| Cycle length: 21 days. Duration of therapy: Maximum: Six cycles. |
| Drug | Dose and route | Administration | Given on days |
| Docetaxel | 75 mg/m2 IV | Dilute in 250 mL NS or D5W¶ to a final concentration of 0.3 to 0.74 mg/mL and administer over 60 minutes. | Day 1 |
| Cisplatin | 75 mg/m2 IV | Dilute in 500 mL NS¶ and administer over 60 minutes or at 1 mg per minute. Do not administer with aluminum needles or IV sets. | Day 1 |
| Fluorouracil (FU) | 750 mg/m2 per day IV | Dilute in 500 to 1000 mL NS or D5W¶ and administer as a continuous infusion over 24 hours. To accommodate an ambulatory pump for outpatient treatment, can be administered undiluted (50 mg/mL) or the total dose can be diluted in 100 to 150 mL NS or D5W¶. | Days 1 through 5 |
| G-CSF | 5 microg/kg per day SC | | Days 6 through 12 |
| Pretreatment considerations: |
| Hydration | - IV fluid to establish a urine flow of at least 100 mL/hour for 2 hours before and 2 hours after cisplatin administration.
- Refer to UpToDate topics on cisplatin nephrotoxicity.
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| Emesis risk | - HIGH (>90% frequency of emesis).
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
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| Prophylaxis for infusion reactions | - Premedicate with dexamethasone prior to docetaxel administration to reduce the incidence and severity of fluid retention and the severity of infusion reactions.[2]
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
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| Vesicant/irritant properties | - Docetaxel and cisplatin are irritants, but can cause significant tissue damage; avoid extravasation.[2,3]
- 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 recommended (incidence of neutropenic fever 14%, even with prophylaxis[1]). In the original protocol, G-CSF was administered to all patients at a dose of 5 microg/kg per day, for 7 days.
- 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 | - The original protocol allowed treatment for AST and ALT ≤2.5 times the ULN (or ≤5 times the ULN in the case of known liver metastasis) and total bilirubin ≤2.5 times the ULN, regardless of the presence of liver metastases.[1] Recommendations in the United States Prescribing Information suggest that docetaxel not be initiated if serum bilirubin is above the ULN, or if the AST and/or ALT are >1.5 times the ULN concomitant with AP >2.5 times the ULN.[3] Dose modifications of FU may be needed for patients with hepatic impairment.[4] The optimal approach to cisplatin therapy in patients with pre-existing renal impairment is unknown; patients with a CrCl <60 mL/min were excluded from the original trial.[1]
- 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.
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| Dose adjustment for known drug interactions | - Caution is required if administering docetaxel with strong CYP3A4 inhibitors.Δ According to the United States Prescribing Information, avoid the use of docetaxel with strong CYP3A4 inhibitors (if possible). If concomitant therapy cannot be avoided, monitor closely for toxicity and consider a docetaxel dose reduction.[2] Docetaxel dose reductions for concomitant therapies should be individualized based on patient factors (eg, performance status) and the intent of therapy (ie, curative or palliative).
- Refer to "Suggested dose modifications for toxicity" below.
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| Monitoring parameters: |
- Assess CBC with differential and platelet count weekly during treatment.
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- Assess basic metabolic panel including creatinine and electrolytes, and liver function tests at least prior to each treatment cycle; assess creatinine and electrolytes more frequently if clinically indicated (eg, diarrhea, vomiting).
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- Monitor for neurotoxicity, diarrhea, fluid retention, and cutaneous toxicity prior to each treatment cycle.
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- Monitor for hearing loss prior to each dose of cisplatin; audiometry as clinically indicated.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - The United States Prescribing Information for docetaxel states that patients should not be retreated with a new cycle of therapy until the ANC is >1500/microL, and platelet count is >100,000/microL.[3] However, the original trial allowed retreatment with a new cycle of therapy if neutrophils were ≥1000/microL and platelets ≥75,000/microL.[1] If the neutrophil nadir was <500/microL or there was febrile neutropenia and/or a nadir platelet count <50,000/microL, and it required more than 8 days to recover from myelosuppression, reduce docetaxel and cisplatin doses by 25% each, and FU dose by 33%; if recovery occurred within 8 days, reduce cisplatin and FU doses by 25% each.[1]
- For a second episode of neutrophils <500/microL or febrile neutropenia and/or platelet count <50,000/microL, reduce docetaxel and cisplatin by 33% of the original dose, and reduce FU by 50% of the original dose. For a nadir >500 but <1000 neutrophils/microL and/or platelets >50,000 but <75,000, and recovery takes longer than 8 days, reduce cisplatin and FU by an additional 25%. For recovery within 8 days, no further dose reduction is recommended.
