Cerebellar Toxicity

Systemic administration of high-dose (greater than 1 g/m²) intravenous ara-C can cause acute cerebellar toxicity.12–15 Onset of neurologic symptoms generally is acute and often is noticed during administration of a multiday regimen.^12,13 Patients exhibit evidence of global cerebellar dysfunction, which manifests as truncal, limb, and gait ataxia, dysarthria, and nystagmus. In some cases, permanent cerebellar dysfunction results; in others, a mild cerebellar syndrome develops that resolves promptly after completion of the chemotherapy.^12,13

Patients with irreversible cerebellar damage have a characteristic and selective loss of Purkinje cells in the cerebellum.¹⁵ The pathogenesis of the specific cellular damage is unknown, and no pathological findings have been described in the cerebella of patients who have recovered from transient cerebellar dysfunction.

The incidence of irreversible cerebellar toxicity with high-dose ara-C regimens has been reported to be 8% to 20%. Factors reported to affect the likelihood of development of cerebellar toxicity include size of current dose, cumulative dose, age (persons older than 50 years are at higher risk), abnormal alkaline phosphatase (alkaline phosphatase greater than or equal to three times normal) and renal status (renal dysfunction with impaired drug clearance is associated with increased risk).13,14,16–18 Whether patients in whom reversible cerebellar dysfunction develops with previous treatment are at higher risk for permanent dysfunction is unknown.

Recent data show that, in animal models, oral application of the antioxidant N-acetylcysteine is able to prevent ara-C–induced behavioral deficits and cellular alterations of the adult cerebellum in a rat model.19,20 However, this treatment has not yet been tested in humans.

Encephalopathy

Acute encephalopathy, often accompanied by seizures, occurs less frequently than cerebellar dysfunction in patients receiving high-dose intravenous ara-C.¹³ In most cases, somnolence and lethargy completely resolve soon after completion of chemotherapy. Patients with persistent encephalopathy usually have had additional medical problems, such as severe infection or metabolic abnormalities.¹⁸ In addition, leukoencephalopathy that is clinically and pathologically indistinguishable from the leukoencephalopathy associated with methotrexate has been reported as a late complication of high-dose intravenous ara-C administration and with administration of ara-C directly into the CSF.¹³

Spinal Cord Toxicity

Direct administration of ara-C into the lumbar thecal space has been reported to cause myeloradiculopathy.21–25 Patients exhibit evidence of both spinal cord and nerve root dysfunction. This complication is uncommon and usually is found only after an extensive course of intrathecal chemotherapy. In many instances, patients have received both intrathecal ara-C and methotrexate.^26,27 When the exclusive use of intrathecal ara-C resulted in spinal cord injury, it was either administered at relatively high doses (100 to 150 mg, three cases) or in liposomal form (50 mg, two cases) where prolonged release of ara-C in the CSF overlapped with systemic high-dose methotrexate and high-dose ara-C.²⁸

Neurologic signs typically are noticed days to weeks after treatment, although myelopathy may develop within minutes of administration. In most cases, loss of neurologic function progresses slowly over days, and only half of patients demonstrate improvement or achieve full recovery.

Several hypotheses have been proposed for the mechanism of chemotherapy-induced myelopathy. Focal damage from injection of hyperosmolar solution,²⁹ barbotage from injection,³⁰ and direct toxic effects of chemotherapy on the spinal cord parenchyma are the most common proposed mechanisms of subacute myelopathy. Histologic examination of the spinal cord shows focal areas of necrosis that are most marked along the periphery of the spinal cord.^22,23,26 Microscopic examination shows axonal swelling with accompanying demyelination.^22,23,26 With chemotherapy-induced spinal cord injury, myelin basic protein levels in the CSF may be elevated before marked neurologic damage occurs.^26,27 For patients with early symptoms, such as paresthesia, back pain, or Lhermitte sign, the level of myelin basic protein in the CSF should be measured. If the level is elevated, further lumbar administration of chemotherapy should be avoided.²⁷

Liposomal Ara-C

Liposomal cytarabine is frequently used because of its convenience, that is, every-2-week dosing because of a long CSF half-life (approximately 140 hours), and its potential improved efficacy compared with free cytarabine and methotrexate.29,30 Although the pharmacokinetics of drug delivery in the CSF is improving with the liposomal ara-C, an increase in the incidence of arachnoiditis has been observed, and isolated cranial nerve palsies may be more frequent. In a recently published retrospective series of 120 adult patients with lymphomatous meningitis who were treated with liposomal ara-C, serious treatment-related neurologic complications developed in 12.5% of patients. Toxicity included bacterial meningitis, chemical meningitis, communicating hydrocephalus, conus medullaris/cauda equine syndrome, decreased visual acuity, encephalopathy, leukoencephalopathy, myelopathy, radiculopathy, and seizures. Distribution of toxicity was similar regardless of the route of administration (ventricular vs. lumbar).^31,32

Other Neurotoxicity Associated with Cytosine Arabinoside

Peripheral neuropathy has been reported after administration of high-dose ara-C.³³ In this report, symmetrical sensorimotor polyneuropathy developed 2 weeks after completion of treatment. Nerve biopsy demonstrated axonal damage with patchy regions of demyelination. In addition, a case of reversible Parkinsonism has been reported after administration of high-dose ara-C.¹³ Onset of tremor, bradykinesia, and masklike facies were observed 3 weeks after completion of treatment. Treatment with carbidopa-levodopa provided only transient improvement. However, all Parkinsonian features resolved over 12 weeks.

Cerebrovascular events caused by l-asparaginase–induced coagulopathy constitute the most common form of neurotoxicity associated with l-asparaginase treatment. Both thrombotic and hemorrhagic strokes have been reported in patients receiving l-asparaginase.36–36 Thrombosis of cerebral venous sinuses also has occurred in patients receiving this agent.³⁷

The clinical manifestations of sinus thrombosis, which usually are acute, include severe headache, nausea, and vomiting caused by the rapid increase in intracranial pressure. Changes in level of consciousness occur most frequently with sagittal sinus thrombosis with bilateral cerebral hemisphere involvement. Although most patients with sinus thrombosis demonstrate acute and rapidly progressive changes in neurologic function, some patients experience only headache and mild neurologic dysfunction.³⁴

Patients in whom neurologic symptoms develop during l-asparaginase therapy should be evaluated with either head computed tomography (CT and CT venography) or magnetic resonance imaging (MRI and MR venography). MRI usually is preferred because it often depicts sinus thrombosis by absence of a flow void in the venous sinus. MRI also depicts early signs of ischemic brain injury, particularly on diffusion-weighted imaging, and punctate hemorrhages also may be seen.

Busulfan

Busulfan administration has been reported to cause generalized tonic-clonic seizures.³⁹ This reaction has been reported with high-dose treatment as a preparative regimen for bone marrow transplantation. Prophylactic treatment with anticonvulsant agents, particularly phenytoin, has been shown to reduce the risk of seizures.⁴⁰ However, phenytoin is contraindicated because of its ability to induce busulfan metabolism and because of possible toxicities. The existing clinical data support the use of benzodiazepines, most notably clonazepam and lorazepam, to prevent busulfan-induced seizures. The second-generation antiepileptic drug levetiracetam possesses the characteristics of optimal prophylaxis for busulfan-induced seizures, and early data of its efficacy are promising, although further study is needed.⁴¹

Methotrexate

Methotrexate can cause acute, subacute, or chronic neurotoxicity.

