Etoposide
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Etoposide: From Small Cell Lung Carcinoma to Ewing Sarcoma
One-Sentence Summary
Etoposide is a topoisomerase II inhibitor chemotherapy, originally used for small cell lung carcinoma and testicular germ cell tumours. The TxGNN model’s top-ranked prediction is well-differentiated fetal adenocarcinoma of the lung, but it has only a single case report behind it. This report therefore focuses on the best-supported prediction, Ewing sarcoma, which has 33 registered clinical trials and 20 publications, including several randomised phase III trials. The use of etoposide in Ewing sarcoma is effectively already standard of care.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Small cell lung carcinoma, testicular cancer / germ cell tumours (seminoma, yolk sac tumour, teratoma) |
| Predicted New Indication | Ewing sarcoma (rank 4 in the TxGNN list; top-ranked prediction is well-differentiated fetal adenocarcinoma of the lung, evidence level L4, Hold) |
| TxGNN Prediction Score | 0.9985 (Ewing sarcoma) |
| Evidence Level | L5 |
| India Market Status | Listed in a compiled Indian medicine price dataset (at least 20) – CDSCO approval status is not included in this data |
| Number of Listed Products | at least 20 |
| Recommended Decision | Proceed with Guardrails |
Other predictions in the list:
| Rank | Predicted Indication | Score | Evidence Level | Decision |
|---|---|---|---|---|
| 1 | Well-differentiated fetal adenocarcinoma of the lung | 0.9994 | L5 | Hold |
| 2 | Primary pulmonary lymphoma | 0.9994 | L5 | Hold |
| 3 | Pulmonary blastoma | 0.9994 | L5 | Research question |
| 4 | Ewing sarcoma | 0.9985 | L1 | Proceed with Guardrails |
| 5 | Botryoid-type embryonal rhabdomyosarcoma of the vagina | 0.9980 | L5 | Hold |
| 6 | Rhabdomyosarcoma | 0.9979 | L1 | Proceed with Guardrails |
| 7 | Embryonal extrahepatic bile duct rhabdomyosarcoma | 0.9976 | L5 | Hold |
| 8 | Parameningeal embryonal rhabdomyosarcoma | 0.9976 | L5 | Hold |
| 9 | Extrahepatic bile duct rhabdomyosarcoma | 0.9975 | L5 | Hold |
| 10 | Prostate embryonal rhabdomyosarcoma | 0.9974 | L5 | Hold |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data was not available in the data compiled for this report. Etoposide is, however, a well-known topoisomerase II inhibitor, a class of cytotoxic drug that causes DNA strand breaks in rapidly dividing cells. Its efficacy in small cell lung carcinoma and germ cell tumours is established, and mechanistically it may be applicable to other rapidly proliferating, chemosensitive malignancies.
Ewing sarcoma is a fast-growing, chemosensitive paediatric and young-adult bone and soft-tissue cancer. A published study notes that it is highly sensitive to genotoxic agents such as etoposide, linked to R-loop accumulation and impaired BRCA1-mediated DNA repair driven by the EWS-FLI1 fusion. Etoposide combined with ifosfamide is already a core component of standard regimens (the alternating VDC/IE schedule), and a randomised phase III trial published in the New England Journal of Medicine showed that adding ifosfamide and etoposide to standard chemotherapy improved outcomes in newly diagnosed disease.
Note that this is effectively a validated standard-of-care use rather than a novel repurposing, though it is not among the drug’s listed original indications. The related rhabdomyosarcoma prediction (rank 6) follows the same logic. The top-ranked lung predictions rest on case reports only, and the very high TxGNN scores reflect network proximity rather than clinical validation.
