title: Sunitinib in refractory adrenocortical carcinoma: a phase II, single-arm, open-label trial.
abstract: BACKGROUND
  Treatment of refractory adrenocortical carcinoma (ACC) is not established. Animal experiments pointed toward adrenal toxicity of sunitinib.
  
  
  OBJECTIVE
  The objective of the study was to determine the antitumor effects of sunitinib in refractory ACC.
  
  
  METHODS
  This was a phase II, open-label trial using a two-stage accrual design.
  
  
  METHODS
  The study was conducted at two tertiary referral centers.
  
  
  METHODS
  Thirty-eight patients with refractory ACC progressing after mitotane and one to three cytotoxic chemotherapies participated in the study.
  
  
  METHODS
  The intervention included sunitinib at a standard dose (50 mg/d, 4 wk on, 2 wk off).
  
  
  METHODS
  Response was defined as progression-free survival (PFS) of 12 wk or longer (first tumor evaluation).
  
  
  RESULTS
  Thirty-five patients could be evaluated for response. Five patients experienced stable disease, 24 had progressive disease, and six patients died from ACC before the first evaluation (naïve estimate five of 35=14.3%, median unbiased response rate 15.4%, 95% confidence interval 5.0-33.4%). The median PFS was 2.8 months. In responders, PFS ranged between 5.6 and 11.2 months and overall survival between 14.0 and 35.5 months. Of 36 serious adverse events, only nine were possibly related to sunitinib. Concomitant mitotane appeared to negatively impact on outcome. Furthermore, a negative correlation between the serum concentrations of sunitinib plus its active metabolite N-desethylsunitinib (SU12662) and mitotane (r=-0.650; P=0.114) was observed in seven evaluable patients suggestive of a relevant drug interaction.
  
  
  CONCLUSIONS
  Sunitinib has modest activity in advanced refractory ACC, which compares favorably with other targeted treatments in these patients. Sunitinib serum levels might have been profoundly reduced by mitotane induced cytochrome P450-3A4 activity attenuating its antitumor activity and adverse effects. Together these findings suggest that sunitinib deserves further investigation in mitotane-naïve ACC patients.
authors: University Hospital, University of Würzburg, Department of Internal Medicine I, Oberdürrbacher Strasse 6, 97080 Würzburg, Germany.
authors: Matthias
authors: M
authors: Kroiss
authors: Marcus
authors: M
authors: Quinkler
authors: Sarah
authors: S
authors: Johanssen
authors: Nielka P
authors: NP
authors: van Erp
authors: Nienke
authors: N
authors: Lankheet
authors: Alexander
authors: A
authors: Pöllinger
authors: Katharina
authors: K
authors: Laubner
authors: Christian J
authors: CJ
authors: Strasburger
authors: Stefanie
authors: S
authors: Hahner
authors: Hans-Helge
authors: HH
authors: Müller
authors: Bruno
authors: B
authors: Allolio
authors: Martin
authors: M
authors: Fassnacht
mesh_terms: D000306:Adrenal Cortex Neoplasms / Q000188:drug therapy* / Q000401:mortality; D018268:Adrenocortical Carcinoma / Q000188:drug therapy* / Q000401:mortality; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects; D018450:Disease Progression; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D008939:Mitotane / Q000008:administration & dosage / Q000009:adverse effects; D011758:Pyrroles / Q000008:administration & dosage* / Q000009:adverse effects; D000077210:Sunitinib; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D007211:Indoles; D011758:Pyrroles; D008939:Mitotane; D000077210:Sunitinib