title: Effective downsizing but enhanced intratumoral heterogeneity following neoadjuvant sorafenib in patients with non-metastatic renal cell carcinoma.
abstract: OBJECTIVE
  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).
  
  
  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.
authors.affiliation: Department of Urology, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. gencay.hatiboglu@med.uni-heidelberg.de.
authors.forename: Gencay
authors.initials: G
authors.lastname: Hatiboglu
authors.affiliation: Department of Urology, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Hohenfellner
authors.affiliation: Molecular Urooncology, Department of Urology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Aysenur
authors.initials: A
authors.lastname: Arslan
authors.affiliation: Department of Urology, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Boris
authors.initials: B
authors.lastname: Hadaschik
authors.affiliation: Department of Urology, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Dogu
authors.initials: D
authors.lastname: Teber
authors.affiliation: Department of Urology, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Jan Philipp
authors.initials: JP
authors.lastname: Radtke
authors.affiliation: Department of Diagnostic and Interventional Radiology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hallscheidt
authors.affiliation: Molecular Urooncology, Department of Urology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Yanis
authors.initials: Y
authors.lastname: Tolstov
authors.affiliation: Institute for Pathology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
authors.affiliation: Medical Oncology, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Grüllich
authors.affiliation: Coordination Centre for Clinical Trials, University of Heidelberg, Heidelberg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Huesing
authors.affiliation: Molecular Urooncology, Department of Urology, University of Heidelberg, Heidelberg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Duensing
authors.affiliation: Department of Urology, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Pahernik
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery*; D004311:Double-Blind Method; D005260:Female; D006498:Hepatectomy; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000601:surgery; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D010865:Pilot Projects; D011446:Prospective Studies; D000077157:Sorafenib; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib
keywords: Neoadjuvant treatment; Renal cell cancer; Sorafenib; Surgery