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An Approach to Chemotherapy-Associated Toxicity

Emergency Medicine Clinics of North America, 1, 32, pages 167 - 203

The effects of chemotherapy in multiple organ systems may be challenging to discern from the sequelae of malignancy and systemic illnesses with concomitant immunocompromise. Chemotherapeutic agents typically affect multiple organ systems. Intrathecal medication errors may pose particularly devastating neurologic consequences and death, often requiring emergent intervention. This article provides an overview of commonly used chemotherapeutic drugs, indications for use, their adverse effects by organ system, and the management of commonly encountered toxicities. Intrathecal medication errors and specific antidotes are discussed in pertinent management sections. Emergency department management should focus on rapid patient assessment, immediate intervention following intrathecal medication errors, exclusion of infection, and excellent supportive care.

Keywords: Adverse effects, Chemotherapy, Cancer, Extravasation, Toxicity.

Key points

 

 

  • Chemotherapy-induced adverse effects are common and may mimic common disease processes.
  • Evaluation of infectious causes of symptoms is important in immunocompromised patients.
  • Emergency medicine management of oral and parenteral chemotherapeutic toxicity entails excellent supportive care.
  • Intrathecal medication errors may require emergent cerebrospinal fluid drainage.
  • Extravasation of vesicants may require emergent administration of specific antidotes.

Introduction

Cancer is the leading cause of death worldwide and the second leading cause of death in the United States. 1 Approximately 13.7 million Americans with a cancer history were alive in January 1, 2012. 2 Given anticipated increases in cancer incidence and prevalence, the emergency medicine physician is likely to encounter patients receiving chemotherapeutic agents. The breadth of chemotherapeutic agents is vast, and adverse effects are, unfortunately, common. Given disease complexity, most patients receive multidrug regimens. Distinguishing disease pathology from the adverse chemotherapeutic effects remains challenging. Cessation of exposure is often necessary to manage severe toxicity.

Chemotherapeutic agent classification

Table 1 lists common chemotherapeutic agents, their mechanisms of action, and commonly used antidotes. 3

Table 1 Chemotherapeutic drugs

Class Agents Mechanism of Action Antidotes
Alkylating agents
  • Busulfan
  • Dacarbazine
  • Nitrogen mustards
    • Chlorambucil
    • Cyclophosphamide
    • Ifosfamide
    • Mechlorethamine
    • Melphalan
  • Nitrosoureas
    • Carmustine
    • Lomustine
    • Semustine c
    • Streptozotocin
  • Platinoids
    • Cisplatin
    • Carboplatin
    • Iproplatin
    • Oxaliplatin
  • Procarbazine
  • Temozolomide
DNA alkylation; formation of DNA crosslinks and adducts; inhibition of DNA synthesis Mesna a
  • Cyclophosphamide and ifosfamide-induced hemorrhagic cystitis
Methylene blue b
  • Ifosfamide-induced encephalopathy
Thiosulfate b
  • Nitrogen mustard skin extravasation
Amifostine a
  • Prevention of cisplatin-induced nephrotoxicity
Antimetabolites
  • Methotrexate
  • Purine analogues
    • Fludarabine
    • Mercaptopurine
    • Pentostatin
    • Thioguanine
  • Pyrimidine analogues
    • Capecitabine
    • Cytarabine
    • 5-Fluorouracil (5-FU)
    • Gemcitabine
Methotrexate
  • Inhibition of dihydrofolate reductase; inhibition of purine synthesis
Purine/pyrimidine analogues
  • Inhibition of DNA synthesis
Leucovorin a and levoleucovorin a
  • Methotrexate toxicity/overdose
Glucarpidase a
  • Methotrexate toxicity/overdose
Uridine triacetate (PN401) b , d
  • 5-Fluorouracil overdose
Antimitotics
  • Taxanes
    • Docetaxel
    • Paclitaxel
  • Vinca alkaloids
    • Vinblastine
    • Vincristine
    • Vindesine (unavailable in United States)
    • Vinorelbine
Taxanes
  • Microtubule stabilization; disruption of microtubule polymerization/depolymerization
Vinca alkaloids
  • Inhibition of microtubule polymerization; microtubule destabilization
Antibiotics
  • Anthracyclines
    • Daunorubicin
    • Doxorubicin
    • Epirubicin
    • Idarubicin
  • Dactinomycin
  • Mitomycin C
  • Mitoxantrone
  • Bleomycin
  • Plicamycin (mithramycin)
Anthracyclines
  • DNA intercalation; free radical formation
Dactinomycin
  • DNA binding; RNA synthesis inhibition
Mitomycin C
  • DNA synthesis inhibition
Mitoxantrone
  • DNA intercalation; topoisomerase II inhibition
Bleomycin
  • Inhibition of DNA and RNA synthesis
Plicamycin
  • Inhibition of RNA transcription
Dexrazoxane a
  • Anthracycline-associated cardiac toxicity and extravasation
Monoclonal antibodies l-asparaginase

Alemtuzumab (CD52)

Apolizumab

Bevacizumab (VEGFR)

Cetuximab (EGFR)

Gemtuzumab (CD33)

Ibritumomab (CD20)

Panitumumab (EGFR)

Rituximab (CD20)

Tositumomab (CD20)

Trastuzumab (HER2)
Monoclonal antibodies specific for cell surface markers
Protein kinase inhibitors Dasatinib (BCR/ABL, Src)

Erlotinib (EGFR)

Gefitinib (EGFR-TK)

Imatinib

Lapatinib (EGFR, HER2)

Sorafenib

Sunitinib
Protein kinase inhibition
Selective estrogen receptor modulators Tamoxifen Estrogen receptor antagonism
Topoisomerase inhibitors
  • Camptothecins
    • Irinotecan
    • Topotecan
  • Epipodophyllotoxins
    • Etoposide
    • Teniposide
Camptothecins
  • Topoisomerase I inhibition
Epipodophyllotoxin
  • Topoisomerase II inhibition

a Approved by the Food and Drug Administration for this indication.

b Not approved by the Food and Drug Administration for this indication.

c Withdrawn from marketing.

d Food and Drug Administration orphan drug designation.

Abbreviations: CD20, B-lymphocyte antigen CD20; CD33, Siglec-3; CD52, cluster of differentiation 52; EGFR, epidermal growth factor receptor; EGFR-TK, epidermal growth factor receptor tirosine kinase; HER2, human epidermal growth factor receptor 2; Src, rous sarcoma oncogene cellular homolog; VEGFR, vascular endothelial growth factor receptor.

Given the rapid advances in cancer research and the evolving complexity of treatment regimens, it is challenging to provide a comprehensive treatment list for each malignancy. In the absence of definitive patient information, Table 2 provides several common chemotherapeutic regimens. 4 These regimens are continually evolving, and their application may vary.

Table 2 Selected adult chemotherapeutic regimens

Malignancy Chemotherapeutic Drugs and Regimens
Acute lymphoblastic leukemia Anthracycline, imatinib, ± l-asparaginase, mercaptopurine, prednisone, teniposide, vincristine
Acute myeloid leukemia Cytarabine, daunorubicin, gemtuzumab, idarubicin, mercaptopurine, ± thioguanine
Bladder CMV: cisplatin, methotrexate, vinblastine
Intravesical: doxorubicin, mitomycin C, thiotepa
MVAC: cisplatin, doxorubicin, methotrexate, vinblastine
Systemic: docetaxel, gemcitabine, ifosfamide, paclitaxel
Brain Carmustine, semustine, temozolomide
Breast AC: cyclophosphamide, doxorubicin
AC-T: cyclophosphamide, doxorubicin, taxane
CAF: cyclophosphamide, doxorubicin, 5-FU
CMF: cyclophosphamide, 5-FU, methotrexate
FEC: cyclophosphamide, epirubicin, 5-FU
Other agents: capecitabine, carboplatin, cisplatin, gemcitabine, mitomycin C, mitoxantrone, paclitaxel, vinblastine, vincristine, vinorelbine
Receptor-specific therapy: lapatinib, tamoxifen, trastuzumab
TAC: cyclophosphamide, docetaxel, doxorubicin
TC: cyclophosphamide, docetaxel
Cervical Cisplatin, 5-FU, gemcitabine, ifosfamide, irinotecan, paclitaxel, topotecan, vinorelbine
Chronic lymphocytic leukemia CHOP: cyclophosphamide, doxorubicin, prednisone, vincristine
CVP: cyclophosphamide, prednisone, vincristine
Cyclophosphamide, fludarabine, pentostatin, rituximab
Chronic myelogenous leukemia Busulfan, cytarabine, imatinib/dasatinib (Philadelphia-chromosome +), vincristine
Colorectal Cetuximab, 5-FU, irinotecan, oxaliplatin, panitumumab
Endometrial Cisplatin, doxorubicin, paclitaxel
Esophageal Carboplatin, cisplatin, etoposide, 5-FU, paclitaxel, vinblastine
Gallbladder Cisplatin, docetaxel, gemcitabine
Gastric Capecitabine, cisplatin, docetaxel, epirubicin, 5-FU, mitomycin C, oxaliplatin
Hepatocellular Sorafenib
Laryngeal Cisplatin, 5-FU
Lung (non–small cell) Bevacizumab, carboplatin, cetuximab, cisplatin, docetaxel, erlotinib, etoposide, gefitinib, gemcitabine, irinotecan, paclitaxel, vinorelbine
Lung (small cell) Cyclophosphamide, doxorubicin, etoposide, gemcitabine, ifosfamide, irinotecan, paclitaxel, platinoids (carboplatin, cisplatin, oxaliplatin), topotecan, vincristine, vinorelbine
Lymphoma (Hodgkin) ABVD: bleomycin, dacarbazine, doxorubicin, vinblastine
BEACOPP: bleomycin, cyclophosphamide, doxorubicin, etoposide, prednisone, procarbazine, vincristine
MOPP: mechlorethamine, prednisone, procarbazine, vincristine
Lymphoma (non-Hodgkin) C-MOPP: cyclophosphamide, doxorubicin, prednisone, procarbazine, vincristine
Chlorambucil, cyclophosphamide, fludarabine, ibritumomab, rituximab, tositumomab
CHOP: cyclophosphamide, doxorubicin, prednisone, vincristine
CVP: cyclophosphamide, prednisone, vincristine
FND: dexamethasone, fludarabine, mitoxantrone
R-CHOP: CHOP, rituximab
Lymphoma (CNS) Carmustine, cyclophosphamide, cytarabine, doxorubicin, methotrexate, methylprednisolone/dexamethasone, procarbazine, teniposide, vincristine
Malignant mesothelioma Carboplatin, cisplatin, cyclophosphamide, doxorubicin, epirubicin, ifosfamide, mitomycin C
Melanoma Carmustine, dacarbazine, lomustine, temozolomide
Polycythemia vera Busulfan, chlorambucil
Ovarian epithelial Cyclophosphamide, doxorubicin, gemcitabine, paclitaxel, platinoids (carboplatin, cisplatin, oxaliplatin)
Ovarian germ cell tumors BEP: bleomycin, cisplatin, etoposide
PVB: bleomycin, cisplatin, vinblastine
VAC: cyclophosphamide, dactinomycin, vincristine
Pancreatic Capecitabine, cisplatin, erlotinib, 5-FU, gemcitabine, mitomycin C, oxaliplatin
Penile Bleomycin, cisplatin, 5-FU, methotrexate, vincristine
Renal cell Bevacizumab, sorafenib, sunitinib
Testicular (seminoma) BEP: bleomycin, etoposide, cisplatin
EP: etoposide, cisplatin
Testicular (nonseminomas) BEP: bleomycin, cisplatin, etoposide
EP: cisplatin, etoposide
PVB: cisplatin, bleomycin, vinblastine
VAB VI: bleomycine, cisplatin, cyclophosphamide, dactinomycin, vinblastine
VIP: cisplatin, etoposide, ifosfamide
VPV: cisplatin, etoposide, vinblastine
Vaginal Bleomycin, cisplatin, 5-FU, mitomycin C, vincristine
Vulvar Bleomycin, cisplatin, 5-FU, mitomycin C

Abbreviations: CNS, central nervous system; 5-FU, 5-fluorouracil.

Some chemotherapeutic regimens in this table may be used off-label.

Chemotherapeutic emergencies

Neurologic Emergencies

Chemotherapeutic agents cause both central and peripheral neurotoxicity. The diagnosis of central neurotoxicity is challenging because it may clinically mimic cancer burden or central nervous system (CNS) infection. Toxicity manifests as encephalopathy with or without seizures, cerebellar syndrome, posterior and multifocal leukocencephalopathies, psychosis, and cranial nerve (CN) palsies. A change in mental status may be due to nonconvulsive status epilepticus and is seen with ifosfamide and cisplatin.22 and 23 Encephalopathy occurs most commonly with ifosfamide and typically resolves several days following cessation of therapy. Vincristine is a potent neurotoxin and leads to a variety of neurologic symptoms from encephalopathy and focal CN palsies to peripheral neuropathy. Other neurologic complications may be due to the route of drug administration. The intrathecal (IT) section provides additional information.

Peripheral neuropathy is often a debilitating condition with limited treatment options and potential for irreversible damage. Peripheral neuropathies are typically sensorimotor and most frequently associated with axonal degeneration. Vincristine, paclitaxel, cisplatin, and oxaliplatin are frequently implicated in development of peripheral neuropathy. Table 3 summarizes commonly encountered neurotoxic effects of respective chemotherapeutic agents. 16

Table 3 Chemotherapeutic neurotoxins

Toxicity Drug
Acute cerebellar syndrome with ataxia Cytarabine

5-FU
Cerebrovascular accident, transient ischemic attack Bevacizumab 5

Cisplatin

Erlotinib 6
CNS hemorrhage l-asparaginase 7

Bevacizumab 5
Cranial nerve palsy Ifosfamide 8

Paclitaxel 9

Vincristine 10
Encephalopathy Cisplatin

Fludarabine

5-FU

Ifosfamide 8

Methotrexate 11

Pentostatin

Vincristine 10
Hemiparesis Methotrexate 11
Occipital encephalopathy Cisplatin

Cytarabine

Fludarabine
Parkinson-like syndrome l-asparaginase 7
Peripheral mixed sensorimotor neuropathy Fludarabine

Vincristine 10

Vinorelbine 12

Taxanes
Peripheral sensory neuropathy9 and 13 Carboplatin 14

Cisplatin 15

Oxaliplatin

Paclitaxel
Peripheral neuropathy with autonomic instability 9 Cisplatin

Paclitaxel

Vincristine 10
Progressive multifocal neuro-encephalopathy Capecitabine

Fludarabine

Rituximab 17
Reversible posterior leukoencephalopathy syndrome Bevacizumab 5

Cisplatin

Cytarabine

Gemcitabine 18

Sorafenib

Sunitinib 19
Sagittal sinus thrombosis l-asparaginase 7
Seizures Busulfan 20

Chlorambucil

Encephalopathy agents

Procarbazine

Temozolomide

Vinblastine 21

Abbreviations: CNS, central nervous system; 5-FU, 5-fluorouracil.

Clinical evaluation

Altered mental status, hallucinations, psychosis, seizures, and coma may be clinical signs of encephalopathy. A persistent change in mental status may reflect nonconvulsive status epilepticus. CN palsies and hemiparesis may be evident on physical examination. Acute cerebellar syndrome with ataxia may be marked with gait instability and vertigo with clinically abnormal cerebellar examination and gait. Reversible posterior leukoencephalopathy syndrome is characterized by headache, altered mental status, seizures, and visual loss. Progressive multifocal neuro-encephalopathy manifests with altered mental status, changes in vision and speech, motor weakness and paralysis, and cognitive deterioration.

Peripheral neuropathy is often a clinical diagnosis. Symptoms of small-fiber neuropathy include burning pain and loss of pain and temperature sensation. Large-fiber neuropathy may present with muscle weakness and loss of proprioception and reflexes.

Diagnostic evaluation

The following laboratory studies and diagnostics may be helpful in the assessment of patients with chemotherapy-induced neurotoxicity:

  • Finger stick glucose in patients with altered mental status to evaluate for hypoglycemia
  • Serum electrolytes
  • Complete blood count (CBC): evaluation of neutropenia, leukocytosis
  • Prothrombin time (PT)/international normalized ratio (INR), partial thromboplastin time (PTT): if considering performing lumbar puncture (LP)
  • Computed tomography (CT) brain without contrast: initial diagnostic tool to exclude hemorrhage and brain mass as causes of neurologic symptoms
  • LP: consider as a part of infectious workup in immunocompromised patients with altered mental status
  • Electroencephalogram: evaluation of nonconvulsive status epilepticus in persistently altered patients
  • Magnetic resonance imaging (MRI): a sensitive modality for evaluation of leukoencephalopathy, nonemergent
  • Electromyography and nerve conduction studies: nonemergent
Management

The management of chemotherapy-induced neurologic toxicity remains supportive following the exclusion of infectious causes. Methylene blue has been used in the management of ifosfamide-induced encephalopathy but is not recommended as a part of emergency department management.

Antidote considerations: Methylene blue

Methylene blue currently does not have approval by the Food and Drug Administration (FDA) for use in ifosfamide-induced encephalopathy and, at this time, cannot be recommended as a part of the emergency department management of ifosfamide-induced encephalopathy. Methylene blue modulates ifosfamide neurotoxicity via different mechanisms.24 and 25 It inhibits monoamine oxidase (MAO), preventing generation of the neurotoxic chloroacetaldehyde metabolite. It promotes oxidation of NADH to NAD+ and, thus, stimulates ifosfamide metabolism and hepatic gluconeogenesis. Methylene blue modulates electron transfer flavoproteins in the mitochondria, restoring oxidative phosphorylation and efficient energy utilization. Methylene blue 1% solution is administered intravenously with an initial dose of 50 mg in adults and a variable daily schedule. 24 Although some studies have demonstrated a decrease in the duration of symptoms, others failed to show a benefit. A transient decrease in numerical oxygen saturation value via pulse oximeter may be seen because of the blue discoloration of the methylene blue. Hemolysis may be seen in neonates or patients with G6PD deficiency.

