Cycle length: 21 days. |
Drug | Dose and route | Administration | Given on days |
Rituximab | 375 mg/m2 IV* | Dilute in NS or D5W¶ to a final concentration of 1 to 4 mg/mL. Initial infusion: Start at 50 mg/hour; escalate in 50 mg/hour increments every 30 minutes to a maximum of 400 mg/hour, as tolerated.[2] In the absence of a severe infusion reaction, for subsequent infusions, administer 20% of the total dose over the first 30 minutes and the remaining 80% over 60 minutes, as tolerated. The 90-minute infusion schedule should NOT be used in patients who have clinically significant cardiovascular disease or a circulating lymphocyte count ≥5000/mm3. For patients not meeting these criteria, the recommended infusion rate for subsequent doses is 100 mg/hour, increased by 100 mg/hour every 30 minutes until a maximum infusion rate of 400 mg/hour is reached. | Day minus 2 of cycle 1 (48 hours prior to initiation of cycle 1), then day 1 of cycles 1 to 3 (four total doses). |
Ifosfamide | 5000 mg/m2 continuous IV infusion | Dilute in NS or D5W¶ to a final concentration of 0.6 to 20 mg/mL and infuse over 24 hours. | Day 4 |
MesnaΔ | 5000 mg/m2 continuous IV infusion | Add to ifosfamide bag and administer over 24 hours. Total concentration of mesna should not exceed 20 mg/mL. | Day 4 |
Carboplatin | AUC◊ = 5 mg/mL per min IV (maximum dose = 800 mg) | Dilute in 250 mL NS¶ and administer over 30 minutes. | Day 4 |
Etoposide | 100 mg/m2 IV daily | Dilute in 500 mL NS or D5W¶ to final concentration <0.4 mg/mL. Infuse over 30 to 60 minutes; if infused more rapidly, severe hypotension may occur. | Days 3 to 5 |
Pretreatment considerations: |
Emesis risk | - HIGH (>90% frequency of emesis) on day 4; MINIMAL to LOW on days 1, 3, and 5.§
- Concomitant administration of aprepitant may increase the risk of ifosfamide neurotoxicity; it is avoided at many institutions.
- Refer to UpToDate topic on "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults".
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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.[3]
- Refer to UpToDate topic "Hemorrhagic cystitis in cancer patients".
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Prophylaxis for infusion reactions | - Premedicate with acetaminophen and diphenhydramine, with or without an H2 blocker, 30 minutes prior to at least the first and second infusions of rituximab.[2]
- Premedication not routinely required for ifosfamide, carboplatin, or etoposide.
- Refer to UpToDate topic on "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy".
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Infection prophylaxis | - Primary prophylaxis with G-CSF is administered as a routine component of this regimen.[1]
- 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".
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Dose adjustment for baseline liver or renal dysfunction | - A lower starting dose of etoposide and ifosfamide doses may be needed for preexisting renal or liver dysfunction.[3,4] Carboplatin dose is calculated based upon renal function; dose adjustment is not necessary for liver dysfunction.[5]
- Before starting treatment with ifosfamide, it is necessary to exclude or correct any urinary tract obstructions.[3]
- 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", "Dosing of anticancer agents in adults", and "Hemorrhagic cystitis in cancer patients".
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Hepatitis screening | - Patients should be screened for hepatitis B and C prior to starting rituximab, and if positive, considered for hepatitis B prophylaxis.
- 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", "Hepatitis B virus: Overview of management", and "Hepatitis B virus reactivation associated with immunosuppressive therapy".
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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 grams/m2.[3] 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 new treatment cycle.
- Refer to UpToDate topic on "Ifosfamide nephrotoxicity".
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- Assay for liver function prior to each treatment cycle.
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- Mesna does not prevent ifosfamide-related hemorrhagic cystitis in all patients. Perform urinalysis on a morning specimen of urine daily, on days 4 and 5.[3]
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- Monitor for ifosfamide-related neurotoxicity (confusion, coma, rarely seizures, weakness, neuropathy, ataxia, cranial nerve dysfunction) daily, on days 4 and 5.[3] CNS 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".
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- Monitor vital signs during etoposide infusion.[5]
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- Carriers of hepatitis B or C should be monitored for clinical and laboratory signs of active infection during and following completion of therapy. Rituximab should be discontinued if reactivation occurs.
- Refer to UpToDate topic 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".
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Suggested dose modifications for toxicity: |
Myelotoxicity | - Delay treatment cycle until the ANC is >1000/microL and platelet count is >50,000/microL.[1] Dose reduction not indicated for intracycle hematologic toxicity.
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Neurotoxicity | - Discontinue ifosfamide treatment for encephalopathy.
- Refer to UpToDate topics on "Overview of neurologic complications of conventional non-platinum cancer chemotherapy".
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Urotoxicity | - If microscopic hematuria (greater than 10 RBCs per high-power field) is present during therapy, then subsequent administration of ifosfamide should be withheld until complete resolution.[3]
- Refer to UpToDate topic 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. |