Gencay Hatiboglu1, Markus Hohenfellner2, Aysenur Arslan3, Boris Hadaschik2, Dogu Teber2, Jan Philipp Radtke2, Peter Hallscheidt4, Yanis Tolstov3, Wilfried Roth5, Carsten Grüllich6, Johannes Huesing7, Stefan Duensing3, Sascha Pahernik2. 1. Department of Urology, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. gencay.hatiboglu@med.uni-heidelberg.de. 2. Department of Urology, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. 3. Molecular Urooncology, Department of Urology, University of Heidelberg, Heidelberg, Germany. 4. Department of Diagnostic and Interventional Radiology, University of Heidelberg, Heidelberg, Germany. 5. Institute for Pathology, University of Heidelberg, Heidelberg, Germany. 6. Medical Oncology, National Center for Tumor Diseases, University of Heidelberg, Heidelberg, Germany. 7. Coordination Centre for Clinical Trials, University of Heidelberg, Heidelberg, Germany.
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.
RCT Entities:
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.
Entities:
Keywords:
Neoadjuvant treatment; Renal cell cancer; Sorafenib; Surgery
Authors: Ronald J Zagoria; Joseph A Pettus; Morgan Rogers; David M Werle; David Childs; John R Leyendecker Journal: Urology Date: 2011-04-13 Impact factor: 2.649
Authors: Brian I Rini; Elizabeth R Plimack; Toshio Takagi; Paul Elson; Laura S Wood; Robert Dreicer; Timothy Gilligan; Jorge Garcia; Zhiling Zhang; Jihad Kaouk; Venkatesh Krishnamurthi; Andrew J Stephenson; Amr Fergany; Eric A Klein; Robert G Uzzo; David Y T Chen; Steven C Campbell Journal: J Urol Date: 2015-03-23 Impact factor: 7.450
Authors: Jonathan L Silberstein; Frederick Millard; Reza Mehrazin; Ryan Kopp; Wassim Bazzi; Christopher J DiBlasio; Anthony L Patterson; Tracy M Downs; Furhan Yunus; Christopher J Kane; Ithaar H Derweesh Journal: BJU Int Date: 2010-11 Impact factor: 5.588
Authors: Grant D Stewart; Fiach C O'Mahony; Alexander Laird; Lel Eory; Alexander L R Lubbock; Alan Mackay; Jyoti Nanda; Marie O'Donnell; Peter Mullen; S Alan McNeill; Antony C P Riddick; Daniel Berney; Axel Bex; Michael Aitchison; Ian M Overton; David J Harrison; Thomas Powles Journal: Clin Cancer Res Date: 2015-05-26 Impact factor: 12.531
Authors: Bartlomiej Waclaw; Ivana Bozic; Meredith E Pittman; Ralph H Hruban; Bert Vogelstein; Martin A Nowak Journal: Nature Date: 2015-08-26 Impact factor: 49.962
Authors: Gursah Kats-Ugurlu; Egbert Oosterwijk; Stijn Muselaers; Jeannette Oosterwijk-Wakka; Christina Hulsbergen-van de Kaa; Mirjam de Weijert; Han van Krieken; Ingrid Desar; Carla van Herpen; Cathy Maass; Rob de Waal; Peter Mulders; William Leenders Journal: Neoplasia Date: 2014-04-13 Impact factor: 5.715
Authors: Kevin Sharpe; Grant D Stewart; Alan Mackay; Christophe Van Neste; Charlotte Rofe; Dan Berney; Irfan Kayani; Axel Bex; Elaine Wan; Fiach C O'Mahony; Marie O'Donnell; Simon Chowdhury; Rukma Doshi; Colan Ho-Yen; Marco Gerlinger; Dawn Baker; Neil Smith; Barry Davies; Anju Sahdev; Ekaterini Boleti; Tim De Meyer; Wim Van Criekinge; Luis Beltran; Yong-Jie Lu; David J Harrison; Andrew R Reynolds; Tom Powles Journal: Clin Cancer Res Date: 2013-10-15 Impact factor: 12.531
Authors: Sebastien J Hotte; Anil Kapoor; Naveen S Basappa; Georg Bjarnason; Christina Canil; Henry J Conter; Piotr Czaykowski; Jeffrey Graham; Samantha Gray; Daniel Y C Heng; Pierre I Karakiewicz; Christian Kollmannsberger; Aly-Khan A Lalani; Scott A North; François Patenaude; Denis Soulières; Phillippe Violette; Eric Winquist; Lori A Wood; Shaan Dudani; Ranjena Maloni; M Neil Reaume Journal: Can Urol Assoc J Date: 2019-10 Impact factor: 1.862
Authors: Justin D Oake; Premal Patel; Luke T Lavallée; Jean-Baptiste Lattouf; Olli Saarela; Laurence Klotz; Ronald B Moore; Anil Kapoor; Antonio Finelli; Ricardo A Rendon; Jun Kawakami; Alan I So; Darrel E Drachenberg Journal: Can Urol Assoc J Date: 2019-07-23 Impact factor: 1.862
Authors: Peter Makhov; Shreyas Joshi; Pooja Ghatalia; Alexander Kutikov; Robert G Uzzo; Vladimir M Kolenko Journal: Mol Cancer Ther Date: 2018-07 Impact factor: 6.261
Authors: Mehmet A Bilen; James F Jiang; Caroline S Jansen; Jacqueline T Brown; Lara R Harik; Aarti Sekhar; Haydn Kissick; Shishir K Maithel; Omer Kucuk; Bradley Carthon; Viraj A Master Journal: Front Oncol Date: 2021-02-01 Impact factor: 6.244