| Cycle length: 21 days. |
| 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 at least 250 mL NS* and administer over 120 minutes. Do not administer with aluminum needles or IV sets. | Day 1 |
| Capecitabine¶ | 625 mg/m2 per dose by mouth | Twice daily (total daily dose 1250 mg/m2). Swallow whole with water within 30 minutes after a meal, with each dose as close to 12 hours apart as possible. Do not cut or crush tablets.Δ | Days 1 through 21 |
| 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.
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| Emesis risk | - Epirubicin plus cisplatin: HIGH.
- Oral capecitabine alone: 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.
- 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.
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| Infection prophylaxis | - Primary prophylaxis with G-CSF is not warranted (incidence of febrile neutropenia with ECX was 0 and 7% in two trials[1,2]).
- 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 | - The optimal approach to cisplatin therapy in patients with preexisting kidney impairment is unknown. In the original ECX protocol, patients were required to have GFR ≥60 mL/min and a serum creatinine within normal range.[2] Lower starting doses of capecitabine may be needed in patients with kidney impairment.[3] Lower starting doses of epirubicin may be needed in patients with preexisting kidney or hepatic impairment.[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 kidney impairment, conventional cytotoxic agents.
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| 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 LVEF was below the normal range.[2]
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| Monitoring parameters: |
- CBC with differential and platelet count on day 1 prior to each treatment cycle.
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- Assess basic metabolic panel including creatinine and liver function tests on day 1 prior to each treatment cycle.
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- Monitor for neurotoxicity prior to each treatment cycle.
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- Monitor for stomatitis, diarrhea, and palmar-plantar erythrodysesthesias during treatment.
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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 as clinically indicated.
- Refer to UpToDate topics on clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity and prevention and management of anthracycline cardiotoxicity.
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- Cardiotoxicity observed with capecitabine includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy. These adverse reactions may be more common in patients with a prior history of coronary artery disease.
- Refer to UpToDate topics on cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines.
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| 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 ECX 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 count 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 capecitabine based on blood counts.
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| Kidney dysfunction | - Hold cisplatin until serum creatinine <1.5 mg/dL and/or BUN <25 mg/dL.[5] In the original trial of ECX, full-dose cisplatin was given 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).
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| Mucositis, diarrhea, nausea and vomiting | - In the original trial, capecitabine was stopped for grade 2 to 3 stomatitis, diarrhea, or nausea and vomiting.[2] If grade 3 toxicity was controlled adequately within two days and after resolution of any grade 2 toxicity, capecitabine was continued at full dose. If grade 2 toxicity occurred a second time, the dose was reduced by 25%; a third time, by 50%; and if it occurred a fourth time, treatment was discontinued. If grade 3 toxicity took longer than two days to resolve, the capecitabine dose for the next cycle was reduced by 25%; if grade 3 toxicity recurred, the dose was reduced by 50%; and if it recurred, the drug was discontinued. For grade 4 mucositis, diarrhea, or nausea or vomiting, the drug was either discontinued or the dose reduced by 50%.[3]
- NOTE: Severe diarrhea, mucositis, and myelosuppression after capecitabine should prompt evaluation for DPD deficiency.
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
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| 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.
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| Palmar-plantar erythrodysesthesias | - In the original trial, capecitabine was withheld for grade 2 or worse palmar-plantar erythrodysesthesias until resolution and the subsequent doses reduced by 15% for grade 2, 30% for grade 3, and 50% for grade 4 toxicity.[2]
- Refer to UpToDate topics on cutaneous complications of conventional chemotherapy agents.
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| Other toxicity (including hepatotoxicity) | - Hold epirubicin until all nonhematologic toxicity resolved to ≤grade 1.[4] Reduce epirubicin dose by 25% for any grade 3/4 nonhematologic toxicity in previous cycles.
- For capecitabine:
- Grade 2: For the first, second, and third occurrence, hold capecitabine.[3] After resolution to grade 1 or less, resume treatment (first occurrence, no dosage adjustment; second occurrence, 75% of the starting dose; third occurrence, 50% of the starting dose). For the fourth occurrence of a grade 2 toxicity, discontinue capecitabine therapy.
- Grade 3: For the first and second occurrence, hold capecitabine therapy. After resolution to grade 1 or less, resume treatment at a reduced dose (first occurrence, 75% of the starting dose; second occurrence, 50% of the starting dose). For the third occurrence of a grade 3 toxicity, discontinue capecitabine.
- Grade 4: Discontinue capecitabine therapy. Alternatively, hold capecitabine therapy, and begin next treatment at 50% of the starting dose when toxicity resolves to grade 1 or less; discontinue treatment for first recurrence of grade 4 toxicity.
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| Doses of capecitabine that are omitted for toxicity are not replaced or restored. Instead, the patient should resume the planned treatment cycles at the modified dose. |
| If there is a change in body weight of at least 10%, doses should be recalculated. |
