Version May 2024
INTRODUCTION — 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. A full understanding of the potential consequences associated with cranial irradiation is needed both to manage potential complications and to properly counsel patients and/or caregivers prior to treatment.
The primary factors influencing the likelihood of developing complications include the volume of normal brain tissue treated, the total radiation dose, and the fractionation schedule. The likelihood of brain toxicity also increases in the young (ie, <5 years old) and in older adults and with use of concurrent or sequential systemic therapies. Poorly characterized genetic factors may also make certain individuals more susceptible to otherwise safe doses of radiation. (See "Delayed complications of cranial irradiation", section on 'Pathophysiology'.)
The complications of radiation therapy (RT) are usually divided into acute effects that can occur during RT or up to six to eight weeks afterwards, early-delayed (subacute) effects that appear up to six months after RT completion, and late effects that can develop six months or more after the completion of RT, sometimes arising many years after treatment. Unlike acute and early-delayed reactions that are usually reversible, late reactions are generally irreversible.
The acute complications of both standard fractionated cranial irradiation and stereotactic radiosurgery (SRS) will be reviewed here. The late complications of cranial irradiation and complications of spinal cord and peripheral nerve irradiation are discussed elsewhere. (See "Delayed complications of cranial irradiation" and "Complications of spinal cord irradiation" and "Brachial plexus syndromes", section on 'Neoplastic and radiation-induced brachial plexopathy' and "Lumbosacral plexus syndromes", section on 'Radiation plexopathy'.)
STANDARD FRACTIONATED RADIATION THERAPY — Acute side effects occurring during standard fractionated brain radiation therapy (RT) using contemporary techniques are typically mild and manageable with basic supportive care. Some of the more common and uncommon toxicities are discussed below. Most self-resolve within days to weeks after RT is completed.
Common acute reactions
Fatigue — Fatigue is one of the most common side effects of cranial irradiation. Up to 90 percent of patients undergoing partial brain irradiation for glioblastoma experience at least grade 1 symptoms (disturbance with some tiredness, but activity not curtailed), and approximately half experience mild to moderate symptoms (decreased activity and increased tiredness, sleeping much of the day, most activities curtailed) [1]. Severe somnolence is rare.
Symptoms may occur as early as the first week of RT but more often become noticeable after two weeks of treatment. Fatigue tends to peak at the end of the treatment course or within one to two weeks after treatment completion, and then slowly resolve over the next several months.
There are limited and conflicting data on the use of modafinil or methylphenidate during RT to counteract fatigue [2]. In a double-blind trial that was terminated prematurely, 68 patients with primary or metastatic brain tumors were randomly assigned to methylphenidate or placebo during RT [3]. Eight weeks after completion of RT, there was no difference in fatigue or cognition compared with placebo.
Loss of appetite — Anorexia is a common symptom with cranial irradiation, occurring in more than half of patients undergoing fractionated cranial RT. Patients typically feel well but have less desire to eat. Most people can still eat when needed but simply do not find food as appealing.
Alopecia and radiation dermatitis — Total or partial alopecia is extremely common after cranial irradiation and may be permanent with higher radiation total doses. Alopecia occurs only where the radiation beams traverse the scalp, so patients receiving partial brain irradiation may develop patchy alopecia. The severity and permanence of alopecia is directly related to dose [4]. Lower doses of radiation cause partial hair thinning. With higher doses, complete patches of alopecia may occur. Hair loss typically begins 2.5 to 3 weeks after the start of RT. Hair regrowth typically begins one to two months after RT completion, and the process is often slower than typical hair growth. With higher radiation doses, hair regrowth can be permanently thinner, and some patients have permanent alopecia. Regrown hair can be more brittle, slightly curly, and/or gray or different from the original color. With modern radiotherapy techniques, permanent alopecia is far less common.
Radiation dermatitis is usually mild and may be treated with soothing moisturizers. Skin/scalp mild erythema commonly occurs three to five weeks into RT, largely dependent on dose to skin and occurring one to two weeks after alopecia has started. Rarely, areas of skin receiving particularly high doses may demonstrate dry or moist desquamation that may benefit from bacteriostatic topical treatments. Otitis externa is common if the ear is within the radiation treatment field.
In patients who have recently begun phenytoin or carbamazepine anticonvulsant therapy, an unusually severe skin reaction or one that extends beyond the RT fields might be the first sign of a developing Stevens-Johnson syndrome [5]. Han Chinese are particularly susceptible, related to HLA-A*3101 and HLA-B*1502 genotypes [6] (see "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis"). A review of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis in patients undergoing RT found that of 61 patients receiving antiseizure medications during radiotherapy, 48 were for prophylaxis rather than seizure treatment [7], an indication that is generally discouraged [8]. In patients who develop rash, the antiseizure medication should be stopped immediately.
Headaches — Mild headaches may occur at any time during cranial irradiation and are often mild enough or transient enough that patients do not require medication. The headaches are often related to direct irradiation and inflammation caused by radiation on irradiated tissues. For headaches that are more troublesome, acetaminophen is typically adequate to resolve the symptom. If not medically contraindicated, ibuprofen is also acceptable, especially if there are concerns about hepatic function and a desire to limit or avoid acetaminophen. A combination of both medications is also acceptable for more refractory headaches.
