Cycle length: 28 days.
Duration of therapy: Treatment is continued until disease progression, unacceptable toxicity, or patient withdrawal. |
| Drug | Dose and route | Administration | Given on days |
| Ramucirumab | 8 mg/kg IV | Dilute with NS to a total volume of 250 mL.*¶ The first dose should be administered over 60 minutes. If tolerated, subsequent infusions may be administered over 30 minutes.[2] Administer prior to paclitaxel on days both agents are administered. | Days 1 and 15 |
| Paclitaxel | 80 mg/m2 IV | Dilute in 250 mL NS* (final concentration of 0.3 to 1.2 mg/mL) and administer over 60 minutes.Δ | Days 1, 8, and 15 |
| Pretreatment considerations: |
| Emesis risk | - LOW (10 to 30%).
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
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| Prophylaxis for infusion reactions | - Premedication with a glucocorticoid and H1 and H2 receptor blockers is standard for paclitaxel. Patients who receive weekly paclitaxel have the potential to receive substantial doses of dexamethasone; ongoing glucocorticoid treatment is unnecessary in most. One option is to administer a lower dexamethasone dose (10 mg IV) with an H1 and H2 receptor blocker 30 minutes prior to the first administration. Glucocorticoid doses can then be tapered by weekly 2-mg decrements in patients without infusion reactions, and eventually discontinued.[3,4]
- For ramucirumab, premedication with an IV H1 receptor antagonist is recommended prior to each infusion.[2] For patients who have experienced a grade 1 or 2 infusion-related reaction, premedicate with an H1 receptor antagonist, dexamethasone (or equivalent), and acetaminophen prior to each subsequent infusion.[2]
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy and infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy.
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| Vesicant/irritant properties | - Paclitaxel 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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| Dose adjustment for baseline liver or kidney dysfunction | - Ramucirumab does not require dose adjustments for liver or renal dysfunction. However, patients with pre-existing Child-Pugh B or C liver dysfunction may have new-onset or worsening encephalopathy, ascites, or hepatorenal syndrome during treatment with ramucirumab. Use in patients with Child-Pugh B or C cirrhosis only if the potential benefits of treatment are judged to outweigh the risks of clinical deterioration.[2]
- A lower starting dose of paclitaxel may be needed in patients with liver impairment.
- Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents and chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents.
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| Cardiovascular issues | - Control hypertension prior to initiating treatment.
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| Monitoring parameters: |
- Monitor for signs/symptoms of infusion reaction.
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- CBC with differential weekly during treatment.
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- Serum electrolytes and liver and renal function tests prior to each new treatment cycle.
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- Prior to each treatment, assess changes in blood pressure, neurologic symptoms/function, signs of GI perforation, and risk for bleeding and/or blood clots. Periodically assess urine protein concentration by dipstick and/or routine urinalysis.
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- Monitor thyroid function during treatment.
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| Suggested dose modifications for toxicity: |
| Infusion related reaction | - For both ramucirumab and paclitaxel:
- Manage symptoms per institutional standards.
- Reduce the infusion rate by 50% for grade 1 to 2 reactions.[2]
- Permanently discontinue for grade 3 to 4 reactions.[2]
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy and infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy.
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| Myelotoxicity | - Initiation of each cycle (day 1) should be delayed until ANC is >1500/microL and the platelet count is >100,000/microL.[1]
- Day 8 and 15 paclitaxel should be held until ANC is >1000/microL and the platelet count is >75,000/microL.[1,5]
- For patients who develop grade 4 hematologic toxicity, the dose of paclitaxel should be reduced by 10 mg/m2 for subsequent courses.[1]
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| Cardiovascular toxicity | - Withhold ramucirumab for severe hypertension until medically controlled. Dose adjustment may be needed for grade 2 or greater hypertension.[1]
- Permanently discontinue for medically significant hypertension that cannot be controlled with antihypertensive therapy or in patients with hypertensive crisis or hypertensive encephalopathy.
- Refer to UpToDate topics on toxicity of molecularly targeted antiangiogenic agents, cardiovascular effects.
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| Hepatotoxicity | - Do not administer treatment on any day if total bilirubin is >1.5 × ULN, and AST/ALT is >3 × ULN (if no liver metastases), or >5 × ULN (if liver metastases).[1]
- Paclitaxel dose may need to be adjusted for hepatic impairment on day 1 of each cycle.[5] However, none of the data used to derive these guidelines were from patients treated with weekly paclitaxel, and it is unknown if these dose reduction schemata are suitable for such patients.
- Discontinue ramucirumab for new occurrence of hepatic encephalopathy or hepatorenal syndrome.[1]
- Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents and chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents.
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| Wound healing | - Withhold ramucirumab for 28 days prior to elective surgery.
- Do not administer ramucirumab for at least 28 days following a major surgical procedure and until the wound is fully healed.
- Discontinue ramucirumab in patients who develop wound healing complications that require medical intervention.
- Refer to UpToDate topics on toxicity of molecularly targeted antiangiogenic agents, non-cardiovascular effects.
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| Neurotoxicity | - For patients who develop severe peripheral neuropathy (≥grade 2) for a week or longer, the dose of paclitaxel should be reduced by 10 mg/m2 for subsequent courses.[1]
- Refer to UpToDate topics on overview of neurologic complications of conventional non-platinum cancer chemotherapy.
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| Proteinuria | - For urine dipstick protein 2+ or greater, hold ramucirumab and perform a 24-hour urine collection for protein measurement. Withhold ramucirumab for urine protein ≥2 g over 24 hours. Reinitiate therapy at reduced dose[2] once urine protein level returns to <2 g over 24 hours. Permanently discontinue in the setting of nephrotic syndrome.
- Refer to UpToDate topics on toxicity of molecularly targeted antiangiogenic agents, non-cardiovascular effects.
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| Other toxicity | - Reduce paclitaxel dose by 10 mg/m2 for all subsequent doses for grade 3 nonhematologic toxicity (expect alopecia) attributed to paclitaxel.[1]
- Discontinue ramucirumab for serious hemorrhage, arterial thromboembolism, nephrotic syndrome, grade 3 or worse heart failure, GI perforation, or RPLS, or any other grade 4 (life-threatening) nonhematologic toxicity thought related to ramucirumab.[1,2]
- Discontinue ramucirumab for a grade 3 or 4 venous thromboembolic event that is considered to be life threatening or that cannot be adequately treated with low-molecular-weight hepatin-based therapy, or that developed during anticoagulant therapy.[1]
- 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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| If there is a change in body weight of at least 10%, doses should be recalculated. |
