5-Aminolevulinic acid for enhanced surgical visualization of high-grade gliomas: a prospective, multicenter study

Abstract

OBJECTIVE Greater extent of resection (EOR) is associated with longer overall survival in patients with high-grade gliomas (HGGs). 5-Aminolevulinic acid (5-ALA) can increase EOR by improving intraoperative visualization of contrast-enhancing tumor during fluorescence-guided surgery (FGS). When administered orally, 5-ALA is converted by glioma cells into protoporphyrin IX (PPIX), which fluoresces under blue 400-nm light. 5-ALA has been available for use in Europe since 2010, but only recently gained FDA approval as an intraoperative imaging agent for HGG tissue. In this first-ever, to the authors’ knowledge, multicenter 5-ALA FGS study conducted in the United States, the primary objectives were the following: 1) assess the diagnostic accuracy of 5-ALA–induced PPIX fluorescence for HGG histopathology across diverse centers and surgeons; and 2) assess the safety profile of 5-ALA FGS, with particular attention to neurological morbidity. METHODS This single-arm, multicenter, prospective study included adults aged 18–80 years with Karnofsky Performance Status (KPS) score > 60 and an MRI diagnosis of suspected new or recurrent resectable HGG. Intraoperatively, 3–5 samples per tumor were taken and their fluorescence status was recorded by the surgeon. Specimens were submitted for histopathological analysis. Patients were followed for 6 weeks postoperatively for adverse events, changes in the neurological exam, and KPS score. Multivariate analyses were performed of the outcomes of KPS decline, EOR, and residual enhancing tumor volume to identify predictive patient and intraoperative variables. RESULTS Sixty-nine patients underwent 5-ALA FGS, providing 275 tumor samples for analysis. PPIX fluorescence had a sensitivity of 96.5%, specificity of 29.4%, positive predictive value (PPV) for HGG histopathology of 95.4%, and diagnostic accuracy of 92.4%. Drug-related adverse events occurred at a rate of 22%. Serious adverse events due to intraoperative neurological injury, which may have resulted from FGS, occurred at a rate of 4.3%. There were 2 deaths unrelated to FGS. Compared to preoperative KPS scores, postoperative KPS scores were significantly lower at 48 hours and 2 weeks but were not different at 6 weeks postoperatively. Complete resection of enhancing tumor occurred in 51.9% of patients. Smaller preoperative tumor volume and use of intraoperative MRI predicted lower residual tumor volume. CONCLUSIONS PPIX fluorescence, as judged by the surgeon, has a high sensitivity and PPV for HGG. 5-ALA was well tolerated in terms of drug-related adverse events, and its application by trained surgeons in FGS for HGGs was not associated with any excess neurological morbidity.

5-aminolevulinic enhanced brain lesions mimic glioblastoma: A case report and literature review

“…The 5-ALA application in the low-grade gliomas seems limited by low fluorescence visibility under the microscope, with a positive fluorescence rate ranging between 0 and 20 %. [ 55 , 56 ] Owing to the heterogeneity of glioma, the anaplastic foci within low-grade glioma, with no evidence of preoperative contrast enhancement on MR, could be detected intraoperatively. However, the general uptake of 5-ALA preoperatively in patients with low-grade glioma needs further studies for evaluation.…”

5-Aminolevulinic Acid as a Theranostic Agent for Tumor Fluorescence Imaging and Photodynamic Therapy

“…The approval allows the use of ALA as an intraoperative imaging probe to facilitate tumor resection in patients with high-grade gliomas (grade III or IV) following a standard oral administration of 20 mg/kg body weight at about 3 h prior to anesthesia. A recently completed multi-center clinical study in the U.S. further confirmed that ALA is well-tolerated and possesses high sensitivity and positive predictive value as a tumor diagnostic agent for high-grade gliomas [ 49 ].…”

In Situ Brain Tumor Detection Using the Raman Spectroscopy Sentry System – Results of a Multicenter Study

“…It can be less useful at discriminating non-tumoral brain in the in ltrative glioma margin since the uorescence signal is lower than in the bulk of the tumor. Despite a high sensitivity and positive predictive value for detecting tumor, speci city and negative predictive value is lower with 5-ALA. 23,24 Hollon et al 25 showed stimulated Raman histology (SRH) could be used on brain biopsy specimens to diagnose brain tumor types. This technique is a form of stain-free, deep learning-based histology that has the potential to replace frozen section histopathologic analyses.…”