Cycle length: 14 days.
Duration of therapy: The original protocol administered up to 12 cycles, followed by maintenance treatment with fluorouracil, leucovorin, and bevacizumab until disease progression, the occurrence of an unacceptable adverse event, or withdrawal of consent. |
| Drug | Dose and route | Administration | Given on days |
| Bevacizumab | 5 mg/kg IV | Dilute into a total volume of 100 mL NS.¶Δ Administer first dose over 90 minutes following oxaliplatin and leucovorin. If well tolerated, the second infusion may be administered over 60 minutes after chemotherapy. If well tolerated, all subsequent doses may be administered over 10 to 30 minutes before chemotherapy.◊[3,4] | Day 1 |
| Irinotecan¶ | 165 mg/m2 IV | Dilute with 500 mL D5WΔ to a final concentration of 0.12 to 2.8 mg/mL and administer over 60 minutes. | Day 1 |
| Oxaliplatin§ | 85 mg/m2 IV | Dilute with 500 mL D5WΔ and administer over two hours after irinotecan. Administer concurrently with leucovorin in separate bags via y-line connection.[5] Shorter oxaliplatin administration schedules (eg, 1 mg/m2 per minute) appear to be safe.[6] | Day 1 |
| LEVOleucovorin¥ | 200 mg/m2 IV | Dilute with 250 mL D5WΔ and administer over two hours, concurrent with oxaliplatin. | Day 1 |
| Fluorouracil (FU) | 2400 to 3200 mg/m2 IV‡ | Dilute in 500 to 1000 mL D5WΔ and administer over 48 hours, after leucovorin. To accommodate an ambulatory pump for outpatient treatment, can be administered undiluted (50 mg/mL). The original protocol used 3200 mg/m2, but many United States oncologists use a lower starting dose (2400 mg/m2) and escalate as tolerated to reach a final dose of 3200 mg/m2. | Day 1 |
| Pretreatment considerations: |
| Emesis risk | - HIGH (>90% frequency of emesis).†
- 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 fluorouracil are 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 | - Routine primary prophylaxis with G-CSF is not warranted (estimated risk of febrile neutropenia 9%[1]). However, given the high rate of grade 3 or 4 neutropenia (approximately 50%), primary prophylaxis may be considered for high-risk patients.
- 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 renal dysfunction | - A lower starting dose of oxaliplatin and irinotecan may be needed for patients with severe renal insufficiency.[7,8]
- A lower starting dose of irinotecan and FU may be needed for patients with hepatic impairment.[8,9]
- 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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| 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.[7] 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: |
- Assess CBC with differential and platelet count, electrolytes (especially potassium and magnesium), and liver and renal function tests prior to each treatment.
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- Irinotecan is associated with early and late diarrhea, both of which may be severe.[8] Patients must be instructed in the early use of loperamide for late diarrhea. Patients who develop diarrhea should be closely monitored and supportive care measures (eg, fluid and electrolyte replacement, loperamide, antibiotics, etc) should be provided as needed. For patients who develop abdominal cramping and/or diarrhea within 24 hours of receiving irinotecan, administer atropine (0.3 mg IV) and premedicate with atropine for later cycles. Doses up to 1 mg of atropine can be given.
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
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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: |
| The specific dose alteration parameters for the FOLFOXIRI plus bevacizumab regimen in colorectal cancer patients are based upon recommendations published as a supplement to the phase III trial.[10] NOTE: Severe diarrhea, mucositis, and myelosuppression after FU should prompt evaluation for DPD deficiency. |
| Myelotoxicity | - Do not retreat with a new cycle unless WBC is ≥3000/microL, granulocyte count is ≥1000/microL, and platelet count is ≥100,000/microL.
- For febrile neutropenia or grade 4 neutropenia >5 days, or grade 3 or 4 thrombocytopenias, reduce irinotecan and oxaliplatin doses for the next cycle by 20 to 25%. For second occurrence, reduce oxaliplatin dose to 60 mg/m2 and the dose of infusional FU an additional 20 to 25%. If nonrecovery after two weeks' delay or third occurrence of granulocytes <1500/microL on day 1, or febrile neutropenia or grade 4 neutropenia at any time during cycle, discontinue treatment.
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| Diarrhea | - Do not retreat with a new cycle of FOLFOXIRI until resolution of diarrhea to grade 1 or less for at least 24 hours without antidiarrheal medication. For diarrhea grade 3, reduce irinotecan and FU doses by 20 to 25% after resolution to grade 1 or less. For grade 4 diarrhea, reduce irinotecan and FU doses by 40 to 50% after resolution to grade 1 or less.
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
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| Mucositis or palmar-plantar erythrodysesthesia | - Do not retreat with a new cycle of FOLFOXIRI until mucositis is grade 1 or less. For hand-foot syndrome that is grade 3 or 4 at the start of a cycle of therapy, stop infusional FU for that cycle.
- For grade 3 mucositis, reduce dose of infusional FU by 20 to 25%. For grade 4 mucositis, reduce dose of infusional FU by 40 to 50%.
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| Neurotoxicity | - For transient grade 3 paresthesias/dysesthesias or grade 2 symptoms lasting more than seven days, decrease oxaliplatin dose by 20 to 25%.[7] Discontinue oxaliplatin for persistent grade 3 or 4 neurotoxicity at the start of a subsequent cycle of therapy.[10]
- 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.[9]
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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.[9,10]
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| Dose modification for toxicities attributable to bevacizumab | - For each cycle, hold bevacizumab until all of the following criteria are met:
- For patient with grade 3 nonpulmonary and non-CNS bleeding, hold until bleeding is resolved and hemoglobin is stable. Do not resume bevacizumab if there is a bleeding diathesis, or an anatomic or pathologic condition that significantly increases the risk of bleeding recurrence.
- For grade 3 heart failure, or grade 3 proteinuria, hold until grade 2 or less.
- For grade 1 or 2 bowel obstruction, hold bevacizumab for patients who experience partial obstruction requiring medical intervention; resume on complete resolution. Patients who experience partial obstruction not requiring medical intervention may continue on bevacizumab.
- For any other unspecified grade 3 bevacizumab-related adverse events, hold bevacizumab until recovery to grade 1 or less.
- Discontinue bevacizumab for hypertensive crisis or hypertensive encephalopathy, grade 3 hypertension not controlled with medication, serious hemorrhage, any arterial thromboembolism, grade 4 proteinuria, gastrointestinal perforation, fistula formation, wound dehiscence, grade 4 heart failure, RPLS, or any other grade 4 toxicity.[4,10] 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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| Other toxicity | - For any other clinically relevant toxicity ≥grade 2, except anemia and alopecia, hold subsequent cycles of chemotherapy until resolution to grade 1 or less. Dose reduction may be justified for subsequent cycles if medically indicated.
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
