Efficient and Effective Use of Exfoliative Markers

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Eugene Fisher
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1 Innovations in Urologic Oncology: Bladder Cancer Efficient and Effective Use of Exfoliative Markers Jared M Whitson, MD April 9 th, 2010, CA URINARY TUMOR MARKERS Future Directions Urinary Tumor Markers Hemoglobin Dipstick Hemoglobin Dipstick Point-of-Care Urinary Cytology BTA-STAT / BTA-TRAK NMP-22 ImmunoCyt Detects hematuria, hemoglobinuria, myoglobinuria 25 cents False positives occur for any GU source not due to bladder cancer UroVysion Follow-up with microscopic evaluation of urine Positive test 2 RBC s/hpf on 2/3 specimen 1

2 Urinary Cytology BTA-STAT / BTA-TRAK Point-of-Care (BTA-STAT) Send out ELISA (BTA-TRAK) >14 U/mL positive Send out to cytopathologist Detects Human Complement H related protein Cost around $60-$100 $10-$15 BTA STAT / $175 BTA-TRAK Often equivocal, atypical, or suspicious Patients already diagnosed with bladder cancer Used in conjunction with cystoscopy Equivocal or Atypical frequent during BCG Not for screening, patients with signs of active infections, patients who have received BCG NMP-22 ImmunoCyt Point of Care (BladderCheck) Send out ELISA (NMP22) >10 U/mL positive Nuclear Matrix Apparatus Protein Send out conjunction cytology Carcinoembryonic Antigen (CEA) and 2 bladder cancer specific mucins Single red or green cell positive $10-$30 (BladderCheck) / $125-$150 (NMP22) Both initial diagnosis patients risk factors or symptoms and monitoring $130-$385 patients known bladder cancer along with cystoscopy Not for screening, or use in patients catheters or stents, or after cystectomy 2

3 UroVysion Comparison of Markers (2006) Send out to specialized lab Fluorescence in situ hybridization detects aneuploidy chromosomes 3,7, and 17 and loss of 9p21 locus 4 cells gains 3,7,17 or 12 cells loss 9p21 $475-$700 in patients with hematuria or monitoring in patients with known bladder cancer Marker Mean Sensitivity (range) Mean Specificity (range) Hgb Dipstick 71% (47%-93%) 67% (51%-84%) Cytology 48% (28%-76%) 96% (81%-100%) BTA-STAT 69% (53%-89%) 74% (54%-93%) BTA-TRAK 62% (17%-78%) 74% (51%-95%) NMP22 68% (31%-92%) 74% (5%-94%) ImmunoCyt 58% (39%-86%) 79% (73%-84%) UroVysion 77% (73%-81%) 98% (96%-100%) Not for use when patient has known untreated tumor Konety Urol Onc 2006 Comparison (2010) Marker Patients Sensitivity (95% CI) Specificity (95% CI) Cytology 22,260 44% (38%-51%) 96% (94%-98%) NMP22 13,885 68% (62%-74%) 79% (74%-84%) ImmunoCyt 4,199 84% (77%-91%) 75% (68%-83%) UroVysion 3,321 76% (65%-84%) 85% (78%-92%) Public Health and Economic Impact Urinary Tumor Markers SCREENING Future Directions Mowatt Health Tech Asscn

4 Screening Screening Dipstick Hematuria studies from the late 1980 s Modern studies investigating markers Patients Dipstick + Bladder Ca PPV US Study ~ % 1.3% 8% UK Study ~600 17% 0.7% 5% Attempt identify higher risk groups Age, smoking, occupational exposure Steiner Lotan Greene Dipstick NMP22 Cytology UroVysion NMP22 Dipstick NMP22 Positive Test 31% 6% 5% 8% 6% 7% 0.5% Urothelial Ca 3% 3% 3% 3% 0.2% 0.3% 0.3% PPV 5% 9% 10% 7% 4% 4% 25% Messing Urol 1995 and Britton BMJ 1989 Steiner BJUI 2008, Lotan J Urol 2009, and Greene J Urol (supp) 2008 Diagnosis Public Health and Economic Impact Sensitivity/Specificity applicable same dz spectrum Urinary Tumor Markers PPV/NPV only applicable same dz prevalence DIAGNOSIS Future Directions Posterior Odds = Prior Odds X LR LR (+) = sensitivity / (1-specificity) LR (-) = (1-sensitivity) / specificity Prob = odds / (1+odds) Odds = prob / (1-prob) 4

