Adverse Effects
Following Irradiation of the Brain or Spine
from Abeloff:
Clinical Oncology, Acute and Early Delayed Effects Following Cranial Irradiation A variety of side effects can occur following radiation to the CNS. These side effects can be divided into acute effects, which occur during the treatment, delayed early effects, which occur within a few months of radiation, and late effects, which occur months to years later. Acute effects following cranial irradiation include fatigue, nausea, headaches, anorexia, and alopecia. Patients often complain of fatigue, not just with cranial radiation, but with radiation to other regions of the body, and as a result they often need to sleep longer than usual or take naps during the day. Patients may experience nausea within hours following the administration of the radiation and headaches during the course of treatment. Nausea is usually well controlled with antiemetics such as ondansetron or granisetron. Nausea and headaches are thought to be caused by radiation-induced edema and can be ameliorated with corticosteroids. Patients who are placed on steroids prior to radiation often continue them when radiotherapy is started. In patients receiving craniospinal radiation, the nausea and anorexia may be compounded by the radiation that the upper gastrointestinal tract receives as a result of exit dose from the spinal field. Hair loss generally starts after the scalp has received 20 to 30 Gy. It is not generally permanent, but regrowth of hair may take months, and often in the regrown hair is thinner or even a different color than the original. In areas that receive a high dose of radiation, especially with tangentially directed fields, alopecia may be permanent. Other acute side effects from cranial irradiation may include accumulation of cerumen in the ear canals and serous otitis media. The most common delayed early effect from radiation is the somnolence syndrome, which is characterized by excessive drowsiness, nausea, and irritability.If it occurs, it generally does so 1 to 3 months after radiation has been completed. This syndrome is thought to be due to transient, diffuse demyelination. It is usually seen following whole-brain irradiation for ALL but can also be seen after radiation for brain tumors. The syndrome resolves spontaneously, but steroids can shorten its duration. Delayed early effects following cranial irradiation can also take the form of focal neurologic signs due to intralesional reactions related to tumor response or perilesional reactions related to edema or demyelination. Brain Necrosis and Neurocognitive Deficits Following Cranial IrradiationThe pathophysiology of late effects from CNS irradiation is poorly understood. Some of the effects may be caused by degenerative changes in the supporting glial cells, whereas others may be caused by vascular changes due to endothelial cell loss and capillary occlusion. One of the most serious late effects from cranial irradiation is brain necrosis, which may cause significant and persistent neurologic injury. It may also produce progressive cerebral edema and mass effect, requiring prolonged corticosteroid use or surgery. Third, it may be confused with tumor growth, resulting in the inappropriate use of antitumor therapies. The onset of radiation necrosis includes behavioral changes—lethargy and dementia, headache and papilledema, and seizure. Clinical signs and symptoms are usually identified from 2 to 3 years after radiation, though confirmed cases have been detected as early as 9 months and as late as 16 years after radiation. The signs and symptoms are strongly related to the site of radiation necrosis; however, the most common symptoms are focal motor deficits. Radionecrosis is often difficult to distinguish from recurrent tumor by CT or MRI, which may show increased signal intensity on T1-weighted images and contrast enhancement on T1-weighted images. PET scanning with FDG may help distinguish viable tumor from necrotic tissue. Often surgical exploration is necessary, not only to establish a diagnosis, but also as a therapeutic intervention by removing the region of necrosis. Histopathologically, the changes seen in radiation-induced necrosis are generally limited to the white matter and include focal coagulative necrosis and demyelination Accurate data regarding the incidence of brain necrosis based on CT/MRI imaging comes from a randomized trial of radiation for low-grade gliomas. In this study, the 2-year actuarial incidence of brain necrosis was 2.5% for patients receiving 50.4 Gy and 5% for those receiving 64.8 Gy. Neurocognitive deficits are often observed following cranial radiation, especially in young children. Many of the sequelae manifest several years after treatment of children with brain tumors, which mandates long-term follow-up. Sequential assessments of neurocognitive function demonstrated progressive deterioration during 6 years after whole-brain radiotherapy in children with ALL treated with 18 Gy of whole-brain irradiation. Numerous studies of neurocognitive function in children following whole-brain irradiation for ALL have been performed. In summary, these studies show that whole-brain irradiation can lead to decline in