Imaging Procedure Using ALA in Finding Residual Tumor in Grade IV Malignant Astrocytoma

• Assess 2 doses of 5-ALA [ Time Frame: 6 hours before midpoint of surgery ] [ Designated as safety issue: Yes ]
  This clinical trial has ALA dose at 2 levels (10 and 20 mg/kg) and ALA administration time at 1 time point (6h). During surgery, the intraoperative fluorescence observations and PpIX concentration measurements will be taken by the surgeon. The second part of each biopsy will have the PpIX concentration determined.
  
  

• Correlation between intensity of in vivo fluorescence and the pathologist's quantification of tumor in biopsy specimens (e.g., percentage of tumor present) as measured by PpIX concentration and intra-operative fluorescence intensity [ Time Frame: Quantitative fluorescence imaging of tumor tissue and normal tissue at approximately the midpoint of surgery and then after maximal resection of the tumor. ] [ Designated as safety issue: No ]
  readings will be taken at the biopsied location with the PpIX point probe by the surgeon.
  
  
• Correlation between the amount and location of residual tumor detected intraoperatively by fluorescence imaging and frameless stereotaxy after maximal resection and the post-operative image enhancement on CT scan and/or MRI [ Time Frame: Tumor tissue samples are obtained at the same two timepoints (the midpoint of surgery and then after maximal resection of the tumor) ] [ Designated as safety issue: No ]
  

OBJECTIVES:

Primary

• Assess 2 doses of 5-ALA, 10kg/mg and 20kg/mg, to determine the optimum ALA dose in terms of both sensitivity and specificity for residual tumor. We will compare residual tumor detection by both in vivo qualitative and quantitative fluorescence imaging using histology of the biopsied tissue as the gold standard.

Secondary

• Assess the correlation between the recorded in vivo qualitative assessment of fluorescence signal from the neurosurgeon with the post-surgical (i.e., ex vivo) absolute PpIX concentration detected both intraoperatively and in ex vivo tissue biopsies.

Tertiary

• To determine the association between the presence of fluorescence in the surgical cavity and the post-operative image enhancement on MRI. This includes the relationship between the amount and location of residual tumor detected by fluorescence, PpIX concentration, and intra-operative frameless stereotaxy following maximal resection versus the amount and location of tumor imaged post-operatively via CT and/or MRI.

OUTLINE: This study will enroll evaluable patients undergoing surgical resection of malignant, grade IV gliomas in both of two groups: those with , newly diagnosed GBM and those with recurrent GBM. Patient, in each group (primary vs recurrent GBM) will be randomized to one of 2 levels of ALA dose (10 and20 mg/kg) to be given orally at 6 hours prior to anticipated midpoint of surgery.

Patients who have consented to this protocol will be randomly assigned to one of two ALA dose groups. Randomization will be stratified by whether the tumor is newly diagnosed (i.e. de novo) or recurrent. The data center will prepare sealed, opaque envelopes with the randomized assignment to ALA dose and administration time and notify the pharmacy of the trial site so that so that the correct ALA dose can be prepared.

• Arm I: Newly diagnosed GBM patients receive oral aminolevulinic acid(10mg/kg)at 6 hours before the midpoint of surgery.
• Arm II: Newly diagnosed GBM patients receive oral aminolevulinic acid (20mg/kg)at 6 hours before the midpoint of surgery.
• Arm III: Recurrent GBM patients receive oral aminolevulinic acid (10mg/kg)at 6 hours before the midpoint of surgery.
• Arm IV: Recurrent GBM patients receive oral aminolevulinic acid (20mg/kg)at 6 hours before the midpoint of surgery.

For both patients with new and recurrent disease, biopsies will be taken at up to six sites identified by the surgeon: in the tumor center, tumor edge, area surrounding the tumor (if safe), areas seen to fluoresce intraoperatively and an area with MR enhancement outside the tumor region (if this can be accomplished safely). Prior to collecting these biopsies readings will be taken at the biopsied location with the PpIX point probe by the surgeon. For each of the 6 biopsies, they will be divided into 3 parts and distributed for further analysis as follows: one portion will be sent to the pathologist for assessment of tumor percentage, one portion will be evaluated by the Division of Biophysics at the University of Toronto for PpIX concentration and the other for assessment of fluorescence.