| Cycle length: 21 days. |
| Drug | Dose and route | Administration | Given on days |
| Doxorubicin | 25 mg/m2 per day IV | Dilute with 50 mL NS or D5W* and administer over one to five minutes. | Days 1, 2, and 3 |
| Ifosfamide | 2000 to 3000 mg/m2 per day IV¶ | Dilute with 250 to 500 mL of NS or D5W* to a final concentration of 0.6 to 20 mg/mL and administer over three hours daily. | Days 1, 2, and 3 |
| MesnaΔ | 1200 to 1800 mg/m2 per day IV (60% of the total daily ifosfamide dose), given in three divided doses | Dilute one-third of the total daily dose in NS or D5W* (total concentration of mesna should not exceed 20 mg/mL) and administer over 15 minutes prior to each daily dose of ifosfamide. Repeat at four and eight hours after the initiation of each dose of ifosfamide daily. | Days 1, 2, and 3 |
| 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 bladder toxicity.[2]
- Refer to UpToDate topics on hemorrhagic cystitis in cancer patients.
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| Emesis risk | - HIGH (>90% risk of emesis).Δ
- Concomitant administration of aprepitant may increase the risk of ifosfamide neurotoxicity;[3-5] 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.
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
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| Infection prophylaxis | - The incidence of febrile neutropenia was not reported in the study; however, severe neutropenia is a frequent adverse event.[1] Primary prophylaxis with hematopoietic growth factors should be considered on an individual basis, particularly for high-risk patients such as those with preexisting neutropenia, advanced disease, poor performance status, or age over 50 years.
- 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. A lower starting dose of doxorubicin may be needed for patients with preexisting liver impairment.[6]
- 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 insufficiency, 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.
|
- 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 3.
- 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 to 3. Central nervous system side effects may be especially problematic for those over age 60.
- Refer to UpToDate topics on overview of neurologic complications of conventional non-platinum cancer chemotherapy.
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- Assess 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 | - No defined dose alterations for myelosuppression were outlined in this study.[1] However, treatment should be delayed until white blood cell count is >4000/microL and platelet count is >100,000/microL. Reduce doses of ifosfamide and doxorubicin by 25% for failure to recover platelets to >100,000/microL by day 28, or for grade 4 neutropenia or febrile neutropenia despite prophylaxis with hematopoietic growth factors, or for platelet count <50,000/microL during any cycle.
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| Neurologic toxicity | - Discontinue ifosfamide for encephalopathy.
- Refer to UpToDate topics on overview of neurologic complications of conventional non-platinum cancer chemotherapy.
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| Bladder toxicity | - For microscopic hematuria (>10 RBC per HPF), withhold ifosfamide until complete resolution. Although formal guidelines are not available, ifosfamide dose adjustment may be needed for patients with grade 3 or worse urotoxicity that has not responded to increases in IV fluids or mesna.[2]
- Refer to UpToDate topics on hemorrhagic cystitis in cancer patients.
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| Kidney toxicity | - A 50% reduction in ifosfamide dose is suggested for creatinine increase up to 1.5 times ULN during therapy, with treatment discontinuation for any increase >1.5 times ULN.[8] In addition, for patients with a normal baseline serum creatinine level, reduce ifosfamide dose for a day 1 serum creatinine of 1.8 mg/dL or greater.
- Refer to UpToDate topics on ifosfamide nephrotoxicity.
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
