Cycle length: Every 21 days for a maximum of 6 cycles, followed by maintenance therapy with bevacizumab and atezolizumab only every 3 weeks until disease progression or unacceptable toxicity.
Duration of therapy: 4 to 6 cycles. |
| Drug | Dose and route | Administration | Given on days |
| Induction therapy (4 to 6 cycles) |
| Atezolizumab | 1200 mg IV | Dilute in 250 mL NS.* The first dose should be administered over 60 minutes. If well tolerated, all subsequent infusions may be administered over 30 minutes.[1] | Day 1 |
| Bevacizumab | 15 mg/kg IV | Dilute into a total volume of 100 mL NS.* The first dose should be administered over 90 minutes. If well tolerated, the second infusion may be administered over 60 minutes. If well tolerated, all subsequent infusions may be administered over 10 to 30 minutes.[2] | Day 1 |
| Paclitaxel | 200 mg/m2 IV | Dilute in 250 to 500 mL NS (final concentration 0.3 to 1.2 mg/mL) and administer over 3 hours starting 1 hour after the completion of bevacizumab infusion; special tubing needed.¶[1] | Day 1 |
| Carboplatin | AUCΔ = 6 mg/mL per min IV | Dilute in 250 mL NS* and administer over 30 minutes (administer 60 minutes after the completion of paclitaxel). | Day 1 |
| Maintenance therapy (until disease progression) |
| Atezolizumab | 1200 mg IV | Dilute in 250 mL NS.* The first dose should be administered over 60 minutes. If well tolerated, all subsequent infusions may be administered over 30 minutes.[1] | Day 1 |
| Bevacizumab | 15 mg/kg IV | Dilute into a total volume of 100 mL NS*. The first dose should be administered over 90 minutes. If well tolerated, the second infusion may be administered over 60 minutes. If well tolerated, all subsequent infusions may be administered over 10 to 30 minutes.[2] | Day 1 |
| Pretreatment considerations: |
| Emesis risk | - MODERATE (MINIMAL when atezolizumab and bevacizumab is are given as maintenance).
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
|
| Prophylaxis for infusion reactions | - Premedicate with dexamethasone plus both an H1 and an H2 receptor antagonist prior to paclitaxel administration. There is no standard premedication for atezolizumab, bevacizumab, or carboplatin.
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
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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.
|
| Infection prophylaxis | - The incidence of grade 3 through 4 neutropenia was approximately 14% in the atezolizumab arm (in combination with bevacizumab, paclitaxel, and carboplatin).[1] The decision to use primary prophylaxis with a hematopoietic growth factor should be individualized according to current guidelines.
- 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.
|
| Dose adjustment for baseline liver or renal dysfunction | - Each carboplatin dose should be calculated based upon renal function by use of the Calvert formula.Δ[3]
- A lower starting dose of paclitaxel may be needed in patients with liver impairment.[4]
- Refer to UpToDate topics on dosing of anticancer agents in adults; 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.
|
| Immune-mediated adverse events or conditions | - Anti-PD-L1 monoclonal antibodies generate an immune response that may aggravate underlying autoimmune disorders or prior immune-related adverse events. There are only limited data on the safety and efficacy of checkpoint inhibitors such as atezolizumab in patients with an underlying autoimmune disorder. Atezolizumab should be used with extreme caution in such individuals. Individual evaluation is required for use of existing immunosuppression agents.
- Refer to UpToDate topics on toxicities associated with checkpoint inhibitor immunotherapy.
|
| Severe or life-threatening infections | - Atezolizumab can cause severe and/or life-threatening infections.
- Withhold or discontinue atezolizumab for severe infections.[2]
- Refer to UpToDate topics on patient selection criteria and toxicities associated with checkpoint inhibitor immunotherapy.
|
| Thyroid function tests | - Assess baseline thyroid function tests (TSH, FT4) prior to initiation of therapy.
|
| Regulatory issues | - An FDA-approved patient medication guide, which is available with the United States Prescribing Information,[5] must be dispensed with atezolizumab.
|
| Monitoring parameters: |
- CBC, with differential and platelet count prior to each cycle of induction therapy.
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- Electrolytes, renal, and liver function before each cycle of induction and maintenance therapy.
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- Assess changes in neurologic function, blood pressure, urine protein concentration, and risk for bleeding prior to each treatment cycle.
