title: Safety and Efficacy of Pazopanib Therapy Prior to Planned Nephrectomy in Metastatic Clear Cell Renal Cancer.
abstract: OBJECTIVE
  The role of cytoreductive nephrectomy in patients with metastatic renal cancer in the era of targeted therapy is uncertain.
  
  
  OBJECTIVE
  To establish the safety and efficacy of upfront pazopanib therapy prior to cytoreductive nephrectomy in previously untreated patients with metastatic clear cell renal cancer.
  
  
  METHODS
  Single-arm phase 2 study of 104 previously untreated patients with metastatic clear cell renal cancer recruited between June 2008 and October 2012 at cancer treatment centers with access to nephrectomy services. The minimum follow-up was 30 months.
  
  
  METHODS
  Patients received 12 to 14 weeks of preoperative pazopanib therapy prior to planned cytoreductive nephrectomy and continued pazopanib therapy after surgery. Treatment was stopped at disease progression.
  
  
  METHODS
  The primary end point was clinical benefit (using Response Evaluation Criteria in Solid Tumors, version 1.1) prior to surgery (at 12-14 weeks). Secondary end points included surgical complications, progression-free survival (PFS), overall survival (OS), and biomarker analysis.
  
  
  RESULTS
  Of 104 patients recruited, 100 patients were assessable for clinical benefit prior to planned nephrectomy; 80 of 104 (76.9%) were men; median [interquartile range] age, 64 [56-71] years). Overall, 84 of 100 (84% [95% CI, 75%-91%]) gained clinical benefit before planned nephrectomy. The median reduction in the size of the primary tumor was 14.4% (interquartile range, 1.4%-21.1%). No patients were unable to undergo surgery as a result of local progression of disease. Nephrectomy was performed in 63 (61%) of patients; 14 (22%) reported surgical complications. The 2 most common reasons for not undergoing surgery were progression of disease (n = 13) and patient choice (n = 9). There was 1 postoperative surgical death. The median PFS and OS for the whole cohort were 7.1 (95% CI, 6.0-9.2) and 22.7 (95% CI, 14.3-not estimable) months, respectively. Patients with MSKCC poor-risk disease or progressive disease prior to surgery had a poor outcome (median OS, 5.7 [95% CI, 2.6-10.8] and 3.9 [95% CI, 0.5-9.1] months, respectively). Surgical complications were observed in 14 (22%) of the nephrectomies. Biomarker analysis from sequential tissue samples revealed a decrease in CD8 expression (20.00 vs 13.75; P = .05) and significant reduction in expression of von Hippel-Lindau tumor suppressor (100 vs 40; P < .001) and C-MET (300 vs 100; P < .001) and increased programmed cell death ligand 1 expression (0 vs 1.5; P < .001) in the immune component. No on-treatment biomarker correlated with response.
  
  
  CONCLUSIONS
  Nephrectomy after upfront pazopanib therapy could be performed safely and was associated with good outcomes in patients with intermediate-risk metastatic clear cell renal cancer.
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Barts Health NHS Trust, London, England2Department of Medical Oncology, Royal Free NHS Foundation Trust, London, England.
authors.forename: Thomas
authors.initials: T
authors.lastname: Powles
authors.affiliation: Department of Oncology, Imperial College, London, England.
authors.forename: Naveed
authors.initials: N
authors.lastname: Sarwar
authors.affiliation: Arden Cancer Centre, University Hospital Coventry, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, England.
authors.forename: Andrew
authors.initials: A
authors.lastname: Stockdale
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Barts Health NHS Trust, London, England.
authors.forename: Shah-Jalal
authors.initials: SJ
authors.lastname: Sarker
authors.affiliation: Department of Medical Oncology, Royal Free NHS Foundation Trust, London, England.
authors.forename: Ekaterini
authors.initials: E
authors.lastname: Boleti
authors.affiliation: Department of Medical Oncology, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, England.
authors.forename: Andrew
authors.initials: A
authors.lastname: Protheroe
authors.affiliation: Beatson West of Scotland Cancer Centre, Glasgow, Scotland.
authors.forename: Robert
authors.initials: R
authors.lastname: Jones
authors.affiliation: Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, England.
authors.forename: Simon
authors.initials: S
authors.lastname: Chowdhury
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Barts Health NHS Trust, London, England.
authors.forename: John
authors.initials: J
authors.lastname: Peters
authors.affiliation: Beatson West of Scotland Cancer Centre, Glasgow, Scotland.
authors.forename: Grenville
authors.initials: G
authors.lastname: Oades
authors.affiliation: Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, England.
authors.forename: Tim
authors.initials: T
authors.lastname: O'Brien
authors.affiliation: Department of Medical Oncology, John Radcliffe Hospital, Oxford University Hospitals NHS Trust, Oxford, England.
authors.forename: Mark
authors.initials: M
authors.lastname: Sullivan
authors.affiliation: Department of Medical Oncology, Royal Free NHS Foundation Trust, London, England.
authors.forename: Michael
authors.initials: M
authors.lastname: Aitchison
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Barts Health NHS Trust, London, England.
authors.forename: Luis
authors.initials: L
authors.lastname: Beltran
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Barts Health NHS Trust, London, England.
authors.forename: Daniel
authors.initials: D
authors.lastname: Worth
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Barts Health NHS Trust, London, England.
authors.forename: Kate
authors.initials: K
authors.lastname: Smith
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Barts Health NHS Trust, London, England.
authors.forename: Constance
authors.initials: C
authors.lastname: Michel
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Barts Health NHS Trust, London, England.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Trevisan
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Barts Health NHS Trust, London, England.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Harvey-Jones
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Barts Health NHS Trust, London, England.
authors.forename: Akhila
authors.initials: A
authors.lastname: Wimalasingham
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Barts Health NHS Trust, London, England.
authors.forename: Anju
authors.initials: A
authors.lastname: Sahdev
authors.affiliation: Barts Cancer Institute, Queen Mary University of London, Barts Health NHS Trust, London, England.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ackerman
authors.affiliation: Cancer Sciences Unit, University of Southampton, Southampton, England.
authors.forename: Simon
authors.initials: S
authors.lastname: Crabb
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D017024:Chemotherapy, Adjuvant; D065426:Cytoreduction Surgical Procedures; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007191:Indazoles; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009392:Nephrectomy; D016016:Proportional Hazards Models; D011743:Pyrimidines / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib