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 NSΔ 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 D5WΔ 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 D5WΔ and administer over 30 to 60 minutes. | Day 1 |
| Following AC, administer: |
| Paclitaxel | 80 mg/m2 IV | Dilute with 250 mL NS or D5WΔ 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 NSΔ 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 topic 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 topic on "Prevention and treatment 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 topic 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 renal dysfunction | - A lower starting dose of cyclophosphamide may be needed in patients with renal or liver impairment.
- A lower starting dose of paclitaxel and doxorubicin may be needed in patients with liver impairment.
- Refer to UpToDate topic on "Chemotherapy nephrotoxicity and dose modification in patients with renal insufficiency: Conventional cytotoxic agents".
- 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".
|
| 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 renal 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 topic on "Overview of neurologic complications of conventional non-platinum cancer chemotherapy".
|
| Dose adjustment for hepatic or renal 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 renal insufficiency: Conventional cytotoxic agents" and "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. |
