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First Published Online November 19, 2008
The Oncologist, Vol. 13, No. 12, 1285-1295, December 2008; doi:10.1634/theoncologist.2008-0130
© 2008 AlphaMed Press

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Neuro-Oncology

Clinical Patterns and Biological Correlates of Cognitive Dysfunction Associated with Cancer Therapy

Jörg Dietricha, Michelle Monjeb, Jeffrey Wefelc, Christina Meyersc

aDepartment of Neurology, Division of Neuro-Oncology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA; bDepartments of Neurology and Developmental Biology, Stanford Institutes of Medicine, Stanford University, Palo Alto, California, USA; cDepartment of Neuro-Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Key Words. Neurotoxicity • Cognitive dysfunction • Chemotherapy • Radiation therapy • Progenitor cells • Neural stem cells

Correspondence: Jörg Dietrich, M.D., Ph.D., Department of Neurology, Division of Neuro-Oncology, Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, Boston, Massachusetts 02114, USA. Telephone: 617-726-3650; Fax: 617-643-2591; e-mail: jdietrich1{at}partners.org

Received June 10, 2008; accepted for publication October 26, 2008; first published online in THE ONCOLOGIST Express on November 19, 2008.

Disclosure: Employment/leadership position: None; Intellectual property rights/inventor/patent holder: None; Consultant/advisory role: Jeffrey Wefel, Genentech; Christina Meyers, Genentech, MGI Pharma, Regeneron; Honoraria: None; Research funding/contracted research: Jeffrey Wefel, AstraZeneca, Schering-Plough; Christina Meyers, Angiochem; Ownership interest: None; Expert testimony: None; Other: None. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.


   Learning Objectives
Top
 Learning Objectives
Abstract
 Introduction
 The Clinical Spectrum of...
 Patterns of Cognitive...
 Neuroimaging Studies in Patients...
 Radiation-Associated...
 Cell-Biological Basis of...
 Cell-Biological Basis of...
 Current Strategies to Limit...
 Summary and Future Perspectives
 Author Contributions
 References
 
After completing this course, the reader should be able to:

  1. Assess the common symptoms of central nervous system toxicity seen in patients treated with chemotherapy and cranial radiation.
  2. Diagnose the patterns of cognitive dysfunction encountered in patients treated for cancer.
  3. Evaluate cranial imaging abnormalities consistent with nervous system toxicity from cancer therapy.
  4. Explain the novel concepts of the cell-biological consequences underlying chemotherapy- and radiation therapy–associated nervous system toxicity.

This article is available for continuing medical education credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 The Clinical Spectrum of...
 Patterns of Cognitive...
 Neuroimaging Studies in Patients...
 Radiation-Associated...
 Cell-Biological Basis of...
 Cell-Biological Basis of...
 Current Strategies to Limit...
 Summary and Future Perspectives
 Author Contributions
 References
 
Standard oncological therapies, such as chemotherapy and cranial radiotherapy, frequently result in a spectrum of neurocognitive deficits that includes impaired learning, memory, attention, and speed of information processing. In addition to classical mechanisms of neurotoxicity associated with chemo- and radiotherapy, such as radiation necrosis and leukoencephalopathy, damage to dynamic progenitor cell populations in the brain is emerging as an important etiologic factor. Radiation- and chemotherapy-induced damage to progenitor populations responsible for maintenance of white matter integrity and adult hippocampal neurogenesis is now believed to play a major role in the neurocognitive impairment many cancer survivors experience.


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
The Clinical Spectrum of...
 Patterns of Cognitive...
 Neuroimaging Studies in Patients...
 Radiation-Associated...
 Cell-Biological Basis of...
 Cell-Biological Basis of...
 Current Strategies to Limit...
 Summary and Future Perspectives
 Author Contributions
 References
 
Treatment strategies designed to target cancer cells are commonly associated with harmful effects to multiple organ systems, including the central nervous system (CNS). Neurotoxic adverse reactions include both acute and delayed complications. Cancer patients may experience a wide range of neurotoxic adverse symptoms, including vascular complications, seizures, mood disorders, and cognitive dysfunction. Cognitive dysfunction has been long recognized as a major problem in long-term survivors in the pediatric population [1, 2]. There is now growing evidence that cancer therapy–associated cognitive dysfunction appears to be a real phenomenon in many adults undergoing treatment for cancer and cannot simply be attributed to stress, fatigue, or depression [3–5].

