title: Temozolomide followed by combined immunotherapy with GM-CSF, low-dose IL2 and IFN alpha in patients with metastatic melanoma.
abstract: The purpose of this study is to determine the toxicity and efficacy of temozolomide (TMZ) p.o. followed by subcutaneous (s.c.) low-dose interleukin-2 (IL2), granulocyte-monocyte colony stimulating factor (GM-CSF) and interferon-alpha 2b (IFN alpha) in patients with metastatic melanoma. A total of 74 evaluable patients received, in four separate cohorts, escalating doses of TMZ (150-250 mg m(-2)) for 5 days followed by s.c. IL2 (4 MIU m(-2)), GM-CSF (2.5 microg kg(-1)) and IFN alpha (5 MIU flat) for 12 days. A second identical treatment was scheduled on day 22 and cycles were repeated in stable or responding patients following evaluation. Data were analysed after a median follow-up of 20 months (12-30 months). The overall objective response rate was 31% (23 out of 74; confidence limits 20.8-42.9%) with 5% CR. Responses occurred in all disease sites including the central nervous system (CNS). Of the 36 patients with responding or stable disease, none developed CNS metastasis as the first or concurrent site of progressive disease. Median survival was 252 days (8.3 months), 1 year survival 41%. Thrombocytopenia was the primary toxicity of TMZ and was dose- and patient-dependent. Lymphocytopenia (grade 3-4 CTC) occurred in 48.5% (34 out of 70) fully monitored patients following TMZ and was present after immunotherapy in two patients. The main toxicity of combined immunotherapy was the flu-like syndrome (grade 3) and transient liver function disturbances (grade 2 in 20, grade 3 in 15 patients). TMZ p.o. followed by s.c. combined immunotherapy demonstrates efficacy in patients with stage IV melanoma and is associated with toxicity that is manageable on an outpatient basis.
authors.affiliation: Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, The Netherlands. g.d.gast@nki.nl
authors.forename: G C
authors.initials: GC
authors.lastname: de Gast
authors.forename: D
authors.initials: D
authors.lastname: Batchelor
authors.forename: M J
authors.initials: MJ
authors.lastname: Kersten
authors.forename: F A
authors.initials: FA
authors.lastname: Vyth-Dreese
authors.forename: J
authors.initials: J
authors.lastname: Sein
authors.forename: W F
authors.initials: WF
authors.lastname: van de Kasteele
authors.forename: W J
authors.initials: WJ
authors.lastname: Nooijen
authors.forename: O E
authors.initials: OE
authors.lastname: Nieweg
authors.forename: M A
authors.initials: MA
authors.lastname: de Waal
authors.forename: W
authors.initials: W
authors.lastname: Boogerd
mesh_terms: D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000627:therapeutic use*; D003606:Dacarbazine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D018572:Disease-Free Survival; D004359:Drug Therapy, Combination; D005134:Eye Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D007167:Immunotherapy; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use; D007376:Interleukin-2 / Q000009:adverse effects / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D020714:Maximum Tolerated Dose; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D008875:Middle Aged; D009367:Neoplasm Staging; D011994:Recombinant Proteins; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000378:metabolism; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D018906:Antineoplastic Agents, Alkylating; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007376:Interleukin-2; D011994:Recombinant Proteins; D003606:Dacarbazine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D000077204:Temozolomide