MAPK Pathway-Guided Treatment for Pediatric Low-Grade Brainstem Glioma
Sameer Farouk Sait, MBBS, reviews the diagnosis and management of a pediatric patient with a focal low-grade brainstem glioma. He emphasizes the importance of distinguishing focal low-grade tumors from high-grade entities such as diffuse intrinsic pontine high-grade glioma (DIPG). Dr Sait also highlights the critical role of molecular profiling, particularly MAPK pathway alterations, including BRAF fusions and BRAF V600E mutations, in guiding therapy selection. The discussion underscores individualized, multidisciplinary strategies that balance effective tumor control with minimizing long-term morbidity and preserving neurocognitive outcomes.
Transcript:
My name is Sameer Farouk Sait and I'm a pediatric neuro-oncologist at Memorial Sloan Kettering Cancer Center in New York City. Today, I will be talking to you about pediatric low-grade glioma, in particular, focal brainstem glioma. Pediatric low-grade gliomas and glioneuronal tumors represent the most frequently encountered brain tumors and account for about one-third of pediatric CNS neoplasms overall. Pediatric low-grade gliomas are defined as either grade 1 or 2 as per the recent WHO classification and encompass a heterogeneous group of tumors of primarily glial histology, including astrocytic, oligodendroglial, as well as mixed neuronal and glial morphology.
Now, brainstem gliomas in particular, as outlined in the case above, account for approximately 13% of all intracranial tumors in children under the age of 14 years. And they have a very heterogeneous biological behavior. These can range from low-grade tumors needing very limited treatment, such as the case in question, to those that are rapidly fatal despite aggressive therapy. And making that distinction between tumors that are likely to behave in a more aggressive fashion and need more aggressive therapy or intensified therapy is very important because the prognosis and the treatment will depend upon all of these and the specific location of the tumor within the brainstem.
In children, the median age at diagnosis is roughly about 5 to 9 years, as was the patient in this case. And there's one known inheritable risk factor for low-grade brainstem gliomas as well as high-grade gliomas in the brainstem, which is neurofibromatosis type 1. So, you usually want to look for physical features of that, such as axillary café-au-lait spots, to rule that genetic predisposition out, because this can have implications not just for surveillance strategies but also for therapeutics that can be used.
Now, focal brainstem gliomas typically tend to arise in the midbrain and the medulla and they're typically discrete well-circumscribed tumors. Histologically under the microscope, they are often pilocytic or diffuse astrocytomas or rarely gangliogliomas, all of which are considered low-grade gliomas. And especially in tumors with a nonpilocytic histology, sometimes there may be more locally invasive growth. And in our patient in question, the focal brainstem glioma actually arises in the cerebella pontine angle. And this brings up important considerations because there was also very infiltrative appearance, as you can see on the MRI scans.
Up to 80% of the brain stem gliomas that occur in the midbrain and the medulla, which is outside the pons, are low grade and the remaining 20% are high grade. However, most of the pontine tumors and including the case here often turn out to be H3K27-altered diffuse midland gliomas. They're also referred to as diffuse intrinsic pontine gliomas. This is a tumor that's usually high grade locally infiltrative and associated with a very poor prognosis and biopsy. In fact, it is not even considered essential to diagnosis when there are typical clinical and imaging features.
However, patients, such as our patient in question who presented with a long prodrome of symptoms and atypical imaging findings, have an increased likelihood of a lesion other than a diffuse intrinsic pontine high-grade glioma (DIPG). And the two differentials that come into play are really in adolescent patients we have to consider that this could be an IDH-mutant brainstem glioma and in younger kids such as this one, if there are certain differences in the imaging or the clinical features, you have to rule out focal brainstem low-grade gliomas, which are driven often by BRAF, but other MAP kinase pathway genes as well.
It's very important to make this distinction because for DIPG, focal radiotherapy remains a standard approach and chemotherapy really has offered no survival benefit and therefore is not recommended in children with DIPG. On the contrary, the adolescents who have IDH-mutant brainstem gliomas will definitely benefit from chemotherapy such as temozolomide, which significantly improve survival for patients with IDH-mutant gliomas and further targeted therapy with the IDH inhibitor vorasidenib has recently demonstrated prolonged progression-free survival in patients with grade 2 IDH-mutant gliomas.
But I think most importantly as is in this case, the prognosis for patients with focal brainstem gliomas that are MAP kinase pathway driven are actually excellent. The overall survival is close to 100%. There have been several advances in the molecular analysis of pediatric low-grade gliomas, including those of the brainstem. And these have identified frequent recurring alterations in the MAP kinase pathway, including characteristic duplications involving the BRAF gene such as the one encountered here in our patient's case, the KIAA1549-BRAF fusion, and less commonly but also importantly the BRAF V600E mutation. So molecular profiling therefore provides very important diagnostic, prognostic, and therapeutic information and therefore should be pursued in all cases.
The signs and symptoms that we see in patients generally reflect the location of the tumor, the presence of hydrocephalus, and/or the age of the child. So, our patient initially presented with some facial nerve involvement as well as signs and symptoms of hydrocephalus. Later, when the patient had a recurrence several years after the initial treatment. And they can often have symptoms related to hydrocephalus such as headaches, vomiting, ataxia, including the cranial nerve deficits. The treatment approach to a child with a focal brainstem glioma requires careful consideration of the anatomical location of the tumor, which actually drives the symptoms that the patient is experiencing as well as is accessibility to surgical resection.
