Chapter 74. Toxicities of Chemotherapy

• Drug toxicity is most often a diagnosis of exclusion.
• Dose, schedule, and drug combinations are key parameters used to determine the likelihood of drug toxicity.
• Not all toxicities are known, and drug regimens are modified constantly.
• Therapy is supportive for most chemotherapy-related toxicities.
• Pelvic and spinal irradiation potentiates the myelosuppressive effects of chemotherapeutic agents.
• Bleomycin and gemcitabine are among the causes of drug-related interstitial lung disease.
• Most cardiac events in cancer patients are related to pre-existing heart disease or direct invasion of the heart by cancer; nonetheless, drug toxicity must be considered, particularly when high-dose cyclophosphamide and anthracyclines have been administered.
• In high-dose regimens, cytosine arabinoside, ifosfamide, and methotrexate may produce dramatic central nervous system syndromes.
• Renal injury is often dose limiting for cisplatin.
• Cytokines such as interleukin-2 have a wide range of toxicities involving virtually all organ systems.
• Many commonly used chemotherapeutic agents and several recently introduced targeted anticancer agents are associated with hypersensitivity reactions.
• Thrombotic microangiopathy is associated with various chemotherapeutic agents, particularly gemcitabine and mitomycin-C.

As more intensive anticancer regimens are being used to achieve cure, an increasing number of oncology patients are admitted to ICUs for complications of treatment. Several principles about drug-induced toxicity should be kept in mind.

Drug toxicity is often a diagnosis of exclusion. The toxic reaction to an antineoplastic drug or drugs is frequently nonspecific clinically and even pathologically. Other causes always should be considered. Infection, a tumor effect, and toxicity from other drugs such as antiemetics or antibiotics frequently are elements of the differential diagnosis.

Dose, schedule, and combination make a difference. Most antineoplastic drugs are given in combination, and drugs and radiation are often combined. The toxicities of a given combination may be more severe than the effects of the individual agents would suggest. Moreover, different drug schedules, such as a continuous infusion versus a single bolus dose, may have very different spectrums of side effects for the same agent. Formerly, the dose-limiting toxicity of most agents was myelosuppression, but the introduction of colony-stimulating factors and the rapidly increasing use of autologous stem cell or marrow reinfusion for rescue after very-high-dose drug regimens have exposed a plethora of new toxicities.

Not all toxicities are known. New drugs and new combinations of drugs are being tried constantly and may be used widely before all toxicities are well characterized. Moreover, the diagnosis of drug reactions that are sporadic rather than dose-related is often difficult, particularly in cancer patients who have many symptoms regardless of treatment. The tables in this chapter list the most common or notorious toxicities and are not intended to be comprehensive.

Treatment is supportive. The importance of a diagnosis of treatment-related toxicity is generally that the offending agent can be stopped, and useless remedies or diagnostic procedures can be withheld. Only rarely is specific therapy indicated.

(See ref. 1.) A great many commonly used antineoplastic agents can cause acute hypersensitivity reactions. These are particularly common with l-asparaginase, taxanes (paclitaxel and docetaxel), and platinum agents. None of these drugs should be administered without antianaphylaxis medications close at hand. Hypersensitivity reactions were the treatment-limiting factor in early trials of paclitaxel, and this agent is now administered routinely after premedication with corticosteroids and antihistamines, which has significantly reduced the incidence of severe reactions. For the taxanes, the reactions may be related partly to the excipients in which they are formulated. With platinum agents, the hypersensitivity often occurs in the second or third use of the regimen. Several recently approved monoclonal antibodies such as rituximab (rituxan) and trastuzumab (herceptin) are also associated with hypersensitivity reactions.2,3 Most of the hypersensitivity reactions associated with antibodies can be managed by slowing the rate of infusion of the agent and by premedicating patients with corticosteroids and antihistamines.

Antitumor drugs also may cause fever in the absence of other symptoms of allergy. Bleomycin, which may cause very high fevers, is particularly notorious. Febrile reactions are also often observed with cytarabine.

(See refs. 4, 5.) Complications of myelosuppression, including infections and bleeding, account for many therapy-related ICU admissions in cancer patients. Management of these problems is discussed elsewhere. Granulocytes (circulating half-life = 6 hours) usually are affected the earliest and most severely, followed by platelets (half-life = 5 to 7 days); red blood cells (RBCs) (half-life = 120 days) are relatively spared unless the patient has received high doses or multiple courses of chemotherapy. Bleeding and other causes of anemia must be considered before a very low hemoglobin level is attributed to antineoplastic chemotherapy alone. There is variation in which cell lines are most suppressed; the nitrosoureas and mitomycin C, for example, typically produce a late, severe thrombocytopenia. For most drugs, the granulocyte count reaches its nadir 7 to 14 days after the administration of a single dose, and recovery occurs by 21 to 28 days. Some agents produce a more delayed pattern (Table 74-1). Patients who have received pelvic or spinal irradiation or who have had multiple courses of chemotherapy suffer more severe and prolonged myelosuppression. The critically ill cancer patient also may have a multitude of other causes for cytopenias, but if doubt exists as to the cause of abnormal blood counts, a bone marrow biopsy should be performed. This procedure can be performed safely on even the sickest patients and is an invaluable aid in excluding many possible diagnoses, particularly marrow infiltration by tumor. Hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF), may be useful in some circumstances.6 Empirical institution of broad-spectrum antibiotic therapy based on clinical presentation can be lifesaving for febrile neutropenic patients.7

(See ref. 4.) Like the cells in the bone marrow, cells of the gastrointestinal tract, from mouth to rectum, proliferate rapidly and therefore are particularly susceptible to damage by antineoplastic drugs. The effects of toxicity range from mild mouth sores to ulcerative stomatitis and severe bloody diarrhea. Breakdown of the mucosal barrier also contributes to morbidity and mortality by providing a portal for the entry of infectious agents, particularly in a neutropenic patient. Agents that commonly cause stomatitis or diarrhea at standard doses are listed in Table 74-2. High-dose chemotherapy regimens used in preparation for bone marrow transplantation frequently cause severe mucositis.

