Neoadjuvant trastuzumab, pertuzumab, carboplatin, and docetaxel followed by adjuvant trastuzumab for HER2-positive* breast cancer^[1]

Cycle length: Every 21 days. Duration of therapy: Prior to surgery (neoadjuvant portion of treatment), administer carboplatin, docetaxel, trastuzumab, and pertuzumab^¶ every 21 days for six cycles. Following surgery, adjuvant treatment consists of 11 cycles of trastuzumab alone to complete one year of trastuzumab.
Drug	Dose and route	Administration	Given on days
Before surgery (neoadjuvant treatment)
Trastuzumab (loading dose)^Δ	8 mg/kg IV	Dilute in 250 mL NS^◊ 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^Δ	6 mg/kg IV	Dilute in 250 mL NS^◊ and administer over 30 minutes. DO NOT mix with D5W and DO NOT infuse as an IV push or bolus.	Cycles 2 to 6: Day 1
Pertuzumab (loading dose)^Δ	840 mg IV	Dilute in 250 mL NS^◊ and administer over 60 minutes for the loading dose. DO NOT mix with D5W and DO NOT infuse as an IV push or bolus.	Cycle 1: Day 1
Pertuzumab^Δ	420 mg IV	Dilute in 250 mL NS^◊ 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 6: Day 1
Carboplatin	AUC^§ = 6 mg/mL per min IV	Dilute in 250 mL NS^◊ and administer over 30 minutes.	Cycles 1 to 6 only: Day 1
Docetaxel	75 mg/m² IV	Dilute in 250 mL NS^◊ to a final concentration of 0.3 to 0.74 mg/mL and administer over 60 minutes.	Cycles 1 to 6 only: Day 1
After surgery (adjuvant treatment)
Trastuzumab (loading dose)^Δ	8 mg/kg IV	Dilute in 250 mL NS^◊ and administer over 90 minutes. DO NOT mix with D5W and DO NOT infuse as an IV push or bolus.	Cycle 7: Day 1
Trastuzumab^Δ	6 mg/kg IV	Dilute in 250 mL NS^◊ and administer over 30 minutes for subsequent doses. DO NOT mix with D5W and DO NOT infuse as an IV push or bolus.	Cycles 8 to 17 to complete one year of trastuzumab: Day 1
Pretreatment considerations:
Emesis risk	MODERATE (30 to 90% risk of emesis) during cycles 1 to 6.^¥ MINIMAL (<10% risk of emesis) during trastuzumab monotherapy. Refer to UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
Prophylaxis for infusion reactions	Premedicate with dexamethasone prior to docetaxel administration.^[2] Premedication is not required for pertuzumab or carboplatin. 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.
Vesicant/irritant properties	Carboplatin is an irritant. Docetaxel is also an irritant but can cause significant tissue damage; avoid extravasation. Refer to UpToDate topics on extravasation injury from chemotherapy and other non-antineoplastic vesicants.
Infection prophylaxis	All cycles should be administered with myeloid growth factor support.^[3] Refer to UpToDate topics on prophylaxis of infection during chemotherapy-induced neutropenia in high-risk adults.
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 in conjunction with alkaline phosphatase >2.5 times the ULN. Each carboplatin dose should be calculated based upon renal function by use of the Calvert formula. Refer to UpToDate topics on chemotherapy hepatotoxicity and dose modification in patients with liver disease, conventional cytotoxic agents; chemotherapy hepatotoxicity and dose modification in patients with liver disease, molecularly targeted agents; and dosing of anticancer agents in adults.
Cardiopulmonary issues	Trastuzumab and pertuzumab are associated with cardiotoxicity;^[4,5] assess baseline LVEF prior to therapy. Patients with a baseline LVEF <55% were excluded from the trial.^[1] Trastuzumab may cause serious pulmonary toxicity and should be used with caution in patients with preexisting pulmonary disease. Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents.
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.^[2] 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.
Monitoring parameters:
CBC with differential and platelet count prior to each cycle during neoadjuvant treatment. They do not need to be checked during adjuvant trastuzumab monotherapy.
Assess electrolytes and liver and renal function prior to each cycle during neoadjuvant treatment. They do not need to be checked during adjuvant trastuzumab monotherapy.
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.^[5] Refer to UpToDate topics on infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy.
Assess cardiac function prior to initiation of neoadjuvant chemotherapy and HER2-directed therapies (pre-cycle 1). In the absence of symptoms, routine cardiac monitoring may not be necessary. However, a reasonable strategy is to reassess cardiac function midway through adjuvant trastuzumab (prior to cycle 7 and cycle 13). In the protocol, LVEF was assessed at baseline and during cycles 2, 4, and 6; before cycle 7; during cycles 10, 12, 15, and 18; and at final visit after completion of combination therapy.^[1] Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents.
Periodic neurologic examination is advised to detect sensory neuropathy.
Suggested dose modifications for toxicity:
Myelotoxicity	Docetaxel should only be administered if the ANC is >1500/microL.^[2] 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).^[2] Carboplatin should only be administered if the platelet count is >100,000/microL. Reduce carboplatin dose by 25% for subsequent cycles in patients who develop severe neutropenia (<500/microL) or thrombocytopenia (<50,000/microL), or in patients who require a longer than one-week delay in treatment due to thrombocytopenia.^[6]
Hepatotoxicity	Docetaxel dose reduction to 60 mg/m² may be needed for patients who develop significant alterations in transaminases and alkaline phosphatase during therapy. 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.
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 pretreatment baseline.^[5] Guidelines for managing cardiac dysfunction during therapy with HER2-targeted agents are available. Refer to UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents.
Pulmonary toxicity	Discontinue trastuzumab for serious pulmonary toxicity. Refer to UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, molecularly targeted agents.
Infusion reactions	Respond as clinically indicated with supportive care and possible discontinuation of therapy for severe reactions. Refer to UpToDate topics on infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy.
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.^[2] Discontinue if toxicity persists. Refer to UpToDate topics on cutaneous side effects of conventional chemotherapy 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.

