Fluorescence-Guided Surgery: A Review on Timing and Use in Brain Tumor Surgery

Abstract

Fluorescence-guided surgery (FGS) allows surgeons to have improved visualization of tumor tissue in the operating room, enabling maximal safe resection of malignant brain tumors. Over the past two decades, multiple fluorescent agents have been studied for FGS, including 5-aminolevulinic acid (5-ALA), fluorescein sodium, and indocyanine green (ICG). Both non-targeted and targeted fluorescent agents are currently being used in clinical practice, as well as under investigation, for glioma visualization and resection. While the efficacy of intraoperative fluorescence in studied fluorophores has been well established in the literature, the effect of timing on fluorophore administration in glioma surgery has not been as well depicted. In the past year, recent studies of 5-ALA use have shown that intraoperative fluorescence may persist beyond the previously studied window used in prior multicenter trials. Additionally, the use of fluorophores for different brain tumor types is discussed in detail, including a discussion of choosing the right fluorophore based on tumor etiology. In the following review, the authors will describe the temporal nature of the various fluorophores used in glioma surgery, what remains uncertain in FGS, and provide a guide for using fluorescence as a surgical adjunct in brain tumor surgery.

MRI-Based Risk Assessment for Incomplete Resection of Brain Metastases

“…Sodium fluorescein is another widely used fluochrome which is extravasated at locations harboring breached blood-brain barrier (e.g. in brain tumors) and equally demonstrated an advantage for EOR as well as survival ( 47 , 48 ). In contrast to 5-ALA, sodium fluorescein provided higher fluorescence rates in brain metastases (ranging from 90% to 95%), making it more suitable for routine metastases resection guidance ( 49 , 50 ).…”

Standard clinical approaches and emerging modalities for glioblastoma imaging

“…However, the first FGS studies in neurosurgery date back to 1948 with the use of fluorescein, which accumulates in extracellular spaces and in areas of a broken blood brain barrier. 120 , 123 ICG, which historically has served as a fluorescence agent for cerebrovascular imaging in neurosurgery, has seen an increase in research studies applied to GBM. Recent studies use what is known as second window ICG imaging, which entails administration of ICG 24 h prior to surgery.…”

“…These fluorescence-enabled microscopes allow the surgeon to visualize the fluorescence light emitted from tumor infiltrated tissue either with their eyes, using surgical oculars, or digitally by means of camera detection. 116 , 119 , 120 Tumor infiltrated tissue will then display a distinct color that enables the surgeon to differentiate it from adjacent, normal brain. Figure 5 demonstrates an example of a patient undergoing 5-ALA FGS, with a conventional white light image on the left ( Figure 5A ), and a fluorescence image on the right ( Figure 5B ), showing the violet-blue background from tissue illumination and the red-pink 5-ALA-induced PpIX fluorescence emitted from a nodular tissue region.…”

“… 116 , 118 The three most used drugs are 5-aminolevulinic acid (5-ALA), indocyanine green (ICG), and fluorescein. 119 , 120 5-ALA leads to endogenous formation of protoporphyrin IX (PpIX), which is a fluorescent tumor biomarker that emits a red-pink fluorescence in the visible range of the spectrum of light (620–710 nm). Fluorescein emits a green-yellow fluorescence with a maximum fluorescence at 521 nm.…”

Neurosurgical Clinical Trials for Glioblastoma: Current and Future Directions

“…However, because sodium fluorescein is found in the tumor extracellular space, non-specific labelling has been reported after surgical manipulation. The overall sensitivity and specificity of fluorescein for gliomas remains approximately 85% and 90%, respectively [ 25 ]. Similarly, indocyanine green has been proposed as an alternative for fluorescent-guided glioma surgery.…”