This article provides a comprehensive analysis of the diagnosis and management of central nervous system (CNS) tumors in adolescents and young adults (AYA), a population defined by the National Cancer Institute (NCI) as individuals aged 15 to 39 years at the time of initial diagnosis. CNS tumors represent the second most common neoplasm in this age group, with an age-adjusted annual incidence of 12 per 100,000. Within this group, malignant brain tumors are the leading cause of cancer-related death in individuals aged 15 to 29, highlighting the need for e`ective and tailored diagnostic and therapeutic approaches.
Gliomas:
Adult-type di`use gliomas are the most common in AYAs, accounting for 15.2% of all brain tumors. The primary molecular alteration in these gliomas is the IDH mutation, which gives rise to three main subtypes: di`use astrocytoma, IDH-mutant; oligodendroglioma, IDH-mutant and 1p/19q-codeleted; and glioblastoma, IDH-wild type (IDH-wt). The distinction between low-grade and high-grade gliomas aids in guiding diagnostic and therapeutic approaches, but molecular markers, such as CDKN2A/B loss, are essential for prognostic stratification.
IDH mutations are rare in pediatric populations but increase with age, peaking in the fourth decade of life. Most (90%) IDH-mutant gliomas harbor the IDH1 R132H mutation, identifiable by immunohistochemistry. Recent data indicate that the frequency of non-canonical mutations, including IDH2, is higher in AYAs compared to older adults. This underscores the importance of detailed molecular characterization for more precise therapeutic interventions.
Following maximal safe resection, some AYA patients with grade 2 IDH-mutant gliomas who have nearly achieved gross total resection may be observed until progression. IDH inhibition is a promising strategy, but AYAs were underrepresented in the INDIGO trial. Questions remain about whether IDH inhibition can delay malignant transformation and its long-term safety.
Medulloblastomas:
The management of medulloblastomas in adolescents and young adults (AYA) requires a multimodal approach, integrating surgery, radiotherapy, and chemotherapy to maximize the chances of cure. Current recommendations emphasize the following practices: surgery aims for the maximal safe resection of the tumor, as the amount of residual tumor is an important prognostic factor.
Complete or near-complete removal is associated with better outcomes. Radiotherapy is a critical component of post-surgical treatment. For patients with standard-risk disease, the dose of craniospinal irradiation (CSI) is being reevaluated for potential reduction to 23.4 Gy, with an additional boost to the tumor bed for a total of up to 54 Gy. This aims to minimize long-term side e`ects while maintaining treatment e`icacy. In high-risk cases, the CSI dose may be increased to 36 Gy, with additional boosts to metastatic sites if feasible.
Adjuvant chemotherapy is used to improve outcomes, especially in high-risk patients. Standardized regimens include the combination of vincristine, cisplatin, and lomustine, with adjustments based on specific risk factors and patient tolerance.
Ependymomas:
The treatment of ependymomas in adolescents and young adults requires a careful and personalized approach, based on specific molecular and clinical characteristics of each case. According to the new classification, ependymomas are divided into 10 subgroups. Management strategies include: surgical resection is the primary treatment for ependymomas, aiming to remove as much of the tumor as possible.
Total resection is associated with better outcomes and may, in some cases, allow for an observational approach instead of immediate adjuvant treatment. Molecular characterization of ependymomas is crucial for accurate diagnosis and treatment stratification. Identifying ZFTA fusions and other genetic alterations can influence therapeutic and prognostic decisions.
DNA methylation profiling and genetic fusion tests are important tools for di`erentiating ependymoma subgroups. Radiotherapy is often used as adjuvant treatment, especially in cases of incomplete resection or when high-risk features are present. Focal radiotherapy is preferred to minimize exposure to healthy tissues, with doses adjusted according to tumor location and grade. While chemotherapy is not standard for all ependymomas, it may be considered in cases of recurrent disease or when surgery and radiotherapy are not viable options. Clinical trials are underway to evaluate the e`icacy of chemotherapeutic agents and targeted therapies in specific subgroups.
Germ Cell Tumors:
Germ cell tumors are rare in the CNS, a`ecting 0.11 per 100,000 AYAs. They are subdivided into germinomas and non-germinomatous tumors, typically located in the suprasellar region, pineal gland, or both, and rarely in other locations such as the basal ganglia. Diagnosis is histopathological and involves marker measurements. Staging should include neuroaxis imaging and CSF cytology analysis. The standard approach includes surgery to establish diagnosis and decompression in symptomatic patients, followed by chemotherapy and radiotherapy. Clinical trials focus on reducing long-term toxicity of these therapies. Including AYA patients in studies is essential to optimize outcomes and tailor treatments to the specific needs of this age group.
General Recommendations:
Standardized Molecular Testing: Essential for guiding precision treatment, standardized molecular testing enables a personalized and e`ective approach for each patient.
Multidisciplinary Collaboration: Crucial for interpreting genetic variants and identifying targeted therapies, ensuring patients receive the most appropriate treatment.
AYA Clinical Trials: Developing trials for the AYA age group, with international collaboration, is vital to improve access to innovative treatments and address knowledge gaps regarding new therapies' e`icacy and safety.
• Transition and Survivorship Programs: These programs are vital for enhancing long-term quality of life, o`ering psychosocial support, oncofertility, and rehabilitation, and facilitating the transition from pediatric to adult care.
The article concludes that collaborative and multidisciplinary e`orts are key to advancing treatment and improving survival and quality of life for AYA patients with CNS tumors. Integrating new technologies and therapeutic approaches, along with comprehensive support, can transform the treatment landscape. Emphasizing precision therapies and clinical trial inclusion is crucial for optimizing management and outcomes, ensuring care tailored to AYA patients' specific needs. Journal: Neuro-Oncology, 2024; Author: Camila A. F. Yamada Mini-CV: Clinical Oncologist at Beneficiência Portuguesa de São Paulo / Chair LACOG Neuro-Oncology Group / Cordinator of Neuro-Oncology Group at SBOC / Member SNOLA
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