No phase III evidence exists for the addition of trastuzumab to some chemotherapy regimens, such as docetaxel/cyclophosphamide. However, those regimens might be in use and are reasonable options, particularly for mitigating cardiotoxicity in certain patients.

— Neelima Denduluri, MD, and colleagues

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As reported in the Journal of Clinical Oncology by Neelima Denduluri, MD, and colleagues, ASCO has adapted a Cancer Care Ontario (CCO) clinical practice guideline on selection of optimal adjuvant chemotherapy for HER2-negative and adjuvant targeted therapy for HER2-positive breast cancer.¹ The adaptation was based on review by an expert ASCO panel co-chaired by Dr. Denduluri, of The US Oncology Network, Virginia Cancer Specialists, Arlington, and Antonio C. Wolff, MD, of Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.

The adapted ASCO recommendations are reproduced here. Those marked by an asterisk are verbatim from the CCO guideline. Others have been substantively adapted or reworded by the ASCO panel.

Recommendations

Use of an Anthracycline-Taxane Regimen: In patients who can tolerate it, use of a regimen containing an anthracycline-taxane is considered the optimal strategy for adjuvant chemotherapy, particularly for patients deemed to be at high risk.*

Optimal-Dose Anthracycline Regimen for Patients for Whom a Taxane Is Contraindicated: For patients with high-risk disease who will not receive a taxane, an optimal-dose anthracycline 3-drug regimen (cumulative dose of doxorubicin ≥ 240 mg/m² or epirubicin ≥ 600 mg/m² but no higher than 720 mg/m²) that contains cyclophosphamide is recommended. The cumulative dose of doxorubicin in 2-drug regimens should not exceed 240 mg/m².

Antonio C. Wolff, MD

Adding Gemcitabine or Capecitabine to an Anthracycline-Taxane Regimen: The addition of gemcitabine or capecitabine to an anthracycline-taxane regimen is not recommended for adjuvant chemotherapy.*

Capecitabine in Patients Aged ≥ 65 Years: In patients aged 65 years or older, capecitabine is not recommended as an adjuvant chemotherapy option in lieu of standard regimens such as doxorubicin/cyclophosphamide or cyclophosphamide/methotrexate/fluorouracil (5-FU; with oral cyclophosphamide).

Cyclophosphamide/Methotrexate/5-FU as an Alternative to Doxorubicin/Cyclophosphamide: For patients in whom an anthracycline-taxane is contraindicated, cyclophosphamide/methotrexate/5-FU (with oral cyclophosphamide) is an acceptable chemotherapy alternative to doxorubicin/cyclophosphamide. Of note, the ASCO panel recommends classic cyclophosphamide/methotrexate/5-FU (oral cyclophosphamide on days 1 to 14 with intravenous [IV] methotrexate/5-FU on days 1 and 8, repeated once every 28 days for 6 cycles) as the default adjuvant cyclophosphamide/methotrexate/5-FU regimen. However, the panel also recognizes that an all-IV cyclophosphamide/methotrexate/5-FU regimen once every 21 days is often used in clinical practice and was accepted by some clinical trials (eg, TAILORx) on the basis of convenience and tolerability despite the absence of efficacy data from randomized controlled trials.

Acceptable Adjuvant Chemotherapy Regimens for Patients With Higher-Risk Early Breast Cancer: These adjuvant chemotherapy regimens can be used for patients with early breast cancer:

• 5-FU/epirubicin/cyclophosphamide × 3 → docetaxel × 3 (superior to 5-FU/epirubicin/cyclophosphamide × 6)
• Doxorubicin/cyclophosphamide × 4 → docetaxel × 4 (superior to doxorubicin/cyclophosphamide × 4)
• Docetaxel/doxorubicin/cyclophosphamide × 6 (superior to 5-FU/doxorubicin/cyclophosphamide × 6)
• Doxorubicin/cyclophosphamide × 4 → paclitaxel administered once per week
• Dose-dense doxorubicin/cyclophosphamide → paclitaxel administered once every 2 weeks

