Vascular Damage

Transient disruption of the blood-brain barrier, possibly initiated by sphingomyelinase-mediated endothelial apoptosis, is thought to be responsible for the acute or early-delayed, steroid-responsive forms of radiation toxicity.^11–13 A vascular theory has also been advocated to explain radiation necrosis. Necrosis would be a consequence of ischemia secondary to blood vessel damage. Vascular damage is indeed prominent during radionecrosis, including thrombosis, hemorrhage, fibrinous exudates, telangiectasias, vascular fibrosis/hyalinization with luminal stenosis, and fibrinoid vascular necrosis. Furthermore, a progressive endothelial cell loss and vessel rarefaction seems to precede white matter necrosis.¹² Thus, a cascade (involving signaling molecules among others) could be initiated at the time of irradiation, producing gradual cell loss throughout the clinically silent period.³ At the molecular level, VEGF seems to play a pivotal role in the endothelial cell loss.⁹ This progressive loss would eventually lead to overt necrosis.¹⁴ Despite these findings, several points argue against a purely ischemic model: first, neurons are very sensitive to ischemia and should be prominently damaged if the lesion was primarily vascular, whereas neurons are in fact largely spared during radionecrosis.¹⁵ Second, vascular damage is not always present in radionecrosis.¹⁶ Other cellular mechanisms may be involved and perpetuate vascular damage or contribute to edema, gliosis, and demyelination in the brain, such as upregulation of diverse adhesion molecules,¹⁷ production of cytokines,^18,19 or cumulative oxidative stress in endothelial cells.

Oligodendrocytes

The demyelinating lesions observed after RT underscore the putative role of oligodendrocytes as a target of radiation damage. Oligodendrocytes are responsible for the production of the myelin sheath in the CNS and derive from progenitor cells such as O-2A. CNS radiation induces depletion of oligodendrocytes and suppresses, at least transiently, the production of oligodendrocyte progenitors,^20–22 possibly through a p53-dependent pathway.^23–25 However, the contribution of demyelination in tissue destruction remains questionable since severely demyelinating conditions such as multiple sclerosis do not lead to overt necrosis.¹⁵

Other CNS Cell Types

Several studies over the past few years have focused on the potential role of neurons, astrocytes, and microglia in the development of radiation-induced lesions, either as primary targets or through alterations of their regulatory capacity.^26–28 Particularly noteworthy is the possible role of microglia²⁹ that may enhance radiation injury through persistent oxidative stress.^30,31 Radiation damage to the subventricular zone, a tissue containing glial and neural stem cells, was reported more than 25 years ago.³² Recent studies have found a dose-dependent reduction of neural stem cells of the subependyma after irradiation in this region.^33,34 Their implication in radiation injury thus seems probable but remains to be elucidated.

As a whole, the development of radiation injury is complex, and results from interactions between vascular cells and oligodendrocytes, as well as neural stem cells and the physiological responses of these cells to injury. A wide range of cell interactions mediated by cytokines and other molecules and the influence of indirect factors such as microglial proliferation or the production of oxidative products resulting from cell destruction may account for the wide variety of lesions observed from a patient to another.

