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Efficacy of urinary biomarkers varies for bladder cancer detection
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Urinary biomarkers failed to detect a substantial portion of patients with bladder cancer and producing false-positive results in others, according to the results of a systematic review and meta-analysis.
Further, the diagnostic accuracy of urine biomarkers appeared especially poor for low-stage and low-grade bladder tumors, according to the researchers.
“Standard methods for diagnosis of bladder cancer involve cytologic evaluation of urine, imaging tests and cystoscopy,” Roger Chou, MD, professor of medicine at Oregon Health and Sciences University, and colleagues wrote. “Because cystoscopy is uncomfortable and costly, alternative diagnostic methods have been sought. Urine-based biomarkers have been developed as potential alternatives or adjuncts to standard tests for the initial diagnosis of bladder cancer or identification of recurrent disease.”
The FDA has approved six urine biomarkers for diagnosis or surveillance of bladder cancer, according to study background.
Chou and colleagues sought to systematically review the evidence on the accuracy of urinary biomarkers for the diagnosis of bladder cancer among adults who showed signs or symptoms of the disease or those being surveilled for recurrent disease.
The researchers used Ovid MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews and available reference lists for studies conducted through June 2015. They identified 57 studies that evaluated the diagnostic accuracy of quantitative or qualitative nuclear matrix protein 22 (NMP22; Alere), qualitative or quantitative bladder tumor antigen (BTA; Polymedco), fluorescent in situ hybridization (FISH), fluorescent immunohistochemistry (ImmunoCyt. Scimedx) and Cxbladder (Pacific Edge Diagnostics).
Sample sizes in the included studies ranged from 26 to 3,916 participants, the mean age ranged from 54 to 77 years, and the proportion of men ranged from 57% to 88%. The proportion of patients diagnosed with bladder cancer ranged from 3% to 88%.
According to the researchers, quantitative NMP22 had a sensitivity of 0.69 (95% CI, 0.62-0.75) and a specificity of 0.77 (95% CI, 0.7-0.83), resulting in a positive likelihood ratio (LR) of 3.05 (95% CI, 2.28-4.1) and a negative LR of 0.4 (95% CI, 0.32-0.5).
Qualitative BTA had a sensitivity of 0.64 (95% CI, 0.58-0.69) and specificity of 0.77 (95% CI, 0.73-0.81), for a positive LR of 2.8 (95% CI, 2.31-3.39) and a negative LR of 0.47 (95% CI, 0.3-0.55). Quantitative BTA had a sensitivity of 0.65 (95% CI, 0.54-0.75) and a specificity of 0.74 (95% CI, 0.64-0.82), for a positive LR of 2.52 (95% CI, 1.86-3.41) and a negative LR of 0.47 (95% CI, 0.37-0.61).
FISH has a sensitivity of 0.63 (95% CI, 0.5-0.75) and a specificity of 0.87 (95% CI, 0.79-0.93), for a positive LR of 5.02 (95% CI, 2.93-8.6) and a negative LR of 0.42 (95% CI, 0.3-0.59).
ImmunoCyt had a sensitivity of 0.78 (95% CI, 0.68-0.85) and a specificity of 0.78 (95% CI, 0.72-0.82), with a positive LR of 3.49 (95% CI, 2.82-4.32) and a negative LR of 0.29 (95% CI, 0.2-0.41).
Cxbladder had a sensitivity of 0.82 (95% CI, 0.7-0.9) and a specificity of 0.85 (95% CI, 0.81-0.88), for a positive LR of 5.53 (95% CI, 4.28-7.15) and a negative LR of 0.21 (95% CI, 0.13-0.36). However, Chou and colleagues noted that only one study of Cxbladder was included, and that they judged the study to have a medium risk for bias.
Based on the LRs, the researchers reported moderate strength of evidence for quantitative NMP22, qualitative BTA, FISH and Immunocyst, with low strength of evidence for the other included biomarkers.
Further, they observed higher sensitivity for initial diagnosis of bladder cancer than for diagnosis of recurrence for some biomarkers, and that sensitivity increased with higher tumor stage or grade.
A head-to-head study comparing the accuracy of quantitative NMP22 and qualitative BTA showed no differences in diagnostic accuracy. Three studies found that ImmunoCyst was associated with a higher sensitivity — but lower specificity — than FISH.
An analysis of 16 studies demonstrated that urinary biomarkers plus cytologic evaluation produced greater sensitivity than biomarkers alone; however, the researchers observed that these studies missed about 10% of bladder cancers.
Study limitations included the inclusion of English-language studies only; the relatively small number of studies of qualitative NMP22, quantitative BTA and Cxbladder; and the potential bias inherent in the included studies.
Of the 57 studies included, the researchers considered two studies at low risk for bias and three studies at high risk for bias; they judged the remaining studies to have a medium risk for bias.
“Urinary biomarkers miss a substantial proportion of patients with bladder cancer and are falsely positive in others,” Chou and colleagues wrote. “Research is needed to understand how the use of urinary biomarkers with other diagnostic tests affects the use of cystoscopy and clinical outcomes.”
Difficulty exists across diagnostic platforms for the detection of low-grade bladder cancer, Phillip H. Abbosh, MD, PhD, and Elizabeth R. Plimack, MD, MS, both of Fox Chase Cancer Center, wrote in an accompanying editorial.
Elizabeth R. Pilmack
“Most patients with newly diagnosed urothelial cancer will have superficial disease, and most of these cases will be low grade or low stage,” Abbosh and Plimack wrote. “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, cellular turnover and necrosis or apoptosis common to these tumors.”
However, Abbosh and Plimack concluded that the lingering questions surrounding biomarkers may not justify the costs for many patients.
“Tumors missed on cystoscopy were also missed by urinary biomarkers,” they wrote. “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.” – by Cameron Kelsall
Disclosure: The Agency for Healthcare Research and Quality provided funding for this study. Chou and two other researchers report grants from the Agency for Healthcare Research and Quality during the conduct of the study. The other researchers report no relevant financial disclosures. Abbosh reports personal fees from Ashion outside of the submitted work. Plimack reports no relevant financial disclosures.
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