As both radiation and chemotherapy alone can be associated with significant toxicity, the combination of radiation and chemotherapy may be, in particular, harmful to the CNS. With advanced treatment regimens and prolonged survival, neurological complications are likely to be observed with increasing frequency. In contrast to a large number of clinical studies and reports documenting neurotoxicity following cancer therapy, much less is known about the metabolic and cellular mechanisms underlying such damage. Previous concepts of possible processes underlying acute and delayed neurotoxicity in cancer patients, such as leukoencephalopathy, have suggested vascular injury, myelin toxicity, or immune-inflammatory mechanisms [6–9]. The cellular processes, however, underlying such treatment side effects remain largely unknown.

The identification and characterization of progenitor cell populations in the adult mammalian CNS have highlighted physiological processes particularly vulnerable to damage from cancer therapies. Stem and precursor cell populations are believed to be crucial to normal memory function and to play key roles in the maintenance of white matter integrity [10–12]. Indeed, recent experimental studies have revealed that toxicity to progenitor cells may be central in understanding delayed treatment side effects, including cognitive impairment and white matter disease [13–15].

Recognition of treatment-related neurologic complications is critically important to any oncologist, because symptoms may be confused with metastatic disease, tumor progression, paraneoplastic disorders, or opportunistic infections, and discontinuation of the offending drug may prevent irreversible CNS injury. The development of any neuroprotective strategy will critically depend on the identification of the exact mechanisms underlying the neurotoxicity. This review summarizes the clinical spectrum of cancer treatment–associated neurotoxicity with special emphasis on cognitive dysfunction. Recent developments in the understanding of the cellular mechanisms underlying cancer therapy–associated neurotoxicity are highlighted.


   THE CLINICAL SPECTRUM OF NEUROTOXICITY FOLLOWING CANCER TREATMENT
Top
 Learning Objectives
 Abstract
 Introduction
 The Clinical Spectrum of...
Patterns of Cognitive...
 Neuroimaging Studies in Patients...
 Radiation-Associated...
 Cell-Biological Basis of...
 Cell-Biological Basis of...
 Current Strategies to Limit...
 Summary and Future Perspectives
 Author Contributions
 References
 
Cancer treatment usually involves various modalities, including surgery, chemotherapy, and radiation. In addition, hormonal agents, steroids, antiepileptic agents, and other novel drugs (e.g., angiogenesis inhibitors) are increasingly used in cancer patients.

Neurotoxicity can result from direct toxic effects of the drug or radiation on the cells of the CNS, or indirectly through metabolic abnormalities, inflammatory processes, or vascular adverse effects. Survival commonly depends on a combined and aggressive treatment approach, and many patients are exposed to both radiation and multiple chemotherapeutic regimens applied sequentially in response to recurrent disease. As both radiation and chemotherapy are associated with significant dose-limiting neurotoxicity, the use of multimodal treatments and the application of multiple chemotherapeutic regimens significantly increase the risk of developing neurotoxicity.

Neurotoxicity has been observed with virtually all categories of chemotherapeutic agents [16–20]. As summarized in Table 1, neurologic complications may range from acute encephalopathy, headache, seizures, visual loss, cerebellar toxicity, and stroke to chronic side effects, including chronic encephalopathy, cognitive decline, and dementia [21–24]. Among the most puzzling aspects of cancer therapy–related toxicity is the occurrence of delayed and progressive neurological decline, even after cessation of treatment.


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  		Table 1. Complications of radiation and chemotherapy

 

   PATTERNS OF COGNITIVE DYSFUNCTION FOLLOWING CHEMOTHERAPY
Top
 Learning Objectives
 Abstract
 Introduction
 The Clinical Spectrum of...
 Patterns of Cognitive...
Neuroimaging Studies in Patients...
 Radiation-Associated...
 Cell-Biological Basis of...
 Cell-Biological Basis of...
 Current Strategies to Limit...
 Summary and Future Perspectives
 Author Contributions
 References
 
Adult patients typically report cognitive symptoms, such as difficulties with memory and attention, soon after initiating treatment. Frequently, these symptoms persist after completion of therapy and are a cause of considerable distress for individuals who are unable to return to their previous academic, occupational, or social activities, or are able to do so only with significant additional mental effort. Long-term evaluation of cancer survivors has raised concerns that cancer and cancer therapy may result in persistent and late emerging cognitive dysfunction [25–27]. This observation has been supported by recent experimental studies. Both radiation and commonly used chemotherapy agents have been shown to cause acute and delayed injury to the CNS [13–15].