Chronic Neurotoxicity

Chronic methotrexate neurotoxicity is known as leukoencephalopathy. This syndrome develops months to years after methotrexate administration and has been seen after both intravenous and intrathecal administration of methotrexate.4–8,52–62 Cranial radiation therapy, particularly when it precedes methotrexate administration, greatly increases the risk of leukoencephalopathy.^5,63,64 In addition, elevated CSF methotrexate concentration has been associated with an increased risk of neurotoxicity.⁵⁴ Younger patients are at higher risk for leukoencephalopathy.^67–67 Clinically, patients show progressive loss of cognitive function and focal neurologic signs, which may progress to profound dementia, coma, or death.^4–6,8,55 Some patients experience seizures as a consequence of widespread neuronal injury. No treatment is known, and the neurologic deficits generally are irreversible. Brain imaging with MRI or CT often shows large areas of abnormalities in cerebral white matter (Fig. 57-1). Elevated levels of myelin basic protein in CSF have been reported in patients with progressive neurologic dysfunction from methotrexate-induced leukoencephalopathy.⁵⁶

Neuropathological examination shows wide areas of coagulative necrosis with swollen axonal cylinders and demyelination.4,52 Regions with vascular changes, particularly microangiopathic calcifications, are characteristic.^58,61 The pathogenesis of leukoencephalopathy is unknown, but results of laboratory studies with brain explant cultures suggest that the primary injury may be neuronal (axonal), and the characteristic demyelination may be a secondary phenomenon.⁶⁸

Vinca Alkaloids

Treatment with vinca alkaloids, particularly vincristine, commonly is associated with neurotoxicity.

The most common neurotoxicity associated with cisplatin is peripheral neuropathy, which is so significant that it is a dose-limiting adverse effect. The neuropathy predominantly involves the large sensory fibers, which mediate vibration and proprioceptive function. Deep tendon reflexes are lost because of toxic effects on the large myelinated sensory fibers, which provide the afferent arm of the reflex arc. Involvement of motor function generally is mild and is seen only in patients with severe sensory neuropathy. Development of neuropathy is dose related. The earliest signs are detected when the cumulative dose exceeds 300 mg/m².¹¹¹ The schedule of administration may be a significant factor, because the reported incidence of neuropathy has been higher in patients receiving treatment on five consecutive days than in patients on a regimen with a shorter dosing schedule but the same cumulative dose.^114–114

Continued treatment with cisplatin in patients with neuropathy can result in severe sensory ataxia that often impairs ambulation. The neuropathy is partially reversible, and patients with mild impairment generally are more likely to experience full recovery.¹¹³ A longitudinal study confirmed that there is often a delay in the onset of neuropathy. Eleven percent of the patients had neuropathy at the end of treatment, but the incidence had increased to 65% 3 months later. One year later, most of the patients had recovered, with only 17% having persistent symptoms.¹¹⁵ A recently published trial demonstrated that long-term serum platinum levels are significantly associated with the severity of neurotoxicity 5 to 20 years after cisplatin-based chemotherapy. Importantly, the relationship remained significant after adjustment for the initial cisplatin dose.¹¹⁶

The pathogenesis of cisplatin-induced neuropathy is unknown. Neuropathological studies have shown involvement of the large sensory fibers with regions of axonal swelling and myelin breakdown and, in more severe cases, axonal loss.¹¹⁷ The spinal cord shows almost exclusive involvement of myelinated axons in the dorsal columns—a finding consistent with the clinical features of vibratory and proprioceptive loss.¹¹⁸ Cisplatin has been shown to induce apoptosis in dorsal root ganglion sensory neurons by covalently binding to nuclear DNA, resulting in DNA damage, subsequent p53 activation, and BAX-mediated apoptosis via the mitochondria and also by causing a reduction in mitochondrial DNA transcription.¹¹⁹

Platinum concentration in peripheral nerve and spinal ganglia was 20 times greater than in the brain in patients at autopsy.¹¹⁵ This finding may explain the predilection of cisplatin for sensory fibers and sparing of the CNS.

Oxaliplatin

Oxaliplatin has been shown to cause two distinct types of neuropathy: acute and chronic.¹³⁵ The acute neuropathy syndrome may begin during oxaliplatin infusion or up to 1 to 2 days after completion of treatment. Patients experience paresthesias and dysesthesias of the hands and feet, jaw tightness, and a sensation of loss of breathing without respiratory distress. This latter syndrome has been named pharyngolaryngodysesthesia.¹³⁶ Dysesthesias constitute the most prominent symptom, although many patients describe pain that is more like muscle spasms of the jaw, tongue, and extremities. Hemibody paresthesias with muscle cramping have been described as an acute syndrome.¹³⁷ Some patients are unable to relax a tensed muscle, such as a grasp, during these episodes. The incidence of acute neuropathy increases with continued dosing, and an increased incidence also has been noted with higher dosing regimens. Overall, acute, severe (grade 3 or 4) neurotoxicity has been estimated to occur in 10% of patients with the initial dose, but increases to 50% by the ninth cycle of treatment.¹³⁸ Most patients experience some resolution of symptoms, but most patients have residual neuropathic symptoms up to 6 months after treatment cessation. The symptoms often return upon subsequent administration of oxaliplatin.¹³⁹ The pathogenesis of acute oxaliplatin neuropathy is thought to be related to drug-induced alterations in voltage-gated sodium channels^140,141 in response to oxalate, a metabolic byproduct of oxaliplatin. In addition, oxalate may interact indirectly with the voltage-gated sodium channels through chelation of calcium and magnesium.

The development of chronic neuropathy from oxaliplatin is related to cumulative dose, with most studies reporting that early neuropathy is noted after a total dose of greater than 540 mg/m². As with cisplatin, chronic oxaliplatin peripheral neuropathy affects large-caliber sensory nerves, with the resultant loss of proprioceptive function as the predominant clinical manifestation. Additionally, the Lhermitte-like phenomenon described with cisplatin also has been reported with oxaliplatin.142,143 The chronic neuropathy may abate over several months after the cessation of treatment, although some reports suggest that symptoms may persist.^144,145

Several approaches have been used to prevent oxaliplatin-induced neurotoxicity, including use of an intermittent oxaliplatin dosing schedule that reduced the incidence of grade 3 neurotoxicity¹⁴⁶ and the concurrent use of neuromodulatory agents, such as antidepressant drugs, antiepileptic agents, or calcium and magnesium infusions.¹⁴⁷

Cyclophosphamide

Cyclophosphamide can indirectly cause metabolic encephalopathy and seizures. High-dose cyclophosphamide can result in SIADH.150–150 When unrecognized, this syndrome can lead to severe hyponatremia, coma, and seizures. Although it is not reported in the literature in association with cyclophosphamide-induced SIADH, rapid correction of hyponatremia can result in central pontine myelinolysis, which is irreversible loss of the central pontine pathways.¹⁵¹ A locked-in syndrome may develop, or a chronic vegetative state can result from central pontine myelinolysis.

