title: A phase II and pharmacodynamic study of sunitinib in relapsed/refractory oesophageal and gastro-oesophageal cancers.
abstract: BACKGROUND
  Blockade of the vascular endothelial growth factor (VEGF) pathway shows evidence of activity in gastro-oesophageal (GE) and oesophageal cancer. We investigated the efficacy of sunitinib, a multikinase VEGF inhibitor, in patients with relapsed/refractory GE/oesophageal cancer.
  
  
  METHODS
  This was a single-stage Fleming phase II study. The primary end point was progression-free survival (PFS) at 24 weeks. If five or more patients out of a total of 25 were free of progressive disease at 24 weeks, sunitinib would be recommended for further study. Patients received sunitinib 37.5 mg orally daily and imaged every 6 weeks. Exploratory correlative analysis included serum growth factors, tumour gene expression and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).
  
  
  RESULTS
  Twenty-five evaluable patients participated in the study. Progression-free survival at 24 weeks was 8% (n=2 patients; confidence interval (CI): 95% 1.4-22.5%), and the duration of best response for the patients was 23 and 72 weeks. Ten patients (42%) had stable disease (SD) for >10 weeks. Overall response rate is 13%. Median PFS is 7 weeks (95% CI: 5.6-11.4 weeks) and the median overall survival is 17 weeks (95% CI: 8.9-25.3 weeks). Most common grade 3/4 toxicities included fatigue (24%), anaemia (20%) thrombocytopenia (16%), and leucopenia (16%). No patients discontinued therapy due to toxicity. Serum VEGF-A and -C levels, tumour complement factor B (CFB) gene expression, and DCE-MRI correlated with clinical benefit, defined as SD or better as best response.
  
  
  CONCLUSIONS
  Sunitinib is well tolerated but only a select subgroup of patients benefited. Serum VEGF-A and -C may be early predictors of benefit. On this study, patients with clinical benefit from sunitinib had higher tumour CFB expression, and thus has identified CFB as a potential predictor for efficacy of anti-angiogenic therapy. These findings need validation from future prospective trials.
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Arthur G James Cancer Hospital and Richard J Solove Research Institute, Columbus, OH 43210, USA.
authors.forename: C
authors.initials: C
authors.lastname: Wu
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Arthur G James Cancer Hospital and Richard J Solove Research Institute, Columbus, OH 43210, USA.
authors.forename: S
authors.initials: S
authors.lastname: Mikhail
authors.affiliation: Center for Biostatistics, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wei
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Arthur G James Cancer Hospital and Richard J Solove Research Institute, Columbus, OH 43210, USA.
authors.forename: C
authors.initials: C
authors.lastname: Timmers
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Arthur G James Cancer Hospital and Richard J Solove Research Institute, Columbus, OH 43210, USA.
authors.forename: S
authors.initials: S
authors.lastname: Tahiri
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Arthur G James Cancer Hospital and Richard J Solove Research Institute, Columbus, OH 43210, USA.
authors.forename: A
authors.initials: A
authors.lastname: Neal
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: J
authors.initials: J
authors.lastname: Walker
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: S
authors.initials: S
authors.lastname: El-Dika
authors.affiliation: Department of Pharmacy, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: M
authors.initials: M
authors.lastname: Blazer
authors.affiliation: Anatomic Pathology Laboratory, Mercy Anderson Hospital, Cincinnati, OH 43210, USA.
authors.forename: J
authors.initials: J
authors.lastname: Rock
authors.affiliation: Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: D J
authors.initials: DJ
authors.lastname: Clark
authors.affiliation: Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: X
authors.initials: X
authors.lastname: Yang
authors.affiliation: Division of Medical Oncology, Departments of Biomedical Informatics and Internal Medicine, The Ohio State University Comprehensive Cancer Center, Arthur G James Cancer Hospital and Richard J Solove Research Institute, Columbus, OH 43210, USA.
authors.forename: J L
authors.initials: JL
authors.lastname: Chen
authors.affiliation: Department of Pathology, Beaumont Medical Center, Grosse Pointe, MI, USA.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA.
authors.forename: M V
authors.initials: MV
authors.lastname: Knopp
authors.affiliation: Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Arthur G James Cancer Hospital and Richard J Solove Research Institute, Columbus, OH 43210, USA.
authors.forename: T
authors.initials: T
authors.lastname: Bekaii-Saab
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D011415:Complement Factor B / Q000032:analysis; D004938:Esophageal Neoplasms / Q000097:blood / Q000188:drug therapy*; D004943:Esophagogastric Junction; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D012008:Recurrence; D000077210:Sunitinib; D059467:Transcriptome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000097:blood; D042582:Vascular Endothelial Growth Factor C / Q000097:blood
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D042582:Vascular Endothelial Growth Factor C; D011415:Complement Factor B; D000077210:Sunitinib