Cytokine Panel for Response to Intravesical Therapy (CyPRIT): Nomogram of Changes in Urinary Cytokine Levels Predicts Patient Response to Bacillus Calmette-Guérin

Abstract

The response of non-muscle-invasive bladder cancer (NMIBC) to intravesical immunotherapy with bacillus Calmette-Guérin (BCG) depends on adequate stimulation of an immune response. Although BCG has been used for decades, we lack tools to accurately predict response in individual patients. To address this deficiency, we initiated a clinical trial in patients with intermediate- and high-risk NMIBC. BCG was administered according to the Southwest Oncology Group protocol. Urine samples were collected for cytokine assay at baseline, immediately before and after BCG instillation at 6 wk, and immediately before and after the third BCG instillation of the first maintenance course. Levels of 12 cytokines were measured, and changes from baseline were calculated after treatment. A total of 130 patients were enrolled. Increases in single cytokines correlated with recurrence, but the best predictor of recurrence was changes in a combination of cytokines. A nomogram (CyPRIT) constructed using urinary levels of nine inducible cytokines (IL-2, IL-6, IL-8, IL-18, IL-1ra, TRAIL, IFN-γ, IL-12[p70], and TNF-α) predicted the likelihood of recurrence with 85.5% accuracy (95% confidence interval 77.9–93.1%).” This cytokine panel and nomogram have potential for identifying patients at risk of tumor recurrence during BCG treatment to guide modification of the dose and duration of BCG immunotherapy.

Trial registration: Clinicaltrials.gov NCT01007058.

Keywords: Bacillus Calmette-Guérin response; Bladder cancer; Nomogram; Prediction; Urinary cytokines.

Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1

Nomogram for calculating the risk of recurrence according to changes in urinary cytokine levels from immediately before to 4 h after instillation of bacillus Calmette-Guérin (BCG) at 6 wk (final instillation of induction BCG). This nomogram reflects the complex interaction between the various cytokines. Note that the probability of recurrence increases exponentially for each unit increase in total nomogram points. Cytokine values for point calculations reflect change from before to after BCG therapy.

Fig. 2

Area under the receiver operating characteristic (ROC) curve for performance in predicting recurrence of non–muscle-invasive bladder cancer after treatment with bacillus Calmette-Guérin (BCG). (A) Model nomogram, (B) change in IL-2 alone, (C) change in IL-6 alone, and (D) change in IL-8 alone. Changes are from immediately before to 4 h after the sixth instillation of BCG (final instillation of induction BCG).