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 This is an original JCO publication from 2016. Please visit the JCO website to access the full article.


Selection of Optimal Adjuvant Chemotherapy Regimens for Early-Stage Breast Cancer and Adjuvant Targeted Therapy for Human Epidermal Growth Factor Receptor 2–Positive Breast Cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline


 Authors

Neelima Denduluri, Mark R. Somerfield, Andrea Eisen, Jamie N. Holloway, Arti Hurria, Tari A. King, Gary H. Lyman, Ann H. Partridge, Melinda L. Telli, Maureen E. Trudeau, and Antonio C. Wolff

THE BOTTOM LINE

Guideline Question

What is the optimal use of cytotoxic chemotherapy and human epidermal growth factor receptor 2 (HER2) –directed therapy?

Target Population

Female patients who are being considered for, or who are receiving, systemic therapy after definitive surgery for early invasive breast cancer, defined largely as invasive cancer stages I to IIA (T1N0-1, T2N0).

Target Audience

Medical oncologists, pathologists, surgeons, oncology nurses, patients, and caregivers.

Recommendations (Note. Recommendations identified by an asterisk are taken verbatim from the Cancer Care Ontario [CCO] guideline. Otherwise, recommendations have been substantively adapted or reworded for clarity by the American Society of Clinical Oncology [ASCO] Panel.)

Use of an Anthracycline-Taxane Regimen

In patients who can tolerate it, use of a regimen containing 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 three-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 two-drug regimens should not exceed 240 mg/m2.

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 Age 65 Years or Older

In patients age 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 (with oral cyclophosphamide).

Cyclophosphamide-Methotrexate-Fluorouracil as an Alternative to Doxorubicin-Cyclophosphamide

For patients in whom anthracycline-taxane is contraindicated, cyclophosphamide-methotrexate-fluorouracil (with oral cyclophosphamide) is an acceptable chemotherapy alternative to doxorubicin-cyclophosphamide. Of note, the ASCO Panel recommends classic cyclophosphamide-methotrexate-fluorouracil (oral cyclophosphamide days 1 to 14 with intravenous [IV] methotrexate-fluorouracil days 1 and 8, repeated once every 28 days for six cycles) as the default adjuvant cyclophosphamide-methotrexate-fluorouracil regimen. However, the Panel also recognizes that an all-IV cyclophosphamide-methotrexate-fluorouracil regimen once every 21 days is often used in clinical practice and was accepted by some clinical trials (eg, TAILORx; Trial Assigning Individualized Options for Treatment [Rx]) 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:

• Fluorouracil-epirubicin-cyclophosphamide × 3 → docetaxel × 3 (superior to fluorouracil-epirubicin-cyclophosphamide × 6)

• Doxorubicin-cyclophosphamide × 4 → docetaxel × 4 (superior to doxorubicin-cyclophosphamide × 4)

• Docetaxel-doxorubicin-cyclophosphamide × 6 (superior to fluorouracil-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-fluorouracil with oral cyclophosphamide for six cycles is another option. As mentioned before, the ASCO Panel recommends classic cyclophosphamide-methotrexate- fluorouracil (oral cyclophosphamide days 1 to 14 with IV methotrexate-fluorouracil days 1 and 8, repeated once every 28 days for six cycles) as the default adjuvant cyclophosphamide-methotrexate-fluorouracil regimen. However, the Panel also recognizes that an all-IV cyclophosphamide-methotrexate-fluorouracil 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 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 → docetaxeltrastuzumab, 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.*

 

More information, including a Data Supplement, a Methodology Supplement, slide sets, and other clinical tools and resources, is available at www.asco.org/adaptations/breastsystemictherapy and www.asco.org/guidelineswiki. Patient information is available at www.cancer.net.

ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care, and that all patients should have the opportunity to participate.

