Difference between revisions of "Breast cancer"

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'''Use of this site is subject to you reading and agreeing with the terms set forth in the [[HemOnc.org_-_A_Hematology_Oncology_Wiki:General_disclaimer|disclaimer]].'''
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Is there a regimen missing from this list?  Would you like to share a different dosage/schedule or an additional reference for a regimen?  Have you noticed an error?  Do you have an idea that will help the site grow to better meet your needs and the needs of many others?  You are [[How_to_contribute|invited to contribute to the site]].
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{{#lst:Editorial board transclusions|breast}}
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''Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the [[Breast_cancer_-_historical|historical regimens page]]. For placebo or observational studies in this condition, please visit [[Breast cancer - null regimens|this page]]. If you still can't find it, please let us know so we can add it!''<br>
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<big>'''Note: this page contains regimens which were not tested in biomarker-selected populations; many of these trials do still include and stratify patients by biomarker status, however. The following links will take you to biomarker-specific subpages:'''
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*Regimens for [[Breast_cancer,_ER-positive|'''ER/PR positive breast cancer are here''']].
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*Regimens for [[Breast_cancer,_HER2-positive|'''HER2 positive breast cancer are here''']].
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*Regimens for [[Breast cancer, ER and HER2 co-expressing|'''ER/HER2 co-expressing ("double positive") breast cancer are here''']].
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*Regimens for [[Breast_cancer,_triple_negative|'''Triple negative breast cancer (TNBC) are here''']].
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*Regimens for [[Breast_cancer,_BRCA-mutated|'''BRCA-mutated breast cancer are here''']].
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*Regimens for [[Breast cancer, PIK3CA-mutated|'''PIK3CA-mutated breast cancer are here''']].
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*Regimens for [[Breast cancer, CNS metastases|'''CNS metastases are here''']].
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*''Because docetaxel and paclitaxel are both often abbreviated as "T," we try to always make clear in the regimen name which agent is being used. For sequential regimens, we use "T" for paclitaxel and "D" for docetaxel; e.g., [[#AC-T|AC-T]] and [[#AC-D|AC-D]].''
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|<div style="background-color: #66FF66; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} regimens on this page</b></font></div>
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|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
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<div style="background-color: #66CCFF; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} variants on this page</b></font></div>
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<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]] |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
 
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=Guidelines=
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'''Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.'''
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==[https://www.asco.org/ ASCO]/CCO==
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*'''2024:''' Al Sukhun et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10793992/ Systemic Treatment of Patients With Metastatic Breast Cancer: ASCO Resource–Stratified Guideline] [https://pubmed.ncbi.nlm.nih.gov/38206277/ PubMed]
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*'''2023:''' Moy et al. [https://doi.org/10.1200/jco.22.02807 Chemotherapy and Targeted Therapy for Endocrine-Pretreated or Hormone Receptor-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update] [https://www.ncbi.nlm.nih.gov/pubmed/36626701 PubMed]
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**'''2022:''' Moy et al. [https://doi.org/10.1200/jco.22.01533 Chemotherapy and Targeted Therapy for Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer That Is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Rapid Recommendation Update] [https://www.ncbi.nlm.nih.gov/pubmed/35926153 PubMed]
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**'''2021:''' Moy et al. [https://doi.org/10.1200/jco.21.01374 Chemotherapy and Targeted Therapy for Patients With Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Update] [https://www.ncbi.nlm.nih.gov/pubmed/34324366 PubMed]
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*'''2022:''' Henry et al. [https://doi.org/10.1200/jco.22.01063 Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update] [https://pubmed.ncbi.nlm.nih.gov/35759724/ PubMed]
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*'''2022:''' Eisen et al. [https://doi.org/10.1200/jco.21.02647 Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: ASCO-OH (CCO) Guideline Update] [https://www.ncbi.nlm.nih.gov/pubmed/35041467 PubMed]
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*'''2021:''' Brackstone et al. [https://doi.org/10.1200/jco.21.00934 Management of the Axilla in Early-Stage Breast Cancer: Ontario Health (Cancer Care Ontario) and ASCO Guideline] [https://pubmed.ncbi.nlm.nih.gov/34279999/ PubMed]
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**'''2017:''' Lyman et al. [https://doi.org/10.1200/jco.2016.71.0947 Sentinel Lymph Node Biopsy for Patients With Early-Stage Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update] [https://pubmed.ncbi.nlm.nih.gov/27937089/ PubMed]
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**'''2014:''' Lyman et al. [https://doi.org/10.1200/jco.2013.54.1177 Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update] [https://pubmed.ncbi.nlm.nih.gov/24663048/ PubMed]
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**'''2005:''' Lyman et al. [https://doi.org/10.1200/jco.2005.08.001 American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer] [https://pubmed.ncbi.nlm.nih.gov/16157938/ PubMed]
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*'''2021:''' Burstein et al. [https://doi.org/10.1200/jco.21.01392 Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Update] [https://www.ncbi.nlm.nih.gov/pubmed/34324367 PubMed]
 +
*'''2021:''' Korde et al. [https://doi.org/10.1200/jco.20.03399 Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/33507815 PubMed]
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*'''2020:''' Denduluri et al. [https://doi.org/10.1200/jco.20.02510 Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update] [https://www.ncbi.nlm.nih.gov/pubmed/33079579 PubMed]
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**'''2018:''' Denduluri et al. [https://doi.org/10.1200/JCO.2018.78.8604 Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO clinical practice guideline focused update] [https://pubmed.ncbi.nlm.nih.gov/29787356/ PubMed]
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**'''2016:''' Harris et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933134/ Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology clinical practice guideline] [https://www.ncbi.nlm.nih.gov/pubmed/26858339 PubMed]
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*'''2020:''' Hassett et al. [https://doi.org/10.1200/jco.19.03120 Management of Male Breast Cancer: ASCO Guideline] [https://pubmed.ncbi.nlm.nih.gov/32058842/ PubMed]
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*'''2017:''' Van Poznak et al. [https://doi.org/10.1200/JCO.2017.75.4614 Role of bone-modifying agents in metastatic breast cancer: an American Society of Clinical Oncology–Cancer Care Ontario focused guideline update] [https://www.ncbi.nlm.nih.gov/pubmed/29035643 PubMed]
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*'''2015:''' van Poznak et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5478102/ Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology Clinical practice guideline] [https://www.ncbi.nlm.nih.gov/pubmed/26195705 PubMed]
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*'''2014:''' Partridge et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076042/ Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Clinical Practice Guideline] [https://www.ncbi.nlm.nih.gov/pubmed/25185096 PubMed]
  
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=Adjuvant endocrine therapy=
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==[https://www.esmo.org/ ESMO]/ESO==
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==Anastrozole (Arimidex) {{#subobject:a052f4|Regimen=1}}==
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*'''2023:''' Loibl et al. [https://doi.org/10.1016/j.annonc.2023.11.016 Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/38101773/ PubMed]
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**'''2019:''' Cardoso et al. [https://academic.oup.com/annonc/article/30/8/1194/5499075 Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/31161190 PubMed]
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===Regimen, Howell et al. 2005 (ATAC); Kaufmann et al. 2007 (ARNO 95); ATAC Trialists' Group et al. 2008 (ATAC); Goss et al. 2013 (NCIC CTG MA.27) {{#subobject:b05e8a|Variant=1}}===
 
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Level of Evidence:
 
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<span
 
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style="background:#00CD00;
 
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border-color:black;
 
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*[[Anastrozole (Arimidex)]] 1 mg PO once per day
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*'''2023:''' Im et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10186487/ Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer] [https://pubmed.ncbi.nlm.nih.gov/37178669/ PubMed]
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*'''2022:''' Paluch-Simon et al. [https://doi.org/10.1016/j.annonc.2022.07.007 ESO–ESMO fifth international consensus guidelines for breast cancer in young women (BCY5)] [https://www.ncbi.nlm.nih.gov/pubmed/35934170 PubMed]
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**'''2020:''' Paluch-Shimon et al. [https://doi.org/10.1016/j.annonc.2020.03.284 ESO–ESMO 4th International Consensus Guidelines for Breast Cancer in Young Women (BCY4)] [https://www.ncbi.nlm.nih.gov/pubmed/32199930 PubMed]
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*'''2021:''' Gennari et al. [https://doi.org/10.1016/j.annonc.2021.09.019 ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer] [https://pubmed.ncbi.nlm.nih.gov/34678411/ PubMed]
  
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'''5-year course of therapy'''
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*'''2018:''' Cardoso et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7360146/ 4th ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4)] [https://pubmed.ncbi.nlm.nih.gov/30032243/ PubMed]
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**'''2017:''' Cardoso et al. [http://www.thebreastonline.com/article/S0960-9776(16)30183-7 3rd ESO-ESMO International consensus guidelines for advanced breast cancer (ABC3)] [https://pubmed.ncbi.nlm.nih.gov/27927580/ PubMed]
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**'''2014:''' Cardoso et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176456/ ESO-ESMO 2nd International consensus guidelines for advanced breast cancer (ABC2)] [https://www.ncbi.nlm.nih.gov/pubmed/25244983 PubMed]
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**'''2012:''' Cardoso et al. [https://www.thebreastonline.com/article/S0960-9776(12)00062-8 1st International consensus guidelines for advanced breast cancer (ABC 1)] [https://www.ncbi.nlm.nih.gov/pubmed/22425534 PubMed]
  
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===References===
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*'''2015:''' Senkus et al. [https://www.esmo.org/Guidelines/Breast-Cancer/Primary-Breast-Cancer Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://www.ncbi.nlm.nih.gov/pubmed/26314782 PubMed]
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# Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS; ATAC Trialists' Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet. 2005 Jan 1-7;365(9453):60-2. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2804%2917666-6/fulltext link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/15639680 PubMed]
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**'''2013:''' Senkus et al. [https://doi.org/10.1093/annonc/mdt284 Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/23970019/ PubMed]
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# Kaufmann M, Jonat W, Hilfrich J, Eidtmann H, Gademann G, Zuna I, von Minckwitz G. Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 Study. J Clin Oncol. 2007 Jul 1;25(19):2664-70. Epub 2007 Jun 11. [http://jco.ascopubs.org/content/25/19/2664.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/17563395 PubMed]
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**'''2011:''' Aebi et al. [https://doi.org/10.1093/annonc/mdr371 Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/21908498/ PubMed]
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# Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists' Group, Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 2008 Jan;9(1):45-53. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2807%2970385-6/fulltext link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18083636 PubMed]
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**'''2010:''' Aebi et al. [https://doi.org/10.1093/annonc/mdq159 Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/20555111/ PubMed]
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# Goss PE, Ingle JN, Pritchard KI, Ellis MJ, Sledge GW, Budd GT, Rabaglio M, Ansari RH, Johnson DB, Tozer R, D'Souza DP, Chalchal H, Spadafora S, Stearns V, Perez EA, Liedke PE, Lang I, Elliott C, Gelmon KA, Chapman JA, Shepherd LE. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial. J Clin Oncol. 2013 Apr 10;31(11):1398-404. doi: 10.1200/JCO.2012.44.7805. Epub 2013 Jan 28. [http://jco.ascopubs.org/content/31/11/1398.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23358971 PubMed]
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**'''2009:''' Kataja & Castiglione. [https://doi.org/10.1093/annonc/mdp114 Primary breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454421/ PubMed]
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**'''2008:''' Pestalozzi & Castiglione. [https://doi.org/10.1093/annonc/mdn071 Primary breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456775/ PubMed]
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**'''2007:''' Pestalozzi. [https://doi.org/10.1093/annonc/mdm015 Primary breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/17491045/ PubMed]
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**'''2005:''' Pestalozzi et al. [https://doi.org/10.1093/annonc/mdi825 ESMO Minimum Clinical Recommendations for diagnosis, adjuvant treatment and follow-up of primary breast cancer] [https://pubmed.ncbi.nlm.nih.gov/15888763/ PubMed]
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**'''2001:''' [https://doi.org/10.1023/a:1017448816215 ESMO Minimum Clinical Recommendations for diagnosis, adjuvant treatment and follow-up of primary breast cancer] [https://pubmed.ncbi.nlm.nih.gov/11583179/ PubMed]
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*'''2012:''' Cardoso et al. [https://doi.org/10.1093/annonc/mds232 Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/22997442/ PubMed]
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**'''2011:''' Cardoso et al. [https://doi.org/10.1093/annonc/mdr372 Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/21908499/ PubMed]
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**'''2010:''' Cardoso et al. [https://doi.org/10.1093/annonc/mdq160 Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/20555067/ PubMed]
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**'''2009:''' Cardoso & Castiglione. [https://doi.org/10.1093/annonc/mdp115 Locally recurrent or metastatic breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/19454439/ PubMed]
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**'''2008:''' Kataja & Castiglione. [https://doi.org/10.1093/annonc/mdn072 Locally recurrent or metastatic breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/18456744/ PubMed]
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**'''2007:''' Kataja. [https://doi.org/10.1093/annonc/mdm016 Recurrent or metastatic breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up] [https://pubmed.ncbi.nlm.nih.gov/17491064/ PubMed]
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**'''2005:''' Kataja et al. [https://doi.org/10.1093/annonc/mdi816 ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of locally recurrent or metastatic breast cancer (MBC)] [https://pubmed.ncbi.nlm.nih.gov/15888735/ PubMed]
  
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==Exemestane (Aromasin) {{#subobject:62ede3|Regimen=1}}==
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==EUSOMA/SIOG==
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*'''2021:''' Biganzoli et al. [https://doi.org/10.1016/s1470-2045(20)30741-5 Updated recommendations regarding the management of older patients with breast cancer: a joint paper from the European Society of Breast Cancer Specialists (EUSOMA) and the International Society of Geriatric Oncology (SIOG)] [https://www.ncbi.nlm.nih.gov/pubmed/34000244 PubMed]
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===Regimen, Coombes et al. 2004; Coombes et al. 2007; Mamounas et al. 2008 (NSABP B-33); Goss et al. 2013 (NCIC CTG MA.27) {{#subobject:31f118|Variant=1}}===
 
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Level of Evidence:
 
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<span
 
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*[[Exemestane (Aromasin)]] 25 mg PO once per day
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*'''2012:''' Biganzoli et al. [https://doi.org/10.1016/s1470-2045(11)70383-7 Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA)] [https://www.ncbi.nlm.nih.gov/pubmed/22469125 PubMed]
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*'''2007:''' Wildiers et al. [https://doi.org/10.1016/s1470-2045(07)70378-9 Management of breast cancer in elderly individuals: recommendations of the International Society of Geriatric Oncology] [https://www.ncbi.nlm.nih.gov/pubmed/18054880 PubMed]
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==KSMO/ESMO==
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*'''2020:''' Park et al. [https://doi.org/10.1016/j.annonc.2020.01.008 Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with early breast cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS] [https://www.ncbi.nlm.nih.gov/pubmed/32081575 PubMed]
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==NCCN==
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*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1419 NCCN Guidelines - Breast Cancer]
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**'''2020:''' Gradishar et al. [https://doi.org/10.6004/Jnccn.2020.0016 Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/32259783/ PubMed]
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**'''2019:''' Telli et al. [https://doi.org/10.6004/Jnccn.2019.5006 NCCN Guidelines Updates: Breast Cancer.] [https://pubmed.ncbi.nlm.nih.gov/31117035/ PubMed]
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**'''2018:''' Giordano et al. [https://doi.org/10.6004/Jnccn.2018.0043 NCCN Guidelines Updates: Breast Cancer.] [https://pubmed.ncbi.nlm.nih.gov/29784737/ PubMed]
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**'''2018:''' Gradishar et al. [https://doi.org/10.6004/Jnccn.2018.0012 Breast Cancer, Version 4.2017, NCCN Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/29523670/ PubMed]
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**'''2017:''' Salerno et al. [https://doi.org/10.6004/Jnccn.2017.0072 NCCN Guidelines Update: Evolving Radiation Therapy Recommendations for Breast Cancer.] [https://pubmed.ncbi.nlm.nih.gov/28515243/ PubMed]
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**'''2016:''' Gradishar et al. [https://doi.org/10.6004/Jnccn.2016.0181 NCCN Guidelines Update: Breast Cancer.] [https://pubmed.ncbi.nlm.nih.gov/27226503/ PubMed]
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**'''2016:''' Gradishar et al. [https://doi.org/10.6004/jnccn.2016.0037 Invasive Breast Cancer Version 1.2016, NCCN Clinical Practice Guidelines in Oncology]  [https://pubmed.ncbi.nlm.nih.gov/26957618/ PubMed]
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**'''2015:''' Gradishar et al. [https://doi.org/10.6004/jnccn.2015.0060 Breast Cancer Version 2.2015] [https://pubmed.ncbi.nlm.nih.gov/25870381/ PubMed]
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**'''2014:''' Gradishar et al. [https://doi.org/10.6004/jnccn.2014.0058 Breast cancer version 3.2014] [https://pubmed.ncbi.nlm.nih.gov/24717572/ PubMed]
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**'''2013:''' Theriault et al. [https://doi.org/10.6004/Jnccn.2013.0098 Breast cancer, version 3.2013: featured updates to the NCCN guidelines.] [https://pubmed.ncbi.nlm.nih.gov/23847214/ PubMed]
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**'''2012:''' Carlson et al. [https://doi.org/10.6004/Jnccn.2012.0086 Metastatic breast cancer, version 1.2012: featured updates to the NCCN guidelines.] [https://pubmed.ncbi.nlm.nih.gov/22773798/ PubMed]
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**'''2011:''' Carlson et al. [https://doi.org/10.6004/Jnccn.2011.0016 Invasive breast cancer.] [https://pubmed.ncbi.nlm.nih.gov/21310842/ PubMed]
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**'''2010:''' Carlson et al. [https://doi.org/10.6004/Jnccn.2010.0087 Breast cancer: noninvasive and special situations.] [https://pubmed.ncbi.nlm.nih.gov/20971842/ PubMed]
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**'''2009:''' Carlson et al. [https://doi.org/10.6004/Jnccn.2009.0012 Breast cancer. Clinical practice guidelines in oncology.] [https://pubmed.ncbi.nlm.nih.gov/19200416/ PubMed]
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**'''2006:''' Carlson et al. NCCN Task Force Report: Adjuvant Therapy for Breast Cancer. [https://pubmed.ncbi.nlm.nih.gov/16507275/ PubMed]
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**'''2005:''' Carlson et al. [https://doi.org/10.6004/Jnccn.2005.0015 Breast cancer.] [https://pubmed.ncbi.nlm.nih.gov/16002000/ PubMed]
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**'''2004:''' Authors not listed. NCCN Guideline update: Breast Cancer Version 1.2004. [https://pubmed.ncbi.nlm.nih.gov/19795602/ PubMed]
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**'''2003:''' Authors not listed. [https://doi.org/10.6004/Jnccn.2003.0016 Breast cancer Clinical Practice Guidelines in Oncology.] [https://pubmed.ncbi.nlm.nih.gov/19768876/ PubMed]
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*[https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1435 NCCN Guidelines - Genetic/Familial High-Risk Assessment: Breast and Ovarian]
  
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'''5-year course of therapy'''
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==SITC==
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*'''2021:''' Emens et al. [http://dx.doi.org/10.1136/jitc-2021-002597 Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of breast cancer] [https://www.ncbi.nlm.nih.gov/pubmed/33822673 PubMed]
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== St Gallen Breast Guidelines ==
 +
*'''2021:''' Burstein et al. [https://doi.org/10.1016/j.annonc.2021.06.023 Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021] [https://www.ncbi.nlm.nih.gov/pubmed/34242744 PubMed]
  
−
===References===
+
*'''2019:''' Burstein et al. [https://doi.org/10.1093/annonc/mdz235 Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019] [https://www.ncbi.nlm.nih.gov/pubmed/31373601 PubMed]
−
# Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM, van de Velde C; Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004 Mar 11;350(11):1081-92. [http://www.nejm.org/doi/full/10.1056/NEJMoa040331 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/15014181 PubMed]
+
*'''2017:''' Curigliano et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6246241/ St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2017] [https://www.ncbi.nlm.nih.gov/pubmed/28838210 PubMed]
−
# Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, Van de Velde CJ, Delozier T, Alvarez I, Del Mastro L, Ortmann O, Diedrich K, Coates AS, Bajetta E, Holmberg SB, Dodwell D, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Forbes J, Castiglione M, Stuart N, Stewart A, Fallowfield LJ, Bertelli G, Hall E, Bogle RG, Carpentieri M, Colajori E, Subar M, Ireland E, Bliss JM; Intergroup Exemestane Study. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 2007 Feb 17;369(9561):559-70. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2807%2960200-1/fulltext link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/17307102 PubMed]
+
*'''2015:''' Coates et al. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511219/ Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015] [https://www.ncbi.nlm.nih.gov/pubmed/25939896 PubMed]
−
# Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, Eisen A, Fehrenbacher L, Farrar WB, Atkins JN, Pajon ER, Vogel VG, Kroener JF, Hutchins LF, Robidoux A, Hoehn JL, Ingle JN, Geyer CE Jr, Costantino JP, Wolmark N. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin Oncol. 2008 Apr 20;26(12):1965-71. Epub 2008 Mar 10. [http://jco.ascopubs.org/content/26/12/1965.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18332472 PubMed]
 
−
# Goss PE, Ingle JN, Pritchard KI, Ellis MJ, Sledge GW, Budd GT, Rabaglio M, Ansari RH, Johnson DB, Tozer R, D'Souza DP, Chalchal H, Spadafora S, Stearns V, Perez EA, Liedke PE, Lang I, Elliott C, Gelmon KA, Chapman JA, Shepherd LE. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial. J Clin Oncol. 2013 Apr 10;31(11):1398-404. doi: 10.1200/JCO.2012.44.7805. Epub 2013 Jan 28. [http://jco.ascopubs.org/content/31/11/1398.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23358971 PubMed]
 
  
−
==Letrozole (Femara) {{#subobject:55e6f9|Regimen=1}}==
+
=Neoadjuvant therapy, sequential regimens=
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
==AC-D {{#subobject:hzzn67|Regimen=1}}==
 +
AC-D: '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>C</u>'''yclophosphamide followed by '''<u>D</u>'''ocetaxel
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 60/600/75 {{#subobject:80y4x4|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7251809/ Kim et al. 2020 (NEST)]
 +
|2012-2014
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer,_ER-positive#Goserelin_.26_Tamoxifen|Goserelin & Tamoxifen]]
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior clinical response
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10361883/ Hwang et al. 2023 (Neo-shorter)]
 +
|2012-11 to 2015-12
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC-D|FEC-D]]; 3 x 3
 +
| style="background-color:#eeee01" |Non-inferior pCR rate (primary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, AC portion (cycles 1 to 4)====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, D portion (cycles 5 to 8)====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 8 cycles (AC x 4; T x 4)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 60/600/100 {{#subobject:80xo14|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1200/JCO.2003.12.005 Bear et al. 2003 (NSABP B-27)]
 +
|rowspan=2|1995-2000
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]]
 +
| style="background-color:#1a9850" |Superior pCR rate (secondary endpoint)<br><br>Did not meet primary endpoint of clinical response rate
 +
|-
 +
|2. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]], then surgery, then [[#Docetaxel_monotherapy|T]]
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.05.078 von Minckwitz et al. 2005 (GeparDuo)]
 +
|1999-2001
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Dose-dense_Docetaxel_.26_Doxorubicin_.28ddAT.29|ddAT]]
 +
| style="background-color:#1a9850" |Superior pCR rate (primary endpoint)<br>pCR rate: 14.3% vs 7%<br>(OR 2.22, 90% CI 1.52-3.24)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen, Goss et al. 2003; Coates et al. 2007 (BIG 1-98), Rasmussen et al. 2008 (BIG 1-98); Goss et al. 2008; Muss et al. 2008 (NCIC CTG MA.17); Crivellari et al. 2008 (BIG 1-98); Jin et al. 2012 (BIG 1-98) {{#subobject:adcf9a|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy, AC portion (cycles 1 to 4)====
−
<span
+
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
−
style="background:#00CD00;
+
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
−
padding:3px 6px 3px 6px;
+
====Chemotherapy, D portion (cycles 5 to 8)====
−
border-color:black;
+
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1
−
border-width:2px;
+
'''21-day cycle for 8 cycles (AC x 4; T x 4)'''
−
border-style:solid;">Phase III</span>
+
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
  
−
*[[Letrozole (Femara)]] 2.5 mg PO once per day
+
===References===
 +
# '''NSABP B-27:''' Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, Wolmark N; National Surgical Adjuvant Breast and Bowel Project. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003 Nov 15;21(22):4165-74. Epub 2003 Oct 14. [https://doi.org/10.1200/JCO.2003.12.005 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14559892/ PubMed] [https://clinicaltrials.gov/study/NCT00002707 NCT00002707]
 +
## '''Update:''' Bear HD, Anderson S, Smith RE, Geyer CE Jr, Mamounas EP, Fisher B, Brown AM, Robidoux A, Margolese R, Kahlenberg MS, Paik S, Soran A, Wickerham DL, Wolmark N. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006 May 1;24(13):2019-27. Epub 2006 Apr 10. [https://doi.org/10.1200/JCO.2005.04.1665 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16606972/ PubMed]
 +
## '''Pooled update:''' Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008 Feb 10;26(5):778-85. Erratum in: J Clin Oncol. 2008 Jun 1;26(16):2793. [https://doi.org/10.1200/JCO.2007.15.0235 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18258986/ PubMed]
 +
# '''GeparDuo:''' von Minckwitz G, Raab G, Caputo A, Schütte M, Hilfrich J, Blohmer JU, Gerber B, Costa SD, Merkle E, Eidtmann H, Lampe D, Jackisch C, du Bois A, Kaufmann M; [[Study_Groups#GBG|GBG]]. Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol. 2005 Apr 20;23(12):2676-85. [https://doi.org/10.1200/JCO.2005.05.078 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15837982/ PubMed] [https://clinicaltrials.gov/study/NCT00793377 NCT00793377]
 +
# '''NEST:''' Kim HJ, Noh WC, Lee ES, Jung YS, Kim LS, Han W, Nam SJ, Gong GY, Kim HJ, Ahn SH. Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in pre-menopausal patients with oestrogen receptor-positive and HER2-negative, lymph node-positive breast cancer. Breast Cancer Res. 2020 May 27;22(1):54. [https://doi.org/10.1186/s13058-020-01288-5 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7251809/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/32460816/ PubMed] [https://clinicaltrials.gov/study/NCT01622361 NCT01622361]
 +
#'''Neo-shorter:''' Hwang I, Kim JE, Jeong JH, Ahn JH, Jung KH, Son BH, Kim HH, Shin J, Lee HJ, Gong G, Kim SB. Randomized phase III trial of a neoadjuvant regimen of four cycles of adriamycin plus cyclophosphamide followed by four cycles of docetaxel (AC4-D4) versus a shorter treatment of three cycles of FEC followed by three cycles of docetaxel (FEC3-D3) in node-positive breast cancer (Neo-shorter; NCT02001506). Breast Cancer Res Treat. 2023 Sep;201(2):193-204. Epub 2023 Jun 26. [https://doi.org/10.1007/s10549-023-06971-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10361883/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37365483/ PubMed] [https://clinicaltrials.gov/study/NCT02001506 NCT02001506]
  
−
'''5-year course of therapy'''
+
==AC-T {{#subobject:633n67|Regimen=1}}==
 +
AC-T: '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>C</u>'''yclophosphamide followed by '''<u>T</u>'''axol (Paclitaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:80c6e6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068051/ Ellis et al. 2011 (SWOG 0012)]
 +
|2001-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#AC-T|AC-T]]; daily cyclophosphamide
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, AC portion (cycles 1 to 5)====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, T portion (cycles 6 to 17)====
 +
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 5 cycles, then 7-day cycle for 12 cycles (AC x 5; T x 12)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# '''SWOG 0012:''' Ellis GK, Barlow WE, Gralow JR, Hortobagyi GN, Russell CA, Royce ME, Perez EA, Lew D, Livingston RB. Phase III comparison of standard doxorubicin and cyclophosphamide versus weekly doxorubicin and daily oral cyclophosphamide plus granulocyte colony-stimulating factor as neoadjuvant therapy for inflammatory and locally advanced breast cancer: SWOG 0012. J Clin Oncol. 2011 Mar 10;29(8):1014-21. Epub 2011 Jan 10. [https://doi.org/10.1200/JCO.2009.27.6543 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068051/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/21220618/ PubMed] [https://clinicaltrials.gov/study/NCT00016406 NCT00016406]
  
 +
==D-AC {{#subobject:1216fd|Regimen=1}}==
 +
D-AC: '''<u>D</u>'''ocetaxel followed by '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:7377be|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401076/ Bear et al. 2012 (NSABP B-40)]
 +
|rowspan=2|2007-2010
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#D-AC.2BBev|D-AC+Bev]]<br>2. [[#TG-AC.2BBev_999|TG-AC+Bev]]<br>3. [[#TX-AC.2BBev_999|TX-AC+Bev]]
 +
| style="background-color:#fc8d59" |Seems to have inferior pCR rate
 +
|-
 +
|4. [[#TG-AC_.28Docetaxel.29_999|TG-AC]]<br>5. [[#TX-AC_.28Docetaxel.29_999|TX-AC]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, D portion (cycles 1 to 4)====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, AC portion (cycles 5 to 8)====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 8 cycles (D x 4; AC x 4)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|surgery]]
 +
</div></div>
 +
===References===
 +
# '''NSABP B-40:''' Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. [https://doi.org/10.1056/NEJMoa1111097 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401076/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22276821/ PubMed] [https://clinicaltrials.gov/study/NCT00408408 NCT00408408]
 +
## '''Update:''' Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Paik S, Swain SM, Mamounas EP, Wolmark N. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1037-1048. Epub 2015 Aug 10. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. [https://doi.org/10.1016/S1470-2045(15)00041-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624323/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26272770/ PubMed]
 +
==D-AC+Bev {{#subobject:23b667|Regimen=1}}==
 +
D-AC+Bev: '''<u>D</u>'''ocetaxel followed by '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>C</u>'''yclophosphamide, with '''<u>Bev</u>'''acizumab
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:d65a23|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401076/ Bear et al. 2012 (NSABP B-40)]
 +
|rowspan=2|2007-2010
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[#D-AC|D-AC]]<br>2. [[#TG-AC_.28Docetaxel.29_999|TG-AC]]<br>3. [[#TX-AC_.28Docetaxel.29_999|TX-AC]]
 +
|style="background-color:#91cf60"|Seems to have superior pCR rate (primary endpoint)
 +
|-
 +
|4. [[#TG-AC.2BBev_999|TG-AC+Bev]]<br>5. [[#TX-AC.2BBev_999|TX-AC+Bev]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, D portion (cycles 1 to 4)====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, AC portion (cycles 5 to 8)====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Targeted therapy, both portions====
 +
*[[Bevacizumab (Avastin)]] as follows:
 +
**Cycles 1 to 6: 15 mg/kg IV once on day 1
 +
'''21-day cycle for 8 cycles (D x 4; AC x 4)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|surgery]]
 +
</div></div>
 +
===References===
 +
# '''NSABP B-40:''' Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. [https://doi.org/10.1056/NEJMoa1111097 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401076/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22276821/ PubMed] [https://clinicaltrials.gov/study/NCT00408408 NCT00408408]
 +
## '''Update:''' Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Paik S, Swain SM, Mamounas EP, Wolmark N. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1037-1048. Epub 2015 Aug 10. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. [https://doi.org/10.1016/S1470-2045(15)00041-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624323/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26272770/ PubMed]
 +
==D-FEC {{#subobject:7ygn67|Regimen=1}}==
 +
D-FEC: '''<u>D</u>'''ocetaxel followed by '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:5b038d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(15)70137-3 Earl et al. 2015 (ARTemis)]
 +
|2009-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#D-FEC.2BBev|D-FEC+Bev]]
 +
| style="background-color:#fc8d59" |Seems to have inferior pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, D portion (cycles 1 to 3)====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, FEC portion (cycles 4 to 6)====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles (D x 3; FEC x 3)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# '''ARTemis:''' Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Abraham J, Thomas J, Provenzano E, Hughes-Davies L, Gounaris I, McAdam K, Chan S, Ahmad R, Hickish T, Houston S, Rea D, Bartlett J, Caldas C, Cameron DA, Hayward L; ARTemis Investigators. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):656-66. Epub 2015 May 11. [https://doi.org/10.1016/S1470-2045(15)70137-3 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25975632/ PubMed] [https://clinicaltrials.gov/study/NCT01093235 NCT01093235]
 +
##'''Update:''' Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Gounaris I, Abraham JE, Hughes-Davies L, McAdam K, Chan S, Ahmad R, Hickish T, Rea D, Caldas C, Bartlett JMS, Cameron DA, Provenzano E, Thomas J, Hayward RL; ARTemis Investigators Group. Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin and cyclophosphamide, for women with HER2 negative early breast cancer: ARTemis Trial. Ann Oncol. 2017 Aug 1;28(8):1817-1824. [https://doi.org/10.1093/annonc/mdx173 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5834079/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28459938/ PubMed]
 +
==D-FEC+Bev {{#subobject:7ygn67|Regimen=1}}==
 +
D-FEC+Bev: '''<u>D</u>'''ocetaxel followed by '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide, with '''<u>Bev</u>'''acizumab
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:a2a6a4|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(15)70137-3 Earl et al. 2015 (ARTemis)]
 +
|2009-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#D-FEC|D-FEC]]
 +
| style="background-color:#91cf60" |Seems to have superior pCR rate (primary endpoint)<br>pCR rate: 22% vs 17%
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, D portion (cycles 1 to 3)====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, FEC portion (cycles 4 to 6)====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
====Targeted therapy, both portions====
 +
*[[Bevacizumab (Avastin)]] as follows:
 +
**Cycles 1 to 4: 15 mg/kg IV once on day 1
 +
'''21-day cycle for 6 cycles (D x 3; FEC x 3)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# '''ARTemis:''' Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Abraham J, Thomas J, Provenzano E, Hughes-Davies L, Gounaris I, McAdam K, Chan S, Ahmad R, Hickish T, Houston S, Rea D, Bartlett J, Caldas C, Cameron DA, Hayward L; ARTemis Investigators. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):656-66. Epub 2015 May 11. [https://doi.org/10.1016/S1470-2045(15)70137-3 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25975632/ PubMed] [https://clinicaltrials.gov/study/NCT01093235 NCT01093235]
 +
##'''Update:''' Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Gounaris I, Abraham JE, Hughes-Davies L, McAdam K, Chan S, Ahmad R, Hickish T, Rea D, Caldas C, Bartlett JMS, Cameron DA, Provenzano E, Thomas J, Hayward RL; ARTemis Investigators Group. Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin and cyclophosphamide, for women with HER2 negative early breast cancer: ARTemis Trial. Ann Oncol. 2017 Aug 1;28(8):1817-1824. [https://doi.org/10.1093/annonc/mdx173 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5834079/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28459938/ PubMed]
 +
==EC-D {{#subobject:8umauq|Regimen=1}}==
 +
EC-D: '''<u>E</u>'''pirubicin and '''<u>C</u>'''yclophosphamide followed by '''<u>D</u>'''ocetaxel
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:dat17g|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2009.23.8303 von Minckwitz et al. 2010 (GeparQuattro)]
 +
|2005-NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#EC-TX_999|EC-TX]]<br>2. [[#EC-T-X_999|EC-T-X]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of pCR rate
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa1111065 von Minckwitz et al. 2012 (GeparQuinto)]
 +
|2007-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#EC-D_.26_Bevacizumab_888|EC-D+Bev]]
 +
| style="background-color:#fc8d59" |Seems to have inferior pCR rate (primary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, EC portion (cycles 1 to 4)====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, D portion (cycles 5 to 8)====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 8 cycles (EC x 4; D x 4)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 
===References===
 
===References===
−
# Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003 Nov 6;349(19):1793-802. Epub 2003 Oct 9. [http://www.nejm.org/doi/full/10.1056/NEJMoa032312 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/14551341 PubMed]
+
# '''GeparQuattro:''' von Minckwitz G, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, Bauerfeind I, Hilfrich J, Eidtmann H, Gerber B, Hanusch C, Kühn T, du Bois A, Blohmer JU, Thomssen C, Dan Costa S, Jackisch C, Kaufmann M, Mehta K, Untch M. Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. J Clin Oncol. 2010 Apr 20;28(12):2015-23. Epub 2010 Mar 22. [https://doi.org/10.1200/JCO.2009.23.8303 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/20308671/ PubMed] [https://clinicaltrials.gov/study/NCT00288002 NCT00288002]
−
# Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol. 2007 Feb 10;25(5):486-92. Epub 2007 Jan 2. [http://jco.ascopubs.org/content/25/5/486.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/17200148 PubMed]
+
## '''Update:''' von Minckwitz G, Rezai M, Fasching PA, Huober J, Tesch H, Bauerfeind I, Hilfrich J, Eidtmann H, Gerber B, Hanusch C, Blohmer JU, Dan Costa S, Jackisch C, Paepke S, Schneeweiss A, Kümmel S, Denkert C, Mehta K, Loibl S, Untch M. Survival after adding capecitabine and trastuzumab to neoadjuvant anthracycline-taxane-based chemotherapy for primary breast cancer (GBG 40--GeparQuattro). Ann Oncol. 2014 Jan;25(1):81-9. Epub 2013 Nov 21. [https://doi.org/10.1093/annonc/mdt410 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24273046/ PubMed]
−
# Rasmussen BB, Regan MM, Lykkesfeldt AE, Dell'Orto P, Del Curto B, Henriksen KL, Mastropasqua MG, Price KN, Méry E, Lacroix-Triki M, Braye S, Altermatt HJ, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Gusterson BA, Thürlimann B, Coates AS, Viale G; BIG 1-98 Collaborative and International Breast Cancer Study Groups. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol. 2008 Jan;9(1):23-8. Epub 2007 Dec 20. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2807%2970386-8/fulltext link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18083065 PubMed]
+
# '''GeparQuinto:''' von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Kreienberg R, Solbach C, Gerber B, Jackisch C, Kunz G, Blohmer JU, Huober J, Hauschild M, Fehm T, Müller BM, Denkert C, Loibl S, Nekljudova V, Untch M; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie–Breast Study Groups. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012 Jan 26;366(4):299-309. [https://doi.org/10.1056/NEJMoa1111065 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22276820/ PubMed] [https://clinicaltrials.gov/study/NCT00567554 NCT00567554]
−
# Goss PE, Ingle JN, Pater JL, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Tu D. Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen. J Clin Oncol. 2008 Apr 20;26(12):1948-55. Epub 2008 Mar 10. [http://jco.ascopubs.org/content/26/12/1948.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18332475 PubMed]
 
−
# Muss HB, Tu D, Ingle JN, Martino S, Robert NJ, Pater JL, Whelan TJ, Palmer MJ, Piccart MJ, Shepherd LE, Pritchard KI, He Z, Goss PE. Efficacy, toxicity, and quality of life in older women with early-stage breast cancer treated with letrozole or placebo after 5 years of tamoxifen: NCIC CTG intergroup trial MA.17. J Clin Oncol. 2008 Apr 20;26(12):1956-64. Epub 2008 Mar 10. [http://jco.ascopubs.org/content/26/12/1956.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18332474 PubMed]
 
−
# Crivellari D, Sun Z, Coates AS, Price KN, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens RJ, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Gladieff L, Rabaglio M, Smith IE, Chirgwin JH, Goldhirsch A. Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial. J Clin Oncol. 2008 Apr 20;26(12):1972-9. Epub 2008 Mar 10. [http://jco.ascopubs.org/content/26/12/1972.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18332471 PubMed]
 
−
# Jin H, Tu D, Zhao N, Shepherd LE, Goss PE. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. J Clin Oncol. 2012 Mar 1;30(7):718-21. doi: 10.1200/JCO.2010.34.4010. Epub 2011 Oct 31. [http://jco.ascopubs.org/content/30/7/718.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/22042967 PubMed]
 
  
−
==Tamoxifen (Nolvadex) {{#subobject:2e0ab1|Regimen=1}}==
+
==EC-T {{#subobject:8um5th|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
EC-T: '''<u>E</u>'''pirubicin and '''<u>C</u>'''yclophosphamide followed by '''<u>T</u>'''axol (Paclitaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:y9ca7g|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdq713 Untch et al. 2011 (PREPARE)]
 +
|2002-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#ddE-ddT-CMF_999|ddE-ddT-CMF]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:dc8bc3|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy, EC portion (cycles 1 to 4)====
−
<span
+
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
−
style="background:#00CD00;
+
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
−
padding:3px 6px 3px 6px;
+
====Chemotherapy, T portion (cycles 5 to 8)====
−
border-color:black;
+
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
−
border-width:2px;
+
'''21-day cycle for 8 cycles (EC x 4; T x 4)'''
−
border-style:solid;">Phase III</span>
+
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# '''PREPARE:''' Untch M, von Minckwitz G, Konecny GE, Conrad U, Fett W, Kurzeder C, Lück HJ, Stickeler E, Urbaczyk H, Liedtke B, Beckmann MW, Salat C, Harbeck N, Müller V, Schmidt M, Hasmüller S, Lenhard M, Nekljudova V, Lebeau A, Loibl S, Fasching PA; Arbeitsgemeinschaft Gynäkologische Onkologie PREPARE investigators. PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel, and CMF versus a standard-dosed epirubicin-cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer--outcome on prognosis. Ann Oncol. 2011 Sep;22(9):1999-2006. Epub 2011 Mar 7. [https://doi.org/10.1093/annonc/mdq713 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21382868/ PubMed] [https://clinicaltrials.gov/study/NCT00544232 NCT00544232]
 +
==EC-ddT {{#subobject:3gjq8f|Regimen=1}}==
 +
EC-ddT: '''<u>E</u>'''pirubicin & '''<u>C</u>'''yclophosphamide, followed by '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>T</u>'''axol (Paclitaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:da33qc|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1016/S1470-2045(13)70554-0 Earl et al. 2013 (Neo-tAnGo)]
 +
|rowspan=2|2005-2007
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#ddT-EC|ddT-EC]]
 +
|style="background-color:#fc8d59"|Seems to have inferior pCR rate
 +
|-
 +
|2. [[#EC-ddTG_999|EC-ddTG]]<br>3. [[#ddTG-EC_999|ddTG-EC]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, EC portion (cycles 1 to 4)====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, ddT portion (cycles 5 to 8)====
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
 +
====Supportive therapy, T portion====
 +
*Primary G-CSF propyhylaxis not provided
 +
'''21-day cycle for 4 cycles, then 14-day cycle for 4 cycles (EC x 4; ddT x 4)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# '''Neo-tAnGo:''' Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, Iddawela M, Abraham J, Hughes-Davies L, Gounaris I, McAdam K, Houston S, Hickish T, Skene A, Chan S, Dean S, Ritchie D, Laing R, Harries M, Gallagher C, Wishart G, Dunn J, Provenzano E, Caldas C; Neo-tAnGo Investigators. Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2x2 factorial randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):201-12. Epub 2013 Dec 19. [https://doi.org/10.1016/S1470-2045(13)70554-0 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24360787/ PubMed] [https://clinicaltrials.gov/study/NCT00070278 NCT00070278]
 +
==FEC-D {{#subobject:fdunvr|Regimen=1}}==
 +
FEC-D: '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide followed by '''<u>D</u>'''ocetaxel
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:947vv2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10361883/ Hwang et al. 2023 (Neo-shorter)]
 +
|2012-11 to 2015-12
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[#AC-D|AC-D]]; 4 x 4
 +
| style="background-color:#eeee01" |Non-inferior pCR rate (primary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, FEC portion (cycles 1 to 3)====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, D portion (cycles 4 to 6)====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
'''21-day cycle for 6 cycles (FEC x 3; D x 3)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
#'''Neo-shorter:''' Hwang I, Kim JE, Jeong JH, Ahn JH, Jung KH, Son BH, Kim HH, Shin J, Lee HJ, Gong G, Kim SB. Randomized phase III trial of a neoadjuvant regimen of four cycles of adriamycin plus cyclophosphamide followed by four cycles of docetaxel (AC4-D4) versus a shorter treatment of three cycles of FEC followed by three cycles of docetaxel (FEC3-D3) in node-positive breast cancer (Neo-shorter; NCT02001506). Breast Cancer Res Treat. 2023 Sep;201(2):193-204. Epub 2023 Jun 26. [https://doi.org/10.1007/s10549-023-06971-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc10361883/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37365483/ PubMed] [https://clinicaltrials.gov/study/NCT02001506 NCT02001506]
 +
==nP-EC {{#subobject:8f6227|Regimen=1}}==
 +
nP-EC: '''<u>n</u>'''ab-'''<u>P</u>'''aclitaxel followed by '''<u>E</u>'''pirubicin & '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:fe2978|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/s1470-2045(15)00542-2 Untch et al. 2016 (GeparSepto)]
 +
|2012-07-30 to 2013-12-23
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#T-EC|T-EC]]
 +
| style="background-color:#1a9850" |Superior pCR rate (primary endpoint)<br>pCR rate: 38% vs 29%<br>(OR 1.53, 95% CI 1.20-1.95)
 +
|-
 +
|}
 +
''Note: this is the dose after study amendment due to increased treatment discontinuation and sensory neuropathy.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, nP portion (cycles 1 to 12)====
 +
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 125 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, EC portion (cycles 13 to 16)====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (nP x 12; EC x 4)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# '''GeparSepto:''' Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Wiebringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Darb-Esfahani S, Schmitt WD, Dan Costa S, Gerber B, Engels K, Nekljudova V, Loibl S, von Minckwitz G; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie—Breast (AGO-B) Investigators. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):345-56. Epub 2016 Feb 8. [https://doi.org/10.1016/s1470-2045(15)00542-2 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26869049/ PubMed] [https://clinicaltrials.gov/study/NCT01583426 NCT01583426]
 +
## '''Update:''' Furlanetto J, Jackisch C, Untch M, Schneeweiss A, Schmatloch S, Aktas B, Denkert C, Wiebringhaus H, Kümmel S, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Costa SD, Gerber B, Nekljudova V, Loibl S, von Minckwitz G. Efficacy and safety of nab-paclitaxel 125 mg/m(2) and nab-paclitaxel 150 mg/m(2) compared to paclitaxel in early high-risk breast cancer: results from the neoadjuvant randomized GeparSepto study (GBG 69). Breast Cancer Res Treat. 2017 Jun;163(3):495-506. Epub 2017 Mar 17. [https://doi.org/10.1007/s10549-017-4200-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28315068/ PubMed]
 +
# '''ETNA:''' Gianni L, Mansutti M, Anton A, Calvo L, Bisagni G, Bermejo B, Semiglazov V, Thill M, Chacon JI, Chan A, Morales S, Alvarez I, Plazaola A, Zambetti M, Redfern AD, Dittrich C, Dent RA, Magazzù D, De Fato R, Valagussa P, Tusquets I. Comparing neoadjuvant nab-paclitaxel vs paclitaxel both followed by anthracycline regimens in women with ERBB2/HER2-negative breast cancer-the Evaluating Treatment with Neoadjuvant Abraxane (ETNA) trial: a randomized phase 3 clinical trial. JAMA Oncol. 2018 Mar 1;4(3):302-308. Epub 2018 Jan 11. [https://doi.org/10.1001/jamaoncol.2017.4612 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5885830/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29327055/ PubMed] [https://clinicaltrials.gov/study/NCT01822314 NCT01822314]
  
−
*[[Tamoxifen (Nolvadex)]] 20 mg PO once per day
+
==nP-ddEC {{#subobject:8fddd7|Regimen=1}}==
 +
nP-ddEC: '''<u>n</u>'''ab-'''<u>P</u>'''aclitaxel followed by '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>E</u>'''pirubicin & '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:fc3c78|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/j.annonc.2023.04.002 Gluz et al. 2023 (WSG-ADAPT-HR+/HER2-)]
 +
|2013-05 to 2019-09
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#ddT-ddEC|ddT-ddEC]]
 +
| style="background-color:#1a9850" |Superior pCR rate (primary endpoint)<br>pCR rate: 20.8% vs 12.9%
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Biomarker eligibility criteria====
 +
*HR+ and HER2-
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, nP portion (cycles 1 to 8)====
 +
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 125 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, ddEC portion (cycles 9 to 12)====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Supportive therapy, ddEC portion (cycles 9 to 12)====
 +
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2, '''given 24 hours after chemotherapy'''
 +
'''7-day cycle for 8 cycles, then 14-day cycle for 4 cycles (nP x 8; ddEC x 4)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
#'''WSG-ADAPT-HR+/HER2-:''' Gluz O, Kuemmel S, Nitz U, Braun M, Lüdtke-Heckenkamp K, von Schumann R, Darsow M, Forstbauer H, Potenberg J, Uleer C, Grischke EM, Aktas B, Schumacher C, Zu Eulenburg C, Kates R, Jóźwiak K, Graeser M, Wuerstlein R, Baehner R, Christgen M, Kreipe HH, Harbeck N. Nab-paclitaxel weekly versus dose-dense solvent-based paclitaxel followed by dose-dense epirubicin plus cyclophosphamide in high-risk HR+/HER2- early breast cancer: results from the neoadjuvant part of the WSG-ADAPT-HR+/HER2- trial. Ann Oncol. 2023 Jun;34(6):531-542. Epub 2023 Apr 14. [https://doi.org/10.1016/j.annonc.2023.04.002 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37062416/ PubMed] [https://clinicaltrials.gov/study/NCT01779206 NCT01779206]
  