Somnolence Syndrome

This condition was first described in the late 1920s in children receiving low-dose RT for scalp ringworm. Several studies reported cases of children who developed somnolence syndrome 5 to 8 weeks after prophylactic cranial RT for leukemia^40,41; other reports have shown that it also occurs in adults. The incidence of somnolence syndrome varies greatly (with figures ranging from 8%⁴¹ to 84%⁴²; this difference is related to various factors including tumor types, radiation dose, fractionation, and diagnostic criteria).⁴³ Prominent symptoms include drowsiness, hypersomnolence, nausea, and anorexia. Headache and/or fever may also be reported. Friends or family often notice irritability, attentional deficits, and short-term memory impairment. The clinical severity of this complication is variable, with extremes ranging from minimal disorders to sleep periods of over 20 hours a day.⁴¹ MRI studies are not contributory. Electroencephalographic abnormalities include nonspecific diffuse slow waves.⁴³ Most studies report a monophasic course of symptoms, usually with a favorable outcome within a few weeks. However, a prospective study on 19 adults treated for primary brain tumors with cranial RT (45 to 55 Gy) reported a biphasic pattern of symptoms with two critical periods (from the 11th to the 21st day and from the 31st to the 35th day) following RT.⁴⁴ Furthermore, in this study, an accelerated fractionation led to significantly more severe drowsiness and fatigue than a conventional scheme. Some authors advocate the use of steroids during and after radiotherapy as prophylactic or symptomatic treatment.⁴⁵ A prospective double-blind randomized trial in leukemic children found that a dose of 4 mg/m² of dexamethasone during cranial radiotherapy reduced the incidence of somnolence syndrome (17.6% vs. 64.3%) as compared to a dose of 2 mg/m².⁴⁶

Worsening of Preexisting Symptoms, or Tumor Pseudoprogression

In patients under treatment for malignant brain tumors, a worsening of preexisting neurological focal deficits leads to concerns over tumor progression, especially when observed in association with features of the somnolence syndrome and with transitory cognitive impairment. This complication arises within 6 weeks to 3 months after RT, and is clinically impossible to differentiate from progressive disease. Neuroimaging may be normal or show edema and contrast enhancement within the tumor bed, a situation that does not allow this syndrome to be differentiated from tumor recurrence and explains why inclusion of patients in experimental regimens for “recurrence” is not indicated during this period⁴⁷; it is worth noting that this radiological pattern can also be associated with no clinical worsening—“pseudoprogression” rates can reach 20% after a concomitant temozolomide and radiotherapy regimen used to treat glioblastoma and may be associated with better tumor response.⁴⁸ Improvement usually follows within a few weeks or months and a close followup of CT or MR scan will show spontaneous regression within 4 to 8 weeks. As in the somnolence syndrome, the treatment lies in supportive care with steroids. Improvements in imaging techniques such as magnetic resonance spectroscopy (MRS) may help in distinguishing between pseudoprogression and true progression but are limited by the fact that residual tumor is often still present within the irradiated area.

Transient Cognitive Decline

A transient cognitive decline can be observed within the first 6 months after cranial RT, mainly affecting attention and recent memory, and may sometimes be associated with a somnolence syndrome. Armstrong et al.⁴⁹ prospectively followed five patients treated for primary brain tumors: memory impairment was conspicuous in all patients 1.5 months after focal cranial RT (43 to 63 Gy), but complete regression was observed after 2.5 to 10.5 months. In another prospective study by Vigliani et al.⁵⁰ comparing 17 patients treated with focal cranial RT (54 Gy) for good-prognosis gliomas and 14 matched control patients who did not undergo RT, 36% of the patients had a significant early-delayed impairment of their reaction test, with a return to normal baseline performance 12 months after RT. This test result was correlated with their occupational status: 69% of the patients could not work at 6 months, whereas 73% had continued or resumed their jobs at 1 year. In our experience, informing patients about this possible difficulty in returning to a normal life (particularly work), at least during the first 6 months following radiotherapy, is useful. Although severe and, in some cases, persistent early-delayed symptoms have been occasionally reported,⁵¹ it is of note that transient cognitive impairment does not appear to be a clear-cut prognostic factor predicting the further development of long-term cognitive disorders.

