Neurotoxicity of Cancer Therapies (Neuro-Oncology December 2020)

Educational Objectives

The goal of this program is to improve diagnosis and management of oncologic disorders affecting the nervous system. After hearing and assimilating this program, the clinician will be better able to:

1. Recognize neurologic complications of chemotherapy for cancer.
2. Identify acute, early-delayed, and late-delayed radiation-induced neurotoxicity in patients treated for cancer.

Summary

Neurotoxicity associated with cancer therapy: Classic forms of acute and subacute neurotoxicity include encephalopathy, seizures, and peripheral neuropathy; typical delayed complications include cognitive decline, neurovascular syndromes, loss of brain volume (atrophy), white matter disease (leukoencephalopathy), and secondary tumors (may occur years or decades after initial treatment).

Chemotherapy-Induced Neurotoxicity

Chemotherapy-induced peripheral neuropathy: Among the most common neurologic complications of cancer therapy and is associated with significant morbidity and reduced quality of life; incidence varies by treatment and patient (30% to 70%); contributing factors include the drug given, overall and cumulative doses, duration of exposure, and part of the nervous system that is affected; the typical presentation is characterized by a painful, length-dependent, predominantly sensory, symmetric peripheral neuropathy; patients report numbness and tingling in the hands and feet, allodynia, hyperalgesia, and dysesthesia.

Chemotherapeutic agents: Taxanes and vinca alkaloids (eg, vincristine) may be associated with motor impairment; platinum compounds (eg, oxaliplatin, carboplatin) may cause acute infusion-associated reactions (eg, orofacial dysesthesia; tingling; acute onset of burning sensations in the face, mouth, throat); platinum compounds may cause distinctive deficits in function of cranial nerves (eg, ototoxicity).

Coasting: A phenomenon that may be observed in a patient treated with platinum drugs; the term coasting refers to delayed onset of peripheral neuropathy that may worsen after treatment is stopped; the condition typically occurs within 1 to 5 months after stopping treatment; however, time to onset after treatment may be as long as 1 year.

Management of chemotherapy-induced peripheral neuropathy: Early recognition is key to altering the course; stopping or reducing the dose of the causative drug typically leads to improvement over time; nerve conduction studies or EMG may be used to monitor the patient; the clinician must rule out other factors that may cause neuropathy (eg, poorly controlled diabetes mellitus, unrecognized vitamin deficiencies, endocrine dysfunction [eg, abnormalities of the thyroid]); results of disease-modifying treatments are mixed; supportive treatment with gabapentin, tricyclic antidepressant agents, or duloxetine is common.

Acute encephalopathy: Associated with many types of chemotherapeutic agents; patients may present with acute confusion, lack of orientation, hallucinations, profound fatigue, or seizures; the condition is typically present hours to 2 days after exposure to the chemotherapeutic agent; the most common causative agents are cyclophosphamide, nitrosoureas, platinum compounds, ifosfamide, antimetabolites (eg, methotrexate, 5-fluorouracil), and antihormonal agents (eg, tamoxifen); acute symptoms likely are associated with disruption of the blood-brain barrier; most patients recover fully with supportive management.

Aseptic meningitis: Typically found in a patient who had intrathecal administration of chemotherapeutic agents; aseptic meningitis is present in 10% to 60% of patients receiving intrathecal methotrexate; signs and symptoms include headache, acute back pain, nausea, vomiting, signs of meningeal irritation, and low-grade fever.

Posterior reversible encephalopathy syndrome: Not uniformly posterior or reversible; clear signs of encephalopathy may not be present; patients may experience headaches, seizures, visual changes, and acute or subacute changes in mental status; drugs associated with this syndrome include platinum compounds, cyclophosphamide (Cytoxan), cytosine arabinoside, 5-fluorouracil, methotrexate, immunomodulators (eg, tacrolimus), and antiangiogenic agents (eg, bevacizumab).

Selective cerebellar toxicity: A rare finding that is classically associated with high-dose cytosine arabinoside; onset is subacute or delayed; patients may develop limb ataxia, dysmetria, impaired fine motor function, abnormalities of eye movement (pathologic nystagmus), imbalance, and encephalopathy with somnolence and nausea.

Chemotherapy-associated leukoencephalopathy: Many chemotherapeutic drugs affect the progenitor cells of myelin-forming cells (oligodendrocyte precursor cells) and mature oligodendrocytes; onset is typically delayed; the condition is irreversible; management is difficult; the condition is associated with methotrexate, cytosine arabinoside, fludarabine, ifosfamide, vincristine, and carmustine; in patients receiving many rounds of chemotherapy for lymphoma of the central nervous system and in children treated for leukemia with high-dose chemotherapy, the risk is high.