−
'''5 to 10 years of therapy'''; Davies et al. 2012 (ATLAS trial) reports improved breast cancer mortality with 10 years of therapy as compared to 5 years of tamoxifen use
+
==T-AC {{#subobject:f5jq1b|Regimen=1}}==
 +
T-AC: '''<u>T</u>'''axol (Paclitaxel), followed by '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:759ubx|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5885830/ Gianni et al. 2018 (ETNA)]
 +
|2013-2015
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#nP-AC_999|nab-Paclitaxel-AC]]<br>1b. [[#nP-EC|nP-EC]]<br>1c. [[#nP-FEC_999|nP-FEC]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, T portion (cycles 1 to 4)====
 +
*[[Paclitaxel (Taxol)]] 90 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 +
====Chemotherapy, AC portion (cycles 5 to 8)====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''28-day cycle for 4 cycles, then 21-day cycle for 4 cycles (T x 4; AC x 4)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# '''ETNA:''' Gianni L, Mansutti M, Anton A, Calvo L, Bisagni G, Bermejo B, Semiglazov V, Thill M, Chacon JI, Chan A, Morales S, Alvarez I, Plazaola A, Zambetti M, Redfern AD, Dittrich C, Dent RA, Magazzù D, De Fato R, Valagussa P, Tusquets I. Comparing neoadjuvant nab-paclitaxel vs paclitaxel both followed by anthracycline regimens in women with ERBB2/HER2-negative breast cancer-the Evaluating Treatment with Neoadjuvant Abraxane (ETNA) trial: a randomized phase 3 clinical trial. JAMA Oncol. 2018 Mar 1;4(3):302-308. Epub 2018 Jan 11. [https://doi.org/10.1001/jamaoncol.2017.4612 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5885830/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29327055/ PubMed] [https://clinicaltrials.gov/study/NCT01822314 NCT01822314]
 +
==T-EC {{#subobject:f57gac|Regimen=1}}==
 +
T-EC: '''<u>T</u>'''axol (Paclitaxel), followed by '''<u>E</u>'''pirubicin & '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 80 mg/m<sup>2</sup> paclitaxel {{#subobject:c347uy|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/s1470-2045(15)00542-2 Untch et al. 2016 (GeparSepto)]
 +
|2012-07-30 to 2013-12-23
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#nP-EC|nP-EC]]
 +
| style="background-color:#d73027" |Inferior pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, T portion (cycles 1 to 12)====
 +
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, EC portion (cycles 13 to 16)====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (T x 12; EC x 4)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 90 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:759920|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5885830/ Gianni et al. 2018 (ETNA)]
 +
|2013-2015
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#nP-AC_999|nP-AC]]<br>1b. [[#nP-EC|nP-EC]]<br>1c. [[#nP-FEC_999|nP-FEC]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, T portion (cycles 1 to 4)====
 +
*[[Paclitaxel (Taxol)]] 90 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 +
====Chemotherapy, EC portion (cycles 5 to 8)====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''28-day cycle for 4 cycles, then 21-day cycle for 4 cycles (T x 4; EC x 4)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# '''GeparSepto:''' Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Wiebringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Darb-Esfahani S, Schmitt WD, Dan Costa S, Gerber B, Engels K, Nekljudova V, Loibl S, von Minckwitz G; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie—Breast (AGO-B) Investigators. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):345-56. Epub 2016 Feb 8. [https://doi.org/10.1016/s1470-2045(15)00542-2 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26869049/ PubMed] [https://clinicaltrials.gov/study/NCT01583426 NCT01583426]
 +
## '''Update:''' Furlanetto J, Jackisch C, Untch M, Schneeweiss A, Schmatloch S, Aktas B, Denkert C, Wiebringhaus H, Kümmel S, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Costa SD, Gerber B, Nekljudova V, Loibl S, von Minckwitz G. Efficacy and safety of nab-paclitaxel 125 mg/m(2) and nab-paclitaxel 150 mg/m(2) compared to paclitaxel in early high-risk breast cancer: results from the neoadjuvant randomized GeparSepto study (GBG 69). Breast Cancer Res Treat. 2017 Jun;163(3):495-506. Epub 2017 Mar 17. [https://doi.org/10.1007/s10549-017-4200-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/28315068/ PubMed]
 +
# '''ETNA:''' Gianni L, Mansutti M, Anton A, Calvo L, Bisagni G, Bermejo B, Semiglazov V, Thill M, Chacon JI, Chan A, Morales S, Alvarez I, Plazaola A, Zambetti M, Redfern AD, Dittrich C, Dent RA, Magazzù D, De Fato R, Valagussa P, Tusquets I. Comparing neoadjuvant nab-paclitaxel vs paclitaxel both followed by anthracycline regimens in women with ERBB2/HER2-negative breast cancer-the Evaluating Treatment with Neoadjuvant Abraxane (ETNA) trial: a randomized phase 3 clinical trial. JAMA Oncol. 2018 Mar 1;4(3):302-308. Epub 2018 Jan 11. [https://doi.org/10.1001/jamaoncol.2017.4612 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5885830/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29327055/ PubMed] [https://clinicaltrials.gov/study/NCT01822314 NCT01822314]
 +
==ddT-EC {{#subobject:3gug1f|Regimen=1}}==
 +
ddT-EC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>T</u>'''axol (Paclitaxel), followed by '''<u>E</u>'''pirubicin & '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:cq33ad|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1016/S1470-2045(13)70554-0 Earl et al. 2013 (Neo-tAnGo)]
 +
|rowspan=2|2005-2007
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|1. [[#EC-ddT|EC-ddT]]
 +
| style="background-color:#91cf60" |Seems to have superior pCR rate (primary endpoint)
 +
|-
 +
|2. [[#EC-ddTG_999|EC-ddTG]]<br>3. [[#ddTG-EC_999|ddTG-EC]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, ddT portion (cycles 1 to 4)====
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
 +
====Supportive therapy, T portion====
 +
*Primary G-CSF propyhylaxis not provided
 +
====Chemotherapy, EC portion (cycles 5 to 8)====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''14-day cycle for 4 cycles, then 21-day cycle for 4 cycles (ddT x 4; EC x 4)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# '''Neo-tAnGo:''' Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, Iddawela M, Abraham J, Hughes-Davies L, Gounaris I, McAdam K, Houston S, Hickish T, Skene A, Chan S, Dean S, Ritchie D, Laing R, Harries M, Gallagher C, Wishart G, Dunn J, Provenzano E, Caldas C; Neo-tAnGo Investigators. Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2x2 factorial randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):201-12. Epub 2013 Dec 19. [https://doi.org/10.1016/S1470-2045(13)70554-0 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/24360787/ PubMed] [https://clinicaltrials.gov/study/NCT00070278 NCT00070278]
  
 +
==ddT-ddEC {{#subobject:8fdta7|Regimen=1}}==
 +
ddT-ddEC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>T</u>'''axol (Paclitaxel), followed by '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>E</u>'''pirubicin & '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:fxoc78|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/j.annonc.2023.04.002 Gluz et al. 2023 (WSG-ADAPT-HR+/HER2-)]
 +
|2013-05 to 2019-09
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#nP-ddEC|nP-ddEC]]
 +
| style="background-color:#d73027" |Inferior pCR rate (primary endpoint)
 +
|-
 +
|}
 +
''Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Biomarker eligibility criteria====
 +
*HR+ and HER2-
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, ddT portion (cycles 1 to 4)====
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, ddEC portion (cycles 5 to 8)====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Supportive therapy, ddEC portion (cycles 5 to 8)====
 +
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2, '''given 24 hours after chemotherapy'''
 +
'''14-day cycle for 8 cycles (ddT x 4; ddEC x 4)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 
===References===
 
===References===
−
# Jaiyesimi IA, Buzdar AU, Decker DA, Hortobagyi GN. Use of tamoxifen for breast cancer: twenty-eight years later. J Clin Oncol. 1995 Feb;13(2):513-29. [http://jco.ascopubs.org/content/13/2/513.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/7844613 PubMed]
+
#'''WSG-ADAPT-HR+/HER2-:''' Gluz O, Kuemmel S, Nitz U, Braun M, Lüdtke-Heckenkamp K, von Schumann R, Darsow M, Forstbauer H, Potenberg J, Uleer C, Grischke EM, Aktas B, Schumacher C, Zu Eulenburg C, Kates R, Jóźwiak K, Graeser M, Wuerstlein R, Baehner R, Christgen M, Kreipe HH, Harbeck N. Nab-paclitaxel weekly versus dose-dense solvent-based paclitaxel followed by dose-dense epirubicin plus cyclophosphamide in high-risk HR+/HER2- early breast cancer: results from the neoadjuvant part of the WSG-ADAPT-HR+/HER2- trial. Ann Oncol. 2023 Jun;34(6):531-542. Epub 2023 Apr 14. [https://doi.org/10.1016/j.annonc.2023.04.002 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/37062416/ PubMed] [https://clinicaltrials.gov/study/NCT01779206 NCT01779206]
−
# Assikis V, Buzdar A, Yang Y, Smith T, Theriault R, Booser D, Valero V, Walters R, Singletary E, Ames F, Hortobagyi G. A phase III trial of sequential adjuvant chemotherapy for operable breast carcinoma: final analysis with 10-year follow-up. Cancer. 2003 Jun 1;97(11):2716-23. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.11396/full link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12767083 PubMed]
 
−
# Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005 May 14-20;365(9472):1687-717. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2805%2966544-0/fulltext link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/15894097 PubMed]
 
−
# Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, Abraham M, Alencar VH, Badran A, Bonfill X, Bradbury J, Clarke M, Collins R, Davis SR, Delmestri A, Forbes JF, Haddad P, Hou MF, Inbar M, Khaled H, Kielanowska J, Kwan WH, Mathew BS, Müller B, Nicolucci A, Peralta O, Pernas F, Petruzelka L, Pienkowski T, Rajan B, Rubach MT, Tort S, Urrútia G, Valentini M, Wang Y, Peto R; for the Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2012 Dec 4. pii: S0140-6736(12)61963-1. doi: 10.1016/S0140-6736(12)61963-1. [Epub ahead of print] [http://www.sciencedirect.com/science/article/pii/S0140673612619631 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23219286 PubMed]
 
  
−
=Adjuvant chemotherapy, HER-2 negative=
+
==T-FAC {{#subobject:f5ccac|Regimen=1}}==
−
==Dose-dense AC -> T {{#subobject:dd7480|Regimen=1}}==
+
T-FAC: '''<u>T</u>'''axol (Paclitaxel), followed by '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, weekly paclitaxel for N0 disease {{#subobject:c3jgny|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.06.232 Green et al. 2005]
 +
|1998-2001
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#T-FAC|T-FAC]]; q3wk paclitaxel
 +
| style="background-color:#91cf60" |Seems to have superior pCR rate (primary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, T portion (cycles 1 to 12)====
 +
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, FAC portion (cycles 13 to 16)====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 4
 +
*[[Doxorubicin (Adriamycin)]] 16.7 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m<sup>2</sup>)
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (T x 12; FAC x 4)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, weekly paclitaxel for N+ disease {{#subobject:c3j1uy|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.06.232 Green et al. 2005]
 +
|1998-2001
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#T-FAC|T-FAC]]; q3wk paclitaxel
 +
| style="background-color:#91cf60" |Seems to have superior pCR rate (primary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
AC -> T: '''<u>A</u>'''driamycin, '''<u>C</u>'''ytoxan -> '''<u>T</u>'''axol
+
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, T portion (cycles 1 to 4)====
 +
*[[Paclitaxel (Taxol)]] 150 mg/m<sup>2</sup> IV over 3 hours once per day on days 1, 8, 15
 +
====Chemotherapy, FAC portion (cycles 5 to 8)====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 4
 +
*[[Doxorubicin (Adriamycin)]] 16.7 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m<sup>2</sup>)
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''28-day cycle for 4 cycles, then 21-day cycle for 4 cycles (T x 4; FAC x 4)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, q3wk paclitaxel {{#subobject:7g1gny|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.06.232 Green et al. 2005]
 +
|1998-2001
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#T-FAC|T-FAC]]; weekly paclitaxel
 +
| style="background-color:#fc8d59" |Seems to have inferior pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, T portion (cycles 1 to 4)====
 +
*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
 +
====Chemotherapy, FAC portion (cycles 5 to 8)====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 4
 +
*[[Doxorubicin (Adriamycin)]] 16.7 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m<sup>2</sup>)
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 8 cycles (T x 4; FAC x 4)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# Green MC, Buzdar AU, Smith T, Ibrahim NK, Valero V, Rosales MF, Cristofanilli M, Booser DJ, Pusztai L, Rivera E, Theriault RL, Carter C, Frye D, Hunt KK, Symmans WF, Strom EA, Sahin AA, Sikov W, Hortobagyi GN. Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol. 2005 Sep 1;23(25):5983-92. Epub 2005 Aug 8. [https://doi.org/10.1200/JCO.2005.06.232 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16087943/ PubMed]
  
−
===Example orders===
+
==T-FEC {{#subobject:ug89g8|Regimen=1}}==
−
*[[Example orders for Dose-dense AC to T in breast cancer]]
+
T-FEC: '''<u>T</u>'''axol (Paclitaxel), followed by '''<u>E</u>'''pirubicin & '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 80/500/100/500 {{#subobject:7g1gny|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2011.36.2079 Kelly et al. 2012 (MDACC ID01-580)]
 +
|2002-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#TX-FEC_.28Docetaxel.29|TX-FEC]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of RFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, T portion (cycles 1 to 12)====
 +
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, FEC portion (cycles 13 to 16)====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (T x 12; FEC x 4)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 90/600/90/600 {{#subobject:ugzzny|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5885830/ Gianni et al. 2018 (ETNA)]
 +
|2013-2015
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#nP-AC_999|nP-AC]]<br>1b. [[#nP-EC|nP-EC]]<br>1c. [[#nP-FEC_999|nP-FEC]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, T portion (cycles 1 to 4)====
 +
*[[Paclitaxel (Taxol)]] 90 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 +
====Chemotherapy, FEC portion (cycles 5 to 8)====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''28-day cycle for 4 cycles, then 21-day cycle for 4 cycles (T x 4; FEC x 4)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
<!-- Presented at the 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2008. -->
 +
# '''MDACC ID01-580:''' Kelly CM, Green MC, Broglio K, Thomas ES, Brewster AM, Valero V, Ibrahim NK, Gonzalez-Angulo AM, Booser DJ, Walters RS, Hunt KK, Hortobagyi GN, Buzdar AU. Phase III trial evaluating weekly paclitaxel versus docetaxel in combination with capecitabine in operable breast cancer. J Clin Oncol. 2012 Mar 20;30(9):930-5. Epub 2012 Feb 13. [https://doi.org/10.1200/JCO.2011.36.2079 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22331946/ PubMed] [https://clinicaltrials.gov/study/NCT00050167 NCT00050167]
 +
# '''ETNA:''' Gianni L, Mansutti M, Anton A, Calvo L, Bisagni G, Bermejo B, Semiglazov V, Thill M, Chacon JI, Chan A, Morales S, Alvarez I, Plazaola A, Zambetti M, Redfern AD, Dittrich C, Dent RA, Magazzù D, De Fato R, Valagussa P, Tusquets I. Comparing neoadjuvant nab-paclitaxel vs paclitaxel both followed by anthracycline regimens in women with ERBB2/HER2-negative breast cancer-the Evaluating Treatment with Neoadjuvant Abraxane (ETNA) trial: a randomized phase 3 clinical trial. JAMA Oncol. 2018 Mar 1;4(3):302-308. Epub 2018 Jan 11. [https://doi.org/10.1001/jamaoncol.2017.4612 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5885830/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29327055/ PubMed] [https://clinicaltrials.gov/study/NCT01822314 NCT01822314]
  
−
===Regimen, Citron et al. 2003 (CALGB C9741) & Burstein et al. 2005 {{#subobject:2ad5c9|Variant=1}}===
+
=Neoadjuvant chemotherapy=
−
Level of Evidence:
+
==Capecitabine & Docetaxel (TX) {{#subobject:9d7c10|Regimen=1}}==
−
<span
+
TX: '''<u>T</u>'''axotere (Docetaxel) & '''<u>X</u>'''eloda (Capecitabine)
−
style="background:#00CD00;
+
<div class="toccolours" style="background-color:#eeeeee">
−
padding:3px 6px 3px 6px;
+
===Regimen {{#subobject:acc1b7|Variant=1}}===
−
border-color:black;
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
border-width:2px;
+
!style="width: 20%"|Study
−
border-style:solid;">Phase III</span>
+
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1007/s10549-007-9672-y Lee et al. 2007]
 +
|2002-2005
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]]
 +
| style="background-color:#91cf60" |Seems to have superior pCR rate (primary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
'''21-day cycle for 4 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# Lee KS, Ro J, Nam BH, Lee ES, Kwon Y, Kwon HS, Chung KW, Kang HS, Kim EA, Kim SW, Shin KH, Kim SK. A randomized phase-III trial of docetaxel/capecitabine versus doxorubicin/cyclophosphamide as primary chemotherapy for patients with stage II/III breast cancer. Breast Cancer Res Treat. 2008 Jun;109(3):481-9. Epub 2007 Jul 26. [https://doi.org/10.1007/s10549-007-9672-y link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17653851/ PubMed]
 +
==Cyclophosphamide & Doxorubicin (AC) {{#subobject:647f67|Regimen=1}}==
 +
AC: '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 4 cycles {{#subobject:b18877|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1997.15.7.2483 Fisher et al. 1997 (NSABP B-18)]
 +
|1988-1993
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|Adjuvant [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]]
 +
| style="background-color:#1a9850" |Superior resectability
 +
|-
 +
|rowspan=2|[https://doi.org/10.1200/JCO.2003.12.005 Bear et al. 2003 (NSABP B-27)]
 +
|rowspan=2|1995-2000
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#AC-D|AC-D]]
 +
| style="background-color:#d73027" |Inferior pCR rate
 +
|-
 +
|2. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]], then surgery, then [[#Docetaxel_monotherapy|T]]
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|[https://doi.org/10.1007/s10549-007-9672-y Lee et al. 2007]
 +
|2002-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Docetaxel_.28TX.29|TX]]
 +
| style="background-color:#fc8d59" |Seems to have inferior pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 4 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*NSABP B-18 & NSABP B-27: [[Surgery#Breast_cancer_surgery|Surgery]]
 +
*Lee et al. 2007: [[Surgery#Breast_cancer_surgery|Surgery]], then adjuvant [[#Capecitabine_.26_Docetaxel_.28TX.29_888|TX]] x 4
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 6 cycles {{#subobject:d63ca0|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdh175 Smith et al. 2004 (TOPIC)]
 +
|1995-1999
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#ECisF_999|ECisF]]
 +
| style="background-color:#ffffbf" |Did not meet co-primary endpoints of RFS/OS
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdi276 Chua et al. 2005 (TOPIC 2)]
 +
|1998-2002
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Epirubicin_.26_Vinorelbine_.28VE.29_999|VE]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.06.156 Evans et al. 2005]
 +
|1999-2001
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Doxorubicin_.28AT.29_999|AD]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# '''NSABP B-18:''' Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB Jr, Fisher ER, Wickerham DL, Wolmark N, DeCillis A, Hoehn JL, Lees AW, Dimitrov NV. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997 Jul;15(7):2483-93. [https://doi.org/10.1200/JCO.1997.15.7.2483 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9215816/ PubMed]
 +
## '''Update:''' Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, Wickerham DL, Begovic M, DeCillis A, Robidoux A, Margolese RG, Cruz AB Jr, Hoehn JL, Lees AW, Dimitrov NV, Bear HD. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998 Aug;16(8):2672-85. [https://doi.org/10.1200/JCO.1998.16.8.2672 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9704717/ PubMed]
 +
## '''Update:''' Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst. 2001;(30):96-102. [https://doi.org/10.1093/oxfordjournals.jncimonographs.a003469 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11773300/ PubMed]
 +
## '''Pooled update:''' Taghian A, Jeong JH, Mamounas E, Anderson S, Bryant J, Deutsch M, Wolmark N. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol. 2004 Nov 1;22(21):4247-54. Epub 2004 Sep 27. [https://doi.org/10.1200/JCO.2004.01.042 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15452182/ PubMed]
 +
## '''Pooled update:''' Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008 Feb 10;26(5):778-85. Erratum in: J Clin Oncol. 2008 Jun 1;26(16):2793. [https://doi.org/10.1200/JCO.2007.15.0235 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18258986/ PubMed]
 +
# '''NSABP B-27:''' Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, Wolmark N; National Surgical Adjuvant Breast and Bowel Project. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003 Nov 15;21(22):4165-74. Epub 2003 Oct 14. [https://doi.org/10.1200/JCO.2003.12.005 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14559892/ PubMed] [https://clinicaltrials.gov/study/NCT00002707 NCT00002707]
 +
## '''Update:''' Bear HD, Anderson S, Smith RE, Geyer CE Jr, Mamounas EP, Fisher B, Brown AM, Robidoux A, Margolese R, Kahlenberg MS, Paik S, Soran A, Wickerham DL, Wolmark N. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006 May 1;24(13):2019-27. Epub 2006 Apr 10. [https://doi.org/10.1200/JCO.2005.04.1665 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16606972/ PubMed]
 +
## '''Pooled update:''' Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008 Feb 10;26(5):778-85. Erratum in: J Clin Oncol. 2008 Jun 1;26(16):2793. [https://doi.org/10.1200/JCO.2007.15.0235 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18258986/ PubMed]
 +
# '''TOPIC:''' Smith IE, A'Hern RP, Coombes GA, Howell A, Ebbs SR, Hickish TF, O'Brien ME, Mansi JL, Wilson CB, Robinson AC, Murray PA, Price CG, Perren TJ, Laing RW, Bliss JM; TOPIC Trial Group. A novel continuous infusional 5-fluorouracil-based chemotherapy regimen compared with conventional chemotherapy in the neo-adjuvant treatment of early breast cancer: 5 year results of the TOPIC trial. Ann Oncol. 2004 May;15(5):751-8. [https://doi.org/10.1093/annonc/mdh175 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15111342/ PubMed]
 +
# Evans TR, Yellowlees A, Foster E, Earl H, Cameron DA, Hutcheon AW, Coleman RE, Perren T, Gallagher CJ, Quigley M, Crown J, Jones AL, Highley M, Leonard RC, Mansi JL; Anglo-Celtic Cooperative Oncology Group. Phase III randomized trial of doxorubicin and docetaxel versus doxorubicin and cyclophosphamide as primary medical therapy in women with breast cancer: an Anglo-Celtic Cooperative Oncology Group study. J Clin Oncol. 2005 May 1;23(13):2988-95. [https://doi.org/10.1200/JCO.2005.06.156 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15860854/ PubMed]
 +
## '''Update:''' Mansi JL, Yellowlees A, Lipscombe J, Earl HM, Cameron DA, Coleman RE, Perren T, Gallagher CJ, Quigley M, Crown J, Jones AL, Highley M, Leonard RC, Evans TR. Five-year outcome for women randomised in a phase III trial comparing doxorubicin and cyclophosphamide with doxorubicin and docetaxel as primary medical therapy in early breast cancer: an Anglo-Celtic Cooperative Oncology Group study. Breast Cancer Res Treat. 2010 Aug;122(3):787-94. Epub 2010 Jun 18. [https://doi.org/10.1007/s10549-010-0989-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20559708/ PubMed]
 +
# '''TOPIC 2:''' Chua S, Smith IE, A'Hern RP, Coombes GA, Hickish TF, Robinson AC, Laing RW, O'Brien ME, Ebbs SR, Hong A, Wardley A, Mughal T, Verrill M, Dubois D, Bliss JM; TOPIC Trial Group. Neoadjuvant vinorelbine/epirubicin (VE) versus standard adriamycin/cyclophosphamide (AC) in operable breast cancer: analysis of response and tolerability in a randomised phase III trial (TOPIC 2). Ann Oncol. 2005 Sep;16(9):1435-41. Epub 2005 Jun 9. [https://doi.org/10.1093/annonc/mdi276 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15946977/ PubMed]
 +
# Lee KS, Ro J, Nam BH, Lee ES, Kwon Y, Kwon HS, Chung KW, Kang HS, Kim EA, Kim SW, Shin KH, Kim SK. A randomized phase-III trial of docetaxel/capecitabine versus doxorubicin/cyclophosphamide as primary chemotherapy for patients with stage II/III breast cancer. Breast Cancer Res Treat. 2008 Jun;109(3):481-9. Epub 2007 Jul 26. [https://doi.org/10.1007/s10549-007-9672-y link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/17653851/ PubMed]
 +
==Dose-dense Cyclophosphamide & Doxorubicin (ddAC) {{#subobject:dcfdd2|Regimen=1}}==
 +
ddAC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>A</u>'''driamycin (Doxorubicin) and '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:daff10|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.02.8621 Burstein et al. 2005]
 +
|2003-2004
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|}
 +
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Supportive therapy====
 +
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2, given 24 hours after chemotherapy
 +
*Burstein et al. 2005, for patients with Hb 10 to 12 g/dL:
 +
**[[Darbepoetin alfa (Aranesp)]] 200 mcg SC once on day 1
 +
***See Burstein et al. 2005 for additional dose adjustments
 +
'''14-day cycle for 4 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Optional neoadjuvant [[#Paclitaxel_monotherapy.2C_dose-dense_.28q2wk.29|dose-dense paclitaxel]], then [[Surgery#Breast_cancer_surgery|surgery]] or [[Surgery#Breast_cancer_surgery|surgery]], then adjuvant [[#Paclitaxel_monotherapy.2C_dose-dense_.28q2wk.29_2|dose-dense paclitaxel]]; this was not a randomization
 +
</div></div>
 +
===References===
 +
# Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. [https://doi.org/10.1200/jco.2005.02.8621 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16293865/ PubMed]
 +
==Dose-dense Docetaxel & Doxorubicin (ddAT) {{#subobject:a5ufer|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:fdgcm2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.05.078 von Minckwitz et al. 2005 (GeparDuo)]
 +
|1999-2001
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#AC-D|AC-D]]
 +
| style="background-color:#d73027" |Inferior pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1, '''given second'''
 +
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1, '''given first'''
 +
====Supportive therapy====
 +
*[[Filgrastim (Neupogen)]] (route/dose not specified) once per day on days 5 to 10
 +
'''14-day cycle for 4 cycles'''
 +
</div></div>
 +
===References===
 +
# '''GeparDuo:''' von Minckwitz G, Raab G, Caputo A, Schütte M, Hilfrich J, Blohmer JU, Gerber B, Costa SD, Merkle E, Eidtmann H, Lampe D, Jackisch C, du Bois A, Kaufmann M; [[Study_Groups#GBG|GBG]]. Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol. 2005 Apr 20;23(12):2676-85. [https://doi.org/10.1200/JCO.2005.05.078 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15837982/ PubMed] [https://clinicaltrials.gov/study/NCT00793377 NCT00793377]
  
−
====Dose-dense AC====
+
==DI EC {{#subobject:31c3a1|Regimen=1}}==
−
*[[Doxorubicin (Adriamycin)]] 60 mg/m2 IV once on day 1
+
DI EC: '''<u>D</u>'''ose-'''<u>I</u>'''ntense '''<u>E</u>'''pirubicin & '''<u>C</u>'''yclophosphamide
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV bolus once on day 1
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:da1317|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdv216 Gonçalves et al. 2015 (UNICANCER PEGASE 07)]
 +
|2001-2005
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 +
|-
 +
|}
 +
''Note: This regimen required hematopoeitic stem cell support; see paper for details.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 150 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 4000 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 4 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]], then adjuvant [[#Docetaxel_.26_Fluorouracil_999|Docetaxel & 5-FU]] versus [[Breast_cancer_-_null_regimens#Observation|no further treatment]]
 +
</div></div>
 +
===References===
 +
# '''UNICANCER PEGASE 07:''' Gonçalves A, Pierga JY, Ferrero JM, Mouret-Reynier MA, Bachelot T, Delva R, Fabbro M, Lerebours F, Lotz JP, Linassier C, Dohollou N, Eymard JC, Leduc B, Lemonnier J, Martin AL, Boher JM, Viens P, Roché H. UNICANCER-PEGASE 07 study: a randomized phase III trial evaluating postoperative docetaxel-5FU regimen after neoadjuvant dose-intense chemotherapy for treatment of inflammatory breast cancer. Ann Oncol. 2015 Aug;26(8):1692-7. Epub 2015 May 5. [https://doi.org/10.1093/annonc/mdv216 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25943350/ PubMed] [https://clinicaltrials.gov/study/NCT02324088 NCT02324088]
  
−
'''14-day cycles x 4 cycles, then proceed to paclitaxel therapy'''
+
==Docetaxel & Epirubicin (DE) {{#subobject:d11f5f|Regimen=1}}==
 +
DE: '''<u>D</u>'''ocetaxel & '''<u>E</u>'''pirubicin
 +
<br>ED: '''<u>E</u>'''pirubicin & '''<u>D</u>'''ocetaxel
 +
<br>ET: '''<u>E</u>'''pirubicin & '''<u>T</u>'''axotere (Docetaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 3 cycles {{#subobject:c1953d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2006.09.1777 Steger et al. 2007 (ABCSG-14)]
 +
|1999-2002
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Epirubicin_.28DE.29|ED]] x 6
 +
| style="background-color:#d73027" |Inferior pCR rate
 +
|-
 +
|[https://doi.org/10.1002/ijc.31217 Chen et al. 2017 (CBCRT01)]
 +
|2011-2015
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Epirubicin_.28DE.29_.26_Endostatin_777|DEE]]
 +
| style="background-color:#d73027" |Inferior ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 3 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 4 cycles {{#subobject:c4484d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/j.ejso.2009.01.002 Han et al. 2009]
 +
|2003-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Epirubicin_.28DE.29|ED]] x 6
 +
| style="background-color:#fc8d59" |Seems to have inferior pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 4 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 6 cycles {{#subobject:c2184d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2006.09.1777 Steger et al. 2007 (ABCSG-14)]
 +
|1999-2002
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Docetaxel_.26_Epirubicin_.28DE.29|ED]] x 3
 +
| style="background-color:#1a9850" |Superior pCR rate (primary endpoint)
 +
|-
 +
|[https://doi.org/10.1016/j.ejso.2009.01.002 Han et al. 2009]
 +
|2003-2005
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Docetaxel_.26_Epirubicin_.28DE.29|ED]] x 4
 +
| style="background-color:#91cf60" |Seems to have superior pCR rate (secondary endpoint)
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdt508 Steger et al. 2013 (ABCSG-24)]
 +
|2004-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#EDC|EDC]]
 +
| style="background-color:#fc8d59" |Seems to have inferior pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# '''ABCSG-14:''' Steger GG, Galid A, Gnant M, Mlineritsch B, Lang A, Tausch C, Rudas M, Greil R, Wenzel C, Singer CF, Haid A, Pöstlberger S, Samonigg H, Luschin-Ebengreuth G, Kwasny W, Klug E, Kubista E, Menzel C, Jakesz R; ABCSG. Pathologic complete response with six compared with three cycles of neoadjuvant epirubicin plus docetaxel and granulocyte colony-stimulating factor in operable breast cancer: results of ABCSG-14. J Clin Oncol. 2007 May 20;25(15):2012-8. [https://doi.org/10.1200/JCO.2006.09.1777 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/17513805/ PubMed]
 +
# Han S, Kim J, Lee J, Chang E, Gwak G, Cho H, Yang KH, Park S, Park K. Comparison of 6 cycles versus 4 cycles of neoadjuvant epirubicin plus docetaxel chemotherapy in stages II and III breast cancer. Eur J Surg Oncol. 2009 Jun;35(6):583-7. Epub 2009 Feb 5. [https://doi.org/10.1016/j.ejso.2009.01.002 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19195817/ PubMed]
 +
# '''ABCSG-24:''' Steger GG, Greil R, Lang A, Rudas M, Fitzal F, Mlineritsch B, Hartmann BL, Bartsch R, Melbinger E, Hubalek M, Stoeger H, Dubsky P, Ressler S, Petzer AL, Singer CF, Muss C, Jakesz R, Gampenrieder SP, Zielinski CC, Fesl C, Gnant M; ABCSG. Epirubicin and docetaxel with or without capecitabine as neoadjuvant treatment for early breast cancer: final results of a randomized phase III study (ABCSG-24). Ann Oncol. 2014 Feb;25(2):366-71. Epub 2013 Dec 16. [https://doi.org/10.1093/annonc/mdt508 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24347519/ PubMed] [https://clinicaltrials.gov/study/NCT00309556 NCT00309556]
 +
# '''CBCRT01:''' Chen J, Yao Q, Huang M, Wang B, Zhang J, Wang T, Ming Y, Zhou X, Jia Q, Huan Y, Wang J, Wang L. A randomized Phase III trial of neoadjuvant recombinant human endostatin, docetaxel and epirubicin as first-line therapy for patients with breast cancer (CBCRT01). Int J Cancer. 2018 May 15;142(10):2130-2138. Epub 2017 Dec 23. [https://doi.org/10.1002/ijc.31217 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29238974/ PubMed] [https://clinicaltrials.gov/study/NCT01479036 NCT01479036]
  
−
Supportive medications (varies depending on reference):
+
==EDC {{#subobject:g55f5f|Regimen=1}}==
−
*Citron et al. 2003: [[Filgrastim (Neupogen)]] 5 mcg/kg (rounded to either 300 or 480 mcg) SC once per day on days 3 to 10 (note: Citron et al. 2003 says the schedule was "filgrastim days 3 to 10 of each cycle (a total of seven doses)," so it is unclear whether 7 or 8 doses was actually used).
+
EDC: '''<u>E</u>'''pirubicin, '''<u>D</u>'''ocetaxel, '''<u>C</u>'''apecitabine
−
*Burstein et al. 2005:  
+
<div class="toccolours" style="background-color:#eeeeee">
−
**[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2, given 24 hours after day 1's chemotherapy
+
===Regimen {{#subobject:d3824d|Variant=1}}===
−
**[[Darbepoetin alfa (Aranesp)]] 200 mcg SC once on day 1 for patients with Hb 10 to 12 g/dL; see Burstein et al. 2005 for additional dose adjustments
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdt508 Steger et al. 2013 (ABCSG-24)]
 +
|2004-2008
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Docetaxel_.26_Epirubicin_.28DE.29|ED]]
 +
| style="background-color:#91cf60" |Seems to have superior pCR rate (primary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 +
'''21-day cycle for 6 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# '''ABCSG-24:''' Steger GG, Greil R, Lang A, Rudas M, Fitzal F, Mlineritsch B, Hartmann BL, Bartsch R, Melbinger E, Hubalek M, Stoeger H, Dubsky P, Ressler S, Petzer AL, Singer CF, Muss C, Jakesz R, Gampenrieder SP, Zielinski CC, Fesl C, Gnant M; ABCSG. Epirubicin and docetaxel with or without capecitabine as neoadjuvant treatment for early breast cancer: final results of a randomized phase III study (ABCSG-24). Ann Oncol. 2014 Feb;25(2):366-71. Epub 2013 Dec 16. [https://doi.org/10.1093/annonc/mdt508 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24347519/ PubMed] [https://clinicaltrials.gov/study/NCT00309556 NCT00309556]
 +
==Epirubicin monotherapy {{#subobject:fdhtd3|Regimen=1}}==
 +
E: '''<u>E</u>'''pirubicin
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:9abq2f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1677/erc.1.00945 Bottini et al. 2005]
 +
|1997-2002
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Epirubicin_.26_Tamoxifen_999|Epirubicin & Tamoxifen]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of clinical RR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once per day on days 1 & 2
 +
'''21-day cycle for 3 to 4 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
#Bottini A, Berruti A, Brizzi MP, Bersiga A, Generali D, Allevi G, Aguggini S, Bolsi G, Bonardi S, Tondelli B, Vana F, Tampellini M, Alquati P, Dogliotti L. Cytotoxic and antiproliferative activity of the single agent epirubicin versus epirubicin plus tamoxifen as primary chemotherapy in human breast cancer: a single-institution phase III trial. Endocr Relat Cancer. 2005 Jun;12(2):383-92. [https://doi.org/10.1677/erc.1.00945 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15947110/ PubMed]
 +
==Epirubicin & Paclitaxel (EP) {{#subobject:38119e|Regimen=1}}==
 +
EP: '''<u>E</u>'''pirubicin & '''<u>P</u>'''aclitaxel
 +
<br>ET: '''<u>E</u>'''pirubicin & '''<u>T</u>'''axol (Paclitaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:040ce0|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2008.20.3133 Untch et al. 2009 (TECHNO)]
 +
|1998-2002
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Dose-dense_E-P_888|ddE-P]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360722/ Frasci et al. 2006]
 +
|1999-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#PET|PET]]
 +
| style="background-color:#fc8d59" |Seems to have inferior pCR rate
 +
|-
 +
|}
 +
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 4 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Frasci et al. 2006: [[Surgery#Breast_cancer_surgery|Surgery]], then adjuvant [[#CMF|CMF]] x 4 or [[#FEC_2|FEC]] x 4, depending on number of involved lymph nodes
 +
*TECHNO: [[Surgery#Breast_cancer_surgery|Surgery]], then adjuvant [[#CMF|CMF]] x 3
 +
</div></div>
 +
===References===
 +
# Frasci G, D'Aiuto G, Comella P, Thomas R, Botti G, Di Bonito M, De Rosa V, Iodice G, Rubulotta MR, Comella G; Southern Italy Cooperative Oncology Group. Weekly cisplatin, epirubicin, and paclitaxel with granulocyte colony-stimulating factor support vs triweekly epirubicin and paclitaxel in locally advanced breast cancer: final analysis of a SICOG phase III study. Br J Cancer. 2006 Oct 23;95(8):1005-12. [https://doi.org/10.1038/sj.bjc.6603395 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360722/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/17047649/ PubMed]
 +
# '''TECHNO:''' Untch M, Möbus V, Kuhn W, Muck BR, Thomssen C, Bauerfeind I, Harbeck N, Werner C, Lebeau A, Schneeweiss A, Kahlert S, von Koch F, Petry KU, Wallwiener D, Kreienberg R, Albert US, Lück HJ, Hinke A, Jänicke F, Konecny GE. Intensive dose-dense compared with conventionally scheduled preoperative chemotherapy for high-risk primary breast cancer. J Clin Oncol. 2009 Jun 20;27(18):2938-45. Epub 2009 Apr 13. [https://doi.org/10.1200/JCO.2008.20.3133 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19364964/ PubMed]
 +
==FAC {{#subobject:8d91b0|Regimen=1}}==
 +
FAC: '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 500/50/500 {{#subobject:b845a59|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3233286/ Arun et al. 2011 (MDACC 91-0156)]
 +
|1992-1997
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#DI_FAC_999|DI FAC]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 4 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 600/50/600 {{#subobject:b99a59|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://journals.sagepub.com/doi/abs/10.1177/030089169708300511 Baldini et al. 1997]
 +
|NR in abstract
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#DES-CAF_999|DES-CAF]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 3 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 1000/50/500 {{#subobject:1bb303|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1999.17.11.3412 Buzdar et al. 1999]
 +
|1994-1998
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Paclitaxel_monotherapy_999|Paclitaxel]]; q3wk x 4
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 4
 +
*[[Doxorubicin (Adriamycin)]] 16.7 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m<sup>2</sup>)
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 4 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]], then adjuvant [[#FAC_2|FAC]] x 4
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 2000/50/100 {{#subobject:1aa303|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/0959-8049(94)90537-1 Scholl et al. 1994 (S6)]
 +
|1986-1990
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|Adjuvant [[#FAC_2|FAC]]
 +
| style="background-color:#91cf60" |Seems to have superior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1, 3, 5, 8
 +
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 5
 +
'''28-day cycle for 4 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# '''S6:''' Scholl SM, Fourquet A, Asselain B, Pierga JY, Vilcoq JR, Durand JC, Dorval T, Palangié T, Jouve M, Beuzeboc P, Garcio-Giralt E, Salmon RJ, de la Rochefordiere A, Campana F, Pouillart P. Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: preliminary results of a randomised trial: S6. Eur J Cancer. 1994;30A(5):645-52. [https://doi.org/10.1016/0959-8049(94)90537-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8080680/ PubMed]
 +
# Baldini E, Gardin G, Giannessi P, Brema F, Camorriano A, Carnino F, Naso C, Pastorino G, Pronzato P, Rosso R, Rubagotti A, Torretta G, Conte PF; North-West Oncology Group. A randomized trial of chemotherapy with or without estrogenic recruitment in locally advanced breast cancer. Tumori. 1997 Sep-Oct;83(5):829-33. [https://journals.sagepub.com/doi/abs/10.1177/030089169708300511 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/9428917/ PubMed]
 +
# Buzdar AU, Singletary SE, Theriault RL, Booser DJ, Valero V, Ibrahim N, Smith TL, Asmar L, Frye D, Manuel N, Kau SW, McNeese M, Strom E, Hunt K, Ames F, Hortobagyi GN. Prospective evaluation of paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer. J Clin Oncol. 1999 Nov;17(11):3412-7. [https://doi.org/10.1200/JCO.1999.17.11.3412 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10550135/ PubMed]
 +
# '''MDACC 91-0156:''' Arun BK, Dhinghra K, Valero V, Kau SW, Broglio K, Booser D, Guerra L, Yin G, Walters R, Sahin A, Ibrahim N, Buzdar AU, Frye D, Sneige N, Strom E, Ross M, Theriault RL, Vadhan-Raj S, Hortobagyi GN. Phase III randomized trial of dose intensive neoadjuvant chemotherapy with or without G-CSF in locally advanced breast cancer: long-term results. Oncologist. 2011;16(11):1527-34. Epub 2011 Oct 31. [https://doi.org/10.1634/theoncologist.2011-0134 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3233286/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22042783/ PubMed]
 +
==FEC {{#subobject:ec48df|Regimen=1}}==
 +
FEC: '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 600/60/600 x 3 {{#subobject:792fef|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdg069 Baldini et al. 2003]
 +
|1992-1997
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Stub#ddFEC|ddFEC]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of pCR rate
 +
|-
 +
|}
 +
''Note: This was a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 3 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]], then adjuvant [[#FEC.2FCMF_888|CEF/CMF]] x 3
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 600/60/600 x 4 {{#subobject:547837|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2001.19.22.4224 van der Hage et al. 2001 (EORTC 10902)]
 +
|1991-1999
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#FEC_2|FEC]]; adjuvant
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 4 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 1000/120/1050 x 6 {{#subobject:c3c026|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2003.05.135 Therasse et al. 2003 (EORTC 10921)]
 +
|1993-1996
 +
|style="background-color:#1a9851"|Phase 3 (C)
 +
|[[#Dose-dense_Cyclophosphamide_.26_Epirubicin_.28ddEC.29_999|ddEC]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Cyclophosphamide (Cytoxan)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
'''28-day cycle for 6 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# '''EORTC 10902:''' van der Hage JA, van de Velde CJ, Julien JP, Tubiana-Hulin M, Vandervelden C, Duchateau L. Preoperative chemotherapy in primary operable breast cancer: results from the European Organisation for Research and Treatment of Cancer trial 10902. J Clin Oncol. 2001 Nov 15;19(22):4224-37. [https://doi.org/10.1200/JCO.2001.19.22.4224 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11709566/ PubMed]
 +
## '''Update:''' van Nes JG, Putter H, Julien JP, Tubiana-Hulin M, van de Vijver M, Bogaerts J, de Vos M, van de Velde CJ; Cooperating Investigators of the EORTC. Preoperative chemotherapy is safe in early breast cancer, even after 10 years of follow-up; clinical and translational results from the EORTC trial 10902. Breast Cancer Res Treat. 2009 May;115(1):101-13. Epub 2008 May 18. [https://doi.org/10.1007/s10549-008-0050-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18484198/ PubMed]
 +
# Baldini E, Gardin G, Giannessi PG, Evangelista G, Roncella M, Prochilo T, Collecchi P, Rosso R, Lionetto R, Bruzzi P, Mosca F, Conte PF. Accelerated versus standard cyclophosphamide, epirubicin and 5-fluorouracil or cyclophosphamide, methotrexate and 5-fluorouracil: a randomized phase III trial in locally advanced breast cancer. Ann Oncol. 2003 Feb;14(2):227-32. [https://doi.org/10.1093/annonc/mdg069 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12562649/ PubMed]
 +
# '''EORTC 10921:''' Therasse P, Mauriac L, Welnicka-Jaskiewicz M, Bruning P, Cufer T, Bonnefoi H, Tomiak E, Pritchard KI, Hamilton A, Piccart MJ; [[Study_Groups#EORTC|EORTC]]. Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study. J Clin Oncol. 2003 Mar 1;21(5):843-50. [https://doi.org/10.1200/JCO.2003.05.135 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/12610183/ PubMed]
 +
==iddEPC {{#subobject:28hga2|Regimen=1}}==
 +
iddEPC: '''<u>i</u>'''ntense '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>E</u>'''pirubicin, '''<u>P</u>'''aclitaxel, '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:65az1d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2018.10.015 Schneeweiss et al. 2018 (GeparOcto)]
 +
|2014-12 to 2016-06
 +
|style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#NPLD_.26_Paclitaxel_999|NPLD & Paclitaxel]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of pCR rate
 +
|-
 +
|}
 +
''Note: G-CSF details are from the adjuvant trial; see paper for exact details.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, iddE portion (cycles 1 to 3)====
 +
*[[Epirubicin (Ellence)]] 150 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, iddP portion (cycles 4 to 6)====
 +
*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, iddC portion (cycles 7 to 9)====
 +
*[[Cyclophosphamide (Cytoxan)]] 2000 mg/m<sup>2</sup> IV once on day 1
 +
====Supportive therapy, all portions (cycles 1 to 9)====
 +
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2 or 4
 +
'''14-day cycle for 9 cycles (iddE x 3; iddP x 3; iddC x 3)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
  
−
====Paclitaxel therapy====
+
===References===
−
*[[Paclitaxel (Taxol)]] 175 mg/m2 IV once on day 1
+
# '''GeparOcto:''' Schneeweiss A, Möbus V, Tesch H, Hanusch C, Denkert C, Lübbe K, Huober J, Klare P, Kümmel S, Untch M, Kast K, Jackisch C, Thomalla J, Ingold-Heppner B, Blohmer JU, Rezai M, Frank M, Engels K, Rhiem K, Fasching PA, Nekljudova V, von Minckwitz G, Loibl S. Intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for neoadjuvant treatment of high-risk early breast cancer (GeparOcto-GBG 84): A randomised phase III trial. Eur J Cancer. 2019 Jan;106:181-192. Epub 2018 Dec 5. [https://doi.org/10.1016/j.ejca.2018.10.015 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30528802/ PubMed] [https://clinicaltrials.gov/study/NCT02125344 NCT02125344]
−
 
