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Metronomic oral low-dose treosulfan chemotherapy combined with cyclooxygenase-2 inhibitor in pretreated advanced melanoma: a pilot study.

Abstract：

PURPOSE:The safety and efficacy of oral metronomic low-dose treosulfan chemotherapy in combination with the cyclooxygenase-2 (COX-2) inhibitor rofecoxib as a compound with antiangiogenic potential, a therapeutic regimen optimally targeting endothelial cells instead of tumor cells, were assessed in pretreated advanced melanoma patients. METHODS:Endothelial cells were analyzed for proliferation, apoptosis and cytotoxicity in response to increasing concentrations of treosulfan, either in the absence or presence of COX-2 inhibitor, to determine whether inhibition of COX-2 enhanced the effect of treosulfan on cell function. In a clinical pilot study, 12 consecutive patients with pretreated advanced melanoma, meeting the eligibility criteria were enrolled. Patients received combined daily treosulfan chemotherapy (500 mg) with rofecoxib (25 mg). Metastatic lesions were assessed every 12 weeks. Patients with responsive or stable disease were eligible for a further 12-week treatment period. Response criteria according to the WHO handbook for reporting results of cancer treatment were applied. Side effects were classified according to the National Cancer Institute's Common Toxicity Criteria v2.0. RESULTS:At noncytotoxic concentrations, treosulfan inhibited endothelial cell proliferation in a dose-dependent fashion. Simultaneous inhibition of COX-2 significantly increased the extent to which treosulfan suppressed cell proliferation, without inducing cytotoxicity. In the pilot study in which 12 patients were treated, toxicity was mild; only hematologic toxicity of grade II was seen. An objective response was noted in one patient, and four patients showed stabilization of their disease for 24 weeks (one) and 36 weeks (three). The patient who had a partial response subsequently showed stable disease for 48 weeks. The median survival time was 13 months. CONCLUSIONS:As increases in response rates following polychemo- or biochemotherapy have not been shown to correlate with prolongation in overall survival, more durable control of metastatic melanoma represents an attractive therapeutic goal. Thus, regimens scheduled to primarily target endothelial cells may potentially provide a palliative alternative that preserves quality of life in the absence of significant treatment-related toxicity.

journal_name

Cancer Chemother Pharmacol

journal_title

Cancer chemotherapy and pharmacology

authors

Spieth K,Kaufmann R,Gille J

doi

10.1007/s00280-003-0678-9

keywords:

subject

Has Abstract

pub_date

2003-11-01 00:00:00

pages

377-82

issue

eissn

0344-5704

issn

1432-0843

journal_volume

pub_type

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Metronomic oral low-dose treosulfan chemotherapy combined with cyclooxygenase-2 inhibitor in pretreated advanced melanoma: a pilot study.