Intrathecal (IT) Emergencies

Patients may present to the emergency department because of errors in IT medication administration associated with chemotherapy. The term intrathecal refers to the space enclosing the cerebrospinal fluid (CSF). Medications may be intentionally placed into the CSF for therapeutic or diagnostic purposes. Examples include IT administration of baclofen via an indwelling catheter or direct administration of antibiotics or chemotherapeutic agents via lumbar puncture. Errors involving the IT space are potentially life threatening because this area can affect the nervous system directly. The routes of IT access are listed in Boxes 1 and 2 . Scenarios may include administration of the wrong agent or wrong route, dosage errors caused by miscalculation, or, in some cases, errors relating to pumps.

 

  • Lumbar Puncture
  • Indwelling device
    • Spinal catheter
    • Ommaya reservoir
  • Surgical exposure in operating room

Box 1 Routes of IT access

 

  • If possible, elevate head
  • Consider CSF drainagea
  • Consult the Poison Control Center (1-800-POISONS)
  • Consult neurosurgery

a Institute life-saving measures (intubation and paralysis) as needed.

Box 2 Management of IT emergencies

Wrong agent or wrong route

Agents that are therapeutic when administered intravenously may produce acute toxicity or present altered toxicity profiles when delivered IT. Typically, agents that are ionic or hyperosmolar injure the CNS, often in a neuroanatomical distribution. For example, there are several high osmolar radiocontrast agents intended for intravenous (IV) use only. High osmolar radiocontrast agents administered IT via LP may precipitate a progression of symptoms termed ascending tonic clonic syndrome, reflecting contrast effects as it moves cephalad. If high osmolar contrast is administered into the ventricles of the brain via an Ommaya reservoir, or during an operative procedure requiring neuroimaging, the clinical presentation may skip the ascending neurologic signs and symptoms seen with lumbar administration (see radiocontrast agents later). 55 Agents such as methotrexate (MTX) may produce a chemical arachnoiditis, even when administered IT with therapeutic intent.

The timing of toxicity onset may depend on the dose and nature of the agent administered. For example, vincristine is intended for IV administration only. It is commonly administered in a chemotherapeutic regimen that also includes IT MTX. Multiple reports document syringe confusion when the treatments are scheduled concurrently. Vincristine toxicity in the CNS may take hours to days to present, often in a neuroanatomical fashion, and may begin with paresthesias and paralysis, ultimately progressing to coma and death. 56 Inadvertent IT vincristine is almost universally fatal despite a benign patient appearance immediately after administration. Another example is local anesthetics intended for the epidural space with inadvertent penetration of the dura. CNS toxicity may manifest as numbness, weakness, or seizures. Patients receiving such treatments in outpatient facilities may present to the emergency department requiring emergent interventions.

Intrathecal dosage errors and pumps

Dosage miscalculations of medications can result in CNS toxicity in a manner that is sometimes paradoxic to the effects noted in IV overdose. An example is IT morphine toxicity. Morphine administered IV has a predictable dose-dependent effect of sedation, miosis, and respiratory depression. An IT overdose of morphine may cause neuroexcitation, 57 which may happen during refilling errors of subcutaneous pumps that deliver IT morphine through a surgically placed tunneled IT catheter. The pump contains a reservoir with an access port for refilling. Medication is pumped in small increments via the catheter into the IT space. The pump also has a second access port contiguous with the catheter and the IT space. Refilling the pump reservoir requires a template and proper training, because access sites are palpated rather than directly visualized. If the wrong port is identified, several weeks of IT morphine may enter the CSF as a bolus and cause profound hypertension and seizures. 57

Sometimes external pumps are used to administer medication IT. An example is baclofen. If the pump empties, malfunctions, or there is a loss of continuity, there may be an abrupt cessation of medication, which may result in withdrawal. Patients administered baclofen by this route for the treatment of spasticity have sometimes suffered life-threatening autonomic instability and seizures with pump malfunction.58, 59, and 60

Most common intrathecal scenarios

The Emergency Medicine practitioner may encounter patients from a radiology suite who were given the wrong IT contrast agent for neuroimaging. Confusion in drug administration is complicated by the multiple names and numbers of contrast agents that do not reflect the osmolarity of the agent. Unfortunately, many radiocontrast dyes that are benign when given IV are hyperosmolar and/or ionic agents and potentially fatal when given IT. This ascending tonic clonic syndrome consists of paresthesias, weakness, and a severe form of myoclonus and muscle spasm that results in rhabdomyolysis, hyperthermia, and contractions severe enough to fracture bones.55 and 61

Management of intrathecal emergencies

There may be IT administration of agents for which there is no prior experience. The presumption should be that the agent is potentially fatal, and timely removal of the CSF is warranted. There is no predictable model for knowing how much medication can be removed after IT drug administration because each drug has unique properties affecting CSF movement. IT drugs administered simultaneously may have different percentages of drug recovery when the CSF is subsequently drained. The only common factor is that the sooner the CSF removal, the more likely the toxic effect is blunted. This point is especially true for an agent such as vincristine in which time to drainage affects survivability. The only documented survivors of erroneous IT vincristine administration had immediate recognition of the error before withdrawal of the lumbar needle and prompt CSF drainage. Even in these cases, the neurologic injuries were devastating.56 and 61 For EM physicians attending to patients with a wrong drug error for CSF, a lumbar needle or catheter, if not already in place, should be accessed. CSF can be drained passively in 10 mL to 20 mL aliquots with interval instillation of preservative-free isotonic fluid equivalent to the aliquot removed. This procedure can be performed repeatedly while other providers investigate if there is any experience with the exposure in the literature.

On very rare occasions, a neurosurgeon will perform a washout with the placement of an IT catheter either in the ventricles or along the spine for infusion of preservative-free isotonic fluid. This catheter is paired with another more distal IT catheter for CSF drainage. This method has been used for life-threatening chemotherapeutic errors. 56

In general, antidotes commonly used for IV or oral overdoses should be avoided IT because such antidotes may be dangerous or even fatal in the CSF. A single exception is carboxypeptidase G2, which can cleave MTX in cases of inadvertent IT MTX overdose. Although carboxypeptidase G2 is FDA approved for IV use only, experience with IT dosing has been well tolerated and efficacious in the setting of IT MTX overdose. 62 Note that, however, MTX’s other antidote, leucovorin, is contraindicated by the IT route.

Cardiovascular Emergencies

Anthracyclines, especially doxorubicin, cause cardiac toxicity in the acute, subacute, and chronic setting. The generation of hydroxyl radicals leading to DNA disruption and myocyte death is thought to underlie cardiotoxicity. 63 Dysrhythmias, ischemic electrocardiographic (ECG) changes, congestive heart failure (CHF), left ventricular dysfunction, pericarditis, myocarditis, and sudden death have been reported within 24 hours of administration. Subacute toxicity is seen within a few weeks, clinically appears as myocarditis with diastolic dysfunction, and is associated with 60% mortality.64 and 65 Chronic toxicity clinically manifests as CHF, left ventricular dysfunction, and dilated cardiomyopathy, with symptoms as early as one month to 10 to 30 years following anthracycline therapy.63, 65, 66, and 67 A cumulative dose is the most important risk factor for chronic toxicity.63, 65, and 66 Mitoxantrone may be associated with dose-dependent cardiac effects similar to anthracyclines. Trastuzumab, an HER2-targeted monoclonal antibody, also carries significant CHF risk. In contrast to anthracyclines, cardiac dysfunction is typically reversible.63 and 66 High-dose cyclophosphamide and 5-fluorouracil (5-FU) may also cause significant cardiac toxicity manifested by dysrhythmias, CHF, and hemorrhagic pericarditis.63 and 65 Table 4 contains a comprehensive list of chemotherapeutic cardiac toxins and their respective clinical effects.63, 64, 65, 66, and 67

Table 4 Chemotherapeutic cardiovascular toxins

Toxicity Drug
Capillary leak syndrome: increase in endothelial permeability Gemcitabine 78
Cardiac ischemia Bevacizumab 5
Capecitabine
Cisplatin
Dasatinib 39
Docetaxel
Erlotinib 6
Fludarabine
5-FU
Paclitaxel
Rituximab
Sorafenib 68
Vinblastine
Vincristine
CHF and left ventricular dysfunction Anthracyclines (daunorubicin, doxorubicin, epirubicin, idarubicin)28, 41, 43, and 45
Cisplatin
Cyclophosphamide (high dose)71 and 72
Cytarabine
Dasatinib 39
Docetaxel
Ifosfamide
Imatinib 30
Lapatinib 74
Mitomycin C 70
Mitoxantrone 69
Paclitaxel
Pentostatin
Sorafenib
Sunitinib 19
Trastuzumab 73
Dysrhythmia Capecitabine
Cisplatin
Cyclophosphamide (high dose)
Daunorubicin
Docetaxel
Doxorubicin
Epirubicin
Fludarabine
5-FU
Idarubicin
Ifosfamide
Mitoxantrone
Paclitaxel 75
Pentostatin
Rituximab
Hypertension Bevacizumab 5
Cisplatin
Etoposide 47
Sorafenib 68
Sunitinib 19
Vinblastine
Vincristine
Vinorelbine
Hypotension Carmustine (rate related)
Etoposide 47
Fludarabine
MTX 11
Paclitaxel
Procarbazine 42
Myocardial necrosis Cyclophosphamide 71
Myocarditis Cyclophosphamide 71
Pericardial fibrosis Bleomycin
Pericarditis and pericardial effusion Bleomycin
Busulfan
Cyclophosphamide 71
Cytarabine
Dasatinib
Imatinib 30
MTX 11
Pentostatin
QT prolongation Dasatinib 39
Lapatinib 74
Sorafenib 68
Sunitinib 19
Sudden cardiac death Cetuximab 76
Thromboembolic complications Bevacizumab 5
Cisplatin 63
Erlotinib
Gemicitabine 18
Irinotecan
l-asparaginase 7
MTX 11
Sunitinib 19
Tamoxifen 77

Abbreviations: CHF, congestive heart failure; MTX, methotrexate.

