Doxorubicin
| Evidence Level: L1 | Predicted Indications: 10 |
Table of Contents
Doxorubicin: From Lymphoma and Leukaemia to Ewing Sarcoma
One-Sentence Summary
Doxorubicin is an anthracycline chemotherapy drug, originally used for lymphomas (Hodgkin and non-Hodgkin) and acute lymphoblastic leukaemia. The TxGNN model predicts it may be effective for Ewing sarcoma, with 29 clinical trials and 20 publications currently supporting this direction, including several large Phase 3 randomised trials in which doxorubicin is part of the standard regimen.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Acute lymphoblastic leukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, Langerhans cell histiocytosis (no approved indication text is available from New Zealand licences) |
| Predicted New Indication | Ewing sarcoma |
| TxGNN Prediction Score | 99.90% |
| Evidence Level | L1 |
| New Zealand Market Status | Cancelled only (no currently valid licences) |
| Number of Authorizations | 7 (all cancelled) |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Doxorubicin is a topoisomerase II inhibitor and DNA intercalator. It acts on rapidly dividing tumour cells, and its pharmacological target in the data compiled for this report is DNA topoisomerase II alpha (TOP2A). Detailed mechanism of action data from the drug database is not available, so this description is based on the mechanistic rationale compiled for the report.
Doxorubicin is already used in lymphoma and leukaemia regimens, and it is a backbone of the VDC/IE regimen for Ewing sarcoma (vincristine, doxorubicin and cyclophosphamide, alternating with ifosfamide and etoposide). Ewing sarcoma is a fast-growing cancer of bone and soft tissue, mainly in children, adolescents and young adults. Cytotoxic drugs that damage DNA in dividing cells are therefore mechanistically suitable.
Note that for Ewing sarcoma, doxorubicin is already part of standard multi-agent therapy. The prediction is thus supported more by established clinical practice than by a new, doxorubicin-specific signal. Most trials test the whole regimen rather than doxorubicin alone.
Clinical Trial Evidence
The data include 29 trials. The most relevant ones are listed below (up to 10, prioritising Phase 3 and directly relevant trials).
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00006734 | Phase 3 | Completed | 587 | Interval-compressed chemotherapy intensification in Ewing sarcoma and related tumours |
| NCT00020566 | Phase 3 | Unknown | 1200 | EURO-E.W.I.N.G.99: chemotherapy with or without radiotherapy, surgery or stem cell transplantation |
| NCT01231906 | Phase 3 | Completed | 642 | Adding vincristine-topotecan-cyclophosphamide to standard 5-drug therapy (including doxorubicin) 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 multi-agent chemotherapy (including doxorubicin) in metastatic Ewing sarcoma |
| NCT00002516 | Phase 3 | Unknown | N/A | EICESS 92: comparison of combination chemotherapy regimens plus surgery and radiotherapy |
| NCT00038142 | Phase 2 | Terminated | 46 | VAC with dexrazoxane, with or without ImmTher, in high-risk Ewing sarcoma; terminated early |
| NCT00003667 | Phase 2 | Completed | N/A | Randomised VAC with dexrazoxane, with or without ImmTher, in newly diagnosed high-risk Ewing sarcoma |
| NCT00002466 | Phase 2 | Completed | N/A | Cyclophosphamide, doxorubicin, vincristine, etoposide and ifosfamide followed by surgery and radiotherapy in peripheral primitive neuroectodermal tumours and Ewing sarcoma |
| NCT06820957 | Phase 2/3 | Terminated | 2 | VIrR added to VDC/IE in metastatic Ewing sarcoma; terminated with very small enrolment |
Several of these are regimen-level trials, so they show doxorubicin as part of an effective combination rather than isolating its own contribution. Some of the larger trials (for example the EURO-E.W.I.N.G.99 and EICESS 92 studies) did not have a relevance grade assigned in the compiled data.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 12594313 | 2003 | RCT | N Engl J Med | Adding ifosfamide and etoposide to standard chemotherapy (including doxorubicin) in newly diagnosed Ewing sarcoma and primitive neuroectodermal tumour of bone |
| 36522207 | 2022 | RCT | Lancet | EE2012: open-label Phase 3 comparison of the two standard European and US chemotherapy regimens |
| 36669140 | 2023 | RCT | J Clin Oncol | Ganitumab with interval-compressed chemotherapy in newly diagnosed metastatic Ewing sarcoma (COG AEWS1221) |
| 23091096 | 2012 | RCT | J Clin Oncol | Interval-compressed chemotherapy in localised Ewing sarcoma (COG) |
| 31952545 | 2020 | RCT protocol | Trials | EURO EWING 2012 protocol comparing two induction/consolidation regimens |
| 37403815 | 2023 | Review | Cancer | Consensus recommendations from the National Ewing Sarcoma Tumor Board |
| 26304893 | 2015 | Review | J Clin Oncol | Current management of Ewing sarcoma and future collaborative approaches |
| 1833556 | 1991 | Dose-intensity analysis | J Natl Cancer Inst | Doxorubicin dose intensity in relation to response and outcome in osteogenic and Ewing sarcoma |
| 30231396 | 2018 | Review | ASCO Educ Book | Predicting and preventing anthracycline-related cardiotoxicity |
| 37651654 | 2023 | Long-term follow-up | J Clin Oncol | Long-term outcomes of interval-compressed chemotherapy in localised Ewing sarcoma (COG AEWS0031) |
New Zealand Market Information
All 7 New Zealand licences for single-agent doxorubicin have been cancelled, so there is currently no marketed doxorubicin product. No approved indication text is available for these licences.
