DESCRIPTION

• Antineoplastic agents are used in the treatment of various malignancies.
• Methotrexate also is used in the treatment of rheumatologic conditions.

FORMS AND USES

Antineoplastic agents include asparaginase (Elspar), bleomycin (Blenoxane), carboplatin (Paraplatin), carmustine (BCNU, BiCNU), chlorambucil (Leukeran), cisplatin (Platinol), cyclophosphamide (Cytoxan, NEOSAR), cytarabine (Cytosar U, Cytogam), dactinomycin (Cosmegen), daunorubicin citrate (DaunoXome), daunorubicin hydrochloride (Cerubidine), doxorubicin (Adriamycin, Rubex), ethylenimine, etoposide (VePesid), fluorouracil (Efudex cream and solution, Fluoroplex cream and solution, Fluothane), ifosfamide (Ifex), lomustine (CCNU, CeeNU), mechlorethamine (Mustargen), melphalan (Alkeran), methotrexate (Rheumatrex), mitomycin (mitomycin C, Mutamycin), nitrosureas, paclitaxel (Taxol), procarbazine (Matulane), streptozocin (Zanosar), vinblastine (Velban, Velsar), and vincristine (Oncovin, Vincasar).

PATHOPHYSIOLOGY

• Methotrexate. A structural analog of folate, it inhibits formation of nucleotides necessary for DNA and RNA synthesis.
• Pyrimidine analogs
  • Cytarabine is a deoxycytidine analog, inhibiting DNA polymerase.
  • 5-Fluorouracil (5-FU) is a uracil analog, blocking thymidylate synthetase and incorporation into RNA and DNA.
• Vinca alkaloids (vincristine and vinblastine) bind tubulin and prevent polymerization into microtubules, interfering in cell replication.
• Etoposide affects DNA topoisomerase, causing DNA strand disruption.
• Taxol binds tubulin, preventing cell replication.
• Antibiotics (dactinomycin, daunorubicin, doxorubicin, bleomycin, and mitomycin) promote breakage and inhibit repair of DNA.
• Asparaginase depletes asparagine pools and inhibits protein synthesis.
• Carboplatin and cisplatin promote DNA crosslinking.
• Alkylating agents [nitrogen mustards (mechlorethamine, cyclophosphamide, ifosfamide, melphalan, and chlorambucil), ethylenimine, alkyl sulfonates, nitrosureas, and triazenes] form reactive intermediates that bind to nucleophilic moieties in DNA.

EPIDEMIOLOGY

• Overdose is uncommon, although adverse effects from therapeutic use are common.
• Toxic effects following exposure are typically moderate.
• Death occurs in patients with severe overdose or those receiving multiple agents with similar toxicities.
• Children are at greater risk for cardiotoxicity from doxorubicin and dactinomycin.
• The elderly are at greater risk for neurotoxicity from cytarabine, carboplatin, and mechlorethamine.

CAUSES

• Poisoning is usually an accidental iatrogenic incident.
• Child neglect or abuse should be considered if the patient is less than 1 year of age, suicide attempt if the patient is over 6 years of age.

RISK FACTORS

• Patients with underlying disease may be at increased risk.
  • Cardiac (dactinomycin, doxorubicin, 5-FU, cisplatin, vinca alkaloids)
  • Renal (cisplatin, streptozocin, nitrosureas, methotrexate, and mithramycin)
  • Pulmonary (bleomycin)
  • Neurologic (taxol, methotrexate, vincristine)
• Patients over 50 years of age or with renal insufficiency are at increased risk of toxicity from cytarabine.
• Risk factors for pulmonary fibrosis with bleomycin include a cumulative dose greater than 450 mg, a single dose greater than 25 mg/m², thoracic radiation, or oxygen administration.
• Mediastinal radiation, preexisting cardiac disease, concomitant use of cyclophosphamide, and use in the pediatric group increase risk of toxicity from doxorubicin and dactinomycin.

DRUG AND DISEASE INTERACTIONS

• Vincristine. Isoniazid and L-asparaginase may enhance neurotoxicity.
• Methotrexate. Nonsteroidal antiinflammatory drugs may increase the incidence of nephrotoxicity.