+
## '''Update:''' Schneeweiss A, Michel LL, Möbus V, Tesch H, Klare P, Hahnen E, Denkert C, Kast K, Pohl-Rescigno E, Hanusch C, Link T, Untch M, Jackisch C, Blohmer JU, Fasching PA, Solbach C, Schmutzler RK, Huober J, Rhiem K, Nekljudova V, Lübbe K, Loibl S; GBG and AGO-B. Survival analysis of the randomised phase III GeparOcto trial comparing neoadjuvant chemotherapy of intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for patients with high-risk early breast cancer. Eur J Cancer. 2022 Jan;160:100-111. Epub 2021 Nov 17. [https://doi.org/10.1016/j.ejca.2021.10.011 link to original article] [https://pubmed.ncbi.nlm.nih.gov/34801353/ PubMed]
−
'''14-day cycles x 4 cycles'''
+
==Paclitaxel monotherapy, dose-dense (q2wk) {{#subobject:fa1c6b|Regimen=1}}==
 +
ddT: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>T</u>'''axol (Paclitaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:b5be66|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.02.8621 Burstein et al. 2005]
 +
|2003-2004
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|}
 +
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*Neoadjuvant [[#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29|ddAC]] x 4
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
 +
====Supportive therapy====
 +
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2
 +
'''14-day cycle for 4 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. [https://doi.org/10.1200/jco.2005.02.8621 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16293865/ PubMed]
 +
==PET {{#subobject:47221e|Regimen=1}}==
 +
PET: '''<u>P</u>'''latinol (Cisplatin), '''<u>E</u>'''pirubicin, '''<u>T</u>'''axol (Paclitaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:181ce0|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360722/ Frasci et al. 2006]
 +
|1999-2004
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Epirubicin_.26_Paclitaxel_.28EP.29|EP]]
 +
| style="background-color:#91cf60" |Seems to have superior pCR rate (primary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cisplatin (Platinol)]] 30 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Paclitaxel (Taxol)]] 120 mg/m<sup>2</sup> IV once on day 1
 +
'''7-day cycle for 12 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# Frasci G, D'Aiuto G, Comella P, Thomas R, Botti G, Di Bonito M, De Rosa V, Iodice G, Rubulotta MR, Comella G; Southern Italy Cooperative Oncology Group. Weekly cisplatin, epirubicin, and paclitaxel with granulocyte colony-stimulating factor support vs triweekly epirubicin and paclitaxel in locally advanced breast cancer: final analysis of a SICOG phase III study. Br J Cancer. 2006 Oct 23;95(8):1005-12. [https://doi.org/10.1038/sj.bjc.6603395 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2360722/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/17047649/ PubMed]
 +
==TAC (Docetaxel) {{#subobject:413b30|Regimen=1}}==
 +
TAC: '''<u>T</u>'''axotere (Docetaxel), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide
 +
<br>ATC: '''<u>A</u>'''driamycin (Doxorubicin), '''<u>T</u>'''axotere (Docetaxel), '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:8dbe27|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://academic.oup.com/jnci/article/100/8/542/931241 von Minckwitz et al. 2008 (GeparTrio)]
 +
|2002-2005
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#TAC_.28Docetaxel.29|TAC]] x 2, then [[Stub#Capecitabine_.26_Vinorelbine|NX]] x 4
 +
| style="background-color:#eeee01" |Non-inferior sonographic response (primary endpoint)
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2013.06.012 Vriens et al. 2013 (INTENS)]
 +
|2006-2009
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#AC-D|AC-D]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of pCR rate
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div></div>
 +
===References===
 +
# '''GeparTrio:''' von Minckwitz G, Kümmel S, Vogel P, Hanusch C, Eidtmann H, Hilfrich J, Gerber B, Huober J, Costa SD, Jackisch C, Loibl S, Mehta K, Kaufmann M; [[Study_Groups#GBG|GBG]]. Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial. J Natl Cancer Inst. 2008 Apr 16;100(8):542-51. Epub 2008 Apr 8. [https://academic.oup.com/jnci/article/100/8/542/931241 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18398097/ PubMed] [https://clinicaltrials.gov/study/NCT00544765 NCT00544765]
 +
##'''Update:''' von Minckwitz G, Kümmel S, Vogel P, Hanusch C, Eidtmann H, Hilfrich J, Gerber B, Huober J, Costa SD, Jackisch C, Loibl S, Mehta K, Kaufmann M; German Breast Group. Intensified neoadjuvant chemotherapy in early-responding breast cancer: phase III randomized GeparTrio study. J Natl Cancer Inst. 2008 Apr 16;100(8):552-62. Epub 2008 Apr 8. [https://doi.org/10.1093/jnci/djn089 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18398094/ PubMed]
 +
# '''INTENS:''' Vriens BE, Aarts MJ, de Vries B, van Gastel SM, Wals J, Smilde TJ, van Warmerdam LJ, de Boer M, van Spronsen DJ, Borm GF, Tjan-Heijnen VC; BOOG. Doxorubicin/cyclophosphamide with concurrent versus sequential docetaxel as neoadjuvant treatment in patients with breast cancer. Eur J Cancer. 2013 Oct;49(15):3102-10. Epub 2013 Jul 10. [https://doi.org/10.1016/j.ejca.2013.06.012 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/23850450/ PubMed] [https://clinicaltrials.gov/study/NCT00314977 NCT00314977]
 +
## '''Update:''' Vriens BEPJ, Vriens IJH, Aarts MJB, van Gastel SM, van den Berkmortel FWPJ, Smilde TJ, van Warmerdam LJC, van Spronsen DJ, Peer PGM, de Boer M, Tjan-Heijnen VCG; BOOG. Improved survival for sequentially as opposed to concurrently delivered neoadjuvant chemotherapy in non-metastatic breast cancer. Breast Cancer Res Treat. 2017 Oct;165(3):593-600. Epub 2017 Jul 3. [https://doi.org/10.1007/s10549-017-4364-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5602024/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28674765/ PubMed]
 +
=Neoadjuvant response criteria=
 +
==Clinical response rate (cRR)==
 +
''Although fairly dated, some trials such as [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107749/ ACOSOG Z1031] make use of the WHO criteria for response to neoadjuvant therapy. Included here primarily for historical purposes.''
 +
</div></div>
 +
===References===
 +
# Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981 Jan 1;47(1):207-14. [https://doi.org/10.1002/1097-0142(19810101)47:1%3C207::AID-CNCR2820470134%3E3.0.CO;2-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7459811/ PubMed]
 +
==Miller-Payne scoring system==
 +
*Grade 1: No change or some changes to individual malignant cells, but no reduction in overall cellularity
 +
*Grade 2: Minor loss of tumor cells (up to 30%), but overall cellularity still high
 +
*Grade 3: An estimated 30 to 90% reduction in the number of tumor cells
 +
*Grade 4: Marked disappearance of tumor cells such that only small clusters or widely dispersed individual cells remain (loss of greater than 90% of tumor cells)
 +
*Grade 5: No invasive cancer cells identifiable in sections from the site of the tumor (carcinoma ''in situ'' may be present)
 +
</div></div>
 +
===References===
 +
# Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, Schofield A, Heys SD. A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast. 2003 Oct;12(5):320-7. [http://www.thebreastonline.com/article/S0960-9776(03)00106-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14659147/ PubMed]
 +
==Residual cancer burden (RCB)==
 +
*The RCB is calculated as follows: RCB = 1.4 (''f<sub>inv</sub>*d<sub>prim</sub>'')<sup>0.17</sup> + [4(1 - 0.75<sup>''LN''</sup>)''d<sub>met</sub>'']<sup>0.17</sup>
 +
**where ''d<sub>prim</sub>'' is derived from the bidimensional diameters of the primary tumor bed in the resected specimen, ''f<sub>inv</sub>'' is the proportion of the primary tumor bed that contains invasive carcinoma, ''LN'' is the number of axillary lymph nodes containing metastatic carcinoma, and ''d<sub>met</sub>'' is the diameter of the largest metastasis in an axillary lymph node.
 +
**The cut-off points are 1.36 and 3.28.
 +
</div></div>
 +
===References===
 +
# Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, Pusztai L. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007 Oct 1;25(28):4414-22. Epub 2007 Sep 4. [https://doi.org/10.1200/JCO.2007.10.6823 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17785706/ PubMed]
 +
==Residual disease in breast and nodes (RDBN)==
 +
*Level 1: pCR in breast and nodes with or without ''in situ'' carcinoma
 +
*Levels 2 to 4: Residual disease, calculated as 0.2 (residual breast tumor size in cm) + index of involved nodes (0 for no positive nodes, 1 for 1 to 4 positive nodes, 2 for 5 to 7 positive nodes, and 3 for 8 positive nodes) + the Scarff–Bloom–Richardson grade (1, 2, or 3). The cut-off points are 3 and 4.3.
 +
</div></div>
 +
===References===
 +
# Chollet P, Abrial C, Durando X, Thivat E, Tacca O, Mouret-Reynier MA, Leheurteur M, Kwiatkowski F, Dauplat J, Penault-Llorca F. A new prognostic classification after primary chemotherapy for breast cancer: residual disease in breast and nodes (RDBN). Cancer J. 2008 Mar-Apr;14(2):128-32. [https://insights.ovid.com/pubmed?pmid=18391619 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18391619/ PubMed]
 +
==Sataloff's classification==
 +
*Breast:
 +
**T-A: Total or nearly total therapeutic effect
 +
**T-B: Greater than 50% therapeutic effect
 +
**T-C: Less than 50% therapeutic effect
 +
**T-D: No therapeutic effect
 +
*Lymph node:
 +
**N-A: Therapeutic effect but no metastasis
 +
**N-B: No metastasis, no therapeutic effect
 +
**N-C: Therapeutic effect but metastasis
 +
**N-D: Metastasis, no therapeutic effect
 +
</div></div>
 +
===References===
 +
# Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Lieber CP, Baloch Z. Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome. J Am Coll Surg. 1995 Mar;180(3):297-306. [https://pubmed.ncbi.nlm.nih.gov/7874340/ PubMed]
 +
==Tumor response ratio==
 +
Calculated as follows: Residual breast disease observed upon pathologic examination divided by the size of the tumor on the pre-neoadjuvant therapy image.
 +
*TRR = 0: pathologic complete response (pCR)
 +
*TRR greater than 0 up to 0.4: strong partial response
 +
*TRR greater than 0.4 up to 1.0: weak partial response (WPR)
 +
*TRR greater than 1.0: tumor growth
 +
</div></div>
 +
===References===
 +
# Miller M, Ottesen RA, Niland JC, Kruper L, Chen SL, Vito C. Tumor response ratio predicts overall survival in breast cancer patients treated with neoadjuvant chemotherapy. Ann Surg Oncol. 2014 Oct;21(10):3317-23. Epub 2014 Jul 25. [https://link.springer.com/article/10.1245/s10434-014-3922-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/25059788/ PubMed]
 +
==ypTNM staging==
 +
This system is proprietary to the AJCC. Please [https://cancerstaging.org/Pages/default.aspx visit their site] or consult the AJCC Manual for further details.
 +
=Adjuvant therapy, sequential regimens=
 +
==A-CMF {{#subobject:68h17c|Regimen=1}}==
 +
A-CMF: '''<u>A</u>'''driamycin (Doxorubicin) followed by '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 75 x 4 --> 600/40/600 x 4 {{#subobject:80hg17|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1200/JCO.2008.19.2567 Gianni et al. 2009 (ECTO)]
 +
|rowspan=2|1996-2002
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#AT-CMF|AT-CMF]]; adjuvant
 +
| style="background-color:#fc8d59" |Seems to have inferior RFS
 +
|-
 +
|2. [[#AT-CMF_999|AT-CMF]]; neoadjuvant
 +
| style="background-color:#d3d3d3" |Not directly compared
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7005671/ Fernando et al. 2019 (SECRAB)]
 +
|1998-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#CMF_.26_RT_888|CMF & RT]]<br>1b. [[#E-CMF_.26_RT_888|E-CMF & RT]]<br>1c. [[#A-CMF_.26_RT_888|A-CMF & RT]]<br>1d. [[#MMM_.26_RT_888|MMM & RT]]
 +
| style="background-color:#d73027" |Inferior LRFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, A portion (cycles 1 to 4)====
 +
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, CMF portion (cycles 5 to 8)====
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (A x 4; CMF x 4)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 75 x 4 --> 600/40/600 x 8 {{#subobject:a45aby|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1991.9.12.2134 Buzzoni et al. 1991 (Milan trial)]
 +
|1982-1987
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#A.2FCMF|A/CMF]] x 12
 +
| style="background-color:#1a9850" |Superior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, A portion (cycles 1 to 4)====
 +
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, CMF portion (cycles 5 to 12)====
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 12 cycles (A x 4; CMF x 8)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 75 x 4 --> 600/50/600 x 8 {{#subobject:a45at3|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://academic.oup.com/jnci/article/96/14/1076/2520847 Leonard et al. 2004]
 +
|1995-1999
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cyclophosphamide_.26_Thiotepa.2C_then_auto_HSCT_999|Cyclophosphamide & Thiotepa with auto HSCT]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, A portion (cycles 1 to 4)====
 +
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, CMF portion (cycles 5 to 12)====
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Methotrexate (MTX)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 4 cycles, then 28-day cycle for 8 cycles (A x 4; CMF x 8)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 75 x 4 --> 1400/80/1200 x 4 {{#subobject:8077qq|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7005671/ Fernando et al. 2019 (SECRAB)]
 +
|1998-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#CMF_.26_RT_888|CMF & RT]]<br>1b. [[#E-CMF_.26_RT_888|E-CMF & RT]]<br>1c. [[#A-CMF_.26_RT_888|A-CMF & RT]]<br>1d. [[#MMM_.26_RT_888|MMM & RT]]
 +
| style="background-color:#d73027" |Inferior LRFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, A portion (cycles 1 to 4)====
 +
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, CMF portion (cycles 5 to 8)====
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (A x 4; CMF x 4)'''
 +
</div></div>
 +
===References===
 +
# '''Milan trial:''' Buzzoni R, Bonadonna G, Valagussa P, Zambetti M. Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes. J Clin Oncol. 1991 Dec;9(12):2134-40. [https://doi.org/10.1200/JCO.1991.9.12.2134 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1960555/ PubMed]
 +
## '''Update:''' Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes: ten-year results. JAMA. 1995 Feb 15;273(7):542-7. [https://jamanetwork.com/journals/jama/fullarticle/387001 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7837388/ PubMed]
 +
# Leonard RC, Lind M, Twelves C, Coleman R, van Belle S, Wilson C, Ledermann J, Kennedy I, Barrett-Lee P, Perren T, Verrill M, Cameron D, Foster E, Yellowlees A, Crown J; Anglo-Celtic Cooperative Oncology Group. Conventional adjuvant chemotherapy versus single-cycle, autograft-supported, high-dose, late-intensification chemotherapy in high-risk breast cancer patients: a randomized trial. J Natl Cancer Inst. 2004 Jul 21;96(14):1076-83. [https://academic.oup.com/jnci/article/96/14/1076/2520847 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15265969/ PubMed]
 +
# '''ECTO:''' Gianni L, Baselga J, Eiermann W, Porta VG, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Cussac AL, Bozhok A, Martinez-Agulló A, Greco M, Byakhov M, Lopez JJ, Mansutti M, Valagussa P, Bonadonna G. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. J Clin Oncol. 2009 May 20;27(15):2474-81. Epub 2009 Mar 30. [https://doi.org/10.1200/JCO.2008.19.2567 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19332727/ PubMed] [https://clinicaltrials.gov/study/NCT00003013 NCT00003013]
 +
# '''SECRAB:''' Fernando IN, Bowden SJ, Herring K, Brookes CL, Ahmed I, Marshall A, Grieve R, Churn M, Spooner D, Latief TN, Agrawal RK, Brunt AM, Stevens A, Goodman A, Canney P, Bishop J, Ritchie D, Dunn J, Poole CJ, Rea DW; SECRAB Investigators. Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial. Radiother Oncol. 2020 Jan;142:52-61. Epub 2019 Nov 27. [https://doi.org/10.1016/j.radonc.2019.10.014 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7005671/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31785830/ PubMed] [https://clinicaltrials.gov/study/NCT00003893 NCT00003893]
  
 +
==ddA-ddT-ddC {{#subobject:2ba5c2|Regimen=1}}==
 +
ddA-ddT-ddC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>A</u>'''driamycin (Doxorubicin), followed by '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>T</u>'''axol (Paclitaxel), followed by '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 60/175/600 {{#subobject:6f231e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1200/jco.2003.09.081 Citron et al. 2003 (CALGB 9741)]
 +
|rowspan=2|1997-1999
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[#A-T-C_999|A-T-C]]<br>2. [[#AC-T_2|AC-T]]
 +
| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br><br>Superior DFS (primary endpoint)
 +
|-
 +
|3. [[#ddAC-ddT|ddAC-ddT]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, ddA portion (cycles 1 to 4)====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, ddT portion (cycles 5 to 8)====
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
 +
====Supportive therapy, ddT portion (cycles 5 to 8)====
 +
*[[Diphenhydramine (Benadryl)]] 12.5 to 50 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
 +
*One of the following H2 blocker choices:
 +
**[[Ranitidine (Zantac)]] 50 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
 +
**[[Cimetidine (Tagamet)]] 300 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
 +
**[[Famotidine (Pepcid)]] 20 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
 +
*One of the following dexamethasone choices:
 +
**[[Dexamethasone (Decadron)]] 10 mg IV once on day 1, within 60 minutes prior to paclitaxel
 +
**[[Dexamethasone (Decadron)]] 10 mg PO once on day 1, at least 60 minutes prior to paclitaxel
 +
**[[Dexamethasone (Decadron)]] 20 mg PO twice on day 1; 6 hours and 12 hours prior to paclitaxel
 +
====Chemotherapy, ddC portion (cycles 9 to 12)====
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Supportive therapy, all portions (cycles 1 to 12)====
 +
*[[Filgrastim (Neupogen)]] 5 mcg/kg (rounded to either 300 or 480 mcg) SC once per day on days 3 to 10
 +
**Note: Citron et al. 2003 says the schedule was "filgrastim days 3 to 10 of each cycle (a total of seven doses)," so it is unclear whether 7 or 8 doses was actually used).
 +
'''14-day cycle for 12 cycles (ddA x 4; ddT x 4; ddC x 4)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 60/200/800 {{#subobject:822b10|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1159/000086987 Kahan et al. 2005]
 +
|2000-2003
 +
| style="background-color:#91cf61" |Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, ddA portion (cycles 1 to 4)====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, ddT portion (cycles 5 to 8)====
 +
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1
 +
====Chemotherapy, ddC portion (cycles 9 to 12)====
 +
*[[Cyclophosphamide (Cytoxan)]] 800 mg/m<sup>2</sup> IV once on day 1
 +
====Supportive therapy, all portions (cycles 1 to 12)====
 +
*[[Filgrastim (Neupogen)]]
 +
'''14-day cycle for 12 cycles (ddA x 4; ddT x 4; ddC x 4)'''
 +
</div></div>
 
===References===
 
===References===
−
# Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. [http://jco.ascopubs.org/content/21/8/1431.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12668651 PubMed]
+
# '''CALGB 9741:''' Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. [https://doi.org/10.1200/jco.2003.09.081 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12668651/ PubMed] [https://clinicaltrials.gov/study/NCT00003088 NCT00003088]
−
# Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. [http://jco.ascopubs.org/content/23/33/8340.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16293865 PubMed]
+
# Kahan Z, Uhercsak G, Hajnal-Papp R, Boda K, Thurzo L. Dose-dense sequential adriamycin-paclitaxel-cyclophosphamide chemotherapy is well tolerated and safe in high-risk early breast cancer. Oncology. 2005;68(4-6):446-53. Epub 2005 Jul 13. [https://doi.org/10.1159/000086987 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16020975/ PubMed]
−
 
+
## '''Update:''' Kelemen G, Uhercsák G, Ormándi K, Eller J, Thurzó L, Kahán Z. Long-term efficiency and toxicity of adjuvant dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy in high-risk breast cancer. Oncology. 2010;78(3-4):271-3. Epub 2010 Jun 7. [https://doi.org/10.1159/000315734 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20523088/ PubMed]
−
==Dose-dense ATC {{#subobject:c9fa7d|Regimen=1}}==
+
==AC-CMF {{#subobject:68ug7c|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
AC-CMF: '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>C</u>'''yclophosphamide followed by '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:807v2z|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.03.0783 Colleoni et al. 2006 (IBCSG 13-93)]
 +
|1993-1999
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.03.5196 Basser et al. 2006 (IBCSG 15-95)]
 +
|1995-2000
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cyclophosphamide_.26_Epirubicin_888|EC]]; dose-intense
 +
| style="background-color:#fc8d59" |Seems to have inferior DFS<sup>1</sup>
 +
|-
 +
|rowspan=2|[https://academic.oup.com/jnci/article/100/2/121/1130035 Francis et al. 2008 (BIG 02-98)]
 +
|rowspan=2|1998-2001
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#A-CMF|A-CMF]]
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|2. [[#A-D-CMF_333|A-D-CMF]]<br>3. [[#AD-CMF_333|AD-CMF]]
 +
| style="background-color:#fee08b" |Might have inferior DFS<sup>2</sup>
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
ATC: '''<u>A</u>'''driamycin, '''<u>T</u>'''axol, '''<u>C</u>'''ytoxan
+
''<sup>1</sup>Reported efficacy for IBCSG 15-95 is based on the 2009 update.''<br>
−
 
+
''<sup>2</sup>Reported efficacy for BIG 02-98 is based on the 2015 update.''
−
===Regimen {{#subobject:90fd28|Variant=1}}===
+
<div class="toccolours" style="background-color:#cbd5e8">
−
Level of Evidence:
+
====Preceding treatment====
−
<span
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
style="background:#EEEE00;
+
</div>
−
padding:3px 6px 3px 6px;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
border-color:black;
+
====Chemotherapy, AC portion (cycles 1 to 4)====
−
border-width:2px;
+
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
−
border-style:solid;">Phase II</span>
+
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
−
 
+
====Chemotherapy, CMF portion (cycles 5 to 7)====
−
'''All cycles given with [[Filgrastim (Neupogen)]] support'''
+
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
−
*[[Doxorubicin (Adriamycin)]] 60 mg/m2 IV day 1
+
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
 
+
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
'''14-day cycles x 4 cycles, THEN'''
+
'''21-day cycle for 4 cycles, then 28-day cycle for 3 cycles (AC x 4; CMF x 3)'''
−
 
+
</div>
−
*[[Paclitaxel (Taxol)]] 200 mg/m2 IV over 3 hours day 1
+
<div class="toccolours" style="background-color:#cbd5e7">
−
 
+
====Subsequent treatment====
−
'''14-day cycles x 4 cycles, THEN'''
+
*Adjuvant [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_3|Tamoxifen]] x 5 y versus [[Breast_cancer_-_null_regimens#Observation|no further treatment]]
−
 
+
</div></div>
−
*[[Cyclophosphamide (Cytoxan)]] 800 mg/m2 IV day 1
 
−
 
 
−
'''14-day cycles x 4 cycles'''
 
−
 
 
−
Alternate dosing per NCCN (primary reference not found):
 
−
<br>'''All cycles given with [[Filgrastim (Neupogen)]] support'''
 
−
*[[Doxorubicin (Adriamycin)]] 60 mg/m2 IV day 1
 
−
 
 
−
'''14-day cycles x 4 cycles, THEN'''
 
−
 
 
−
*[[Paclitaxel (Taxol)]] 175 mg/m2 IV day 1
 
−
 
 
−
'''14-day cycles x 4 cycles, THEN'''
 
−
 
 
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV day 1
 
−
 
 
−
'''14-day cycles x 4 cycles'''
 
−
 
 
 
===References===
 
===References===
−
# Kahan Z, Uhercsak G, Hajnal-Papp R, Boda K, Thurzo L. Dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy is well tolerated and safe in high-risk early breast cancer. Oncology. 2005;68(4-6):446-53. Epub 2005 Jul 13. [http://content.karger.com/produktedb/produkte.asp?DOI=86987&typ=pdf link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16020975 PubMed]
+
#'''IBCSG 15-95:''' Basser RL, O'Neill A, Martinelli G, Green MD, Peccatori F, Cinieri S, Coates AS, Gelber RD, Aebi S, Castiglione-Gertsch M, Viale G, Price KN, Goldhirsch A; International Breast Cancer Study Group. Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95. J Clin Oncol. 2006 Jan 20;24(3):370-8. [https://doi.org/10.1200/jco.2005.03.5196 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16421418/ PubMed] [https://clinicaltrials.gov/study/NCT00002784 NCT00002784]
−
# Kelemen G, Uhercsák G, Ormándi K, Eller J, Thurzó L, Kahán Z. Long-term efficiency and toxicity of adjuvant dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy in high-risk breast cancer. Oncology. 2010;78(3-4):271-3. Epub 2010 Jun 7. [http://content.karger.com/produktedb/produkte.asp?DOI=000315734&typ=pdf link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/20523088 PubMed]
+
##'''Update:''' Colleoni M, Sun Z, Martinelli G, Basser RL, Coates AS, Gelber RD, Green MD, Peccatori F, Cinieri S, Aebi S, Viale G, Price KN, Goldhirsch A; International Breast Cancer Study Group. The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up. Ann Oncol. 2009 Aug;20(8):1344-51. Epub 2009 May 25. [https://doi.org/10.1093/annonc/mdp024 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2720817/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19468030/ PubMed]
 +
# '''IBCSG 13-93:''' Colleoni M, Gelber S, Goldhirsch A, Aebi S, Castiglione-Gertsch M, Price KN, Coates AS, Gelber RD; International Breast Cancer Study Group. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol. 2006 Mar 20;24(9):1332-41. Epub 2006 Feb 27. [https://doi.org/10.1200/JCO.2005.03.0783 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16505417/ PubMed]
 +
# '''BIG 02-98:''' Francis P, Crown J, Di Leo A, Buyse M, Balil A, Andersson M, Nordenskjöld B, Lang I, Jakesz R, Vorobiof D, Gutiérrez J, van Hazel G, Dolci S, Jamin S, Bendahmane B, Gelber RD, Goldhirsch A, Castiglione-Gertsch M, Piccart-Gebhart M; BIG. Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial. J Natl Cancer Inst. 2008 Jan 16;100(2):121-33. Epub 2008 Jan 8. Erratum in: J Natl Cancer Inst. 2008 Nov 19;100(22):1655. [https://academic.oup.com/jnci/article/100/2/121/1130035 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/18182617/ PubMed] [https://clinicaltrials.gov/study/NCT00174655 NCT00174655]
 +
## '''Update:''' Oakman C, Francis PA, Crown J, Quinaux E, Buyse M, De Azambuja E, Margeli Vila M, Andersson M, Nordenskjöld B, Jakesz R, Thürlimann B, Gutiérrez J, Harvey V, Punzalan L, Dell'orto P, Larsimont D, Steinberg I, Gelber RD, Piccart-Gebhart M, Viale G, Di Leo A. Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trial. Ann Oncol. 2013 May;24(5):1203-11. Epub 2013 Jan 4. [https://doi.org/10.1093/annonc/mds627 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23293111/ PubMed]
 +
## '''Update:''' Sonnenblick A, Francis PA, Azim HA Jr, de Azambuja E, Nordenskjöld B, Gutiérez J, Quinaux E, Mastropasqua MG, Ameye L, Anderson M, Lluch A, Gnant M, Goldhirsch A, Di Leo A, Barnadas A, Cortes-Funes H, Piccart M, Crown J. Final 10-year results of the Breast International Group 2-98 phase III trial and the role of Ki67 in predicting benefit of adjuvant docetaxel in patients with oestrogen receptor positive breast cancer. Eur J Cancer. 2015 Aug;51(12):1481-9. Epub 2015 Jun 11. [https://doi.org/10.1016/j.ejca.2015.03.018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26074397/ PubMed]
  
−
==AC {{#subobject:77b0fd|Regimen=1}}==
+
==AC-D {{#subobject:68hg67|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
AC-D: '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>C</u>'''yclophosphamide followed by '''<u>D</u>'''ocetaxel
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, q3wk docetaxel 75 mg/m<sup>2</sup> {{#subobject:80hgca|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan="2"|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6668007/ Watanabe et al. 2017 (NSAS BC-02)]
 +
| rowspan = 2|2001-2006
 +
| rowspan = 2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#AC-T_2|AC-T]]<br>2. [[Breast_cancer_-_historical#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel]] x 8
 +
| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br>(HR 0.75, 95% CI 0.57-0.98)
 +
|-
 +
|3. [[#Docetaxel_monotherapy|Docetaxel]] x 8
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior DFS (primary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
AC: '''<u>A</u>'''driamycin, '''<u>C</u>'''yclophosphamide
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
===Example orders===
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
*[[Example orders for AC in breast cancer]]
+
</div>
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen, Shulman et al. 2012 (CALGB 40101) {{#subobject:ac3513|Variant=1}}===
+
====Chemotherapy, AC portion (cycles 1 to 4)====
−
Level of Evidence:
+
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
−
<span
+
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
−
style="background:#00CD00;
+
====Chemotherapy, D portion (cycles 5 to 8)====
−
padding:3px 6px 3px 6px;
+
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
−
border-color:black;
+
'''21-day cycle for 8 cycles (AC x 4; D x 4)'''
−
border-width:2px;
+
</div></div><br>
−
border-style:solid;">Phase III</span>
+
<div class="toccolours" style="background-color:#eeeeee">
−
 
+
===Regimen variant #2, q3wk docetaxel 100 mg/m<sup>2</sup> {{#subobject:807gua|Variant=1}}===
−
*[[Doxorubicin (Adriamycin)]] 60 mg/m2 IV once on day 1
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV once on day 1
+
!style="width: 20%"|Study
−
 
+
!style="width: 20%"|Dates of enrollment
−
'''14-day cycles x 4 cycles'''; the study protocol originally specified 21-day cycles but was amended to 14-day cycles after results of [[#Dose-dense_AC_-.3E_T | CALGB 9741 - Citron et al. 2003]] were available
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
 
+
!style="width: 20%"|Comparator
−
Supportive medications:
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
*Recommended growth factor support with one of the following:
+
|-
−
**[[Filgrastim (Neupogen)]] 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
+
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743943/ Sparano et al. 2008 (ECOG E1199)]
−
**[[Sargramostim (Leukine)]] 250 to 500 mcg/m2 SC on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
+
| rowspan="2" |1999-2002
−
**[[Pegfilgrastim (Neulasta)]] 6 mg SC, administered once 24 to 36 hours after chemotherapy
+
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
−
 
+
|1. [[#AC-T_2|AC-T]]; q3wk paclitaxel
 +
| style="background-color:#91cf60" |Seems to have superior DFS (primary endpoint)
 +
|-
 +
|2. [[#AC-T_2|AC-T]]; weekly paclitaxel<br> 3. [[#AC-D_2|AC-D]]; weekly docetaxel
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935316/ Swain et al. 2010 (NSABP B-30)]
 +
|rowspan=2|1999-2004
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|1. [[#Docetaxel_.26_Doxorubicin_.28AT.29_888|AT]]
 +
| style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)
 +
|-
 +
|2. [[#TAC_.28Docetaxel.29_2|TAC]]
 +
| style="background-color:#d9ef8b" |Might have superior OS (primary endpoint)
 +
|-
 +
|[https://doi.org/10.1200/jco.2010.28.5437 Eiermann et al. 2011 (BCIRG-005)]
 +
|2000-2003
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#TAC_.28Docetaxel.29_2|TAC]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS60
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, AC portion (cycles 1 to 4)====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, D portion (cycles 5 to 8)====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
'''21-day cycle for 8 cycles (AC x 4; D x 4)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, weekly docetaxel {{#subobject:199d79|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743943/ Sparano et al. 2008 (ECOG E1199)]
 +
| rowspan="2" |1999-2002
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|1. [[#AC_T_2|AC-T]]; q3wk paclitaxel
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|2. [[#AC_T_2|AC-T]]; weekly paclitaxel<br> 3. [[#AC_D_2|AC-D]]; q3wk docetaxel
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, AC portion (cycles 1 to 4)====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, D portion (cycles 5 to 16)====
 +
*[[Docetaxel (Taxotere)]] 35 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
'''21-day cycle for 4 cycles, then 7-day cycle for 12 cycles (AC x 4; D x 12)'''
 +
</div></div>
 
===References===
 
===References===
−
# Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L. Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003 Mar 15;21(6):976-83. [http://jco.ascopubs.org/content/21/6/976.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/12637460 PubMed]
+
<!-- Presented in part at the San Antonio Breast Cancer Symposium, San Antonio, Texas, December 8–11, 2007, and the American Society of Clinical Oncology meeting, Chicago, June 1–4, 2005. -->
−
# Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol. 2005 Jun 1;23(16):3686-96. Epub 2005 May 16. [http://jco.ascopubs.org/content/23/16/3686.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/15897552 PubMed]
+
# '''ECOG E1199:''' Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. [https://doi.org/10.1056/NEJMoa0707056 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743943/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18420499/ PubMed] [https://clinicaltrials.gov/study/NCT00004125 NCT00004125]
−
# Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL, Sandbach J, Hyman WJ, Richards DA, Mennel RG, Boehm KA, Meyer WG, Asmar L, Mackey D, Riedel S, Muss H, Savin MA. Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. J Clin Oncol. 2009 Mar 10;27(8):1177-83. Epub 2009 Feb 9. [http://jco.ascopubs.org/content/27/8/1177.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/19204201 PubMed]
+
## '''Update:''' Sparano JA, Zhao F, Martino S, Ligibel JA, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Long-term follow-up of the E1199 phase III trial evaluating the role of taxane and schedule in operable breast cancer. J Clin Oncol. 2015 Jul 20;33(21):2353-60. Epub 2015 Jun 15. [https://doi.org/10.1200/jco.2015.60.9271 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500829/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26077235/ PubMed]
−
# Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Jul 23. [Epub ahead of print] [http://jco.ascopubs.org/content/early/2012/07/23/JCO.2011.40.6405.long link to original article] '''contains verified protocol''' [http://jco.ascopubs.org/content/suppl/2012/07/23/JCO.2011.40.6405.DC1/Protocol.pdf link to study protocol PDF] [http://www.ncbi.nlm.nih.gov/pubmed/22826271 PubMed]  
+
# '''NSABP B-30:''' Swain SM, Jeong JH, Geyer CE Jr, Costantino JP, Pajon ER, Fehrenbacher L, Atkins JN, Polikoff J, Vogel VG, Erban JK, Rastogi P, Livingston RB, Perez EA, Mamounas EP, Land SR, Ganz PA, Wolmark N. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med. 2010 Jun 3;362(22):2053-65. [https://doi.org/10.1056/NEJMoa0909638 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935316/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20519679/ PubMed] [https://clinicaltrials.gov/study/NCT00003782 NCT00003782]
 +
<!-- Presented in part at the 28th Annual San Antonio Breast Cancer Symposia, December 8-11, 2005, San Antonio, TX, and at the 31st Annual San Antonio Breast Cancer Symposia, December 10-14, 2008, San Antonio, TX. -->
 +
# '''BCIRG-005:''' Eiermann W, Pienkowski T, Crown J, Sadeghi S, Martín M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press M, Sauter G, Lindsay MA, Riva A, Buyse M, Drevot P, Taupin H, Mackey JR. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol. 2011 Oct 10;29(29):3877-84. Epub 2011 Sep 12. [https://doi.org/10.1200/jco.2010.28.5437 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21911726/ PubMed] [https://clinicaltrials.gov/study/NCT00312208 NCT00312208]
 +
## '''Update:''' Mackey JR, Pieńkowski T, Crown J, Sadeghi S, Martín M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press MF, Sauter G, Lindsay M, Houé V, Buyse M, Drevot P, Hitier S, Bensfia S, Eiermann W; Translational Research In Oncology (TRIO)/ Breast Cancer International Research Group (BCIRG)-005 investigators. Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial. Ann Oncol. 2016 Jun;27(6):1041-7. Epub 2016 Mar 2. [https://doi.org/10.1093/annonc/mdw098 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26940688/ PubMed]
 +
# '''NSAS BC-02:''' Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. [https://doi.org/10.1002/cncr.30421 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6668007/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28081304/ PubMed]
  
−
==AC -> T (Taxol) {{#subobject:64fc77|Regimen=1}}==
+
==AC-T {{#subobject:633n67|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
AC-T: '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>C</u>'''yclophosphamide followed by '''<u>T</u>'''axol (Paclitaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, weekly paclitaxel {{#subobject:6516e6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743943/ Sparano et al. 2008 (ECOG E1199)]
 +
| rowspan="2" |1999-2002
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|1. [[#AC-T_2|AC-T]]; q3wk paclitaxel
 +
| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>OS60: 89.7% vs 86.5%<br>(HR 0.76, 98.3% CI 0.58-0.98)
 +
|-
 +
|2. [[#AC-D_2|AC-D]]; q3wk docetaxel<br>3. [[#AC-D_2|AC-D]]; weekly docetaxel
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6118403/ Miller et al. 2018 (ECOG E5103)]
 +
|2007-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#AC-T_.26_Bevacizumab_999|AC-T & Bevacizumab]]<br>1b. [[#ddAC-T_.26_Bevacizumab_999|ddAC-T & Bevacizumab]]<br>2a. [[#AC-T_.26_Bevacizumab_999|AC-T & Bevacizumab]], then [[#Bevacizumab_monotherapy|Bevacizumab]]<br>2b. [[#ddAC-T_.26_Bevacizumab_999|ddAC-T & Bevacizumab]], then [[#Bevacizumab_monotherapy|Bevacizumab]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of IDFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7007289/ Fehrenbacher et al. 2019 (NSABP B-47)]
 +
|2011-2015
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#AC-TH_999|AC-TH]]<br>1b. [[#Dose-dense_AC-TH_999|ddAC-TH]]<br>1c. [[#TCH_999|TCH]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of IDFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
AC -> T: '''<u>A</u>'''driamycin, '''<u>C</u>'''ytoxan -> '''<u>T</u>'''axol
+
<div class="toccolours" style="background-color:#fdcdac">
 +
====Biomarker eligibility criteria====
 +
*NSABP B-47: HER2 IHC of 1+ or 2+ with FISH ratio less than 2 or HER2 gene copy number less than 4
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, AC portion (cycles 1 to 4)====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, T portion (cycles 5 to 16)====
 +
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 4 cycles, then 7-day cycle for 12 cycles (AC x 4; T x 12)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
===Example orders===
+
===Regimen variant #2, q3wk paclitaxel 175 mg/m<sup>2</sup> {{#subobject:80c6e6|Variant=1}}===
−
*[[Example orders for AC to T (Taxol) in breast cancer]]
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
 
+
!style="width: 20%"|Study
−
===Regimen {{#subobject:6b14dd|Variant=1}}===
+
!style="width: 20%"|Dates of enrollment
−
Level of Evidence:
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
<span
+
!style="width: 20%"|Comparator
−
style="background:#00CD00;
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
padding:3px 6px 3px 6px;
+
|-
−
border-color:black;
+
|rowspan=2|[https://doi.org/10.1200/jco.2003.02.063 Henderson et al. 2003 (INT 0148/CALGB 9344)]
−
border-width:2px;
+
|rowspan=2|1994-1999
−
border-style:solid;">Phase III</span>
+
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-RT-esc)
−
 
+
|1. [[Breast_cancer_-_historical#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]]; standard-dose<br>2. [[Breast_cancer_-_historical#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]]; high-dose<br>3. [[Breast_cancer_-_historical#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]]; very high-dose
−
*[[Doxorubicin (Adriamycin)]] 60 mg/m2 IV once on day 1
+
| style="background-color:#1a9850" |Superior OS (secondary endpoint)
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV once on day 1
+
|-
−
 
+
|4. [[#AC-T_2|AC-T]]; high-dose AC<br>5. [[#AC-T_2|AC-T]]; very high-dose AC
−
'''21-day cycles x 4 cycles, then'''
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
−
 
+
|-
−
*[[Paclitaxel (Taxol)]] 80 mg/m2 IV over 1 hour once on day 1
+
|rowspan=2|[https://doi.org/10.1200/jco.2003.09.081 Citron et al. 2003 (CALGB 9741)]
−
 
+
|rowspan=2|1997-1999
−
'''1-week cycles x 12 cycles/weeks'''
+
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
−
 
+
|1. [[#A-T-C_999|A-T-C]]
−
Alternate schedule for Paclitaxel (Taxol):
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
−
*[[Paclitaxel (Taxol)]] 175 mg/m2 IV over 3 hours once on day 1
+
|-
−
 
+
|2. [[#ddA-ddC-ddT|ddA-ddC-ddT]]<br>3. [[#ddAC-ddT|ddAC-ddT]]
−
'''3-week cycles x 4 cycles'''
+
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
| rowspan="3" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743943/ Sparano et al. 2008 (ECOG E1199)]
 +
| rowspan="3" |1999-2002
 +
| rowspan="3" style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#AC-T_2|AC-T]]; weekly paclitaxel
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|2. [[#AC-D_2|AC-D]]; q3wk docetaxel
 +
| style="background-color:#fc8d59" |Seems to have inferior DFS
 +
|-
 +
|3. [[#AC-D_2|AC-D]]; weekly docetaxel
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|[https://doi.org/10.1200/JCO.2009.24.1000 Loesch et al. 2010]
 +
|2000-2002
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Complex_multipart_regimens#Loesch_et_al._2010|See link]]
 +
| style="background-color:#ffffbf" |[[Complex_multipart_regimens#Loesch_et_al._2010|See link]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799234/ Burnell et al. 2009 (NCIC-CTG MA.21)]
 +
|2000-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#ddEC-T|ddEC-T]]<br>2. [[#FEC_2|CEF]]
 +
| style="background-color:#d73027" |Inferior RFS
 +
|-
 +
|rowspan="2"|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6668007/ Watanabe et al. 2017 (NSAS BC-02)]
 +
| rowspan = 2|2001-2006
 +
| rowspan = 2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#AC-D_2|AC-D]]<br>2. [[#Docetaxel_monotherapy|Docetaxel]] x 8
 +
| style="background-color:#fc8d59" |Seems to have inferior OS (secondary endpoint)
 +
|-
 +
|3. [[Breast_cancer_-_historical#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel]] x 8
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior DFS (primary endpoint)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172658/ Sparano et al. 2018 (TAILORx)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer,_ER-positive_-_null_regimens#Observation|No chemotherapy]]
 +
| style="background-color:#eeee01" |Non-inferior IDFS (primary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Eligibility criteria====
 +
*TAILORx: Oncotype DX score of 11 to 25
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, AC portion (cycles 1 to 4)====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, T portion (cycles 5 to 8)====
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1  
 +
'''21-day cycle for 8 cycles (AC x 4; T x 4)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
 +
===Regimen variant #3, q3wk paclitaxel 225 mg/m<sup>2</sup> {{#subobject:80c6uv|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.10.517 Mamounas et al. 2005 (NSABP B-28)]
 +
|1995-1998
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Breast_cancer_-_historical#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]] x 4
 +
| style="background-color:#1a9850" |Superior DFS (co-primary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, AC portion (cycles 1 to 4)====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, T portion (cycles 5 to 8)====
 +
*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV over 3 hours once on day 1
 +
'''21-day cycle for 8 cycles (AC x 4; T x 4)'''
 +
</div></div>
 
===References===
 
===References===
−
# Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L. Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003 Mar 15;21(6):976-83. [http://jco.ascopubs.org/content/21/6/976.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/12637460 PubMed]
+
# '''INT 0148/CALGB 9344:''' Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003 Mar 15;21(6):976-83. [https://doi.org/10.1200/jco.2003.02.063 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12637460/ PubMed]
−
# Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. [http://jco.ascopubs.org/content/21/8/1431.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12668651 PubMed]
+
# '''CALGB 9741:''' Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. [https://doi.org/10.1200/jco.2003.09.081 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12668651/ PubMed] [https://clinicaltrials.gov/study/NCT00003088 NCT00003088]
−
# Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol. 2005 Jun 1;23(16):3686-96. Epub 2005 May 16. [http://jco.ascopubs.org/content/23/16/3686.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/15897552 PubMed]
+
# '''NSABP B-28:''' Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol. 2005 Jun 1;23(16):3686-96. Epub 2005 May 16. [https://doi.org/10.1200/jco.2005.10.517 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15897552/ PubMed]
−
# Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. [http://www.nejm.org/doi/full/10.1056/NEJMoa052122 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16236738 PubMed]
+
<!-- Presented in part at the San Antonio Breast Cancer Symposium, San Antonio, Texas, December 8–11, 2007, and the American Society of Clinical Oncology meeting, Chicago, June 1–4, 2005. -->
−
# Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. [http://www.nejm.org/doi/full/10.1056/NEJMoa0707056 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18420499 PubMed]
+
# '''ECOG E1199:''' Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. [https://doi.org/10.1056/NEJMoa0707056 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743943/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/18420499/ PubMed] [https://clinicaltrials.gov/study/NCT00004125 NCT00004125]
−
# Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83. [http://www.nejm.org/doi/full/10.1056/NEJMoa0910383 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/21991949 PubMed]
+
## '''Update:''' Sparano JA, Zhao F, Martino S, Ligibel JA, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Long-term follow-up of the E1199 phase III trial evaluating the role of taxane and schedule in operable breast cancer. J Clin Oncol. 2015 Jul 20;33(21):2353-60. Epub 2015 Jun 15. [https://doi.org/10.1200/jco.2015.60.9271 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500829/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26077235/ PubMed]
 +
# '''NCIC-CTG MA.21:''' Burnell M, Levine MN, Chapman JA, Bramwell V, Gelmon K, Walley B, Vandenberg T, Chalchal H, Albain KS, Perez EA, Rugo H, Pritchard K, O'Brien P, Shepherd LE. Cyclophosphamide, epirubicin, and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol. 2010 Jan 1;28(1):77-82. Epub 2009 Nov 9. [https://doi.org/10.1200/JCO.2009.22.1077 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799234/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19901117/ PubMed] [https://clinicaltrials.gov/study/NCT00014222 NCT00014222]
 +
# Loesch D, Greco FA, Senzer NN, Burris HA, Hainsworth JD, Jones S, Vukelja SJ, Sandbach J, Holmes F, Sedlacek S, Pippen J, Lindquist D, McIntyre K, Blum JL, Modiano MR, Boehm KA, Zhan F, Asmar L, Robert N. Phase III multicenter trial of doxorubicin plus cyclophosphamide followed by paclitaxel compared with doxorubicin plus paclitaxel followed by weekly paclitaxel as adjuvant therapy for women with high-risk breast cancer. J Clin Oncol. 2010 Jun 20;28(18):2958-65. Epub 2010 May 17. [https://doi.org/10.1200/JCO.2009.24.1000 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20479419/ PubMed]
 +
# '''NSAS BC-02:''' Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. [https://doi.org/10.1002/cncr.30421 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6668007/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28081304/ PubMed]
 +
# '''TAILORx:''' Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. [https://doi.org/10.1056/NEJMoa1804710 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172658/ link to PMC article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/29860917/ PubMed] [https://clinicaltrials.gov/study/NCT00310180 NCT00310180]
 +
# '''ECOG E5103:''' Miller KD, O'Neill A, Gradishar W, Hobday TJ, Goldstein LJ, Mayer IA, Bloom S, Brufsky AM, Tevaarwerk AJ, Sparano JA, Le-Lindqwister NA, Hendricks CB, Northfelt DW, Dang CT, Sledge GW Jr. Double-blind phase III trial of adjuvant chemotherapy with and without bevacizumab in patients with lymph node-positive and high-risk lymph node-negative breast cancer (E5103). J Clin Oncol. 2018 Sep 1;36(25):2621-2629. Epub 2018 Jul 24. [https://doi.org/10.1200/JCO.2018.79.2028 link to original article] '''refers to ECOG E1199 protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6118403/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30040523/ PubMed] [https://clinicaltrials.gov/study/NCT00433511 NCT00433511]
 +
# '''NSABP B-47:''' Fehrenbacher L, Cecchini RS, Geyer CE Jr, Rastogi P, Costantino JP, Atkins JN, Crown JP, Polikoff J, Boileau JF, Provencher L, Stokoe C, Moore TD, Robidoux A, Flynn PJ, Borges VF, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020 Feb 10;38(5):444-453. Epub 2019 Dec 10. [https://doi.org/10.1200/jco.19.01455 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7007289/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31821109/ PubMed] [https://clinicaltrials.gov/study/NCT01275677 NCT01275677]
 +
#'''USON 01062:''' [https://clinicaltrials.gov/study/NCT00089479 NCT00089479]
  
−
==AC -> T (Taxotere) {{#subobject:b7307c|Regimen=1}}==
+
==ddAC-T {{#subobject:bug936|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
ddAC-T: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>C</u>'''yclophosphamide followed by '''<u>T</u>'''axol (Paclitaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:chnz10|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6118403/ Miller et al. 2018 (ECOG E5103)]
 +
|2007-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#AC-T_.26_Bevacizumab_999|AC-T & Bevacizumab]]<br>1b. [[#ddAC-T_.26_Bevacizumab_999|ddAC-T & Bevacizumab]]<br>2a. [[#AC-T_.26_Bevacizumab_999|AC-T & Bevacizumab]], then [[#Bevacizumab_monotherapy|Bevacizumab]]<br>2b. [[#ddAC-T_.26_Bevacizumab_999|ddAC-T & Bevacizumab]], then [[#Bevacizumab_monotherapy|Bevacizumab]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of IDFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7007289/ Fehrenbacher et al. 2019 (NSABP B-47)]
 +
|2011-2015
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#AC-TH_999|AC-TH]]<br>1b. [[#Dose-dense_AC-TH_999|ddAC-TH]]<br>1c. [[#TCH_999|TCH]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of IDFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
AC -> T: '''<u>A</u>'''driamycin, '''<u>C</u>'''ytoxan -> '''<u>T</u>'''axotere
+
''Note: Fehrenbacher et al. 2019 does not explicitly describe the use of filgrastim, but it is typically used for the dose-dense portion of this regimen.''
−
 
+
<div class="toccolours" style="background-color:#fdcdac">
−
===Example orders===
+
====Biomarker eligibility criteria====
−
*[[Example orders for AC to T (Taxotere) in breast cancer]]
+
*NSABP B-47: HER2 IHC of 1+ or 2+ with FISH ratio less than 2 or HER2 gene copy number less than 4
−
 
+
</div>
−
===Regimen {{#subobject:199d79|Variant=1}}===
+
<div class="toccolours" style="background-color:#cbd5e8">
−
Level of Evidence:
+
====Preceding treatment====
−
<span
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
style="background:#00CD00;
+
</div>
−
padding:3px 6px 3px 6px;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
border-color:black;
+
====Chemotherapy, ddAC portion (cycles 1 to 4)====
−
border-width:2px;
+
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
−
border-style:solid;">Phase III</span>
+
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
−
 
+
====Supportive therapy, ddAC portion (cycles 1 to 4)====
−
*[[Doxorubicin (Adriamycin)]] 60 mg/m2 IV day 1
+
*[[Filgrastim (Neupogen)]] 5 mcg/kg (rounded to either 300 or 480 mcg) SC once per day on days 3 to 10
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV day 1
+
====Chemotherapy, T portion (cycles 5 to 16)====
−
 
+
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once on day 1
−
'''21-day cycles x 4 cycles, THEN'''
+
'''14-day cycle for 4 cycles, then 7-day cycle for 12 cycles (AC x 4; T x 12)'''
−
 
+
</div></div>
−
*[[Docetaxel (Taxotere)]] 100 mg/m2 IV day 1
 
−
 
 
−
'''21-day cycles x 4 cycles'''
 
  
 