Clinical evaluation

The evaluation of chemotherapy-induced cardiac toxicity is fraught with challenges. A physician should maintain a broad differential diagnosis and exclude common causes of cardiac symptoms. CHF resulting from left ventricular dysfunction manifests with symptoms of shortness of breath, orthopnea, and signs of pulmonary edema on auscultation. Hypoxia and severe respiratory distress may be seen clinically with significant pulmonary edema. Cardiac ischemia and pericarditis typically present with chest pain or referred cardiac pain. Pericarditis symptoms often improve with sitting forward and worsen with the supine position. Pericardial effusion may be asymptomatic or may lead to significant hemodynamic compromise caused by cardiac tamponade. Thromboembolic complications may affect any vascular system and result in strokes, myocardial infarction, pulmonary embolism, and vascular compromise of extremities. The clinical evaluation of myocarditis may be challenging. Symptoms are often vague, with the presence or absence of chest pain, generalized weakness, signs of hemodynamic instability, and pulmonary edema with advanced disease. Dysrhythmia may manifest as syncope, transient lightheadedness, weakness or frank cardiac arrest from a nonperfused rhythm. Capillary leak syndrome, described following gemcitabine administration, may clinically appear similarly to CHF with peripheral and pulmonary edema.

Diagnostic evaluation

The following laboratory studies and diagnostics are recommended for the assessment of patients with chemotherapy-induced cardiac toxicity:

  • ECG
  • Cardiac monitor
  • Chest radiograph (CXR)
  • Brain natriuretic peptide
  • Cardiac troponin
  • Liver function testing (LFTs): hypoalbuminemia may be seen with capillary leak syndrome
  • Serum electrolytes to exclude correctable causes of dysrhythmia
  • Bedside cardiac ultrasound: evaluation of pericardial effusion or tamponade
Management

Patients who develop anthracycline-associated cardiotoxicity should avoid further anthracycline exposure. The emergency department management of cardiovascular toxicity (ischemia, CHF, dysrhythmia, pericarditis, tamponade, and thromboembolic events) is similar to the management from cardiogenic and vascular causes. Capillary leak syndrome may be managed with volume repletion if hypotension is present, vasopressor therapy, albumin repletion, diuresis, and steroids. 78 Patients with advanced CHF may require inotropic support. Patients receiving anthracycline chemotherapy may also receive dexrazoxane. This decision is made by the oncology team and is typically not a part of emergent management.

Antidotal considerations: Dexrazoxane

Dexrazoxane inhibits doxorubicin-induced generation of hydroxyl radicals. 66 The coadministration of dexrazoxane in patients receiving doxorubicin chemotherapy demonstrated statistically lower incidence of anthracycline-associated CHF and left ventricular dysfunction.79, 80, and 81 According to the American Society of Clinical Oncology, dexrazoxane may be recommended in patients who received more than 300 mg/m2 doxorubicin and may benefit from continued doxorubicin therapy.82 and 83

Hematopoietic Emergencies

Most chemotherapeutic agents are associated with transient bone marrow suppression. Box 3 contains a comprehensive list of agents that lead to significant myelosuppression. A decrease in the bone marrow cell lines may have the potential for serious complications as well as early cessation of chemotherapy. Box 3 outlines agents most commonly associated with myelosuppression.

 

Alemtuzumab 26
Busulfan 20
Capecitabine 29
Carboplatin 14
Carmustine 31
Chlorambucil
Cisplatin 15
Cytarabine 34
Dacarbazine 36
Dactinomycin 38
Dasatinib 39
Daunorubicin 41
Docetaxel
Doxorubicin 43
Epirubicin 45
Etoposide 47
Fludarabine 49
5-fluorouracil 51
Gemcitabine 53
Gemtuzumab
Ibritumomab 27
Idarubicin 28
Ifosfamide 8
Imatinib 30
Irinotecan 32
Lomustine 33
Mechlorethamine
Melphalan 35
Mercaptopurine 37
Methotrexate 11
Oxaliplatin
Paclitaxel
Pentostatin 40
Procarbazine 42
Rituximab
Streptozotocin 44
Temozolomide 46
Teniposide 48
Thioguanine 50
Topotecan 52
Tositumomab 54
Vinblastine 21
Vinorelbine

Box 3 Agents most commonly associated with bone marrow suppression

Neutropenia is one of the most significant dose-limiting complications of chemotherapy, especially seen with docetaxel and paclitaxel. Granulocytopenia is a dose-limiting reaction of vinorelbine administration. Leukopenia is frequently seen with MTX, mitomycin C, mitoxantrone, dacarbazine, trastuzumab, and dose-dependent cyclophosphamide therapy. Hemolytic anemia has been described following procarbazine and fludarabine therapy.

Thrombocytopenia is noted with bone marrow suppression and thrombotic angiopathy. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are manifestations of thrombotic angiopathy. TTP is a pentad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, fever, neurologic abnormalities, and renal injury. HUS shares features of MAHA and thrombocytopenia without neurologic abnormalities. Mitomycin C and gemcitabine are the most commonly implicated agents in HUS.53 and 70 The following chemotherapeutic agents are also associated with thrombotic angiopathy: daunorubicin, bleomycin, carboplatin, cisplatin, tamoxifen, as well as targeted therapy with alemtuzumab, bevacizumab, erlotinib, sunitinib, and imatinib.6, 84, 85, and 86 Alemtuzumab therapy has been associated with severe hemolytic anemia. Coagulopathy and subsequent bleeding is described with l-asparaginase therapy because of depression of clotting factors. 7 Bleeding has also been noted with dasatinib therapy due to both thrombocytopenia and platelet dysfunction. 39

Clinical manifestations

Clinical manifestations of bone marrow suppression may be challenging to distinguish from those of cancer burden. Neutropenia and leukopenia may lead to local or disseminated infection given severe immunocompromised state. Anemia typically manifests with a variety of symptoms depending on the degree and the organ affected. Clinical symptoms include generalized weakness, exercise intolerance, shortness of breath, and pallor. Severe anemia and subsequent lack of oxygen delivery may result in end-organ ischemia. Thrombocytopenia may be asymptomatic or may manifest with petechiae, ecchymosis, purpura, and may result in life-threatening bleeding. Thrombotic microangiopathy presents as a constellation of symptoms, including hemolysis, thrombocytopenia, and impaired neurologic or renal function. Symptoms of hemolytic anemia vary depending on severity of hemolysis and include generalized weakness, pallor, abdominal pain, and altered mental status. TTP is associated with hemolysis and signs of thrombocytopenia. Other symptoms such as nausea, vomiting, abdominal pain, malaise, joint pain, and myalgia have been described. HUS is often seen in children and is associated with petechiae and purpura of the lower extremities and renal compromise.

Diagnostic evaluation

The following laboratory studies and diagnostics may be helpful in the assessment of patients with chemotherapy-induced hematologic toxicity:

  • CBC with differential and platelets
  • Peripheral blood smear: evaluate for presence of schistocytes seen with hemolysis, disseminated intravascular coagulation
  • PT/INR, PTT fibrinogen
  • LFTs: elevated indirect bilirubin with hemolysis
  • Lactate dehydrogenase (LDH): elevated during hemolysis
  • Serum haptoglobin: decreased during hemolysis
  • Direct Coombs assay: exclusion of immunologic cause of hemolysis
Management

The management of neutropenia and leukopenia is supportive. Recombinant hematopoietic growth factors, such as granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor (GM-CSF), may be used to stimulate the production of bone marrow cell lineages.87 and 88 The treatment of anemia and thrombocytopenia is supportive. Symptomatic patients may require transfusion of blood products. Coagulopathy is treated with factor repletion. The management of thrombotic microangiopathy depends on the severity of hemolysis and thrombocytopenia. Platelet transfusion may be necessary for patients with severe thrombocytopenia or major bleeding. Consultation with a hematology specialist is recommended in cases of severe hemolysis and a potential need for plasma exchange. 85 Febrile neutropenic patients should have rapid assessment for a source of infection and empiric antibiotic coverage to prevent overwhelming sepsis.

