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23.12.2016 | ORIGINAL ARTICLE | Ausgabe 4/2017

Langenbeck's Archives of Surgery 4/2017

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

Zeitschrift:
Langenbeck's Archives of Surgery > Ausgabe 4/2017
Autoren:
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
Wichtige Hinweise
Stefan Duensing and Sascha Pahernik contributed equally to this work

Abstract

Objectives

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).

Materials and methods

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.

Results

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.

Conclusions

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.

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