BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is characterized by high constitutive vascular endothelial growth factor A (VEGF-A) production that induces a specific vascular phenotype. We previously reported that this phenotype may allow shedding of multicellular tumor fragments into the circulation, possibly contributing to the development of metastasis. Disruption of this phenotype through inhibition of VEGF signaling may therefore result in reduced shedding of tumor fragments and improved prognosis. To test this hypothesis, we investigated the effect of neoadjuvant sorafenib treatment on tumor cluster shedding. PATIENTS AND METHODS: Patients with renal cancer (n = 10, of which 8 have ccRCC) received sorafenib for 4 weeks before tumor nephrectomy. The resection specimens were perfused, and the perfundate was examined for the presence of tumor clusters. Effects of the treatment on the tumor morphology and overall survival were investigated (follow-up of 2 years) and compared with a carefully matched control group. RESULTS: Neoadjuvant sorafenib treatment induced extensive ischemic tumor necrosis and, as expected, destroyed the characteristic ccRCC vascular phenotype. In contrast to the expectation, vital groups of tumor cells with high proliferation indices were detected in postsurgical renal venous outflow in 75% of the cases. Overall survival of patients receiving neoadjuvant treatment was reduced compared to a control group, matched with regard to prognostic parameters. CONCLUSIONS: These results suggest that neoadjuvant sorafenib therapy for ccRCC does not prevent shedding of tumor fragments. Although this is a nonrandomized study with a small patient group, our results suggest that neoadjuvant treatment may worsen survival through as yet undefined mechanisms.
BACKGROUND:Clear cell renal cell carcinoma (ccRCC) is characterized by high constitutive vascular endothelial growth factor A (VEGF-A) production that induces a specific vascular phenotype. We previously reported that this phenotype may allow shedding of multicellular tumor fragments into the circulation, possibly contributing to the development of metastasis. Disruption of this phenotype through inhibition of VEGF signaling may therefore result in reduced shedding of tumor fragments and improved prognosis. To test this hypothesis, we investigated the effect of neoadjuvant sorafenib treatment on tumor cluster shedding. PATIENTS AND METHODS: Patients with renal cancer (n = 10, of which 8 have ccRCC) received sorafenib for 4 weeks before tumor nephrectomy. The resection specimens were perfused, and the perfundate was examined for the presence of tumor clusters. Effects of the treatment on the tumor morphology and overall survival were investigated (follow-up of 2 years) and compared with a carefully matched control group. RESULTS: Neoadjuvant sorafenib treatment induced extensive ischemic tumor necrosis and, as expected, destroyed the characteristic ccRCC vascular phenotype. In contrast to the expectation, vital groups of tumor cells with high proliferation indices were detected in postsurgical renal venous outflow in 75% of the cases. Overall survival of patients receiving neoadjuvant treatment was reduced compared to a control group, matched with regard to prognostic parameters. CONCLUSIONS: These results suggest that neoadjuvant sorafenib therapy for ccRCC does not prevent shedding of tumor fragments. Although this is a nonrandomized study with a small patient group, our results suggest that neoadjuvant treatment may worsen survival through as yet undefined mechanisms.
Authors: Thomas Powles; Christian Blank; Simon Chowdhury; Simon Horenblas; John Peters; Jonathan Shamash; Naveed Sarwar; Ekaterini Boleti; Anju Sahdev; Tim O'Brien; Dan Berney; Luis Beltran; Paul Nathan; John Haanen; Axel Bex Journal: Eur Urol Date: 2011-05-17 Impact factor: 20.096
Authors: Ingrid M E Desar; J Hans F M Jacobs; Christina A Hulsbergen-vandeKaa; Wim J G Oyen; Peter F A Mulders; Winette T A van der Graaf; Gosse J Adema; Carla M L van Herpen; I Jolanda J M de Vries Journal: Int J Cancer Date: 2010-11-12 Impact factor: 7.396
Authors: Marcella M Baldewijns; Iris J H van Vlodrop; Peter B Vermeulen; Patricia M M B Soetekouw; Manon van Engeland; Adriaan P de Bruïne Journal: J Pathol Date: 2010-06 Impact factor: 7.996
Authors: C Lance Cowey; Chirag Amin; Raj S Pruthi; Eric M Wallen; Matthew E Nielsen; Gayle Grigson; Cathy Watkins; Keith V Nance; Jeffrey Crane; Mark Jalkut; Dominic T Moore; William Y Kim; Paul A Godley; Young E Whang; Julia R Fielding; W Kimryn Rathmell Journal: J Clin Oncol Date: 2010-02-16 Impact factor: 44.544
Authors: E Barrascout; J Medioni; F Scotte; J Ayllon; A Mejean; C A Cuenod; Eric Tartour; R Elaidi; S Oudard Journal: Bull Cancer Date: 2010 Impact factor: 1.276
Authors: Matthias Krusch; Julia Salih; Manuela Schlicke; Tina Baessler; Kerstin Maria Kampa; Frank Mayer; Helmut Rainer Salih Journal: J Immunol Date: 2009-12-15 Impact factor: 5.422
Authors: Gursah Kats-Ugurlu; Ilse Roodink; Mirjam de Weijert; Dorien Tiemessen; Cathy Maass; Kiek Verrijp; Jeroen van der Laak; Rob de Waal; Peter Mulders; Egbert Oosterwijk; William Leenders Journal: J Pathol Date: 2009-11 Impact factor: 7.996
Authors: John M L Ebos; Christina R Lee; William Cruz-Munoz; Georg A Bjarnason; James G Christensen; Robert S Kerbel Journal: Cancer Cell Date: 2009-03-03 Impact factor: 31.743
Authors: Katarina Koruza; A Briana Murray; Brian P Mahon; Jesse B Hopkins; Wolfgang Knecht; Robert McKenna; S Zoë Fisher Journal: Int J Mol Sci Date: 2020-07-25 Impact factor: 5.923
Authors: Sanne A M van Lith; Ilse Roodink; Joost J C Verhoeff; Petri I Mäkinen; Jari P Lappalainen; Seppo Ylä-Herttuala; Jos Raats; Erwin van Wijk; Ronald Roepman; Stef J Letteboer; Kiek Verrijp; William P J Leenders Journal: Oncotarget Date: 2016-11-01