The reported incidence of chemotherapy-related cognitive dysfunction is in the range of 15%–70% [3, 28, 29]. The most frequently described cognitive problems include difficulties with memory, attention, information-processing speed, and organization (i.e., executive dysfunction). Formal neuropsychological assessment typically uncovers difficulty with attention that parallels patient reports of "spacing out" and losing concentration at times. Inefficiency of working memory, information-processing speed, and executive function corresponds to patient reports of disorganization, difficulty multitasking, and overall slowness in performing tasks. Memory testing generally reveals reduced learning efficiency and memory retrieval problems in the context of relatively better memory consolidation. This pattern of cognitive performance has suggested a preferential dysfunction of the frontal and subcortical white matter networks.

Anticancer agents affect brain function through both direct and indirect pathways. It is also conceivable that additional variables play important roles, including the timing of treatment, combination of different treatment modalities, patient age, integrity of the blood–brain barrier, and cognitive function prior to treatment initiation. In addition, treatment-induced metabolic abnormalities, hormonal abnormalities, inflammatory cytokine activation, medical comorbidities (e.g., anemia, liver and renal dysfunction), other cancer-related symptoms (e.g., fatigue), and injury to other body organs (e.g., cardiotoxicity) have all been implicated in the pathogenesis of neurocognitive dysfunction [30].

Genetic risk factors may also play an important role in the manifestation of cognitive dysfunction. Polymorphisms that alter the pharmacodynamics of chemotherapeutic agents may place certain individuals at greater risk through greater exposure to potentially toxic agents secondary to less detoxification and/or greater permeability of agents across the blood–brain barrier [31–33]. For instance, polymorphisms modulating the folic acid pathway have been associated with diminished intelligence in children with leukemia treated with methotrexate [34]. The relationships between polymorphisms in genes responsible for various repair processes (e.g., apolipoprotein E) and the development of cognitive dysfunction are increasingly recognized [35, 36]. Recent studies have also examined the relationship between brain-derived neurotrophic factor and memory [37], and between catechol-o-methyl transferase and executive function [38]. There is evidence that polymorphisms in these genes are related to differences in cognitive function in healthy individuals. It is unknown if these same polymorphisms confer an additional risk in patients exposed to a potentially neurotoxic treatment.


   NEUROIMAGING STUDIES IN PATIENTS TREATED WITH CHEMOTHERAPY
Top
 Learning Objectives
 Abstract
 Introduction
 The Clinical Spectrum of...
 Patterns of Cognitive...
 Neuroimaging Studies in Patients...
Radiation-Associated...
 Cell-Biological Basis of...
 Cell-Biological Basis of...
 Current Strategies to Limit...
 Summary and Future Perspectives
 Author Contributions
 References
 
Imaging studies have provided evidence that structural and functional CNS changes occur in a significant number of patients treated with chemotherapy [39, 40]. Some agents, such as methotrexate or carmustine, are well known to cause a leukoencephalopathy syndrome, especially when administered at a high dose, intrathecally, or in combination with cranial radiotherapy [41–44]. Nonenhancing, confluent, periventricular white matter lesions, necrosis, ventriculomegaly, and cortical atrophy characterize this syndrome. White matter abnormalities following high-dose chemotherapy have been detected in up to 70% of treated individuals and usually have a delayed onset of several months [40, 45] (Fig. 1).


Figure 1
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  		Figure 1. Chemotherapy-induced leukoencephalopathy. (A): Axial MRI from a 44-year-old patient with AML showing diffuse T2/FLAIR hyperintensities affecting bilateral subcortical white matter. The patient received intrathecal Ara-C. (B): Axial MRI from a 55-year-old patient with CML with extensive T2/FLAIR hyperintensities in subcortical white matter following i.v. methotrexate and intrathecal Ara-C plus vincristine.

Abbreviations: AML, acute myeloid leukemia; Ara-C, cytosine arabinoside; CML, chronic myeloid leukemia; FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging.

 
Recent functional imaging studies have revealed alterations in brain activity in long-term survivors. Using positron emission tomography imaging, alterations in resting metabolism and cerebral blood flow in the basal ganglia, inferior frontal gyrus, and cerebellum were detectable during a memory activation paradigm in breast patients treated 5–10 years prior with a tamoxifen-containing chemotherapy regimen [46].

Inagaki et al. [47] found smaller gray and white matter volumes in multiple brain regions (including prefrontal, hippocampal, and parahippocampal structures) using magnetic resonance imaging (MRI) in breast cancer patients 1 year after treatment with chemotherapy. Although evaluation at a 3-year timepoint following treatment was not conclusive, the reduced volumes at 1 year significantly correlated with poor performance measures of attention and visual memory. Gray and white matter volume loss and hippocampal atrophy following chemotherapy have also been reported by other groups [39, 48, 49]. Baehring and Fulbright described a delayed leukoencephalopathy syndrome with distinct diffusion-weighted imaging abnormalities on MRI indicative of toxic white matter damage. This syndrome appeared to mimic a stroke-like syndrome and was seen mainly in patients receiving methotrexate, 5-fluorouracil (5-FU), carmofur, and capecitabine [50].