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| Renal dysfunction | - CrCl should be determined prior to each cycle, and reduce cisplatin dose by 33% if CrCl >40 mL/min but <60 mL/min.[1] For CrCl <40 mL/min, stop cisplatin for up to 3 weeks. If recovery to ≥60 mL/min, and another cause found, reduce cisplatin dose by 33%.[1] If no other cause is found, discontinue cisplatin at the discretion of the clinician.
- Refer to UpToDate topics on chemotherapy nephrotoxicity and dose modification in patients with kidney impairment, conventional cytotoxic agents.
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| Neurotoxicity | - Neuropathy usually is seen with cumulative doses of cisplatin >400 mg/m2, although there is marked interindividual variation. Reduce cisplatin dose 25% for grade 1 neurotoxicity for >14 days.[1] Reduce docetaxel by 25%, and cisplatin by 33% for grade 2 peripheral neuropathy and discontinue both drugs for grade 3 neuropathy.[1] If recovery to <grade 2 neurotoxicity, may restart docetaxel with a 25% dose reduction. Permanently discontinue both docetaxel and cisplatin for grade 4 neurotoxicity.
- Stop cisplatin for grade 3 or worse hearing impairment during therapy.
- Refer to UpToDate topics on overview of neurologic complications of platinum-based chemotherapy.
- There is no recommended dose for resumption of FU administration following development of hyperammonemic encephalopathy, acute cerebellar syndrome, confusion, disorientation, ataxia, or visual disturbances; the drug should be permanently discontinued.[4]
- Refer to UpToDate topics on overview of neurologic complications of conventional non-platinum cancer chemotherapy.
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| Gastrointestinal toxicity | - For the second episode of grade 2 diarrhea, reduce subsequent FU dose by 25%. Hold FU, docetaxel, and cisplatin treatment for any grade 3 or worse diarrhea and restart with a 25% lower dose of FU after recovery to grade 0 or 1.[1] For the second episode of grade 3 diarrhea, reduce subsequent FU doses by an additional 25% after recovery to ≤grade 1. Discontinue all treatment for grade 4 diarrhea.
- For the first episode of grade 2 mucositis, reduce subsequent FU doses by 25%. For the first episode of grade 3 stomatitis, stop chemotherapy. If recovery to grade 0 or 1 within 3 weeks, reduce docetaxel and cisplatin by 25%, and FU by 50% for subsequent doses. For second episode of grade 3 or first episode of grade 4 mucositis, stop chemotherapy.
- NOTE: Severe diarrhea, mucositis, and myelosuppression after FU should prompt evaluation for DPD deficiency.
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents and oral toxicity associated with chemotherapy.
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| Cutaneous erythema/desquamation/HFS | - For ≥grade 2 toxicity despite optimal local therapy, hold FU and resume only when it recovers to grade ≤1.[1] For the second appearance of grade 2, or first appearance of grade 3 symptoms, reduce subsequent doses of FU by 25%. Stop docetaxel for up to 3 weeks for grade 3 symptoms; if it recovers to ≤grade 2, reduce subsequent docetaxel dose by 25%. Discontinue docetaxel for grade 4 HFS.
- Refer to UpToDate topics on cutaneous side effects of conventional chemotherapy agents.
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| Hepatotoxicity | - Guidelines on dose reductions for intracycle hepatotoxicity from the original protocol are less stringent than those provided in the United States Prescribing Information for docetaxel given in conjunction with cisplatin and FU. For intracycle increases of AST/ALT >2.5 but ≤5 times the ULN, and AP <2.5 times the ULN or AST/ALT >1.5 to ≤5 times the ULN and AP >2.5 to ≤5 times the ULN, hold treatment until recovery to grade 0 or 1, and reduce subsequent docetaxel by 25%. Discontinue docetaxel if AST/ALT is >5 times the ULN and/or AP is >5 times the ULN.[3] The original trial suggested holding docetaxel for any AST/ALT >3 times the ULN or bilirubin ≥1.5 times the ULN; resume only after recovery to ≤grade 1 within three weeks, with a 25% dose reduction. Discontinue if recovery is more prolonged.
- Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents.
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| Cardiotoxicity | - Cardiotoxicity observed with FU includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, ECG changes, and cardiomyopathy. There is no recommended dose for resumption of FU administration following development of cardiac toxicity, and the drug should be discontinued.[4]
- Refer to UpToDate topics on fluoropyrimidine-associated cardiotoxicity.
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
