Letter to the Editor. Sodium fluorescein versus 5-aminolevulinic acid to visualize high-grade gliomas

Eric Suero Molina Dr med, MBA and Benjamin Brokinkel Dr med
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  • University Hospital of Münster, Germany
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TO THE EDITOR: With great interest we have read the article by Hansen and coauthors1 (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 [published online October 4, 2019]. J Neurosurg. doi:10.3171/2019.6.JNS191531). After carefully reading this report, we believe that several points merit mention given our own extensive experience with fluorescein.2–4

The authors present a retrospective evaluation of two cohorts of patients harboring high-grade gliomas who received either 5-aminolevulinic acid (5-ALA; n = 158) at a dose of 20 mg/kg body weight (BW) or fluorescein (n = 48) at 200 mg (regardless of BW) prior to fluorescence-guided resection (FGR). During the study period, the department changed from 5-ALA to fluorescein, and the authors now retrospectively compare resection rates, progression-free survival (PFS), and overall survival (OS) in the two cohorts.

The authors report that they achieved similar resection rates regardless of the fluorochrome. Remarkably, however, the two cohorts present with different outcomes. Patients operated on with fluorescein demonstrated a longer PFS and a minimally longer OS with a hazard ratio of 0.66 for the fluorescein group (p = 0.06), which suggests superior survival in an underpowered study. Extent of resection (EOR) has repetitively been acknowledged as one of the strongest predictors of prognosis.5,6 Thus, if the authors’ results were accepted to be valid, the only explanation for differing outcomes would be an intrinsic anti-glioma activity of fluorescein. This would be a very surprising finding indeed, seeing that so many rational approaches and medical trials in malignant gliomas have failed. Furthermore, no possible intrinsic anti-tumor mechanism of fluorescein can be envisioned.

The answer to this unexpected observation may be simpler. The authors describe complete resection of contrast-enhancing tumor (CRET) of only 30% in the 5-ALA group and 36.2% in the fluorescein group. These values are remarkably low and cannot be considered standard in modern neurosurgery. Resection rates were not even this low in the white-light control arm in the old randomized 5-ALA phase III trial published in 2006.7 In that study, which was among the first experiences with the use of 5-ALA, surgeons achieved a 65% rate of complete resection in the 5-ALA group, compared to 35% in the white-light microscopy group.7 Modern reports document CRET in more than 89% of patients when using 5-ALA.8 Even Neira et al.,9 in their earlier assessment of fluorescein, achieved CRET in 84% of cases, without finding any significantly increased resection rates compared to those with conventional microsurgery.

While the low resection rates may provide one good explanation, other factors, such as changes in nonsurgical therapy at the authors’ center over time, the distinctly shorter follow-up period in the 5-ALA group, or the different sizes of the compared cohorts, may have also contributed to the authors’ results.

The authors also state that “fluorescein shows only the area of MRI-depicted contrast enhancement.”1 This statement is worrisome and questions the scientific assumptions of this work. Fluorescein is merely a marker of blood-brain barrier disruption and has been proven to be non–tumor specific.10 Immediately after injection, fluorescein will be present in all perfused tissues, including normal brain. After several hours (2–3 hours in our experience), extravasation in regions of blood-brain barrier disruption will be observed, i.e., the contrast-enhancing tissue, something we have termed “pseudoselectivity.”4 With time, however, fluorescein will propagate into the peritumoral edema zone, outside the resection target.2–4 This “edema marker” quality was already demonstrated in 199311 and was further mentioned as problematic the first time fluorescein was documented in the context of tumor surgery in 1948.12 Hence, fluorescein-induced fluorescence must not be blindly pursued, and, in fact, the figure provided in their article clearly demonstrates the unspecific fluorescence of the dye (e.g., yellow staining of the cortex far outside the resection zone; see their Fig. 1).

