Letter to the Editor. Cost-effectiveness of sodium fluorescein in high-grade gliomas

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  • San Bortolo Hospital, Vicenza, Italy
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TO THE EDITOR: We read with great interest the article by Hansen et al.3 (Hansen RW, Pedersen CB, Halle B, et al: Comparison of 5-aminolevulinic acid and sodium fluorescein for intraoperative tumor visualization in patients with high-grade gliomas: a single-center retrospective study. J Neurosurg [epub ahead of print October 4, 2019. DOI: 10.3171/2019.6.JNS191531]). Their retrospective study compares 5-aminolevulinic acid (5-ALA) with sodium fluorescein in the resection of high-grade gliomas (HGGs), showing a comparable extent of resection with the two agents. The authors concluded that fluorescein is a viable alternative to 5-ALA, a conclusion that harbors an important economic impact since fluorescein is inexpensive compared to 5-ALA. The authors admit that the patients were not randomly assigned; instead, there was a departmental shift from 5-ALA to fluorescein because of the cost-effectiveness of the latter. For the same reason, we have shifted from 5-ALA to fluorescein over the years in our department. We were glad to read the results of this study given our aim of always improving the quality of care of our patients; however, caution must be exercised in the data interpretation. One randomized controlled trial showed that 5-ALA in HGG increases the extent of resection and overall survival by optimizing visualization and thus the completeness of tumor resection through the agent’s accumulation in the tumor cells.4 The use of 5-ALA may be synergistic with other strategies.1 Several studies, but none with level I evidence, have indicated the utility of sodium fluorescein in HGG surgery. Fluorescein extravagates in the absence of the blood-brain barrier and accumulates in the tumor via a mechanism similar to gadolinium contrast on MRI. 5-ALA detects tumor cells outside the contrast-enhancing layer on MRI.2 In our experience, fluorescein is also present outside the contrast-enhancing lesion on MRI, but because of the edema, and thus is not entirely reliable.

The cost-effectiveness message about fluorescein is important; however, as the authors suggest, studies with level I evidence are needed.

Disclosures

The authors report no conflict of interest.

References

  • 1

    Della Puppa A, Lombardi G, Rossetto M, Rustemi O, Berti F, Cecchin D, : Outcome of patients affected by newly diagnosed glioblastoma undergoing surgery assisted by 5-aminolevulinic acid guided resection followed by BCNU wafers implantation: a 3-year follow-up. J Neurooncol 131:331340, 2017

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  • 2

    Della Puppa A, Rustemi O, Rampazzo E, Persano L: Combining 5-aminolevulinic acid fluorescence and intraoperative magnetic resonance imaging in glioblastoma surgery: a histology-based evaluation. Neurosurgery 80:E188E190, 2017 (Letter)

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  • 3

    Hansen RW, Pedersen CB, Halle B, Korshoej AR, Schulz MK, Kristensen BW, : Comparison of 5-aminolevulinic acid and sodium fluorescein for intraoperative tumor visualization in patients with high-grade gliomas: a single-center retrospective study. J Neurosurg [epub ahead of print October 4, 2019. DOI: 10.3171/2019.6.JNS191531]

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  • 4

    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 7:392401, 2006

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  • 1 Odense University Hospital, Clinical Institute, University of Southern Denmark and BRIDGE (Brain Research—Interdisciplinary Guided Excellence), Odense, Denmark;
  • 2 Aarhus University Hospital, Aarhus, Denmark;
  • 3 Odense University Hospital, Odense, Denmark; and
  • 4 Odense Patient Data Explorative Network, Odense, Denmark

Response

We thank the authors for their interest in our work.

The overall goal in HGG surgery is maximal safe resection. Substances that visualize tumor tissue, such as 5-ALA and fluorescein, play an important role in achieving this goal by increasing resection rates without compromising the safety of the procedure.1,5 Other modalities such as pre- and intraoperative MRI, neuronavigation, and awake surgical procedures2 are also tools that can be used to increase precision and the degree of resection, and as long as the modality used results in maximal safe tumor resection, the choice of modality is probably less important.

Several studies have indicated that fluorescein is effective for HGG surgery, but none with level I evidence, as is the case for 5-ALA.5 Even dual labeling has been investigated.4 Obviously, the results of a prospective randomized controlled trial directly comparing 5-ALA and fluorescein would be of interest, and we would be happy to participate in such a trial. As mentioned in our study, 5-ALA is believed to detect HGG cells outside the gadolinium contrast-enhancing region on MRI and thus perhaps better represents the diffuse transition from HGG to healthy tissue (comparable to FLAIR MRI sequences). When using fluorescein, the enhancement is comparable to that of gadolinium contrast on MRI; therefore, the surgeon should always keep the preoperative MRI and tumor location in mind so that tumor cells in non-eloquent brain areas adjacent to the contrast enhancement can also be removed.

