| Cycle length: 21 days. |
| Drug | Dose and route | Administration | Given on days |
| Bevacizumab | 7.5 mg/kg IV | Dilute into a total volume of 100 mL NS* and administer the first dose over 90 minutes following oxaliplatin. If tolerated, then administer second dose over 60 minutes after oxaliplatin. If tolerated, then administer all subsequent doses over 30 minutes before oxaliplatin. | Day 1 |
| Oxaliplatin | 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¶ | 850 mg/m2 per dose by mouth | Twice daily (total dose 1700 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.Δ | Evening of day 1 to morning of day 15 |
| Pretreatment considerations: |
| Emesis risk | - Oxaliplatin plus bevacizumab: MODERATE.
- 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.
- Refer to UpToDate topics on infusion reactions to therapeutic monoclonal antibodies used for cancer therapy and infusion reactions to systemic chemotherapy.
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| Vesicant/irritant properties | - Oxaliplatin is an irritant but 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 not indicated (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 kidney dysfunction | - Lower starting doses of oxaliplatin and capecitabine may be needed for kidney impairment.
- Refer to UpToDate topics on chemotherapy nephrotoxicity and dose modification in patients with kidney impairment, 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 | - 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 weekly during treatment.
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- Assess electrolytes (especially potassium and magnesium) and liver and kidney function every three weeks prior to treatment.
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- Assess changes in blood pressure, urine protein concentration, neurologic function, and risk for bleeding prior to each treatment.
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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. These adverse reactions may be more common in patients with a prior history of coronary artery disease.
- 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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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Delay treatment one week if the total WBC count is <3000/microL, ANC is <1500/microL, or the platelets count is <100,000/microL on day 1. If treatment is delayed for two weeks or delayed for one week on two separate occasions, reduce the doses of oxaliplatin and capecitabine by 10 to 20%. Subsequent treatment cycles should be delayed until ANC ≥1500/microL and platelets ≥75,000/microL.
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| Neurologic toxicity | - In the original trial, oxaliplatin dose was decreased by 25% for grade 3 paresthesias and dysesthesias lasting longer than seven days, and the drug discontinued for grade 4 or persistent grade 3 paresthesia/dysesthesias.[1] The United States Prescribing Information suggests dose reduction for persistent NCI-CTC grade 2 neurosensory events (sensory alteration or paresthesias including tingling but not interfering with ADLs) and discontinuation of oxaliplatin for persistent grade 3 (objective sensory loss or paresthesias including tingling interfering with function but not ADLs) or grade 4 neurosensory events.[3]
- Refer to UpToDate topics on overview of neurologic complications of platinum-based chemotherapy.
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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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| 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] 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 DPD deficiency.
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
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| Other toxicity (including heptotoxicity) | - Interrupt capecitabine and delay oxaliplatin for any grade 2 or worse 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.
- Reduce the dose of oxaliplatin by 25% for any drug-related grade 3 toxicity.
- For capecitabine:
- Grade 2: For the first, second, and third occurrence, hold capecitabine therapy. 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).[5] 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.
- Discontinue bevacizumab for hypertensive crisis or hypertensive encephalopathy, serious hemorrhage, arterial thromboembolism, nephrotic syndrome, gastrointestinal perforation, fistula formation, or RPLS.[6] Bevacizumab should not be administered within 28 days of surgery, and it should be suspended prior to elective surgery.
- Refer to UpToDate topics on toxicity of molecularly targeted antiangiogenic agents, non-cardiovascular effects and "Toxicity of molecularly targeted antiangiogenic agents, cardiovascular effects.
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| Doses of capecitabine that are omitted for toxicity are not replaced. The patient should resume planned treatment cycles at the modified dose. |
| If there is a change in body weight of at least 10%, doses should be recalculated. |
