| Cycle length: 21 days until disease progression or maximum of six cycles. |
| Drug | Dose and route | Administration | Given on days |
| Doxorubicin | 25 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 |
| IV mesna | 0.5 g/m2 IV bolus prior to each day's dose of ifosfamide, then 1.5 g/m2 IV concurrently with ifosfamide (mix in same bag) | Dilute 0.5 g/m2 bolus dose in NS* (total concentration of mesna should not exceed 20 mg/mL) and administer over 15 minutes prior to each daily dose of ifosfamide. Dilute mesna 1.5 g/m2 dose in same 1000 mL NS bag as ifosfamide dose and deliver over four hours. | Days 1 through 4 |
| Ifosfamide | 2.5 g/m2 per day IV | After mesna bolus (500 mg/m2), dilute with 1000 mL NS* and administer concurrently with mesna (1.5 g/m2) in the same bag over four hours daily. | Days 1 through 4 |
| Oral mesna¶ | 1 g/m2 | Orally at two and six hours after completion of each day's ifosfamide infusion (round to nearest 400-mg tablet size). | Days 1 through 4 |
| Pegfilgrastim | 6 mg subcutaneously | Single injection. | Day 6, at least 24 hours after completing chemotherapy |
| 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 topic on "Hemorrhagic cystitis in cancer patients".
|
| 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 topic on "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults".
|
| Prophylaxis for infusion reactions | - There is no standard premedication regimen.
- Refer to UpToDate topic on "Infusion reactions to systemic chemotherapy".
|
| Vesicant/irritant properties | - Doxorubicin is a vesicant; avoid extravasation. Administer infusional regimens through a central venous line.
- Refer to UpToDate topic on "Extravasation injury from chemotherapy and other non-antineoplastic vesicants".
|
| Infection prophylaxis | - Primary prophylaxis with G-CSF is indicated with this regimen. The risk of febrile neutropenia with this regimen was >20%,[1] even with primary prophylaxis in all patients.
- Refer to UpToDate topic 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".
|
| Dose adjustment for baseline liver or renal dysfunction | - In the original protocol, patients were excluded if they had a baseline total bilirubin of greater than 30 micromol/L (1.8 mg/dL) or a serum creatinine of greater than 120 micromol/L (1.4 mg/dL) or CrCl (by Cockroft and Gault method) less than 65 mL/min.[1] A lower initial ifosfamide dose may be needed for patients with preexisting renal 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" and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents" and "Chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency: Conventional cytotoxic agents".
|
| 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".
|
| 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, renal 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 topic on "Ifosfamide nephrotoxicity".
|
- 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.[2]
- Refer to UpToDate topic on "Hemorrhagic cystitis in cancer patients".
|
- Monitor for neurotoxicity (confusion, coma, rarely seizures, weakness, neuropathy, ataxia, cranial nerve dysfunction) daily on days 1 through 5. Central nervous system side effects may be especially problematic for those over age 60.
- Refer to UpToDate topic on "Overview of neurologic complications of conventional non-platinum cancer chemotherapy".
|
- Assess liver function tests prior to each treatment cycle.
|
- Monitor cumulative doxorubicin dose. Reassess LVEF periodically during therapy as clinically indicated.
|
| Suggested dose modifications for toxicity: |
| Myelotoxicity | - In the original protocol, patients had to have an absolute neutrophil count greater than 2000/microL and platelet count greater than 100,000/microL prior to initiating therapy.[1] The original protocol specified a one week delay for subsequent cycles for incomplete hematologic recovery.[1] A 20% dose reduction was performed for repeated neutropenic septic episodes despite growth factor support per protocol.[1] If the ifosfamide dose is adjusted, the mesna dose should also be modified to maintain the mesna-to-ifosfamide ratio.
|
| Neurologic toxicity | - Formal guidelines are not provided for dose reduction in the event of neurotoxicity in the United States Prescribing Information. The original protocol recommended discontinuation of treatment for ≥grade 3 toxicity.[1] The United States Prescribing Information recommends discontinuation of treatment for encephalopathy.[2] Some centers advocate IV alkalinization to reduce the incidence of encephalopathy, but this is not a standard practice.
- Refer to UpToDate topic on "Overview of neurologic complications of conventional non-platinum cancer chemotherapy".
|
| Renal toxicity | - In the original protocol, treatment was discontinued if serum creatinine was >2.5 ULN or CrCl (by Cockroft and Gault method) was <60 mL/min.[1] If ifosfamide dose is adjusted, the mesna dose should also be modified to maintain the mesna-to-ifosfamide ratio.
- Refer to UpToDate topic "Ifosfamide nephrotoxicity".
|
| Bladder toxicity | - If microscopic hematuria (>10 RBC per HPF) is present, withhold ifosfamide until complete resolution.[2] Although formal guidelines are not available, reduced ifosfamide dose may be needed for patients with grade 3 or worse cystitis that has not responded to increases in IV fluids or mesna.
- Refer to UpToDate topic on "Hemorrhagic cystitis in cancer patients".
|
| Cardiotoxicity | - In the original protocol, treatment was discontinued if LVEF dropped below 45% or if there was a drop of >20% from baseline (confirmed three to five days later).[1]
|
| If there is a change in body weight of at least 10%, doses should be recalculated. |
