5-Aminolevulinic Acid False-Positive Rates in Newly Diagnosed and Recurrent Glioblastoma: Do Pseudoprogression and Radionecrosis Play a Role? A Meta-Analysis

Abstract

BackgroundSeveral studies have confirmed the impact of 5-aminolevulinic acid (5-ALA) on the extent of resection in newly diagnosed glioblastoma (GBM). However, there are controversies on the 5-ALA fluorescence status in recurrent GBM surgery, with specific reference to pseudoprogression or radionecrosis; therefore, the safety and accuracy of surgical planning in 5-ALA-assisted procedures in the recurrent context are still unclear.Materials and MethodsThis is a systematic review and meta-analysis of comparative studies on the use of 5-ALA in newly diagnosed and recurrent GBM, consistently conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Data on fluorescence status and correlation between fluorescence and histological findings were collected. We performed a meta-analysis of proportions to estimate the pooled rates of each outcome.ResultsThree online medical databases (PubMed, Scopus, Cochrane Library) were screened, 448 articles were evaluated, and 3 papers were finally included for data analysis. Fluorescence rate was not different between newly diagnosed and recurrent GBM [p = 0.45; odds ratio (OR): 1.23; 95% CI: 0.72–2.09; I2 = 0%], while the rate of 5-ALA fluorescence-positive areas not associated with histological findings of GBM cells was higher in recurrent GBM (p = 0.04; OR: 0.24; 95% CI: 0.06–0.91; I2 = 19%). Furthermore, there were no cases of radionecrosis in false-positive samples, while inflammation and signs of pseudoprogression were found in 81.4% of the cases.Discussion and ConclusionsTherefore, a robust awareness of 5-ALA potentialities and pitfalls in recurrent GBM surgery should be considered for a cognizant surgical strategy. Further clinical trials could confirm the results of the present meta-analysis.

Technical Pearls to Effectively Use 5-ALA in Fluorescence-Guided Tumor Resection—5 Lessons from the Operating Room

“…Notably, all of these conditions share a conspicuous number of immune cells which, as mentioned before, can display fluorescence due to 5-ALA uptake and metabolism. In addition, the macroscopic fluorescence in bacterial brain abscesses could be explained by the bacteria capability to elaborate porphyrin precursors, since they are useful cofactors for their growth [ 19 , 20 , 21 ] ( Figure 6 ).…”

The in vitro anti‐cancer synergy of neurokinin‐1 receptor antagonist, aprepitant, and 5‐aminolevulinic acid in glioblastoma

“…In addition, 5-ALA increased the accumulation of intracellular PpIX in GBM cells, which is consistent with several other studies. 40,41 There is a close relation between 5-ALA-induced PpIX accumulation and tumor cell cytotoxicity and apoptosis. It has been suggested that the accumulated PpIX enhances cytotoxic and apoptosisinducing effects through regulation of reactive oxygen species generation, cytokine and chemokine production, and increasing p53 expression level as well as Bax/Bcl-2 ratio.…”

5-Aminolevulinic Acid-Induced Protoporphyrin IX Fluorescence Imaging for Tumor Detection: Recent Advances and Challenges

“…Another challenge is the non-specific accumulation of PpIX in nontumor tissues. PpIX fluorescence in non-neoplastic tissues has been reported in regions of inflammatory infiltration around HGG, reactive gliosis in patients receiving adjuvant therapy for recurrent HGG, and LNs accompanied by lymph follicles [ 13 , 15 , 55 , 111 , 120 ]; peritumoral inflammatory conditions and elevated reactive mitotic activity could provide an explanation for the false-positive findings [ 55 ]. Some researchers have suggested that PpIX deposition in inflammatory lesions is associated with intracellular iron metabolism [ 107 , 108 ]; however, the precise mechanism is unknown.…”

“…Especially in the case of 5-ALA PDD of recurrent HGG, critical interpretation of intraoperative fluorescence is required because non-specific PpIX fluorescence can be seen in inflammatory lesions [ 55 , 120 ]. Additionally, in other neoplasms, it is important to reduce the false-positive rate owing to non-specific PpIX accumulation to improve the performance of 5-ALA PDD.…”