===References===
 
===References===
−
# Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. [http://www.nejm.org/doi/full/10.1056/NEJMoa0707056 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18420499 PubMed]
+
# '''ECOG E5103:''' Miller KD, O'Neill A, Gradishar W, Hobday TJ, Goldstein LJ, Mayer IA, Bloom S, Brufsky AM, Tevaarwerk AJ, Sparano JA, Le-Lindqwister NA, Hendricks CB, Northfelt DW, Dang CT, Sledge GW Jr. Double-blind phase III trial of adjuvant chemotherapy with and without bevacizumab in patients with lymph node-positive and high-risk lymph node-negative breast cancer (E5103). J Clin Oncol. 2018 Sep 1;36(25):2621-2629. Epub 2018 Jul 24. [https://doi.org/10.1200/JCO.2018.79.2028 link to original article] '''refers to ECOG E1199 protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6118403/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30040523/ PubMed] [https://clinicaltrials.gov/study/NCT00433511 NCT00433511]
 +
# '''NSABP B-47:''' Fehrenbacher L, Cecchini RS, Geyer CE Jr, Rastogi P, Costantino JP, Atkins JN, Crown JP, Polikoff J, Boileau JF, Provencher L, Stokoe C, Moore TD, Robidoux A, Flynn PJ, Borges VF, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020 Feb 10;38(5):444-453. Epub 2019 Dec 10. [https://doi.org/10.1200/jco.19.01455 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7007289/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31821109/ PubMed] [https://clinicaltrials.gov/study/NCT01275677 NCT01275677]
  
−
==Paclitaxel (Taxol) {{#subobject:5218a|Regimen=1}}==
+
==ddAC-ddT {{#subobject:b594g6|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
ddAC-ddT: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>C</u>'''yclophosphamide followed by '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>T</u>'''axol (Paclitaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 4x4 {{#subobject:cyrqd0|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1200/jco.2003.09.081 Citron et al. 2003 (CALGB 9741)]
 +
|rowspan=2|1997-1999
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[#A-T-C_999|A-T-C]]<br>2. [[#AC-T_2|AC-T]]
 +
| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br><br>Superior DFS (primary endpoint)
 +
|-
 +
|3. [[#ddA-ddC-ddT|ddA-ddC-ddT]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757290/ Swain et al. 2013 (NSABP B-38)]
 +
| rowspan="2" |2004-2007
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#TAC_.28Docetaxel.29_2|TAC]] x 6
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|2. [[#ddAC-ddPG_999|ddAC-ddPG]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172658/ Sparano et al. 2018 (TAILORx)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer,_ER-positive_-_null_regimens#Observation|No chemotherapy]]
 +
| style="background-color:#eeee01" |Non-inferior IDFS (primary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen, Shulman et al. 2012 (CALGB 40101) {{#subobject:d853ac|Variant=1}}===
+
<div class="toccolours" style="background-color:#fdcdac">
−
Level of Evidence:
+
====Eligibility criteria====
−
<span
+
*TAILORx: Oncotype DX score of 11 to 25
−
style="background:#00CD00;
+
</div>
−
padding:3px 6px 3px 6px;
+
<div class="toccolours" style="background-color:#cbd5e8">
−
border-color:black;
+
====Preceding treatment====
−
border-width:2px;
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
border-style:solid;">Phase III</span>
+
</div>
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Paclitaxel (Taxol)]] 175 mg/m2 IV over 3 hours on day 1
+
====Chemotherapy, ddAC portion (cycles 1 to 4)====
−
 
+
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
−
'''14-day cycles x 4 cycles'''
+
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
−
 
+
====Supportive therapy, ddAC portion (cycles 1 to 4)====
−
Supportive medications:
+
*[[Filgrastim (Neupogen)]] 5 mcg/kg (rounded to either 300 or 480 mcg) SC once per day on days 3 to 10
−
*Diphenhydramine (Benadryl) 12.5-50 mg IV 30-60 minutes prior to paclitaxel
+
**Note: Citron et al. 2003 says the schedule was "filgrastim days 3 to 10 of each cycle (a total of seven doses)," so it is unclear whether 7 or 8 doses was actually used).
 +
====Chemotherapy, ddT portion (cycles 5 to 8)====
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
 +
====Supportive therapy, ddT portion (cycles 5 to 8)====
 +
*[[Diphenhydramine (Benadryl)]] 12.5 to 50 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
 
*One of the following H2 blockers:
 
*One of the following H2 blockers:
−
**Ranitidine (Zantac) 50 mg IV 30-60 minutes prior to paclitaxel
+
**[[Ranitidine (Zantac)]] 50 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
−
**Cimetidine (Tagamet) 300 mg IV 30-60 minutes prior to paclitaxel
+
**[[Cimetidine (Tagamet)]] 300 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
−
**Famotidine (Pepcid) 20 mg IV 30-60 minutes prior to paclitaxel
+
**[[Famotidine (Pepcid)]] 20 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
 
*One of the following dexamethasone choices:
 
*One of the following dexamethasone choices:
−
**[[Dexamethasone (Decadron)]] 10 mg IV <60 minutes prior to paclitaxel
+
**[[Dexamethasone (Decadron)]] 10 mg IV once on day 1, within 60 minutes prior to paclitaxel
−
**[[Dexamethasone (Decadron)]] 10 mg PO >60 minutes prior to paclitaxel
+
**[[Dexamethasone (Decadron)]] 10 mg PO once on day 1, at least 60 minutes prior to paclitaxel
−
**[[Dexamethasone (Decadron)]] 20 mg PO 6 hours and 12 hour prior to paclitaxel
+
**[[Dexamethasone (Decadron)]] 20 mg PO twice on day 1; 6 hours and 12 hours prior to paclitaxel
−
*Recommended growth factor support with one of the following:
+
*Recommended growth factor support with one of the following choices:
−
**[[Filgrastim (Neupogen)]] 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC on days 3-10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"  
+
**[[Filgrastim (Neupogen)]] 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"  
−
**[[Sargramostim (Leukine)]] 250-500 mcg/m2 SC on days 3-10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"  
+
**[[Sargramostim (Leukine)]] 250 to 500 mcg/m<sup>2</sup> SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"  
−
**[[Pegfilgrastim (Neulasta)]] 6 mg SC, administered once 24-36 hours after chemotherapy
+
**[[Pegfilgrastim (Neulasta)]] 6 mg SC once, given 24 to 36 hours after chemotherapy
 +
***GIM2: a mid-protocol amendment suggested giving the pegilgrastim at least 72 h after chemotherapy
 +
'''14-day cycle for 8 cycles (ddAC x 4; ddT x 4)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 6x6 {{#subobject:33516a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268253/ Budd et al. 2014 (SWOG S0221)]
 +
|2003-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#AC-ddT_999|AC-ddT]]; continuous AC<br>2. [[#AC-T_999|AC-T]]; continuous AC & weekly paclitaxel<br>3. [[#AC-T_999|AC-T]]; weekly paclitaxel
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, ddAC portion (cycles 1 to 6)====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, ddT portion (cycles 7 to 12)====
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
 +
====Supportive therapy, all portions (cycles 1 to 12)====
 +
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2
 +
'''14-day cycle for 12 cycles (ddAC x 6; ddT x 6)'''
 +
</div></div>
  
 
===References===
 
===References===
−
# Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Jul 23. [Epub ahead of print] [http://jco.ascopubs.org/content/early/2012/07/23/JCO.2011.40.6405.long link to original article] '''contains verified protocol''' [http://jco.ascopubs.org/content/suppl/2012/07/23/JCO.2011.40.6405.DC1/Protocol.pdf link to study protocol PDF] [http://www.ncbi.nlm.nih.gov/pubmed/22826271 PubMed]  
+
# '''CALGB 9741:''' Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. [https://doi.org/10.1200/jco.2003.09.081 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12668651/ PubMed] [https://clinicaltrials.gov/study/NCT00003088 NCT00003088]
 +
# '''NSABP B-38:''' Swain SM, Tang G, Geyer CE Jr, Rastogi P, Atkins JN, Donnellan PP, Fehrenbacher L, Azar CA, Robidoux A, Polikoff JA, Brufsky AM, Biggs DD, Levine EA, Zapas JL, Provencher L, Northfelt DW, Paik S, Costantino JP, Mamounas EP, Wolmark N. Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial. J Clin Oncol. 2013 Sep 10;31(26):3197-204. Epub 2013 Aug 12. [https://doi.org/10.1200/JCO.2012.48.1275 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757290/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23940225/ PubMed] [https://clinicaltrials.gov/study/NCT00093795 NCT00093795]
 +
# '''SWOG S0221:''' Budd GT, Barlow WE, Moore HC, Hobday TJ, Stewart JA, Isaacs C, Salim M, Cho JK, Rinn KJ, Albain KS, Chew HK, Burton GV, Moore TD, Srkalovic G, McGregor BA, Flaherty LE, Livingston RB, Lew DL, Gralow JR, Hortobagyi GN. SWOG S0221: a phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer. J Clin Oncol. 2015 Jan 1;33(1):58-64. Epub 2014 Nov 24. [https://doi.org/10.1200/JCO.2014.56.3296 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268253/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/25422488/ PubMed] [https://clinicaltrials.gov/study/NCT00070564 NCT00070564]
 +
# '''TAILORx:''' Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. [https://doi.org/10.1056/NEJMoa1804710 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172658/ link to PMC article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/29860917/ PubMed] [https://clinicaltrials.gov/study/NCT00310180 NCT00310180]
  
−
==TAC {{#subobject:ed77a6|Regimen=1}}==
+
==AT-CMF {{#subobject:0ed69b|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
AT-CMF: '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>T</u>'''axol (Paclitaxel) followed by '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:61e706|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1200/JCO.2008.19.2567 Gianni et al. 2009 (ECTO)]
 +
|rowspan=2|1996-2002
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[#A-CMF|A-CMF]]
 +
| style="background-color:#91cf60" |Seems to have superior RFS (primary endpoint)<br>RFS84: 76% vs 69%<br>(HR 0.73, 95% CI 0.57-0.97)
 +
|-
 +
|2. [[#AT-CMF_999|AT-CMF]]; neoadjuvant
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, AT portion (cycles 1 to 4)====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1
 +
====Chemotherapy, CMF portion (cycles 5 to 8)====
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (AT x 4; CMF x 4)'''
 +
</div></div>
 +
===References===
 +
# '''ECTO:''' Gianni L, Baselga J, Eiermann W, Porta VG, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Cussac AL, Bozhok A, Martinez-Agulló A, Greco M, Byakhov M, Lopez JJ, Mansutti M, Valagussa P, Bonadonna G. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. J Clin Oncol. 2009 May 20;27(15):2474-81. Epub 2009 Mar 30. [https://doi.org/10.1200/JCO.2008.19.2567 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19332727/ PubMed] [https://clinicaltrials.gov/study/NCT00003013 NCT00003013]
 +
==CMF-E {{#subobject:fdhr3c|Regimen=1}}==
 +
CMF-E: '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil, followed by '''<u>E</u>'''pirubicin
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:b83fae|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1200/JCO.1990.8.8.1310 Boccardo et al. 1990 (GROCTA-1)]
 +
|rowspan=2|1983-1987
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_3|Tamoxifen]] x 5 y
 +
| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
 +
|-
 +
|2. [[#CMFT-ET_888|CMFT-ET]]
 +
|style="background-color:#d73027"|Inferior OS<sup>1</sup>
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy is based on the 2011 update.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, CMF portion (cycles 1 to 6)====
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, E portion (cycles 7 to 10)====
 +
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 10 cycles (CMF x 6; E x 4)'''
 +
</div></div>
 +
===References===
 +
# '''GROCTA-1:''' Boccardo F, Rubagotti A, Bruzzi P, Cappellini M, Isola G, Nenci I, Piffanelli A, Scanni A, Sismondi P, Santi L, Genta F, Saccani F, Sassi M, Malacarne P, Donati D, Farris A, Castagnetta L, Di Carlo A, Traina A, Galletto L, Smerieri F, Buzzi F; Breast Cancer Adjuvant Chemo-Hormone Therapy Cooperative Group. Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, estrogen receptor-positive breast cancer patients: results of a multicentric Italian study. J Clin Oncol. 1990 Aug;8(8):1310-20. [https://doi.org/10.1200/JCO.1990.8.8.1310 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2199618/ PubMed]
 +
## '''Update:''' Boccardo F, Guglielmini P, Parodi A, Rubagotti A. Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, oestrogen receptor-positive breast cancer patients: very late results of the 'gruppo di ricerca per la chemio-ormonoterapia adiuvante (GROCTA)' 01-Trial in early breast cancer. Breast Cancer Res Treat. 2011 Apr;126(3):653-61. Epub 2011 Feb 24. [https://doi.org/10.1007/s10549-011-1405-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21347647/ PubMed]
 +
==D-EC {{#subobject:fd4ug8|Regimen=1}}==
 +
D-EC: '''<u>D</u>'''ocetaxel followed by '''<u>E</u>'''pirubicin and '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:1aad71|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1007/s10549-009-0468-0 Polyzos et al. 2009]
 +
|1995-2004
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#FEC_2|FEC]]
 +
| style="background-color:#91cf60" |Seems to have superior DFS60 (primary endpoint)<br>DFS60: 72.6% vs 67.2%
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
TAC: '''<u>T</u>'''axotere, '''<u>A</u>'''driamycin, '''<u>C</u>'''ytoxan
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, D portion (cycles 1 to 4)====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
====Chemotherapy, EC portion (cycles 5 to 8)====
 +
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 700 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 8 cycles (D x 4; EC x 4)'''
 +
</div></div>
 +
===References===
 +
# Polyzos A, Malamos N, Boukovinas I, Adamou A, Ziras N, Kalbakis K, Kakolyris S, Syrigos K, Papakotoulas P, Kouroussis C, Karvounis N, Vamvakas L, Christophyllakis C, Athanasiadis A, Varthalitis I, Georgoulias V, Mavroudis D; Hellenic Oncology Research Group. FEC versus sequential docetaxel followed by epirubicin/cyclophosphamide as adjuvant chemotherapy in women with axillary node-positive early breast cancer: a randomized study of the Hellenic Oncology Research Group (HORG). Breast Cancer Res Treat. 2010 Jan;119(1):95-104. Epub 2009 Jul 28. [https://doi.org/10.1007/s10549-009-0468-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19636702/ PubMed]
 +
==D-FEC {{#subobject:fdhg38|Regimen=1}}==
 +
D-FEC: '''<u>D</u>'''ocetaxel followed by '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide
 +
<br>T-CEF: '''<u>T</u>'''axotere (Docetaxel) followed by <u>C</u>'''yclophosphamide, '''<u>E</u>'''pirubicin, '''<u>F</u>'''luorouracil'''
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:1zzk71|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/s1470-2045(09)70307-9 Joensuu et al. 2009 (FinXX)]
 +
|2004-2007
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#TX-CEX|TX-CEX]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy is based on the 2022 update.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, D portion (cycles 1 to 3)====
 +
*[[Docetaxel (Taxotere)]] 80 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
====Chemotherapy, FEC portion (cycles 4 to 6)====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles (D x 3; FEC x 3)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2 {{#subobject:bfeef2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| [https://doi.org/10.1056/NEJMoa053028 Joensuu et al. 2006 (FinHer)]
 +
| 2000-2003
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#V-FEC|V-FEC]]
 +
| style="background-color:#1a9850" |Superior DDFS (secondary endpoint)
 +
|-
 +
|}
 +
''Note: this was the study design for HER2-negative patients.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]] with [[Surgery#Axillary_lymph_node_dissection|axillary lymph node dissection]] or [[Surgery#Sentinel_lymph_node_biopsy|sentinel lymph node biopsy]], within 12 weeks
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, D portion (cycles 1 to 3)====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
====Chemotherapy, FEC portion (cycles 4 to 6)====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles (D x 3; FEC x 3)'''
 +
</div></div>
 +
===References===
 +
<!-- no pre-pub disclosed -->
 +
# '''FinHer:''' Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. [https://doi.org/10.1056/NEJMoa053028 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16495393/ PubMed] ISRCTN76560285
 +
## '''Update:''' Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. Epub 2009 Nov 2. [https://doi.org/10.1200/JCO.2008.21.4577 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19884557/ PubMed]
 +
# '''FinXX:''' Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Asola R, Kokko R, Ahlgren J, Auvinen P, Hemminki A, Paija O, Helle L, Nuortio L, Villman K, Nilsson G, Lahtela SL, Lehtiö K, Pajunen M, Poikonen P, Nyandoto P, Kataja V, Bono P, Leinonen M, Lindman H; FinXX Study Investigators. Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer: an open-label, randomised controlled trial. Lancet Oncol. 2009 Dec;10(12):1145-51. Epub 2009 Nov 10. [https://doi.org/10.1016/s1470-2045(09)70307-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19906561/ PubMed] [https://clinicaltrials.gov/study/NCT00114816 NCT00114816]
 +
## '''Update:''' Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Kokko R, Ahlgren J, Auvinen P, Paija O, Helle L, Villman K, Nyandoto P, Nilsson G, Pajunen M, Asola R, Poikonen P, Leinonen M, Kataja V, Bono P, Lindman H. Adjuvant capecitabine, docetaxel, cyclophosphamide, and epirubicin for early breast cancer: final analysis of the randomized FinXX trial. J Clin Oncol. 2012 Jan 1;30(1):11-8. Epub 2011 Nov 21. [https://doi.org/10.1200/JCO.2011.35.4639 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22105826/ PubMed]
 +
## '''Update:''' Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola A, Tanner M, Ahlgren J, Auvinen P, Lahdenperä O, Villman K, Nyandoto P, Nilsson G, Poikonen-Saksela P, Kataja V, Bono P, Junnila J, Lindman H. Adjuvant Capecitabine for Early Breast Cancer: 15-Year Overall Survival Results From a Randomized Trial. J Clin Oncol. 2022 Apr 1;40(10):1051-1058. Epub 2022 Jan 12. [https://doi.org/10.1200/jco.21.02054 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8966968/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35020465/ PubMed]
  
−
===Regimen {{#subobject:9660e9|Variant=1}}===
+
==E-CMF {{#subobject:fd4rf3|Regimen=1}}==
−
Level of Evidence:
+
E-CMF: '''<u>E</u>'''pirubicin followed by '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil
−
<span
+
<div class="toccolours" style="background-color:#eeeeee">
−
style="background:#00CD00;
+
===Regimen variant #1, 100/750/50/600 {{#subobject:agbd2f|Variant=1}}===
−
padding:3px 6px 3px 6px;
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
border-color:black;
+
!style="width: 20%"|Study
−
border-width:2px;
+
!style="width: 20%"|Dates of enrollment
−
border-style:solid;">Phase III</span>
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
 
+
!style="width: 20%"|Comparator
−
*[[Docetaxel (Taxotere)]] 75 mg/m2 IV over 1 hour on day 1 (administered third, one hour after cyclophosphamide)
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
*[[Doxorubicin (Adriamycin)]] 50 mg/m2 IV over 15 minutes on day 1 (administered first)
+
|-
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m2 IV over 1 to 5 minutes on day 1 (administered second)
+
|[https://doi.org/10.1056/nejmoa052084 Poole et al. 2006 (BR9601)]
−
*[[Dexamethasone]] 8 mg PO every 12 hours x 6 total doses, starting the day before treatment
+
|1996-2001
−
*Ciprofloxacin 500 mg PO BID on days 5-14 of every cycle (prophylaxis)
+
| style="background-color:#1a9851" |Phase 3 (E-esc)
−
*G-CSF not originally routinely administered unless patients had febrile neutropenia, but NCCN currently recommends routine filgrastim support:
+
|[[#CMF|CMF]] x 6
−
:*[[Filgrastim (Neupogen)]] 5 mcg/kg SC on days 4-11
+
| style="background-color:#1a9850" |Superior OS<sup>1</sup> (co-primary endpoint)<br>OS60: 84% vs 78%<br>(HR 0.76, 95% CI 0.65-0.89)
−
:*Lenograstim 150 mcg/m2 on days 4-11
+
|-
−
 
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7005671/ Fernando et al. 2019 (SECRAB)]
−
'''21-day cycles x 6 cycles'''
+
|1998-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#CMF_.26_RT_888|CMF & RT]]<br>1b. [[#E-CMF_.26_RT_888|E-CMF & RT]]<br>1c. [[#A-CMF_.26_RT_888|A-CMF & RT]]<br>1d. [[#MMM_.26_RT_888|MMM & RT]]
 +
| style="background-color:#d73027" |Inferior LRFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7840116/ Delaloge et al. 2020 (MINDACT)]
 +
|2007-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Docetaxel_.28TX.29_999|TX]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy is based on the 2012 update.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, E portion (cycles 1 to 4)====
 +
*[[Epirubicin (Ellence)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, CMF portion (cycles 5 to 8)====
 +
*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
 +
*[[Methotrexate (MTX)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 8 cycles (E x 4; CMF x 4)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 100/1200/80/1200 {{#subobject:5u5d2f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/nejmoa052084 Poole et al. 2006 (NEAT)]
 +
|1996-2001
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#CMF|CMF]] x 6
 +
| style="background-color:#1a9850" |Superior OS<sup>1</sup> (co-primary endpoint)<br>OS60: 84% vs 78%<br>(HR 0.76, 95% CI 0.65-0.89)
 +
|-
 +
|[https://doi.org/10.1159/000315735 Boccardo et al. 2010]
 +
|1997-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#T-EV_999|T-EV]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of OS
 +
|-
 +
|[https://doi.org/10.1007/s10549-010-1257-5 Amadori et al. 2010 (IRST-IBIS-03)]
 +
|1997-2004
 +
|style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#CMF-E|CMF-E]]
 +
|style="background-color:#ffffbf"|Did not meet endpoint of OS60
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7005671/ Fernando et al. 2019 (SECRAB)]
 +
|1998-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#CMF_.26_RT_888|CMF & RT]]<br>1b. [[#E-CMF_.26_RT_888|E-CMF & RT]]<br>1c. [[#A-CMF_.26_RT_888|A-CMF & RT]]<br>1d. [[#MMM_.26_RT_888|MMM & RT]]
 +
| style="background-color:#d73027" |Inferior LRFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2687939/ Ellis et al. 2009 (TACT)]
 +
|2001-2003
 +
|style="background-color:#1a9851"|Phase 3 (C)
 +
|[[#FEC-D_2|FEC-D]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of DFS
 +
|-
 +
|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489700/ Cameron et al. 2017 (TACT2)]
 +
|rowspan=2|2005-2008
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#E-X|E-X]]
 +
| style="background-color:#eeee01" |Non-inferior TTR (primary endpoint)
 +
|-
 +
|2. [[#ddE-CMF_999|ddE-CMF]]<br>3. [[#ddE-X|ddE-X]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of TTR
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy is based on the 2012 update.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, E portion (cycles 1 to 4)====
 +
*[[Epirubicin (Ellence)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, CMF portion (cycles 5 to 8)====
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (E x 4; CMF x 4)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
 +
===Regimen variant #3, 100/1400/80/1200 ("classic CMF") {{#subobject:91td2f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/nejmoa052084 Poole et al. 2006 (NEAT)]
 +
|1996-2001
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#CMF|CMF]] x 6
 +
| style="background-color:#1a9850" |Superior OS<sup>1</sup> (co-primary endpoint)<br>OS60: 84% vs 78%<br>(HR 0.76, 95% CI 0.65-0.89)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7005671/ Fernando et al. 2019 (SECRAB)]
 +
|1998-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#CMF_.26_RT_888|CMF & RT]]<br>1b. [[#E-CMF_.26_RT_888|E-CMF & RT]]<br>1c. [[#A-CMF_.26_RT_888|A-CMF & RT]]<br>1d. [[#MMM_.26_RT_888|MMM & RT]]
 +
| style="background-color:#d73027" |Inferior LRFS
 +
|-
 +
|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489700/ Cameron et al. 2017 (TACT2)]
 +
|rowspan=2|2005-2008
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#E-X|E-X]]
 +
| style="background-color:#eeee01" |Non-inferior TTR (primary endpoint)
 +
|-
 +
|2. [[#ddE-CMF_999|ddE-CMF]]<br>3. [[#ddE-X|ddE-X]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of TTR
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7840116/ Delaloge et al. 2020 (MINDACT)]
 +
|2007-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Docetaxel_.28TX.29_999|TX]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy is based on the 2012 update.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, E portion (cycles 1 to 4)====
 +
*[[Epirubicin (Ellence)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, CMF portion (cycles 5 to 8)====
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (E x 4; CMF x 4)'''
 +
</div></div>
 +
===References===
 +
<!-- no pre-pub disclosed -->
 +
# '''NEAT:''' Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. [https://doi.org/10.1056/nejmoa052084 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17079759/ PubMed] [https://clinicaltrials.gov/study/NCT00003577 NCT00003577]
 +
## '''Update:''' Earl HM, Hiller L, Dunn JA, Vallier AL, Bowden SJ, Jordan SD, Blows F, Munro A, Bathers S, Grieve R, Spooner DA, Agrawal R, Fernando I, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, McAdam K, Foster L, Leonard RC, Twelves CJ, Cameron D, Bartlett JM, Pharoah P, Provenzano E, Caldas C, Poole CJ; NEAT Investigators and the SCTBG. Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials. Br J Cancer. 2012 Oct 9;107(8):1257-67. Epub 2012 Sep 11. [https://doi.org/10.1038/bjc.2012.370 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494422/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23047592/ PubMed]
 +
<!-- no pre-pub disclosed -->
 +
# '''BR9601:''' Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. [https://doi.org/10.1056/nejmoa052084 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17079759/ PubMed] [https://clinicaltrials.gov/study/NCT00003012 NCT00003012]
 +
## '''Update:''' Earl HM, Hiller L, Dunn JA, Vallier AL, Bowden SJ, Jordan SD, Blows F, Munro A, Bathers S, Grieve R, Spooner DA, Agrawal R, Fernando I, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, McAdam K, Foster L, Leonard RC, Twelves CJ, Cameron D, Bartlett JM, Pharoah P, Provenzano E, Caldas C, Poole CJ; NEAT Investigators and the SCTBG. Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials. Br J Cancer. 2012 Oct 9;107(8):1257-67. Epub 2012 Sep 11. [https://doi.org/10.1038/bjc.2012.370 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494422/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23047592/ PubMed]
 +
# '''TACT:''' Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. [https://doi.org/10.1016/S0140-6736(09)60740-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2687939/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19447249/ PubMed] ISRCTN79718493
 +
# Boccardo F, Amadori D, Guglielmini P, Sismondi P, Farris A, Agostara B, Gambi A, Catalano G, Faedi M, Rubagotti A. Epirubicin followed by cyclophosphamide, methotrexate and 5-fluorouracil versus paclitaxel followed by epirubicin and vinorelbine in patients with high-risk operable breast cancer. Oncology. 2010;78(3-4):274-81. Epub 2010 Jun 8. [https://doi.org/10.1159/000315735 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/20530973/ PubMed]
 +
# '''IRST-IBIS-03:''' Amadori D, Silvestrini R, De Lena M, Boccardo F, Rocca A, Scarpi E, Schittulli F, Brandi M, Maltoni R, Serra P, Ponzone R, Biglia N, Gianni L, Tienghi A, Valerio MR, Bonginelli P, Amaducci L, Faedi M, Baldini E, Paradiso A. Randomized phase III trial of adjuvant epirubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) versus CMF followed by epirubicin in patients with node-negative or 1-3 node-positive rapidly proliferating breast cancer. Breast Cancer Res Treat. 2011 Feb;125(3):775-84. Epub 2010 Dec 4. [https://doi.org/10.1007/s10549-010-1257-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21132360/ PubMed] [https://clinicaltrials.gov/study/NCT01031030 NCT01031030]
 +
# '''TACT2:''' Cameron D, Morden JP, Canney P, Velikova G, Coleman R, Bartlett J, Agrawal R, Banerji J, Bertelli G, Bloomfield D, Brunt AM, Earl H, Ellis P, Gaunt C, Gillman A, Hearfield N, Laing R, Murray N, Couper N, Stein RC, Verrill M, Wardley A, Barrett-Lee P, Bliss JM; TACT2 Investigators. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2017 Jul;18(7):929-945. Epub 2017 Jun 7. [https://doi.org/10.1016/S1470-2045(17)30404-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489700/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28600210/ PubMed] [https://clinicaltrials.gov/study/NCT00301925 NCT00301925]
 +
##'''HRQoL analysis:''' Velikova G, Morden JP, Haviland JS, Emery C, Barrett-Lee P, Earl H, Bloomfield D, Brunt AM, Canney P, Coleman R, Verrill M, Wardley A, Bertelli G, Ellis P, Stein R, Bliss JM, Cameron D; TACT2 Trial Management Group. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer (UK TACT2; CRUK/05/19): quality of life results from a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2023 Dec;24(12):1359-1374. Epub 2023 Nov 2. Erratum in: Lancet Oncol. 2023 Dec;24(12):e459. [https://doi.org/10.1016/s1470-2045(23)00460-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37926100/ PubMed]
 +
# '''SECRAB:''' Fernando IN, Bowden SJ, Herring K, Brookes CL, Ahmed I, Marshall A, Grieve R, Churn M, Spooner D, Latief TN, Agrawal RK, Brunt AM, Stevens A, Goodman A, Canney P, Bishop J, Ritchie D, Dunn J, Poole CJ, Rea DW; SECRAB Investigators. Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial. Radiother Oncol. 2020 Jan;142:52-61. Epub 2019 Nov 27. [https://doi.org/10.1016/j.radonc.2019.10.014 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7005671/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31785830/ PubMed] [https://clinicaltrials.gov/study/NCT00003893 NCT00003893]
 +
# '''MINDACT:''' Delaloge S, Piccart M, Rutgers E, Litière S, van 't Veer LJ, van den Berkmortel F, Brain E, Dudek-Peric A, Gil-Gil M, Gomez P, Hilbers FS, Khalil Z, Knox S, Kuemmel S, Kunz G, Lesur A, Pierga JY, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Thompson AM, Viale G, Zoppoli G, Vuylsteke P, Tryfonidis K, Poncet C, Bogaerts J, Cardoso F; MINDACT investigators and the TRANSBIG Consortium. Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial. J Clin Oncol. 2020 Apr 10;38(11):1186-1197. Epub 2020 Feb 21. [https://doi.org/10.1200/jco.19.01371 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7840116/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32083990/ PubMed] [https://clinicaltrials.gov/study/NCT00433589 NCT00433589]
 +
==ddE-iddCMF {{#subobject:fdaj93|Regimen=1}}==
 +
ddE-iddCMF: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>E</u>'''pirubicin, followed by '''<u>i</u>'''ntense '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:91cbc2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdi366 Fountzilas et al. 2005 (HE 10/97)]
 +
|1997-2000
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#ddE-T-iddCMF|ddE-T-iddCMF]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, ddE portion (cycles 1 to 4)====
 +
*[[Epirubicin (Ellence)]] 110 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, CMF portion (cycles 5 to 7)====
 +
*[[Cyclophosphamide (Cytoxan)]] 840 mg/m<sup>2</sup> IV once on day 1
 +
*[[Methotrexate (MTX)]] 57 mg/m<sup>2</sup> IV once on day 1
 +
*[[Fluorouracil (5-FU)]] 840 mg/m<sup>2</sup> IV once on day 1
 +
====Supportive therapy, all portions (cycles 1 to 7)====
 +
*[[Filgrastim (Neupogen)]]
 +
'''14-day cycle for 7 cycles (ddE x 4; iddCMF x 3)'''
 +
</div></div>
 
===References===
 
===References===
−
# Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C; Breast Cancer International Research Group 001 Investigators. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med. 2005 Jun 2;352(22):2302-13. [http://www.nejm.org/doi/full/10.1056/NEJMoa043681 link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15930421 PubMed]
+
# '''HE 10/97:''' Fountzilas G, Skarlos D, Dafni U, Gogas H, Briasoulis E, Pectasides D, Papadimitriou C, Markopoulos C, Polychronis A, Kalofonos HP, Siafaka V, Kosmidis P, Timotheadou E, Tsavdaridis D, Bafaloukos D, Papakostas P, Razis E, Makrantonakis P, Aravantinos G, Christodoulou C, Dimopoulos AM; Hellenic Cooperative Oncology Group. Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol. 2005 Nov;16(11):1762-71. Epub 2005 Sep 7. [https://doi.org/10.1093/annonc/mdi366 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16148021/ PubMed]
  
−
==TC {{#subobject:2d2f0e|Regimen=1}}==
+
==E-D {{#subobject:8knrf3|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
E-D: '''<u>E</u>'''pirubicin followed by '''<u>D</u>'''ocetaxel
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:bf8gub|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.32.7254 Coombes et al. 2011 (DEVA)]
 +
|1997-2005
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Epirubicin_monotherapy_2|Epirubicin]]
 +
| style="background-color:#1a9850" |Superior DFS (primary endpoint)<br>DFS60: 79.5% vs 72.7%<br>(HR 0.68, 95% CI 0.52-0.91)<br><br>Superior OS (secondary endpoint)<br>OS60: 88.9% vs 81.8%<br>(HR 0.66, 95% CI 0.46-0.94)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
TC: '''<u>T</u>'''axotere, '''<u>C</u>'''ytoxan
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, E portion (cycles 1 to 3)====
 +
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
====Chemotherapy, D portion (cycles 4 to 6)====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
'''28-day cycle for 3 cycles, then 21-day cycle for 3 cycles (E x 3; D x 3)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
===Regimen {{#subobject:e9499f|Variant=1}}===
+
===Regimen variant #2 {{#subobject:bf8gub|Variant=1}}===
−
Level of Evidence:
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
<span
+
!style="width: 20%"|Study
−
style="background:#00CD00;
+
!style="width: 20%"|Dates of enrollment
−
padding:3px 6px 3px 6px;
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
border-color:black;
+
!style="width: 20%"|Comparator
−
border-width:2px;
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
border-style:solid;">Phase III</span>
+
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584474/ Mavroudis et al. 2017 (HORG CT/01.04)]
 +
|2001-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Epirubicin_999|Docetaxel & Epirubicin]]
 +
| style="background-color:#d9ef8b" |Might have superior DFS (primary endpoint)<br>DFS60: 92.6% vs 88.2%<br>(HR 0.63, 95% CI 0.39-1.01)
 +
|-
 +
|}
 +
''Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, E portion (cycles 1 to 4)====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV over 5 to 15 minutes once on day 1
 +
====Chemotherapy, D portion (cycles 5 to 8)====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
'''21-day cycle for 8 cycles (E x 4; D x 4)'''
 +
</div></div>
  
−
'''All cycles given with [[Filgrastim (Neupogen)]] support'''
+
===References===
−
*[[Docetaxel (Taxotere)]] 75 mg/m2 IV day 1
+
<!-- Presented at the 46th Annual Meeting of the American Society of Clinical Oncology, June 4-8, 2010, Chicago, IL. -->
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV day 1
+
# '''DEVA:''' Coombes RC, Bliss JM, Espie M, Erdkamp F, Wals J, Tres A, Marty M, Coleman RE, Tubiana-Mathieu N, den Boer MO, Wardley A, Kilburn LS, Cooper D, Thomas MW, Reise JA, Wilkinson K, Hupperets P. Randomized, phase III trial of sequential epirubicin and docetaxel versus epirubicin alone in postmenopausal patients with node-positive breast cancer. J Clin Oncol. 2011 Aug 20;29(24):3247-54. Epub 2011 Jul 18. [https://doi.org/10.1200/JCO.2010.32.7254 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21768453/ PubMed] ISRCTN89772270
 +
# '''HORG CT/01.04:''' Mavroudis D, Saloustros E, Boukovinas I, Papakotoulas P, Kakolyris S, Ziras N, Christophylakis C, Kentepozidis N, Fountzilas G, Rigas G, Varthalitis I, Kalbakis K, Agelaki S, Hatzidaki D, Georgoulias V; Hellenic Oncology Research Group. Sequential vs concurrent epirubicin and docetaxel as adjuvant chemotherapy for high-risk, node-negative, early breast cancer: an interim analysis of a randomised phase III study from the Hellenic Oncology Research Group. Br J Cancer. 2017 Jul 11;117(2):164-170. Epub 2017 Jun 22. [https://doi.org/10.1038/bjc.2017.158 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584474/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28641315/ PubMed] [https://clinicaltrials.gov/study/NCT00424606 NCT00424606]
  
−
'''21-day cycles x 4 cycles'''
+
==E-X {{#subobject:fd4xx3|Regimen=1}}==
 +
E-X: '''<u>E</u>'''pirubicin followed by '''<u>X</u>'''eloda (Capecitabine)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:xxx4ba|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489700/ Cameron et al. 2017 (TACT2)]
 +
|rowspan=2|2005-2008
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|1. [[#E-CMF|E-CMF]]
 +
| style="background-color:#eeee01" |Non-inferior TTR (primary endpoint)
 +
|-
 +
|2. [[#ddE-CMF_999|ddE-CMF]]<br>3. [[#ddE-X|ddE-X]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of TTR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, E portion (cycles 1 to 4)====
 +
*[[Epirubicin (Ellence)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, X portion (cycles 5 to 8)====
 +
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 +
'''21-day cycle for 8 cycles (E x 4; X x 4)'''
 +
</div></div>
 +
===References===
 +
# '''TACT2:''' Cameron D, Morden JP, Canney P, Velikova G, Coleman R, Bartlett J, Agrawal R, Banerji J, Bertelli G, Bloomfield D, Brunt AM, Earl H, Ellis P, Gaunt C, Gillman A, Hearfield N, Laing R, Murray N, Couper N, Stein RC, Verrill M, Wardley A, Barrett-Lee P, Bliss JM; TACT2 Investigators. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2017 Jul;18(7):929-945. Epub 2017 Jun 7. [https://doi.org/10.1016/S1470-2045(17)30404-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489700/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28600210/ PubMed] [https://clinicaltrials.gov/study/NCT00301925 NCT00301925]
 +
##'''HRQoL analysis:''' Velikova G, Morden JP, Haviland JS, Emery C, Barrett-Lee P, Earl H, Bloomfield D, Brunt AM, Canney P, Coleman R, Verrill M, Wardley A, Bertelli G, Ellis P, Stein R, Bliss JM, Cameron D; TACT2 Trial Management Group. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer (UK TACT2; CRUK/05/19): quality of life results from a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2023 Dec;24(12):1359-1374. Epub 2023 Nov 2. Erratum in: Lancet Oncol. 2023 Dec;24(12):e459. [https://doi.org/10.1016/s1470-2045(23)00460-6 link to original article] [https://pubmed.ncbi.nlm.nih.gov/37926100/ PubMed]
 +
==EC-CMF {{#subobject:xk9g7c|Regimen=1}}==
 +
EC-CMF: '''<u>E</u>'''pirubicin & '''<u>C</u>'''yclophosphamide followed by '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:80ghx1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.03.0783 Colleoni et al. 2006 (IBCSG 13-93)]
 +
|1993-1999
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.03.5196 Basser et al. 2006 (IBCSG 15-95)]
 +
|1995-2000
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cyclophosphamide_.26_Epirubicin_888|EC]]; dose-intense
 +
| style="background-color:#fc8d59" |Seems to have inferior DFS<sup>1</sup>
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy is based on the 2009 update.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, EC portion (cycles 1 to 4)====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, CMF portion (cycles 5 to 7)====
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''21-day cycle for 4 cycles, then 28-day cycle for 3 cycles (EC x 4; CMF x 3)'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Adjuvant [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_3|Tamoxifen]] x 5 y versus [[Breast_cancer_-_null_regimens#Observation|no further treatment]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2 {{#subobject:80ghd1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361407/ Kümmel et al. 2006]
 +
|1996-2000
 +
|style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#ddEC-ddCMF|ddEC-ddCMF]]
 +
| style="background-color:#fee08b" |Might have inferior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, EC portion (cycles 1 to 4)====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, CMF portion (cycles 5 to 7)====
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 7 cycles (EC x 4; CMF x 3)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3 {{#subobject:80ghd1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2004.07.026 Zander et al. 2004]
 +
|1993-2000
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cyclophosphamide.2C_Mitoxantrone.2C_Thiotepa.2C_then_auto_HSCT_333|Cyclophosphamide, Mitoxantrone, Thiotepa with auto HSCT]]
 +
| style="background-color:#fee08b" |Might have inferior EFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, EC portion (cycles 1 to 4)====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, CMF portion (cycles 5 to 7)====
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''21-day cycle for 4 cycles, then 28-day cycle for 3 cycles (EC x 4; CMF x 3)'''
 +
</div></div>
 +
===References===
 +
# Zander AR, Kröger N, Schmoor C, Krüger W, Möbus V, Frickhofen N, Metzner B, Schultze W, Berdel WE, Koenigsmann M, Thiel E, Wandt H, Possinger K, Trümper L, Kreienberg R, Carstensen M, Schmidt EH, Jänicke F, Schumacher M, Jonat W. High-dose chemotherapy with autologous hematopoietic stem-cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: first results of a randomized trial. J Clin Oncol. 2004 Jun 15;22(12):2273-83. Epub 2004 Apr 26. [https://doi.org/10.1200/JCO.2004.07.026 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15111618/ PubMed]
 +
#'''IBCSG 15-95:''' Basser RL, O'Neill A, Martinelli G, Green MD, Peccatori F, Cinieri S, Coates AS, Gelber RD, Aebi S, Castiglione-Gertsch M, Viale G, Price KN, Goldhirsch A; International Breast Cancer Study Group. Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95. J Clin Oncol. 2006 Jan 20;24(3):370-8. [https://doi.org/10.1200/jco.2005.03.5196 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16421418/ PubMed] [https://clinicaltrials.gov/study/NCT00002784 NCT00002784]
 +
##'''Update:''' Colleoni M, Sun Z, Martinelli G, Basser RL, Coates AS, Gelber RD, Green MD, Peccatori F, Cinieri S, Aebi S, Viale G, Price KN, Goldhirsch A; International Breast Cancer Study Group. The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up. Ann Oncol. 2009 Aug;20(8):1344-51. Epub 2009 May 25. [https://doi.org/10.1093/annonc/mdp024 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2720817/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/19468030/ PubMed]
 +
# '''IBCSG 13-93:''' Colleoni M, Gelber S, Goldhirsch A, Aebi S, Castiglione-Gertsch M, Price KN, Coates AS, Gelber RD; International Breast Cancer Study Group. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol. 2006 Mar 20;24(9):1332-41. Epub 2006 Feb 27. [https://doi.org/10.1200/JCO.2005.03.0783 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16505417/ PubMed]
 +
# Kümmel S, Krocker J, Kohls A, Breitbach GP, Morack G, Budner M, Blohmer JU, Elling D. Randomised trial: survival benefit and safety of adjuvant dose-dense chemotherapy for node-positive breast cancer. Br J Cancer. 2006 May 8;94(9):1237-44. [https://doi.org/10.1038/sj.bjc.6603085 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361407/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16622463/ PubMed]
 +
## '''Update:''' Reinisch M, Gluz O, Ataseven B, Blohmer JU, Budner M, Dittmer-Grabowski C, Kohls A, Krocker J, Kümmel A, Hagemann F, Rüland A, Traut A, Kümmel S. Updated Survival Analysis after a Median Follow-up of 12 Years of an Anthracycline-Containing Adjuvant Prospective Multicentre, Randomised Phase III Trial on Dose-Dense Chemotherapy in Primary Node-Positive, High-Risk Breast Cancer Patients. Breast Care (Basel). 2019 Jun;14(3):159-164. Epub 2018 Sep 5. [https://doi.org/10.1159/000491792 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6600045/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31316314/ PubMed]
  
 +
==ddEC-ddCMF {{#subobject:7yfc7c|Regimen=1}}==
 +
ddEC-ddCMF: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>E</u>'''pirubicin & '''<u>C</u>'''yclophosphamide followed by '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:80ghx1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S0140-6736(05)67784-7 Nitz et al. 2005 (WSG AM-01)]
 +
|1995-2002
 +
|style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cyclophosphamide_.26_Epirubicin_.28EC.29|EC]], then [[Breast_cancer_-_historical#ECT.2C_then_auto_HSCT|ECT with auto HSCT]] x 2
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361407/ Kümmel et al. 2006]
 +
|1996-2000
 +
|style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#EC-CMF|EC-CMF]]
 +
| style="background-color:#d9ef8b" |Might have superior OS (secondary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, ddEC portion (cycles 1 to 4)====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, ddCMF portion (cycles 5 to 7)====
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV over 1 to 2 hours once on day 1
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
====Supportive therapy, both portions (cycles 1 to 7)====
 +
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day on days 5 to 12
 +
'''14-day cycle for 7 cycles (ddEC x 4; ddCMF x 3)'''
 +
</div></div>
 
===References===
 
===References===
−
# Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL, Sandbach J, Hyman WJ, Richards DA, Mennel RG, Boehm KA, Meyer WG, Asmar L, Mackey D, Riedel S, Muss H, Savin MA. Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. J Clin Oncol. 2009 Mar 10;27(8):1177-83. Epub 2009 Feb 9. [http://jco.ascopubs.org/content/27/8/1177.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/19204201 PubMed]
+
# '''WSG AM-01:''' Nitz UA, Mohrmann S, Fischer J, Lindemann W, Berdel WE, Jackisch C, Werner C, Ziske C, Kirchner H, Metzner B, Souchon R, Ruffert U, Schütt G, Pollmanns A, Schmoll HJ, Middecke C, Baltzer J, Schrader I, Wiebringhaus H, Ko Y, Rösel S, Schwenzer T, Wernet P, Hinke A, Bender HG, Frick M; West German Study Group. Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial. Lancet. 2005 Dec 3;366(9501):1935-44. Erratum in: Lancet. 2006 Mar 4;367(9512):730. [https://doi.org/10.1016/S0140-6736(05)67784-7 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16325695/ PubMed]
 +
# Kümmel S, Krocker J, Kohls A, Breitbach GP, Morack G, Budner M, Blohmer JU, Elling D. Randomised trial: survival benefit and safety of adjuvant dose-dense chemotherapy for node-positive breast cancer. Br J Cancer. 2006 May 8;94(9):1237-44. [https://doi.org/10.1038/sj.bjc.6603085 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361407/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16622463/ PubMed]
 +
## '''Update:''' Reinisch M, Gluz O, Ataseven B, Blohmer JU, Budner M, Dittmer-Grabowski C, Kohls A, Krocker J, Kümmel A, Hagemann F, Rüland A, Traut A, Kümmel S. Updated Survival Analysis after a Median Follow-up of 12 Years of an Anthracycline-Containing Adjuvant Prospective Multicentre, Randomised Phase III Trial on Dose-Dense Chemotherapy in Primary Node-Positive, High-Risk Breast Cancer Patients. Breast Care (Basel). 2019 Jun;14(3):159-164. Epub 2018 Sep 5. [https://doi.org/10.1159/000491792 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6600045/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31316314/ PubMed]
  
−
==FAC, CAF {{#subobject:1e6621|Regimen=1}}==
+
==ddEC-ddT {{#subobject:7jh9cc|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
ddEC-ddCMF: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>E</u>'''pirubicin & '''<u>C</u>'''yclophosphamide followed by '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:1dchx1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1016/s0140-6736(14)62048-1 Del Mastro et al. 2015 (GIM2)]
 +
|rowspan=2|2003-2006
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[#EC-T_2|EC-T]]<br>2. [[#FEC-P|FEC-P]]
 +
| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>OS60: 94% vs 89%<br>(HR 0.65, 95% CI 0.51-0.84)<br><br>Superior DFS (primary endpoint)<br>DFS60: 81% vs 76%<br>(HR 0.77, 95% CI 0.65-0.92)
 +
|-
 +
|3. [[#ddFEC-ddT_.28Paclitaxel.29_999|ddFEC-ddT]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
FAC: '''<u>F</u>'''ive-FU, '''<u>A</u>'''driamycin, '''<u>C</u>'''ytoxan
+
''Note: a mid-protocol amendment of GIM2 suggested giving the pegfilgrastim at least 72 h after chemotherapy.''
−
CAF: '''<u>C</u>'''ytoxan, '''<u>A</u>'''driamycin, '''<u>F</u>'''ive-FU
+
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, ddEC portion (cycles 1 to 4)====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, ddT portion (cycles 5 to 8)====
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
 +
====Supportive therapy, both portions (cycles 1 to 8)====
 +
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2
 +
'''14-day cycle for 8 cycles (ddEC x 4; ddT x 4)'''
 +
</div></div>
 +
===References===
 +
# '''GIM2:''' Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 x 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. [https://doi.org/10.1016/s0140-6736(14)62048-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25740286/ PubMed] [https://clinicaltrials.gov/study/NCT00433420 NCT00433420]
 +
##'''Update:''' Del Mastro L, Poggio F, Blondeaux E, De Placido S, Giuliano M, Forestieri V, De Laurentiis M, Gravina A, Bisagni G, Rimanti A, Turletti A, Nisticò C, Vaccaro A, Cognetti F, Fabi A, Gasparro S, Garrone O, Alicicco MG, Urracci Y, Mansutti M, Poletti P, Correale P, Bighin C, Puglisi F, Montemurro F, Colantuoni G, Lambertini M, Boni L; Gruppo Italiano Mammella Investigators. Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial. Lancet Oncol. 2022 Dec;23(12):1571-1582. Epub 2022 Nov 10. [https://doi.org/10.1016/s1470-2045(22)00632-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36370716/ PubMed]
  
