Rapid angiogenesis onset after discontinuation of sunitinib treatment of renal cell carcinoma patients

Clinical Cancer Research, 05/15/2012

Griffioen AW et al. – This study describes for the first time the angiostatic response in human primary renal cancers at the tissue level upon treatment with VEGF targeted therapy. Discontinuation of treatment with tyrosine kinase inhibitors leads to accelerated angiogenesis. The results of the current study contribute important data to the ongoing discussion on the discontinuation of treatment with kinase inhibitors.

Methods

  • Phase II trials of VEGF pathway targeted therapy given prior to cytoreductive surgery were performed with metastatic RCC patients with the primary tumor in situ, to investigate the necessity of nephrectomy.
  • Primary tumor tissues were obtained and assessed for angiogenesis parameters.
  • Results were compared to similar analyses on untreated tumors.

Results

  • Sunitinib or bevacizumab pretreatment resulted in a significant reduction of microvessel density in the primary tumor.
  • Also, an increase in vascular pericyte coverage was found in sunitinib-pretreated tumors, consistent with efficient angiogenesis inhibition.
  • Expression of several key regulators of angiogenesis was suppressed in pretreated tissues, among which VEGFR-1 and -2, angiopoietin-1 and -2 and PDGF-B.
  • In addition, apoptosis in tumor and endothelial cells was induced. 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 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.

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