Despites Advances, Treatment-Related Sequelae Remain Problematic in Pediatric Neuro-oncology

Get Permission

The management of pediatric brain and spinal cord tumors is extremely complex, as are the survivorship issues in this highly vulnerable patient population. To shed light on the current clinical reality in this setting, The ASCO Post recently spoke with Katherine E. Warren, MD, an internationally recognized expert in pediatric neuro-oncology. Her work focuses on rational, pharmacokinetic-based drug development for children with brain tumors, and she is a leading innovator in developing new means of drug delivery.

Katherine E. Warren, MD

Katherine E. Warren, MD

Dr. Warren is Director of the Pediatric Neuro-Oncology Department at the Dana-Farber Cancer Institute, Boston. Basically, her work is attempting to improve the status quo outcomes and outlooks for children with central nervous system (CNS) tumors. She hopes to do that by tying together results from her preclinical work and clinical trials and translating those combined efforts to children with CNS cancers.

Early Research at the NCI

Please talk a bit about your tenure at the National Cancer Institute and how that experience edified your current work at Boston Children’s Hospital.

I was at the NCI for more than 25 years, focusing on translating preclinical work, particularly relating to CNS pharmacology and pharmacokinetic studies in early clinical trials to develop new therapies. In the early 2000s, when we began to evaluate molecularly targeted agents in the clinic, we were essentially applying what was being used in adult oncology in the pediatric setting without understanding the underlying biology of the pediatric tumors. Between 2005 and 2010, we began doing a lot of molecular testing. At one point, we had a eureka moment, realizing CNS pediatric brain tumors were different from those in adults, which led us to begin investigating the biology behind them as a different subset than in the adult population.

The big issue came with temozolomide, which was approved by the U.S. Food and Drug Administration in adults with glioblastoma, combined with radiotherapy, followed by temozolomide alone. However, we did multiple studies using this approach in pediatric gliomas, and it had no activity at all. That was the first clue about the difference between adult and pediatric brain tumors.

The second clue was found in targeted molecular drugs, determining whether the target was even present; when we began to investigate that, we saw the same targets, for the most part, were not present in kids. So, this was a pivotal point in our understanding of pediatric CNS tumors, which has helped us chart a new and better way forward.

Clinical Crossroad

Please describe any advances that have led to more accurate diagnosis of the various subtypes of these heterogeneous tumors.

We are actually at a crossroad in this clinical issue. Most of our treatment paradigms are based on histology of tumors under a microscope. However, over the past few years, we have been getting some molecular information regarding the target. The question is, do we change our treatment based on this information, or do we wait until the patient’s tumor fails to respond to standard treatment based on histology and then initiate the molecularly targeted agent? This is the clinical conundrum we’re currently facing.

There are some tumor types, low-grade gliomas for instance, in which survival is fairly good, upward of 90%. However, there are a number of toxicities related to standard treatments. So, is this a group of patients we would want to start on targeted therapies to evaluate the potential success? Will the targeted therapies be as successful as standard care considering the toxicities involved, some of which we may not know the extent of for another 10 or 20 years? Everything we do is risk vs benefit. That can be pretty tricky, considering the speed at which new advances and agents are being developed.

“Realizing CNS pediatric brain tumors were different from those in adults led us to begin investigating the biology behind them as a different subset from that in adults.”
— Katherine E. Warren, MD

Tweet this quote

Beyond Survival Rates

Surveillance, Epidemiology, and End Results (SEER) data describe the survival of pediatric CNS tumors, including low-grade gliomas, at about 70%. Briefly, could you give the readers a sense of what that number actually means?

To begin, a survival rate of 70% comes at a price for those kids who do survive. Many survivors have long-term sequelae from the tumor or its treatment. Moreover, given the heterogeneity of pediatric CNS tumors, the majority of tumors are low-grade gliomas, which is where you see this 70% survival rate. However, kids with diffuse intrinsic pontine glioma and high-grade glioma have dismal survival numbers, less than 5%.

Once again, the key is the risk/benefit ratio. If you have a child with a tumor who is likely to survive, you want to treat that child with the least toxic therapy possible. However, for a child with little chance of survival, we need to treat it with all the big guns in our toolkit, moving the bar as far as possible.

Blood-Brain Barrier

Have there been practice-changing advances in medical oncology in this challenging setting?

In pediatric oncology, we have the added complication of the blood-brain barrier, which prevents about 95% of agents from reaching optimal concentration at the tumor site. So, many of the molecularly targeted agents and immunotherapies do not have demonstrable efficacy in this setting.

Moreover, when you have a tumor in the pediatric brain, the skull cannot adequately expand to deal with the inflammation commonly caused by immunotherapy. For that reason, immunotherapies in this setting are under strict clinical investigation. Although we may be able to “turn on” some of the immune responses, we have to be able to mediate the response if it goes out of control.

To bypass the blood-brain barrier, we are investigating techniques to deliver a therapy directly to the tumor site under slow, continuous pressure. However, there are still some issues with this novel approach. For instance, it may not reach the entire tumor, missing some cancer cells. This approach is under serious investigation, which we hope will give us a way to partner with more systemic therapy down the line.

The biggest advance in pediatric neuro-oncology has been the development of agents targeting BRAF-driven tumors. BRAF is a common mutation found in pilocytic astrocytoma and gliomas. BRAF inhibitors have demonstrated efficacy against these tumor types. That said, we’re still investigating these agents in this setting, and we don’t know the long-term effects they will have on patients. They are showing promise, however, which is a good thing.

Survivorship Issues

Please give our readers a sense of the survivorship issues faced in this vulnerable population.

Unfortunately, since our therapies are targeting a developing brain, many survivors in the pediatric population have lasting neurocognitive issues. Psychosocial issues, such as anxiety, are common among our patients, potentially leading to problems in school, later in the job market, and in their ability to live independently. There is a long list of sequelae attached to survivorship in this highly vulnerable patient population, but we are making progress.

Moving Forward

Please close with a bit about your current research and a thought on what gives you optimism moving forward.

I came to Dana-Farber because I feel the science and dedication to advancing the field of pediatric neuro-oncology are fantastic. The hard-won knowledge that pediatric brain tumors differ from those in the adult population was a groundbreaking step in our ability to treat these children.

We plan to open a diffuse intrinsic pontine glioma center, where we can more carefully evaluate our patients and offer them promising therapies throughout their disease course. My colleagues and I recently published a paper in Science Translational Medicine identifying more than 400 drugs that are active against diffuse intrinsic pontine glioma tumor cells in the laboratory.1 Now we need to optimize the dosing, concentration, and delivery. I am very optimistic our collaborative efforts will result in new therapies that will vastly improve the outcomes and quality of life for pediatric patients with CNS tumors.

DISCLOSURE: Dr. Warren has received research support from Celgene and serves on advisory committees for yMAbs and Oncoceutics.


1. Lin GL, Wilson KM, Ceribelli M, et al: Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening. Sci Transl Med 11(519), 2019.