Fotemustine in palliative treatment of metastatic cutaneous and ocular melanoma – clinical experience and preliminary results

Fotemustine is a new nitrosourea derivative, classified among alkylating agents. Pre-clinical studies have revealed its strong antitumor activity against many malignant cell lines, such as leukemia (P388, L 1210), melanoma (B16), lung cancer (Lewis, LX-16, MX-1), colon cancer (C38, Co26) and histiocytic lymphoma (M5076). Common with other nitrosourea derivatives pharmacokinetic properties of fotemustine, particularly good penetration through blood-brain barrier, open the possibility for use of this drug in treatment of primary and metastatic brain tumors. This assumption is supported with results of clinical trials, in which fotemustine was effective in the treatment of malignant gliomas, and melanomas with brain metastases. Oncological Department of Military Institute of Medicine was the first in Poland to use fotemustine to a large extent in the treatment of metastatic malignant melanoma. In the period between June 2002 and end of September 2003 a total number of 21 patients underwent treatment with fotemustine. Sixteen patients from this group were evaluated. This number included 12 patients with metastatic cutaneous melanoma and 4 with ocular melanoma. Half of the patients were treated with fotemustine alone (100 mg/m² on day 1, 8 and 15, five-week rest period, then 100 mg/m² every 21 days) and the rest received chemotherapy schedule which consisted of fotemustine 100 mg/m² on day 1, DTIC 250 mg/m² on days 2–5, and IFN-alpha-2B 3 mln u./m2 in three subcutaneous injections per week. All six patients with brain metastases received whole brain irradiation prior to the beginning of chemotherapy. Both chemotherapy schedules were well tolerated, with the predominant hematological toxicity, with grade III–IV thrombocytopenia in 37.5% and grade III–IV neutropenia in 43% of patients. Non-hematological toxicity consisted of nausea, and transient elevation of blood transaminases. There were no other adverse events exceeding WHO grade II toxicity. The objective response rate was 12.5% (two patients) and another three patients had prolonged disease stabilization (over 24 weeks). The mean survival time (OS) was 26±8 weeks, and the mean progression-free survival (PFS) was 20±7 weeks. In the subgroup of patients with metastases to the brain OS (29.86±16.48 w.) and PFS (26.57±14.38) were longer than in the group with no brain metastases (26.98±10.7 w. and 17.37±8.46 weeks, respectively). This difference was however of no statistical significance. Our preliminary experience corresponds to the published data, indicating that fotemustine is a well tolerated and active agent in chemotherapy of advanced malignant melanoma, particularly in patients with brain metastases.