title: Randomized, Prospective Double-Blinded Study Comparing 3 Different Doses of 5-Aminolevulinic Acid for Fluorescence-Guided Resections of Malignant Gliomas.
abstract: BACKGROUND
  Five-aminolevulinic acid (5-ALA) is used for fluorescence-guided resections of malignant glioma at a dose of 20 mg/kg; yet, it is unknown whether lower doses may also provide efficacy.
  
  
  OBJECTIVE
  To perform a double-blinded randomized study comparing 3 different doses of 5-ALA.
  
  
  METHODS
  Twenty-one patients with suspected malignant glioma were randomly assigned to 0.2, 2, or 20 mg/kg 5-ALA. Investigators were unaware of dose. Intraoperatively, regions of interest were first defined in tumor core, margin, and adjacent white matter under white light. Under violet-blue illumination, the surgeon's impression of fluorescence was recorded per region, followed by spectrometry and biopsy. Plasma was collected after administration and analyzed for 5-ALA and protoporphyrin IX (PPIX) content.
  
  
  RESULTS
  The positive predictive value of fluorescence was 100%. Visual and spectrometric fluorescence assessment showed 20 mg/kg to elicit the strongest fluorescence in tumor core and margins, which correlated with cell density. Spectrometric and visual fluorescence correlated significantly. A 10-fold increase in 5-ALA dose (2-20 mg/kg) resulted in a 4-fold increase of fluorescence contrast between marginal tumor and adjacent brain. t max for 5-ALA was 0.94 h for 20 mg/kg (0.2 kg: 0.50 h, 2 mg/kg: 0.61 h). Integrated PPIX plasma levels were 255.8 and 779.9 mcg*h/l (2 vs 20 mg/kg). Peak plasma concentrations were observed at 1.89 ± 0.71 and 7.83 ± 0.68 h (2 vs 20 mg/kg; average ± Standard Error of Mean [SEM]).
  
  
  CONCLUSIONS
  The highest visible and measurable fluorescence was yielded by 20 mg/kg. No fluorescence was elicited at 0.2 mg/kg. Increasing 5-ALA doses did not result in proportional increases in tissue fluorescence or PPIX accumulation in plasma, indicating that doses higher than 20 mg/kg will not elicit useful increases in fluorescence.
authors.affiliation: Department of Neurosurgery, University of Münster, Münster, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Stummer
authors.affiliation: Laser-Research Laboratory, LIFE-Center at University Hospital of Munich, Munich, Germany.
authors.forename: Herbert
authors.initials: H
authors.lastname: Stepp
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Otmar D
authors.initials: OD
authors.lastname: Wiestler
authors.affiliation: Medac GmbH, Gesellschaft für klinische Spezialpräparate mbH, Wedel, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Pichlmeier
mesh_terms: D000622:Aminolevulinic Acid / Q000008:administration & dosage / Q000627:therapeutic use; D001921:Brain / Q000000981:diagnostic imaging / Q000601:surgery; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000601:surgery; D005910:Glioma / Q000000981:diagnostic imaging / Q000601:surgery; D006801:Humans; D061848:Optical Imaging / Q000379:methods*; D025321:Surgery, Computer-Assisted / Q000379:methods*
chemical_list: D000622:Aminolevulinic Acid
keywords: 5-ALA; Aminolevulinic acid; Fluorescence-guided resections; Histology; Malignant glioma; Randomized study; Spectrography