Treatment

Candida and herpesviruses commonly cause or worsen stomatitis and esophagitis. Clostridium difficile always should be considered in hospitalized patients with diarrhea, particularly those receiving antibiotics, even if they also have received diarrhea-producing anticancer therapy.

Patients' mouths should be kept scrupulously clean with the use of soft swabs and saline or peroxide rinses. The discomfort caused by stomatitis may be severe. If topical anesthetics do not control the pain, systemic narcotics should be administered in ample doses. Diarrhea and stomatitis often severely compromise enteral feeding. Intravenous alimentation should be considered early.

Irinotecan8

Irinotecan (CPT-11) is an agent used frequently in the treatment of colon cancer and is somewhat unusual in having severe diarrhea in the absence of mucositis as one of its most significant side effects. Two distinct types of diarrhea have been described. The first is an early-onset diarrhea occurring during infusion of the drug or within 30 minutes of infusion. This reaction is part of an acute cholinergic response and can be controlled with atropine, 0.5 to 1.0 mg intravenously. The second type usually appears 6 to 10 days after drug administration, may be linked to a secretory process in the small intestine, and can be massive (>10 L/d). Early recognition and aggressive treatment with loperamide and octreotide can be useful in controlling this late-onset diarrhea.

A large number of antineoplastic drugs can cause pulmonary symptoms (Table 74-3). Furthermore, lungs are a common site for metastases and infections, complicating the diagnostic process in patients with advanced cancer. Pulmonary toxicity syndromes reported include acute pleuritic chest pain, hypersensitivity lung disease, and noncardiogenic pulmonary edema,9–12 but the vast majority of cases fall into the pneumonitis/fibrosis category described below. This type of toxicity classically is associated with the “three B's”: busulfan, bleomycin, and BCNU (carmustine), and for many agents, it is sporadic rather than dose related.11Methotrexate lung toxicity may be similar in terms of symptoms but is believed to be a form of hypersensitivity reaction.13–15 Unlike lung toxicity associated with other antitumor agents, it also may be associated with hilar adenopathy. Some of the newly approved agents, such as all-trans-retinoic acid (tretinoin) and gefitinib (iressa) have been associated with unique pulmonary toxicities.16–18 All-trans-retinoic acid (ATRA, tretinoin) is a derivative of vitamin A used in the treatment of acute promyelocytic leukemia (APL). It is associated with the unique retinoic acid syndrome, consisting of high fever, fluid retention, pulmonary infiltrates, and respiratory distress, which may occur in as many as 25% of APL patients treated with ATRA. This can be seen as soon as 2 days after beginning therapy. The syndrome has been attributed to pulmonary leukostasis but is not always associated with exceedingly high peripheral white blood cell (WBC) counts. Treatment with dexamethasone may be helpful. Gefitinib, an oral inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, was approved for the treatment of refractory lung cancer and has been reported to cause interstitial lung disease (ILD) in about 1% of the patients worldwide; approximately one-third of the reported cases have been fatal.18 Patients often present with acute onset of dyspnea, with or without cough and low-grade fever. Prompt discontinuation of the agent with adequate supportive care is recommended when ILD is suspected. Trastuzumab also has been reported recently to cause organizing pneumonia19; however, details regarding the prevalence or underlying mechanisms of the toxicity are not well understood. If such pulmonary toxicity is determined eventually to be class-specific, then as an increasing number of monoclonal antibodies get approved for the treatment of cancer, such toxicities will become more common.

Clinical Presentation

The onset of pneumonitis/fibrosis associated with the classic cytotoxic agents may occur after prolonged, continuous treatment, as is typical for busulfan; after only a few cycles of therapy, as may occur with bleomycin; or even years after therapy has ended, as can occur with BCNU. Signs and symptoms frequently are nonspecific and range from mild to life threatening. Patients invariably present with dyspnea. A dry cough, fatigue, fever, and end-expiratory rales are common but not universal features. Hemoptysis is not typical, and this finding should suggest another diagnosis. The symptoms typically appear gradually over several weeks, but acute presentations are not unusual. A patient with this disorder who is ill enough to arrive in the ICU generally will be hypoxic, with diffuse pulmonary infiltrates visible on chest x-ray, and the full spectrum of possible causes for this presentation, including infection, irradiation, cardiogenic edema, pulmonary embolus, hemorrhage, leukoagglutinin reaction, and progressive tumor, must be considered.

Histopathology

The histopathology closely resembles that of idiopathic diffuse interstitial pulmonary fibrosis. There is endothelial cell swelling, necrosis of type I pneumocytes, and atypical proliferation of type II pneumocytes, with generalized fibrosis in end-stage disease. The character of the inflammatory infiltrate, when one is present, is variable; a finding of eosinophilia suggests a hypersensitivity reaction, which may be particularly responsive to corticosteroids.14,15

Diagnostic Testing

The chest x-ray in drug-associated pneumonitis/fibrosis generally is normal or reveals a basilar or diffuse reticulonodular pattern, but atypical findings on chest x-ray should not rule out this diagnosis. Bleomycin is particularly notorious for occasionally producing a nodular appearance, which may mimic recurrent tumor, and methotrexate may be associated with a pleural effusion or hilar adenopathy. Pulmonary function tests reveal a reduced diffusing capacity for carbon monoxide (DlCO) and, sometimes, a restrictive ventilatory defect. Since the histologic findings are not specific, even a lung biopsy may not absolutely establish the diagnosis of drug-induced toxicity, although it is usually helpful. In the case of acutely ill cancer patients with hypoxia and diffuse pulmonary infiltrates, both the choice of which patients are appropriate candidates for lung biopsy and the timing of the procedure remain controversial.20,21

Treatment

Treatment for drug-associated pneumonitis/fibrosis is supportive. The precipitating agent should be discontinued. While there are no good data establishing the efficacy of corticosteroid therapy, there are many anecdotal reports of its usefulness, and it is often given a trial. The syndrome may be reversible, particularly in mild cases, or it may be progressive even in the absence of further exposure to the drug.

