| Drug | Dose and route | Administration | Given on days |
| Epirubicin | 50 mg/m2 IV | Administer into a free-flowing IV solution with NS,* generally over 3 to 20 minutes. | Day 1 |
| Cisplatin | 60 mg/m2 IV | Dilute with 250 mL NS* and administer over two hours. Do not administer with aluminum needles or IV sets. | Day 1 |
| Fluorouracil (FU) | 200 mg/m2 per day IV | Infuse through a central line as a continuous infusion via a portable infusion device. | Daily for up to six months |
| Pretreatment considerations: |
| Hydration | - Give IV fluid to establish a urine flow of at least 100 mL/hour for at least two hours prior to and two hours after cisplatin administration.
- Refer to UpToDate topics on cisplatin nephrotoxicity.
|
| Emesis risk | - Epirubicin plus cisplatin: HIGH; daily low-dose continuous infusion.
- FU: LOW.
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
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| Prophylaxis for infusion reactions | - There are no recommended premedications to prevent infusion reactions with the ECF regimen.
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
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| Vesicant/irritant properties | - Epirubicin is a vesicant; cisplatin is an irritant but can cause significant tissue damage. Avoid extravasation of either agent.
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
|
| Infection prophylaxis | - Primary prophylaxis with G-CSF is not warranted (incidence of grade 3 or 4 febrile neutropenia was 9% in one trial;[3] in a second trial, 14% developed either febrile neutropenia or infection[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.
|
| Dose adjustment for baseline liver or kidney dysfunction | - The optimal approach to cisplatin therapy in patients with preexisting kidney impairment is unknown. In the original ECF protocol, cisplatin was not given to patients with a GFR <40 mL/min, full-dose cisplatin was administered to patients with a GFR ≥60 mL/min, and if the GFR was between 40 and 60 mL/min, the dose of cisplatin (in mg) equaled the GFR value in mL/min.[2] Lower starting doses of epirubicin may be needed in patients with preexisting kidney or hepatic impairment.[4] Lower starting doses of FU may be needed with severe liver impairment.[5]
- 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 impairment, conventional cytotoxic agents.
|
| Cardiac issues | - Epirubicin is associated with dose-dependent cardiomyopathy, the incidence of which is related to cumulative dose. Assess baseline LVEF prior to initiating therapy. Epirubicin is contraindicated for patients with recent myocardial infarction, severe myocardial dysfunction, severe arrhythmias, or prior treatment with maximum cumulative doses of anthracyclines. In the original protocol, patients were excluded from receiving epirubicin if their baseline LVEF was less than 50%.[2]
|
| Monitoring parameters: |
- CBC with differential and platelet count on day 1 prior to each treatment cycle.
|
- Assess basic metabolic panel including creatinine and liver function tests once per cycle on day 1 prior to each treatment cycle.
|
- Monitor for neurotoxicity prior to each treatment cycle.
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- Monitor for hearing loss prior to each dose of cisplatin; audiometry as clinically indicated.
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- Monitor cumulative epirubicin dose. Reassess LVEF periodically during ECF therapy as clinically indicated.
- Refer to UpToDate topics on clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity and prevention and management of anthracycline cardiotoxicity.
|
| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Hold epirubicin until the platelets are ≥100,000/microL and the ANC is ≥1500/microL.[4] In the original ECF protocol, cisplatin and epirubicin doses were delayed by one week or until myelosuppression was resolved if the platelet count was <100,000/microL or the total WBC was <2000/microL on day 1.[2] The dose of epirubicin was reduced by 25% for a second episode of treatment delay due to myelosuppression or for febrile neutropenia. There were no dose reductions for infusional FU based on blood counts, but the United States Prescribing Information recommends treatment discontinuation for neutropenia (WBC <3500/microL or rapidly declining) or platelet count <100,000/microL.[5]
|
| Kidney dysfunction | - Hold cisplatin until serum creatinine <1.5 mg/dL and/or BUN <25 mg/dL.[6] In the original trial of ECF, full-dose cisplatin was given each cycle if the estimated GFR was >60 mL/min, and the drug was held if the estimated GFR was <40 mL/min.[2] For an estimated GFR of 40 to 60 mL/min, the dose of cisplatin (in mg) was equivalent to the estimated GFR (in mL/min).[2]
|
| Mucositis or diarrhea | - In the original protocol, a treatment break from FU was recommended for grade 2 or worse diarrhea. Treatment was withheld until symptoms resolved, then restarted at 150 mg/m2 per day for grade 2 toxicity, and at 100 mg/m2 per day for grade 3 or 4 toxicity.[2]
- NOTE: Severe diarrhea and mucositis after FU should prompt evaluation for DPD deficiency.
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
|
| Neurotoxicity | - Neuropathy usually is seen with cumulative doses of cisplatin >400 mg/m2, although there is marked interindividual variation. Patients with mild neuropathy can continue to receive full cisplatin doses. If neuropathy interferes with function, the risk of potentially disabling neurotoxicity must be weighed against the benefit of continued treatment.
- Refer to UpToDate topics on overview of neurologic complications of conventional non-platinum cancer 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]
|
| Palmar-plantar erythrodysesthesias | - In the original trial, FU was withheld for one week for any grade of palmar-plantar erythrodysesthesia and then restarted at a dose of 150 mg/m2 per day.[2]
- Refer to UpToDate topics on cutaneous complications of conventional chemotherapy agents.
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| Cardiotoxicity | - Cardiotoxicity observed with FU includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic 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 | - Hold epirubicin until all nonhematologic toxicity resolves to ≤grade 1.[4] Reduce epirubicin dose by 25% for any grade 3/4 nonhematologic toxicity in previous cycles.
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
