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Chou R, Dana T. Screening Adults for Bladder Cancer: Update of the 2004 Evidence Review for the US Preventive Services Task Force [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2010 Oct. (Evidence Syntheses, No. 78.)

3Results

Key Question 1. Is there direct evidence that screening for bladder cancer reduces morbidity or mortality?

Summary

We identified no randomized, controlled trials of screening for bladder cancer. Three observational studies found screening for bladder cancer associated with decreased risk of bladder cancer mortality or lower stage at diagnosis (or trends toward decreased risks), but were difficult to interpret due to important methodological shortcomings.21–23

Evidence

We identified no randomized, controlled trials of screening for bladder cancer. One older prospective study24 was included in the previous USPSTF report, with results reported for up to 8.5 years of follow-up (Table 2). For this update, we included results through 14 years of follow-up. The study evaluated screening in community-dwelling men ages 50 or older (n=1,575), with a comparison group consisting of patients newly diagnosed with bladder cancer and entered in a statewide registry (n=511). About half of the men invited to participate in the study declined. Screening was based on repeated urine self-testing at home for up to 1 year. 16 percent (258/1575) of screened men had hematuria, and 1.3 percent (21/1575) were diagnosed with bladder cancer, including one case of muscle-invasive cancer (0.06 percent). The proportion of bladder cancers that were classified as low-grade and superficial at the time of diagnosis was similar in the screen-detected and cancer registry groups (52 percent vs. 57 percent; relative risk [RR], 0.92 [95% confidence interval, 0.61–1.4]). The proportion of high-grade, superficial bladder cancers was higher in the screened group (43 percent vs. 19 percent; RR, 2.2 [95% CI, 1.3–3.7]), with a non-statistically significant trend toward a decreased proportion of invasive bladder cancers (5 percent vs. 24 percent; RR, 0.20 [95% CI, 0.03–1.4]). After 14 years of follow-up, the risk of bladder cancer death was lower in the screened group compared to the cancer registry patients (0 percent or 0/21 vs. 20 percent or 104/509; p=0.01), primarily due to a decrease in risk in patients with high-grade or invasive cancers (0 percent or 0/10 vs. 38 percent or 77/200; p=0.01).22 Largely due to the effects on bladder cancer-related mortality, the risk of all-cause mortality was also lower in the screened group (43 percent or 9/21 vs. 74 percent or 377/509; RR, 0.58 [95% CI, 0.35–0.95]). We rated this study as poor quality because it did not assemble an inception cohort of comparable unscreened subjects. Results are highly susceptible to confounding due to differences between the screened patients and those entered in the registry, lead-time bias, length-time bias, sparse data (due to no deaths in the screened group), and other factors. No attempt was made to adjust or control for potential confounders. The study reported bladder cancer rates among the cohort of men invited to enroll in the screening study but who declined (based on cases reported to the statewide registry). Rates of new bladder cancers were identical among screened patients and those who did not participate in the study (1.3 percent vs. 1.2 percent), but clinical outcomes were not compared. We identified two other poor-quality studies that met inclusion criteria and were not included in the prior evidence review (Table 2).21, 23 A cohort study found that in aluminum production workers exposed to benzene-soluble coal tar-pitch volatile chemicals, there were non-statistically significant trends toward a higher proportion of early-stage bladder cancer at diagnosis (77 percent vs. 67 percent) and increased 5-year survival (RR, 0.54 [95% CI, 0.20–1.48]) after annual urine cytology screening was instituted compared to before the screening program.23 This study was rated poor quality because it evaluated a historical control group and did not attempt to adjust or control for confounders. A case-control study found that persons who died from bladder cancer had lower odds of having received a screening urinalysis in the previous 5 years, after adjustment for smoking status and occupational bladder cancer exposure (odds ratio [OR], 0.60 [95% CI, 0.41–0.87).21 This study was rated poor quality because it could not accurately ascertain the reason that urinalyses were obtained.

Table 2. Screening Studies.

Table 2

Screening Studies.

Other prospective studies on bladder cancer screening did not meet inclusion criteria because they were uncontrolled, but may provide some information regarding the yield of screening in different populations. Two European studies of older (>60 years), average-risk men screened with urine dipstick for hematuria found bladder cancer in 0.5 percent (5/1096)25 and 0.7 percent (17/2356) of subjects.26 A study of higher-risk men and women with ≥ 40 packs/year smoking history found that 3.3 percent (6/183) had bladder cancer identified following one-time screening with a battery of tests (urine dipstick, NMP22, and cytology).27 A study of higher-risk men and women with >10-year history of smoking or >15-year history of a high-risk occupation found 0.2 percent (3/1502) had bladder cancer following one-time screening with a test for NMP22.28 One study that periodically screened workers with occupational exposures to BNA or benzidine with urinalysis, cytology, and/or urine biomarkers identified bladder cancer in 1.0 percent (3/304) of subjects.29

Key Question 2. What are the accuracy and reliability of urinalysis for hematuria, urine cytology, and urine biomarkers for identification of bladder cancer?

