title: Phase I trial of sirolimus combined with radiation and cisplatin in non-small cell lung cancer.
abstract: OBJECTIVE
  The safety and tolerability of sirolimus combined with thoracic radiation and cisplatin was evaluated in patients with lung cancer. In parallel, the effects of sirolimus were studied in a murine model of radiation pneumonitis.
  
  
  METHODS
  The phase I trial evaluated standard three-dimensional conformal thoracic radiation therapy (60 Gy) and weekly cisplatin (25 mg/m2 i.v.) in combination with escalating doses of oral sirolimus. Sirolimus drug levels and inhibition of mTOR signaling to ribosomal S6 protein were assessed in blood. The effects of sirolimus administered during and after whole thoracic radiation of C57BL6/J mice were evaluated by monitoring mouse breathing rates and survival.
  
  
  RESULTS
  Seven patients with stage III lung cancer were accrued to the clinical study. None of the four patients treated with 2 mg/day sirolimus developed dose-limiting toxicities. Three patients were treated with 5 mg/day sirolimus, and one patient at this dose level had dose-limiting toxicity of grade 3 dysphagia. However, the maximally tolerated dose of sirolimus in this regimen was not defined because the study was terminated prematurely because of loss of funding. In the mouse experiments, concomitant sirolimus treatment was not associated with an increase in radiation-associated morbidity or mortality.
  
  
  CONCLUSIONS
  Combination therapy with sirolimus, radiation, and cisplatin was well tolerated in patients.
authors.affiliation: Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA. sarkaria.jann@mayo.edu
authors.forename: Jann N
authors.initials: JN
authors.lastname: Sarkaria
authors.forename: Paul
authors.initials: P
authors.lastname: Schwingler
authors.forename: Steven E
authors.initials: SE
authors.lastname: Schild
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Grogan
authors.forename: Ann C
authors.initials: AC
authors.lastname: Mladek
authors.forename: Sumithra J
authors.initials: SJ
authors.lastname: Mandrekar
authors.forename: Angelina D
authors.initials: AD
authors.lastname: Tan
authors.forename: Takao
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Randolph S
authors.initials: RS
authors.lastname: Marks
authors.forename: Hirohito
authors.initials: H
authors.lastname: Kita
authors.forename: Robert C
authors.initials: RC
authors.lastname: Miller
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Limper
authors.forename: Edward B
authors.initials: EB
authors.lastname: Leof
mesh_terms: D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy*; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011379:Prognosis; D020123:Sirolimus / Q000008:administration & dosage; D015996:Survival Rate
chemical_list: D002945:Cisplatin; D020123:Sirolimus