Rapid Angiogenesis Onset after Discontinuation of Sunitinib Treatment of Renal Cell Carcinoma Patients

Abstract

Purpose To investigate the angiogenic changes in primary tumor tissue of renal cell carcinoma (RCC) patients treated with vascular endothelial growth factor (VEGF)-targeted therapy. Experimental design 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. Conclusion 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.

89Zr-Bevacizumab PET Visualizes Heterogeneous Tracer Accumulation in Tumor Lesions of Renal Cell Carcinoma Patients and Differential Effects of Antiangiogenic Treatment

“…Preclinical studies showed increased invasiveness and metastasis after a short sunitinib course (4,5). Moreover, a profound expansion of proliferating endothelial cells was demonstrated in primary RCCs after neoadjuvant sunitinib (28), which was not observed after bevacizumab, despite similar histologic features suggestive of vascular normalization (28). These findings support our observation of different tumor biology after sunitinib and bevacizumab/IFNa.…”

Can individualized sunitinib dose and schedule changes optimize outcomes for kidney cancer patients?

“…These data show that most of the benefit from sunitinib may be achieved well before Day 28 and that the treatment break should be shorter than 14 days to avoid the tumour progression that can occur during treatment interruption. [12][13][14] Minimum toxicity in patients on the 50 mg four/two schedule predicts for inferior response, PFS, and OS We were the first to report significantly inferior response, PFS, and OS in renal cell carcinoma (RCC) patients experiencing minimal toxicity from sunitinib on the standard 50 mg four/two schedule compared to patients that developed toxicity and underwent the individualized dose/schedule changes developed in our centre. 8,15 The outcomes for 172 patients (79% clear-cell histology; sunitinib given as firstline therapy in 59%) were analyzed retrospectively.…”

The role of neoadjuvant therapy in the management of locally advanced renal cell carcinoma

“…It has also been noted that therapy may alter tumor biology of metastatic disease adversely [Griffioen et al 2012]. Moreover, although recent studies have shown no increase in overall complication rates and minor wound delay complications , toxicity of therapy and its increase in surgical morbidity has been suggested as a possible downside.…”