Keywords
chemotherapy, delirium, myelopathy, neuropathy, radiotherapy, seizure, toxicity
Chemotherapy and radiation therapy (RT) are two of the major modalities used to treat cancer. Their goal is to kill or inactivate enough cancer cells so that the body’s own defenses can control the disease without unacceptable damage to normal tissue. Unfortunately, both RT and chemotherapy are relatively nonspecific and depend on their ability to damage rapidly dividing cells. The therapeutic/toxic ratio is often low; even in highly sensitive tumors such as acute lymphoblastic leukemia, Hodgkin disease, and germ cell tumors, for which the cure rate is high, many patients suffer serious side effects of therapy, either immediately or months to years later.
The nervous system may be expected to be relatively insensitive to the side effects of cancer therapy. It is protected from exposure to many chemotherapeutic agents by the blood–brain, blood–cerebrospinal fluid (CSF), and blood–nerve barriers. Furthermore, most neurons do not reproduce, and glial cells reproduce only slowly, thus affording protection against agents directed against dividing cells. Nevertheless, nervous system toxicity is common, second only to myelosuppression as a reason for limiting the dose of chemotherapy, and often is also dose limiting for RT. This chapter describes the side effects of these therapeutic modalities on both the central and peripheral nervous systems. Chemotherapeutic agents and radiotherapeutic approaches that are used widely in clinical practice are emphasized, with particular attention to newer agents.
Chemotherapy
Table 28-1 classifies the major chemotherapeutic agents that have been reported to cause central nervous system (CNS) or peripheral nervous system (PNS) toxicity. Table 28-2 lists the neurotoxic signs caused by agents commonly used in cancer patients; details can be found elsewhere.
| Neurotoxicity | Neurotoxicity | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Agents | Drug | PNS | CNS † | Muscle | Agents | Drug | PNS | CNS † | Muscle |
| Antimetabolites | 5-Azacitidine | + | + | ?+ | Podophyllotoxins | Etoposide (VP-16) | ?+ | ?+ | − |
| 5-Fluorouracil | − | ++ | − | Teniposide (VM-26) | ?+ | ?+ | − | ||
| Capecitabine | ?+ | + | − | Monoclonal antibodies | Bevacizumab | − | + | − | |
| Cladribine | − | + | − | Ipilimumab | + | + | − | ||
| Cytarabine | + | + | − | Rituximab | − | + | − | ||
| Fludarabine | − | ++ | − | Small molecule inhibitors | Bortezomib | ++ | − | − | |
| Gemcitabine | ?+ | ?+ | + | Carfilzomib | + | + | − | ||
| Methotrexate | − | ++ | − | Gefitinib | − | + | − | ||
| Nelarabine | ++ | + | − | Imatinib | − | + | − | ||
| Pemetrexed | + | − | − | Selumetinib | − | + | + | ||
| Pentostatin | + | + | − | Sorafenib | ++ | + | − | ||
| Alkylating agents | Carmustine (BCNU) | − | + | − | Sunitinib | − | ++ | − | |
| Chlorambucil | − | ?+ | − | Tipifarnib | ++ | + | − | ||
| Cyclophosphamide | − | ?+ | − | Vemurafenib | − | + | − | ||
| Ifosfamide | − | ++ | − | Other Biologics | Cyclosporine | + | + | + | |
| Lomustine (CCNU) | − | + | − | Interferons | + | ++ | − | ||
| Temozolomide | − | + | − | Interleukins | − | ++ | − | ||
| Thiotepa | − | + | − | Lenalidomide | + | − | − | ||
| Platinums | Carboplatin | + | − | − | Mycophenolate mofetil | + | + | − | |
| Cisplatin | ++ | ++ | − | Tacrolimus | − | + | − | ||
| Oxaliplatin | ++ | − | − | Thalidomide | ++ | − | − | ||
| Taxanes | Cabazitaxel | ++ | − | + | Miscellaneous | Dexamethasone | − | ++ | ++ |
| Docetaxel | + | − | + | DTIC (Dacarbazine) | − | ?+ | − | ||
| Nab-paclitaxel | ++ | − | + | Hexamethylmelamine | + | + | − | ||