Headaches may also be due to mass effect from tumor, and this etiology is important to differentiate as the management is different. Concomitant progression of neurologic deficits and new or worsening somnolence, when seen with worsening headaches, may signal increased peritumoral edema and/or tumor progression. Glucocorticoids to reduce cerebral pressure are the primary approach when cerebral edema and tumor mass effect are suspected, rather than pain medications. (See "Management of vasogenic edema in patients with primary and metastatic brain tumors".)
Nausea and vomiting — Nausea and vomiting may occur occasionally as a side effect of cranial irradiation. This is far less common than simple loss of appetite. Antiemetics or corticosteroids are used to prevent or mitigate symptoms. (See "Radiotherapy-induced nausea and vomiting: Prophylaxis and treatment".)
Worsening of preexisting neurologic symptoms — Symptoms related to the tumor can initially worsen with RT. This is related to reactive swelling that mimics tumor growth and causes worsening or recurrence of symptoms.
Patients with recognized significant pretreatment cerebral edema should begin glucocorticoids (eg, dexamethasone 2 to 4 mg daily) just prior to initiating and during RT [9]. Maintaining the dose for the first two weeks of RT can prevent clinical deterioration due to transiently worsened peritumoral edema. An increase in glucocorticoid dose is sometimes beneficial if symptoms worsen during the course of RT, similarly due to reactive cerebral edema. Any taper during RT should be gradual, and worsening of symptoms may require a short-term increase until RT has been completed. (See "Management of vasogenic edema in patients with primary and metastatic brain tumors".)
Other acute reactions
Hearing problems — Soft tissue swelling around the inner ear and, less commonly, serous otitis media may occur during RT, resulting in a conductive hearing loss. This typically resolves within a few weeks of RT completion. Persistence of symptoms may occasionally require evaluation to determine whether there is fluid that is amenable to myringotomy for symptomatic benefit [10].
Parotitis — Acute parotitis and symptomatic or asymptomatic hyperamylasemia is an uncommon complication of some cranial irradiation, most commonly with whole brain RT (WBRT); it occurs when the edge of the radiation portal incidentally irradiates the parotid gland [11]. The acute symptoms include fever, pain, swelling, and tenderness. Nonsteroidal antiinflammatory drugs or glucocorticoids are typically used to treat radiation-associated parotitis with prompt response within less than a day.
Uncommon acute reactions
Acute encephalopathy — Acute encephalopathy may occur when radiation fractions >3 Gy are administered to a large brain volume, particularly in patients with elevated intracranial pressure (ICP). Symptoms include severe headache, nausea, drowsiness, and focal neurologic deficits and fever [12]; in extremely rare cases, death may occur due to cerebral herniation. This effect is thought to be due to disruption of the blood-brain barrier leading to cerebral edema. With a better understanding of the relationship between dose, schedule, and toxicity, acute encephalopathy is rare with modern treatment techniques. WBRT is generally administered in fractions of ≤3 Gy, or to much lower overall doses (eg, 20 Gy in five fractions); with these schedules, the risk of severe acute encephalopathy is negligible.
Early-delayed reactions — Examples of early-delayed reactions to cranial irradiation include the following.
Persistent fatigue — Although variable, many patients notice persistence of mild fatigue over the course of weeks or months after RT completion. For some patients, reduced stamina is more prominent than fatigue. Pacing daily activities is the best approach to managing lingering tiredness after RT. This usually resolves as more time elapses from completion of RT.
Both fatigue and daytime sleepiness can be multifactorial, and other reversible causes should also be evaluated and treated. (See "Approach to the adult patient with fatigue" and "Approach to the patient with excessive daytime sleepiness".)
Transient focal neurologic symptoms — Some patients undergo a delayed transient worsening of symptoms that can suggest tumor progression, with headache and/or recurrence of pretreatment neurologic symptoms and signs. The likely etiology is a combination of tumor response and peritumoral edema.
Reversible defects in memory also occur and do not necessarily predict long-term impairment [13,14]. In a prospective study of 10 patients with low-grade tumors treated with limited field radiation in doses from 46 to 63 Gy, a transient decline in verbal long-term memory was observed 1.5 months after completion of RT [13]. This deficit was transient, however, and patients had returned to baseline by one year.
Pseudoprogression — In addition to well-defined clinical syndromes, the routine use of cranial magnetic resonance imaging (MRI) has led to the identification of an increase in or reappearance of MRI contrast enhancement weeks to months after completion of RT; this is a transient abnormality but can be hard to distinguish from tumor progression. Patients are often asymptomatic or minimally symptomatic.
This phenomenon is most common in the first several months after concurrent radiation therapy and temozolomide in patients being treated for high-grade glioma. This is discussed in more detail separately. (See "Management of recurrent high-grade gliomas", section on 'Early progression versus pseudoprogression'.)