   RADIATION-ASSOCIATED NEUROTOXICITY AND COGNITIVE DYSFUNCTION
Top
 Learning Objectives
 Abstract
 Introduction
 The Clinical Spectrum of...
 Patterns of Cognitive...
 Neuroimaging Studies in Patients...
 Radiation-Associated...
Cell-Biological Basis of...
 Cell-Biological Basis of...
 Current Strategies to Limit...
 Summary and Future Perspectives
 Author Contributions
 References
 
Unlike chemotherapy effects on the brain, the adverse effects of radiation on the CNS have been long recognized [9, 16, 51–53]. Neurologic and/or neuropsychological dysfunction is often the greatest dose-limiting factor of radiotherapy. Cognitive dysfunction, including impairment of learning and memory, is among the most common sequelae of radiotherapy. Cranial radiotherapy causes a debilitating cognitive decline in both children [54–56] and adults [51, 57, 58]. The toxicity of radiation is likely synergistic with concurrent chemotherapy [51], although the possible synergistic effect of multimodality therapy has yet to be fully delineated.

The currently reported risk factors for developing neurological complications of radiation include age <7 or >60 years, >2-Gy dose per fraction, cumulative dose, volume of brain irradiated, hyperfractionation schedules, shorter overall treatment time, concomitant or subsequent use of chemotherapy, and the presence of comorbid vascular risk factors (e.g., diabetes) [51, 59]. Differences in reported cognitive dysfunction (the incidence varies in the range of 0%–86%) may, in part, be related to differences in treatment variables, study methodology, and the disease that is being treated.

Radiation encephalopathy has been separated into three stages: acute reaction, early–delayed reaction, and late–delayed reaction [60]. Within the first several weeks of therapy, patients may experience acute declines in focal neurologic deficits. These effects are possibly related to increased edema, which has been supported by the observation that steroid treatment often results in clinical improvement. Early–delayed adverse effects, such as the "somnolence syndrome," usually occur within 1–6 months of treatment, and are thought to be a result of demyelination [61]. This syndrome is characterized by somnolence, fatigue, and cognitive dysfunction consistent with dysfunction of the frontal network systems. Slowed information-processing speed, word and memory retrieval deficits, diminished executive function and attention, and decreased fine motor dexterity are characteristic of the early–delayed syndrome [51, 62, 63].

Late–delayed side effects occur months to years after cessation of treatment and are largely irreversible and progressive. Patients typically exhibit progressive deficits in memory, visual motor processing, quantitative skills, and attention [64]. Hippocampal dysfunction may be a causal mechanism underlying aspects of these neuropsychological sequelae. In a study by Abayomi, the severity of cognitive deterioration correlated with the radiation dosage delivered to the medial temporal lobes [65]. As mentioned above, both the radiation dose and volume of brain irradiated contribute to cognitive outcome. Thus, strategies such as conformal radiotherapy (CRT), designed to spare as much brain tissue as possible, have been shown to result in a better cognitive outcome when compared with whole-brain radiotherapy [66, 67]. However, CRT of supratentorial structures also negatively affects cognition when compared with no radiation at all [68]. Cognitive dysfunction following radiotherapy ranges from mild memory loss to frank dementia or encephalopathy. Neurocognitive evaluations in patients who survive >12 months following radiotherapy have yielded conflicting results. For example, neuropsychological testing in a cohort of patients who received paranasal sinus radiation, between 20 months and 20 years prior, revealed that 80% of the patients exhibited impaired memory, and approximately 33% manifested slowed visuomotor speed, executive dysfunction, and poor fine-motor dexterity [62]. Others have failed to find significant late–delayed neurocognitive dysfunction as a result of radiotherapy [69, 70].

In more severe cases of late–delayed radiation injury, imaging and histopathological studies may demonstrate focal necrosis and/or leukoencephalopathy [8, 71–74] (Fig. 2). Radiation-induced leukoencephalopathy may be associated with progressive brain atrophy and hydrocephalus, and patients may present with cognitive decline, gait abnormalities, and urinary incontinence [75]. However, the more common mild-to-moderate cognitive impairment is inconsistently associated with radiological findings, and frequently occurs in patients with normal-appearing neuroimaging [76].


