Clinically useful tumor fluorescence greater than 24 hours after 5-aminolevulinic acid administration
- Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan, United States.
Adam M. Robin, Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan, United States.
DOI:10.25259/SNI_836_2021Copyright: © 2022 Surgical Neurology International This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, transform, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
How to cite this article: Sameah Haider, Travis Matthew Hamilton, Rachel J. Hunt, Ian Y. Lee, Adam M. Robin. Clinically useful tumor fluorescence greater than 24 hours after 5-aminolevulinic acid administration. 25-Mar-2022;13:99
How to cite this URL: Sameah Haider, Travis Matthew Hamilton, Rachel J. Hunt, Ian Y. Lee, Adam M. Robin. Clinically useful tumor fluorescence greater than 24 hours after 5-aminolevulinic acid administration. 25-Mar-2022;13:99. Available from: https://surgicalneurologyint.com/surgicalint-articles/11491/
Background: 5-aminolevulinic acid (5-ALA) is a valuable surgical adjuvant used for the resection of glioblastoma multiforme (GBM). Since Food and Drug Administration approval in 2017, 5-ALA has been used in over 37,000 cases. The current recommendation for peak efficacy and intraoperative fluorescence is within 4 h after administration. This narrow time window imposes a perioperative time constraint which may complicate or preclude the use of 5-ALA in GBM surgery.
Case Description: This case report describes the prolonged activity of 5-ALA in a 66-year-old patient with a newly diagnosed GBM lesion within the left supramarginal gyrus. An awake craniotomy with language and sensorimotor mapping was planned along with 5-ALA fluorescence guidance. Shortly, after receiving the preoperative 5-ALA dose, the patient developed a fever. Surgery was postponed for an infectious disease workup which proved negative. The patient was taken to surgery the following day, 36 h after 5-ALA administration. Despite the delay, intraoperative fluorescence within the tumor remained and was sufficient to guide resection. Postoperative imaging confirmed a gross total resection of the tumor.
Conclusion: The use of 5-ALA as an intraoperative adjuvant may still be effective for patients beyond the recommended 4-h window after initial administration. Reconsideration of current use of 5-ALA is warranted.
Keywords: 5-ALA, 5-Aminolevulinic acid, GBM, Glioblastoma multiforme
High-grade gliomas (HGG) represent the most common primary intracranial tumor with an estimated 13,000–17,000 newly diagnosed cases each year.[
Since the US Food and Drug Administration’s approval of 5-aminolevulinic acid (5-ALA) in February 2017, over 37,000 patients with glioblastoma multiforme (GBM) have been operated on with the aid of FGS. The current recommended dose of 5-ALA is 20 mg/kg body-weight, administered orally 2–4 h before induction of anesthesia.[
5-ALA is a prodrug with selective intracellular conversion to protoporphyrin IX, the fluorescent downstream metabolite of 5-ALA that preferentially accumulates in high-grade tumor cells to glow under blue-light illumination.[
A 66-year-old right-handed male initially presented with mild cognitive difficulty, dysphasia and progressive difficulty walking. On examination, a subtle neglect, acalculia, extinction to double simultaneous stimuli, and right-sided apraxia were noted. Evaluation with MRI demonstrated a partially cystic contrast-enhancing mass in the dominant supramarginal gyrus with fluid-attenuated inversion recovery positive signal intensity extending above to the superior parietal lobule, suggestive of glioma [
Preoperative magnetic resonance imaging (MRI) of the brain with and without contrast demonstrating contrast-enhancing left parietal cystic lesion. (a) Axial MRI T1-weighted, (b) axial T1-weighted with gadolinium, (c) sagittal T1-weighted with gadolinium, and (d) coronal T1-weighted with gadolinium.
On arrival to the preoperative area, a 20 mg/kg oral dose of 5-ALA was given at 5:50 AM, within 2 h of surgery. Before transport to the operative suite, the patient developed a fever of 38.8°C, which increased to 39.4°C on repeat evaluation. After consultation with our clinical trials team and anesthesia, surgery was deferred in favor of further evaluation of the cause of the fever. He was transferred to the intensive care unit and kept under light precautions in the interim. His fever was self-limiting. Further evaluation revealed no infectious etiology. Surgery was rescheduled for the following morning at 9:30 AM, more than 24 h after administration of 5-ALA.
During surgery, cortical mapping demonstrated several areas critical for language function. The non-enhancing lesion was found to be in an area that, when stimulated, resulted in movement of the opposite arm and face as well as dysesthetic pain in a similar distribution. After cortical mapping and partial white light resection, the first utilization of fluorescence came a full 32 h after 5-ALA administration [
IRB approval was not obtained as this is a case report, negating the requirements for review. The patient’s identity was not disclosed or compromised.
Intraoperative view of fluorescent, pathologic tissue visualized through a small corticotomy window. Photo taken at the onset of the resective portion of the surgery, approximately 33 h after administration of 5-aminolevulinic acid. Normal brain parenchyma did not fluoresce and all pathologic specimens that fluoresced were positive for tumor.
Intraoperative navigation depicting location of biopsy sample and visualized fluorescence under blue-light illumination in the (a) coronal plane, (b) sagittal plane, (c) axial plane, and (d) microscope luminescence control window. The time stamp indicates approximately 32 h after initial administration of 5-aminolevulinic acid. The blue lines in (a), (b), and (c) indicate location of fluorescent biopsy sample depicted in (d).
The use of 5-ALA FGS as an adjunct for visualization and resection of GBM was approved in June 2017. Since then, there have been multiple articles reporting the efficacy, dosing, and outcomes relative to the volume of tumor resected.[
The rationale for exogenous 5-ALA administration 2–4 h before anesthetic induction is predicated on both the aforementioned dose-response studies and the likelihood that anesthetic administration, patient positioning, setup, craniotomy, and initial macroscopic white-light tumor debulking constitute the initial 3–4 h time period after 5-ALA administration, with the anticipated microscopic blue-light tumor resection occurring in the 4–7 h time frame after dosing.[
ALA is an endogenous metabolite of the mitochondria, which is further metabolized to produce protoporphyrin IX (PpIX). Exogenous/oral 5-ALA is thought to be preferentially metabolized by cells that undergo a high rate of proliferation (i-67, MIB-1 index, and WHO grade).[
There are many factors that can affect the active metabolic plasma concentration of 5-ALA, including antibiotics and seizure medications such as phenytoin.[
Irrespective of the degree of metabolic clearance, tumor fluorescence with 5-ALA is often heterogeneous.[
The prospect of working outside the recommended 2–4 h time frame from the administration of 5-ALA to induction of anesthesia allows for greater flexibility in the event of unanticipated scheduling constraints. Our findings also raise the plausibility of whether patients may take 5-ALA the evening before surgery as opposed to 3–5:00 AM the day of surgery. Further evaluation of the temporal characteristics of tissue fluorescence following 5-ALA administration in humans undergoing brain tumor resections would be of value.
The authors certify that they have obtained all appropriate patient consent.
There are no conflicts of interest.
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