User Tools

Site Tools


5_aminolevulinic_acid

5 aminolevulinic acid (ALA)

δ-Aminolevulinic acid (dALA or δ-ALA or 5ala or 5-aminolevulinic acid ) is the first compound in the porphyrin synthesis pathway.

It facilitates tumor identification; its use improves gross total resection rates and prolongs progression free survival in patients with high grade gliomas 1).

Indications

Doses

The highest visible and measurable fluorescence was yielded by 20 mg/kg. No fluorescence was elicited at 0.2 mg/kg. Increasing 5-ALA doses did not result in proportional increases in tissue fluorescence or PPIX accumulation in plasma, indicating that doses higher than 20 mg/kg will not elicit useful increases in fluorescence 2).


Application of 5mg/kg ALA was evaluated as equally reliable as the higher dose regarding the diagnostic performance when guidance was performed using a spectroscopic system. Moreover, no PpIX was detected in the skin of the patients 3).

Over time, several other tumour entities have been identified to metabolize 5-ALA and show a similar fluorescence pattern during surgical resection.

Further research is warranted to determine the role of 5-ALA accumulation in post-ischaemic and inflammatory brain tissue 4).

The positive predictive values (PPVs), of utilizing the most robust ALA fluorescence intensity (lava-like orange) as a predictor of tumor presence is high. However, the negative predictive values (NPVs), of utilizing the absence of fluorescence as an indicator of no tumor is poor. ALA intensity is a strong predictor for degree of tumor cellularity for the most fluorescent areas but less so for lower ALA intensities. Even in the absence of tumor cells, reactive changes may lead to ALA fluorescence 5).

Complications

Despite its benefits, 5-ALA has not reached widespread popularity in the United States, primarily because of lack of Food and Drug Administration (FDA) approval. Even if it were approved, 5-ALA does have specific limitations including low depth of penetration, autofluorescence of background parenchyma


Findings suggest that the administration of 5-ALA or the combined effect of 5-ALA, anaesthesia and tumour resection can cause a mild and reversible elevation in liver enzymes. It therefore appears safe to change the regime of monitoring. Routine blood samples are thus abolished, though caution remains necessary in patients with known liver impairment 6).

For near infrared imaging, additional investigators have explored fluorescein as well as novel near-infrared (NIR) agents 7) 8) 9)

Reviews

Senders et al., systematically review all clinically tested fluorescent agents for application in fluorescence guided surgery (FGS) for glioma and all preclinically tested agents with the potential for FGS for glioma.

They searched the PubMed and Embase databases for all potentially relevant studies through March 2016.

They assessed fluorescent agents by the following outcomes: rate of gross total resection (GTR), overall and progression free survival, sensitivity and specificity in discriminating tumor and healthy brain tissue, tumor-to-normal ratio of fluorescent signal, and incidence of adverse events.

The search strategy resulted in 2155 articles that were screened by titles and abstracts. After full-text screening, 105 articles fulfilled the inclusion criteria evaluating the following fluorescent agents: 5 aminolevulinic acid (5-ALA) (44 studies, including three randomized control trials), fluorescein (11), indocyanine green (five), hypericin (two), 5-aminofluorescein-human serum albumin (one), endogenous fluorophores (nine) and fluorescent agents in a pre-clinical testing phase (30). Three meta-analyses were also identified.

5-ALA is the only fluorescent agent that has been tested in a randomized controlled trial and results in an improvement of GTR and progression-free survival in high-grade gliomas. Observational cohort studies and case series suggest similar outcomes for FGS using fluorescein. Molecular targeting agents (e.g., fluorophore/nanoparticle labeled with anti-EGFR antibodies) are still in the pre-clinical phase, but offer promising results and may be valuable future alternatives. 10).

1)
Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392–401.
2)
Stummer W, Stepp H, Wiestler OD, Pichlmeier U. Randomized, Prospective Double-Blinded Study Comparing 3 Different Doses of 5-Aminolevulinic Acid for Fluorescence-Guided Resections of Malignant Gliomas. Neurosurgery. 2017 Apr 1. doi: 10.1093/neuros/nyx074. [Epub ahead of print] PubMed PMID: 28379547.
3)
Haj-Hosseini N, Richter J, Hallbeck M, Wårdell K. Low dose 5-aminolevulinic acid: Implications in spectroscopic measurements during brain tumor surgery. Photodiagnosis Photodyn Ther. 2015 Mar 25. pii: S1572-1000(15)00031-9. doi: 10.1016/j.pdpdt.2015.03.004. [Epub ahead of print] PubMed PMID: 25818546.
4)
Behling F, Hennersdorf F, Bornemann A, Tatagiba M, Skardelly M. 5-Aminolevulinic acid accumulation in a cerebral infarction mimicking high-grade glioma, a case report. World Neurosurg. 2016 May 10. pii: S1878-8750(16)30271-6. doi: 10.1016/j.wneu.2016.05.009. [Epub ahead of print] PubMed PMID: 27178236.
5)
Lau D, Hervey-Jumper SL, Chang S, Molinaro AM, McDermott MW, Phillips JJ, Berger MS. 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. 2015 Nov 6:1-10. [Epub ahead of print] PubMed PMID: 26544781.
6)
Offersen CM, Skjoeth-Rasmussen J. Evaluation of the risk of liver damage from the use of 5-aminolevulinic acid for intra-operative identification and resection in patients with malignant gliomas. Acta Neurochir (Wien). 2016 Nov 10. [Epub ahead of print] PubMed PMID: 27832337.
7)
Shinoda J, Yano H, Yoshimura SI, et al. Fluorescence-guided resection of glioblastoma multiforme by using high-dose fluorescein sodium. Technical note. J Neurosurg. 2003;99(3):597–603.
8)
Rey-Dios R, Cohen-Gadol AA. Technical principles and neurosurgical applications of fluorescein fluorescence using a microscope-integrated fluorescence module. Acta Neurochir (Wien). 2013;155(4):701–706.
9)
Swanson KI, Clark PA, Zhang RR, et al. Fluorescent cancer-selective alkylphosphocholine analogs for intraoperative glioma detection. Neurosurgery. 2015;76(2):115–123.
10)
Senders JT, Muskens IS, Schnoor R, Karhade AV, Cote DJ, Smith TR, Broekman ML. Agents for fluorescence-guided glioma surgery: a systematic review of preclinical and clinical results. Acta Neurochir (Wien). 2017 Jan;159(1):151-167. doi: 10.1007/s00701-016-3028-5. Review. PubMed PMID: 27878374; PubMed Central PMCID: PMC5177668.
5_aminolevulinic_acid.txt · Last modified: 2017/08/01 21:56 by administrador