Doxorubicin
| Evidence Level: L1 | Predicted Indications: 8 |
Table of Contents
- Doxorubicin
- Pharmacist Assessment Report
- Doxorubicin: From Lymphoma and Leukaemia to Ewing Sarcoma
- One-Sentence Summary
- Quick Overview
- Why is This Prediction Reasonable?
- Clinical Trial Evidence
- Literature Evidence
- Australia Market Information
- Cytotoxicity
- Safety Considerations
- Conclusion and Next Steps
- Other Predicted Indications (Summary)
- Disclaimer
Doxorubicin: From Lymphoma and Leukaemia to Ewing Sarcoma
One-Sentence Summary
Doxorubicin is an anthracycline cytotoxic agent, originally used for lymphoblastic leukaemia, Hodgkin and non-Hodgkin lymphoma, and related blood cancers. The TxGNN model predicts it may be effective for Ewing sarcoma, with 28 clinical trials and 20 publications currently supporting this direction. Doxorubicin is already a backbone drug in standard multi-agent Ewing sarcoma regimens (VDC/IE), so the prediction is consistent with established clinical use.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Acute lymphoblastic leukaemia, Hodgkin lymphoma, non-Hodgkin lymphoma, mantle cell lymphoma, Langerhans cell histiocytosis (the ARTG indication text is not available) |
| Predicted New Indication | Ewing sarcoma |
| TxGNN Prediction Score | 0.9990 |
| Evidence Level | L1 |
| Australia Market Status | Listed on the PBS Schedule (2 of 2 items) – TGA (ARTG) registration status is not included in this data |
| Number of PBS Items | 2 (valid: 2) |
| Recommended Decision | Proceed with Guardrails |
Why is This Prediction Reasonable?
Detailed mechanism of action data is not available in the data compiled for this report. Doxorubicin is generally understood to be a topoisomerase II inhibitor and DNA intercalator, which is cytotoxic to rapidly dividing tumour cells. This general description comes from standard pharmacology rather than the compiled data.
Its efficacy in lymphoid cancers is established. Ewing sarcoma is also a rapidly proliferating, chemotherapy-sensitive tumour. Doxorubicin is already a core component of the standard multi-agent regimens used there (vincristine, doxorubicin and cyclophosphamide, alternating with ifosfamide and etoposide).
The high TxGNN score (0.999) is therefore in line with current practice. Importantly, doxorubicin’s effect cannot be separated from the other drugs in these combinations, because it is almost never given alone in Ewing sarcoma.
Clinical Trial Evidence
Many trials were identified. The most relevant are listed below. Most are combination-chemotherapy studies, so they do not isolate doxorubicin’s own contribution.
| Trial Number | Phase | Status | Enrolment | Key Findings |
|---|---|---|---|---|
| NCT00006734 | Phase 3 | Completed | 587 | Randomised comparison of chemotherapy intensification through interval compression in Ewing sarcoma and related tumours |
| NCT01231906 | Phase 3 | Completed | 642 | Adding vincristine-topotecan-cyclophosphamide to a standard 5-drug regimen (including doxorubicin) in non-metastatic Ewing sarcoma |
| NCT02063022 | Phase 3 | Completed | 278 | Standard versus intensified treatment in non-metastatic Ewing sarcoma |
| NCT02306161 | Phase 3 | Active, not recruiting | 312 | Ganitumab added to multi-agent chemotherapy (including doxorubicin) in newly diagnosed metastatic Ewing sarcoma |
| NCT00020566 | Phase 3 | Unknown | 1200 | EURO-E.W.I.N.G.99: combination chemotherapy with or without radiotherapy and stem cell transplant |
| NCT00002516 | Phase 3 | Unknown | N/A | EICESS 92: comparison of combination chemotherapy regimens plus surgery and radiotherapy |
| NCT00003667 | Phase 2 | Completed | N/A | Randomised VAC plus dexrazoxane, with or without ImmTher, in high-risk Ewing sarcoma |
| NCT00002466 | Phase 2 | Completed | N/A | Multi-agent chemotherapy followed by resection and radiotherapy in peripheral primitive neuroectodermal tumours and Ewing sarcoma |
| NCT00949325 | Phase 1/2 | Completed | 24 | Temsirolimus plus liposomal doxorubicin in recurrent soft tissue and bone sarcoma |
| NCT06820957 | Phase 2/3 | Terminated | 2 | Vincristine-irinotecan-regorafenib added to VDC/IE in metastatic Ewing sarcoma; ended early with very little data |
No ANZCTR identifiers were included in the data compiled for this report.