neurocognitive function, an effect which appears to be greater with younger children and higher doses of radiation (24 Gy) but which can be seen with 18 Gy. An interaction between methotrexate (intrathecal or high-dose systemic) and whole-brain irradiation may also be causing these late effects. Studies of patients treated for PNET/medulloblastoma have uniformly shown poor outcomes in terms of intelligence, memory, language, attention, academic skills, psychosocial function, and quality of life, even in patients treated as adults.Many of these patients received 36 Gy to the whole brain followed by a boost to a total dose of 54 to 55.8 Gy to the posterior fossa. Data suggest that these patients have a decline in their IQ values because of an inability to acquire new skills and information at a rate comparable to their healthy same-age peers, rather than to a loss of previously acquired information and skills. These neurocognitive deficits have been correlated with loss of white matter in the brain, and the younger the patient when given radiation, the more severe the deficits. Mulhern and associates performed an analysis of neurocognitive function after treatment for brain tumors, pooling data from 22 studies with a total of 544 patients. They showed that the most critical factors influencing intellectual outcome are the dose of radiation and young age at the time of radiation. Younger children (<4 years old) who received whole-brain radiation showed a 14-point decrease in IQ compared with older children. Accordingly, current therapeutic strategies do not use whole-brain radiation in children younger than 3 years and try to reduce radiation doses. Accurate assessment of the effects of changes in cranial radiation on neurocognitive development in young children is complicated by important methodologic and study design problems. A common concern is that measurement of IQ, per se, is neither a sensitive nor specific method of assessing the cognitive impairments of these patients. Accordingly, efforts have been made to establish and validate reliable and easy-to-use instruments for assessing IQ as well as other neuropsychological aspects. Another treatment complication associated with cranial radiotherapy is leukoencephalopathy, which is most often associated with intravenous or IT methotrexate (MTX) and cranial radiation. Young age is also an important risk factor; however, leukoencephalopathy can affect all age groups. Histologically multifocal white matter destruction with loss of myelin occurs, especially in the periventricular regions. MRI scans show these periventricular abnormalities. CT scans may also show intracerebral microcalcifications due to mineralizing microangiopathy. The clinical expression of leukoencephalopathy ranges from mild evidence of white matter injury on neuroimaging studies to severe necrotizing leukoencephalopathy with profound neurologic impairment and, in some cases, death. Mild or subclinical cases are more common than severe necrotizing leukoencephalopathy. The bulk of the experience comes from children who received 24 Gy whole-brain radiation along with high doses of intravenous (IV) and intrathecal (IT) MTX. The incidence of leukoencephalopathy is low in patients who receive cranial radiation therapy (RT) and IT MTX or cranial radiation and IV MTX but may be as high as 45% in patients who receive all three treatments. In general MTX is most toxic when given during or following radiation. Although the majority of the literature on neurocognitive function following cranial irradiation concerns children, some data are available for adults. Taphoorn and associates found no significant differences in neurocognitive function in patients with low-grade gliomas who received radiation (45 to 63 Gy) versus those who did not. In another retrospective study, young adults with low-grade brain tumors treated with 54 to 56 Gy of radiation to limited fields often showed a transient early delayed drop in neuropsychological performance at 6 months; however, the risk of long-term cognitive dysfunction was low, at least out to 4 years. In a North Central Cancer Treatment Group (NCCTG) randomized study of 64.8 versus 50.4 Gy for low-grade gliomas, data regarding cognitive performance were collected prospectively. Analysis of this data with a median follow-up of 7.4 years in the patients still alive showed that the vast majority of patients with normal baseline MMSE (mini-mental status examinations) maintained these after radiotherapy. Patients with abnormal MMSE prior to RT were more likely to have an improvement in cognitive abilities than deterioration after receiving RT. Armstrong and coworkers conducted prospective, comprehensive, longitudinal neuropsychological testing on 26 adult patients with low-grade supratentorial brain tumors, mostly gliomas, who had received radiotherapy. Nine patients underwent testing 6 years following radiotherapy. No declines were noted in most neurocognitive tests. Seven of the 37 neuropsychological tests showed improvement over 6 years. However, declines in selected tests of cognitive function, such as visual memory, emerged only at 5 years. Based on these and other studies, one recent review on the neurocognitive effects of radiotherapy on patients with low-grade gliomas came to the conclusion that the weight of evidence suggests only sporadic, limited neurocognitive damage from focal radiotherapy at the doses usually prescribed. These patients do not appear to suffer from widespread cognitive impairment or dementia. Less data are available on the cognitive functioning of survivors of high-grade gliomas. One study found that most long-term survivors of high-grade glioma experienced significant cognitive difficulties.