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 topic on "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults".
|
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".
|
Vesicant/irritant properties | - Paclitaxel can cause significant tissue damage; avoid extravasation.
- Refer to UpToDate topic on "Extravasation injury from chemotherapy and other non-antineoplastic vesicants".
|
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".
|
Cardiovascular issues | - Control hypertension prior to initiating treatment.
|
Monitoring parameters: |
- Monitor for signs/symptoms of infusion reaction.
|
- CBC with differential weekly during treatment.
|
- Serum electrolytes and liver and renal function tests prior to each new treatment cycle.
|
- 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.
|
- Monitor thyroid function during treatment.
|
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".
|
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]
|
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 topic on "Toxicity of molecularly targeted antiangiogenic agents: Cardiovascular effects".
|
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".
|
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 topic on "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects".
|
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 topic on "Overview of neurologic complications of conventional non-platinum cancer chemotherapy".
|
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 topic on "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects".
|
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".
|
If there is a change in body weight of at least 10%, doses should be recalculated. |