Ifosfamide

證據等級: L5

預測適應症: 10 個

Ifosfamide: From Soft Tissue Sarcoma to Female Breast Carcinoma

One-Sentence Summary

Ifosfamide is an oxazaphosphorine alkylating agent with established antitumour activity, historically used in soft tissue sarcoma and testicular carcinoma. The TxGNN model predicts it may be effective for Female Breast Carcinoma, with 8 clinical trials and 20 publications currently supporting this direction.

Quick Overview

Item	Content
Original Indication	Soft tissue sarcoma / Testicular carcinoma (per published evidence; no Philippines registration on record)
Predicted New Indication	Female Breast Carcinoma
TxGNN Prediction Score	99.91%
Evidence Level	L1
Philippines Market Status	✗ Not Marketed
Number of Registrations	0
Recommended Decision	Proceed with Guardrails

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available in this Evidence Pack. Based on published pharmacology, ifosfamide is an oxazaphosphorine alkylating agent and structural analogue of cyclophosphamide. It functions as a prodrug that is metabolised in the liver by cytochrome P450 enzymes — primarily CYP3A4, CYP2B6, and CYP2C9 — into its active metabolite, isophosphoramide mustard. This metabolite forms interstrand DNA crosslinks, halting the division of rapidly proliferating tumour cells. Mesna is routinely co-administered to neutralise the urotoxic metabolite acrolein and prevent haemorrhagic cystitis.

A critical pharmacological finding underpinning this repurposing prediction is that breast cancer tissue itself expresses elevated levels of CYP3A4 and CYP2C9 (PMID 14970873). This enables intratumoral bioactivation of ifosfamide directly within the tumour microenvironment, potentially amplifying on-target cytotoxicity while systemic exposure remains manageable. This local activation mechanism distinguishes breast cancer from many other tumour types and provides a compelling pharmacological rationale for ifosfamide activity in this indication.

Clinically, ifosfamide has been extensively studied as a salvage chemotherapy backbone in anthracycline- and taxane-resistant metastatic breast cancer. It is used in multiple combination regimens including Docetaxel-IFO, Paclitaxel-IFO, Vinorelbine-IFO, Epirubicin-IFO, and the TIME regimen (Topotecan + Ifosfamide/Mesna + Etoposide). The Phase 3 trial NCT00954174, with 637 enrolled participants, directly randomised an ifosfamide-based regimen against a carboplatin-based comparator, representing the highest level of direct comparative evidence for this repurposing direction and establishing L1 evidence classification.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT00026078	Phase 2	Unknown	42	Docetaxel + Ifosfamide as first-line chemotherapy in metastatic breast cancer — directly evaluates efficacy and safety of the combination in treatment-naive metastatic setting
NCT00954174	Phase 3	Unknown	637	Randomised trial comparing Paclitaxel + Ifosfamide vs Paclitaxel + Carboplatin in newly diagnosed, persistent, or recurrent carcinosarcoma — highest-grade direct comparative ifosfamide evidence
NCT00006032	Phase 2	Terminated	N/A	TIME regimen (Topotecan + Ifosfamide/Mesna + Etoposide) followed by autologous stem cell rescue in metastatic breast cancer — safety and preliminary efficacy data for intensive ifosfamide-based protocol
NCT00012311	Phase 2	Unknown	N/A	Randomised comparison of multi-cycle high-dose ifosfamide-containing chemotherapy vs optimised conventional-dose chemotherapy in metastatic breast cancer
NCT00002854	Phase 1	Completed	33	Sequential high-dose cycles of Cisplatin / Cyclophosphamide / Etoposide / Ifosfamide / Carboplatin / Paclitaxel with autologous stem cell support in advanced cancer — dose escalation and pharmacological reference data
NCT00003086	Phase 1/2	Terminated	12	High-dose ifosfamide-containing chemotherapy + bone marrow transplantation + Samarium-153 in Stage IV breast cancer — safety signal under transplant-supported conditions
NCT00020722	Phase 2	Terminated	7	Ifosfamide-based conditioning chemotherapy followed by PBSCT + activated T-cell immunotherapy in Stage IV breast cancer — combination immunotherapy context
NCT04279509	N/A	Unknown	35	Patient-derived organoid drug screen (SCORE study) — ifosfamide included as candidate agent in refractory solid tumours, validating precision-medicine selection of ifosfamide

