title: Interferon alpha plus 13-cis-retinoic acid modulation of BCL-2 plus paclitaxel for recurrent small-cell lung cancer (SCLC): an Eastern Cooperative Oncology Group study (E6501).
abstract: BACKGROUND
  Patients with recurrent small-cell lung cancer (SCLC) have dismal outcomes. The failure of salvage therapy is due to the possible development of resistance mechanisms, such as the upregulation of the anti-apoptosis protein, Bcl-2. We conducted a phase II study to evaluate if modulation of Bcl-2 with 13-cis-retinoic acid (13-CRA) and interferon alpha could improve response rates when combined with paclitaxel in patients with recurrent SCLC.
  
  
  METHODS
  Patients with recurrent SCLC and measurable disease were treated with interferon alpha at 6 million units/m² subcutaneously and 13-CRA 1 mg/kg orally on days 1 and 2 and paclitaxel 75 mg/m² intravenously on day 2 of each week for 6 weeks of an 8-week treatment cycle. Treatment was continued until disease progression, development of unacceptable toxicity, or withdrawal of consent. The primary endpoint was response rate with secondary endpoints of progression-free survival (PFS) and overall survival (OS). Bcl-2 levels were assessed in peripheral blood mononuclear cells (PBMCs).
  
  
  RESULTS
  Thirty-seven patients were enrolled; 34 were included in the intention-to-treat analysis as 3 patients were ineligible for the study. There were 3 partial responses (9 %), and 5 patients had stable disease (15 %) as best response. The median PFS was 2 months, and median OS was 6.2 months. Although mean Bcl-2 protein levels decreased with therapy in PBMCs, there was no association between Bcl-2 levels and response rate or survival.
  
  
  CONCLUSIONS
  Despite sound pre-clinical evidence, the addition of 13-CRA and interferon alpha to paclitaxel did not improve outcomes for recurrent SCLC.
authors.affiliation: Winship Cancer Institute, Emory University, Atlanta, GA, USA.
authors.forename: Rathi N
authors.initials: RN
authors.lastname: Pillai
authors.forename: Joseph
authors.initials: J
authors.lastname: Aisner
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Dahlberg
authors.forename: John S
authors.initials: JS
authors.lastname: Rogers
authors.forename: Robert S
authors.initials: RS
authors.lastname: DiPaola
authors.forename: Seena
authors.initials: S
authors.lastname: Aisner
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.forename: Joan H
authors.initials: JH
authors.lastname: Schiller
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D018288:Carcinoma, Small Cell / Q000097:blood / Q000188:drug therapy; D064146:Chemotherapy-Induced Febrile Neutropenia / Q000503:physiopathology; D015331:Cohort Studies; D057239:Early Termination of Clinical Trials; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015474:Isotretinoin / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D007970:Leukopenia / Q000139:chemically induced / Q000503:physiopathology; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000097:blood / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000097:blood; D012720:Severity of Illness Index; D055752:Small Cell Lung Carcinoma / Q000097:blood / Q000188:drug therapy*; D016019:Survival Analysis
chemical_list: D015415:Biomarkers; C554156:IFNA1 protein, human; D016898:Interferon-alpha; D019253:Proto-Oncogene Proteins c-bcl-2; D015474:Isotretinoin; D017239:Paclitaxel