title: Tyrosine kinase inhibitor sorafenib decreases 111In-girentuximab uptake in patients with clear cell renal cell carcinoma.
abstract: Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of metastatic clear cell renal cell carcinoma (RCC). Although TKIs have demonstrated good clinical efficacy, the lack of complete responses, the chronic nature of the treatment, and the side effects are clear disadvantages. An interesting new approach in the treatment of clear cell RCC is antibody-mediated therapy with the chimeric anti-carbonic anhydrase IX (CAIX) antibody girentuximab (cG250). As the results of several girentuximab trials become available, the question arises of whether TKI treatment can be combined with girentuximab-based therapy. In this study, we assessed the effect of the widely used TKI sorafenib on the tumor-targeting potential of (111)In-labeled girentuximab.
  
  
  METHODS
  (111)In-girentuximab imaging was performed on 15 patients suspected of having a renal malignancy, with surgery being part of their treatment plan. Of these, 10 patients were treated in a neoadjuvant setting with sorafenib (400 mg orally twice daily). Five patients received treatment during 1 wk, and 5 patients received treatment during 4 wk. In both sorafenib-treated groups, baseline and posttreatment tumor targeting of (111)In-girentuximab were compared. Surgery was performed 3 d after the last image acquisition. Five additional patients were included as a control group and had only a single (111)In-girentuximab injection and scintigraphy without any treatment. Distribution of (111)In-girentuximab was determined scintigraphically ex vivo in a 1-cm lamella of the resected tumorous kidney. Expression of CAIX and of the vascular marker CD31 was determined immunohistochemically on specimens of both tumor and normal kidney tissue.
  
  
  RESULTS
  Treatment with sorafenib resulted in a marked decrease of (111)In-girentuximab uptake in the tumor in clear cell RCC patients, especially in the group treated for 4 wk (mean change in both sorafenib-treated groups, -38.4%; range, +9.1% to -79.4%). Immunohistochemical analysis showed markedly reduced CD31 expression and vessel density in the sorafenib-treated groups but no differences in CAIX expression between the sorafenib-treated groups and the nontreated patients.
  
  
  CONCLUSIONS
  Treatment with sorafenib resulted in a treatment duration-dependent significantly decreased uptake of (111)In-girentumab in clear cell RCC lesions. These results indicate that the efficacy of antibody-mediated treatment or diagnosis modalities is hampered by TKI treatment.
authors.affiliation: Radboud university medical center, Department of Urology, Nijmegen, The Netherlands.
authors.forename: Constantijn H J
authors.initials: CH
authors.lastname: Muselaers
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Stillebroer
authors.forename: Ingrid M E
authors.initials: IM
authors.lastname: Desar
authors.forename: Marye J
authors.initials: MJ
authors.lastname: Boers-Sonderen
authors.forename: Carla M L
authors.initials: CM
authors.lastname: van Herpen
authors.forename: Mirjam C A
authors.initials: MC
authors.lastname: de Weijert
authors.forename: Johan F
authors.initials: JF
authors.lastname: Langenhuijsen
authors.forename: Egbert
authors.initials: E
authors.lastname: Oosterwijk
authors.forename: William P J
authors.initials: WP
authors.lastname: Leenders
authors.forename: Otto C
authors.initials: OC
authors.lastname: Boerman
authors.forename: Peter F A
authors.initials: PF
authors.lastname: Mulders
authors.forename: Wim J G
authors.initials: WJ
authors.lastname: Oyen
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics*; D002292:Carcinoma, Renal Cell / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007205:Indium Radioisotopes / Q000493:pharmacokinetics*; D007680:Kidney Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011877:Radionuclide Imaging; D000077157:Sorafenib
chemical_list: D000911:Antibodies, Monoclonal; C106533:G250 monoclonal antibody; D007205:Indium Radioisotopes; D010671:Phenylurea Compounds; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D009536:Niacinamide; D000077157:Sorafenib; D011505:Protein-Tyrosine Kinases
keywords: CAIX; girentuximab; imaging; renal cell carcinoma; tyrosine kinase inhibitor