BACKGROUND: CNS metastases develop in nearly half of patients with advanced melanoma and in 15-20 % CNS is the first site of relapse. Median overall survival is short, ranging from 2 to 4 months, and 1-year survival is only 10 to 15 %. THA has been shown to have both antiangiogenetic and immunomodulating effects. TMZ is an oral alkylating agent with an excellent oral bio-availability and it is highly lipophilic with an ability to penetrate the blood-brain barrier. TMZ and THA in combination were tested in patients with brain metastases from malignant melanoma (MM).

METHODS: Between June 2004 and February 2007 patients with measurable metastatic melanoma in progression and PS < 1 received TMZ in a dose of 150 mg/m2 qd for 7 days, followed by 7 days off therapy and THA in 200 mg qd, both orally administered. Concomitant treatment with steroids was allowed. PBMCs were collected from the last 14 consecutive patients for evaluation of immune parameters.

RESULTS: 40 screened patients were eligible and evaluable for response and 39 were evaluable for toxicity. 25 patients had asymptomatic and 15 symptomatic brain metastases. The toxicity was primarily grade 1-2 with no grade 4 or treatment related deaths. Four patients had tromboembolic events grade 3. One pt obtained a CR and 5 PR in the CNS, while 2 had CR and 4 PR outside CNS. Overall response rate was 17.5%. We found a significant positive correlation between lymphopenia and objective response.

CONCLUSIONS: The combination treatment was well tolerated but with more frequent thromboembolic events compared to single drug TMZ or THA. The treatment demonstrated activity in CNS as well as outside CNS. The correlation between lymphopenia and objective response needs further investigation.

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