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900 PART 7: Hematologic and Oncologic Disorders

40% of patients and is characterized by peripheral neuropathy with weak- of administration. Ifosfamide can precipitate encephalopathy in 10% to
ness in the lower extremities, which if severe, can mimic Guillain-Barre 25% manifesting as decreased attention and agitation within hours of
Syndrome. Other associated symptoms can include headache and altered administration lasting 1 to 4 days. High-dose ara-C can cause encepha-
consciousness. The mechanism of neurotoxicity is unknown. 82 lopathy in 10% to 30%, again within 24 hours of administration and
Another manifestation of cancer therapy–induced neurotoxicity, resolves weeks after discontinuation. High-dose ara-C can also cause
particularly with VEGF inhibitors due to their tendency to cause hyper- painful corneal toxicity associated with blurred vision, photophobia, and
tension, is posterior reversible encephalopathy syndrome or PRES. PRES conjunctival injection, which can be prevented and treated with gluco-
is a clinical radiographic syndrome of headache, altered consciousness, corticoid eye drops. Cerebellar syndrome has also been described with
visual disturbances, and seizures associated with characteristic sym- high-dose cytarabine and includes dysarthria, ataxia, and nystagmus.
metrical white matter edema in the posterior cerebral hemispheres on Intrathecal methotrexate administration can cause aseptic meningitis in
MRI. These findings are frequently accompanied by hypertension and 10% of patients and manifests as headache, lethargy, and nuchal rigidity.
hypertensive crisis may precede the syndrome by ≥24 hours. PRES Overdosage of intrathecal MTX can cause fatal myeloencephalopathy
is a well-described complication of anticancer therapies including manifest by seizure and coma. Subacute central neurologic toxicity
tacrolimus, cyclosporine, cisplatin, 5-FU, capecitabine, bevacizumab, associated with moderate to high doses of MTX can occur weeks to
sorafenib, and sunitinib. The mechanism is secondary to acute endothelial months after administration and may present with aphasia, dysarthria,
damage leading to microangiopathy with cerebrovascular dysregulation hemiparesis, seizures, and behavioral abnormalities while chronic neu-
and vasogenic edema. Treatment is largely supportive with antihyper- rotoxicity occurring greater than 6 months after therapy in combination
85
tensives and discontinuation of inciting agent. 82 with whole brain XRT is very common (>90%) and can present as
Another worrisome, though uncommon, complication of the VEGF dementia, ataxia, and incontinence. All-trans-retinoic acid commonly
inhibitor bevacizumab is intratumoral bleeding in patients with cerebral causes headache and in some cases can be associated with increased
metastasis leading to intracerebral hemorrhage. While this concern intracranial pressure due to idiopathic intracranial hypertension as
is practical, no clear incidence has been determined as patients with evidence by papilledema. The peripheral and central manifestations of
87
cerebral metastases were largely excluded from these drug studies. In neurotoxicity due to chemotherapy are presented in Table 95-7.
addition, in published series of 21 patients treated with bevacizumab
and anticoagulation, only 3 patients developed asymptomatic, small ■
intraparenchymal hemorrhages. 86 HYPERSENSITIVITY REACTIONS
Central nervous system toxicity can also occur following treat- A hypersensitivity reaction is defined as an unexpected reaction to an
ment with anticancer therapies. Busulfan, in about 10% of patients agent that is not consentient with that drug’s known toxicity profile.
receiving high-dose therapy, can precipitate seizures within 24 hours Hypersensitivity reactions may be immune or nonimmune mediated.

TABLE 95-7 Neurotoxicities
Toxicity Common Agents Presentation Comments
Peripheral neuropathy Vincristine Painful polyneuropathy and autonomic neuropathy • 60%-100% incidence
>5 mg Sensory symptoms— hypoesthesia and dysesthesia • Presentation dependent on dose
30-50 mg Autonomic effects seen in 1/3 of patients (orthostatic
hypotension, bladder dysfunction)
Paclitaxel Sensory neuropathy with loss of DTRs and painful myalgias • Incidence 50%-70%
Single dose >250 mg/m 2 Acute paraesthesia and progressive sensory-motor • Dose-dependent effects are largely
Cumulative dose >1000 mg/m 2 neuropathy reversible
Cisplatin (dose >400 mg/m ) 2 Sensory neuropathy associated with paresthesias, ataxia, • Incidence 30%-100%
decreased DTRs • Symptoms typically resolve within 1 year
Oxaliplatin Paresthesias and dysesthesias in hands and feet, periorally • Incidence ranges 40%-90%
Acutely following infusion (30-60 min) and pharyngolaryngeally, associated with jaw tightness, • Acute onset following infusion is reversible
Cumulative dose >750 mg/m 2 exacerbated by cold exposure over hours to days while toxicity due to
Noncold-related paresthesias and dysesthesias with cumulative dose may resolve months after
sensory loss, ataxia, and functional impairment discontinuation
Thalidomide (doses 25-1600 mg/m ) 2 Painless paresthesias of hand and feet with diminished • Incidence of 30%-70%
Earlier onset (1-2 mo) with higher sensation to light touch/pinprick and loss of DTRs; • Recovery is slow and incomplete
doses, later onset (8-12 mo) with autonomic neuropathy leading to constipation
lower doses
Bortezomib Severe debilitating neuropathic pain • ∼70% of cases reversible
Nelarabine LE weakness and paresthesia, severe cases may mimic
Guillain-Barre syndrome
Central Neurotoxicity
Encephalopathy High-dose cytarabine, ifosfamide Decreased attention, agitation
Posterior reversible encepha- Tacrolimus; cyclosporin; cisplatin, Headache, altered mental status, seizure, visual • Characteristic MRI finding of symmetrical
lopathy (PRES) 5-FU; capecitabine; bevacizumab; disturbances, and hypertension white matter edema in the posterior
sorafenib; sunitinib cerebral hemispheres
Corneal toxicity High-dose cytarabine Blurred vision, photophobia, conjunctival injection • Glucocorticoid eye drops may be used for
prevention and treatment
Cerebellar syndrome High-dose cytarabine Dysarthria, nystagmus, ataxia

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