LETTER TO THE EDITOR - BRAIN TUMORS

What does fluorescence depict in glioma surgery?

Florian Stockhammer

Received: 5 June 2013 /Accepted: 7 June 2013 /Published online: 25 June 2013# Springer-Verlag Wien 2013

Dear Editor,The article by Schebesch and coworkers about their experi-ences using sodium fluorescein (FL) in glioma resection [6]was most interesting.

In their retrospective analysis, the authors report on 35glioblastoma patients in whom tumour resection wasperformed using the novel YELLOW 560 nm filter on aPentero 900 microscope after intraoperative application ofFL. The fluorescence application was rated as “helpful” in allpatients operated for glioblastoma. Preliminary data showed agreater than 95 % resection rate in 80 % of the contrast-enhancing tumours. At the end of the paper, the authorsannounce that a prospective randomized trial is planned tohelp improve progression-free survival in glioma patients afterFL-facilitated resection.

I fully agree with the critical comment on this paper byDiez Valle and Tejada Solis [1] and would like to contributefurther remarks.

Sodium fluorescein certainly is an interesting tool forintraoperative visualisation of a disturbed blood–brain barrier(BBB), as seen with gadolinium enhancement in MR scans.However, in glioma surgery, we have progressed far beyondresection of contrast-enhancing glioma tissue: in regard toglioma transformation and infiltration, nowadays the metabo-lism of the tumour can be visualized before a disruption of theBBB occurs. Amino acid positron emission tomography(FET-PET) can detect larger tumour spread and is more sen-sitive for focal malignant transformation than contrast en-hancement in MR scans [2, 7]. Therefore, future measures ofglioma resection should focus on FET-PET rather than con-trast enhancement on MRI.

Fluorescence by 5-aminolevulinic acid (5-ALA) is basedon tumour metabolism and is not dependent on disrupted

BBB [5, 9]. In correspondence with the tumour spreaddepicted by FET-PET, application of 5-ALA fluorescenceresults in glioma resection that is often much more extensivethan the anticipated by MR contrast enhancement [7]. Sincebevacizumab is now increasingly used in glioma treatment,the contrast enhancement becomes even less dependable forestimating the extent of recurrent glioma, whereas visualiza-tion on the basis of 5-ALA fluorescence remains plausible[10].

Schebesch and coworkers consider it an advantage thatFL is administered in the short term, whereas 5-ALAmust beapplied 3 h prior to surgery. However, even in their patientgroup, all of the surgeries were planned [6]; emergencyglioma resections are rare and can usually be postponed byacute edema treatment. Even when metastasis is suspected,application of 5-ALA before planned resection makes sensefor the case that glioma is found unexpectedly [3].

According to the readout measurements reported bySchebesch et al., in more than 80 % of their patients, resec-tion of more than 95 % of the tumour was possible. This isactually a relatively poor resection rate, as the threshold foran effective glioma resection must be at least 98 % [4]. Ofnote, complete resection (100 %) was reported in 65 % ofpatients in an prospective trial setting using 5-ALA fluores-cence [8].

From an economic standpoint, 5-ALA is relatively expen-sive, costing €950,- at a dosage of 1.5 g (Gliolan TM, MedacGermany). However, the method and the drug have beenapproved by the European Medicines Agency (EMA). Wemust accept the reality that safe and effective patient care hasits price, particularly when a treatment is tested by multicentreprospective randomized trials including 322 patients [8]. In thefuture when a generic 5-ALA becomes available, obviouslythe costs will sink significantly. Calculating the cost of FL as€25,- is inadmissible, as no approval for the resection ofgliomas took place.

Furthermore, I am concerned about this retrospective anal-ysis, consisting of a series of individual treatment attempts.

F. Stockhammer (*)Department of Neurosurgery, University Medicine Göttingen,Göttingen, Germanye-mail: florian.stockhammer@gmx.de

Acta Neurochir (2013) 155:1479–1480DOI 10.1007/s00701-013-1798-6

Despite planned surgery, patients were withheld from effec-tive 5-ALA fluorescence guided resection, which is usuallyoffered in the author’s center. In my opinion, this constitutesan undertreatment.

For upcoming trials in glioma surgery, any new resectiontechnique must compare to 5-ALA fluorescence-guided re-section as the current gold standard.

Conflicts of interest None.

References

1. Diez Valle R, Tejada Solis S (2013) Answer to: “sodium fluorescein-guided resection under the YELLOW 560-nm surgical microscopefilter in malignant brain tumor surgery-a feasibility study”. ActaNeurochir (Wien) 155(4):693–669. doi:10.1007/s00701-013-1752-7

2. Ewelt C, Floeth FW, Felsberg J, Steiger HJ, Sabel M, Langen KJ,Stoffels G, Stummer W (2011) Finding the anaplastic focus indiffuse gliomas: the value of Gd-DTPA enhanced MRI, FET-PET,and intraoperative, ALA-derived tissue fluorescence. Clin NeurolNeurosurg 113:541–547

3. Kamp MA, Santacroce A, Zella S, Reichelt DC, Felsberg J, SteigerHJ, Cornelius JF, Sabel M (2012) Is it a glioblastoma? in dubio pro5-ALA! Acta Neurochir (Wien) 154:1269–1273

4. Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W,DeMonte F, Lang FF, McCutcheon IE, Hassenbusch SJ, HollandE, Hess K, Michael C, Miller D, Sawaya R (2001) A multivariateanalysis of 416 patients with glioblastoma multiforme: prognosis,extent of resection, and survival. J Neurosurg 95:190–198

5. Olivo M, Wilson BC (2004) Mapping ALA-induced PPIX fluores-cence in normal brain and brain tumour using confocal fluorescencemicroscopy. Int J Oncol 25:37–45

6. Schebesch KM, Proescholdt M, Hohne J, Hohenberger C, Hansen E,Riemenschneider MJ, Ullrich W, Doenitz C, Schlaier J, Lange M,Brawanski A (2013) Sodium fluorescein-guided resection under theYELLOW560 nm surgical microscope filter in malignant brain tumorsurgery—a feasibility study. Acta Neurochir (Wien) 155:693–699

7. Stockhammer F, Misch M, Horn P, Koch A, Fonyuy N, Plotkin M(2009) Association of F18-fluoro-ethyl-tyrosin uptake and 5-aminolevulinic acid-induced fluorescence in gliomas. Acta Neurochir(Wien) 151:1377–1383

8. Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, ReulenHJ (2006) Fluorescence-guided surgery with 5-aminolevulinic acid forresection of malignant glioma: a randomised controlled multicentrephase III trial. Lancet Oncol 7:392–401

9. Stummer W, Stocker S, Novotny A, Heimann A, Sauer O, KempskiO, Plesnila N, Wietzorrek J, Reulen HJ (1998) In vitro and in vivoporphyrin accumulation by C6 glioma cells after exposure to 5-aminolevulinic acid. J Photochem Photobiol B 45:160–169

10. Wachter D, Kallenberg K, Wrede A, Schulz-Schaeffer W, Behm T,Rohde V (2012) Fluorescence-guided operation in recurrent glio-blastoma multiforme treated with bevacizumab-fluorescence of thenoncontrast enhancing tumor tissue? J Neurol Surg A Cent EurNeurosurg 73:401–406

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