**6.1. Pathogenesis of cognitive impairment**

The mechanisms by which chemotherapy-induced cognitive impairment are unclear [96].

Chemotherapy may reduce the number of neural stem/progenitor cells, which have role in memory and learning ability [97], and neural precursor cells are chemo-sensitivity, neural stem, and line age-restricted progenitor cells that form, among other cell types, the myelinat‐ ing oligodendrocytes in the frontal white matter [98].

Primary pathological lesions including demyelination, inflammation, and microvascular injury [99]. Also mature oligodendrocytes are chemo-sensitive at lower dosage than those required to kill tumor cells [100].

Multiple chemotherapeutic agents affect hippocampal neurogenesis causing decrease in cell proliferation within the germinal region of the hippocampus and development of cognitive deficit [101].

Genetic role in chemotherapy-induced cognitive decline may be impilicated, and there is increased risk of cognitive impairment after RT with the apolipoprotein E4 alleles [102].

#### **6.2. Cognitive impairment of chemotherapeutic agents**

Chemotherapy added to slow the tumor progression especially in children to postpone radiation therapy or to reduce the dose of radiation therapy to decrease the neurocognitive sequelae of increasing doses of RT. Neurotoxic side-effects of chemotherapy alone can be difficult, because most patients of brain tumor have been treated with RT and chemotherapy [103].

The evidence that chemotherapy alone causes neurocognitive effects is not consistent. Studies have concluded that chemotherapy effects are negligible and not clinically significant compared to craniospinal irradiation (CSI) [104].

Neurotoxicity of chemotherapy arises during, or shortly after, chemoterapy. RT causes disturbance in BBB, so the toxicity of chemotherapy increased when was given during or after RT. In these cases, the chemotherapeutic drugs reach higher concentrations in brain tissue because of leakage of the blood–brain barrier due to RT. Intrathecal chemotherapy has higher CNS toxicity compared to systemic chemotherapy [105].

Chemotherapeutic agents, such as BCNU, CDDP, cytosine arabinoside, and intrathecal or intravenous methotrexate, have toxic effect to the CNS. Chemotherapy-related cognitive impairment in primary CNS lymphoma was observed in one or more domains: (attention, executive function, memory, psychomotor speed, and language). Other studies have shown that cognitive stability or cognitive improvement during chemotherapy provided that the tumor was responsive to chemotherapy treatment [106, 107]. Uses of high-dose IV methotrex‐ ate or interathecal methotrexate with radiation therapy result in dementia particularly when the radiation is given prior to the methotrexate. Leukoencephalopathy more commonly occurs. MRI shows bilateral periventricular white matter changes. The radiation therapy disrupts the BBB and results in increased permeability of the white matter to the methotrexate [108].

Copeland et al. [109] concluded that chemotherapy had only a slight effect on neurocogni‐ tive status and was confined to perceptual motor skills with observed age effect on perform‐ ance IQ.

Chemotherapeutic agents, such as BCNU, cisplatin, and cytarabine, have proved to be more toxic to neural precursor cells than cancer cells [110]. Carmustine, methotrexate, and cytara‐ bine have been found to induce central neurotoxicity to neural stem cell populations located in the subventricular zone and dentate gyrus [99].

Prabhu et al. [111] conducted a study on LGG patients and concluded that the addition of chemotherapy procarbazine, lomustine, and vincristine (PCV) to RT for LGGs did not result in significant MMSE score decline when compared to RT alone.

Regarding the HRQOL, there is a short-lasting negative impact of PCV chemotherapy on HRQOL during and shortly after treatment, but no long-term effects on HRQOL have been established [112].

Patients with previously untreated anaplastic astrocytoma, OA, or oligodendroglioma were evaluated for the long-term efficacy and safety of accelerated fractionated RT combined with intravenous carboplatin. In a phase II study conducted by Levin et al. [113], they found that after RT, patients received procarbazine, lomustine (CCNU), and vincristine (PCV) for 1 year or until tumor progression, 10% of those patients developed serious clinical neurologic deterioration and/or dementia requiring full-time caregiver attention.

Hilverda et al. [114] reported that glioblastoma patients undergoing RT with concomitant and adjuvant temozolomide treatment did not develop cognitive deterioration.

In LGG patients, temozolomide is not only successful in terms of extending the survival duration but also has been proven to maintain or even improve HRQOL while patients are on treatment [115].

Patients with recurrent high-grade glioma (HGG), successfully treated with temozolomide, achieved significant improvement in the HRQOL domains, whereas patients with disease progression had significant deterioration in most HRQOL domains [116].
