Letter to the Editor. A new approach for local tumor control

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  • 1 Institute of Neurosurgery, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University, Rome, Italy
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TO THE EDITOR: We read with great interest the paper by Schipmann et al.1 (Schipmann S, Müther M, Stögbauer L, et al. Combination of ALA-induced fluorescence-guided resection and intraoperative open photodynamic therapy for recurrent glioblastoma: case series on a promising dual strategy for local tumor control. J Neurosurg. 2021;134[2]:426–436). The authors present a combined 5-aminolevulinic acid (5-ALA) and photodynamic therapy (PDT) approach in the treatment of recurrent high-grade gliomas (HGGs). Their experience has proved to be an innovative and safe method for local tumor control, an effort for which they should be commended. In particular, they brought the discussion to bear on a crucial issue of such 5-ALA use in the treatment of recurrent HGG, which is currently done on a case-by-case basis and without a proper consensus.2

In the literature and in general practice, 5-ALA’s indisputable role has been well underlined for newly diagnosed HGG cases, whereas its significance and its possible pitfalls in recurrent HGGs are de facto less clear. As is widely acknowledged, an accurate differentiation of glioma recurrence from treatment-induced changes is of paramount importance because it can change the patient’s management. Against this background, we want to emphasize 5-ALA heterogeneity in the “recurrent setting” and the need to properly address this feature in order to better integrate it with other techniques such as PDT.3

As a matter of fact, the presence of inflammatory tissue, as in the case of peritumoral reactive inflammation, pseudoprogression, or radiation-induced necrosis, may influence the intraoperative fluorescence detection. Therefore, surgeons must be aware that not everything that glitters is gold—a critical awareness of 5-ALA potentialities and drawbacks in recurrent gliomas is necessary.

With specific focus on pseudoprogression and radiation necrosis,4 we believe it is important to point out 5-ALA heterogeneous behavior in such cases in order to properly design future studies in which investigators are able to properly select patients who, during a second surgery with 5-ALA, become eligible for PDT, and to avoid resections improperly exceeding planned limits.

Pseudoprogression, which constitutes a strong reaction to effective therapy and is associated with damage to the endothelium, is linked to a high responsiveness to 5-ALA. Different studies have suggested the presence of a peritumoral inflammatory state, and an increased reactive mitotic activity could explain these false-positive results. This is relevant in order to avoid patients’ exposure to unnecessary treatment5 and to tailor resection, especially in eloquent areas. Furthermore, there are currently no data on PDT selectivity in this context.

A different consideration has to be made for radiation necrosis. The paper points out that PDT has high selectivity for tumor cells, having shown no effect in a patient operated on for suspected recurrence and with 5-ALA positivity, but in whom histological analysis revealed the lesion to be radionecrosis. However, we want to highlight how 5-ALA behavior in radiation necrosis has been linked to conflicting evidence—further studies are needed to better clarify this issue in order to provide an improved selection of candidates for the dual approach.6,7

In thanking the author for providing such interesting food for thought, we wish that future studies on the topic will take our suggestion.

Disclosures

The authors report no conflict of interest.

References

  • 1

    Schipmann S , Müther M , Stögbauer L , et al. Combination of ALA-induced fluorescence-guided resection and intraoperative open photodynamic therapy for recurrent glioblastoma: case series on a promising dual strategy for local tumor control . J Neurosurg . 2021 ;134 (2 ):426 436 .

    • Search Google Scholar
    • Export Citation
  • 2

    Birzu C , French P , Caccese M , et al. Recurrent glioblastoma: from molecular landscape to new treatment perspectives . Cancers (Basel) . 2020 ;13 (1 ):47 .

    • Search Google Scholar
    • Export Citation
  • 3

    La Rocca G , Sabatino G , Menna G , et al. 5-aminolevulinic acid false positives in cerebral neuro-oncology: not all that is fluorescent is tumor. A case-based update and literature review . World Neurosurg .2020 ;137 :187 193 .

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    • Export Citation
  • 4

    Zikou A , Sioka C , Alexiou GA , et al. Radiation necrosis, pseudoprogression, pseudoresponse, and tumor recurrence: imaging challenges for the evaluation of treated gliomas . Contrast Media Mol Imaging . 2018 ;2018 :6828396 .

