| Cycle length: Every 21 days for three cycles. |
| Drug | Dose and route | Administration | Given on days |
| Docetaxel | 75 mg/m2 IV | Dilute in 250 mL NS* to a final concentration of 0.3 to 0.74 mg/mL and administer over 60 minutes. | Day 1 |
| Cisplatin | 100 mg/m2 IV | Dilute in 250 mL NS* and administer over 30 minutes to three hours. Do not administer with aluminum needles or IV sets. | Day 1 |
| Fluorouracil (FU) | 1000 mg/m2/day IV | Dilute in 500 to 1000 mL D5W or NS* and administer as a continuous infusion over 24 hours. | Days 1 through 4 |
| Pretreatment considerations: |
| Hydration | - IV fluid to establish a urine flow of at least 100 mL/hour for two hours before and two hours after cisplatin administration. Total hydration of 2 to 3 liters NS on day 1 and 1 to 2 liters NS on day 2 to prevent nephrotoxicity.
- Refer to UpToDate topic on "Cisplatin nephrotoxicity".
|
| Emesis risk | - HIGH (>90% frequency of emesis).
- Refer to UpToDate topic on "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults".
|
| Prophylaxis for infusion reactions | - Premedicate with dexamethasone prior to docetaxel administration.
- Refer to UpToDate topic on "Infusion reactions to systemic chemotherapy".
|
| Infection prophylaxis | - Prophylactic therapy with a fluoroquinolone antibiotic is indicated on days 5 to 15 of each cycle because of the high frequency of grade 3 or 4 neutropenia.[1] Primary prophylaxis with recombinant G-CSF was not permitted in the original protocol.
- Refer to UpToDate topic 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".
|
| Vesicant/irritant properties | - Docetaxel and cisplatin are irritants, but can cause significant tissue damage; avoid extravasation.
- Refer to UpToDate topic on "Extravasation injury from chemotherapy and other non-antineoplastic vesicants".
|
| Dose adjustment for baseline liver or renal dysfunction | - Docetaxel should not be given if bilirubin is >ULN, or if AST and/or ALT >1.5 times the ULN with AP >2.5 times the ULN.[2] Dose adjustments for FU may be needed for patients with hepatic impairment.[2] The optimal approach to cisplatin therapy in patients with pre-existing renal impairment is unknown. Such patients 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 hepatotoxicity and dose modification in patients with liver disease: Molecularly targeted agents" and "Chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency: Conventional cytotoxic agents".
|
| Dose adjustment for known drug interactions | - Caution is required if administering docetaxel with strong CYP3A4 inhibitors.¶ 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.
|
| Monitoring parameters: |
- CBC, differential, and platelet count on day 1 on each cycle.
|
- Creatinine and electrolytes on day 5 or 6 of each treatment cycle; additional hydration of 1 liter of NS is recommended.
|
- Basic metabolic panel, including creatinine and electrolytes, and liver function tests prior to each treatment cycle.
|
- Monitor for neurotoxicity, diarrhea, and palmar-plantar erythrodysesthesias prior to each treatment cycle.
|
- Monitor for hearing loss prior to each dose of cisplatin; audiometry as clinically indicated.
|
- Patients with renal impairment, hyperuricemia, and bulky tumors are at risk for TLS and should undergo correction of dehydration and lowering of high serum uric acid levels prior to treatment initiation, and be closely monitored for TLS during and after treatment.
- Refer to UpToDate topics on "Tumor lysis syndrome: Definition, pathogenesis, clinical manifestations, etiology and risk factors" and "Tumor lysis syndrome: Prevention and treatment".
|
| Suggested dose modifications for toxicity: |
| Gastrointestinal toxicity | - Doses of docetaxel and FU should be reduced for grade 3 or 4 diarrhea or mucositis:[2]
|
| Toxicity | Dose adjustment |
| Diarrhea grade 3 | First episode: Reduce FU dose by 20%.
Second episode: Reduce FU dose by an additional 20%. |
| Diarrhea grade 4 | First episode: Reduce docetaxel and FU doses by 20%.
Second episode: Discontinue treatment. |
| Stomatitis/mucositis grade 3 | First episode: Reduce FU dose by 20%.
Second episode: Stop FU only at all subsequent cycles.
Third episode: Reduce docetaxel dose by 20%. |
| Stomatitis/mucositis grade 4 | First episode: Stop FU only at all subsequent cycles.
Second episode: Reduce docetaxel dose by 20%. |
- NOTE: Severe diarrhea, mucositis, and myelosuppression or severe, prolonged neutropenia and/or thrombocytopenia after FU should prompt evaluation for DPD deficiency.
- Refer to UpToDate topic on "Enterotoxicity of chemotherapeutic agents".
|
| Hepatotoxicity | - Docetaxel should not be given if bilirubin is >ULN, or if AST and/or ALT >1.5 times the ULN with AP >2.5 times the ULN.[2] For intracycle increases of AST/ALT >2.5 to ≤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, docetaxel should be reduced by 20%. In case of AST/ALT >5 times the ULN and/or AP >5 times the ULN, docetaxel should be stopped.[2]
- Refer to UpToDate topic 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".
|
| Myelotoxicity | - Patients should not be retreated with docetaxel until the neutrophil count is >1500/microL.[2] In the original protocol, G-CSF was allowed during the second and/or subsequent cycles in case of febrile neutropenia, or documented infection with neutropenia, or neutropenia lasting more than seven days. If an episode of febrile neutropenia, prolonged neutropenia, or neutropenic infection occurs, the United States Prescribing Information suggests reduction of docetaxel dose from 75 to 60 mg/m2. If subsequent episodes of complicated neutropenia occur, the docetaxel dose should be reduced further from 60 mg/m2 to 45 mg/m2. In case of grade 4 thrombocytopenia, the docetaxel dose should be reduced from 75 mg/m2 to 60 mg/m2.
|
| Nephrotoxicity | - Hold cisplatin until serum creatinine <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), creatinine clearance should be determined prior to next cycle, and cisplatin dose reduced if <60 mL/min.
- Refer to UpToDate topic on "Cisplatin nephrotoxicity".
|
| Neurologic toxicity | - Neuropathy usually is seen with cumulative doses of cisplatin >400 mg/m2, although there is marked interindividual variation. Reduce cisplatin dose 20% for grade 2 peripheral neuropathy and discontinue for grade 3 neuropathy.[2]
- Refer to UpToDate topic 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.[3]
|
| Palmar-plantar erythrodysesthesia | - Hold FU for grade 2 or greater palmar-plantar erythrodysesthesia, and reduce subsequent dose by 20%.[3]
- Refer to UpToDate topic on "Cutaneous complications of conventional chemotherapy agents".
|
| 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.[3]
|
| Other toxicity | - For other grade 3 or worse toxicity except for alopecia and anemia, delay chemotherapy (maximum of two weeks) until resolution to <grade 1, then restart if medically appropriate.
|
| If there is a change in body weight of at least 10%, doses should be recalculated. |
