Etoposide
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
- Etoposide
- Etoposide: From Small Cell Lung Carcinoma and Germ Cell Tumours to Well-Differentiated Fetal Adenocarcinoma of the Lung
Etoposide: From Small Cell Lung Carcinoma and Germ Cell Tumours to Well-Differentiated Fetal Adenocarcinoma of the Lung
One-Sentence Summary
Etoposide is a topoisomerase II inhibitor chemotherapy, originally used for small cell lung carcinoma and testicular germ cell tumours (including seminoma and yolk sac tumour). The TxGNN model's top-ranked prediction is well-differentiated fetal adenocarcinoma of the lung, but this rests on no clinical trials and 1 case report/review. Evidence is much stronger for the lower-ranked predictions Ewing sarcoma (28 related trials, several Phase 3 RCTs) and rhabdomyosarcoma (13 related trials, including a Phase 3 trial).
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Small cell lung carcinoma; testicular cancer and germ cell tumours (from the knowledge graph; the local licence record has no indication text) |
| Predicted New Indication | Well-differentiated fetal adenocarcinoma of the lung (rank 1). The best-supported predictions are Ewing sarcoma and rhabdomyosarcoma, discussed below |
| TxGNN Prediction Score | 99.94% |
| Evidence Level | L5 for the rank 1 prediction (the only literature is a case report and review, so L4 as scored in the data compiled for this report; no trials). L1 for Ewing sarcoma and rhabdomyosarcoma |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 1 |
| Recommended Decision | Hold (rank 1); Proceed with Guardrails (Ewing sarcoma, rhabdomyosarcoma) |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Etoposide is known as a topoisomerase II inhibitor: it causes DNA strand breaks that kill rapidly dividing cells. It is established in small cell lung cancer and germ cell tumours, and mechanistically may be applicable to other fast-growing tumours.
For the rank 1 prediction, well-differentiated fetal adenocarcinoma is one component of pulmonary blastoma, a rare lung malignancy. Etoposide is already used in lung cancer, and platinum/etoposide regimens are applied to pulmonary blastoma by analogy. The high score appears to reflect network proximity to lung cancer in the knowledge graph rather than direct clinical data.
The more clinically grounded predictions are the sarcomas. Etoposide combined with ifosfamide is an established backbone of Ewing sarcoma chemotherapy (alternating VDC/IE regimens) and is used in rhabdomyosarcoma. A caveat applies: etoposide is given within multi-drug regimens, so its separate contribution cannot be isolated, and in these cancers it is already standard of care, so it is arguably not a novel repurposing.
Clinical Trial Evidence
Rank 1 (well-differentiated fetal adenocarcinoma of the lung): Currently no related clinical trials registered.
Ewing sarcoma (rank 4), selected trials:
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00002516 | Phase 3 | Unknown | N/A | EICESS 92: randomised comparison of etoposide-containing chemotherapy regimens plus surgery and radiotherapy |
| NCT00006734 | Phase 3 | Completed | 587 | Interval-compressed chemotherapy in Ewing sarcoma and related tumours |
| NCT01231906 | Phase 3 | Completed | 642 | Adding vincristine-topotecan-cyclophosphamide to standard five-drug chemotherapy (including etoposide) in non-metastatic disease |
| 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 multi-agent chemotherapy in metastatic Ewing sarcoma |
| NCT00020566 | Phase 3 | Unknown | 1200 | EURO-E.W.I.N.G.99: chemotherapy with or without radiotherapy, surgery or stem cell support |
| NCT00002466 | Phase 2 | Completed | N/A | Cyclophosphamide, doxorubicin, vincristine, etoposide and ifosfamide followed by resection and radiotherapy |
| NCT02727387 | Phase 2 | Completed | 155 | High-dose chemotherapy, radiotherapy and consolidation in metastatic Ewing sarcoma |
| NCT00002643 | Phase 2 | Completed | 130 | Intensive therapy with growth factor support in metastatic Ewing's tumour |
| NCT01864109 | Phase 2 | Active, not recruiting | 83 | Irinotecan and temozolomide added to high-dose alkylator-based chemotherapy |
Rhabdomyosarcoma (rank 6), selected trials:
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00003052 | Phase 3 | Completed | 340 | Etoposide + ifosfamide + doxorubicin with or without regional hyperthermia in high-risk soft tissue sarcoma |
| NCT00025363 | Phase 2 | Completed | 150 | Window study of irinotecan schedules in relapsed rhabdomyosarcoma; etoposide role secondary |
| NCT00025441 | Phase 2 | Completed | N/A | MMT 98: combination chemotherapy in metastatic rhabdomyosarcoma |
| NCT02574728 | Phase 2 | Active, not recruiting | 46 | Sirolimus with metronomic low-dose etoposide/cyclophosphamide in relapsed paediatric tumours |
Other predictions (primary pulmonary lymphoma, pulmonary blastoma, and the rarer rhabdomyosarcoma subtypes) have no registered trials.