Ifosfamide

The most common manifestation of neurotoxicity associated with ifosfamide is encephalopathy. Severe ifosfamide-induced encephalopathy has been reported in children and adults.152–156 This neurotoxicity is dose dependent and may be fatal. Neurologic deterioration usually begins within hours of administration of ifosfamide.^152,154,156 Confusion, hallucinations, and aphasia are the most common initial signs. Progression to coma generally is rapid. Some patients also exhibit clinical evidence of seizure activity or myoclonus with intermittent twitching of the extremities.^152,155 Electroencephalography (EEG) shows severe slowing with delta wave activity and can display evidence of seizure activity.^152,155 In most cases, encephalopathy completely resolves over several days after cessation of therapy, although in one study, investigators found persistent mental status changes in some patients 10 weeks after treatment.¹⁵⁷ A recent study of 60 patients reported the incidence of ifosfamide neurotoxicity to be 26%.¹⁵⁸ Several risk factors have been reported to predispose patients to development of neurotoxicity from ifosfamide. These factors include low serum albumin concentration,¹⁵⁶ high serum creatinine concentration, pelvic cancer,¹⁵⁹ and previous treatment with cisplatin.¹⁶⁰ Altered mental status before treatment and bolus or rapid infusion have also been described as a predisposing factor to development of neurotoxicity from ifosfamide.^161,162 A recent report, however, could not confirm any risk factor except age, with an increased incidence of encephalopathy in younger patients.¹⁵⁸ Ifosfamide treatment has been associated with an extrapyramidal syndrome characterized by choreoathetosis, blepharospasm, and opisthotonic posturing.^163,164 Data from case reports indicate that methylene blue is an option in the treatment of ifosfamide-induced encephalopathy. However, the lack of controlled clinical trials and the possibility of spontaneous resolution of encephalopathy calls the effectiveness of methylene blue into question.¹⁶⁵ Thiamine and albumin have also been described as options for treatment and prophylaxis of ifosfamide-induced encephalopathy.¹⁶⁶

5-Fluorouracil (5-FU) causes acute cerebellar dysfunction. Patients experience moderate to severe gait ataxia, scanning speech, appendicular ataxia marked by severe dysmetria, and often nystagmus.167–170 These neurologic abnormalities resolve completely within several days after completion of therapy. The incidence of cerebellar toxicity has been reported to be 3% to 7% and correlates with dose and the interval between treatments.¹⁷⁰

Fludarabine

Fludarabine can cause a variety of neurologic toxicities ranging from a mild peripheral neuropathy to severe altered mental status with hallucinations, motor weakness, paralysis, or seizures. At high doses, white matter changes, particularly in the occipital lobes and brainstem, have been reported.¹⁸¹ The severe neurotoxicity may produce progressive worsening to death over the course of weeks to months. Visual disturbances are the most commonly reported symptom and result from cortical blindness, visual pathway demyelination, and/or retinal bipolar cell loss. Resolution of neurotoxicity rarely occurs, with most patients experiencing irreversible and severe dysfunction. The risk factors for toxicity at recommended doses have not been identified.

Fludarabine is distinctive among agents causing central nervous system toxicity in that its clinical effects do not manifest until weeks to months after exposure.¹⁸² The risk of development of progressive multifocal leukoencephalopathy due to an infection with the JC virus may be increased with fludarabine treatment. Diagnosis requires biopsy of involved brain or polymerase chain reaction testing of CSF.¹⁸³

Nitrosoureas, most commonly carmustine (BCNU), can cause encephalopathy characterized by a progressive decline in cognitive function, development of seizures, coma, and death.186–186 This complication most commonly is observed with intracarotid or supraophthalmic arterial delivery of nitrosourea, although a similar syndrome has been reported in patients who receive very high dose intravenous carmustine treatment.¹⁸⁷ Histopathologically, the toxicity associated with intraarterial therapy is characterized by necrosis, regions of demyelination, edema, and axonal loss limited to the region perfused by the intraarterial therapy. Because the predominant changes have been seen in the white matter, the condition is called leukoencephalopathy; the changes are indistinguishable from those seen with methotrexate and ara-C treatment. Similar pathological changes are seen with high-dose intravenous carmustine, but both cerebral hemispheres are involved.¹⁸⁷ In addition, focal brain necrosis has been reported with intraarterial nitrosourea treatment. This toxicity is thought to be a consequence of “streaming” of the drug along the vessel wall, without mixing with arterial blood.¹⁸⁸ This stream of concentrated drug may flow into a small branch of the artery. A small region of brain (or tumor) thus receives an enormous dose of drug, and focal necrosis results.

A biodegradable polymer containing BCNU has been shown to be effective in the management of recurrent malignant glioma. The BCNU-impregnated polymer also has been approved for treatment of newly diagnosed glioblastoma. This treatment usually is followed by conventional external beam radiation therapy.¹⁸⁹ The treatment combination may increase the incidence of treatment-associated necrosis. The wafers are placed into the tumor cavity after surgical resection. Results of clinical trials indicate that the local therapy is well tolerated, although an increase in peritumoral edema necessitates a temporary increase in corticosteroid dose, and reports of treatment-associated infections and necrosis have been made.^192–192

Procarbazine

Early reports of procarbazine use describe neurotoxicity, both peripheral and CNS toxicity, as common adverse effects of treatment.

Paclitaxel and Docetaxel

Paclitaxel is associated with a syndrome of subacute aches and pains, “paclitaxel-associated acute pain syndrome” (P-aps), and with peripheral neuropathy. This pain syndrome causes significant morbidity, with an incidence of up to 70% in patients receiving treatment with paclitaxel. It manifests with diffuse aching discomfort, most often in the legs, hips, and lower back, although it can be widespread.¹⁹⁷

The nature and temporal profile of P-aps distinguishes it as a separate entity from chemotherapy-induced peripheral neuropathy, which can be a devastating long-term consequence of this drug. Chemotherapy-induced peripheral neuropathy has been described in up to 70% of patients receiving treatment with paclitaxel. An association exists between the presence and severity of P-aps and the eventual development of sensory neuropathy.198,199

In phases 1 and 2 testing of paclitaxel, myelosuppression was the dose-limiting toxicity. Since colony-stimulating factors (e.g., granulocyte macrophage and granulocyte-colony stimulating factors) have become widely available, however, peripheral neuropathy has become the dose-limiting toxicity.1,2

The neuropathy is predominantly sensory, particularly affecting small-caliber (pain and temperature) sensory fibers.199,200 The effect on motor fibers and large-caliber sensory fibers (vibration and proprioception) is less severe. Nerve conduction studies of large myelinated nerve fibers show evidence of both axonal injury and demyelination.²⁰⁰ Neuropathy generally occurs at doses greater than 200 mg/m² and is more frequent when the drug is given every three weeks at a higher dose compared with once a week at a lower dose.²⁰¹ Symptoms usually develop 1 to 3 days after treatment. Overall the prognosis is good, because much of the neurologic dysfunction reverses over several weeks. However, continued treatment in the setting of existing neuropathy causes progressive neurologic toxicity that may not resolve. The peripheral neuropathy associated with docetaxel appears to be similar to that with paclitaxel in preliminary reports, although in a randomized trial, the incidence and severity were less with docetaxel.^204–204 Peripheral neuropathy also is being reported with other microtubule-stabilizing agents such as the epothilones.^205,206

A case report of transient vocal cord paralysis resulting from use of paclitaxel has been described.²⁰⁷

Encephalopathy has also been described as an adverse effect of paclitaxel. In one series, transient encephalopathy was reported to occur within hours of administration of standard doses of paclitaxel. All patients had undergone previous brain radiation therapy, and all recovered within hours.²⁰⁸ Acute encephalopathy was reported to occur in six patients receiving a very high intravenous dose of paclitaxel (greater than 600 mg/m²). Encephalopathy developed between 7 and 23 days after treatment. Three patients recovered, and the other three patients died of progressive coma. Autopsy revealed generalized white matter atrophy.²⁰⁹ Chronic neurocognitive changes also have been reported with extensive administration of taxanes.²¹⁰

Tamoxifen

Tamoxifen, as with other hormonal agents, is associated with headache.²¹¹ Tamoxifen can cause reversible retinal dysfunction at the conventional antiestrogen doses used for breast cancer therapy.^214–214 At higher doses, reversible encephalopathy with delusions, somnolence, and cerebellar dysfunction has been reported.^217–217 Several cases of sinus vein thrombosis in patients treated with tamoxifen have been described.^218,219

Toxicity Associated with IL-2 Treatment

In one series of five patients, the development of neuro-ophthalmic complications was temporally associated with intravenous IL-2 treatment.223,224 Reported abnormalities included transient scotomata, diplopia, amaurosis fugax, and visual field cuts.

Interferons

Systemic administration of interferon affects both the CNS and the peripheral nervous system.

Thalidomide and Lenalidomide

Thalidomide has both immunomodulatory and antiangiogenic properties, has shown significant activity in multiple myeloma, and is being evaluated in the management of several other cancers.²³⁵ Somnolence, the predominant adverse effect, is dose-related, and the drug can be titrated in most patients to a level of tolerance. Peripheral neuropathy is treatment limiting. Rates of neuropathy after thalidomide treatment vary from 15% to 70%. The neuropathy has been characterized as sensory-motor axonal polyneuropathy manifesting as painful paresthesia or numbness.²³⁶ Severity of symptoms correlates with cumulative dose and duration of therapy. Factors influencing the risk of neurotoxicity include prior neuropathy, age, previous chemotherapy, and vitamin B12 and/or folate deficiency. The mainstay of neuropathy prevention is dose reduction or withdrawal of thalidomide, which can lead to symptom resolution in up to 16 weeks; however, in some cases, the neuropathy is irreversible.^237,238

A person’s risk of developing a peripheral neuropathy after thalidomide treatment has been linked to single nucleotide polymorphisms in genes governing repair mechanisms and inflammation in the peripheral nervous system.²³⁹ Nerve biopsy and examination reveal distal axonal degeneration and demyelination. Studies of lenalidomide indicate that peripheral neuropathy may occur in a smaller percentage of patients compared with thalidomide.^240,241

Bevacizumab

Bevacizumab is a humanized monoclonal antibody against vascular endothelial growth factor (VEGF) that has shown activity in a wide variety of cancer types including colon, lung, and renal cell cancers and glioblastoma. Exacerbation of hypertension is a commonly reported toxicity and may be related to the development of PRES, described in detail later in this chapter.242,243 Bevacizumab increases the risks of hemorrhage and thromboembolism, although an analysis identifying four trials of anti-VEGF therapy in patients with brain metastases found a negligible rate of intracranial bleeding.²⁴⁴ Patients with high-grade glioma who are undergoing anticoagulation in addition to treatment with bevacizumab have an elevated hemorrhage risk, although the serious hemorrhage rate remains low (3%), suggesting that bevacizumab can be safely administered with anticoagulation in most patients.^245,246

In multiple studies, bevacizumab has been reported to increase the risk of stroke. A pooled analysis of five randomized trials showed an increase in stroke from 0.5% to 1.7%.²⁴⁷ In addition, two cases of dural sinus venous thrombosis have been reported in patients during treatment with bevacizumab.^248,249

Sorafenib

Sorafenib is an oral agent that is an RAF kinase inhibitor. Sorafenib inhibits VEGF receptors 2 and 3 and platelet-derived growth factor receptor-β. Hypertension is a common toxicity with this agent, and as with bevacizumab therapy, reports of PRES are now emerging.250,251

Bortezomib

Bortezomib is a proteosome inhibitor that has demonstrated activity in multiple myeloma. Peripheral neuropathy, predominantly a sensory neuropathy, initially was reported during early phase 1 trials. A prospective study evaluated the occurrence of neuropathy in a group of 256 patients with refractory myeloma who were treated with standard dosing schedules of bortezomib.²⁵² The incidence of neuropathy was estimated to be approximately 35%, and neuropathy was more common in patients receiving bortezomib at 1.3 mg/m² than in those who received a dosage of 1.0 mg/m². The cumulative dose also correlated with severity of the neuropathy, as did the presence of neuropathy before the initiation of treatment. Most patients experienced either partial or complete resolution with cessation of treatment.

Two cases of acute axonal motor neuropathies associated with paralytic ileus, urinary retention, and impotence occurring early in the course of bortezomib treatment have been described. Both patients had previously been exposed to other neurotoxic agents including vincristine and thalidomide and had co-morbid conditions associated with neurologic damage, namely chronic renal failure and autoimmune hepatitis.²⁵³

Sunitinib

Sunitinib is a polytyrosine kinase inhibitor that inhibits the intracellular tyrosine kinase domain of the VEGF, platelet-derived growth factor, and c-KIT receptor; it is used for gastrointestinal stromal tumors and advanced kidney cancer. This drug may be related to the development of PRES.²⁵⁴

Imatinib

Imatinib is an oral tyrosine kinase inhibitor that is used in treating chronic myelogenous leukemia and gastrointestinal stromal tumors. The main neurologic side effects of imatinib are muscle cramping and myalgias.²⁵⁵ Intracranial bleeding is a rare complication of imatinib therapy. In a retrospective study of 121 patients with chronic myelogenous leukemia who were treated with imatinib, subdural hematomas developed in seven patients. In three of the patients the subdural hematomas were not associated with thrombocytopenia or other risk factors.²⁵⁶ In addition, in clinical trials when patients with high-grade glioma were treated with imatinib, significant intratumoral hemorrhages were observed.^257,258 One case report described muscle edema, creatine kinase elevation, and rhabdomyolysis with myoglobinuria in a young woman treated with imitanib.²⁵⁹

Ipilimumab

Ipilimumab is a human monoclonal antibody against cytotoxic T lymphocyte antigen-4 that activates the immune system. It is approved for the treatment of metastatic melanoma. Ipilimumab is associated with multiple autoimmune adverse effects, including hypophysitis with hypopituitarism, which has been reported in 0% to 17% of patients involved in ipilimumab trials.262–262

Other immune-related adverse effects that have been described are inflammatory myopathy, as well as peripheral neuropathy and an autoimmune syndrome that emulates Guillain-Barré syndrome.²⁶³ A case report of PRES during ipilimumab therapy has also been described.²⁶⁴

Central Nervous System Effects

Cranial radiation therapy can cause acute, subacute, and chronic neurotoxicity. The volume of brain treated, total dose, and dose fraction are the most important determinants of toxicity, although some variation in patient susceptibility is apparent. Additionally, radiotherapy can indirectly affect the CNS by damaging the blood vessels and increasing the risk of brain cancer.²⁶⁵

Diffuse Injury

Diffuse injury manifests as global neurologic dysfunction, with cognitive decline, personality change, confusion, and lethargy, and it can progress to dementia, obtundation, or coma.267,273 Clinically, mild to moderate forms of cognitive impairment are more common than severe dementia. Short-term memory, executive functions, attention, and judgment are mainly affected.²⁸⁰ Symptoms usually appear several years after the radiation exposure. Diffuse white matter changes are found on CT or MRI, manifesting as low attenuation on CT scans and high signal intensity in the periventricular and subcortical white matter on T2-weighted and proton-density MR images.^283–283 Mass effect and focal neurologic signs are not common, although late in the course, seizures and motor dysfunction can occur.

