| Cycle length: 14 days. |
| Drug | Dose and route | Administration | Given on days |
| Oxaliplatin¶ | 85 mg/m2 IV | Dilute in 500 mL D5WΔ and administer over two hours (prior to leucovorin). Shorter oxaliplatin administration schedules (eg, 1 mg/m2 per minute) appear to be safe.[2] | Day 1 |
| Leucovorin◊ | 400 mg/m2 IV | Dilute in 250 mL D5WΔ and administer over two hours (after oxaliplatin). | Day 1 |
| Irinotecan§ | 180 mg/m2 IV | Dilute in 500 mL D5WΔ and administer over 90 minutes. Administer concurrent with the last 90 minutes of leucovorin infusion, in separate bags, using a Y-line connection. | Day 1 |
| Fluorouracil (FU) | 400 mg/m2 IV bolus | Give undiluted (50 mg/mL) as a slow IV push over five minutes (administer immediately after leucovorin). | Day 1 |
| FU | 2400 mg/m2 IV | Dilute in 500 to 1000 mL 0.9% NS or D5WΔ and administer as a continuous IV infusion over 46 hours (begin immediately after FU IV bolus). To accommodate an ambulatory pump for outpatient treatment, can be administered undiluted (50 mg/mL) or the total dose diluted in 100 to 150 mL NS.Δ | 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 | - 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 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 warranted. However, given the risk of grade 3 or 4 neutropenia (46%[1]), primary prophylaxis with G-CSF is used at many institutions.
- 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 severe kidney insufficiency.[3,4] A lower starting dose of irinotecan and FU may be needed for patients with hepatic impairment.[4,5]
- NOTE: We do not recommend administration of FOLFIRINOX unless serum bilirubin is normal.
- 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.[3] 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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- 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.[4] 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 during later cycles. 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.
- 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: |
| Myelotoxicity | - Do not retreat unless neutrophil count is ≥1500/microL and platelets are ≥75,000/microL.
- Neutropenia
- The following dose reduction guidelines for hematologic toxicity were provided in the original protocol:[1] 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 eliminate bolus FU and leucovorin. For second occurrence: Reduce oxaliplatin dose to 60 mg/m2. If nonrecovery after two-week 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
- The following dose reduction guidelines for hematologic toxicity were provided in the original protocol:[1] If day 1 treatment delayed for platelet count <75,000/microL, reduce oxaliplatin dose to 60 mg/m2 and reduce both the bolus and continuous infusion FU to 75% of original doses. For second occurrence, reduce irinotecan dose to 150 mg/m2. If nonrecovery after two-week 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 FOLFIRINOX 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 eliminate bolus FU. For second occurrence, reduce the oxaliplatin dose to 60 mg/m2 and the continuous FU dose to 75% of original dose. 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 hand-foot syndrome | - For grade 3 to 4 toxicity, reduce dose of both bolus and infusional FU by 25%.
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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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| Neurologic toxicity | - For transient grade 3 paresthesias/dysesthesias or grade 2 symptoms lasting >7 days, decrease oxaliplatin dose by 25%.[3] 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.[5]
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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.[5]
|
| 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.[4]
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
