Measuring the Efficacy and Value of Urothelial Cancer Urinary Biomarkers

The initial diagnosis of bladder cancer most often occurs after an episode of gross or microscopic hematuria. The recommended work-up for gross hematuria includes cystoscopy, cytologic evaluation, and imaging (1). The risk for tumors during a hematuria work-up ranges from 2% to 20% and depends on whether the patient had gross or microscopic hematuria, as well as tobacco exposure, sex, exposure to radiation or occupational carcinogens, and history of urologic tumors. Up to 30% of patients with newly diagnosed bladder cancer will have muscle-invasive disease at the initial diagnosis, suggesting an opportunity for screening tests to identify disease in earlier stages before the onset of hematuria. However, screening requires the availability of a highly sensitive and specific test to both properly identify patients who need further work-up and avoid the unnecessary testing and costs of evaluating true-negative results. For example, patients with microhematuria have a 1% to 5% risk for associated tumors. Therefore, cystoscopy and imaging evaluation of this group as a whole is probably not cost-effective due to the low positive predictive value for urologic cancer and the high false-positive rate associated with urinalysis and microscopy (2). Thus, an unmet need exists for better noninvasive screening techniques, such as urine-based biomarkers. In addition, patients with superficial bladder cancer tend to have recurrent but not progressive disease, necessitating life-long surveillance. Therefore, surveillance is another setting in which urinary biomarkers would be valuable. Five such biomarkers have been approved by the U.S. Food and Drug Administration for screening patients with symptoms or surveillance of patients with a history of bladder tumors. In this issue, Chou and colleagues (3) report a systematic review and meta-analysis of these biomarkers. Antibody-based detection of nuclear matrix protein 22 (NMP22) (BladderChek [Alere]) is a point-of-care immunochromatographic test that detects a protein released into urine as bladder cancer cells go through apoptosis. Another immunochromatographic antibody-based test detects bladder tumor antigen (BTA stat [Polymedco]). Fluorescent in situ hybridization (FISH) (UroVysion [Abbott Molecular]) detects genetic alterations common in bladder cancer, such as amplification in chromosomes 3, 7, and 17 and loss of 9p21 (4). The CDKN2A gene is located on 9p21 and encodes one of the most commonly lost tumor suppressor genes in human cancer, and its loss is detected by FISH. ImmunoCyt (Scimedx) is an immunohistochemical test that marks cytologic samples for mucin and carcinoembryonic antigen (5). Cxbladder (Pacific Edge Diagnostics USA), a technique that is based on reverse transcriptase polymerase chain reaction, detects 5 messenger RNAs that are expressed in urothelial cancer (6). In their review, Chou and colleagues identified 57 studies evaluating performance characteristics of these 5 urinary biomarkers. They found that NMP22 and bladder tumor antigen were the most studied, with approximately 20 studies each. Cxbladder had 1 study with sufficient quality for inclusion in the meta-analysis. ImmunoCyt and FISH had 14 and 11 studies, respectively. ImmunoCyt had the highest sensitivity in evaluating patients with symptoms (85%) or those undergoing surveillance (75%). Fluorescent in situ hybridization had the highest specificity (95%) in evaluating symptoms, and qualitative NMP22 was the most specific in detecting recurrent disease (83%). No test stood head and shoulders above the rest, and few studies compared multiple biomarkers head-to-head. To put these data into context, most patients with newly diagnosed urothelial cancer will have superficial disease, and most of these cases will be low-grade or low-stage. Detecting these lesions is inherently more difficult because of the similarity of normal exfoliated urothelial cells and low-grade urothelial tumors. High-grade disease is more easily distinguishable due to more pronounced differences in genetics, expression profiles, cell turnover, and necrosis or apoptosis common to these tumors. Cytologic evaluation of urine provides a high-water mark for detection of high-grade disease, with sensitivity and specificity up to 90% and 95%, respectively (7, 8). However, it clearly falls short in detecting low-grade disease, with sensitivity as low as 50% in some studies (9). Thus, the potential usefulness of molecular tests would be greatest in patients with lower-grade disease. However, the addition of molecular tests that do not exempt clinicians from using other means to clinch a diagnosis (such as cystoscopy with biopsy) would probably add more cost without benefit. Are urinary biomarkers, with or without cytologic evaluation, adequate to avoid cystoscopy in patients with low-grade or low-stage disease? Also, what is the cost of missing a low-grade or low-stage tumor if a cytologic result is negative in the absence of cystoscopy? Few data exist to answer these questions decisively. To evaluate cost-effectiveness, studies need to evaluate presymptomatic patients or those with early-onset hematuria with 1 of these 5 tests, or a combination thereof, in addition to cystoscopy, cytologic evaluation, and imaging. The economics of each evaluation and management algorithm would then be modeled for the current recommended work-up or with selective use of cystoscopy, cytologic evaluation, or imaging only in patients with positive results. Biomarkers would provide value only if they circumvented the need for invasive evaluation or the need for more costly management if diagnoses were made earlier. Cost-effectiveness analyses would also need to incorporate estimated costs of missed diagnoses and overdiagnoses. Existing cost-effectiveness estimates suggest that even in patients with a history of superficial bladder cancer (and thus a higher a priori positive predictive value), cystoscopy-only is the most cost-effective strategy for detection of tumors (10). Furthermore, tumors missed on cystoscopy were also missed by urinary biomarkers. Thus, until urinary biomarkers become available that are sufficiently accurate to supplant the current recommended detection algorithms in biomarker-negative patients, they will not be a cost-effective addition to strategies to detect bladder cancer.