Ophthalmologic Emergencies

Chemotherapy-induced ocular toxicity may range from self-resolving conjunctivitis to loss of vision. Table 5 lists common chemotherapeutic ocular toxins and their respective toxicity.89 and 90

Table 5 Chemotherapeutic ocular toxins

Toxicity Drug
Conjunctivitis Busulfan
Cetuximab
Cyclophosphamide
Cytarabine
Doxorubicin
5-FU
Ifosfamide
Imatinib
MTX 11
Corneal perforation Erlotinib 6
Corneal ulceration Erlotinib 6
Cortical blindness Carboplatin
Cisplatin 15
Etoposide
Vincristine
Glaucoma Carmustine
Keratitis Busulfan
Chlorambucil
Cyclophosphamide
Cytarabine
5-FU
Keratoconjunctivitis sicca Busulfan
Cyclophosphamide
Ocular CN palsy Vincristine
Optic atrophy Lomustine
Vincristine
Optic neuritis Carboplatin
Carmustine
Cisplatin 15
Etoposide
Oxaliplatin
Paclitaxel
Optic neuropathy Cytarabine
5-FU
MTX (IT)
Paclitaxel
Vincristine
Papilledema Chlorambucil
Cisplatin 15
Procarbazine 42
Retinal hemorrhage Carmustine
Chlorambucil
Procarbazine 42
Clinical evaluation

Symptoms may range from blurry vision to ocular pain and loss of vision. Patients with ocular complaints necessitate a thorough eye examination that entails the documentation of visual acuity, slit lamp examination, and fluorescein staining. Ocular pressure determination is important if there is clinical concern for glaucoma.

Diagnostic evaluation

Although MRI may be useful in the evaluation of the optic nerve, it is often beyond the scope of an emergency department evaluation.

Management

The management is typically supportive. Ophthalmology follow-up is important for patients with chemotherapy-induced ocular toxicity.

Otolaryngologic Emergencies

Ototoxicity is a recognized complication of cisplatin and carboplatin chemotherapy.14, 15, 91, and 92 Both agents are associated with sensorineural bilateral high-frequency hearing loss and eventually low-frequency hearing loss with cumulative dose. 93 Ototoxicity is consequential in both adults and children and may affect language development in children. CN VIII dysfunction may occur following vincristine chemotherapy. Jaw osteonecrosis has been reported with sunitinib therapy. 19

Clinical evaluation

Changes in hearing are seen in patients with ototoxicity. Patients with CN VIII dysfunction may have vertigo. Jaw osteonecrosis typically presents with pain at the affected site.

Diagnostic evaluation

Patients with clinical signs of ototoxicity, such as tinnitus, decreased hearing, and impaired balance, should be referred for audiologic testing. CT imaging may be necessary for the diagnosis of jaw osteonecrosis.

Management

Although there are several trials evaluating the role of antioxidants for otoprotection during chemotherapy, the treatment of hearing loss remains supportive. Therapy for jaw osteonecrosis may require multidisciplinary involvement.

Pulmonary Emergencies

Chemotherapy-induced pulmonary toxicity may be challenging to diagnose given its rare occurrence (<10%) and propensity to mimic infection or metastatic lung disease. It may present a diagnostic challenge with a normal appearance of CXR for days despite the presence of clinical symptoms. Bleomycin is the most well-studied chemotherapeutic pulmonary toxin.94 and 95 Chemotherapy-induced pulmonary toxicity may manifest as a hypersensitivity reaction, interstitial pneumonitis, noncardiogenic pulmonary edema, pleural effusions, nodular changes, and bronchiolitis obliterans and organizing pneumonitis (BOOP), and progressive pulmonary fibrosis. High mortality rates are reported following therapy with busulfan, chlorambucil, and melphalan. Nitrosourea therapy is associated with delayed onset of pulmonary fibrosis, noted 17 years following treatment for pediatric intracranial tumors. 96 Table 6 contain a comprehensive list of pulmonary toxins and their respective clinical effects.99 and 100

Table 6 Chemotherapeutic pulmonary toxins

Toxicity Drug
BOOP Bleomycin
Cetuximab
Chlorambucil
Cyclophosphamide
MTX
Mitomycin C
Bronchospasm Pentostatin 40
Vincristine 10
Hemoptysis Bevacizumab 5
Hypersensitivity pneumonitis Cetuximab
Fludarabine 49
MTX
Paclitaxel (Cremophor-EL)
Vinblastine
Interstitial pneumonitis Bleomycin
Carmustine
Cetuximab
Chlorambucil
Cyclophosphamide
Dactinomycin 38
Docetaxel
Erlotinib 6
Etoposide
Gefitinib 97
Gemcitabine
Gemtuzumab 98
Irinotecan 32
Lapatinib 74
Mitomycin C
Mitoxantrone 69
MTX 11
Paclitaxel
Panitumumab
Procarbazine 42
Topotecan 52
Vinorelbine 12
Noncardiogenic pulmonary edema Cytarabine
Dasatinib (volume retention)
Docetaxel
Erlotinib (volume retention) 6
Gemcitabine
Gemtuzumab 98
Imatinib (volume retention) 30
Pleural effusions Dasatinib 39
Docetaxel
Imatinib 30
MTX
Palcitaxel
Procarbazine 42
Pulmonary arterial hypertension Dasatinib 39
Pulmonary fibrosis Azathioprine
Bleomycin
Busulfan
Carmustine 31
Chlorambucil
Cyclophosphamide
Erlotinib
Fludarabine
Gefitinib
Ifosfamide
Lomustine
Melphalan
Mercaptopurine
Mitomycin C
MTX
Oxaliplatin
Panitumumab
Procarbazine
Clinical evaluation

Hypersensitivity pneumonitis typically manifests with bronchospasm and may entail other hypersensitivity symptoms, such as urticaria. Interstitial pneumonitis and pulmonary fibrosis are both associated with progressively worsening dyspnea and cough. Low-grade fever is common in patients with interstitial pneumonitis and may confuse the clinical picture in immunocompromised patients. The presence of hypoxia depends on the degree of pulmonary involvement. Pulmonary embolism (PE) and infection may present similarly and must be considered in the differential diagnosis of oncological patients with respiratory complaints.

Diagnostic evaluation

The following diagnostics are recommended for the assessment of chemotherapy-induced pulmonary toxicity:

  • CXR
    • Interstitial pneumonitis: interstitial and alveolar infiltrates
    • Pulmonary fibrosis: initial lack of radiographic findings; bibasilar interstitial markings, ground-glass reticular pattern
  • CT chest: may be more sensitive in early detection of disease; protocol for evaluation of PE when diagnosis is entertained
  • Pulmonary function tests: typically demonstrate restrictive pattern with decreased lung volumes in pulmonary fibrosis
  • Bronchoscopy and biopsy: may be necessary for definitive diagnosis and exclusion of underlying infection or metastatic disease; emergent if patients present with hemoptysis
Management

The mainstay of management is the removal of the offending agent, institution of steroid therapy, and supportive care. Patients who present with cough, dyspnea, fever, and evidence of hypoxia following chemotherapy are at risk for the development of acute respiratory distress syndrome (ARDS). Empiric antibiotics with pulmonary coverage should be initiated in immunocompromised patients with cough, hypoxia, dyspnea, and fever. Although most cases of hypersensitivity and interstitial pneumonitis respond to steroid therapy, pulmonary fibrosis typically has a protracted course and poor response to conventional treatment. Although oxygen is considered a risk factor for worsening bleomycin-associated pulmonary toxicity, it should be administered during emergency management of patients with hypoxia. In most other circumstances, however, oxygen therapy is helpful.

Gastrointestinal Emergencies

Mucositis

Mucositis refers to inflammation of the oral mucosa. The extension of mucositis into the oral tissues, such as lips, teeth, and periodontal tissues, is referred to as stomatitis. Inflammation may extend the length of the gastrointestinal (GI) tract, manifesting as esophagitis, gastritis, enteritis, colitis, and proctitis. Mucositis is often seen following therapy with chemotherapeutic agents that affect the rapidly dividing gastrointestinal epithelium. The pathophysiology of mucositis entails injury to the mucosal barrier by reactive oxygen species (ROS). 101 Mucositis causes significant pain, impedes adequate nutrition and healing, impairs patients’ quality of life. Ulcerations may serve as a nidus for infection in an immunocompromised patient.

Oral mucositis is frequently caused by MTX, dactinomycin, 5-FU, vincristine, and vinblastine. Table 7 contains a comprehensive list of agents associated with oral mucositis.101 and 102 If patients are taking MTX, the appearance of mucositis should prompt an evaluation for MTX toxicity (see MTX section later). Table 7 contains the a comprehensive list of agents that cause mucositis. Esophageal mucositis is caused by MTX, 5-FU, paclitaxel, and docetaxel. Mucositis of the small intestine is seen following therapy with MTX, bleomycin, and cyclophosphamide. Irinotecan is a unique chemotherapeutic agent that predisposes to colonic mucositis.

