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 acute lymphoblastic leukaemia, Hodgkin and non-Hodgkin lymphoma, mantle cell lymphoma and Langerhans cell histiocytosis. The TxGNN model predicts it may be effective for Ewing sarcoma, a prediction that is already supported by 28 clinical trials and 20 publications in the data compiled for this report, including several randomised Phase 3 trials of regimens that contain doxorubicin. Doxorubicin is already a backbone drug in standard Ewing sarcoma regimens, so this is better understood as confirmation of current practice than as a brand-new use.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Acute lymphoblastic leukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, Langerhans cell histiocytosis (from the knowledge graph; the Singapore licence records contain no indication text) |
| Predicted New Indication | Ewing sarcoma |
| TxGNN Prediction Score | 99.90% |
| Evidence Level | L1 |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 11 |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data was not available in the drug record. In general, doxorubicin is a topoisomerase II inhibitor and DNA intercalator. It damages DNA and kills rapidly dividing tumour cells.
Its original indications are haematological cancers, in which doxorubicin is already a standard component of regimens such as CHOP and ABVD. Ewing sarcoma is a fast-growing bone and soft-tissue cancer that mainly affects children, adolescents and young adults. It is treated with multi-agent chemotherapy, and doxorubicin is a core drug in the VDC/IE and VAC/VAI regimens (vincristine, doxorubicin, cyclophosphamide, alternating with ifosfamide and etoposide). Because both diseases respond to DNA-damaging chemotherapy, the model's prediction is mechanistically plausible.
An important caveat: the Phase 3 evidence evaluates whole regimens, not doxorubicin alone. The contribution of doxorubicin cannot be separated from the other agents.
Clinical Trial Evidence
The data compiled for this report list 28 trials. The table shows the 10 most relevant, with randomised and directly doxorubicin-related trials prioritised.
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00006734 | Phase 3 | Completed | 587 | Randomised comparison of interval-compressed (intensified) chemotherapy in Ewing sarcoma and related tumours |
| NCT01231906 | Phase 3 | Completed | 642 | Adding vincristine-topotecan-cyclophosphamide to the standard 5-drug regimen (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 (IGF-1R antibody) 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 transplant |
| NCT00002516 | Phase 3 | Unknown | Not reported | EICESS 92: comparison of combination chemotherapy regimens plus surgery and radiotherapy |
| NCT00038142 | Phase 2 | Terminated | 46 | VAC plus dexrazoxane with or without ImmTher in high-risk Ewing sarcoma; stopped early, so conclusions are limited |
| NCT00003667 | Phase 2 | Completed | Not reported | Randomised VAC plus dexrazoxane with or without ImmTher in newly diagnosed high-risk disease |
| NCT00002466 | Phase 2 | Completed | Not reported | Five-drug chemotherapy (including doxorubicin) followed by resection and radiotherapy |
| NCT06820957 | Phase 2/3 | Terminated | 2 | VIrR added to VDC/IE in metastatic Ewing sarcoma; terminated with only 2 patients |
Several other trials (for example NCT00949325, NCT00544778 and NCT01864109) are small, terminated or not centred on doxorubicin.
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 12594313 | 2003 | RCT | N Engl J Med | Tested adding ifosfamide and etoposide to standard chemotherapy in newly diagnosed Ewing sarcoma and primitive neuroectodermal tumour of bone |
| 36522207 | 2022 | RCT (Phase 3) | Lancet | EE2012: compared the European and US standard chemotherapy strategies in newly diagnosed Ewing sarcoma |
| 36669140 | 2023 | RCT (Phase 3) | J Clin Oncol | Ganitumab plus interval-compressed chemotherapy in metastatic Ewing sarcoma (Children's Oncology Group) |
| 23091096 | 2012 | RCT | J Clin Oncol | Interval-compressed chemotherapy in localised Ewing sarcoma |
| 37651654 | 2023 | Long-term follow-up | J Clin Oncol | Long-term outcomes of localised Ewing sarcoma treated with interval-compressed chemotherapy (AEWS0031) |
| 37403815 | 2023 | Consensus guideline | Cancer | National Ewing Sarcoma Tumor Board recommendations on standard of care |
| 26304893 | 2015 | Review | J Clin Oncol | Current management of Ewing sarcoma and future approaches |
| 20152770 | 2010 | Review | Lancet Oncol | Survival improved from about 10% before chemotherapy to about 75% for localised disease; metastatic disease still fares badly |
| 1833556 | 1991 | Dose-intensity analysis | J Natl Cancer Inst | Analysed the influence of doxorubicin dose intensity on outcome in Ewing sarcoma and osteosarcoma |
| 30231396 | 2018 | Review | ASCO Educ Book | Anthracyclines are central to childhood cancer therapy, including Ewing sarcoma, but cause cardiotoxicity |
Singapore Market Information
There are 11 valid single-ingredient registrations. The records contain no approved-indication text. The table lists 5 of them.
