Analysis of plasma cytokines and angiogenic factors in patients with pretreated urothelial cancer receiving Pazopanib: the role of circulating interleukin-8 to enhance the prognostic accuracy

Background: Pazopanib achieved the end point of clinical activity in pretreated patients with urothelial cancer in a single-group, phase 2 trial. The objective was to identify biological predictors of clinical benefit to pazopanib in these patients. Methods: EDTA blood samples were collected at baseline (T0) and after 4 weeks (T1) of treatment, together with radiological imaging in all 41 patients to analyse plasma circulating angiogenic factor levels by multiplex ELISA plates. Changes from T0 to T1 in marker levels were matched with response with the covariance analysis. Univariable and multivariable analyses evaluated the association with overall survival (OS), adjusted for prespecified clinical variables. Net reclassification improvement (NRI) tested the performance of the recognised Cox model. Results: Increasing IL8(T1) level associated with lower response probability at covariance analysis (P = 0.010). Both IL8(T0) (P = 0.019) and IL8(T1) (P = 0.004) associated with OS and the prognostic model, including clinical variables and IL8(T1) best-predicted OS after backward selection. The NRI for this model was 39%. When analysed as a time-varying covariate, IL8(T1) level <80 pg ml(-1) portended significantly greater response (similar to 80%) and 6-month OS (similar to 60%) probability than level >= 80. Conclusion: IL8-level changes during pazopanib allowed for a prognostic improvement and were associated with response probability.