UroVysion fluorescence in situ hybridisation (FISH) assay: November 2005 MSAC Application 1084 Assessment report

THE PROCEDURE: Fluorescence in situ hybridisation (FISH) is a technique which detects chromosomal and genetic aberrations at the cellular level by using fluorescent-labelled nucleic acid probes. In bladder cancer, numerous chromosomal abnormalities have been identified which are associated with both the development and progression of the disease. The UroVysion FISH assay consists of a four-colour, four-probe mixture of DNA probe sequences homologous to specific regions on chromosomes 3, 7, 9 and 17. The assay is designed to detect aneuploidy of chromosomes 3, 7 and 17, and the loss of the 9p21 locus on chromosome 9. This set of probes was selected for testing on the basis of reports in the scientific literature that associated these changes in DNA (chromosome copy number changes or deletion of the locus) with bladder cancer (Vysis 2005). The Vysis UroVysion probe mixture contains chromosome enumeration probe (CEP) 3 SpectrumRed, CEP 7 SpectrumGreen and CEP 17 SpectrumAqua, which hybridise to the centromere regions of chromosomes 3, 7 and 17 respectively, and locus-specific identifier (LSI) 9p21 SpectrumGold, which hybridises to the p16 gene at 9p21. The process of performing FISH using the UroVysion assay first involves fixing cells from urine samples on microscope slides. The DNA is denatured to its single-stranded form and allowed to hybridise with the UroVysion DNA probes. Following hybridisation, unbound probe is removed by a series of washes, and the nuclei are counterstained with DAPI (4,6-diamidino-2-phenylindole), a DNA-specific stain that fluoresces blue (Vysis 2005). Specific hybridisation of the UroVysion probes is viewed through a fluorescence microscope equipped with appropriate excitation and emission filter sets allowing visualisation of the red, green, aqua, and gold fluorescent signals. The probes specific for chromosomes 3, 7, and 17 and the 9p21 region are counted by microscopic examination of the nuclei, which are easily distinguished by the DAPI staining. Interpretation of results involves recording the DNA probe profile (the number of probe signals of each colour) to determine whether there is aneusomy of chromosomes 3, 7 or 17, or deletion of the 9p21 locus. MEDICAL SERVICES ADVISORY COMMITTEE - ROLE AND APPROACH: The Medical Services Advisory Committee (MSAC) was established by the Australian Government to strengthen the role of evidence in health financing decisions in Australia. MSAC advises the Minister for Health and Ageing on the evidence relating to the safety, effectiveness and cost-effectiveness of new and existing medical technologies and procedures, and under what circumstances public funding should be supported. A rigorous assessment of evidence is thus the basis of decision-making when funding is sought under Medicare. A team from the National Health and Medical Research Council’s Clinical Trials Centre was engaged to conduct a systematic review of literature on the UroVysion FISH assay for the detection of bladder cancer recurrence. An advisory panel with expertise in this area then evaluated the evidence and provided advice to MSAC. MSAC'S ASSESSMENT OF THE UROVYSION FISH ASSAY FOR DETECTING RECURRENT BLADDER CANCER: The evaluators worked with members of the advisory panel to develop specific questions on the use of the UroVysion FISH assay for detecting recurrence of transitional cell carcinoma (TCC) of the bladder. The question addressed in this review is: - What is the value of the UroVysion FISH Assay in conjunction with cystoscopy versus cystoscopy alone to diagnose recurrence of TCC in patients who have previously been diagnosed with TCC of the bladder who would undergo cystoscopy under local anaesthetic? A comprehensive search strategy was developed to identify systematic reviews and controlled trials of the safety, effectiveness or cost-effectiveness of the UroVysion FISH assay. In addition to electronic database searches, reference lists of identified publications were hand-searched, and publications were provided by the company submitting the application. Seven publications met criteria for inclusion in the report. CLINICAL NEED: Bladder cancer is one of the most common cancers in Western society. In Australia in 2001, bladder cancer was the fifth most common cancer among men and the eight most common cancer overall (AIHW 2004b). It was associated with 3.1% of all cancer deaths among men, and 2.5% of cancer deaths overall (AIHW 2004b). The incidence of bladder cancer has steadily increased between 1991 and 2001 at an average rate of 0.1% per annum for males and 0.7% per annum for females (AIHW 2004b). Furthermore, in Australia in 2002–03, there were 15 672 hospital separations (both public and private) for malignant neoplasm of the bladder (ICD-10-AM principal diagnosis code C67), which corresponds to 4.01 separations per 10 000 population (AIHW 2004a). These separations included 47 248 patient days, with an average length of stay for each separation of 3.02 days (AIHW 2004a). Recurrence of bladder cancer is common: 60% to 80% of patients with papillary tumours experience recurrence after initial destruction of the papillary lesions (Newling et al. 1995). Tumours are most likely to recur in the first year after transurethral resection (Debruyne & Witjes 1999), and patients are closely monitored for recurrence after their initial presentation and treatment. In patients who initially present with superficial tumours, the majority of recurrent tumours are also superficial, but about 15% of patients will develop tumour progression with bladder muscle invasion (Van Erps & Denis 1999). SAFETY: None of the seven studies included in this review reported complications from the UroVysion test, cystoscopy or any of the comparators. As the UroVysion FISH Assay is a non-invasive