Neurotoxic Effects of Childhood Cancer Therapy and Its Potential Neurocognitive Impact

INTRODUCTION

A new era of treatment for childhood cancer has welcomed an increasing number of long-term survivors, for whom acute and late neurologic and neurocognitive sequelae related to their cancer and treatment directly affects overall cognitive functioning.¹ It is estimated that one-third of all survivors and 40%-100% of brain tumor survivors experience cancer-related cognitive impairment (CRCI).² Frequently observed deficits include impairments in memory, attention, visual-motor integration, and executive function, which can contribute to poor academic performance, low educational attainment, and low levels of gainful employment.³ Reduced education attainment and employment can, in turn, have a significant impact on survivors' economic status and quality of life.⁴

CONTEXT

• Key Objective

• How do the neurotoxic effects of traditional and emerging chemotherapies potentially affect neurocognitive outcomes?

• Knowledge Generated

• There is growing body of evidence that traditional treatments and emerging therapies influence the development of cancer-related neurocognitive impairments, which can progress over time. More long-term data are needed to better characterize chronic neurologic deficits and neurocognitive outcomes related to use of all modalities of treatment for childhood cancer, and in particular emerging immunotherapy and molecularly targeted therapies.

• Relevance

• This article provides an overview of the factors that contribute to impaired neurocognitive function in childhood cancer survivors and provides a framework for consideration of potential areas for primary prevention by reducing treatment-related toxicity, as well as informing potential interventions.

CRCI varies in severity based on age at diagnosis, underlying cancer diagnosis, intensity and duration of CNS-directed therapy, and sex.^5,6 CRCI is well characterized in the brain tumor and acute lymphoblastic leukemia (ALL) populations; however, a growing body of evidence suggests that most long-term survivors suffer some degree of CRCI.^7,8 There are multiple tumor- and treatment-related factors that can progress over time and lead to significant functional impairments (Fig 1). In addition, environmental or psychosocial factors, medical comorbidities and host factors, such as age at diagnosis or treatment and genetic polymorphisms, can influence the development of CRCI, although they are outside the scope of this review. Importantly, many survivors and their families are unaware of the risks.

FIG 1.

Schema summarizing treatment-related factors, tumor factors, and individual or patient factors that influence development of neurocognitive dysfunction in childhood cancer survivors. ^aDenotes contributing factors outside of the scope of this review.

In this review, we summarize the neurologic and neurocognitive toxicities associated with treatment. We examine the impact of neurotoxicity on neurocognitive functioning in childhood cancer survivors and provide considerations for prevention and amelioration.

TREATMENT-RELATED TOXICITY

Neurologic toxicity can result from the direct effects of treatment, including neurosurgery, radiation therapy, and chemotherapy. The onset of symptoms may occur acutely, as an immediate effect of the treatment, during treatment with sustained impact on neurologic function, or delayed presentation years after completion of treatment (Table 1). Although some of the neurologic toxicities are quite rare, they can be associated with significant morbidity and long-lasting impact on cognitive function (Table 2). Given that most patients undergo multimodality approaches to treatment and often multiagent chemotherapy regimens, it may be impossible to identify an independent contribution of a specific agent to a particular neurotoxicity.

TABLE 1.

Frequency and Chronicity Treatment-Related Neurotoxicity

TABLE 2.

Treatment-Induced Neurotoxicity and Associated Neurocognitive Impairments

Neurosurgery

Surgical resection remains the mainstay of therapy for most primary brain tumors, both to provide histologic diagnosis and to reduce tumor burden. Deficits and long-term effects of surgery are multifactorial. Tumor location and size influence symptoms at presentation, resectability, and presence or absence of neurologic deficits.

Direct sequelae from surgical removal are also often location-dependent and can result in development of neurologic deficits including focal weakness, neurosensory deficits, ataxia, and perioperative hemorrhage or vascular injury, all of which can affect cognitive function.⁹ For example, visual field deficits can result from resection along the visual pathways. The hypothalamic-pituitary axis is often affected by both tumor and surgery, resulting in hormonal deficits, impaired sleep-wake cycles, and memory deficits. Syndrome of inappropriate antidiuretic secretion is the release of antidiuretic hormone in the absence of physiologic stimuli. Syndrome of inappropriate antidiuretic secretion results in chronic hyponatremia, which can lead to confusion, lethargy, seizures, and/or coma,¹⁰ as well as long-term attention deficits, gait disturbances, and cognitive impairments.¹¹