PREGNANCY AND LACTATION

• Most antineoplastics are known teratogens.
• Streptozocin, asparaginase, and dactinomycin. US FDA Pregnancy Category C. The drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in animals or women.
• Antineoplastics. US FDA Pregnancy Category D. Positive evidence of human fetal risk exists, but benefits in certain situations (e.g., life-threatening situations or serious diseases) may make use of the drug acceptable despite its risks.
• Fluorouracil and methotrexate if used for rheumatoid arthritis or psoriasis. US FDA Pregnancy Category X. Studies in animals or humans have demonstrated fetal abnormalities or there is evidence of fetal risk based on human experience, or both, and the risk clearly outweighs any possible benefit.

Section Outline:

• DESCRIPTION
• FORMS AND USES
• PATHOPHYSIOLOGY
• EPIDEMIOLOGY
• CAUSES
• RISK FACTORS
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

DIFFERENTIAL DIAGNOSIS

Toxicologic causes of vomiting and diarrhea followed by bone marrow depression and possibly neurotoxicity include podophyllum, colchicine, arsenic, other heavy metal ingestion, and ricin.

SIGNS AND SYMPTOMS

Asparaginase

Hypersensitivity reactions (5%-20%), coagulopathy, pancreatitis, and decreased insulin production.

Bleomycin

Pulmonary fibrosis occurs in 5% of patients.

Carboplatin

• Nausea, vomiting and diarrhea are common.
• Myelosuppression is a dose-limiting effect.
• Hepatotoxicity occurs at high doses (greater than 1,500-2,000 mg/m²). Fatal hepatotoxicity has occurred.
• Tinnitus and hearing loss occur at high doses.
• Peripheral neuropathy is more common in patients over 65 years of age.
• Renal insufficiency is associated with high dose (greater than 800-1,600 mg/m²) and preexisting renal impairment.
• Hypomagnesemia, hypokalemia, hyponatremia, hypocalcemia, and anaphylaxis also have been reported.

Chlorambucil

Nausea, vomiting, bone marrow depression, seizures, ataxia, coma, irritability, and renal failure (rarely) have occurred.

Cisplatin

• Adverse effects include renal insufficiency (dose-limiting effect), tinnitus, high-frequency hearing loss, hypocalcemia, hypomagnesemia, hypophosphatemia, hypokalemia, anaphylactoid reactions, ataxia, sensory peripheral neuropathy, seizures, autonomic dysfunction, extrapyramidal effects, nausea, vomiting, and diarrhea, and increased liver enzyme levels.
• Neurotoxic effects are most often associated with a cumulative dose of 300 mg/m².
• Overdose effects include nausea, vomiting, diarrhea, hearing loss, respiratory failure, confusion, renal failure, increased liver enzyme levels, neurotoxicity, and myelosuppression.

Cyclophosphamide and Ifosfamide

• Hemorrhagic cystitis (5%-10%) is the most common adverse effect.
• Renal insufficiency, nausea, vomiting, diarrhea, stomatitis, syndrome of inappropriate secretion of antidiuretic hormone, hyperglycemia, and bone marrow suppression (leukopenia nadir at 7-12 days, thrombocytopenia at 10-15 days) may occur.
• High-dose ifosfamide may cause metabolic acidosis, mental status changes, cerebellar dysfunction, seizures, coma, and polyneuropathy.
• High-dose cyclophosphamide may cause cardiotoxicity, including decreased ECG voltage, and increased left ventricular mass at doses greater than 2.5 g/m²/day.

Cytarabine

Cerebellar dysfunction, personality changes, parkinsonism, sensory peripheral neuropathy, and coma may develop.

Doxorubicin and Dactinomycin

• Overdose causes nausea, vomiting, diarrhea, stomatitis, and myelosuppression.
• Acute cardiotoxicity usually consists of ST changes and decreased ejection fraction and resolves within 24 hours.
• Acute myocarditis and pericarditis with conduction abnormalities are less common.
• Chronic cardiotoxicity is characterized by decreased ejection fraction and congestive heart failure and is related to the cumulative dose (greater than 20% incidence with total dose greater than 550 mg/m² doxorubicin or 950 mg/m² dactinomycin).
• Extravasation may cause significant local tissue destruction, swelling, pain, burning sensation, ulceration, and necrosis.

