Hypertension and Circulating Cytokines and Angiogenic Factors in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma Treated With Sunitinib: Results From a Phase II Trial

Abstract

Background. We evaluated the significance of hypertension developing during vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor (VEGFR‐TKI) treatment and a group of cytokines and angiogenic factors (CAFs) in advanced non‐clear cell renal cell carcinoma (nccRCC) patients treated with sunitinib in a phase II study. Materials and Methods. Using multiplex assays, we analyzed the levels of 38 CAFs in plasma at baseline and after 4 weeks of sunitinib therapy. Sunitinib benefit was defined as a partial response or stable disease using the Response Evaluation Criteria in Solid Tumors lasting ≥4 months. Cox proportional hazards regression models were used to assess the associations among hypertension, CAFs, and progression‐free (PFS) and overall survival (OS). Results. Fifty‐seven patients were evaluable; 53 had baseline CAF levels available. The median PFS and OS were 2.9 months (95% confidence interval [CI], 1.4–5.5) and 16.8 months (95% CI, 10.7–27.4), respectively. Sunitinib benefit was observed in 21 patients (37%). However, 33 patients (60%) developed hypertension during treatment, although no association was found with survival or response. Elevated baseline soluble tumor necrosis factor (TNF) receptor I, interleukin‐8, growth‐regulated oncogene, transforming growth factor‐α, and VEGFR‐2 levels were associated with an increased risk of death on multivariate analysis. Conclusion. We found no association between the development of hypertension and survival or sunitinib benefit in advanced nccRCC. TNF and angiogenic/immunomodulatory mediators were identified for evaluation as markers of prognosis and VEGFR‐TKI benefit in future studies. Implications for Practice: The present study describes the first analysis of hypertension and a relatively large set of circulating cytokines and angiogenic factors in patients with advanced non‐clear cell renal cell carcinoma (nccRCC) treated with sunitinib. No association was found between hypertension and patient outcomes. However, a group of candidate circulating biomarkers was identified, in particular, those associated with tumor necrosis factor and CXCR1/2 signaling, with probable biological and clinical significance in nccRCC, warranting confirmation in future studies.

Cancer‑associated fibroblasts regulate the biological behavior of cancer cells and stroma in gastric cancer (Review)

“…CAFs are a major source of angiogenic factors including VEGF, angiopoietin 1, basic fibroblast proliferation factor, TGF-β1, PDGF, tumor necrosis factor α, hepatocyte growth factor, insulin-like growth factor-1 and monocyte chemoattractant protein-1 (MCP-1) (68,69). Accumulating evidence demonstrated that hypoxia serves a critical function in the angiogenic process of GC by upregulating the secretion of angiogenic factors from CAFs, including VEGF and angiopoietin (53,67,70,71). Additionally, angiogenesis at the primary and metastatic site may be associated with SDF-1 and thrombospondin-1 secretion from CAFs (66,72).…”

A randomized phase II trial comparing chemoimmunotherapy with or without bevacizumab in previously untreated patients with chronic lymphocytic leukemia

“…The paradoxical post-treatment increase in VEGF levels observed in our study may have been temporary and preceding a following steady decrease, as already observed in other studies where therapeutic agents modulating the microenvironment are employed. [ 43 – 45 ] Unfortunately, we were not able to discern if this occurred as in this study VEGF levels were only done at baseline and at the time of response and not re-measured beyond the end-of-treatment assessment.…”

Cell death-related molecules and biomarkers for renal cell carcinoma targeted therapy

“…Bortezomib pretreatment enhanced pro-caspase-8 activation and sensitized RCC to TRAIL-mediated apoptosis [47]. TNF and angiogenic or immunomodulatory mediators (e.g., interleukin-8, TGF-α, and VEGFR-2) were correlated with the risk of death, and they might be identified as markers of prognosis for benefit from VEGFR-TKIs in future studies [48]. The levels of soluble FasL (sFasL) in plasma and keratinocyte death mediated by the Fas/FasL interaction were significantly correlated with the hand-foot skin reaction caused by sunitinib [49].…”