Late effects — Late effects are persistent or new symptoms beyond six months from RT completion. These include radiation necrosis, neurocognitive deficits, cerebrovascular effects, neuroendocrine dysfunction, and secondary tumor formation. These and other delayed complications are reviewed elsewhere. (See "Delayed complications of cranial irradiation".)
STEREOTACTIC RADIOSURGERY — Stereotactic radiosurgery (SRS) involves the administration of a single or very limited number of high doses of ionizing radiation to a small, well-demarcated tumor or other target within the cranium. The complications of SRS differ from those of conventional fractionated cranial irradiation because SRS is restricted to a small target volume and it utilizes a much higher dose in a single fraction.
The initial evaluation of the acute toxicity of SRS was derived from a dose escalation study conducted by the Radiation Therapy Oncology Group (RTOG) in 156 patients with primary (36 percent) or recurrent metastatic brain tumors (64 percent) [15,16]. In this population, the maximum tolerated doses of single-fraction SRS were established as 24 Gy, 18 Gy, and 15 Gy for tumors ≤20 mm, 21 to 30 mm, and 31 to 40 mm in maximum diameter, respectively. At these dose levels, the rates of acute grade 3 to 5 central nervous system (CNS) toxicity ranged from 0 to 17 percent in the three groups, with the higher rates in patients with larger tumors [16]. Long-term toxicities for these treatment schedules are not well characterized, and thus these high doses should be judiciously used. Few clinical indications merit single-fraction SRS doses in excess of 18 to 20 Gy.
Severe acute reactions — Subsequent experience based upon contemporary tumor volume and dose recommendations suggests that severe acute reactions are rare. As an example, in one series that included 835 consecutive patients undergoing SRS, 18 had a neurologic event within seven days of treatment (eg, new focal deficit or seizure) and three died [17].
In addition to dose, the volume, location of the treated lesion, prior irradiation, and any concurrent systemic therapies including chemotherapy, targeted agents, and immune therapies may affect the incidence of post-SRS seizures. In a small series, seizures following radiotherapy were more common in patients whose lesions were located in the motor cortex rather than elsewhere in the brain [18].
Less common acute reactions — Milder symptoms including nausea, dizziness, and headache may occur within the first week or two after SRS but are uncommon. If a specific toxicity is anticipated, as with treatment near the area postrema (nausea center) in the brainstem, a short course of glucocorticoids is recommended around the time of radiosurgery. This generally eliminates the acute toxicity.
While many patients will do well without prophylactic treatment, many clinicians routinely prescribe a short course of benzodiazepines or glucocorticoids before and/or after radiosurgery unless there is a contraindication. The intent is to reduce the risk of reactive symptoms such as seizure or headache that might occur as a result of transient post-radiosurgery edema in the treated volume. Matters of optimal dose and patient selection have not been addressed in formal clinical trials. Sedation is the primary concern with benzodiazepines. Numerous common side effects of glucocorticoids should be considered prior to use, including but not limited to insomnia, hyperactivity, increased appetite, weight gain, and hyperglycemia. Over time, there can be significant weight gain, ease of bruising, and depression of the immune system. Fortunately, such long-term dependency on glucocorticoids is rare. (See "Major adverse effects of systemic glucocorticoids".)
In addition to its potential neurotoxicity, SRS involves immobilization of the patient's head in a rigid frame during treatment. For some facilities, the rigid head frame commonly used to immobilize patients is tightly fixed to the skull with pins that penetrate the skin. As a result, temporary discomfort and self-limited bruising at the pin placement sites can occur immediately following the procedure. Frameless positioning systems that do not use invasive pins that penetrate skin are now more commonly used and have markedly improved the tolerability of this treatment [19-21].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Hair loss from cancer treatment (The Basics)")
SUMMARY
●Overview – Cranial irradiation is associated with risks of various acute and late toxicities, and these risks should be acknowledged and discussed during the pretreatment counseling session with any patient for whom cranial irradiation is recommended. (See 'Introduction' above.)
●Standard fractionation
•Common acute reactions – Acute effects of radiation are those that occur during the course of treatment. Some of the more common adverse effects include transient worsening of baseline neurologic symptoms due to cerebral edema, fatigue, anorexia, nausea and vomiting, alopecia, and dermatitis. (See 'Common acute reactions' above.)
•Uncommon acute reactions – Uncommon acute reactions include conductive hearing loss and parotitis. Acute encephalopathy is rare with modern treatment techniques. (See 'Other acute reactions' above.)
•Early-delayed reactions – Early-delayed reactions that may occur several months after brain irradiation include transient focal neurologic symptoms with or without increased contrast enhancement on magnetic resonance imaging (MRI; ie, pseudoprogression). (See 'Early-delayed reactions' above.)
●Stereotactic radiosurgery
•Acute reactions – With stereotactic radiosurgery, appropriate limitation of radiation doses and treatment volume make severe acute reactions rare. Less severe reactions (nausea, dizziness, seizures, new headache) may be seen within two weeks after treatment. (See 'Stereotactic radiosurgery' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Brian Kavanagh, MD, MPH, and Ari Ballonoff, MD, who contributed to an earlier version of this topic review.
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