title: Phase II study of temozolomide and thalidomide in patients with metastatic melanoma in the brain: high rate of thromboembolic events (CALGB 500102).
abstract: BACKGROUND
  Preliminary studies suggesting that extended-dose temozolomide with thalidomide is safe and active in patients with metastatic melanoma have led to frequent use of this oral regimen. To confirm these observations the combination was tested in a multicenter Phase II trial in patients with melanoma brain metastases.
  
  
  METHODS
  Eligible patients had melanoma brain metastases, with or without systemic metastases. The primary endpoint was response rate in brain metastases. Patients received temozolomide at a dose of 75 mg/m2/day for 6 weeks with a 2-week rest between cycles, and thalidomide (escalated to 400 mg/day for patients age < 70 years or to 200 mg/day for patients age > or = 70 years). A 2-stage design required > or = 3 responses in the first 21 patients before enrolling 29 additional patients in the second stage.
  
  
  RESULTS
  Sixteen eligible patients were enrolled. No objective responses were observed. The median survival was 23.9 weeks. Seven patients withdrew because of tumor progression; 7 were removed during Cycle 1 because of adverse events, including allergic reaction (1 patient), severe fatigue (1 patient), sudden death (1 patient), and thromboembolic events (pulmonary embolism in 3 patients and deep vein thrombosis in 1 patient); 2 patients withdrew when the study was suspended and subsequently closed. No associations could be established between baseline characteristics and toxicity.
  
  
  CONCLUSIONS
  The proportion of patients with lethal or potentially life-threatening adverse events was high (0.31, 95% confidence interval, 0.11-0.59), and the absence of objective responses made it unlikely that further accrual would demonstrate the efficacy of the regimen. These observations provide little support for the use of this combination for melanoma brain metastases unless safe and effective methods to prevent thrombosis are developed.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Krown
authors.forename: Donna
authors.initials: D
authors.lastname: Niedzwiecki
authors.forename: Wen-Jen
authors.initials: WJ
authors.lastname: Hwu
authors.forename: Lydia
authors.initials: L
authors.lastname: Hodgson
authors.forename: Alan N
authors.initials: AN
authors.lastname: Houghton
authors.forename: Frank G
authors.initials: FG
authors.lastname: Haluska
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary*; D008875:Middle Aged; D011655:Pulmonary Embolism / Q000139:chemically induced; D012878:Skin Neoplasms / Q000473:pathology; D015996:Survival Rate; D000077204:Temozolomide; D013792:Thalidomide / Q000008:administration & dosage*; D017211:Treatment Failure; D020246:Venous Thrombosis / Q000139:chemically induced; D028761:Withholding Treatment
chemical_list: D013792:Thalidomide; D003606:Dacarbazine; D000077204:Temozolomide