title: Results from a randomized phase III study comparing combined treatment with histamine dihydrochloride plus interleukin-2 versus interleukin-2 alone in patients with metastatic melanoma.
abstract: OBJECTIVE
  Reactive oxidative species (ROS) produced by phagocytic cells have been ascribed a role in the localized suppression of lymphocyte function within malignant tumors. Histamine has been shown to inhibit ROS formation and possibly synergize with cytokines to permit activation of natural killer cells and T cells. This study was designed to determine whether the addition of histamine to a subcutaneous (SC) regimen of interleukin-2 (IL-2) would improve the survival of metastatic melanoma patients.
  
  
  METHODS
  A phase III, multicenter, randomized, parallel group study comparing IL-2 plus histamine with IL-2 alone was conducted in 305 patients with advanced metastatic melanoma. Patients were randomized to IL-2 (9 MIU/m(2) bid SC on days 1 to 2 of weeks 1 and 3, and 2 MIU/m(2) bid SC on days 1 to 5 of weeks 2 and 4) with or without histamine (1.0 mg bid SC days 1 to 5, weeks 1 to 4). The primary end point, survival, was prospectively applied to all randomized patients (intent-to-treat-overall population, ITT-OA) and all patients having liver metastases at randomization (ITT-LM population). Secondary end points included safety of the combined treatment, time to disease progression, and response rate.
  
  
  RESULTS
  Combined treatment with histamine plus IL-2 significantly improved overall survival in the ITT-LM population (P =.004) and showed a trend for improved survival in the ITT population (P =.125). Grade 3 and 4 adverse events were comparable in the two arms.
  
  
  CONCLUSIONS
  Use of histamine as an adjunct to IL-2 is safe, well tolerated, and associated with a statistically significant prolongation of survival compared with IL-2 alone in metastatic melanoma patients with liver involvement. Further trials to confirm and understand the role of histamine in this combination treatment are underway.
authors.affiliation: Melanoma Center, University of Pittsburgh Cancer Institute, 200 Lothrop Street, Pittsburgh, PA 15213-2582, USA. agarwalass@msx.upmc.edu
authors.forename: Sanjiv S
authors.initials: SS
authors.lastname: Agarwala
authors.forename: John
authors.initials: J
authors.lastname: Glaspy
authors.forename: Steven J
authors.initials: SJ
authors.lastname: O'Day
authors.forename: Malcolm
authors.initials: M
authors.lastname: Mitchell
authors.forename: John
authors.initials: J
authors.lastname: Gutheil
authors.forename: Eric
authors.initials: E
authors.lastname: Whitman
authors.forename: Rene
authors.initials: R
authors.lastname: Gonzalez
authors.forename: Evan
authors.initials: E
authors.lastname: Hersh
authors.forename: Lynn
authors.initials: L
authors.lastname: Feun
authors.forename: Robert
authors.initials: R
authors.lastname: Belt
authors.forename: Frank
authors.initials: F
authors.lastname: Meyskens
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Hellstrand
authors.forename: Diana
authors.initials: D
authors.lastname: Wood
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Gehlsen
authors.forename: Peter
authors.initials: P
authors.lastname: Naredi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D003257:Consumer Product Safety; D004357:Drug Synergism; D005260:Female; D006632:Histamine / Q000008:administration & dosage; D006801:Humans; D007279:Injections, Subcutaneous; D007376:Interleukin-2 / Q000008:administration & dosage; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality; D015996:Survival Rate; D014481:United States / Q000453:epidemiology
chemical_list: D007376:Interleukin-2; D006632:Histamine