title: Phase II study of extended-dose temozolomide in patients with melanoma.
abstract: OBJECTIVE
  We conducted a phase II trial of extended-dose temozolomide (TMZ) in patients with melanoma to test the hypothesis that the approximately 30% response rate observed in patients treated with extended-dose TMZ with antiangiogenic agents was caused by TMZ alone. We hypothesized that expression of methylguanine methyltransferase (MGMT) in the tumor would correlate with drug resistance to TMZ.
  
  
  METHODS
  Patients with stage IV or unresectable stage III melanoma were treated with TMZ 75 mg/m(2)/d for 6 weeks followed by a 2-week rest period. Cycles were repeated until progression. Patients were stratified by M1c disease or not. The primary end point was objective response proportion. MGMT expression was assessed by methylation-specific pyrosequencing of the promoter and by immunohistochemistry.
  
  
  RESULTS
  Forty-nine patients (25 with M1c disease) were assessable. Three patients (12.5%) in each cohort experienced partial responses; there were no complete responses. Ten patients (21%) had stable disease lasting more than 24 weeks. Median time to progression was 3.3 months. Median survival was 10.1 months; survival was similar in the two cohorts. The estimated 18-month survival was 27%. There was no correlation between response and either immunohistochemistry staining for MGMT or for MGMT promoter methylation. Seventy-five percent of patients developed CD4(+) lymphopenia after three cycles.
  
  
  CONCLUSIONS
  Extended-dose TMZ therapy did not result in a 30% responses rate, which has been observed using extended-dose TMZ with antiangiogenic agents. Response did not correlate with MGMT expression or promoter methylation as a continuous variable, suggesting that other resistance mechanisms are important.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Petra
authors.initials: P
authors.lastname: Rietschel
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.forename: Susan
authors.initials: S
authors.lastname: Krown
authors.forename: Scott
authors.initials: S
authors.lastname: Gerst
authors.forename: Achim A
authors.initials: AA
authors.lastname: Jungbluth
authors.forename: Klaus
authors.initials: K
authors.lastname: Busam
authors.forename: Katherine
authors.initials: K
authors.lastname: Smith
authors.forename: Irene
authors.initials: I
authors.lastname: Orlow
authors.forename: Katherine
authors.initials: K
authors.lastname: Panageas
authors.forename: Paul B
authors.initials: PB
authors.lastname: Chapman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects; D001483:Base Sequence; D017252:CD3 Complex / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D003606:Dacarbazine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008545:Melanoma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D008875:Middle Aged; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D015996:Survival Rate; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D018906:Antineoplastic Agents, Alkylating; D017252:CD3 Complex; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide