Ependymoma

Disclaimer

The information provided in this review is intended for general informational purposes only. It is not intended to be a substitute for professional medical advice, diagnosis, or treatment.

Always seek the advice of your physician or other qualified healthcare provider with any questions you may have regarding a medical condition. Feel free to share this information page with them.

Overview

In this paper, we aim to communicate and share the insights garnered from MyChild’sCancer’s second opinion program (www.MyChildsCancer.org/our-services). 

Through this program, we at MyChild’sCancer harness the expertise of a global network of specialists to offer second opinions for children with cancer facing complex circumstances.

We are a non-profit organization and our services are offered at no cost to you and to the families we support. 

Our objective in this paper is to share the knowledge compiled from world-renowned experts’ opinions on individual cases, to equip parents and doctors worldwide with information and tools to take proactive steps in managing the child’s condition and ideally improve treatment outcomes. 

We start with the basic info, moving into biology and treatment options, and we end with insights from real cases discussed by lead experts. 

This review was prepared by Christina Katanov, a family coordinator at MyChild’sCancer, and was approved by the experts mentioned in it.

Last reviewed on 10/2024

Childhood Cancer Name:

Ependymoma

What is Ependymoma?

Ependymoma is a primary tumor, which means that it starts in either the brain or spine. The brain and spine are part of the central nervous system (CNS).

Ependymomas arise from the cells lining the ventricles (the fluid containing spaces within the brain) and central canal within the spinal cord.

Characteristics:

Ependymomas are relatively rare tumors, accounting for 2–3% of all primary brain tumors. About 30% of pediatric ependymomas are diagnosed in children younger than three years of age. It is the third most common type of childhood brain tumor. The cause is unknown.

Biology:

The most common types of cells in the central nervous system are neurons and glial cells. Tumors from neurons are rare. Glial cells are the cells that support the brain. Tumors that occur from these cells are called gliomas. Glial cell subtypes of the CNS include Astrocytes, Oligodendrocytes and Ependymal cells.

Main types of Ependymoma:

There are different subtypes and grades.

• Myxopapillary ependymomas (grade I): Typically, slow-growing tumors in the spinal cord.
• Ependymomas (grade II): The most common of the ependymal tumors. This type can be further divided into the following subtypes, including cellular ependymomas, papillary ependymomas, clear cell ependymomas, and tancytic ependymomas.
• Anaplastic ependymomas (grade III): grows more rapidly and is more likely to spread to other parts of the brain and spine.

Most children have grade II or III variants of ependymoma in the brain. However, there is no significant behavioral difference between grade II and III tumors. The risk of tumor relapse or progression following standard treatments is influenced by clinical and biological factors, including histopathological and molecular characteristics.

Childhood Cancer Localization:

Brain, spine.

Ependymomas in children usually appear in the brain, most commonly in the fourth ventricle or back part of the brain. Within this region, there are two subtypes: PFA (Posterior Fossa A) and PFB (Posterior Fossa B). 

• PFA ependymomas often seen in younger children, typically characterized by aggressive behavior and loss of H3K27me3 staining.
• In contrast, PFB ependymomas generally exhibiting a more indolent behavior, and are often found in older patients.

Common Mutations in Ependymoma

Several genetic mutations and molecular alterations are associated with ependymomas. Some of the common mutations include:

• ZFTA-RELA Fusion: This is a hallmark of supratentorial ependymomas in children and young adults. The fusion of these genes leads to the activation of the NF-κB signaling pathway, promoting tumor growth.
• YAP1 Fusion: Another fusion gene identified in a subset of supratentorial ependymomas, particularly in infants and young children.
• Chromosome 1q Gain: Commonly seen in various types of ependymomas, this genetic alteration is associated with a poorer prognosis.
• NF2 Mutation: Associated with spinal ependymomas and sometimes with intracranial ependymomas, particularly in adults.
• 6q Loss: Loss of genetic material on the long arm of chromosome 6 is another alteration observed in posterior fossa ependymoma (PFA). This genetic loss has been linked to poorer outcomes and may contribute to tumorigenesis by affecting tumor suppressor genes located in this region.

Childhood Cancer Noticeable Symptoms

Ependymomas appear in different locations within the brain and spinal column; symptoms depend on the location and size of the tumor. The biology may also be different based on the location.

• In babies, increased head size may be one of the first symptoms. Irritability, sleeplessness, unsteady gait (walking) and vomiting may develop as the tumor grows.
• In older children and adults, nausea, vomiting, and headache (mostly in the morning) are the most common symptoms.

Childhood Cancer Diagnostic method

CT scan (computed tomography), MRI (magnetic resonance imaging), biopsy, Lumbar puncture.

• CT scan or MRI is used in the initial evaluation of children suspected of having a tumor in the brain.
• Biopsy or surgical removal of tumor tissue for microscopic evaluation is necessary to make a definitive diagnosis.
• Evaluation of cerebrospinal fluid may be performed after surgery to detect tumor spread through the cerebrospinal fluid.
• A spine MRI is generally done, ideally prior to surgery if possible.

Childhood Cancer Treatment

Surgery, radiation therapy (traditional and proton beam) & chemotherapy.

Surgery

• Surgery is the most important step of the treatment.  Surgery is the initial standard treatment for ependymoma, the neurosurgeon will attempt to remove as much of the tumor as possible without causing damage to the normal brain. The role of surgery is critical in ependymoma, and clinical trials have shown a 40-50% difference in survival between children with complete and incomplete resection. For this reason, when a first resection is incomplete, the recommendation is to consider a second (and sometime a third) intervention to remove the residual tumor. 
• External beam radiation 
• Conformal beam radiation therapy is a type of external beam radiation that contours the radiation beams to the shape of the tumor.

It’s important to note that a complete removal of the tumor is sometimes not possible because of the tumor location and concerns about damaging the surrounding normal brain tissue. The expertise of the neurosurgeons is critical in this context. 

Chemotherapy

• The role of chemotherapy in treating ependymomas remains unclear. A recent trial by the Children’s Oncology Group found no benefit of chemotherapy in children with ependymoma, and a similar trial is ongoing in Europe. While chemotherapy is still used in some centers, there is limited evidence that it improves survival. It is primarily reserved for patients with residual tumors after surgery to aid in a second operation.

Radiation therapy

• Radiation therapy is beneficial and is the standard of care after surgery for ependymomas, with greater effectiveness following complete tumor resection. In cases of incomplete resection, the benefits are less clear, and most children experience tumor progression eventually. Radiotherapy is also an option during relapse, with re-irradiation becoming common for recurrent ependymomas. Advances in techniques now allow radiotherapy for children as young as 12 months. For non-metastatic disease, local radiotherapy is standard in first-line treatment (as opposed to craniospinal irradiation). To minimize side effects to surrounding tissue, conformal techniques like stereotactic radiotherapy and IMRT are recommended, with proton therapy being the preferred choice for children.
• For tumors that have metastasized throughout the brain and spine, craniospinal irradiation is recommended. The role of chemotherapy in this context remains uncertain.
• High-dose chemotherapy with autologous stem cell rescue has not shown any benefit in newly diagnosed or recurrent ependymoma. 

Biopsy

• In some instances, depending on the tumor type, if a tumor cannot be safely resected and can be accurately diagnosed through imaging alone, a biopsy may not provide any benefit for the treatment plan. Nevertheless, surgical resection remains the standard of care for children with ependymoma

Late effects of the treatment

Some treatments, while increasing survival, may have significant side effects on children. Prior to treatment, your child may undergo neuropsychological testing.

Follow up, late effects

MRI scans of the brain and/or spinal cord are usually done every three to four months for the first two years following diagnosis.

The main goals include

Preserve patient´s life.

Parents’ tips - From Parents of Children with Ependymoma

• As parents, the best advice we can give to others with children battling Ependymoma is to discard all expectations you might have of your child, appreciate your child for who they are, take nothing for granted, and take heart from small victories. – Shannon (Ethan’s Dad), Grade II Ependymoma, 1.5 years old (2012) https://www.cern-foundation.org/awareness/story/making-the-most-of-every-day-with-ethan
• Cancer does not only affect the patient’s life but every single person in the child’s life. The brothers and sisters have to learn to live with part-time parents in and out of their lives as they arrange and re-arrange their schedules to keep up with everything. The siblings have to learn how to live without their brother or sister when they do go. – Kimberly (Ryan’s Mom), Ependymoma, Dx at the age of 4 (2007).
• You need to find out if the medical center where your child is diagnosed is an appropriate place for his or her treatment. The care of children with brain tumors requires multiple types of specialists (including neurosurgeons, oncologists, radiation oncologists, endocrinologists and many others).
• Do not hesitate to ask how many pediatric brain tumor patients they treat each year. Generally speaking, those that have the highest volume of childhood brain tumor patients also have greater knowledge of the disease, treatment options, and clinical trials.