The main risk factors for diffuse injury include the volume of brain treated, concurrent or adjuvant chemotherapy directed at the CNS, and use of short-course and high-dose fraction regimens. Other risk factors are increasing age and vascular risk factors such as diabetes and hypertension.²⁸⁴ The incidence is difficult to determine, but reports have shown neurologic and imaging changes in 32% to 50% of patients subjected to radiation therapy.^282,283,285

The pathogenesis of diffuse radiation injury is not known, although distinctive neuropathological changes have been described. The most prominent pathological finding is vascular changes in the small arteries and arterioles. Hyalinization of the vessel walls with occlusion is common.²⁸³ In addition, areas of necrosis, gliosis, and demyelination are found. Impaired neuronal stem cell function and decreased neurogenesis have also been described.²⁸⁶ Modern radiation techniques have been developed to protect the hippocampus to reduce memory defect; however, the efficacy of these techniques has not yet been proven.²⁸⁷ No treatment has been established for global brain injury. However, donepezil may be useful for the cognitive decline.²⁸⁸

Necrotizing Leukoencephalopathy

Necrotizing leukoencephalopathy is the most severe form of neurologic toxicity associated with radiation therapy. It is most common when CNS-directed chemotherapy is combined with radiation therapy. This syndrome was described earlier in this chapter in the discussion of methotrexate-associated toxicity. The incidence of leukoencephalopathy is much greater in patients who receive chemotherapy after cranial radiation therapy than in patients receiving either treatment alone or in those receiving chemotherapy before the initiation of radiation therapy.²⁸⁹

Mineralizing angiopathy has occurred in pediatric patients receiving both intrathecal methotrexate and radiation therapy.²⁹⁰ The changes frequently are diagnosed as dystrophic calcifications during neuroradiologic examinations. Histopathological analysis reveals deposits of calcium in small blood vessels, often with surrounding regions of necrotic brain. The clinical significance of these changes is uncertain.

Endocrinologic Effects

Cranial radiation therapy has been associated with a wide spectrum of endocrinologic effects.²⁹¹ Most of these effects are attributed to damage to the hypothalamic-pituitary axis. These effects are generally dose dependent and may manifest several years after completion of the radiation treatment. Results of several studies have suggested differing vulnerability among the various endocrine loops.²⁹² Growth hormone deficiency and stimulation of precocious puberty have occurred at doses as low as 18 Gy.²⁹³ Deficiency of gonadotropins, thyroid-stimulating hormone, and corticotropin usually results only when the hypothalamic-pituitary axis receives more than 40 Gy.²⁹⁴ Similarly, hyperprolactinemia occurs most often in young women who receive more than 40 Gy of radiation therapy. Careful long-term monitoring of these patients is critical.²⁹⁵ Appropriate hormone replacement therapy or prolactin suppression treatment should prevent sequelae.

Indirect Effects of Radiation on the CNS

Radiation can damage the endothelia of cerebral vasculature, causing accelerated atherosclerosis, stenosis, and occlusion, leading to stroke. The typical latency of these phenomena is several years.296,297 In children, radiation can cause occlusion of blood vessels and development of a moyamoya-like pattern of collateral vessels. This phenomenon has been described mainly in association with neurofibromatosis 1, which is a known risk factor for vasculopathy.²⁹⁸ Brain and spinal vascular malformations, including cavernomas and, rarely, aneurysms, have also been described.²⁹⁹ The risk of developing other brain tumors in patients treated with CNS radiation is seven times that of the general population. Three types of brain tumors have been associated with prior cranial radiation: meningioma, glioma, and sarcoma.³⁰⁰

Radiation Myelopathy

Several distinct syndromes have resulted from the effects of radiation injury to the spinal cord: an acute syndrome manifesting as paraplegia or quadriplegia; early transient myelopathy; delayed progressive myelopathy; and an anterior horn, lower motor neuron syndrome.

The acute syndrome is rare with the dosing schedules currently being used. Case reports state that weakness evolves over a few hours or days.³⁰¹ The syndrome probably is caused by acute necrotizing radiation injury due to rapidity of onset and failure of neurologic recovery.

The early transient form appears 6 to 12 weeks after treatment.³⁰² Most patients exhibit Lhermitte sign—an electrical shock–like sensation down the spine with neck flexion. No neurologic deficits are found, imaging is usually intact, and the symptoms resolve spontaneously over several weeks. Transient demyelination is hypothesized to be the cause of the symptoms.

Delayed progressive radiation myelopathy is the most common radiation therapy–induced spinal cord disorder, although it is relatively rare. Signs and symptoms generally develop 6 months to 1 year after completion of radiation therapy, although some data suggest that the latent period may be as long as 18 months to 2 years.³⁰³ The clinical picture may vary from patient to patient. Some patients have monoplegia, and others may have paraplegia or quadriplegia. Sensory symptoms are generally more severe than motor symptoms. Some patients have Brown-Séquard syndrome. Progression may take several years.³⁰¹ The pathogenesis of spinal radiation injury is not completely understood. Radiation might damage myelin production and might induce secretion of cytokines that might cause inflammatory response.^301,302 Pathological examination reveals rarefaction of spinal cord white matter with small areas of necrosis. Degeneration of myelin sheaths and loss of oligodendrocytes have been noted. Other causes of spinal cord dysfunction need to be excluded, including intramedullary tumor or infection, multiple sclerosis, vitamin B12 deficiency, sarcoidosis, and Lyme disease. No treatment exists, and most patients experience progressive neurologic dysfunction over months to years.³⁰⁴

Lower motor neuron syndrome occurs after spinal cord radiation therapy. Patients exhibit pure motor signs of weakness, atrophy, and fasciculations.³⁰¹ The syndrome manifests 3 months to 2 years after radiation treatment and is similar to polio. The pathogenesis is unknown. Hypotheses include loss of anterior horn cell neurons and radiation-induced injury to motor nerve roots. No treatment exists, with supportive care being the only option.

Peripheral Nerve Toxicity

Peripheral nerves are relatively resistant to the effects of radiation therapy. Early effects, which develop within 2 days of a single large-fraction treatment in an experimental animal system, include changes in vascular permeability of the nerve, changes in bioelectrical activity, and abnormal microtubule assembly in the axon.³⁰⁵ Late changes include fibrosis in the nerve sheath and angiopathic changes in the small arterioles that provide the vascular supply to the nerve.³⁰⁶ Use of large (>25 Gy) single doses or extended fractionated treatment to a very high total dose (>80 Gy) is thought to be necessary for injury to the peripheral nerves. Similar changes have been found for some cranial nerves.

The optic nerve and chiasm are susceptible to delayed injury from radiation. The radiation injury results in progressive, painless unilateral vision loss or constriction of the visual field. Lower cranial nerves can also be injured by radiation to the skull base, which can result, for example, in unilateral tongue atrophy.