Subacute Rhombencephalitis

Distinct from brainstem radionecrosis, which occurs later, early-delayed subacute rhombencephalitis may be observed about 1 to 3 months after RT using portals involving the brainstem, as in ocular, pituitary, or head and neck tumors. The clinical picture includes ataxia, dysarthria, diplopia, and/or nystagmus as well as auditory loss. In some cases, the cerebrospinal fluid analysis shows inflammatory changes. MRI may demonstrate white matter abnormalities appearing as grossly round or more extensive T1-weighted hypointensities and T2-weighted hyperintensities affecting the brainstem and the cerebellar peduncles; the lesions may enhance after gadolinium injection.^52,53 The condition usually improves progressively over a few weeks to a few months, either spontaneously or with steroids, but coma and death have been reported in rare cases.^54,55

Focal Brain Radionecrosis

Focal radionecrosis constitutes a challenging complication of radiation therapy because it often mimics tumor recurrence and its functional consequences can be devastating. This complication may occur not only in patients who received local RT for a primary or metastasic brain tumor but also in patients without brain lesions with a history of RT for extraparenchymal lesions, in whom normal brain was included in the radiation field (head and neck or pituitary tumors, meningiomas, skull osteosarcomas). A classical example is the bilateral medial temporal lobe necrosis that results from RT for pituitary or nasopharyngeal tumors. This once frequent complication of conventional RT has become rarer over the last 20 years, as a consequence of the generalized use of safer irradiation protocols. It has been shown that the upper limits of a “safe dose” were defined by a total dose of 55 to 60 Gy administered to a focal field with fractions of 1.8 to 2 Gy per day. Vascular risk factors such as diabetes, old age, and associated chemotherapy may also favor the potential development of radionecrosis. However, patients without any particular risk factors may develop radiation necrosis, probably because of an individual, unpredictable sensitivity to irradiation.⁵⁶ The focal delivery of a single large radiation fraction during “radiosurgery” may also lead to focal necrosis of the brain adjacent to the irradiated lesion. In arteriovenous malformations (AVM), the incidence of brain necrosis ranges from less than 5% to 20% of cases, with location and volume found to be the main risk factors.^57–59 After standard RT, radiation necrosis generally occurs within 1 to 2 years,⁶⁰ but it has also been observed after several decades. As described above, shorter latencies (as short as 3 months) have also been reported, especially in patients treated with interstitial brachytherapy⁶¹ or radiosurgery. Patients may experience seizures (first symptom in about 50% of cases), intracranial hypertension, and/or focal neurological deficits.^62–64 Such symptoms closely mimic tumor recurrence or progression.

Diagnosing radiation necrosis is often a challenge. In many cases, CT and MR scans show a tumor-like pattern, often indistinguishable from tumor progression or recurrence.⁶⁵ As diagnostic assessment based on clinical and standard neuroimaging data is difficult, many studies have tried to address the problem of noninvasive differentiation between tumor recurrence/progression and radionecrosis. Positron emission tomography (PET) with ¹⁸F-fluorodeoxyglucose⁶⁶ or ¹¹C-methionine, single photon emission computed tomography (SPECT) with ²⁰¹thallium or marked methoxy-isobutyl-isonitrile (99mTc-MIBI),⁶⁷ and, more recently, the use of 3-[¹²³]iodo-alpha-methyl-l-tyrosine (IMT)^68,69 have been used to assess the nature of the lesions. In typical cases, radionecrosis is characterized by hypometabolism and tumoral growth by hypermetabolism. The more recent development of magnetic resonance spectroscopy (MRS) seems promising⁷⁰: spectral analysis of necrosis areas shows an overall, harmonious decrease of metabolite peaks, and a possible increase of lipids corresponding to cellular necrosis; no lactate peak is observed.^71,72 However, none of these techniques offers 100% sensitivity or specificity.^73,74 One of the reasons for limitations is the frequent coexistence of radiation-induced necrosis with viable tumor tissue within the same area, a situation that obviously renders clear cut distinction impossible.³⁷ In some cases, angiography may provide further information, with an avascular mass seen in patients with radionecrosis; however, the risks and benefits of this procedure must be carefully weighed. While neuropathological examination remains the diagnostic standard (Figure 17-2),⁷⁵ even pathological analysis may be difficult because of the frequent mixture of both residual/recurrent tumor and radiation necrosis within the lesion.¹³

