| Cycle length: 14 days. |
| Drug | Dose and route | Administration | Given on days |
| Bevacizumab | 5 mg/kg IV | Dilute into a total volume of 100 mL NS.¶ The first dose should be administered over 90 minutes following chemotherapy. If well tolerated, the second infusion may be administered over 60 minutes after irinotecan and leucovorin. If well tolerated, all subsequent doses may be administered over 10 to 30 minutes before chemotherapy.Δ[3,4] | Day 1 |
| Irinotecan | 180 mg/m2 IV◊ | Dilute in 500 mL D5W¶ and administer over 90 minutes (can be administered concurrently with leucovorin via y-site connection). | Day 1 |
| Leucovorin§ | 400 mg/m2 IV | Dilute in 250 mL D5W¶ and administer over two hours. | Day 1 |
| Fluorouracil (FU), bolus | 400 mg/m2 IV | Slow IV push over five minutes (administer immediately after leucovorin). | Day 1 |
| FU, infusional | 2400 mg/m2 IV | Dilute in 500 to 1000 mL D5W¶ 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.¶ | Day 1 |
| Pretreatment considerations: |
| Emesis risk | - MODERATE (30 to 90%).
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
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| Prophylaxis for infusion reactions | - There is no standard premedication regimen for prophylaxis of infusion reactions.
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| Infection prophylaxis | - Primary prophylaxis with G-CSF is not justified (estimated risk of febrile neutropenia approximately 5%[2]).
- 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 baseline liver or kidney dysfunction | - A lower starting dose of FU and irinotecan may be needed for patients with liver impairment. A lower starting dose of irinotecan may be needed for patients with severe kidney impairment.
- 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 kidney impairment, conventional cytotoxic agents.
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| Diarrhea | - Irinotecan is associated with early and late diarrhea, both of which may be severe. For patients who develop abdominal cramps and/or diarrhea within 24 hours of treatment, administer atropine (0.3 to 0.6 mg IV) and premedicate with atropine during later cycles. Patients must be instructed in the early use of loperamide as a treatment for late diarrhea.
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
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| Monitoring parameters: |
- Obtain CBC with differential and platelet count prior to each treatment.
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- Assess electrolytes and liver and kidney function prior to each treatment.
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- Patients who develop diarrhea should be closely monitored and supportive care measures (eg, fluid and electrolyte replacement, loperamide, antibiotics, etc) provided as needed. Do not retreat until resolution of diarrhea for at least 24 hours without antidiarrheal medication.
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- Assess changes in blood pressure, urine protein concentration, and risk for bleeding prior to each treatment.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Each treatment should be delayed until ANC is >1500/microL and the platelet count is >100,000/microL. United States Prescribing Information suggests irinotecan dose reduction for grade 2 or worse hematologic toxicity (including febrile neutropenia) during treatment.[5]
- A different approach is used by some clinicians. If treatment is delayed for two weeks or delayed for one week on two separate occasions, the day 1 FU bolus is eliminated. With the second occurrence, reduce the FU infusion dose by 20% and reduce irinotecan dose to 150 mg/m2.
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| Diarrhea | - Withhold treatment until resolution of diarrhea for at least 24 hours off all antidiarrheal medications. The United States Prescribing Information suggests decreasing the irinotecan dose for patients with grade 2 or higher diarrhea in the prior cycle.[5] Withhold FU for grade 2 or worse diarrhea and restart at a lower dose after complete resolution.[6]
- NOTE: Severe diarrhea, mucositis, and myelosuppression after FU should prompt evaluation for DPD deficiency.
- 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.[6]
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| Cardiotoxicity | - Cardiotoxicity observed with FU includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, ECG changes, and cardiomyopathy. There is no recommended dose for resumption of FU administration following development of cardiac toxicity, and the drug should be discontinued.[6]
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| Other toxicity | - For other nonhematologic toxicities, if grade 2, hold treatment until ≤grade 1; if grade 3 or 4, hold treatment until ≤grade 2.[5] The United States Prescribing Information suggests decreasing the irinotecan dose for patients with grade 2 or higher nonhematologic toxicity in the prior cycle (except alopecia, anorexia or asthenia). Discontinue bevacizumab for hypertensive crisis or hypertensive encephalopathy, serious hemorrhage, arterial thromboembolism, nephrotic syndrome, gastrointestinal perforation, fistula formation, or RPLS.[3] Bevacizumab should not be administered within 28 days of surgery, and it should be suspended prior to elective surgery.
- Refer to UpToDate topics on toxicity of molecularly targeted antiangiogenic agents, non-cardiovascular effects and toxicity of molecularly targeted antiangiogenic agents, cardiovascular effects.
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