SUMMARY OF RECOMMENDATIONS

CCO Guideline Clinical TopicFinal RecommendationsASCO Adaptation
Use of an anthracycline-taxane regimenIn patients who can tolerate it, use of a regimen containing anthracycline-taxane is considered the optimal strategy for adjuvant chemotherapy, particularly for patients deemed to be at high risk.Not adapted
Optimal-dose anthracycline regimen for patients with highrisk breast cancer who will not receive a taxaneFor patients with high-risk disease who will not receive a taxane, an optimal-dose anthracycline three-drug regimen (cumulative dose of doxorubicin ≥ 240 mg/m2 or epirubicin ≥ 600 but no higher than 720 mg/m2 ) that contains cyclophosphamide is recommended. The cumulative dose of doxorubicin in two-drug regimens should not exceed 240 mg/m2.In light of findings from studies of anthracycline-based two-drug regimens testing a cumulative dose of doxorubicin > 240 mg/m2 , the ASCO panel modified the CCO recommendation to indicate that cumulative dose of doxorubicin in two-drug regimens should not exceed 240 mg/m2.
Adding gemcitabine or capecitabine to an anthracyclinetaxane regimenThe addition of gemcitabine or capecitabine to an anthracycline-taxane regimen is not recommended for adjuvant chemotherapy.Not adapted
Capecitabine in patients 65 years of age and olderIn patients age 65 years or older, capecitabine is not recommended as an adjuvant chemotherapy option in lieu of standard regimens like AC or CMF (oral cyclophosphamide).The ASCO panel modified the CCO recommendation to reflect that patients in the clinical trial reported by Muss et al7 were age 65 years or older.
CMF as an alternative to ACFor patients in whom anthracycline-taxane is contraindicated, CMF (with oral cyclophosphamide) is an acceptable chemotherapy alternative to AC. Of note, the ASCO panel recommends classic CMF (oral cyclophosphamide days 1-14 with IV CMF days 1 and 8, repeated every 28 days for six cycles) as the default adjuvant CMF regimen. However, the panel also recognizes that an all-IV CMF regimen every 21 days is often used in clinical practice and was accepted by some clinical trials such as TAILORx based on convenience and tolerability, despite absence of efficacy data from randomized controlled trials.The ASCO panel modified the CCO recommendation to include a comment on the use of an all-IV CMF regimen.
Acceptable adjuvant chemotherapy regimens for patients with higher risk earlystage breast cancer

These adjuvant chemotherapy regimens can be used for patients with early-stage breast cancer:

• FEC × 3 → T × 3 (superior to FEC × 6)

• AC × 4 → T × 4 (superior to AC × 4)

• Docetaxel-doxorubicin-cyclophosphamide × 6 (superior to 5-fluorouracil-doxorubicin-cyclophosphamide × 6)

• AC × 4 → paclitaxel (P) administered weekly • Dose-dense AC → P (every 2 weeks)

