Cycle length: Every 21 days.
Duration of therapy: For a maximum of 6 cycles or until disease progression, unacceptable toxicity, or request to discontinue treatment. |
| Drug | Dose and route | Administration | Given on days |
| Paclitaxel | 80 mg/m2 IV | Dilute in 250 mL NS¶ or D5W and administer over 1 hour.Δ[3] | Days 1 and 8 |
| Gemcitabine | 1000 mg/m2 IV | Dilute in 250 mL NS¶ (concentration no more than 40 mg/mL) and administer over 30 to 60 minutes after paclitaxel infusion completion.[4,5] | Days 1 and 8 |
| Cisplatin | 70 mg/m2 IV | Dilute in 250 mL NS¶ and administer over 60 minutes (or at 1 mg/min) following the completion of gemcitabine infusion.◊[6] Do not administer with needles or intravenous sets that contain aluminum parts. Aluminum reacts with cisplatin, causing precipitate formation and a loss of potency. | Day 1 |
| Pretreatment considerations: |
| Hydration | - Administer isotonic saline with electrolyte supplementation before and after cisplatin infusion. Although clinical practice is variable, one approach is to administer isotonic saline with 20 mEq/L of potassium chloride and 2 grams/L of magnesium sulfate. Administer a minimum of 1000 mL over 2 to 3 hours prior to and a minimum of 500 mL over the 2 hours following cisplatin administration.
- Induction of diuresis minimizes the risk of cisplatin nephrotoxicity. IV fluid should be sufficient to establish a urine flow of at least 100 mL/hour for at least 2 hours prior to and 2 hours after cisplatin administration.[6]
- Refer to UpToDate topics on cisplatin nephrotoxicity.
|
| Emesis risk | - HIGH on day 1.
- MODERATE on day 8.
- 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.
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
|
| Vesicant/irritant properties | - Paclitaxel and cisplatin are irritants but 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 febrile neutropenia was approximately 13% for this regimen.[2] The decision to use primary prophylaxis with a hematopoietic growth factor should be individualized according to institutional guidelines.
- In the original protocol, if there was a treatment delay due to an ANC less than 1500 cells/microL during a cycle, prophylactic granulocyte-macrophage colony stimulating factor was provided at the next cycle starting on day 9 for 7 days.[1] Other options include pegylated G-CSF (pegfilgrastim) 6 mg SC, or other biosimilars, administered on day 9 (24 hours after chemotherapy administration on day 8).
- For episodes of afebrile grade 4 neutropenia observed on day 8 or day 15, the original protocol was amended to provide prophylactic granulocyte-macrophage colony stimulating factor at the next cycle, starting on day 9 for 7 days.[1] Other options include pegylated G-CSF (pegfilgrastim) 6 mg SC, or other biosimilars, administered on day 9 (24 hours after chemotherapy administration on day 8).
- 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 kidney dysfunction | - The optimal approach to cisplatin therapy in patients with pre-existing kidney impairment is unknown. Patients with a serum creatinine level greater than 2 mg/dL were excluded from the original protocol.[2]
- A lower starting dose for gemcitabine and 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 nephrotoxicity and dose modification in patients with kidney impairment, conventional cytotoxic agents.
|
| Monitoring parameters: |
- CBC with differential and platelet count weekly during treatment.
|
- Serum electrolytes and liver and kidney function tests weekly during treatment.
|
- Frequent vital sign monitoring, particularly during the first hour of paclitaxel infusion, is recommended.
- Monitor for infusion/hypersensitivity reactions with cisplatin administration.
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
|
- Monitor for hearing loss prior to each dose of cisplatin; audiometry as clinically indicated.
- Refer to UpToDate topics on overview of neurologic complications of platinum-based chemotherapy.
|
- Assess change in neurologic function prior to each treatment cycle.
- Refer to UpToDate topics on prevention and treatment of chemotherapy-induced peripheral neuropathy and overview of neurologic complications of platinum-based chemotherapy.
|
- Assess pulmonary function at baseline and as clinically indicated.
- Refer to UpToDate topics on pulmonary toxicity associated with systemic antineoplastic therapy.
|
- Monitor for thrombotic microangiopathy with gemcitabine administration, which can present with hemolytic uremia.
- Refer to UpToDate topics on chemotherapy nephrotoxicity and dose modification in patients with kidney impairment, conventional cytotoxic agents.
|
| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Day 1:
- Treatment should not begin until the ANC count is greater than or equal to 1500 cells/microL and platelets are greater than or equal to 100,000/microL.[1,2]
- For episodes of febrile neutropenia or grade 4 thrombocytopenia, a 25% dose reduction was required for both paclitaxel and gemcitabine with subsequent cycles.[1]
- For G-CSF recommendations, please see section above on "Infection prophylaxis".
- Day 8:
- Reduce doses of both gemcitabine and paclitaxel by 50% if ANC is between 500 and 1000 cells/microL or if the platelet count is between 50,000 and 75,000 cells/microL on the day of treatment.[1]
- Reduce doses of both gemcitabine and paclitaxel by 25% if platelet count is between 75,000 to 100,000 cells/microL.[1]
- Omit treatment if the ANC is less than 500 cells/microL or if the platelet count is less than 50,000 cells/microL.[1]
- For G-CSF recommendations, please see section above on "Infection prophylaxis".
|
| Kidney toxicity | - For treatment with palliative intent and creatinine clearance between 50 to 60 mL/min reduce the cisplatin dose by 25%; for creatinine clearance less than 50 mL/min the use of cisplatin is not recommended.[8]
- In the original protocol, for creatinine clearance between 40 and 55 mL/min the cisplatin dose was reduced by 50% and for creatinine clearance less than 40 mL/min chemotherapy was discontinued.[1]
|
| Hepatic toxicity | - For grade 3 or 4 hepatotoxicity, chemotherapy was discontinued in the original protocol.[1]
|
| Neurotoxicity | - For grade 3 or higher neurotoxicity, chemotherapy was discontinued in the original protocol.[1]
|
| Mucositis | - For grade 3 or 4 mucositis, reduce doses of both paclitaxel and gemcitabine by 25% with subsequent cycles.[1]
|
| If there is a change in body weight of at least 10%, doses should be recalculated. |