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- Assess thyroid function tests and blood glucose every one to two cycles during treatment (both induction and maintenance) and/or as clinically indicated.
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- Monitor for infusion reactions.
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- Monitor for signs and symptoms of immune-mediated adverse events (eg, colitis, diarrhea, hepatitis, hypophysitis, adrenal insufficiency, thyroid disorders, infection, cardiovascular, pneumonitis, renal, dermatologic, neurologic, ocular toxicity, etc).
|
| Suggested dose modifications for toxicity:◊ |
| Myelotoxicity | - Treatment with paclitaxel and carboplatin should be delayed until the ANC is ≥1500/microL and platelet count is ≥100,000/microL.[1] Treatment may be delayed up to 21 days from the last dose to allow sufficient recovery. Reduce dose of paclitaxel by 25% and reduce carboplatin to AUC 4.5 for febrile neutropenia or platelet count nadir of <25,000/microL or platelet count nadir <50,000/microL with bleeding or requiring transfusion during prior cycle, or if counts have not recovered in 3 weeks.[1] An alternative to dose reduction is the institution of hematopoietic growth factor support. The carboplatin dose should be decreased by 25% in patients whose platelet count nadir is <50,000/microL for longer than 5 days.[3]
- All dose reductions should be maintained for subsequent cycles.[1]
- Consider discontinuing therapy if a patient qualifies for a third dose reduction.
|
| Renal/hepatic toxicity | - Alterations in renal function during therapy may require a recalculation of the carboplatin dose. Paclitaxel dose may need to be adjusted for moderate to severe hepatic impairment during the prior cycle, with dose adjustments extrapolated from those recommended for patients with hepatic impairment at baseline, as outlined in the United States Prescribing Information.[4]
- Refer to UpToDate topics on dosing of anticancer agents in adults; 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.
|
| Neurotoxicity | - For grade 2 or worse neuropathy, hold paclitaxel until recovery to ≤grade 1, then resume treatment with a 25% (grade 2) or 50% (grade ≥3) dose reduction of paclitaxel.[1] These per-protocol recommendations differ slightly from the United States Prescribing Information, which suggests for patients who develop severe neuropathy (grade 3 or 4) for a week or longer, the dose of paclitaxel be reduced by 20% for subsequent courses.[4]
|
| Gastrointestinal toxicity | - Reduce carboplatin and docetaxel doses by 25% for grade 3 or 4 diarrhea, oral mucositis, or nausea and vomiting despite adequate antiemetics.
|
| Immune-related adverse events◊ | - Dose reductions of atezolizumab are not recommended; treatment is withheld or discontinued to manage toxicities.
- In general, if an immune-mediated adverse event is suspected, evaluate appropriately to confirm or exclude other causes. Based on the type and severity of the reaction, withhold treatment and administer systemic corticosteroids. Upon resolution to ≤grade 1, initiate corticosteroid taper.
- Immune-mediated adverse reactions that do not resolve with systemic corticosteroids may be managed with other systemic immunosuppressants (based on limited data). Discontinue atezolizumab permanently for severe or grade 3 immune-mediated adverse event that is recurrent or life threatening.
|
| Regulatory issues | - Guidelines for managing specific toxicities, including immune-mediated adverse events, are available in the United States Prescribing Information for atezolizumab,[5] from ASCO,[6] from the MASCC,[7] from the NCCN,[8] and from the SITC.[9]
|
| Other toxicity | - For any grade 3 or 4 nonhematologic toxicities not mentioned above, withhold paclitaxel and/or carboplatin until recovery to ≤grade 1. Resume treatment with a 25% dose reduction (grade 3) or a 50% dose reduction (grade 4).[1]
- No dose reduction is permitted for bevacizumab.[1,2] Discontinue bevacizumab for hypertensive crisis or hypertensive encephalopathy, serious hemorrhage, arterial thromboembolism, nephrotic syndrome, GI perforation, fistula formation, or RPLS.[2] Do not administer within 28 days of surgery.
- Refer to UpToDate topics on toxicity of molecularly targeted antiangiogenic agents, non-cardiovascular effects; toxicity of molecularly targeted antiangiogenic agents, cardiovascular effects; and toxicities associated with checkpoint inhibitor immunotherapy.
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