−
===Regimen #1, Martin et al. 2005 (BCIRG 001) {{#subobject:63e780|Variant=1}}===
+
==EC-D {{#subobject:8d8duq|Regimen=1}}==
−
Level of Evidence:
+
EC-D: '''<u>E</u>'''pirubicin and '''<u>C</u>'''yclophosphamide followed by '''<u>D</u>'''ocetaxel
−
<span
+
<br>EC-T: '''<u>E</u>'''pirubicin and '''<u>C</u>'''yclophosphamide followed by '''<u>T</u>'''axotere (Docetaxel)
−
style="background:#00CD00;
+
<div class="toccolours" style="background-color:#eeeeee">
−
padding:3px 6px 3px 6px;
+
===Regimen variant #1, 3+3 cycles {{#subobject:8d62d4|Variant=1}}===
−
border-color:black;
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
border-width:2px;
+
!style="width: 20%"|Study
−
border-style:solid;">Phase III</span>
+
!style="width: 20%"|Dates of enrollment
−
 
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
*[[Fluorouracil (5-FU)]] 500 mg/m2 IV over 15 minutes on day 1 (administered second)
+
!style="width: 20%"|Comparator
−
*[[Doxorubicin (Adriamycin)]] 50 mg/m2 IV over 15 minutes on day 1 (administered first)
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m2 IV over 1 to 5 minutes on day 1 (administered third)
+
|-
−
*If patients had febrile neutropenia or infection: Ciprofloxacin 500 mg PO BID on days 5-14 of every cycle (prophylaxis)
+
|[https://doi.org/10.1200/JCO.2017.72.3494 Ejlertsen et al. 2017 (DBCG 07-READ)]
−
*G-CSF not originally routinely administered unless patients had febrile neutropenia:
+
|2008-2012
−
:*[[Filgrastim (Neupogen)]] 5 mcg/kg SC on days 4-11
+
| style="background-color:#1a9851" |Phase 3 (C)
−
:*Lenograstim 150 mcg/m2 on days 4-11
+
|[[#Cyclophosphamide_.26_Docetaxel_.28TC.29|TC]] x 6
−
 
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
−
'''21-day cycles x 6 cycles'''
+
|-
−
 
+
|}
−
===Regimen #2, Assikis et al. 2003 {{#subobject:dfb0b0|Variant=1}}===
+
<div class="toccolours" style="background-color:#fdcdac">
−
Level of Evidence:
+
====Biomarker eligibility criteria====
−
<span
+
*TOP2A normal as determined by FISH
−
style="background:#00CD00;
+
</div>
−
padding:3px 6px 3px 6px;
+
<div class="toccolours" style="background-color:#cbd5e8">
−
border-color:black;
+
====Preceding treatment====
−
border-width:2px;
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
border-style:solid;">Phase III</span>
+
</div>
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Fluorouracil (5-FU)]] 500 mg/m2 IV on days 1 & 8 or days 1 & 4
+
====Chemotherapy, EC portion (cycles 1 to 3)====
−
*[[Doxorubicin (Adriamycin)]] 50 mg/m2 IV on day 1 or via 72-hour continuous infusion
+
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1  
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m2 IV on day 1
+
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
−
 
+
====Chemotherapy, D portion (cycles 4 to 6)====
−
'''21-day cycles x 6 cycles'''
+
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1
−
 
+
'''21-day cycle for 6 cycles (EC x 3; D x 3)'''
−
===Regimen #3, Bull et al. 1978 {{#subobject:f18a6a|Variant=1}}===
+
</div></div><br>
−
Level of Evidence:
+
<div class="toccolours" style="background-color:#eeeeee">
−
<span
+
===Regimen variant #2, 4+4 cycles {{#subobject:22hy7f|Variant=1}}===
−
style="background:#00CD00;
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
padding:3px 6px 3px 6px;
+
!style="width: 20%"|Study
−
border-color:black;
+
!style="width: 20%"|Dates of enrollment
−
border-width:2px;
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
border-style:solid;">Phase III</span>
+
!style="width: 20%"|Comparator
−
 
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m2 IV once per day on days 1 to 14
+
|-
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m2 IV on days 1 & 8
+
|[https://doi.org/10.1200/JCO.2015.61.9510 Martín et al. 2015 (GEICAM 2003-10)]
−
*[[Fluorouracil (5-FU)]] 500 mg/m2 IV on days 1 & 8
+
|2004-2007
−
 
+
| style="background-color:#1a9851" |Phase 3 (C)
−
'''28-day cycles x 6 cycles'''
+
|[[#ET-X_999|ET-X]] x 4+4
 +
| style="background-color:#91cf60" |Seems to have superior IDFS (primary endpoint)<br>IDFS60: 86% vs 82%<br>(HR 0.77, 95% CI 0.61-0.97)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, EC portion (cycles 1 to 4)====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1  
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, D portion (cycles 5 to 8)====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
'''21-day cycle for 8 cycles (EC x 4; D x 4)'''
 +
</div></div>
 +
===References===
 +
# '''WSG-AGO EC-Doc:''' Nitz U, Gluz O, Huober J, Kreipe HH, Kates RE, Hartmann A, Erber R, Moustafa Z, Scholz M, Lisboa B, Mohrmann S, Möbus V, Augustin D, Hoffmann G, Weiss E, Böhmer S, Kreienberg R, Du Bois A, Sattler D, Thomssen C, Kiechle M, Jänicke F, Wallwiener D, Harbeck N, Kuhn W. Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression. Ann Oncol. 2014 Aug;25(8):1551-7. Epub 2014 May 14. Erratum in: Ann Oncol. 2017 Nov 1;28(11):2899. [https://doi.org/10.1093/annonc/mdu186 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24827128/ PubMed] [https://clinicaltrials.gov/study/NCT02115204 NCT02115204]
 +
# '''GEICAM 2003-10:''' Martín M, Ruiz Simón A, Ruiz Borrego M, Ribelles N, Rodríguez-Lescure A, Muñoz-Mateu M, González S, Margelí Vila M, Barnadas A, Ramos M, Del Barco Berron S, Jara C, Calvo L, Martínez-Jáñez N, Mendiola Fernández C, Rodríguez CA, Martínez de Dueñas E, Andrés R, Plazaola A, de la Haba-Rodríguez J, López-Vega JM, Adrover E, Ballesteros AI, Santaballa A, Sánchez-Rovira P, Baena-Cañada JM, Casas M, del Carmen Cámara M, Carrasco EM, Lluch A. Epirubicin plus cyclophosphamide followed by docetaxel versus epirubicin plus docetaxel followed by capecitabine as adjuvant therapy for node-positive early breast cancer: results from the GEICAM/2003-10 study. J Clin Oncol. 2015 Nov 10;33(32):3788-95. Epub 2015 Sep 28. [https://doi.org/10.1200/JCO.2015.61.9510 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26416999/ PubMed] [https://clinicaltrials.gov/study/NCT00129935 NCT00129935]
 +
# '''DBCG 07-READ:''' Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen MB, Knoop AS, Højris I, Ewertz M, Balslev E, Danø H, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. Adjuvant cyclophosphamide and docetaxel with or without epirubicin for early TOP2A-normal breast cancer: DBCG 07-READ, an open-label, phase III, randomized trial. J Clin Oncol. 2017 Aug 10;35(23):2639-2646. Epub 2017 Jun 29. [https://doi.org/10.1200/JCO.2017.72.3494 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28661759/ PubMed] [https://clinicaltrials.gov/study/NCT00689156 NCT00689156]
  
 +
==EC-T {{#subobject:8d8dy1|Regimen=1}}==
 +
EC-T: '''<u>E</u>'''pirubicin and '''<u>C</u>'''yclophosphamide followed by '''<u>T</u>'''axol (Paclitaxel)
 +
<br>EC-P: '''<u>E</u>'''pirubicin and '''<u>C</u>'''yclophosphamide followed by '''<u>P</u>'''aclitaxel
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 75/600 {{#subobject:8hgaz4|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8486325/ Yu et al. 2021 (SPECTRUM<sub>brca</sub>)]
 +
|2011-2016
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#EP-T_333|EP-T]]
 +
| style="background-color:#fee08b" |Might have inferior DFS60
 +
|-
 +
|}
 +
''Note: this trial should not be confused with the one by the same name in head & neck cancer.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, EC portion (cycles 1 to 4)====
 +
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, T portion (cycles 5 to 16)====
 +
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 4 cycles, then 7-day cycle for 12 cycles (EC x 4; T x 12)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 90/600 {{#subobject:8hhyg4|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/s1470-2045(17)30319-4 Earl et al. 2017 (tAnGo)]
 +
|2001-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#EC-TG_.28Paclitaxel.29_999|EC-TG]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|rowspan=2|[https://doi.org/10.1016/s0140-6736(14)62048-1 Del Mastro et al. 2015 (GIM2)]
 +
|rowspan=2|2003-2006
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#ddEC-ddT_.28Paclitaxel.29|ddEC-ddT]]<br>2. [[#ddFEC-ddT_.28Paclitaxel.29_999|ddFEC-ddT]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|3. [[#FEC-P|FEC-P]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9958529/ Yuan et al. 2023 (CH-BC-006)]
 +
|2010-06-01 to 2016-06-30
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Epirubicin_.26_Paclitaxel_.28EP.29|EP]]
 +
| style="background-color:#eeee01" |Non-inferior DFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, EC portion (cycles 1 to 4)====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, T portion (cycles 5 to 8)====
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
 +
'''21-day cycle for 8 cycles (EC x 4; T x 4)'''
 +
</div></div>
 
===References===
 
===References===
−
# Bull JM, Tormey DC, Li SH, Carbone PP, Falkson G, Blom J, Perlin E, Simon R. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978 May;41(5):1649-57. [http://www.ncbi.nlm.nih.gov/pubmed/348293 PubMed]
+
# '''GIM2:''' Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; GIM. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 x 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. [https://doi.org/10.1016/s0140-6736(14)62048-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25740286/ PubMed] [https://clinicaltrials.gov/study/NCT00433420 NCT00433420]
−
# Buzdar AU, Kau SW, Smith TL, Hortobagyi GN. Ten-year results of FAC adjuvant chemotherapy trial in breast cancer. Am J Clin Oncol. 1989 Apr;12(2):123-8. [http://www.ncbi.nlm.nih.gov/pubmed/2705401 PubMed]
+
##'''Update:''' Del Mastro L, Poggio F, Blondeaux E, De Placido S, Giuliano M, Forestieri V, De Laurentiis M, Gravina A, Bisagni G, Rimanti A, Turletti A, Nisticò C, Vaccaro A, Cognetti F, Fabi A, Gasparro S, Garrone O, Alicicco MG, Urracci Y, Mansutti M, Poletti P, Correale P, Bighin C, Puglisi F, Montemurro F, Colantuoni G, Lambertini M, Boni L; Gruppo Italiano Mammella Investigators. Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial. Lancet Oncol. 2022 Dec;23(12):1571-1582. Epub 2022 Nov 10. [https://doi.org/10.1016/s1470-2045(22)00632-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36370716/ PubMed]
−
# Assikis V, Buzdar A, Yang Y, Smith T, Theriault R, Booser D, Valero V, Walters R, Singletary E, Ames F, Hortobagyi G. A phase III trial of sequential adjuvant chemotherapy for operable breast carcinoma: final analysis with 10-year follow-up. Cancer. 2003 Jun 1;97(11):2716-23. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.11396/full link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12767083 PubMed]
+
# '''tAnGo:''' Earl HM, Hiller L, Howard HC, Dunn JA, Young J, Bowden SJ, McDermaid M, Waterhouse AK, Wilson G, Agrawal R, O'Reilly S, Bowman A, Ritchie DM, Goodman A, Hickish T, McAdam K, Cameron D, Dodwell D, Rea DW, Caldas C, Provenzano E, Abraham JE, Canney P, Crown JP, Kennedy MJ, Coleman R, Leonard RC, Carmichael JA, Wardley AM, Poole CJ; tAnGo trial collaborators. Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Jun;18(6):755-769. Epub 2017 May 4. [https://doi.org/10.1016/s1470-2045(17)30319-4 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28479233/ PubMed] [https://clinicaltrials.gov/study/NCT00039546 NCT00039546]
−
# Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C; Breast Cancer International Research Group 001 Investigators. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med. 2005 Jun 2;352(22):2302-13. [http://www.nejm.org/doi/full/10.1056/NEJMoa043681 link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15930421 PubMed]
+
#'''SPECTRUM<sub>brca</sub>:''' Yu KD, Ge JY, Liu XY, Mo M, He M, Shao ZM; SPECTRUM Investigators. Cyclophosphamide-Free Adjuvant Chemotherapy for Ovarian Protection in Young Women With Breast Cancer: A Randomized Phase 3 Trial. J Natl Cancer Inst. 2021 Oct 1;113(10):1352-1359. [https://doi.org/10.1093/jnci/djab065 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc8486325/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33822134/ PubMed] [https://clinicaltrials.gov/study/NCT01026116 NCT01026116]
−
# Hutchins LF, Green SJ, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol. 2005 Nov 20;23(33):8313-21. [http://jco.ascopubs.org/content/23/33/8313.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16293862 PubMed]
+
#'''CH-BC-006:''' Yuan P, Kang Y, Ma F, Fan Y, Wang J, Wang X, Yue J, Luo Y, Zhang P, Li Q, Xu B. Effect of Epirubicin Plus Paclitaxel vs Epirubicin and Cyclophosphamide Followed by Paclitaxel on Disease-Free Survival Among Patients With Operable ERBB2-Negative and Lymph Node-Positive Breast Cancer: A Randomized Clinical Trial. JAMA Netw Open. 2023 Feb 1;6(2):e230122. [https://doi.org/10.1001/jamanetworkopen.2023.0122 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9958529/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/36826820/ PubMed] [https://clinicaltrials.gov/study/NCT01134523 NCT01134523]
 +
#'''CH-BC-012:''' [https://clinicaltrials.gov/study/NCT01378533 NCT01378533]
 +
#'''Fudan BC MASTER:''' [https://clinicaltrials.gov/study/NCT01314833 NCT01314833]
  
−
==FAC+MV {{#subobject:eb48eb|Regimen=1}}==
+
==ddEC-T {{#subobject:ajbo85|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
ddEC-T: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>E</u>'''pirubicin and '''<u>C</u>'''yclophosphamide, followed by '''<u>T</u>'''axol (Paclitaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:bc9489|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799234/ Burnell et al. 2009 (NCIC-CTG MA.21)]
 +
|rowspan=2|2000-2005
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[#AC-T_2|AC-T]]
 +
| style="background-color:#1a9850" |Superior RFS (primary endpoint)<br>RFS36: 89.5% vs 85%<br>(HR 0.60, 95% CI 0.44-0.80)
 +
|-
 +
|2. [[#FEC_2|FEC]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS<br>RFS36: 89.5% vs 90.1%<br>(HR 0.89, 95% CI 0.64-1.22)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
FAC+MV: '''<u>F</u>'''ive-FU, '''<u>A</u>'''driamycin, '''<u>C</u>'''ytoxan, '''<u>M</u>'''ethotrexate, '''<u>V</u>'''inblastine
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
''Not commonly used but was a comparator arm; for reference purposes only.''
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
 
+
</div>
−
===Regimen, Assikis et al. 2003 {{#subobject:883648|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy, ddEC portion (cycles 1 to 6)====
−
<span
+
*[[Epirubicin (Ellence)]] 120 mg/m<sup>2</sup> IV once on day 1  
−
style="background:#00CD00;
+
*[[Cyclophosphamide (Cytoxan)]] 830 mg/m<sup>2</sup> IV once on day 1
−
padding:3px 6px 3px 6px;
+
====Supportive therapy, ddEC portion (cycles 1 to 6)====
−
border-color:black;
+
*[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day on days 2 to 13
−
border-width:2px;
+
*[[Epoetin alfa (Procrit)]] 40,000 units SC once per day on days 1 & 8
−
border-style:solid;">Phase III</span>
+
====Chemotherapy, T portion (cycles 7 to 10)====
−
 
+
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
−
*[[Fluorouracil (5-FU)]] 500 mg/m2 IV on days 1 & 8 or days 1 & 4
+
'''14-day cycle for 6 cycles, then 21-day cycle for 4 cycles (ddEC x 6; T x 4)'''
−
*[[Doxorubicin (Adriamycin)]] 50 mg/m2 IV on day 1 or via 72-hour continuous infusion
+
</div></div>
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m2 IV on day 1
 
−
 
 
−
'''21-day cycles x 6 cycles, followed by:'''
 
−
 
 
−
*[[Methotrexate (MTX)]] 75 mg/m2 IV on day 1 with leucovorin rescue
 
−
*[[Vinblastine (Velban)]] 1.7 mg/m2 as a continuous infusion days 1 to 5
 
−
 
 
−
'''21 to 28-day cycles x 4 cycles'''
 
−
 
 
 
===References===
 
===References===
−
# Assikis V, Buzdar A, Yang Y, Smith T, Theriault R, Booser D, Valero V, Walters R, Singletary E, Ames F, Hortobagyi G. A phase III trial of sequential adjuvant chemotherapy for operable breast carcinoma: final analysis with 10-year follow-up. Cancer. 2003 Jun 1;97(11):2716-23. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.11396/full link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/12767083 PubMed]
+
# '''NCIC-CTG MA.21:''' Burnell M, Levine MN, Chapman JA, Bramwell V, Gelmon K, Walley B, Vandenberg T, Chalchal H, Albain KS, Perez EA, Rugo H, Pritchard K, O'Brien P, Shepherd LE. Cyclophosphamide, epirubicin, and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol. 2010 Jan 1;28(1):77-82. Epub 2009 Nov 9. [https://doi.org/10.1200/JCO.2009.22.1077 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799234/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19901117/ PubMed] [https://clinicaltrials.gov/study/NCT00014222 NCT00014222]
−
 
+
==iddEnPC {{#subobject:28hgzn|Regimen=1}}==
−
==CEF, FEC {{#subobject:3613b7|Regimen=1}}==
+
iddEnPC: '''<u>i</u>'''ntense '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>E</u>'''pirubicin, '''<u>n</u>'''ab-'''<u>P</u>'''aclitaxel, '''<u>C</u>'''yclophosphamide
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:ca3ug1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2021.07.033 Möbus et al. 2021 (GAIN-2)]
 +
|2012-2017
 +
|style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#dtEC-dtD_999|dtEC-dtD]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of iDFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
CEF: '''<u>C</u>'''ytoxan, '''<u>E</u>'''pirubicin, '''<u>F</u>'''ive-FU
+
''Note: growth factor support is not specifically mentioned in the manuscript. The details below for pegfilgrastim are based on the GAIN trial of iddEPC.''
−
FEC -> T: '''<u>F</u>'''ive-FU, '''<u>E</u>'''pirubicin, '''<u>C</u>'''ytoxan
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
===Regimen {{#subobject:978850|Variant=1}}===
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
Level of Evidence:
+
</div>
−
<span
+
<div class="toccolours" style="background-color:#b3e2cd">
−
style="background:#00CD00;
+
====Chemotherapy, iddE portion (cycles 1 to 3)====
−
padding:3px 6px 3px 6px;
+
*[[Epirubicin (Ellence)]] 150 mg/m<sup>2</sup> IV once on day 1  
−
border-color:black;
+
====Chemotherapy, iddnP portion (cycles 4 to 6)====
−
border-width:2px;
+
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 330 mg/m<sup>2</sup> IV once on day 1  
−
border-style:solid;">Phase III</span>
+
====Chemotherapy, iddC portion (cycles 7 to 9)====
−
 
+
*[[Cyclophosphamide (Cytoxan)]] 2000 mg/m<sup>2</sup> IV once on day 1
−
*[[Cyclophosphamide (Cytoxan)]] 75 mg/m2 PO once per day on days 1 to 14
+
====Supportive therapy, all portions (cycles 1 to 9)====
−
*[[Epirubicin (Ellence)]] 60 mg/m2 IV on days 1 & 8
+
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2 or 4
−
*[[Fluorouracil (5-FU)]] 500 mg/m2 IV on days 1 & 8
+
'''14-day cycle for 9 cycles (iddE x 3; iddnP x 3; iddC x 3)'''
−
*With cotrimoxazole support
+
</div></div>
−
 
 
−
'''28-day cycles x 6 cycles'''
 
−
 
 
 
===References===
 
===References===
−
# Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, Findlay B, Warr D, Bowman D, Myles J, Arnold A, Vandenberg T, MacKenzie R, Robert J, Ottaway J, Burnell M, Williams CK, Tu D. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1998 Aug;16(8):2651-8. [http://jco.ascopubs.org/content/16/8/2651.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/9704715 PubMed]
+
#'''GAIN-2:''' Möbus V, Lück HJ, Ladda E, Klare P, Schmidt M, Schneeweiss A, Grischke EM, Wachsmann G, Forstbauer H, Untch M, Marmé F, Blohmer JU, Jackisch C, Huober J, Stickeler E, Reinisch M, Link T, Sinn BV, Janni W, Denkert C, Furlanetto J, Engels K, Solbach C, Schmatloch S, Rey J, Burchardi N, Loibl S; GBG and AGO-B. Phase III randomised trial comparing intense dose-dense chemotherapy to tailored dose-dense chemotherapy in high-risk early breast cancer (GAIN-2). Eur J Cancer. 2021 Oct;156:138-148. Epub 2021 Aug 24. [https://doi.org/10.1016/j.ejca.2021.07.033 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/34450552/ PubMed] [https://clinicaltrials.gov/study/NCT01690702 NCT01690702]
−
# Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulié P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Genève J, Asselain B. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006 Dec 20;24(36):5664-71. Epub 2006 Nov 20. [http://jco.ascopubs.org/content/24/36/5664.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/17116941 PubMed]
+
==iddEPC {{#subobject:28ad40|Regimen=1}}==
−
# Martín M, Rodríguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Munárriz B, Rodríguez CA, Crespo C, de Alava E, López García-Asenjo JA, Guitián MD, Almenar S, González-Palacios JF, Vera F, Palacios J, Ramos M, Gracia Marco JM, Lluch A, Alvarez I, Seguí MA, Mayordomo JI, Antón A, Baena JM, Plazaola A, Modolell A, Pelegrí A, Mel JR, Aranda E, Adrover E, Alvarez JV, García Puche JL, Sánchez-Rovira P, Gonzalez S, López-Vega JM; GEICAM 9906 Study Investigators. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by Paclitaxel for early breast cancer. J Natl Cancer Inst. 2008 Jun 4;100(11):805-14. Epub 2008 May 27. [http://jnci.oxfordjournals.org/content/100/11/805.long link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18505968 PubMed]
+
iddEPC: '''<u>i</u>'''ntense '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>E</u>'''pirubicin, '''<u>P</u>'''aclitaxel, '''<u>C</u>'''yclophosphamide
−
 
+
<br>IDD-ETC: '''<u>I</u>'''ntense '''<u>D</u>'''ose-'''<u>D</u>'''ense '''<u>E</u>'''pirubicin, '''<u>T</u>'''axol (Paclitaxel), '''<u>C</u>'''yclophosphamide
−
==CMF {{#subobject:fb4c46|Regimen=1}}==
+
<div class="toccolours" style="background-color:#eeeeee">
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
===Regimen {{#subobject:ca391d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2009.24.7643 Möbus et al. 2010 (AGO-iddEPC)]
 +
|1998-2003
 +
|style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#EC-T_2|EC-T]]
 +
| style="background-color:#1a9850" |Superior OS<sup>1</sup> (secondary endpoint)<br>OS120: 69% vs 59%<br>(HR 0.72, 95% CI 0.60-0.87)
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdx203 Möbus et al. 2017 (GAIN)]
 +
|2004-2008
 +
|style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#ddEC-XP_999|ddEC-XP]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
CMF: '''<u>C</u>'''ytoxan, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''ive-FU
+
''<sup>1</sup>Reported efficacy for AGO-iddEPC is based on the 2018 update.''<br>
−
 
+
''Note: this dosing of cyclophosphamide was after a mid-protocol amendment of GAIN.''
−
===Regimen {{#subobject:8a712c|Variant=1}}===
+
<div class="toccolours" style="background-color:#cbd5e8">
−
Level of Evidence:
+
====Preceding treatment====
−
<span
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
style="background:#00CD00;
+
</div>
−
padding:3px 6px 3px 6px;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
border-color:black;
+
====Chemotherapy, iddE portion (cycles 1 to 3)====
−
border-width:2px;
+
*[[Epirubicin (Ellence)]] 150 mg/m<sup>2</sup> IV once on day 1
−
border-style:solid;">Phase III</span>
+
====Chemotherapy, iddP portion (cycles 4 to 6)====
−
 
+
*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV once on day 1
−
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m2 PO once per day on days 1 to 14
+
====Chemotherapy, iddC portion (cycles 7 to 9)====
−
*[[Methotrexate (MTX)]] 40 mg/m2 IV on days 1 & 8
+
*[[Cyclophosphamide (Cytoxan)]] 2000 mg/m<sup>2</sup> IV once on day 1
−
*[[Fluorouracil (5-FU)]] 600 mg/m2 IV on days 1 & 8
+
====Supportive therapy, all portions (cycles 1 to 9)====
−
 
+
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2 or 4
−
'''28-day cycles x 6 cycles'''
+
'''14-day cycle for 9 cycles (iddE x 3; iddP x 3; iddC x 3)'''
−
 
+
</div></div>
 
===References===
 
===References===
−
# Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, De Lena M, Tancini G, Bajetta E, Musumeci R, Veronesi U. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976 Feb 19;294(8):405-10. [http://www.nejm.org/doi/full/10.1056/NEJM197602192940801 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/1246307 PubMed]
+
# '''AGO-iddEPC:''' Moebus V, Jackisch C, Lueck HJ, du Bois A, Thomssen C, Kurbacher C, Kuhn W, Nitz U, Schneeweiss A, Huober J, Harbeck N, von Minckwitz G, Runnebaum IB, Hinke A, Kreienberg R, Konecny GE, Untch M. Intense dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide compared with conventionally scheduled chemotherapy in high-risk primary breast cancer: mature results of an AGO phase III study. J Clin Oncol. 2010 Jun 10;28(17):2874-80. Epub 2010 May 10. [https://doi.org/10.1200/JCO.2009.24.7643 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20458045/ PubMed]
−
# Bull JM, Tormey DC, Li SH, Carbone PP, Falkson G, Blom J, Perlin E, Simon R. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978 May;41(5):1649-57. [http://www.ncbi.nlm.nih.gov/pubmed/348293 PubMed]
+
## '''Update:''' Möbus V, Jackisch C, Lück HJ, du Bois A, Thomssen C, Kuhn W, Nitz U, Schneeweiss A, Huober J, Harbeck N, von Minckwitz G, Runnebaum IB, Hinke A, Konecny GE, Untch M, Kurbacher C; AGO Breast Study Group (AGO-B). Ten-year results of intense dose-dense chemotherapy show superior survival compared with a conventional schedule in high-risk primary breast cancer: final results of AGO phase III iddEPC trial. Ann Oncol. 2018 Jan 1;29(1):178-185. [https://doi.org/10.1093/annonc/mdx690 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29069370/ PubMed]
−
# '''Review:''' Goldhirsch A, Colleoni M, Coates AS, Castiglione-Gertsch M, Gelber RD. Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: are all CMFs alike? The International Breast Cancer Study Group (IBCSG). Ann Oncol. 1998 May;9(5):489-93. [http://annonc.oxfordjournals.org/content/9/5/489.long link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/9653488 PubMed]
+
# '''GAIN:''' Möbus V, von Minckwitz G, Jackisch C, Lück HJ, Schneeweiss A, Tesch H, Elling D, Harbeck N, Conrad B, Fehm T, Huober J, Müller V, Bauerfeind I, du Bois A, Loibl S, Nekljudova V, Untch M, Thomssen C; German Breast Group; AGO Breast Study Group (AGO-B); NOGGO. German Adjuvant Intergroup Node-positive Study (GAIN): a phase III trial comparing two dose-dense regimens (iddEPC versus ddEC-PwX) in high-risk early breast cancer patients. Ann Oncol. 2017 Aug 1;28(8):1803-1810. [https://doi.org/10.1093/annonc/mdx203 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28459941/ PubMed] [https://clinicaltrials.gov/study/NCT00196872 NCT00196872]
−
# Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, Findlay B, Warr D, Bowman D, Myles J, Arnold A, Vandenberg T, MacKenzie R, Robert J, Ottaway J, Burnell M, Williams CK, Tu D. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1998 Aug;16(8):2651-8. [http://jco.ascopubs.org/content/16/8/2651.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/9704715 PubMed]
 
−
# Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M, Nogaret JM. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol. 2001 Jun 15;19(12):3103-10. [http://jco.ascopubs.org/content/19/12/3103.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/11408507 PubMed]
 
−
# Hutchins LF, Green SJ, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol. 2005 Nov 20;23(33):8313-21. [http://jco.ascopubs.org/content/23/33/8313.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16293862 PubMed]
 
−
# Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. [http://www.nejm.org/doi/full/10.1056/NEJMoa052084 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/17079759 PubMed]
 
  
−
==Epirubicin -> CMF {{#subobject:b1a874|Regimen=1}}==
+
==EP-ddCMF {{#subobject:3yg7c3|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
EP-ddCMF: '''<u>E</u>'''pirubicin & '''<u>P</u>'''aclitaxel followed by '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:r424ee|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdm539 Fountzilas et al. 2007 (HE 10/00)]
 +
|2000-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#ddE-ddP-ddCMF_999|ddE-ddP-ddCMF]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
CMF: '''<u>C</u>'''ytoxan, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''ive-FU
+
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT, prior to becoming a standard comparator arm.''
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
===Regimen, Poole et al. 2006 (NEAT/BR9601) {{#subobject:a58086|Variant=1}}===
+
====Preceding treatment====
−
Level of Evidence:
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
<span
+
</div>
−
style="background:#00CD00;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
padding:3px 6px 3px 6px;
+
====Chemotherapy, EP portion (cycles 1 to 4)====
−
border-color:black;
+
*[[Epirubicin (Ellence)]] 83 mg/m<sup>2</sup> IV once on day 1
−
border-width:2px;
+
*[[Paclitaxel (Taxol)]] 187 mg/m<sup>2</sup> IV once on day 1
−
border-style:solid;">Phase III</span>
+
====Chemotherapy, ddCMF portion (cycles 5 to 7)====
−
 
+
*[[Cyclophosphamide (Cytoxan)]] 840 mg/m<sup>2</sup> IV once on day 1
−
*[[Epirubicin (Ellence)]]  
+
*[[Methotrexate (MTX)]] 57 mg/m<sup>2</sup> IV once on day 1
−
 
+
*[[Fluorouracil (5-FU)]] 840 mg/m<sup>2</sup> IV once on day 1
−
'''4 cycles, followed by:'''
+
====Supportive therapy, ddCMF portion (cycles 5 to 7)====
−
 
+
*[[:Category:Granulocyte colony-stimulating factors|G-CSF]] (dose not specified) SC once per day on days 2 to 10
−
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m2 PO once per day on days 1 to 14
+
'''21-day cycle for 4 cycles, then 14-day cycle for 3 cycles (EP x 4; ddCMF x 3)'''
−
*[[Methotrexate (MTX)]] 40 mg/m2 IV on days 1 & 8
+
</div></div>
−
*[[Fluorouracil (5-FU)]] 600 mg/m2 IV on days 1 & 8
 
−
 
 
 
===References===
 
===References===
−
# Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. [http://www.nejm.org/doi/full/10.1056/NEJMoa052084 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/17079759 PubMed]
+
# '''HE 10/00:''' Fountzilas G, Dafni U, Gogas H, Linardou H, Kalofonos HP, Briasoulis E, Pectasides D, Samantas E, Bafaloukos D, Stathopoulos GP, Karina M, Papadimitriou C, Skarlos D, Pisanidis N, Papakostas P, Markopoulos C, Tzorakoeleftherakis E, Dimitrakakis K, Makrantonakis P, Xiros N, Polichronis A, Varthalitis I, Karanikiotis C, Dimopoulos AM; Hellenic Cooperative Oncology Group. Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: safety analysis of the Hellenic Cooperative Oncology Group randomized phase III trial HE 10/00. Ann Oncol. 2008 May;19(5):853-60. Epub 2007 Nov 27. [https://doi.org/10.1093/annonc/mdm539 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18042835/ PubMed]
 +
## '''Update:''' Gogas H, Dafni U, Karina M, Papadimitriou C, Batistatou A, Bobos M, Kalofonos HP, Eleftheraki AG, Timotheadou E, Bafaloukos D, Christodoulou C, Markopoulos C, Briasoulis E, Papakostas P, Samantas E, Kosmidis P, Stathopoulos GP, Karanikiotis C, Pectasides D, Dimopoulos MA, Fountzilas G. Postoperative dose-dense sequential versus concomitant administration of epirubicin and paclitaxel in patients with node-positive breast cancer: 5-year results of the Hellenic Cooperative Oncology Group HE 10/00 phase III Trial. Breast Cancer Res Treat. 2012 Apr;132(2):609-19. Epub 2011 Dec 21. [https://doi.org/10.1007/s10549-011-1913-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22187126/ PubMed]
  
−
==EC {{#subobject:8d8dbe|Regimen=1}}==
+
==FAC-T {{#subobject:fduic3|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
FAC-T: '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide followed by '''<u>T</u>'''axol (Paclitaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:04f8a6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2012.46.9841 Martín et al. 2013 (GEICAM 2003-02)]
 +
|2003-2008
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#FAC_2|FAC]] x 6
 +
|style="background-color:#91cf60" |Seems to have superior DFS (primary endpoint)<br>(HR 0.73, 95% CI 0.54-0.99)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
EC: '''<u>E</u>'''pirubicin, '''<u>C</u>'''ytoxan
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
===Regimen {{#subobject:aead26|Variant=1}}===
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
Level of Evidence:
+
</div>
−
<span
+
<div class="toccolours" style="background-color:#b3e2cd">
−
style="background:#00CD00;
+
====Chemotherapy, FAC portion (cycles 1 to 4)====
−
padding:3px 6px 3px 6px;
+
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
−
border-color:black;
+
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
−
border-width:2px;
+
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
−
border-style:solid;">Phase III</span>
+
====Chemotherapy, T portion (cycles 5 to 12)====
−
 
+
*[[Paclitaxel (Taxol)]] 100 mg/m<sup>2</sup> IV once on day 1
−
*[[Epirubicin (Ellence)]] 100 mg/m2 IV day 1  
+
'''21-day cycle for 4 cycles, then 7-day cycle for 8 cycles (FAC x 4; T x 8)'''
−
*[[Cyclophosphamide (Cytoxan)]] 830 mg/m2 IV day 1
+
</div></div>
−
 
 
−
'''21-day cycles x 8 cycles'''
 
−
 
 
 
===References===
 
===References===
−
# Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M, Nogaret JM. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol. 2001 Jun 15;19(12):3103-10. [http://jco.ascopubs.org/content/19/12/3103.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/11408507 PubMed]
+
# '''GEICAM 2003-02:''' Martín M, Ruiz A, Ruiz Borrego M, Barnadas A, González S, Calvo L, Margelí Vila M, Antón A, Rodríguez-Lescure A, Seguí-Palmer MA, Muñoz-Mateu M, Dorca Ribugent J, López-Vega JM, Jara C, Espinosa E, Mendiola Fernández C, Andrés R, Ribelles N, Plazaola A, Sánchez-Rovira P, Salvador Bofill J, Crespo C, Carabantes FJ, Servitja S, Chacón JI, Rodríguez CA, Hernando B, Álvarez I, Carrasco E, Lluch A. Fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus FAC followed by weekly paclitaxel as adjuvant therapy for high-risk, node-negative breast cancer: results from the GEICAM/2003-02 study. J Clin Oncol. 2013 Jul 10;31(20):2593-9. Epub 2013 Jun 3. [https://doi.org/10.1200/jco.2012.46.9841 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23733779/ PubMed] [https://clinicaltrials.gov/study/NCT00129389 NCT00129389]
 +
==FEC-D {{#subobject:fduea3|Regimen=1}}==
 +
FEC-D: '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide followed by '''<u>D</u>'''ocetaxel
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 3 x 3 {{#subobject:9hu942|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2006.07.3916 Roché et al. 2006 (FNCLCC PACS 01)]
 +
|1997-2000
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#FEC_2|FEC]] x 6
 +
| style="background-color:#1a9850" |Superior OS<sup>1</sup> (secondary endpoint)<br>OS96: 83.2% vs 78%<br>(aHR 0.75, 95% CI 0.62-0.92)<br><br>Seems to have superior DFS60 (primary endpoint)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7583247/ de Gregorio et al. 2020 (SUCCESS-A)]
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC-DG_999|FEC-DG]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|[https://doi.org/10.1007/s12032-013-0457-3 Sakr et al. 2013]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#FEC_2|FEC]]; FEC 100 x 6
 +
| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br><br>Seems to have superior DFS60 (primary endpoint)
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2018.06.025 Campone et al. 2018 (UCBG 2-08)]
 +
|2007-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC-Ixabepilone_999|FEC-Ixabepilone]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS60
 +
|-
 +
|[https://jamanetwork.com/journals/jama/fullarticle/2579866 Foukakis et al. 2016 (PANTHER)]
 +
|2007-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|Dose-dense tailored chemotherapy
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7840116/ Delaloge et al. 2020 (MINDACT)]
 +
|2007-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Docetaxel_.28TX.29_999|TX]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy for FNCLCC PACS 01 is based on the 2012 update.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, FEC portion (cycles 1 to 3)====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
====Chemotherapy, D portion (cycles 4 to 6)====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
'''21-day cycle for 6 cycles (FEC x 3; D x 3)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
==FEC -> T (Taxotere) {{#subobject:f28719|Regimen=1}}==
+
===Regimen variant #2, 4 x 4 {{#subobject:9hu942|Variant=1}}===
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2687939/ Ellis et al. 2009 (TACT)]
 +
|2001-2003
 +
|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
 +
|1a. [[#E-CMF|E-CMF]]<br>1b. [[#FEC_2|FEC]] x 8
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of DFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
FEC -> T: '''<u>F</u>'''ive-FU, '''<u>E</u>'''pirubicin, '''<u>C</u>'''ytoxan -> '''<u>T</u>'''axotere
+
''Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.''
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
===Regimen {{#subobject:99d167|Variant=1}}===
+
====Preceding treatment====
−
Level of Evidence:
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
<span
+
</div>
−
style="background:#00CD00;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
padding:3px 6px 3px 6px;
+
====Chemotherapy, FEC portion (cycles 1 to 4)====
−
border-color:black;
+
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
−
border-width:2px;
+
*[[Epirubicin (Ellence)]] 40 mg/m<sup>2</sup> IV once on day 1  
−
border-style:solid;">Phase III</span>
+
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
−
 
+
====Chemotherapy, D portion (cycles 5 to 8)====
−
*[[Fluorouracil (5-FU)]] 500 mg/m2 IV day 1
+
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1
−
*[[Epirubicin (Ellence)]] 100 mg/m2 IV day 1  
+
'''21-day cycle for 8 cycles (FEC x 4; D x 4)'''
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m2 IV day 1
+
</div></div>
−
 
 
−
'''21-day cycles x 3 cycles, THEN'''
 
−
 
 
−
*[[Docetaxel (Taxotere)]] 100 mg/m2 IV day 1
 
−
 
 
−
'''21-day cycles x 3 cycles'''
 
  
 
===References===
 
===References===
−
# Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulié P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Genève J, Asselain B. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006 Dec 20;24(36):5664-71. Epub 2006 Nov 20. [http://jco.ascopubs.org/content/24/36/5664.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/17116941 PubMed]
+
<!-- Presented in oral format at the 27th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004. -->
−
 
+
# '''FNCLCC PACS 01:''' Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulié P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Genève J, Asselain B. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006 Dec 20;24(36):5664-71. Epub 2006 Nov 20. [https://doi.org/10.1200/jco.2006.07.3916 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17116941/ PubMed]
−
==FEC -> T (Taxol) {{#subobject:c2b268|Regimen=1}}==
+
## '''Update:''' Coudert B, Asselain B, Campone M, Spielmann M, Machiels JP, Pénault-Llorca F, Serin D, Lévy C, Romieu G, Canon JL, Orfeuvre H, Piot G, Petit T, Jerusalem G, Audhuy B, Veyret C, Beauduin M, Eymard JC, Martin AL, Roché H; UNICANCER Breast Group. Extended benefit from sequential administration of docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide regimen for node-positive breast cancer: the 8-year follow-up results of the UNICANCER-PACS01 trial. Oncologist. 2012;17(7):900-9. Epub 2012 May 18. [https://doi.org/10.1634/theoncologist.2011-0442 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399644/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22610153/ PubMed]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
# '''TACT:''' Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. [https://doi.org/10.1016/S0140-6736(09)60740-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2687939/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19447249/ PubMed] ISRCTN79718493
 +
# Sakr H, Hamed RH, Anter AH, Yossef T. Sequential docetaxel as adjuvant chemotherapy for node-positive or/and T3 or T4 breast cancer: clinical outcome (Mansoura University). Med Oncol. 2013 Mar;30(1):457. Epub 2013 Jan 16. [https://doi.org/10.1007/s12032-013-0457-3 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23322524/ PubMed]
 +
# '''PANTHER:''' Foukakis T, von Minckwitz G, Bengtsson NO, Brandberg Y, Wallberg B, Fornander T, Mlineritsch B, Schmatloch S, Singer CF, Steger G, Egle D, Karlsson E, Carlsson L, Loibl S, Untch M, Hellström M, Johansson H, Anderson H, Malmström P, Gnant M, Greil R, Möbus V, Bergh J; Swedish Breast Cancer Group; German Breast Group; Austrian Breast & Colorectal Cancer Study Group. Effect of tailored dose-dense chemotherapy vs standard 3-weekly adjuvant chemotherapy on recurrence-free survival among women with high-risk early breast cancer: a randomized clinical trial. JAMA. 2016 Nov 8;316(18):1888-1896. [https://jamanetwork.com/journals/jama/fullarticle/2579866 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27825007/ PubMed] [https://clinicaltrials.gov/study/NCT00798070 NCT00798070]
 +
# '''UCBG 2-08:''' Campone M, Lacroix-Triki M, Roca L, Spielmann M, Wildiers H, Cottu P, Kerbrat P, Levy C, Desmoulins I, Bachelot T, Winston T, Eymard JC, Uwer L, Duhoux FP, Verhoeven D, Jaubert D, Coeffic D, Orfeuvre H, Canon JL, Asselain B, Martin AL, Lemonnier J, Roché H. UCBG 2-08: 5-year efficacy results from the UNICANCER-PACS08 randomised phase III trial of adjuvant treatment with FEC100 and then either docetaxel or ixabepilone in patients with early-stage, poor prognosis breast cancer. Eur J Cancer. 2018 Nov;103:184-194. Epub 2018 Sep 26. [https://doi.org/10.1016/j.ejca.2018.06.025 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30267987/ PubMed] [https://clinicaltrials.gov/study/NCT00630032 NCT00630032]
 +
# '''MINDACT:''' Delaloge S, Piccart M, Rutgers E, Litière S, van 't Veer LJ, van den Berkmortel F, Brain E, Dudek-Peric A, Gil-Gil M, Gomez P, Hilbers FS, Khalil Z, Knox S, Kuemmel S, Kunz G, Lesur A, Pierga JY, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Thompson AM, Viale G, Zoppoli G, Vuylsteke P, Tryfonidis K, Poncet C, Bogaerts J, Cardoso F; MINDACT investigators and the TRANSBIG Consortium. Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial. J Clin Oncol. 2020 Apr 10;38(11):1186-1197. Epub 2020 Feb 21. [https://doi.org/10.1200/jco.19.01371 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7840116/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32083990/ PubMed] [https://clinicaltrials.gov/study/NCT00433589 NCT00433589]
 +
# '''SUCCESS-A:''' de Gregorio A, Häberle L, Fasching PA, Müller V, Schrader I, Lorenz R, Forstbauer H, Friedl TWP, Bauer E, de Gregorio N, Deniz M, Fink V, Bekes I, Andergassen U, Schneeweiss A, Tesch H, Mahner S, Brucker SY, Blohmer JU, Fehm TN, Heinrich G, Lato K, Beckmann MW, Rack B, Janni W. Gemcitabine as adjuvant chemotherapy in patients with high-risk early breast cancer-results from the randomized phase III SUCCESS-A trial. Breast Cancer Res. 2020 Oct 23;22(1):111. [https://doi.org/10.1186/s13058-020-01348-w link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7583247/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/33097092/ PubMed] [https://clinicaltrials.gov/study/NCT02181101 NCT02181101]
 +
==ddFEC-ddD {{#subobject:45dbc1|Regimen=1}}==
 +
ddFEC-D: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide followed by dose-dense '''<u>D</u>'''ocetaxel
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:05e37f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1007/s10549-014-3202-5 Saloustros et al. 2014 (HORG CT/04.22)]
 +
|2004-2007
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Dose-dense FEC-T|ddFEC-T]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS36
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdw274 Mavroudis et al. 2016 (HORG CT/07.17)]
 +
|2007-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cyclophosphamide_.26_Docetaxel_.28TC.29|TC]]
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior DFS36
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
FEC -> T: '''<u>F</u>'''ive-FU, '''<u>E</u>'''pirubicin, '''<u>C</u>'''ytoxan -> '''<u>T</u>'''axol
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
===Regimen {{#subobject:82ae3d|Variant=1}}===
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
Level of Evidence:
+
</div>
−
<span
+
<div class="toccolours" style="background-color:#b3e2cd">
−
style="background:#00CD00;
+
====Chemotherapy, ddFEC portion (cycles 1 to 4)====
−
padding:3px 6px 3px 6px;
+
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1  
−
border-color:black;
+
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1  
−
border-width:2px;
+
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
−
border-style:solid;">Phase III</span>
+
====Chemotherapy, ddD portion (cycles 5 to 8)====
−
 
+
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
−
*[[Fluorouracil (5-FU)]] 600 mg/m2 IV day 1
+
====Supportive therapy, both portions (cycles 1 to 8)====
−
*[[Epirubicin (Ellence)]] 90 mg/m2 IV day 1  
+
*[[:Category:Granulocyte_colony-stimulating_factors|G-CSF]] support (drug/dose/schedule not specified)
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV day 1
+
'''14-day cycle for 8 cycles (ddFEC x 4; ddD x 4)'''
−
 
+
</div></div>
−
'''21-day cycles x 4 cycles, THEN 3 weeks of no treatment, THEN'''
 
−
 
 
−
*[[Paclitaxel (Taxol)]] 100 mg/m2 IV day 1
 
−
 
 
−
'''1-week cycles x 8 cycles/weeks'''
 
−
 
 
 
===References===
 
===References===
−
# Martín M, Rodríguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Munárriz B, Rodríguez CA, Crespo C, de Alava E, López García-Asenjo JA, Guitián MD, Almenar S, González-Palacios JF, Vera F, Palacios J, Ramos M, Gracia Marco JM, Lluch A, Alvarez I, Seguí MA, Mayordomo JI, Antón A, Baena JM, Plazaola A, Modolell A, Pelegrí A, Mel JR, Aranda E, Adrover E, Alvarez JV, García Puche JL, Sánchez-Rovira P, Gonzalez S, López-Vega JM; GEICAM 9906 Study Investigators. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by Paclitaxel for early breast cancer. J Natl Cancer Inst. 2008 Jun 4;100(11):805-14. Epub 2008 May 27. [http://jnci.oxfordjournals.org/content/100/11/805.long link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18505968 PubMed]
+
# '''HORG CT/04.22:''' Saloustros E, Malamos N, Boukovinas I, Kakolyris S, Kouroussis C, Athanasiadis A, Ziras N, Kentepozidis N, Makrantonakis P, Polyzos A, Christophyllakis C, Georgoulias V, Mavroudis D. Dose-dense paclitaxel versus docetaxel following FEC as adjuvant chemotherapy in axillary node-positive early breast cancer: a multicenter randomized study of the Hellenic Oncology Research Group (HORG). Breast Cancer Res Treat. 2014 Dec;148(3):591-7. Epub 2014 Nov 16. [https://doi.org/10.1007/s10549-014-3202-5 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25399229/ PubMed] [https://clinicaltrials.gov/study/NCT00431080 NCT00431080]
 +
# '''HORG CT/07.17:''' Mavroudis D, Matikas A, Malamos N, Papakotoulas P, Kakolyris S, Boukovinas I, Athanasiadis A, Kentepozidis N, Ziras N, Katsaounis P, Saloustros E, Georgoulias V; HORG. Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2016 Oct;27(10):1873-8. Epub 2016 Aug 8. [https://doi.org/10.1093/annonc/mdw274 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27502729/ PubMed] [https://clinicaltrials.gov/study/NCT01985724 NCT01985724]
  
−
==No additional therapy {{#subobject:65fa3b|Regimen=1}}==
+
==FEC-P {{#subobject:fd16bz|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
FEC-P: '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide followed by '''<u>P</u>'''aclitaxel
 +
<br>FEC-T: '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide followed by '''<u>T</u>'''axol (Paclitaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:9hu942|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[http://jnci.oxfordjournals.org/content/100/11/805.long Martín et al. 2008 (GEICAM 9906)]
 +
|1999-2002
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#FEC_2|FEC]] x 6
 +
| style="background-color:#1a9850" |Superior DFS60 (primary endpoint)<br>DFS60: 78.5% vs 72.1%<br>(HR 0.77, 95% CI 0.62-0.95)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
===Regimen {{#subobject:a964de|Variant=1}}===
+
====Preceding treatment====
−
Level of Evidence:
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
<span
+
</div>
−
style="background:#00CD00;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
padding:3px 6px 3px 6px;
+
====Chemotherapy, FEC portion (cycles 1 to 4)====
−
border-color:black;
+
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
−
border-width:2px;
+
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
−
border-style:solid;">Phase III</span>
+
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
−
 