[146] However, all the patients on this study had received whole-brain irradiation as part of their treatment, which is no longer standard treatment for high-grade gliomas. Cranial irradiation can result in arterial vascular problems such as vessel obliteration or narrowing resulting in a stroke-like syndrome.[147] These complications are rare, but when they occur they are more likely to happen following radiation of the parasellar region. Endocrine Deficits Following Cranial or Spinal IrradiationEndocrine problems are common following cranial irradiation, particularly in children. They include growth hormone deficiency, thyroid dysfunction, and gonadal dysfunction. The hypothalamus is more radiosensitive than the pituitary gland and is responsible for endocrine dysfunction at lower doses. However, at higher doses (>40 Gy), both the anterior pituitary gland and the hypothalamus contribute to endocrine dysfunction. Of all the hormones, growth hormone is the most likely to show deficiency following irradiation. Growth hormone deficiency is seen in the majority of children who have received whole-brain irradiation. One study found that in children with ALL given 24 Gy to the whole brain, 56% developed growth hormone deficiency, whereas no such problems were seen in children given 18 Gy, at least at 4 years. The latency of onset is dose-dependent, being shorter with higher doses. Growth may be further impaired by spinal irradiation, which directly affects vertebral body growth center. Precocious puberty may also occur following relatively low doses, on the order of 18 Gy. However, deficiencies in the other hormones such as gonadotropins, thyroid-stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH) are rare below 40 Gy.Thyroid dysfunction is common in patients treated with high-dose radiotherapy for brain tumors. Constine and coworkers studied endocrine function in 32 patients with brain tumors not involving the hypothalamic-pituitary region who received 39.6 to 70.2 Gy to this region. Sixty-five percent of patients developed hypothalamic or pituitary hypothyroidism. Fourteen of 23 (61%) postpubertal patients had evidence of hypogonadism as manifested by oligomenorrhea or low estradiol levels or low testosterone levels. Fifty percent had mild hyperprolactinemia. Subtle abnormalities in adrenal function were seen in 35% of patients. In patients receiving craniospinal radiation, hypothyroidism may also occur secondary to exit dose to the thyroid gland. In a study of patients treated for brain tumors not involving the hypothalamic-pituitary axis from the Christie Hospital in Manchester, the incidence of hypothyroidism was 15% versus 33% (P = .013), respectively, for patients receiving cranial or craniospinal irradiation. The mean spinal dose was 29 Gy, and the exit dose to the thyroid gland ranged from 10 to 15 Gy. Optic Neuropathy Following Cranial IrradiationIrradiation of tumors that are close to the optic nerves or optic chiasm may result in sufficient dose to these structures so that optic neuropathy is a concern. Two major classes of optic neuropathy are recognized, anterior optic neuropathy and retrobulbar optic neuropathy. The former is thought to be due to vascular injury affecting the nerve head inside the globe anterior or adjacent to the lamina cribrosa. This type is associated with swelling of the optic head, in contrast to retrobulbar optic neuropathy, which is due to more proximal injury to the optic nerve. Diagnostic criteria for retrobulbar optic neuropathy include (1) visual loss (monocular or binocular) accompanied by corresponding visual field defects, (2) funduscopic examination often showing a pale optic disk but without edema, (3) onset 6 months to several years following radiation therapy that delivered a significant dose to the optic nerve/chiasm, and (4) no radiologic evidence of visual pathway compression.MRI scans may show pathologic contrast enhancement of the region of the optic nerve/chiasm that received a high dose of radiation. Parsons and coworkers examined radiation-induced optic neuropathy in patients treated for primary extracranial head and neck tumors at the University of Florida.