Brachial and lumbar plexopathies warrant a separate discussion. These syndromes result from radiation injury to the nerve fibers in the plexus. Brachial plexopathy, caused by axillary radiation therapy for breast cancer, is most common.³⁰⁷ Lumbar plexopathy is more commonly associated with pelvic external beam radiation therapy, although local radioactive seed implantation (brachytherapy) may result in local nerve damage.³⁰⁵

A mid and reversible plexopathy can occur as a subacute complication of radiation therapy. Delayed brachial plexopathy manifests as numbness and weakness of the arm. Delayed lumbar plexopathy usually manifests as asymmetric bilateral leg weakness with predominance of the lower plexus (L5-S1) innervated muscles. The diagnosis of delayed radiation plexopathy can be difficult and requires excluding tumor infiltration as the cause of the symptoms. This process is most difficult with brachial plexus dysfunction and in patients with apical lung cancer or metastatic breast cancer. The distinguishing features in comparing radiation with tumor brachial plexopathy have been described extensively.³⁰⁷ None of the criteria is absolute, although tumor infiltration is more likely to be painful and involve the lower nerve roots (C7-T1) than is radiation injury, which is less likely to cause severe pain and generally involves higher roots (C5 and C6). Acute reversible radiation injury to the brachial plexus has been described. This condition is often painful, although the pain generally is mild. Patients experience weakness and atrophy in a C6-T1 distribution. Spontaneous but gradual recovery is typical.³⁰⁸

The treatment of radiation-induced brachial plexus neuropathy depends on the grade of severity of injury. In cases of mild injuries, conservative treatment is indicated, including nonnarcotic and narcotic analgesics and anesthetic interventions. Severe cases may require surgical exploration to allow the neural elements to be released from fibrotic tissue and prevent fibrosis of the vascular supply to the nerve.³⁰⁹ Radiation has also been reported to accelerate vascular injury, causing segmental obstruction of the subclavian artery.³¹⁰ This condition usually is painless. The motor and sensory loss evolves quickly, without subsequent progression or improvement.

Lumbosacral plexopathy is less common than radiation-related brachial plexopathy.³¹¹ Onset of signs and symptoms usually is delayed until at least 1 year after radiation treatment. Pain is usual and mild. The pathogenesis is uncertain, although fibrosis causing nerve compression and ischemia is a likely cause. The diagnosis of radiation-related lumbosacral plexopathy is made by excluding tumor infiltration. Imaging (MRI or CT) often is useful, although in select cases, surgical exploration may be required.

Muscle Injury from Radiation Treatment

Muscle is thought to be relatively resistant to the effects of radiation therapy, although several studies have suggested that at higher doses (greater than 50 Gy), significant late toxicity may occur.²²² Early effects are uncommon, symptoms generally are found after 1 year, and the onset of changes has been reported as late as 10 years after radiation therapy. Signs and symptoms include muscle contractures, loss of function, pain, extremity edema, and pathological fractures. The synergy of the toxic effects with those of chemotherapy is uncertain, although most patients have received both modalities.³⁰⁶ No treatment other than conservative measures, including physical therapy, have been established.

Chronic Encephalopathy and Dementia

Diagnostic Evaluation

A thorough search for a treatable underlying cause of encephalopathy should be undertaken in all affected patients. The diagnosis of chemotherapy-induced encephalopathy is made by excluding other potential causes. Ordering of diagnostic tests is dictated by findings on the physical and neurologic evaluations. Patients with focal neurologic abnormalities require early imaging studies (CT or MRI), although certain metabolic disorders (e.g., hypoglycemia) can manifest as focal neurologic deficits. A metabolic evaluation, including measurement of electrolytes, renal and liver function tests, measurement of oxygenation, serum calcium and magnesium, serum ammonia, and possibly thyroid and adrenal function testing, should be performed for most patients. Careful review of prescribed and over-the-counter medications may provide critical information. In some cases, blood and urine toxicology screening may be necessary. EEG often is helpful in directing the evaluation by indicating the presence of structural abnormalities (e.g., periodic localizing epileptiform discharges or focal slowing) or may indicate a global metabolic process (e.g., diffuse slowing with Delta waves or triphasic waves in hepatic encephalopathy). Patients who have subclinical status epilepticus may present with encephalopathy; in these cases, the EEG findings are diagnostic. Lumbar puncture often is needed to exclude infectious or neoplastic meningitis. In most cases, head MRI or CT should be performed before lumbar puncture to look for a mass lesion in the brain that would make lumbar puncture unsafe. The search for the underlying cause often is revealing. One group of investigators reported uncovering the cause of encephalopathy in 31 of 37 patients.³¹³

The differential diagnosis for seizures in patients with cancer includes an extensive list of possible causes. Causal factors can be broadly classified into toxic-metabolic and structural causes. Metabolic factors include hepatic and renal failure resulting from tumor growth or treatment toxicity, electrolyte abnormalities such as hypercalcemia from bone destruction or parathyroid hormone effect, hypomagnesemia from chemotherapy (cisplatin) or excessive vomiting, hyponatremia from SIADH or salt-wasting nephropathy (cisplatin), hypoxia, hyperglycemia from pancreatic failure (streptozocin), and glucose intolerance (corticosteroids). Several chemotherapeutic agents are known to be the direct cause of seizures (Table 57-1).

PRES, as described in a previous section, can manifest with seizures, with typical reversible imaging appearance and symptomatology that is shared by a diverse array of causes. Structural causes of seizures include brain metastasis, dural metastasis, and meningeal carcinoma. Ischemic and hemorrhagic vascular events also may provoke seizures. A tumor-induced hypercoagulable state may greatly increase the risk of stroke or venous sinus thrombosis.³³⁸ A similar hypercoagulable state can be seen with l-asparaginase treatment. The paraneoplastic syndrome marantic endocarditis often results in cerebrovascular events, as can infectious endocarditis, a potential complication of treatment-induced neutropenia.²³² Cisplatin can cause vasospasm of the intracranial vessels, producing a stroke.³³⁹ Furthermore, immunocompromised patients are at greater risk for CNS infection (including bacterial and fungal meningitis), brain abscess, and viral encephalitis (including progressive multifocal leukoencephalopathy).

Headache

Patients with cancer are primarily susceptible to headache from brain metastases, leptomeningeal disease, hydrocephalus, sinus vein thrombosis, and infections.

Many chemotherapy drugs can cause headache as a component of PRES syndrome. Aseptic (chemical) meningitis might be caused by intrathecal therapy, as described earlier in this chapter. Chemotherapy agents that are frequently associated with headache are hormonal agents, interferon therapy, and high doses of fludarabine and carmustine. All trans-retinoic acid is highly associated with headache and can cause pseudotumor cerebri.³⁴⁰ The new tyrosine kinase inhibitors, imatinib, nilotinib, and dasatinib, cause headache in a relatively high percentage of patients.³⁴¹ The diagnostic evaluation generally involves evaluation similar to that described for encephalopathy.