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    • Export Citation
  • 5

    Ellingson BM , Chung C , Pope WB , et al. Pseudoprogression, radionecrosis, inflammation or true tumor progression? Challenges associated with glioblastoma response assessment in an evolving therapeutic landscape . J Neurooncol . 2017 ;134 (3 ):495 504 .

    • Search Google Scholar
    • Export Citation
  • 6

    Miyatake SI , Kuroiwa T , Kajimoto Y , et al. Fluorescence of non-neoplastic, magnetic resonance imaging-enhancing tissue by 5-aminolevulinic acid: case report . Neurosurgery . 2007 ;61 (5 ):E1101 E1104 .

    • Search Google Scholar
    • Export Citation
  • 7

    Kamp MA , Felsberg J , Sadat H , et al. 5-ALA-induced fluorescence behavior of reactive tissue changes following glioblastoma treatment with radiation and chemotherapy . Acta Neurochir (Wien) . 2015 ;157 (2 ):207 214 .

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  • 1 University Hospital Münster, Germany

Response

With great interest have we read the letter to the editor from Menna et al. regarding our publication on open PDT, and we thank the authors for their interest in our research.

We agree that accurate detection of tumor recurrence is of paramount importance for patient management, and we are aware that it is not always possible to reliably differentiate tumor progression from treatment-related changes with conventional imaging techniques.1

However, with our use of advanced imaging modalities and the Response Assessment in Neuro-Oncology (RANO) criteria2 before allocating a glioma patient with suspicion of tumor recurrence or progression to further surgical treatment (including open PDT), we reach a high certainty for the detection of tumor tissue and for distinguishing recurrent tumor from pseudoprogression or radiation necrosis.

These advanced imaging modalities include MR spectroscopy, reaching a sensitivity and specificity of 91% and 95%, respectively;3 MR perfusion;1 and PET studies using 11C-MET or 18F-FET as tracers.4–6 With the use of 18F-FET PET, a sensitivity of up to 100% and specificity of 91% can be expected.6 When in doubt, the combination of several imaging modalities can help to increase sensitivity and help in making clinical decisions. These data together with our experience in daily routine use of these advanced imaging modalities have led to the fact that distinguishing between tumor progression or recurrence and posttherapeutic changes is no longer a limiting issue. Because progression and ultimately death are inevitable in malignant gliomas, with no generally accepted treatment options after progression, early detection of progression by using multiple methods is an integral part of modern neuro-oncological management.

In addition, histological assessment of intraoperative frozen sections, a routine procedure in our department, does also help to confirm the diagnosis of recurrent tumor before application of PDT.

With this degree of patient selection, we have a very low risk of operating on patients without real tumor progression and underlying pseudoprogression. This lowers the remaining uncertainty of the reported higher false-positive fluorescence rate of 5-ALA in recurrent HGGs. In addition, several studies have shown a high positive predictive value for the use of 5-ALA in recurrent gliomas.7–9 The specificity of 5-ALA is related to the intensity of fluorescence. Areas with strong fluorescence are accompanied by a high predictive value for the presence of tumor tissue. In areas with weak fluorescence, the false-positive rate is higher. However, histologically these areas are characterized by an abundance of gliotic tissue in combination with inflammatory and reactive cells, but with only a little normal brain.8–10 Consequently, resection of these areas or treatment with PDT is not likely to cause functional impairment.

We agree that there are currently no data on PDT selectivity in the context of tumor recurrence. However, the fact that the one patient who was included in our study and in whom histology revealed that radiation necrosis had no effect of PDT on postoperative MRI suggests a certain selectivity of this treatment strategy.

In summary, overtreatment of patients with pseudoprogression can generally be avoided. With modern imaging modalities and intraoperative frozen sections, a high certainty for the detection of real tumor progression can be achieved. This is particularly important because patients with recurrent HGGs have a dismal prognosis and our suggested treatment strategy of re-resection and open PDT offers a promising treatment option.

