Central nervous system: Symptoms and toxicities

Background

Palliative radiotherapy (RT) is frequently recommended for the treatment of cancer progression within the central nervous system (CNS). The most common indications for palliative RT to this region include brain metastases, spinal metastases, spinal cord compression, leptomeningeal carcinomatosis, and palliative-intent treatment of primary brain neoplasms in the elderly or poor-performance-status patients. Radiation treatment modalities in this setting generally consist of external beam radiation and stereotactic radiosurgery. Expected treatment toxicity depends on a number of factors, including treatment dose, disease location, dose per fraction, concurrent systemic therapies, and radiation modality.

Toxicity can largely be divided into three phases: acute, sub-acute, and late effects. Acute symptoms from radiation to the CNS can generally be managed with a minimal decline in the quality of life for the patient. Late effects are less likely to be observed in palliative CNS cases, given the overall unfavorable prognosis and limited life expectancy in this patient population ( Table 29.1 ).

TABLE 29.1

Management of Symptoms and Treatment-Related Toxicities of the Central Nervous System

Symptom	Pharmacologic	Nonpharmacologic	Comments/When to Use
Headaches	Prophylaxis: steroids, only if high risk Mild: acetaminophen or NSAIDs PRN Moderate/Severe: glucocorticoids such as dexamethasone		Headaches are generally an acute, self-limited toxicity that can be managed with supportive care alone. If treatment remains refractory to analgesics and glucocorticoids, further work up with CNS imaging should be considered to rule out other etiologies.
Nausea/ vomiting	Prophylaxis: for CSI treatment—antiemetics with or without dexamethasone pre-RT	Decreased dose per fraction; if possible, reduce the dose to brainstem, area postrema, dorsal vagal complex, and vestibules Proton therapy if using CSI (i.e., for leptomeningeal disease)	Patients receiving RT to the brain alone are at low risk for nausea and antiemetics can be used as rescue therapy as needed. Patients receiving CSI are at moderate risk for nausea and prophylaxis with antiemetics +/- steroids prior to RT should be considered.
	Mild: 5HT-3 receptor antagonists: ondansetron or palonosetron; metoclopramide; prochlorperazine
Fatigue		Physical activity/exercise as tolerated, adequate nutrition, reduce RT dose, reduce number of fractions, use of conformal techniques (i.e., HA-WBRT for brain metastases)	The majority of patients will report fatigue during palliative CNS RT. Multiple studies have shown improvement in fatigue with exercise and conformal RT (i.e., HA-WBRT compared to WBRT). Stimulants have not shown to have a significant benefit.
Alopecia	Permanent alopecia: topical minoxidil	Transient alopecia: Conformal RT techniques (i.e., “field in field” 3D conformal RT; HA-WBRT); hair prosthesis Permanent alopecia: hair transplantation	At palliative RT doses, alopecia is generally transient. Conformal RT techniques may be used to reduce scalp dose and dose inhomogeneities.
Neurocognitive dysfunction	Prophylaxis: Concurrent memantine with and after WBRT; methylphenidate; donepezil	Prophylaxis: Treatment with SRS (rather than WBRT) for limited brain metastases; hippocampal avoidance WBRT for more extensive brain metastases	Symptoms may include memory impairment, decreased attention, and delayed information processing. For patients with limited brain metastases, SRS should be considered over WBRT when feasible. In more extensive disease, concurrent HA-WBRT with memantine should be considered to reduce neuro-cognitive sequelae.
Pituitary/ hypothalamic dysfunction	Hormone replacement for deficiency	Prophylaxis: Consider fertility preservation for young patients with treatment fields including the pituitary/hypothalamus; conformal RT modalities (IMRT) to reduce pituitary dose	Pituitary/ hypothalamic dysfunction is generally a long-term side effect seen less frequently with palliative CNS patients given their limited prognosis. Referral should be made to endocrinology for further work up when pituitary dysfunction is suspected.
Radionecrosis	Steroids; bevacizumab	Surgical resection; LITT; hyperbaric oxygen treatment	While radionecrosis is rarely seen after palliative radiation doses with external beam RT (i.e., WBRT), it is a more frequent occurrence after SRS, which is commonly used for the treatment of brain metastases. In many cases, asymptomatic radiographic changes can be closely monitored before intervening with medical or surgical management.
Optic toxicity	High dose steroids; bevacizumab; vitamin E; pentoxifylline	Hyperbaric oxygen treatment	RION is a rare complication after palliative RT and is a diagnosis of exclusion. Work up should include MRI, referral to ophthalmology, visual field testing, labs, and consideration of lumbar puncture to rule out other etiologies. Unfortunately, RION often has an unrelenting course despite treatment.
Ototoxicity	Acute: steroids	Prophylaxis: conformal RT technique with dose reduction to the cochlea Acute: myringotomy tube Late effect : auditory rehabilitation, assistive hearing device	In the acute setting, ototoxicity may result from conductive hearing loss as a result of inflammation in the auditory apparatus resulting in otitis media. Referral to ENT should be made in cases that are not self-limited in the acute setting. Delayed toxicity is generally sensorineural. Patients at high risk should be monitored closely with surveillance audiograms for early intervention.

