Treosulfan in the treatment of metastatic melanoma: from chemosensitivity testing to clinical trials.

The therapy of metastatic malignant melanoma is limited by poor responses and short overall survival. Thus it remains important to identify and test potential new drugs in this disease. To examine the effects of the bifunctional alkylating cytostatic treosulfan, an in vitro microplate ATP bioluminescence assay (ATP-TCA) was used. Five highly chemoresistant melanoma cell lines and melanoma cells freshly isolated from metastases surgically resected from stage IV melanoma patients (n = 10) were incubated with treosulfan. Three cell lines and eight of ten tested tumor cells isolated from melanoma metastases showed tumor growth inhibition after incubation with treosulfan. Therefore, 14 patients with rapidly progressing stage IV malignant melanoma who were pretreated with at least one standard chemotherapy regimen received treosulfan. In this population of patients with highly refractory advanced melanoma one complete remission (7.1%), two partial remissions (14.3%), and three cases of stable disease (21.4%) were observed. Median time to progression and median overall survival for all patients measured from the beginning of treosulfan treatment were 5 months [95% confidence interval (CI) 1.98-2.57 months] and 9 months (95% CI 3.92-8.69 months), respectively. On the basis of these data a multicenter phase II trial was initiated. A total of 31 patients with stage IV melanoma were included and treated second-line with 8 g/m2 i.v. treosulfan. From this group 26 patients were evaluable. No objective remission (CR, PR) was observed, 5 of 26 patients (19%) had stable disease, and 21 patients had progressive disease. Median overall survival was 6.5 months (95% CI 3.1-10 months). Toxicity of treosulfan was moderate. Patients with treosulfan-sensitive melanoma metastases showed better response rates and prolonged survival compared with patients who were not tested before treosulfan treatment. We therefore suggest further studies with first-line treosulfane alone or in combination with gemcitabine or cytosine arabinoside together with pretherapeutic chemosensitivity testing that may help to select patients who might benefit from specific chemotherapy.