Your child has cancer. These are words every parent dreads. Perhaps no type of cancer strikes more fear than brain cancer.
Pediatric brain cancer is the leading cause of cancer-related deaths in children, according to the National Brain Tumor Society. For a diagnosis of a diffuse intrinsic pontine glioma (DIPG), most often seen in children under age 10, experts put the 5-year survival rate at around 2 percent (DIPG statistics. https://dipg.org/dipg-stats). The average survival for this rare cancer is under 1 year.
“These tumors behave in a horrible fashion,” summed up Mark Souweidane, MD, Director of Pediatric Neurological Surgery at Weill Cornell Brain and Spine Tumor Center in New York City.
The location of the DIPG makes it especially dangerous, even when compared against other gliomas. Carl Koschmann, MD, a pediatric oncologist at University of Michigan's C.S. Mott's Children's Hospital in Ann Arbor, explained, “The tumor is enmeshed fully with functioning brain stem. We can't resect just the tumor; it would always come with some brain.” More specifically, a DIPG is interwoven into the pons, the vital section of the brain stem that controls breathing. Surgical removal of the entire tumor is impossible.
Oncologists diagnose DIPG through MRI. They were not able to study the tumor tissue, which prevented an examination of the tumor's epigenetic changes. Until recently, a biopsy of the tumor tissue for in-depth analysis was controversial.
A select group of pediatric neurosurgeons are using intraoperative MRI to guide them through the precarious procedure of excising brain tissue for biopsy. Pediatric oncologists use the data collected from sequencing both the tumor and the young patient's healthy tissue to develop personalized treatment recommendations. They are bringing a small glimmer of hope to those diagnosed with this fatal cancer.
Real-Time Tumor Views
Intraoperative MRI gives surgeons a real-time visualization of the brain and their progress during surgery. To accomplish this, there must be both an MRI machine specially designed for use in the operating room, and an operating room specially outfitted to accommodate the machine. Guided by the images, neurosurgeons can safely and precisely remove the targeted tissue via a 2 mm needle biopsy. The power of the machine is the same as in diagnostic imaging, offering anatomically strong images (The Surgical Benefits of Intraoperative MRI Johns Hopkins Medicine Podcasts).
Koschmann believes the minimum standard of care for children diagnosed with a DIPG should be a consultation with a neurosurgeon who has performed brain stem biopsy. Parents might be more willing to consider biopsy if they speak to someone who has experience with the procedure.
“Most of the work is centered on surgical planning,” Souweidane explained. “What is the safe route into the tumor?” Neurosurgeons are concerned over the insertion site and the path of the catheter. Using intraoperative MRI allows for critical preservation of normal tissue. They interpret the MRI readings to take the tumor samples when the patient is under general anesthesia. The MRI enhances the surgeons' ability to resect tissue that will be usable for sequencing.
At the University of Michigan, among other facilities with this technology, the MRI machine is mounted onto ceiling rails and moved into the operating room when needed. Crucially, the surgical site remains sterile and the patient does not move.
A biopsy of the DIPG is not without risks. The patient can bleed into the tumor and create swelling that affects breathing and causes them to need a ventilator. Stroke is another risk, as is the small, but present risk of death. “The risk of the biopsy has decreased as more and more surgeons become comfortable with the procedure,” Koschmann noted.
It is still vital that neurosurgeons have conversations with the patients' families before the procedures. “We counsel families that biopsies are considered a research procedure,” explained Rajen Mody, MBBS, a pediatric oncologist at University of Michigan's C.S. Mott's Children's Hospital. Biopsy will guide oncologists toward appropriate therapies.
Genetically Customized Therapies
“Each patient's cancer is a fingerprint of genes that have been mutated,” stated Koschmann. Researchers sequence both the DIPG tissue and the child's healthy tissue for DNA and RNA, and apply the results to radiation, currently the standard of care.
“As soon as we have genetic information, we change their treatment,” Mody noted. Radiation therapy can be customized for the tumor's unique makeup. Radiation, though, is simply a way to ease the child's symptoms. It is not a cure. Currently, there is no cure for DIPG.
Biopsy is an important step in the long journey toward better treatment for these patients. A DIPG biopsy shows oncologists if a particular patient is eligible for any clinical trials or alternate therapies, based on the tumor's mutations. Biopsy and tumor sequencing are required to enroll in a clinical trial. The potential benefits to the child outweigh the risks of the procedure. Koschmann recalled a DIPG patient whose tumor was driven by a mutation more commonly seen in leukemia. He worked with precision medicine and pharmacology to find a drug traditionally prescribed for leukemia with a reasonable chance of crossing the blood-brain barrier.
Searching for Applicable Drugs
There is a need to put the data collected from the biopsies into research for new treatments. “We need to develop drugs that penetrate blood-brain barrier in a form a little child will take,” noted Mody.
The information gathered from biopsy and the sequencing of the tumor has the potential to benefit more than that individual patient.
“There becomes a fine line between what is patient-specific and what is holistic. Researchers are trying to further the field of drug discovery,” Souweidane remarked.
There are researchers studying how to deliver chemotherapeutic agents and studying immunotherapy. Global collaboration and sharing genetic data are crucial. Michigan Medicine researchers are working with colleagues around the globe. “We need to develop therapies simultaneously,” Mody said. “We're trying to move mountains here.”
Some researchers, including Souweidane, recently published promising study results of convection-enhanced delivery for DIPG. Systemically delivered chemo has worked well in pediatric stomach cancer and some nervous system cancers. They wanted to apply the method to these tumors.
They tested the feasibility, safety, and proof of principle of their concept. Chemotherapeutic agents were directly administered into the brain stem tumors through surgically inserted infusion cannulas. This method would let doctors increase the amount of drugs delivered. It would avoid the systemwide toxicity that comes from traditional chemotherapy methods, which have universally failed (Lancet Oncol 2018; https://doi.org/10.1016/S1470-2045(18)30322-X). Their study opens the door to re-explore such agents. “With tightly structured parameters, it can be done safely,” Souweidane concluded.
Families Lead the Charge
Mody and Koschmann's work in this area is part of the Chad Carr Pediatric Brain Tumor Center at the University of Michigan, named for a 5-year-old who lost his battle with DIPG. They expressed gratitude to the Carr family for funding research into this and other brain cancers.
Credit is due to the foundations, grassroots organizations, and families who push this research forward and raise money, Souweidane acknowledged. “It's such a rare tumor, there had been very little attention and financial intervention. The drive of patients' families and various organizations has helped investigators get to the table. DIPG is now front and center at pediatric neurology meetings, having caught the attention of researchers. “That's a huge success story,” Souweidane noted.
“We've made as much progress in the last 2-3 years as we have in the past 30 years,” Mody remarked.
Danielle Love is a contributing writer.