Ifosfamide
| Evidence Level: L5 | Predicted Indications: 10 |
Table of Contents
Ifosfamide: From Cancer Chemotherapy to Female Breast Carcinoma
One-Sentence Summary
Ifosfamide is an alkylating chemotherapy drug that is registered in Singapore as an injectable anticancer product. The TxGNN model predicts it may be effective for female breast carcinoma. Support comes from 6 clinical trials (mostly older, early-phase, combination-regimen studies) and about 20 publications (reviews, Phase 2 studies and small cohorts), but no completed randomized Phase 2/3 trial isolates ifosfamide's effect in breast cancer.
Quick Overview
| Item | Content |
|---|---|
| Original Indication | Not stated in the Singapore registration record; ifosfamide is a cytotoxic anticancer agent (best known in sarcoma and germ cell tumours) |
| Predicted New Indication | Female breast carcinoma |
| TxGNN Prediction Score | 99.91% |
| Evidence Level | L3 (reviews, Phase 2 studies and cohorts; no completed Phase 2/3 RCT) |
| Singapore Market Status | ✓ Marketed |
| Number of Registrations | 1 |
| Recommended Decision | Hold |
Why is This Prediction Reasonable?
Ifosfamide is a prodrug. The liver activates it through cytochrome P450 enzymes to isophosphoramide mustard, which cross-links DNA and triggers apoptosis in rapidly dividing tumour cells. Detailed mechanism-of-action data were not available in the data compiled for this report, so this description reflects the drug's established pharmacology.
Breast cancer cells are proliferative and can respond to DNA-damaging alkylators. Ifosfamide has been tested in advanced or metastatic breast cancer both alone and in combination with docetaxel, vinorelbine, etoposide, paclitaxel and mitoxantrone. It has also been used in high-dose regimens with stem cell support. Published reviews report single-agent response rates of roughly 7–30% in pretreated patients, with higher rates in combinations.
Ifosfamide is not a standard breast cancer agent, and most of this evidence is from the 1990s and early 2000s. Recent data are limited to selected subtypes, namely metaplastic breast cancer and malignant phyllodes tumours. The prediction is therefore plausible but not strongly supported by modern evidence.
Clinical Trial Evidence
| Trial Number | Phase | Status | Enrollment | Key Findings |
|---|---|---|---|---|
| NCT00026078 | Phase 2 | Unknown | 42 | Docetaxel plus ifosfamide as first-line therapy in metastatic breast cancer; directly tests ifosfamide, but no results are posted |
| NCT00012311 | Phase 2 | Unknown | Not reported | Randomized comparison of multi-cycle high-dose chemotherapy versus optimized conventional chemotherapy in metastatic breast cancer; ifosfamide's contribution cannot be isolated |
| NCT00002854 | Phase 1 | Completed | 33 | Sequential high-dose cisplatin, cyclophosphamide, etoposide, ifosfamide, carboplatin and paclitaxel with stem cell support in advanced cancer; feasibility and safety study |
| NCT00006032 | Phase 2 | Terminated | Not reported | Intensive-dose topotecan, ifosfamide/mesna and etoposide followed by autologous stem cell rescue in metastatic breast cancer; combination design confounds attribution |
| NCT00003086 | Phase 1/2 | Terminated | 12 | Samarium-153 within a double autologous transplant in stage IV breast cancer; ifosfamide is a background component |
| NCT00020722 | Phase 2 | Terminated | 7 | Activated T cells after stem cell transplant in stage IV breast cancer; ifosfamide is peripheral to the tested intervention |
Literature Evidence
| PMID | Year | Type | Journal | Key Findings |
|---|---|---|---|---|
| 14586149 | 2003 | Review | Oncology | Ifosfamide in advanced breast cancer: single-agent response rates of 7–30% in pretreated patients; mesna has largely removed the dose-limiting urotoxicity; combinations show higher response rates |
| 1720382 | 1991 | Review | Drugs | Broad review of ifosfamide/mesna activity, pharmacokinetics and efficacy across cancers; mostly non-comparative studies |
| 1390313 | 1992 | Review | Annals of Oncology | History of ifosfamide in breast cancer; about 20% objective response as monotherapy in early trials |
| 39306877 | 2024 | Cohort | Current Problems in Cancer | Experience with first-line ifosfamide-based chemotherapy in metaplastic breast cancer, a subtype that responds poorly to standard anthracycline/taxane regimens |
