In 9 studies that used urine cytology, 10 (9%) of 112 patients with recurrence were identified by positive cytology. In 13 studies that used upper tract imaging, 40 (25%) of 161 patients with recurrence were identified by imaging. Put another way, approximately 2000 urine cytology examinations or 800 radiologic examinations were performed to identify 1 patient with urinary tract recurrence. Reviewers stated that they were unable to determine whether there was a survival advantage in patients whose tumors were identified by cytology or urinary tract imaging compared with those detected by symptoms because the data on this subject were poor. The Picozzi review did not discuss the use of urinary tumor markers for diagnosis of UUT recurrence.
Section Summary: Urinary Tumor Markers in Individuals With a History of Bladder Cancer
No studies were identified that focused specifically on the use of urinary tumor markers for detecting UUT recurrences in patients with a history of bladder cancer. Several studies have evaluated urinary tumor markers for detecting UUT disease in samples of patients both with and without a history of urinary carcinoma. Available studies generally found that urinary tumor markers had higher sensitivity but not higher specificity than cytology, and combining urinary markers and cytology improved diagnostic accuracy.
Clinical Utility
Because of the potential consequences of missing a diagnosis of recurrent bladder cancer, it is unlikely that the schedule of cystoscopies will be altered unless the sensitivity of urinary marker(s) approaches 100%. Some have suggested that consideration be given to lengthening the intervals of cystoscopy in patients with low levels of an accurate marker and low-grade bladder cancer. In addition, while urinary tumor markers might not alter the schedule of cystoscopies, if their results suggest a high likelihood of tumor recurrence, the resulting cystoscopy might be performed more thoroughly, or investigation of the UUT might be initiated (Grocela, 2000). Direct evidence that outcomes are improved or not worsened with an altered schedule would be useful.
No controlled studies were identified that prospectively evaluated health outcomes in patients managed with and without the use of urinary tumor marker tests. In addition, we found no published studies comparing different cystoscopy protocols, used in conjunction with urinary markers, to monitor recurrence. We did find uncontrolled prospective and retrospective studies.
A 2011 study by Shariat et al used a decision curve analysis to assess the impact of urinary marker testing using the NMP22 assay on the decision to refer for cystoscopy and concluded that the marker did not aid clinical decision making in most cases (Shariat, 2011). The study included 2222 patients with non-muscle-invasive bladder cancer and negative cytology, at various stages of surveillance. (Patients with positive urinary cytology were excluded, because standard practice is to refer those patients for cystoscopy.) According to the study protocol, all patients underwent cystoscopy, and 581 (26%) were found to have disease recurrence; of these, 234 (40%) had disease progression. NMP22 level was found to be significantly associated with both disease recurrence and progression (p<0.001 for both). In the analysis, the clinical net benefit of the NMP22 test was evaluated by summing the benefits (true positives), subtracting the harms (false positives), and weighing these values by the “threshold probability,” defined as the minimum probability of bladder cancer or recurrence at which a patient or clinician would opt for cystoscopy. The investigators found only a small clinical net benefit for the NMP22 test over the strategy of “cystoscopy for all patients,” and this benefit occurred only at threshold probabilities over 8%. For example, for patients with at least a 15% risk of recurrence, using a model
containing age, sex, and NMP22, 229 (23%) cystoscopies could be avoided, 236 (90%) recurrences would be identified, and 25 (15%) recurrences would be missed. Thus, for clinicians or patients who would opt for cystoscopy even if patients had a low risk of recurrence (eg, 5%), NMP22 would not add clinical benefit and the optimal strategy would be to offer cystoscopy to all at-risk patients. The authors attributed the low clinical net benefit to the high risk of bladder cancer recurrence in patients with negative cytology.
A 2014 study by Kim et al examined data on the FISH test with the aim of determining whether the urinary marker could modify the surveillance schedule in patients with non-muscle-invasive bladder cancer who had suspicious cytology but a negative surveillance cystoscopy (Kim, 2014). The standard surveillance protocol at the study institution was providing cystoscopy and urinary cytology every 3 to 6 months. A total of 243 patients who met the previous criteria had FISH testing and a subgroup of 125 patients had subsequent surveillance cystoscopy 2 to 6 months after reflex FISH. Cystoscopy findings were positive in 17 (7%) patients. FISH results were not significantly associated with the results of the next cystoscopy (odds ratio [OR], 0.84; 95% CI, 0.26 to 2.74; p=1.0). Because of this lack of short-term association between FISH results and cystoscopy, the authors concluded that FISH has limited ability to modify the surveillance schedule in non-muscle-invasive bladder cancer.
Section Summary: Clinical Utility of Diagnosis and Management of Individuals With Symptoms or
History of Bladder Cancer
There is a lack of direct evidence that health outcomes improve in patients managed with urinary tumor marker tests compared with those managed without tumor marker tests. And there is a lack of direct evidence that cystoscopy protocols can be changed when urinary tumor marker tests are used. The available studies have found low potential clinical benefit of urinary tumor marker testing for patients with non-muscle-invasive bladder cancer in terms of avoiding cystoscopy or lengthening intervals between cystoscopies.
URINARY MARKERS FOR SCREENING ASYMPTOMATIC INDIVIDUALS FOR BLADDER CANCER
Clinical Context and Test Purpose
The purpose of screening testing with urinary markers in asymptomatic individuals at population-level risk is to detect disease at an earlier stage than it would present otherwise at a stage when treatment would allow improved outcomes.
The question addressed in this evidence review is: Does population-level screening with urinary markers for bladder cancer improve outcomes in asymptomatic individuals?
The ideal study for evaluating the effectiveness of a screening program is a randomized controlled trial (RCT) comparing outcomes in patients who did and did not participate in a screening program. In 2010, the U.S. Preventive Services Task Force updated its evidence review on screening adults for bladder cancer (Chou, 2010). The quality of evidence was rated low that screening for bladder cancer reduces morbidity or mortality. There were no RCTs, and only 1 prospective study, rated as poor quality. The systematic review did not identify any studies evaluating the sensitivity or specificity of diagnostic tests for bladder patients in asymptomatic average-risk patients. Moreover, reviewers did not identify any suitable studies on whether treatment of screen-detected bladder cancer reduces disease-specific morbidity and mortality, or on potential harms of screening for bladder cancer. Reviewers concluded: “major gaps in evidence make it impossible to reach any reliable conclusions about screening.”
Several uncontrolled studies have reported findings of screening studies. In 2013, Bangma et al reported on a population-based program with men in The Netherlands (Bangma, 2013). The study evaluated the feasibility of screening using urine-based markers and examined performance characteristics of screening tests. The screening protocol consisted of 14 days of home urine testing for hematuria. Men with at least 1 positive home hematuria test underwent screening for 4 urine-based molecular markers. Men with at least 1 positive urine-based test were recommended to undergo cystoscopy. Of 6500 men invited to participate in screening, 1984 (30.5%) agreed and 1747 (88.1%) underwent hematuria testing. Of these, 409 (23.4%) tested positive for hematuria and 385 (94%) underwent urine-based marker testing. The number of men testing positive for each marker was 14 (3.6%) for NMP22, 33 (8.6%) for microsatellite analysis, 6 (1.6%) for FGFR3, and 40 (10.4%) for CH3. Cystoscopy was recommended for 75 men, and 71 actually underwent the procedure. Cancer was diagnosed in 4 (0.002%) of 1747 men who underwent screening (3 bladder cancers, 1 kidney cancer). Although men in the study who tested negative on screening tests didnot receive further testing, the investigators were able to link participants’ data to a Dutch cancer registry data. They determined that 2 cancers (1 bladder cancer, 1 kidney cancer) had been diagnosed in men who completed the protocol; they were considered false negatives. Considering these data, the sensitivity of any urine-based marker was 80% (95% CI, 28.4% to 99.5%) and the specificity was 95.9% (95% CI, 94.9% to 96.8%). The sensitivity and specificity of the FDA-approved NMP22 test was 25% (95% CI, 0.63% to 80.6%) and 96.6% (95% CI, 94.2% to 98.2%). The screening program had low diagnostic yield.