References

  • 1

    van Dijken BRJ , van Laar PJ , Smits M , et al. Perfusion MRI in treatment evaluation of glioblastomas: clinical relevance of current and future techniques . J Magn Reson Imaging . 2019 ;49 (1 ):11 22 .

    • Search Google Scholar
    • Export Citation
  • 2

    Chukwueke UN , Wen PY . Use of the Response Assessment in Neuro-Oncology (RANO) criteria in clinical trials and clinical practice . CNS Oncol . 2019 ;8 (1 ):CNS28 .

    • Search Google Scholar
    • Export Citation
  • 3

    van Dijken BRJ , van Laar PJ , Holtman GA , van der Hoorn A . Diagnostic accuracy of magnetic resonance imaging techniques for treatment response evaluation in patients with high-grade glioma, a systematic review and meta-analysis . Eur Radiol . 2017 ;27 (10 ):4129 4144 .

    • Search Google Scholar
    • Export Citation
  • 4

    Bashir A , Mathilde Jacobsen S , Mølby Henriksen O , et al. Recurrent glioblastoma versus late posttreatment changes: diagnostic accuracy of O-(2-[18F]fluoroethyl)-L-tyrosine positron emission tomography (18F-FET PET) . Neuro Oncol . 2019 ;21 (12 ):1595 1606 .

    • Search Google Scholar
    • Export Citation
  • 5

    Deuschl C , Kirchner J , Poeppel TD , et al. 11C-MET PET/MRI for detection of recurrent glioma . Eur J Nucl Med Mol Imaging . 2018 ;45 (4 ):593 601 .

    • Search Google Scholar
    • Export Citation
  • 6

    Galldiks N , Dunkl V , Stoffels G , et al. Diagnosis of pseudoprogression in patients with glioblastoma using O-(2-[18F]fluoroethyl)-l-tyrosine PET . Eur J Nucl Med Mol Imaging . 2015 ;42 (5 ):685 695 .

    • Search Google Scholar
    • Export Citation
  • 8

    Lau D , Hervey-Jumper SL , Chang S , et al. 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 . 2016 ;124 (5 ):1300 1309 .

    • Search Google Scholar
    • Export Citation
  • 9

    Nabavi A , Thurm H , Zountsas B , et al. Five-aminolevulinic acid for fluorescence-guided resection of recurrent malignant gliomas: a phase II study . Neurosurgery . 2009 ;65 (6 ):1070 1077 .

    • Search Google Scholar
    • Export Citation
  • 10

    Chohan MO , Berger MS . 5-aminolevulinic acid fluorescence guided surgery for recurrent high-grade gliomas . J Neurooncol . 2019 ;141 (3 ):517 522 .

    • Search Google Scholar
    • Export Citation

Artist’s illustration of the classic mulberry appearance of a cavernoma. This illustration represents the Seven Cavernomas series by Dr. Michael Lawton, a collection of articles defining the tenets and techniques for the treatment of cavernous malformations, a taxonomy for classifying these lesions, and the nuances of their surgical approaches. Artist: Peter M. Lawrence. Used with permission from Barrow Neurological Institute, Phoenix, Arizona. See the article by Garcia et al. (pp 671–682).

Contributor Notes

Correspondence Grazia Menna: mennagrazia@gmail.com.

INCLUDE WHEN CITING Published online May 7, 2021; DOI: 10.3171/2021.2.JNS21409.

Disclosures The authors report no conflict of interest.

  • 1

    Schipmann S , Müther M , Stögbauer L , et al. Combination of ALA-induced fluorescence-guided resection and intraoperative open photodynamic therapy for recurrent glioblastoma: case series on a promising dual strategy for local tumor control . J Neurosurg . 2021 ;134 (2 ):426 436 .

    • Search Google Scholar
    • Export Citation
  • 2

    Birzu C , French P , Caccese M , et al. Recurrent glioblastoma: from molecular landscape to new treatment perspectives . Cancers (Basel) . 2020 ;13 (1 ):47 .

    • Search Google Scholar
    • Export Citation
  • 3

    La Rocca G , Sabatino G , Menna G , et al. 5-aminolevulinic acid false positives in cerebral neuro-oncology: not all that is fluorescent is tumor. A case-based update and literature review . World Neurosurg .2020 ;137 :187 193 .