Cerebellar mutism syndrome is estimated to be seen in 8%-32% of children 12-48 hours after posterior fossa surgery and is characterized by loss of verbal expression, pseudobulbar dysfunction, poor attention and eye contact, incontinence, and emotional lability. Neuroimaging studies reveal damage to the outflow tract of the dentatothalamocortical pathway.¹² Although it was once thought that the symptoms of cerebellar mutism syndrome were transient, there is now evidence that there is an elevated risk for poor long-term neurocognitive outcomes.¹³

Hydrocephalus and need for CSF diversion or shunt placement have been identified as independent risk for lower scores on tests of intelligence, memory, and quality of life.¹⁴

Radiation Therapy

Radiation therapy remains an important component of cancer treatment in children. Impact depends on age, disease status, concomitant therapies, length of survival, and specific radiation features such as dose, size of the field, fractionation schema, and type of radiation (eg, proton, photon, and conformal techniques). Radiation injury can occur acutely and in months to years after completion of treatment. Neurotoxicity can occur by direct injury to the neurons or glia and indirectly by inducing vascular injury.¹⁵ Cranial radiation is a well-established risk factor for development of CRCI.¹⁶

Radiation-induced vascular injury from moderate to high doses of radiation results in swelling of the endothelium, occlusions, and necrosis.¹⁷ The slow renewal of vascular endothelium slows the healing process and contributes to vascular leakage (microbleeds), mineralizing microangiopathy (cerebral calcifications), and stroke.¹⁸ Radiation to the neck is also a risk factor for stroke via endothelial damage.¹⁹ Lifestyle and chronic aging conditions such as hypertension and hypercholesterolemia may affect cognitive function more than burden of microbleeds and cerebral calcifications.^20,21 A subset of survivors who receive cranial irradiation experienced stroke-like migraine attack after radiation therapy syndrome, which presents 1-35 years after radiation with focal neurologic deficits and/or seizures,^22,23 in addition to persistent cognitive impairment.²⁴

Indirect injury via vascular damage and direct injury to oligodendrocytes lead to myelin loss and demyelination and manifests as leukoencephalopathy,¹⁷ which is correlated with dose and volume of radiation.²⁵ Estimates of leukoencephalopathy are limited by small mixed-population studies (leukemia and brain tumor survivors) and short-term follow-up periods.²⁶ Loss of white matter integrity (fractional anisotropy and white matter volume) is associated with low intellectual scores.^27,28

Traditional Chemotherapy

Neurotoxicities associated with traditional chemotherapeutic agents are well described in the literature and are summarized in Table 1. The incidence, timing of onset, and duration of these effects vary based on the route of administration, dosage, and extent of therapy.

Acute encephalopathy occurs with a number of commonly used chemotherapeutic agents.²⁹ Characteristics include development of altered mental status with impairments in cognition, memory, concentration, orientation, and/or consciousness. Symptoms can improve with withdrawal of the offending agent or after use of an antidote such as methylene blue in the case of ifosfamide-induced encephalopathy.³⁰ Posterior reversible encephalopathy syndrome (PRES) is associated with methotrexate, cisplatin, cytarabine, isofosfamide, and vincristine, and is thought to be caused by a loss of cerebral blood pressure regulation and neuroinflammation, resulting in subcortical vasogenic edema on magnetic resonance imaging (MRI). PRES can be associated with significant acute neurologic and neurocognitive sequelae, with some suggestion of persistent, nonreversible, neurocognitive impairments in a subset of patients.³¹

Cerebellar dysfunction is an acute chemotherapy-induced encephalopathy associated with high-dose cytarabine and fluorouracil, resulting in ataxia, dysarthria, confusion, and disorientation.^32,33 Symptoms can be reduced by discontinuing the offending agent, but evidence suggests that mild or moderate dysarthria and gait abnormalities persist, with a risk of recurrence after subsequent administration.³⁴

Methotrexate is associated with a brief, reversible, stroke-like syndrome, characterized by dysarthria, hemiparesis, and lack of restricted diffusion on MRI.^35-38 Methotrexate is also associated with leukoencephalopathy and long-term cognitive impairment.³⁹ There is growing evidence that cumulative risk for leukoencephalopathy is a function of time and repeated exposure and that more chronic forms of leukoencephalopathy can progress to a more permanent impairment of neurologic function.^40-42 ALL survivors with methotrexate-induced leukoencephalopathy experience poorer attention and executive functioning compared with survivors without leukoencephalopathy.⁴³ The combination of cranial irradiation, intrathecal and intravenous methotrexate, and corticosteroids results in loss of brain volume.^44,45 Additionally, corticosteroids are an emerging independent risk factor for memory deficits in children < 10 years of age.^46,47

Seizures can be caused by chemotherapeutic agents (Table 1). Children who experience seizures during therapy have a higher risk for poorer attention, working memory, and processing speed.⁴⁸ The necessary use of anticonvulsants can further contribute to cognitive dysfunction in survivors.