| Paclitaxel | ++ | − | + | Ixabepilone | ++ | − | − | ||
| Vinca alkaloids | Vinblastine | + | − | − | L-Asparaginase | − | + | − | |
| Vincristine | ++ | + | ?+ | Procarbazine | + | + | − | ||
| Vinorelbine | + | − | − | Retinoids | + | ++ | − | ||
| Suramin | ++ | + | − | ||||||
| Tamoxifen | − | + | − | ||||||
| Acute Encephalopathy (Delirium) |
| 5-Azacytidine, 5-fluorouracil, asparaginase, bevacizumab, capecitabine, carmustine, cisplatin, cladribine, corticosteroids, cyclophosphamide, cyclosporin A, cytarabine, dacarbazine, docetaxel, etoposide (HD), fludarabine, gemcitabine, hydroxyurea, ifosfamide, imatinib, interferons, interleukins 1 and 2, methotrexate (HD, IV, IT), nelarabine, nitrosoureas (HD or arterial), paclitaxel, pentostatin, procarbazine, tacrolimus, tamoxifen, thalidomide, thiotepa (HD), tipifarnib, vincristine |
| Seizures |
| 5-Fluorouracil, amifostine, asparaginase, bevacizumab, busulfan (HD), carmustine, cisplatin, corticosteroids, cyclophosphamide (HD), cyclosporin A, cytarabine, dacarbazine, docetaxel, erythropoietin, etanercept, etoposide (HD), fludarabine (HD), gemcitabine, hydroxyurea, ifosfamide, interferon, interleukin-2, letrozole, leuprolide, methotrexate, nelarabine, octreotide, paclitaxel, pentostatin (HD), temozolomide, teniposide, thalidomide, topotecan (IT), vincristine |
| Headaches Without Meningitis |
| 5-Fluorouracil, anastrozole, asparaginase, carmustine, capecitabine, cetuximab, cisplatin, cladribine, corticosteroids, cytarabine, erlotinib, estramustine, etoposide, fludarabine, gefitinib, gemtuzamab, hydroxyurea, ibritumomab, imatinib, interferons, interleukins, isotretinoin, ixabepilone, letrozole, leuprolide, methotrexate, nelarabine, panitumumab, procarbazine, retinoic acid, rituximab (IV & IT), sorafenib, sunitinib, tamoxifen, temozolomide, thalidomide, thiotepa, topotecan, traztusumab, vemurafenib, vincristine |
| Visual Loss |
| 5-Fluorouracil, bevacizumab, carboplatin, carmustine, cisplatin, cytarabine, etanercept, etoposide, fludarabine, interferon, interleukin, ipilimumab, isotretinoin, methotrexate, nitrosoureas (IA), oxaliplatin, paclitaxel, pentostatin, tamoxifen, vincristine |
| Chronic Encephalopathy (Dementia) |
| 5-Fluorouracil, carmofur, carmustine, cisplatin, cytarabine, dacarbazine, fludarabine, ifosfamide, interferon-alpha, methotrexate, rituximab (IT), topotecan (IT) |
| Peripheral Neuropathy |
| 5-Azacitidine, 5-fluorouracil, bortezomib, cabazitaxel, capecitabine, carboplatin, carfilzomib, cisplatin, cladribine, cytarabine, docetaxel, etoposide, fludarabine, gemcitabine, ifosfamide, interferon, ipilimumab, ixabepilone, lenalidomide, nab-paclitaxel, nelarabine, oxaliplatin, paclitaxel, pemetrexed, pentostatin, procarbazine, sorafenib, sunitinib, teniposide, thalidomide, tipifarnib, vinca alkaloids |
| Cerebellar Dysfunction (Ataxia) |
| 5-Fluorouracil, cyclosporin A, cytarabine, nelarabine, procarbazine, vinblastine, vincristine |
| Myelopathy (Intrathecal Drugs) |
| Cytarabine, methotrexate, thiotepa |
| Aseptic Meningitis |
| Cytarabine (IT), IVIg, methotrexate (IT), monoclonal antibodies, rituximab (IT), thiotepa (IT), topotecan (IT) |
Antimetabolites
Fludarabine
Fludarabine (2-fluoroadenosine arabinoside) is active against a variety of lymphoproliferative neoplasms. It is highly immunosuppressive and has been associated with the development of progressive multifocal leukoencephalopathy (PML) in some patients. In addition, fludarabine can cause delayed neurotoxicity leading to a severe encephalopathy and occasionally cortical blindness. Older patients and those receiving higher doses of the drug are at greatest risk.
