A Phase I Trial of Continuously Infused Intratumoral Bleomycin for the Treatment of Recurrent Glioblastoma Multiforme

Intratumoral (IT) chemotherapy has theoretical advantages in the treatment of brain tumors. The blood–brain barrier is not a factor in drug delivery, and large concentrations of drug can be instilled in the tumor with little systemic toxicity. Bleomycin has activity against gliomas and is a cell cycle selective agent whose efficacy should be enhanced by continuous infusion. We performed a phase I trial to test the feasibility of IT chemotherapy using a refillable, sustained release device, and to determine the maximum tolerable dose of IT bleomycin. The study was an open-ended dose escalation study. A modified Ommaya reservoir (containing a semipermeable membrane) was implanted with the delivery tube in the center of the tumor. Groups of three patients with recurrent glioblastoma multiforme were entered at progressively higher dose levels of bleomycin. The study closed when all patients at a given starting dose level developed toxicity. Nine patients received doses ranging from 5 to 34U/wk; the median total cumulative dose was 195 U. No dose limiting systemic toxicity was detected. Neurologic toxicity occurred only at doses above 16U/wk. We conclude that continuously infused IT bleomycin is well tolerated; the MTD (and recommended dose for a phase II efficacy trial) of IT bleomycin is 16U/wk.