NEUROTOXICITIES OF EMERGING TREATMENTS

Immunotherapy

Over the past decade, significant advances have been made in the development of therapies that use the immune system to target cancer cells. These therapies, including adoptive cell therapy, immune checkpoint inhibitors, vaccine, and oncolytic virus-based therapies, have demonstrated promising efficacy with some tumor types, primarily in adults.⁴⁹ Along with the on-target effects of these agents, adverse events include neurologic toxicities that occur with varying frequency depending on the modality of therapy. Although long-term neurocognitive data are lacking and less well defined, the neurologic sequelae can be associated with significant morbidity and mortality (Table 1).

Adoptive Cell Therapy

Adoptive cellular therapy uses a patient's own immune cells (T cells and natural killer cells) to induce an immune response when infused back into the patient. Chimeric antigen receptor T-cell therapy is the most well studied and includes approved agents such as tisagenlecleucel and axicabtagene ciloleucel.⁵⁰ Neurotoxicity is a well-described phenomenon with these therapies; specifically, the immune effector cell-associated neurotoxicity syndrome may occur in 30%-50% of pediatric patients.⁵¹ Neurologic symptoms of immune effector cell-associated neurotoxicity syndrome may consist of headache, tremor, expressive aphasia, impaired attention, apraxia, and lethargy. Seizures are also described, and many centers recommend prophylactic antiseizure medication at the time of therapy. Cerebral edema and increased intracranial pressure resulting from proinflammatory cytokine release, endothelial activation, and disruption of the blood-brain barrier can be severe,⁵² necessitating close monitoring with ophthalmologic examinations, imaging, and lumbar puncture as indicated. Newer agents including bispecific T-cell engagers such as blinatumomab are being used more commonly and have a similar risk of neurotoxicity as chimeric antigen receptor T therapy.⁵³

Immune Checkpoint Inhibitors

Immune checkpoint inhibitors such as the CTLA4 inhibitors (ipilimumab) and progressive disease-1/progressive disease-L1 inhibitors (nivolumab and pembrolizumab) are monoclonal antibodies that relieve the tumor-related blockade of the normal T-cell response, allowing both restored intratumoral T-cell activation and increased antitumor activity.⁵⁴ Neurologic adverse events are reported in 2%-5% of patients (Table 1)^55,56 and often occur within several weeks after starting the medication, with variable long-term recovery.⁵⁷ Treatment includes discontinuation of the immune checkpoint inhibitor and initiation of corticosteroids, as well as intravenous immunoglobulin and biologic anti-inflammatory agents, if severe.^58,59

Oncolytic Viruses and Vaccine Therapy

Other immunotherapies include oncolytic viruses, which are genetically modified to attack the tumor cells and to stimulate an immune response.⁶⁰ Therapeutic cancer vaccines also trigger immune activation by using peptides from known tumor-associated antigens, dendritic cells with antigen priming, or personalized neoantigens from patient-specific tumor tissue.⁶¹ These therapies appear to be fairly well tolerated with limited neurologic adverse effects, but mild symptoms may include headache and myalgias.⁶² Importantly, all types of immunotherapy can produce a local immune-related inflammatory response; for patients with primary brain tumors, this can result in the phenomenon termed pseudoprogression, with local edema and risk of herniation.⁶³ Treatment typically includes discontinuation of the treatment and administration of corticosteroids.

Anti-CD20 Monoclonal Antibodies

Headache and peripheral neuropathy are reported in 10%-15% of patients treated with CD20-depleting antibodies such as rituximab, used commonly in lymphoma and lymphoproliferative disorders. Resulting immunosuppression predisposes patients to opportunistic infections of the CNS and in particular risk of JC (human polyomavirus) virus reactivation and progressive multifocal leukoencephalopathy.^64,65 Rare cases of stroke, seizure, serotonin syndrome, and PRES have also been reported.⁶⁶

Molecularly Targeted Therapies

The use of molecularly targeted therapies and combinations of these medications has become increasingly prevalent for many types of cancer. Many of these agents have neurologic toxicity, although the incidence is variable and inconsistently reported across studies (Table 1).⁶⁷ Large studies in pediatric populations are limited and without long-term data.