Figure 17-2 Radionecrosis in the cortex and subcortical white matter in a patient who had received radiation treatment for a high-grade glioma. A, Border zone between gliotic brain tissue (Gl) and area of radionecrosis, showing loss of cells, rarefaction of the tissue, and occasional foci of necrosis (Ne). B, Vascular changes with thickening and hyalinization of vessel walls. This example is from the transition zone between gliotic and rarefied tissue. C, Immunohistochemical staining for the neuronal marker NeuN showing occasional neurons labeled in brown (upper part), and in the lower part, the area of rarefaction with an entire loss of neurons. D, The same area stained for the astrocyte marker GFAP showing brisk reactive astrocytes on the top, and a transition to an acellular area below, containing only astrocyte processes and hardly any viable cells (Ne). Scale bar 250 μm (A, C), 60 μm (B), and 500 μm (D).

Resection of necrotic foci is often the best treatment in symptomatic cases. Steroids are generally used, with possible long-term improvement³⁷; however, steroid dependence does occur. Other treatments have been reported in this setting, but their efficacy has not yet been addressed in large studies: anticoagulants have been prescribed by Glantz et al.⁷⁶ in eight glioma patients (seven with histological evidence of necrosis) after the failure of steroids, leading to improvement in five patients. In our experience, anticoagulants have been somewhat disappointing. Further assessment of this therapy is required to confirm those results. Some authors have advocated the use of hyperbaric oxygen (HBO), with the rationale that HBO increases the tissue pO₂ and enhances angiogenesis. Chuba et al.⁷⁷ treated ten patients with CNS radionecrosis (proved by biopsy in eight cases) with 100% oxygen at 2.0 to 2.4 atm for 90 to 120 minutes/session in at least 20 sessions. All patients were stabilized or improved initially, and the six surviving patients showed durable improvement after 3 to 36 months. However, most patients were given steroids, and the respective effect of each treatment is not clear. HBO treatment was also reported to improve radionecrosis due to radiosurgery.^78,79 The possible role of HBO in radiation-induced neurotoxicity needs to be evaluated in prospective trials.⁸⁰ Other drugs or combinations such as pentoxifylline, alpha-tocopherol,⁸¹ low-iron diet, desferrioxamine, and pentobarbital¹ have also been proposed occasionally without definite evidence of efficacy. The usefulness of radioprotective agents such as difluoromethylornithine (DMO),⁸² U-74389G (a 21 aminosteroid⁸³), or others^84–87 in reducing the risk of necrosis remains to be determined. Preclinical studies have suggested that embryonic stem cell-derived glial precursors could be used as myelinating transplants in demyelinated postradiation experimental lesions.⁸⁸

Several assays have been developed to identify individuals at risk for radiation sensitivity, such as analysis of the survival fraction of cultured skin fibroblasts after 2 Gy irradiation,⁵⁶ study of radiation-induced chromosomal aberrations, search for the ataxia-telangectasia mutation, and the G2 cell-cycle phase delay analysis.^1,89 However, to date, such assessments have not reached the clinical setting.

Cognitive Dysfunction and Leukoencephalopathy

Late-delayed cognitive impairment covers a wide continuum of patterns ranging from mild dysfunction to severe (and sometimes fatal) dementia, and has become an important concern over the last 20 years. The impact (and awareness) of this complication has grown partly because of a better assessment of quality-of-life data in clinical practice, but also because of a growing population of long-term survivors with tumor stability or remission.

Considering cognitive dysfunction as a consequence of RT alone would result in a considerable overestimation of the incidence of radiation-induced sequelae. Cognitive impairment may be the consequence of complex interactions⁹⁰ between preexisting cognitive abnormalities (especially in the case of brain tumors), brain tumor growth, concomitant treatments (such as chemotherapy, antiepileptic⁹¹ or psychotropic drugs), paraneoplastic encephalomyelitis, and endocrine dysfunction. In practice, this should lead to a precise individual workup in patients with potential radiation-induced cognitive impairment, but also to a careful and critical interpretation of the higher cognitive dysfunction rates found in the literature. Interestingly, a study comparing 195 low-grade glioma patients (104 had undergone RT during the previous years) to low-grade hematological patients and controls, showed that cognitive dysfunction was mostly tumor-related; patients treated with doses per fraction over 2 Gy were the only ones to develop RT-linked memory impairment.⁹² A more recent study of these patients followed up for 12 years has shown a progressive cognitive decline in attentional and executive tasks in patients treated with radiotherapy fractions less than 2 Gy/fraction compared with unirradiated patients, which was not apparent after 6 years follow-up.^92a

