ACTR-82. LASER INTERSTITIAL THERMAL THERAPY (LITT) OF RECURRENT GLIOBLASTOMA (GBM) INDUCES TEMPORARY DISRUPTION OF THE PERITUMORAL BLOOD BRAIN BARRIER (BBB) AND MAY IMPROVE EFFICACY OF CHEMOTHERAPY WITH POOR CNS PENETRATION

Abstract

Inadequate drug delivery across the BBB is a major limiting factor in brain cancer therapy. Since most GBM recurrences occur within the peritumoral region where infiltrating glioma cells reside, peritumoral BBB disruption may help improve drug delivery and efficacy. LITT, a minimally invasive cytoreductive treatment for brain tumors, may disrupt the peritumoral BBB as evidenced by post-ablation contrast enhancement. Forty patients with recurrent bevacizumab-naïve GBM will be equally randomized to weekly low-dose doxorubicin, a BBB-impermeant chemotherapy, either immediately (Early Dox) or 6 weeks after LITT (Late Dox). The degree of post-LITT peritumoral BBB disruption was measured by the vascular transfer constant (Ktrans) in dynamic contrast-enhancement brain MRI. Serum levels of brain-specific enolase (BSE) were quantified as an independent measure of BBB disruption. The primary endpoint is 6-month PFS rate (6-PFS). Peritumoral Ktrans levels peaked immediately post-LITT, followed by a gradual decline for the next 4 weeks. Similarly, serum BSE concentrations increased shortly after LITT and peaked in 1–3 weeks before decreasing to baseline by 6 weeks. For the first 28 evaluable patients, 12 and 16 were randomized to Early and Late Doxo, respectively. Demographic and molecular markers were balanced between the two cohorts. As of 5/16/17, four patients in Early and 2 in Late Dox cohorts have neither progressed nor reached the primary endpoint (range 3–5 months). For those who have reached the primary endpoint, 6-PFS was 75% (6/8) (95% CI: 35–97%) vs. 42.9% (6/14) (95% CI: 18–71%) for the Early vs. Late Dox, respectively (Fisher exact, p=0.156). The only grade 3–4 toxicity was neutropenia observed in 2 (8%) patients. LITT induces temporary peritumoral BBB disruption lasting 4–6 weeks. This window provides a rare opportunity to enhance local delivery of potentially efficacious but BBB-impermeant therapeutic agents. Initial results using doxorubicin trend toward support for this hypothesis.