Etoposide

• Nausea, vomiting, and diarrhea are common.
• Myelosuppression is dose limiting; granulocyte nadir at 7 to 14 days, platelets at 9 to 16 days.
• Hepatic injury may develop at high doses (600-2,400 mg/m²).
• Hypotension occurs with rapid intravenous infusion.
• Hypersensitivity reactions (bronchospasm and hypotension) and peripheral neuropathy also may occur.

Fluorouracil

• Vomiting, diarrhea, and lower gastrointestinal bleeding may occur.
• Lethargy, coma, ataxia, and upper motor neuron lesions with high intravenous doses or carotid arterial infusions may occur.
• ECG changes, myocardial ischemia, dilated cardiomyopathy, and cardiogenic shock may occur, usually in patients with preexisting cardiac disease.
• Bone marrow depression is dose limiting; granulocyte nadir occurs at 9 to 14 days, platelet nadir at 7 to 14 days.
• Extravasation causes local tissue irritation.

Mechlorethamine

• Eyes are irritated with splash contact.
• Ototoxicity, neurotoxicity (more common at high dose and older patients), CNS depression, nausea, vomiting, and bone marrow depression can occur.

Methotrexate

• Nausea and vomiting may begin within hours; mucositis, stomatitis, and diarrhea often develop within 7 to 14 days.
• Bone marrow suppression develops in 6 to 9 days and may last 2 weeks.
• Hepatic injury is associated with high or chronic dosing and usually resolves within 2 weeks of discontinuation.
• Acute tubular necrosis is reported with high intravenous doses.
• Increases in creatinine are associated with methotrexate levels greater than 4.5 µg/dl.
• Pulmonary effects may include infiltrates, dyspnea, cough, and tachypnea.
• Seizures, hemiparesis, behavioral changes, and reflex abnormalities have been associated with high intravenous doses.
• Intrathecal administration has been associated with chemical arachnoiditis (headache, neck stiffness, dizziness, fever, CSF pleocytosis), increased intracranial pressure and motor abnormalities (paresis, paraplegia, cranial nerve palsies, and ataxia).
• Necrotizing leukoencephalopathy includes cognitive disorders that can be delayed and is associated with intrathecal therapy or high intravenous doses given concurrently with cranial radiation.

Nitrosureas (Carmustine and Lomustine)

• Delayed bone marrow suppression (platelet nadir at 4 weeks, leukocytes at 5 weeks) may occur.
• Hypotension and tachycardia may occur with high-dose carmustine.
• Pulmonary fibrosis, CNS depression, nausea, vomiting, increased liver enzyme levels, and renal insufficiency can occur.
• Extravasation may cause serious local tissue destruction.

Paclitaxel (Taxol)

• Neutropenia is the dose-limiting effect.
• Other adverse effects include hypotension, dysrhythmias, congestive heart failure, headache, seizures, sensory neuropathy, coma, myalgias, pulmonary edema, anaphylaxis, autonomic neuropathy, mucositis, colonic perforation, increased liver function tests, renal insufficiency, optic neuritis, hypokalemia, nausea and vomiting, and ileus.
• Extravasation causes local tissue irritation.

Procarbazine

• A weak monoamine oxidase inhibitor, it may cause hypertension when administered with an indirect-acting sympathomimetic.
• Other effects include interstitial pneumonitis, paresthesia, neuropathy, hallucinations, seizures, coma, tremor, nausea, vomiting, diarrhea, and bone marrow suppression.

Vinblastine

• Myelosuppression is usually the dose-limiting effect; granulocyte nadir is at 7 to 14 days.
• Syndrome of inappropriate secretion of antidiuretic hormone, nausea, vomiting, myalgia, paresthesia, peripheral neuropathy, seizures and increased liver enzyme levels may occur.
• Extravasation may cause serious local tissue destruction.

Vincristine

• Symmetrical sensorimotor peripheral neuropathy (paresthesia, ataxia, decreased reflexes, and weakness) is generally the dose-limiting effect.
• Optic neuropathy, syndrome of inappropriate secretion of antidiuretic hormone, and bone marrow suppression also have been reported.
• In overdose, stomatitis, vomiting, diarrhea, fever, delirium, coma, seizures, and neuralgia may develop.
• Extravasation may cause significant local tissue destruction.

