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A Deeper Dive: Promising Novel Approach to Treating Malignant Fourth Ventricular Brain Tumors

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In Advance podcast Episode 4: “Two Novel Studies Seek to Improve Outcomes in Children with Malignant Fourth Ventricular Brain Tumors,” pediatric neurosurgeon David I. Sandberg, MD, FACS, FAAP, director of pediatric neurosurgery at McGovern Medical School at UTHealth Houston and director of Pediatric Neurosurgery at Children’s Memorial Hermann Hospital discusses a novel experimental approach to treating pediatric patients with medulloblastoma and other malignant posterior fossa brain tumors—direct infusion of chemotherapeutic agents into the fourth ventricle of the brain, the location of the most common malignant brain tumors in children.

Dr. Sandberg serves as co-director of the combined pediatric brain tumor program between Children’s Memorial Hermann Hospital and MD Anderson Cancer Center. The Pediatric Brain Tumor Program brings together a team of UTHealth Houston specialists affiliated with Children’s Memorial Hermann Hospital and MD Anderson Children’s Cancer Hospital to serve you and your patients with new and advanced ways to diagnose and treat childhood brain tumors.

Current Treatments “Inadequate”

As Dr. Sandberg explains in the podcast, when children have recurrent malignant tumors in the brain, current treatments are inadequate, and most children die of their disease.

“Medulloblastoma and ependymoma typically fill the fourth ventricle,” says Dr. Sandberg. “Initial surgical resection is often incomplete due to adherence of tumor to the brainstem, which constitutes the floor of the fourth ventricle. Postoperative adjuvant treatment typically includes radiation therapy and systemic chemotherapy, both of which can be associated with significant morbidity, especially in young children. Further, when these tumors recur, local recurrence is often accompanied by leptomeningeal spread via cerebrospinal fluid (CSF) pathways, emphasizing the importance of treatments which address both local disease and central nervous system (CNS) spread.”

Previous human studies for various malignancies have utilized intrathecal or intraventricular chemotherapy in order to increase drug concentrations within the CSF while minimizing systemic exposure. Treatment has been administered either by repeated lumbar punctures or via a ventricular access device connected to a catheter inserted into the lateral ventricle of the brain. Dr. Sandberg says repeated lumbar punctures are painful, sometimes technically challenging, and often require sedation in children.

A Novel Approach: Fourth Ventricle Infusions

In 2004, Dr. Sandberg hypothesized that patients with malignant posterior fossa brain tumors could be safely treated by infusing chemotherapeutic drugs directly into the fourth ventricle of the brain, enabling physicians to optimize local and regional drug concentrations and improve tumor control rates. Whereas catheter placement into the lateral ventricle requires a separate surgical procedure, direct catheter placement into the fourth ventricle could be performed at the time of surgery for primary or recurrent tumor resection without requiring an additional operation.

To begin to test this hypothesis, Dr. Sandberg developed translational models of direct infusion of chemotherapy into the fourth ventricle in animal models.  Between 2004 and 2012, Dr. Sandberg led several studies testing the safety and pharmacokinetics of direct infusion of etoposide and methotrexate (MTX) (commonly used drugs for treating pediatric malignant brain tumors) into animal models. These studies concluded that the infusions caused no new neurological deficits.

First Trial in Humans

In 2013, a team of researchers from Children’s Memorial Hermann Hospital, UTHealth Houston and MD Anderson, led by Dr. Sandberg, conducted the first clinical trial in which chemotherapeutic agents were directly infused into the fourth ventricles of humans. The study’s primary objective was to demonstrate that chemotherapy could be safely infused into the fourth ventricle without causing new neurological deficits or evidence of damage to the adjacent brainstem or cerebellum on magnetic resonance imaging (MRI) scans. The second objective was to assess if MTX infusions into the fourth ventricle, without any simultaneous systemic chemotherapy, would provide any measurable disease response.

This pilot trial demonstrated that low-dose MTX can be infused into the fourth ventricle in human patients with recurrent, malignant tumors without causing recognized neurological deficits or other significant toxicity, and it offered proof of principle that intraventricular chemotherapy may be effective in treating malignant brain tumors. Significantly, all three patients with recurrent medulloblastoma had decreased tumor size after infusions.