test performed on voided urine, there are minimal or no risks to the safety of the patient providing the urine sample. As urine is a body fluid, universal blood and body fluid precautions should be followed to ensure the safety of staff involved in the collection, transport and analysis of the urine samples. In comparison to the UroVysion test, cystoscopies are invasive procedures and are associated with known adverse effects. These include bladder rupture, stranguria, bleeding and urinary tract infections, although it would appear that the incidence of serious complications following cystoscopy is rare, and although minor complications are more common, they usually resolve spontaneously within 48 hours and are likely to be of minimal clinical significance. EFFECTIVENESS: Seven diagnostic accuracy studies were identified for inclusion in the review. In general, the quality of the studies was fair, with one study of high quality and one study of low quality. The studies include a total of 1072 patients, with sample sizes ranging from 19 to 451, and a median of 86. These sample sizes include patients with a history of bladder cancer, patients being investigated for bladder cancer who have no history of bladder cancer, and healthy controls or patients without suspected bladder cancer. Considering only those patients being monitored for bladder cancer recurrence, there were a total of 558 patients, with sample sizes ranging from 19 to 176, and a median of 51. Four of the included studies provided sufficient data for the reconstruction of two-bytwo tables of results in patients being monitored for recurrence. The other three studies presented only values of sensitivity or specificity. Owing to statistically significant heterogeneity in the estimates of UroVysion accuracy across studies, a single pooled estimate of test accuracy could not be obtained. The sensitivity of the UroVysion test ranged from 48% to 86%, and the specificity ranged from 34.3% to 100%. Differences in the types of patients included in the trials, the reference standard used and the quality of the trials is likely to have contributed to the variation between studies. The potential impact of the UroVysion test on clinical practice was determined from the results of the studies, which were used to gain estimates of the likelihood ratios (LRs) of the UroVysion test. The positive LRs ranged from 1.3 to 21.1, and the negative LRs ranged from 0.2 to 0.5. Applying these LRs to various pretest probabilities of recurrence (based on risk of recurrence and period of follow-up) revealed that for most patients, the use of the UroVysion test does not greatly increase the probability of detecting recurrence. Clinical impact is likely to be greatest in patients with a high risk of recurrence who have undergone at least one year of follow-up. In these patients, current practice is to give patients a cystoscopy under local anaesthetic (LA), and a large proportion undergo a second cystoscopy under general anaesthetic (GA) (owing to high rates of recurrence). Using the result of the UroVysion test to determine the type of anaesthetic for cystoscopy means that only a small number of patients will unnecessarily undergo cystoscopy under GA (owing to a false positive UroVysion test), while the majority of patients will have to undergo only one cystoscopy (compared with current practice). The post-test probabilities show that in patients with a low risk of recurrence who are early in their follow-up, the chance of missing a recurrence following a negative UroVysion test is small, but the probability of missing a recurrence increases in patients with higher risks or in patients at later stages in their follow-up. This problem of false negatives is not of clinical significance if the UroVysion test is only to be used in conjunction with cystoscopy, as the recurrence will be detected by cystoscopy. COST-EFFECTIVENESS: The reviewers developed an economic model comparing a clinical pathway where patients undergo cystoscopy under LA followed by a cystoscopy under GA if they have a positive result to a pathway where patients initially undergo the UroVysion test, the result of which informs whether a patient undergoes cystoscopy under LA or GA. The model showed that at both the 3-month follow-up and at 5 years (cumulative costs over a 5-year follow-up period), the costs of following the UroVysion clinical pathway exceeded the costs of following the current-practice clinical pathway. At 5 years, the cost of following the UroVysion pathway was $7835, compared to $5959 for following current practice. Therefore, the UroVysion clinical pathway increased the expected cost for patients until first recurrence by $1876 over current practice. As the cost analysis is conditional on the rate of recurrence, the costs of procedures, the sensitivity and specificity of the UroVysion test, and the specificity of LA cystoscopy, one-way sensitivity analysis and a best-case scenario were used to allow for the uncertainty of the parameters used in the model. In general, under any plausible variation of evidence of accuracy, costs or rates of recurrence, the use of the UroVysion test remained more costly than current practice given the expected diagnostic pathways. As diagnostic pathways with and without the UroVysion test are expected to have equivalent clinical outcomes, the UroVysion clinical pathway was dominated by (more expensive while having equivalent effects relative to) current practice. RECOMMENDATION: MSAC recommended that on the strength of evidence pertaining to UroVysion fluorescence in situ hybridisation (FISH) assay public funding should not be supported for this procedure. The clinical usefulness of the test is limited by the sensitivity and expense of the test and the cost effectiveness was not demonstrated. - The Minister for Health and Ageing accepted/rejected this recommendation on 28 March 2006. -