Authors' recommendations: TAP’s overview of the post-2005 literature indicates both substantial recent publication activity and the lack of studies at the higher levels of diagnostic test evaluation necessary to change the conclusions of the MSAC (2005) review of UroVysion FISH. Additional diagnostic accuracy studies with imperfect cytology as the gold standard and narrative reviews contribute little to the body of knowledge.The single post-MSAC comprehensive systematic review (van Rhijn, 2005; Table 2) further confirms that studies to that date were limited to the diagnostic accuracy level and do not support replacing cystoscopy- or cytology-based surveillance by urine markers. The single relevant trial of surveillance protocols (Denzinger, 2007) tested 5-amino-levulinic acid-induced fluorescence diagnosis against white light cystoscopy and found a statistical advantage to fluorescent diagnosis at 8 years. Yoder (2007) also report that 27% of patients without immediate cystoscopic evidence of recurrence will have positive FISH; 63% of “anticipatory positives” developed recurrent cancer during 29-month follow up, the majority of which were low-grade.More recent primary research also fails to provide fully definitive answers. A direct comparison of UroVysion to cytology and quantitative cytology (Moonen, 2007) concludes that UroVysion provides no improvement over current cytology-based surveillance protocols. Another primary research report (Gudjonnson, 2007; available to TAP only in abstract form also confirms MSAC’s conclusion (Table 2, Appendix) that UroVysion’s low sensitivity limits clinical usefulness. With TAP’s caveat regarding their relatively small (175 FU visits) diagnostic accuracy study and with insufficient detail in the abstract to judge study quality, Gudjonsson (2007) conclude:“...the UroVysion urinary test has too low sensitivity to be considered as an alternative to cystoscopy in surveillance of patients with superficial bladder cancer. UroVysion ishowever valuable for detecting CIS in the bladder. Its use should be considered in patients with a history of high grade urothelial cancer, patients with equivocal cystoscopic findings and patients with inconclusive or atypical urine cytology.”Finally, bladder cancer is a cigarette-associated disease for which many aspects of optimal management, including surveillance for recurrence with newer biomarkers, have yet to be fully defined, as does optimal allocation of societal resources to prevention versus treatment.The optimal cut point for a FISH positive diagnosis remains to be determined, the test is not in a position to replace cytology, and no trial directly comparing FISH to other tests and reporting health outcomes in patients under surveillance for recurrent bladder non-muscle invasive cancer (stratified by grade and stage under a standardized nomenclature) has been reported or is in progress, from 2005 to 2007, nor has an economic evaluation based on the results of such a trial.Three 2006 narrative summaries (Liou; Black; Nielsen) of biomarkers for detection and surveillance of urothelial cancer warrant repetition in 2007:“The ideal urinary bladder tumor test is still unavailable, but the eventual “gold standard“’ will consist of multiplex assays that analyze nucleic acids and proteins for detection. In addition, these tests would also reveal to the clinician both prognostic information and therapeutic targets for personalized medical treatment.” (Liou, 2006).None of these markers has proved sensitive and specific enough to replace cystoscopy. Others, such as nuclear matrix protein 22 (NMP22) and UroVysion, appear to have some utility when used to complement or replace cytology. The other applications (replacement or reduction in number of cystoscopies, predicting recurrence or progression, substitution or concurrent use with cytology, predicting or monitoring response to treatment) have not been adequately studied for any given marker. While multiple molecular markers exist for bladder cancer, their full clinical utility will not be realized until more multicenter trials are conducted to verify their efficacy and safety in the monitoring of patients with superficial bladder cancer.” Black (2006).“This assay (UroVysion FISH) received FDA approval in January 2005. Different studies have selected a threshold of either >10 or >20% aneuploid cells as the cutoff for a positive test. The lower threshold results in increased sensitivity for low-grade lesions and though such gains often come at the cost of slower specificity, at least one study utilizing the > 10% threshold did not find substantial sacrifices in terms of specificity. In ay event, standardization of the criterion for a positive test represents one outstanding issue that must be resolved for translation of this strategy to broader clinical application.” Nielsen (2006).

Project Status: Completed

URL for project: http://www4.va.gov/VATAP/docs/BladderCancerSurveillance2008tm.pdf

Year Published: 2007

English language abstract: An English language summary is available

Publication Type: Not Assigned

Country: United States

Organisation Name: VA Technology Assessment Program

Contact Address: Liz Adams, VA Technology Assessment Program, Office of Patient Care Services (11T), VA Boston Healthcare System Room 4D-142, 150 South Huntington Avenue, Boston, MA 02130 USA Tel: +1 617 278 4469; Fax: +1 617 264 6587;

Contact Name: elizabeth.adams@med.va.gov

Contact Email: elizabeth.adams@med.va.gov

Copyright: VA Technology Assessment Program (VATAP)