Cycle length: 21 days.
Total cycles: 4 cycles. |
| Drug | Dose and route | Administration | Given on days |
| Paclitaxel | 250 mg/m2 IV | Dilute in 1000 mL NS or D5W* and administer over 24 hours;¶ special tubing needed. | Day 1 |
| MesnaΔ | 300 mg/m2 IV bolus prior to each dose of ifosfamide, then 300 mg/m2 IV bolus at 4 and 8 hours after the start of ifosfamide administration each day (total daily mesna dose 900 mg/m2)◊ | Mix in 100 mL NS or D5W* and administer over 15 minutes. Total concentration of mesna should not exceed 20 mg/mL.[2] | Daily, days 2 through 5 |
| Ifosfamide | 1500 mg/m2 per day IV | Mix in 250 mL NS or D5W* or sterile water for injection to a final concentration of 0.6 to 20 mg/mL and infuse over 60 minutes. | Daily, days 2 through 5 |
| Cisplatin | 25 mg/m2 per day IV | Dilute in 250 mL NS* and administer over 30 to 60 minutes (or at 1 mg/min).§ Do not administer with aluminum needles or sets. | Daily, days 2 through 5 |
| Pretreatment considerations: |
| Hydration | - Cisplatin: Induction of diuresis minimizes the risk of cisplatin nephrotoxicity. Hydration with 1 to 2 L of IV fluids is recommended to establish adequate urinary output (>100 mL/hour) for at least 2 hours prior to and 2 hours after cisplatin administration.[3]
- Alternatively, pretreatment hydration with 1 to 2 L of fluid can be infused for 8 to 12 hours prior to each dose of cisplatin.[3]
- Refer to UpToDate topics on cisplatin nephrotoxicity.
- Ifosfamide: Adequate hydration (at least 2 L of oral or IV fluids per day) should be maintained with ifosfamide to reduce the risk of ifosfamide-related bladder toxicity.[4]
- Refer to UpToDate topics on chemotherapy and radiation-related hemorrhagic cystitis in cancer patients.
|
| Emesis risk | - HIGH (>90% frequency of emesis).
- Concomitant administration of a neurokinin 1 receptor antagonist (eg, aprepitant) may increase the risk of ifosfamide neurotoxicity; it is avoided at many institutions.
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
|
| Prophylaxis for infusion reactions | - Premedicate with dexamethasone plus both an H1 and an H2 receptor antagonist prior to paclitaxel administration.[5] Routine prophylaxis not indicated for cisplatin or ifosfamide.
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
|
| Vesicant/irritant properties | - Paclitaxel can cause significant tissue damage; avoid extravasation.
- Cisplatin is an irritant but can cause significant tissue damage; avoid extravasation.
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
|
| Infection prophylaxis | - Primary prophylaxis with hematopoietic growth factors is indicated; despite the use of primary prophylaxis hematopoietic growth factors in this regimen, the incidence of neutropenic fever was 48%.[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.
|
| Dose adjustment for baseline liver or renal dysfunction | - A lower starting dose of paclitaxel may be needed in patients with pre-existing liver impairment.
- A lower starting dose of ifosfamide may be needed for patients with pre-existing renal or liver impairment.
- The optimal approach to cisplatin therapy in patients with pre-existing renal impairment is unknown. Patients are typically treated with cisplatin regardless of renal function since treatment intent is curative, but appropriate clinical judgement is necessary.
- Before starting treatment, it is essential to exclude or correct any pre-existing urinary tract obstruction.
- Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents and chemotherapy nephrotoxicity and dose modification in patients with kidney impairment, conventional cytotoxic agents.
|
| Hemorrhagic cystitis prevention | - Mesna does not prevent hemorrhagic cystitis in all patients.
- Perform urinalysis on a morning specimen of urine for hematuria daily during ifosfamide administration. If microscopic hematuria (ie, greater than 10 RBCs per high-power field) is present, then subsequent administration of ifosfamide should be withheld until complete resolution.
- Refer to UpToDate topics on chemotherapy and radiation-related hemorrhagic cystitis in cancer patients.
|
| Neurotoxicity issues | - There is an increased risk of encephalopathy for those with prior history of ifosfamide-related encephalopathy, renal dysfunction, low serum albumin, and those with concomitant use of aprepitant or prior cisplatin treatment. Monitor for CNS toxicity and discontinue ifosfamide treatment for encephalopathy.
- Refer to UpToDate topics on overview of neurologic complications of conventional non-platinum cancer chemotherapy.
|
| Monitoring parameters: |
- CBC with differential and platelet count prior to each new treatment cycle.
|
- Assess electrolytes (especially potassium, magnesium, and phosphate) and renal function daily during administration and prior to each new treatment cycle.
|
- Assess liver function tests daily during administration and prior to each new treatment cycle.
|
- Check urinalysis (or urine dipstick) prior to and during ifosfamide administration to monitor for hemorrhagic cystitis.
|
- Monitor for ifosfamide-related neurotoxicity (eg, encephalopathy, coma, rarely seizures, weakness, neuropathy, ataxia, cranial nerve dysfunction) daily, on days 2 through 5.
- Refer to UpToDate topics on overview of neurologic complications of non-platinum cancer chemotherapy.
|
- Assess changes in neurologic function, including neuropathy and/or paresthesias, prior to each treatment cycle.
|
- Monitor for hearing loss prior to each dose of cisplatin; audiometry as clinically indicated.
|
| Suggested dose modifications for toxicity: |
| Myelosuppression | - Cycles 2 to 4: In order to initiate subsequent cycles of therapy, patients must have an ANC ≥0.45 × 103 cells/mm3 and platelet count ≥75 × 106 cells/mm3.[1,6] No dose reductions were allowed in this protocol for hematologic toxicity. However, if patients developed treatment-related toxicity, a delay in the next cycle until recovery from the toxicity was allowed, with the next cycle administered at full dose.
|
| Hemorrhagic cystitis | - Withhold further ifosfamide and continue the daily mesna if urinalysis shows 10 or more erythrocytes per high-powered field until hematuria is resolved.[4]
- Refer to UpToDate topics on chemotherapy and radiation-related hemorrhagic cystitis in cancer patients.
|
| Nephrotoxicity | - Cisplatin: The United States Prescribing Information for cisplatin recommends that the drug be withheld until serum creatinine is <1.5 mg/dL and/or BUN is <25 mg/dL.[3]
- Ifosfamide: Ifosfamide is associated with cumulative nephrotoxicity and electrolyte abnormalities, 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.
- Refer to UpToDate topics on ifosfamide nephrotoxicity.
|
| Neurologic toxicity | - Cisplatin: Neuropathy is usually not seen until cumulative doses of cisplatin >400 mg/m2, although there is marked interindividual variation. Patients with mild neuropathy can continue to receive full cisplatin doses. However, if the neuropathy interferes with function, the risk of potentially disabling neurotoxicity must be weighed against the benefit of continued treatment.
- Refer to UpToDate topics on overview of neurologic complications of platinum-based chemotherapy.
- Ifosfamide: CNS toxicities can be severe and result in encephalopathy and death. CNS side effects may be especially problematic for those over age 60. Discontinue ifosfamide treatment for encephalopathy.
- Refer to UpToDate topics on overview of neurologic complications of non-platinum cancer chemotherapy.
- Paclitaxel: In cases of severe symptomatic peripheral neuropathy, a dose reduction of 20% is recommended for all subsequent courses of paclitaxel.[5]
- Refer to UpToDate topics on overview of neurologic complications of conventional non-platinum cancer chemotherapy and prevention and treatment of chemotherapy-induced peripheral neuropathy.
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
