title: Phase I trial of carboplatin/paclitaxel/bortezomib and concurrent radiotherapy followed by surgical resection in Stage III non-small cell lung cancer.
abstract: BACKGROUND
  Despite advances in Stage III NSCLC, the mortality from the disease remains >70%. Disease recurrence can occur both locally and systemically. Trimodality therapy may improve outcome by maximizing local control. The purpose of this study was to perform a phase I trial of bortezomib (PS-341, Velcade) in addition to chemotherapy with carboplatin AUC=2 and paclitaxel 50mg/m(2) and concurrent radiotherapy (61 Gy) as induction treatment in a trimodality approach.
  
  
  METHODS
  Patients with pathologically documented Stage III a (N2) or selected IIIb (N3) disease were eligible. Bortezomib was administered on days 1, 4, 15, 18 during the 6-week induction chemoradiotherapy. Cohorts of three patients were entered and observed for toxicity during chemoradiotherapy and for 2 weeks afterwards. Surgical resection was attempted in the patients who had mediastinal sterilization. All patients were to receive consolidation chemotherapy with carboplatin AUC=6 and paclitaxel 200mg/m(2).
  
  
  RESULTS
  Twelve patients in three cohorts were enrolled. The addition of bortezomib was well tolerated, with no unexpected toxicities during the induction phase. However, there were three postoperative deaths (two pneumonitis and one from failure of the bronchopulmonary flap). The trial was halted as a consequence of these toxicities.
  
  
  CONCLUSIONS
  While this approach was well tolerated in terms of acute toxicity, the apparently delayed toxicity was severe and unpredictable. It does not appear that bortezomib can be safely administered as part of preoperative chemoradiotherapy for lung cancer. However, there was a high incidence of complete pathologic response and cautious exploration of this agent in the non-operative setting is appropriate.
authors.affiliation: University of Maryland Greenebaum Cancer Center, 22 S Greene Street, Baltimore, MD 21201, United States of America. medelman@umm.edu
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Edelman
authors.forename: Whitney
authors.initials: W
authors.lastname: Burrows
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Krasna
authors.forename: Michelle
authors.initials: M
authors.lastname: Bedor
authors.forename: Ruth
authors.initials: R
authors.lastname: Smith
authors.forename: Mohan
authors.initials: M
authors.lastname: Suntharalingam
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D003131:Combined Modality Therapy; D057239:Early Termination of Clinical Trials; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D011013:Pneumonectomy / Q000009:adverse effects*; D011183:Postoperative Complications; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects; D011878:Radiotherapy / Q000009:adverse effects; D012131:Respiratory Insufficiency / Q000209:etiology*
chemical_list: D001897:Boronic Acids; D011480:Protease Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D016190:Carboplatin; D017239:Paclitaxel