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Etoposide: Mechanism, Adverse Effects, Contraindications, and Dosing

Mechanism of Action of Etoposide:

After interacting with DNA topoisomerase II, etoposide stabilizes the cleavable complex and causes double-strand DNA breaks, which trigger apoptosis, particularly in the S and G2 phases of the cell cycle.

Urologic Indications of Etoposide:

Etoposide is used in combination chemotherapy for the following urologic malignancies: metastatic testicular germ cell tumors or extragonadal germ cell tumors (BEP or PEI combinations), adrenocortical carcinoma, Wilms tumor, and genitourinary rhabdomyosarcoma.

Pharmacokinetics of Etoposide:

Intravenous administration is standard for etoposide, but an oral formulation is also available with variable bioavailability (approximately 50%). Protein binding is about 97%. Hepatic metabolization involving CYP3A4 and P-glycoprotein. The elimination half-life averages around 8 hours. In cases of hepatic or renal impairment, clearance decreases, and systemic exposure increases.

Adverse Effects of Etoposide:

• Bone marrow suppression: leukopenia (especially neutropenia), thrombocytopenia, and anemia. Nadir typically occurs after 7–14 days, with recovery in roughly 20 days.
• Nausea and vomiting are common (30%); prophylactic antiemetic therapy is recommended. Diarrhea occurs in about 2–10%, and anorexia in 10%.
• Mucositis and gingival bleeding.
• Alopecia (60%).
• Hepatic enzyme elevations and hepatic dysfunction in up to 3%.
• Hyperuricemia, particularly in patients with tumor lysis syndrome.
• Hypersensitivity reactions up to anaphylaxis occur in 1–2%.
• Mutagenic risk: very rarely therapy-related secondary malignancies such as leukemia. After three BEP cycles, the absolute risk is low (0.5%), and etoposide exposure is a key risk factor.
• Potential gonadotoxicity; effective contraception is necessary during treatment and for an appropriate period after therapy.

Drug Interactions with Etoposide:

Avoid live vaccines during therapy and for a period after immunosuppression. Use caution in individuals with alcohol use disorder because the intravenous solution contains ethanol. Clinically relevant interactions include cyclosporine (increased exposure of etoposide), strong CYP3A4 and P-glycoprotein inhibitors or inducers (altered clearance), and warfarin (increased INR).

Contraindications to Etoposide:

Known severe hypersensitivity to etoposide or formulation components. Pregnancy and lactation. Severe hepatic or renal insufficiency.

Dosing of Etoposide:

Etoposide for Testicular Tumors:

BEP Combination:

100 mg/m² on days 1, 2, 3, 4, and 5 as a short intravenous infusion over one hour; cycle length 21 days (see BEP regimen).

PEI Combination:

75 mg/m² on days 1, 2, 3, 4, and 5 as a short intravenous infusion over one hour; cycle length 21 days (see PEI regimen).

Etoposide for Adrenocortical Carcinoma, Wilms Tumor, and Rhabdomyosarcoma:

Refer to pediatric and adult oncology guidelines and disease-specific textbooks for regimen selection and dosing details.

References

  Deutsche Version: Nebenwirkungen und Kontraindikationen von Etoposid

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