Figure 2
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  		Figure 2. Radiation-induced neurotoxicity. (A): Axial MRI scan of a 70-year-old patient with CNS lymphoma treated with whole-brain radiation and systemic methotrexate. The MRI shows bihemispheric T2/FLAIR hyperintensities consistent with radiation-induced leukoencephalopathy. (B): Axial MRI scan (T1 plus gadolinium) of a 49-year-old patient with nasopharyngeal carcinoma and prior radiation therapy showing radiation necrosis involving both temporal lobes.

Abbreviations: CNS, central nervous system; FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging.

 
Whereas acute radiation toxicity may be the result of vascular toxicity, blood–brain barrier disruption, or fluid and electrolyte shifts [77, 78], the mechanisms of chronic radiation damage are probably related to long-term damage to various neural cell types, including stem and progenitor cells, in combination with metabolic derangements and inflammatory responses [79–82]. As discussed in more detail below, ongoing adult hippocampal neurogenesis may be one of the important physiological processes critically disrupted in cancer patients.


   CELL-BIOLOGICAL BASIS OF RADIATION-INDUCED NEUROTOXICITY: EFFECTS ON HIPPOCAMPAL NEUROGENESIS
Top
 Learning Objectives
 Abstract
 Introduction
 The Clinical Spectrum of...
 Patterns of Cognitive...
 Neuroimaging Studies in Patients...
 Radiation-Associated...
 Cell-Biological Basis of...
Cell-Biological Basis of...
 Current Strategies to Limit...
 Summary and Future Perspectives
 Author Contributions
 References
 
Located in the medial temporal lobes, the hippocampal formation plays a central role in learning and memory [83]—functions prominently affected by radiation. Neural stem cells, self-renewing cells that generate neurons, astroglia, and oligodendroglia, as well as lineage-restricted precursor cells, exist in the postnatal and adult brains of all mammals studied to date, including humans [84, 85]. Neural stem cells, neuronal precursor cells, and glial precursor cells are collectively known as neural progenitor cells (NPCs) (Fig. 3). In the hippocampus, a major site of postnatal/adult neurogenesis, NPCs generate newborn dentate gyrus granule cell neurons throughout life, and this process of hippocampal neurogenesis is thought to be critical for normal hippocampal function [85] (Fig. 4). Animal studies have elucidated the pathological effects of radiation on hippocampal progenitor cell biology. Work in such models has demonstrated that exposure to therapeutic doses of irradiation results in increased apoptosis [86–88], decreased cell proliferation, and decreased neuronal differentiation in the neurogenic region of the hippocampus [13, 86, 89]. A single, clinically relevant dose of radiation in the rat results in a >95% decrease in absolute production of new neurons throughout the entire volume of the hippocampus [13], essentially ablating neurogenesis in these animals.


Figure 3
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  		Figure 3. Cellular lineage relationships in the mammalian CNS. Simplified diagram showing the lineage relationship between both immature and mature cell types in the CNS. Multipotent NSCs give rise to neurons, astrocytes, and myelin-forming oligodendrocytes through the generation of lineage-committed progenitor cell populations. Tripotential GRP cells can differentiate into both astrocytes and oligodendrocytes through the generation of O-2A/OPCs. Mature astrocytes may be derived from APCs, and mature neurons may be generated via NRP cells. Additional lineage-committed cell populations, such as putative oligodendrocyte–neuron progenitor cells, are not shown.

Abbreviations: APC, astrocyte precursor cell; CNS, central nervous system; GRP, glial-restricted precursor; NRP, neuron-restricted precursor; NSC, neural stem cell; O-2A/OPC, oligodendrocyte precursor cell.

 


Figure 4
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  		Figure 4. Hippocampal neurogenesis. (A): Schematic representation of the hippocampal formation in the rodent brain. The GCL of the dentate gyrus is highlighted in grey. Neural precursor cells reside in the SGZ— a thin lamina between the GCL and the hilus. (B): Confocal micrograph illustrating newborn neurons within the neurogenic region of the dentate gyrus. The neurons are labeled by the early neuron-specific marker doublecortin.

Abbreviations: GCL, granule cell layer; SGZ, subgranular zone.

 
The direct isolation of equivalent numbers of NPCs from hippocampi 1 month after exposure to increasing doses of irradiation demonstrated that an acute ablation of the NPC population does not occur [13]. However, NPCs exhibited impaired growth potential in a radiation dose–dependent manner [13], possibly because of radiation-induced DNA damage and subsequent mitotic catastrophe. The striking decrease in cell proliferation within the neurogenic region in the months following radiation probably results from both acute cell death and the impaired proliferative potential of the precursor pool.

