Agents for fluorescence-guided glioma surgery: a systematic review of preclinical and clinical results

Abstract

BackgroundFluorescence-guided surgery (FGS) is a technique used to enhance visualization of tumor margins in order to increase the extent of tumor resection in glioma surgery. In this paper, we systematically review all clinically tested fluorescent agents for application in FGS for glioma and all preclinically tested agents with the potential for FGS for glioma.MethodsWe searched the PubMed and Embase databases for all potentially relevant studies through March 2016. We assessed fluorescent agents by the following outcomes: rate of gross total resection (GTR), overall and progression-free survival, sensitivity and specificity in discriminating tumor and healthy brain tissue, tumor-to-normal ratio of fluorescent signal, and incidence of adverse events.ResultsThe search strategy resulted in 2155 articles that were screened by titles and abstracts. After full-text screening, 105 articles fulfilled the inclusion criteria evaluating the following fluorescent agents: 5-aminolevulinic acid (5-ALA) (44 studies, including three randomized control trials), fluorescein (11), indocyanine green (five), hypericin (two), 5-aminofluorescein-human serum albumin (one), endogenous fluorophores (nine) and fluorescent agents in a pre-clinical testing phase (30). Three meta-analyses were also identified.Conclusions5-ALA is the only fluorescent agent that has been tested in a randomized controlled trial and results in an improvement of GTR and progression-free survival in high-grade gliomas. Observational cohort studies and case series suggest similar outcomes for FGS using fluorescein. Molecular targeting agents (e.g., fluorophore/nanoparticle labeled with anti-EGFR antibodies) are still in the pre-clinical phase, but offer promising results and may be valuable future alternatives.

Lcn2-derived Circular RNA (hsa_circ_0088732) Inhibits Cell Apoptosis and Promotes EMT in Glioma via the miR-661/RAB3D Axis

“…Furthermore, the incidence of glioma has been continuously increasing (4). Although surgery is the main method for treating glioma, the tumor tissue cannot be completely removed (5,6). While radiotherapy and chemotherapy provide certain curative effects on glioma, various side effects associated with those treatments limit their therapeutic effect (7,8).…”

5-Aminolevulinic Acid–Protoporphyrin IX Fluorescence-Guided Surgery for CNS Tumors

“…In this study, gross-total resection was obtained in 65% of patients using 5-ALA and only 35% in patients without 5-ALA. This dye is the only agent tested in a multi-center randomized controlled trial approved for clinical use in Europe, Asia and Australia 6,8 .…”

“…Since the beginning of 2000's 5-ALA was widely described as a reliable adjuvant tool for malignant gliomas and metastatic brain tumors removal [3][4][5] . Although routinely used in Europe, Asia and Australia, in the USA the 5-ALA is considered a drug, rather than a dye, and is not yet approved by the US Food and Drug Administration (FDA) for use in humans 6 .…”

Current Standards of Care in Glioblastoma Therapy

“…The use of 5-ALA increases the rate of gross total resection, in randomized controlled trials (65% vs. 35%) and in observational studies (from 25 to 94.3%) (25,26), and also increases PFS (8.6 vs. 4.8 months) and the 6-month PFS (PFS6) (46% vs. 28%) (27, 28). The increase in gross total resection rate and PFS was confirmed by three meta-analyses performed to evaluate the literature on 5-ALA. Fluorescein is another option but was not tested in randomized controlled trials (25). Fluorescence near eloquent areas should be managed carefully.…”