Ifosfamide
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
- Ifosfamide
- Pharmacist Assessment Report
- Ifosfamide: From Cytotoxic Chemotherapy (Alkylating Agent) to Female Breast Carcinoma
- One-Sentence Summary
- Quick Overview
- Why is This Prediction Reasonable?
- Clinical Trial Evidence
- Literature Evidence
- India Market Information
- Cytotoxicity
- Safety Considerations
- Conclusion and Next Steps
- Disclaimer
Ifosfamide: From Cytotoxic Chemotherapy (Alkylating Agent) to Female Breast Carcinoma
One-Sentence Summary
Ifosfamide is an injectable alkylating chemotherapy drug, marketed in India under 15 registrations. The registration records compiled for this report do not list an approved indication text. The TxGNN model predicts it may be useful in female breast carcinoma, with 6 clinical trials (all Phase 1/2, none with results) and 20 publications pointing in this direction. The evidence is mostly small Phase 2 studies and reviews, and ifosfamide is not a standard-of-care breast cancer agent.
Quick Overview
| Item | Content |
|---|---|
| Predicted New Indication | Female breast carcinoma |
| TxGNN Prediction Score | 0.9991 |
| Evidence Level | L5 (Phase 2 studies, cohorts and reviews; no completed Phase 2/3 RCT) |
| India Market Status | Listed in a compiled Indian medicine price dataset (15 of 15) – CDSCO approval status is not included in this data |
| Number of Listed Products | 15 (valid: 15) |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Detailed mechanism-of-action data are not available in the compiled dataset. Ifosfamide is known to be an alkylating prodrug. The liver activates it through cytochrome P450 enzymes to isophosphoramide mustard, which cross-links DNA and triggers apoptosis in rapidly dividing tumour cells.
Ifosfamide is an analogue of cyclophosphamide, a drug long used in breast cancer, so activity in this disease is mechanistically plausible. Published work supports this. Single-agent response rates of roughly 7–30% have been reported in pretreated advanced breast cancer. Phase 2 combinations with vinorelbine, mitoxantrone, etoposide, paclitaxel and docetaxel have also been reported.
Several limitations apply:
- Most of the evidence is from the 1990s and early 2000s.
- Ifosfamide is not part of standard breast cancer regimens.
- The newer retrospective support is limited to rare subsets, such as metaplastic breast cancer and malignant phyllodes tumours.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00026078 | Phase 2 | Unknown | 42 | Docetaxel plus ifosfamide as first-line chemotherapy in metastatic breast cancer. This is the most direct test of the drug in the target indication; no results are posted. |
| NCT00012311 | Phase 2 | Unknown | Not reported | Randomised comparison of multi-cycle high-dose chemotherapy with stem cell support versus optimised conventional chemotherapy in metastatic breast cancer. Ifosfamide is likely part of the regimen but is not the tested variable. |
| NCT00002854 | Phase 1 | Completed | 33 | Sequential high-dose cisplatin, cyclophosphamide, etoposide/ifosfamide, carboplatin and paclitaxel with stem cell support in advanced cancer. Provides feasibility and safety data. |
| NCT00006032 | Phase 2 | Terminated | Not reported | TIME regimen (topotecan, ifosfamide/mesna, etoposide) with autologous stem cell rescue in metastatic breast cancer. Confounded by the transplant. |
| NCT00003086 | Phase 1/2 | Terminated | 12 | Samarium-153 with sequential autologous transplant in stage IV breast cancer. Ifosfamide is not the focus. |
| NCT00020722 | Phase 2 | Terminated | 7 | Activated T cells after stem cell transplant in stage IV breast cancer. Only tangentially related to ifosfamide. |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 14586149 | 2003 | Review | Oncology | Ifosfamide is active in breast cancer. Single-agent response rates are 7–30% in pretreated patients, and combinations with active drugs look more promising. Mesna has largely removed the main dose-limiting toxicity, urotoxicity. |
| 39306877 | 2024 | Cohort | Current Problems in Cancer | Experience with first-line ifosfamide-based chemotherapy in metaplastic breast cancer, a rare variant that responds poorly to standard anthracycline/taxane regimens. |
| 8918497 | 1996 | Phase 2 study | J Clin Oncol | Ifosfamide plus vinorelbine as first-line chemotherapy for metastatic breast cancer. |
| 8445421 | 1993 | Phase 2 study | J Clin Oncol | Ifosfamide plus mitoxantrone as first-line chemotherapy for metastatic breast carcinoma. |
| 11932893 | 2002 | Phase 2 study | Cancer | 24-hour paclitaxel plus ifosfamide in anthracycline-resistant metastatic breast carcinoma. |
| 9226029 | 1997 | Clinical study | Tumori | Ifosfamide plus etoposide in previously treated advanced breast cancer, evaluating response and toxicity. |
| 2112056 | 1990 | Clinical study | Cancer Chemother Pharmacol | Ifosfamide/etoposide with mesna uroprotection in 44 patients with refractory advanced breast cancer. |
| 1390313 | 1992 | Review | Ann Oncol | Ifosfamide shows about 20% objective response as monotherapy in breast cancer and has been combined with other agents. |
| 1720382 | 1991 | Review | Drugs | Review of ifosfamide/mesna: its antineoplastic activity, pharmacokinetics and efficacy. Mesna has almost eliminated haemorrhagic cystitis. |
| 39074497 | 2024 | Cohort | J Natl Compr Canc Netw | Propensity-matched study of adjuvant chemotherapy and long-term prognosis in malignant phyllodes tumours of the breast. |
India Market Information
There are 15 valid single-ingredient registrations, all injectable. The 5 main ones are listed below. Approved indication text is not recorded in the registration data.
