title: High dose intermittent sorafenib shows improved efficacy over conventional continuous dose in renal cell carcinoma.
abstract: BACKGROUND
  Renal cell carcinoma (RCC) responds to agents that inhibit vascular endothelial growth factor (VEGF) pathway. Sorafenib, a multikinase inhibitor of VEGF receptor, is effective at producing tumor responses and delaying median progression free survival in patients with cytokine refractory RCC. However, resistance to therapy develops at a median of 5 months. In an effort to increase efficacy, we studied the effects of increased sorafenib dose and intermittent scheduling in a murine RCC xenograft model.
  
  
  METHODS
  Mice bearing xenografts derived from the 786-O RCC cell line were treated with sorafenib according to multiple doses and schedules: 1) Conventional dose (CD) continuous therapy; 2) high dose (HD) intermittent therapy, 3) CD intermittent therapy and 4) HD continuous therapy. Tumor diameter was measured daily. Microvessel density was assessed after 3 days to determine the early effects of therapy, and tumor perfusion was assessed serially by arterial spin labeled (ASL) MRI at day 0, 3, 7 and 10.
  
  
  RESULTS
  Tumors that were treated with HD sorafenib exhibited slowed tumor growth as compared to CD using either schedule. HD intermittent therapy was superior to CD continous therapy, even though the total dose of sorafenib was essentially equivalent, and not significantly different than HD continuous therapy. The tumors exposed to HD sorafenib had lower microvessel density than the untreated or the CD groups. ASL MRI showed that tumor perfusion was reduced to a greater extent with the HD sorafenib at day 3 and at all time points thereafter relative to CD therapy. Further the intermittent schedule appeared to maintain RCC sensitivity to sorafenib as determined by changes in tumor perfusion.
  
  
  CONCLUSIONS
  A modification of the sorafenib dosing schedule involving higher dose intermittent treatment appeared to improve its efficacy in this xenograft model relative to conventional dosing. MRI perfusion imaging and histologic analysis suggest that this benefit is related to enhanced and protracted antiangiogenic activity. Thus, better understanding of dosing and schedule issues may lead to improved therapeutic effectiveness of VEGF directed therapy in RCC and possibly other tumors.
authors.affiliation: Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Xiaoen
authors.initials: X
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: S Nahum
authors.initials: SN
authors.lastname: Goldberg
authors.forename: Manoj
authors.initials: M
authors.lastname: Bhasin
authors.forename: Victoria
authors.initials: V
authors.lastname: Brown
authors.forename: David C
authors.initials: DC
authors.lastname: Alsop
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.forename: James W
authors.initials: JW
authors.lastname: Mier
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
authors.forename: Rupal S
authors.initials: RS
authors.lastname: Bhatt
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000008:administration & dosage* / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D009536:Niacinamide / Q000031:analogs & derivatives; D010477:Perfusion; D010671:Phenylurea Compounds; D011725:Pyridines / Q000008:administration & dosage* / Q000627:therapeutic use*; D000077157:Sorafenib; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib