Established and emerging uses of 5-ALA in the brain: an overview
5-aminolevulinic acid (5-ALA) was approved by the FDA in June 2017 as an intra-operative optical imaging agent for patients with gliomas (suspected World Health Organization Grades III or IV on preoperative imaging) as an adjunct for the visualization of malignant tissue during surgery. 5-ALA fluorescence-guided surgery (FGS) has been in widespread use in Europe and other continents since 2007.
We reviewed the data available and summarize the most important known uses of 5-ALA FGS and its potential future applications.
The technique has been extensively studied, and more than 300 papers have been published on this topic. Visualization of high-grade glioma tissue is robust and reproducible, and can impact the extent of tumor resection and patient outcomes. 5-ALA FGS for other kind of tumors needs further development.
Keywords5-Aminolevulinic acid Glioma Glioblastoma Fluorescence-guided surgery
This study did not receive any funding.
Compliance with ethical standards
Conflict of interest
Walter Stummer has received speaker and consultant fees by Carl Zeiss, Leica, Medac, NXDC. Constantinos Hadjipanayis is a consultant for NXDC and Synaptive Medical Inc. He will receive potential royalties from NXDC. He has also received speaker fees by Carl Zeiss and Leica. Ricardo Díez Valle has received speaker fees by Medac.
Research involving human participants or animals
This article does not contain any studies with human participants or animals performed by any of the authors.
- 2.Albert FKMD, Forsting MMD, Sartor KMD et al (1994) Early postoperative magnetic resonance imaging after resection of malignant glioma: objective evaluation of residual tumor and its influence on regrowth and prognosis. Neurosurgery 34:45–61Google Scholar
- 5.Zhao S, Wu J, Wang C et al (2013) Intraoperative fluorescence-guided resection of high-grade malignant gliomas using 5-aminolevulinic acid-induced porphyrins: a systematic review and meta-analysis of prospective studies. PLoS ONE 8:e63682. https://doi.org/10.1371/journal.pone.0063682 CrossRefGoogle Scholar
- 7.Marko NF, Weil RJ, Schroeder JL et al (2014) Extent of resection of glioblastoma revisited: personalized survival modeling facilitates more accurate survival prediction and supports a maximum-safe-resection approach to surgery. J Clin Oncol 32:774–782. https://doi.org/10.1200/JCO.2013.51.8886 CrossRefGoogle Scholar
- 11.Stummer W, Reulen HJ, Meinel T et al (2008) Extent of resection and survival in glioblastoma multiforme: identification of and adjustment for bias. Neurosurgery 62:564–576. https://doi.org/10.1227/01.neu.0000317304.31579.17 CrossRefGoogle Scholar
- 13.Jaber M, Wolfer J, Ewelt C et al (2016) The value of 5-aminolevulinic acid in low-grade gliomas and high-grade gliomas lacking glioblastoma imaging features: an analysis based on fluorescence, magnetic resonance imaging, 18F-fluoroethyl tyrosine positron emission tomography, and tumor molecular. Neurosurgery 78:401–411. https://doi.org/10.1227/NEU.0000000000001020 discussion 411 CrossRefGoogle Scholar
- 15.Stummer W, Tonn JC, Goetz C et al (2014) 5-Aminolevulinic acid-derived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging. Neurosurgery 74:310–320. https://doi.org/10.1227/NEU.0000000000000267 CrossRefGoogle Scholar
- 16.Coburger J, Engelke J, Scheuerle A et al (2014) Tumor detection with 5-aminolevulinic acid fluorescence and Gd-DTPA-enhanced intraoperative MRI at the border of contrast-enhancing lesions: a prospective study based on histopathological assessment. Neurosurg Focus 36:E3. https://doi.org/10.3171/2013.11.FOCUS13463 CrossRefGoogle Scholar
- 18.Roberts DW, Valdes PA, Harris BT et al (2011) Coregistered fluorescence-enhanced tumor resection of malignant glioma: relationships between delta-aminolevulinic acid-induced protoporphyrin IX fluorescence, magnetic resonance imaging enhancement, and neuropathological parameters. Clinical article. J Neurosurg 114:595–603. https://doi.org/10.3171/2010.2.JNS091322 CrossRefGoogle Scholar
- 19.Lau D, Hervey-Jumper SL, Chang S et al (2015) A prospective Phase II clinical trial of 5-aminolevulinic acid to assess the correlation of intraoperative fluorescence intensity and degree of histologic cellularity during resection of high-grade gliomas. J Neurosurg. https://doi.org/10.3171/2015.5.JNS1577 Google Scholar
- 27.von Campe G, Moschopulos M, Hefti M (2012) 5-Aminolevulinic acid-induced protoporphyrin IX fluorescence as immediate intraoperative indicator to improve the safety of malignant or high-grade brain tumor diagnosis in frameless stereotactic biopsies. Acta Neurochir (Wien) 154:585–588. https://doi.org/10.1007/s00701-012-1290-8 discussion 588 CrossRefGoogle Scholar
- 28.Widhalm G, Minchev G, Woehrer A et al (2012) Strong 5-aminolevulinic acid-induced fluorescence is a novel intraoperative marker for representative tissue samples in stereotactic brain tumor biopsies. Neurosurg Rev 35:381–391. https://doi.org/10.1007/s10143-012-0374-5;10.1007/s10143-012-0374-5 discussion 391 CrossRefGoogle Scholar
- 35.Schucht P, Knittel S, Slotboom J et al (2014) 5-ALA complete resections go beyond MR contrast enhancement: shift corrected volumetric analysis of the extent of resection in surgery for glioblastoma. Acta Neurochir (Wien) 156:305–312. https://doi.org/10.1007/s00701-013-1906-7;discussion 312 CrossRefGoogle Scholar
- 39.Coburger J, Scheuerle A, Pala A et al (2017) Histopathological insights on imaging results of intraoperative magnetic resonance imaging, 5-aminolevulinic acid, and intraoperative ultrasound in glioblastoma surgery. Neurosurgery 81:165–174. https://doi.org/10.1093/neuros/nyw143 CrossRefGoogle Scholar
- 43.Hickmann A-K, Nadji-Ohl M, Hopf NJ (2015) Feasibility of fluorescence-guided resection of recurrent gliomas using five-aminolevulinic acid: retrospective analysis of surgical and neurological outcome in 58 patients. J Neurooncol 122:151–160. https://doi.org/10.1007/s11060-014-1694-9 CrossRefGoogle Scholar
- 45.Tykocki T, Michalik R, Bonicki W, Nauman P (2012) Fluorescence-guided resection of primary and recurrent malignant gliomas with 5-aminolevulinic acid. Preliminary results. Neurol Neurochir Pol 46:47–51Google Scholar
- 48.Nabavi A, Thurm H, Zountsas B et al (2009) Five-aminolevulinic acid for fluorescence-guided resection of recurrent malignant gliomas: a phase ii study. Neurosurgery 65:1070–1077. https://doi.org/10.1227/01.NEU.0000360128.03597.C7 CrossRefGoogle Scholar
- 57.Morofuji Y, Matsuo T, Hayashi Y et al (2008) Usefulness of intraoperative photodynamic diagnosis using 5-aminolevulinic acid for meningiomas with cranial invasion: technical case report. Neurosurgery 62:102–104. https://doi.org/10.1227/01.neu.0000317378.22820.46 Google Scholar
- 67.Kamp MA, Munoz-Bendix C, Mijderwijk HJ, Turowski B, Dibué-Adjei M, von Saß C, Cornelius JF, Steiger HJ, Rapp M, Sabel M (2018) Is 5-ALA fluorescence of cerebral metastases a prognostic factor for local recurrence and overall survival? J Neuroncol. https://doi.org/10.1007/s11060-018-03066-y Google Scholar
- 70.Bernal Garcia LM, Cabezudo Artero JM, Marcelo Zamorano MB, Gilete Tejero I (2015) Fluorescence-guided resection with 5-aminolevulinic Acid of subependymomas of the fourth ventricle: report of 2 cases: technical case report. Neurosurgery 11(Suppl 2):E364–E371. https://doi.org/10.1227/NEU.0000000000000682 discussion E371 CrossRefGoogle Scholar
- 72.Inoue T, Kanamori M, Sonoda Y et al (2008) Glioblastoma multiforme developing separately from the initial lesion 9 years after successful treatment for gliomatosis cerebri: a case report. Neurol Surg 36:709–715Google Scholar
- 74.Stummer W, Beck T, Beyer W et al (2008) Long-sustaining response in a patient with non-resectable, distant recurrence of glioblastoma multiforme treated by interstitial photodynamic therapy using 5-ALA: case report. J Neurooncol 87:103–109. https://doi.org/10.1007/s11060-007-9497-x CrossRefGoogle Scholar