What are the side effects of etoposide?

Etoposide Side Effects

Etoposide's dose-limiting toxicity is myelosuppression, with predictable granulocyte nadirs at 7-14 days and platelet nadirs at 9-16 days post-administration, typically recovering by day 20 without cumulative toxicity. 1

Hematologic Toxicity (Most Critical)

Myelosuppression is the primary dose-limiting adverse effect:

• Leukopenia occurs in 60-91% of patients (severe <1,000 WBC/mm³ in 3-17% of cases) 1
• Thrombocytopenia affects 22-41% of patients (severe <50,000 platelets/mm³ in 1-20%) 1
• Anemia develops in up to 33% of patients 1
• Fever and infection commonly accompany neutropenia, with death from myelosuppression reported 1
• Bone marrow recovery is typically complete by day 20, with no cumulative toxicity 1, 2

Critical monitoring requirement: Verify platelet count ≥100,000/mm³ and absolute neutrophil count ≥1,000/mm³ before each cycle 3

Gastrointestinal Toxicity

Nausea and vomiting are the major GI toxicities:

• Occur in 31-43% of patients, generally mild to moderate severity 1
• Treatment discontinuation required in only 1% of patients 1
• Usually controlled with standard antiemetic therapy 1
• Mucositis/esophagitis ranges from mild to severe 1
• Stomatitis occurs in 1-6% of patients 1
• Diarrhea affects 1-13% of patients 1
• GI toxicities are slightly more frequent with oral versus intravenous administration 1

Cardiovascular Effects

Hypotension following rapid IV administration:

• Occurs in 1-2% of patients receiving IV etoposide 1
• Transient, not associated with cardiac toxicity or ECG changes 1
• Prevention: Administer by slow IV infusion over 30-60 minutes 1
• Management: Cessation of infusion and fluid administration; restart at slower rate 1

Hypersensitivity Reactions

Anaphylactic-like reactions are potentially life-threatening:

• Occur in 0.7-2% of patients receiving IV etoposide, <1% with oral capsules 1
• Manifestations: Chills, fever, tachycardia, bronchospasm, dyspnea, hypotension 1
• Facial/tongue swelling, laryngospasm, back pain, loss of consciousness reported 1
• Can occur during the initial infusion 1
• Usually respond to cessation of infusion plus pressor agents, corticosteroids, antihistamines 1
• Fatal reactions have been reported 1

Dermatologic Toxicity

Alopecia is common and reversible:

• Occurs in 8-66% of patients 1
• Sometimes progresses to total baldness 1
• Reversible after treatment completion 1
• Rash, urticaria, pruritus reported infrequently at recommended doses 1

High-Dose Specific Toxicities

When doses exceed standard ranges (>2.4-3.0 g/m²):

• Mucositis becomes dose-limiting 4
• Hepatic dysfunction increases 4
• Metabolic acidosis reported 1
• Pulmonary toxicity (interstitial pneumonitis/fibrosis) can occur 1

Serious but Rare Adverse Events

Secondary malignancies:

• Acute leukemia with or without preleukemic phase reported rarely 1
• Occurs in association with other antineoplastic agents 1
• Second primary malignancy identified in real-world pharmacovigilance data 5

Other rare but significant toxicities:

• Peripheral neurotoxicity (1-2%) 1
• Transient cortical blindness, optic neuritis 1
• Stevens-Johnson syndrome, toxic epidermal necrolysis 1
• Seizures (occasionally associated with allergic reactions) 1
• Thrombotic microangiopathy 5
• Ototoxicity 5
• Nephropathy 5
• Ovarian failure 5

Schedule and Dose-Dependent Considerations

Toxicity varies significantly by administration schedule:

• Multiple dosing over 3-5 consecutive days is superior to weekly single doses 2
• Continuous IV infusion allows higher total doses (4.2 g/m²) with similar toxicity profile 4
• Prolonged and severe myelosuppression occurs with combination regimens (e.g., with cyclophosphamide and clofarabine) 6

Renal Impairment Adjustments

Dose reduction required for renal dysfunction:

• Etoposide is primarily cleared by kidneys (50% recovered in urine) 7
• Dose reduction recommended for impaired renal function based on age-specific norms 6
• No dose reduction needed for isolated hyperbilirubinemia or elevated transaminases 6, 8

Time-to-Onset Profile

Most adverse events occur early:

• Median time-to-onset is 10 days (IQR 2-32 days) 5
• 73.8% of cases occur within the first month after administration 5

Gender-Specific Signals

Males show higher risk for:

• Pneumonia and cardiac infarction 5

Females show higher risk for:

• Drug resistance and ototoxicity 5

Critical Clinical Pitfalls

• Never administer as rapid IV bolus - always infuse over 30-60 minutes to prevent hypotension 1
• Monitor for hypersensitivity during the first infusion specifically 1
• Ensure adequate antimicrobial prophylaxis (Pneumocystis, fungi, viruses) during treatment due to severe immunosuppression 6, 8
• Check complete blood counts before each cycle; delay treatment if ANC <1,000/mm³ or platelets <100,000/mm³ 3