Evidence and clinical relevance of tumor flare in patients who discontinue tyrosine kinase inhibitors for treatment of metastatic renal cell carcinoma

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. Design, setting, and participants: 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. Outcome measurements and statistical analysis: 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. Results and limitations: 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 0.16 cm/mo (interquartile range [IQR] 0.07 to 0.53) and 0.70 cm/mo (IQR 0.21-1.46), respectively ( p = 0.001). In the overall population, the median TF was 0.55 cm/mo (IQR 0.08-1.22) and differed according to the reason for discontinuation: 0.15 cm/mo for response, 0.95 cm/mo for toxicity, and 1.66 cm/mo for progression.When TFwas 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. Patient summary: 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.