| Cycle length: 14 days. Duration of therapy: In the original trial, preoperative FLOT was given every 14 days for 4 cycles. Following surgery, postoperative FLOT was given every 14 days for 4 cycles.[1] |
| Drug | Dose and route | Administration | Given on days |
| Docetaxel | 50 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 |
| Oxaliplatin | 85 mg/m2 IV | Dilute in 500 mL D5W* and administer over two hours (oxaliplatin and leucovorin can be administered concurrently in separate bags using a Y-connector). | Day 1 |
| Leucovorin | 200 mg/m2 IV¶ | Dilute in 250 mL D5W* and administer over two hours concurrent with oxaliplatin. | Day 1 |
| Fluorouracil (FU) | 2600 mg/m2 IV | Dilute in 500 to 1000 mL D5W* and administer over 24 hours (begin immediately after completion of leucovorin infusion). 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.* | Day 1 |
| Pretreatment considerations: |
| Emesis risk | - MODERATE (between 30 and 90% frequency of emesis).Δ
- Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
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| Prophylaxis for infusion reactions and fluid retention | - Premedicate with dexamethasone prior to docetaxel administration.[2] Premedication is not routinely indicated for oxaliplatin, leucovorin, or FU.
- Refer to UpToDate topics on infusion reactions to systemic chemotherapy.
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| Vesicant/irritant properties | - Docetaxel, oxaliplatin, and FU are classified as irritants, but docetaxel and oxaliplatin can cause significant tissue damage; avoid extravasation. Many centers routinely infuse oxaliplatin through a central venous line because of local pain with infusion into a peripheral vein, but others consider it not mandatory.
- Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
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| Infection prophylaxis | - Although the incidence of febrile neutropenia with FLOT4 in the metastatic disease setting was ≤5%[3] in the perioperative setting (with curative intent), primary prophylaxis with GM-CSF has been routinely utilized at many institutions because of the high rate of grade 3 or 4 neutropenia with this regimen.[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 | - Lower starting doses of FU may be needed for patients with liver impairment. The United States Prescribing Information indicates that docetaxel should not be administered to patients with a serum bilirubin above the ULN or to patients with transaminase elevations >1.5 times the ULN in conjunction with ALP >2.5 times the ULN. However, the trial allowed enrollment of patients with a serum bilirubin ≤1.5 times the ULN.[1] A lower starting dose of oxaliplatin may be needed for severe renal impairment.[4]
- Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents; 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.
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| Cardiac issues | - QT prolongation and ventricular arrhythmias have been reported after oxaliplatin. ECG monitoring is recommended if therapy is initiated in patients with heart failure, bradyarrhythmias, coadministration of drugs known to prolong the QT interval, and electrolyte abnormalities. Avoid oxaliplatin in patients with congenital long QT syndrome. Correct hypokalemia and hypomagnesemia prior to initiating oxaliplatin.
- Refer to UpToDate topics on cardiotoxicity of cancer chemotherapy agents other than anthracyclines, HER2-targeted agents, and fluoropyrimidines.
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| Maneuvers to prevent neurotoxicity | - Pharmacologic methods to prevent/delay the onset of oxaliplatin-related neuropathy are controversial due to the absence of large clinical trials proving benefit. Counsel patients to avoid exposure to cold during and for approximately 48 hours after each infusion.
- Refer to UpToDate topics on overview of neurologic complications of platinum-based chemotherapy.
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| 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.
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| Monitoring parameters: |
- CBC with differential and platelet count prior to each treatment.
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- Assess electrolytes (especially potassium and magnesium) and liver and renal function prior to each treatment.
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- Assess changes in neurologic function prior to each treatment.
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- Monitor for diarrhea, palmar-plantar erythrodysesthesias, mucositis, paresthesia/dysesthesia, and fluid retention.
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- 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.
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| Suggested dose modifications for toxicity: |
| Myelotoxicity | - Do not start a new cycle until WBC count is ≥3000/microL independent of the granulocyte count, platelet count is >100,000/microL, and there is no other toxicity >grade 1.[3] The original protocol specified a 25% dose reduction for docetaxel and oxaliplatin for patients who experienced febrile neutropenia despite G-CSF use, thrombocytopenia causing bleeding, or any other dose-limiting hematologic toxicity(ies).[1] Further reduction of docetaxel and oxaliplatin to 50% of the original dose is recommended for recurrence of hematologic toxicity after the first dose reduction.[1]
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| Hepatotoxicity | - Do not treat with a new cycle unless the total bilirubin is <1.3 mg/dL. For intracycle increases of AST/ALT >2.5 but ≤5 times the ULN with ALP <2.5 times the ULN or AST/ALT >1.5 to ≤5 times the ULN with ALP >2.5 to ≤5 times the ULN, reduce docetaxel by 20%.[2] Discontinue docetaxel if AST/ALT is >5 times the ULN and/or ALP is >5 times the ULN.[2]
- 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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| Diarrhea | - For diarrhea exceeding grade 2, a 25% dose reduction for both docetaxel and FU is recommended.[3] Do not restart treatment until diarrhea is ≤grade 1.[3]
- NOTE: Severe diarrhea, mucositis, and myelosuppression after FU should prompt evaluation for DPD deficiency.
- Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.
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| Cardiotoxicity | - Cardiotoxicity observed with FU includes angina, myocardial infarction/ischemia, dysrhythmias, acute pulmonary edema, heart failure, cardiac arrest, and sudden death.
- Refer to UpToDate topics on fluoropyrimidine-associated 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.[5]
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| Pulmonary toxicity | - Withhold oxaliplatin for unexplained pulmonary symptoms until interstitial lung disease or pulmonary fibrosis is excluded.
- Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, cytotoxic agents and taxane-induced pulmonary toxicity.
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| Cutaneous and mucosal toxicity | - Hold FU for grade 2 or greater palmar-plantar erythrodysesthesia, and reduce subsequent dose by 20%.[5] For mucositis exceeding grade 2, reduce dose of docetaxel and FU by 25%.[3]
- Refer to UpToDate topics on cutaneous side effects of conventional chemotherapy agents and oral toxicity associated with chemotherapy.
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| Neurologic toxicity | - For paresthesia or dysesthesia persisting between cycles, reduce oxaliplatin dose by 25%.[3] For paresthesia or dysesthesia with pain or functional impairment lasting between 7 and 14 days, reduce oxaliplatin by 50%.[3] However, if paresthesia or dysesthesia with pain or functional impairment persists between cycles, oxaliplatin is omitted in further cycles until resolution.[3]
- Refer to UpToDate topics on cutaneous side effects of conventional chemotherapy agents, overview of neurologic complications of platinum-based chemotherapy, and oral toxicity associated with 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.[5]
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| Other nonhematologic toxicity | - In the original protocol, all agents were reduced by 25% for nonhematologic toxicity(ies) exceeding grade 2.[1] A further reduction of all agents to 50% of the original dose was recommended if toxicities recurred after the first dose reduction.[1]
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| If there is a change in body weight of at least 10%, doses should be recalculated. |
