Cycle length: 21 days.
Total cycles: 4. |
| Drug | Dose and route | Administration | Given on days |
| Cisplatin | 20 mg/m2 IV per day | Dilute with 250 mL NS* and administer over one hour. Do not administer with aluminum needles or IV sets. | Days 1 to 5 |
| Etoposide¶ | 75 mg/m2 IV per day | Dilute with 500 mL NS* (concentration <0.4 mg/mL) and administer over 1 hour. | Days 1 to 5 |
| Ifosfamide¶ | 1200 mg/m2 per day IV infusion | Dilute with sterile water for injection* to a concentration of 50 mg/mL. Solution may be further diluted with either NS, D5W, LR, or sterile water for injection to achieve a final concentration of 0.6 to 20 mg/mL. Administer over a minimum of 30 minutes. | Days 1 to 5 |
| Mesna¶ | 240 mg/m2 IV bolus at the time of ifosfamide infusion, then 240 mg/m2 IV bolus at 4 and 8 hours after ifosfamide initiation each day (total daily mesna dose 720 mg/m2)[2] | Dilute with NS* to achieve a final concentration of 20 mg/mL.[2] Administer as IV bolus. Can mix with ifosfamide. This three-dose fractionated dosing schedule should be repeated on each day that ifosfamide is administered. | Days 1 to 5 |
| Pretreatment considerations: |
| Hydration | - Induction of diuresis using IV NS minimizes the risk of cisplatin nephrotoxicity and ifosfamide bladder toxicity. At least 2000 mL of NS should be administered at a rate of 100 to 125 mL per hour throughout the five days of treatment and continued for at least two hours after the last doses of cisplatin/ifosfamide.
- Refer to UpToDate topics on cisplatin nephrotoxicity and hemorrhagic cystitis in cancer patients.
|
| Emesis risk | - HIGH (>90% frequency of emesis).
- Concomitant administration of 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.
|
| Vesicant/irritant properties | - Cisplatin is an irritant but can cause significant tissue damage; avoid extravasation.[3]
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
|
| Infection prophylaxis | - Primary prophylaxis with G-CSF is administered as a routine component of this regimen.[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 kidney dysfunction | - Dose adjustment in the setting of baseline kidney impairment (ie, creatinine >3.0 mg/dL or GFR <50 mL/min) requires a balanced discussion of the goals of treatment and the risks of cisplatin.
- A lower starting dose of ifosfamide may be needed in patients with pre-existing kidney or liver impairment.
- Before starting treatment with ifosfamide, it is necessary to exclude or correct any urinary tract obstructions.
- 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; chemotherapy nephrotoxicity and dose modification in patients with kidney impairment, conventional cytotoxic agents; and hemorrhagic cystitis in cancer patients.
|
| Monitoring parameters: |
- CBC with differential and platelet count weekly during treatment.
|
- Assess liver function tests prior to each treatment cycle.
|
- Cisplatin is associated with significant nephrotoxicity. Ifosfamide is associated with cumulative nephrotoxicity, mostly at a total dose above 60 grams/m2.[4] 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 new treatment cycle.
- Refer to UpToDate topics on ifosfamide nephrotoxicity and cisplatin nephrotoxicity.
|
- Mesna does not prevent hemorrhagic cystitis in all patients.[2] Perform a baseline pretreatment urinalysis and monitor for the development of gross hematuria and urine output. Refer to UpToDate topics on hemorrhagic cystitis in cancer patients.
|
- Monitor for ifosfamide-related neurotoxicity (confusion, coma, rarely seizures, weakness, neuropathy, ataxia, cranial nerve dysfunction) daily, on days 1 through 5. CNS side effects may be especially problematic for those over age 60.
- Refer to UpToDate topics on neurologic complications of conventional non-platinum cancer chemotherapy.
|
- Monitor vital signs during etoposide infusion.
|
- Monitor for hearing loss prior to each dose of cisplatin; audiometry as clinically indicated.
|
| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Unless clinically essential, a repeat course of therapy should not be started with an absolute neutrophil count below 450/μL[5] and/or a platelet count below 50,000/μL.[4]Δ
- For patients who experience neutropenic fever despite G-CSF prophylaxis, UpToDate contributors administer antibiotic prophylaxis for future cycles.
- Dose reductions of chemotherapy for febrile neutropenia are not advised. Such dose reductions can lead to inferior cancer-specific outcomes,[6] which are more likely to occur than severe sepsis from subsequent cycles without dose reduction.
- 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.
|
| Neurotoxicity | - Neuropathy usually is seen after cumulative doses of cisplatin beyond 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.[3]
- Discontinue ifosfamide treatment for encephalopathy.
- Refer to UpToDate topics on overview of neurologic complications of conventional non-platinum cancer chemotherapy and overview of neurologic complications of platinum-based chemotherapy.
|
| Nephrotoxicity and urotoxicity | - Cisplatin – It is recommended that subsequent doses of cisplatin be withheld until the serum creatinine is <3.0 mg/dL. Refer to UpToDate topics on cisplatin nephrotoxicity.
- Ifosfamide – Dose modification of ifosfamide may be necessary in patients who develop kidney impairment while on treatment, but specific recommendations for dose adjustments are clinically variable. Ifosfamide has been safely administered with dialysis in patients with end-stage kidney disease.[7]
- Ifosfamide is associated with cumulative nephrotoxicity and electrolyte abnormalities, mostly at a total dose above 60 grams/m2. Clinical manifestations may include hypophosphatemia, kidney potassium wasting, metabolic acidosis with a normal ion gap, and, rarely, polyuria due to nephrogenic diabetes insipidus. Refer to UpToDate topics on ifosfamide nephrotoxicity.
- 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. Refer to UpToDate topics on hemorrhagic cystitis in cancer patients.
|
| If there is a change in body weight of at least 10%, doses should be recalculated. |