Experts

• Find a center: http://www.cern-foundation.org/referrals
• For Stereotactic radiosurgery, Johns Hopkins Comprehensive Subependymoma and Ependymoma Research center: http://www.hopkinsmedicine.org/neurology_neurosurgery/research/labs/subependymoma_ependymoma_research/
• St. Jude is the only pediatric cancer research center that does not charge its patients´ families for treatment that is not covered by insurance. Thus, St. Jude has never refused to treat a child because of the family’s inability to pay.

Testimonial

N/A at the moment

Hospitals/ Treatment Centers:

• St. Jude Children´s Research Hospital: https://www.stjude.org/disease/ependymoma.html
• American Brain Tumor Association: http://www.abta.org/brain-tumor-information/types-of-tumors/ependymoma.html?referrer=https://www.google.co.il/
• Johns Hopkins medicine: https://www.hopkinsmedicine.org/neurology_neurosurgery/research/labs/subependymoma_ependymoma_research/subependymoma_ependymoma.html

Links for more info

• St. Jude Children´s Research Hospital: https://www.stjude.org/disease/ependymoma.html
• American Brain Tumor Association: http://www.abta.org/brain-tumor-information/types-of-tumors/ependymoma.html?referrer=https://www.google.co.il/
• Answers to Questions You May Have When Your Child Is Diagnosed With a Brain Tumor http://www.curethekids.org/assets/documents/family-support/answers_web.pdf
• Ependymoma Guide, Collaborative Ependymoma Research Network: http://www.cern-foundation.org/uploads/docs/Ependymoma_Guide_2.pdf
• EpendyFamilies is a support group of families with a children whohas been diagnosed with ependymoma: https://www.facebook.com/groups/ependyparents/
• Fighting Ependymoma: http://www.fightingependymoma.org.uk/index.php/how-to-help
• The Childhood Brain Tumor Foundation http://www.childhoodbraintumor.org/medical-information/brain-tumor-types-and-imaging/item/84-ependymomas

Reseacrh

To understand how brain tumors develop in children and identify personalized treatment strategies visit ‘The Pacific Pediatric Neuro-Oncology Consortium (PNOC)’-  http://www.pnoc.us/about 

Experts’ opinion on management of patients with recurrent ependymoma:

In this section, we aim to communicate and share the insights gathered from MyChild’sCancer’s second opinion program (MyChildsCancer Services), where our goal is to find the best expert and treatment for each child’s unique circumstances.

The information below was given in specific and individual cases and does not serve as a treatment recommendation. In these cases, we have consulted with the following experts, who also approved this content:

Prof. Eric Bouffet, Professor of Pediatrics, Division of Hematology/Oncology, The Hospital for Sick Children, Toronto Canada.

Prof. Stefan Rutkowski, Professor for Pediatric Hematology and Oncology, Director of Department of Pediatric Hematology and Oncology at UKE, Hamburg, Germany.

Disclaimer

The information provided in this review is intended for general informational purposes only. It is not intended to be a substitute for professional medical advice, diagnosis, or treatment. 

Always seek the advice of your physician or other qualified healthcare provider with any questions you may have regarding a medical condition. Feel free to share this information page with them.

The inclusion of clinical trials in this review does not imply endorsement or recommendation by MyChild’sCancer. The decision to participate in a clinical trial should be made in consultation with your healthcare provider and after carefully considering the risks and potential benefits associated with the trial.

Local relapse management:

Based on data from St Jude and Toronto, it is now clear that, if feasible with acceptable risks, the optimal option for patients with recurrent ependymoma who experience a local relapse is the resection of the recurrent tumor followed by local radiotherapy. If patients had received radiotherapy during first-line treatment, the feasibility and dose-volume concepts of re-irradiation must be clarified individually, in accordance with the first radiotherapy plan and the MRI-images at relapse.