5 Diagnosis Diagnosis Microscopic Hematuria -- Risk Bladder Ca ~3% Gross Hematuria -- Risk Bladder Ca ~20% Eliminate cystoscopy with negative test? Marker Sensitivity Specificity LR (-) Probability Hgb Dipstick 71% 67% % Cytology 44% 96% % BTA-STAT 69% 74% % BTA-TRAK 62% 74% % NMP22 68% 79% % ImmunoCyt 84% 75% % UroVysion 76% 85% % Eliminate cystoscopy with negative test? Marker Sensitivity Specificity LR (-) Probability Hgb Dipstick 71% 67% % Cytology 44% 96% % BTA-STAT 69% 74% % BTA-TRAK 62% 74% % NMP22 68% 79% % ImmunoCyt 84% 75% % UroVysion 76% 85% % Monitoring Monitoring LG Ta -- Recurrence 1 st yr is 37% (~9%/eval) HG Ta,T1,CIS -- Recurrence 1 st yr is 55% (~14%/eval) Eliminate cystoscopy with negative test? With negative cysto positive marker require biopsy? Marker Sensitivity Specificity LR (-) Probability Hgb Dipstick 8% 67% % Cytology 12% 96% % BTA-STAT 47% 74% % BTA-TRAK 63% 74% % NMP22 61% 79% % ImmunoCyt 80% 75% % UroVysion 45% 85% % Cysto sensitivity-85% specificity-70% LR(-) = 0.2. Post-cysto probability 3% Marker Sensitivity Specificity LR (+) Probability LR (-) Probability Hgb Dipstick 76% 67% 2.3 7% % Cytology 64% 96% % % NMP22 79% 79% % % ImmunoCyt 85% 75% % % UroVysion 91% 85% % % adapted from Lotan Urol 2003 and Lokeshwar Urol 2005 adapted from Lotan Urol 2003 Lokeshwar Urol

6 Cost-Effectiveness Public Health and Economic Impact Urinary Tumor Markers COST-EFFECTIVENESS Future Directions Lotan J Urol 2002 Cost-Effectiveness Cost-Effectiveness Closer to a true cost-effectiveness analysis 2010 Cytology and cystoscopy least effective strategy year life expectancy ~$30k per year of life saved Cysto+ImmunoCyt followed PDD TURBT dx and cysto follow-up most effective strategy year life expectancy ~$400k per year of life saved However, this still doesn t involve patient perspective Patient Perspective on Urinary Markers to Replace Cystoscopy 102 patients UMC, The Netherlands 89% prefer cysto over marker if sensitivity <90% Males, older patients, fewer prior cystos, fewer recurrences associated lower accepted sensitivity 200 patients MSKCC 75% required accuracy of >95% Males and >pain during procedure associated lower accepted accuracy Mowatt Health Tech Asscn 2010 Vriesema Urol 2000 and Yossepowitch J Urol

7 REFLEX TESTING Public Health and Economic Impact Urinary Tumor Markers FUTURE DIRECTIONS Lotan J Urol 2008 PROGNOSIS EARLY DETECTION IVT FAILURE Whitson BJUI 2009 Whitson Int Braz J Urol

