| Cycle length: 14 days. |
| Drug | Dose and route | Administration | Given on days |
| 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.[2] Shorter oxaliplatin administration schedules (eg, 1 mg/m2 per minute) appear to be safe.[3] | 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 5%[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 kidney dysfunction | - A lower starting dose of oxaliplatin and irinotecan may be needed for patients with severe kidney insufficiency.[4,5] A lower starting dose of irinotecan and FU may be needed for patients with hepatic impairment.[5,6]
- 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.[4] 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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- Irinotecan is associated with early and late diarrhea, both of which may be severe.[5] 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 to 0.6 mg IV) and premedicate with atropine for later cycles.
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
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- Assess changes in neurologic function prior to each treatment.
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| Suggested dose modifications for toxicity: |
| The specific dose alteration parameters for the FOLFOXIRI regimen in colorectal cancer patients were not published in the original phase III trial.[1] The following suggestions are based upon dose reductions used in a trial using a comparable regimen (FOLFIRINOX) for advanced pancreatic cancer.[7] |
| Myelotoxicity | - Do not retreat unless granulocyte count ≥1500/microL and platelet count is ≥75,000/microL.
- Neutropenia:
- If day 1 treatment delayed for granulocytes <1500/microL or febrile neutropenia or grade 4 neutropenia >7 days, reduce irinotecan dose to 150 mg/m2 and reduce the continuous infusion FU to 75% of original doses. For second occurrence, reduce oxaliplatin dose to 60 mg/m2 and the dose of infusional FU an additional 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.
- Thrombocytopenia:
- If day 1 treatment delayed for platelet count is <75,000/microL, reduce oxaliplatin dose to 60 mg/m2 and reduce the continuous infusion FU to 75% of original doses. For second occurrence, reduce irinotecan dose to 150 mg/m2. If nonrecovery after two weeks delay or third occurrence of platelets <75,000/microL, discontinue treatment. For grade 3 or 4 thrombocytopenia during treatment, reduce oxaliplatin dose to 60 mg/m2 and the infusional FU dose to 75% of the original dose. For the second occurrence, reduce dose of irinotecan to 150 mg/m2 and the dose of infusional FU an additional 25%. Discontinue treatment for third occurrence.
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| Diarrhea | - Do not retreat with FOLFOXIRI until resolution of diarrhea for at least 24 hours without antidiarrheal medication. For diarrhea grade 3 or 4, or diarrhea with fever and/or grade 3 or 4 neutropenia, reduce irinotecan dose to 150 mg/m2 and the continuous FU dose to 75% of original dose. For second occurrence, reduce the oxaliplatin dose to 60 mg/m2 and the dose of infusional FU an additional 25%. Discontinue treatment for third occurrence.
- 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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| Mucositis or palmar-plantar erythrodysesthesia | - For grade 3 to 4 toxicity, reduce dose of infusional FU by 25%.
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| Neurotoxicity | - For transient grade 3 paresthesias/dysesthesias or grade 2 symptoms lasting more than seven days, decrease oxaliplatin dose by 25%.[4] Discontinue oxaliplatin for grade 4 or persistent grade 3 paresthesia/dysesthesia.
- 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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| 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 toxicity | - Any other toxicity ≥grade 2, except anemia and alopecia, can justify dose reduction if medically indicated.
- For other nonhematologic toxicities, if grade 2, hold treatment until ≤grade 1; if grade 3 or 4, hold treatment until ≤grade 2.[5]
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