+
====Chemotherapy, P portion (cycles 5 to 12)====
−
''Used as a comparator arm, historically; here for reference purposes only.''
+
*[[Paclitaxel (Taxol)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
'''21-day cycle for 4 cycles, then 7-day cycle for 8 cycles (FEC x 4; P x 8)'''
 +
</div></div>
  
 
===References===
 
===References===
−
# Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, De Lena M, Tancini G, Bajetta E, Musumeci R, Veronesi U. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976 Feb 19;294(8):405-10. [http://www.nejm.org/doi/full/10.1056/NEJM197602192940801 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/1246307 PubMed]
+
# '''GEICAM 9906:''' Martín M, Rodríguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Munárriz B, Rodríguez CA, Crespo C, de Alava E, López García-Asenjo JA, Guitián MD, Almenar S, González-Palacios JF, Vera F, Palacios J, Ramos M, Gracia Marco JM, Lluch A, Alvarez I, Seguí MA, Mayordomo JI, Antón A, Baena JM, Plazaola A, Modolell A, Pelegrí A, Mel JR, Aranda E, Adrover E, Alvarez JV, García Puche JL, Sánchez-Rovira P, Gonzalez S, López-Vega JM; GEICAM. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst. 2008 Jun 4;100(11):805-14. Epub 2008 May 27. [http://jnci.oxfordjournals.org/content/100/11/805.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18505968/ PubMed] [https://clinicaltrials.gov/study/NCT00129922 NCT00129922]
−
 
+
# '''GIM2:''' Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; GIM. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 x 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. [https://doi.org/10.1016/s0140-6736(14)62048-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25740286/ PubMed] [https://clinicaltrials.gov/study/NCT00433420 NCT00433420]
−
==T (Taxotere) -> FEC {{#subobject:45c144|Regimen=1}}==
+
##'''Update:''' Del Mastro L, Poggio F, Blondeaux E, De Placido S, Giuliano M, Forestieri V, De Laurentiis M, Gravina A, Bisagni G, Rimanti A, Turletti A, Nisticò C, Vaccaro A, Cognetti F, Fabi A, Gasparro S, Garrone O, Alicicco MG, Urracci Y, Mansutti M, Poletti P, Correale P, Bighin C, Puglisi F, Montemurro F, Colantuoni G, Lambertini M, Boni L; Gruppo Italiano Mammella Investigators. Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial. Lancet Oncol. 2022 Dec;23(12):1571-1582. Epub 2022 Nov 10. [https://doi.org/10.1016/s1470-2045(22)00632-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36370716/ PubMed]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
==T-FEC {{#subobject:ug8h8g|Regimen=1}}==
 +
T-FEC: '''<u>T</u>'''axol (Paclitaxel), followed by '''<u>E</u>'''pirubicin & '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:7y2gny|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2011.36.2079 Kelly et al. 2012 (MDACC ID01-580)]
 +
|2002-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#TX-FEC_.28Docetaxel.29|TX-FEC]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of RFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
T -> FEC: '''<u>T</u>'''axotere -> '''<u>F</u>'''ive-FU, '''<u>E</u>'''pirubicin, '''<u>C</u>'''ytoxan
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
===Regimen {{#subobject:bfeef2|Variant=1}}===
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
Level of Evidence:
+
</div>
−
<span
+
<div class="toccolours" style="background-color:#b3e2cd">
−
style="background:#00CD00;
+
====Chemotherapy, T portion (cycles 1 to 12)====
−
padding:3px 6px 3px 6px;
+
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once on day 1
−
border-color:black;
+
====Chemotherapy, FEC portion (cycles 13 to 16)====
−
border-width:2px;
+
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
−
border-style:solid;">Phase III</span>
+
*[[Epirubicin (Ellence)]] 100 mg/m<sup>2</sup> IV once on day 1
−
 
+
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
−
*[[Docetaxel (Taxotere)]] 100 mg/m2 IV over 1 hour on day 1
+
'''7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (T x 12; FEC x 4)'''
−
 
+
</div></div>
−
'''21-day cycles x 3 cycles, THEN'''
 
−
 
 
−
*[[Fluorouracil (5-FU)]] 600 mg/m2 IV day 1
 
−
*[[Epirubicin (Ellence)]] 60 mg/m2 IV day 1  
 
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV day 1
 
−
 
 
−
'''21-day cycles x 3 cycles'''
 
−
 
 
−
===Monitoring===
 
−
*Cardiac function: echocardiogram at baseline, after last cycle of FEC, 12 months after completion of chemotherapy, and 36 months after completion of chemotherapy
 
−
 
 
 
===References===
 
===References===
−
# Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. [http://www.nejm.org/doi/full/10.1056/NEJMoa053028 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16495393 PubMed]
+
<!-- Presented at the 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 30-June 3, 2008. -->
−
 
+
# '''MDACC ID01-580:''' Kelly CM, Green MC, Broglio K, Thomas ES, Brewster AM, Valero V, Ibrahim NK, Gonzalez-Angulo AM, Booser DJ, Walters RS, Hunt KK, Hortobagyi GN, Buzdar AU. Phase III trial evaluating weekly paclitaxel versus docetaxel in combination with capecitabine in operable breast cancer. J Clin Oncol. 2012 Mar 20;30(9):930-5. Epub 2012 Feb 13. [https://doi.org/10.1200/JCO.2011.36.2079 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22331946/ PubMed] [https://clinicaltrials.gov/study/NCT00050167 NCT00050167]
−
==V -> FEC {{#subobject:84c1e0|Regimen=1}}==
+
==TX-CEX {{#subobject:fdhg38|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
TX-CEX: '''<u>T</u>'''axotere (Docetaxel) & '''<u>X</u>'''eloda (Capecitabine) followed by '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''pirubicin, '''<u>X</u>'''eloda (Capecitabine)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:1zzk71|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/s1470-2045(09)70307-9 Joensuu et al. 2009 (FinXX)]
 +
|2004-2007
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#D-FEC_2|D-FEC]]
 +
| style="background-color:#91cf60" |Superior RFS (primary endpoint)<br>RFS36: 93% vs 89%<br>(HR 0.66, 95% CI 0.47-0.94)<br><br>Seems to have superior OS<sup>1</sup> (secondary endpoint)<br>OS180: 77.6% vs 73.3%<br>(HR 0.81, 95% CI 0.66-0.99)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
V -> FEC: '''<u>V</u>'''inorelbine -> '''<u>F</u>'''ive-FU, '''<u>E</u>'''pirubicin, '''<u>C</u>'''ytoxan
+
''<sup>1</sup>Reported OS efficacy is based on the 2022 update.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, TX portion (cycles 1 to 3)====
 +
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
*[[Capecitabine (Xeloda)]] 900 mg/m<sup>2</sup> PO twice per day on days 1 to 15
 +
====Chemotherapy, CEX portion (cycles 4 to 6)====
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Capecitabine (Xeloda)]] 900 mg/m<sup>2</sup> PO twice per day on days 1 to 15
 +
'''21-day cycle for 6 cycles (TX x 3; CEX x 3)'''
 +
</div></div>
 +
===References===
 +
# '''FinXX:''' Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Asola R, Kokko R, Ahlgren J, Auvinen P, Hemminki A, Paija O, Helle L, Nuortio L, Villman K, Nilsson G, Lahtela SL, Lehtiö K, Pajunen M, Poikonen P, Nyandoto P, Kataja V, Bono P, Leinonen M, Lindman H; FinXX Study Investigators. Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer: an open-label, randomised controlled trial. Lancet Oncol. 2009 Dec;10(12):1145-51. Epub 2009 Nov 10. [https://doi.org/10.1016/s1470-2045(09)70307-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19906561/ PubMed] [https://clinicaltrials.gov/study/NCT00114816 NCT00114816]
 +
## '''Update:''' Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Kokko R, Ahlgren J, Auvinen P, Paija O, Helle L, Villman K, Nyandoto P, Nilsson G, Pajunen M, Asola R, Poikonen P, Leinonen M, Kataja V, Bono P, Lindman H. Adjuvant capecitabine, docetaxel, cyclophosphamide, and epirubicin for early breast cancer: final analysis of the randomized FinXX trial. J Clin Oncol. 2012 Jan 1;30(1):11-8. Epub 2011 Nov 21. [https://doi.org/10.1200/JCO.2011.35.4639 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22105826/ PubMed]
 +
## '''Update:''' Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola A, Tanner M, Ahlgren J, Auvinen P, Lahdenperä O, Villman K, Nyandoto P, Nilsson G, Poikonen-Saksela P, Kataja V, Bono P, Junnila J, Lindman H. Adjuvant Capecitabine for Early Breast Cancer: 15-Year Overall Survival Results From a Randomized Trial. J Clin Oncol. 2022 Apr 1;40(10):1051-1058. Epub 2022 Jan 12. [https://doi.org/10.1200/jco.21.02054 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8966968/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35020465/ PubMed]
  
 +
==V-FEC {{#subobject:84c1e0|Regimen=1}}==
 +
V-FEC: '''<u>V</u>'''inorelbine followed by '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 
===Regimen {{#subobject:712969|Variant=1}}===
 
===Regimen {{#subobject:712969|Variant=1}}===
−
Level of Evidence:
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
<span
+
!style="width: 20%"|Study
−
style="background:#00CD00;
+
!style="width: 20%"|Dates of enrollment
−
padding:3px 6px 3px 6px;
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
border-color:black;
+
!style="width: 20%"|Comparator
−
border-width:2px;
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
border-style:solid;">Phase III</span>
+
|-
 +
| [https://doi.org/10.1056/NEJMoa053028 Joensuu et al. 2006 (FinHer)]
 +
| 2000-2003
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#D-FEC_2|D-FEC]]
 +
| style="background-color:#d73027" |Inferior DDFS
 +
|-
 +
|}
 +
''Note: this is the study design for patients with HER2-negative disease.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy, V portion (cycles 1 to 3)====
 +
*[[Vinorelbine (Navelbine)]] as follows:
 +
**Cycles 1 & 2: 25 mg/m<sup>2</sup> IV over 5 to 10 minutes once per day on days 1, 8, 15
 +
**Cycle 3: 25 mg/m<sup>2</sup> IV over 5 to 10 minutes once per day on days 1 & 8
  
−
*[[Vinorelbine (Navelbine)]] 24 mg/m2 IV over 5 to 10 minutes once per day on days 1, 8, 15
+
====Chemotherapy, FEC portion (cycles 4 to 6)====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles (V x 3; FEC x 3)'''
 +
</div></div>
  
−
'''21-day cycles x 3 cycles, THEN'''
+
===References===
−
 
+
<!-- no pre-pub disclosed -->
−
*[[Fluorouracil (5-FU)]] 600 mg/m2 IV day 1
+
# '''FinHer:''' Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. [https://doi.org/10.1056/NEJMoa053028 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16495393/ PubMed] ISRCTN76560285
−
*[[Epirubicin (Ellence)]] 60 mg/m2 IV day 1
+
## '''Update:''' Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. Epub 2009 Nov 2. [https://doi.org/10.1200/JCO.2008.21.4577 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19884557/ PubMed]
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV day 1
 
−
 
 
−
'''21-day cycles x 3 cycles'''
 
−
 
 
−
===Monitoring===
 
−
*Cardiac function: echocardiogram at baseline, after last cycle of FEC, 12 months after completion of chemotherapy, and 36 months after completion of chemotherapy
 
  
 +
=Adjuvant chemotherapy=
 +
==Bevacizumab monotherapy {{#subobject:c254bd|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:6c056e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401076/ Bear et al. 2012 (NSABP B-40)]
 +
|2007-2010
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Complex_multipart_regimens#NSABP_B-40|See link]]
 +
|[[Complex_multipart_regimens#NSABP_B-40|See link]]
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*Neoadjuvant [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_.26_Bevacizumab|AC+Bev]] x 4, then [[Surgery#Breast_cancer_surgery|surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
 +
'''21-day cycle for 10 cycles'''
 +
</div></div>
 +
===References===
 +
# '''NSABP B-40:''' Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. [https://doi.org/10.1056/NEJMoa1111097 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401076/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22276821/ PubMed] [https://clinicaltrials.gov/study/NCT00408408 NCT00408408]
 +
## '''Update:''' Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Paik S, Swain SM, Mamounas EP, Wolmark N. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1037-1048. Epub 2015 Aug 10. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. [https://doi.org/10.1016/S1470-2045(15)00041-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624323/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26272770/ PubMed]
 +
==Capecitabine monotherapy {{#subobject:e058c1|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:9cc782|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082436/ Muss et al. 2009 (CALGB 49907)]
 +
|2001-2006
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|Investigator's choice of:<br>1a. [[Breast_cancer_-_historical#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]] x 4<br>1b. [[#CMF|CMF]] x 6
 +
| style="background-color:#fc8d59" |Seems to have inferior RFS<sup>1</sup> (primary endpoint)
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa1612645 Masuda et al. 2017 (CREATE-X)]
 +
|2007-2012
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|Standard therapy
 +
| style="background-color:#1a9850" |Superior DFS (primary endpoint)<br>DFS60: 74.1% vs 67.6%<br>(HR 0.70, 95% CI 0.53-0.92)<br><br>Superior OS (secondary endpoint)<br>OS60: 89.2% vs 83.6%<br>(HR 0.59, 95% CI 0.39-0.90)
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy for CALGB 49907 is based on the 2019 update.''<br>
 +
''Note: patients in CALGB 49907 received a maximum of 6 cycles. All patients in CREATE-X had residual disease at time of surgical resection. Concomitant endocrine therapy was allowed.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*CALGB 49907: [[Surgery#Breast_cancer_surgery|Surgery]]
 +
*CREATE-X: Neoadjuvant [[Regimen_classes#Chemotherapy-based_regimen|chemotherapy]] containing anthracycline, taxane, or both, then [[Surgery#Breast_cancer_surgery|surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 +
'''21-day cycle for 6 to 8 cycles'''
 +
</div></div>
 +
===References===
 +
# '''CALGB 49907:''' Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Becker HP, Kartcheske PA, Wheeler JD, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Magrinat G, Parker BA, Hart RD, Grenier D, Norton L, Hudis CA, Winer EP; CALGB. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009 May 14;360(20):2055-65. Erratum in: N Engl J Med. 2009 Oct 22;361(17):1714. Magrinat, Gutav [corrected to Magrinat, Gustav]. [https://doi.org/10.1056/NEJMoa0810266 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082436/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19439741/ PubMed] [https://clinicaltrials.gov/study/NCT00024102 NCT00024102]
 +
##'''Update:''' Muss HB, Polley MC, Berry DA, Liu H, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Kartcheske PA, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Sutton LM, Magrinat G, Parker BA, Hart RD, Grenier D, Hurria A, Jatoi A, Norton L, Hudis CA, Winer EP, Carey L. Randomized Trial of Standard Adjuvant Chemotherapy Regimens Versus Capecitabine in Older Women With Early Breast Cancer: 10-Year Update of the CALGB 49907 Trial. J Clin Oncol. 2019 Sep 10;37(26):2338-2348. Epub 2019 Jul 24. [https://doi.org/10.1200/jco.19.00647 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6900836/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31339827/ PubMed]
 +
# '''CREATE-X:''' Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, Kuroi K, Im SA, Park BW, Kim SB, Yanagita Y, Ohno S, Takao S, Aogi K, Iwata H, Jeong J, Kim A, Park KH, Sasano H, Ohashi Y, Toi M; Japan Breast Cancer Research Group; Korean Breast Cancer Study Group; Korean Cancer Study Group. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017 Jun 1;376(22):2147-2159. [https://doi.org/10.1056/NEJMoa1612645 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28564564/ PubMed] UMIN000000843
 +
==CMF {{#subobject:fb4c46|Regimen=1}}==
 +
CMF: '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 600/40/600 x 6 {{#subobject:92cca2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1097/00000421-200108000-00001 Ron et al. 2001]
 +
|1988-1992
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer_-_historical#FNC|CNF]]
 +
| style="background-color:#fc8d59" |Seems to have inferior DFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 600/40/600 x 6 to 8 {{#subobject:92xjr2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172658/ Sparano et al. 2018 (TAILORx)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer,_ER-positive_-_null_regimens#Observation|No chemotherapy]]
 +
| style="background-color:#eeee01" |Non-inferior IDFS (primary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Eligibility criteria====
 +
*TAILORx: Oncotype DX score of 11 to 25
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 to 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 600/40/600 x 8, q4wk {{#subobject:93cae2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/NEJM199710023371401 Overgaard et al. 1997 (DBCG 82b)]
 +
|1982-1989
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 +
|[[Complex_multipart_regimens#DBCG_82b|See link]]
 +
| style="background-color:#1a9850" |[[Complex_multipart_regimens#DBCG_82b|See link]]
 +
|-
 +
|}
 +
''Note: in DBCG 82b, radiotherapy was given between cycles 1 & 2.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Mastectomy|Mastectomy]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''28-day cycle for 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 600/40/600 x 9 {{#subobject:93iqe2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2007.01.009 Ejlertsen et al. 2007 (DBCG 89D)]
 +
|1990-1998
 +
|style="background-color:#1a9851"|Phase 3 (C)
 +
|[[#FEC_2|FEC]] x 9
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|}
 +
''Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 9 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, 600/60/600 x 6 {{#subobject:93jg3c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdg260 Martin et al. 2003 (GEICAM 8701)]
 +
|1987-1991
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FAC_2|FAC]]; 500/50/500 x 6
 +
| style="background-color:#fee08b" |Might have inferior DFS
 +
|-
 +
|}
 +
''Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Methotrexate (MTX)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #6, 700/30/700 x 24 {{#subobject:8ba32c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1995.13.1.33 Clahsen et al. 1995 (EORTC 09771)]
 +
|1976-1980
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Breast_cancer_-_null_regimens#Observation|Observation]]
 +
| style="background-color:#91cf60" |Seems to have superior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 50 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] 15 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 350 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''1-month cycle for 24 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #7, 750/50/600 x 6-8 ("Scottish Breast Group schedule") {{#subobject:7a96ee|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/0140-6736(93)90812-U Stewart et al. 1993]
 +
|1980-1990
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[Breast_cancer_-_historical#CMFP|CMFP]]<br>2. [[#Bilateral_oophorectomy_999|Bilateral oophorectomy]]<br>3. [[#Oophorectomy_.26_Prednisolone_999|Oophorectomy & Prednisolone]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 +
|-
 +
|[https://doi.org/10.1056/nejmoa052084 Poole et al. 2006 (BR9601)]
 +
|1996-2001
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#E-CMF|E-CMF]] x 4+4
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7005671/ Fernando et al. 2019 (SECRAB)]
 +
|1998-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#CMF_.26_RT_888|CMF & RT]]<br>1b. [[#E-CMF_.26_RT_888|E-CMF & RT]]<br>1c. [[#A-CMF_.26_RT_888|A-CMF & RT]]<br>1d. [[#MMM_.26_RT_888|MMM & RT]]
 +
| style="background-color:#d73027" |Inferior LRFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
 +
*[[Methotrexate (MTX)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 to 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #8, 840/50/800 {{#subobject:17bzcj|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://www.surgjournal.com/article/0039-6060(80)90244-5/fulltext Hubay et al. 1980]
 +
|rowspan=2|NR
 +
|rowspan=2 style="background-color:#1a9851" |Randomized (C)
 +
|1. [[#CMFT|CMFT]]
 +
| style="background-color:#fc8d59" |Seems to have inferior RFS
 +
|-
 +
|2. [[#CMFT_.26_BCG_999|CMFT & BCG]]
 +
| style="background-color:#ffffbf" |Did not meet endpoints of RFS/OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 30 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycle for 12 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #9, 1000/80/1000 x 6 {{#subobject:8abc32|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1007/s12282-009-0132-x Kimura et al. 2009]
 +
|1996-2000
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC_2|FEC]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #10, 1000/80/1200 x 6 {{#subobject:831237|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2002.05.042 Jonat et al. 2002 (ZEBRA)]
 +
|1990-1996
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Goserelin_monotherapy_999|Goserelin]] x 2 y
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|[https://doi.org/10.1200/jco.2006.08.8534 Schmid et al. 2007 (TABLE)]
 +
|1995-1998
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer,_ER-positive#Leuprolide_monotherapy|Leuprolide]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]], within 6 weeks
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #11, 1120/60/1000 x 12 {{#subobject:61d518|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=3|[https://doi.org/10.1007/BF01806239 Brincker et al. 1983 (DBCG 77B)]
 +
|rowspan=3|1977-1983
 +
|rowspan=3 style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[Breast_cancer_-_historical#Cyclophosphamide_monotherapy|Cyclophosphamide]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 +
|-
 +
|2. [[Breast_cancer_-_historical#Levamisole_monotherapy|Levamisole]]
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|3. [[Breast_cancer_-_null_regimens#Observation|No chemotherapy]]
 +
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup> (secondary endpoint)
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy versus no chemotherapy is based on the 2010 update.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 80 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''1-month cycle for 12 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #12, 1120/64/960 x 12 {{#subobject:611b18|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S0140-6736(84)92684-9 Howell et al. 1984]
 +
|1976-1983
 +
|style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Breast_cancer_-_null_regimens#Observation|Observation]]
 +
| style="background-color:#1a9850" |Superior RFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 80 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] 32 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 4800 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycle for 12 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#ee6b6e">
 +
===Regimen variant #13, 1200/80/1200 x 1 {{#subobject:3dbcd1|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#f01e2c"
 +
|<small><span style="color:white;">'''Historic variant'''</span></small>
 +
|-
 +
|}
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/NEJM198902233200804 Goldhirsch et al. 1989 (LCBS V)]
 +
|1981-1985
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Breast_cancer_-_null_regimens#Observation|No further treatment]]
 +
| style="background-color:#91cf60" |Seems to have superior DFS
 +
|-
 +
|}
 +
''Note: leucovorin was not used for antineoplastic effect in this regimen.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Mastectomy|Mastectomy]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
====Supportive therapy====
 +
*[[Leucovorin (Folinic acid)]] 15 mg IV once on day 2, then 15 mg PO once on day 9
 +
'''8-day course'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #14, 1200/80/1200 x 4 {{#subobject:37c8be|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdu564 Perrone et al. 2014 (ELDA)]
 +
|2003-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_monotherapy|Docetaxel]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
''Note: In ELDA, this protocol was for ER/PR+ patients.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycle for 4 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #15, 1200/80/1200 x 6 ("Classical" IV) {{#subobject:958ae2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/NEJM199710023371402 Ragaz et al. 1997]
 +
|1978-1986
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#CMF_.26_RT_888|CMF & RT]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|[https://doi.org/10.1200/JCO.1996.14.1.35 Coombes et al. 1996]
 +
|1984-1992
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC_2|FEC]]
 +
| style="background-color:#ffffbf" |Did not meet co-primary endpoints of RFS/OS
 +
|-
 +
|[https://doi.org/10.1007/s10549-007-9844-9 Taucher et al. 2007 (ABCSG-07)]
 +
|1991-1999
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#CMF_999|CMF]]; neoadjuvant
 +
| style="background-color:#91cf60" |Seems to have superior RFS
 +
|-
 +
|[https://doi.org/10.1056/nejmoa052084 Poole et al. 2006 (NEAT)]
 +
|1996-2001
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#E-CMF|E-CMF]] x 4+4
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7005671/ Fernando et al. 2019 (SECRAB)]
 +
|1998-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#CMF_.26_RT_888|CMF & RT]]<br>1b. [[#E-CMF_.26_RT_888|E-CMF & RT]]<br>1c. [[#A-CMF_.26_RT_888|A-CMF & RT]]<br>1d. [[#MMM_.26_RT_888|MMM & RT]]
 +
| style="background-color:#d73027" |Inferior LRFS
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdu564 Perrone et al. 2014 (ELDA)]
 +
|2003-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_monotherapy|Docetaxel]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
''Note: In ELDA, this protocol was for ER/PR- patients.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #16, 1400/60/1200 x 12 {{#subobject:d1gh15|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1016/0277-5379(89)90203-4 Rubens et al. 1989 (EORTC 10792)]
 +
|rowspan=2|1979-1985
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[Breast_cancer_-_null_regimens#Observation|Observation]]
 +
| style="background-color:#ffffbf" |Did not meet endpoint of OS
 +
|-
 +
|2. [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_3|Tamoxifen]]<br>3. [[#CMFT|CMFT]]
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|}
 +
''Note: this trial had a complex efficacy analysis; see paper for details.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycle for 12 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #17, 1400/80/1000 x 6 {{#subobject:d1abf4|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2008.18.3939 Watanabe et al. 2009 (NSAS BC-01)]
 +
|1996-2001
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#UFT_monotherapy_999|UFT]]
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior RFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #18, 1400/80/1200 x 3 {{#subobject:16ad91|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan = 2|[https://doi.org/10.1200/JCO.1996.14.6.1885 Castiglione-Gertsch et al. 1996 (IBCSG VI)]
 +
|rowspan = 2|1986-1993
 +
|rowspan = 2 style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|1. [[#CMF|CMF]] x 6
 +
| style="background-color:#fc8d59" |Seems to have inferior DFS
 +
|-
 +
|2. [[#CMF|CMF]] x 3, with re-introduction<br>3. [[#CMF|CMF]] x 6, with re-introduction
 +
| style="background-color:#fee08b" |Might have inferior DFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycle for 3 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Adjuvant [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_3|Tamoxifen]] x 5 y versus [[Breast_cancer_-_null_regimens#Observation|no further treatment]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #19, 1400/80/1200 x 6 {{#subobject:dcd1f4|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://pubmed.ncbi.nlm.nih.gov/394864 Tancini et al. 1979 (CALGB 7581)]
 +
|1975-NR
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[#CMF|CMF]] x 12
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 +
|-
 +
|[https://doi.org/10.1200/JCO.1996.14.1.35 Coombes et al. 1996]
 +
|1984-1992
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC_2|FEC]]
 +
| style="background-color:#ffffbf" |Did not meet co-primary endpoints of RFS/OS
 +
|-
 +
|rowspan = 2|[https://doi.org/10.1200/JCO.1996.14.6.1885 Castiglione-Gertsch et al. 1996 (IBCSG VI)]
 +
|rowspan = 2|1986-1993
 +
|rowspan = 2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#CMF|CMF]] x 3
 +
| style="background-color:#91cf60" |Seems to have superior DFS
 +
|-
 +
|2. [[#CMF|CMF]] x 3, with re-introduction<br> 3. [[#CMF|CMF]] x 6, with re-introduction
 +
| style="background-color:#fee08b" |Might have inferior DFS
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1200/jco.2001.19.12.3103 Piccart et al. 2001 (Belgian trial)]
 +
|rowspan=2|1988-1996
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29|EC]]; full-dose
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 +
|-
 +
|2. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29|EC]]; moderate-dose
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 +
|-
 +
|[https://doi.org/10.1200/jco.1998.16.8.2651 Levine et al. 1998 (NCIC-CTG MA.5)]
 +
|1989-1993
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC_2|CEF]]
 +
| style="background-color:#d73027" |Inferior RFS
 +
|-
 +
|[https://doi.org/10.1200/JCO.2000.18.17.3125 Amadori et al. 2000]
 +
|1989-1993
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Breast_cancer_-_null_regimens#Observation|Observation]]
 +
| style="background-color:#91cf60" |Seems to have superior DFS
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.08.071 Hutchins et al. 2005 (INT-0102)]
 +
|1989-1993
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FAC_2|CAF]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|[https://doi.org/10.1200/JCO.2002.05.042 Jonat et al. 2002 (ZEBRA)]
 +
|1990-1996
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Goserelin_monotherapy_999|Goserelin]] x 2 y
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|[https://doi.org/10.1200/jco.2001.19.4.931 Fisher et al. 2001 (NSABP B-23)]
 +
|1991-1998
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer_-_historical#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|[https://doi.org/10.1093/jnci/djk108 Adjuvant Breast Cancer Trials Collaborative Group 2007 (NCRI ABC-CT)]
 +
|1992-2000
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Breast_cancer_-_null_regimens#Observation|Observation]]
 +
| style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)<br>(aHR 0.83, 95% CI 0.70-0.99)
 +
|-
 +
|[https://doi.org/10.1056/nejmoa052084 Poole et al. 2006 (NEAT)]
 +
|1996-2001
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#E-CMF|E-CMF]] x 4+4
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7005671/ Fernando et al. 2019 (SECRAB)]
 +
|1998-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#CMF_.26_RT_888|CMF & RT]]<br>1b. [[#E-CMF_.26_RT_888|E-CMF & RT]]<br>1c. [[#A-CMF_.26_RT_888|A-CMF & RT]]<br>1d. [[#MMM_.26_RT_888|MMM & RT]]
 +
| style="background-color:#d73027" |Inferior LRFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082436/ Muss et al. 2009 (CALGB 49907)]
 +
|2001-2006
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_monotherapy|Capecitabine]]
 +
| style="background-color:#91cf60" |Seems to have superior OS<sup>1</sup> (secondary endpoint)<br>RFS120: 56% vs 50%<br>(HR 0.80, 95% CI 0.62-0.98)<br><br>Seems to have superior RFS (primary endpoint)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172658/ Sparano et al. 2018 (TAILORx)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer,_ER-positive_-_null_regimens#Observation|No chemotherapy]]
 +
| style="background-color:#eeee01" |Non-inferior IDFS (primary endpoint)
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy for CALGB 49907 is based on the 2019 update.''<br>
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Eligibility criteria====
 +
*TAILORx: Oncotype DX score of 11 to 25
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycle for 6 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*NSABP B-23 and INT-0102: Adjuvant [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_3|tamoxifen]] x 5 years versus [[Breast_cancer_-_null_regimens#Placebo|placebo]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #20, 1400/80/1200 x 12 {{#subobject:8a712c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/NEJM197602192940801 Bonadonna et al. 1976]
 +
|1973-1975
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Breast_cancer_-_null_regimens#Observation|Observation]]
 +
| style="background-color:#1a9850" |Superior RFS
 +
|-
 +
|[https://pubmed.ncbi.nlm.nih.gov/394864 Tancini et al. 1979 (CALGB 7581)]
 +
|1975-NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#CMF|CMF]] x 6
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 +
|-
 +
|[https://doi.org/10.1200/JCO.1996.14.4.1136 Misset et al. 1996 (OncoFrance)]
 +
|1978-1981
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer_-_historical#AVCF|AVCF]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(19900115)65:2%3C200::AID-CNCR2820650203%3E3.0.CO;2-Q Tormey et al. 1990 (ECOG E5177)]
 +
|1978-1982
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[Breast_cancer_-_historical#CMFP|CMFP]]<br>2. [[Breast_cancer_-_historical#CMFPT|CMFPT]]
 +
| style="background-color:#ffffbf" |Did not meet co-primary endpoints of TTR/OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycle for 12 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. [http://www.nejm.org/doi/full/10.1056/NEJMoa053028 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16495393 PubMed]
+
# Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, De Lena M, Tancini G, Bajetta E, Musumeci R, Veronesi U. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976 Feb 19;294(8):405-10. [https://doi.org/10.1056/NEJM197602192940801 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1246307/ PubMed]
 +
## '''Update:''' Bonadonna G, Rossi A, Valagussa P, Banfi A, Veronesi U. The CMF program for operable breast cancer with positive axillary nodes: updated analysis on the disease-free interval, site of relapse and drug tolerance. Cancer. 1977 Jun;39(6 Suppl):2904-15. [https://doi.org/10.1002/1097-0142(197706)39:6%3C2904::AID-CNCR2820390677%3E3.0.CO;2-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/326384/ PubMed]
 +
## '''Update:''' Bonadonna G, Valagussa P, Rossi A, Tancini G, Brambilla C, Zambetti M, Veronesi U. Ten-year experience with CMF-based adjuvant chemotherapy in resectable breast cancer. Breast Cancer Res Treat. 1985;5(2):95-115. [https://doi.org/10.1007/bf01805984 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3839424/ PubMed]
 +
## '''Update:''' Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995 Apr 6;332(14):901-6. [https://doi.org/10.1056/NEJM199504063321401 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7877646/ PubMed]
 +
# '''CALGB 7581:''' Tancini G, Bajetta E, Marchini S, Valagussa P, Bonadonna G, Veronesi U. Preliminary 3-year results of 12 versus 6 cycles of surgical adjuvant CMF in premenopausal breast cancer. Cancer Clin Trials. 1979 Winter;2(4):285-92. [https://pubmed.ncbi.nlm.nih.gov/394864/ PubMed]
 +
## '''Update:''' Tancini G, Bonadonna G, Valagussa P, Marchini S, Veronesi U. Adjuvant CMF in breast cancer: comparative 5-year results of 12 versus 6 cycles. J Clin Oncol. 1983 Jan;1(1):2-10. [https://doi.org/10.1200/JCO.1983.1.1.2 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6366125/ PubMed]
 +
# Hubay CA, Pearson OH, Marshall JS, Rhodes RS, Debanne SM, Mansour EG, Hermann RE, Jones JC, Flynn WJ, Eckert C, McGuire WL. Antiestrogen, cytotoxic chemotherapy, and bacillus Calmette-Guerin vaccination in stage II breast cancer: a preliminary report. Surgery. 1980 May;87(5):494-501. [https://www.surgjournal.com/article/0039-6060(80)90244-5/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/7368100/ PubMed]
 +
## '''Update:''' Hubay CA, Pearson OH, Marshall JS, Rhodes RS, DeBanne SM, Rosenblatt J, Mansour EG, Hermann RE, Jones JC, Flynn WJ, Eckert C, McGuire WL. Adjuvant chemotherapy, antiestrogen therapy and immunotherapy for stage II breast cancer: 45-month follow-up of a prospective, randomized clinical trial. Cancer. 1980 Dec 15;46(12 Suppl):2805-8. [https://doi.org/10.1002/1097-0142(19801215)46:12%2B%3C2805::AID-CNCR2820461413%3E3.0.CO;2-H link to original article] [https://pubmed.ncbi.nlm.nih.gov/7004624/ PubMed]
 +
# '''DBCG 77B:''' Brincker H, Mouridsen HT, Andersen KW. Adjuvant chemotherapy with cyclophosphamide or CMF in premenopausal women with stage II breast cancer. Breast Cancer Res Treat. 1983;3(1):91-5. [https://doi.org/10.1007/BF01806239 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/6347278/ PubMed]
 +
## '''Update:''' Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Andersson M, Kamby C, Knoop AS; Danish Breast Cancer Cooperative Group. Cyclophosphamide, methotrexate, and fluorouracil; oral cyclophosphamide; levamisole; or no adjuvant therapy for patients with high-risk, premenopausal breast cancer. Cancer. 2010 May 1;116(9):2081-9. [https://doi.org/10.1002/cncr.24969 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20186830/ PubMed]
 +
# Howell A, Bush H, George WD, Howat JM, Crowther D, Sellwood RA, Rubens RD, Hayward JL, Bulbrook RD, Fentiman IS, Chaudary M. Controlled trial of adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil for breast cancer. Lancet. 1984 Aug 11;2(8398):307-11. [https://doi.org/10.1016/S0140-6736(84)92684-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6146861/ PubMed]
 +
# '''LCBS V:''' Goldhirsch A, Gelber RD; Ludwig Breast Cancer Study Group. Prolonged disease-free survival after one course of perioperative adjuvant chemotherapy for node-negative breast cancer. N Engl J Med. 1989 Feb 23;320(8):491-6. [https://doi.org/10.1056/NEJM198902233200804 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2644533/ PubMed]
 +
# '''ECOG E5177:''' Tormey DC, Gray R, Gilchrist K, Grage T, Carbone PP, Wolter J, Woll JE, Cummings FJ. Adjuvant chemohormonal therapy with cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen compared with CMF for premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial. Cancer. 1990 Jan 15;65(2):200-6. [https://doi.org/10.1002/1097-0142(19900115)65:2%3C200::AID-CNCR2820650203%3E3.0.CO;2-Q link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2403834/ PubMed]
 +
# Stewart HJ, Forrest APM, Hawkins RA, Prescott RJ, Smith DC, Everington D, Richards MA, George WD; Scottish Cancer Trials Breast Group and ICRF Breast Unit Guy's Hospital London. Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast carcinoma: the Scottish trial. Lancet. 1993 May 22;341(8856):1293-8. [https://doi.org/10.1016/0140-6736(93)90812-U link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8098446/ PubMed]
 +
# '''EORTC 09771:''' Clahsen PC, van de Velde CJ, Welvaart K, Repelaer van Driel OJ, Sylvester RJ; Cooperating Investigators. Ten-year results of a randomized trial evaluating prolonged low-dose adjuvant chemotherapy in node-positive breast cancer: a joint European Organisation for Research and Treatment of Cancer-Dutch Breast Cancer Working Party Study. J Clin Oncol. 1995 Jan;13(1):33-41. [https://doi.org/10.1200/JCO.1995.13.1.33 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7799039/ PubMed]
 +
# Coombes RC, Bliss JM, Wils J, Morvan F, Espié M, Amadori D, Gambrosier P, Richards M, Aapro M, Villar-Grimalt A, McArdle C, Pérez-López FR, Vassilopoulos P, Ferreira EP, Chilvers CE, Coombes G, Woods EM, Marty M; International Collaborative Cancer Group. Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. J Clin Oncol. 1996 Jan;14(1):35-45. [https://doi.org/10.1200/JCO.1996.14.1.35 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8558217/ PubMed]
 +
# '''OncoFrance:''' Misset JL, di Palma M, Delgado M, Plagne R, Chollet P, Fumoleau P, Le Mevel B, Belpomme D, Guerrin J, Fargeot P, Metz R, Ithzaki M, Hill C, Mathé G. Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: final report after a 16-year median follow-up duration. J Clin Oncol. 1996 Apr;14(4):1136-45. [https://doi.org/10.1200/JCO.1996.14.4.1136 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8648368/ PubMed]
 +
# '''IBCSG VI:''' Castiglione-Gertsch M, Goldhirsch A; International Breast Cancer Study Group. Duration and reintroduction of adjuvant chemotherapy for node-positive premenopausal breast cancer patients. J Clin Oncol. 1996 Jun;14(6):1885-94. [https://doi.org/10.1200/JCO.1996.14.6.1885 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8656257/ PubMed]
 +
## '''Pooled QoL analysis:''' Hürny C, Bernhard J, Coates AS, Castiglione-Gertsch M, Peterson HF, Gelber RD, Forbes JF, Rudenstam CM, Simoncini E, Crivellari D, Goldhirsch A, Senn HJ; International Breast Cancer Study Group. Impact of adjuvant therapy on quality of life in women with node-positive operable breast cancer. Lancet. 1996 May 11;347(9011):1279-84. Erratum in: Lancet 1997 Jul 26;350(9073):298. [https://doi.org/10.1016/s0140-6736(96)90936-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8622502/ PubMed]
 +
#'''EORTC 10792:''' Rubens RD, Bartelink H, Engelsman E, Hayward JL, Rotmensz N, Sylvester R, van der Schueren E, Papadiamantis J, Vassilaros SD, Wildiers J, Winter PJ. Locally advanced breast cancer: the contribution of cytotoxic and endocrine treatment to radiotherapy - an EORTC Breast Cancer Co-operative Group Trial (10792). Eur J Cancer Clin Oncol. 1989 Apr;25(4):667-78. [https://doi.org/10.1016/0277-5379(89)90203-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2653846/ PubMed]
 +
##'''Update:''' Bartelink H, Rubens RD, van der Schueren E, Sylvester R. Hormonal therapy prolongs survival in irradiated locally advanced breast cancer: a European Organization for Research and Treatment of Cancer Randomized Phase III Trial. J Clin Oncol. 1997 Jan;15(1):207-15. [https://doi.org/10.1200/jco.1997.15.1.207 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8996144/ PubMed]
 +
# '''DBCG 82b:''' Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, Kjaer M, Gadeberg CC, Mouridsen HT, Jensen MB, Zedeler K. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy: Danish Breast Cancer Cooperative Group 82b trial. N Engl J Med. 1997 Oct 2;337(14):949-55. [https://doi.org/10.1056/NEJM199710023371401 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9395428/ PubMed]
 +
# Ragaz J, Jackson SM, Le N, Plenderleith IH, Spinelli JJ, Basco VE, Wilson KS, Knowling MA, Coppin CM, Paradis M, Coldman AJ, Olivotto IA. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med. 1997 Oct 2;337(14):956-62. [https://doi.org/10.1056/NEJM199710023371402 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/9309100/ PubMed]
 +
# '''Review:''' Goldhirsch A, Colleoni M, Coates AS, Castiglione-Gertsch M, Gelber RD; International Breast Cancer Study Group. Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: are all CMFs alike?. Ann Oncol. 1998 May;9(5):489-93. [https://doi.org/10.1023/a:1008236502420 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/9653488/ PubMed]
 +
# '''NCIC-CTG MA.5:''' Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, Findlay B, Warr D, Bowman D, Myles J, Arnold A, Vandenberg T, MacKenzie R, Robert J, Ottaway J, Burnell M, Williams CK, Tu D; National Cancer Institute of Canada Clinical Trials Group. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol. 1998 Aug;16(8):2651-8. [https://doi.org/10.1200/jco.1998.16.8.2651 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9704715/ PubMed]
 +
## '''Update:''' Levine MN, Pritchard KI, Bramwell VH, Shepherd LE, Tu D, Paul N; National Cancer Institute of Canada Clinical Trials Group. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol. 2005 Aug 1;23(22):5166-70. [https://doi.org/10.1200/JCO.2005.09.423 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16051958/ PubMed]
 +
## '''Subgroup analysis:''' Pritchard KI, Shepherd LE, O'Malley FP, Andrulis IL, Tu D, Bramwell VH, Levine MN; National Cancer Institute of Canada Clinical Trials Group. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med. 2006 May 18;354(20):2103-11. [https://doi.org/10.1056/NEJMoa054504 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16707747/ PubMed]
 +
# Amadori D, Nanni O, Marangolo M, Pacini P, Ravaioli A, Rossi A, Gambi A, Catalano G, Perroni D, Scarpi E, Giunchi DC, Tienghi A, Becciolini A, Volpi A. Disease-free survival advantage of adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with node-negative, rapidly proliferating breast cancer: a randomized multicenter study. J Clin Oncol. 2000 Sep;18(17):3125-34. [https://doi.org/10.1200/JCO.2000.18.17.3125 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10963641/ PubMed]
 +
## '''Update:''' Amadori D, Nanni O, Volpi A, Casadei Giunchi D, Marangolo M, Livi L, Ravaioli A, Rossi AP, Gambi A, Luzi Fedeli S, Perroni D, Scarpi E, Becciolini A, Silvestrini R. Phase III randomized multicenter study on the effects of adjuvant CMF in patients with node-negative, rapidly proliferating breast cancer: twelve-year results and retrospective subgroup analysis. Breast Cancer Res Treat. 2008 Mar;108(2):259-64. Epub 2007 May 26. [https://doi.org/10.1007/s10549-007-9593-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17530429/ PubMed]
 +
# '''NSABP B-23:''' Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, Dimitrov NV, Atkins JN, Abramson N, Merajver S, Romond EH, Kardinal CG, Shibata HR, Margolese RG, Farrar WB. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001 Feb 15;19(4):931-42. [https://doi.org/10.1200/jco.2001.19.4.931 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11181655/ PubMed]
 +
## '''Update:''' Fisher B, Jeong JH, Anderson S, Wolmark N. Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst. 2004 Dec 15;96(24):1823-31. [https://doi.org/10.1093/jnci/djh338 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15601638/ PubMed]
 +
# '''Belgian trial:''' Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M, Nogaret JM. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol. 2001 Jun 15;19(12):3103-10. [https://doi.org/10.1200/jco.2001.19.12.3103 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11408507/ PubMed]
 +
## '''Update:''' de Azambuja E, Paesmans M, Beauduin M, Vindevoghel A, Cornez N, Finet C, Ries F, Closon-Dejardin MT, Kerger J, Gobert P, Focan C, Tagnon A, Dolci S, Nogaret JM, di Leo A, Piccart-Gebhart MJ. Long-term benefit of high-dose epirubicin in adjuvant chemotherapy for node-positive breast cancer: 15-year efficacy results of the Belgian multicentre study. J Clin Oncol. 2009 Feb 10;27(5):720-5. Epub 2008 Dec 22. [https://doi.org/10.1200/JCO.2008.17.2155 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19103732/ PubMed]
 +
# Ron IG, Wigler N, Borovik R, Brufman G, Rizel S, Shani A, Brenner J, Farbstein H, Dale A, Inbar MJ, Brenner HJ, Chaitchik S, Catane R. CMF (cyclophosphamide, methotrexate, 5-fluorouracil) versus CNF (cyclophosphamide, mitoxantrone, 5-fluorouracil) as adjuvant chemotherapy for stage II lymph-node positive breast cancer: a phase III randomized multicenter study. Am J Clin Oncol. 2001 Aug;24(4):323-7. [https://doi.org/10.1097/00000421-200108000-00001 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11474254/ PubMed]
 +
# '''ZEBRA:''' Jonat W, Kaufmann M, Sauerbrei W, Blamey R, Cuzick J, Namer M, Fogelman I, de Haes JC, de Matteis A, Stewart A, Eiermann W, Szakolczai I, Palmer M, Schumacher M, Geberth M, Lisboa B; Zoladex Early Breast Cancer Research Association Study. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: the Zoladex Early Breast Cancer Research Association study. J Clin Oncol. 2002 Dec 15;20(24):4628-35. [https://doi.org/10.1200/JCO.2002.05.042 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12488406/ PubMed]
 +
# '''GEICAM 8701:''' Martin M, Villar A, Sole-Calvo A, Gonzalez R, Massuti B, Lizon J, Camps C, Carrato A, Casado A, Candel MT, Albanell J, Aranda J, Munarriz B, Campbell J, Diaz-Rubio E; GEICAM. Doxorubicin in combination with fluorouracil and cyclophosphamide (iv FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (iv CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Ann Oncol. 2003 Jun;14(6):833-42. [https://doi.org/10.1093/annonc/mdg260 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/12796019/ PubMed]
 +
# '''INT-0102:''' Hutchins LF, Green SJ, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of intergroup protocol INT-0102. J Clin Oncol. 2005 Nov 20;23(33):8313-21. [https://doi.org/10.1200/jco.2005.08.071 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16293862/ PubMed]
 +
<!-- no pre-pub disclosed -->
 +
# '''NEAT:''' Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. [https://doi.org/10.1056/nejmoa052084 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17079759/ PubMed] [https://clinicaltrials.gov/study/NCT00003577 NCT00003577]
 +
## '''Update:''' Earl HM, Hiller L, Dunn JA, Vallier AL, Bowden SJ, Jordan SD, Blows F, Munro A, Bathers S, Grieve R, Spooner DA, Agrawal R, Fernando I, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, McAdam K, Foster L, Leonard RC, Twelves CJ, Cameron D, Bartlett JM, Pharoah P, Provenzano E, Caldas C, Poole CJ; NEAT Investigators and the SCTBG. Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials. Br J Cancer. 2012 Oct 9;107(8):1257-67. Epub 2012 Sep 11. [https://doi.org/10.1038/bjc.2012.370 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494422/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23047592/ PubMed]
 +
<!-- no pre-pub disclosed -->
 +
# '''BR9601:''' Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. [https://doi.org/10.1056/nejmoa052084 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17079759/ PubMed] [https://clinicaltrials.gov/study/NCT00003012 NCT00003012]
 +
## '''Update:''' Earl HM, Hiller L, Dunn JA, Vallier AL, Bowden SJ, Jordan SD, Blows F, Munro A, Bathers S, Grieve R, Spooner DA, Agrawal R, Fernando I, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, McAdam K, Foster L, Leonard RC, Twelves CJ, Cameron D, Bartlett JM, Pharoah P, Provenzano E, Caldas C, Poole CJ; NEAT Investigators and the SCTBG. Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials. Br J Cancer. 2012 Oct 9;107(8):1257-67. Epub 2012 Sep 11. [https://doi.org/10.1038/bjc.2012.370 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494422/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/23047592/ PubMed]
 +
# '''DBCG 89D:''' Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Cold S, Edlund P, Ewertz M, Jensen BB, Kamby C, Nordenskjold B, Bergh J. Improved outcome from substituting methotrexate with epirubicin: results from a randomised comparison of CMF versus CEF in patients with primary breast cancer. Eur J Cancer. 2007 Mar;43(5):877-84. Epub 2007 Feb 16. [https://doi.org/10.1016/j.ejca.2007.01.009 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17306974/ PubMed]
 +
# '''NCRI ABC-CT:''' Adjuvant Breast Cancer Trials Collaborative Group. Polychemotherapy for early breast cancer: results from the international adjuvant breast cancer chemotherapy randomized trial. J Natl Cancer Inst. 2007 Apr 4;99(7):506-15. [https://doi.org/10.1093/jnci/djk108 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17405995/ PubMed] [https://clinicaltrials.gov/study/NCT00002582 NCT00002582]
 +
<!-- Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002; the San Antonio Breast Cancer Symposium, San Antonio, TX, December 3-6, 2003; the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004; and the San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004. -->
 +
# '''TABLE:''' Schmid P, Untch M, Kossé V, Bondar G, Vassiljev L, Tarutinov V, Lehmann U, Maubach L, Meurer J, Wallwiener D, Possinger K. Leuprorelin acetate every-3-months depot versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in premenopausal patients with node-positive breast cancer: the TABLE study. J Clin Oncol. 2007 Jun 20;25(18):2509-15. [https://doi.org/10.1200/jco.2006.08.8534 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17577027/ PubMed]
 +
# '''ABCSG-07:''' Taucher S, Steger GG, Jakesz R, Tausch C, Wette V, Schippinger W, Kwasny W, Reiner G, Greil R, Dubsky P, Poestlberger S, Tschmelitsch J, Samonigg H, Gnant M; ABCSG. The potential risk of neoadjuvant chemotherapy in breast cancer patients--results from a prospective randomized trial of the Austrian Breast and Colorectal Cancer Study Group (ABCSG-07). Breast Cancer Res Treat. 2008 Nov;112(2):309-16. Epub 2007 Dec 14. [https://doi.org/10.1007/s10549-007-9844-9 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/18080748/ PubMed]
 +
# '''NSAS BC-01:''' Watanabe T, Sano M, Takashima S, Kitaya T, Tokuda Y, Yoshimoto M, Kohno N, Nakagami K, Iwata H, Shimozuma K, Sonoo H, Tsuda H, Sakamoto G, Ohashi Y. Oral uracil and tegafur compared with classic cyclophosphamide, methotrexate, fluorouracil as postoperative chemotherapy in patients with node-negative, high-risk breast cancer: National Surgical Adjuvant Study for Breast Cancer 01 trial. J Clin Oncol. 2009 Mar 20;27(9):1368-74. Epub 2009 Feb 9. [https://doi.org/10.1200/JCO.2008.18.3939 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19204202/ PubMed] [https://clinicaltrials.gov/study/NCT00152191 NCT00152191]
 +
# '''TACT:''' Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. [https://doi.org/10.1016/S0140-6736(09)60740-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2687939/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19447249/ PubMed] ISRCTN79718493
 +
# '''CALGB 49907:''' Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Becker HP, Kartcheske PA, Wheeler JD, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Magrinat G, Parker BA, Hart RD, Grenier D, Norton L, Hudis CA, Winer EP; CALGB. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009 May 14;360(20):2055-65. Erratum in: N Engl J Med. 2009 Oct 22;361(17):1714. Magrinat, Gutav [corrected to Magrinat, Gustav]. [https://doi.org/10.1056/NEJMoa0810266 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3082436/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19439741/ PubMed] [https://clinicaltrials.gov/study/NCT00024102 NCT00024102]
 +
##'''Update:''' Muss HB, Polley MC, Berry DA, Liu H, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Kartcheske PA, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Sutton LM, Magrinat G, Parker BA, Hart RD, Grenier D, Hurria A, Jatoi A, Norton L, Hudis CA, Winer EP, Carey L. Randomized Trial of Standard Adjuvant Chemotherapy Regimens Versus Capecitabine in Older Women With Early Breast Cancer: 10-Year Update of the CALGB 49907 Trial. J Clin Oncol. 2019 Sep 10;37(26):2338-2348. Epub 2019 Jul 24. [https://doi.org/10.1200/jco.19.00647 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6900836/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31339827/ PubMed]
 +
# Kimura M, Tominaga T, Takatsuka Y, Toi M, Abe R, Koyama H, Takashima S, Nomura Y, Miura S, Kimijima I, Tashiro H, Ohashi Y; Adjuvant CEF Research Group for Breast Cancer. Randomized trial of cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil with node-positive breast cancer in Japan. Breast Cancer. 2010 Jul;17(3):190-8. Epub 2009 Jul 3. [https://doi.org/10.1007/s12282-009-0132-x link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19575284/ PubMed]
 +
# '''ELDA:''' Perrone F, Nuzzo F, Di Rella F, Gravina A, Iodice G, Labonia V, Landi G, Pacilio C, Rossi E, De Laurentiis M, D'Aiuto M, Botti G, Forestieri V, Lauria R, De Placido S, Tinessa V, Daniele B, Gori S, Colantuoni G, Barni S, Riccardi F, De Maio E, Montanino A, Morabito A, Daniele G, Di Maio M, Piccirillo MC, Signoriello S, Gallo C, de Matteis A. Weekly docetaxel versus CMF as adjuvant chemotherapy for older women with early breast cancer: final results of the randomized phase III ELDA trial. Ann Oncol. 2015 Apr;26(4):675-82. Epub 2014 Dec 8. [https://doi.org/10.1093/annonc/mdu564 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25488686/ PubMed] [https://clinicaltrials.gov/study/NCT00331097 NCT00331097]
 +
# '''TAILORx:''' Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. [https://doi.org/10.1056/NEJMoa1804710 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172658/ link to PMC article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/29860917/ PubMed] [https://clinicaltrials.gov/study/NCT00310180 NCT00310180]
 +
# '''SECRAB:''' Fernando IN, Bowden SJ, Herring K, Brookes CL, Ahmed I, Marshall A, Grieve R, Churn M, Spooner D, Latief TN, Agrawal RK, Brunt AM, Stevens A, Goodman A, Canney P, Bishop J, Ritchie D, Dunn J, Poole CJ, Rea DW; SECRAB Investigators. Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial. Radiother Oncol. 2020 Jan;142:52-61. Epub 2019 Nov 27. [https://doi.org/10.1016/j.radonc.2019.10.014 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7005671/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31785830/ PubMed] [https://clinicaltrials.gov/study/NCT00003893 NCT00003893]
  
