title: Long-term Safety of Sunitinib in Metastatic Renal Cell Carcinoma.
abstract: BACKGROUND
  Metastatic renal cell carcinoma (mRCC) patients receiving first-line sunitinib typically survive >2 yr, with chronic treatment sometimes extending to ≥6 yr.
  
  
  OBJECTIVE
  To analyze long-term safety with sunitinib in mRCC patients.
  
  
  METHODS
  Data were pooled from 5739 patients in nine trials, comprising seven phase II studies, a phase III study, and an expanded-access trial in various treatment settings (e.g., cytokine refractory or treatment-naïve).
  
  
  METHODS
  Interval and cumulative time-period analyses evaluated the incidence of treatment-related adverse events (TRAEs) for up to 6 yr, in the overall population and in those with long-term (≥2 yr) sunitinib treatment.
  
  
  CONCLUSIONS
  Among long-term patients (n=807), most TRAEs occurred initially in the first year and then decreased in frequency; TRAEs following this pattern included decreased appetite, diarrhea, dysgeusia, dyspepsia, fatigue, hypertension, mucosal inflammation, nausea, and stomatitis. However, hypothyroidism increased by interval analysis from 6% at 0-<6 mo to 42% at 5-<6 yr and by cumulative analysis from 14% at 0-<1 yr to 36% over 6 yr. Grade 3/4 TRAEs in long-term patients peaked during the first year and then steadily decreased. The overall population displayed only minor differences from long-term patients, with no clinically significant differences between grade ≥3 TRAE profiles (<5% difference in incidence rates at all intervals). Limitations included retrospective design, assessment variability, lack of pharmacokinetic data, and absence of baseline characteristics for long-term patients.
  
  
  CONCLUSIONS
  Prolonged sunitinib was not associated with new types or increased severity of TRAEs. Except hypothyroidism, toxicity was not cumulative.
  
  
  RESULTS
  More than 800 mRCC patients received sunitinib for between 2 and 6 yr without experiencing new or more severe treatment-related toxicity. Clinicians may be able to prescribe chronic sunitinib treatment for as long as patients continue to derive clinical benefit, without untoward additional risk.
authors.affiliation: IRCCS San Matteo University Hospital Foundation, Pavia, Italy. Electronic address: camillo.porta@gmail.com.
authors.forename: Camillo
authors.initials: C
authors.lastname: Porta
authors.affiliation: Royal Marsden Hospital NHS Trust, London, UK.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Gore
authors.affiliation: Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA.
authors.forename: Brian I
authors.initials: BI
authors.lastname: Rini
authors.affiliation: Gustave Roussy, Villejuif, France.
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.affiliation: Pfizer Oncology, New York, NY, USA.
authors.forename: Subramanian
authors.initials: S
authors.lastname: Hariharan
authors.affiliation: Pfizer Oncology, New York, NY, USA.
authors.forename: Lorna P
authors.initials: LP
authors.lastname: Charles
authors.affiliation: Pfizer Oncology, New York, NY, USA.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Yang
authors.affiliation: Pfizer Oncology, New York, NY, USA.
authors.forename: Liza
authors.initials: L
authors.lastname: DeAnnuntis
authors.affiliation: Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Motzer
mesh_terms: D000855:Anorexia / Q000139:chemically induced; D000970:Antineoplastic Agents / Q000009:adverse effects*; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000556:secondary*; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003967:Diarrhea / Q000139:chemically induced; D004408:Dysgeusia / Q000139:chemically induced; D004415:Dyspepsia / Q000139:chemically induced; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D006801:Humans; D006973:Hypertension / Q000139:chemically induced; D007037:Hypothyroidism / Q000139:chemically induced; D007211:Indoles / Q000009:adverse effects*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D052016:Mucositis / Q000139:chemically induced; D009325:Nausea / Q000139:chemically induced; D011758:Pyrroles / Q000009:adverse effects*; D013280:Stomatitis / Q000139:chemically induced; D000077210:Sunitinib; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D000077210:Sunitinib
keywords: Long-term safety; Renal cell carcinoma; Sunitinib; Toxicity; Treatment-related adverse events