title: Temozolomide and cisplatin in avdanced malignant melanoma.
abstract: BACKGROUND
  Temozolomide (TMZ) is an oral alkylating agent; it produces DNA methyl adducts, which are removed by the DNA repair enzyme AGAT. In vitro studies suggest that CDDP may enhance the antitumor activity of TMZ due to the ability of cisplatin (CDDP) to down-regulate AGAT activity. In a previous phase I study, the combination of TMZ and CDDP was tested, and the recommended dose for each drug was defined. On the basis of these results, we designed a phase II study to evaluate the activity and safety profile of the TMZ-CDDP association in patients with advanced melanoma.
  
  
  METHODS
  From March 2001 to March 2002, 37 patients with metastatic melanoma, not amenable to surgery, were enrolled in this study. All eligible patients were treated with the combination of CDDP 75 mg/m2 i.v. d 1, TMZ 200 mg/m2 p.o. days 1-5 recycled every 4 weeks. Interferon alpha2b (IFN alpha2b) was administered at the end of chemotherapy to responsive patients at the dose of 5 M.I. U s.c. 3 times a week for 1 year.
  
  
  RESULTS
  A total of 174 courses were administered, with a median number of 4 courses/patient (range 1-10). After chemotherapy, 9 CRs and 9 PRs were observed for an overall response rate of 48.6% (95% C.I., 31.9%-65.6%). One of 5 patients with initial brain metastases showed a complete response to the therapy. Five out of 9 CR patients were still with no evidence of recurrence, ranging from 28+ to 82+ weeks. The median survival time was 48 weeks. The schedule was well tolerated, with the most frequent adverse events reported being nausea and vomiting (59%), alopecia (14%) and fatigue (11%), all well controlled by supportive therapy. Haemotological toxicities were mild to moderate. Side-effects attributable to IFN alpha2b were also mild and manageable.
  
  
  CONCLUSIONS
  The combination of TMZ and CDDP seems to be active in untreated patients with advanced melanoma. Absence of recurrence in the majority (5/9; 56%) of CR patients seems to indicate that IFN may act on the duration of the response to chemotherapy. The schedule was well tolerated, with nausea and vomiting as the most frequent adverse events.
authors.affiliation: National Tumor Institute Via M Semmola, 80131 Naples, Italy. antoniodaponte@libero.it
authors.forename: Antonio
authors.initials: A
authors.lastname: Daponte
authors.forename: Paolo Antonio
authors.initials: PA
authors.lastname: Ascierto
authors.forename: Adriano
authors.initials: A
authors.lastname: Gravina
authors.forename: Mariateresa
authors.initials: M
authors.lastname: Melucci
authors.forename: Stefania
authors.initials: S
authors.lastname: Scala
authors.forename: Alessandro
authors.initials: A
authors.lastname: Ottaiano
authors.forename: Ester
authors.initials: E
authors.lastname: Simeone
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palmieris
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Comella
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage*; D003606:Dacarbazine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009362:Neoplasm Metastasis; D011994:Recombinant Proteins; D012878:Skin Neoplasms / Q000188:drug therapy*; D015996:Survival Rate; D000077204:Temozolomide; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D003606:Dacarbazine; D002945:Cisplatin; D000077204:Temozolomide