In 2009, Lotan et al published a prospective study in which 1502 individuals at high-risk of bladder cancer due to age plus smoking and/or occupational exposure were screened (Lotan, 2009). The study used the NMP22 BladderChek test and was supported by the test manufacturer. Individuals with positive BladderChek tests underwent additional testing, beginning with urinalysis. Those found to have infection on urinalysis were treated and their urine was retested; others who tested positive received cystoscopy and cytology. Individuals with a negative BladderChek test did not have to undergo additional testing. Eighty-five (5.7%) of the 1502 participants had a positive BladderChek test. Two of the 85 patients were found to have bladder cancer (noninvasive), yielding a positive predictive value of 2.4%. There was also 1 case of atypia. Follow-up at a mean of 12 months was obtained for 1309 (87%) of 1502 screened patients. No additional cancers were diagnosed in the group that had had positive BladderChek tests. Two participants with negative BladderChek screen had been diagnosed with bladder cancer; both tumors were less than 1 cm. Because no follow-up tests were done on participants who initially tested negative, it is unclear whether these were false-negative findings or new cancers. The authors report that the cancer prevalence in this population was lower than expected, which could be due in part to the large proportion who had previously undergone urinalysis. Study limitations included lack of follow-up testing on approximately 20% of participants who tested positive and lack of early cystoscopy and incomplete 1-
year telephone follow-up in those who tested negative. Because of these limitations, accurate test operating characteristics (eg, sensitivity) cannot be calculated.
Section Summary: Urinary Markers for Screening Asymptomatic Individuals for Bladder Cancer
We found no RCTs evaluating the impact of screening for bladder cancer on health outcomes in asymptomatic individuals. There is also insufficient observational evidence on the diagnostic accuracy of urinary tumor markers used to screen asymptomatic individuals for bladder cancer.
SUMMARY OF EVIDENCE
For individuals who have signs and/or symptoms of bladder cancer or a history of bladder cancer who receive urinary tumor marker tests, the evidence includes a number of diagnostic accuracy studies, metaanalyses, as well as a decision curve analysis and 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 tend to have higher sensitivity but lower or similar specificity than cytology. Also, they found that combining tumor marker tests with cytology can improve overall diagnostic accuracy. 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; ie, controlled studies prospectively evaluating health outcomes in patients managed with and without 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. The 2010 systematic review (conducted for the U.S. Preventive Services Task Force [USPSTF]) did not identify any randomized controlled trials, the preferred trial design to evaluate the impact of population-based screening, and found only 1 prospective study that USPSTF 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.
PRACTICE GUIDELINES AND POSITION STATEMENTS
National Comprehensive Cancer Network
The National Comprehensive Cancer Network (v.2.2017) bladder cancer guidelines include consideration for urinary urothelial tumor markers every 3 months along with urine cytology for the first 2 years of followup for high-risk patients with non-muscle-invasive bladder cancer (category 2B recommendation) (NCCN, 2017).
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 (Chang, 2016). Statements on the use of urine markers after the diagnosis of bladder of cancer are summarized as follows:
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 (Davis, 2012):
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) (USPSTF, 2015).
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2019. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Two studies prospectively evaluated the use of Xpert Bladder Cancer Monitor in follow up of patients with a history of non-muscle invasive bladder cancer. Elia et al followed 230 patients, of whom 52 patients had a new recurrence of non-muscle invasive bladder cancer (Elia, 2018). In these patients, Xpert Bladder Cancer Monitor demonstrated an overall sensitivity of 46.2% and specificity of 77%; cytology demonstrated an overall sensitivity of 11.5% and specificity of 97.2%. Pichler et al followed140 patients, of whom 43 patients had a new recurrence of non-muscle invasive bladder cancer (Pichler, 2018). In these patients, Xpert Bladder Cancer Monitor demonstrated an overall sensitivity of 84% and specificity of 91%; cytology demonstrated an overall sensitivity of 33% and specificity of 94%. Blinding was not discussed for either study; studies were further limited by a short follow up period.
