Chemotherapy regimens for HER2-positive* breast cancer: Doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) and trastuzumab (H)^[1]

Cycle length: AC is given every 21 days for four cycles. Paclitaxel (T) and trastuzumab (H) are given every seven days of a 28 day cycle for three cycles (ie, weekly for 12 weeks). Following completion of T, H is given weekly for a total treatment duration of 52 weeks.^¶
Drug	Dose and route	Administration	Given on days
Doxorubicin	60 mg/m² IV	Dilute with NS^Δ to a final concentration of 2 mg/mL and administer as an IV bolus over three to five minutes into a free-flowing IV infusion of NS or D5W.^Δ The presence of local erythematous streaking along the vein as well as facial flushing may be signs that administration is too rapid. If needed, doxorubicin can be further diluted after reconstitution in NS or D5W^Δ and given as a slow IV infusion administered over 15 to 60 minutes.^[2]	Day 1
Cyclophosphamide	600 mg/m² IV	Dilute with 250 to 500 mL NS or D5W^Δ and administer over 30 to 60 minutes.	Day 1
Following AC, administer:
Paclitaxel	80 mg/m² IV	Dilute with 250 mL NS or D5W^Δ to a final concentration of 0.3 to 1.2 mg/mL and administer over one hour; special tubing needed.^◊	Weekly for 12 weeks^§
Trastuzumab	4 mg/kg IV loading dose for the first dose, followed by 2 mg/kg for all subsequent doses	Dilute in 250 mL NS^Δ and administer over 90 minutes for the loading dose and over 30 minutes for subsequent doses. DO NOT mix with D5W, and DO NOT infuse as an IV push or bolus.	Weekly for 52 weeks^¶
Pretreatment considerations:
Hydration	Patients receiving cyclophosphamide should maintain adequate oral hydration (2 to 3 L/day during administration and for one to two days thereafter) and void frequently to reduce the risk of hemorrhagic cystitis. Refer to UpToDate topics on hemorrhagic cystitis in cancer patients.
Emesis risk	During AC: HIGH (>90% frequency of emesis). During paclitaxel plus trastuzumab, and trastuzumab alone: LOW (10 to 30% risk of emesis). Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
Prophylaxis for infusion reactions	Paclitaxel may cause severe hypersensitivity reactions. Premedication regimen should include dexamethasone plus both an H1 and an H2 receptor antagonist 30 to 60 minutes prior to paclitaxel administration. Trastuzumab may also cause infusion reactions. 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 systemic chemotherapy and infusion reactions to therapeutic monoclonal antibodies used for cancer therapy.
Vesicant/irritant properties	Doxorubicin is a vesicant; avoid extravasation. Administer infusional regimens through a central venous line. Paclitaxel can cause significant tissue damage; avoid extravasation. Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
Infection prophylaxis	Primary prophylaxis with G-CSF not indicated during any phase of therapy.
Dose adjustment for baseline liver or kidney dysfunction	A lower starting dose of cyclophosphamide may be needed in patients with kidney or liver impairment. A lower starting dose of paclitaxel and doxorubicin may be needed in patients with liver impairment. Refer to UpToDate topics on chemotherapy nephrotoxicity and dose modification in patients with kidney impairment, 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.
Cardiac issues	Doxorubicin is associated with cardiomyopathy, the incidence of which is related to cumulative dose. Assess baseline LVEF prior to administration (NOTE: may not need this for adjuvant breast cancer regimens). Doxorubicin is contraindicated for patients with recent myocardial infarction, severe myocardial dysfunction, severe arrhythmia, or previous therapy with high cumulative doses of doxorubicin or any other anthracyclines.^[1] Trastuzumab is associated with cardiotoxicity. An assessment of LVEF should be done after completion of the anthracycline and prior to initiation of trastuzumab. Patients with a normal baseline LVEF and no signs or symptoms of heart failure on physical examination may proceed with therapy. Refer to UpToDate topics on clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity, prevention and management of anthracycline cardiotoxicity, and cardiotoxicity of trastuzumab and other HER2-targeted agents.
Pulmonary issues	Trastuzumab has been associated with serious pulmonary toxicity and should be used with caution in patients with preexisting pulmonary disease.^[3]
Monitoring parameters:
CBC with differential and platelet count weekly during treatment with AC and paclitaxel (or every three weeks if dosing paclitaxel every three weeks).
Serum electrolytes and liver and kidney function tests prior to each treatment cycle of AC and paclitaxel.
Assess changes in neurologic function prior to each treatment cycle of paclitaxel.
Assess cardiac function prior to AC, prior to initiation of trastuzumab, and every three months after starting trastuzumab therapy.
Patients should be closely monitored for infusion reactions, especially during the first two courses of trastuzumab. Standing orders should be in place to allow immediate intervention without waiting for the physician to arrive.
Suggested dose modifications for toxicity:
Myelotoxicity	Subsequent cycles should be delayed until the absolute neutrophil count is >1000/microL and platelet count >100,000/microL. If there is more than a three-week delay in treatment, a dose reduction of 25% is recommended.^[1]
Neurologic toxicity	For patients who develop severe neuropathy (grade 3 or 4) that persists for a week or longer, the dose of paclitaxel should be reduced by 20% for subsequent courses of paclitaxel; hold if severe toxicity persists after dose reduction.^[4] Refer to UpToDate topics on overview of neurologic complications of conventional non-platinum cancer chemotherapy.
Dose adjustment for hepatic or kidney dysfunction	Guidelines for managing doxorubicin, cyclophosphamide, and paclitaxel doses in patients who have changes in kidney or liver function during therapy are addressed in detail separately. Refer to UpToDate topics on chemotherapy nephrotoxicity and dose modification in patients with kidney impairment, 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.
Cardiotoxicity	Guidelines for managing doxorubicin and trastuzumab in patients with symptomatic cardiac dysfunction or asymptomatic changes in LVEF during therapy are addressed in detail separately. Refer to UpToDate topics on clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity, prevention and management of anthracycline cardiotoxicity, and cardiotoxicity of trastuzumab and other HER2-targeted agents.
Pulmonary toxicity	Discontinue trastuzumab if patients develop ARDS, interstitial pneumonitis, or pulmonary fibrosis. Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, molecularly targeted agents.
If there is a change in body weight of at least 10%, doses should be recalculated.

