Barrow 5-ALA Intraoperative Confocal Evaluation Trial

Gliomas are the most common primary brain tumor, yet are associated with a 12-14 month overall survival in the United States. Mounting evidence suggests that survival improves with greater extent of resection, yet achieving a complete radiographic resection is challenging due to the tumor's infiltrating nature. Oral 5-aminolevulinic acid (5-ALA/Gliolan®) is a natural compound that, when administered to patients within 3 hours prior to surgery, is selectively metabolized by glioma cells and induces a red/pink fluorescence under blue light that facilitates intraoperative identification of tumor margins. While this compound is used as a standard-of-care agent in Europe, it remains under examination by the Food and Drug Administration (FDA). A recent multicenter randomized, single-blind, controlled study in Germany demonstrated a significant improvement in the rate of complete resection for high-grade gliomas, as compared to conventional microneurosurgery (65% vs. 34%) (Stummer et al., Lancet Oncology 2006).

Patients with presumed newly-diagnosed glioma will be entered into the trial. On the basis of their expected extent of resection (low vs. high), they will be stratified in one of 2 groups - Group 1 (expected high extent or resection) or Group 2 (expected low extent of resection). Following stratification, patients with newly-diagnosed disease will be randomized to receive either study drug (5-ALA/Gliolan®) or placebo (ascorbic acid) prior to surgery. Those who have had previous biopsy only without further treatment will be eligible for randomization. Intraoperatively, 5-ALA/Gliolan® patients will undergo resection with combined fluorescence microscopy and confocal microscopy. Placebo patients will undergo resection with standard light microscopy. Postoperatively, patients will have an MRI scan with and without contrast within 48 hours of surgery. Subsequent analysis of each patient will include assessment of the primary endpoint, that is,volume of residual disease (VRD) by volumetrically quantifying the tumor before and after surgery using T1-weighted contrast-enhancement (high-grade gliomas) or T2-weighted hyperintensity (low-grade gliomas). Similarly, volumetric extent of resection will also be measured. Other secondary endpoints will include overall survival (OS), progression-free survival (PFS), and National Institute of Health Stroke Scale (NIHSS) (collected at baseline, 7-10 days post-op and at 6, 12, 18, and 24 months post op).

The Barrow 5-ALA Intraoperative Confocal (BALANCE) study will quantify the impact of 5-ALA/Gliolan(R) on low- and high-grade glioma extent of resection. To enhance the efficacy of 5-ALA/Gliolan(R), particularly for low-grade gliomas that fluoresce less vigorously due to their comparatively lower cellular metabolism, intraoperative confocal microscopy will be used to amplify microscopic fluorescence at the tumor margins. The investigators' hypothesis is that, for both low- and high-grade gliomas, 5-ALA/Gliolan(R) fluorescence in conjunction with intraoperative confocal microscopy will significantly lower the VRD.

Goals:

1. To determine the impact of intraoperative fluorescence and confocal microscopy on the volume of residual disease following resection of a newly-diagnosed glioma.