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)

Cancer Chemother Pharmacol. 2014 Jul;74(1):177-83. doi: 10.1007/s00280-014-2427-7. Epub 2014 May 24.

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.

Conclusion: Despite sound pre-clinical evidence, the addition of 13-CRA and interferon alpha to paclitaxel did not improve outcomes for recurrent SCLC.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antineoplastic Combined Chemotherapy Protocols / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers / blood
  • Carcinoma, Small Cell / blood
  • Carcinoma, Small Cell / drug therapy
  • Chemotherapy-Induced Febrile Neutropenia / physiopathology
  • Cohort Studies
  • Early Termination of Clinical Trials
  • Female
  • Follow-Up Studies
  • Humans
  • Interferon-alpha / administration & dosage
  • Interferon-alpha / adverse effects
  • Interferon-alpha / therapeutic use*
  • Isotretinoin / administration & dosage
  • Isotretinoin / adverse effects
  • Isotretinoin / therapeutic use*
  • Leukocytes, Mononuclear / metabolism
  • Leukopenia / chemically induced
  • Leukopenia / physiopathology
  • Lung Neoplasms / blood
  • Lung Neoplasms / drug therapy
  • Male
  • Middle Aged
  • Neoplasm Recurrence, Local / blood
  • Neoplasm Recurrence, Local / drug therapy*
  • Paclitaxel / administration & dosage
  • Paclitaxel / adverse effects
  • Paclitaxel / therapeutic use*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / blood
  • Severity of Illness Index
  • Small Cell Lung Carcinoma / blood
  • Small Cell Lung Carcinoma / drug therapy*
  • Survival Analysis

Substances

  • Biomarkers
  • IFNA1 protein, human
  • Interferon-alpha
  • Proto-Oncogene Proteins c-bcl-2
  • Isotretinoin
  • Paclitaxel