Table 7 Chemotherapeutic agents associated with oral mucositis

Class Agents
Alkylating agents Carboplatin

Chlorambucil

Cisplatin

Cyclophosphamide

Dacarbazine

Lomustine

Mechlorethamine

Melphalan
Antimetabolites Capecitabine

Cytarabine

Fludarabine

5-FU 51

Gemcitabine

Mercaptopurine

MTX

Pentostatin

Thioguanine
Antibiotics Dactinomycin

Daunorubicin

Doxorubicin

Epirubicin

Idarubicin

Mitomycin C
Antimitotic agents Docetaxel

Paclitaxel
Topoisomerase inhibitors Etoposide
Tyrosine kinase inhibitors Dasatinib

Sorafenib

Sunitinib
Nausea and vomiting

Chemotherapy-induced nausea and vomiting (CINV) is common and may lead to malnutrition, significant volume depletion, and may affect adherence to the chemotherapy regimen. Simulation of serotonergic receptors (5-HT3) of the chemoreceptor trigger zone (CTZ) in area postrema in the fourth cerebral ventricle is the primary mechanism for nausea.102 and 103 Other mechanisms included modulation of dopaminergic receptors in the CTZ and stimulation of the vomiting center in the reticular formation. In addition to vagal and cerebral cortical input, vomiting center is regulated by the interaction of substance P with a neurokinin-1 (NK-1) receptor. Table 8 lists chemotherapeutic agents with high and moderate emetogenic potential. 104

Table 8 CINV high and moderate emetogenicity agents

Emetogenicity Drug
High (>90%) Carmustine

Cisplatin 15

Cyclophosphamide (>1500 mg/m2)

Dacarbazine 36

Dactinomycin

Mechlorethamine

Streptozotocin 44

Temozolomide 46
Moderate (30%–90%) Carboplatin

Cyclophosphamide (<1500 mg/m2)

Cytarabine (>1 g/m2)

Daunorubicin

Doxorubicin

Epirubicin

Idarubicin

Ifosfamide

Irinotecan

Methotrexate

Oxaliplatin
Diarrhea

Diarrhea is a frequent adverse effect of chemotherapy. Irinotecan and 5-FU induced diarrhea is associated with significant morbidity and mortality.32, 51, 105, and 106 The pathophysiology of chemotherapy-induced diarrhea is not well understood and is likely multifactorial. Bloody diarrhea may be an extension of mucositis seen with high doses of 5-FU, and has a high mortality rate. 102 Concomitant neutropenia may contribute to the risk for enteric sepsis. Cytotoxic damage to the intestinal epithelium may lead to increased permeability and translocation of gut bacteria. 105

Constipation

Severe constipation may be precipitated by opioid therapy for management of cancer-related pain.

GI hemorrhage and perforation

Gastrointestinal hemorrhage is potential complications of bevacizumab, dasatinib, rituximab, erlotinib, imatinib, and sorafenib therapy.5, 6, 17, 30, 39, and 68 GI perforation has been described with bevacizumab, rituximab, erlotinib, imatinib, and sorafenib therapy.5, 6, 17, 30, and 68

Pancreatitis

L-asparaginase therapy is uniquely associated with hemorrhagic pancreatitis. 7

Liver injury

Chemotherapy-induced hepatotoxicity is fortunately uncommon. However, it may alter metabolism of many drugs metabolized by the P450 hepatic microsomal system and evolve into hepatic failure. Mechanisms of injury are thought to be idiosyncratic and immunologic. 107 Table 9 provides a comprehensive list of chemotherapeutic hepatotoxins. 107

Table 9 Chemotherapeutic hepatic toxins

Toxicity Drug
Biliary stricture Fluorodeoxyuridine (5-FU metabolite, intra-arterial)
Cholestasis Cisplatin

Gemcitabine

Mercaptopurine
Granulomatous hepatitis Procarbazine
Hepatic cirrhosis MTX (chronic low dose)
Hepatic fibrosis MTX (chronic low dose)
Hepatic necrosis Dacarbazine 36

Mercaptopurine 37

Plicamycin

Thioguanine 50
Hepatocellular injury l-asparaginase 7

Busulfan 20

Carboplatin

Capecitabine

Carmustine

Chlorambucil

Cisplatin

Cytarabine

Dactinomycin

Docetaxel 108

Erlotinib 6

Etoposide

5-FU (IV)

Fluorodeoxyuridine (5-FU metabolite, intra-arterial)

Gefitinib 97

Gemcitabine 109

Imatinib 30

Irinotecan

Lapatinib 74

Lomustine

Melphalan

Mercaptopurine

MTX 11

Oxaliplatin

Paclitaxel

Plicamycin 144

Procarbazine 42

Sorafenib 68

Streptozotocin 44

Sunitinib 19

Tamoxifen

Thioguanine

Vinorelbine 12
Hepatorenal syndrome Erlotinib 6
Sclerosing cholangitis Fluorodeoxyuridine (5-FU metabolite, intra-arterial)
Venoocclusive disease Dacarbazine 36

Dactinomycin 38

Gemtuzumab 98

Melphalan 35

Thioguanine 50
Clinical evaluation

Although several tools are available for grading oral mucositis by the National Cancer Institute Common Toxicity Criteria and the World Health Organization, the severity depends on the presence of pain and the ability to tolerate oral nutrition. Ulcerations are typically present on the oral mucosa and may be painless or painful, and associated with or without erythema and edema. Severe edema may lead to airway compromise.

Esophagitis, gastritis, colitis, and proctitis typically present with pain in the affected region. Dysphagia and retrosternal pain are typical symptoms of esophagitis. Abdominal pain, nausea, vomiting, and diarrhea may be seen with gastritis, enteritis, and colitis.

The assessment of the frequency of emesis, ability to tolerate oral intake, and presence of blood are important in the evaluation of CINV. Although hematemesis is not an expected clinical finding of CINV, it may be suggestive of mucositis or an esophageal tear during forceful emesis. It is challenging to discern an infectious versus a drug-induced cause of diarrhea in immunocompromised patients. The severity of diarrhea depends on volume depletion, presence of blood, abdominal pain, fever, decrease in urine output, and change in mental status as a result of profound dehydration.

Constipation may be mild or severe. Patients who present to the emergency department for the management of opioid-induced constipation may have less than three bowel movements per week, sensation of incomplete evacuation, abdominal discomfort/pain, bloating, nausea, and emesis. Small-bowel obstruction should be considered in patients with risk factors, such as abdominal cancer, prior surgeries, and/or ill appearance.

GI bleed may be painless or painful. Significant blood loss may manifest with generalized weakness and signs of end-organ ischemia caused by a lack of oxygen delivery. Clinical examination may demonstrate abdominal pain and signs of peritonitis in gastrointestinal perforation.

Epigastric abdominal pain is a common clnical finding in pancreatitis. Pain may radiate to the back and may be associated with nausea and vomiting. Severe pancreatitis may lead to significant electrolyte abnormalities.

Clinical signs and symptoms of hepatic toxicity are typically a late finding unless routinely monitored with laboratory analyses. Nausea, vomiting, abdominal pain, ascites, jaundice, and peripheral edema may be signs of liver injury. Failure of coagulation factor synthesis may lead to bleeding, prolonged PT/INR, and thrombocytopenia with petechiae, ecchymosis, and/or purpura. Hepatic encephalopathy is a late finding and typically manifests with lethargy, confusion, and/or asterixis on physical examination.

Diagnostic evaluation

The following laboratory and diagnostic tests are suggested for the assessment of chemotherapy-induced GI conditions:

  • Serum electrolytes
  • CBC: evaluate for presence of infection or in the setting of acute blood loss
  • LFTs: exclusion of biliary pathology
  • PT/INR, PTT: evaluation of synthetic function
  • Plain radiographs (including chest imaging): may be helpful in assessment of intraperitoneal air
  • CT abdomen/pelvis: may be considered if suspicion for infectious enteritis/colitis or perforation not seen on plain radiograph
  • Endoscopy or colonoscopy: establishment of diagnosis of esophageal/enteric/colonic mucositis
Management

Emergency department management of oral mucositis entails the assessment of the airway. In patients without evidence of airway compromise, outpatient management centers on good oral hygiene and avoidance of oral irritants. Topical viscous lidocaine and oral and IV opioids may be provided for pain relief in the emergency department. Although there are no specific recommendations, caution is advisable in prescribing outpatient viscous lidocaine and benzocaine. Absorption may be enhanced through denuded skin, with the potential for systemic toxicity. Although outside the scope of emergency medicine management, mucosal coating agents and keratinocyte growth factor-1 agents have been used during inpatient and outpatient management of mucositis.110, 111, 112, 113, and 114

Emergency department management of esophagitis and gastritis are symptomatic. Proton pump inhibitors or H2 blockers are recommended.110, 111, and 115 The management of enteritis and colitis is supportive. It is imperative to assess for presence of infectious enteritis/colitis in immunocompromised patient.

Supportive care is the mainstay of therapy for CINV. Patients are often volume depleted and require volume resuscitation with IV crystalloid. Antiemetics are critical in controlling nausea and vomiting. Ondansetron, a first-generation 5-HT3 antagonist, is first-line therapy in the management of CINV. 116 Dexamethasone should be considered in patients with persistent emesis. Benzodiazepines, olanzapine, and metoclopramide have been used in the treatment of intractable emesis. 117 NK-1 antagonists, such as aprepitant, and fosaprepitant are used in both outpatient and inpatient settings and may be considered in patients with intractable emesis following the consultation with oncologist.