Clinical Trial Evidence
The table lists the most relevant of the 33 trials registered for Ewing sarcoma, prioritising randomised phase III studies and those graded most relevant.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00006734 | Phase 3 | Completed | 587 | Interval-compressed chemotherapy regimens plus radiotherapy/surgery in Ewing sarcoma and related tumours |
| NCT01231906 | Phase 3 | Completed | 642 | Adding vincristine-topotecan-cyclophosphamide to the standard 5-drug regimen (including etoposide) in non-metastatic Ewing sarcoma |
| NCT02063022 | Phase 3 | Completed | 278 | Dose intensification versus standard treatment in non-metastatic Ewing sarcoma |
| NCT02306161 | Phase 3 | Active, not recruiting | 312 | Ganitumab added to multiagent chemotherapy (including etoposide) in newly diagnosed metastatic Ewing sarcoma |
| NCT00020566 | Phase 3 | Unknown | 1200 | EURO-E.W.I.N.G.99: chemotherapy with or without radiotherapy, surgery or stem cell transplant |
| NCT00002516 | Phase 3 | Unknown | N/A | EICESS 92: randomised comparison of combination chemotherapy regimens plus surgery and radiotherapy |
| NCT00002466 | Phase 2 | Completed | N/A | Cyclophosphamide, doxorubicin, vincristine, etoposide and ifosfamide followed by resection and radiotherapy in peripheral PNET or Ewing sarcoma |
| NCT02727387 | Phase 2 | Completed | 155 | High-dose chemotherapy, radiotherapy and consolidation in metastatic Ewing sarcoma |
| NCT01864109 | Phase 2 | Active, not recruiting | 83 | Irinotecan and temozolomide added to alkylator-based chemotherapy in newly diagnosed Ewing sarcoma |
| NCT07194044 | Phase 1 | Recruiting | 15 | Schedule-enhancement approach in widely metastatic Ewing sarcoma |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 12594313 | 2003 | RCT | N Engl J Med | Adding ifosfamide and etoposide to standard chemotherapy for newly diagnosed Ewing sarcoma/PNET of bone |
| 23091096 | 2012 | RCT | J Clin Oncol | Interval-compressed VDC/IE chemotherapy in localised Ewing sarcoma (Children’s Oncology Group) |
| 36522207 | 2022 | RCT (Phase 3) | Lancet | EE2012: comparison of two chemotherapy strategies in newly diagnosed Ewing sarcoma |
| 36669140 | 2023 | RCT (Phase 3) | J Clin Oncol | Ganitumab with interval-compressed chemotherapy in metastatic Ewing sarcoma |
| 31952545 | 2020 | RCT protocol | Trials | EURO EWING 2012 protocol |
| 37403815 | 2023 | Consensus guideline | Cancer | National Ewing Sarcoma Tumor Board management recommendations |
| 39713774 | 2024 | Retrospective study | Sarcoma | Oral etoposide in 33 adolescent and adult patients with relapsed or refractory Ewing sarcoma |
| 29513652 | 2018 | Mechanistic study | Nature | EWS-FLI1 causes R-loops and blocks BRCA1 repair, explaining sensitivity to etoposide |
| 26304893 | 2015 | Review | J Clin Oncol | Current management and future approaches in Ewing sarcoma |
| 20152770 | 2010 | Review | Lancet Oncol | Overview of Ewing sarcoma treatment and outcomes |
India Market Information
Etoposide is marketed in India with 20 valid single-ingredient registrations (injection and oral capsule). Approved indication text was not available for any of them. Five of the main registrations:
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| 81663 | Etonco 100mg Injection | Vial of 1 injection | Not provided |
| 89369 | Fytosid 100mg Injection | Vial of 5 ml injection | Not provided |
| 175247 | Posid 100mg Injection | Vial of 5 ml injection | Not provided |
| 177778 | Posid 100mg Capsule | Strip of 4 capsules | Not provided |
| 74872 | Etoplast 50mg Capsule | Strip of 12 capsules | Not provided |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (topoisomerase II inhibitor, epipodophyllotoxin class) |
| Myelosuppression Risk | High (the contraindication data compiled for this report lists thrombocytopenia, neutropenia, leukopenia, agranulocytosis and anaemia) |
| Emetogenicity Classification | Low to moderate (general drug-class knowledge; not drawn from the compiled data) |
| Monitoring Items | Complete blood count with differential, liver and renal function |
| Handling Protection | Must follow cytotoxic drug handling regulations |
Please refer to the package insert warnings and precautions for further detail.
Safety Considerations
- Disease-level contraindication signals (knowledge graph, not label text): thrombocytopenia, neutropenia, leukopenia, agranulocytosis, anaemia (including macrocytic anaemia), impaired renal function, drug-induced liver injury, metabolic acidosis, interstitial lung disease and pulmonary fibrosis.
- Drug Interactions: 495 interactions were identified. The ones listed below are the moderate-level interactions: aprepitant, rolapitant, metronomidazole, tinidazole, eliglustat, rosuvastatin and simvastatin. Levofloxacin is a minor interaction. Others (e.g., cimetidine, amphotericin B, morphine, pantoprazole) have an unclassified severity level.
Package-insert warnings and contraindications were not available, so please refer to the package insert for the full safety information.
Conclusion and Next Steps
Decision: Proceed with Guardrails (for Ewing sarcoma and, by the same logic, rhabdomyosarcoma). The remaining predictions (lung adenocarcinoma variant, pulmonary lymphoma, pulmonary blastoma and rare rhabdomyosarcoma subtypes) should stay at Hold, since they rest on case reports, indirect literature or no study at all.
Rationale: Multiple randomised phase III trials and a consensus guideline support etoposide plus ifosfamide in Ewing sarcoma, so the evidence is strong (L1). The use is already standard of care rather than a new discovery, and the drug is widely marketed in India.
To proceed, the following is needed:
- Package insert warnings and contraindications for the Indian-registered products, and their approved indication text, to confirm whether Ewing sarcoma is covered on-label
- Detailed mechanism-of-action data from DrugBank
- A safety plan covering paediatric dosing, myelosuppression, secondary leukaemia risk and cumulative toxicity monitoring
- Use within cooperative-group or institutional protocols, with a review of the drug interactions above (notably the antiemetic NK1 antagonists)
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.