interleukin-8 and pazopanib

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.. 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.. 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.. IL8-level changes during pazopanib allowed for a prognostic improvement and were associated with response probability.

Topics: Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Biomarkers, Tumor; Carcinoma, Transitional Cell; Cytokines; Enzyme-Linked Immunosorbent Assay; Humans; Indazoles; Interleukin-8; Multimodal Imaging; Positron-Emission Tomography; Prognosis; Proportional Hazards Models; Pyrimidines; Sulfonamides; Tomography, X-Ray Computed; Urologic Neoplasms

Despite the initial clinical benefit, resistance to antiangiogenic therapies develops through the activation of alternative pathways. We measured plasma levels of circulating angiogenic factors to explore their predictive role in metastatic renal cell carcinoma (mRCC) patients treated with pazopanib.. mRCC patients receiving first-line pazopanib were prospectively enrolled. The levels of circulating interleuchine (IL)-6, IL-8, stromal derived factor-1, vascular endothelial growth factor-A, hepatocyte growth factor (HGF), osteopontin, and E-selectin were quantified at baseline and every 4 weeks until disease progression (PD). Patients were dichotomized into "low" and "high" subgroups by a cutoff point defined by the respective median circulating angiogenic factor (CAF) value at baseline. Then, association with the objective response was determined. Changes in CAF levels between baseline and PD were also compared.. Among 25 patients included in the final data set, 6 patients were still on treatment. As best response, 12 patients presented a partial response (48%), 9 showed stable disease, and 4 showed PD. The median follow-up was 31.9 months. The median progression-free survival was 14.8 months. Low baseline levels of IL-6, IL-8, HGF, and osteopontin were found to be significantly associated with objective response. In addition, patients with low baseline levels of HGF showed longer progression-free survival and overall survival, whereas patients with low baseline levels of IL-8 showed longer overall survival. Among patients experiencing PD, the median plasma levels of stromal derived factor-1 and vascular endothelial growth factor-A were significantly higher compared with the baseline (P=0.01; P=0.011). Conversely, the median levels of E-selectin were significantly lower compared with the baseline (P=0.017).. Changes in levels of selected CAFs were associated with response/resistance to pazopanib in mRCC patients.

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Chemokine CXCL12; Disease Progression; Drug Resistance, Neoplasm; E-Selectin; Female; Hepatocyte Growth Factor; Humans; Indazoles; Interleukin-6; Interleukin-8; Kidney Neoplasms; Male; Middle Aged; Osteopontin; Progression-Free Survival; Prospective Studies; Pyrimidines; Response Evaluation Criteria in Solid Tumors; Sulfonamides; Survival Rate; Translational Research, Biomedical; Vascular Endothelial Growth Factor A

In two clinical trials of the vascular endothelial growth factor (VEGF) receptor inhibitor pazopanib in advanced renal cell carcinoma (mRCC), we found interleukin-6 as predictive of pazopanib benefit. We evaluated the prognostic significance of candidate cytokines and angiogenic factors (CAFs) identified in that work relative to accepted clinical parameters.. Seven preselected plasma CAFs (interleukin-6, interleukin-8, osteopontin, VEGF, hepatocyte growth factor, tissue inhibitor of metalloproteinases (TIMP-1), and E-selectin) were measured using multiplex ELISA in plasma collected pretreatment from 343 mRCC patients participating in the phase 3 registration trial of pazopanib vs placebo (NCT00334282). Tumour burden (per sum of longest diameters (SLD)) and 10 other clinical factors were also analysed for association with overall survival (OS; based on initial treatment assignment).. Osteopontin, interleukin-6, and TIMP-1 were independently associated with OS in multivariable analysis. A model combining the three CAFs and five clinical variables (including SLD) had higher prognostic accuracy than the International Metastatic Renal Cell Carcinoma Database Consortium criteria (concordance-index 0.75 vs 0.67, respectively), and distinguished two groups of patients within the original intermediate risk category.. A prognostic model incorporating osteopontin, interleukin-6, TIMP-1, tumour burden, and selected clinical criteria increased prognostic accuracy for OS determination in mRCC patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Renal Cell; Cytokines; E-Selectin; Female; Hemoglobins; Hepatocyte Growth Factor; Humans; Indazoles; Interleukin-6; Interleukin-8; Kidney Neoplasms; L-Lactate Dehydrogenase; Leukocyte Count; Male; Middle Aged; Neutrophils; Osteopontin; Prognosis; Pyrimidines; Sulfonamides; Survival Rate; Time-to-Treatment; Tissue Inhibitor of Metalloproteinase-1; Tumor Burden; Vascular Endothelial Growth Factor A

We evaluated germline single nucleotide polymorphisms (SNPs) for association with overall survival (OS) in pazopanib- or sunitinib-treated patients with advanced renal cell carcinoma (aRCC).. The discovery analysis tested 27 SNPs within 13 genes from a phase III pazopanib trial (N=241, study 1). Suggestive associations were then pursued in two independent datasets: a phase III trial (COMPARZ) comparing pazopanib vs sunitinib (N=729, study 2) and an observational study of sunitinib-treated patients (N=89, study 3).. In study 1, four SNPs showed nominally significant association (P≤0.05) with OS; two of these SNPs (rs1126647, rs4073) in IL8 were associated (P≤0.05) with OS in study 2. Because rs1126647 and rs4073 were highly correlated, only rs1126647 was evaluated in study 3, which also showed association (P≤0.05). In the combined data, rs1126647 was associated with OS after conservative multiple-test adjustment (P=8.8 × 10(-5); variant vs reference allele hazard ratio 1.32, 95% confidence interval: 1.15-1.52), without evidence for heterogeneity of effects between studies or between pazopanib- and sunitinib-treated patients.. Variant alleles of IL8 polymorphisms are associated with poorer survival outcomes in pazopanib- or sunitinib-treated patients with aRCC. These findings provide insight in aRCC prognosis and may advance our thinking in development of new therapies.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Antineoplastic Agents; Carcinoma, Renal Cell; Clinical Trials, Phase III as Topic; Female; Humans; Indazoles; Indoles; Interleukin-8; Kidney Neoplasms; Male; Middle Aged; Polymorphism, Single Nucleotide; Pyrimidines; Pyrroles; Randomized Controlled Trials as Topic; Sulfonamides; Sunitinib; Survival Analysis; Young Adult