Cerebellar dysfunction in patients who have cancer occurs most commonly with metastatic spread to the cerebellum or brainstem. Meningeal carcinomatosis occasionally causes cerebellar signs by infiltrating cerebellar pathways. Patients with structural cerebellar lesions often show asymmetric dysfunction, which can be useful in differentiating this condition from drug-induced cerebellar toxicity. Paraneoplastic cerebellar degeneration is characterized by subacute progressive loss of cerebellar function.342,343 Patients usually have symmetric loss of all cerebellar function and exhibit appendicular and truncal ataxia, nystagmus, and scanning speech. This paraneoplastic syndrome occurs most commonly with lung cancer but also has been associated with gynecologic cancers, breast cancer, and Hodgkin disease. Many patients have antibodies in the serum, including anti-Yo, anti-Ri, anti-Hu, anti-CV2/CRMP5, anti-Ma2, anti-Tr, and anti-Zic4. Only two antibodies, anti-Yo and anti-Tr, are predominantly associated with cerebellar dysfunction; the other paraneoplastic antibodies are often associated with symptoms involving other areas of the nervous system.³⁴²

5-FU and ara-C can cause reversible cerebellar toxicity. Ara-c can sometimes cause permanent irreversible damage to the cerebellar Purkinje cells. The result is truncal ataxia, unsteady gait, dysarthria, and nystagmus.12–15,167–170 The dysfunction usually is symmetric. MRI findings immediately after chemotherapy are normal, but in the irreversible cases, cerebellar atrophy often is detected by MRI months later.

Cranial neuropathy in patients with cancer most commonly indicates the presence of meningeal carcinomatosis, tumor involvement of the bones of the cranial base with encroachment of neural foramina, or rarely, brainstem metastasis.³⁴³ Chemotherapy-induced cranial neuropathy is rare. Vincristine can cause cranial nerve palsy; extraocular eye movement abnormalities are most common.^76,80,94 Intraventricular administration of drugs and of biologic response–modifying agents can cause transient cranial nerve palsy, which often is due to abnormalities in CSF circulation.³⁴⁴

In both neoplastic meningitis and drug-induced cranial nerve palsy, the seventh (facial) cranial nerve most commonly is affected. Unfortunately, there is little to differentiate the clinical manifestations of drug-induced nerve palsy from those of neoplastic meningitis. Both conditions can involve several cranial nerves, be indolent in onset, and demonstrate spontaneous resolution. Therefore examination of the CSF is critical in the care of patients with suggestive signs and symptoms. In addition to neoplastic meningitis, tumor encroachment on neural foramina at the skull base from bone metastasis can cause cranial nerve palsy, as can small intraparenchymal lesions (e.g., tumor, infarct, or hemorrhage), although such lesions are rare.

Optic neuropathy can be seen in patients with neoplastic meningitis, lymphoma, or leukemia with infiltration of the optic nerve.345,346 In addition, compression from cranial base tumors and radiation therapy can cause similar loss of vision. Optic neuritis, characterized by unilateral or bilateral loss of vision, has been reported as a very rare paraneoplastic syndrome associated with small cell lung cancer.³⁴⁷ Retinopathy most commonly is associated with intracarotid administration of nitrosoureas and cisplatin.^{131,132,190,191} High concentrations of drug flow into the ophthalmic artery, which supplies the retina, causing severe pain and often complete loss of vision. Newer techniques, allowing administration above the ophthalmic artery, have reduced the incidence of this local toxicity.

Intravenous cisplatin administration has been associated with optic disk swelling and optic neuropathy.123,124 This reaction is idiosyncratic, and the mechanism is unknown.

The most common cause of spinal cord dysfunction in patients is epidural cord compression, either from direct extension of bone metastasis or from paravertebral spread through the intervertebral foramina (see Chapter 49). Intramedullary tumor and extramedullary intradural tumors can have myelopathic manifestations.³⁴⁸ Similarly, epidural abscess and hematoma can be clinically indistinguishable from epidural tumor. Encephalomyelitis is a frequently described paraneoplastic syndrome associated with several types of tumors, particularly small cell lung cancer.³⁴⁹ A rare paraneoplastic myelopathy has been described with lung cancer, renal cell carcinoma, and Hodgkin disease. This syndrome is characterized by subacute progression of spinal cord dysfunction, usually in the thoracic region, although damage occasionally occurs at several levels. Pathological examination reveals segmental necrosis.

Lumbar intrathecal administration of methotrexate and ara-C can result in focal myelopathy.21–27 Symptoms and signs appear hours to days after treatment and can include sensory loss, upper and lower motor neuron dysfunction, radiating pain (similar to Lhermitte sign), and bowel and bladder incontinence. The myelopathy may be transient or progressive; complete irreversible paraplegia usually is seen with progressive dysfunction. Myelopathy also has been reported with spinal radiation therapy. A rare, acute syndrome develops over days. The more common chronic myelopathy with radiation therapy develops months after completion of treatment.

Peripheral neuropathy is a common paraneoplastic syndrome. Mild sensorimotor neuropathy is the most common neuropathy in patients with cancer.³⁵⁰ The cause is unknown, but the condition is a distinct entity, separate from the diffuse weakness associated with cachexia. Rare pure motor and pure sensory paraneoplastic neuropathies also have been described. Sensory neuronopathy, which is most common with small cell lung cancer, causes severe sensory loss.^351,352 The intense inflammatory reaction and neuronal destruction in the dorsal root ganglia have led to use of the term dorsal root ganglionitis. Some patients are found to have anti-Hu and anti anti-CV2 antibodies in serum.^352,353

Motor neuronopathy manifests as isolated lower motor neuron loss.³⁵⁴ This syndrome has been found in both patients with Hodgkin lymphoma and those with non-Hodgkin lymphoma. The pathogenesis of this pure motor syndrome is unknown. Other causes of neuropathy that should be considered are diabetes, thyroid dysfunction, vitamin B12 deficiency, and alcoholic neuropathy.

The incidence of chemotherapy-induced peripheral neuropathy varies from 30% to 40% of patients receiving chemotherapy and depends on the type of cytotoxic drug, the duration of administration, cumulative dose, and preexisting peripheral neuropathy. Several cancer chemotherapeutic agents (listed in Table 57-2) cause peripheral neuropathy. The peripheral neuropathy resulting from chemotherapy is temporally related to administration for most agents. Cisplatin is an exception, and delayed neuropathy occurs in some patients.

Carcinomatous meningitis can manifest as multilevel radiculopathy, initially mimicking peripheral neuropathy. Likewise, brachial and lumbar plexopathy can occur from tumor infiltration as anterograde growth along the nerve sheath from the leptomeningeal involvement.

Myopathy is a rare symptom in cancer, and is usually the consequence of treatment. Dermatomyositis and polymyositis are inflammatory myopathies differentiated by the presence and the absence of a rash, respectively.355,356 Dermatomyositis and polymyositis have been associated with many tumors, most commonly adenocarcinomas of the cervix, lung, ovaries, pancreas, bladder, and stomach. The relative risk of malignancy appears to be higher among patients with dermatomyositis than among those with polymyositis. Patients have an elevated serum creatine kinase (CK) level.

Although myopathy is a rare complication of chemotherapy, it has been described with the use of paclitaxel and vincristine.77,357

Interferon and other biological response modifying agents can cause myalgia, but no evidence of muscle dysfunction or breakdown is found upon histopathological examination of muscle biopsy specimens. Cisplatin and other agents that induce electrolyte abnormalities (e.g., hypomagnesemia) can cause muscle cramping.