The ASCO panel modified the CCO list of acceptable adjuvant chemotherapy regimens to remove the “dose-dense, dose-intense epirubicin-cyclophosphamide→ P” regimen due to higher toxicity and lack of overall survival benefit.
Adjuvant regimen when an anthracycline is not preferredTC x 4 is recommended as an alternative to AC x 4 and offers improved DFS and OS. Classic CMF with oral cyclophosphamide for 6 cycles is another option. Of note, the ASCO panel recommends classic CMF (oral cyclophosphamide days 1-14 with IV MF days 1 and 8, repeated every 28 days for 6 cycles) as the default adjuvant CMF regimen. However, the panel also recognizes that an all-IV CMF regimen every 21 days is often employed in clinical practice and was accepted by some clinical trials such as TAILORx based on convenience and tolerability, despite absence of efficacy data from randomized controlled trials.The ASCO panel modified the CCO recommendation to specify that TC should be administered for four cycles and added the statement to the recommendation that, based on the Oxford Overview, CMF for 6 cycles offers “equivalent”2(p437) outcomes and is an alternative to AC every 3 weeks x 4. The ASCO panel also modified the CCO recommendation to include a comment on the use of an all-IV CMF regimen.
Patient selection and adjuvant trastuzumab therapyOnly 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.The ASCO panel modified the CCO patient selection recommendation slightly to make it consistent with the ASCO-College of American Pathologists guideline10 definition of “positive for HER2” as an average HER2 gene copy number of ≥ 6 per cell nucleus.
Trastuzumab plus chemotherapy in patients with higher risk HER2- positive diseaseTrastuzumab plus chemotherapy is recommended for all patients with HER2-positive, node-positive breast cancer and for patients with HER2-positive, node-negative breast cancer greater than 1 cm in size.Not adapted
Trastuzumab plus chemotherapy in patients with HER2-positive disease if T1a/b N0Trastuzumab therapy can be considered in small, nodenegative tumors (≤ 1 cm).The ASCO panel adapted the CCO recommendation in light of data published since the CCO guideline was completed to make the recommendation more definitive regarding the use of trastuzumab plus chemotherapy in patients with small, node-negative tumors.
Selection of chemotherapy regimens in patients receiving trastuzumabTrastuzumab can be administered with any acceptable adjuvant chemotherapy regimenNot adapted
Use of trastuzumab and an anthracycline-containing regimenThe administration of trastuzumab concurrently with the anthracycline component of a chemotherapy regimen is not recommended because of the potential for increased cardiotoxicity.The ASCO panel adapted the CCO recommendation to omit the word “generally” from the CCO recommendation, which reads “The administration of trastuzumab concurrently with the anthracycline component of a chemotherapy regimen is generally not recommended because of the potential for increased cardiotoxicity.”
Concurrent administration of adjuvant trastuzumab and nonanthracycline chemotherapy regimensTrastuzumab should be preferentially administered concurrently (not sequentially) with a non-anthracycline chemotherapy regimen.The ASCO panel adapted the CCO recommendation to indicate a preference for concurrent versus sequential administration of trastuzumab and non-anthracycline chemotherapy.
Trastuzumab-based chemotherapy-trastuzumab regimens for patients at higher risk of cardiotoxicityLess cardiotoxicity is seen with TCH than with AC → TH, and TCH is recommended for patients at higher risk for cardiotoxicityNot adapted
Addition of trastuzumab to chemotherapy regimens not evaluated in a phase III trialNo phase III evidence exists for the addition of trastuzumab to some chemotherapy regimens, such as TC. However, those regimens might be in use and are reasonable options, particularly to mitigate cardiotoxicity in certain patients.Not adapted
Duration of trastuzumab therapy and cardiac function assessmentPatients should be offered 1 year total of adjuvant trastuzumab, with regular assessments of cardiac function during that periodNot adapted

Abbreviations: AC, doxorubicin-cyclophosphamide; AC → TH, doxorubicin/cyclophosphamide-docetaxel/trastuzumab; CCO, Cancer Care Ontario; CMF, cyclophosphamidemethotrexate--fluorouracil; DFS, disease-free survival; FEC, fluorouracil-epirubicin-cyclophosphamide; HER2, human epidermal growth factor receptor 2; IV, intravenous; OS, overall survival; T, docetaxel; TC, docetaxel-cyclophosphamide; TH, docetaxel-trastuzumab.


ASCO Guideline Disclaimer: The clinical practice guidelines and other guidance published herein are provided by the American Society of Clinical Oncology, Inc. (“ASCO”) to assist practitioners in clinical decision making. The information therein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating physician, as the information does not account for individual variation among patients. Recommendations reflect high, moderate or low confidence that the recommendation reflects the net effect of a given course of action.  The use of words like “must,” “must not,” “should,” and “should not” indicate that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating physician in the context of treating the individual patient. Use of the information is voluntary.  ASCO provides this information on an “as is” basis, and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions.


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