Etoposide: Topoisomerase 2 Inhibitor in Chemotherapy of Malignant Diseases
Etoposide is a semisynthetic podophyllotoxin derivative from the plant Podophyllum peltatum. It was approved in 1983 and is a central cytostatic agent in many oncological combination regimens. Known brand names are Vepesid, Etopophos (intravenous) and generics available as both capsules and concentrate for infusion.
Etoposide acts as a topoisomerase 2 inhibitor and has its established place in the treatment of small cell lung carcinoma, testicular carcinoma, lymphomas and in high dose chemotherapy before stem cell transplantation. Despite significant adverse effects, especially bone marrow suppression and secondary leukemia risk, etoposide remains an indispensable component of modern oncology.
Mechanism of Action
Etoposide stabilizes the complex of DNA and topoisomerase 2 enzyme in a state where the DNA double helix is severed with double strand breaks. Topoisomerase 2 is normally an enzyme that temporarily cuts, unwinds and rejoins DNA during replication and transcription. Stabilization of the cleavable complex prevents rejoining of DNA, resulting in permanent double strand breaks.
These DNA double strand breaks activate DNA damage response in the tumor cell and lead to apoptosis, especially in late S phase and G2 phase of the cell cycle. Etoposide therefore acts in a cell cycle specific manner and is most effective in proliferating tissues. Also, it has a direct effect on tubulin polymerization, which contributes to its antimitotic activity.
Pharmacokinetically, oral bioavailability is good at approximately 50 percent, but is dose dependent and variable. Half life approximately 6 to 8 hours, elimination via kidney and bile. Dose adjustment is required in renal insufficiency.
Areas of Application
- Small cell lung carcinoma (SCLC): in combination with cisplatin or carboplatin (PE/CE regimen), often with atezolizumab or durvalumab in first line
- Non small cell lung carcinoma (NSCLC): in some regimens
- Testicular carcinoma: as BEP regimen (bleomycin etoposide cisplatin), standard with high cure rate
- Non Hodgkin lymphomas and Hodgkin lymphoma: as CHOEP, BEACOPP, EPOCH regimen
- Acute lymphoblastic leukemia and acute myeloid leukemia: in some regimens
- Sarcomas (Ewing sarcoma, rhabdomyosarcoma): in pediatric oncology
- High dose therapy before stem cell transplantation
- Hemophagocytic lymphohistiocytosis (HLH) emergency therapy
Dosage and Administration
Standard intravenous: 100 to 120 mg/m² body surface area on day 1 to 3 or day 1 to 5 of a 21 or 28 day cycle, combined with other cytostatic agents.
Oral: 100 to 200 mg/m² daily, approximately twice as high a dose as intravenous due to lower bioavailability. Taken with or without food.
In renal insufficiency: dose adjustment is required if creatinine clearance is below 50 ml/min. Infusion duration: at least 30 to 60 minutes, as rapid infusion can lead to severe hypotension. Blood pressure monitoring during infusion.
Adverse Effects
Very common: bone marrow suppression with neutropenia (nadir 7 to 14 days), anemia and thrombocytopenia; nausea, vomiting, diarrhea, mucositis, alopecia usually reversible; increase in liver transaminases.
Common: hypotension with rapid infusion, allergic reactions, skin hyperpigmentation, taste disturbances, fatigue.
Serious: secondary acute myeloid leukemia (AML) with incidence approximately 1 to 3 percent over lifetime, especially with characteristic 11q23 MLL gene rearrangements; infertility in men and women; lung toxicity with interstitial pneumonitis; peripheral neuropathy rare; allergic and anaphylactoid reactions especially with etoposide phosphate (Etopophos), which requires phosphate ester hydrolysis to the active form.
Important: secondary leukemia typically occurs 2 to 5 years after etoposide therapy, with short latency and poor prognosis. Patients should be informed of this risk before therapy.
Interactions
- Other myelotoxic agents: additive bone marrow suppression
- Cyclosporine: increased etoposide levels and toxicity
- Warfarin: increased INR possible
- Phenytoin and phenobarbital: decreased etoposide levels through CYP3A4 induction
- Live vaccines: contraindicated during and several months after therapy
- Radiotherapy: additive bone marrow suppression and mucositis
Special Notes
Pregnancy and breastfeeding: contraindicated as it is teratogenic, mutagenic and carcinogenic. Secure contraception during and at least 6 months after therapy for both sexes. Family planning discussion and possibly cryopreservation of oocytes or sperm before start of therapy.
Before each cycle: complete blood count with differential, creatinine, liver transaminases. Therapy interruption if neutrophils below 1,500 per microliter or platelets below 100,000 per microliter.
Emergencies in case of allergy: immediate therapy interruption in case of anaphylactoid reaction, epinephrine, antihistamines, glucocorticoids and intensive monitoring. Etopophos can be attempted as alternative if reaction to etoposide, but reaction risk exists here as well.
Follow up for secondary malignancies: long term hematological follow up with annual blood count over at least 10 years due to secondary AML risk.
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Frequently Asked Questions
What does topoisomerase 2 inhibition mean?
Topoisomerase 2 is an enzyme that temporarily cuts, unwinds and rejoins DNA during cell division. Etoposide stabilizes the complex in a state with broken DNA, so the break sites are not repaired. The tumor cell recognizes the severe DNA damage and dies through apoptosis. Since tumor cells divide more actively than most healthy cells, they are particularly susceptible.
Why is there risk for a second cancer?
Etoposide can induce mutations in normal cells, especially hematopoietic stem cells, through DNA damage, which can lead to secondary acute myeloid leukemia. The risk is approximately 1 to 3 percent over lifetime, depends on total dose and concomitant therapies and typically occurs 2 to 5 years after therapy. Long term hematological follow up is required.
How long does it take for my blood count to recover?
The nadir of neutrophils occurs 7 to 14 days after etoposide administration, recovery usually occurs within 21 days. During the neutropenic phase there is increased infection risk, careful hygiene and possibly antibiotic prophylaxis with GCSF (filgrastim) support are standard.
Does etoposide affect fertility?
Yes. Etoposide is gonadotoxic and can cause temporary or permanent infertility in men and women. Cryopreservation of sperm or oocytes should be considered before start of therapy in patients with desire for children.
Sources
- EMA Product Information Etoposide Preparations
- DGHO Onkopedia, Small Cell Lung Carcinoma and Testicular Carcinoma
- Gelbe Liste, Etoposide Active Ingredient Profile
- BfArM, Federal Institute for Drugs and Medical Devices
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