Prevention

The key to prevention of permanent neurologic damage is to initiate a system for monitoring for toxicity. For example, patients receiving intrathecal chemotherapy are at risk of chemotherapy-induced myelopathy, an often irreversible toxicity. These patients may report vague neurologic symptoms or radicular back pain during the course of treatment that may be an early sign of neurologic damage. Findings at neurologic examination may not indicate loss of function, but an elevated CSF myelin basic protein level indicates that with subsequent treatment, the risk of myelopathy is high.26,27

Vincristine treatment can cause peripheral neuropathy. Some patients exhibit autonomic neuropathy out of proportion to the sensorimotor neuropathy. The autonomic dysfunction can lead to intestinal dysmotility, ileus, and viscus perforation. Therefore all patients undergoing vincristine chemotherapy should be carefully evaluated for the development of abdominal symptoms. Obstipation from vincristine would mandate avoidance of further vincristine treatment.

Modification of Drug Dosing or Order

In certain treatment regimens, altering the order of the drugs administered can result in a marked decrease in the risk of neurotoxic complications. The risk of methotrexate-induced leukoencephalopathy after therapy for meningeal leukemia or carcinoma is reduced if the chemotherapy treatments, particularly intrathecal chemotherapy, precede cranial radiation therapy.⁵ The reason for this schedule-dependent toxicity is unknown. It has been suggested that radiation opens the blood-brain barrier, thereby increasing exposure of the brain to subsequent chemotherapy effects. Other regimens in which dose order seems important include combination chemotherapy with cisplatin and ifosfamide. Patients receiving cisplatin before ifosfamide are at greater risk for ifosfamide-induced encephalopathy.¹⁶⁰ Discontinuation and reintroduction of oxaliplatin administration in a stop-and-go strategy showed the same response rate with a lower incidence of neuropathy in the OPTIMOX study. When the toxicity is severe, a dose reduction may be considered; however, it might reduce overall and disease-free survival, especially in the adjuvant setting, and thus it is necessary to carefully weigh the benefits with the risk of treatment toxicity.

Protective Agents

Interest continues in developing agents that either block development of certain chemotherapy-induced neuropathies or help reverse toxicity. However, clinical evidence for the efficacy of these strategies is sparse. Several neuroprotective strategies, including calcium/magnesium infusion, amifostine, glutathione (GSH), glutamine, acetyl-l-carnitine, and erythropoietin have been investigated.23–25,27–31,56–58 Published reports of studies of neuroprotection during chemotherapy have recently been reviewed.^363,364 Erythropoietin has been shown to prevent cisplatin and docetaxel-induced neurotoxicity without compromising chemotherapeutic activity and increasing tumor growth in animal studies.^365,366 These results are very promising, especially because of its concomitant use against hematologic toxicity; however, this neuroprotective effect requires additional confirmation.

The agent ORG 2766 has been reported to protect against cisplatin neuropathy. This drug, a synthetic analog of corticotropin, was tested in a double-blind, placebo-controlled trial in which patients with ovarian cancer underwent intensive cisplatin therapy. A dose-related protective effect was found.35,367,368 However, in a following study that included patients treated with vincristine, ORG 2766 did not provide protection from vincristine-induced neuropathy.³⁶⁹

Amifostine, an organic thiophosphate, serves as an antioxidant and protects normal cells from the effects of radiation. Amifostine has been tested as a neuroprotectant with paclitaxel therapy in two phase 3 studies. A study of non–small cell lung cancer found a reduction in the incidence of radiation esophagitis but not in paclitaxel-induced neuropathy.³⁷⁰ In a second study of ovarian cancer, the incidence of grade 3 and grade 4 peripheral neuropathy was significantly reduced.³⁷¹ Amifostine is accompanied by serious adverse effects, such as hypotension; therefore more clinical evidence is needed before standard use with this agent can be recommended.

Glutamine also has been evaluated as a neuroprotectant for the peripheral nervous system.³⁷² Two pilot studies suggested glutamine (10 g three times a day for 4 days) as a neuroprotective agent without interfering with chemotherapy response.^372,373 Accordingly, a randomized trial with patients who had colorectal cancer reported significantly less neuropathy in the glutamine arm (15 g twice a day for 7 consecutive days) compared with control subjects.³⁷⁴ However, in this study no differences in electrophysiological examination were found between the groups. Another randomized pilot study revealed no difference in the use of glutamate at a dose of 500 mg.³⁷⁵

A wide variety of agents have been reported as putative toxicity-modulating agents. Acetyl-l-carnitine has been reported to lessen neuropathic symptoms in patients treated with paclitaxel or cisplatin.³⁷⁶ Because vitamin E is an antioxidant, it also was proposed as a neuroprotective agent; however, no convincing evidence indicates that vitamin E is effective in the prevention of chemotherapy-induced neuropathy. Alpha-lipoic acid, a broad-spectrum antioxidant, reportedly may help ameliorate symptoms from docetaxel and cisplatin or oxaliplatin neuropathy. Leucovorin may be helpful in reversing acute methotrexate-induced encephalopathy and somnolence.³⁷ The administration of methylene blue has been reported to accelerate recovery from ifosfamide-induced encephalopathy.³⁷⁷ No known therapy exists for chemotherapy-induced leukoencephalopathy once brain injury has developed.

The acute neuropathic syndrome associated with oxaliplatin has generated special interest because of the painful nature of this toxicity. Various treatments including infusions of calcium gluconate, oral gabapentin, oral carbamazepine, intravenous amifostine, and intravenous glutathione have been used to prevent the development of this complication.132,378 Infusions of calcium gluconate and alpha-lipoic acid also have been used to treat the acute neuropathy once it has developed.

Recognition of Groups at High Risk for Development of Neurotoxicity

Certain patients are at high risk for the development of treatment-related neurotoxicity. Patients with underlying peripheral neuropathy (e.g., Charcot-Marie-Tooth disease and diabetic neuropathy) and patients who abuse alcohol and have a poor nutritional state have been reported to be much more susceptible to the development of severe neuropathy, including potentially fatal autonomic neuropathy.379,380 Such patients need careful monitoring with immediate cessation of treatment if autonomic dysfunction develops. Similarly, in patients in whom peripheral neuropathy may be a component of the cancer, such as multiple myeloma, the use of a neurotoxic agent such as bortezomib may increase the likelihood and severity of neuropathy.²⁴⁰

Patients with meningeal tumors (e.g., carcinoma, leukemia, and lymphoma) often require extensive intrathecal chemotherapy. An intraventricular reservoir often is placed for this purpose. Before the reservoir system is used to administer chemotherapy, it is essential that correct placement and normal CSF flow be confirmed. This procedure is most readily performed by injecting indium 111–labeled albumin into the lateral ventricle through the reservoir system.381,382 Not only does this test help confirm catheter placement, but also monitoring the flow of tracer at 6, 24, and 48 hours helps determine the presence of abnormalities of clearance from the ventricular system or drug resorption at the arachnoid granulations. Figure 57-3 shows normal CSF flow and resorption of tracer through the arachnoid granulations. By contrast, Figures 57-4 and 57-5 show poor outflow from the lateral ventricles persisting 24 hours after contrast injection. Poor clearance of drug markedly increases the neurotoxicity of intraventricular treatment. Patients with poor ventricular outflow may need local radiation therapy for restoration of normal flow before instillation of chemotherapeutic agents.

Irreversible ototoxicity from cisplatin administration is more severe in patients with underlying hearing loss. Hearing loss with cisplatin also may be accelerated when the inner ear region and temporal lobe are included in the irradiated field.¹¹⁸ Radiation treatment before or after cisplatin administration can cause this synergistic ototoxicity.