Adjuvant Regimen When an Anthracycline Is Not Preferred: Docetaxel/cyclophosphamide × 4 is recommended as an alternative to doxorubicin/cyclophosphamide × 4 and offers improved disease-free survival and overall survival. Classic cyclophosphamide/methotrexate/5-FU with oral cyclophosphamide for six cycles is another option. As mentioned, the ASCO panel recommends classic cyclophosphamide/methotrexate/5-FU (oral cyclophosphamide on days 1 to 14 with IV methotrexate/5-FU on days 1 and 8, repeated once every 28 days for 6 cycles) as the default adjuvant cyclophosphamide/methotrexate/5-FU regimen. However, the panel also recognizes that an all-IV cyclophosphamide/methotrexate/5-FU regimen once every 21 days is often used in clinical practice and was accepted by some clinical trials (eg, TAILORx) on the basis of its convenience and tolerability despite the absence of efficacy data from randomized controlled trials.

Patient Selection and Adjuvant Trastuzumab (Herceptin) Therapy: Only patients with HER2-positive breast cancer (overexpressed based on immunohistochemistry [3+] or amplified based on in situ hybridization [ratio ≥ 2.0 or average HER2 copy number ≥ 6.0]) should be offered adjuvant trastuzumab.

Trastuzumab Plus Chemotherapy in Patients With Higher-Risk HER2-Positive Disease: Trastuzumab plus chemotherapy is recommended for all patients with HER2-positive, node-positive breast cancer and for patients with HER2-positive, node-negative breast cancer (> 1 cm).*

Trastuzumab Plus Chemotherapy in Patients With HER2-Positive T1a-b N0 Disease: Trastuzumab therapy can be considered in small, node-negative tumors (≤ 1 cm).

Selection of Chemotherapy Regimens in Patients Receiving Trastuzumab: Trastuzumab can be administered with any acceptable adjuvant chemotherapy regimen.*

Use of Trastuzumab and an Anthracycline-Containing Regimen: The administration of trastuzumab concurrently with the anthracycline component of a chemotherapy regimen is not recommended because of the potential for increased cardiotoxicity.

Concurrent Administration of Adjuvant Trastuzumab and Non-Anthracycline Chemotherapy Regimens: Trastuzumab should be preferentially administered concurrently (not sequentially) with a non-anthracycline chemotherapy regimen.

Trastuzumab-Based Chemotherapy or Trastuzumab Regimens for Patients at Higher Risk of Cardiotoxicity: Less cardiotoxicity is seen with docetaxel/carboplatin/trastuzumab than with doxorubicin/cyclophosphamide → docetaxel/trastuzumab, and docetaxel/carboplatin/trastuzumab is recommended for patients at higher risk for cardiotoxicity.*

Addition of Trastuzumab to Chemotherapy Regimens Not Evaluated in a Phase III Trial: No phase III evidence exists for the addition of trastuzumab to some chemotherapy regimens, such as docetaxel/cyclophosphamide. However, those regimens might be in use and are reasonable options, particularly for mitigating cardiotoxicity in certain patients.*

Duration of Trastuzumab Therapy and Cardiac Function Assessment: Patients should be offered 1 year total of adjuvant trastuzumab, with regular assessments of cardiac function during that period.* ■

Disclosure: Dr. Denduluri has received institutional research funding from Genentech, Amgen, and Novartis.

Reference

1. Denduluri N, Somerfield MR, Eisen A, et al: Selection of optimal adjuvant chemotherapy regimens for human epidermal growth factor receptor 2-negative and adjuvant targeted therapy for HER2-positive breast cancers: An American Society of Clinical Oncology guideline adaptation of the Cancer Care Ontario clinical practice guideline. J Clin Oncol 34:2416-2427, 2016.