Methotrexate
Methotrexate causes both acute and delayed neurotoxicity. The side effects associated with intrathecal administration are discussed on page 599, where the various neurologic side effects of methotrexate are also tabulated.
A stroke-like syndrome affecting adults or children occasionally follows systemic high-dose methotrexate infusion. The disorder usually follows the second or third treatment by 5 or 6 days and is characterized by alternating hemiparesis associated with aphasia and sometimes encephalopathy or coma. Seizure activity is rare, and the electroencephalogram (EEG) is typically slow. Magnetic resonance imaging (MRI) shows foci of hyperintensity on fluid-attenuated inversion recovery (FLAIR) sequences, and diffusion-weighted imaging (DWI) sequences display well-delineated hyperintense areas affecting the deep white matter that do not conform to a single vascular territory. Apparent diffusion coefficient maps demonstrate decreased signal intensity in a corresponding distribution, suggesting restricted diffusion, similar to an acute vascular event. Patients generally recover spontaneously in 48 to 72 hours with complete or partial resolution of the imaging abnormalities. Recurrences are rare with subsequent treatments. The pathogenesis is unknown, but it may be related to brain glucose metabolism, which decreases following intravenous infusion of high-dose methotrexate in rats.
Leukoencephalopathy may appear months to years following therapy, beginning either insidiously or abruptly. The disorder generally follows repeated doses of intravenous high-dose methotrexate or intrathecal methotrexate, but it may occur after standard doses as well. Although the syndrome can be caused by methotrexate alone, it is enhanced by brain RT and the combination of systemic and intrathecal drug. The sequence of administration is probably also important; when methotrexate is administered concurrently with or follows cranial RT, the synergy is particularly toxic. Patients may recover slowly over weeks or months, their symptoms may stabilize with a mild-to-moderate cognitive deficit, or there may be relentless progression with spastic hemiparesis or quadriparesis, severe dementia, and coma, ending in death. Seizures can occur, usually late in the course. The MRI reveals cerebral atrophy, bilateral and diffuse periventricular white matter hyperintensities on T2-weighted or FLAIR sequences, ventricular dilatation, and, sometimes, cortical calcifications ( Fig. 28-1 ). Neurologic signs are usually preceded by radiographic white matter changes, and identical radiographic findings may be seen in patients years after prophylactic treatment with intrathecal or intravenous methotrexate, even in the absence of RT. Similar findings may occasionally be seen in asymptomatic patients who have received methotrexate. Focal gadolinium enhancement may be present in the early stages, but it typically does not persist. No effective treatment exists.
Cytarabine (Cytosine Arabinoside)
Intravenous high-dose cytarabine (ara-C) may cause central or peripheral neurologic disorders. Cerebellar dysfunction occurs most frequently in older patients and in those with preexisting renal dysfunction, usually at a cumulative dose≥36 g/m 2 ; however, it has been reported after a single dose of 3 g/m 2 . Patients develop dysarthria, nystagmus, and appendicular and gait ataxia. Confusion, lethargy, and somnolence may also occur. With cessation of the drug, complete resolution of symptoms and signs generally occurs within 2 weeks, but some have persistent deficits.
Peripheral neuropathy, which may be axonal or demyelinating, is a rare complication of ara-C. Other reported toxicities include seizures, intracranial hypertension, reversible ocular toxicity (blurred vision, photophobia, burning eye pain, and blindness), pseudobulbar palsy, Horner syndrome, the “painful legs, moving toes” syndrome, brachial plexopathy, bilateral lateral rectus palsies, and acute aseptic meningitis following intravenous injection. There is no treatment for any of the neurotoxic effects of ara-C, but many patients recover spontaneously.
