| Cycle length: 14 days. |
| Drug | Dose and route | Administration | Given on days |
| Liposomal irinotecan | 70 mg/m2 IV¶ | Dilute in 500 mL D5W or NSΔ and administer over 90 minutes. | Day 1 |
| Leucovorin◊ | 400 mg/m2 IV | Dilute in 250 mL NS or D5WΔ and administer over 30 minutes. | Day 1 |
| Fluorouracil (FU) | 2400 mg/m2 IV | Dilute in 500 to 1000 mL NS or D5WΔ and administer over 46 hours. To accommodate an ambulatory pump for outpatient treatment, can be administered undiluted (50 mg/mL) or the total dose can be diluted in 100 to 150 mL NS.Δ | Day 1 |
| Pretreatment considerations: |
| Emesis risk | - MODERATE (30 to 90% risk of emesis).
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
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| Prophylaxis for infusion reactions | - Administration of a corticosteroid is recommended 30 minutes prior to liposomal irinotecan.
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| Infection prophylaxis | - Primary prophylaxis with G-CSF is not recommended for all patients (estimated risk of febrile neutropenia is approximately 3%[1]). However, given the 27% rate of grade 3 or 4 neutropenia in the NAPOLI trial and the black box warning about potentially fatal neutropenic sepsis,[3] primary prophylaxis should be considered on an individual basis, particularly for high-risk patients such as those with pre-existing neutropenia, advanced disease, poor performance status, or patients age 65 years or older.
- 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.
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| Dose adjustment for liver or renal dysfunction | - A lower starting dose of FU may be needed for patients with liver impairment.[4] There are no recommended dose adjustments available for liposomal irinotecan for patients with severe renal impairment or in patients with a total bilirubin above the upper limit of normal.[3]
- 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; and chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency, conventional cytotoxic agents.
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| Monitoring parameters: |
- Obtain CBC with differential and platelet count on days 1 and 8 of each treatment cycle and more frequently if clinically indicated.
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- Assess electrolytes and liver and renal function prior to each treatment.
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- Monitor closely for diarrhea. Patients who develop diarrhea should be closely monitored and supportive care measures (eg, fluid and electrolyte replacement, loperamide, antibiotics, etc) provided as needed. For patients who develop abdominal cramps and/or diarrhea within 24 hours of treatment, administer atropine (0.25 to 1 mg subcutaneously or IV push) and premedicate with atropine during later cycles.
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- Liposomal irinotecan can cause severe and fatal interstitial lung disease. Withhold the drug in patients with new or progressive dyspnea, cough, or fever, pending diagnostic evaluation, and permanently discontinue if interstitial lung disease is confirmed.
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- Cardiotoxicity observed with FU includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy.
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- NOTE: Severe diarrhea, mucositis, and/or myelosuppression after the first dose of FU and/or liposomal irinotecan should prompt evaluation for DPD deficiency (for FU) and UGT1A1*28 allele polymorphism (for liposomal irinotecan).
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Withhold therapy if the ANC is <1500/microL, if the platelet count is <100,000/microL, or if neutropenic fever occurs. Reduce the liposomal irinotecan dose for grade 3 to 4 neutropenia or thrombocytopenia, or neutropenic fever following recovery in subsequent cycles.[3]
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| Diarrhea | - Initiate loperamide for late-onset diarrhea of any severity. Administer IV or SC atropine (unless clinically contraindicated) for early-onset diarrhea of any severity. Withhold subsequent treatment for grade 3 or worse diarrhea until resolution of diarrhea for at least 24 hours off antidiarrheal medications.[3] Following recovery to ≤grade 1, resume liposomal irinotecan at a reduced dose. Withhold FU for grade 2 or worse diarrhea and restart at a lower dose after complete resolution.
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
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| Neurologic toxicity | - There is no recommended dose for resumption of FU administration following development of hyperammonemic encephalopathy, acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances; the drug should be permanently discontinued.[4]
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| Cardiotoxicity | - Cardiotoxicity observed with FU includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. There is no recommended dose for resumption of FU administration following development of cardiac toxicity, and the drug should be discontinued.[4]
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| Other toxicity | - For any other grade 3 or 4 adverse reactions due to liposomal irinotecan, withhold treatment until recovery to ≤grade 1. Following recovery, resume irinotecan at a lower dose. Liposomal irinotecan should be discontinued for any anaphylactic reactions, and any interstitial lung disease.[3]
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
