| Cycle length: 14 days. |
| Drug | Dose and route | Administration | Given on days |
| Trastuzumab | 6 mg/kg IV (loading dose) | Dilute in 250 mL NS¶ and administer over 90 minutes for the loading dose. Do not mix with D5W and do not infuse as an IV push or bolus. | Day 1 (cycle 1 only) |
| Trastuzumab | 4 mg/kg IV | Dilute in 250 mL NS¶ and administer over 30 minutes. Do not mix with D5W and do not infuse as an IV push or bolus. | Day 1 of every subsequent cycle, starting with cycle 2 |
| OxaliplatinΔ | 85 mg/m2 IV | Dilute with 500 mL D5W¶ and administer over two hours. 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.[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)§ | 400 mg/m2 IV bolus | Slow IV push (over two to five minutes). Administer immediately after leucovorin. | Day 1 |
| FU | 2400 mg/m2 total dose IV | Dilute with 500 to 1000 mL D5W¶ and administer as continuous IV 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 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 for FOLFOX. Most clinicians do not routinely premedicate prior to the first trastuzumab dose. However, patients may be instructed to self-administer acetaminophen or an NSAID if flu-like symptoms develop within 24 hours of drug administration.
- Refer to UpToDate topics on infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy and infusion reactions to systemic chemotherapy.
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| Vesicant/irritant properties | - Oxaliplatin and FU are classified as irritants, but oxaliplatin (rare) 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 renal dysfunction | - A lower starting dose of oxaliplatin may be needed for severe renal impairment.[3] 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 renal insufficiency, conventional cytotoxic agents.
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| Maneuvers to prevent neurotoxicity | - Counsel patients to avoid exposure to cold during and for approximately 72 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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| Cardiopulmonary issues | - Prolongation of the corrected QT interval (QTc) and ventricular arrhythmias has 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 QTc interval, and electrolyte abnormalities. Avoid oxaliplatin in patients with congenital long QT syndrome. Correct hypokalemia and hypomagnesemia prior to initiating oxaliplatin. Cases of pulmonary fibrosis are rarely reported with oxaliplatin.
- Trastuzumab is associated with cardiotoxicity; assess baseline LVEF prior to therapy and then at least every three months during therapy.[4] Patients with heart failure or a baseline LVEF <50% were excluded from the study.[1] Trastuzumab may cause serious pulmonary toxicity and should be used with caution in patients with preexisting pulmonary disease.
- Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents.
- Cardiotoxicity observed with FU includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy.
- Refer to UpToDate topics on cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines.
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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 renal function every two weeks prior to each treatment.
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- Assess changes in neurologic function prior to each treatment.
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- Monitor for infusion reactions, especially during the first two courses of trastuzumab.
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- Monitor for mucositis, diarrhea, and palmar-plantar erythrodysesthesias during treatment.
- Refer to UpToDate topics on oral toxicity associated with chemotherapy, cutaneous side effects of conventional chemotherapy agents, and enterotoxicity of chemotherapeutic agents.
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- Assess cardiac function as clinically indicated.
- Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Delay treatment cycle by one week for absolute neutrophil count <1500/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, eliminate FU bolus. With the second occurrence, reduce infusional FU by 20% and reduce oxaliplatin dose from 85 to 65 mg/m2.[3]
- NOTE: Severe myelosuppression after FU should prompt evaluation for DPD deficiency.
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| Neurologic toxicity | - Withhold oxaliplatin for persisting grade 2 or any grade 3 paresthesias/dysesthesias until recovery.[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 permanent discontinuation for persistent grade 3 neurosensory events.[3]
- Refer to UpToDate topics on overview of neurologic complications of platinum-based chemotherapy.
- 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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| Gastrointestinal toxicity | - Withhold treatment for grade 2 or worse diarrhea, and restart at a 20% lower dose of all agents after complete resolution. The United States Prescribing Information recommends dose reduction of oxaliplatin to 65 mg/m2 as well as a reduction of bolus FU and infusional FU after recovery from grade 3 or 4 diarrhea during the prior cycle.[3]
- NOTE: Severe diarrhea, mucositis, and myelosuppression after FU should prompt evaluation for DPD deficiency.[5]
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
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| Cardiotoxicity | - Assess LVEF at least every three months during trastuzumab.[4] The United States Prescribing Information recommends withholding trastuzumab for at least four weeks for LVEF ≥16% decrease from baseline or LVEF below normal limits and ≥10% decrease from baseline; repeat LVEF assessment every four weeks. May resume trastuzumab treatment if LVEF returns to normal limits within four to eight weeks and remains at ≤15% decrease from baseline value. Discontinue permanently for persistent (>8 weeks) LVEF decline or for >3 incidents of treatment interruptions for cardiomyopathy.[4] Guidelines for managing cardiac dysfunction during therapy with HER2-targeted agents are available.
- Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents.
- 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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| Pulmonary toxicity | - Discontinue trastuzumab for serious 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, molecularly targeted agents and pulmonary toxicity associated with antineoplastic therapy, cytotoxic agents.
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