“Chemobrain” or “chemofog”: These terms are not scientifically accurate but are used to describe cognitive changes commonly found in patients treated with chemotherapy; the terms encompass difficulties with memory and multitasking; cognitive testing by a neuropsychologist may indicate deficits in attention, concentration, processing speed, learning, memory, and executive function.

Radiation-Induced Neurotoxicity

Time to onset: Radiation-induced neurotoxicity may be acute, early-delayed, or late-delayed.

Acute radiation-induced neurotoxicity: Complications that occur days to weeks after exposure of the brain to radiation include changes in mental status, fatigue, and exacerbation of preexisting neurologic conditions; the majority of patients are treated with steroids; in most cases, acute problems resolve, and deficits are not permanent.

Case: A 37-year-old man with a history of medulloblastoma in the right cerebellum underwent resection followed by craniospinal radiation therapy; he also received carboplatin, vincristine, and lomustine, and he tolerated the drugs well; more than 10 years after treatment, the patient remains in remission; however, he has developed progressive cognitive impairment, dysarthria, motor deficits, poor coordination, and urinary incontinence; because of imbalance and recurrent falls, he uses a wheelchair.

Management: The clinician should first use imaging to rule out recurrence of disease; signs suggesting delayed complications of treatment to the central nervous system (eg, loss of brain volume, communicating hydrocephalus) are present; microbleeds are an adverse effect of cranial irradiation; in such patients, classic symptoms include impairments in gait and cognition, and urinary continence.

Delayed radiation-induced neurotoxicity: Typically occurs months to years after treatment and is progressive and irreversible; the chief complication is cognitive decline; these patients may develop leukoencephalopathy, tissue necrosis and loss of volume in the brain, and secondary complications (eg, vasculopathy, endocrinopathy); treatment is supportive; risk factors include young age, advanced age, type of treatment, cumulative dose of radiation, high fraction size, adjuvant chemotherapy, cardiovascular comorbidities, and genetic factors.

Radiation necrosis: A distinct, severe form of late toxicity; radiation necrosis may be associated with leukoencephalopathy; a contrast-enhancing lesion in the previously irradiated area may be revealed on imaging within a year of treatment or decades later; this form of toxicity mimics a recurrent tumor; biopsy of the brain or serial imaging is typically required to rule out recurrence and establish the diagnosis.

Stroke: Radiation therapy is a risk factor; irradiation causes endothelial injury and chronic inflammation of large, medium, and small blood vessels; in children who receive radiation therapy, risk for development of strokelike syndromes years after treatment is high; large-vessel injury and carotid stenosis are associated with infarction or transient ischemic attacks and are found in as many as 50% of patients treated with radiation therapy for cancers of the head and neck.

Strokelike migraine attacks after radiation therapy: A rare form of delayed toxicity to the central nervous system caused by irradiation; the pathology of SMART (strokelike migraine attacks after radiation therapy) syndrome is not completely understood; the hypothesized cause is dysregulation of cerebrovascular systems and structures; patients may present with SMART syndrome decades after treatment; the condition may mimic delayed recurrence of the tumor; although the majority of patients recover, recurrence of SMART syndrome is possible.

Neurotoxicity Associated With Antiangiogenic Agents

Effects of neurotoxicity: Bevacizumab blocks the effects of vascular endothelial growth factor; the hallmark of antiangiogenic agents is neurovascular complications; they include thromboembolic events (eg, pulmonary embolism, stroke) and increase in risks for infarction and bleeding; the risk for bleeding is as high as 5% and is considered acceptable.

Readings

Dietrich J. Neurotoxicity of cancer therapies. Continuum (Minneap Minn) 2020;26(6, Neuro-oncology).

Disclosures

For this program, the following was disclosed: Dr Dietrich has received personal compensation for serving as a consultant for Blue Earth Diagnostics and Unum Therapeutics and publishing royalties from Wolters Kluwer N.V.

Unlabeled Use of Products/Investigational Use Disclosure: Dr Dietrich reports no disclosure.

To view disclosures of planning committee members with relevant financial relationships, visit: legacy.audio-digest.org/continuumaudio/committee. All other members of the planning committee report nothing to disclose.

The material presented in Continuum Audio has been made available by the AAN for educational purposes only and is not intended to represent the only method or procedure for the medical situations discussed but rather to present an approach, view, statement, or opinion of the speaker(s), which may be helpful to others who face similar situations. Opinions expressed by the speakers are not necessarily those of the AAN, its affiliates, or the publisher. The AAN, its affiliates, and the publisher disclaim any liability to any party for the accuracy, completeness, efficacy, or availability of the material contained in this program (including drug dosages) or for any damages arising out of the use or nonuse of any of the material contained in this program.

Acknowledgements

CME/CE INFO

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The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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Lecture ID:

CA090609

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.