Cycle length: 4 weeks.
Duration of therapy: Maximum of 8 cycles. |
| 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 |
| Pegylated liposomal doxorubicin (PLD) | 30 mg/m2 IV | Dilute in 250 or 500 mL D5W*¶ and infuse initially at a rate of 1 mg/min to minimize risk of infusion reactions. If none are observed, increase rate of infusion to complete administration over one hour. | Day 1 |
| Pretreatment considerations: |
| Emesis risk | - MODERATE on day 1 and LOW on day 8.
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
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| Vesicant/irritant properties | - PLD is an irritant but it 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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| Prophylaxis for infusion reactions | - The original protocol administered premedication with an H1 and an H2 receptor antagonist plus hydrocortisone 125 mg on day 1.
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
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| Infection prophylaxis | - Primary prophylaxis with G-CSF is not warranted. Although the exact incidence of febrile neutropenia was not reported with this regimen, the incidence of grade 3 or 4 neutropenia was only 17%.[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 renal dysfunction | - Although the original protocol permitted standard doses for patients with a total bilirubin up to 3 mg/dL, and for transaminase levels up to seven times the institutional limit of normal[1], lower starting doses for gemcitabine and PLD may be needed for 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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| Cardiac issues | - PLD is associated with cardiomyopathy, the incidence of which is related to total dose. Assess baseline LVEF¶ prior to administration. PLD is contraindicated for patients with recent myocardial infarction, severe myocardial dysfunction, severe arrhythmia, or previous therapy with high cumulative doses of doxorubicin or other anthracycline-type drug.[2]
- 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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| Monitoring parameters: |
- CBC with differential and platelet count weekly during treatment.
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- Assess basic metabolic panel (including serum creatinine) and liver function prior to each cycle or when otherwise clinically indicated during treatment.
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- Monitor for infusion reactions.
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- Monitor for palmar-plantar erythrodysesthesia and stomatitis.
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- Monitor the cumulative dose of PLD. Reassess LVEF periodically during treatment with PLD as clinically indicated. In clinical practice, PLD appears to have significantly less cardiotoxicity than unencapsulated anthracyclines, but this does not preclude the need to monitor cardiac function.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - A new cycle should not be initiated unless the ANC is ≥1500 cells/microL and platelets are ≥100,000/microL.[1] The original protocol recommended a decrease in the day 8 gemcitabine by 50% for grade 1 thrombocytopenia or grade 2 neutropenia; withhold for higher grades of thrombocytopenia or neutropenia on the day of treatment.[1] The original protocol provided no dose reduction guidelines for PLD in response to myelotoxicity. However, the United States Prescribing Information recommends a 25% dose reduction in PLD dose for nadir ANC <500 cells/microL or platelet count <25,000/microL.[2]
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| Cardiotoxicity | - For deterioration in cardiac function associated with use of PLD, the benefit of continued therapy should be carefully evaluated against the risk of producing irreversible cardiac damage.[2]
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| Cutaneous and mucosal toxicity | - For ≥grade 2 palmar-plantar erythrodysesthesia, the original protocol recommended 25% reduction in PLD dose.[1] The United States Prescribing Information recommends delay in therapy for to up to two weeks or until resolved to grade 0 or 1 for ≥grade 2 palmar-plantar erythrodysesthesia or stomatitis, and reduce dose by 25% for grade 3 or 4 toxicity; discontinue if toxicity persists.[2]
- Refer to UpToDate topics on oral toxicity associated with chemotherapy and cutaneous side effects of conventional chemotherapy agents.
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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 topic on drug-induced thrombotic microangiopathy.
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| Hepatotoxicity | - Gemcitabine is commonly associated with a transient rise in serum transaminases, but these are seldom of clinical significance. There is insufficient information from clinical studies to allow clear dose recommendations in these patients.
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| Infusion reactions | - For flank pain, flushing, shortness of breath, and/or chest tightness during PLD, stop the infusion immediately; after resolution, restart treatment at reduced rate.[2] For recurrent infusion reactions, discontinue PLD and consider desensitization if severe (signs/symptoms of anaphylaxis). However, most reactions are mild, and many patients are able to tolerate a rechallenge using additional premedication and limiting the initial infusion rate to ≤1 mg/min.
- Refer to UpToDate topic on infusion reactions to systemic chemotherapy.
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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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| If there is a change in body weight of at least 10%, doses should be recalculated. |