This table is provided as an example of how to administer this regimen; there may be other acceptable methods. This regimen must be administered by a clinician trained in the use of chemotherapy, who should use independent medical judgment in the context of individual circumstances to make adjustments, as necessary.

ARDS: acute respiratory distress syndrome; CBC: complete blood count; D5W: 5% dextrose in water; FISH: fluorescence in situ hybridization; G-CSF: granulocyte colony stimulating factors; HER2: human epidermal growth factor receptor 2; IHC: immunohistochemical; IV: intravenous; LVEF: left ventricular ejection fraction; NS: normal saline; NSAID: nonsteroidal anti-inflammatory drug.

* High levels of HER2 overexpression, as determined by either 3+ IHC or positive FISH, are used to select patients for therapy with trastuzumab. Refer to UpToDate topic on "HER2 and predicting response to therapy in breast cancer".
¶ Trastuzumab can also be administered as a 4 mg/kg loading dose week 1, then 2 mg/kg weekly (maintenance dose) for a total of 12 weeks (concurrent with paclitaxel), followed one week later by 6 mg/kg infused over 30 to 90 minutes every three weeks to complete a total 52 weeks of therapy. For patients who miss a dose by more than one week, the loading dose (weekly: 4 mg/kg; three weekly: 8 mg/kg) should be repeated before resuming the maintenance dose.
Δ Diluent solutions should not be modified without consulting a detailed reference due to potential incompatibility(ies).
◊ Paclitaxel can be administered in NS, D5W, or NS/D5W at varying concentrations between 0.3 to 1.2 mg/mL. Use glass or polypropylene bottles or polypropylene or polyolefin plastic bags, and administer through polyethylene-lined administration sets with a microporous membrane 0.22 microns or less.
§ Paclitaxel can be administered weekly (80 mg/m²) for 12 weeks, or it can be given as a dose of 175 mg/m² every 21 days for four cycles.^[1]

References:

Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005; 353:1673.
Doxorubicin hydrochloride injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on September 26, 2019).
Trastuzumab injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on September 26, 2019).
Paclitaxel injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on September 26, 2019).

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Chemotherapy regimens for HER2-positive* breast cancer: Doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) and trastuzumab (H)[1]

Chemotherapy regimens for HER2-positive* breast cancer: Doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) and trastuzumab (H)^[1]