8 Conclusions References Hard to find high risk group; Low PPV No prospective study survival benefit Microhematuria marker negative no cysto? Gross Hematuria little role for markers Low Risk ImmunoCyt? High Risk not significantly better cytology Lack of data particularly re: patient preferences 1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, CA: a cancer journal for clinicians 2009;59(4): Botteman MF, Pashos CL, Redaelli A, Laskin B, Hauser R. The health economics of bladder cancer: a comprehensive review of the published literature. PharmacoEconomics 2003;21(18): Riley GF, Potosky AL, Lubitz JD, Kessler LG. Medicare payments from diagnosis to death for elderly cancer patients by stage at diagnosis. Medical care 1995;33(8): Konety BR, Joyce GF, Wise M. Bladder and upper tract urothelial cancer. The Journal of urology 2007;177(5): Konety BR. Molecular markers in bladder cancer: a critical appraisal. Urologic oncology 2006;24(4): Mowatt G, Zhu S, Kilonzo M, et al. Systematic review of the clinical effectiveness and costeffectiveness of photodynamic diagnosis and urine biomarkers (FISH, ImmunoCyt, NMP22) and cytology for the detection and follow-up of bladder cancer. Health technology assessment (Winchester, England);14(4):1-331, iii-iv. 7. Messing EM, Young TB, Hunt VB, et al. Comparison of bladder cancer outcome in men undergoing hematuria home screening versus those with standard clinical presentations. Urology 1995;45(3):387-96; discussion Britton JP, Dowell AC, Whelan P. Dipstick haematuria and bladder cancer in men over 60: results of a community study. BMJ (Clinical research ed 1989;299(6706): Steiner H, Bergmeister M, Verdorfer I, et al. Early results of bladder-cancer screening in a high-risk population of heavy smokers. BJU international 2008;102(3): 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. The Journal of urology 2009;182(1):52-7; discussion Greene K. Results from the firefighters bladder cancer screening study. Journal of Urology 2008;179(4 (supp)):323. References (cont.) 12. Lotan Y, Roehrborn CG. Sensitivity and specificity of commonly available bladder tumor markers versus cytology: results of a comprehensive literature review and meta-analyses. Urology 2003;61(1):109-18; discussion Lokeshwar VB, Habuchi T, Grossman HB, et al. Bladder tumor markers beyond cytology: International Consensus Panel on bladder tumor markers. Urology 2005;66(6 Suppl 1): Lotan Y, Roehrborn CG. Cost-effectiveness of a modified care protocol substituting bladder tumor markers for cystoscopy for the followup of patients with transitional cell carcinoma of the bladder: a decision analytical approach. The Journal of urology 2002;167(1): Vriesema JL, Poucki MH, Kiemeney LA, Witjes JA. Patient opinion of urinary tests versus flexible urethrocystoscopy in follow-up examination for superficial bladder cancer: a utility analysis. Urology 2000;56(5): Yossepowitch O, Herr HW, Donat SM. Use of urinary biomarkers for bladder cancer surveillance: patient perspectives. The Journal of urology 2007;177(4): ; discussion Lotan Y, Bensalah K, Ruddell T, Shariat SF, Sagalowsky AI, Ashfaq R. Prospective evaluation of the clinical usefulness of reflex fluorescence in situ hybridization assay in patients with atypical cytology for the detection of urothelial carcinoma of the bladder. The Journal of urology 2008;179(6): Whitson J, Berry A, Carroll P, Konety B. A multicolour fluorescence in situ hybridization test predicts recurrence in patients with high-risk superficial bladder tumours undergoing intravesical therapy. BJU international 2009;104(3): Whitson JM, Berry AB, Carroll PR, Konety BR. UroVysion testing can lead to early identification of intravesical therapy failure in patients with high risk non-muscle invasive bladder cancer. Int Braz J Urol 2009;35(6):664-70; discussion

MEDICAL POLICY SUBJECT: URINARY TUMOR MARKERS FOR BLADDER CANCER. POLICY NUMBER: CATEGORY: Technology Assessment

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