CNS, Central nervous system; CSI, craniospinal irradiation; ENT, ear, nose, and throat; HA-WBRT, hippocampal-avoidance whole brain radiation; IMRT, intensity modulated radiotherapy; LITT, laser interstitial therapy; MRI, magnetic resonance imaging; NSAIDs, nonsteroidal anti-inflammatory drugs; PRN, as needed; RION, radiation induced optic neuropathy; RT, radiotherapy; SRS, stereotactic radiosurgery.

Headaches

Patients with CNS disease may experience headaches of varying severity, either from the tumor itself or as an acute reaction to radiation. During treatment, headaches may occur as a result of edema and increased pressure in the brain. Treatment should begin promptly with nonsteroidal antiinflammatory drugs (NSAIDs) or analgesics such as acetaminophen as needed. However, if symptoms remain refractory, glucocorticoids offer an effective treatment option in many cases. Steroids induce an anti-inflammatory response which can decrease the edema often underlying treatment-induced headaches. If headaches are severe and intractable despite steroids, further work up with CNS imaging should be considered to rule out etiologies that would require additional intervention, such as hydrocephalus or tumor progression.

Rarely, headaches may also manifest as a late effect of radiation as stroke-like migraine attacks after radiation therapy (SMART) syndrome. However, this syndrome usually occurs many years after RT, making it rare in the setting of palliative radiation. Work up includes CNS imaging (computer tomography [CT]/magnetic resonance imaging [MRI]) and electroencephalogram (EEG) to rule out other etiologies. Steroids and antiepileptics may offer some treatment benefit for these patients. ^,

Nausea

Nausea, secondary to brain irradiation, is thought to arise from the chemoreceptor trigger zone in the medulla. Approximately 35% of patients undergoing RT to the brain may experience nausea and/or vomiting. Radiation dose to multiple regions, including the brainstem, area postrema, dorsal vagal complex, and vestibules, has been significantly associated with an increased incidence of nausea in patients receiving RT to the head and neck region. ^, The high dose per fraction employed in palliative radiation may also increase the potential risk of nausea and emesis. The Multinational Association of Supportive Care in Cancer (MASCC) and the European Society of Medical Oncology (ESMO) consensus guidelines for radiation-induced nausea classify RT to the brain as “low risk” for inducing nausea, and craniospinal irradiation (CSI) as “moderate risk.”

Treatment can comprise antinausea medication, including 5-hydroxytryptamine (5HT3) receptor antagonists such as ondansetron or palonosetron, and glucocorticoids (i.e., dexamethasone). For patients with consistent nausea shortly after receipt of RT, prophylactic treatment with ondansetron pretreatment can be considered. Glucocorticoids can also reduce the incidence of nausea secondary to treatment-related edema. When the intent of RT is palliation, adequate rescue treatment and prophylaxis with antiemetic agents, when indicated, are imperative to maintain quality of life and reduce symptom burden.

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