Targeted agents include angiogenesis inhibitors (eg, bevacizumab)⁶⁸ and signal transduction inhibitors that target cell surface receptors and intracellular proteins such as epidermal growth factor receptor or platelet-derived growth factor receptor (eg, erlotinib and imatinib),⁶⁹ BRAF (eg, sorafenib, dabrafenib, and vemurafenib),^70,71 MEK inhibitors 1/2 (eg, selumetinib and trametinib),⁷² mammalian target of rapamycin (eg, everolimus and sirolimus), and neurotrophin receptor tyrosine kinase (eg, larotrectinib and entrectinib).⁷³ Gene expression modulators often target known transcription factors at different levels, from DNA binding to protein-protein interactions to epigenetic alterations.⁷⁴ Specific neurotoxicity of many of these agents, such as the HDAC inhibitors (eg, panobinostat), is emerging.⁷⁵

Impact of Medical Comorbidities on Cognitive Function

Long-term survivors are at increased risk for chronic late cardiovascular, pulmonary, and endocrine-associated health conditions, which may affect cognitive function. Severe and life-threatening cardiac, pulmonary, and endocrine events in osteosarcoma survivors are associated with worse memory and slower processing speed, independent of chemotherapy exposure.⁷ Similarly, chemotherapy-induced reduction in exercise tolerance has been shown to be associated with worse verbal intelligence, focused attention, verbal fluency, working memory, motor speed, and memory span in ALL survivors.⁷⁶ Radiation-associated cardiomyopathy and heart failure have been linked to leukoencephalopathy, reduced cognitive fluency, working memory, sustained attention, and naming speed in Hodgkin lymphoma survivors.⁷⁷

Data on the impact of preexisting comorbidities on neurocognitive outcomes in childhood cancer survivors are sparse. In childhood brain tumor survivors, epilepsy can be associated with cognitive deficits, independent of tumor- and treatment-related variables.⁷⁸ Hydrocephalus, CNS infections, trauma, intraventricular hemorrhage, low birth weight, and asphyxia are known determinants of cognitive status in noncancer childhood populations.⁷⁹

Endocrinopathies have been reported in up to 50% of childhood cancer survivors.⁸⁰ There are emerging data demonstrating the impact of both growth hormone and sex hormone deficiency on neurocognitive function. Childhood ALL survivors with growth hormone deficiency had poorer vocabulary, processing speed, cognitive flexibility, and verbal fluency.⁸¹ Male childhood ALL survivors with low dehydroepiandrosterone-sulfate levels demonstrated worse attention outcomes after controlling for CNS-directed therapy.⁸²

Neurosensory deficits, such as visual impairment and sensorineural hearing loss, and peripheral neuropathy can also affect cognitive function.^83-85 In a multi-institutional cohort study of childhood cancer survivors, peripheral neuropathy was associated with higher levels of anxiety or depression, reduced attention, and peer conflict or social withdrawal symptoms, all of which affect cognitive function.⁸⁶ Early identification and treatment of psychologic comorbidities is important for overall quality of life as well as cognitive functioning.

A significant proportion of adult survivors of childhood cancer report disrupted sleep, sleep disordered, breathing, increased daytime sleepiness, and fatigue.⁸⁷ Excessive daytime sleepiness is seen in up to 60% of children with cancer and 80% of children with tumors involving the hypothalamus, thalamus, and brainstem.⁸⁸ Given the prevalence of sleep disorders and known impact of sleep on cognition, it is important to screen and evaluate survivors carefully.

STRATEGIES FOR PREVENTION OR INTERVENTION

The improved survival and increased years of life saved after medical therapy for childhood cancer has prompted parallel exploration of strategies to evaluate, prevent, and remediate the neurologic toxicity and neurocognitive impact of cancer therapy. A requirement for these strategies is better recognition, delineation, and understanding of the specific neurotoxicities.

Insults to the central and peripheral nervous system can have profound impact on neurocognitive functioning. Therefore, efforts to determine effective ways to prevent neurologic sequelae are imperative. One challenge of neurologic toxicity is that it often represents the final common pathway caused by different insults. One example is stroke symptoms (Fig 2). Stroke symptoms can result from the acute effects of chemotherapy, such as methotrexate, because of acquired antithrombin or fibrinogen deficiency related to asparaginase, from B-cell–mediated effect on the cerebrovascular system after anti-CD20 treatment, and from radiation vasculopathy, because of vascular narrowing and/or accelerated atherosclerosis. Strategies for prevention of stroke and other neurologic toxicities, therefore, must consider the specific etiology, in as much as this is possible.

