Effect Of Preoperative Antiangiogenic Treatment And Subsequent Discontinuation On Angiogenesis In The Primary Tumor In Patients With Rcc.

350 Background: Angiogenic changes in primary tumor tissue of renal cell carcinoma (RCC) patients treated with VEGF-targeted therapy has not been previously studied.A total of 57 primary tumor samples from various retrospective and prospective studies of presurgical sunitinib or bevacizumab were used. In these studies targeted therapy was given with the primary tumor in situ prior to cytoreductive nephrectomy, to investigate impact of therapy on primary tumors. Primary tumor tissues were assessed for microvessel density (MVD), proliferating endothelial cells, pericyte coverage, apoptosis of tumor or endothelial cells and molecular expression of angiogenesis regulators. Results of tumors pretreated with sunitinib discontinued at different intervals before surgery, were compared to similar analyses of untreated and bevacizumab-pretreated tumors.Sunitinib and bevacizumab pretreatment resulted in a significant reduction of MVD, as well as an increase in vascular pericyte coverage in the primary tumor (sunitinib samples) consistent with efficient angiogenesis inhibition. Expression of several key regulators of angiogenesis were found to be suppressed in sunitinib pretreated tissues, among which VEGFR-1 and -2, angiopoietin-1 and -2 and PDGF-B. Apoptosis was induced both by sunitinib and bevacizumab pretreatment. Interestingly, in sunitinib pretreated tissues a dramatic increase of the number of proliferating endothelial cells was observed, which was not the case in bevacizumab pretreated and untreated tumors. A positive correlation with the interval between halting the therapy and surgery was found, suggesting a compensatory angiogenic response caused by the discontinuation of sunitinib treatment.This study describes the antiangiogenic response in human primary renal cancers upon treatment with VEGF targeted therapy. Treatment discontinuation of tyrosine kinase inhibitors with short half life leads to accelerated angiogenesis. The results of the current study contribute important data to the ongoing discussion on the discontinuation of treatment with tyrosine kinase inhibitors.