| Cycle length: Every 21 days. Duration of therapy: Prior to surgery (neoadjuvant portion of treatment), administer four cycles of docetaxel, trastuzumab, and pertuzumab.¶ Following surgery, adjuvant treatment consists of three 21-day cycles of FEC plus trastuzumab followed by trastuzumab alone to complete a total of 51 weeks of trastuzumab. |
| Drug | Dose and route | Administration | Given on days |
| Before surgery (neoadjuvant treatment) |
| Pertuzumab | 840 mg IV (loading dose) | Dilute in 250 mL NSΔ and administer over 60 minutes. DO NOT mix with D5W and DO NOT infuse as an IV push or bolus. | Cycle 1: Day 1 |
| Pertuzumab | 420 mg IV | Dilute in 250 mL NSΔ and administer over 30 to 60 minutes. DO NOT mix with D5W and DO NOT infuse as an IV push or bolus. | Cycles 2 to 4: Day 1 |
| Trastuzumab◊ | 8 mg/kg IV (loading dose) | Dilute in 250 mL NSΔ and administer over 90 minutes. DO NOT mix with D5W and DO NOT infuse as an IV push or bolus. | Cycle 1: Day 1 |
| Trastuzumab◊ | 6 mg/kg IV | Dilute in 250 mL NSΔ and administer over 30 minutes. DO NOT mix with D5W and DO NOT infuse as an IV push or bolus. | Cycles 2 to 4: Day 1 |
| Docetaxel | 75 mg/m2 IV | Dilute in 250 mL NSΔ to a final concentration of 0.3 to 0.74 mg/mL and administer over 60 minutes. | Cycles 1 to 4: Day 1 |
| After surgery (adjuvant treatment)§ |
| Fluorouracil (FU) | 600 mg/m2 IV | Administer undiluted (50 mg/mL) as an IV push bolus over five minutes. | Cycles 5 to 7: Day 1 |
| Epirubicin | 90 mg/m2 IV | Administer into a free-flowing IV infusion of NS over 3 to 20 minutes. | Cycles 5 to 7: Day 1 |
| Cyclophosphamide | 600 mg/m2 IV | Dilute with 250 to 500 mL NS or D5WΔ and administer over 30 to 60 minutes. | Cycles 5 to 7: Day 1 |
| Trastuzumab◊ | 8 mg/kg IV (loading dose) | Dilute in 250 mL NSΔ and administer over 90 minutes. DO NOT mix with D5W and DO NOT infuse as an IV push or bolus. | Cycle 8: Day 1 |
| Trastuzumab◊ | 6 mg/kg IV | Dilute in 250 mL NSΔ and administer over 30 minutes for subsequent doses. DO NOT mix with D5W and DO NOT infuse as an IV push or bolus. | Cycles 9 to 20 to complete 51 weeks of trastuzumab:¥ Day 1 |
| 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.[2]
- Refer to UpToDate topics on hemorrhagic cystitis in cancer patients.
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| Emesis risk | - LOW (10 to 30%) during the neoadjuvant portion of treatment (cycles 1 to 4);
HIGH (>90%) during the adjuvant portion with FEC (cycles 5 to 7);
MINIMAL (<10%) during monotherapy with trastuzumab (cycles 8 to 17). - Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
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| Prophylaxis for infusion reactions | - Premedicate with dexamethasone prior to docetaxel administration.[3] Premedication is not routinely indicated for pertuzumab or during FEC. 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-related reactions to therapeutic monoclonal antibodies used for cancer therapy and infusion reactions to systemic chemotherapy.
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| Vesicant/irritant properties | - Epirubicin is a vesicant; avoid extravasation. Docetaxel 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.
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| Infection prophylaxis | - Primary prophylaxis with G-CSF is not indicated for neither neoadjuvant nor adjuvant portions of this regimen (incidence of neutropenic fever during cycles 1 to 4 of this regimen was 8%[1]). Although not noted in initial report of the NEOSPHERE trial[1], the rate of febrile neutropenia associated with FEC is approximately 10%.[4,5]
- Refer to UpToDate topics on prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults.
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| Dose adjustment for baseline liver or renal dysfunction | - 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.[3] Dose modification of FU may be needed for patients with hepatic impairment.[6] A lower starting dose of cyclophosphamide and epirubicin may be needed for patients with renal or hepatic impairment.[2,7]
- 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.
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| Cardiac issues | - Trastuzumab and pertuzumab are associated with cardiotoxicity;[8,9] assess baseline LVEF prior to therapy. Patients with a baseline LVEF <55% were excluded from the study.[1]
- Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents.
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| Pulmonary issues | - Trastuzumab may cause serious pulmonary toxicity and should be used with caution in patients with preexisting pulmonary disease.
- Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, molecularly targeted agents.