FIG 2.

Stroke is the final common pathway of multiple different etiologies of neurologic injury. Radiation-induced vasculopathy and vascular narrowing result in reduced blood flow. L-Asparaginase induces an acquired deficiency in antithrombin and fibrinogen, key factors in the coagulation cascade. Antiangiogenesis drugs such as bevacizumab act directly on the endothelial cell, resulting in arterial thromboembolic events. Strategies for prevention and amelioration should thus address the specific inciting factor.

As above, cognitive deficits resulting from neurologic toxicity often represent the end result of the composite treatment, often with a combination of surgery, radiation, and multiagent chemotherapy. Table 3 delineates selected preventative approaches and symptomatic treatments. Reduction in treatment-related neurologic toxicity has occurred with advances in neurosurgical techniques, use of neuroprotective agents, and improved radiation techniques. The goal of treatment is to maintain or improve outcomes while simultaneously reducing treatment-related toxicity.

TABLE 3.

Potential Strategies for Prevention and Intervention of Neurologic Toxicities

Modern literature suggests that maximum extent of tumor resection with preservation of neurologic function is associated with improved overall outcome. Improved image guidance including diffusion tensor imaging, functional MRI, and preoperative planning have been important in mitigating at least some of the impact from surgery as well as improved extent of resection and reduction of residual tumor volume.^89,90 Over the past decade, there have been advances in chemotherapeutic strategies, including optimization of administration of chemotherapy, metronomic treatment,⁹¹ concomitant use of chemotherapy and radiation therapy to the CNS, and administration directly into the intrathecal or intraventricular compartment. Refinements in the clinical and molecular stratification of tumors have facilitated a movement toward risk-adapted treatment planning as well as identification of the next-generation promising molecularly targeted therapies.⁹²

Because of concerns over neurocognitive sequelae from radiation, there is renewed interest in reduction of total radiation dose, both for solid tumors and primary brain tumors. The use of fractionated and conformal techniques effectively reduces toxicity to the surrounding tissue. With proton beam radiotherapy, there is also less radiation to surrounding tissues. This reduces the area at risk for injury and may spare some aspects of neurocognitive functioning.⁹³

Although the mechanism is different, neurologic and neurocognitive deficits in survivors of childhood primary brain tumors and leukemia may resemble similar challenges in the general population. For example, deficits in sustained attention may be indistinguishable on neurocognitive testing from attention-deficit disorder in the general population. As a consequence, many of the traditional pharmacologic and metacognitive strategies to improve deficits related to attention, stroke, sleep disorders, and hearing loss have also been demonstrated to improve neurocognitive functioning among survivors (Table 3). Specific rehabilitation and pharmacologic interventions are addressed separately in this Special Series.

A limitation of this review is the quality of the existing literature on treatment-related neurotoxicity and related neurocognitive outcomes. As noted, most patients receive multimodality and multiagent cancer-directed therapy, making it difficult to impossible to completely parse out the individual contributions from each treatment. In addition, most studies include retrospective data of pooled treatment protocols. Comparisons between studies are difficult since treatment regimens can vary significantly between institutions^94,95 or between treatment eras at the same institution.¹ Importantly, most studies reported are case reports or small case series, and are limited by small sample sizes.

Future studies should attempt to address these limitations by collecting data prospectively from large, multi-institutional consortiums and with controls for variations in treatment regimens and confounders outlined in this review. Additionally, future research must include prospective collection of data for neurologic and neurocognitive toxicities related to emerging therapies and bone marrow transplant survivors, as there is little long-term experience in this burgeoning survivor population.

In Conclusion, with newer treatments and longer overall survival leading to growing numbers of survivors of childhood cancer, there is an increasing impact of neurologic and cognitive toxicity. More long-term data are needed to better characterize the risks related to all modalities of treatment, and in particular emerging immunotherapy and molecularly targeted therapies. Education of parents, patients, and medical providers is critical.

AUTHOR CONTRIBUTIONS

Conception and design: All authors

Collection and assembly of data: Nicholas S. Phillips, Nicole J. Ullrich

Data analysis and interpretation: Nicholas S. Phillips, Nicole J. Ullrich

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Neurotoxic Effects of Childhood Cancer Therapy and Its Potential Neurocognitive Impact

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