Summary

No study evaluated the diagnostic accuracy of screening tests for bladder cancer in asymptomatic persons without a prior history of bladder cancer. A subgroup analysis from one study of patients without gross hematuria reported a sensitivity of 0.45, specificity of 0.86, and positive predictive value of 0.11 (bladder cancer prevalence 4 percent), but included patients with dysuria.30 Positive predictive values were less than 10 percent in screening studies of asymptomatic persons, including high-risk populations.

Evidence

No study evaluated the diagnostic accuracy of screening tests for bladder cancer in asymptomatic persons. All studies, even those that did not focus on patients with previously diagnosed bladder cancer,31–33 enrolled patients with gross hematuria and/or urinary symptoms such as dysuria, typically in referral settings. Only one study provided data to calculate the diagnostic accuracy of NMP22 compared to cystoscopy in a subgroup of patients without gross hematuria (with or without dysuria).30 The study reported a sensitivity of 0.45 (17/38 [95% CI, 0.29–0.62]) and specificity of 0.86 (889/1028 [95% CI, 0.84–0.88]) for a positive likelihood ratio of 3.3 (95% CI, 2.2–4.9) and negative likelihood ratio of 0.64 (95% CI, 0.48–0.85). The positive predictive value was 0.11 (17/156 [95% CI, 0.07–0.17), with a bladder cancer prevalence of 4 percent (38/1066 [95% CI, 3–5]). By comparison, the positive predictive value in patients with gross hematuria (bladder cancer prevalence 18 percent) was 0.43 (26/61).

Six studies reported positive predictive values in screened asymptomatic patients, but did not meet inclusion criteria because other markers of diagnostic accuracy could not be calculated, since patients with negative screening tests did not undergo cystoscopy.24, 25, 27–29, 34 The positive predictive value of screening (one-time testing for hematuria or NMP22) ranged from 3 percent to 5 percent in three studies25, 28, 34 in which the bladder cancer prevalence was <1 percent, including one study that enrolled higher-risk patients based on smoking and occupational history.28 The positive predictive value was 8 percent in three studies with a prevalence ranging from 1 percent to 3 percent, based on screening with repeated urinalysis or one-time screening with multiple tests (urinalysis, cytology, and urine biomarkers),24, 27, 29 including one study of people with high-risk occupational exposures.29

Key Question 3. Does treatment of screen-detected bladder cancer reduce morbidity and mortality from this disease?

We identified no randomized trials or controlled observational studies of treatment for screen-detected or superficial bladder cancer compared to no treatment.

Key Question 4. What are the harms of screening for bladder cancer or treatment of screen-detected bladder cancer?

Summary

We identified no randomized, controlled trials or controlled observational studies on harms of treatment compared to no treatment. In one large uncontrolled observational study, bleeding and perforation occurred in 2.8 percent and 1.3 percent of patients treated with TURBT, respectively.35

Evidence

Potential harms of screening for bladder cancer can occur in the evaluation of positive tests or with subsequent treatments. Follow-up of positive screenings typically includes cystoscopy and may include imaging studies. Potential harms include anxiety, labeling, discomfort or pain related to cystoscopy, and complications related to cystoscopy and biopsy (such as perforation, bleeding, or infection) and imaging (such as effects related to use of intravenous contrast or radiation exposure).36–39 Screening could also increase the overall exposure to additional procedures and treatments due to earlier initiation of routine surveillance and frequent recurrences of tumor.

We identified no controlled studies that directly measured harms associated with screening for bladder cancer. Compared to higher-prevalence populations, lower-prevalence populations would be exposed to a greater potential for unnecessary harms due to higher false-positive rates of screening (see Key Question 2). However, we identified no studies estimating the magnitude of harms associated with unnecessary procedures.

We also identified no controlled studies comparing harms of treatment of screen-detected bladder cancer versus no treatment. Although one large (n=2,821) uncontrolled observational study reported rates of bleeding (2.8 percent) and perforation (1.3 percent) with TURBT, it isn’t possible to estimate the incremental harms that may have occurred due to screening from this data.35 In this study, the presence of larger (>3 cm) or more (≥3) tumors increased the risk of complications. Higher tumor stage did not correlate with increased risk.