Refining Glioblastoma Surgery through the Use of Intra-Operative Fluorescence Imaging Agents

Abstract

Glioblastoma (GBM) is the most aggressive adult brain tumour with a dismal 2-year survival rate of 26–33%. Maximal safe resection plays a crucial role in improving patient progression-free survival (PFS). Neurosurgeons have the significant challenge of delineating normal tissue from brain tumour to achieve the optimal extent of resection (EOR), with 5-Aminolevulinic Acid (5-ALA) the only clinically approved intra-operative fluorophore for GBM. This review aims to highlight the requirement for improved intra-operative imaging techniques, focusing on fluorescence-guided imaging (FGS) and the use of novel dyes with the potential to overcome the limitations of current FGS. The review was performed based on articles found in PubMed an.d Google Scholar, as well as articles identified in searched bibliographies between 2001 and 2022. Key words for searches included ‘Glioblastoma’ + ‘Fluorophore’+ ‘Novel’ + ‘Fluorescence Guided Surgery’. Current literature has favoured the approach of using targeted fluorophores to achieve specific accumulation in the tumour microenvironment, with biological conjugates leading the way. These conjugates target specific parts overexpressed in the tumour. The positive results in breast, ovarian and colorectal tissue are promising and may, therefore, be applied to intracranial neoplasms. Therefore, this design has the potential to produce favourable results in GBM by reducing the residual tumour, which translates to decreased tumour recurrence, morbidity and ultimately, mortality in GBM patients. Several preclinical studies have shown positive results with targeted dyes in distinguishing GBM cells from normal brain parenchyma, and targeted dyes in the Near-Infrared (NIR) emission range offer promising results, which may be valuable future alternatives.

The diagnostic accuracy of intraoperative differentiation and delineation techniques in brain tumours

“…An interesting new approach targets known tumour-specific ligands, such as EGFR. These fluorophores accumulate in a specific part overexpressed in the tumour and can be employed to visualise the tumour intra-operatively [ 75 , 76 ]. Epidermal growth factor receptor (EGFR) protein is highly expressed in the majority of HGG and therefore a promising target.…”

“…Future research should investigate different fluorophores, targets, and possible combinations with other fluorescent agents (e.g., 5-ALA and EGFR-targeting fluorophore), to determine the administration schedule and optimal dose [ 78 , 79 ]. Currently, numerous fluorescent probes are still under early clinical and preclinical investigation [ 75 ].…”

Combining Pr3+-Doped Nanoradiosensitizers and Endogenous Protoporphyrin IX for X-ray-Mediated Photodynamic Therapy of Glioblastoma Cells

“…Two major developments have improved treatment outcomes for GBM patients: fluorescence-guided surgery and intraoperative radiotherapy (IORT). Fluorescence-guided surgery uses the visualization of fluorescent molecules in malignant tissues for more precise resection, and IORT delivers a high dose of low-energy X-rays to the surface of a tumor bed immediately after resection. , The keV-energy X-rays used in IORT have a shallow tissue penetration range; thus, high doses of radiation can be applied to the resection site while sparing adjacent healthy tissues. IORT is performed using a single dose of 20 Gy, whereas traditional external beam radiotherapy (RT) is administered in 2 Gy fractions to achieve a total dose of 60 Gy over the span of weeks. , However, a single-shot dose of 20 Gy does not achieve complete tumor cell elimination, since GBM cells are highly radiation-resistant .…”

Next‐generation agents for fluorescence‐guided glioblastoma surgery

“…Glioblastoma is the highest and most common form of malignancy affecting the CNS, and it represents one of the deadliest forms of adult cancer. Indeed, even with maximal treatment, defined as maximal safe surgical resection followed by radiotherapy and adjuvant temozolomide (TMZ), 2 patients show a low median survival rate corresponding to a dismal 2‐year survival of 26%–33% 3 . In addition, they are often subjected to a high recurrence incidence 3 .…”