Intraoperative Use of I.V. Sodium Fluorescein in Suspected CNS Tumors

Official title

Use of i.v. Sodium Fluorescein as a Fluorescent Intra-operative Tracer in Patients With Suspected Malignant Neoplasms of the CNS

Overview

The FLUO.CER.TUM study is a prospective observational clinical trial conducted at the IRCCS Foundation Neurological Institute "Carlo Besta" in Milan, Italy. It investigates the intraoperative use of intravenous sodium fluorescein as a fluorescent tracer to assist in the surgical resection of suspected malignant tumors of the central nervous system (CNS). These tumors typically present as contrast-enhancing masses on pre-operative MRI or CT scans. Malignant brain tumors are notoriously difficult to fully resect due to challenges in distinguishing tumor margins from healthy tissue. Sodium fluorescein, a dye that accumulates in areas where the blood-brain barrier is disrupted, offers a promising solution by enhancing tumor visualization during surgery. When used with a dedicated surgical microscope equipped with a fluorescence filter, fluorescein can help surgeons identify and remove more tumor tissue, potentially improving patient outcomes. The study aims to evaluate the effectiveness and safety of fluorescein-guided surgery in a real-world clinical setting. Approximately 800 patients of any age and gender, with suspected aggressive CNS lesions, will be enrolled. Each patient will receive 5 mg/kg of sodium fluorescein intravenously at the induction of anesthesia. Surgery will be performed using fluorescence-guided techniques, and patients will undergo pre- and post-operative imaging to assess the extent of resection. Clinical and neurological evaluations will also be conducted to monitor outcomes and any adverse effects. The primary objective is to qualitatively assess the intraoperative fluorescence characteristics of CNS tumors. Secondary objectives include measuring the extent of tumor resection, evaluating post-operative neurological function, and documenting any side effects related to fluorescein administration. The study adheres to ethical standards, including informed consent and approval by an ethics committee, and will be conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. Data will be anonymized and securely stored, with results potentially published following appropriate review and approval.

Detailed description

This clinical study investigates the intraoperative use of intravenous sodium fluorescein as a fluorescent tracer to assist in the surgical resection of aggressive tumors of the central nervous system (CNS). These tumors typically present as contrast-enhancing masses on pre-operative MRI or CT scans. The study is conducted at the IRCCS Foundation Neurological Institute "Carlo Besta" in Milan and follows a prospective observational design.

Malignant CNS tumors are often difficult to completely remove due to the challenge of distinguishing tumor margins from healthy brain tissue. This limitation affects prognosis, especially in high-grade gliomas. Sodium fluorescein, a dye historically used in ophthalmology, accumulates in areas where the blood-brain barrier is disrupted-such as in aggressive brain tumors-making it a potentially ideal agent for enhancing intraoperative visualization. When used with a surgical microscope equipped with a dedicated fluorescence filter, fluorescein allows surgeons to better identify tumor tissue during resection.

The study includes approximately 800 patients of any age and gender, all presenting with suspected aggressive CNS lesions based on contrast-enhanced imaging. Each patient receives 5 mg/kg of sodium fluorescein intravenously at the induction of anesthesia. Surgery is performed using fluorescence-guided techniques, and patients undergo pre- and post-operative imaging to assess the extent of resection. Clinical and neurological evaluations are conducted before and after surgery, with follow-up extending to the third post-operative day.

The primary objective is to qualitatively assess the intraoperative fluorescence characteristics of CNS tumors. Secondary objectives include evaluating the extent of tumor resection based on early post-operative imaging, monitoring neurological outcomes, and documenting any adverse reactions to fluorescein. Safety parameters such as blood pressure, heart rate, oxygen saturation, temperature, and renal function are monitored according to guidelines from the Italian Medicines Agency (AIFA).

Ethical approval is obtained from the appropriate Ethics Committee, and all patients provide informed consent prior to participation. The study complies with Good Clinical Practice (GCP) and the Declaration of Helsinki. Data are anonymized and stored securely, and results may be published following review and approval by the involved parties.

