Cycle length: 21 days.
Total cycles: 6 to 10.
Following completion of chemotherapy, single-agent bevacizumab maintenance therapy may be continued on an every three week schedule until disease progression or toxicity. |
| Drug | Dose and route | Administration | Given on days |
| Gemcitabine | 1000 mg/m2 IV | Dilute in 250 mL NS¶ and administer over 30 minutes. | Days 1 and 8 |
| Carboplatin | AUC* = 4 mg/mL per min IV | Dilute in 250 mL NS¶ and administer over one hour. | Day 1 |
| Bevacizumab | 15 mg/kg IV | Dilute into a total volume of 100 mL NS.¶ Administer first dose over 90 minutes, before carboplatin and gemcitabine. If well tolerated, the second infusion may be administered over 60 minutes. If well tolerated, all subsequent infusions may be administered over 30 minutes.Δ[2] | Day 1 |
| Pretreatment considerations: |
| Emesis risk | - MODERATE on day 1; LOW on day 8.◊
- 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 systemic chemotherapy.
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| Vesicant/irritant properties | - Carboplatin and gemcitabine are irritants.
- 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 indicated (risk of febrile neutropenia <2%).[1]
- Refer to UpToDate topics on prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults.
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| Dose adjustment for baseline liver or renal dysfunction | - Each carboplatin dose should be calculated based upon renal function by use of the Calvert formula.* A lower starting dose for gemcitabine 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; chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents; and dosing of anticancer agents in adults.
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| Monitoring parameters: |
- CBC with differential prior to treatment on days 1 and 8.
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- Assess electrolytes and liver and renal function prior to each new cycle of treatment.
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- Assess changes in neurologic function, blood pressure, and risk for bleeding prior to each new cycle of treatment. Urine protein/creatinine ratio should be obtained when appropriate.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - For initiation of each new treatment cycle, ANC ≥1500/microL, Hb ≥8.5 g/dL, and platelet count ≥100,000/microL.[1] If day 8 ANC 1000 to 1499/microL and/or platelets 75,000 to 99,999/microL, reduce gemcitabine dose by 50%. If day 8 ANC <1000/microL and/or platelets <75,000/microL, omit gemcitabine dose.[3]
- For intracycle febrile neutropenia, ANC <500/microL for more than five days, ANC <100/microL for more than three days, or any platelet count <25,000/microL, reduce gemcitabine dose to 800 mg/m2 for both days 1 and 8. If toxicities recur despite dose reduction, permanently delete the day 8 gemcitabine dose.
- Discontinue carboplatin and gemcitabine if hematologic recovery does not occur within three weeks.
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| Thrombotic microangiopathy | - Thrombotic microangiopathy (TMA, also sometimes called thrombotic thrombocytopenic purpura [TTP] or hemolytic uremic syndrome [HUS]) has been associated with gemcitabine, in individuals who have received a large or small cumulative dose.[3] Consider the possibility of TMA if the patient develops Coombs-negative hemolysis, thrombocytopenia, renal failure, and/or neurologic findings. Management consists of drug discontinuation and supportive care, without plasma exchange, as long as there is high confidence in a drug-induced etiology rather than TTP.
- Refer to UpToDate topics on drug-induced thrombotic microangiopathy.
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| Nephrotoxicity | - Alterations in renal function during therapy may require a recalculation of the carboplatin dose.
- Refer to UpToDate topics on dosing of anticancer agents in adults.
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| Pulmonary toxicity | - A variety of manifestations of pulmonary toxicity have been reported with gemcitabine.[3] Discontinue gemcitabine immediately and permanently.
- Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, cytotoxic agents.
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| Other toxicity | - For severe (grade 3 or 4) nonhematologic toxicities, gemcitabine should be held or decreased by 50% based on clinical judgement.[1] Discontinue bevacizumab for hypertensive crisis or hypertensive encephalopathy, serious (≥grade 2) hemorrhage, arterial thromboembolism, nephrotic syndrome, gastrointestinal perforation, fistula formation, or RPLS, severe venous thromboembolism, and severe heart failure.[1,2] Do not administer bevacizumab within 28 days of surgery or until wounds are fully healed.[2]
- 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. |
