| 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 oxaliplatin and leucovorin. If well tolerated, all subsequent doses may be administered over 10 to 30 minutes before chemotherapy.¶[2,3] | Day 1 |
| Oxaliplatin | 85 mg/m2 IVΔ | Dilute with 500 mL D5W* and administer over two hours (on days 1 and 15, oxaliplatin and leucovorin can be administered concurrently in separate bags using a Y-connector). Shorter oxaliplatin administration schedules (eg, 1 mg/m2 per minute) appear to be safe.[4] | Day 1 |
| Leucovorin◊ | 400 mg/m2 IV | Dilute with 250 mL D5W* and administer over two hours, concurrent with oxaliplatin. | Day 1 |
| Fluorouracil (FU) | 2400 mg/m2 IV | Dilute with 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.
- 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.
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
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| Vesicant/irritant properties | - Oxaliplatin and FU are classified as irritants, but oxaliplatin can cause significant tissue damage; avoid extravasation.
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
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| Infection prophylaxis | - Primary prophylaxis with G-CSF is not justified (estimated risk of febrile neutropenia <5%[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.
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| Dose adjustment for baseline liver or kidney dysfunction | - A lower starting dose of oxaliplatin may be needed for severe kidney impairment.[5] A lower starting dose of FU may be needed for patients with liver 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 insufficiency, conventional cytotoxic agents.
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| Maneuvers to prevent neurotoxicity | - Pharmacologic methods to prevent/delay the onset of oxaliplatin-related neuropathy are controversial due to the absence of large clinical trials proving benefit. Counsel patients to avoid exposure to cold during and for approximately 48 hours after each infusion. Prolongation of the oxaliplatin infusion time from two to six hours may mitigate acute neurotoxicity.
- Refer to UpToDate topics on overview of neurologic complications of platinum-based chemotherapy.
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| Cardiac issues | - QT prolongation and ventricular arrhythmias have been reported after oxaliplatin. ECG monitoring is recommended if therapy is initiated in patients with heart failure, bradyarrhythmias, coadministration of drugs known to prolong the QT interval, and electrolyte abnormalities. Avoid oxaliplatin in patients with congenital long QT syndrome. Correct hypokalemia and hypomagnesemia prior to initiating oxaliplatin.
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| Monitoring parameters: |
- CBC with differential and platelet count prior to each treatment.
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- Assess electrolytes (especially potassium and magnesium) and liver and kidney function prior to each treatment.
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- Assess changes in blood pressure, urine protein concentration, neurologic function, and risk for bleeding prior to each treatment.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Delay treatment cycle one week for ANC <1200/microL, or platelets <75,000/microL on the day of treatment. If treatment is delayed for two weeks or delayed for one week on two separate occasions, reduce infusional FU by 20% and reduce oxaliplatin dose from 85 to 65 mg/m2.
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| Neurologic toxicity | - For grade 3 paresthesias/dysesthesias lasting longer than seven days, decrease oxaliplatin dose by 25%. Discontinue oxaliplatin for grade 4 or persistent grade 3 paresthesia/dysesthesia.[1] The United States Prescribing Information recommends a dose reduction in oxaliplatin to 65 mg/m2 for persistent grade 2 neurosensory events that do not resolve, and discontinuation for persistent grade 3 neurosensory events.[5]
- 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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| Diarrhea | - Delay next treatment by one week for any diarrhea above baseline.[1] Delay by an additional week if diarrhea not resolved to ≤grade 1. For grade 3 or 4 diarrhea, restart at a lower dose after complete resolution.[1] The United States Prescribing Information recommends dose reduction of oxaliplatin to 65 mg/m2 as well as a reduction of infusional FU after recovery from grade 3 or 4 diarrhea during the prior cycle.[5]
- 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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| Pulmonary toxicity | - Oxaliplatin has rarely been associated with pulmonary toxicity. Withhold oxaliplatin for unexplained pulmonary symptoms until interstitial lung disease or pulmonary fibrosis is excluded.
- Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, cytotoxic agents.
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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 toxicities | - Delay treatment cycle by one week for any other toxicity >grade 1 (except alopecia, hypertension, and asthenia). Delay an additional week if the toxicity has not resolved to ≤grade 1. Reduce FU and oxaliplatin doses for grade 3 or 4 mucositis, vomiting, and grade 3 other nonhematologic toxicities. Discontinue bevacizumab for hypertensive crisis or hypertensive encephalopathy, serious hemorrhage, arterial thromboembolism, nephrotic syndrome, gastrointestinal perforation, fistula formation, or RPLS.[2] Do not administer bevacizumab within 28 days of surgery; suspend 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. |
