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Ifosfamide 2000 mg/m 2 per day IV Dilute with NS to a final concentration of 0.6 to 20 mg/mL and administer over two hours daily. First dose on day 1 can be mixed with first bolus dose of mesna in the same bag. Days 1 through 5

Mesna * 1600 mg/m 2 IV on day 1, followed by 1200 mg/m 2 IV daily Administer 400 mg/m 2 in NS over two hours with initial ifosfamide dose on day 1. Total concentration of mesna should not exceed 20 mg/mL. Then immediately start daily infusion of mesna 1200 mg/m 2 in 2000 mL 5 percent dextrose in water with 100 mEq/L sodium acetate, 20 mEq/L of potassium acetate, and 4 mEq/L of magnesium sulfate; and administer over 22 hours on day 1. For days 2 through 5, the total dose of mesna with electrolytes is administered over 24 hours per day. Total concentration of mesna should not exceed 20 mg/mL. Days 1 through 5 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 "Cystitis in patients with cancer". •

Emesis risk: HIGH (>90 percent risk of emesis). Refer to UpToDate topic on "Prevention and treatment of chemotherapy-induced nausea and vomiting". Concomitant administration of aprepitant may increase the risk of ifosfamide neurotoxicity [3-5] ; its use is avoided at some institutions. •

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-neoplastic vesicants". •

Infection prophylaxis: The risk of febrile neutropenia with this regimen was >20 percent [1] . Therefore, primary prophylaxis with granulocyte colony stimulating factors is justified. Refer to UpToDate topic on "Use of granulocyte colony stimulating factors in patients with chemotherapy-induced neutropenia". •

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 1.5 mg/dL or a serum creatinine of greater than 1.5 mg/dL [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" and "Chemotherapy-related nephrotoxicity and dose modification in patients with renal insufficiency". •

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 topic on "Cardiotoxicity of anthracycline-like chemotherapy agents". Monitoring parameters: • CBC with differential and platelet count weekly during treatment. • Ifosfamide is associated with cumulative nephrotoxicity, mostly at a total dose above 60 grams/m 2 . 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] . Monitor a morning specimen of urine for hematuria daily, on days 1 through 5. Refer to UpToDate topic on "Cystitis in patients with cancer". • 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 "Neurologic complications of 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 alterations for toxicity: In the original protocol, initial dose modification for treatment related toxicity included a decrease in ifosfamide dose from 10,000 mg/m 2 to 8000 mg/m 2 per cycle, with the same doxorubicin dose (75 mg/m 2 per cycle); the second level of dose reduction was a decrease in doxorubicin dose to 60 mg/m 2 per cycle, in addition to the reduced ifosfamide dose of 8000 mg/m 2 per cycle [1] . Additional dose modification guidelines were not provided. If ifosfamide dose is adjusted, the mesna dose should also be modified to maintain the mesna-to-ifosfamide ratio (mesna dose 60 percent of the daily ifosfamide dose). •

Myelotoxicity: Delay treatment cycle until the absolute neutrophil count is ≥1500 cells/mm 3 and platelet count is ≥100,000/mm 3 . Dose reduce for a failure to recover platelets to 100,000/mm 3 by day 28 or thrombocytopenia with bleeding, or requirement for platelet transfusions for seven or more days, and for febrile neutropenia with significant morbidity (documented infection or sepsis syndrome) despite use of granulocyte colony stimulating factors [1] . •

Neurologic toxicity: Although formal guidelines are not provided by the manufacturer, reduce the ifosfamide dose or administer the same dose over a greater number of days for reversible grade 2 to 3 central nervous system toxicity [1] . Discontinue for ≥grade 3 toxicity. Refer to UpToDate topic on "Neurologic complications of non-platinum cancer chemotherapy". •

Renal toxicity: In the original protocol, ifosfamide dose reduction was recommended for a day 1 serum creatinine of 1.8 mg/dL or greater [1] . If ifosfamide dose is adjusted, the mesna dose should also be modified to maintain the mesna-to-ifosfamide ratio (mesna dose 60 percent of the daily ifosfamide dose). •

Bladder toxicity: If microscopic hematuria (greater than 10 RBC per high power field) is present, withhold ifosfamide until complete resolution. Although formal guidelines are not available, dose reduce ifosfamide for patients with grade 3 or worse urotoxicity that has not responded to increases in IV fluids or mesna [1] . •

Other toxicity: For patients with grade 3 or worse mucositis, reduce duration of doxorubicin infusion to two days; if recurrent grade 3 or 4 mucositis, reduce the daily dose by 20 percent [1] . If there is a change in body weight of at least 10 percent, doses should be recalculated. This table is provided as an example of how to administer this regimen; there may be other acceptable methods. This regimen must be administered by a clinician trained in the use of chemotherapy. The clinician is expected to use his or her independent medical judgment in the context of individual circumstances to make adjustments, as necessary. IV: intravenous; LVEF: left ventricular ejection fraction; CBC: complete blood count; RBC: red blood cells. * If necessary, oral mesna may be used; however, oral mesna is not recommended for the initial dose [8] . If the oral route is chosen, patients should receive an initial IV dose of mesna (at 20 percent of the daily dose of ifosfamide) prior to the day 1 ifosfamide administration, followed by oral mesna tablets at 40 percent of the daily ifosfamide dose per dose, administered at two and six hours after the initiation of each dose of ifosfamide. This same dosing schedule is repeated on each day that ifosfamide is administered. The total daily mesna dose is 100 percent of the ifosfamide dose when the oral route is used. If patients vomit within two hours of taking a dose of mesna, they should repeat the dose or receive an IV dose of mesna [9] . References: Patel SR, et al. Am J Clin Oncol 1998; 21:317. IFEX (ifosfamide) injection. US FDA-approved package insert. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed January 3, 2012.) Durand JP, et al. Ann Oncol 2007; 18:808. Jarkowski A. Am J Health-Syst Pharm 2008; 65:2229. Howell JE, et al. J Oncol Pharm Practice 2008; 14:157. Adriamycin (doxorubicin hydrochloride) injection. US FDA-approved package insert. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed January 3, 2012). MESNA injection (solution). US FDA-approved package insert. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed January 3, 2012). Hensley ML, et al. J Clin Oncol 2009; 27:127. MESNEX (mesna) tablets. US FDA-approved package insert. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed January 3, 2012).