title: Alternating Treatment With Pazopanib and Everolimus vs Continuous Pazopanib to Delay Disease Progression in Patients With Metastatic Clear Cell Renal Cell Cancer: The ROPETAR Randomized Clinical Trial.
abstract: OBJECTIVE
  To our knowledge, this is the first randomized clinical trial evaluating an alternating treatment regimen in an attempt to delay disease progression in clear cell renal cell carcinoma.
  
  
  OBJECTIVE
  To test our hypothesis that an 8-week rotating treatment schedule with pazopanib and everolimus delays disease progression, exhibits more favorable toxic effects, and improves quality of life when compared with continuous treatment with pazopanib.
  
  
  METHODS
  This was an open-label, randomized (1:1) study (ROPETAR trial). In total, 101 patients with treatment-naive progressive metastatic clear cell renal cell carcinoma were enrolled between September 2012 and April 2014 from 17 large peripheral or academic hospitals in The Netherlands and followed for at least one year.
  
  
  METHODS
  First-line treatment consisted of either an 8-week alternating treatment schedule of pazopanib 800 mg/d and everolimus 10 mg/d (rotating arm) or continuous pazopanib 800 mg/d (control arm) until progression. After progression, patients made a final rotation to either pazopanib or everolimus monotherapy (rotating arm) or initiated everolimus (control arm).
  
  
  METHODS
  The primary end point was survival until first progression or death. Secondary end points included time to second progression or death, toxic effects, and quality of life.
  
  
  RESULTS
  A total of 52 patients were randomized to the rotating arm (median [range] age, 65 [44-87] years) and 49 patients to the control arm (median [range] age, 67 [38-82] years). Memorial Sloan Kettering Cancer Center risk category was favorable in 26% of patients, intermediate in 58%, and poor in 15%. Baseline characteristics and risk categories were well balanced between arms. One-year PFS1 for rotating treatment was 45% (95% CI, 33-60) and 32% (95% CI, 21-49) for pazopanib (control). Median time until first progression or death for rotating treatment was 7.4 months (95% CI, 5.6-18.4) and 9.4 months (95% CI, 6.6-11.9) for pazopanib (control) (P = .37). Mucositis, anorexia, and dizziness were more prevalent in the rotating arm during first-line treatment. No difference in quality of life was observed.
  
  
  CONCLUSIONS
  Rotating treatment did not result in prolonged progression-free-survival, fewer toxic effects, or improved quality of life. First-line treatment with a vascular endothelial growth factor inhibitor remains the optimal approach in metastatic clear cell renal cell carcinoma.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT01408004.
authors.affiliation: University Medical Center Utrecht, Department of Medical Oncology, Utrecht, the Netherlands.
authors.forename: Geert A
authors.initials: GA
authors.lastname: Cirkel
authors.affiliation: Franciscus Gasthuis, Department of Medical Oncology, Rotterdam, the Netherlands.
authors.forename: Paul
authors.initials: P
authors.lastname: Hamberg
authors.affiliation: Erasmus MC Cancer Institute, Department of Medical Oncology, Rotterdam, the Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Sleijfer
authors.affiliation: Amphia Hospital, Department of Medical Oncology, Breda, the Netherlands.
authors.forename: Olaf J L
authors.initials: OJL
authors.lastname: Loosveld
authors.affiliation: Maxima Medical Center, Department of Medical Oncology, Eindhoven, the Netherlands.
authors.forename: M Wouter
authors.initials: MW
authors.lastname: Dercksen
authors.affiliation: St Antonius Hospital, Department of Medical Oncology, Nieuwegein, the Netherlands.
authors.forename: Maartje
authors.initials: M
authors.lastname: Los
authors.affiliation: Medical Center Leeuwarden, Department of Medical Oncology, Leeuwarden, the Netherlands.
authors.forename: Marco B
authors.initials: MB
authors.lastname: Polee
authors.affiliation: Zuyderland Medical Center, Department of Medical Oncology, Heerlen, the Netherlands.
authors.forename: Franchette
authors.initials: F
authors.lastname: van den Berkmortel
authors.affiliation: Maastricht University Medical Center, Department of Medical Oncology, Maastricht, the Netherlands.
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Aarts
authors.affiliation: Elisabeth Tweesteden Hospital, Department of Medical Oncology, Tilburg, the Netherlands.
authors.forename: Laurens V
authors.initials: LV
authors.lastname: Beerepoot
authors.affiliation: University Medical Center Utrecht, Department of Medical Oncology, Utrecht, the Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Groenewegen
authors.affiliation: University Medical Center Utrecht, Department of Medical Oncology, Utrecht, the Netherlands3Erasmus MC Cancer Institute, Department of Medical Oncology, Rotterdam, the Netherlands.
authors.forename: Martijn P
authors.initials: MP
authors.lastname: Lolkema
authors.affiliation: Isala Clinics, Department of Medical Oncology, Zwolle, the Netherlands.
authors.forename: Metin
authors.initials: M
authors.lastname: Tascilar
authors.affiliation: Haga Hospital, Department of Medical Oncology, Den Haag, the Netherlands.
authors.forename: Johanna E A
authors.initials: JEA
authors.lastname: Portielje
authors.affiliation: Zuyderland Medical Center, Department of Medical Oncology, Sittard-Geleen, the Netherlands.
authors.forename: Frank P J
authors.initials: FPJ
authors.lastname: Peters
authors.affiliation: Academic Medical Center, Department of Medical Oncology, Amsterdam, the Netherlands.
authors.forename: Heinz-Josef
authors.initials: HJ
authors.lastname: Klümpen
authors.affiliation: Netherlands Cancer Institute, Department of Biometrics, Amsterdam, the Netherlands.
authors.forename: Vincent
authors.initials: V
authors.lastname: van der Noort
authors.affiliation: Netherlands Cancer Institute, Department of Medical Oncology, Amsterdam, the Netherlands.
authors.forename: John B A G
authors.initials: JBAG
authors.lastname: Haanen
authors.affiliation: University Medical Center Utrecht, Department of Medical Oncology, Utrecht, the Netherlands16Netherlands Cancer Institute, Department of Medical Oncology, Amsterdam, the Netherlands.
authors.forename: Emile E
authors.initials: EE
authors.lastname: Voest
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000401:mortality; D018450:Disease Progression; D018572:Disease-Free Survival; D000068338:Everolimus / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D007191:Indazoles; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D011743:Pyrimidines / Q000008:administration & dosage* / Q000009:adverse effects; D011788:Quality of Life; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects
chemical_list: D007191:Indazoles; D011743:Pyrimidines; D013449:Sulfonamides; C516667:pazopanib; D000068338:Everolimus