In contrast to the effects on neurogenesis, gliogenesis appears to be relatively preserved following irradiation [13]. This specific inhibition of neurogenesis has been proven to be a result of a failure of the neurogenic microenvironment, as shown by stem cell isolation and transplantation experiments. NPCs isolated from an irradiated hippocampus retain the ability to make neurons in vitro, whereas healthy, nonirradiated NPCs transplanted into the irradiated hippocampus failed to produce neurons. Disruption of the microenvironment necessary for neurogenesis by radiation is characterized by two prominent alterations in the neurogenic niche of the hippocampus. First, there is a disruption of the close anatomic relationship of NPCs to the microvasculature within the neurogenic region [13]. Second, radiation causes a striking microglial inflammatory response [13, 90]. This finding is intriguing, because microglial inflammation and subsequent elaboration of proinflammatory cytokines inhibit neurogenesis [90–92]. Furthermore, microglial inflammation alone is sufficient to cause disruption of the neurovascular relationship [90], and treatment with an anti-inflammatory agent restores the anatomical relationship of NPCs with the microvasculature in the neurogenic region. Notably, anti-inflammatory therapy restores neurogenesis following systemic inflammatory challenge with lipopolysaccharide [90]. The nonsteroidal agent indomethacin, which functions both as a cyclo-oxygenase-I/II inhibitor and as a direct peroxisome proliferator-activated receptor-{gamma} agonist, was administered during and after cranial radiation. Indomethacin therapy resulted in 35% fewer activated microglia within the neurogenic region of the hippocampus and a 250% higher absolute number of newly generated neurons relative to animals irradiated without anti-inflammatory intervention [90]. Despite significant improvement, however, anti-inflammatory therapy alone did not restore neurogenesis to baseline levels. The effect on hippocampal function remains unclear. More potent anti-inflammatory/antimicroglial agents may confer a greater benefit in restoring neurogenesis. Experiments are currently ongoing to identify the most efficacious agent.

Recent work suggests that observations made in animal models of radiation-induced neurotoxicity may also apply to cancer patients [93]. Postmortem analysis of hippocampal neurogenesis in patients with medulloblastoma, performed 2–23 years following the completion of radiotherapy, revealed a tenfold lower rate of neurogenesis compared with age- and sex-matched controls. These findings suggest long-lasting damage to hippocampal neurogenesis caused by the cumulative effects of treatment, including cranial irradiation, chemotherapy, and steroid therapy, as well as endogenous factors related to the disease process itself [93]. One of the cases in this study, however, offered a unique opportunity to examine the effects of radiotherapy alone. One patient suffered a unilateral recurrence of her tumor adjacent to, but not invading, one hippocampus, and therefore received additional focal radiotherapy to that region. The contralateral hippocampus thus served as an internal control for systemic factors such as chemotherapy. Relative to the internal control hippocampus, the side with the additional radiation exposure exhibited a 79% lower rate of neurogenesis, a 59% lower rate of overall cell proliferation within the neurogenic region, a 200% higher number of activated microglia, and relative preservation of gliogenesis [93]. These findings mirror those from the rodent model of radiotherapy and confirm ablation of human neurogenesis following cranial radiation therapy.


   CELL-BIOLOGICAL BASIS OF CHEMOTHERAPY-INDUCED NEUROTOXICITY
Top
 Learning Objectives
 Abstract
 Introduction
 The Clinical Spectrum of...
 Patterns of Cognitive...
 Neuroimaging Studies in Patients...
 Radiation-Associated...
 Cell-Biological Basis of...
 Cell-Biological Basis of...
Current Strategies to Limit...
 Summary and Future Perspectives
 Author Contributions
 References
 
There is now compelling evidence that many chemotherapeutic agents directly target the normal cells of the nervous system. Methotrexate, for example, is associated with a relatively high frequency of neurotoxicity, which may be severe and progressive, especially if the drug is administered after radiation therapy. The majority of cancer treatments affect a diverse range of normal cell types, resulting in a broad spectrum of toxicities to multiple organ systems. The conventional view has been that cytotoxic drugs preferentially target rapidly dividing cells, such as glial cells and endothelial cells. More recent studies indicate, however, that the mechanisms of neurotoxicity are far more complex than simply toxic effects on proliferating cells alone.