2020 Update
A literature search was conducted through March 2020. There was no new information identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
The National Comprehensive Cancer Network (v.6.2020) bladder cancer guidelines include consideration for urinary urothelial tumor markers every 3 months along with urine cytology for the first 2 years of follow-up for high-risk patients with non-muscle-invasive bladder cancer (category 2B recommendation) (NCCN, 2020). The guidelines include the following statement: "Many of these tests have a better sensitivity for detecting bladder cancer than urinary cytology, but specificity is lower. Considering this, evaluation of urinary urothelial tumors may be considered during surveillance of high-risk non-muscle-invasive bladder cancer. However, it remains unclear whether these tests offer additional information that is useful for detection and management of non-muscle-invasive bladder tumors."
In 2020, the American Urological Association/Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction published a guideline on the diagnosis, evaluation, and follow-up of microhematuria (Barocas, 2020). This guideline recommended the following with regard to urinary markers:
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Two studies prospectively evaluated the use of Xpert Bladder Cancer Monitor in a follow-up of patients with a history of non-muscle invasive bladder cancer. The study by D'Elia et al followed 416 patients, of whom 168 patients had a new recurrence of non-muscle invasive bladder cancer. In these patients, Xpert Bladder Cancer Monitor demonstrated an overall sensitivity of 52.4% and specificity of 78.4%; cytology demonstrated an overall sensitivity of 17.9% and specificity of 98.5% (D’Elia, 2021).
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through March 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
The purpose of screening tests for urinary markers in asymptomatic individuals is to detect disease at an earlier stage than it would present otherwise when treatment would permit improved outcomes. Screening for polyps is currently conducted by colonoscopy, with a U.S. Preventive Services Task Force recommendation of screening every 10 years beginning at 45 years of age (USPSTF, 2021). Colonoscopy is invasive and uncomfortable and results in poor compliance with screening recommendations. The availability of a noninvasive test for precancerous polyps could improve referral for colonoscopy and early detection of colon cancer.
The following practices are currently being used to assess asymptomatic individuals at population-level risk of colon cancer: colonoscopy and fecal testing. The U.S. Preventive Services Task Force has recommended screening for colon cancer starting at age 45 and continuing until age 75 (USPSTF, 2021). The criterion standard for screening for adenomatous polyps is a colonoscopy. Alternative methods for screening include computed tomography colonography and fecal tests.
The USPSTF recommendation for screening for colorectal cancer "does not include serum tests, urine tests, or capsule endoscopy for colorectal cancer screening because of the limited available evidence on these tests and because other effective tests are available" (USPSTF, 2021).
The NCCN colorectal cancer screening guidelines (v.3.2022) do not mention use of urinary tumor markers for detection of colon cancer in asymptomatic individuals at population-level risk of colon cancer (NCCN, 2022). Colonoscopy or fecal testing are recommended for screening purposes in these individuals.
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through December 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
The Bladder EpiCheck DNA methylation biomarker test was evaluated in 2 prospective clinical trials which have only been described in the FDA review of data for the 510(k) premarket submission (US FDA, 2023). One clinical trial enrolled 674 adults urothelial carcinoma who had undergone resection within 12 months prior and were undergoing cystoscopy surveillance. Patients provided voided urine specimens at up to 3 study visits (baseline and 2 surveillance visits). Valid Bladder EpiCheck and gold standard (cytology or combined cystoscopy/pathology) results were obtained for 449 patients. Bladder EpiCheck was found to have an accuracy of 78.8%, sensitivity of 66.7%, and specificity of 84.2%, with positive and negative predictive values of 65.3% and 85.1%, respectively. In the second study, Bladder EpiCheck was compared to the predicate approval device, UroVysion in 352 matched patients (specific patient characteristics and matching criteria not described) using the same gold standard reference. Bladder EpiCheck was found to be similar to UroVysion, with numerically higher sensitivity (difference, 4.82%; 95% CI, -5.7 to 15.3) and numerically lower specificity (difference, -2.97%; 95% CI, -7.8 to 1.9).