HER2: human epidermal growth factor receptor 2; IV: intravenous; NS: normal saline; D5W: 5% dextrose in water; AUC: area under the concentration × time curve; NSAID: nonsteroidal anti-inflammatory drug; ULN: upper limit of normal; LVEF: left ventricular ejection fraction; CYP3A4: cytochrome P450 3A4; CBC: complete blood count; ANC: absolute neutrophil count; IHC: immunohistochemical staining; FISH: fluorescence in situ hybridization; GFR: glomerular filtration rate; NCCN: National Comprehensive Cancer Network.

* High levels of HER2 overexpression, as determined by either 3+ IHC or positive FISH, are used to select patients for therapy with trastuzumab and pertuzumab. Refer to UpToDate topic on "HER2 and predicting response to therapy in breast cancer".

¶ Administer trastuzumab, pertuzumab, carboplatin, and docetaxel sequentially, with carboplatin and docetaxel administered after trastuzumab and pertuzumab. During neoadjuvant treatment, wait 30 to 60 minutes following pertuzumab to begin carboplatin.^[1]

Δ A repeat loading dose of trastuzumab is required if scheduled treatment has been delayed for over one week, which is the case for patients resuming trastuzumab after definitive surgery. If adverse reactions occur for which discontinuation of trastuzumab or pertuzumab is indicated, both drugs should be discontinued. Dose modifications of trastuzumab and pertuzumab were not allowed in the original protocol.^[1]

◊ Diluent solutions should not be modified without consulting a detailed reference due to potential incompatibility(ies).

§ AUC is converted to a patient-specific carboplatin dose (in mg) according to the renal function by using the Calvert formula. The Calvert formula is total dose (mg) = (target AUC) × (GFR + 25). If using measured serum creatinine, limit the maximal GFR for the calculation to 125 mL/min. Refer to UpToDate topic on "Dosing of anticancer agents in adults".

¥ Consensus-based guidelines from the NCCN classify higher carboplatin doses (AUC ≥4) as highly emetogenic; by contrast, the American Society of Clinical Oncology and the Multinational Association for Supportive Care in Cancer guidelines consider all carboplatin doses to be moderately emetogenic. Although many institutions classify carboplatin-containing regimens as moderately emetogenic, a benefit for adding a neurokinin 1 receptor antagonist on day 1 has been shown in many studies; additional prophylaxis beyond day 1 for delayed emesis is not needed for most patients. Refer to UpToDate topic on "Prevention and treatment of chemotherapy-induced nausea and vomiting in adults".

‡ A list of strong and moderate CYP3A4 inhibitors is available as a separate table in UpToDate. Specific interactions may be determined by use of the Lexicomp drug interactions program included within UpToDate.

References:

Schneeweiss A, et al. Annals of Oncology 2013; 24:2278.
Docetaxel injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on March 15, 2022).
Van Belle H, et al. Breast Cancer Res Treat 2021; 190:357.
Trastuzumab injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on October 30, 2019).
Pertuzumab injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on October 30, 2019).
Carboplatin injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on October 30, 2019).

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Neoadjuvant trastuzumab, pertuzumab, carboplatin, and docetaxel followed by adjuvant trastuzumab for HER2-positive* breast cancer[1]

Neoadjuvant trastuzumab, pertuzumab, carboplatin, and docetaxel followed by adjuvant trastuzumab for HER2-positive* breast cancer^[1]