Neurosurgical resection

The possibility of neurosurgical resection varies depending on the tumor location. Tumors within deep subcortical regions are more difficult to operate on because of access. When resection is possible for a brain tumor, the extent of resection (i.e., GTR, NTR, and STR) depends on location and how clearly defined the borders are; that is, it depends on the invasiveness of the tumor on surrounding brain tissue and whether the brain tissue is amenable to being removed (i.e., some functions may be too important and thus spared in the resection). It is more challenging to achieve total resection of tumors with anaplasia, extensive vascular proliferation, and/or necrosis, making tumors with these qualities characterized as malignant (grades III and IV, e.g., anaplastic astrocytoma and GBM). Regardless, neurosurgery, when warranted, is a significant medical procedure that brings with it an array of potential complications (e.g., craniotomy, hydrocephalus, and need for shunt placement).

Cranial radiation therapy

Radiation can be delivered in varying doses, as well as to the whole brain or to more focused regions [9]. There is an abundance of literature to suggest that CRT is associated with significant cognitive deficits across various domains, including attention, learning, memory, processing speed, visual-spatial skills, and higher-order executive functions [9]. Greatest risk for cognitive impairment has been found when CRT is administered in higher fractionated doses (i.e., greater than 2 Gy), in higher total dosage overall, with larger brain volume treated, for longer duration of treatment, in combination with chemotherapy, when used in patients under 7 years old or older than 60 years old, or used with individuals with vascular risk factors [10–12]. Radiation therapy is thought to damage cognitive function by means of metabolic and white matter changes, necrosis, and by affecting neuronal function and synaptic plasticity [13]. Radiation therapy can also result in encephalopathy, which can be acute (less than two weeks after treatment), early delayed (one to four months after treatment), or late delayed (more than 4 months after treatment), and can result in lethargy, cognitive and behavioral changes, as well as changes associated with tumor/CRT location [6]. Importantly, suspected encephalopathy must be distinguished from tumor recurrence. Radiation therapy can also induce brain edema, thus corticosteroids are often administered prophylactically [6] and come with their own set of potential side effects.

Chemotherapy

Many chemotherapy agents for brain tumors are delivered intrathecally (directly into cerebrospinal fluid) or by intraarterial means, and the protection of the blood–brain barrier makes an effect on brain tumors difficult in many instances. Many adverse effects have been identified following chemotherapy treatment, including alopecia, fatigue, nausea, constipation, headache, and cognitive deficits [6]. In addition, chemotherapy can result in neurotoxicity and brain edema, which often warrants close monitoring and prophylactic corticosteroid treatment [6], similar to CRT. Cognitive impairment is hypothesized to result from direct neurotoxic damage, injury to glial cells, damage to neuroprotective hormones, DNA damage due to oxidative stress, and/or immune dysregulation [14]. Similar to CRT, damage following chemotherapy is associated with cumulative dose, intensity of individual doses, and duration/quantity of cycles of treatment [14].