    • Search Google Scholar
    • Export Citation
  • 4

    Zikou A , Sioka C , Alexiou GA , et al. Radiation necrosis, pseudoprogression, pseudoresponse, and tumor recurrence: imaging challenges for the evaluation of treated gliomas . Contrast Media Mol Imaging . 2018 ;2018 :6828396 .

    • Search Google Scholar
    • Export Citation
  • 5

    Ellingson BM , Chung C , Pope WB , et al. Pseudoprogression, radionecrosis, inflammation or true tumor progression? Challenges associated with glioblastoma response assessment in an evolving therapeutic landscape . J Neurooncol . 2017 ;134 (3 ):495 504 .

    • Search Google Scholar
    • Export Citation
  • 6

    Miyatake SI , Kuroiwa T , Kajimoto Y , et al. Fluorescence of non-neoplastic, magnetic resonance imaging-enhancing tissue by 5-aminolevulinic acid: case report . Neurosurgery . 2007 ;61 (5 ):E1101 E1104 .

    • Search Google Scholar
    • Export Citation
  • 7

    Kamp MA , Felsberg J , Sadat H , et al. 5-ALA-induced fluorescence behavior of reactive tissue changes following glioblastoma treatment with radiation and chemotherapy . Acta Neurochir (Wien) . 2015 ;157 (2 ):207 214 .

    • Search Google Scholar
    • Export Citation
  • 1

    van Dijken BRJ , van Laar PJ , Smits M , et al. Perfusion MRI in treatment evaluation of glioblastomas: clinical relevance of current and future techniques . J Magn Reson Imaging . 2019 ;49 (1 ):11 22 .

    • Search Google Scholar
    • Export Citation
  • 2

    Chukwueke UN , Wen PY . Use of the Response Assessment in Neuro-Oncology (RANO) criteria in clinical trials and clinical practice . CNS Oncol . 2019 ;8 (1 ):CNS28 .

    • Search Google Scholar
    • Export Citation
  • 3

    van Dijken BRJ , van Laar PJ , Holtman GA , van der Hoorn A . Diagnostic accuracy of magnetic resonance imaging techniques for treatment response evaluation in patients with high-grade glioma, a systematic review and meta-analysis . Eur Radiol . 2017 ;27 (10 ):4129 4144 .

    • Search Google Scholar
    • Export Citation
  • 4

    Bashir A , Mathilde Jacobsen S , Mølby Henriksen O , et al. Recurrent glioblastoma versus late posttreatment changes: diagnostic accuracy of O-(2-[18F]fluoroethyl)-L-tyrosine positron emission tomography (18F-FET PET) . Neuro Oncol . 2019 ;21 (12 ):1595 1606 .

    • Search Google Scholar
    • Export Citation
  • 5

    Deuschl C , Kirchner J , Poeppel TD , et al. 11C-MET PET/MRI for detection of recurrent glioma . Eur J Nucl Med Mol Imaging . 2018 ;45 (4 ):593 601 .

    • Search Google Scholar
    • Export Citation
  • 6

    Galldiks N , Dunkl V , Stoffels G , et al. Diagnosis of pseudoprogression in patients with glioblastoma using O-(2-[18F]fluoroethyl)-l-tyrosine PET . Eur J Nucl Med Mol Imaging . 2015 ;42 (5 ):685 695 .

    • Search Google Scholar
    • Export Citation
  • 8

    Lau D , Hervey-Jumper SL , Chang S , et al. 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 . 2016 ;124 (5 ):1300 1309 .

    • Search Google Scholar
    • Export Citation
  • 9

    Nabavi A , Thurm H , Zountsas B , et al. Five-aminolevulinic acid for fluorescence-guided resection of recurrent malignant gliomas: a phase II study . Neurosurgery . 2009 ;65 (6 ):1070 1077 .

    • Search Google Scholar
    • Export Citation
  • 10

    Chohan MO , Berger MS . 5-aminolevulinic acid fluorescence guided surgery for recurrent high-grade gliomas . J Neurooncol . 2019 ;141 (3 ):517 522 .

    • Search Google Scholar
    • Export Citation

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