On the other hand, 5-ALA is specifically metabolized by tumor cells and is a proxy for tumor cellularity. We know that around 10%–20% of tumor cell density is needed to create fluorescence that can be detected visually.13 This resection margin extends beyond the region of contrast enhancement and has been associated with a better outcome.14

It must be remembered that fluorescent dyes and FGR are merely surgical techniques or tools and are not alone responsible for resection outcomes. The information acquired from these tools is only as good as the surgeon using said tools, and in any assessment of intraoperative tools, the principles of case selection as well as mapping and monitoring of neurological functions have to be respected.15 5-ALA does not go “deeper” into the brain, as stated by the authors—it depicts the metabolic active tumor tissue. It is not about “tempting” the surgeon, it is about understanding the disease and actively deciding which tumor regions to resect.

Hansen and coworkers conclude that fluorescein can be used as a viable alternative to 5-ALA, a conclusion that may not be supported by the data presented. However, we agree with the authors in their beliefs that the efficacy of fluorescein in glioma surgery has not been well documented, nor well compared to 5-ALA, and that the patient numbers in the published fluorescein studies are lower than those in the studies investigating 5-ALA, with the fluorescein studies lacking both randomization and control groups.1 We believe that only multicenter randomized controlled trials will give answers to this question, but there is little here to support such an effort.

Disclosures

The authors report no conflict of interest.

References

  • 1

    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 [published online October 4, 2019]. J Neurosurg. doi:10.3171/2019.6.JNS191531

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  • 2

    Suero Molina E, Ewelt C, Warneke N, et al. Dual labeling with 5-aminolevulinic acid and fluorescein in high-grade glioma surgery with a prototype filter system built into a neurosurgical microscope: technical note [published online April 26, 2019]. J Neurosurg. doi:10.3171/2018.12.JNS182422

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  • 3

    Suero Molina E, Stummer W. Where and when to cut? Fluorescein guidance for brain stem and spinal cord tumor surgery—technical note. Oper Neurosurg (Hagerstown). 2018;15(3):325331.

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  • 4

    Suero Molina E, Wölfer J, Ewelt C, et al. Dual-labeling with 5-aminolevulinic acid and fluorescein for fluorescence-guided resection of high-grade gliomas: technical note. J Neurosurg. 2018;128(2):399405.

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  • 5

    Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. 2001;95(2):190198.

    • Search Google Scholar
    • Export Citation
  • 6

    Sanai N, Berger MS. Extent of resection influences outcomes for patients with gliomas. Rev Neurol (Paris). 2011;167(10):648654.

  • 7

    Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392401.

    • Search Google Scholar
    • Export Citation
  • 8

    Schucht P, Beck J, Abu-Isa J, et al. Gross total resection rates in contemporary glioblastoma surgery: results of an institutional protocol combining 5-aminolevulinic acid intraoperative fluorescence imaging and brain mapping. Neurosurgery. 2012;71(5):927936.

    • Search Google Scholar
    • Export Citation
  • 9

    Neira JA, Ung TH, Sims JS, et al. Aggressive resection at the infiltrative margins of glioblastoma facilitated by intraoperative fluorescein guidance. J Neurosurg. 2017;127(1):111122.

    • Search Google Scholar
    • Export Citation
  • 10

    Diaz RJ, Dios RR, Hattab EM, et al. 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. 2015;122:13601369.

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    • Export Citation
  • 11

    Stummer W, Gotz C, Hassan A, et al. Kinetics of Photofrin II in perifocal brain edema. Neurosurgery. 1993;33(6):10751082.

  • 12

    Moore GE, Peyton WT, French LA, Walker WW. The clinical use of fluorescein in neurosurgery. The localization of brain tumors. J Neurosurg. 1948;5(4):392398.

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    • Export Citation
  • 13

    Stummer W, Tonn JC, Goetz C, et al. 5-Aminolevulinic acid-derived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging. Neurosurgery. 2014;74(3):310320.

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    • Export Citation
  • 14

    Schucht P, Knittel S, Slotboom J, et al. 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). 2014;156(2):305312.

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  • 15

    Stummer W, Suero Molina E. Fluorescence imaging/agents in tumor resection. Neurosurg Clin N Am. 2017;28(4):569583.

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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
  • | 4 Odense Patient Data Explorative Network, Odense, Denmark

Response

We thank the authors for their interest in our work and comments on our study. Although most of the points mentioned are already discussed in the Discussion section of our article, their comments deserve a reply.

