Neoadjuvant sunitinib for surgically complex advanced renal cell cancer of doubtful resectability: initial experience with downsizing to reconsider cytoreductive surgery.
ABSTRACT To evaluate neoadjuvant sunitinib in patients with synchronous metastatic renal cell cancer (mRCC) to downsize surgically complex tumours and reconsider cytoreductive surgery.
Retrospective analysis of ten consecutive mRCC patients treated with sunitinib in an expanded access program who presented with surgically complex primary tumours or bulky locoregional metastases. Surgery-limiting tumour sites (SLTSs) were defined as primary or retroperitoneal lesions with direct invasion of adjacent organs or encasement of vital structures on imaging. Patients received sunitinib 50 mg/day for 4 weeks on and 2 weeks off to be followed by cytoreductive surgery after downsizing and individual reassessment. Response was measured according to Response Evaluation Criteria in Solid Tumours (RECIST).
Six out of ten SLTSs revealed a reduction of tumour size with a median of 14% according to RECIST. None of the ten SLTSs had a partial response (PR), whilst at distant metastatic sites one complete remission and two PRs occurred. Downsizing of SLTSs appeared most prominent in the first 2-4 months, which resulted in reconsidering cytoreductive nephrectomy in three patients. These three tumours invaded the liver on imaging and were reduced by 11, 18 and 20%.
In this patient group with mRCC and surgically complex primary tumours or locoregional metastases, downsizing of SLTSs by neoadjuvant sunitinib was limited. Cytoreductive surgery was reconsidered in three patients. Given the overall reduction in tumour burden by sunitinib alone, further investigation to define the role of cytoreductive surgery is warranted.
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ABSTRACT: Background Previous studies have shown a modest impact of tyrosine kinase inhibitors on primary renal tumors. Those studies were mostly retrospective and heterogeneous in their eligibility criteria with regard to histology, disease stage, duration of therapy, and time off therapy prior to surgery. Objective To prospectively investigate the safety and efficacy of axitinib in downsizing tumors in patients with nonmetastatic biopsy-proven clear cell renal cell carcinoma (ccRCC). Design, setting, and participants This was a single-institution, single-arm phase 2 clinical trial. Patients with locally advanced nonmetastatic biopsy-proven ccRCC were eligible. Intervention Patients received axitinib 5 mg for up to 12 wk. Axitinib was continued until 36 h prior to surgery. Patient underwent partial or radical nephrectomy after axitinib therapy. Outcome measurements and statistical analysis The primary outcome was objective response rate prior to surgery. Secondary outcomes included safety, tolerability, and quality of life. A dedicated radiologist independently reviewed all computed tomography scans to evaluate for response using Response Evaluation Criteria in Solid Tumors (RECIST). Results and limitations A total of 24 patients were treated. Twenty-two patients continued axitinib for 12 wk; 1 patient continued axitinib for 11 wk and underwent surgery as planned. One patient stopped treatment at 7 wk due to adverse events (AEs). Median reduction of primary renal tumor diameter was 28.3%. Eleven patients experienced a partial response per RECIST; 13 had stable disease. There was no progression of disease while on axitinib. The most common AEs were hypertension, fatigue, oral mucositis, hypothyroidism, and hand-foot syndrome. Postoperatively, 2 grade 3 and 13 grade 2 complications were noted. No grade 4 or 5 complications occurred. Functional Assessment of Cancer Therapy-Kidney Specific Index-15 changed over time, with quality of life worsening while on therapy, but by week 19, it was not statistically different from screening. Limitations include single-arm design and small patient numbers. Conclusions Axitinib was clinically active and reasonably well tolerated in the neoadjuvant setting in patients with locally advanced nonmetastatic ccRCC. Patient summary In this prospective clinical trial, we found that axitinib, when given prior to surgery, results in significant shrinking of kidney cancers. Larger studies are needed prior to further clinical use. Trial registration This clinical trial was registered with clinicaltrials.gov (NCT01263769).European Urology 01/2014; · 10.48 Impact Factor
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ABSTRACT: Hand-foot syndrome (HFS) is a side effect of sunitinib with considerable impact on quality of life. Seasonal variation and hyperhydrosis are possibly correlated to occurrence of HFS. Therefore, we proposed to study the prevalence of HFS in different seasons retrospectively and to study the relationship between sunitinib sweat secretion and HFS prospectively. A retrospective cohort of 19 patients treated with sunitinib was used to determine seasonal prevalence of HFS. In a prospective study, sunitinib and N-desethyl sunitinib levels in sweat patches of 25 patients treated with sunitinib were quantified and correlated to severity of HFS. In the retrospective cohort, the patients suffered from more severe HFS during summertime compared with the rest of the year. In the prospective study, the cumulative amounts of sunitinib plus metabolite measured in the patches of the on-treatment phase (median 129.4 ng/patch) were higher than the off-treatment phase (median 39.5 ng/patch). A tendency was observed towards increasing amounts of drug per patch with increasing severity of HFS. Patients experienced more HFS in summer time compared to other seasons. However, no statistically significant correlation between sunitinib sweat secretion and severity of HFS could be demonstrated within our patient cohort.European Journal of Clinical Pharmacology 08/2013; · 2.74 Impact Factor
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ABSTRACT: Introduction: Antiangiogenic therapy is considered to be the backbone of treatment strategy in metastatic renal cell carcinoma (mRCC). New, more focused, targeted drugs are emerging, while other targeted drugs oriented toward resistance or alternative mechanisms are under development. Areas covered: Antiangiogenic agents include two types of agents: the monoclonal antibody, targeting vascular endothelial growth factor (VEGF), bevacizumab and the tyrosine kinase inhibitors (TKIs). Data regarding efficacy and safety of these agents are reported. Differences between the first generation of TKIs, sunitinib, sorafenib, and the new generation, pazopanib, axitinib and tivozanib are also detailed. Most of these agents have been approved in the treatment of kidney cancer in specific settings of the disease. Expert opinion: The class of antiangiogenic drugs for treatment of mRCC is already relatively full. After 'me-too' drugs, more targeted drugs against VEGFR have been developed but have to demonstrate a benefit in first-line treatment. Another option for the development is to combine a known drug with an antiangiogenic inhibition profile and at least one additional target involved in resistance to an antiangiogenic or in an alternative pathway. The cost of approach with targeted drugs, including antiangiogenics, has led to a tremendous increase in the cost of care in mRCC.Expert Opinion on Emerging Drugs 12/2013; 18(4):495-511. · 2.48 Impact Factor