Intrathecal Melphalan Therapy of Human Neoplastic Meningitis

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 x IO5 or 5 x IO6 TE-67I human rhabdomyosarcoma cells or 5 x 10'' 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 HIMsolution, with clinical and histolÃ3gica! 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 HIMsolution revealed dose-dependent clinical and histolÃ3gica! evidence for toxicity at all dosages. Treatment of TE-671 with a single dose of 2.0 HIMintrathecal 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 HIMmelphalan with a multiple dose regimen at 0.25 or 0.5 HIM melphalan in the treatment of TE-671 revealed increases in median survival of 50% for 1.0 mM, 57% for 2.0 HIM,79% for 0.5 HIM,and 111 % for 0.25 mM concentrations. Comparison of a single dose of I 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.