Early morphological studies on rats exposed to methotrexate and misonidazole suggested that glial progenitor cells might be particularly vulnerable to cytotoxic agents [94]. A single-dose application of methotrexate into the ventricles of rats was associated with ventricular dilatation, edema, and visible destruction of the ependymal cell layer. Numerous glial cells with pyknotic nuclei were observed in the gray and white matter, with increased numbers of microglial cells. There was also a rapid reduction in the number of nuclei per unit area in the rostral extension of the subependymal plate, with a 30% reduction seen 1–2 days after methotrexate administration. A similar reduction was seen in the number of mitotic cells. Other experimental studies suggest that exposure to numerous cytotoxic agents, including cyclophosphamide, cisplatin, ifosfamide, and thiotepa, is associated with significant and dose-dependent neurotoxicity, evident in the cortex, basal ganglia, and hippocampus in 7-day-old animals [95]. These studies, however, did not provide a lineage-based analysis of the toxic effects of chemotherapy.

Recent studies have revealed further insight into the biological basis of chemotherapy-associated CNS toxicity, showing that self-renewing lineage-committed NPCs, which are the direct ancestors of all differentiated cell types of the CNS (Fig. 3), and nondividing mature oligodendrocytes (myelin-forming cells) are the most vulnerable cell populations to multiple chemotherapeutic agents [14]. In contrast, mature astrocytes and neurons are significantly less vulnerable at comparable drug dosages. Consistent with in vitro observations, systemic application of BCNU, cisplatin, and cytosine arabinoside was associated with increased cell death of oligodendrocytes and NPCs in animal models. Interestingly, initial impairment of cell proliferation and increased cell death following a single exposure to chemotherapeutic agents was followed by a marked rebound in cell proliferation, suggesting a limited repair potential following cytotoxic insult. However, repetitive drug exposure resulted in long-term suppression of cell division and prolonged cell death in the subventricular zone, the hippocampus, and major white matter tracts.

Other groups reported similar findings after systemic application of thiotepa [96] and methotrexate [97]. Systemic application of these drugs was associated with a dose-dependent inhibition of hippocampal cell proliferation in vivo. In addition, methotrexate has been shown to result in impaired cognitive performance in animal models [97, 98].

Damage to NPCs offers a compelling explanation for delayed toxicities, including progressive dementias and white matter abnormalities. Further insights into the mechanisms of delayed toxicity have come from a recent study examining the effects of the commonly used agent 5-FU on the CNS [15]. Consistent with previous studies [14], clinically relevant doses of systemically applied 5-FU resulted in significant toxicity to nondividing oligodendrocytes and lineage-committed progenitor cells. A persistent suppression of progenitor cell proliferation in the subventricular zone, the hippocampus, and the corpus callosum was associated with increased cell death in the same brain regions. Intriguingly, treatment with 5-FU resulted in delayed and extensive myelin damage detectable 6 months post-treatment. Moreover, functional studies using auditory brainstem responses revealed marked slowing of impulse conductivity and increases in interpeak latencies, consistent with profound myelin toxicity. Unlike CNS damage caused by irradiation, 5-FU–associated injury did not correlate with either chronic inflammation or extensive vascular damage. This study has offered the first scientific explanation for delayed myelin toxicity, as it has been frequently encountered in cancer patients treated with chemotherapy. It is conceivable that long-term and progressive cognitive decline in cancer survivors is the result of a combination of decreased proliferation of NPCs, impaired hippocampal neurogenesis, and damage to white matter tracts.


   CURRENT STRATEGIES TO LIMIT OR PREVENT NEUROTOXICITY AND COGNITIVE DECLINE
Top
 Learning Objectives
 Abstract
 Introduction
 The Clinical Spectrum of...
 Patterns of Cognitive...
 Neuroimaging Studies in Patients...
 Radiation-Associated...
 Cell-Biological Basis of...
 Cell-Biological Basis of...
 Current Strategies to Limit...
Summary and Future Perspectives
 Author Contributions
 References
 
Chemotherapy and radiation therapy remain necessary components in the management of most types of cancer. Although not all patients experience treatment-related neurotoxicity, for many patients cognitive symptoms are distressing and debilitating. It is critical to explore therapies that may prevent side effects or minimize the impact and extent of symptoms. Ideally, these interventions should both be tailored to the symptom (e.g., anemia, fatigue, memory deficit) and be based on the hypothesized mechanism.

Clinical experience and research have alerted clinicians to the risks involved with certain regimens and administration schedules as outlined above, such that many neurotoxicities have been reduced while continuing to achieve adequate cancer control [16, 99]. In cases where a specific mechanism underlying the neurotoxicity has been characterized, targeted treatment strategies have been explored. For example, naltrexone (i.e., a µ-opioid receptor antagonist) was effective in relieving neurotoxic side effects in patients undergoing interferon treatment for hematological malignancies [100]. Others demonstrated a benefit of pretreatment with paroxetine (e.g., selective serotonin reuptake inhibitor) in minimizing depression in melanoma patients receiving interferon treatment [101]. However, empirically supported therapies for persistent cognitive and neurobehavioral dysfunction are limited. Stimulant therapies have proven effective in treating cognitive dysfunction in cancer patients [102]. Preliminary data suggest that high doses of {alpha}-tocopherol may improve cognitive function (i.e., memory and executive function) in patients with temporal lobe necrosis after radiation for nasopharyngeal carcinoma [103]. Trials of anti-inflammatory therapies during and/or after radiotherapy are in the early stages of planning and execution.

In patients with radiation-induced hydrocephalus, ventriculoperitoneal shunting has been shown to result in symptomatic improvement in most patients, although incontinence and gait difficulties are more likely to improve than cognitive dysfunction [75].

Additional pharmacologic interventions commonly used to treat other diseases affecting cognitive function are currently being investigated [104]. For example, donepezil, a reversible acetylcholinesterase inhibitor used to treat Alzheimer's type dementia, has been shown to improve cognitive function, mood, and quality of life in patients treated with radiation therapy for brain tumors [105]. Cognitive and behavioral intervention strategies used in stroke and traumatic brain injury survivors may also be employed. These interventions often focus on compensatory strategy training, stress management, energy conservation, and psychoeducation. Of the available techniques, external memory aids (e.g., memory notebooks, pagers) have been among the most widely used interventions [106].


   SUMMARY AND FUTURE PERSPECTIVES
Top
 Learning Objectives
 Abstract
 Introduction
 The Clinical Spectrum of...
 Patterns of Cognitive...
 Neuroimaging Studies in Patients...
 Radiation-Associated...
 Cell-Biological Basis of...
 Cell-Biological Basis of...
 Current Strategies to Limit...
 Summary and Future Perspectives
Author Contributions
 References
 
Increased understanding of the mechanisms underlying neurotoxicity and cognitive dysfunction in cancer patients will be critical to design and optimize individual therapies, and to developing means for selective neuroprotection. Damage to NPCs has offered a compelling explanation for delayed toxicities, such as progressive dementias, cerebral atrophies, and white matter disease. There are likely a number of cofactors and mechanisms that mediate the risk for an individual patient of developing neurotoxicity and cognitive dysfunction.

Given the negative impact of inflammatory responses on cell plasticity, neurogenesis, and cognitive function, the use of anti-inflammatory agents or specific cytokine antagonists in conjunction with standard rehabilitative approaches may hold great promise. Another potential treatment approach may entail the stimulation of endogenous cell repair, gliogenesis, and neurogenesis in cancer patients to prevent delayed side effects, such as demyelination associated with certain chemotherapy agents.


   AUTHOR CONTRIBUTIONS
Top
 Learning Objectives
 Abstract
 Introduction
 The Clinical Spectrum of...
 Patterns of Cognitive...
 Neuroimaging Studies in Patients...
 Radiation-Associated...
 Cell-Biological Basis of...
 Cell-Biological Basis of...
 Current Strategies to Limit...
 Summary and Future Perspectives
 Author Contributions
References
 
Conception/design: Jörg Dietrich, Michelle Monje

Manuscript writing: Jörg Dietrich, Michelle Monje, Jeffrey Wefel, Christina Meyers

Final approval of manuscript: Jörg Dietrich


   ACKNOWLEDGMENTS
Top
 Learning Objectives
 Abstract
 Introduction
 The Clinical Spectrum of...
 Patterns of Cognitive...
 Neuroimaging Studies in Patients...
 Radiation-Associated...
 Cell-Biological Basis of...
 Cell-Biological Basis of...
 Current Strategies to Limit...
 Summary and Future Perspectives
 Author Contributions
 References
 
This work was funded with generous support from the Hagerty Foundation for Glioma Research (M.M.), the J.P. Wilmot Cancer Foundation (J.D.), and the Deutsche Forschungsgemeinschaft (J.D.). Jörg Dietrich and Michelle Monje contributed equally to this work.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 The Clinical Spectrum of...
 Patterns of Cognitive...
 Neuroimaging Studies in Patients...
 Radiation-Associated...
 Cell-Biological Basis of...
 Cell-Biological Basis of...
 Current Strategies to Limit...
 Summary and Future Perspectives
 Author Contributions
 References
 

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