Primary outcome measures

• Intraoperative Fluorescence Characteristics: Fluorescence Intensity of CNS Tumors [Time frame: During surgical procedure]
• Intraoperative Fluorescence Characteristics: Fluorescence Distribution of CNS Tumors [Time frame: During surgery]
• Intraoperative Fluorescence Characteristics: Fluorescence Clarity of CNS Tumors [Time frame: During surgery]

Secondary outcome measures (3)

• Extent of Tumor Resection [Time frame: Within 72 hours post-surgery]
• Post-operative Neurological Function [Time frame: Within 72 hours post-surgery]
• Adverse Reactions to Fluorescein [Time frame: Up to 3 days post-surgery]

Eligibility criteria

Inclusion criteria

• Patients of both genders, at any age.
• Patients with suspected aggressive lesion of the CNS, as suggested by pre-operative MRI or CT with i.v. contrast agent administration.

Exclusion criteria

• Impossibility to give consent due to cognitive deficits or language disorder.
• Known allergy to contrast agents and/or history of previous anaphylactic shocks.
• Known severe previous adverse reactions to Fluorescein
• Acute myocardial infarction or stroke in the last 90 days.
• Severe renal failure;
• Severe hepatic failure;
• Women in their first trimester of pregnancy or lactation.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Italy · 1 center

• Fondazione IRCCS Istituto Neurologico Carlo Besta — Milan

Publications

• Roberts DW, Hartov A, Kennedy FE, Miga MI, Paulsen KD. Intraoperative brain shift and deformation: a quantitative analysis of cortical displacement in 28 cases. Neurosurgery. 1998 Oct;43(4):749-58; discussion 758-60. doi: 10.1097/00006123-199810000-00010. PMID 9766300
• Rasmussen IA Jr, Lindseth F, Rygh OM, Berntsen EM, Selbekk T, Xu J, Nagelhus Hernes TA, Harg E, Haberg A, Unsgaard G. Functional neuronavigation combined with intra-operative 3D ultrasound: initial experiences during surgical resections close to eloquent brain areas and future directions in automatic brain shift compensation of preoperative data. Acta Neurochir (Wien). 2007;149(4):365-78. doi: 10. PMID 17308976
• Ramirez C, Bowman C, Maurage CA, Dubois F, Blond S, Porchet N, Escande F. Loss of 1p, 19q, and 10q heterozygosity prospectively predicts prognosis of oligodendroglial tumors--towards individualized tumor treatment? Neuro Oncol. 2010 May;12(5):490-9. doi: 10.1093/neuonc/nop071. Epub 2010 Feb 14. PMID 20156805
• Pedersen MW, Meltorn M, Damstrup L, Poulsen HS. The type III epidermal growth factor receptor mutation. Biological significance and potential target for anti-cancer therapy. Ann Oncol. 2001 Jun;12(6):745-60. doi: 10.1023/a:1011177318162. PMID 11484948
• Ohue S, Kumon Y, Nagato S, Kohno S, Harada H, Nakagawa K, Kikuchi K, Miki H, Ohnishi T. Evaluation of intraoperative brain shift using an ultrasound-linked navigation system for brain tumor surgery. Neurol Med Chir (Tokyo). 2010;50(4):291-300. doi: 10.2176/nmc.50.291. PMID 20448420
• Kwan AS, Barry C, McAllister IL, Constable I. Fluorescein angiography and adverse drug reactions revisited: the Lions Eye experience. Clin Exp Ophthalmol. 2006 Jan-Feb;34(1):33-8. doi: 10.1111/j.1442-9071.2006.01136.x. PMID 16451256
• Koc K, Anik I, Cabuk B, Ceylan S. Fluorescein sodium-guided surgery in glioblastoma multiforme: a prospective evaluation. Br J Neurosurg. 2008 Feb;22(1):99-103. doi: 10.1080/02688690701765524. PMID 18224529
• Heimberger AB, Crotty LE, Archer GE, Hess KR, Wikstrand CJ, Friedman AH, Friedman HS, Bigner DD, Sampson JH. Epidermal growth factor receptor VIII peptide vaccination is efficacious against established intracerebral tumors. Clin Cancer Res. 2003 Sep 15;9(11):4247-54. PMID 14519652

Identifiers

NCT: NCT07233954 · FLUO.CER.TUM

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