The treatment of chemotherapy-induced diarrhea is often supportive and entails volume and electrolyte repletion. Antibiotics may be warranted in patients with a concern for infectious diarrhea. Loperamide may be used with caution as a first-line therapy in patients with noninfectious chemotherapy-induced diarrhea. Reassessment within 24 to 48 hours is necessary for patients who are discharged to home with loperamide. Octreotide is advised as a second-line agent for severe and refractory diarrhea. 118

Methylnaltrexone should be considered for the management of opioid-induced constipation in patients with advanced cancer receiving palliative care with a prior insufficient response to laxative therapy. 119 It is approved by the FDA for this indication. Only one dose should be administered in the emergency department. It is typically dosed every other day, without exceeding one dose in a 24-hour period. Subcutaneous administration of 8 mg is recommended for patients weighing 38 to 62 kg. Subcutaneous administration of 12 mg is recommended for those patients who weigh between 62 and 114 kg. Subcutaneous administration of 0.15 mg/kg is suggested for those patients who weigh less than 38 kg or greater than 114 kg. A pharmacist should be consulted to verify the correct dose for patients weighing more than 114 kg.

Supportive care, observation, reversal of coagulopathy with blood products, and gastroenterology consultation is the mainstay of management in GI hemorrhage.

Clinical signs of peritonitis should prompt an emergent surgical consultation. GI perforation warrants surgical management.

Withdrawal of the offending agent and supportive care are the mainstays of therapy in patients with chemotherapy-induced hepatotoxicity. In cases of severe hepatotoxicity, transplant consultation should be considered.

Renal Emergencies

Renal injury may be broadly classified into prerenal, intrinsic renal, and postrenal. Prerenal injury typically results from hypovolemia. Direct renal injury, precipitation of drugs or metabolites in the renal tubules, ischemia, glomerular disease, and damage to the renal vasculature may lead to intrinsic nephrotoxicity. Postrenal injury results from mechanical outflow obstruction. Chemotherapy may affect the tubules, renal parenchyma, and renal vasculature. Cisplatin is a well-recognized chemotherapeutic nephrotoxin. Drugs that affect the proximal tubule may result in Fanconi syndrome, which is characterized by renal wasting of phosphate, glucose, potassium, and bicarbonate.120 and 121 Volume depletion and acidic urine predispose to the precipitation of MTX and metabolites into the renal tubules. HUS is a manifestation of thrombotic angiopathy, manifests with the constellation of microangiopathic hemolytic anemia, thrombocytopenia, fever, and renal injury, which is likely caused via fibrin deposition of afferent arterioles and glomeruli.122, 123, and 124 A list of nephrotoxins with the respective toxicity are outlined in Table 10 .120, 121, and 122

Table 10 Chemotherapeutic nephrotoxins

Toxicity Drug
Acute renal insufficiency Carboplatin 14

Erlotinib 6

Irinotecan 32

Nitrosoureas (carmustine, lomustine, streptozotocin)

Oxaliplatin

Pentostatin
Acute tubular necrosis Cisplatin

Ifosfamide

Imatinib
Chronic kidney disease Cisplatin

Ifosfamide

Nitrosoureas (carmustine, lomustine, streptozotocin)
Crystal nephropathy MTX
HUS123 and 124 Bleomycin

Cisplatin

Gemcitabine

Mitomycin C
Renal tubular acidosis Streptozotocin 44
Tubulopathy Cisplatin 15

Ifosfamide (chloroacetaldehyde metabolite)
Clinical evaluation

Nephrotoxicity may manifest with decreased urine production as well as nausea and vomiting in cases of uremia. Electrolyte abnormalities may present with alteration of consciousness, effects on cardiac conduction, myopathy, or weakness.

Diagnostic evaluation

The following laboratory studies are suggested for the evaluation of chemotherapy-induced nephrotoxicity:

  • Serum electrolytes
  • Urinalysis: assessment of proteinuria, glucosuria
  • Urine sodium, potassium, phosphorus, uric acid, and glucose: may be seen in Fanconi syndrome
  • CBC, LFTs, PT/PTT, LDH, and peripheral smear: evaluation of HUS (thrombocytopenia, hemolysis with anemia and indirect hyperbilirubinemia, elevated serum LDH, and schistocytes)
Management

Management of intrinsic renal damage is supportive. The decision to initiate hemodialysis should be discussed with the consulting nephrologist. The hematological emergencies section reviews HUS management. Precipitation of MTX in the renal tubules may be treated with urinary alkalinization (see the MTX section). Amifostine is an antidote that is used for the prevention of cisplatin-induced nephrotoxicity.

Antidotal considerations: Amifostine

Amifostine is approved by the FDA for the prevention of cisplatin-induced nephrotoxicity.82 and 83 Patients receiving cisplatin chemotherapy are pretreated with amifostine. 125 It is not part of the emergency department management of cisplatin-induced nephrotoxicity.

Genitourinary Emergencies

The most important complication of chemotherapy in the bladder is development of hemorrhagic cystitis. The acrolein metabolite of cyclophosphamide and ifosfamide is a causative agent.121, 122, and 126 Although several mechanisms have been proposed, acrolein promotes the generation of ROS, leading to oxidative cellular damage in uroepithelium. 126 Urinary retention may be seen during vincristine chemotherapy. 10

Clinical evaluation

Hematuria and urinary discomfort are typically present with hemorrhagic cystitis. Painful and palpable bladder distention may be evident with urinary retention.

Diagnostic evaluation

The following diagnostics are suggested for the evaluation of hemorrhagic cystitis:

  • Urinalysis with microscopic analysis: evaluation of hematuria
  • CBC: monitor for anemia in patients with gross hematuria
  • Urine culture
Management

Emergency department management for hemorrhagic cystitis is supportive. Foley insertion and bladder irrigation may be helpful in cases of obstructive hematuria and subsequent urinary retention. Mesna is an antidote used for the prevention of ifosfamide- and cyclophosphamide-induced hemorrhagic cystitis.

Antidotal considerations: Mesna (sodium 2-mercaptoethanesulfonate)

Mesna is approved by the FDA for the prevention of hemorrhagic cystitis in patients receiving ifosfamide or high-dose cyclophosphamide chemotherapy.82 and 83 It is available in both oral and IV formulations. Mesna binds the acrolein metabolite, preventing it from entering the uroepithelium. 126 Mesna coadministration is recommended in patients receiving high-dose cyclophosphamide to prevent urothelial toxicity.82 and 83 It is not part of the emergency department management of hemorrhagic cystitis.

Dermatologic Emergencies

Cutaneous reactions, such as alopecia, mucosal lesions, epidermal lesions, nail changes, and hypersensitivity reactions, are commonly seen following chemotherapy. This section focuses on drugs that cause erythema multiforme (EM), Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and hypersensitivity reactions that are pertinent to emergency medicine.

The following chemotherapeutic agents are associated with EM/SJS/TEN:

Both immune and nonimmune mechanisms have been implicated in hypersensitivity reactions. Most reactions occur within several minutes to several hours of drug administration. The following chemotherapeutic agents may cause anaphylaxis:

Paclitaxel and docetaxel are associated with non–immune-mediated anaphylactoid reactions. 129 Infusion reactions are characterized by hypotension, confusion, fever, chills, and wheezing. 94 They are commonly associated with bleomycin, alemtuzumab, ibritumomab, rituximab, panitumumab therapy.17, 27, and 130 Nonfatal infusion hypersensitivity reactions were reported with bevacizumab, cetuximab, gemtuzumab, tositumomab, trastuzumab, and teniposide.5, 48, 54, 73, 76, and 98

Clinical evaluation

EM typically presents as skin macules that develop into raised erythematous target lesions. EM minor lesions are limited to epidermis and are acral in distribution. EM major lesions involve one or more mucous membranes in addition to the epidermis, with epidermal detachment in less than 10% of the body surface area. SJS is a spectrum of EM with lesions extending into truncal and facial distribution, mucosal involvement, and epidermal detachment of 10% and 30% of the total body surface area. TEN is the most severe form, with diffuse lesions including both epidermis and mucosa, with epidermal detachment in more than 30% of the total body surface area. Clinical signs and symptoms of hypersensitivity range from urticaria to anaphylaxis. Hypoxia, pulmonary infiltrates, ARDS, myocardial infarction, dysrhythmia, and/or cardiogenic shock may be seen following severe infusion reactions.

Diagnostic evaluation

Laboratory studies and imaging are generally unhelpful in the diagnosis of hypersensitivity reaction, anaphylaxis, or EM/SJS/TEN. Dermatologic consultation for biopsy may be helpful, but is not typically a part of emergent management.

Management

The emergency department management of anaphylaxis involves discontinuation of the offending agent, treatment with histamine antagonists, and steroids. Epinephrine should be used in severe anaphylaxis with hemodynamic instability and/or airway compromise. SJS/TEN treatment necessitates immediate removal of the offending agent volume resuscitation, and aggressive wound care. Consultation with a burn center for potential transfer is warranted in cases of extensive epidermal detachment.