| Authorization Number | Product Name | Dosage Form | Manufacturer |
|---|---|---|---|
| 104310 | Holoxan 1gm Injection | Vial, injection | Zydus Cadila |
| 110220 | Ifos 1gm Injection | Vial, injection | Cipla Ltd |
| 111208 | Ipamide 2gm Injection | Vial, injection | Fresenius Kabi India Pvt Ltd |
| 209864 | Soloxan with Mesna 2gm Injection | Vial, injection | Vhb Life Sciences Inc |
| 87255 | Fosfa 2gm Injection | Vial, injection | Getwell Oncology Pvt Ltd |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (oxazaphosphorine alkylating agent, prodrug) |
| Myelosuppression Risk | High (leukopenia, thrombocytopenia and anaemia are expected) |
| Emetogenicity Classification | Moderate to high, depending on dose |
| Monitoring Items | CBC with differential, renal function and electrolytes (including potassium), liver function and bilirubin, urinalysis for haematuria, neurological status |
| Handling Protection | Must follow cytotoxic drug handling regulations. Concurrent mesna uroprotection is standard. |
Safety Considerations
- Disease-related cautions (from the TxGNN knowledge graph, not label text): The graph links ifosfamide to contraindication or caution with kidney disease, liver disease, gallbladder disease, thrombocytopenia, leukopenia, anaemia, potassium deficiency, hyperbilirubinaemia (including Gilbert syndrome), renal tubular acidosis, Fanconi syndrome and pyoureter.
- Secondary malignancy signal: Literature in the compiled data links ifosfamide-containing chemotherapy to therapy-related myelodysplastic syndrome and secondary leukaemia in cancer survivors.
- Drug interactions: 471 interactions were found. The examples reviewed were mostly moderate:
- Amphotericin B (including the lipid complex), kanamycin and neomycin
- Aprepitant, bupropion, metoclopramide and morphine
- Sulfonylureas and glinides (glimepiride, glipizide, glyburide, chlorpropamide, tolazamide, acetohexamide, nateglinide, repaglinide)
- Dronabinol, nabilone and scopolamine
Levofloxacin was minor.
Please refer to the package insert for official warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale: The mechanism is plausible and a body of Phase 2 literature supports activity in metastatic breast cancer. However, the supporting trials are old, small and unresolved (unknown or terminated, with no posted results), and ifosfamide is not a standard-of-care breast cancer agent. It also carries significant haematological, renal and neurological toxicity. This supports treating it as a research question, not advancing it as a development candidate.
Among the other TxGNN predictions, rhabdomyosarcoma has far stronger support. It is backed by several completed Phase 3 trials in soft tissue sarcoma and by ifosfamide’s established role in rhabdomyosarcoma regimens. It would be the better candidate to prioritise, with guardrails (mesna uroprotection, nephrotoxicity, neurotoxicity and myelosuppression monitoring). The myelodysplastic syndrome, cytopenia and anaemia predictions are not biologically supported, because ifosfamide causes those conditions.
To proceed, the following is needed:
- Results or publication of the unresolved Phase 2 breast cancer trials, or a new randomised trial in a defined subset such as metaplastic breast cancer or malignant phyllodes tumours
- Detailed mechanism-of-action data from DrugBank
- Package insert warnings and contraindications from the Indian regulator’s records, including approved indication text
- A comparison of benefit and toxicity against current standard breast cancer regimens
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.