title: Phase II study of everolimus in refractory testicular germ cell tumors.
abstract: BACKGROUND
  Testicular germ cell tumors (TGCTs) represent a highly curable disease; however, a small proportion of patients develop disease recurrence. Loss of the tumor-suppressor gene phosphatase and tensin homolog marks the transition from intratubular germ cell neoplasia to invasive GCT and is correlated with disease progression. Inactivation of phosphatase and tensin homolog is associated with deregulation of the PI3K/Akt pathway and increased mammalian target of rapamycin signaling. This study aimed to determine the efficacy and toxicity of a mammalian target of rapamycin inhibitor, everolimus, in patients with refractory TGCTs.
  
  
  METHODS
  From December 2011 to February 2015, 15 patients with refractory GCTs were enrolled in the phase II study. All patients were pretreated with at least 2 cisplatin-based therapies; 4 tumors (26.7%) were absolutely refractory to cisplatin and 9 patients (60.0%) had visceral nonpulmonary metastases. Everolimus was administered at a dose of 10mg daily until progression or unacceptable toxicity. The primary end point was the objective response rate, according to Response Evaluation Criteria in Solid Tumors.
  
  
  RESULTS
  No objective response was observed, but 6 patients (40.0%) achieved 12-week progression-free survival. During a median follow-up period of 3.6 months (range: 1-35.1mo), all patients experienced disease progression and 11 patients (80.0%) died. Median progression-free survival was 1.7 months (95% CI: 1.1-4.0mo) and median overall survival was 3.6 months (95% CI: 2.0-11.0mo).
  
  
  CONCLUSIONS
  This study failed to achieve its primary end point and our data suggest limited efficacy of everolimus against unselected heavily pretreated refractory TGCTs.
  
  
  CONCLUSIONS
  Everolimus showed limited efficacy in unselected heavily pretreated refractory TGCTs. Prolonged disease stabilization could be achieved in selected patients.
authors.affiliation: 2nd Department of Oncology, Faculty of Medicine, Comenius University, National Cancer Institute, Bratislava, Slovakia; Translational Research Unit, Faculty of Medicine, Comenius University, National Cancer Institute, Bratislava, Slovakia; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia. Electronic address: misomego@gmail.com.
authors.forename: Michal
authors.initials: M
authors.lastname: Mego
authors.affiliation: 2nd Department of Oncology, Faculty of Medicine, Comenius University, National Cancer Institute, Bratislava, Slovakia; Translational Research Unit, Faculty of Medicine, Comenius University, National Cancer Institute, Bratislava, Slovakia; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia.
authors.forename: Daniela
authors.initials: D
authors.lastname: Svetlovska
authors.affiliation: 1st Department of Oncology, Faculty of Medicine, Comenius University, St. Elisabeth Cancer Institute, Bratislava, Slovakia; Department of Medical Oncology, St. Elizabeth Cancer Institute, Bratislava, Slovakia.
authors.forename: Vera
authors.initials: V
authors.lastname: Miskovska
authors.affiliation: 2nd Department of Oncology, Faculty of Medicine, Comenius University, National Cancer Institute, Bratislava, Slovakia; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia.
authors.forename: Jana
authors.initials: J
authors.lastname: Obertova
authors.affiliation: 2nd Department of Oncology, Faculty of Medicine, Comenius University, National Cancer Institute, Bratislava, Slovakia; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia.
authors.forename: Patrik
authors.initials: P
authors.lastname: Palacka
authors.affiliation: 2nd Department of Oncology, Faculty of Medicine, Comenius University, National Cancer Institute, Bratislava, Slovakia; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia.
authors.forename: Jan
authors.initials: J
authors.lastname: Rajec
authors.affiliation: Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Sycova-Mila
authors.affiliation: 2nd Department of Oncology, Faculty of Medicine, Comenius University, National Cancer Institute, Bratislava, Slovakia; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia.
authors.forename: Michal
authors.initials: M
authors.lastname: Chovanec
authors.affiliation: 2nd Department of Oncology, Faculty of Medicine, Comenius University, National Cancer Institute, Bratislava, Slovakia; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia.
authors.forename: Katarina
authors.initials: K
authors.lastname: Rejlekova
authors.affiliation: Department of Medical Oncology, St. Elizabeth Cancer Institute, Bratislava, Slovakia.
authors.forename: Peter
authors.initials: P
authors.lastname: Zuzák
authors.affiliation: 1st Department of Oncology, Faculty of Medicine, Comenius University, St. Elisabeth Cancer Institute, Bratislava, Slovakia; Department of Medical Oncology, St. Elizabeth Cancer Institute, Bratislava, Slovakia.
authors.forename: Dalibor
authors.initials: D
authors.lastname: Ondrus
authors.affiliation: 1st Department of Oncology, Faculty of Medicine, Comenius University, St. Elisabeth Cancer Institute, Bratislava, Slovakia; Department of Medical Oncology, St. Elizabeth Cancer Institute, Bratislava, Slovakia.
authors.forename: Stanislav
authors.initials: S
authors.lastname: Spanik
authors.affiliation: 2nd Department of Oncology, Faculty of Medicine, Comenius University, National Cancer Institute, Bratislava, Slovakia.
authors.forename: Maria
authors.initials: M
authors.lastname: Reckova
authors.affiliation: 2nd Department of Oncology, Faculty of Medicine, Comenius University, National Cancer Institute, Bratislava, Slovakia; Department of Medical Oncology, National Cancer Institute, Bratislava, Slovakia.
authors.forename: Jozef
authors.initials: J
authors.lastname: Mardiak
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D000068338:Everolimus / Q000627:therapeutic use*; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D016879:Salvage Therapy; D015996:Survival Rate; D013736:Testicular Neoplasms / Q000188:drug therapy* / Q000473:pathology; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D000068338:Everolimus
keywords: Everolimus; PTEN; Refractory; Testicular germ cell tumors; mTOR inhibition