Some studies have looked at the impact of biological prognostic parameters, e.g. 1q gain in posterior fossa ependymoma, that has been identified as a marker of poor outcome more than 10 years ago. The evidence that 6q loss is a marker of poor prognosis is more recent, this has been described in 2021. In a report from Toronto, patients with ependymoma associated with 6q loss were divided in 2 groups: 1q gain+6q loss versus 1q balanced and 6q loss. Both groups seem to behave poorly, with early relapses. In the context of isolated 6q loss, most relapses are local (Baroni et al., Neuro-Oncology 2021).

Experience from SickKids Toronto and St. Jude Memphis indicates that patients with recurrent ependymoma have better outcomes when receiving craniospinal irradiation (CSI), while others still prefer to use local radiotherapy at relapse. It is crucial to note that once radiotherapy has been administered twice to the local site, craniospinal irradiation cannot be offered in the event of a new recurrence.

Distant relapse management:

If feasible, one option for treatment of distant relapses of ependymoma is craniospinal irradiation (CSI). Local treatment of these distant relapses tends to lead to new relapses in other parts of the brain or spine. The St. Jude experience showed that all patients with distant relapses who received CSI had improved outcomes, with 17 out of 31 patients being long-term survivors​ (Tsang et al., Neuro-Oncology 2019). However, some groups prefer to give local conformal radiotherapy to the primary tumor and to metastases (without CSI), if the number and size of the metastatic lesions allows for this. Thus, the modalities of Irradiation should be decided individually, based on the specific constellation.

The consequences of CSI in young children:

• Effect on growth and other endocrine deficits due to the radiotherapy to the spine and the pituitary gland.
• Cognitive side effects with an impact on learning.

Additional treatment options (examples):

Metformin:

Recent laboratory data have shown that metformin, an antidiabetic medication, increases trimethylation and suppresses tumor growth in posterior fossa ependymoma cells (PFA), which typically lose this modification. Metformin, known for its minimal side effects, has demonstrated therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Following a 2021 publication (Panwalkar et al., Science Translational Medicine 2021) many patients have been treated with metformin, although no formal clinical trial has confirmed its activity. Discussions with colleagues worldwide reveal that metformin is being used either alone or in combination with oral etoposide.

Optune:

Optune, is a device that delivers Tumor Treating Fields (TTF) to the tumor. Although experience in children is still limited, ependymoma is included in the PBTC-048 clinical trial. Preclinical work with TTF has shown some activity against ependymoma (Makimoto et al., Neurology International 2021). Treatment with Optune requires a significant commitment, as patients need to wear the device for at least 18 hours per day and must keep their heads shaved​.

Review of options currently in clinical trials.

Important: these options require the patient to show progression. 

1. CAR-T Cell (PBTC-059)
2. Omburtamab, which is a monoclonal antibody that carries radioactive iodine and delivers radiotherapy to the tumor (PBTC-058 – this trial is currently closed due to temporary discontinuation in the production on omburtamab).
3. 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. This trial is open in Houston, Texas and is based on the expression of HER2 on the surface of ependymoma cells. However, not data are currently available regarding efficacy.
4. Infusion of 5-Azacytidine (5-AZA) Into the Fourth Ventricle or Resection Cavity in Children and Adults with Recurrent Posterior Fossa Ependymoma: A Phase I Study. This is an early phase trial as well without any efficacy data.
5. Pilot Study of the Effect of Trastuzumab and GM-CSF on Children with Recurrent Ependymoma. Same comment.
6. Pediatric Trial of Indoximod with Chemotherapy and Radiation for Children with Progressive Brain Tumors or Newly Diagnosed DIPG. Dr Ted Johnson (Johnson, Theodore THJOHNSON@augusta.edu) is very approachable and passionate about indoximob. However, the efficacy of Indoximob remains to be proven.
7. PNOC023: Open Label Phase 1 and Target Validation Study of ONC206 in Children and Young Adults with Newly Diagnosed or Recurrent Diffuse Midline Glioma (DMG), and Other Recurrent Primary Malignant Central Nervous System (CNS) Tumors. This trial is open in Zurich. ONC206 is at a very early stage of development and there are no data currently suggestion activity in ependymomas.
8. Everolimus: Data from the German HIT-REZ study group collected outside of a clinical trial suggests some activity for the use of everolimus in relapsed ependymoma. Data suggested that monotherapy may be more effective than use in combination with other drugs (Adolph JE et al, Journal of Neuro-Oncology 2021).