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Doxorubicin 60 mg/m 2 IV Dilute with normal saline (NS) 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 5 percent dextrose in water (D5W). 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 and given as a slow IV infusion administered over 15 to 60 minutes [2] . Day 1

Cyclophosphamide 600 mg/m 2 IV Dilute with 250 to 500 mL NS or D5W and administer over 30 to 60 minutes. Rapid infusions may produce nasal burning or congestion that is relieved by slowing the rate. Day 1 Following AC, administer:

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. •

Prophylaxis for infusion reactions: Paclitaxel may cause severe hypersensitivity reactions. Premedication regimen should include dexamethasone (either 20 mg orally twelve and six hours before, or 20 mg IV 30 minutes before drug administration) plus both an H1 (diphenhydramine 25 to 50 mg IV) and an H2 receptor antagonist (ranitidine 50 mg or famotidine 20 mg IV) 30 to 60 minutes prior to paclitaxel administration. Severe infusion reactions (eg, skin rash, flushing, dyspnea, urticaria, back pain, hypotension, chest pain, tachycardia) occur primarily during the first and second infusions, typically within the first hour after the start of the infusion. Further information on infusion reactions, including management, is available. Trastuzumab may also cause infusion reactions. These can be severe, though most are mild; they typically occur during or within 24 hours of the first infusion. The most common symptoms are fever, chills, nausea, headache, abdominal pain, and dyspnea; less often are vomiting, dizziness, rash, rhinitis, or hypotension. Most clinicians do not routinely premedicate prior to the first trastuzumab dose.

NOTE: Trastuzumab infusion should be discontinued for anaphylaxis (bronchospasm, hypotension, angioedema). Further information on infusion reactions and their management is available. 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 and can cause significant tissue damage if an extravasation occurs. For peripheral infusions, the IV line should be recently placed into a large, intact vein, with good blood return established immediately prior to starting the infusion. The IV or catheter site should be continuously monitored throughout drug administration infusion. If extravasation occurs, apply ice to the site and consider use of dexrazoxane. Paclitaxel can cause significant tissue damage; avoid extravasation. Refer to UpToDate topic on "Extravasation injury from chemotherapy and other non-neoplastic vesicants". •

Dose adjustment for baseline liver or renal dysfunction: Dose adjustment is not necessary for doxorubicin or paclitaxel in renal impairment. The need for cyclophosphamide dose reduction in renal insufficiency is controversial. For patients with preexisting hepatic impairment, dose adjustments in doxorubicin, cyclophosphamide, and paclitaxel may be needed. The available data suggest that disposition of trastuzumab is not altered based on serum creatinine (≤2 mg/dL). Refer to UpToDate topic on "Chemotherapy-related nephrotoxicity and dose modification in patients with renal insufficiency". For patients with preexisting hepatic impairment, dose adjustments in doxorubicin, cyclophosphamide, and paclitaxel may be needed. Refer to UpToDate topic on "Chemotherapy hepatotoxicity and dose modification in patients with liver disease". •

Cardiac issues: A baseline assessment of LVEF is recommended, with periodic reassessment during therapy. The risk of doxorubicin-associated cardiac dysfunction is related to cumulative dose. The risk for cardiotoxicity is increased in patients with underlying heart disease, when anthracyclines are used concurrently with other cardiotoxic agents (including paclitaxel and trastuzumab) or radiation, and in patients previously treated with mediastinal or chest wall irradiation. 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 [2] . Trastuzumab is associated with cardiotoxicity, and reassessment of LVEF prior to therapy (after completion of AC) is indicated. Information on use of trastuzumab according to baseline cardiac evaluation is available. Refer to UpToDate topics on "Cardiotoxicity of anthracycline-like chemotherapy agents" and "Cardiotoxicity of trastuzumab". •

Pulmonary issues: Trastuzumab has been associated with serious pulmonary toxicity (including acute respiratory distress syndrome [ARDS] and interstitial pneumonitis) 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 and prior to initiation of trastuzumab. • Assess cardiac function prior to trastuzumab and at 3, 6, 9, 12, and 18 months after starting trastuzumab. • During treatment with AC and paclitaxel, assess line site periodically during infusion of chemotherapy for signs and symptoms of extravasation. • 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 alterations for toxicity: •

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 percent for subsequent courses of paclitaxel; hold if severe toxicity persists after dose reduction. Refer to UpToDate topic on "Neurologic complications of non-platinum chemotherapy". •

Dose adjustment for hepatic or renal dysfunction: Guidelines for managing doxorubicin, cyclophosphamide, and paclitaxel in patients who have changes in kidney or liver function during therapy are addressed in detail separately. Refer to UpToDate topics on "Chemotherapy-related nephrotoxicity and dose modification in patients with renal insufficiency" and "Chemotherapy hepatotoxicity and dose modification in patients with liver disease". •

Cardiotoxicity: Guidelines for managing trastuzumab in patients with symptomatic cardiac dysfunction or asymptomatic changes in LVEF during therapy are addressed in detail separately. Refer to UpToDate topic on "Cardiotoxicity of trastuzumab". •

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" and "Taxane-induced pulmonary toxicity". If there is a change in body weight of at least 10 percent, dose should be recalculated for all drugs. This table is provided as an example of how to administer this regimen; there are other acceptable methods. This regimen must be administered by a clinician trained in the use of chemotherapy. The clinician is expected to use his or her independent medical judgment in the context of individual circumstances to make adjustments, as necessary. IV: intravenous; LVEF: left ventricular ejection fraction; ARDS: acute respiratory distress syndrome; CBC: complete blood count. * High levels of HER2 overexpression, as determined by either 3+ immunohistochemical staining (IHC) or positive fluorescence in situ hybridization (FISH), are used to select patients for therapy with trastuzumab. Refer to UpToDate topic on "HER2 and predicting response to therapy in breast cancer". Δ Trastuzumab can also be administered as a 4 mg/kg loading dose week 1, then 2 mg/kg weekly 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. ◊ 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/m 2 ) for 12 weeks, or it can be given as a dose of 175 mg/m 2 every 21 days for four cycles [1] . References: Romond EH, et al. N Engl J Med 2005; 353:1673. Adriamycin (doxorubicin hydrochloride) injection. US FDA-approved manufacturer's package insert. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on December 20, 2011). Herceptin (trastuzumab) injection. US FDA-approved manufacturer's package insert. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on December 20, 2011).