Assessing the clinical benefit of nuclear matrix protein 22 in the surveillance of patients with nonmuscle-invasive bladder cancer and negative cytology: a decision-curve analysis

Abstract

Background: Several studies have demonstrated that abnormal levels of nuclear matrix protein 22 (NMP22) are associated with bladder cancer and have led to the approval of NMP22 as a urinary biomarker by the US Food and Drug Administration. Nonetheless, the clinical significance of NMP22 remains unclear. The objective of this study was to use decision analysis to determine whether NMP22 improves medical decision-making.

Methods: The current study included 2222 patients who had a history of nonmuscle-invasive bladder cancer and current negative cytology. The authors developed models to predict cancer recurrence or progression to muscle-invasive disease using voided NMP22 levels, cystoscopy, age, and sex. Clinical net benefit was calculated by summing the benefits (true-positives), subtracting the harms (false-positives), and weighting these values by the threshold probability at which a patient or clinician would opt for cytoscopy.

Results: After cystoscopy, 581 patients (26%) had cancer identified. The NMP22 level was associated significantly with bladder cancer recurrence and progression (P < .001 for both). The use of NMP22 in a model with age and sex was associated with better patient outcomes than performing cystoscopy on everyone and produced threshold probabilities > 8% for recurrence and > 3% for progression. Only offering cystoscopy to those who had a risk > 15% reduced the number of cystoscopies by 229 while missing only 25 cancer recurrences per 1000 men with negative cytology. The current study was limited by its multicenter design.

Conclusions: For clinicians who would perform a cystoscopy at a threshold of 5% for recurrence or 1% for progression, NMP22 did not aid clinical decision-making. For less risk-averse clinicians who would only perform a cystoscopy at a threshold probability >thinsp;8% for recurrence or > 3% for progression, NMP22 helped to indicate which patients required cystoscopy and which could be spared this procedure.

Fig. 1

Risk curves for NMP22 levels in 2,222 patients with previous non–muscle-invasive bladder urothelial carcinoma and negative cytology. NMP22 levels are along the x axis, and the corresponding predicted probability of disease recurrence (solid line) or progression (dashed line) is along the y axis. Probabilities shown are for a 68-year-old male. The distribution of NMP22 levels is shown by the histogram, with quartiles indicated by the shading.

Fig. 2

Decision-curve analysis of bladder cancer recurrence using NMP22, age and gender compared to just age and gender in 2,222 patients with previous non–muscle-invasive bladder urothelial carcinoma and negative cytology. Dashed line: prediction model with NMP22, age and gender. Black line: prediction model with only age and gender. Horizontal line along x axis: assumes all patients will experience disease recurrence (= all patients need to undergo cystoscopy). Solid grey line: assumes no patient will experience disease recurrence (= none of the patients needs to undergo cystoscopy).

Fig. 3

Decision-curve analysis of bladder cancer progression using NMP22, age and gender in 2,222 patients with previous non–muscle-invasive bladder urothelial carcinoma and negative cytology. Age and gender alone were not different from performing a cystoscopy on all strategy. Dashed line: prediction model with NMP22, age and gender. Horizontal line along x axis: assumes all patients will experience disease progression (= all patients need to undergo cystoscopy). Solid grey line: assumes no patient will experience disease progression (= none of the patients needs to undergo cystoscopy).