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| 2224097 | Doxorubicin Ebewe | Inj 2 mg per ml, 50 ml vial | Not available (cancelled) |
| 2224070 | Doxorubicin Ebewe | Inj 2 mg per ml, 5 ml vial | Not available (cancelled) |
| 2224089 | Doxorubicin Ebewe | Inj 2 mg per ml, 25 ml vial | Not available (cancelled) |
| 2427214 | Arrow-Doxorubicin | Inj 2 mg per ml, 100 ml vial | Not available (cancelled) |
| 2204185 | Baxter | Inj 1 mg for ECP | Not available (cancelled) |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (anthracycline; topoisomerase II inhibitor and DNA intercalator) |
| Myelosuppression Risk | High (the compiled safety data link doxorubicin to neutropenia, leukopenia, thrombocytopenia and anaemia as conditions of concern) |
| Emetogenicity Classification | Please refer to the package insert warnings and precautions |
| Monitoring Items | CBC with differential, liver function (including bilirubin), cardiac function (cumulative anthracycline cardiotoxicity requires monitoring) |
| Handling Protection | Must follow cytotoxic drug handling regulations |
Dexrazoxane has been studied as a cardioprotectant in Ewing sarcoma regimens containing doxorubicin.
Safety Considerations
- Contraindication-related conditions (from the knowledge graph, not label text): liver failure, liver disease, hyperbilirubinaemia, heart disease, cardiomyopathy, congestive heart failure, heart conduction disease, sudden cardiac arrest, neutropenia, leukopenia, thrombocytopenia, anaemia, agranulocytosis, and infectious or fungal disease. These come from a knowledge graph and should be confirmed against the official package insert.
- Drug interactions: no drug-drug interactions were identified. The only interaction record is pharmacological, listing DNA topoisomerase II alpha (TOP2A) as the molecular target.
For label-based warnings and contraindications, please refer to the package insert, which could not be obtained for this report.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Multiple completed Phase 3 randomised trials and several RCT publications place doxorubicin within standard multi-agent therapy for Ewing sarcoma (evidence level L1). However, the evidence supports the combination regimen rather than doxorubicin alone, and no doxorubicin product is currently licensed in New Zealand.
To proceed, the following is needed:
- Medsafe package insert warnings and contraindications (a blocking data gap for safety screening)
- Detailed mechanism of action data from the drug database
- Confirmation of access to a licensed or unapproved-medicine supply route in New Zealand, since all licences are cancelled
- A cardiac monitoring plan covering cumulative anthracycline dose and cardioprotection (such as dexrazoxane)
- Clarification of doxorubicin's own contribution within the VDC/IE regimen
Other Predicted Indications
The other predicted indications are weaker or less directly supported.
| Rank | Predicted Indication | TxGNN Score | Evidence Level | Decision |
|---|---|---|---|---|
| 2 | Well-differentiated fetal adenocarcinoma of the lung | 99.86% | L5 | Hold |
| 3 | Primary pulmonary lymphoma | 99.85% | L4 | Hold |
| 4 | Pulmonary blastoma | 99.85% | L3 | Research Question |
| 5 | Chronic myelogenous leukaemia, BCR-ABL1 positive | 99.77% | L3 | Hold |
| 6 | Monocytic leukaemia | 99.74% | L4 | Hold |
| 7 | Botryoid-type embryonal rhabdomyosarcoma of the vagina | 99.72% | L4 | Hold |
| 8 | Parameningeal embryonal rhabdomyosarcoma | 99.71% | L4 | Hold |
| 9 | Rhabdomyosarcoma | 99.70% | L1 | Research Question |
| 10 | Ganglioneuroblastoma | 99.70% | L4 | Hold |
Rhabdomyosarcoma has large Phase 3 trials in soft tissue sarcoma, but these are mostly adult or non-rhabdomyosarcoma populations, so direct evidence is less certain. Pleuropulmonary blastoma has an ongoing Phase 3 trial (NCT06647953) without results yet.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.