They posit that the relatively low resection rates may explain the differences in PFS within the population. This topic is already included in the Discussion section: “Compared to existing literature, EOR in this study was relatively low. As delineation was performed manually, bias regarding determination between contrast enhancement in the diffuse tumor border, and thereby potential overestimation of tumor residue, is considered the best explanation of this concern.” As they correctly mention, “EOR has repetitively been acknowledged as one of the strongest predictors of prognosis.” The prognosis in our cohort (PFS: 8.7 months for 5-ALA, 9.2 months for fluorescein; OS: 14.75 months for 5-ALA and 19.75 months for fluorescein) is fully comparable to that in the existing literature on patients with high-grade glioma.1,2 Using the authors’ own deduction, it would seem unlikely that an estimated low EOR is not underestimating the actual EOR given the prognosis in terms of OS and PFS in our study. In addition, comparing EOR in our retrospective study, which includes all malignant gliomas, with those in prospective randomized studies is misleading.

As our study was conducted on pre-existing data, one cannot expect an even distribution of participants. Suero Molina and Brokinkel mention that “the distinctly shorter follow-up period in the 5-ALA group . . . may have also contributed to the authors’ results” (i.e., a significant difference in PFS). Median PFS and OS are some of the most frequently reported measures of survival, and as they are both within the median follow-up time, this explanation does not seem compelling. If, however, one assumes that this line of thinking is appropriate, the authors’ reference to the follow-up time is incorrect, as we did not report a shorter follow-up time for 5-ALA (46.7 months for 5-ALA and 21.2 months for fluorescein).

The authors criticize our statement that “fluorescein shows only the area of MRI-depicted contrast enhancement.” We agree that with time, and as a consequence of resection, fluorescein visualizes, among other structures, the peritumoral edema zone. However, in contrast to their statement, the study they cite concludes that “our intraoperative observations and histopathological analysis demonstrate a good correlation between intraoperative fluorescein fluorescence and gadolinium enhancement on MR imaging.”3

We agree that FGR, neuronavigation, and other modalities themselves are not responsible for the resection outcomes. As they play a key part in guiding the surgeon performing the resection, and as the variety of techniques, tools, and modalities to choose from are significant, comparison of the different tools is important from both a patient-oriented and an economic point of view. As mentioned in our study, “prospective randomized controlled trials are needed to further investigate these findings,” but performing such a study would be unethical; thus, retrospective evaluation of pre-existing data on this exact topic, as was done in our study, is necessary.

Finally, the authors state that “Hansen and coworkers conclude that fluorescein can be used as a viable alternative to 5-ALA, a conclusion that may not be supported by the data presented.” Unfortunately, this represents a considerable misunderstanding of an otherwise quite specific conclusion. Our study was performed to investigate retrospectively an already widely adopted approach of preoperative fluorescein visualization of high-grade glioma (and to compare it to 5-ALA), and within the comprehensively described limits of our study, we concluded from the collected data that “fluorescein was found to produce EOR and postoperative residual tumor volume comparable to 5-ALA. In addition, the use of fluorescein resulted in longer PFS compared to 5-ALA.” We agree that the definite answer to this can only be given by randomized controlled trials, but as mentioned previously, we believe that calculations based on retrospective data play an important role in motivating such studies, and our study contributes just that.

References

  • 1

    Acerbi F, Broggi M, Schebesch KM, et al. Fluorescein-guided surgery for resection of high-grade gliomas: a multicentric prospective phase II study (FLUOGLIO). Clin Cancer Res. 2018;24(1):5261.

    • Search Google Scholar
    • Export Citation
  • 2

    Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392401.

    • Search Google Scholar
    • Export Citation
  • 3

    Diaz RJ, Dios RR, Hattab EM, et al. 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. 2015;122(6):13601369.

    • Search Google Scholar
    • Export Citation

Illustration from Nelson et al. (pp 1516–1526). Artists: Ethan Tyler, Erina He, and Alan Hoofring. Medical Arts, Office of Research Services, National Institutes of Health.

