| Cycle length: 21 days. |
| Drug | Dose and route | Administration | Given on days |
| Trastuzumab | Loading dose: 8 mg/kg IV | 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) |
| Trastuzumab | 6 mg/kg IV | Dilute in 250 mL NS¶ and administer over 30 to 90 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 | 130 mg/m2 IV | Dilute in 500 mL D5W¶ and administer over two hours. Shorter oxaliplatin administration schedules (eg, 1 mg/m2 per minute) appear to be safe.[2] | Day 1 |
| Capecitabine◊ | 1000 mg/m2 orally per dose | Twice daily (total dose 2000 mg/m2 per day); 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.§ | Days 1 to 14 |
| Pretreatment considerations: |
| Emesis risk | - Oxaliplatin: MODERATE.
- Oral capecitabine: LOW.
- 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 oxaliplatin. 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 is classified as an irritant, but can cause significant tissue damage (rare); 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 <20%[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 | - Lower starting doses of oxaliplatin and capecitabine may be needed for renal impairment.
- Refer to UpToDate topics on 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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| Cardiac issues | - Prolongation of the corrected QT (QTc) interval 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. Pulmonary toxicity is rarely reported with oxaliplatin.
- Trastuzumab is associated with cardiomyopathy; assess baseline LVEF prior to therapy and at least every three months during therapy.[3] Patients with heart failure, coronary artery disease, myocardial infarction in the prior six months, or baseline LVEF <50% were excluded from the study.[1] Trastuzumab may also cause serious pulmonary toxicity and should be used with caution in patients with preexisting pulmonary disease.
- Refer to UpToDate topics on cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines and cardiotoxicity of trastuzumab and other HER2-targeted agents.
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| Monitoring parameters: |
- Obtain CBC with differential and platelet count prior to each treatment.
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- Assess electrolytes and liver and renal function every three weeks prior to each new treatment.
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- Assess changes in neurologic function prior to each treatment.
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- Assess cardiac function every three months during therapy or as clinically indicated.
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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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- More frequent anticoagulant response (INR or prothrombin time) monitoring is necessary for patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy.
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- Cardiotoxicity observed with capecitabine includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic changes, and cardiomyopathy.
- Refer to UpToDate topics on cardiotoxicity of non-anthracycline cancer chemotherapy agents.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - A new cycle of treatment should not start until neutrophils recover to >1500/microL and platelets recover to >100,000/microL. Interrupt capecitabine for any grade 2 or worse hematologic toxicity and delay treatment with both capecitabine and oxaliplatin until complete recovery or improvement to ≤grade 1.[4] Reduce the capecitabine dose by 25% in subsequent cycles at the first occurrence of a grade 2 or grade 3 toxicity, and by 50% at the second occurrence of a given grade 2 or grade 3 toxicity or at the first occurrence of a grade 4 event. After recovery, reduce oxaliplatin by 25% for any intracycle grade 3 or 4 neutropenia or thrombocytopenia. Discontinue capecitabine and oxaliplatin permanently if, despite dose reduction, hematologic toxicity occurs for the third time at grade 2 or grade 3, or a second time at grade 4.
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| Neurotoxicity | - 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.[5]
- Refer to UpToDate topics on overview of neurologic complications of platinum-based chemotherapy.
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| Gastrointestinal toxicity | - Interrupt capecitabine and delay oxaliplatin for any grade 2 or worse gastrointestinal toxicity; restart treatment only after complete recovery or improvement to ≤grade 1.[4,6] After recovery, reduce the dose of oxaliplatin by 25% after the first episode of grade 3 or worse diarrhea or mucositis. Reduce the capecitabine dose by 25% in subsequent cycles at the first occurrence of grade 2 or 3 toxicity, and by 50% at the second occurrence of a given grade 2 or grade 3 toxicity or at the first occurrence of a grade 4 event. Discontinue capecitabine permanently if, despite dose reduction, a given toxicity occurs for the third time at grade 2 or grade 3, or a second time at grade 4.[4]
- NOTE: Severe diarrhea, mucositis, and myelosuppression after capecitabine should prompt evaluation for dihydropyrimidine dehydrogenase deficiency.
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
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| Cardiotoxicity | - Assess LVEF at least every three months during trastuzumab.[3] In the original trial, if LVEF decreased by 10 points from baseline and to below 50%, trastuzumab was withheld and a repeat LVEF assessment performed within three weeks.[1] If LVEF failed to improve, discontinuation of trastuzumab was suggested. The United States Prescribing Information suggests withholding trastuzumab for at least four weeks for LVEF ≥16% decrease from baseline or LVEF below normal limits and ≥10% decrease from baseline, and repeat LVEF 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.[3] 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.
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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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| Other toxicities (including hepatotoxicity) | - Interrupt capecitabine and delay oxaliplatin for any grade 2 or worse other non-neurologic toxicity (except alopecia); restart treatment only after complete recovery or improvement to ≤grade 1.[4]
- Patients with grade 3 or 4 hyperbilirubinemia may resume capecitabine once toxicity has reduced to grade ≤2, but at a reduced dose.[4]
- Reduce the dose of oxaliplatin for subsequent cycles by 25% for drug-related grade 3 toxicity. Reduce the capecitabine dose by 25% in subsequent cycles at the first occurrence of a grade 2 or grade 3 toxicity, and by 50% at the second occurrence of a given grade 2 or grade 3 toxicity or at the first occurrence of a grade 4 event.
- Discontinue capecitabine permanently if, despite dose reduction, a given toxicity occurs for the third time at grade 2 or grade 3, or a second time at grade 4.[4]
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| Doses of capecitabine omitted for toxicity are not replaced or restored; instead the patient should resume with the next planned treatment cycle. |
| If there is a change in body weight of at least 10%, doses should be recalculated. |