[158] Out of 215 optic nerves at risk, they found anterior optic neuropathy in five nerves and retrobulbar optic neuropathy in 12 nerves. No injuries were observed in 106 optic nerves that received less than 59 Gy. The 15-year actuarial risk of optic nerve neuropathy after 60 Gy or more was 11% when daily fractions less than 1.9 Gy were used versus 47% when 1.9 Gy or more were used. The data cited here suggest that the optic nerve/chiasm tolerance is at least 59 Gy; however, the University of Florida population did not include patients with intracranial tumors compressing the optic nerve/chiasm. Possibly, in the latter situation the tolerance of the optic nerve/chiasm is lower because of ischemic injury. Patients with pituitary adenomas or craniopharyngiomas have been reported to develop optic neuropathy after doses as low as 45 to 50 Gy, although in many of these cases the daily fraction size was greater than 2 Gy. Based on these results, most investigators currently recommend limiting the optic chiasm/nerve dose to 50 Gy in 1.8- to 2-Gy fractions in the treatment of pituitary adenomas or craniopharyngiomas. For other brain tumors requiring higher doses, most radiation oncologists would try to restrict the optic nerve/chiasm dose to 55 Gy or lower. Adherence to these guidelines should keep the risk of radiation-induced optic neuropathy extremely low (1% or less) but unfortunately will not completely eliminate it. Second Neoplasms Following Cranial IrradiationSecond neoplasms including malignant gliomas and meningiomas remain relatively uncommon consequences of radiation therapy for brain tumors. Recent reports raise concerns that the addition of adjuvant chemotherapy may increase the risk of second malignancies in long-term survivors of childhood brain tumors. This finding may be especially true after prolonged use of alkylating agents and etoposide with or without radiation. Myelopathy Following Spinal IrradiationA delayed early effect that can be seen after irradiation of the cervical spine is Lhermitte's sign, which is characterized by an electric shock-like sensation precipitated by forward neck flexion.[164] The symptoms typically start weeks to a few months after radiation. They are maximal at first but abate with time without the development of any objective signs. The paresthesias most commonly occur in the lumbosacral region but can also involve the upper and lower extremities and the upper back. This transient form of Lhermitte's sign can occur after doses of radiation well within accepted spinal cord tolerance and is not associated with any permanent late sequelae. The pathogenesis is thought to due to an inhibitory effect on oligodendrocytes that results in transient reversible demyelination. However, a more ominous form of Lhermitte's sign can present after a longer latency period following radiation (at least a year), which then progresses to chronic radiation myelopathy. Chronic myelopathy is the most catastrophic late effect that can occur following spinal cord irradiation. Nearly half of patients who develop chronic myelopathy will die from complications. A biphasic distribution occurs in the latency period from radiation to the onset of myelopathy. The early peak is from 12 to 14 months and the second peak from 24 to 28 months. The pathologic insults that lead to myelopathy include damage to oligodendoglial cells, causing demyelination and white matter necrosis, and death of endothelial cells, resulting in vascular injury. Some patients develop partial neurologic dysfunction, and others progress to complete paraplegia or quadriplegia. No clinical or radiologic findings are pathognomonic for radiation-induced myelopathy. Therefore, the diagnosis is usually made by a combination of (1) neurologic findings corresponding to a level just below the irradiated region, (2) a history of spinal cord irradiation to a high dose (>45 Gy) at least 6 months prior to the onset of symptoms, (3) MRI findings of increased intensity on T2-weighted images in the irradiated region, and (4) exclusion of other etiologies. The MRI findings in spinal cord myelopathy can mimic tumor recurrence with gadolinium enhancement on MRI The probability of developing chronic radiation myelopathy is dependent not only on the total dose delivered to the spinal cord but also on the fraction size. It is now well recognized that larger fraction sizes are associated with more severe later effects. However, this relationship was not always appreciated, and many of the cases of chronic myelopathy described in the literature occurred in patients who received 40 to 60 Gy to the cord in large daily fractions (2.45 to 5 Gy). Using standard fraction sizes (1.8 to 2 Gy/day), a commonly observed limit for dose to the spinal cord is 45 Gy. In a study of the incidence of myleitis after irradiation of the cervical cord, Marcus and Million found that out of 1112 patients, only 2 (0.18%) developed chronic radiation myelopathy. Two of 471 patients (0.42%) receiving between 45 and 50 Gy developed this complication. No patient out of 442 who received between 40 and 45 Gy and no patient out of 75 who received greater than 50 Gy developed myelitis. The authors' conclusion was that even when going to 50 to 55 Gy to the cervical cord, the likelihood of developing chronic myelopathy was extremely low. However, it is possible to see myelitis even if the spinal cord dose is limited to 45 Gy. This paper mentioned reports in the literature of myelitis developing at doses less than 45 Gy or even less than 40 Gy, using 1.8 to 2 Gy daily fractions. However, this development would be extremely rare. It is estimated that the risk of developing chronic myelopathy at this dose is 0.2% or less.
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