Contributor Notes

Correspondence Eric Suero Molina: eric.suero@ukmuenster.de.

INCLUDE WHEN CITING Published online January 24, 2020; DOI: 10.3171/2019.12.JNS193180.

Disclosures The authors report no conflict of interest.

  • 1

    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 [published online October 4, 2019]. J Neurosurg. doi:10.3171/2019.6.JNS191531

    • Search Google Scholar
    • Export Citation
  • 2

    Suero Molina E, Ewelt C, Warneke N, et al. Dual labeling with 5-aminolevulinic acid and fluorescein in high-grade glioma surgery with a prototype filter system built into a neurosurgical microscope: technical note [published online April 26, 2019]. J Neurosurg. doi:10.3171/2018.12.JNS182422

    • Search Google Scholar
    • Export Citation
  • 3

    Suero Molina E, Stummer W. Where and when to cut? Fluorescein guidance for brain stem and spinal cord tumor surgery—technical note. Oper Neurosurg (Hagerstown). 2018;15(3):325331.

    • Search Google Scholar
    • Export Citation
  • 4

    Suero Molina E, Wölfer J, Ewelt C, et al. Dual-labeling with 5-aminolevulinic acid and fluorescein for fluorescence-guided resection of high-grade gliomas: technical note. J Neurosurg. 2018;128(2):399405.

    • Search Google Scholar
    • Export Citation
  • 5

    Lacroix M, Abi-Said D, Fourney DR, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. 2001;95(2):190198.

    • Search Google Scholar
    • Export Citation
  • 6

    Sanai N, Berger MS. Extent of resection influences outcomes for patients with gliomas. Rev Neurol (Paris). 2011;167(10):648654.

  • 7

    Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392401.

    • Search Google Scholar
    • Export Citation
  • 8

    Schucht P, Beck J, Abu-Isa J, et al. Gross total resection rates in contemporary glioblastoma surgery: results of an institutional protocol combining 5-aminolevulinic acid intraoperative fluorescence imaging and brain mapping. Neurosurgery. 2012;71(5):927936.

    • Search Google Scholar
    • Export Citation
  • 9

    Neira JA, Ung TH, Sims JS, et al. Aggressive resection at the infiltrative margins of glioblastoma facilitated by intraoperative fluorescein guidance. J Neurosurg. 2017;127(1):111122.

    • Search Google Scholar
    • Export Citation
  • 10

    Diaz RJ, Dios RR, Hattab EM, et al. 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. 2015;122:13601369.

    • Search Google Scholar
    • Export Citation
  • 11

    Stummer W, Gotz C, Hassan A, et al. Kinetics of Photofrin II in perifocal brain edema. Neurosurgery. 1993;33(6):10751082.

  • 12

    Moore GE, Peyton WT, French LA, Walker WW. The clinical use of fluorescein in neurosurgery. The localization of brain tumors. J Neurosurg. 1948;5(4):392398.

    • Search Google Scholar
    • Export Citation
  • 13

    Stummer W, Tonn JC, Goetz C, et al. 5-Aminolevulinic acid-derived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging. Neurosurgery. 2014;74(3):310320.

    • Search Google Scholar
    • Export Citation
  • 14

    Schucht P, Knittel S, Slotboom J, et al. 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). 2014;156(2):305312.

    • Search Google Scholar
    • Export Citation
  • 15

    Stummer W, Suero Molina E. Fluorescence imaging/agents in tumor resection. Neurosurg Clin N Am. 2017;28(4):569583.

  • 1

    Acerbi F, Broggi M, Schebesch KM, et al. Fluorescein-guided surgery for resection of high-grade gliomas: a multicentric prospective phase II study (FLUOGLIO). Clin Cancer Res. 2018;24(1):5261.

    • Search Google Scholar
    • Export Citation
  • 2

    Stummer W, Pichlmeier U, Meinel T, et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006;7(5):392401.

    • Search Google Scholar
    • Export Citation
  • 3

    Diaz RJ, Dios RR, Hattab EM, et al. 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. 2015;122(6):13601369.

    • Search Google Scholar
    • Export Citation

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