Bleomycin22

Bleomycin is a particularly frequent and well-studied cause of pneumonitis. Bleomycin is thought to cause direct injury to the pulmonary capillary endothelium and type I pneumocytes, which leads to stimulation of an inflammatory cascade. Bleomycin toxicity is sporadic rather than dose related below a threshold cumulative total dose of 450 to 500 mg; above this threshold, the incidence rises dramatically.

Attempts have been made to predict and prevent pulmonary toxicity by serially monitoring the DlCO. Stopping therapy in patients with a significant decrease in DlCO is strongly recommended, but this practice has not been shown to alter the incidence of fatal toxicity. Many patients may present with acute decline in pulmonary function weeks to months after a normal DlCO. Age over 70 years, prior or concurrent radiation therapy to the lungs, and concurrent treatment with cyclophosphamide or methotrexate are reported to potentiate bleomycin lung toxicity. Pre-existing lung disease has not been shown to be a risk factor.

The danger posed by oxygen therapy after treatment with bleomycin is a source of some controversy in the scant literature on the subject. Some small studies have reported a high incidence of severe postoperative respiratory distress in bleomycin-treated patients, which they attributed to a high intraoperative concentration of inspired oxygen (FiO2).22–24 Most authors recommend limiting intra- and perioperative FiO2 in these patients to the lowest safe concentrations.

(See ref. 25.) The vast majority of cardiac events in cancer patients are related to pre-existing heart disease or to involvement of the myocardium or pericardium by tumor, not to anticancer drugs, most of which produce cardiac damage rarely and sporadically, if at all (Table 74-4). Anthracyclines are the exception. Doxorubicin and daunorubicin have very similar effects on the heart; doxorubicin is used much more commonly, and its cardiac effects have been better studied. Trastuzumab also has been reported to cause cardiac dysfunction in patients that is similar to the cardiomyopathy associated with anthracyline therapy.26 Cardiovascular toxicity is also associated with the use of immunomodulatory agents such as interferon and interleukin-2 (IL-2), which will be addressed separately in the section describing the toxicities associated with biologic agents.

Electrocardiographic Changes and Arrhythmias

Cisplatin and other drugs may produce secondary effects through alterations in plasma potassium, calcium, and magnesium levels. Direct effects appear to be caused mainly by the anthracyclines and paclitaxel. Electrocardiographic (ECG) changes occur in up to 40% of patients during doxorubicin infusion. The most frequently noted effects are nonspecific ST-T wave changes, but premature atrial and ventricular contractions, sinus tachycardia, and decreased QRS voltage are also common; almost every conceivable type of arrhythmia has been reported. While sudden death attributed to acute anthracycline-induced arrhythmia has been reported, it is extremely rare; cardiac monitoring during drug infusion is not warranted. The ECG changes are, with the possible exception of the decreased QRS voltage, transient. They are not a reason to discontinue therapy and are not associated with the subsequent development of heart failure.

Paclitaxel27, 28

Paclitaxel causes asymptomatic, reversible sinus bradycardia, with heart rates ranging from 30 to 50 beats per minute, in up to 29% of patients during a 24-hour infusion. More serious bradyarrhythmias, including third-degree heart block, have been observed but are rare. Myocardial infarction and atrial and ventricular tachyarrhythmias also have been noted, but their relationship to paclitaxel therapy is uncertain.

Myocardial Ischemia and Infarction29

Anticancer drugs very rarely cause myocardial ischemia or infarction. Radiation therapy to the heart may result in accelerated atherogenesis, but this effect becomes symptomatic only years after treatment. The vinca alkaloids have been reported to precipitate myocardial infarction in a few instances, sometimes when given with bleomycin, which is known to cause Raynaud's phenomenon and other vasospastic symptoms. Up to 4% of patients treated with 5-fluorouracil (5-FU) have been reported to suffer anginal symptoms, and a greater number have transient asymptomatic ECG changes suggestive of ischemia30; prolonged infusions appear to cause more problems. Myocardial infarction may occur. The mechanism is unknown, but agents such as nitrates and calcium channel blockers, which reverse vasospasm, may be helpful. Capecitabine, an orally administered prodrug of 5-FU, causes many of the toxicities associated with prolonged infusion of 5-FU, including cardiac toxicities.31

Cardiomyopathy and Pericarditis

The anthracyclines and high-dose cyclophosphamide may produce fatal cardiomyopathies. Trastuzumab, which is used in the treatment of breast cancer, also has been associated with cardiomyopathy.

Anthracyclines and Trastuzumab26,32 –35

The myocarditis-pericarditis syndrome consists of an acute drop in ejection fraction seen in the hours to weeks after drug administration. This reaction sometimes is associated with a pericardial effusion and may result in the sudden death of the patient from severe congestive failure. Fortunately, it is exceedingly rare.

The classic subacute presentation of cardiomyopathy, on the other hand, develops in from 1% to 10% of patients receiving 550 mg/m2 of doxorubicin, with a steep rise in incidence in patients treated with cumulative doses greater than 600 mg/m2. Symptoms usually appear around 30 to 60 days after what appears to have been the precipitating dose of doxorubicin, but they may be noted a year or more after the end of treatment. Patients develop tachycardia, dyspnea, cardiomegaly, and peripheral and pulmonary edema. Pathologic changes are similar to those seen in cardiomyopathy of other causes.

