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Far-distant metastases along the CSF pathway of glioblastoma multiforme during continuous low-dose chemotherapy with temozolomide and celecoxib

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Abstract

Glioblastoma multiforme is the most common and most malignant primary brain tumour. Prognosis after diagnosis remains poor despite recent advances in adjuvant therapy. Treatment of choice is gross surgical resection and combined radio-chemotherapy with temozolomide as chemotherapeutic agent. Experimental continuous low-dose chemotherapy with temozolomide in combination with a cyclooxygenase-2 inhibitor has shown encouraging effects on progression-free survival and overall survival in patients, but leads to a high proportion of distant recurrences. Here, we describe extreme far-distant metastases along the neural axis of glioblastoma multiforme in four patients receiving metronomic antiangiogenic chemotherapy and review the literature to discuss possible mechanisms.

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Authors and Affiliations

  1. Department of Neurosurgery, Medical Faculty of the University of Heidelberg, Mannheim, Germany

    Marcel Seiz, Ioannis Pechlivanis, Christian F. Freyschlag, Kirsten Schmieder & Jochen Tuettenberg

  2. Department of Neuroradiology, Medical Faculty of the University of Heidelberg, Mannheim, Germany

    Ingo Nölte

  3. Department of Neurosurgery, Charité Universitätsmedizin, Berlin, Germany

    Peter Vajkoczy

  4. Department of Neurosurgery, University Hospital Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1–3, 68167, Mannheim, Germany

    Christian F. Freyschlag

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  1. Marcel Seiz
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  2. Ingo Nölte
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  3. Ioannis Pechlivanis
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  4. Christian F. Freyschlag
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  7. Jochen Tuettenberg
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Correspondence to Christian F. Freyschlag.

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Comments

Karl Frei, Zurich, Switzerland

Despite optimal treatment, the median survival for patients is only 12 to 15 months, and therefore, more effective and targeted therapies are still needed for this devastating disease.

Seiz et al. describes in a series of four patients far-distant relapses of GBM along the neural axis after surgical tumor removal, radiotherapy and during continous low-dose chemotherapy with temozolomide and the antiangiogenic COX-2 inhibitor celecoxib. This is in contrast to their recent findings showing a good effect on progression-free and overall survival in GBM patients when using this therapy regime, but leading to an increased rate (20/32 patients) of metastasis (>3 cm of the original localisation), but not far distant along the neural axis. The manuscript is focused on therapy-induced factors leading to increased invasiveness and spreading of the tumor cells. The two main factors are pointed out: (1) metastases related to operative procedures (in one patient, the temporal horn of the left ventricle was opened during surgery) and (2) metastases following adjuvant antiangiogenic treatment (in two patients, the initial tumor was controlled by chemotherapy and distant metastsasis occurred without second surgical approach). The phenomenon that angiogenic therapy increases the rate of distant metastasis has been described under experimental conditions especially with perivascular infiltration of tumor cells “coopting” the preexisting vasculature to guarantee nutrition under hypoxia. However, the underlying mechanisms of this increased invasiveness and escape of tumor cells are still not known.

Extra-cranial metastases from GBM are quite rare, with an incidence of <2% reported in the published literature. In general, they are asymptomatic and found only at autopsy. Factors contributing to the limited incidence of metastatic disease include the dense impassable dura, the unique extracellular matrix of the brain, the tough basement membrane that surrounds intracerebral blood vessels, the lack of true lymphatics and limited patient survival. However, by the development of novel therapies for this aggressive tumor, we may witness an increase in the incidence of neural and extraneural metastasis of these challenging tumors. As described in this study, in GBM patients, metastases have to be considered after tumor recurrence and under antiangiogenic therapy; distant metastases should be kept in mind despite of good local tumor control.

Benoit JM Pirotte, Brussels, Belgium

Marcel Seiz and coworkers from Heidelberg addressed the unusual problem of extreme far-distant metastases along the CSF pathway of glioblastoma multiforme in four patients receiving metronomic antiangiogenic chemotherapy with temozolomide and celecoxib and discussed the possible mechanisms. Indeed, seeding of glioblastoma is rarely observed by everyone of us. Usually, this represents an additional feature of darker prognosis in an individual. However, when seeding occurs, it always reminds the clinician that some mechanism of tumor progression might remain unknown or different from one tumor to another. It illustrates as well the heterogeneous phenotypic patterns of high-grade gliomas. Additionally, it also suggests that increasing patients' survival might allow other mechanisms of tumor invasiveness to take place. Herein, the authors provide an analysis of the microscopic tumor behavior. They suggest to take into account not only the mitotic activity but also the motility and invasiveness of cancer cells and emphasize that a potential effect of some treatments might be to select some other metabolic pathways and to orientate cell activity in unpredicted directions. Last but not least, the present paper has the merit to emphasize that whereas in primary or recurrent malignant tumors adjacent to or in the ventricular system or in approaches with opening basal cisterns, malignant cell seeding along the neural axis has to be kept in mind. The first consequence of that statement is that patients who died from glioblastomas are not candidates to organ donation anymore.

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Seiz, M., Nölte, I., Pechlivanis, I. et al. Far-distant metastases along the CSF pathway of glioblastoma multiforme during continuous low-dose chemotherapy with temozolomide and celecoxib. Neurosurg Rev 33, 375–381 (2010). https://doi.org/10.1007/s10143-010-0253-x

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