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Infusion of 5-Azacytidine (5-AZA) into the fourth ventricle or resection cavity in children with recurrent posterior Fossa Ependymoma: a pilot clinical trial

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Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Background

DNA methylation inhibitors are logical therapeutic candidates for ependymomas originating in the posterior fossa of the brain. Our objective was to test the safety of infusing 5-Azacytidine (5-AZA), a DNA methylation inhibitor, directly into cerebrospinal fluid (CSF) spaces of the fourth ventricle or tumor resection cavity in children with recurrent ependymoma originating in the posterior fossa.

Materials and methods

In patients with recurrent ependymoma whose disease originated in the posterior fossa, a maximal safe subtotal tumor resection was performed. At the conclusion of the tumor resection, a catheter was surgically placed into the fourth ventricle or tumor resection cavity and attached to a ventricular access device. CSF flow from the posterior fossa to the sacrum was confirmed by CINE phase contrast magnetic resonance imaging (MRI) postoperatively. 12 consecutive weekly 10 milligram (mg) infusions of 5-Azacytidine (AZA) were planned. Disease response was monitored with MRI scans and CSF cytology.

Results

Six patients were enrolled. One patient was withdrawn prior to planned 5-AZA infusions due to surgical complications after tumor resection. The remaining five patients received 8, 12, 12, 12, and 12 infusions, respectively. There were no serious adverse events or new neurological deficits attributed to 5-AZA infusions. All five patients with ependymoma who received 5-AZA infusions had progressive disease. Two of the five patients, however, were noted to have decrease in the size of at least one intraventricular lesion.

Conclusion

5-AZA can be infused into the fourth ventricle or posterior fossa tumor resection cavity without causing neurological toxicity. Future studies with higher doses and/or increased dosing frequency are warranted.

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Acknowledgements

The authors would like to thank Ian’s Friends Foundation for grant support that helped to fund this study. We would also like to thank Allyson Lack for her assistance with image formatting. Above all, we would like to thank the brave patients who enrolled in this trial and their wonderful families.

Funding

This study was partially funded by grant support from Ian’s Friends Foundation (no grant number) that was awarded to David Sandberg, M.D.

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Authors and Affiliations

  1. Division of Pediatric Neurosurgery, Departments of Pediatric Surgery and Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston and Mischer Neuroscience Center, 6431 Fannin St., MSB 5.140, Houston, TX, 77030, USA

    David I. Sandberg, Stephen Fletcher & Manish N. Shah

  2. Division of Pediatric Neurosurgery, Department of Pediatric Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, USA

    Bangning Yu, Emilie Miesner, Jennifer Sabin & Sarah Smith

  3. Division of Neuroradiology, Department of Diagnostic and Interventional Imaging, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, USA

    Rajan Patel

  4. Vivian L. Smith Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, USA

    John Hagan & Rachael W. Sirianni

  5. Developmental and Stem Cell Biology Program, The Arthur and Sonia Labatt Brain Tumour Center, Division of Neurosurgery, Hospital for Sick children, Toronto, ON, Canada

    Michael D. Taylor

  6. Department of Surgery, Department of Laboratory Medicine and Pathobiology and Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada

    Michael D. Taylor

Authors
  1. David I. Sandberg
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  2. Bangning Yu
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  3. Rajan Patel
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  4. John Hagan
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  5. Emilie Miesner
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  6. Jennifer Sabin
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  7. Sarah Smith
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  8. Stephen Fletcher
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  9. Manish N. Shah
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  10. Rachael W. Sirianni
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  11. Michael D. Taylor
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Corresponding author

Correspondence to David I. Sandberg.

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Conflict of interest

All authors (Bangning Yu, M.D., Ph.D., Rajan Patel, M.D., Emilie Miesner, PA-C, Jennifer Sabin, PA-C, Sarah Smith, PA-C, Stephen Fletcher, D.O., Manish N. Shah, M.D., and Michael D. Taylor, M.D., Ph.D.) declare that they have no conflicts of interest. Author David Sandberg, M.D. received grant support from Ian’s Friends Foundation to support this study as noted above. Dr. Sandberg also received a speaker honorarium from Aesculap in 2017 for a talk at the International Society for Pediatric Neurosurgery on a topic unrelated to this study. Author John Hagan, Ph.D., has received financial support from GlaxoSmithKline for research that is unrelated to this study. Author Rachael Sirianni, Ph.D., currently receives grant support from Ian’s Friends Foundation and the National Institutes of Health, and she has received grant funding in the past from the Rick Oehme Foundation, the Ben and Catherine Ivy Foundation, the ALS Association, the Barrow Neurological Foundation, the National Science Foundation, and the Department of Defense. Author Rachael Sirianni, Ph.D. owns stock in the company NP Therapeutics, Inc. and works as a consultant for the Ian’s Friends Foundation. None of these relationships for Dr. Sirianni have any connection to the current study.

Ethical Approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national search committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants in the study.

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Sandberg, D.I., Yu, B., Patel, R. et al. Infusion of 5-Azacytidine (5-AZA) into the fourth ventricle or resection cavity in children with recurrent posterior Fossa Ependymoma: a pilot clinical trial. J Neurooncol 141, 449–457 (2019). https://doi.org/10.1007/s11060-018-03055-1

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  • DOI: https://doi.org/10.1007/s11060-018-03055-1

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