Cycle length: 21 days.
Duration of therapy: Maximum of four cycles. |
| Drug | Dose and route | Administration | Given on days |
| Gemcitabine | 1000 mg/m2 IV | Dilute in 250 mL NS* (concentration no more than 40 mg/mL) and administer over 30 to 60 minutes. | Days 1 and 8 |
| Cisplatin¶ | 70 mg/m2 IV | Dilute in 250 mL NS* and administer over 60 minutes (or at 1 mg/min).¶ Do not administer with aluminum needles or sets. | Day 1 |
| Pretreatment considerations: |
| Hydration | - Due to the potential for nephrotoxicity associated with cisplatin, pretreatment hydration with 1 to 2 L of fluid is recommended prior to cisplatin administration; adequate post hydration and urinary output (>100 mL/hour) should be maintained for 24 hours after administration.[3]
- Refer to UpToDate topics on cisplatin nephrotoxicity.
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| Emesis risk | - HIGH (>90% risk of emesis) on day 1; LOW (10 to 30% risk of emesis) 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 | - Routine prophylaxis not indicated.
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
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| Vesicant/irritant properties | - Cisplatin is an irritant but 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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| Infection prophylaxis | - Primary prophylaxis with G-CSF is not justified. The risk of febrile neutropenia was not reported in the original trial, but fewer than 6% had grade 4 neutropenia.[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 pre-existing baseline liver or renal dysfunction | - The optimal approach to cisplatin therapy in patients with pre-existing renal impairment is unknown. Patients with borderline renal dysfunction (CrCl between 50 and 60 mL/min) may be offered an alternative regimen consisting of gemcitabine (1000 mg/m2) and a split dose of cisplatin (35 mg/m2) on days 1 and 8 of a 21-day cycle for four cycles.[2] The optimal approach to cisplatin therapy in patients with further pre-existing renal impairment is unknown, as such patients were excluded from both trials.[1,2]
- A lower starting dose of gemcitabine may be needed for patients with liver impairment.
- Refer to UpToDate topics on cisplatin nephrotoxicity; 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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| Monitoring parameters: |
- CBC with differential and platelet count prior to each treatment; more frequently as clinically indicated.
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- Assess electrolytes, renal, and liver function prior to each treatment; more frequently as clinically indicated.
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- Monitor for hearing loss prior to each dose of cisplatin; audiometry as clinically indicated.
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- Assess changes in neurologic function prior to each new cycle.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Each new cycle should not begin until the WBC is ≥3500/microL and platelet count is ≥100,000/microL.[1] Gemcitabine should be omitted on day 8 of the scheduled treatment if the ANC is <1000/microL or the platelet count is <50,000/microL on that day.[1] Reduce day 8 gemcitabine dose by 25% for platelet count 50,000 to 75,000/microL on that day.
- Further cycle adjustments: If febrile neutropenia or grade 4 thrombocytopenia during prior cycle, reduce subsequent gemcitabine doses by 25%.
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| Neurologic toxicity | - Neuropathy most often is seen with cumulative doses of cisplatin >400 mg/m2, although there is marked interindividual variation. Patients with mild neuropathy can continue to receive full cisplatin doses. However, if the neuropathy interferes with function, the risk of potentially disabling neurotoxicity must be weighed against the benefit of continued treatment. In the original trial, the dose of cisplatin was modified in the event of severe neurotoxicity.[1]
- Refer to UpToDate topics on overview of neurologic complications of platinum-based chemotherapy.
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| Pulmonary toxicity | - A variety of manifestations of pulmonary toxicity have been reported with gemcitabine. Discontinue the drug immediately and permanently.[4]
- Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, cytotoxic agents.
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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.
- 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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| Nephrotoxicity | - For each new cycle, hold cisplatin until serum creatinine is ≤1.5 mg/dL and/or BUN <25 mg/dL. For grade ≥2 nephrotoxicity during treatment (creatinine >1.5 times normal value despite adequate hydration), CrCl should be determined prior to next cycle, and cisplatin dose reduced if <60 mL/min. In the original protocol, cisplatin dose was reduced by 25% if the serum creatinine level during the prior cycle was 1.6 to 2 mg/dL, and omitted for creatinine >2 mg/dL.
- Refer to UpToDate topics on cisplatin nephrotoxicity.
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| 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. Consider the possibility of TMA if the patient develops Coombs-negative hemolysis, thrombocytopenia, renal failure, and/or neurologic findings.[4] 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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| Other toxicity | - Patients with grade 3 or 4 nonhematologic toxicities other than alopecia may receive a 50% reduced dose of gemcitabine on day 8 or have the dose omitted per clinician discretion.[1]
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
