title: GM-CSF with biochemotherapy (cisplatin, DTIC, tamoxifen, IL-2 and interferon-alpha): a phase I trial in melanoma.
abstract: BACKGROUND
  Ineffective tumour antigen processing is recognised as an important cause of failure of immunotherapy in melanoma. GM-CSF may augment the cytotoxic lymphocyte response by activating antigen-presenting cells. This study evaluates a schedule combining GM-CSF with biochemotherapy.
  
  
  METHODS
  Nineteen patients with advanced malignant melanoma received cisplatin (25 mg/m2 days 1-3). dacarbazine (220 mg/m2 days 1-3), interleukin-2 (9 MIU/m2/24 h) and interferon-alpha2b (5 MIU/m2) both days 6-10 and days 17-21, and tamoxifen 40 mg/day continuously. Subcutaneous GM-CSF was given in escalating doses to three cohorts: 1) 450 microg/m2 days 4-5 and 15-16; 2) as 1) plus 225 microg/m2 days 6-10 and 17-21; 3) 450 microg/m2 days 4-10 and 15-21. Each cycle was 28 days.
  
  
  RESULTS
  Constitutional side effects were the major non-haematological toxicity and lymphopaenia the main haematological toxicity. Six patients responded (32%, 95% confidence interval: 13%-57%), two patients had complete remission. There was an apparent trend for increasing responses with increasing GM-CSF dose; zero of six responses in cohort 1, two of seven in cohort 2 and three of six in cohort 3 (P = 0.016). Median overall survival was 6.2 months. Increasing GM-CSF doses significantly increased serum concentrations of neopterin and TNF-alpha.
  
  
  CONCLUSIONS
  The combination of GM-CSF with biochemotherapy is feasible and there appears to be a dose-response relationship with GM-CSF in terms of host immunological response, and possibly clinical efficacy.
authors.affiliation: Melanoma Unit, Royal Marsden NHS Trust, London, UK.
authors.forename: M M
authors.initials: MM
authors.lastname: Vaughan
authors.forename: J
authors.initials: J
authors.lastname: Moore
authors.forename: P G
authors.initials: PG
authors.lastname: Riches
authors.forename: S R
authors.initials: SR
authors.lastname: Johnston
authors.forename: R P
authors.initials: RP
authors.lastname: A'Hern
authors.forename: M E
authors.initials: ME
authors.lastname: Hill
authors.forename: T
authors.initials: T
authors.lastname: Eisen
authors.forename: M J
authors.initials: MJ
authors.lastname: Ayliffe
authors.forename: J M
authors.initials: JM
authors.lastname: Thomas
authors.forename: M E
authors.initials: ME
authors.lastname: Gore
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D015331:Cohort Studies; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005240:Feasibility Studies; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000401:mortality / Q000556:secondary; D008875:Middle Aged; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D016898:Interferon-alpha; D007376:Interleukin-2; D013629:Tamoxifen; D003606:Dacarbazine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D002945:Cisplatin