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| References: |
Shirodkar SP, Lokeshwar VB.(2009) Potential new markers in the early detection of bladder cancer. Curr Opin Urol 2009; 19(5):488-93. Abd El-Hakim TF, El-Shafie MK, Abdou AG, et al.(2014) Value of urinary survivin as a diagnostic marker in bladder cancer. Anal Quant Cytopathol Histpathol. Jun 2014;36(3):121-127. PMID 25141488 American Urological Association. Bladder Cancer Clinical Guideline. Chapter 1: The Management of Bladder Cancer: Diagnosis and Treatment Recommendations. Available at: http://www.auanet.org/content/guidelines-and-quality-care/clinical-guidelines/main-reports/bladcan07/chapter1.pdf Accessed April 2010. Bangma CH, Loeb S, Busstra M et al.(2013) Outcomes of a bladder cancer screening program using home hematuria testing and molecular markers. . Eur Urol 2013; 64(1):41-7. Bangma CH, Loeb S, Busstra M et al.(2013) Outcomes of a bladder cancer screening program using home hematuria testing and molecular markers. Eur Urol 2013; 64(1):41-7. Barocas DA, Boorjian SA, Alvarez RD, et al.(2020) Microhematuria: AUA/SUFU Guideline. J Urol. Oct 2020; 204(4): 778-786. PMID 32698717 Breen V, Kasabov N, Kamat AM, et al.(2015) 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 C DE, Pycha A, Folchini DM, et al.(2018) Diagnostic predictive value of Xpert Bladder Cancer Monitor in the follow-up of patients affected by non-muscle invasive bladder cancer. J Clin Pathol. Oct 24 2018. PMID 30355587 Canadian Task Force on Preventive Health Care. Screening for Bladder Cancer. Available at www.ctfphc.org. Acccesed April 2010. Chahal R, Darshane A, Browning A, et al.(2001) Evaluation of the clinical value of urinary NMP-22 as a marker in the screening and surveillance of transitional cell carcinoma of the urinary bladder. Eur Urol 2001; 40(4): 415-20; discussion 421. Chou R, Buckley D, Fu R, et al.(2015) Emerging Approaches to Diagnosis and Treatment of Non–Muscle-Invasive Bladder Cancer (Comparative Effectiveness Review No. 153). Rockville, MD: Agency for Healthcare Research and Quality; 2015. Chou R, Dana T.(2010) Screening adults for bladder cancer: a review of the evidence for the U.S. Preventive Services Task Force. Ann Int Med; 2010; 153:461-468. Compérat E, Amin MB, Cathomas R, et al.(2022) Current best practice for bladder cancer: a narrative review of diagnostics and treatments. Lancet. Nov 12 2022; 400(10364): 1712-1721. PMID 36174585 D'Elia C, Folchini DM, Mian C, et al.(2021) Diagnostic value of Xpert (R) Bladder Cancer Monitor in the follow-up of patients affected by non-muscle invasive bladder cancer: an update. Ther Adv Urol. Jan-Dec 2021; 13: 1756287221997183. PMID 33747133 Davis R, Jones JS, Barocas DA, et al.(2012) Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults: AUA guideline. J Urol. Dec 2012;188(6 Suppl):2473-2481. PMID 23098784 Dimashkieh H, Wolff DJ, Smith TM et al.(2013) Evaluation of UroVysion and cytology for bladder cancer detection: a study of 1835 paired urine samples with clinical and histologic correlation. Cancer Cytopathol 2013; 121(10):591-7. Dimashkieh H, Wolff DJ, Smith TM et al.(2013) Evaluation of UroVysion and cytology for bladder cancer detection: a study of 1835 paired urine samples with clinical and histologic correlation. Cancer Cytopathol 2013; 121(10):591-7. Droller MJ.(2002) Current concepts of tumor markers in bladder cancer. Urol Clin North Am 2002; 29(1):229-34. Eissa S, Swellam M, Shehata H et al.(2010) Expression of HYAL1 and survivin RNA as diagnostic molecular markers for bladder cancer. J Urol 2010; 183(2):493-8. Fernandez CA, Millholland JM, Zwarthoff EC, et al.(2012) A noninvasive multi-analyte diagnostic assay: combining protein and DNA markers to stratify bladder cancer patients. Res Rep Urol. 2012;4(17-26):17-26. PMID 24199176 Freidrich MG, Hellstern A, Hautmann SH, et al.