Doxorubicin, Ifosfamide, and Mesna (AIM) Regimen Dosing
The AIM regimen for soft tissue sarcoma consists of doxorubicin 75 mg/m² (given as 25 mg/m² per day on days 1-3) plus ifosfamide 10 g/m² over 4 days with mesna and pegfilgrastim support, repeated every 3 weeks for up to 6 cycles. 1
Standard Dosing Schedule
Doxorubicin Component
- 75 mg/m² total dose administered as 25 mg/m² per day on days 1-3 1
- Alternative: 75 mg/m² as single intravenous bolus on day 1 or as 72-hour continuous infusion 1
Ifosfamide Component
- 10 g/m² total dose administered over 4 days (2.5 g/m² per day) 1
- Alternative standard dosing: 3,750 mg/m² on days 1 and 2 (total 7.5 g/m²) 2
- Lower-intensity option: 1.2 g/m² per day as continuous infusion over 5 days (total 6 g/m²) 3
Mesna Uroprotection Protocol
- For standard-dose ifosfamide (<2.5 g/m²/day): Mesna at 60% of total daily ifosfamide dose, given as three bolus doses—15 minutes before ifosfamide, then 4 and 8 hours after 4
- For continuous infusion: Mesna 20% of ifosfamide dose as bolus, followed by continuous infusion equal to 40% of ifosfamide dose, continuing 12-24 hours after ifosfamide completion 4
- FDA-approved oral regimen: IV mesna bolus at 20% of ifosfamide dose at time of administration, then oral mesna tablets at 40% of ifosfamide dose at 2 and 6 hours after each ifosfamide dose (total daily mesna = 100% of ifosfamide dose) 4, 5
Supportive Care
- Pegfilgrastim (G-CSF) should be administered with the intensified regimen to manage neutropenia 1
- Maintain diuresis of 200 ml/hour during therapy 6
- Patients should urinate frequently, especially upon waking, to prevent acrolein-induced hemorrhagic cystitis 5
Clinical Context and Indications
When to Use AIM Regimen
- Unresectable or stage IV soft tissue sarcoma where AIM is the most active chemotherapy regimen in unselected patient populations 4
- Good performance status patients (WHO 0-1, age 18-60 years) with high-grade sarcoma where tumor shrinkage is the specific goal 1
- Selected histologic subtypes with greater ifosfamide sensitivity: synovial sarcoma, undifferentiated pleomorphic sarcoma 4
- Neoadjuvant setting when downstaging is needed to facilitate resection 4
Important Limitations
- Do NOT use for leiomyosarcoma: Doxorubicin plus dacarbazine is preferred, as ifosfamide combination may be detrimental in this subtype 4
- Not recommended for low-grade tumors 4
Treatment Duration and Monitoring
Cycle Schedule
Critical Toxicity Management
- Grade 3-4 neutropenia occurs in 42-43% of patients 1
- Febrile neutropenia occurs in 46% with intensified regimen vs 13% with doxorubicin alone 1
- Grade 3-4 thrombocytopenia in 33% vs <1% with doxorubicin alone 1
- Encephalopathy can occur with both standard and high-dose ifosfamide regimens 6
- If patient vomits within 2 hours of oral mesna, repeat the dose or switch to IV mesna 4, 5
Alternative Dosing Considerations
Ambulatory 5-Day Infusion
For patients requiring outpatient treatment, ifosfamide 6 g/m² plus mesna 6 g/m² as 1:1 concentration continuous infusion over 5 days (1.2 g/m² per day each) is feasible and well-tolerated 3
High-Dose Ifosfamide (Second-Line)
For patients progressing on standard doses, high-dose ifosfamide 12-14 g/m²/cycle administered over 6 or 14 days with G-CSF and mesna support can circumvent tumor resistance 4
Evidence Quality and Nuances
The survival benefit of AIM over doxorubicin alone is controversial. The EORTC 62012 trial showed no significant overall survival difference (14.3 vs 12.8 months, HR 0.83, p=0.076), though progression-free survival (7.4 vs 4.6 months, p=0.003) and response rates (26% vs 14%, p<0.0006) significantly favored the combination 1. An earlier ECOG trial showed response rate improvement (34% vs 20%, p=0.04) with median survival of 11.5 vs 8.8 months 2.
Therefore, use AIM when tumor shrinkage is the specific therapeutic goal (e.g., to enable surgical resection or palliate symptoms from tumor bulk), but not routinely for palliation given the substantially higher toxicity without proven survival benefit 1.