Extravasation Emergencies

Extravasation of chemotherapeutic agents may lead to skin irritation, devastating skin necrosis, and compartment syndrome. 131 Chemotherapeutic agents characterized as vesicants, such as anthracyclines, vinca alkaloids, and nitrogen mustard, cause an inflammatory response and have the potential to cause severe tissue damage. 129 Chemotherapeutic irritants, including platinoids, taxanes, anthracyclines, dactinomycin, mitomycin C, mitoxantrone, and topoisomerase inhibitors, cause skin irritation, swelling, and pain. The physical examination may demonstrate local skin erythema, edema, tenderness to palpation, blistering, ulceration, and tissue necrosis. 129

The treatment involves immediate cessation of the infusion. The IV cannula should be left in place, with aspiration of the extravasated drug attempted rapidly through the cannula. Intermittent cooling may be effective in reducing pain and irritation from the irritant compounds. Direct ice compress application for 6 to 12 hours may be helpful following mechlorethamine extravasation. 132 Given the potential for severe toxicity and skin necrosis, extravasation of vesicant chemotherapeutic agents should be addressed rapidly.

Antidotes are available for the treatment of anthracyclines, vinca alkaloid, and nitrogen mustard extravasation. Intravenous dexrazoxane should be started within 6 hours of anthracycline extravasation. It is administered once daily over 1 to 2 hours for 3 consecutive days via large-bore IV opposite the affected extremity. A dose of 1000 mg/m2 (max 2000 mg) IV should be administered within 6 hours of extravasation, followed by a repeat 1000 mg/m2 IV (max 2000 mg) on the second day and a third dose of 500 mg/m2 IV on the third day. Dose adjustments may be necessary is patients with renal impairment. 133 Hyaluronidase is locally injected at the site of vinca alkaloid extravasation, along with application of warm compresses, to promote diffusion of the agent. The recommended initial total dosing is 150 units subcutaneously with 25-ga or 27-ga needle divided in 5 different injections around the extravasation site. A local subcutaneous injection of one-sixth molar solution of sodium thiosulfate may be used for nitrogen mustard (mechlorethamine) extravasation. Please see the mechlorethamine package insert for sodium thiosulfate dilution instructions to achieve an appropriate concentration.

Patients who have sustained anthracycline, vinca alkaloid, and mechlorethamine extravasation injuries should be observed for a minimal period of 24 hours or longer depending on the type of extravasation and symptoms.

Patients with pain, erythema, or swelling at the site of an indwelling thoracic access port should be evaluated for infection or extravasation of chemotherapeutics caused by the formation of a fibrous sheath encapsulating the line. This condition is diagnosed by the inability to draw back on the line but relative ease in flushing the line. If this occurs, imaging of the chest with CT is warranted.

Methotrexate

MTX is widely used for treatment of rheumatologic disease, trophoblastic disease, malignancy, and as a part of an immunosuppressant regimen in organ transplantation. It is administered for therapeutic abortion. MTX is a structural analogue of folic acid. It prevents DNA and RNA synthesis by inhibiting dihydrofolate reductase (DHFR) and thymidylate synthetase, and inhibits de novo purine synthesis via the inhibition of 5-aminoimidazole-4-carboxamide ribonucleotide transformylase. 134 MTX toxicity depends on the dose, duration of administration, and renal clearance. Toxicity from MTX accumulation may be seen with impaired renal function or renal toxic medications. MTX forms crystals in the renal tubule acidic milieu. 135 Toxicity may be prolonged in patients with anasarca, pleural effusions, and ascites because of the prolonged redistribution from the third space compartment to the plasma during elimination.

Clinical evaluation

Clinical MTX toxicity may be challenging to recognize, especially in patients without a history of overt overdose. Nausea and vomiting may be seen within 2 to 4 hours of high-dose MTX (1000 mg/m2 or more). Mucositis, stomatitis, and diarrhea may manifest within 1 to 2 weeks. Bone marrow toxicity and pancytopenia typically occur within the first 2 weeks. High-dose MTX may also lead to nephrotoxicity, further decreasing clearance and potentiating toxicity. Neurologic manifestations, such as acute and chronic leukoencephalopathy, paresis a transient acute neurologic syndrome, and seizures, may be noted following high-dose IV administration. 136

Diagnostic evaluation

All patients undergoing therapeutic abortion with MTX should have an evaluation of renal function. The following laboratory and diagnostic studies may be helpful in evaluating patients with MTX toxicity:

  • CBC with differential: assessment of bone marrow suppression
  • Serum electrolytes
  • LFTs: assessment of hepatotoxicity
  • MTX concentration
  • CT brain without contrast: workup of altered mental status
  • LP: consider as a part of infectious workup in immunocompromised patients with altered mental status
  • MRI brain: more sensitive in assessment of encephalopathy, nonemergent
Management

The treatment involves the cessation of MTX exposure and the administration of activated charcoal in cases of acute oral ingestion. IV hydration and urine alkalinization are important in preventing precipitation of MTX and its metabolites in the renal tubules. Sodium bicarbonate 150 mEq is added to 1 L of D5W and infused at 1.5 to 2.0 times the maintenance to alkalinize urine (pH 7–8). Serum potassium monitoring with sufficient repletion is important given intracellular potassium shifts seen with alkalinization. Hypokalemia leads to aciduria in exchange for potassium reabsorption in the tubules. Monitor serum pH closely to prevent a pH greater than 7.55.

Bone marrow suppression may be treated with GM-CSF. Leucovorin rescue should be initiated immediately on recognition of toxicity. Carboxypeptidase G2 should be considered in patients with acute MTX overdose or significant toxicity caused by decreased renal clearance.

Antidotal considerations: Leucovorin (folinic acid)

Leucovorin is a reduced, active form of folic acid used to treat acute and chronic MTX toxicity. Unlike folic acid, it does not require DHFR for conversion for activation. 137 The administration of leucovorin bypasses DHFR inhibition and promotes purine nucleotide and thymidylate synthesis. Leucovorin dosing should ideally match MTX serum concentration. 135 MTX concentrations greater than 1 × 10−8 mol/L (0.01 μmol/L) are associated with inhibition of DNA synthesis. 137 Because laboratory determinations of MTX concentrations may be delayed, an empiric dose of leucovorin 100 mg/m2 IV over 15 to 30 minutes should be administered on recognition of MTX overdose or chronic toxicity. 138 It should be repeated every 3 to 6 hours. The administration rates should not exceed 160 mg/min because of leucovorin’s calcium content. 139 Benzyl alcohol-free preparations are used for neonates. Treatment should be continued for at least 3 days. The duration of MTX toxicity depends on the dose and renal function. Longer leucovorin dosing may be required in patients with ascites, pleural effusions, and bone marrow toxicity because the half-life of MTX may not accurately reflect intracellular concentrations. A nomogram may be used as a guide for treatment. 140 Ideally, treatment should be continued until the serum MTX concentration is less than 1 × 10−8 mol/L in the absence of bone marrow suppression. Adverse effects are uncommon and limited to parenteral administration. Allergic or anaphylactoid reactions and rare seizures 141 have been reported. Hypercalcemia may be noted with high doses and prolonged administration. Leucovorin administration may enhance the toxicity of 5-FU. Leucovorin should never be administered IT.

Antidotal considerations: Carboxypeptidase G2 (glucarpidase)

Carboxypeptidase G2, a recombinant enzyme, inactivates folate and MTX by cleaving the C-terminal glutamate residues. 142 It cleaves MTX into 4-deoxy-4-amino-N10-methylpteroid acid (DAMPA) and glutamate moieties. Carboxypeptidase G2 received FDA approval in 2012 for the IV treatment of MTX toxicity in patients with a serum MTX concentration of greater than 1 μmol/L and the presence of impaired renal function. Aggressive therapy with leucovorin should be initiated before the consideration of carboxypeptidase G2. The serum MTX concentration should be obtained before carboxypeptidase G2 administration. The DAMPA metabolite interferes with MTX immunoassay and overestimates the serum MTX concentration for at least 48 hours. A single dose of 50 U/kg is administered over 5 minutes. 143 Leucovorin should not be administered 2 hours before or after carboxypeptidase G2 therapy, given the risk of leucovorin inactivation. Adverse events are rare following IV administration. Paresthesias, flushing, nausea, and vomiting occur most commonly.

Unlike leucovorin, carboxypeptidase G2 may be provided IT following IT MTX toxicity (off label); 2000 U is administered IT over 5 minutes (see also the IT section). 62

Summary

The recognition of the toxicity of chemotherapeutic agents is challenging. The use of combination therapy, the potential of a single agent to affect multiple body systems, and the resemblance of clinical symptoms to both cancer and non–cancer-related illness present a diagnostic dilemma. The emergency department management should focus on the evaluation of infectious cause of symptoms and other potential emergent conditions. IT emergencies should be immediately addressed because recognition and time to intervention are the most important factors in the prevention of significant neurologic morbidity and death. There are few specific antidotes that would change the course of illness in the emergency department setting: leucovorin for MTX overdose, carboxypeptidase G2 for the management of IT MTX overdose, and dexrazoxane/hyaluronidase/sodium thiosulfate for the management of extravasation injuries. The Poison Control Center (1-800-POISONS) should be notified following overdose or unintentional erroneous route of administration. The management of most chemotherapy-induced adverse effects is supportive.

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Footnotes

a Weill Cornell Medical College, New York Presbyterian Hospital, 525 East 68th Street, New York, NY 10065, USA

b Department of Emergency Medicine, New York City Poison Control Center, Bellevue Hospital Center, NYU School of Medicine, 462 First Avenue, Room A-345A, New York, NY 10016, USA

Corresponding author.

Disclosure: The authors have no financial relationships to disclose.


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