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Cranial irradiation is used to treat patients with primary or metastatic brain tumors and as prophylaxis for selected patients at high risk of neoplastic involvement of the nervous system. Radiotherapy is the most effective non-surgical treatment of brain tumors and beyond the improvement in overall survival for a subset of patients over the last few decades, there is an effort to minimize potential adverse effects leading to possible worsening in quality of life (QoL), especially worsening of neurocognitive function. The hippocampus has been known to be important in memory formation and pre-clinical models show loss of hippocampal stem cells with radiation as well as changes in architecture and function of mature neurons. Cognitive outcomes in clinical studies are beginning to provide evidence of cognitive effects associated with hippocampal dose and the cognitive benefits of hippocampal avoidance (HA). The purpose of this review is to provide a brief overview of studies that provide a rationale for HA and provide summary of published feasibility studies in order to help clinicians prepare for clinical usage of these complex and challenging techniques. Neurotoxicity of whole brain irradiation (WBI) has been investigated mostly in the presence of brain metastasis. Several trials have assessed the effect of prophylactic cranial irradiation (PCI) on neurocognitive function and QoL. RTOG 0214 and 0212 reported a significant decrease in Hopkins Verbal Learning Test (HVLT) scores at 3, 6, and 12 months after PCI. Recently phase 2 and 3 (PREMER) clinical trials have shown preserved cognitive function following HA. The introduction of IMRT (Intensity Modulated Radiation Therapy) and VMAT (Volumetric Modulated Arc Therapy) enables the reduction of radiation dose to the hippocampus in the delivery of cranial irradiation. The single-arm phase II RTOG-0933 trial evaluated an anatomic-avoidance strategy to promote cognitive preservation and showed that reduced radiation dose to the hippocampal neural stem-cell compartment was associated with a smaller decline in recall (P < .001) compared to a historical control. Based on these results, the phase III NRG-CC001 trial evaluated WBI with memantine with or without hippocampal avoidance (HA). There were no significant differences in survival outcomes. However, risk of cognitive failure was significantly lower in the HA arm than in the control arm (HR, 0.76; 95% CI, 0.60–0.98; P = .03). The Spanish Lung Cancer Group phase III trial (PREMER) provided the first clinical evidence that sparing the hippocampus during PCI in patients with small-cell lung cancer better preserves cognitive function. In contrast, NKI-Dutch Cancer Society phase III trial, investigating the neurocognitive decline at 4 months after treatment of HA-PCI compared with PCI did not show a significant difference between the two arms. The different results may be related to several reasons among others the use of different memory tests and the modality in which the material to learn is presented. In summary, HA for PCI and WBI using IMRT/VMAT may be considered as a potential strategy to improve cognitive preservation in lung cancer patients. A current randomized trial, NRG CC009, is comparing SRS to hippocampal-sparing WBRT plus memantine when the local treatment is delivered with stereotactic radiotherapy (SRT)/radiosurgery (SRS).