(2002) Clinical use of urinary markers for the detection and prognosis of bladder carcinoma: comparison of immunocytology with monoclonal antibodies against Lewis X and 486p3/12 with the BTA STAT and NMP-22 tests. J Urol 2002;168(2):470-4. Giannopoulos A, Manousakas T, Gounari A, et al.(2001) Comparative evaluation of the diagnostic performance of BTA STAT test, NMP-22, and urinary bladder cancer antigen for primary and recurrent bladder tumors. J Urol 2001; 166(2):470-5. Grocela JA, McDougal WS.(2000) Utility of nuclear matrix protein (NMP-22) in the detection of recurrent bladder cancer. Urol Clin North Am 2000; 27(1):47-51. Grossfeld GD, Litwin MS, et al.(2001) Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy - part II: patient evaluation, cytology, voided markers, imaging, cystoscopy, nephrology evaluation, and follow-up. Urology 2001; 57:604-10. Grossman HB, Messing E, et al.(2005) Detection of bladder cancer using a point-of-care proteomic assay. JAMA 2005; 293:810-816. Guo A, Wang X, Gao L, et al.(2014) 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. PMID 24940462 He H, Han C, Hao L, et al.(2016) ImmunoCyt test compared to cytology in the diagnosis of bladder cancer: A metaanalysis. Oncol Lett. Jul 2016;12(1):83-88. PMID 27347104 Horstmann M, Bontrup H, Hennenlotter J et al.(2010) Clinical experience with surviving as a biomarker for urothelial bladder cancer. World J Urol 2010 [Epub ahead of print]. Horstmann M, Patschan O, Hennenlotter J et al.(2009) Combinations of urine-based tumor markers in bladder cancer surveillance. Scand J Urol Nephrol 2009; 43(6):461-6. Kim PH, Sukhu R, Cordon BH et al.(2013) Reflex fluorescence in situ hybridization assay for suspicious urinary cytology in bladder cancer patients with negative surveillance cystoscopy. BJU Int 2013. Kim PH, Sukhu R, Cordon BH et al.(2013) Reflex fluorescence in situ hybridization assay for suspicious urinary cytology in bladder cancer patients with negative surveillance cystoscopy. BJU Int 2013. Lahme S, Bichler KH, et al.(2003) 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(PPtA):111-9. Lai Y, Ye J, Chen J et al.(2010) UPK3A: a promising novel urinary marker for the detection of bladder cancer. Urology 2010 [Epub ahead of print]. Lodde M, Mian C, Wiener H, et al.(2001) Detection of upper urinary tract transitional cell carcinoma with ImmunoCyt: a preliminary report. Urology. Sep 2001;58(3):362-366. PMID 11549481 Lotan Y, Elias K, Svatek RS et al.(2009) 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. Mowatt G, Zhu S, Kilonzo M et al.(2010) Systematic review of the clinical effectiveness and cost-effectiveness of photodynamic diagnosis and urine biomarkers (FISH,ImmunoCyt, NMP22) and cytology for the detection and follow-up of bladder cancer. Health Technol Assess 2010; 14(4):1-331. National Comprehensive Cancer Network (NCCN).(2020) Clinical Practice Guidelines in Oncology: Bladder Cancer. Version 6.2020. https://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Accessed October 28, 2020 National Comprehensive Cancer Network (NCCN).(2022) Clinical Practice Guidelines in Oncology: Colorectal Cancer Screening. Version 3.2022. https://www.nccn.org/professionals/physician_gls/pdf/colorectal_screening.pdf. Accessed October 19, 2022. National Comprehensive Cancer Network®. NCCN Clinical Practice Guidelines in Oncology™. Bladder Cancer V.2.2012. Available online at: http://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf . Last accessed April 2012. National Comprehensive Cancer Network®.(2009) NCCN Clinical Practice Guidelines in Oncology™.Bladder Cancer including Upper Tract Tumors and Urothelial Carcinoma of the Prostate v.1.2009. Available at: www.nccn.org. Accessed April 2010. Nisman B, Yutkin V, Peretz T et al.