Total dose is the single most important risk factor for the development of doxorubicin-related cardiomyopathy. There is no cutoff dose below which cardiomyopathy never occurs. Many patients, even those with severe failure, respond well to conventional therapy, and the ejection fraction gradually may return toward normal. However, some of these patients have recurrent symptoms 5 or more years later. Less commonly, such late cardiac decompensation is seen in patients who never had subacute symptoms. There has been particular concern over anthracycline-treated survivors of childhood cancers, up to 57% of whom have abnormalities of left ventricular contractility after treatment. Adults, however, are affected by late cardiac symptoms as well, and these sequelae may occur in patients who received only moderate cumulative doses of doxorubicin. There is no specific therapy for anthracycline-induced cardiotoxicity once it has occurred; care is supportive. Further administration of anthracycline is contraindicated.

Detailed data analyses from various clinical trials conducted with trastuzumab26 suggest that its cardiotoxic potential is highest when it is used with other chemotherapeutic agents, especially anthracylines. Single-agent therapy with trastuzumab seems to be safer, and most patients' clinical symptoms are well controlled with congestive heart failure therapy. Ongoing clinical trials with the agent potentially will provide greater insight into the risk factors and mechanisms that lead to the cardiac dysfunction associated with this agent.

Cyclophosphamide and Ifosfamide25,36,37

Both cyclophosphamide and ifosfamide have minimal cardiac toxicity at standard doses. However, when used at high doses, both agents can cause severe myopericarditis and arrhythmias. The major nonhematologic dose-limiting toxicity of cyclophosphamide is a severe hemorrhagic myopericarditis, which usually is seen only at doses higher than 1.5 g/m2, as are used typically in marrow-ablative regimens. Total ifosfamide doses far in excess of 1000 mg/m2 usually have been associated with cardiotoxicity, and these patients generally develop cardiac toxicity within 2 weeks of receiving the drug. In its most virulent form, cyclophosphamide-induced cardiotoxicity appears within 48 hours of the last drug dose. Patients die rapidly of cardiogenic shock. More typically, edema, tachycardia, and tachypnea develop 7 to 10 days after therapy, usually preceded by a decrease in QRS amplitude on the electrocardiogram. Not all patients who have a decrease in QRS amplitude will develop symptoms. However, a hemorrhagic or serosanguineous pericardial effusion develops frequently, with possible signs of tamponade. Pericardiocentesis usually does not produce any clinical improvement, possibly because of the severity of the underlying myocardial damage.

Treatment is supportive. If patients survive the acute phase, complete recovery can be expected, and there may be no residual evidence of cardiac damage even at autopsy.

(See ref. 1.) Only rarely will the neurologic toxicity (Table 74-5) of an anticancer drug be severe enough to be the primary reason for admission to the ICU. Neurologic problems are common in cancer patients, but local effects of tumor produce most of them, e.g., brain or epidural metastases. The antiemetic and pain medications given to patients often include combinations of high doses of corticosteroids, narcotics, and benzodiazepines, all of which can cause dramatic neurologic changes that must be considered when symptoms developing acutely after therapy are being evaluated.

Peripheral Neuropathy

Peripheral neuropathies are frequent side effects of some very widely used anticancer drugs. Paclitaxel and docetaxel can cause glove-stocking paresthesias and, rarely, motor dysfunction. Symptoms often improve within months after therapy is stopped. Cisplatin likewise commonly causes a peripheral neuropathy that is primarily sensory and may progress to disabling ataxia. Symptoms may continue to worsen after treatment is completed and may persist for years. Cisplatin also can cause tinnitus and deafness and, more rarely, Lhermitte's sign (painful electric shock–like sensations elicited by neck flexion or extension), autonomic neuropathy, seizures, transient cortical blindness, and retinal injury. Acute and chronic neuropathy also has been the dose-limiting toxicity of oxaliplatin, a recently approved third-generation platinum agent.38 Oxaliplatin causes an acute and reversible sensory neuropathy in up to 95% of patients treated with the agent and causes a more chronic sensory neuropathy in 15% to 20% of patients who have received cumulative dose in excess of 780 mg/m2. A few patients who have received more than 1000 mg/m2 of the agent have been described to develop Lhermittes's sign and urinary retention. Most cases of chronic peripheral neuropathies associated with oxaliplatin have been reversible. An acute and reversible syndrome of pharyngolarngeal dysesthesias has been reported to occur in 1% to 2% of patients. This toxicity often is extremely distressing to the patient owing to the overwhelming sensation of difficulty with breathing and swallowing. These symptoms frequently are triggered or exaggerated by cold exposure. Given the disturbing subjective nature of the toxicity and the fact that it is common and reversible, all patients need to be educated regarding this toxicity to avoid panic and unnecessary medical interventions.

Vinca alkaloids are tubulin poisons that disrupt microtubule function in neuronal axons. Vincristine is the most neurotoxic vinca alkaloid. The most common toxic manifestation of vincristine is a symmetric mixed sensorimotor neuropathy, which may, in severe cases, progress to quadriparesis. It is dose related and gradual in onset. Deep tendon reflexes are lost. Peripheral nerve conduction velocities are characteristically normal despite severe clinical deficits. Paresthesias and motor weakness may or may not improve gradually. No treatment is known to heal vinca-related neuropathies. Vincristine has been administered intrathecally accidentally; this is invariably fatal.