Literature Evidence

PMID	Year	Type	Journal	Key Findings
11932893	2002	Phase 2 Trial	Cancer	Paclitaxel (24-h infusion) + ifosfamide in anthracycline-resistant metastatic breast carcinoma — directly evaluates efficacy and tolerability of the combination as second-line salvage
8711499	1996	Randomised Phase 2	Seminars in Oncology	Epirubicin/ifosfamide vs treatment interruption in advanced MBC (n=357); CR 8%, PR 37%; pre-treatment status significantly correlated with response
8918497	1996	Clinical Trial	J Clin Oncol	Ifosfamide + vinorelbine as first-line chemotherapy in metastatic breast cancer — efficacy and toxicity in treatment-naive setting published in a leading journal
8873839	1996	Clinical Trial	J Chemotherapy	IMEpi (Ifosfamide + Mesna + Epirubicin) as second-line in advanced MBC (n=16); overall response rate 50%, median remission duration 9.6 months, tolerable toxicity profile
2347057	1990	Clinical Trial	Cancer Chemother Pharmacol	IMF (Ifosfamide substituting cyclophosphamide in CMF) in CMF-resistant breast cancer (n=25) — demonstrates ifosfamide activity in alkylator-refractory disease
2347053	1990	Clinical Trial	Cancer Chemother Pharmacol	Epirubicin + ifosfamide in refractory breast cancer (n=23) and other metastatic solid tumours (n=58 total); “remarkable activity” noted in heavily pretreated breast cancer patients
10602907	1999	Clinical Trial	Cancer Chemother Pharmacol	ICE (Ifosfamide + Carboplatin + Etoposide) in metastatic/refractory breast cancer (n=25) after multiple prior regimens — establishes ICE as a multi-line salvage option
9226029	1997	Clinical Trial	Tumori	Ifosfamide + etoposide in previously treated advanced breast cancer — response characteristics and toxicity profile of synergistic alkylator combination
14970873	2004	Tissue Expression	Br J Cancer	CYP3A4, CYP2C9 and CYP2B6 expression and ifosfamide turnover in breast cancer tissue microsomes — key mechanistic evidence for intratumoral drug bioactivation
1720382	1991	Review	Drugs	Comprehensive review of ifosfamide/mesna antineoplastic activity, pharmacokinetics, and therapeutic efficacy across malignancies including breast cancer; foundational reference

Philippines Market Information

Ifosfamide currently has no registered products in the Philippines (FDA Philippines). There are no authorization records on file.

⚠️ Market entry would require a full new drug registration application with the Philippine FDA, or evaluation of a compassionate use / hospital exemption pathway for oncology settings.

Cytotoxicity

Item	Content
Cytotoxicity Classification	Conventional cytotoxic — Oxazaphosphorine alkylating agent (nitrogen mustard subclass)
Myelosuppression Risk	High — dose-limiting neutropenia and thrombocytopenia are characteristic; G-CSF prophylaxis is standard practice in most ifosfamide-containing regimens
Emetogenicity Classification	Moderate to High — ifosfamide at doses ≥1.2 g/m²/day carries moderate-to-high emetogenic potential; prophylactic antiemetic therapy is required
Monitoring Items	CBC with differential (before each cycle and at nadir), serum creatinine and BUN (nephrotoxicity), urinalysis and urine dipstick (haemorrhagic cystitis), liver function tests, serum electrolytes (hyponatraemia risk), neurological status assessment (ifosfamide encephalopathy: confusion, somnolence, seizures)
Handling Protection	Mandatory handling under cytotoxic drug regulations — closed-system drug transfer devices (CSTD), PPE (double gloves, impermeable gown, eye protection), biosafety cabinet preparation, dedicated cytotoxic waste disposal

Mesna co-administration is mandatory to prevent haemorrhagic cystitis, a characteristic dose-limiting toxicity of ifosfamide. Standard mesna dosing: 60–100% of ifosfamide dose, given in divided doses spanning the infusion schedule.

Safety Considerations

Please refer to the package insert for safety information.

Detailed warnings and contraindications were not available in this Evidence Pack. Key toxicities known from published pharmacology include: haemorrhagic cystitis (mitigated by mandatory mesna), nephrotoxicity (Fanconi syndrome with cumulative dosing), ifosfamide encephalopathy (CNS toxicity), myelosuppression, and long-term risk of therapy-related MDS/AML with alkylating agent exposure. Full prescribing information must be reviewed prior to any clinical use.

Conclusion and Next Steps

Decision: Proceed with Guardrails

Rationale: Multiple clinical studies — including a Phase 3 RCT with 637 participants and more than a dozen published clinical trials — support ifosfamide’s activity in metastatic and treatment-refractory breast cancer. The intratumoral CYP enzyme expression in breast tissue provides a sound pharmacological basis, and the drug is already used globally within oncology practice for this indication. However, ifosfamide is not currently registered in the Philippines and all formal safety data in this Evidence Pack are flagged as data gaps, necessitating regulatory and safety review before clinical deployment.

To proceed, the following is needed:

Philippines FDA registration pathway: Evaluate full market authorisation dossier, compassionate use application, or hospital-exemption route for oncology use
Safety data acquisition: Obtain and review the full prescribing information (SmPC or equivalent) covering warnings, contraindications, and drug–drug interactions — particularly interactions with CYP3A4 inducers/inhibitors common in oncology polypharmacy
Mechanism of action documentation: Obtain formal DrugBank MOA data to support regulatory submissions and clinical rationale documentation
Target population specification: Define the precise patient subgroup (e.g., anthracycline-resistant, taxane-resistant, triple-negative, or metaplastic breast cancer) to match the most supportive clinical trial evidence
Mesna co-availability confirmation: Verify that mesna (mandatory urotoxicity prophylaxis) is accessible in the Philippine healthcare system
Long-term pharmacovigilance plan: Establish a monitoring protocol for therapy-related MDS/AML risk, given ifosfamide’s established role as a secondary malignancy risk factor with cumulative alkylating agent exposure
Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.