PROCEDURES AND LABORATORY TESTS

Essential Tests

• Complete blood count and platelet count. Myelosuppression is common at therapeutic doses of many antineoplastics; nadir counts usually develop after 7 to 14 days.
• Serum electrolytes, BUN, and creatinine tests are used to detect effects of prolonged vomiting and diarrhea. Nephrotoxicity may be caused by taxol, methotrexate, cyclophosphamide, cisplatin, and carboplatin.
• Ifosfamide may cause metabolic acidosis.

Recommended Tests

• Liver function tests (methotrexate, vinblastine, taxol, cisplatin, carboplatin, and etoposide). Hepatotoxicity may develop with therapeutic doses.
• ECG (doxorubicin, cyclophosphamide, dactinomycin, and fluorouracil). Cardiac toxicity may develop with therapeutic use.
• Methotrexate level is used to calculate an appropriate dose of leucovorin after methotrexate overdose.
• Urinalysis (cyclophosphamide and ifosfamide) is used to evaluate for hemorrhagic cystitis.
• Serum magnesium and phosphorus (carboplatin and cisplatin) are measured to detect hypomagnesemia and hypophosphatemia during therapeutic use.
• ECG, serum acetaminophen and aspirin levels are used in overdose setting to screen for occult ingestion.
• Audiometry may be useful after overdose of cisplatin and carboplatin, which cause hearing loss with therapeutic use.
• Electromyogram/nerve conduction velocity may be useful in patients with evidence of peripheral neuropathy after overdose of taxol, cisplatin, cytarabine, vincristine, vinblastine, carboplatin, etoposide, ifosfamide, and procarbazine.
• Echocardiography or radionuclide scan is used to detect doxorubicin cardiac toxicity.
• Chest radiograph may be useful after bleomycin overdose to detect pulmonary fibrosis.

Section Outline:

• DIFFERENTIAL DIAGNOSIS
• SIGNS AND SYMPTOMS
  • Asparaginase
  • Bleomycin
  • Carboplatin
  • Chlorambucil
  • Cisplatin
  • Cyclophosphamide and Ifosfamide
  • Cytarabine
  • Doxorubicin and Dactinomycin
  • Etoposide
  • Fluorouracil
  • Mechlorethamine
  • Methotrexate
  • Nitrosureas (Carmustine and Lomustine)
  • Paclitaxel (Taxol)
  • Procarbazine
  • Vinblastine
  • Vincristine
• PROCEDURES AND LABORATORY TESTS
  • Essential Tests
  • Recommended Tests

• Treatment should focus on supporting cardiovascular function, detecting myelosuppression, and treating anemia, bleeding, and infection.
• Dose and time of exposure should be determined for all substances involved.

DIRECTING PATIENT COURSE

The health-care professional should call the poison control center when:

• Severe effects are present.
• Toxic effects are not consistent with antineoplastic poisoning.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

The patient should be referred to a health-care facility when:

• Attempted suicide or homicide is possible.
• Patient or caregiver seems unreliable.
• Any toxic effects develop.
• Coingestant, drug interaction, or underlying disease presents an unusual problem.

Admission Considerations

Inpatient management is warranted for patients with severe thrombocytopenia, anemia, or neutropenia; cardiac toxicity, suspected neutropenic sepsis, renal insufficiency, hepatotoxicity, mental status changes, seizures, or methotrexate toxicity requiring leucovorin therapy.

DECONTAMINATION

Out of Hospital

If acute ingestion has occurred, emesis should be induced with ipecac within 1 hour of ingestion for alert pediatric or adult patients if health-care evaluation will be delayed.

In Hospital

• If acute ingestion has occurred, gastric lavage should be performed in pediatric (tube size 24-32 French) or adult (tube size 36-42 French) patients for large ingestion presenting within 1 hour of ingestion or if serious effects are present.
• One dose of activated charcoal (1-2 g/kg) should be administered without a cathartic if a substantial ingestion has occurred within the previous few hours.

ANTIDOTES

Folic acid (Leucovorin) is a specific antidote for methotrexate poisoning.