The approval of thalidomide for the treatment of multiple myeloma has increased the clinical use of the agent. Both reversible and irreversible sensory neuropathies have been well documented with the use of thalidomide in up to 60% of patients with chronic use. Nerve conduction studies indicate that the symptoms most probably result from axonal damage. The symptoms can range from mild reversible parasthesias to more severe irreversible sensory neuropathies if the agent is not withdrawn in patients with progressive peripheral neuropathy. Central nervous system manifestations are common, including sedation, dizziness, muscle incoordination, fatigue, unsteady gait, tremulousness, mood changes, confusion, and weakness.39,40

Cranial Nerve Palsies

Various cranial nerve palsies, including vocal cord paralysis, dysphagia, optic atrophy (rare), ptosis, ophthalmoplegias, and facial nerve paralysis, are seen in up to 10% of vincristine-treated patients. Unlike the peripheral nerve findings, cranial neuropathies may be abrupt in onset and mimic a brainstem stroke. They tend to be bilateral and usually are reversible with discontinuation of the drug.

Autonomic Neuropathy

Autonomic symptoms, including ileus, bladder atony, impotence, and orthostatic hypotension, may occur even in patients with no sign of peripheral nerve toxicity. Severe paralytic ileus presenting as an acute abdomen is not rare and can occur acutely or following long-term administration of vincristine, vinblastine, or vinorelbine. It is usually reversible over the course of several days. Nasogastric tube drainage is the only standard therapy; metoclopramide has been reported to be helpful and may be tried if there is no suspicion of mechanical obstruction.

L-Asparaginase

Between 25% and 50% of patients receiving l-asparaginase on a wide variety of dosing schedules will have some evidence of cerebral dysfunction, adults more often than children. The toxicity ranges from mild depression and drowsiness to confusion, stupor, and coma. Evidence of encephalopathy often occurs on the first day after administration and usually clears rapidly after the end of therapy. The syndrome resembles hepatic encephalopathy and may or may not be associated with high ammonia levels. The electroencephalogram (EEG) in most cases shows a diffuse slowing that returns to normal when the drug is stopped. l-Asparaginase itself does not cause focal neurologic abnormalities, but thrombotic and hemorrhagic cerebrovascular accidents due to asparaginase-induced clotting abnormalities have been reported. Patients on l-asparaginase can develop exceedingly low fibrinogen levels (with elevated prothrombin time), and this can be corrected with cryoprecipitate.

Cytosine Arabinoside41

Cytosine arabinoside (Ara-C, cytarabine) is not neurotoxic when used at conventional doses (100 to 200 mg/m2). However, at high doses (e.g., 2 to 3 g/m2 twice daily, as given for the treatment of acute leukemia), a 10% to 20% incidence of cerebellar and cerebral toxicity is observed. Larger cumulative doses and age over 55 years are associated with more frequent and more irreversible neurologic damage.

The cerebellar changes are more common and usually more severe than the cerebral ones. The onset of symptoms is usually 5 to 7 days after the start of Ara-C therapy (within 24 hours of the final dose on a typical schedule). Mild cerebellar findings may include intention tremor, dysarthria, and horizontal nystagmus; in severe cases, limb and truncal ataxia may render the patient completely unable to walk or even eat unaided. Cerebral symptoms range from mild somnolence to disorientation, memory loss, and coma. Seizures have been reported. EEGs show diffuse slowing; findings on lumbar puncture and computed tomographic (CT) scan are normal. Toxicity may abate over a few days to weeks or may be irreversible. Rarely, it is fatal. Supportive care and withdrawal of Ara-C are the only therapies. Intrathecal Ara-C has not been associated with cerebellar toxicity, although it rarely may cause a paralysis similar to that described below with intrathecal methotrexate.

Methotrexate42

Like Ara-C, methotrexate used in conventional doses is not neurotoxic. However, when used at very high doses (1 to 7 g/m2), cytotoxic levels are achieved in the cerebrospinal fluid (CSF), and a 2% to 15% incidence of various transient central nervous system (CNS) syndromes has been reported. The time of onset ranges from several hours to several weeks after treatment, with a mean of about a week. Signs develop abruptly and often resemble a stroke, with, for example, hemiplegia and a speech disorder. Neurologic findings may fluctuate; focal or generalized seizures are common. Electrolyte levels and results of radiologic studies are normal, EEGs show a variety of abnormalities, and examination of the CSF may or may not reveal an elevated protein level. The mechanism of these neurologic reactions is unknown, and care generally is supportive. There are reports that aminophylline can reverse early neurotoxicity in children, presumably by displacement of adenosine from its receptor by aminophylline.43 In any case, patients recover completely over several days, and symptoms may or may not recur with subsequent courses.

Intrathecal methotrexate also can cause neurologic damage. The most common symptom is an acute arachnoiditis, which resolves over 12 to 72 hours without sequelae. Rarely, the presentation is severe enough to mimic bacterial meningitis. Very rarely, an acute reaction, which may include paralysis, cranial nerve palsies, or seizures, is seen. Examination of the CSF may show increased pressure, high protein concentrations, and a reactive pleocytosis. Recovery often, but not always, is complete. A necrotizing leukoencephalopathy sometimes occurs after the combination of cranial irradiation and intrathecal methotrexate, but this is a delayed effect that usually begins insidiously months after treatment.

Ifosfamide44,45

High-dose ifosfamide therapy is associated with encephalopathy that can present with a wide variety of symptoms ranging from subtle sensorimotor deficits to severe mental status changes and even death. Early recognition of the toxicity and discontinuation of the agent are sufficient to reverse the toxicity over a period of 24 to 48 hours in most cases. Intravenous methylene blue can be useful in reversing the neurologic deficits associated with ifosfamide encephalopathy.

(See ref. 46.) Cisplatin is the only antineoplastic drug used frequently in current oncologic practice that causes renal failure at conventional doses. Hyperuricemic nephropathy with or without a full-blown tumor lysis syndrome may occur following rapid cell lysis in sensitive cancers with large tumor volumes; it is not the effect of any particular drug and is discussed elsewhere. Uric acid levels also can be rapidly lowered by the use of rasburicase.