Nelarabine
Nelarabine is a purine analog that is used in the treatment of T-cell acute lymphoblastic leukemia. Motor or sensory neuropathy, or both, occurs in approximately 20 percent of patients. Central neurotoxicity most frequently involves somnolence and fatigue that begins approximately 1 week after drug administration. Other symptoms may include headache, seizures, ataxia, tremor, amnesia, and paraplegia. The deficits may not be reversible, and drug discontinuation is recommended.
Gemcitabine
Gemcitabine is a deoxycytidine analogue. Sensory neuropathy occurs in approximately 10 percent of patients, and an autonomic neuropathy has been reported. Gemcitabine may also cause an acute myositis. Patients present with painful symmetric weakness of the proximal muscles, with elevation of serum creatine kinase levels. Symptoms resolve rapidly with discontinuation of the drug and may respond to corticosteroids. Patients often do not have symptoms following additional doses of the drug. Gemcitabine may also cause a focal myositis hours to days after administration, in a muscle group within a field previously irradiated months or years earlier, a phenomenon referred to as “radiation recall.” Many other agents have also been associated with radiation recall, including capecitabine and docetaxel.
Microtubule Agents
Ixabepilone
Ixabepilone is an epothilone that stabilizes microtubules and induces apoptosis. A predominantly sensory neuropathy is the most common neurotoxicity, occurring in more than 60 percent of patients. The neuropathy is generally mild-to-moderate and improves with drug discontinuation, typically within 1 to 2 months. Alternatively, the dose can be reduced if the severity is no worse than grade 2 by National Cancer Institute common toxicity criteria, being discontinued if the severity reaches grade 3. Less common neurologic side effects include headache and dizziness.
Taxanes
Paclitaxel and Docetaxel
Approximately 60 percent of patients receiving paclitaxel (Taxol) at≤250 mg/m 2 per dose develop paresthesias of the hands and feet that do not usually progress and may resolve even with continued therapy. The neuropathy is predominantly sensory, affecting all modalities. Paclitaxel causes axonal damage with secondary demyelination, probably reflecting cell body damage. A few patients also develop proximal muscle weakness that resolves; it is usually associated with the peripheral neuropathy. Acute arthralgias and myalgias of the legs that curtail activity may occur 2 to 3 days after a course of paclitaxel and can last for 2 to 4 days. Rarely, encephalopathy and seizures occur. Docetaxel causes the same type of sensory neuropathy as paclitaxel but in general has less neurotoxicity. Paclitaxel or docetaxel neuropathy is enhanced by prior or subsequent neurotoxic chemotherapy, particularly with cisplatin or vinorelbine. Data from animal models suggest that lithium, ibudilast, and cannabinoid receptor agonists may be neuroprotective against paclitaxel-induced peripheral neuropathy, but to date there are insufficient human data to support any neuroprotective agents against taxane-induced (or any chemotherapy-induced) peripheral neuropathy.
Nab-paclitaxel
Nab-paclitaxel, an albumin-bound formulation of paclitaxel, has a higher incidence of grade 3 sensory neuropathy compared to standard paclitaxel. Patients may improve with discontinuation, and the drug may be rechallenged at a reduced dose.
Cabazitaxel
Cabazitaxel is a semisynthetic taxane that can be effective in docetaxel- and paclitaxel-resistant tumors. Peripheral neuropathy can occur but is rarely severe.
Vincristine
Vincristine affects primarily the peripheral nerves but can also be toxic to the CNS, cranial nerves, and autonomic nervous system ( Table 28-3 ). Vinorelbine and vinblastine are much less neurotoxic. A dose-limiting sensorimotor neuropathy appears in virtually all patients. The earliest complaint is of tingling and paresthesias of the fingertips and later of the toes. Fine movements of the fingers and toes are often eventually impaired. Objective sensory loss is uncommon, but weakness, especially of the extensors of the feet and hands, is frequent. Foot drop is either unilateral or bilateral; unilateral foot drop is more common in patients who have lost weight and habitually sit with crossed legs, causing fibular (peroneal) nerve compression. The weakness is usually tolerable, but rarely patients may become bedbound or quadriparetic, particularly if there is a preexisting neuropathy. The sensory symptoms, weakness, and loss of muscle-stretch reflexes are reversible, but may require months to improve after the medication is stopped. Neurophysiologic studies show an axonal neuropathy.
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