• Indications
  • Toxic methotrexate levels (1,000 µmol/L at 0 hours, 10 µmol/L at 24 hours, 0.5 µmol/L at 48 hours, or 0.05 µmol/L at 72 hours).
  • Leucovorin should be administered at lower levels in patients with renal insufficiency or delayed methotrexate elimination.
• Contraindications. None.
• Method of administration
  • Dose depends on levels, see nomogram or table in package insert.
  • Range is 10 to 1,000 mg/m² every 6 hours orally, intramuscularly, or intravenously.
• Potential adverse effects. Anaphylactoid reactions.

ADJUNCTIVE TREATMENT

Amifostine

• Indications
  • Protective against cisplatin-induced neurotoxicity and cyclophosphamide-induced myelosuppression
  • Not studied in patients with overdoses but may have some utility
• Contraindications. Known hypersensitivity.
• Method of administration. 910 mg/m² intravenous infusion over 15 minutes.
• Adverse effects. Hypotension, dizziness, somnolence, hypocalcemia, hypomagnesemia, and flushing.

Dexrazoxane (Zinecard)

• Indications. Protection against doxorubicin-induced cardiac toxicity.
• Contraindications. Known allergy to dexrazoxane.
• Method of administration. 1,000 mg/m² intravenously or 10:1 dexrazoxane:doxorubicin ratio.
• Adverse effects. Nausea, vomiting, increased levels of liver function tests, myelosuppression, hypocalcemia, increased prothrombin time/partial thromboplastin time or international normalized ratio and increased amylase.

Granulocyte Colony-Stimulating Factor (GCSF)

• Indications. Neutropenia (absolute granulocyte count of less than 500/mm³ or less than 1,000/mm³ with fever or sepsis).
• Contraindications. Known hypersensitivity.
• Method of administration. 5 µg/kg/day subcutaneously or intravenously.
  • Adverse effects. Hypotension, bone pain, and hypersensitivity reaction.

Sodium Bicarbonate

Urinary alkalinization may help prevent nephrotoxicity in methotrexate overdose; adult dose is a solution of 1 L D5W with 132 mEq sodium bicarbonate administered at two to three times maintenance fluid rates to maintain a urine pH of greater than 7.5; pediatric dose is 88 mEq sodium bicarbonate/L D5W.

Seizures

• A patent airway must be ensured.
• A benzodiazepine should be administered for initial control. If seizures persist or recur, another anticonvulsant such as phenobarbital should be added.
• Hypotension is treated with isotonic fluid infusion, the Trendelenburg position, and vasopressors if needed; dopamine is preferred, and norepinephrine is added for refractory hypotension.

Dysrhythmias or Conduction Abnormalities

• Seizures should be controlled and acidemia corrected.
• If QRS widening or dysrhythmias persist, sodium bicarbonate is administered at 1 to 2 mEq/kg intravenous bolus, repeated as needed to narrow QRS; arterial pH should not exceed 7.55.
• Lidocaine is used for ventricular tachycardia or multifocal premature ventricular complexes; adult dose is 50 to 100 mg intravenous bolus followed by infusion of 2 to 4 mg/min, titrated to desired effect; pediatric dose is 1 mg/kg bolus followed by infusion of 20 to 50 µg/kg/min, titrated to effect; bolus dose may be repeated in 10 to 15 minutes.
• If lidocaine is unsuccessful, bretylium is administered at 5 mg/kg over 1 minute; if unsuccessful, it is administered 10 mg/kg over 1 minute, repeated as necessary to total dose of 30 mg/kg.

Extravasation

• Infusion is stopped and as much infusate as possible is aspirated. The drug should then be diluted by injecting 10 to 15 ml 0.9% saline into the site.
• The limb is elevated and ice applied for 20 minutes four times a day.
• For vinca alkaloids or etoposide, warm compresses are applied or hyaluronidase (150 units hyaluronidase/L 0.9% saline) is infiltrated into the site to promote systemic uptake.
• Topical DMSO 100% every 6 hours has been used for extravasation caused by mitomycin-C, doxorubicin, or daunorubicin.
• Mechlorethamine. Infiltration with sodium thiosulfate 2% to 5% is used.
• Mitomycin-C extravasation is treated with topical DMSO 100% every 6 hours or subcutaneous infiltration with pyridoxine 100 mg/ml.
• Early surgical evaluation is needed for extra-vasation caused by doxorubicin, extravasation over a joint, or any case where tissue destruction is developing.
• Hydrocortisone infiltration (50 to 200 mg subcutaneously or intradermally) for doxorubicin and vinca alkaloids.