Cyclophosphamide and ifosfamide can cause a hemorrhagic cystitis that is difficult to manage and occasionally is fatal and is described separately in the next section. Table 74-6 lists the common renal abnormalities caused by antineoplastic drugs.

Cisplatin47,48

Renal injury characterized pathologically by focal necrosis of the distal tubules and collecting ducts is a dose-limiting toxicity of cisplatin. Acute renal failure can occur. Vigorous pretreatment hydration with saline solution minimizes but does not eliminate the damage; all patients will have some decline in glomerular filtration rate with a sufficient dose. Aminoglycoside therapy and pre-existing renal dysfunction are believed to increase the incidence. The creatinine level begins to rise a few days after therapy, peaks at 3 to 14 days, and then usually declines toward pretreatment levels. Toxicity is cumulative; multiple courses and higher doses produce more severe and less reversible damage.

Cisplatin also causes a variety of electrolyte disorders. Renal magnesium wasting, not necessarily associated with azotemia, is seen in half the patients receiving cisplatin and may persist for years. Although serum magnesium levels often are strikingly low, and symptomatic muscular irritability has been reported, most patients are asymptomatic. Of particular concern in the ICU are the hypocalcemia and hypokalemia that frequently accompany the magnesium wasting and that may be refractory to treatment if serum magnesium levels are not corrected first. Aminoglycosides should be used with extreme caution. Oral magnesium therapy is of uncertain benefit; intravenous or intramuscular doses should be administered. Renal salt wasting resulting in hyponatremia and symptomatic orthostatic hypotension also has been reported.

Methotrexate

High doses of methotrexate (>50 mg/kg) are potentially quite toxic and normally are given in the hospital with careful hydration and urine alkalinization to promote drug excretion. Plasma methotrexate levels are measured after drug administration, and leucovorin rescue is continued until the drug concentration has fallen to a safe level. Despite these precautions, an acute azotemia believed to result from the precipitation of methotrexate crystals in the distal nephron can be seen. Methotrexate-induced renal failure is usually, although not always, reversible over the 2 to 3 weeks following drug withdrawal. However, because the kidney is the primary route of excretion for methotrexate, dangerously high drug levels will persist for some time. This situation can produce other morbidity, particularly cytopenias and mucositis. A similar situation occurs when methotrexate has been given inadvertently to a patient with a third-space fluid reservoir, such as a pleural effusion or ascites, from which the drug is released only gradually. Administration of leucovorin until plasma levels of methotrexate fall below 5 × 10–8 M is beneficial in avoiding various toxicities described earlier. Doses of leucovorin need to be increased in patients with high plasma levels of methotrexate and will not completely prevent toxicity. Methotrexate also can be dialyzed using high-flux hemodialysis membranes49; hence hemodialysis also could be considered for reversing acute methotrexate toxicity along with high-dose leucovorin rescue. Carboxypeptidase-G2 is an enzyme that cleaves the terminal glutamate from methotrexate and can decrease methotrexate levels rapidly in patients with renal failure.50 Food and Drug Administration (FDA) approval for this agent is being sought, but at this time it is only available for compassionate emergent use from the National Cancer Institute.

All myelosuppresive agents potentially can cause thrombocytopenia and resulting bleeding complications. This section will focus more on some severe and specific complications associated with cancer therapies. Hemorrhagic cystitis is a well-described complication that occurs in patients treated with cyclophosphamide and ifosfamide. Thrombotic microangiopathies also have been described with various chemotherapeutic agents and will be discussed in this section. Among the recently approved agents, thalidomide has been associated with a significant risk of thromboembolic complications. This risk is much greater when the agent is administered in combination with various chemotherapeutic agents, and clinicians administering thalidomide need to be vigilant about the potential occurrence of this complication.39,51

Hemorrhagic Cystitis52,53

Urologic complications, including bladder fibrosis, bladder cancer, and hemorrhagic cystitis, are among the most troublesome side effects of cyclophosphamide and ifosfamide.

Susceptibility to hemorrhagic cystitis is somewhat idiosyncratic, and symptoms can occur after a few small doses, but the incidence is much higher with prolonged or high-dose therapy. Excretion of the BK human polyoma virus has been associated with a greater incidence of hemorrhagic cystitis in bone marrow transplant patients. Ifosfamide, an analog of cyclophosphamide, produces even more urothelial toxicity.

Prevention

Local bladder irritation from acrolein, one of the metabolites of cyclophosphamide, is believed to cause the damage. Sodium-2-mercaptoethane sulfonate (mesna) can help to prevent it by providing free sulfhydryl groups, which neutralize the acrolein in the urine. Ifosfamide should not be administered without sodium-2-mercaptoethane sulfonate. Sodium-2-mercaptoethane sulfonate is not useful in treating established cystitis. Adequate prehydration with frequent voiding to decrease the length of time the acrolein is in contact with the bladder is also an important prevention measure, particularly with high single doses of cyclophosphamide. Hypotonic solutions should not be used to hydrate patients receiving high-dose cyclophosphamide therapy.

Clinical Presentation

The acute form of hemorrhagic cystitis appears within the first few days of drug treatment. Symptoms range from minimal hematuria with mild dysuria, urgency, and frequency to massive hemorrhage requiring transfusion. The thrombocytopenia seen with high doses of cyclophosphamide aggravates the blood loss. The bleeding usually is self-limited and will stop after a median duration of a month, even in severe cases, if the patient can be supported that long.

Treatment

Mild episodes do not require treatment other than cessation of drug therapy. In serious cases, vigorous hydration to promote urine flow, maintenance of adequate platelet counts (50,000/μ L), and constant bladder irrigation through a large-bore catheter are indicated. The catheter must be kept free of obstructing clots, which can cause renal obstruction with severe pain.

