Primary brain tumors are the second most common cancers seen in pediatrics, affecting approximately 4,500 children per year. According to Neha Patel, MD, pediatric neurooncologist in the Department of Pediatric Hematology/Oncology at Cleveland Clinic Children’s, clinical outcomes for children with brain tumors have remained inferior to other pediatric cancers. Not all children with brain tumors are cured, and many survivors of brain tumors face life-long health issues. These inferior outcomes are related to the clinical behaviors of tumors and variations in response of tumors to standard therapeutic approaches. This is true even with tumors that are morphologically and radiologically similar, says Dr. Patel.
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Adult versus pediatric brain tumors
Brain tumors differ greatly between childhood and adulthood in terms of their types, biology, location, symptoms and treatment. In adults, the most common tumors that occur in the brain are metastatic cancers that originate from the skin, lungs, breast or gut. In contrast, in pediatrics, tumors from the body rarely metastasize to the brain; the majority of brain tumors in children arise directly from brain cells.
Low-grade gliomas are the most common primary brain tumors seen in pediatrics, while high-grade gliomas and meningiomas comprise the majority of adult primary brain tumors. Meningiomas are extremely rare in children. Conversely, embryonal tumors, such as medulloblastomas, are more frequently seen in children but rarely in adults.
Another key difference between adults and children is that morphologically similar tumors are significantly different in their molecular aberrations, clinical behavior and response to treatments. For instance, a low-grade glioma in a child is less likely to transform into a malignant high-grade glioma, while the reverse is true in adults, she says. In addition, childhood tumors tend to be more treatment-responsive than their adult counterparts.
Brain tumors in adolescents (14 to18 years old) and young adults (<40 years age) represent a unique category. Dr. Patel reports that in this age group, known as AYA, brain tumors have overlapping features in terms of types, biology and location between those occurring in young children and those developing in older adults. Diffuse astrocytomas that are frequently seen in adults are commonly noted in the AYA age group and can share similar molecular characteristics with adult tumors. Similarly, medulloblastomas that are common in children may be observed in young adults. The AYA group also has an increased incidence of meningiomas, the second most common primary brain tumor occurring in young adults. One of the added challenges faced in the AYA group is that these patients often delay seeking medical attention when they experience symptoms, she says. Thus, by the time they receive a diagnosis, the tumors may have already advanced.
“Recent advancements in the genetic mapping of pediatric brain tumors have been game-changing,” reports Dr. Patel. Multiplatform profiling of numerous pediatric brain tumors has unearthed extensive information about genomic aberrations and the molecular processes that are disrupted and allowed for subtyping of tumors.
“It is now understood that even morphologically identical tumors can be distinct in their mutational patterns, signaling-pathway alterations and gene-expression profiles and, most importantly, in their response to a range of therapies,” states Dr. Patel, who adds that these advances have led to the characterization of a new genome-driven integrated classification of pediatric brain tumors.
This novel, refined classification system integrates molecular information from the genomic landscape as well as histopathological characteristics of different tumors. Each entity under the new classification is associated with distinct clinical outcomes. Integrating morphological and genomic information enables more precise diagnosis, treatment and risk prediction, and has paved the way for personalized medicine. “The result is that the deeper understanding of the biology of childhood brain tumors has provided clinicians with an opportunity to provide molecularly targeted therapies that have superior efficacy and less toxicity than previous treatments,” she says.
In addition to molecularly targeted therapies, immunotherapies are providing a novel way to attack cancer cells and have been shown to improve outcomes in many refractory cancers. The application of immunotherapy to brain tumors can be challenging, however, reports Dr. Patel. Several types of immunotherapy are being investigated for brain tumors, including modulation of cytokines, tumor-specific vaccines, oncolytic viruses, adoptive transfer of engineered immune cells and checkpoint blockade, including cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1).
“The recent success of chimeric antigen receptor (CAR)-T cell therapy in leukemia has created a surge of interest for its application in solid tumors, including brain tumors,” she says. “However, success of these immunotherapies is limited by the relative immunosuppressive effects of pediatric brain tumors and the heterogeneity of the tumor microenvironment.”
Holistic care essential to recovery
“Caring for children with brain tumors is no small feat, and we seek to provide care that is holistic, multifaceted, attentive, intuitive and proactive,” Dr. Patel observes. “A collaborative approach between the neurooncologist, neurosurgeon, radiation oncologist, neuroradiologist and neuropathologist is crucial in formulating a precise diagnosis and in determining the best treatment for a child’s brain tumor.” Treatment decisions are made dependent on the type of tumor, age of the child and symptoms associated with the tumor. Some children may require no treatment, while others may need surgical removal of the tumor, chemotherapy or radiation therapy or a combination of interventions. Integration of nutritionists, physical therapists and psychologists onto the team are also critical to recovery.
Brighter future for patients with pediatric brain tumors
Knowledge of the molecular landscape and tumor microenvironment and how they can influence clinical behavior and resilience to tumor-directed therapies has shifted the paradigm to more personalized treatments and created a brighter future for pediatric brain tumors. “While chemotherapy and radiotherapy are important treatment modalities for many brain tumor types, the future lies in combining these therapies with biology-specific targeted treatment as well as immunotherapies,” says Dr. Patel. “We can finally hope that children with brain tumors will have improved clinical outcomes, as well as a better quality of life moving into adulthood.”