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN10992P | K. U. Doxorubicin HCl for Injection 10 mg/vial | Powder for injection solution | Not stated in the records |
| SIN16102P | Chemodox Concentrate for Infusion 2 mg/ml | Solution for injection | Not stated in the records |
| SIN13676P | Ebedoxo 2 mg/ml Injection | Concentrate for injection solution | Not stated in the records |
| SIN10426P | Caelyx Concentrate for Infusion 2 mg/ml | Injection | Not stated in the records |
| SIN10566P | Adriamycin Solution for Injection 2 mg/ml | Injection | Not stated in the records |
All formulations are injectable (conventional and liposomal products).
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (anthracycline; topoisomerase II inhibitor) |
| Myelosuppression Risk | High (the knowledge graph links doxorubicin to contraindications in neutropenia, leukopenia, thrombocytopenia, anaemia and agranulocytosis) |
| Emetogenicity Classification | Moderate to high at typical doses, based on the drug class; please confirm against the package insert |
| Monitoring Items | Complete blood count with differential, liver function, renal function, and cardiac function (echocardiography or LVEF) before and during treatment, with long-term cardiac follow-up |
| Handling Protection | Must follow cytotoxic drug handling regulations |
Safety Considerations
Contraindications (from the knowledge graph, not from label text): liver failure and liver disease, thrombocytopenia, neutropenia, leukopenia, agranulocytosis, anaemia, heart disease (including cardiomyopathy, heart failure, heart conduction disease and sudden cardiac arrest), infectious disease and G6PD deficiency. Other graph entries (for example gallbladder disease, hyperbilirubinaemia and Gilbert syndrome) also appear. These require confirmation against the approved package insert.
Cardiotoxicity: the literature highlights anthracycline-related cardiotoxicity as a major limitation, especially in children and young adults (PMID 30231396). Dexrazoxane was used in some Ewing sarcoma trials as cardioprotection.
Drug Interactions: the interaction screen returned 100 interacting drugs. The main high-severity ones are:
- Major: dolasetron, cisapride, papaverine
- Moderate (examples): ondansetron, granisetron, palonosetron, aprepitant, rolapitant, dexamethasone, clarithromycin, levofloxacin, famotidine, loperamide
Several of these are antiemetics and QT-prolonging agents that are commonly co-prescribed with chemotherapy, so concurrent use needs review.
Please also refer to the package insert for the full warnings, as label warning text was not available for this report.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Several completed randomised Phase 3 trials and large literature reports support doxorubicin-containing regimens in Ewing sarcoma, which is why the evidence level is L1. However, those trials test whole regimens rather than doxorubicin alone, and the drug is already used in this setting. The cardiac and bone-marrow toxicity profile requires strict safeguards.
To proceed, the following is needed:
- Package insert warnings and contraindications from the Singapore Health Sciences Authority (HSA), which are currently missing and block the safety screening
- Approved-indication text for the Singapore licences, to confirm whether Ewing sarcoma or sarcoma is already covered
- Detailed mechanism-of-action data from DrugBank
- A cardiac monitoring plan with cumulative-dose limits and consideration of cardioprotection
- Confirmation of which regimen and dose would be used in Singapore practice
Other predicted indications (for reference): soft-tissue sarcoma and rhabdomyosarcoma carry L1 evidence (Phase 3 trials NCT00003052 and NCT00003212), with a Proceed with Guardrails recommendation, although those trials mainly involved adult soft-tissue sarcoma and doxorubicin is not part of the current standard regimens for paediatric rhabdomyosarcoma. Pleuropulmonary blastoma and chronic myelogenous leukaemia are research questions with limited or indirect evidence. The remaining predictions (primary pulmonary lymphoma, monocytic leukaemia, rare rhabdomyosarcoma subtypes, ganglioneuroblastoma and fetal adenocarcinoma of the lung) are on Hold because of very limited direct evidence.
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.