Clinical utility of 5-aminolevulinic acid HCl to better visualize and more completely remove gliomas

Abstract

Surgical resection is typically the first line of treatment for gliomas. However, the neurosurgeon faces a major challenge in achieving maximal resection in high-grade gliomas as these infiltrative tumors make it difficult to discern tumor margins from normal brain with conventional white-light microscopy alone. To aid in resection of these infiltrative tumors, fluorescence-guided surgery has gained much popularity in intraoperative visualization of malignant gliomas, with 5-aminolevulinic acid (5-ALA) leading the way. First introduced in an article in Neurosurgery, 5-ALA has since become a safe, effective, and inexpensive method to visualize and improve resection of gliomas. This has undoubtedly led to improvements in the clinical course of patients as demonstrated by the increased overall and progression-free survival in patients with such devastating disease. This literature review aims to discuss the major studies and trials demonstrating the clinical utility of 5-ALA and its ability to aid in complete resection of malignant gliomas.

Keywords: 5-ALA; aminolevulinic acid; fluorescence; glioblastoma multiforme; high-grade glioma; resection.

Figure 1

Intraoperative photographs obtained in a patient with GBM. Notes: 5-ALA administration showing the resection cavity under normal light conditions (left) and illuminated with blue light, demonstrating robust lava-like, orange 5-ALA fluorescence representing residual tumor (right). Reprinted with permission from Lau D, Hervey-Jumper SL, Chang S, et al. A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas. J Neurosurg. 2016;124(5):1300–1309. Abbreviations: GBM, glioblastoma multiforme; 5-ALA, 5-aminolevulinic acid.

Figure 2

Representative intraoperative photographs showing grading of 5-ALA fluorescence intensities. Notes: Top: Photograph of normal brain parenchyma and tumor under normal light conditions (left) and illuminated with blue light (right). Nonenhancing tissue is shown in normal brain (−) and a lava-like orange fluorescence is shown in tumor (*). Bottom: Photographs showing intraoperative fluorescence intensities 0 through 3, with 0= no fluorescence; 1= mild brightness, pink; 2= moderate brightness, orange; and 3= robust brightness, lava-like orange. Representative images of H&E-stained sections showing histopathological scoring of tumor biopsies. (A) Tumor score 0 showing no definitive neoplastic cells, with relative preservation of cytoarchitecture, including neurons (black arrowhead). (B) Tumor score 1 showing low abundance of infiltrating tumor cells (white arrowhead). (C) Tumor score 2 showing moderate abundance of tumor cellularity with increased infiltration of tumor cells (white arrowheads) within visible brain cytoarchitecture, such as neurons (black arrowhead). (D) Tumor score 3 appearing highly cellular, with abundant tumor cells and no preserved normal brain cytoarchitecture. Original magnification ×200. Reprinted with permission from Lau D, Hervey-Jumper SL, Chang S, et al. A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas. J Neurosurg. 2016;124(5):1300–1309. Abbreviations: 5-ALA, 5-aminolevulinic acid; H&E, hematoxylin and eosin.

Figure 3

Forest plot for sensitivity and specificity of 5-ALA-guided resection of GBM in studies included in a meta-analysis from Zhao et al. Note: Reproduced from Zhao S, Wu J, Wang C, et al. Intraoperative fluorescence-guided resection of high-grade malignant gliomas using 5-aminolevulinic acid-induced porphyrins: a systematic review and meta-analysis of prospective studies. PLoS One. 2013;8(5):e63682. Abbreviations: 5-ALA, 5-aminolevulinic acid; GBM, glioblastoma multiforme; CI, confidence interval.

Figure 4

High-magnification fluorescence and histological images following treatment of U87-MGΔEGFR tumors (ie, those with epidermal growth factor receptors) with epidermal growth factor-fluorescing ligand demonstrating no fluorescence in the normal tissue. Notes: (Left) Fluorescence image showing tumor margin and no fluorescence in the surrounding normal brain; (right) corresponding histological image showing the tumor boundary.