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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.[3] 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 every three weeks prior to each cycle during neoadjuvant and adjuvant treatment when chemotherapy is being administered (cycles 1 to 7). These labs are not required during trastuzumab monotherapy (cycles 8 to 20).
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- Serum electrolytes and liver and renal function tests every three weeks prior to each cycle during neoadjuvant and adjuvant treatment when chemotherapy is being administered (cycles 1 to 7). These labs are not required during trastuzumab monotherapy (cycles 8 to 20).
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- Monitor for diarrhea and cutaneous toxicity (palmar-plantar erythrodysesthesias) during FEC.
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- Monitor for infusion reactions, especially during the first two courses of trastuzumab and pertuzumab.
- Refer to UpToDate topics on infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy.
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- Assess changes in neurologic function prior to each cycle of docetaxel.
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- It is recommended to observe the patient for one hour after the initial dose of pertuzumab and for 30 minutes after all subsequent doses for signs of infusion reactions.[8]
- Refer to UpToDate topics on infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy.
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- In the clinical trial, LVEF was assessed every second cycle[1], but there are no standard guidelines for cardiac monitoring in routine clinical practice. A reasonable strategy is to assess cardiac function prior to initiation of both neoadjuvant chemotherapy (pre-cycle 1), adjuvant chemotherapy (pre-cycle 5), and adjuvant trastuzumab monotherapy (pre-cycle 8). During adjuvant trastuzumab, consider repeating evaluation every 12 weeks (prior to cycles 12 and 16) and if clinically indicated.
- Refer to UpToDate topics on clinical manifestations, monitoring, and diagnosis of anthracycline-induced cardiotoxicity, prevention and management of anthracycline cardiotoxicity, cardiotoxicity of trastuzumab and other HER2-targeted agents.
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| Suggested dose modifications for toxicity:† |
| Myelotoxicity | - During the neoadjuvant portion: Docetaxel should only be administered if the ANC is >1500/microL. Reduce docetaxel dose by 25% for subsequent cycles in patients who develop severe prolonged neutropenia (<500/microL lasting seven days or more), febrile neutropenia, or a grade 4 infection (ie, an infection with life-threatening consequences).[3]
- During the adjuvant portion of therapy with FEC: Based on the original FEC trial in metastatic breast cancer, if the ANC is <1500/microL and platelets are <100,000/microL on day 1 of each cycle, therapy should be delayed until counts recover. For midcycle platelet count <40,000/microL and ANC <500/microL, reduce epirubicin by 10 mg/m2.[1,4]
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| Hepatotoxicity | - Docetaxel dose reduction to 60 mg/m2 may be needed for patients who develop significant alterations in transaminases and alkaline phosphatase during therapy.[3]
- 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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| Cardiotoxicity | - Hold both trastuzumab and pertuzumab during the neoadjuvant portion of this protocol if the LVEF drops to <50% with a 10% or greater absolute decrease below baseline. Guidelines for managing cardiac dysfunction during therapy with HER2-targeted agents are available.[1]
- Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents.
- Do not start adjuvant chemotherapy (FEC) if the patient has cardiac symptoms, or if the LVEF has fallen >10% below the lower limit of normal, or if there has been >15% drop in LVEF from the patient's baseline. During FEC treatment, if cardiac symptoms develop, or the LVEF falls to ≥10% below the lowest limit of normal, or there is a ≥15% drop below the patient's baseline, discontinue epirubicin.[4]
- 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.[6]
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| Pulmonary toxicity | - Discontinue trastuzumab for serious pulmonary toxicity.
- Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, molecularly targeted agents.
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| Cutaneous, mucosal, and neurologic toxicity | - For severe or cumulative cutaneous reactions (erythema and desquamation), grade 3 or 4 stomatitis, or moderate neurosensory signs and/or symptoms, reduce docetaxel dose to 60 mg/m2.[3] Discontinue if toxicity persists. During FEC portion or adjuvant therapy, hold FU for ≥grade 2 palmar-plantar erythrodysesthesia and reduce subsequent dose by 20%.[6]
- Refer to UpToDate topics on cutaneous side effects of conventional chemotherapy agents.
- 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.[6]
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| Gastrointestinal toxicity | - During neoadjuvant treatment (cycles 1 to 4), delay docetaxel for grade 2 or worse diarrhea and restart at a 20% lower dose after complete resolution; reduce docetaxel by 20% for the first episode of grade 3 diarrhea. During adjuvant treatment (cycles 5 to 7), hold FU for grade 2 or worse diarrhea or mucositis and restart at a 20% lower dose after complete resolution. For the first episode of grade 3 to 4 diarrhea or grade 3 to 4 mucositis, reduce FU by 20%; subsequent episodes, reduce both FU and epirubicin by 20%[5] or discontinue treatment.
- 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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| If there is a change in body weight of at least 10%, doses should be recalculated. |
