title: Interferon-alpha and interleukin-2 in the treatment of metastatic melanoma. Comparison of two phase II trials.
abstract: BACKGROUND
  Interferon-alpha (IFN alpha) and interleukin-2 (IL-2) are active agents against malignant melanoma. There is, however, no consensus on the optimal dosing schedule of both drugs. This is a report of two sequential immunotherapy trials in patients with metastatic melanoma using two different IL-2 dosing schedules.
  
  
  METHODS
  Schedule A consists of IFN alpha, 10 million U/m2/day subcutaneously for 5 days, followed by continuous intravenous infusion of IL-2, 1 mg/m2/24 hours for 5 days. Schedule B consists of the same dose of IFN alpha, but a modified regimen of IL-2. To improve the induction of high-affinity IL-2 receptors, the initial IL-2 dose was increased (1 mg/m2/6 hours, followed by 1 mg/m2/12 hours, and 1 mg/m2/24 hours). To reduce toxicity, the dose was reduced thereafter to 0.25 mg/m2/24 hours for the following 3 days. Both regimens were repeated after 4 weeks.
  
  
  RESULTS
  27 patients were treated with schedule A with a response rate of 18% (1 complete response [CR], 4 partial responses [PR]), 95% confidence interval, 6-36%. The response rate in 27 patients treated with schedule B was 41% (3 CR, 8 PR), 95% confidence interval, 22-61%. Severe, often dose-limiting toxicity was associated with IL-2 in schedule A, particularly hypotension and fluid retention. Toxicity was reduced significantly in schedule B. Maximal serum levels of soluble CD25 were 17,022 +/- 13,070 U/ml in schedule A, and 31,148 +/- 4227 U/ml in schedule B (P < or = 0.01). Serum levels of TNF alpha were significantly lower in schedule B than in schedule A, as were the side effects.
  
  
  CONCLUSIONS
  Toxicity of IL-2 is reduced by modifying the schedule of administration, which also enhances the immunologic response and appears to increase the response rate.
authors.affiliation: Department of Hematology/Oncology, University of Heidelberg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Keilholz
authors.forename: C
authors.initials: C
authors.lastname: Scheibenbogen
authors.forename: W
authors.initials: W
authors.lastname: Tilgen
authors.forename: L
authors.initials: L
authors.lastname: Bergmann
authors.forename: E
authors.initials: E
authors.lastname: Weidmann
authors.forename: E
authors.initials: E
authors.lastname: Seither
authors.forename: M
authors.initials: M
authors.lastname: Richter
authors.forename: B
authors.initials: B
authors.lastname: Brado
authors.forename: P S
authors.initials: PS
authors.lastname: Mitrou
authors.forename: W
authors.initials: W
authors.lastname: Hunstein
mesh_terms: D000328:Adult; D000368:Aged; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007022:Hypotension / Q000209:etiology; D016898:Interferon-alpha / Q000627:therapeutic use*; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D015375:Receptors, Interleukin-2 / Q000032:analysis; D012878:Skin Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D016898:Interferon-alpha; D007376:Interleukin-2; D015375:Receptors, Interleukin-2