| 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 |
| Oxaliplatin | 130 mg/m2 IV¶ | Dilute with 500 mL D5W* and administer over two hours. Shorter oxaliplatin administration schedules (eg, 1 mg/m2 per minute) appear to be safe.[3] | Day 1 |
| CapecitabineΔ | 625 mg/m2 per dose by mouth | Twice daily; take with water within 30 minutes after a meal. Capecitabine tablets should be swallowed whole. Do not crush or cut tablets.◊ | Days 1 through 21 |
| Pretreatment considerations: |
| Emesis risk | - Epirubicin plus oxaliplatin: MODERATE (30 to 90% risk of emesis).
- Oral capecitabine alone: LOW (10 to 30% risk of emesis).
- 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 prophylaxis of infusion reactions with this regimen.
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
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| Vesicant/irritant properties | - Epirubicin is a vesicant; oxaliplatin 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 the EOX regimen was 10% 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 | - Lower starting doses of capecitabine and oxaliplatin may be needed in patients with kidney impairment.[4,5] Lower starting doses of epirubicin may be needed in patients with pre-existing kidney or hepatic impairment.[6]
- 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. 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 | - 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 EOX protocol, patients were excluded from receiving epirubicin if their LVEF was below the normal range.[2]
- 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 on day 1 prior to each treatment cycle.
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- Assess electrolytes (especially magnesium and phosphate) and liver and kidney function once per cycle on day 1.
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- Monitor for stomatitis, diarrhea, and palmar-plantar erythrodysesthesias during therapy.
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- Monitor for neurotoxicity prior to each treatment cycle.
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- Monitor cumulative epirubicin dose. Reassess LVEF periodically during EOX 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.
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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. In the original EOX protocol, day 1 epirubicin doses were delayed until the platelet count was ≥100,000/microL and the total WBC count was ≥2000/microL.[2] The dose of epirubicin was reduced by 25% for a second episode of treatment delay due to myelosuppression or for febrile neutropenia. Oxaliplatin was delayed by one week if the neutrophil count was <1000/microL or the platelet count was <75,000/microL. After recovery from grade 2 to 4 thrombocytopenia or grade 3 or 4 neutropenia, the dose of oxaliplatin was reduced to 100 mg/m2. There were no dose reductions for capecitabine based on blood counts.
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| Mucositis, diarrhea, nausea and vomiting | - In the original protocol, capecitabine was stopped if patients developed grade 2 or 3 stomatitis, diarrhea, or nausea and vomiting.[2] If grade 3 toxicity was controlled adequately within two days, capecitabine was resumed at full dose after resolution to ≤grade 1 toxicity. If grade 2 toxicity recurred, the dose was reduced by 25%; a third time, by 50%, and after the fourth episode, 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 again, the drug was discontinued. For grade 4 mucositis, diarrhea, or nausea or vomiting, the drug was either discontinued or the dose reduced by 50%. For persistent grade 3 to 4 diarrhea or stomatitis after appropriate capecitabine reduction, the dose of oxaliplatin was reduced to 100 mg/m2.
- 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 | - In the original protocol, oxaliplatin was delayed for one week for persistent grade 1 or worse neuropathy.[2] After recovery of persisting grade 1 to 2 neuropathy between cycles, or for any grade 3 to 4 neuropathy lasting for 7 to 14 days, the dose of oxaliplatin was reduced to 100 mg/m2. Omit oxaliplatin for persistent grade 3 to 4 neuropathy lasting longer than 14 days.
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| Palmar-plantar erythrodysesthesias | - In the original trial, capecitabine was withheld for grade 2 or higher 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 side effects of conventional chemotherapy agents.
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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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| Other toxicity (including hepatotoxicity) | - Hold epirubicin until all nonhematologic toxicity resolves to ≤grade 1.[6] 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.[4] 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 therapy.
- 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.
- Patients with grade 3 or 4 hyperbilirubinemia may resume capecitabine once toxicity has reduced to grade ≤2, but at a reduced dose.[4]
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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.[4] |
| If there is a change in body weight of at least 10%, doses should be recalculated. |
