Trastuzumab plus fluorouracil and cisplatin for HER2-overexpressing* advanced esophagogastric cancer^[1]

Dilute in 250 mL NS^¶ and administer over 30 minutes or at a rate of 1 mg/min.

Alternative: Dilute in 2000 mL 5% dextrose in half NS (0.45%)^¶ containing 37.5 g of mannitol and infuse over a six- to eight-hour period.^[2]

Do not administer with aluminum needles or sets.

• IV fluid to establish a urine flow of at least 100 mL/hour for at least two hours prior to and two hours after cisplatin administration.
• Alternative: Pretreatment hydration with 1 to 2 L of fluid infused for 8 to 12 hours prior to each dose of cisplatin.^[2]
• Refer to UpToDate topics on cisplatin nephrotoxicity.

• HIGH (>90% risk of emesis); prophylaxis for acute and delayed nausea and emesis through days 1 to 4 is warranted.
• Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
• According to the NCCN Antiemesis Guidelines, cisplatin doses >50 mg/m² are considered of high emetic risk. While it is true the FU given on days 2 through 5 is low risk, it may be confusing for practitioners to state that antiemetic risk is only high on day 1, since the period of nausea may last for several days.

• Routine prophylaxis not indicated for cisplatin or FU. Most clinicians do not routinely premedicate prior to the first trastuzumab dose. However, patients may be instructed to self-administer acetaminophen or an NSAID if flu-like symptoms develop within 24 hours of drug administration.
• Refer to UpToDate topics on infusion reactions to therapeutic monoclonal antibodies used for cancer therapy and infusion reactions to systemic chemotherapy.

• 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.

• Primary prophylaxis with G-CSF is not indicated (estimated risk of febrile neutropenia with this regimen is 5%^[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.

• The optimal approach to cisplatin therapy in patients with preexisting renal impairment is unknown. A lower starting dose of FU may be needed for patients with liver impairment.
• Refer to UpToDate topics on chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency, conventional cytotoxic agents; 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.

• Obtain CBC with differential and platelet count prior to each new treatment cycle.

• Assess electrolytes and liver and renal function prior to each new treatment cycle.

• Monitor for hearing loss prior to each dose of cisplatin; audiometry as clinically indicated.

• Monitor for infusion reactions, especially during the first two courses of trastuzumab.

• Hold new course of treatment until ANC is ≥1500/microL and platelet count is ≥100,000/microL.

• Withhold FU for grade 2 or worse diarrhea and restart at a lower dose after complete resolution.
• NOTE: Severe diarrhea, mucositis, and myelosuppression after FU should prompt evaluation for DPD deficiency.
• Refer to UpToDate topics on enterotoxicity of chemotherapeutic agents.

• Hold cisplatin until serum creatinine is <1.5 mg/dL and/or BUN is <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 (or switch to carboplatin) if <60 mL/min. While this is clinically appropriate, there is not a specific reference in the United States Prescribing Information outlining a change to carboplatin based on creatinine clearance of <60 mL/min.

• Assess LVEF at least every three months during trastuzumab.^[3] The United States Prescribing Information recommends withholding trastuzumab for at least four weeks for LVEF ≥16% decrease from baseline or LVEF below lower limit of normal and ≥10% decrease from baseline; repeat LVEF assessment every four weeks. May resume trastuzumab treatment if LVEF returns to normal limits within four to eight weeks and remains at ≤15% decrease from baseline value. Discontinue permanently for persistent (>8 weeks) LVEF decline or for >3 incidents of treatment interruption for cardiomyopathy.
• Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents.
• Cardiotoxicity observed with FU includes myocardial infarction/ischemia, angina, dysrhythmias, cardiac arrest, cardiac failure, sudden death, electrocardiographic 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]

• Discontinue trastuzumab for serious pulmonary toxicity.
• Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, molecularly targeted agents.

• Neuropathy usually 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.^[2]
• 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]