title: Bortezomib (PS-341) in relapsed or refractory extensive stage small cell lung cancer: a Southwest Oncology Group phase II trial (S0327).
abstract: BACKGROUND
  In preclinical models, the proteasome inhibitor bortezomib (PS-341) inhibits the growth of small cell lung cancer (SCLC) by inhibiting the antiapoptotic Bcl-2 signaling pathway. We conducted a phase II trial of PS-341 in previously treated patients with platinum-sensitive and -refractory extensive stage SCLC to determine response rate, toxicity, and survival.
  
  
  METHODS
  Patients with histologically confirmed SCLC, measurable disease, Zubrod performance status 0-1, and previous treatment with platinum-based therapy were enrolled. They were stratified by platinum-sensitivity status: sensitive (relapse >90 days after platinum) or refractory (progression during or < or =90 days after platinum). PS-341 was administered at 1.3 mg/m intravenously on days 1, 4, 8, and 11 every 21 days.
  
  
  RESULTS
  Of 56 eligible patients, 28 were platinum sensitive and 28 refractory. Twenty-nine patients (52%) had received two or more previous chemotherapy regimens. One platinum-refractory patient had a confirmed partial response. A majority of assessable patients (91%) progressed. Median progression-free survival and overall survival were 1 month and 3 months, respectively. Ten patients (18%) discontinued treatment due to adverse events or side effects.
  
  
  CONCLUSIONS
  Although PS-341 induced a response in a patient with platinum-refractory disease, it has limited single-agent activity in this heavily pretreated cohort. As shown in preclinical models, testing of PS-341 in combination with an apoptotic trigger such as chemotherapy, is a rational clinical approach. A trial of topotecan plus PS-341 has been initiated to test this concept.
authors.affiliation: University of California, Davis Cancer Center, Sacramento, CA 95817, USA. primo.lara@ucdmc.ucdavis.edu
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.forename: Kari
authors.initials: K
authors.lastname: Chansky
authors.forename: Angela M
authors.initials: AM
authors.lastname: Davies
authors.forename: Wilbur A
authors.initials: WA
authors.lastname: Franklin
authors.forename: Paul H
authors.initials: PH
authors.lastname: Gumerlock
authors.forename: Perry P
authors.initials: PP
authors.lastname: Guaglianone
authors.forename: James N
authors.initials: JN
authors.lastname: Atkins
authors.forename: Nichole
authors.initials: N
authors.lastname: Farneth
authors.forename: Philip C
authors.initials: PC
authors.lastname: Mack
authors.forename: John J
authors.initials: JJ
authors.lastname: Crowley
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects; D000069286:Bortezomib; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016001:Confidence Intervals; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005500:Follow-Up Studies; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D011336:Probability; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects; D012074:Remission Induction; D018570:Risk Assessment; D016019:Survival Analysis
chemical_list: D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib