**6.3. Sleep disorder**

Neuro-oncology patients may suffer from sleep disorders including disturbed sleep-wake rhythm, increased sleep duration, disturbed sleep timing, and daytime sleepiness that significantly affect their daily performance and their QoL. Disturbed pattern of sleep is more often experienced in children suffering from hypothalamic, pituitary, or brain stem lesions as well as in those treated with craniospinal radiotherapy. Excessive somnolence and psychoso‐ cial functioning with fatigue are common complaints of such patients. Routine evaluation of sleep habits during may help better understanding the mechanisms underlining these disorders and present possible interventions (e.g., melatonin, cognitive therapy, bright light therapy, medications, and/or physical activities) [65].

#### **6.4. Vascular malformations**

An increased risk of vascular malformations was noticed with radiotherapy. Radiation can weaken the vessel wall and result in cerebral cavernous malformation, telangiectasias of capillaries, and aneurysms. Radiation is believed to stimulate angiogenesis factors leading to these vascular malformations. Cerebral cavernous malformations were experienced six times higher in those treated with radiotherapy than in the control population. Most of these lesions are asymptomatic, but a subset may be presented with seizures, headaches, and hemorrhag‐ es that may require surgical intervention.

Telangiectasias are commonly found in brain tissue obtained from patients treated with radiotherapy, with thin-walled, dilated tortuous vascular channels, associated with perivas‐ cular leukocyte infiltration. These abnormalities may become symptomatic after bleeding but are usually considered as benign finding [66].

Small vessel vasculopathy with mineralizing microangiopathy of the basal ganglia and subcortical white matter has also been reported months to years after completion of radia‐ tion of the brain [67]. Most patients are asymptomatic, but some investigators have correlat‐ ed their presence with behavioral disorders, neurological deterioration, and dementia.

Moyamoya vasculopathy was reported in pituitary and chiasmatic tumor patients treated with and without radiation. This vasculopathy is a progressive stenosis of the supraclinoid internal carotid arteries leading to the development of collateral blood vessel formation. Radiation to the circle of Willis and neurofibromatosis type I (NF1) have been identified as risk factors [28].

#### **6.5. Seizures**

Childhood Cancer Survivor Study (CCSS) reported the prevalence of epilepsy in long-term survivors of childhood brain tumors as 25%. Many of them had their first seizure more than 5 years after diagnosis of their cancer [68]. Seizures were more frequent in patients treated with RT >30 Gy to any cortical area and more frequent in children treated at young age or who underwent repeated brain tumor excisions. Methotrexate has also been related to late seizure onset, especially with the resulted necrotizing leukoencephalopathy.

#### **6.6. Ototoxicity**

High doses of platinum have been reported to cause irreversible early- or delayed-onset hearing loss. Platinum targets the outer hair cells in the organ of Corti and the cochleal wall epithelium. These late complications create hearing affection and hence affect speech devel‐ opment, learning, communication, school performance, social interaction, and overall QoL. Platinum ototoxicity is characterized by a dose-dependent high-frequency sensorineural hearing loss with tinnitus. The magnitude of ototoxicity was influenced by the young age at the start of treatment, the high cumulative doses of platinum compounds (>400 mg/m2 for cisplatin and carboplatin), and the use of concomitant ototoxic treatments including CNS RT [69]. Genetic polymorphisms in enzymes responsible for platinum metabolism (e.g., gluta‐ thione S-transferase, thiopurine methyltransferase, catechol O-methyltransferase) may contribute to the severity of hearing loss [70, 71].

RT to the cochlea or cranial nerve VIII can also cause sensorineural hearing loss. Cranial RT used alone results in ototoxicity when cochlear dosage exceeds 32 Gy. Young age, presence of a brain tumor, and/or hydrocephalus can increase susceptibility to hearing loss. When used concomitantly with platinum, RT can have a synergistic effect and it substantially exacer‐ bates the hearing loss associated with chemotherapy, especially in the high-frequency speech range. RT to temporal lobe (>30 Gy) and to posterior fossa (≥50 Gy) was reported to be associated with an increased risk of tinnitus, and hearing loss.

Early detection of ototoxicity in children is of extreme importance in the prevention of severe hearing impairment that may affect speech recognition. Various strategies have been consid‐ ered to minimize platinum ototoxicity. Radiation reduction dose to the cochlea has been investigated, including the use of 3D conformal RT, IMRT, and proton therapy [72]. Once treatment is completed, long-term audiometric monitoring should continue.

## **6.7. Visual affection**

**6.4. Vascular malformations**

466 Neurooncology - Newer Developments

**6.5. Seizures**

**6.6. Ototoxicity**

es that may require surgical intervention.

are usually considered as benign finding [66].

An increased risk of vascular malformations was noticed with radiotherapy. Radiation can weaken the vessel wall and result in cerebral cavernous malformation, telangiectasias of capillaries, and aneurysms. Radiation is believed to stimulate angiogenesis factors leading to these vascular malformations. Cerebral cavernous malformations were experienced six times higher in those treated with radiotherapy than in the control population. Most of these lesions are asymptomatic, but a subset may be presented with seizures, headaches, and hemorrhag‐

Telangiectasias are commonly found in brain tissue obtained from patients treated with radiotherapy, with thin-walled, dilated tortuous vascular channels, associated with perivas‐ cular leukocyte infiltration. These abnormalities may become symptomatic after bleeding but

Small vessel vasculopathy with mineralizing microangiopathy of the basal ganglia and subcortical white matter has also been reported months to years after completion of radia‐ tion of the brain [67]. Most patients are asymptomatic, but some investigators have correlat‐ ed their presence with behavioral disorders, neurological deterioration, and dementia.

Moyamoya vasculopathy was reported in pituitary and chiasmatic tumor patients treated with and without radiation. This vasculopathy is a progressive stenosis of the supraclinoid internal carotid arteries leading to the development of collateral blood vessel formation. Radiation to the circle of Willis and neurofibromatosis type I (NF1) have been identified as risk factors [28].

Childhood Cancer Survivor Study (CCSS) reported the prevalence of epilepsy in long-term survivors of childhood brain tumors as 25%. Many of them had their first seizure more than 5 years after diagnosis of their cancer [68]. Seizures were more frequent in patients treated with RT >30 Gy to any cortical area and more frequent in children treated at young age or who underwent repeated brain tumor excisions. Methotrexate has also been related to late seizure

High doses of platinum have been reported to cause irreversible early- or delayed-onset hearing loss. Platinum targets the outer hair cells in the organ of Corti and the cochleal wall epithelium. These late complications create hearing affection and hence affect speech devel‐ opment, learning, communication, school performance, social interaction, and overall QoL. Platinum ototoxicity is characterized by a dose-dependent high-frequency sensorineural hearing loss with tinnitus. The magnitude of ototoxicity was influenced by the young age at the start of treatment, the high cumulative doses of platinum compounds (>400 mg/m2

cisplatin and carboplatin), and the use of concomitant ototoxic treatments including CNS RT [69]. Genetic polymorphisms in enzymes responsible for platinum metabolism (e.g., gluta‐

for

onset, especially with the resulted necrotizing leukoencephalopathy.

CCSS reported in adult survivors of childhood brain tumors, blindness in one or both eyes in 13%, cataracts in 3%, and double vision in 17% [68]. Although cataracts are known compli‐ cation of RT, prolonged use of corticosteroid such as dexamethasone can also contribute to the development of posterior subcapsular cataracts. Ophthalmologic complications were report‐ ed in optic pathway glioma and craniopharyngioma in 20–70% of patients. Poor visual outcome has been frequently reported in the posterior chiasmatic area. Long-standing obstructive hydrocephalus can lead to severe optic atrophy and blindness.

#### **6.8. Secondary neoplasms**

The increase in survival in childhood tumors was accompanied with the emergence of secondary neoplasms as a long-term complication of treatment reaching up to 3–4% at 20 years post treatment [73]. Leukemia and primary CNS tumors have a tendency to develop into a subsequent CNS tumor. Armstrong et al. [74] reported 20 (1.1%) second CNS tumors out of 1877 survivors of CNS malignancies. They also observed 171 (9.1%) neoplasms classified as "benign" tumors including 59 meningiomas and 112 nonmelanoma skin cancers in these long survivors. The overall cumulative incidence of a subsequent neoplasm at 25 years was estimated to be 10.7%. Generally, the most common malignancies are malignant astrocyto‐ mas, followed by sarcomas and occasionally supratentorial primitive neuroectodermal tumors (sPNET). The cumulative incidence of secondary CNS such as glioblastomas pla‐ teaued at 15 years, whereas the cumulative incidence of meningiomas continues to increase beyond 35 years post treatment [75]. Although these secondary tumors have similar histolog‐ ical appearance to the primary tumors, they typically behave more aggressively and are resistant to treatment [76]. Moreover, the meningiomas have also been found to be more often atypical and prone to relapse. The development of secondary CNS tumors is most likely

multifactorial, but RT certainly contributes to this process. The vast majority of secondary malignant neoplasm (SMN) appears within the radiation field. The cumulative incidence of SMNs at 25 years was 7.1% for children who received more than 50 Gy to the cranium compared to 1% for children who did not receive cranial irradiation. A linear dose response could be illustrated with an increased relative risk of 0.33% for gliomas and 1.06% for meningiomas per Gy. The chemotherapy contribution to the development of secondary CNS malignancy is more difficult to assess partly due to the use of combination chemotherapy regimens. Alkylating drugs, especially cyclophosphamide and epipodophyllotoxins, such as etoposide, have been reported to increase the cumulative incidence of second malignancies [77]. The presence of accompanying somatic mutations may predispose for the development of second malignancy. Patients with p53 (Li-Fraumeni syndrome) are more likely to develop SMN including sarcoma, primary brain tumor, and acute lymphoblastic leukemia (ALL).

Therapy may be tailored in order to avoid or reduce the combination of RT and certain chemotherapy agents. Alkylating drugs, especially cyclophosphamide and epipodophyllo‐ toxins, such as etoposide, have been reported to increase the cumulative incidence of second malignancies up to 4% [77]. Other somatic mutations such as the ataxia telangiectasia mutated gene (ATM) known to be involved in DNA repair may possibly play a role. Finally, metabo‐ lism and detoxification might also be involved in the development of second malignancy especially in those with acute nonlymphocytic leukemia (ANLL) and acute myeloid leuke‐ mia (AML).
