Docetaxel, carboplatin, and trastuzumab (TCH) for adjuvant therapy of HER2-positive breast cancer^[1,2]

Cycle length: 21 days (docetaxel and carboplatin for 6 cycles, trastuzumab for 1 year).
Drug	Dose and route	Administration	Given on days
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.	Day 1 (cycles 1 to 6)
Carboplatin	AUC^Δ = 6 mg/mL per min IV	Dilute in 250 mL NS^¶ and administer over 30 to 60 minutes.	Day 1 (cycles 1 to 6)
Trastuzumab,^◊ loading dose^§	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.	Day 1 (cycle 1)
Trastuzumab,^◊ maintenance dose	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.	Day 1 (cycle 2 and beyond, to complete one year of trastuzumab)
Pretreatment considerations:
Emesis risk	MODERATE for cycles 1 to 6; LOW for trastuzumab-only cycles (cycles 7 and beyond).^¥ Refer to the UpToDate topics on prevention of chemotherapy-induced nausea and vomiting in adults.
Prophylaxis for infusion reactions	Premedicate with dexamethasone prior to docetaxel administration.^[1,2] 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 the 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 the 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] Myelotoxicity is uncommon when trastuzumab is continued alone. Refer to the UpToDate topics on use of granulocyte colony stimulating factors in adult patients with chemotherapy-induced neutropenia and conditions other than acute leukemia, myelodysplastic syndrome, and hematopoietic cell transplantation.
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.^[2] Each carboplatin dose should be calculated based upon renal function by use of the Calvert formula.^Δ Refer to the 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 is associated with cardiotoxicity; assess baseline LVEF prior to therapy as discussed below, under "Monitoring parameters". Patients with an abnormal LVEF at baseline 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 the UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents and pulmonary toxicity associated with antineoplastic therapy, molecularly 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. These do not need to be checked during adjuvant trastuzumab monotherapy.
Assess electrolytes and liver and renal function prior to each cycle. These do not need to be checked during adjuvant trastuzumab monotherapy.
Monitor for diarrhea frequently during treatment with docetaxel and carboplatin.
Assess changes in neurologic function prior to each cycle of docetaxel and carboplatin.
Assess cardiac function at baseline, every three months during treatment, upon completion, and every six months for at least two years following completion of trastuzumab as a component of adjuvant therapy.^[4] Refer to the UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents.
Review medication history prior to each cycle to evaluate risk of drug-drug interactions with docetaxel.
Suggested dose modifications for toxicity:
Myelotoxicity	ANC should be >1500/mm³ and platelets >100,000/mm³ to initiate subsequent cycles.^[1] If ANC is <1500/mm³ or platelets <100,000, delay therapy until recovery. If platelets are <100,000/mm³ on day 1 of any cycle, carboplatin dose should be reduced to AUC 5 and docetaxel should be reduced to 60 mg/m² upon recovery of platelets to >100,000/mm³.
Hepatotoxicity	Docetaxel dose reduction to 60 mg/m² may be needed for patients who develop significant alterations in transaminases and alkaline phosphatase during therapy.^[2] Refer to the 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	LVEF ≥16% decrease from baseline or LVEF below normal limits and ≥10% decrease from baseline: Withhold treatment for at least four weeks and repeat LVEF every four weeks.^[4] May resume trastuzumab treatment if LVEF returns to normal limits within four to eight weeks and remains at ≤15% decrease from baseline value. Discontinue permanently for persistent (>8 weeks) LVEF decline or for >3 incidents of treatment interruptions for cardiomyopathy.^[4] Guidelines for managing cardiac dysfunction during therapy with HER2-targeted agents are available. Refer to the UpToDate topics on cardiotoxicity of trastuzumab and other HER2-targeted agents.
Pulmonary toxicity	Discontinue trastuzumab for serious pulmonary toxicity.^[4] Refer to the UpToDate topics on pulmonary toxicity associated with antineoplastic therapy, molecularly targeted agents.
Gastrointestinal toxicity	For recurrent episodes of grade 2 to 3 diarrhea or any grade 3 stomatitis, docetaxel doses should be reduced to 60 mg/m² for subsequent cycles.^[1] If grade 3 stomatitis recurs, reduce docetaxel further to 50 mg/m².^[1]
Infusion reactions	Respond as clinically indicated with supportive care and possible discontinuation of therapy for severe reactions. Refer to the UpToDate topics on infusion reactions to therapeutic monoclonal antibodies used for cancer therapy and infusion reactions to systemic chemotherapy.
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; AUC: area under the concentration × time curve; D5W: 5% dextrose in water; 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; BSA: body surface area; GFR: glomerular filtration rate; IHC: immunohistochemical staining; FISH: fluorescence in situ hybridization; NCCN: National Comprehensive Cancer Network.

* If the calculated BSA of the patient is >2.2 m², the dose of docetaxel should be calculated with BSA 2.2 m². The patient's actual body weight should be used to calculate BSA.^[1]

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

Δ AUC is converted to a patient-specific carboplatin dose (in mg) according to 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.^[5,6] Refer to the UpToDate topic on "Dosing of anticancer agents in adults" and the UpToDate calculator "Calculator: AUC dose calculation for carboplatin (Calvert formula)".

◊ 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 the UpToDate topic on "HER2 and predicting response to therapy in breast cancer".

§ A repeat loading dose of trastuzumab is required if scheduled treatment has been delayed for over one week.[4]

¥ 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:

Slamon D, et al. N Engl J Med 2011; 365(14): 1273.
Docetaxel injection. United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on March 15, 2022).
NCCN Guidelines: Myeloid growth factors. Version 2.2018. (Available online at nccn.org/professionals/physician_gls/pdf/myeloid_growth.pdf, accessed on October 30, 2019).
Trastuzumab injection United States Prescribing Information. US National Library of Medicine. (Available online at dailymed.nlm.nih.gov, accessed on October 30, 2019).
Griggs JJ, et al. J Clin Oncol 2012; 30:1553.
NCCN Chemotherapy Order Templates Appendix B: Carboplatin dosing. (Available online at nccn.org/professionals/OrderTemplates/PDF/appendix_B.pdf, accessed on October 30, 2019).

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Docetaxel, carboplatin, and trastuzumab (TCH) for adjuvant therapy of HER2-positive breast cancer[1,2]

Docetaxel, carboplatin, and trastuzumab (TCH) for adjuvant therapy of HER2-positive breast cancer^[1,2]