Trial Information

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.

Sub-goals:

1. To assess the feasibility and utility of combining intraoperative fluorescence with
confocal microscopy.

2. To determine the impact of this combined approach in improving volumetric extent of
resection.

3. To determine the impact of this combined approach in improving overall survival and
6-month progression-free survival.