Glutamic Acid

May be used to prevent vincristine-induced neurotoxicity. A dose of 500 mg should be administered three times a day.

Hydration

Hydration reduces cisplatin nephrotoxicity and may reduce severity of hemorrhagic cystitis from cyclophosphamide and ifosfamide; adult dose is 5 to 6 L of an appropriate intravenous fluid per day. Furosemide is added at 10 mg every 8 to 12 hours or more as needed to maintain fluid balance.

Intrathecal Overdose

Intrathecal overdose or inadvertent intrathecal administration of an agent not designed for that use is initially treated with immediate removal of as much CSF as is clinically reasonable (usually 20 ml in an adult).

• Intrathecal methotrexate overdose has been treated with ventriculolumbar perfusion with warm normal saline or serial removal of 20-ml portions of CSF and replacement with equal volumes of warmed preservative-free normal saline (total volume exchanged 200-250 ml).
• Inadvertent intrathecal vincristine administration has been treated with CSF aspiration followed by ventriculolumbar perfusion with fresh frozen plasma.

Fluorouracil-induced Myelosuppression

This may be prevented with 300 mg allopurinol three times a day, but there has been no reported experience in its use in treating an overdose.

Section Outline:

• DIRECTING PATIENT COURSE
  • Admission Considerations
• DECONTAMINATION
  • Out of Hospital
  • In Hospital
• ANTIDOTES
• ADJUNCTIVE TREATMENT
  • Amifostine
  • Dexrazoxane (Zinecard)
  • Granulocyte Colony-Stimulating Factor (GCSF)
  • Sodium Bicarbonate
  • Seizures
  • Dysrhythmias or Conduction Abnormalities
  • Extravasation
  • Glutamic Acid
  • Hydration
  • Intrathecal Overdose
  • Fluorouracil-induced Myelosuppression

PATIENT MONITORING

Patients who develop dysrhythmias, hemodynamic instability, chronic heart failure, bleeding, mental status changes, seizures, respiratory failure, or hepatic failure should be monitored in an ICU.

EXPECTED COURSE AND PROGNOSIS

• Most patients recover with supportive care.
• Permanent renal insufficiency and central or peripheral neurologic deficits may develop after overdose or therapeutic use.
• Patients with severe myelosuppression may succumb to neutropenic sepsis or uncontrolled bleeding.

DISCHARGE CRITERIA/INSTRUCTIONS

• From the emergency department
  • Asymptomatic patients may be discharged if they have nontoxic methotrexate levels (if involved) and after gastrointestinal decontamination, 6 hours of observation, and psychiatric evaluation, if needed.
  • Outpatient follow-up needs to be arranged prior to discharge for laboratory studies and neurologic evaluation as appropriate.
• From the hospital
  • Patients may be discharged when able to tolerate oral feedings, mental status is improving, renal and hepatic function is stabilized, bleeding is controlled, and severe anemia or thrombocytopenia is improving.
  • Outpatient follow-up needs to be arranged prior to discharge for laboratory studies and neurologic evaluation as appropriate.

Section Outline:

• PATIENT MONITORING
• EXPECTED COURSE AND PROGNOSIS
• DISCHARGE CRITERIA/INSTRUCTIONS

Because some effects (e.g., myelosuppression), may not develop for more than a week after exposure, a follow-up appointment must be arranged prior to discharge.

Poisoning by other and unspecified drugs and medicinal substances.

See Also: SECTION II, Extravasation, Hypotension, and Seizures chapters; SECTION III, Folic Acid chapter.

RECOMMENDED READING

Wang RY, Calabresi P. Antineoplastic agents. In: Goldfrank LR, Flomenbaum NE, Lewin NA, et al., eds. Goldfrank's toxicologic emergencies. 6th ed. Norwalk, CT: Appleton & Lange, 1998.

Author: Katherine M. Hurlbut

Reviewer: Richard C. Dart