Intravesical instillation of a variety of agents has been reported to control bleeding. Formalin is the best established of these agents, but formalin administration may have significant side effects, including pain, fibrosis, and renal papillary necrosis. It must be given with the patient under anesthesia. Urinary diversion also may be useful. In intractable cases, hypogastric artery embolization may be attempted, and severe intractable cases sometimes even require cystectomy with urinary diversion.51–53

Microangiopathic Hemolytic Anemia54–60

Thrombotic microangiopathy has been associated with various cancers as well as cancer therapies; thus it sometimes can cause a diagnostic dilemma. Among the various cancer treatments associated with the process, mitomycin C has been associated most closely with a syndrome of renal failure with microangiopathic hemolytic anemia. However, various other agents, such as bleomycin, cisplatin, interferon, and gemcitabine, also have been associated with microangiopathy. Thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS) also can be a late complication (usually occurring within 1 year) of both allogeneic and autologous bone marrow transplantation. In both settings, the symptoms resemble those of idiopathic HUS; hypertension, renal failure, and anemia predominate rather than fever and neurologic signs. Conventional plasmapheresis, which is standard therapy for sporadic TTP, does not appear to be as effective in these drug-induced disorders. The prognosis in mitomycin C–associated HUS has been reported to be very poor; staphylococcal protein A immunoadsorption may be useful. The severity of the presentation and the prognosis in transplant patients are variable. Plasma exchange with cryosupernatant, protein A immunoadsorption, intravenous immunoglobulin administration, and glucocorticoid administration are of uncertain benefit.

(See ref. 61.) Although a large number of cytoxic agents can damage the liver in a variety of ways, few of them do so regularly with any severity when used in conventional doses (Table 74-7). However, veno-occlusive disease (VOD) of the liver is a major toxicity of high-dose regimens given before transplantation.

Veno-Occlusive Disease of the Liver62

VOD is seen sporadically and rarely with a number of cytotoxic drugs, particularly antimetabolites, at conventional doses. Much more important, it has an incidence of up to 20% and is a common cause of death in patients given a variety of high-dose chemotherapy regimens or chemoradiotherapy combinations prior to infusion of autologous or allogeneic marrow or stem cells. Clinically, VOD resembles Budd-Chiari syndrome. The diagnosis is based on the presence of at least two of the triad of jaundice, hepatomegaly or right upper quadrant pain, and ascites or unexplained weight gain. Hyperbilirubinemia, which generally precedes hepatomegaly and ascites by several days, usually is out of proportion to increases in transaminase concentrations.

Symptoms begin at a mean of 10 days after marrow reinfusion, whereas graft-versus-host disease, one of the major differential diagnoses in patients who have had an allogeneic transplant, more often develops after day 20. Most deaths associated with VOD occur by day 35 after transplantation, and the majority of recoveries are evident by this time. However, late-onset VOD occurs with some regimens. The pain may be acute and severe enough to suggest an abdominal catastrophe such as pancreatitis, bowel infarction, biliary obstruction, peritonitis, or pyogenic liver abscess. Drugs, such as cyclosporine, and sepsis may cause laboratory abnormalities that mimic those seen in VOD.

Pathologically, early VOD is characterized by subintimal edema and hemorrhage within small central venules and centrilobular congestion. This picture progresses to fibrous obliteration of the central venule lumina and centrilobular sinusoidal fibrosis.

Diagnosis of VOD remains largely based on the clinical picture. Percutaneous biopsy usually is contraindicated because patients generally are thrombocytopenic, may be refractory to platelet transfusions, and may have a coagulopathy caused by liver dysfunction. Transvenous liver biopsies and measurement of the hepatic venous pressure gradient (elevated in VOD) are safer but still may result in fatal hemorrhage. Ultrasound studies may show an increased mean hepatic artery resistive index or reversal of portal venous flow. However, definitive findings tend to occur late, when the disease is obvious clinically. No therapies for VOD have been evaluated in prospective, randomized fashion. Standard supportive care for liver failure is indicated (see Chap. 73 and 83).

(See refs. 63–68.) A number of cytokines are available for widespread use, and new ones are constantly undergoing testing. Each has a unique toxicity profile that depends on dose, schedule, and combination with other cytokines or with other anticancer drugs, but they tend to share a spectrum of side effects, probably related to the “cytokine cascade,” that are different from those of most chemotherapeutic agents. These include typical side effects of interferon, such as fever and myalgia, and a side effect of high-dose IL-2 treatment that consists of a sepsis-like capillary leak syndrome that can lead to hypotension and cardiovascular collapse. Attempts at fluid resuscitation may lead to pulmonary edema, and use of vasopressors may be necessary. The capillary leak syndrome, like most cytokine toxicities, resolves rapidly after discontinuation of therapy. Arrhythmias and myocardial infarction also may be seen and may result either from fluid shifts or from direct myocardial toxicity. CNS toxicity is frequent and may be related to the vascular leak phenomenon or to the function of cytokines as messenger molecules with the CNS. CNS toxicity usually is reversible, but it may persist for days after cessation of treatment.

A detailed list of the side effects of IL-2 treatment that are seen at the recommended doses for renal cancer (600,000 U/kg every 8 hours for 14 doses) is given in Table 74-8 as a prototype of cytokine toxicities.

(See refs. 69–77.) The tremendous gains made in cancer biology in the past 10 to 15 years have led to the development of agents that inhibit specific targets such as surface receptors or intra- and extracellular proteins that are thought to play a key role in the development or progression of various malignancies, and these agents are often referred to as targeted therapies. Several new monoclonal antibodies and small-molecule kinase inhibitors have been approved by the FDA in the last 5 years for various therapeutic indications. With increasing use of targeted agents, a range of new clinical toxicities is being recognized and reported. Compared with various classic cytotoxic agents discussed earlier, the clinical experience with the newer targeted agents is limited; hence details regarding the prevalence and underlying pathologic mechanisms of the toxicities currently are sparse and will continue to evolve. This section describes some of the more severe adverse events that have been reported with the various targeted agents.

