title: Evidence and Clinical Relevance of Tumor Flare in Patients Who Discontinue Tyrosine Kinase Inhibitors for Treatment of Metastatic Renal Cell Carcinoma.
abstract: BACKGROUND
  Several tyrosine kinase inhibitors (TKIs) and one monoclonal antibody targeting the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis have been approved for the treatment of metastatic renal cell carcinoma (mRCC). Preclinical data suggest that cessation of anti-VEGF therapy may generate a tumor flare (TF) but its clinical relevance is still questionable.
  
  
  OBJECTIVE
  This analysis investigates the occurrence of tumor flare and its prognostic role after discontinuation of anti-VEGFR TKIs in patients affected by mRCC.
  
  
  METHODS
  Patients with mRCC treated with first-line sunitinib or pazopanib at standard dosages were screened. Patients included in the analysis were required to have: (1) discontinued treatment because of progression of disease or intolerable toxicity or sustained response; (2) evaluation of tumor growth rates immediately before (GR1) and after discontinuation (GR2); and (3) no treatment during evaluation of GR2.
  
  
  METHODS
  Overall survival (OS) was the main outcome. TF was calculated as the difference between the GR values (TF=GR2 - GR1). Cox proportional hazards regression was used to assess the prognostic role.
  
  
  CONCLUSIONS
  Sixty-three consecutive patients were analyzed; the median duration of treatment was 9.3 mo, the median progression-free survival (PFS) was 11.1 mo, and the median OS was 41.5 mo. The reasons for treatment discontinuation were sustained response (partial response/stable disease) in 15.9%, toxicity in 22.2%, and progression of disease in 61.9% of cases. The median GR1 and GR2 were 0.16cm/mo (interquartile range [IQR] -0.07 to 0.53) and 0.70cm/mo (IQR 0.21-1.46), respectively (p=0.001). In the overall population, the median TF was 0.55cm/mo (IQR 0.08-1.22) and differed according to the reason for discontinuation: 0.15cm/mo for response, 0.95cm/mo for toxicity, and 1.66cm/mo for progression. When TF was compared to other prognostic variables, Cox analysis confirmed its prognostic role (hazard ratio 1.11, 95% confidence interval 1.001-1.225; p=0.048).
  
  
  CONCLUSIONS
  This study reports clinical evidence that TKI discontinuation results in acceleration of tumor GR and induces TF, which can negatively affect the prognosis of mRCC patients.
  
  
  RESULTS
  In this report, we looked at the outcomes for patients affected by metastatic kidney tumors who discontinued treatment with antiangiogenic agents. We found that tumor regrowth after discontinuation of therapy was related to the reason for discontinuation: regrowth was higher in patients who discontinued treatment because of disease progression, and lower in patients who discontinued treatment because of a sustained response. Moreover, we found that the higher the growth rate, the shorter the survival. We conclude that discontinuation of antiangiogenic agents may cause an increase in tumor growth rate, which is related to patient survival.
authors.affiliation: Medical Oncology Department, Institut Gustave Roussy, Villejuif, France; Department of Radiology, Oncology and Human Pathology, Sapienza University of Rome, Rome, Italy. Electronic address: roberto.iacovelli@alice.it.
authors.forename: Roberto
authors.initials: R
authors.lastname: Iacovelli
authors.affiliation: Medical Oncology Department, Institut Gustave Roussy, Villejuif, France; Department of Medical Oncology, University of Verona, Verona, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Massari
authors.affiliation: Medical Oncology Department, Institut Gustave Roussy, Villejuif, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Albiges
authors.affiliation: Medical Oncology Department, Institut Gustave Roussy, Villejuif, France.
authors.forename: Yohann
authors.initials: Y
authors.lastname: Loriot
authors.affiliation: Medical Oncology Department, Institut Gustave Roussy, Villejuif, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Massard
authors.affiliation: Medical Oncology Department, Institut Gustave Roussy, Villejuif, France.
authors.forename: Karim
authors.initials: K
authors.lastname: Fizazi
authors.affiliation: Medical Oncology Department, Institut Gustave Roussy, Villejuif, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary; D018450:Disease Progression; D005260:Female; D006801:Humans; D007191:Indazoles; D007211:Indoles / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D011743:Pyrimidines / Q000627:therapeutic use*; D011758:Pyrroles / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*; D000077210:Sunitinib; D028761:Withholding Treatment
chemical_list: D020533:Angiogenesis Inhibitors; D007191:Indazoles; D007211:Indoles; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; C516667:pazopanib; D000077210:Sunitinib
keywords: Growth rate; Metastatic renal cell carcinoma (mRCC); Pazopanib; Sunitinib; Treatment cessation; Treatment discontinuation; Tumor flare; Tyrosine kinase inhibitors