Intra-Arterial Drug Delivery: A Promising Approach for Inoperable Pediatric Brain Tumors
“Treatment options for pediatric brain tumors can be more nuanced than in adults. Treatment side effects and toxicity of delivery drugs to developing brains are further complicated by the vast complexity of tumors we see in this age group when compared with adults,” says Jeffrey P. Greenfield, MD, PhD, a pediatric neurosurgeon at NewYork-Presbyterian/Weill Cornell Medical Center and Co-Director of the Children’s Brain Tumor Project at Weill Cornell Medicine. This groundbreaking research initiative was launched a decade ago by Dr. Greenfield and Mark M. Souweidane, MD, Director, of Pediatric Neurosurgery at NewYork-Presbyterian/Weill Cornell.
“When discussing adult brain tumors as a distinction, there are only a few types of tumors that we generally refer to,” continues Dr. Greenfield. “In the pediatric landscape, however, there are literally 30 or 40 and some say as high as 70 or 80 different subtypes. The vast majority of children with these brain tumors have not seen a significant change in our ability to treat them effectively. There are a handful of dramatic success stories, but there are still some pediatric brain tumors that literally have a zero percent survival rate.”
Designing new routes of administration for targeted agents, antibodies, or classic chemotherapies to inoperable brain tumors is central to the mission of the Children’s Brain Tumor Project. “Delivery of drugs directly to brain tumors using arteries as conduits has been demonstrated in adults, but the delivery method had not previously been tested in children with high-grade pediatric brain tumors, including high-grade glioma and DIPG,” says Dr. Greenfield. “This is a precise surgical approach to deliver chemotherapy drugs by threading delicate microcatheters to specific areas of the brain to increase drug concentration at the tumor site while reducing the potential for systemic side effects.”
To determine the safety and efficacy of this method in the pediatric population, Dr. Greenfield initiated a first-in-kind clinical trial with his colleagues at NewYork-Presbyterian/Weill Cornell, including Jared Knopman, MD, Director of Cerebrovascular Surgery and Interventional Neuroradiology, and Y. Pierre Gobin, MD, an internationally recognized interventional neuroradiologist who described the safety and efficacy of intra-arterial delivery of chemotherapy for retinoblastoma 20 years ago. Heather McCrea, MD, PhD, a pediatric neurosurgeon at Nicklaus Children’s Hospital in Miami, was also a key member of the research team having worked on the concept phase of the trial with Dr. Greenfield during her residency at New York-Presbyterian/Weill Cornell several years earlier.
Ten patients with diffuse intrinsic pontine glioma (DIPG) and three patients with high-grade glioma were treated in the trial, which focused on delivering a combination of drugs, bevacizumab and cetuximab, through local arteries that directly feed a brain tumor – mirroring Dr. Gobin’s approach used for eye cancer in children. Prior to receiving the drugs to treat the tumor, the 13 patients were also given a dose of mannitol to open the blood-brain barrier and allow for the bevacizumab and cetuximab to better penetrate the tumor.
The findings of the phase 1 trial, published in the August 2021 issue of Journal of Neurosurgery: Pediatrics, show intra-arterial delivery to be safe in pediatric patients with no severe side effects. All patients underwent MRI on post procedure day 1 to rule out stroke or hemorrhage. No patients demonstrated these complications. Two patients experienced grade 1 epistaxis and two patients had a grade 1 rash. Additionally:
- 6 of the 10 symptomatic patients exhibited subjective improvement
- 92 percent showed decreased enhancement on MRI day 1 post treatment
- 5 of 10 patients who underwent MRI at 1 month had progressive disease and 5 had stable disease on FLAIR, whereas contrast-enhanced scans demonstrated progressive disease in 4 patients, stable disease in 2 patients, partial response in 2 patients, and complete response in 1 patient
- Mean overall survival for the 10 DIPG patients was 519 days (17.3 months), with a mean post-treatment survival of 214.8 days (7.2 months)
“With the increase in the average survival time for children with DIPG to 17.3 months compared with less than one year that is typical for this terminal disease, Weill Cornell Medicine recently approved expansion into a multicenter trial.” — Dr. Jeffrey Greenfield
The research team is now conducting repeat monthly dosing to evaluate whether additional doses allow for better control of the disease. The extended clinical trial (NCT01884740) is available for enrollment of patients with relapsed/refractory glioma under the age of 22 at Weill Cornell Medicine for repeat dosing and patients will soon be able to enroll at the University of Miami/Jackson Health System as well.
“Depending on the characteristics of the tumor, intra-arterial delivery is a promising approach to treating certain brain tumors, as are other approaches such as convection-enhanced delivery,” adds Dr. Greenfield. “These strategies allow for direct drug delivery to the tumor, effectively bypassing the blood-brain barrier and reducing the systemic toxicity that is experienced with standard intravenous chemotherapy. The safety of this delivery method will also allow for investigation of additional agents through this method in the future targeted specifically to drugs determined by tumor profiling/precision medicine approaches.”
Intra-arterial delivery of bevacizumab and cetuximab utilizing blood-brain barrier disruption in children with high-grade glioma and diffuse intrinsic pontine glioma: Results of a phase I trial. McCrea HJ, Ivanidze J, O'Connor A, Hersh EH, Boockvar JA, Gobin YP, Knopman J, Greenfield JP. Journal of Neurosurgery: Pediatrics. 2021 Aug 6;28(4):371-379.
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