Cycle length: 14 days.
Duration of therapy: Until disease progression, intolerance, resectability of liver metastases.¶ |
| Drug | Dose and route | Administration | Given on days |
| Panitumumab | 6 mg/kg IV | Dilute to a total volume of 100 mLΔ with NS◊ and administer over 60 minutes§ using a low-protein-binding 0.2-micron or 0.22-micron in-line filter. | Day 1 |
| Irinotecan¥ | 150 mg/m2 IV | Dilute with 500 mL D5W◊ 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 D5W◊ and administer over two hours after irinotecan. Administer concurrently with leucovorin in separate bags via y-line connection.[2] | 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 to 3000 mg/m2 IV | Dilute in 500 to 1000 mL D5W◊ 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 3000 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 3000 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 | - Routine premedication not indicated.
- 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 2%[1]). However, given the high rate of grade 3 or 4 neutropenia with this regimen (approximately 16%), 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 renal insufficiency.[3,4] A lower starting dose of irinotecan and FU may be needed for patients with hepatic impairment.[4,5] Dose adjustments for irinotecan may be needed for patients with increased serum bilirubin.[4]
- 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.[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 in certain settings (patients with heart failure, bradyarrhythmias, coadministration of drugs known to prolong the QT interval, or 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 (including magnesium, calcium, and potassium) and liver and renal function prior to each dose. Monitor serum calcium, magnesium, and potassium levels weekly for eight weeks after completion of therapy.[6]
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- Irinotecan is associated with early and late diarrhea, both of which may be severe.[4] 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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- Monitor for skin rash and for evidence of keratitis or ulcerative keratitis.
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- Monitor for signs or symptoms of pulmonary toxicity.
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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 modified FOLFOXIRI plus panitumumab regimen in colorectal cancer patients were published as a supplement to the original phase II trial.[1] |
| Myelotoxicity | - Do not start a new cycle of therapy unless granulocyte count is ≥1500/microL and platelet count is >75,000/microL.[1]
|
| Neutropenia | - For grade 3 or 4 neutropenia without fever during prior cycle, or febrile neutropenia with neutrophil count ≥0.5 to <1.0 × 109/L and no life-threatening sepsis, reduce doses of all cytotoxic agents by 25% once recovered, and initiate prophylactic G-CSF, if not given previously.[1] For febrile neutropenia with neutrophil count <0.5 × 109/L or life-threatening sepsis, reduce doses of all cytotoxic agents by 50% for the next cycle, once recovered, and initiate prophylactic G-CSF, if not given previously. For patients with febrile septic neutropenia with diarrhea, initiate secondary prophylaxis with G-CSF, and antibiotic prophylaxis with levofloxacin 500 mg once daily. For second occurrence of grade 3 or 4 neutropenia without fever, reduce doses of all cytotoxic agents to 50% of original. If nonrecovery after three weeks, or third occurrence of grade 3 or 4 neutropenia without fever, or second recurrence of febrile neutropenia, discontinue treatment unless it is in the patient's best interest to continue on FU plus leucovorin with or without panitumumab.
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| Thrombocytopenia | - For nadir platelet count <50,000/microL, reduce doses of all cytotoxic agents by 25%, once recovered.[1] For second occurrence, reduce doses of all cytotoxic agents to 50% of original dose, once recovered. If nonrecovery after three weeks' delay or third occurrence of platelets <50,000/microL, discontinue treatment unless it is in the patient's best interest to continue on FU plus leucovorin with or without panitumumab.
|
| Diarrhea | - Do not start a new cycle of therapy until resolution of diarrhea to grade 1 or less without antidiarrheal medication.[1]
- For diarrhea grade 3 or 4 during the prior cycle, reduce doses of all cytotoxic agents by 25%.[1] For second occurrence, reduce doses of all cytotoxic agents to 50% 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 palmar-plantar erythrodysesthesia | - Do not start a new cycle of therapy unless stomatitis and hand-foot syndrome have resolved to grade 1 or less.[1]
- For grade 3 to 4 toxicity during the prior cycle, reduce doses of all cytotoxic agents by 25%.[1] For the second occurrence, reduce doses of all cytotoxic agents to 50% of original dose.
|
| Neurotoxicity | - Do not start a new cycle of therapy unless peripheral neurotoxicity is <grade 3 unless benefits outweigh risks.[1]
- For transient grade 3 paresthesias/dysesthesias or grade 2 symptoms lasting more than seven days during the prior cycle, the US Prescribing Information suggests a decrease in the 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]
|
| Dermatologic toxicity | - Withhold dose of panitumumab for symptomatic skin- or nail-related toxicity requiring opioids, systemic steroids, or felt to be intolerable by the subject; skin or nail infection requiring IV antibiotic or IV antifungal treatment; need for surgical debridement; or any skin- or nail-related serious adverse event.[1]
- Severe dermatologic reactions, such as acneiform rash, require withholding panitumumab for one dose, then resume at 100% dose if toxicity resolves.[1] For second recurrence, withhold one or two doses, and reduce subsequent dose by 20% once toxicity resolves. For third occurrence, further reduce panitumumab dose by another 20% once toxicity resolves. For fourth occurrence or lack of toxicity resolution for up to three weeks, discontinue panitumumab.
- Refer to UpToDate topics on acneiform eruption secondary to epidermal growth factor receptor (EGFR) and MEK inhibitors.
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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.
- Permanently discontinue panitumumab in patients developing pulmonary fibrosis/interstitial lung disease.[6]
- Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, cytotoxic agents and pulmonary toxicity associated with antineoplastic therapy, molecularly targeted 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.[5]
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| Other toxicity | - Any other grade 3 or 4 toxicity except anemia and alopecia can justify dose reduction for all cytotoxic agents by 25%.[1]
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