−
=Adjuvant chemotherapy, HER-2 positive=
+
==CMFT {{#subobject:acff18|Regimen=1}}==
−
==AC -> H (CALGB 40101) {{#subobject:9492d1|Regimen=1}}==
+
CMFT: '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil, '''<u>T</u>'''amoxifen
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 600/40/600 x 9, 30 x 12 mo {{#subobject:9f63d1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1016/S0140-6736(98)09201-0 Overgaard et al. 1999 (DBCG 82C)]
 +
|rowspan=2|1982-1990
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_3|Tamoxifen]]
 +
| style="background-color:#1a9850" |Superior DFS<sup>1</sup>
 +
|-
 +
|2. [[#Tamoxifen_.26_RT_999|Tamoxifen & RT]]
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy for this arm versus tamoxifen monotherapy is based on the 2013 update.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] as follows:
 +
**Cycles 1 to 9: 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Methotrexate (MTX)]] as follows:
 +
**Cycles 1 to 9: 40 mg/m<sup>2</sup> IV once on day 1
 +
*[[Fluorouracil (5-FU)]] as follows:
 +
**Cycles 1 to 9: 600 mg/m<sup>2</sup> IV once on day 1
 +
====Endocrine therapy====
 +
*[[Tamoxifen (Nolvadex)]] 30 mg PO once per day on days 1 to 28
 +
'''28-day cycle for 13 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 780/80/1000 x 6, 20 x 2 yr {{#subobject:9ajbd1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2736822/ Park et al. 2009 (Taiho 91023033)]
 +
|1996-2000
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#UFT_.26_Tamoxifen_888|UFT & Tamoxifen]]
 +
| style="background-color:#eeee01" |Non-inferior RFS60
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] as follows:
 +
**Cycles 1 to 6: 65 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] as follows:
 +
**Cycles 1 to 6: 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] as follows:
 +
**Cycles 1 to 6: 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
====Endocrine therapy====
 +
*[[Tamoxifen (Nolvadex)]] 20 mg PO once per day on days 1 to 28
 +
'''28-day cycle for 26 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 840/50/800/40 x 12 {{#subobject:9f63d1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://www.surgjournal.com/article/0039-6060(80)90244-5/fulltext Hubay et al. 1980]
 +
|rowspan=2|NR
 +
|rowspan=2 style="background-color:#1a9851" |Randomized (E-RT-esc)
 +
|1. [[#CMF|CMF]]
 +
| style="background-color:#91cf60" |Seems to have superior RFS
 +
|-
 +
|2. [[#CMFT_.26_BCG_999|CMFT & BCG]]
 +
| style="background-color:#ffffbf" |Did not meet endpoints of RFS/OS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
AC -> H: '''<u>A</u>'''driamycin, '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''erceptin
+
<div class="toccolours" style="background-color:#cbd5e8">
−
===Regimen {{#subobject:178b98|Variant=1}}===
+
====Preceding treatment====
−
Level of Evidence:
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
<span
+
</div>
−
style="background:#00CD00;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
padding:3px 6px 3px 6px;
+
====Chemotherapy====
−
border-color:black;
+
*[[Cyclophosphamide (Cytoxan)]] 30 mg/m<sup>2</sup> PO twice per day on days 1 to 14
−
border-width:2px;
+
*[[Methotrexate (MTX)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
border-style:solid;">Phase III</span>
+
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
 
+
====Endocrine therapy====
−
AC:
+
*[[Tamoxifen (Nolvadex)]] 20 mg PO twice per day
−
*[[Doxorubicin (Adriamycin)]] 60 mg/m2 IV on day 1
+
'''28-day cycle for 12 cycles'''
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV on day 1
+
</div></div>
−
 
 
−
Supportive medications:
 
−
*Recommended growth factor support with one of the following:
 
−
**[[Filgrastim (Neupogen)]] 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC on days 3-10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
 
−
**[[Sargramostim (Leukine)]] 250-500 mcg/m2 SC on days 3-10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
 
−
**[[Pegfilgrastim (Neulasta)]] 6 mg SC, administered once 24-36 hours after chemotherapy
 
−
 
 
−
'''14-day cycles x 4 cycles'''; the study protocol originally specified 21-day cycles but was amended to 14-day cycles after results of [[#Dose-dense_AC_-.3E_T | CALGB 9741 - Citron et al. 2003]] were available
 
−
 
 
−
Trastuzumab (Herceptin) to begin 3-8 weeks after the completion of AC:
 
−
*One of the following doses & schedules of trastuzumab:
 
−
**[[Trastuzumab (Herceptin)]] 4 mg/kg IV x1 as the loading dose, then 2 mg/kg IV every week thereafter
 
−
**[[Trastuzumab (Herceptin)]] 8 mg/kg IV x1 as the loading dose, then 6 mg/kg IV every 3 weeks thereafter
 
−
 
 
−
'''52-week course'''
 
−
 
 
 
===References===
 
===References===
−
# Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Jul 23. [Epub ahead of print] [http://jco.ascopubs.org/content/early/2012/07/23/JCO.2011.40.6405.long link to original article] '''contains verified protocol''' [http://jco.ascopubs.org/content/suppl/2012/07/23/JCO.2011.40.6405.DC1/Protocol.pdf link to study protocol PDF] [http://www.ncbi.nlm.nih.gov/pubmed/22826271 PubMed]  
+
# Hubay CA, Pearson OH, Marshall JS, Rhodes RS, Debanne SM, Mansour EG, Hermann RE, Jones JC, Flynn WJ, Eckert C, McGuire WL. Antiestrogen, cytotoxic chemotherapy, and bacillus Calmette-Guerin vaccination in stage II breast cancer: a preliminary report. Surgery. 1980 May;87(5):494-501. [https://www.surgjournal.com/article/0039-6060(80)90244-5/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/7368100/ PubMed]
 +
## '''Update:''' Hubay CA, Pearson OH, Marshall JS, Rhodes RS, DeBanne SM, Rosenblatt J, Mansour EG, Hermann RE, Jones JC, Flynn WJ, Eckert C, McGuire WL. Adjuvant chemotherapy, antiestrogen therapy and immunotherapy for stage II breast cancer: 45-month follow-up of a prospective, randomized clinical trial. Cancer. 1980 Dec 15;46(12 Suppl):2805-8. [https://doi.org/10.1002/1097-0142(19801215)46:12%2B%3C2805::AID-CNCR2820461413%3E3.0.CO;2-H link to original article] [https://pubmed.ncbi.nlm.nih.gov/7004624/ PubMed]
 +
# '''NSABP B-20:''' Fisher B, Dignam J, Wolmark N, DeCillis A, Emir B, Wickerham DL, Bryant J, Dimitrov NV, Abramson N, Atkins JN, Shibata H, Deschenes L, Margolese RG. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst. 1997 Nov 19;89(22):1673-82. [https://academic.oup.com/jnci/article/89/22/1673/2526493 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9390536/ PubMed]
 +
## '''Pooled update:''' Fisher B, Jeong JH, Bryant J, Anderson S, Dignam J, Fisher ER, Wolmark N; National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet. 2004 Sep 4-10;364(9437):858-68. [https://doi.org/10.1016/S0140-6736(04)16981-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/15351193/ PubMed]
 +
## '''Pooled update:''' Taghian AG, Jeong JH, Mamounas EP, Parda DS, Deutsch M, Costantino JP, Wolmark N. Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol. 2006 Aug 20;24(24):3927-32. [https://doi.org/10.1200/JCO.2006.06.9054 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16921044/ PubMed]
 +
# '''DBCG 82C:''' Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M, Kamby C, Kjaer M, Gadeberg CC, Rasmussen BB, Blichert-Toft M, Mouridsen HT. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet. 1999 May 15;353(9165):1641-8. [https://doi.org/10.1016/S0140-6736(98)09201-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10335782/ PubMed]
 +
## '''Update:''' Ejlertsen B, Jensen MB, Elversang J, Rasmussen BB, Andersson M, Andersen J, Nielsen DL, Cold S, Mouridsen HT. One year of adjuvant tamoxifen compared with chemotherapy and tamoxifen in postmenopausal patients with stage II breast cancer. Eur J Cancer. 2013 Sep;49(14):2986-94. Epub 2013 Jun 8. [https://doi.org/10.1016/j.ejca.2013.05.006 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23756360/ PubMed]
 +
# '''Taiho 91023033:''' Park Y, Okamura K, Mitsuyama S, Saito T, Koh J, Kyono S, Higaki K, Ogita M, Asaga T, Inaji H, Komichi H, Kohno N, Yamazaki K, Tanaka F, Ito T, Nishikawa H, Osaki A, Koyama H, Suzuki T. Uracil-tegafur and tamoxifen vs cyclophosphamide, methotrexate, fluorouracil, and tamoxifen in post-operative adjuvant therapy for stage I, II, or IIIA lymph node-positive breast cancer: a comparative study. Br J Cancer. 2009 Aug 18;101(4):598-604. Epub 2009 Jul 28. Erratum in: Br J Cancer. 2009 Sep 15;101(6):1031. [https://doi.org/10.1038/sj.bjc.6605218 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc2736822/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19638976/ PubMed] [https://clinicaltrials.gov/study/NCT00152178 NCT00152178]
  
−
==AC -> weekly TH (Taxol) {{#subobject:ca565e|Regimen=1}}==
+
==Cyclophosphamide & Docetaxel (TC) {{#subobject:faf430|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
TC: '''<u>T</u>'''axotere (Docetaxel) & '''<u>C</u>'''yclophosphamide
 +
<br>DC: '''<u>D</u>'''ocetaxel & '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 4 cycles {{#subobject:e9499f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2006.06.5391 Jones et al. 2006 (USOR 9735)]
 +
|1997-1999
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[Breast_cancer_-_historical#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]]
 +
| style="background-color:#91cf60" |Seems to have superior OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172658/ Sparano et al. 2018 (TAILORx)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer,_ER-positive_-_null_regimens#Observation|No chemotherapy]]
 +
| style="background-color:#eeee01" |Non-inferior IDFS (primary endpoint)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549453/ Blum et al. 2017 (USOR 06-090)]
 +
|2007-2009
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[#TAC_.28Docetaxel.29_2|TAC]]
 +
| style="background-color:#fc8d59" |Seems to have inferior IDFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549453/ Blum et al. 2017 (NSABP-46-I/USOR 07132)]
 +
|2009-2012
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#TAC_.28Docetaxel.29_2|TAC]]
 +
| style="background-color:#fc8d59" |Seems to have inferior IDFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549453/ Blum et al. 2017 (NSABP B-49)]
 +
|2012-04-04 to 2013-11-21
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[#TAC_.28Docetaxel.29_2|TAC]]
 +
| style="background-color:#fc8d59" |Seems to have inferior IDFS (primary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
AC -> weekly TH: '''<u>A</u>'''driamycin, '''<u>C</u>'''ytoxan -> weekly '''<u>T</u>'''axol, '''<u>H</u>'''erceptin
+
''Note: Blum et al. 2017 is a pooled analysis of three RCTs, some of which had arms other than TAC and TC. Refer to the paper for further details.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Eligibility criteria====
 +
*TAILORx: Oncotype DX score of 11 to 25
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Supportive therapy====
 +
*Most protocols: all cycles given with [[Filgrastim (Neupogen)]] support
 +
'''21-day cycle for 4 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
===Regimen {{#subobject:a9e75c|Variant=1}}===
+
===Regimen variant #2, 6 cycles {{#subobject:d321b7|Variant=1}}===
−
Level of Evidence:
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
<span
+
!style="width: 20%"|Study
−
style="background:#00CD00;
+
!style="width: 20%"|Dates of enrollment
−
padding:3px 6px 3px 6px;
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
border-color:black;
+
!style="width: 20%"|Comparator
−
border-width:2px;
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
border-style:solid;">Phase III</span>
+
|-
−
 
+
|[https://doi.org/10.1093/annonc/mdw274 Mavroudis et al. 2016 (HORG CT/07.17)]
−
*[[Doxorubicin (Adriamycin)]] 60 mg/m2 IV day 1
+
|2007-2013
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV day 1
+
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
−
 
+
|[[#Dose-dense_FEC-D|ddFEC-D]]
−
'''21-day cycles x 4 cycles, THEN'''
+
| style="background-color:#ffffbf" |Inconclusive whether non-inferior DFS36 (primary endpoint)
−
 
+
|-
−
*[[Paclitaxel (Taxol)]] 80 mg/m2 IV over 1 hour day 1
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174181/ de Gregorio et al. 2022 (LMU Success C)]
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV with first dose of paclitaxel, then 2 mg/kg IV on subsequent weeks
+
|2008-2011
−
 
+
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
−
'''1-week cycles x 12 cycles/weeks, THEN'''
+
|[[#FEC-D_2|FEC-D]]
−
 
+
| style="background-color:#ffffbf" |Inconclusive whether non-inferior DFS<sup>1</sup> (primary endpoint)
−
*EITHER [[Trastuzumab (Herceptin)]] 2 mg/kg IV, '''1-week cycles x 40 additional cycles/weeks to complete a total of 52 weeks of therapy'''
+
|-
−
*OR [[Trastuzumab (Herceptin)]] 6 mg/kg IV, '''3-week cycles x 14 additional cycles/weeks to complete a total of 52 weeks of therapy'''
+
|[https://doi.org/10.1200/JCO.2017.72.3494 Ejlertsen et al. 2017 (DBCG 07-READ)]
−
 
+
|2008-2012
−
===Monitoring===
+
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
−
*Cardiac function: echocardiogram at baseline, then every 3 months while on Trastuzumab (Herceptin)
+
|[[#EC-D_2|EC-D]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br>DFS60: 88.3% vs 87.9%<br>(HR 1.00, 95% CI 0.78-1.28)
 +
|-
 +
|[https://doi.org/10.1200/JCO.18.00028 Nitz et al. 2019 (WSG PlanB)]
 +
|2009-02 to 2011-12
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[#EC-D_2|EC-D]]
 +
| style="background-color:#eeee01" |Non-inferior DFS (primary endpoint)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7007289/ Fehrenbacher et al. 2019 (NSABP B-47)]
 +
|2011-2015
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#AC-TH_999|AC-TH]]<br>1b. [[#Dose-dense_AC-TH_999|ddAC-TH]]<br>1c. [[#TCH_999|TCH]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of IDFS
 +
|-
 +
|}
 +
''<sup>1</sup>LMU Success C was designed as a non-inferiority trial but was reported using a superiority design post-hoc analysis.''<br>
 +
''Note: de Gregorio et al. 2022 was a pooled update and also the first report of LMU Success C.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Biomarker eligibility criteria====
 +
*DBCG 07-READ: TOP2A normal as determined by FISH
 +
*NSABP B-47: HER2 IHC of 1+ or 2+ with FISH ratio less than 2 or HER2 gene copy number less than 4
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1  
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles'''
 +
</div></div>
  
 
===References===
 
===References===
−
# Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. [http://www.nejm.org/doi/full/10.1056/NEJMoa052122 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16236738 PubMed]
+
# '''USOR 9735:''' Jones SE, Savin MA, Holmes FA, O'Shaughnessy JA, Blum JL, Vukelja S, McIntyre KJ, Pippen JE, Bordelon JH, Kirby R, Sandbach J, Hyman WJ, Khandelwal P, Negron AG, Richards DA, Anthony SP, Mennel RG, Boehm KA, Meyer WG, Asmar L. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol. 2006 Dec 1;24(34):5381-7. Erratum in: J Clin Oncol. 2007 May 1;25(13):1819. [https://doi.org/10.1200/jco.2006.06.5391 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17135639/ PubMed]
 +
## '''Update:''' Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL, Sandbach J, Hyman WJ, Richards DA, Mennel RG, Boehm KA, Meyer WG, Asmar L, Mackey D, Riedel S, Muss H, Savin MA. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology research trial 9735. J Clin Oncol. 2009 Mar 10;27(8):1177-83. Epub 2009 Feb 9. [https://doi.org/10.1200/jco.2008.18.4028 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19204201/ PubMed]
 +
# '''HORG CT/07.17:''' Mavroudis D, Matikas A, Malamos N, Papakotoulas P, Kakolyris S, Boukovinas I, Athanasiadis A, Kentepozidis N, Ziras N, Katsaounis P, Saloustros E, Georgoulias V; HORG. Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2016 Oct;27(10):1873-8. Epub 2016 Aug 8. [https://doi.org/10.1093/annonc/mdw274 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27502729/ PubMed] [https://clinicaltrials.gov/study/NCT01985724 NCT01985724]
 +
# '''USOR 06-090:''' Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. [https://doi.org/10.1200/JCO.2016.71.4147 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549453/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28398846/ PubMed] [https://clinicaltrials.gov/study/NCT00493870 NCT00493870]
 +
##'''Pooled update:''' Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. [https://doi.org/10.1200/jco.23.01428 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11095853/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/38335467/ PubMed]
 +
# '''NSABP-46-I/USOR 07132:''' Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. [https://doi.org/10.1200/JCO.2016.71.4147 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549453/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28398846/ PubMed] [https://clinicaltrials.gov/study/NCT00887536 NCT00887536]
 +
##'''Pooled update:''' Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. [https://doi.org/10.1200/jco.23.01428 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11095853/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/38335467/ PubMed]
 +
# '''NSABP B-49:''' Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. [https://doi.org/10.1200/JCO.2016.71.4147 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549453/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28398846/ PubMed] [https://clinicaltrials.gov/study/NCT01547741 NCT01547741]
 +
##'''Pooled update:''' Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. [https://doi.org/10.1200/jco.23.01428 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11095853/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/38335467/ PubMed]
 +
# '''DBCG 07-READ:''' Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen MB, Knoop AS, Højris I, Ewertz M, Balslev E, Danø H, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. Adjuvant cyclophosphamide and docetaxel with or without epirubicin for early TOP2A-normal breast cancer: DBCG 07-READ, an open-label, phase III, randomized trial. J Clin Oncol. 2017 Aug 10;35(23):2639-2646. Epub 2017 Jun 29. [https://doi.org/10.1200/JCO.2017.72.3494 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28661759/ PubMed] [https://clinicaltrials.gov/study/NCT00689156 NCT00689156]
 +
# '''TAILORx:''' Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. [https://doi.org/10.1056/NEJMoa1804710 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172658/ link to PMC article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/29860917/ PubMed] [https://clinicaltrials.gov/study/NCT00310180 NCT00310180]
 +
# '''WSG PlanB:''' Nitz U, Gluz O, Clemens M, Malter W, Reimer T, Nuding B, Aktas B, Stefek A, Pollmanns A, Lorenz-Salehi F, Uleer C, Krabisch P, Kuemmel S, Liedtke C, Shak S, Wuerstlein R, Christgen M, Kates RE, Kreipe HH, Harbeck N; West German Study Group. West German Study PlanB trial: adjuvant four cycles of epirubicin and cyclophosphamide plus docetaxel versus six cycles of docetaxel and cyclophosphamide in HER2-negative early breast cancer. J Clin Oncol. 2019 Apr 1;37(10):799-808. Epub 2019 Feb 20. [https://doi.org/10.1200/JCO.18.00028 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30785826/ PubMed] [https://clinicaltrials.gov/study/NCT01049425 NCT01049425]
 +
##'''Pooled update:''' de Gregorio A, Janni W, Friedl TWP, Nitz U, Rack B, Schneeweiss A, Kates R, Fehm T, Kreipe H, Christgen M, Kuemmel S, Trapp E, Wuerstlein R, Hartkopf A, Clemens M, Reimer T, Haberle L, Fasching PA, Gluz O, Harbeck N. The impact of anthracyclines in intermediate and high-risk HER2-negative early breast cancer-a pooled analysis of the randomised clinical trials PlanB and SUCCESS C. Br J Cancer. 2022 Jun;126(12):1715-1724. Epub 2022 Feb 22. [https://doi.org/10.1038/s41416-021-01690-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174181/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35194193/ PubMed]
 +
# '''NSABP B-47:''' Fehrenbacher L, Cecchini RS, Geyer CE Jr, Rastogi P, Costantino JP, Atkins JN, Crown JP, Polikoff J, Boileau JF, Provencher L, Stokoe C, Moore TD, Robidoux A, Flynn PJ, Borges VF, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020 Feb 10;38(5):444-453. Epub 2019 Dec 10. [https://doi.org/10.1200/jco.19.01455 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7007289/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31821109/ PubMed] [https://clinicaltrials.gov/study/NCT01275677 NCT01275677]
 +
#'''LMU Success C:''' de Gregorio A, Janni W, Friedl TWP, Nitz U, Rack B, Schneeweiss A, Kates R, Fehm T, Kreipe H, Christgen M, Kuemmel S, Trapp E, Wuerstlein R, Hartkopf A, Clemens M, Reimer T, Haberle L, Fasching PA, Gluz O, Harbeck N. The impact of anthracyclines in intermediate and high-risk HER2-negative early breast cancer-a pooled analysis of the randomised clinical trials PlanB and SUCCESS C. Br J Cancer. 2022 Jun;126(12):1715-1724. Epub 2022 Feb 22. [https://doi.org/10.1038/s41416-021-01690-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9174181/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35194193/ PubMed] [https://clinicaltrials.gov/study/NCT00847444 NCT00847444]
 +
#'''ASTER 70s:''' [https://clinicaltrials.gov/study/NCT01564056 NCT01564056]
  
−
==AC -> TH (Taxol) {{#subobject:f7899c|Regimen=1}}==
+
==Dose-dense Cyclophosphamide & Doxorubicin (ddAC) {{#subobject:b52056|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
ddAC: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>A</u>'''driamycin (Doxorubicin) and '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 60/600 x 4 {{#subobject:cdafd0|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="3" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494835/ Shulman et al. 2012 (CALGB 40101)]
 +
| rowspan="3" |2002-2008
 +
| rowspan="3" style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|1. [[#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29_2|ddAC]] x 6
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 +
|-
 +
|2. [[#Paclitaxel_monotherapy.2C_dose-dense_.28q2wk.29_2|ddT]] x 4
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 +
|-
 +
|3. [[#Paclitaxel_monotherapy.2C_dose-dense_.28q2wk.29_2|ddT]] x 6
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172658/ Sparano et al. 2018 (TAILORx)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer,_ER-positive_-_null_regimens#Observation|No chemotherapy]]
 +
| style="background-color:#eeee01" |Non-inferior IDFS (primary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
AC -> TH: '''<u>A</u>'''driamycin, '''<u>C</u>'''ytoxan -> '''<u>T</u>'''axol, '''<u>H</u>'''erceptin
+
''Note: CALGB 40101 originally specified 21-day cycles but was amended to 14-day cycles after results of CALGB 9741 were available.''
−
 
+
<div class="toccolours" style="background-color:#fdcdac">
−
===Regimen {{#subobject:87716b|Variant=1}}===
+
====Eligibility criteria====
−
Level of Evidence:
+
*TAILORx: Oncotype DX score of 11 to 25
−
<span
+
</div>
−
style="background:#00CD00;
+
<div class="toccolours" style="background-color:#cbd5e8">
−
padding:3px 6px 3px 6px;
+
====Preceding treatment====
−
border-color:black;
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
border-width:2px;
+
</div>
−
border-style:solid;">Phase III</span>
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
*[[Doxorubicin (Adriamycin)]] 60 mg/m2 IV day 1
+
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV day 1
+
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
−
 
+
====Supportive therapy====
−
'''21-day cycles x 4 cycles, THEN'''
+
*(varies depending on reference):
−
 
+
*CALGB 40101: one of the following:
−
*[[Paclitaxel (Taxol)]] 175 mg/m2 IV over 3 hours day 1
+
**[[Filgrastim (Neupogen)]] 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV with first dose of paclitaxel, then 2 mg/kg IV on days 8 & 15 of cycle 1; in cycles 2-4, [[Trastuzumab (Herceptin)]] is 2 mg/kg IV on days 1, 8, 15
+
**[[Sargramostim (Leukine)]] 250 to 500 mcg/m<sup>2</sup> SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
−
 
+
**[[Pegfilgrastim (Neulasta)]] 6 mg SC once, given 24 to 36 hours after chemotherapy
−
'''21-day cycles x 4 cycles, THEN'''
+
'''14-day cycle for 4 cycles'''
−
 
+
</div></div><br>
−
*EITHER [[Trastuzumab (Herceptin)]] 2 mg/kg IV, '''1-week cycles x 40 additional cycles/weeks to complete a total of 52 weeks of therapy'''
+
<div class="toccolours" style="background-color:#eeeeee">
−
*OR [[Trastuzumab (Herceptin)]] 6 mg/kg IV, '''3-week cycles x 14 additional cycles/weeks to complete a total of 52 weeks of therapy'''
+
===Regimen variant #2, 60/600 x 6 {{#subobject:b6b259|Variant=1}}===
−
 
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
===Monitoring===
+
!style="width: 20%"|Study
−
*Cardiac function: echocardiogram at baseline, then every 3 months while on Trastuzumab (Herceptin)
+
!style="width: 20%"|Dates of enrollment
−
 
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2018.07.013 van Rossum et al. 2018 (MATADOR)]
 +
|2004-2012
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#TAC_.28Docetaxel.29_2|TAC]]
 +
| style="background-color:#ffffbf" |Did not meet secondary endpoints of RFS/OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1  
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Supportive therapy====
 +
*[[Pegfilgrastim (Neulasta)]] 6 mg SC once on day 2
 +
'''14-day cycle for 6 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. [http://www.nejm.org/doi/full/10.1056/NEJMoa052122 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16236738 PubMed]
+
# '''CALGB 40101:''' Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. [https://doi.org/10.1200/jco.2011.40.6405 link to original article] '''contains dosing details in manuscript''' [https://ascopubs.org/doi/suppl/10.1200/jco.2011.40.6405/suppl_file/Protocol.pdf link to study protocol PDF] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494835/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22826271/ PubMed] [https://clinicaltrials.gov/study/NCT00041119 NCT00041119]
−
# Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83. [http://www.nejm.org/doi/full/10.1056/NEJMoa0910383 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/21991949 PubMed]
+
## '''Update:''' Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. Epub 2014 Jun 16. [https://doi.org/10.1200/jco.2013.53.7142 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105484/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24934787/ PubMed]
 +
# '''TAILORx:''' Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. [https://doi.org/10.1056/NEJMoa1804710 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172658/ link to PMC article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/29860917/ PubMed] [https://clinicaltrials.gov/study/NCT00310180 NCT00310180]
 +
# '''MATADOR:''' van Rossum AGJ, Kok M, van Werkhoven E, Opdam M, Mandjes IAM, van Leeuwen-Stok AE, van Tinteren H, Imholz ALT, Portielje JEA, Bos MMEM, van Bochove A, Wesseling J, Rutgers EJ, Linn SC, Oosterkamp HM; MATADOR Trialists' Group. Adjuvant dose-dense doxorubicin-cyclophosphamide versus docetaxel-doxorubicin-cyclophosphamide for high-risk breast cancer: first results of the randomised MATADOR trial (BOOG 2004-04). Eur J Cancer. 2018 Oct;102:40-48. [https://doi.org/10.1016/j.ejca.2018.07.013 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30125761/ PubMed] ISRCTN61893718
  
−
==Dose-dense AC -> TH (Taxol) {{#subobject:65c9a8|Regimen=1}}==
+
==Cyclophosphamide & Epirubicin (EC) {{#subobject:8d8dbe|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
EC: '''<u>E</u>'''pirubicin and '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 60/500 x 8 {{#subobject:50bd25|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1200/jco.2001.19.12.3103 Piccart et al. 2001 (Belgian trial)]
 +
|rowspan=2|1988-1996
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|1. [[#CMF|CMF]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 +
|-
 +
|2. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29|EC]]; high-dose
 +
| style="background-color:#fc8d59" |Seems to have inferior EFS (primary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 75/600 x 4 {{#subobject:2e39fe|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdh016 Pico et al. 2004 (GEICAM 9401)]
 +
|1995-2000
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[#ECT_.28Tamoxifen.29_888|ECT (Tamoxifen)]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS60
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 4 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Adjuvant [[#Tamoxifen_monotherapy_888|tamoxifen]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 100/830 x 8 {{#subobject:aead26|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1200/jco.2001.19.12.3103 Piccart et al. 2001 (Belgian trial)]
 +
|rowspan=2|1988-1996
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[#CMF|CMF]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of EFS
 +
|-
 +
|2. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29|EC]]; moderate-dose
 +
| style="background-color:#91cf60" |Seems to have superior EFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 830 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 120/600 x 4 (high-dose) {{#subobject:24260d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2003.03.034 Papaldo et al. 2003]
 +
|1991-1994
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cyclophosphamide_.26_Epirubicin_.28EC.29_.26_Lonidamine_999|EC & Lonidamine]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS60
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362268/ Vici et al. 2011 (GOIM 9902)]
 +
|1999-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#D-EC_999|D-EC]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS60
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
AC -> TH: '''<u>A</u>'''driamycin, '''<u>C</u>'''ytoxan -> '''<u>T</u>'''axol, '''<u>H</u>'''erceptin
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
===Regimen {{#subobject:4c0f4a|Variant=1}}===
+
*Papaldo et al. 2003: [[Surgery#Breast_cancer_surgery|Surgery]]
−
Level of Evidence:
+
*GOIM 9902: [[Surgery#Breast_cancer_surgery|Surgery]]
−
<span
+
</div>
−
style="background:#EEEE00;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
padding:3px 6px 3px 6px;
+
====Chemotherapy====
−
border-color:black;
+
*[[Epirubicin (Ellence)]] 120 mg/m<sup>2</sup> IV once on day 1  
−
border-width:2px;
+
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
−
border-style:solid;">Phase II</span>
+
'''21-day cycle for 4 cycles'''
−
 
+
</div></div>
−
'''All cycles given with [[Filgrastim (Neupogen)]] support'''
 
−
*[[Doxorubicin (Adriamycin)]] 60 mg/m2 IV day 1
 
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV day 1
 
−
 
 
−
'''14-day cycles x 4 cycles, THEN'''
 
−
 
 
−
*[[Paclitaxel (Taxol)]] 175 mg/m2 IV over 3 hours day 1
 
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV with first dose of paclitaxel, then 2 mg/kg IV on day 8 of cycle 1; in cycles 2-4, [[Trastuzumab (Herceptin)]] is 2 mg/kg IV on days 1 & 8
 
−
 
 
−
'''14-day cycles x 4 cycles, THEN'''
 
−
 
 
−
*EITHER [[Trastuzumab (Herceptin)]] 2 mg/kg IV, '''1-week cycles x 44 additional cycles/weeks to complete a total of 52 weeks of therapy'''
 
−
*OR [[Trastuzumab (Herceptin)]] 6 mg/kg IV, '''3-week cycles x 15 additional cycles/weeks to complete a total of 52 weeks of therapy'''
 
−
 
 
−
===Monitoring===
 
−
*Cardiac function: echocardiogram at baseline, then every 3 months while on Trastuzumab (Herceptin)
 
−
 
 
 
===References===
 
===References===
−
# Dang C, Fornier M, Sugarman S, Troso-Sandoval T, Lake D, D'Andrea G, Seidman A, Sklarin N, Dickler M, Currie V, Gilewski T, Moynahan ME, Drullinsky P, Robson M, Wasserheit-Leiblich C, Mills N, Steingart R, Panageas K, Norton L, Hudis C. The safety of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel with trastuzumab in HER-2/neu overexpressed/amplified breast cancer. J Clin Oncol. 2008 Mar 10;26(8):1216-22. [http://jco.ascopubs.org/content/26/8/1216.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18323546 PubMed]
+
# '''Belgian trial:''' Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M, Nogaret JM. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol. 2001 Jun 15;19(12):3103-10. [https://doi.org/10.1200/jco.2001.19.12.3103 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11408507/ PubMed]
 +
## '''Update:''' de Azambuja E, Paesmans M, Beauduin M, Vindevoghel A, Cornez N, Finet C, Ries F, Closon-Dejardin MT, Kerger J, Gobert P, Focan C, Tagnon A, Dolci S, Nogaret JM, di Leo A, Piccart-Gebhart MJ. Long-term benefit of high-dose epirubicin in adjuvant chemotherapy for node-positive breast cancer: 15-year efficacy results of the Belgian multicentre study. J Clin Oncol. 2009 Feb 10;27(5):720-5. Epub 2008 Dec 22. [https://doi.org/10.1200/JCO.2008.17.2155 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19103732/ PubMed]
 +
# Papaldo P, Lopez M, Cortesi E, Cammilluzzi E, Antimi M, Terzoli E, Lepidini G, Vici P, Barone C, Ferretti G, Di Cosimo S, Nistico C, Carlini P, Conti F, Di Lauro L, Botti C, Vitucci C, Fabi A, Giannarelli D, Marolla P. Addition of either lonidamine or granulocyte colony-stimulating factor does not improve survival in early breast cancer patients treated with high-dose epirubicin and cyclophosphamide. J Clin Oncol. 2003 Sep 15;21(18):3462-8. [https://doi.org/10.1200/JCO.2003.03.034 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/12972521/ PubMed]
 +
# '''GEICAM 9401:''' Pico C, Martin M, Jara C, Barnadas A, Pelegri A, Balil A, Camps C, Frau A, Rodriguez-Lescure A, Lopez-Vega JM, De La Haba J, Tres A, Alvarez I, Alba E, Arcusa A, Oltra A, Batista N, Checa T, Perez-Carrion R, Curto J; GEICAM. Epirubicin-cyclophosphamide adjuvant chemotherapy plus tamoxifen administered concurrently versus sequentially: randomized phase III trial in postmenopausal node-positive breast cancer patients: a GEICAM 9401 study. Ann Oncol. 2004 Jan;15(1):79-87. [https://doi.org/10.1093/annonc/mdh016 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/14679124/ PubMed]
 +
# '''GOIM 9902:''' Vici P, Brandi M, Giotta F, Foggi P, Schittulli F, Di Lauro L, Gebbia N, Massidda B, Filippelli G, Giannarelli D, Di Benedetto A, Mottolese M, Colucci G, Lopez M. A multicenter phase III prospective randomized trial of high-dose epirubicin in combination with cyclophosphamide (EC) versus docetaxel followed by EC in node-positive breast cancer: GOIM (Gruppo Oncologico Italia Meridionale) 9902 study. Ann Oncol. 2012 May;23(5):1121-9. Epub 2011 Sep 28. [https://doi.org/10.1093/annonc/mdr412 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3362268/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21965475/ PubMed]
 +
# '''GIM2:''' Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 x 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. [https://doi.org/10.1016/s0140-6736(14)62048-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25740286/ PubMed] [https://clinicaltrials.gov/study/NCT00433420 NCT00433420]
 +
##'''Update:''' Del Mastro L, Poggio F, Blondeaux E, De Placido S, Giuliano M, Forestieri V, De Laurentiis M, Gravina A, Bisagni G, Rimanti A, Turletti A, Nisticò C, Vaccaro A, Cognetti F, Fabi A, Gasparro S, Garrone O, Alicicco MG, Urracci Y, Mansutti M, Poletti P, Correale P, Bighin C, Puglisi F, Montemurro F, Colantuoni G, Lambertini M, Boni L; Gruppo Italiano Mammella Investigators. Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial. Lancet Oncol. 2022 Dec;23(12):1571-1582. Epub 2022 Nov 10. [https://doi.org/10.1016/s1470-2045(22)00632-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36370716/ PubMed]
  
−
==TCH (Carboplatin) {{#subobject:1b999b|Regimen=1}}==
+
==Docetaxel monotherapy {{#subobject:45c144|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
D: '''<u>D</u>'''ocetaxel
 +
<br>T: '''<u>T</u>'''axotere (Docetaxel)
 +
<br>dT: '''<u>d</u>'''oce'''<u>T</u>'''axel
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:199d79|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2003.12.005 Bear et al. 2003 (NSABP B-27)]
 +
|1995-2000
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Complex_multipart_regimens#NSABP_B-27|See link]]
 +
|[[Complex_multipart_regimens#NSABP_B-27|See link]]
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
TCH: '''<u>T</u>'''axotere, '''<u>C</u>'''arboplatin, '''<u>H</u>'''erceptin
+
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
−
 
+
<div class="toccolours" style="background-color:#cbd5e8">
−
===Regimen {{#subobject:7a8d90|Variant=1}}===
+
====Preceding treatment====
−
Level of Evidence:
+
*NSABP B-27: Neoadjuvant [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]] x 4, then [[Surgery#Breast_cancer_surgery|surgery]]
−
<span
+
</div>
−
style="background:#00CD00;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
padding:3px 6px 3px 6px;
+
====Chemotherapy====
−
border-color:black;
+
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1
−
border-width:2px;
+
'''21-day cycle for 4 cycles'''
−
border-style:solid;">Phase III</span>
+
</div></div>
−
 
 
−
*[[Docetaxel (Taxotere)]] 75 mg/m2 IV day 1
 
−
*[[Carboplatin (Paraplatin)]] AUC 6 IV day 1
 
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV on cycle 1 day 1, then 2 mg/kg IV on day 8 & 15 of cycle 1; then in cycles 2-6, [[Trastuzumab (Herceptin)]] is 2 mg/kg IV on days 1, 8, 15
 
−
 
 
−
'''21-day cycles x 6 cycles, THEN'''
 
−
 
 
−
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV day 1
 
−
 
 
−
'''3-week cycles x 12 additional cycles/weeks to complete a total of 52 weeks of therapy'''
 
−
 
 
−
===Monitoring===
 
−
*Cardiac function: echocardiogram at baseline, then every 3 months while on Trastuzumab (Herceptin)
 
−
 
 
 
===References===
 
===References===
−
# Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83. [http://www.nejm.org/doi/full/10.1056/NEJMoa0910383 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/21991949 PubMed]
+
# '''NSABP B-27:''' Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, Wolmark N; National Surgical Adjuvant Breast and Bowel Project. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003 Nov 15;21(22):4165-74. Epub 2003 Oct 14. [https://doi.org/10.1200/JCO.2003.12.005 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14559892/ PubMed] [https://clinicaltrials.gov/study/NCT00002707 NCT00002707]
−
 
+
## '''Update:''' Bear HD, Anderson S, Smith RE, Geyer CE Jr, Mamounas EP, Fisher B, Brown AM, Robidoux A, Margolese R, Kahlenberg MS, Paik S, Soran A, Wickerham DL, Wolmark N. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006 May 1;24(13):2019-27. Epub 2006 Apr 10. [https://doi.org/10.1200/JCO.2005.04.1665 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16606972/ PubMed]
−
==TCH (Cyclophosphamide) {{#subobject:b0421b|Regimen=1}}==
+
## '''Pooled update:''' Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008 Feb 10;26(5):778-85. Erratum in: J Clin Oncol. 2008 Jun 1;26(16):2793. [https://doi.org/10.1200/JCO.2007.15.0235 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18258986/ PubMed]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
# '''NSAS BC-02:''' Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. [https://doi.org/10.1002/cncr.30421 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6668007/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28081304/ PubMed]
 +
==Epirubicin & Paclitaxel (EP) {{#subobject:332a92|Regimen=1}}==
 +
EP: '''<u>E</u>'''pirubicin & '''<u>P</u>'''aclitaxel
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:4824ee|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9958529/ Yuan et al. 2023 (CH-BC-006)]
 +
|2010-06-01 to 2016-06-30
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[#EC-T_2|EC-P]]
 +
| style="background-color:#eeee01" |Non-inferior DFS (primary endpoint)<br>DFS60: 86% vs 80.6%<br>(HR 0.82, 95% CI 0.61-1.10)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
TCH: '''<u>T</u>'''axotere, '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''erceptin
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
===Regimen, Jones et al. 2013 {{#subobject:d3aba1|Variant=1}}===
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
Level of Evidence:
+
</div>
−
<span
+
<div class="toccolours" style="background-color:#b3e2cd">
−
style="background:#EEEE00;
+
====Chemotherapy====
−
padding:3px 6px 3px 6px;
+
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
−
border-color:black;
+
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
−
border-width:2px;
+
'''21-day cycle for 6 cycles'''
−
border-style:solid;">Phase II</span>
+
</div></div>
−
 
 
−
====Induction therapy====
 
−
''Chemotherapy started within 84 days of surgery.''
 
−
*[[Docetaxel (Taxotere)]] 75 mg/m2 IV over 1 hour once on day 1
 
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV over 15 to 30 minutes once on day 1
 
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV over 90 minutes once on cycle 1 day 1; then [[Trastuzumab (Herceptin)]] 2 mg/kg IV over 30 to 60 minutes once per day on cycle 1 days 8 & 15; then [[Trastuzumab (Herceptin)]] 2 mg/kg IV over 30 to 60 minutes once per day on days 1, 8, 15 of cycles 2 and on
 
−
 
 
−
'''21-day cycles x 4 cycles, then proceed to trastuzumab monotherapy'''
 
−
 
 
−
Supportive medications:
 
−
*Use of [[Filgrastim (Neupogen)]] or [[Pegfilgrastim (Neulasta)]] was allowed.
 
−
*Prophylactic antibiotics were not recommended.
 