And it's important to remember that the long-term prognosis for patients with brainstem low-grade gliomas, just like with other pediatric types of low-grade gliomas, is excellent. And so your therapy or the focus of your management is often minimizing morbidity while maintaining that excellent survival. Optimal treatment requires a dedicated team of neurosurgeons, radiation oncologists and neuro-oncologists, as well as neuropsychologists, social workers, and occupational and physical therapists. Both surgery and radiation as well as chemotherapy play a role in the management of patients with these brainstem gliomas.
Historically, the location of brainstem gliomas was always considered to preclude surgery because it's one of the eloquent areas of the CNS and most patients will often only end up with a biopsy. That was the case for our patient in question as well where surgical resection was not deemed feasible and a stereotactic biopsy led to the diagnosis. Approximately 30% of resected tumors will progress and require further therapy and sometimes the second operation can be considered if they have surgically accessible disease. But otherwise, the most reasonable option for adjuvant therapy in these patients is chemotherapy.
And that's what led to us using chemotherapy in the first-line setting for this patient. This patient was treated with a combination of carboplatin and vincristine per the COG protocol and this is a very widely used chemotherapy regimen for children. There's also data to show that single-agent carboplatin monotherapy is equally effective in these patients and is often used in many centers. With regard to radiation therapy, this can provide a significant prolongation of the progression-free survival and good tumor control, but can also be associated with significant morbidity, especially in very young children. And these long-term effects can include neurocognitive issues, endocrinopathies and vascular issues leading to strokes as well as secondary treatment malignancies. Radiation really is limited to older children and adults, particularly when they've had multiple recurrences in order to minimize late morbidity. And as I alluded to earlier, chemotherapy really is playing an increasing role in the management of these children in order to delay using radiation therapy.
And then finally we have to talk about molecular targeted therapies. These are agents that target specific molecular signaling pathways that are driving the growth of pediatric low-grade gliomas. And a number of these agents are already approved for use. So the examples that are relevant to all pediatric low-grade gliomas, including brainstem gliomas, are the combination of trametinib and dabrafenib. Trametinib is a MEK inhibitor and dabrafenib is a first-generation RAF inhibitor.
It's important to understand what a first-generation RAF inhibitor is, which actually inhibits BRAF monomers. This drug combination is approved for using in children 1 year of age and older who have BRAF V600E-mutant low-grade gliomas who require systemic therapy. And this approval was based on published data from a phase 3 randomized controlled trial. And more recently, tovorafenib, a type 2 RAF inhibitor, is also FDA approved for patients 6 months of age and older with a relapsed or refractory pediatric low-grade glioma harboring either a BRAF V600E mutation or BRAF fusion, based on the results of a single-arm phase 2 trial.
It's important to understand some of the differences between these drugs. So dabrafenib, as I referred to earlier, is a first-generation RAF inhibitor that blocks BRAF monomers. However, tovorafenib actually is a type 2 RAF inhibitor that blocks BRAF dimers in addition to the monomers. And this is important because the tumors that are driven by BRAF V600E mutations are actually driven by BRAF monomers, and therefore dabrafenib actually is the treatment of choice for patients with BRAF V600E mutations. Whereas the patients who have BRAF fusions have signaling that's driven by BRAF dimer formation and they're actually insensitive or refractory to agents such as dabrafenib, which in fact can even cause paradoxical activation and accelerate tumor growth when used in patients with BRAF fusions.
So therefore, it's very important to molecularly characterize these patients and understand that there are important differences between patients who have BRAF V600E mutations and those who have BRAF fusions, which will guide the appropriate choice of therapy and therefore, for our patient in question where the tumor is driven by a BRAF fusion, the combination of dabrafenib and trametinib would be the least favored approach here because dabrafenib, like I explained before, is a first-generation RAF inhibitor that really blocks RAF monomers but leaves the dimers intact and can actually increase signaling through that pathway because of paradoxical activation.
Another important consideration that impacts the treatment of children with low-grade glioma is that because as I explained before, the overall survival is excellent nearing close to a hundred percent. In these brainstem patients, the therapy is really only indicated in the event of a subtotally resected tumor and when there's significant morbidity associated with the tumor. And the treatment goal is really not just long-term tumor control, but also to minimize treatment-related morbidity. And most pediatric low-grade gliomas have alterations in the BRAF pathway and other components of the MAP kinase pathway, but all of these can trigger cellular senescence and this phenomenon is termed oncogene induced senescence and accounts for the relatively benign behavior of low-grade gliomas such that the natural history is that most of these tumors senesce or stop growing or plateau in terms of their growth trajectory after puberty is completed and therefore they may not continue to need treatment once a child has completed their growth spurt. And therefore, in patients such as this one where we are sort of getting closer to that time point where a patient we believe may be approaching this oncogenic senescence in their tumor, watchful waiting in the absence of obvious symptomatic progression would also be a reasonable option.
In summary, treatment strategies for patients with focal brainstem gliomas must be individualized and consider physical genetic and cognitive factors. For example, some patients may have neurofibromatosis type 1, a genetic predisposition syndrome and treatment could be deferred in these patients if the tumor progression is limited and the patient is asymptomatic and for most other patients incomplete receptor lesions will recur. So, treatment should probably not be deferred. Additionally, mounting evidence suggests that multidisciplinary evaluation of CNS tumor survivors is important in addition to the physical and medical issues associated with therapy.
Attention has to be paid to cognition and even patients getting surgery for a low-grade brainstem glioma can have significant functional impairments. All patients should be considered at risk. And to deal with these issues, you do need a team of psychologists and neuropsychologists and school liaison specialists as well. And since childhood is a fluid period of attainment of different abilities, there needs to be a sort of dynamic monitoring of all of these functional domains for these patients to ensure that they have continued attainment of future milestones at appropriate ages.
