Effective downsizing but enhanced intratumoral heterogeneity following neoadjuvant sorafenib in patients with non-metastatic renal cell carcinoma

To evaluate the safety and feasibility of sorafenib prior to surgery for downsizing tumors in patients with non-metastatic cT1-3 renal tumors together with a characterization of functional intratumoral heterogeneity (ITH).

The effects of 4-week sorafenib prior to curative surgery were assessed in a prospective, single-center, randomized, placebo-controlled, double-blinded, pilot trial in patients with T1-3N0M0 renal cell carcinoma (RCC). Patients received sorafenib or placebo for 28 days prior to surgery. MRI was performed at baseline and prior to surgery to calculate tumor volume. The clinical responses were further characterized on the molecular level by immunohistochemical stainings for Ki-67, cleaved caspase-3, and CD31.

After enrolling 20 patients into the study, 14 patients were randomized, of which 12 patients were available for analysis. While no significant change in tumor volume was seen for placebo (range = -24.2-0.2%) a reduction of 29.0% (range = -4.9-61.1%) was detected for sorafenib (p < 0.05). Primary renal tumor diameter changed from 10.6 cm (range = 6.5-10.8) to 10.7 cm (range = 6.7-11.1) in the placebo group, and from 5.4 cm (range = 4.3-7.3) to 4.4 cm (range = 3.5-6.8) for the sorafenib group, at baseline vs. 28 days of treatment. Correlative assessment of proliferation, apoptosis, and microvessel density revealed an enhanced degree of functional ITH in treated patients suggesting adaptive and/or regenerative processes with potential relevance for the development of drug resistance.

Sorafenib in standard dosage, given preoperatively for 28 days, was clinically active in downsizing tumors in patients with locally confined, non-metastatic RCC together but led to an enhanced functional ITH in the residual tumor tissue.

Langenbeck's archives of surgery. 2016 Dec 23 [Epub ahead of print]

Gencay Hatiboglu, Markus Hohenfellner, Aysenur Arslan, Boris Hadaschik, Dogu Teber, Jan Philipp Radtke, Peter Hallscheidt, Yanis Tolstov, Wilfried Roth, Carsten Grüllich, Johannes Huesing, Stefan Duensing, Sascha Pahernik

Department of Urology, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. ., Department of Urology, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany., Molecular Urooncology, Department of Urology, University of Heidelberg, Heidelberg, Germany., Department of Diagnostic and Interventional Radiology, University of Heidelberg, Heidelberg, Germany., Institute for Pathology, University of Heidelberg, Heidelberg, Germany., Medical Oncology, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany., Coordination Centre for Clinical Trials, University of Heidelberg, Heidelberg, Germany.

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