Beginning in 2017, Dr. Sandberg and his research team conducted a clinical trial studying 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. The study concluded that 5-AZA can be infused into the fourth ventricle or posterior fossa tumor resection cavity without causing neurological toxicity. 

And in 2019, Dr. Sandberg and his researchers studied the safety and pharmacokinetics of short- and long-term administration of MTX110 (soluble panobinostat) into the fourth ventricle of animal models, concluding that MTX110 can be safely infused into the fourth ventricle in animal models at supratherapeutic doses.

Two Clinical Trials Underway

Dr. Sandberg and his team of researchers are currently recruiting participants for two clinical trials focusing on ependymoma and medulloblastoma infusing.

Clinical Trial: Combination Intraventricular Chemotherapy Pilot Study: 5-Azacytidine (5-AZA) and Trastuzumab Infusions Into the Fourth Ventricle or Resection Cavity in Children and Adults With Recurrent or Residual Posterior Fossa Ependymoma

Dr. Sandberg says ependymoma is a great target for this (fourth ventricular infusion) approach, as standard chemotherapy drugs almost invariably don’t work. “The success rate with standard chemotherapy given orally or by vein has almost no impact on the majority of kids with recurrent ependymoma,” he says, adding, “These tumors are relentless.”

According to the American Cancer Society, about 2,000 children and adults in the United States are diagnosed with ependymoma each year. The overall 5-year survival rate is 83.9%.

“We’ve had preliminary success with a drug called 5-azacytidine, which caused shrinkage of some of the tumors we treated in our last trial, but it wasn't enough. It didn't cure children. So, we've added a second drug called trastuzumab, which is active against ependymoma. We're hoping that the combination of these drugs will have an even greater impact,” he says.

Patients who enroll in the trial will receive weekly 10 mg intraventricular 5-AZA infusions and weekly 21 mg intraventricular trastuzumab infusions for 6 consecutive weeks.

All patients will undergo an MRI of the brain and total spine within 7 days after the final 5-AZA and trastuzumab infusion to determine their response to the treatment and to assess for any signal changes in the brain or spine caused by the infusions. Additionally, there will be 30-day and 90-day follow-up assessments by telephone or in person.

Enrollment is limited to 10 study participants. To be eligible, a participant will be between 1 and 80 years old and must have histologically verified ependymoma that originated in the back of the head, with recurrence or progression anywhere in the brain and/or spine. Patients are also eligible if they have a residual tumor that has not been completely cleared despite prior treatments.

To learn more, visit

Clinical Trial: Infusion of Panobinostat (MTX110) Into the Fourth Ventricle or Tumor Resection Cavity in Children and Adults with Recurrent Medulloblastoma: A Pilot Study

For medulloblastoma, the team is focused on a specific formulation of panobinostat, MTX110, which Dr. Sandberg says has shown great activity against medulloblastoma in the laboratory. “We're really hopeful that infusing this drug directly into the fourth ventricle is going to have a great impact on the disease process.”

According to the American Cancer Society, an estimated 357 people, including 217 children ages 14 and younger, are diagnosed with medulloblastoma every year. The 5-year survival rate is 72.1%. Currently, patients with medulloblastoma undergo surgery and then receive radiation therapy and chemotherapy, both of which can be associated with considerable short- and long-term side effects.

Patients participating in the trial will undergo surgery for maximum safe tumor resection with simultaneous placement of a ventricular access device (VAD) into the fourth ventricle or posterior fossa tumor resection cavity. Enrolled patients will receive four infusions per week of panobinostat for 6 consecutive weeks, for a total of 24 infusions.

The study will enroll five participants. Eligible patients include patients with histologically verified medulloblastoma with recurrence or progression involving anywhere in the brain and/or spine.

For more information, visit

What began as a hypothesis nearly 20 years ago has become a promising new means of treating children with posterior fossa brain tumors. “Through this novel approach, we are endeavoring to give hope to families whose children have these horrible tumors, especially given current treatment options are inadequate,” says Dr. Sandberg. 

Through the collaboration of UTHealth Houston specialists like Dr. Sandberg, The University of Texas MD Anderson Cancer Center Children’s Cancer Hospital and Children’s Memorial Hermann Hospital, dramatic advances are being made in the treatment and survival of patients with these tumors.

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