Literature Evidence
Ewing sarcoma (rank 4):
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 12594313 | 2003 | RCT | N Engl J Med | Adding ifosfamide and etoposide to standard chemotherapy in newly diagnosed Ewing sarcoma/PNET of bone |
| 36522207 | 2022 | RCT | Lancet | EE2012: comparison of two chemotherapy regimens in newly diagnosed Ewing sarcoma |
| 23091096 | 2012 | RCT | J Clin Oncol | Interval-compressed chemotherapy with alternating VDC and ifosfamide-etoposide cycles in localised disease |
| 36669140 | 2023 | RCT | J Clin Oncol | Ganitumab with interval-compressed chemotherapy in metastatic Ewing sarcoma |
| 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 disease |
Rhabdomyosarcoma (rank 6):
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 11846301 | 2001 | Randomised window trial | J Pediatr Hematol Oncol | Ifosfamide/etoposide superior to vincristine/melphalan in metastatic disease |
| 26503200 | 2016 | Clinical trial | J Clin Oncol | COG intensive multi-agent therapy with dose-compressed ifosfamide/etoposide in high-risk disease |
| 9849484 | 1998 | Clinical trial/cohort | Eur J Cancer | Alternating VDC and etoposide/ifosfamide in intermediate-risk disease |
| 17091486 | 2008 | Pilot study | Pediatr Blood Cancer | VDC/IE compared with IRS-IV in intermediate-risk disease |
Rank 1 (well-differentiated fetal adenocarcinoma of the lung) and pulmonary blastoma:
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 33107372 | 2020 | Case report/Review | J Int Med Res | Classic biphasic pulmonary blastoma treated with surgery and nedaplatin plus paclitaxel; no standard guidelines exist |
| 9452262 | 1998 | Case report/Review | Cancer | Pulmonary blastoma with 7-year remission and review of chemotherapy experience |
| 11955657 | 2002 | Case report/Review | Lung Cancer | Radiosensitive blastoma; additional cisplatin and etoposide produced no further regression |
For primary pulmonary lymphoma, the retrieved literature is mostly about SCLC, general lymphoma or transplant regimens, with only case reports specific to the condition.
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN10059P | ETOPOSIDE-TEVA INJECTION 20 mg/ml (Pharmachemie BV) | Injection | Not recorded in the licence data |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (topoisomerase II inhibitor) |
| Myelosuppression Risk | High. The knowledge graph lists leukopenia, neutropenia, thrombocytopenia, agranulocytosis and anaemia as contraindication-related conditions |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | Complete blood count with differential, liver and renal function |
| Handling Protection | Must follow cytotoxic drug handling regulations |
Safety Considerations
- Contraindication-related conditions (knowledge graph, not label text): thrombocytopenia, neutropenia, agranulocytosis, leukopenia, anaemia (including macrocytic anaemia), interstitial lung disease, pulmonary fibrosis, impaired renal function, metabolic acidosis, and drug-induced liver injury.
- Drug interactions: 100 interactions were found. Moderate-level examples include aprepitant, rolapitant, metronomidazole, tinidazole, eliglustat, rosuvastatin and simvastatin. Levofloxacin is minor. Several others (e.g., cimetidine, pantoprazole, doxycycline, amphotericin B) have no assigned severity.
The Singapore package insert warnings and contraindications were not available for this report; please refer to the package insert for authoritative safety information.
Conclusion and Next Steps
Decision: Hold for the rank 1 prediction (well-differentiated fetal adenocarcinoma of the lung); Proceed with Guardrails for Ewing sarcoma and rhabdomyosarcoma
Rationale:
- The top-ranked prediction has no trials and only a case report/review, and the high score reflects proximity to lung cancer rather than clinical data.
- Ewing sarcoma and rhabdomyosarcoma have multiple Phase 3 trials and RCT-level publications. However, etoposide is already standard of care there within multi-drug regimens, so this is not a novel repurposing.
- The remaining predictions (primary pulmonary lymphoma, pulmonary blastoma, and rarer rhabdomyosarcoma subtypes) rest on case reports, small series or no data, and stay at Hold or research-question level.
To proceed, the following is needed:
- The Singapore package insert (warnings, contraindications and approved indications), which is a blocking gap for safety screening
- Detailed mechanism of action data from DrugBank
- Confirmation of whether the Singapore licence covers sarcoma use, and any route or formulation requirements (route compatibility has not yet been assessed)
- A myelosuppression monitoring plan and review of interacting drugs for the target population
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.