Sunitinib for advanced renal cell cancer : Clinical and pharmacodynamic aspects

Purpose: Nephrectomy before immunotherapy in patients with metastatic renal cell cancer (RCC) will improve patient outcome. In addition, the primary tumor is known to be refractory to cytokines. Sunitinib is nowapproved for treatment of advanced RCC, but its effect on the primary tumor has yet to be reported. Experimental Design: All patients treated with sunitinib for advanced RCC without prior nephrectomy were reviewed and sequential computed tomography scans were evaluated for response in the primary tumor as well as metastases according to Response Evaluation Criteria in Solid Tumors.Volumes of primary tumors and central necrotic areas were measured with the perimeter method. Results: Computed tomography scans were available for evaluation of response in 17 of 22 patients with a primary tumor in situ (1patient with two primaries). According to Response Evaluation Criteria in Solid Tumors, 4 patients had a partial response, 12 had stable disease, and 1had progressive disease.The one-dimensional longest diameter of the primary tumor correlated with the volumetric measurements both at baseline and at the time of evaluation of response. Excluding the patient withprogressive disease, themedian volume reductionwas 31%associated with a median increase in the volume of necrosis of 39%. Three patients underwent nephrectomy and tumors showed extensive necrotic areas next to small fields of vital tumor cells. Conclusions: Sunitinib can induce a significant reduction in volume of primary renal cell tumors. Further trials need to address the role of nephrectomy in advanced RCC patients on sunitinib treatment. Until recently, cytokine therapy was the only treatment for metastatic renal cell cancer (mRCC), but less than 20% of patients benefit from a response (1). Responsiveness of the primary tumor to immunotherapy is very rare (2–4). For that reason, patients with synchronous metastases and a resectable primary tumor in situ will undergo a nephrectomy as part of a multimodality approach. This approach is largely supported by data from two randomized phase III clinical trials showing a longer overall survival in patients with nephrectomy followed by IFN-a versus patients on IFN-a alone (5–7). An additional feature in favor of nephrectomy is the rare phenomenon of spontaneous regression of metastases (8). It has also been argued that nephrectomy may improve the response to immunotherapy by reduction of immunosuppressive factors produced by the primary tumor. There are several subtypes of renal cell cancer (RCC), of which f75% contain clear cell carcinoma histology. At least 60% of these tumors is associated with inactivation of the von Hippel-Lindau tumor suppressor gene. This leads to elevated protein levels of hypoxia-inducible factor a and consequent overexpression of vascular endothelial growth factor and platelet-derived growth factor (9). These growth factors promote tumor angiogenesis, which likely contributes to the hypervascularity of RCC. Inhibitors of angiogenesis have proven efficacy in RCC, and among them is sunitinib (SU011248 or Sutent; Pfizer Pharmaceuticals Group). Sunitinib is an oral tyrosine kinase inhibitor of the vascular endothelial growth factor receptors, the platelet-derived growth factor receptors, flt-3, and c-Kit, and has been approved for the treatment of advanced RCC. In a randomized phase III clinical trial, sunitinib has shown an objective response rate of 31%, which was significantly higher than the 6% in patients that received IFN-a (10). The progression-free survival of the sunitinib treatment group was 11 months, whereas that of the IFN-a group was only 5 months (10). Based on current data available, sunitinib is now the preferred drug for first-line treatment of most mRCC patients (1). Presently, there is little experience with the effects of sunitinib on the primary tumor in patients that present with mRCC. Therefore, we conducted a retrospective analysis of the Cancer Therapy: Clinical Authors’Affiliations: Departments of Medical Oncology and Radiology,VU University medical center; and Departments of Urology and Medical Oncology, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands Received 9/3/07; revised12/6/07; accepted12/24/07. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Requests for reprints: Epie Boven, Department of Medical Oncology, VU University medical center, De Boelelaan 1117, 1081HVAmsterdam, the Netherlands. Phone: 31-20-4444336; Fax: 31-20-4444355; E-mail: e.boven@vumc.nl. F2008 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-4089 www.aacrjournals. org Clin Cancer Res 2008;14(8) April 15, 2008 2431