Repetitive photodynamic therapy of malignant brain tumors

The probability of achieving local control with current single-shot, intraoperative photodynamic therapy (PDT) treatments of intracerebral gliomas seems improbable due to the length of time required to deliver adequate light fluences to depths of 1-2 cm in the resection margin. Additionally, due to the short doubling time of many malignant gliomas, the kill rate per cell doubling indicates that it seems unlikely that a single treatment would be sufficient to prevent tumor recurrence. Multiple repetitive treatments would therefore seem required. In this publication we primarily review our work examining the effects of repetitive PDT on malignant brain tumor cells both in vitro and in vivo. The in vitro therapy response of human and rat glioma spheroids to 5-aminolevulinic acid (ALA)-mediated PDT in repetitive form was investigated. The results indicated that PDT repeated at relatively long intervals (weeks) was more effective at inhibiting spheroid growth than either daily fractionated PDT or single-treatment regimes. The in vivo response to repetitive treatment was evaluated in a rodent glioma model where BT4C cell line tumors were established in the brains of inbred BD-IX rats. Microfluorometry of frozen tissue sections showed that PpIX is produced with a 10-20:1 tumor to normal tissue selectivity ratio 4 hr after ALA injection. Preliminary evidence of increased efficacy of repetitive PDT and low fluence rate treatment is presented.