Intrathecal Melphalan Therapy of Human Neoplastic Meningitis in Athymic Nude Rats

Abstract

We report the activity and toxicity of intrathecal melphalan in the treatment of human neoplastic meningitis in the subarachnoid space of athymic nude rats. Animals received injections via chronic indwelling subarachnoid catheters with 5 × 10⁵ or 5 × 10⁶ TE-671 human rhabdomyosarcoma cells or 5 × 10⁶ D-54 MG human glioma cells and were treated with melphalan on days 8, 5, or 5, respectively. Melphalan toxicity in nontumor-bearing rats was assessed at single doses of a 2.0, 3.0, 4.0, or 5.0 mm solution, with clinical and histological evidence of neurotoxicity observed at the 4.0 and 5.0 mm levels. Multiple-dose toxicity studies using a dosing schedule of twice a week for two weeks with a 0.25, 0.5, 0.75, 1.0, 1,5, or 2 mm solution revealed dose-dependent clinical and histological evidence for toxicity at all dosages. Treatment of TE-671 with a single dose of 2.0 mm intrathecal melphalan produced an increase in median survival of 442% compared with saline controls (P < 0.003). Comparison of a single dose of 1.0 or 2.0 mm melphalan with a multiple dose regimen at 0.25 or 0.5 mm melphalan in the treatment of TE-671 revealed increases in median survival of 50% for 1.0 mm, 57% for 2.0 mm, 79% for 0.5 mm, and 111% for 0.25 mm concentrations. Comparison of a single dose of 1 mm melphalan with multiple doses of 0.25 mm melphalan in the treatment of D-54 MG revealed an increase in median survival of 475+% for each of the regimens. Intrathecal melphalan may be an important new addition in the treatment of neoplastic meningitis and is currently being evaluated clinically in a Phase 1 trial.