Recent studies seem to confirm that RT plays a limited part in cognitive decline when using modern irradiation procedures.^93–95 Nevertheless, several factors have been clearly linked to an increased risk of leukoencephalopathy (Figure 17-3):

Figure 17-3 Axial FLAIR-weighted MRI of the brain showing a diffuse bilateral hypersignal of the hemispheric white matter compatible with severe radio-induced leukoencephalopathy, in a 52-year-old female patient treated with whole brain radiotherapy for brain metastases of an adenocarcinoma of the breast 15 years ago.

Methotrexate (MTX) is clearly implicated in combined toxicity; neurotoxic by itself, it is responsible for frequent cognitive dysfunction when associated with RT. In children, most studies to date have concluded that the combination of cranial irradiation and intrathecal MTX was associated with declines in both IQ and achievement scores.¹⁰³ In adults treated with WBRT (40 Gy + 14 Gy boost) and a combination of intravenous and intrathecal MTX for CNS lymphoma, the incidence of severe progressive cognitive impairment increases with age, reaching 83% in patients over 60 years.^104,105 The timing of MTX chemotherapy is important, because the cognitive dysfunction rate is higher whenever MTX is prescribed during or after RT. This drug should therefore be given before irradiation. Data about the neurotoxicity of other combinations are sparse, but agents such as nitrosourea, cisplatin, etoposide, cytarabine, or actinomycin D are also suspected to increase radiation-induced cognitive toxicity. Multidrug regimens or high-dose chemotherapy combined with WBRT are probably associated with a higher risk of neurotoxicity.¹⁰⁶ Although there is a progressive continuum between mild to moderate cognitive impairment and severe fatal dementia, we will consider the two conditions separately.

Radiation-Induced Mild to Moderate Cognitive Impairment

A mild to moderate cognitive dysfunction is more frequent in long-term survivors than real dementia. The features of this condition are not perfectly defined, as results greatly vary according to the studies, probably due to neuropsychological evaluation procedures, duration of follow-up, and population discrepancies.¹⁰⁷

In most reported cases, cognitive impairment affects mainly attention and short-term memory, while intellectual functions are generally preserved as assessed by neuropsychological evaluations. Nevertherless, most patients have to decrease or even discontinue their professional activities. CT scan may be abnormal, showing periventricular hypodensities, an increase in the normal interface between white and gray matter, and ventricular enlargement. However, there seems to be no correlation between CT-scan abnormalities and the degree of cognitive impairment. MRI shows variable degrees of T2-weighted hyperintensities in the white matter, with a gross correlation between neuropsychological status and white matter lesions (Figures 17-3 and 17-4).¹⁰⁸

Figure 17-4 Axial FLAIR-weighted MRI of the brain showing a mild difuse white matter hypersignal and severe cortico-subcortical atrophy in a 53-year-old male treated with whole brain radiotherapy and high dose methotrexate chemotherapy 8 years ago for a primary central nervous system lymphoma.

The course of the disease is difficult to predict: some patients deteriorate slowly while the majority apparently remains stable. Progression to dementia is seldom reported. There is no recognized treatment for this syndrome although some authors have advocated the use of methylphenidate for symptomatic relief.¹⁰⁹ More recently, anticholinesterase drugs have been used with encouraging results.¹¹⁰ Data from animal studies have also shown that the administration of erythropoietin (EPO) may prevent cognitive impairment.¹¹¹

Free-radical scavengers, such as amifostin or angiotensin-converting enzyme inhibitor (ACEi) could have a protective effect.^111b Amifostin is already under clinical investigation with controversial results,^111c but to date, despite encouraging preclinical data, no trial has been conducted with ACEi.