(2009) The follow-up of patients with non-muscle-invasive bladder cancer by urine cytology, abdominal ultrasound and urine CYFRA 21-1: A pilot study. Anticancer Res 2009; 29(10):4281-6. Parker J, Spiess PE.(2011) Current and emerging bladder cancer urinary biomarkers. ScientificWorldJournal. 2011;11:1103-1112. PMID 21623456 Pichler R, Fritz J, Tulchiner G, et al.(2018) Increased accuracy of a novel mRNA-based urine test for bladder cancer surveillance. BJU Int. Jan 2018;121(1):29-37. PMID 28941000 Picozzi S, Ricci C, Gaeta M, et al.(2012) Upper urinary tract recurrence following radical cystectomy for bladder cancer:a meta-analysis on 13,185 patients. J Urol. Dec 2012;188(6):2046-2054. PMID 23083867 Placer J, Espinet B, et al.(2002) 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; 42:547-52. Ponsky LE, Sharma S, Pandrangi L, et al.(2001) Screening and monitoring for bladder cancer: refining the use of NMP-22. J Urol 2001; 166(1):75-8. Rieger-Christ KM, Mourtzinos A, Lee PJ, et al.(2003) Identification of fibroblast growth factor receptor 3 mutations in urine sediment DNA samples complements cytology in bladder tumor detection. Cancer. Aug 15 2003;98(4):737-744. PMID 12910517 Sarosdy MF, Schelhammer P, et al.(2001) Clinical evaluation of a multi-target fluorescent in situ hybridization assay for detection of bladder cancer. J Urol 2001; 168:1950-4. Stampfer DS, Carpinito GA, Rodriguez-Villanueva J, et al.(1998) Evaluation of NMP-22 in the detection of transitional cell carcinoma of the bladder. J Urol 1998; 159(2):394-8. Sturgeon CM, Duffy MJ, Hofmann BR et al.(2010) National Academy of Clinical Biochemistry Laboratory Medicine practice guidelines for use of tumor markers in liver, bladder, cervical and gastric cancers. Clin Chem 2010 [Epub ahead of print]. Sullivan PS, Nooraie F, Sanchez H et al.(2009) Comparison of ImmunoCyt, UroVysion and urine cytology in detection of recurrent urothelial carcinoma. Cancer Cytopathol 2009; 117(3):167-73. Svatek RS, Sagalowsky AI, Lotan Y.(2006) Economic impact of screening for bladder cancer using bladder tumor markers: a decision analysis. Urol Oncol 2006; 24(4):338-43. Todenhofer T, Hennenlotter J, Esser M, et al.(2014) Stepwise application of urine markers to detect tumor recurrence in patients undergoing surveillance for non-muscle-invasive bladder cancer. Dis Markers. 2014;2014:973406. PMID 25587206 U.S. Preventive Services Task Force. Screening for Bladder Cancer in Adults: Recommendation Statement. August 2011. Available online http://www.ahrq.gov/clinic/3rduspstf/bladder/blacanrs.pdf. Last accessed April 2012. US Food and Drug Administration (FDA).(2023) 510(k) Summary for Bladder EpiCheck Test (K203245). May 2023; https://www.accessdata.fda.gov/cdrh_docs/pdf20/K203245.pdf. Accessed October 22, 2023 US Preventative Services Task Force (USPSTF).(2021) Colorectal cancer screening. 2021; https://www.uspreventiveservicestaskforce.org/uspstf/document/RecommendationStatementFinal/colorectal-cancer-screening. Accessed October 16, 2022. Xu C, Zeng Q, Hou J, et al.(2011) Utility of a modality combining FISH and cytology in upper tract urothelial carcinoma detection in voided urine samples of Chinese patients. Urology. Mar 2011;77(3):636-641. PMID 21256577 Zuiverloon TC, Beukers W, van der Keur KA, et al.(2013) Combinations of urinary biomarkers for surveillance of patients with incident nonmuscle invasive bladder cancer: the European FP7 UROMOL project. J Urol. May 2013;189(5):1945-1951. PMID 23201384 Zuiverloon TC, van der Aa MN, van der Kwast TH, et al.(2010) Fibroblast growth factor receptor 3 mutation analysis on voided urine for surveillance of patients with low-grade non-muscle-invasive bladder cancer. Clin Cancer Res. Jun 01 2010;16(11):3011-3018. 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