| 39074497 | 2024 | Cohort | JNCCN | Propensity-matched study of adjuvant chemotherapy and long-term prognosis in breast malignant phyllodes tumours |
| 8918497 | 1996 | Phase 2 trial | Journal of Clinical Oncology | Ifosfamide plus vinorelbine as first-line chemotherapy for metastatic breast cancer |
| 11932893 | 2002 | Phase 2 trial | Cancer | 24-hour paclitaxel plus ifosfamide in anthracycline-resistant metastatic breast carcinoma |
| 8445421 | 1993 | Phase 2 trial | Journal of Clinical Oncology | Ifosfamide plus mitoxantrone as first-line chemotherapy for metastatic breast cancer |
| 9226029 | 1997 | Phase 2 trial | Tumori | Ifosfamide plus etoposide in previously treated advanced breast cancer, evaluating response and toxicity |
| 2347057 | 1990 | Clinical study | Cancer Chemother Pharmacol | Ifosfamide substituted for cyclophosphamide in the CMF regimen in 25 patients with CMF-refractory or relapsed breast cancer |
Singapore Market Information
| Authorization Number | Product Name | Dosage Form | Approved Indication |
|---|---|---|---|
| SIN01699P | HOLOXAN FOR INJECTION 1 g/25 ml (Baxter Oncology GmbH) | Injection, powder, for solution | Not specified in the registration record |
Cytotoxicity
| Item | Content |
|---|---|
| Cytotoxicity Classification | Conventional cytotoxic (alkylating agent, oxazaphosphorine class) |
| Myelosuppression Risk | High (leukopenia, thrombocytopenia and anaemia are expected; a therapy-related myeloid neoplasm risk is also documented in the literature) |
| Emetogenicity Classification | Moderate to high, depending on dose |
| Monitoring Items | CBC with differential, renal function and electrolytes (including potassium), liver function, urinalysis for haematuria, neurological status |
| Handling Protection | Must follow cytotoxic drug handling regulations; mesna co-administration is routinely used for uroprotection |
Safety Considerations
- Disease associations flagged in the knowledge graph (drug-disease contraindication links, not package-insert text): kidney disease, liver disease, gallbladder disease, thrombocytopenia, leukopenia, anaemia (including macrocytic anaemia), potassium deficiency, hyperbilirubinemia (including hereditary forms and Gilbert syndrome), renal tubular acidosis, Fanconi renotubular syndrome and pyoureter.
- Drug interactions: 100 interactions were identified, mostly moderate. Examples include amphotericin B (including the lipid complex), the aminoglycosides kanamycin and neomycin, aprepitant, bupropion, morphine, metoclopramide, scopolamine, dronabinol and nabilone. Several sulfonylureas and glinides also interact (chlorpropamide, glimepiride, glipizide, glyburide, tolazamide, acetohexamide, nateglinide, repaglinide). Levofloxacin is a minor interaction.
Please refer to the package insert for label-based warnings and contraindications.
Conclusion and Next Steps
Decision: Hold
Rationale: The breast cancer evidence is mostly older Phase 1/2 work and reviews, and ifosfamide is not a standard breast cancer drug. No completed randomized trial isolates its contribution. The safety profile is demanding (myelosuppression, nephrotoxicity, neurotoxicity, urotoxicity). Without modern comparative data, this does not justify moving forward. Note that another TxGNN prediction for this drug, rhabdomyosarcoma, has much stronger support: several completed Phase 3 sarcoma trials and established ifosfamide-based regimens. That indication may be a better candidate for "Proceed with Guardrails", provided rhabdomyosarcoma-specific Phase 3 data are confirmed.
To proceed, the following is needed:
- Contemporary comparative data (preferably randomized) for ifosfamide in breast cancer, for example in metaplastic breast cancer or anthracycline- and taxane-resistant disease
- Results from the unknown-status trials (NCT00026078, NCT00012311)
- The approved indication wording and package-insert warnings for the Singapore product (SIN01699P)
- Detailed mechanism-of-action data
- A safety monitoring plan covering renal, neurological, haematological and urinary toxicity, plus secondary malignancy risk
Disclaimer
This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.