Radiation-Induced Brain Tumors

The precise role of RT in the development of a tumor is difficult to determine and cannot be assessed with certainty, in great part because these tumors have no distinctive features compared to unirradiated patients. However, data from animal and epidemiological studies indicate that irradiated patients or animals are more likely to develop a second brain tumor than would have been expected from the control data.¹¹⁷

The relative risk of developing a radiation-induced tumor has been studied in several large studies. A study by Ron et al. of 10,834 patients treated with low-dose cranial and cervical irradiation for Tinea capitis (mean dose to neural tissue: 1.5 Gy) showed a relative risk of developing a tumor of 6.9; the risk for glioma was 2.6.¹¹⁸

In another study of 10,106 survivors of childhood cancers by the British Childhood Cancer Research Group,¹¹⁹ the relative risk of developing a secondary CNS tumor was 7. Most other studies have found similar results.^120,121 However, the risk is probably higher in patients treated for acute lymphoblastic leukemia (ALL): a large retrospective cohort study of 9720 children¹²² found a relative risk of developing a nervous system tumor as high as 22. In another setting, a large study on second brain tumors in 426 patients with pituitary adenoma treated with surgery and radiotherapy showed a 2.4% risk at 20 years.¹²¹

Criteria for a radiation-induced tumor include: (a) long interval between radiotherapy and the occurrence of the second tumor (the mean onset delay is 12 years, with cases ranging from 1 to 40 years); (b) tumor growth within the radiation portal or at its margins; (c) a different histological subtype. After stereotactic radiosurgery, radiation-induced neoplasms are extremely rare, with only four reported cases in the literature.¹²³ Three types of tumors have been reported to be linked with cranial irradiation: meningioma in about 70% of cases, glioma in 20%, and sarcoma in fewer than 10%. More than 300 cases of radiation-induced meningiomas have been reported in the literature; female predominance is less prominent than in spontaneous meningiomas.¹²⁴ The risk of occurrence correlates with radiation dose: low-dose RT induced a relative risk of 9.5 in one study,¹¹⁸ whereas high-dose RT was linked to a relative risk of 37.¹²⁰ The tumor emerges after a long latency period: a review found extremes ranging from 2 to 63 years (mean 18.7 years) after high-dose RT.¹²⁵

Most patients (68%) had been irradiated during childhood, and the interval between RT and the onset of the tumor was shorter in younger patients; however, the radiation dose did not influence the latency. Radiation-induced meningiomas are often multiple and recurrent with malignant histological features.^126,127 Unlike sporadic meningiomas, NF2 gene inactivation and chromosome 22q deletions seem to be less frequent in radiation-induced meningiomas, while other chromosomal lesions (especially loss of 1p) possibly induced by irradiation, may be more important in the development of these tumors.^128,129

Radiation-induced gliomas are much less frequent. Since 1960, about 120 cases have been reported in the English literature;^130,131 fewer than half of them were glioblastomas. In the group of patients treated with RT for acute leukemia, multifocality occurred in 20% of cases. The median delay of onset ranges from 6 to 9 years.¹³¹ The prognosis of these tumors is poor: intrinsic resistance to treatment as well as previously received aggressive therapies considerably limits the applicable therapies.

Molecular alterations are apparently the same in sporadic and radiation-induced gliomas.¹³² Fewer than 40 cases of sarcomas have been reported to date, different and they consist of several histological types (e.g., gliosarcomas, meningiosarcomas, neurofibrosarcomas).¹¹⁷

Radiation Vasculopathy

Distinct from radionecrosis, in which severe lesions of the arterioles and capillaries constitute a cardinal feature, radiation can induce other types of vascular damage leading to stroke or intracerebral hemorrhage.