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01-01-2019 | Clinical Study

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

Authors: David I. Sandberg, Bangning Yu, Rajan Patel, John Hagan, Emilie Miesner, Jennifer Sabin, Sarah Smith, Stephen Fletcher, Manish N. Shah, Rachael W. Sirianni, Michael D. Taylor

Published in: Journal of Neuro-Oncology | Issue 2/2019

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 One patient was withdrawn prior to planned 5-AZA infusions due to surgical complications after tumor resection.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.

Merchant TE, Li C, Xiong X, Kun LE, Boop FA, Sanford RA (2009) Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol 10(3):258–266CrossRefPubMedPubMedCentral

Bouffet E, Hawkins CE, Ballourah W, Taylor MD, Bartels UK, Schoenhoff N, Tsangaris E, Huang A, Kulkarni A, Mabbot DJ et al (2012) Survival benefit for pediatric patients with recurrent ependymoma treated with reirradiation. Int J Radiat Oncol Biol Phys 83(5):1541–1548CrossRefPubMed

Bouffet E, Tabori U, Huang A, Bartels U (2009) Ependymoma: lessons from the past, prospects for the future. Childs Nerv Syst 25(11):1383–1384CrossRefPubMed

Figarella-Branger D, Civatte M, Bouvier-Labit C, Gouvernet J, Gambarelli D, Gentet JC, Lena G, Choux M, Pellissier JF (2000) Prognostic factors in intracranial ependymomas in children. J Neurosurg 93(4):605–613CrossRefPubMed

Sandberg DI, Crandall KM, Petito CK, Padgett KR, Landrum J, Babino D, He D, Solano J, Gonzalez-Brito M, Kuluz JW (2008) Chemotherapy administration directly into the fourth ventricle in a new piglet model. J Neurosurg Pediatr 1(5):373–380CrossRefPubMed

Sandberg DI, Crandall KM, Koru-Sengul T, Padgett KR, Landrum J, Babino D, Petito CK, Solano J, Gonzalez-Brito M, Kuluz JW (2010) Pharmacokinetic analysis of etoposide distribution after administration directly into the fourth ventricle in a piglet model. J Neuro-Oncology 97(1):25–32CrossRef

Sandberg DI, Solano J, Petito CK, Mian A, Mou C, Koru-Sengul T, Gonzalez-Brito M, Padgett KR, Luqman A, Buitrago JC et al (2010) Safety and pharmacokinetic analysis of methotrexate administered directly into the fourth ventricle in a piglet model. J Neuro-Oncology 100(3):397–406CrossRef

Sandberg DI, Peet MM, Johnson MD, Cole P, Koru-Sengul T, Luqman AW (2012) Chemotherapy administration directly into the fourth ventricle in a nonhuman primate model. J Neurosurg Pediatr 9(5):530–541CrossRefPubMed

Sandberg DI, Kerr ML (2016) Ventricular access device placement in the fourth ventricle to treat malignant fourth ventricle brain tumors: technical note. Childs Nerv Syst 32(4):703–707CrossRefPubMed

10.

Sandberg DI, Rytting M, Zaky W, Kerr M, Ketonen L, Kundu U, Moore BD, Yang G, Hou P, Sitton C et al (2015) Methotrexate administration directly into the fourth ventricle in children with malignant fourth ventricular brain tumors: a pilot clinical trial. J Neuro-Oncology 125(1):133–141CrossRef

11.

Wongtrakoongate P (2015) Epigenetic therapy of cancer stem and progenitor cells by targeting DNA methylation machineries. World J Stem Cells 7(1):137–148CrossRefPubMedPubMedCentral

12.

Mack SC, Witt H, Piro RM, Gu L, Zuyderduyn S, Stutz AM, Wang X, Gallo M, Garzia L, Zayne K et al (2014) Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 506(7489):445–450CrossRefPubMedPubMedCentral

13.

McCully CL, Rodgers L, Cruz R, Peer C, Figg WD, Warren K: plasma and cerebrospinal fluid pharmacokinetics of 5-azacytidine following intravenous, intranasal, and intrathecal administration in a non-human primate model. In: International Symposium on Pediatric Neuro-Oncology, Liverpool 2016

14.

Heideman RL, McCully C, Balis FM, Poplack DG (1993) Cerebrospinal fluid pharmacokinetics and toxicology of intraventricular and intrathecal arabinosyl-5-azacytosine (fazarabine, NSC 281272) in the nonhuman primate. Investig New Drugs 11(2–3):135–140CrossRef

15.

Lansky SB, List MA, Lansky LL, Ritter-Sterr C, Miller DR (1987) The measurement of performance in childhood cancer patients. Cancer 60(7):1651–1656CrossRefPubMed

16.

Patel RP, Sitton CW, Ketonen LM, Hou P, Johnson JM, Romo S, Fletcher S, Shah MN, Kerr M, Zaky W et al (2018) Phase-contrast cerebrospinal fluid flow magnetic resonance imaging in qualitative evaluation of patency of CSF flow pathways prior to infusion of chemotherapeutic and other agents into the fourth ventricle. Childs Nerv Syst 34(3):481–486CrossRefPubMed

Title: Infusion of 5-Azacytidine (5-AZA) into the fourth ventricle or resection cavity in children with recurrent posterior Fossa Ependymoma: a pilot clinical trial
Authors: David I. Sandberg
Bangning Yu
Rajan Patel
John Hagan
Emilie Miesner
Jennifer Sabin
Sarah Smith
Stephen Fletcher
Manish N. Shah
Rachael W. Sirianni
Michael D. Taylor
Publication date: 01-01-2019
Publisher: Springer US
Published in: Journal of Neuro-Oncology / Issue 2/2019
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-018-03055-1

At a glance: The STEP trials

Springer Medicine

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

Abstract

Background

Materials and methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Materials and methods

Results

Conclusion

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