Monoclonal Antibodies26,69–71

The past few years have seen several new humanized monoclonal antibodies approved for the management of hematologic and solid malignancies. It is anticipated that the common toxicities, such as acute infusion reactions, associated with the antibodies most likely will be similar for the different antibodies, whereas specific toxicities, such as cardiac toxicity associated with trastuzumab,26 most likely will be related to the modulation of the targeted pathway by each specific antibody. Rituximab (rituxan) is a chimeric anti-CD20 antibody that is now used routinely for the treatment of various lymphoid malignancies. Recent case reports have implicated this antibody in various dermatologic and systemic toxicities.69,70 The toxicities have ranged from mild cutaneous reactions to the much more severe Stevens-Johnson syndrome and serum sickness; the toxicities generally have resolved with discontinuation of therapy in conjunction with supportive care and steroids. The cytokines released by the targeted malignant cells, as well as the antibody itself, have been implicated as the cause of these adverse events. The specifics of the underlying pathology are poorly understood, but treating physicians should be aware of such severe toxicities because they are anticipated to become more common with increasing use of these agents. Some monoclonal antibodies that are currently in clinical use are conjugated to either a cytotoxic entity or a radioisotope.71 The rationale behind their development is that the antibody will bring the lethal conjugated cytotoxic compounds specifically into proximity with the targeted neoplastic cells and potentially enhance the cytotoxicity of the agents. The radioisotope-labeled antibodies frequently are associated with prolonged myelosuppresion.

Antiangiogenic Agents72–74

Recognition of the importance of angiogenesis in the progression and propagation of various malignancies has led to an increased emphasis on the development of agents that inhibit the complex process of angiogenesis. Although thalidomide and the monoclonal antibody bevacizumab (avastin) are the only antiangiogenic agents currently approved for cancer therapy, many other agents in this class are in advanced stages of development and are anticipated to be approved in the near future. The most serious adverse events that have been described with this class of agents are bleeding, thromboses, and hypertension, and the underlying mechanisms of these toxicities are still being defined. Hence the recommendations for management or prevention of the vascular complications are also evolving. In general, for patients with the most severe complications, discontinuation of the antiangiogenic agent with the appropriate medical therapy is the most prudent approach currently. Reversible hypertension and proteinuria also have been observed routinely for various antiangiogenic therapies. Generally, both toxicities can be managed medically or can be reversed by discontinuation of the therapeutic agent.

The observation that thalidomide has modest antiangiogenic properties led to a renewed interest in its use as an anticancer agent, and the initial clinical investigation led to its approval for the treatment of multiple myeloma. Besides the well-publicized teratogenic and neurologic toxicities, it also has been associated with high rates of thromboembolic complications in several cancer clinical trials. Patients receiving thalidomide in combination with other chemotherapeutic agents seem to be the most susceptible to the thrombotic complications.39,71 Various approaches to managing patients with these complications have been proposed from the more conservative approach of discontinuing thalidomide therapy in patients with marginal benefit from the agent to reinitiating thalidomide therapy after appropriate stable anticoagulation therapy has been established. Uniform management guidelines for such complications will emerge only after more clinical experience with this class of agents has been gained.

Small-Molecule Tyrosine Kinase Inhibitors75–77

Many of the tyrosine kinase inhibitors that were thought initially to be highly specific are in some instances not as specific in their inhibitory capacity and are demonstrating activity against malignancies that they were not designed to treat initially.75–77 Hence they are being described here as another class of cancer agents that will be used more routinely for management of different malignancies. The reader should note that the predominant toxicities of many kinase inhibitors will not always be the same and eventually will be dictated by the pathways predominantly inhibited by each agent. This section will limit the discussion only to currently FDA-approved agents.

One of the most publicized tyrosine kinase inhibitors is imatinib mesylate (gleevec, STI-571).75 Imatinib mesylate is an orally administered drug that inhibits the Bcr-Abl protein-tyrosine kinase. The Bcr-Abl fusion protein is the result of the pathognomonic 9,22 chromosome translocation that causes chronic myelogenous leukemia (CML). Imatinib mesylate treatment resulted in both hematologic and cytogenetic responses in CML patients and led to approval of the agent in United States in 2001. Subsequent studies also demonstrated that imatinib mesylate also was active against gastrointestinal stromal tumors (GISTs) that overexpress the platelet-derived growth factor receptor kinase.75 Some of the common toxicities associated with the agent consist of mild nausea, emesis, edema, and dermatologic reactions. However, about 2% to 4% of patients have been reported to have severe fluid retention in the forms of pleural and pericardial effusions, as well as severe cutaneous reactions. The severe adverse events have been observed more commonly in patients receiving the higher doses (≥600 mg/d) of the agent. Gefitinib, the epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor approved for the treatment of lung cancer, results in mild to moderately severe skin rash and diarrhea in most patients in addition to the rare but severe pulmonary toxicity discussed earlier.18 Both toxicities are relatively easy to manage with dose reduction or supportive care when they are mild; however, in about 5% to 10% of the patients, both rash and diarrhea can be quite severe, requiring discontinuation of therapy and aggressive supportive care. Finally, as mentioned earlier in this section, oncologic therapies are anticipated to undergo some dramatic changes in the next few years with the introduction of several novel agents that differ from the traditional cytotoxic agents both in their mechanisms of action and in their typical toxicity profiles. As a result, clinicians will be challenged initially with limitations in information regarding some of the uncommon and potentially severe toxicities of the newer agents, and this will require diligence and patience while the clinical experience with such agents increases and some practice standards are established.