| Cycle length: 21 days. |
| Drug | Dose and route | Administration | Given on days |
| Doxorubicin | 20 mg/m2 per day IV | Dilute with 1000 mL NS* and administer as a continuous IV infusion over 24 hours daily. | Days 1 through 3 |
| Ifosfamide | 1500 mg/m2 per day IV | Dilute with 500 mL NS* to a final concentration of 0.6 to 20 mg/mL and administer over two hours daily. | Days 1 through 4 |
| Mesna¶ | Total daily dose 900 mg/m2 IV | Administer 300 mg/m2 in NS or D5W* in water over one hour prior to each daily dose of ifosfamide. Total concentration of mesna should not exceed 20 mg/mL. Repeat at four and eight hours after the initiation of each dose of ifosfamide daily. | Days 1 through 4 |
| Pretreatment considerations: |
| Hydration | - Adequate hydration (at least two liters of oral or IV fluids per day) should be maintained with ifosfamide to reduce the risk of ifosfamide bladder toxicity.[2]
- Refer to UpToDate topics on hemorrhagic cystitis in cancer patients.
- The choice of hydration fluid is empiric and may vary by institution and protocol. The original protocol administered 500 mL of D5W containing electrolytes (sodium acetate 120 mEq/L [equal to 120 mmol/L], magnesium sulfate 500 mg/L [equal to 2.03 mmol/L], and potassium acetate 40 mEq/L [equal to 40 mmol/L]) over one hour before the start of each dose of ifosfamide, and maintenance hydration of the same hydration fluid over one hour at the completion of each ifosfamide dose; IV fluid was discontinued after completion of the eight-hour dose of mesna on each treatment day.[1]
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| Emesis risk | - HIGH (>90% risk of emesis).
- Concomitant administration of aprepitant may increase the risk of ifosfamide neurotoxicity;[2-5] its use is avoided at some institutions.
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
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| Prophylaxis for infusion reactions | - There is no standard premedication regimen.
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
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| Vesicant/irritant properties | - Doxorubicin is a vesicant; avoid extravasation. Infusional regimens should be administered through a central venous line.
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
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| Infection prophylaxis | - This regimen was designed to include primary prophylaxis with a granulocyte colony stimulating factor in all cycles.[1]
- Refer to UpToDate topics on use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation.
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| Dose adjustment for baseline liver or kidney dysfunction | - A lower initial ifosfamide dose may be needed for patients with preexisting kidney or liver impairment.[2] A lower starting dose of doxorubicin may be needed for patients with preexisting liver impairment.[6]
- Before starting treatment with ifosfamide, it is necessary to exclude or correct any urinary tract obstructions.
- Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents; chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents; and chemotherapy nephrotoxicity and dose modification in patients with kidney impairment, conventional cytotoxic agents.
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| Cardiac issues | - Doxorubicin is associated with cardiomyopathy, the incidence of which is related to the cumulative dose. Assess baseline LVEF prior to administration. Doxorubicin is contraindicated for patients with recent myocardial infarction, severe myocardial dysfunction, severe arrhythmia, or previous therapy with high cumulative doses of doxorubicin or any other anthracyclines.[6]
- Refer to UpToDate topics on clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity and prevention and management of anthracycline cardiotoxicity.
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| Monitoring parameters: |
- CBC with differential and platelet count weekly during treatment.
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- Ifosfamide is associated with cumulative nephrotoxicity, mostly at a total dose above 60 g/m2. Clinical manifestations may include hypophosphatemia, kidney potassium wasting, metabolic acidosis with a normal ion gap, and rarely, polyuria due to nephrogenic diabetes insipidus. Assess creatinine and electrolytes, including potassium and phosphate, daily during treatment and prior to each subsequent treatment cycle.
- Refer to UpToDate topics on ifosfamide nephrotoxicity.
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- Mesna does not prevent hemorrhagic cystitis in all patients.[7] Perform urinalysis on a morning specimen of urine for hematuria daily, on days 1 through 4.
- Refer to UpToDate topics on hemorrhagic cystitis in cancer patients.
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- Monitor for ifosfamide neurotoxicity (confusion, coma, rarely seizures, weakness, neuropathy, ataxia, cranial nerve dysfunction) daily on days 1 through 4. Central nervous system side effects may be especially problematic in those over age 60.
- Refer to UpToDate topics on overview of neurologic complications of conventional non-platinum cancer chemotherapy.
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- Assay liver function tests prior to each treatment cycle.
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- Monitor cumulative doxorubicin dose. Reassess LVEF periodically during therapy as clinically indicated.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Delay treatment cycle until the absolute neutrophil count is ≥1500/microL and platelet count is ≥100,000/microL.[1] Discontinue for >2 week delay in recovery. Reduce doses of doxorubicin and ifosfamide by 10% for febrile neutropenia despite the use of hematopoietic growth factors.
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| Neurologic toxicity | - Discontinue ifosfamide treatment for encephalopathy.
- Refer to UpToDate topics on overview of neurologic complications of conventional non-platinum cancer chemotherapy.
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| Kidney toxicity | - In the original protocol, a 50% dose reduction for ifosfamide was recommended for creatinine rise to 1.5 times ULN during therapy; treatment was discontinued or rise of >1.5 times ULN.[1] In addition, among patients with a normal baseline serum creatinine level, we suggest ifosfamide dose reduction for a day 1 serum creatinine of 1.8 mg/dL or greater.
- Refer to UpToDate topics on ifosfamide nephrotoxicity.
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| Bladder toxicity | - For microscopic hematuria (>10 RBC per HPF) despite mesna, withhold ifosfamide until complete resolution. Although formal guidelines are not available from the US Food and Drug Administration, reduce ifosfamide dose for grade 3 or worse hemorrhagic cystitis not responding to an increase in IV fluids and mesna.
- Refer to UpToDate topics on hemorrhagic cystitis in cancer patients.
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