Literature Evidence
| 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 and primitive neuroectodermal tumour of bone |
| 36522207 | 2022 | RCT (Phase 3) | Lancet | EE2012: comparison of two chemotherapy regimens in newly diagnosed Ewing sarcoma |
| 36669140 | 2023 | RCT (Phase 3) | J Clin Oncol | Ganitumab with interval-compressed chemotherapy in metastatic Ewing sarcoma |
| 23091096 | 2012 | RCT | J Clin Oncol | Interval-compressed chemotherapy (alternating VDC and IE) in localised Ewing sarcoma |
| 31952545 | 2020 | RCT protocol | Trials | EURO EWING 2012 protocol comparing induction and consolidation regimens |
| 37651654 | 2023 | Long-term follow-up | J Clin Oncol | Long-term outcomes of interval-compressed chemotherapy in localised Ewing sarcoma (AEWS0031) |
| 37403815 | 2023 | Review | Cancer | Consensus recommendations from the National Ewing Sarcoma Tumor Board |
| 26304893 | 2015 | Review | J Clin Oncol | Current management and future approaches in Ewing sarcoma |
| 1833556 | 1991 | Dose-intensity analysis | J Natl Cancer Inst | Influence of doxorubicin dose intensity on response and outcome in osteogenic and Ewing sarcoma |
| 30231396 | 2018 | Review | ASCO Educ Book | Predicting and preventing anthracycline-related cardiotoxicity |
Australia Market Information
| ARTG Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| ARTG 4361M | Adriamycin | Solution for I.V. injection or intravesical administration, doxorubicin hydrochloride 50 mg in 25 mL single dose vial | Not available in the compiled data |
| ARTG 4364Q | Caelyx | Suspension for I.V. infusion, pegylated liposomal doxorubicin hydrochloride 20 mg in 10 mL | Not available in the compiled data |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (anthracycline class) |
| Myelosuppression Risk | High (neutropenia, thrombocytopenia and anaemia are listed as concerns in the data compiled for this report) |
| Emetogenicity Classification | Moderate to high (general class knowledge; please confirm against the Product Information) |
| Monitoring Items | Full blood count with differential, liver function (including bilirubin), renal function, and cardiac assessment (e.g. echocardiography) before and during treatment, with cumulative dose tracking |
| Handling Protection | Must follow cytotoxic drug handling regulations |
Safety Considerations
- Contraindications flagged in the knowledge graph (these are model-derived associations, not label text): liver failure and liver disease, hyperbilirubinaemia, thrombocytopenia, neutropenia, leukopenia, agranulocytosis, anaemia, heart disease, cardiomyopathy, congestive heart failure, heart conduction disease, sudden cardiac arrest, active infectious disease (including fungal infection), G6PD deficiency, and gallbladder disease.
- Drug Interactions: 100 interactions were found. Major-level interactions include dolasetron, cisapride and papaverine. Moderate-level interactions include ondansetron, granisetron, palonosetron, aprepitant, rolapitant, dexamethasone, clarithromycin, levofloxacin, famotidine, loperamide and eliglustat, among others. Several of these are common supportive-care drugs, so antiemetic and supportive regimens need review.
- Cardiotoxicity: the literature highlights cumulative anthracycline cardiotoxicity (PMID 30231396), especially important in children and young adults, who make up most Ewing sarcoma patients.
Warnings and contraindications from the TGA Product Information were not available. Please refer to the TGA-approved Product Information (PI) for authoritative safety information.
Conclusion and Next Steps
Decision: Proceed with Guardrails
Rationale: Several large completed Phase 3 randomised trials and multiple RCTs use doxorubicin-containing regimens as standard therapy in Ewing sarcoma, which supports L1 evidence for the regimen. However, these studies test the combination, not doxorubicin alone, and both formulations on the ARTG are listed without approved indication text.
To proceed, the following is needed:
- Confirm the approved indications for Adriamycin and Caelyx from the TGA Product Information, and check whether Ewing sarcoma is already covered or would be off-label
- Obtain the Product Information warnings and contraindications, which are currently missing
- Obtain detailed mechanism of action data from DrugBank
- Establish a cardiac monitoring plan with a cumulative dose limit, and consider cardioprotection (e.g. dexrazoxane, as studied in NCT00038142 and NCT00003667)
- Review the interactions with antiemetics and other supportive drugs, particularly the major-level interactions
- Define the paediatric versus adult treatment setting and the supporting regimen (VDC/IE)
Other Predicted Indications (Summary)
| Rank | Predicted Indication | Evidence Level | Recommendation |
|---|---|---|---|
| 2 | Well-differentiated fetal adenocarcinoma of the lung | L5 | Hold |
| 3 | Primary pulmonary lymphoma | L3 | Research Question |
| 4 | Pulmonary blastoma | L3 | Proceed with Guardrails |
| 5 | Chronic myelogenous leukaemia, BCR-ABL1 positive | L3 | Research Question (tyrosine kinase inhibitors are standard of care) |
| 6 | Monocytic leukaemia | L4 | Hold |
| 7 | Botryoid-type embryonal rhabdomyosarcoma of the vagina | L5 | Hold |
| 8 | Parameningeal embryonal rhabdomyosarcoma | L5 | Hold |
| 9 | Rhabdomyosarcoma | L1 | Proceed with Guardrails (many trials enrol mixed soft tissue sarcoma populations) |
| 10 | Ganglioneuroblastoma | L4 | Hold |
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.