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 (∼80%) and 6-month OS (∼60%) probability than level ≥ 80.


CONCLUSIONS
IL8-level changes during pazopanib allowed for a prognostic improvement and were associated with response probability.
Department of Medical Oncology, Medical Oncology 2 Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy.
A
A
Necchi
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
M
M
Pennati
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
N
N
Zaffaroni
Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
E
E
Landoni
Department of Medical Oncology, Medical Oncology 2 Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy.
P
P
Giannatempo
Department of Medical Oncology, Medical Oncology 2 Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy.
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D
Raggi
Department of Radiology, Columbia University Medical Center and New York Presbyterian Hospital, New York, New York, USA.
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LH
Schwartz
Department of Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
C
C
Morosi
Nuclear Medicine and PET Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
F
F
Crippa
Department of Medical Oncology, Medical Oncology 2 Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy.
E
E
Farè
Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
N
N
Nicolai
Department of Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
R
R
Lanocita
Department of Medical Oncology, University Hospital of Verona-Borgo Trento, Verona, Italy.
T
T
Sava
Department of Medical Oncology, Ospedale S. Maria Misericordia, Udine, Italy.
C
C
Sacco
Department of Medical Oncology, Ospedali Riuniti, Bergamo, Italy.
C
C
Messina
Department of Medical Oncology, Institute for Cancer Research and Treatment (IRCC), Candiolo, Turin, Italy.
C
C
Ortega
Department of Medical Oncology, Medical Oncology 2 Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy.
F G
FG
De Braud
Department of Surgery, Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
R
R
Salvioni
Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
M G
MG
Daidone
1] Department of Medical Oncology, Medical Oncology 2 Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, Milan 20133, Italy [2] University of Milan School of Medicine, Milan, Italy.
A M
AM
Gianni
Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
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L
Mariani
D043925:Angiogenesis Inducing Agents / Q000097:blood*; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood; D002295:Carcinoma, Transitional Cell / Q000097:blood / Q000188:drug therapy; D016207:Cytokines / Q000097:blood*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007191:Indazoles; D016209:Interleukin-8 / Q000097:blood*; D064847:Multimodal Imaging; D049268:Positron-Emission Tomography; D011379:Prognosis; D016016:Proportional Hazards Models; D011743:Pyrimidines / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D014057:Tomography, X-Ray Computed; D014571:Urologic Neoplasms / Q000097:blood* / Q000188:drug therapy*
D043925:Angiogenesis Inducing Agents; D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; C508606:CXCL8 protein, human; D016207:Cytokines; D007191:Indazoles; D016209:Interleukin-8; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib