The Systems Theory provides a valuable conceptual framework for analyzing biological complexity, particularly in oncology, where the multiple interactions between biological subsystems can influence tumor initiation, progression, and treatment response. This approach facilitates the integration of data derived from genomics, metabolomics, routine medical analyses, and the clinical examination of the patient, thus overcoming the limitations of the reductionist model. By applying the principles of living systems, new tumor vulnerabilities can be identified, as well as models of cellular, metabolic, and informational organization. The use of systems theory in oncology may contribute to the development of personalized and precision medicine, improving diagnostic and prognostic methods, and enhancing the efficiency of personalized therapies with the aim of improving therapeutic outcomes and the patient’s quality of life.

Background: Brain tumors represent a major cause of neurological morbidity and mortality, often requiring radiotherapy as a central component of treatment. While advances in radiation techniques have improved tumor control, increasing attention has been directed toward radiation-induced effects on healthy brain tissue, particularly regarding neuronal function and cognitive outcomes. Objective: This review aims to provide a structured synthesis of current evidence on radiation-induced neuronal dysfunction, integrating dose–volume parameters, neuroimaging biomarkers, and clinical neurological manifestations. Methods: A structured literature review was conducted using electronic databases including PubMed, Scopus, and Web of Science. Relevant studies evaluating dose–volume effects, neuroimaging findings, and clinical outcomes following cranial radiotherapy were included. Results: Dose–volume histogram (DVH) parameters, including mean brain dose and intermediate-dose volumes (V10–V30), as well as hippocampal dose, were identified as key factors associated with cognitive decline and neuronal dysfunction. Conventional MRI detects structural changes such as white matter injury and radionecrosis, while advanced techniques including diffusion tensor imaging (DTI) and functional MRI (fMRI) reveal microstructural damage and network disruption. These imaging findings correlate with a spectrum of clinical manifestations ranging from subtle cognitive impairment to significant neurological deficits. Conclusions: Radiation-induced neuronal dysfunction represents a complex and multifactorial process that extends beyond localized tissue injury. Integrating dose–volume considerations with advanced imaging biomarkers may improve risk stratification and support the development of neuroprotective strategies in patients undergoing cranial radiotherapy.