Intraoperative fluorescence will likely continue to be a key part of the surgical treatment of HGG in the future. As fluorescein (as opposed to 5-ALA) extravagates passively through a leaky blood-brain barrier (BBB),3 this opens up its potential use in cerebral metastases, as the neovascularization of these tissues also lacks BBB. Future research on fluorescein-guided resection of metastases will, we hope, shed light on whether or not this group of patients benefits from intraoperative fluorophores.

References

  • 1

    Acerbi F, Broggi M, Schebesch KM, Höhne J, Cavallo C, De Laurentis C, : Fluorescein-guided surgery for resection of high-grade gliomas: a multicentric prospective phase II study (FLUOGLIO). Clin Cancer Res 24:5261, 2018

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    • Export Citation
  • 2

    Barone F, Alberio N, Iacopino DG, Giammalva GR, D’Arrico C, Tagnese W, : Brain mapping as helpful tool in brain glioma surgical treatment toward the “perfect surgery”? Brain Sci 8:192, 2018

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    • Export Citation
  • 3

    Diaz RJ, Dios RR, Hattab EM, Burrell K, Rakopoulos P, Sabha N, : Study of the biodistribution of fluorescein in glioma-infiltrated mouse brain and histopathological correlation of intraoperative findings in high-grade gliomas resected under fluorescein fluorescence guidance. J Neurosurg 122:13601369, 2015

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    • Export Citation
  • 4

    Schwake M, Stummer W, Suero Molina EJ, Wolfer J: Simultaneous fluorescein sodium and 5-ALA in fluorescence-guided glioma surgery. Acta Neurochir (Wien) 157:877879, 2015

    • Search Google Scholar
    • Export Citation
  • 5

    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 7:392401, 2006

    • Search Google Scholar
    • Export Citation

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Contributor Notes

Correspondence Oriela Rustemi: orielarustemi@libero.it.

INCLUDE WHEN CITING Published online December 13, 2019; DOI: 10.3171/2019.10.JNS192817.

Disclosures The authors report no conflict of interest.

  • 1

    Della Puppa A, Lombardi G, Rossetto M, Rustemi O, Berti F, Cecchin D, : Outcome of patients affected by newly diagnosed glioblastoma undergoing surgery assisted by 5-aminolevulinic acid guided resection followed by BCNU wafers implantation: a 3-year follow-up. J Neurooncol 131:331340, 2017

    • Search Google Scholar
    • Export Citation
  • 2

    Della Puppa A, Rustemi O, Rampazzo E, Persano L: Combining 5-aminolevulinic acid fluorescence and intraoperative magnetic resonance imaging in glioblastoma surgery: a histology-based evaluation. Neurosurgery 80:E188E190, 2017 (Letter)

    • Search Google Scholar
    • Export Citation
  • 3

    Hansen RW, Pedersen CB, Halle B, Korshoej AR, Schulz MK, Kristensen BW, : Comparison of 5-aminolevulinic acid and sodium fluorescein for intraoperative tumor visualization in patients with high-grade gliomas: a single-center retrospective study. J Neurosurg [epub ahead of print October 4, 2019. DOI: 10.3171/2019.6.JNS191531]

    • Search Google Scholar
    • Export Citation
  • 4

    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 7:392401, 2006

    • Search Google Scholar
    • Export Citation
  • 1

    Acerbi F, Broggi M, Schebesch KM, Höhne J, Cavallo C, De Laurentis C, : Fluorescein-guided surgery for resection of high-grade gliomas: a multicentric prospective phase II study (FLUOGLIO). Clin Cancer Res 24:5261, 2018

    • Search Google Scholar
    • Export Citation
  • 2

    Barone F, Alberio N, Iacopino DG, Giammalva GR, D’Arrico C, Tagnese W, : Brain mapping as helpful tool in brain glioma surgical treatment toward the “perfect surgery”? Brain Sci 8:192, 2018

    • Search Google Scholar
    • Export Citation
  • 3

    Diaz RJ, Dios RR, Hattab EM, Burrell K, Rakopoulos P, Sabha N, : Study of the biodistribution of fluorescein in glioma-infiltrated mouse brain and histopathological correlation of intraoperative findings in high-grade gliomas resected under fluorescein fluorescence guidance. J Neurosurg 122:13601369, 2015

    • Search Google Scholar
    • Export Citation
  • 4

    Schwake M, Stummer W, Suero Molina EJ, Wolfer J: Simultaneous fluorescein sodium and 5-ALA in fluorescence-guided glioma surgery. Acta Neurochir (Wien) 157:877879, 2015

    • Search Google Scholar
    • Export Citation
  • 5

    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 7:392401, 2006

    • Search Google Scholar
    • Export Citation

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