−
 
 
−
====Trastuzumab monotherapy====
 
−
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV once on day 1
 
−
 
 
−
'''21-day cycles, given until patient receives 1 year total of trastuzumab therapy'''
 
−
 
 
 
===References===
 
===References===
−
# Jones SE, Collea R, Paul D, Sedlacek S, Favret AM, Gore I Jr, Lindquist DL, Holmes FA, Allison MA, Brooks BD, Portillo RM, Vukelja SJ, Steinberg MS, Stokoe C, Crockett MW, Wang Y, Asmar L, Robert NJ, O'Shaughnessy J. Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Lancet Oncol. 2013 Sep 2. pii: S1470-2045(13)70384-X. doi: 10.1016/S1470-2045(13)70384-X. [Epub ahead of print] [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2813%2970384-X/fulltext link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/24007746 PubMed]
+
#'''CH-BC-006:''' Yuan P, Kang Y, Ma F, Fan Y, Wang J, Wang X, Yue J, Luo Y, Zhang P, Li Q, Xu B. Effect of Epirubicin Plus Paclitaxel vs Epirubicin and Cyclophosphamide Followed by Paclitaxel on Disease-Free Survival Among Patients With Operable ERBB2-Negative and Lymph Node-Positive Breast Cancer: A Randomized Clinical Trial. JAMA Netw Open. 2023 Feb 1;6(2):e230122. [https://doi.org/10.1001/jamanetworkopen.2023.0122 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9958529/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/36826820/ PubMed] [https://clinicaltrials.gov/study/NCT01134523 NCT01134523]
−
 
+
==Epirubicin monotherapy {{#subobject:fda4d3|Regimen=1}}==
−
==TH (CALGB 40101) {{#subobject:dc66e8|Regimen=1}}==
+
E: '''<u>E</u>'''pirubicin
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:f04ubx|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.32.7254 Coombes et al. 2011 (DEVA)]
 +
|1997-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#E-D|E-D]]
 +
| style="background-color:#d73027" |Inferior OS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
TH: '''<u>T</u>'''axol, '''<u>H</u>'''erceptin
+
<div class="toccolours" style="background-color:#cbd5e8">
−
===Regimen {{#subobject:a4b465|Variant=1}}===
+
====Preceding treatment====
−
Level of Evidence:
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
<span
+
</div>
−
style="background:#00CD00;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
padding:3px 6px 3px 6px;
+
====Chemotherapy====
−
border-color:black;
+
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
border-width:2px;
+
'''28-day cycle for 6 cycles'''
−
border-style:solid;">Phase III</span>
+
</div></div>
−
 
 
−
====Initial TH therapy====
 
−
*[[Paclitaxel (Taxol)]] 175 mg/m2 IV over 3 hours once on day 1
 
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV once on cycle 1 day 1, then 2 mg/kg IV once on day 8 of cycle 1; then in cycles 2-4, Trastuzumab (Herceptin) is 2 mg/kg IV once daily on days 1 & 8
 
−
 
 
−
'''14-day cycles x 4 cycles'''
 
−
 
 
−
Supportive medications:
 
−
*Diphenhydramine (Benadryl) 12.5-50 mg IV once 30-60 minutes prior to paclitaxel
 
−
*One of the following H2 blockers:
 
−
**Ranitidine (Zantac) 50 mg IV once 30-60 minutes prior to paclitaxel
 
−
**Cimetidine (Tagamet) 300 mg IV once 30-60 minutes prior to paclitaxel
 
−
**Famotidine (Pepcid) 20 mg IV once 30-60 minutes prior to paclitaxel
 
−
*One of the following dexamethasone choices:
 
−
**[[Dexamethasone (Decadron)]] 10 mg IV once <60 minutes prior to paclitaxel
 
−
**[[Dexamethasone (Decadron)]] 10 mg PO once >60 minutes prior to paclitaxel
 
−
**[[Dexamethasone (Decadron)]] 20 mg PO 6 hours and 12 hours prior to paclitaxel
 
−
*Recommended growth factor support with one of the following:
 
−
**[[Filgrastim (Neupogen)]] 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once daily on days 3-10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
 
−
**[[Sargramostim (Leukine)]] 250-500 mcg/m2 SC once daily on days 3-10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
 
−
**[[Pegfilgrastim (Neulasta)]] 6 mg SC once, given 24-36 hours after chemotherapy
 
−
 
 
−
====Trastuzumab (Herceptin) to continue after the completion of TH====
 
−
*One of the following doses & schedules of trastuzumab:
 
−
**[[Trastuzumab (Herceptin)]] 2 mg/kg IV once per week
 
−
**[[Trastuzumab (Herceptin)]] 6 mg/kg IV once every 3 weeks
 
−
 
 
−
'''44-week course''', which, counting doses given as part of TH, will result in a total of 52 weeks of trastuzumab therapy
 
−
 
 
 
===References===
 
===References===
−
# Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Jul 23. [Epub ahead of print] [http://jco.ascopubs.org/content/early/2012/07/23/JCO.2011.40.6405.long link to original article] '''contains verified protocol''' [http://jco.ascopubs.org/content/suppl/2012/07/23/JCO.2011.40.6405.DC1/Protocol.pdf link to study protocol PDF] [http://www.ncbi.nlm.nih.gov/pubmed/22826271 PubMed]  
+
<!-- Presented at the 46th Annual Meeting of the American Society of Clinical Oncology, June 4-8, 2010, Chicago, IL. -->
−
 
+
# '''DEVA:''' Coombes RC, Bliss JM, Espie M, Erdkamp F, Wals J, Tres A, Marty M, Coleman RE, Tubiana-Mathieu N, den Boer MO, Wardley A, Kilburn LS, Cooper D, Thomas MW, Reise JA, Wilkinson K, Hupperets P. Randomized, phase III trial of sequential epirubicin and docetaxel versus epirubicin alone in postmenopausal patients with node-positive breast cancer. J Clin Oncol. 2011 Aug 20;29(24):3247-54. Epub 2011 Jul 18. [https://doi.org/10.1200/JCO.2010.32.7254 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21768453/ PubMed] ISRCTN89772270
−
==T -> H (CALGB 40101) {{#subobject:55e970|Regimen=1}}==
+
==Dose-dense Epirubicin monotherapy {{#subobject:fda8g3|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
ddE: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>E</u>'''pirubicin
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:9134b2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223601/ Fountzilas et al. 2014 (HE10/05)]
 +
|2005-2008
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
T -> H: '''<u>T</u>'''axol, '''<u>H</u>'''erceptin
+
''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
−
===Regimen {{#subobject:c88ace|Variant=1}}===
+
<div class="toccolours" style="background-color:#cbd5e8">
−
Level of Evidence:
+
====Preceding treatment====
−
<span
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
style="background:#00CD00;
+
</div>
−
padding:3px 6px 3px 6px;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
border-color:black;
+
====Chemotherapy====
−
border-width:2px;
+
*[[Epirubicin (Ellence)]] 110 mg/m<sup>2</sup> IV once on day 1
−
border-style:solid;">Phase III</span>
+
'''14-day cycle for 3 cycles'''
−
 
+
</div>
−
====Initial Paclitaxel (Taxol) therapy====
+
<div class="toccolours" style="background-color:#cbd5e7">
−
*[[Paclitaxel (Taxol)]] 175 mg/m2 IV over 3 hours once on day 1
+
====Subsequent treatment====
−
 
+
*[[#CMF_2|CMF]]; intensified
−
'''14-day cycles x 4 cycles'''
+
</div></div>
−
 
 
−
Supportive medications:
 
−
*Diphenhydramine (Benadryl) 12.5-50 mg IV once 30-60 minutes prior to paclitaxel
 
−
*One of the following H2 blockers:
 
−
**Ranitidine (Zantac) 50 mg IV once 30-60 minutes prior to paclitaxel
 
−
**Cimetidine (Tagamet) 300 mg IV once 30-60 minutes prior to paclitaxel
 
−
**Famotidine (Pepcid) 20 mg IV once 30-60 minutes prior to paclitaxel
 
−
*One of the following dexamethasone choices:
 
−
**[[Dexamethasone (Decadron)]] 10 mg IV once <60 minutes prior to paclitaxel
 
−
**[[Dexamethasone (Decadron)]] 10 mg PO once >60 minutes prior to paclitaxel
 
−
**[[Dexamethasone (Decadron)]] 20 mg PO 6 hours and 12 hours prior to paclitaxel
 
−
*Recommended growth factor support with one of the following:
 
−
**[[Filgrastim (Neupogen)]] 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once daily on days 3-10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"  
 
−
**[[Sargramostim (Leukine)]] 250-500 mcg/m2 SC once daily on days 3-10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
 
−
**[[Pegfilgrastim (Neulasta)]] 6 mg SC once, given 24-36 hours after chemotherapy
 
−
 
 
−
====Trastuzumab (Herceptin) to start after the completion of paclitaxel====
 
−
One of the following doses & schedules of trastuzumab:
 
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV once as the loading dose, then 2 mg/kg IV once per week thereafter
 
−
*[[Trastuzumab (Herceptin)]] 8 mg/kg IV once as the loading dose, then 6 mg/kg IV every 3 weeks thereafter
 
−
 
 
−
'''52-week course of therapy'''
 
−
 
 
 
===References===
 
===References===
−
# Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Jul 23. [Epub ahead of print] [http://jco.ascopubs.org/content/early/2012/07/23/JCO.2011.40.6405.long link to original article] '''contains verified protocol''' [http://jco.ascopubs.org/content/suppl/2012/07/23/JCO.2011.40.6405.DC1/Protocol.pdf link to study protocol PDF] [http://www.ncbi.nlm.nih.gov/pubmed/22826271 PubMed]  
+
# '''HE10/05:''' Fountzilas G, Dafni U, Papadimitriou C, Timotheadou E, Gogas H, Eleftheraki AG, Xanthakis I, Christodoulou C, Koutras A, Papandreou CN, Papakostas P, Miliaras S, Markopoulos C, Dimitrakakis C, Korantzopoulos P, Karanikiotis C, Bafaloukos D, Kosmidis P, Samantas E, Varthalitis I, Pavlidis N, Pectasides D, Dimopoulos MA. Dose-dense sequential adjuvant chemotherapy followed, as indicated, by trastuzumab for one year in patients with early breast cancer: first report at 5-year median follow-up of a Hellenic Cooperative Oncology Group randomized phase III trial. BMC Cancer. 2014 Jul 15;14:515. [https://doi.org/10.1186/1471-2407-14-515 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223601/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25026897/ PubMed]
  
−
==TH (Taxotere) -> FEC {{#subobject:87988b|Regimen=1}}==
+
==FAC {{#subobject:1e6621|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
FAC: '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide
 +
<br>CAF: '''<u>C</u>'''yclophosphamide, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>F</u>'''luorouracil
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 500/40/500 x 6 {{#subobject:041nc6|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1111/j.1349-7006.2007.00639.x Tokuda et al. 2007 (JCOG 9208)]
 +
|1993-1999
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
TH -> FEC: '''<u>T</u>'''axotere, '''<u>H</u>'''erceptin -> '''<u>F</u>'''ive-FU, '''<u>E</u>'''pirubicin, '''<u>C</u>'''ytoxan
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
===Regimen {{#subobject:8a1397|Variant=1}}===
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
Level of Evidence:
+
</div>
−
<span
+
<div class="toccolours" style="background-color:#b3e2cd">
−
style="background:#00CD00;
+
====Chemotherapy====
−
padding:3px 6px 3px 6px;
+
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
−
border-color:black;
+
*[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV once on day 1
−
border-width:2px;
+
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
−
border-style:solid;">Phase III</span>
+
'''21-day cycle for 6 cycles'''
−
 
+
</div>
−
*[[Docetaxel (Taxotere)]] 100 mg/m2 IV over 1 hour on day 1
+
<div class="toccolours" style="background-color:#cbd5e7">
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV on cycle 1 day 1, then 2 mg/kg IV on days 8 & 15 of cycle 1; then in cycles 2-3, [[Trastuzumab (Herceptin)]] is 2 mg/kg IV on days 1, 8, 15
+
====Subsequent treatment====
−
 
+
*[[#Cyclophosphamide_.26_Thiotepa.2C_then_auto_HSCT_888|Cyclophosphamide & Thiotepa, then auto HSCT]] consolidation followed by adjuvant [[#Tamoxifen_monotherapy_888|tamoxifen]] versus adjuvant [[#Tamoxifen_monotherapy_888|tamoxifen]]
−
'''21-day cycles x 3 cycles, THEN'''
+
</div></div><br>
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
*[[Fluorouracil (5-FU)]] 600 mg/m2 IV day 1
 
−
*[[Epirubicin (Ellence)]] 60 mg/m2 IV day 1
 
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV day 1
 
−
 
 
−
'''21-day cycles x 3 cycles'''
 
−
 
 
−
===Monitoring===
 
−
*Cardiac function: echocardiogram at baseline, after last cycle of FEC, 12 months after completion of chemotherapy, and 36 months after completion of chemotherapy
 
  
 +
===Regimen variant #2, 500/50/500 x 6 {{#subobject:63e780|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdg260 Martin et al. 2003 (GEICAM 8701)]
 +
|1987-1991
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#CMF|CMF]]
 +
| style="background-color:#d9ef8b" |Might have superior DFS
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa043681 Martin et al. 2005 (BCIRG 001)]
 +
|1997-1999
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#TAC_.28Docetaxel.29_2|TAC]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa0910320 Martín et al. 2010 (GEICAM 9805)]
 +
|1999-2003
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#TAC_.28Docetaxel.29_2|TAC]]
 +
| style="background-color:#d73027" |Inferior DFS
 +
|-
 +
|[https://doi.org/10.1200/jco.2012.46.9841 Martín et al. 2013 (GEICAM 2003-02)]
 +
|2003-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FAC-T|FAC-T]]
 +
| style="background-color:#fc8d59" |Seems to have inferior DFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7840116/ Delaloge et al. 2020 (MINDACT)]
 +
|2007-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Docetaxel_.28TX.29_999|TX]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
''Infusion times per Martin et al. 2005 (BCIRG 001).''
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV over 15 minutes once on day 1, '''given second'''
 +
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV over 15 minutes once on day 1, '''given first'''
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV over 1 to 5 minutes once on day 1, '''given third'''
 +
**A HemOnc.org user reached out to us and said their institutional practice is to infuse cyclophosphamide over 20 to 30 minutes to decrease the likelihood of head and sinus pain.
 +
====Supportive therapy====
 +
*If patients had febrile neutropenia or infection: [[Ciprofloxacin (Cipro)]] 500 mg PO twice per day on days 5 to 14
 +
*If patients had febrile neutropenia, one of the following:
 +
**[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day on days 4 to 11
 +
**[[Lenograstim (Granocyte)]] 150 mcg/m<sup>2</sup> SC once per day on days 4 to 11
 +
'''21-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 500/50/500 until max anthracycline {{#subobject:2cnc3v|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1988.6.4.679 Hurteloup 1988 (FESG)]
 +
|1982-1984
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC_2|FEC]]
 +
| style="background-color:#ffffbf" |Did not meet endpoint of OS50%
 +
|-
 +
|}
 +
''Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 11 cycles (maximum cumulative doxorubicin dose of 550 mg/m<sup>2</sup>)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 800/40/400 x 6 {{#subobject:23cb8b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1056/NEJM199405053301801 Wood et al. 1994 (CALGB 8541)]
 +
|rowspan=2|1985-NR
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|1. [[#FAC_2|FAC]]; 600/30/300 x 4
 +
| style="background-color:#1a9850" |Superior OS
 +
|-
 +
|2. [[#FAC_2|FAC]]; 1200/60/600 x 4
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup> IV once on day 1
 +
'''28-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#ee6b6e">
 +
===Regimen variant #5, 800/40/400 until max doxorubicin {{#subobject:53e7a0|Variant=1}}===
 +
{| class="wikitable" style="color:white; background-color:#f01e2c"
 +
|<small><span style="color:white;">'''Historic variant'''</span></small>
 +
|-
 +
|}
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(19840201)53:3%3C384::AID-CNCR2820530303%3E3.0.CO;2-G Buzdar et al. 1984]
 +
|1977-1980
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FAC_.26_BCG_999|FAC + BCG]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
''Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles until cumulative doxorubicin dose of 300 mg/m<sup>2</sup> reached.'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*After reaching cumulative maximum doxorubicin, patients would go on to receive: maintenance [[#CMF|CMF]]. This is now obsolete.
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #6, 1000/50/500 x 8 {{#subobject:a3523e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://academic.oup.com/jnci/article/92/3/225/2965047 Hortobagyi et al. 2000]
 +
|1990-1997
 +
| style="background-color:#91cf61" |Non-randomized part of RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 4
 +
*[[Doxorubicin (Adriamycin)]] 16.7 mg/m<sup>2</sup>/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m<sup>2</sup>)
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 8 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#CEP.2C_then_auto_HSCT_999|CEP with auto HSCT]] consolidation versus [[Breast_cancer_-_null_regimens#Observation|no further treatment]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #7, 1000/60/1400 x 6 {{#subobject:f18a6a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.05.551 Davidson et al. 2005 (ECOG E5188)]
 +
|1989-1994
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.08.071 Hutchins et al. 2005 (INT-0102)]
 +
|1989-1993
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#CMF|CMF]]
 +
| style="background-color:#91cf60" |Seems to have superior OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140679/ Albain et al. 2009 (SWOG-8814)]
 +
|1989-1995
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Complex_multipart_regimens#SWOG-8814|See link]]
 +
| style="background-color:#d9ef8b" |[[Complex_multipart_regimens#SWOG-8814|See link]]
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa030684 Tallman et al. 2003 (INT-0121)]
 +
|1991-1998
 +
| style="background-color:#91cf61" |Non-randomized part of RCT
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
'''28-day cycle for 6 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*INT-0121: [[#Cyclophosphamide_.26_Thiotepa.2C_then_auto_HSCT_888|Cyclophosphamide & thiotepa, then auto HSCT]] consolidation versus [[Breast_cancer_-_null_regimens#Observation|no further chemotherapy]]
 +
*ECOG E5188: Adjuvant [[#Goserelin_monotherapy_999|Goserelin]] x 5 y versus [[Breast_cancer,_ER-positive#Goserelin_.26_Tamoxifen|Goserelin & Tamoxifen]] x 5 y versus [[Breast_cancer_-_null_regimens#Observation|no further treatment]]
 +
*SWOG-8814: Adjuvant [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_3|Tamoxifen]] x 5 y
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #8, 1200/60/600 x 4 {{#subobject:7953f3|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1056/NEJM199405053301801 Wood et al. 1994 (CALGB 8541)]
 +
|rowspan=2|1985-NR
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#FAC_2|FAC]]; 600/30/300 x 4
 +
| style="background-color:#1a9850" |Superior OS
 +
|-
 +
|2. [[#FAC_2|FAC]]; 800/40/400 x 6
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
''Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''28-day cycle for 4 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #9, 1200/60/600 x 6 {{#subobject:7abnf3|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7840116/ Delaloge et al. 2020 (MINDACT)]
 +
|2007-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Docetaxel_.28TX.29_999|TX]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
''Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''28-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #10, 2000/50/100 x 4 {{#subobject:1ahi03|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/0959-8049(94)90537-1 Scholl et al. 1994 (S6)]
 +
|1986-1990
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|Neoadjuvant [[#FAC|FAC]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|}
 +
''Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1, 3, 5, 8
 +
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 5
 +
'''28-day cycle for 4 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. [http://www.nejm.org/doi/full/10.1056/NEJMoa053028 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16495393 PubMed]
+
# Buzdar AU, Blumenschein GR, Smith TL, Powell KC, Hortobagyi GN, Yap HY, Schell FC, Barnes BC, Ames FC, Martin RG, Hersh EM. Adjuvant chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide, with or without Bacillus Calmette-Guérin and with or without irradiation in operable breast cancer: a prospective randomized trial. Cancer. 1984 Feb 1;53(3):384-9. [https://doi.org/10.1002/1097-0142(19840201)53:3%3C384::AID-CNCR2820530303%3E3.0.CO;2-G link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/6362814/ PubMed]
 +
## '''Update:''' Buzdar AU, Kau SW, Smith TL, Hortobagyi GN. Ten-year results of FAC adjuvant chemotherapy trial in breast cancer. Am J Clin Oncol. 1989 Apr;12(2):123-8. [https://doi.org/10.1097/00000421-198904000-00007 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2705401/ PubMed]
 +
# '''FESG:''' Hurteloup P; French Epirubicin Study Group. A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol. 1988 Apr;6(4):679-88. [https://doi.org/10.1200/JCO.1988.6.4.679 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/2895801/ PubMed]
 +
# '''CALGB 8541:''' Wood WC, Budman DR, Korzun AH, Cooper MR, Younger J, Hart RD, Moore A, Ellerton JA, Norton L, Ferree CR, Colangelo Ballow A, Frei E, Henderson IC. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994 May 5;330(18):1253-9. Erratum in: N Engl J Med 1994 Jul 14;331(2):139. [https://doi.org/10.1056/NEJM199405053301801 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8080512/ PubMed]
 +
## '''Subgroup analysis:''' Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Koerner F, Cirrincione CT, Budman DR, Wood WC, Barcos M, Henderson IC. c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med. 1994 May 5;330(18):1260-6. Erratum in: N Engl J Med 1994 Jul 21;331(3):211. [https://doi.org/10.1056/NEJM199405053301802 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7908410/ PubMed]
 +
# '''S6:''' Scholl SM, Fourquet A, Asselain B, Pierga JY, Vilcoq JR, Durand JC, Dorval T, Palangié T, Jouve M, Beuzeboc P, Garcio-Giralt E, Salmon RJ, de la Rochefordiere A, Campana F, Pouillart P. Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: preliminary results of a randomised trial: S6. Eur J Cancer. 1994;30A(5):645-52. [https://doi.org/10.1016/0959-8049(94)90537-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8080680/ PubMed]
 +
# Hortobagyi GN, Buzdar AU, Theriault RL, Valero V, Frye D, Booser DJ, Holmes FA, Giralt S, Khouri I, Andersson B, Gajewski JL, Rondon G, Smith TL, Singletary SE, Ames FC, Sneige N, Strom EA, McNeese MD, Deisseroth AB, Champlin RE. Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst. 2000 Feb 2;92(3):225-33. [https://academic.oup.com/jnci/article/92/3/225/2965047 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10655439/ PubMed]
 +
# '''GEICAM 8701:''' Martin M, Villar A, Sole-Calvo A, Gonzalez R, Massuti B, Lizon J, Camps C, Carrato A, Casado A, Candel MT, Albanell J, Aranda J, Munarriz B, Campbell J, Diaz-Rubio E; GEICAM. Doxorubicin in combination with fluorouracil and cyclophosphamide (iv FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (iv CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Ann Oncol. 2003 Jun;14(6):833-42. [https://doi.org/10.1093/annonc/mdg260 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/12796019/ PubMed]
 +
# '''INT-0121:''' Tallman MS, Gray R, Robert NJ, LeMaistre CF, Osborne CK, Vaughan WP, Gradishar WJ, Pisansky TM, Fetting J, Paietta E, Lazarus HM. Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med. 2003 Jul 3;349(1):17-26. [https://doi.org/10.1056/NEJMoa030684 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12840088/ PubMed]
 +
<!-- no pre-pub disclosed -->
 +
# '''BCIRG 001:''' Martín M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C; Breast Cancer International Research Group. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med. 2005 Jun 2;352(22):2302-13. [https://doi.org/10.1056/NEJMoa043681 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15930421/ PubMed] [https://clinicaltrials.gov/study/NCT00688740 NCT00688740]
 +
## '''Update:''' Mackey JR, Martín M, Pienkowski T, Rolski J, Guastalla JP, Sami A, Glaspy J, Juhos E, Wardley A, Fornander T, Hainsworth J, Coleman R, Modiano MR, Vinholes J, Pinter T, Rodríguez-Lescure A, Colwell B, Whitlock P, Provencher L, Laing K, Walde D, Price C, Hugh JC, Childs BH, Bassi K, Lindsay MA, Wilson V, Rupin M, Houé V, Vogel C; TRIO/BCIRG 001 investigators. Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial. Lancet Oncol. 2013 Jan;14(1):72-80. Epub 2012 Dec 12. [https://doi.org/10.1016/S1470-2045(12)70525-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23246022/ PubMed]
 +
# '''ECOG E5188:''' Davidson NE, O'Neill AM, Vukov AM, Osborne CK, Martino S, White DR, Abeloff MD. Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: results from INT 0101 (E5188). J Clin Oncol. 2005 Sep 1;23(25):5973-82. Epub 2005 Aug 8. [https://doi.org/10.1200/JCO.2005.05.551 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16087950/ PubMed]
 +
# '''INT-0102:''' Hutchins LF, Green SJ, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of intergroup protocol INT-0102. J Clin Oncol. 2005 Nov 20;23(33):8313-21. [https://doi.org/10.1200/jco.2005.08.071 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16293862/ PubMed]
 +
# '''JCOG 9208:''' Tokuda Y, Tajima T, Narabayashi M, Takeyama K, Watanabe T, Fukutomi T, Chou T, Sano M, Igarashi T, Sasaki Y, Ogura M, Miura S, Okamoto S, Ogita M, Kasai M, Kobayashi T, Fukuda H, Takashima S, Tobinai K; Autologous Bone Marrow Transplantation Study Group; Breast Cancer Study Group of the Japan Clinical Oncology Group (JCOG). Phase III study to evaluate the use of high-dose chemotherapy as consolidation of treatment for high-risk postoperative breast cancer: Japan Clinical Oncology Group study, JCOG 9208. Cancer Sci. 2008 Jan;99(1):145-51. Epub 2007 Oct 25. [https://doi.org/10.1111/j.1349-7006.2007.00639.x link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17970786/ PubMed]
 +
# '''SWOG-8814:''' Albain KS, Barlow WE, Ravdin PM, Farrar WB, Burton GV, Ketchel SJ, Cobau CD, Levine EG, Ingle JN, Pritchard KI, Lichter AS, Schneider DJ, Abeloff MD, Henderson IC, Muss HB, Green SJ, Lew D, Livingston RB, Martino S, Osborne CK; Breast Cancer Intergroup of North America. Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009 Dec 19;374(9707):2055-2063. Epub 2009 Dec 10. [https://doi.org/10.1016/S0140-6736(09)61523-3 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140679/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20004966/ PubMed] [https://clinicaltrials.gov/study/NCT00929591 NCT00929591]
 +
<!-- no pre-pub disclosed -->
 +
# '''GEICAM 9805:''' Martín M, Seguí MA, Antón A, Ruiz A, Ramos M, Adrover E, Aranda I, Rodríguez-Lescure A, Grosse R, Calvo L, Barnadas A, Isla D, Martinez del Prado P, Ruiz Borrego M, Zaluski J, Arcusa A, Muñoz M, López Vega JM, Mel JR, Munarriz B, Llorca C, Jara C, Alba E, Florián J, Li J, López García-Asenjo JA, Sáez A, Rios MJ, Almenar S, Peiró G, Lluch A; GEICAM. Adjuvant docetaxel for high-risk, node-negative breast cancer. N Engl J Med. 2010 Dec 2;363(23):2200-10. [https://doi.org/10.1056/NEJMoa0910320 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21121833/ PubMed] [https://clinicaltrials.gov/study/NCT00121992 NCT00121992]
 +
<!-- Presented in part at the 48th Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2012, Chicago, IL. -->
 +
# '''GEICAM 2003-02:''' Martín M, Ruiz A, Ruiz Borrego M, Barnadas A, González S, Calvo L, Margelí Vila M, Antón A, Rodríguez-Lescure A, Seguí-Palmer MA, Muñoz-Mateu M, Dorca Ribugent J, López-Vega JM, Jara C, Espinosa E, Mendiola Fernández C, Andrés R, Ribelles N, Plazaola A, Sánchez-Rovira P, Salvador Bofill J, Crespo C, Carabantes FJ, Servitja S, Chacón JI, Rodríguez CA, Hernando B, Álvarez I, Carrasco E, Lluch A. Fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus FAC followed by weekly paclitaxel as adjuvant therapy for high-risk, node-negative breast cancer: results from the GEICAM/2003-02 study. J Clin Oncol. 2013 Jul 10;31(20):2593-9. Epub 2013 Jun 3. [https://doi.org/10.1200/jco.2012.46.9841 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23733779/ PubMed] [https://clinicaltrials.gov/study/NCT00129389 NCT00129389]
 +
# '''MINDACT:''' Delaloge S, Piccart M, Rutgers E, Litière S, van 't Veer LJ, van den Berkmortel F, Brain E, Dudek-Peric A, Gil-Gil M, Gomez P, Hilbers FS, Khalil Z, Knox S, Kuemmel S, Kunz G, Lesur A, Pierga JY, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Thompson AM, Viale G, Zoppoli G, Vuylsteke P, Tryfonidis K, Poncet C, Bogaerts J, Cardoso F; MINDACT investigators and the TRANSBIG Consortium. Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial. J Clin Oncol. 2020 Apr 10;38(11):1186-1197. Epub 2020 Feb 21. [https://doi.org/10.1200/jco.19.01371 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7840116/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32083990/ PubMed] [https://clinicaltrials.gov/study/NCT00433589 NCT00433589]
  
−
==vH -> FEC {{#subobject:ca8dff|Regimen=1}}==
+
==FEC {{#subobject:3613b7|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
FEC: '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide
 +
<br>CEF: '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''pirubicin, '''<u>F</u>'''luorouracil
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 500/50/500 x 6 ("FEC 50") {{#subobject:24ca82|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1200/JCO.2003.04.148 Fumoleau et al. 2003 (FASG 01)]
 +
|rowspan=2|1986-1990
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#FEC_2|FEC]]; FEC 50 x 3
 +
| style="background-color:#d9ef8b" |Might have superior OS
 +
|-
 +
|2. [[#FEC_2|FEC]]; FEC 75 x 3
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS120
 +
|-
 +
|[http://www.jle.com/fr/revues/bdc/e-docs/epirubicin_based_chemotherapy_as_adjuvant_treatment_for_poor_prognosis_node_negative_breast_cancer_10_year_follow_up_results__272048/article.phtml Héry et al. 2006 (FASG 03)]
 +
|1988-1994
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Breast_cancer_-_null_regimens#Observation|Observation]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS120
 +
|-
 +
|[https://doi.org/10.1080/02841860510029987 Arriagada et al. 2005]
 +
|1989-1996
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Breast_cancer_-_null_regimens#Observation|Observation]]
 +
| style="background-color:#1a9850" |Superior DFS
 +
|-
 +
|[https://doi.org/10.1200/JCO.2001.19.3.602 Bonneterre 2001 (FASG 05)]
 +
|1990-1993
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC_2|FEC]]; FEC 100 x 6
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdl107 Roché et al. 2006 (FASG 06)]
 +
|1990-1998
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer,_ER-positive#Goserelin_.26_Tamoxifen_2|Goserelin & Tamoxifen]] x 3y
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS60
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172658/ Sparano et al. 2018 (TAILORx)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer,_ER-positive_-_null_regimens#Observation|No chemotherapy]]
 +
| style="background-color:#eeee01" |Non-inferior IDFS (primary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
VH -> FEC: '''<u>V</u>'''inorelbine, '''<u>H</u>'''erceptin -> '''<u>F</u>'''ive-FU, '''<u>E</u>'''pirubicin, '''<u>C</u>'''ytoxan
+
''Note: This was the lower bound of epirubicin dosing for TAILORx.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Eligibility criteria====
 +
*TAILORx: Oncotype DX score of 11 to 25
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
===Regimen {{#subobject:f78da8|Variant=1}}===
+
===Regimen variant #2, 500/50/500 until max anthracycline {{#subobject:24cmax|Variant=1}}===
−
Level of Evidence:
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
<span
+
!style="width: 20%"|Study
−
style="background:#00CD00;
+
!style="width: 20%"|Dates of enrollment
−
padding:3px 6px 3px 6px;
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
border-color:black;
+
!style="width: 20%"|Comparator
−
border-width:2px;
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
border-style:solid;">Phase III</span>
+
|-
−
 
+
|[https://doi.org/10.1200/JCO.1988.6.4.679 Hurteloup 1988 (FESG)]
−
*[[Vinorelbine (Navelbine)]] 24 mg/m2 IV over 5 to 10 minutes once per day on days 1, 8, 15
+
|1982-1984
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV on cycle 1 day 1, then 2 mg/kg IV on days 8 & 15 of cycle 1; then in cycles 2-3, [[Trastuzumab (Herceptin)]] is 2 mg/kg IV on days 1, 8, 15
+
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
−
 
+
|[[#FAC_2|FAC]]
−
'''21-day cycles x 3 cycles, THEN'''
+
| style="background-color:#ffffbf" |Did not meet endpoint of OS50%
−
 
+
|-
−
*[[Fluorouracil (5-FU)]] 600 mg/m2 IV day 1
+
|}
−
*[[Epirubicin (Ellence)]] 60 mg/m2 IV day 1  
+
''Note: While this was a negative study, this arm was better tolerated in the treated population and this study likely established the popularity of epirubicin-based regimens in Europe.''
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV day 1
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
'''21-day cycles x 3 cycles'''
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
 
+
</div>
−
===Monitoring===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*Cardiac function: echocardiogram at baseline, after last cycle of FEC, 12 months after completion of chemotherapy, and 36 months after completion of chemotherapy
+
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 15 cycles (maximum cumulative epirubicin dose of 720 mg/m<sup>2</sup>)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 500/60/500 x 4 {{#subobject:ea8219|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/j.ijrobp.2005.10.011 Rouëssé et al. 2006]
 +
|1994-1999
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FNC_.26_RT_999|FNC & RT]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
''Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 4 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 500/90/500 x 5 {{#subobject:djfc33|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa022794 Rodenhuis et al. 2003 (Dutch National Study)]
 +
|1993-1999
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC_2|FEC]] x 4, then [[Breast_cancer_-_historical#CTCb.2C_then_auto_HSCT|CTCb with auto HSCT]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<sup>1</sup>
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy for the Dutch National Study is based on the 2020 update.''<br>
 +
''Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 5 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, 500/100/500 x 4 ("FEC 100") {{#subobject:9cee26|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2017.03.004 Kerbrat et al. 2017 (UCBG-0106)]
 +
|2002-2006
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[#FEC_2|FEC]]; FEC 100 x 6
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS60
 +
|-
 +
|}
 +
''Note: This was an experimental arm that did not meet its primary endpoint; included here because it represents a de-escalation strategy.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 4 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #6, 500/100/500 x 6 ("FEC 100") {{#subobject:8382ec|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2001.19.3.602 Bonneterre 2001 (FASG 05)]
 +
|1990-1993
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[#FEC_2|FEC]]; FEC 50 x 6
 +
| style="background-color:#1a9850" |Superior OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359910/ Kerbrat et al. 2007 (FASG 09)]
 +
|1993-1998
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Epirubicin_.26_Vinorelbine_.28VE.29_999|VE]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|[https://doi.org/10.1200/jco.2006.07.3916 Roché et al. 2006 (FNCLCC PACS 01)]
 +
|1997-2000
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC-D_2|FEC-D]]
 +
| style="background-color:#d73027" |Inferior OS<sup>1</sup>
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2013.09.023 Delbaldo et al. 2013 (Trial B2000)]
 +
|2000-2002
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC-P|FEC-P]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdu186 Nitz et al. 2014 (WSG-AGO EC-Doc)]
 +
|2000-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#EC-D_2|EC-D]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|[https://doi.org/10.1200/jco.2009.23.0946 Spielmann et al. 2009 (FNCLCC PACS 04)]
 +
|2001-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Epirubicin_.28DE.29|ED]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<sup>2</sup>
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2017.03.004 Kerbrat et al. 2017 (UCBG-0106)]
 +
|2002-2006
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC_2|FEC]]; FEC 100 x 4
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS60
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9194919/ Geyer et al. 2022 (NSABP B-36)]
 +
|2004-05-20 to 2008-07-25
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Breast_cancer_-_historical#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]] x 4
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS<br>DFS9y: 79.4% vs 80.1%<br>(HR 1.09, 95% CI 0.92-1.29)
 +
|-
 +
|[https://doi.org/10.1007/s12032-013-0457-3 Sakr et al. 2013]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC-D_2|FEC-D]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172658/ Sparano et al. 2018 (TAILORx)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer,_ER-positive_-_null_regimens#Observation|No chemotherapy]]
 +
| style="background-color:#eeee01" |Non-inferior IDFS (primary endpoint)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7840116/ Delaloge et al. 2020 (MINDACT)]
 +
|2007-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Docetaxel_.28TX.29_999|TX]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy for FNCLCC PACS 01 is based on the 2012 update.''<br>
 +
''<sup>2</sup>Reported efficacy for FNCLCC PACS 04 is based on the 2019 update.''<br>
 +
''Note: This was the upper bound of epirubicin dosing in TAILORx.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Eligibility criteria====
 +
*TAILORx: Oncotype DX score of 11 to 25
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #7, 600/50/600 x 8 {{#subobject:85d304|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1996.14.1.35 Coombes et al. 1996]
 +
|1984-1992
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#CMF|CMF]]
 +
| style="background-color:#ffffbf" |Did not meet co-primary endpoints of RFS/OS
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2016.03.001 Coombes et al. 2016 (HMFEC)]
 +
|1992-2000
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC_2|FEC]]; FEC 75
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
''Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #8, 600/60/600 x 4 {{#subobject:32aa4a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2001.19.22.4224 van der Hage et al. 2001 (EORTC 10902)]
 +
|1991-1999
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC|FEC]]; neoadjuvant
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|}
 +
''Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 4 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #9, 600/60/600 x 6 {{#subobject:d13a49|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://academic.oup.com/jnci/article/97/23/1724/2521486 Venturini et al. 2005 (MIG-1)]
 +
|1992-1997
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Stub#ddFEC|ddFEC]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdp602 Sirohi et al. 2010 (TRAFIC)]
 +
|1995-2002
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#ECisF_999|ECisF]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 +
|-
 +
|[http://link.springer.com/article/10.1007/s10549-015-3655-1 del Mastro et al. 2015 (GONO-MIG5)]
 +
|1996-2001
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Epirubicin_.26_Paclitaxel_.28EP.29_2|EP]] x 4
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|}
 +
''Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #10, 600/60/600 x 8 {{#subobject:695f44|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2687939/ Ellis et al. 2009 (TACT)]
 +
|2001-2003
 +
|style="background-color:#1a9851"|Phase 3 (C)
 +
|[[#FEC-D_2|FEC-D]]
 +
|style="background-color:#ffffbf"|Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
''Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #11, 600/60/600 x 9 {{#subobject:cfbcd1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2007.01.009 Ejlertsen et al. 2007 (DBCG 89D)]
 +
|1990-1998
 +
|style="background-color:#1a9851"|Phase 3 (E-switch-ic)
 +
|[[#CMF|CMF]]
 +
| style="background-color:#1a9850" |Superior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 9 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #12, 600/90/600 x 6 {{#subobject:916209|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[http://jnci.oxfordjournals.org/content/100/11/805.long Martín et al. 2008 (GEICAM 9906)]
 +
|1999-2002
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC-P|FEC-P]]
 +
| style="background-color:#d73027" |Inferior DFS60
 +
|-
 +
|}
 +
''Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1  
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #13, 700/75/700 x 6 {{#subobject:31e320|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1007/s10549-009-0468-0 Polyzos et al. 2009]
 +
|1995-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#D-EC|D-EC]]
 +
| style="background-color:#fc8d59" |Seems to have inferior DFS60
 +
|-
 +
|}
 +
''Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 700 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 700 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #14, 1000/50/500 x 6 {{#subobject:caf441|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2001.19.19.3929 Paradiso et al. 2001]
 +
|1989-1994
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Breast_cancer_-_null_regimens#Observation|Observation]]
 +
| style="background-color:#91cf60" |Seems to have superior DFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #15, 1000/120/740 x 6 ("Canadian CEF (IV)") {{#subobject:97uj50|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7840116/ Delaloge et al. 2020 (MINDACT)]
 +
|2007-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Docetaxel_.28TX.29_999|TX]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
''Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Cyclophosphamide (Cytoxan)]] 370 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #16, 1000/120/1050 x 6 ("FEC 120"; "Canadian CEF") {{#subobject:978850|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.1998.16.8.2651 Levine et al. 1998 (NCIC-CTG MA.5)]
 +
|1989-1993
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
 +
|[[#CMF|CMF]]
 +
| style="background-color:#1a9850" |Superior RFS
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdi166 Coombes et al. 2005 (ICCG HDT trial)]
 +
|1993-2001
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC_2|FEC]] x 3, then HDT
 +
| style="background-color:#ffffbf" |Did not meet co-primary endpoints of RFS/EFS/OS
 +
|-
 +
|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799234/ Burnell et al. 2009 (NCIC-CTG MA.21)]
 +
|rowspan = 2|2000-2005
 +
|rowspan = 2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#AC-T_2|AC-T]]
 +
| style="background-color:#1a9850" |Superior RFS (primary endpoint)<br>RFS36: 90.1% vs 85%<br>(HR 0.67, 95% CI 0.50-0.89)
 +
|-
 +
|2. [[#ddEC-T|ddEC-T]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984804/ Janni et al. 2016 (ADEBAR)]
 +
|2001-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#EC-D_2|EC-D]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7840116/ Delaloge et al. 2020 (MINDACT)]
 +
|2007-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Docetaxel_.28TX.29_999|TX]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Cyclophosphamide (Cytoxan)]] 75 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
'''28-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
 +
===Regimen variant #17, 1200/50/1200 x 6 {{#subobject:d46835|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1996.14.1.35 Coombes et al. 1996]
 +
|1984-1992
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#CMF|CMF]]
 +
| style="background-color:#ffffbf" |Did not meet co-primary endpoints of RFS/OS
 +
|-
 +
|}
 +
''Note: This was an experimental arm that did not meet its primary endpoint; however, based on a subgroup analysis, it became a preferred regimen.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycle for 6 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. [http://www.nejm.org/doi/full/10.1056/NEJMoa053028 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16495393 PubMed]
+
# '''FESG:''' Hurteloup P; French Epirubicin Study Group. A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol. 1988 Apr;6(4):679-88. [https://doi.org/10.1200/JCO.1988.6.4.679 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/2895801/ PubMed]
 +
# Coombes RC, Bliss JM, Wils J, Morvan F, Espié M, Amadori D, Gambrosier P, Richards M, Aapro M, Villar-Grimalt A, McArdle C, Pérez-López FR, Vassilopoulos P, Ferreira EP, Chilvers CE, Coombes G, Woods EM, Marty M; International Collaborative Cancer Group. Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. J Clin Oncol. 1996 Jan;14(1):35-45. [https://doi.org/10.1200/JCO.1996.14.1.35 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8558217/ PubMed]
 +
# '''NCIC-CTG MA.5:''' Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, Findlay B, Warr D, Bowman D, Myles J, Arnold A, Vandenberg T, MacKenzie R, Robert J, Ottaway J, Burnell M, Williams CK, Tu D; National Cancer Institute of Canada Clinical Trials Group. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol. 1998 Aug;16(8):2651-8. [https://doi.org/10.1200/jco.1998.16.8.2651 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9704715/ PubMed]
 +
## '''Update:''' Levine MN, Pritchard KI, Bramwell VH, Shepherd LE, Tu D, Paul N; National Cancer Institute of Canada Clinical Trials Group. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol. 2005 Aug 1;23(22):5166-70. [https://doi.org/10.1200/JCO.2005.09.423 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16051958/ PubMed]
 +
## '''Subgroup analysis:''' Pritchard KI, Shepherd LE, O'Malley FP, Andrulis IL, Tu D, Bramwell VH, Levine MN; National Cancer Institute of Canada Clinical Trials Group. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med. 2006 May 18;354(20):2103-11. [https://doi.org/10.1056/NEJMoa054504 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16707747/ PubMed]
 +
# '''FASG 05:''' Bonneterre J; French Adjuvant Study Group. Benefit of a high-dose epirubicin regimen in adjuvant chemotherapy for node-positive breast cancer patients with poor prognostic factors: 5-year follow-up results of French Adjuvant Study Group 05 randomized trial. J Clin Oncol. 2001 Feb 1;19(3):602-11. [https://doi.org/10.1200/JCO.2001.19.3.602 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/11157009/ PubMed]
 +
## '''Update:''' Bonneterre J, Roché H, Kerbrat P, Brémond A, Fumoleau P, Namer M, Goudier MJ, Schraub S, Fargeot P, Chapelle-Marcillac I. Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol. 2005 Apr 20;23(12):2686-93. [https://doi.org/10.1200/JCO.2005.05.059 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15837983/ PubMed]
 +
# Paradiso A, Schittulli F, Cellamare G, Mangia A, Marzullo F, Lorusso V, De Lena M. Randomized clinical trial of adjuvant fluorouracil, epirubicin, and cyclophosphamide chemotherapy for patients with fast-proliferating, node-negative breast cancer. J Clin Oncol. 2001 Oct 1;19(19):3929-37. [https://doi.org/10.1200/JCO.2001.19.19.3929 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11579113/ PubMed]
 +
# '''EORTC 10902:''' van der Hage JA, van de Velde CJ, Julien JP, Tubiana-Hulin M, Vandervelden C, Duchateau L. Preoperative chemotherapy in primary operable breast cancer: results from the European Organisation for Research and Treatment of Cancer trial 10902. J Clin Oncol. 2001 Nov 15;19(22):4224-37. [https://doi.org/10.1200/JCO.2001.19.22.4224 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11709566/ PubMed]
 +
## '''Update:''' van Nes JG, Putter H, Julien JP, Tubiana-Hulin M, van de Vijver M, Bogaerts J, de Vos M, van de Velde CJ; Cooperating Investigators of the EORTC. Preoperative chemotherapy is safe in early breast cancer, even after 10 years of follow-up; clinical and translational results from the EORTC trial 10902. Breast Cancer Res Treat. 2009 May;115(1):101-13. Epub 2008 May 18. [https://doi.org/10.1007/s10549-008-0050-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18484198/ PubMed]
 +
# '''FASG 01:''' Fumoleau P, Kerbrat P, Romestaing P, Fargeot P, Brémond A, Namer M, Schraub S, Goudier MJ, Mihura J, Monnier A, Clavère P, Serin D, Seffert P, Pourny C, Facchini T, Jacquin JP, Sztermer JF, Datchary J, Ramos R, Luporsi E. Randomized trial comparing six versus three cycles of epirubicin-based adjuvant chemotherapy in premenopausal, node-positive breast cancer patients: 10-year follow-up results of the French Adjuvant Study Group 01 trial. J Clin Oncol. 2003 Jan 15;21(2):298-305. [https://doi.org/10.1200/JCO.2003.04.148 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12525522/ PubMed]
 +
# '''Dutch National Study:''' Rodenhuis S, Bontenbal M, Beex LV, Wagstaff J, Richel DJ, Nooij MA, Voest EE, Hupperets P, van Tinteren H, Peterse HL, TenVergert EM, de Vries EG; Netherlands Working Party on Autologous Transplantation in Solid Tumors. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med. 2003 Jul 3;349(1):7-16. [https://doi.org/10.1056/NEJMoa022794 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12840087/ PubMed] [https://clinicaltrials.gov/study/NCT03087409 NCT03087409]
 +
## '''Update:''' Rodenhuis S, Bontenbal M, van Hoesel QG, Smit WM, Nooij MA, Voest EE, van der Wall E, Hupperets P, van Tinteren H, Peterse JL, van de Vijver MJ, de Vries EG; Netherlands Working Party on Autologous Transplantation in Solid Tumours. Efficacy of high-dose alkylating chemotherapy in HER2/neu-negative breast cancer. Ann Oncol. 2006 Apr;17(4):588-96. Epub 2006 Jan 30. [https://doi.org/10.1093/annonc/mdl001 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16446318/ PubMed]
 +
## '''Update:''' Steenbruggen TG, Steggink LC, Seynaeve CM, van der Hoeven JJM, Hooning MJ, Jager A, Konings IR, Kroep JR, Smit WM, Tjan-Heijnen VCG, van der Wall E, Bins AD, Linn SC, Schaapveld M, Jacobse JN, van Leeuwen FE, Schröder CP, van Tinteren H, de Vries EGE, Sonke GS, Gietema JA. High-Dose Chemotherapy With Hematopoietic Stem Cell Transplant in Patients With High-Risk Breast Cancer and 4 or More Involved Axillary Lymph Nodes: 20-Year Follow-up of a Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Apr 1;6(4):528-534. [https://doi.org/10.1001/jamaoncol.2019.6276 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7042796/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31999296/ PubMed]
 +
# Arriagada R, Spielmann M, Koscielny S, Le Chevalier T, Delozier T, Rémé-Saumon M, Ducourtieux M, Tursz T, Hill C. Results of two randomized trials evaluating adjuvant anthracycline-based chemotherapy in 1146 patients with early breast cancer. Acta Oncol. 2005;44(5):458-66. [https://doi.org/10.1080/02841860510029987 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16118079/ PubMed]
 +
# '''ICCG HDT trial:''' Coombes RC, Howell A, Emson M, Peckitt C, Gallagher C, Bengala C, Tres A, Welch R, Lawton P, Rubens R, Woods E, Haviland J, Vigushin D, Kanfer E, Bliss JM. High dose chemotherapy and autologous stem cell transplantation as adjuvant therapy for primary breast cancer patients with four or more lymph nodes involved: long-term results of an international randomised trial. Ann Oncol. 2005 May;16(5):726-34. Epub 2005 Apr 7. [https://doi.org/10.1093/annonc/mdi166 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15817602/ PubMed]
 +
# '''MIG-1:''' Venturini M, Del Mastro L, Aitini E, Baldini E, Caroti C, Contu A, Testore F, Brema F, Pronzato P, Cavazzini G, Sertoli MR, Canavese G, Rosso R, Bruzzi P; Mammella InterGruppo. Dose-dense adjuvant chemotherapy in early breast cancer patients: results from a randomized trial. J Natl Cancer Inst. 2005 Dec 7;97(23):1724-33. [https://academic.oup.com/jnci/article/97/23/1724/2521486 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16333028/ PubMed]
 +
## '''Update:''' Blondeaux E, Lambertini M, Michelotti A, Conte B, Benasso M, Dellepiane C, Bighin C, Pastorino S, Levaggi A, Alonzo A, Poggio F, Buzzatti G, Molinelli C, Fregatti P, Bertoglio S, Boccardo F, Del Mastro L. Dose-dense adjuvant chemotherapy in early breast cancer patients: 15-year results of the Phase 3 Mammella InterGruppo (MIG)-1 study. Br J Cancer. 2020 May;122(11):1611-1617. Epub 2020 Mar 31. [https://doi.org/10.1038/s41416-020-0816-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7251109/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32231293/ PubMed]
 +
# '''FASG 06:''' Roché H, Kerbrat P, Bonneterre J, Fargeot P, Fumoleau P, Monnier A, Clavère P, Goudier MJ, Chollet P, Guastalla JP, Serin D. Complete hormonal blockade versus epirubicin-based chemotherapy in premenopausal, one to three node-positive, and hormone-receptor positive, early breast cancer patients: 7-year follow-up results of French Adjuvant Study Group 06 randomised trial. Ann Oncol. 2006 Aug;17(8):1221-7. Epub 2006 May 26. [https://doi.org/10.1093/annonc/mdl107 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16731539/ PubMed]
 +
# '''FASG 03:''' Héry M, Bonneterre J, Roché H, Luporsi E, Kerbrat P, Namer M, Fumoleau P, Monnier A, Fargeot P. Epirubicin-based chemotherapy as adjuvant treatment for poor prognosis, node-negative breast cancer: 10-year follow-up results of the French Adjuvant Study Group 03 trial. Bull Cancer. 2006 Oct;93(10):E109-14. [http://www.jle.com/fr/revues/bdc/e-docs/epirubicin_based_chemotherapy_as_adjuvant_treatment_for_poor_prognosis_node_negative_breast_cancer_10_year_follow_up_results__272048/article.phtml link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/17074656/ PubMed]
 +
# Rouëssé J, de la Lande B, Bertheault-Cvitkovic F, Serin D, Graïc Y, Combe M, Leduc B, Lucas V, Demange L, Nguyen TD, Castèra D, Krzisch C, Villet R, Mouret-Fourme E, Garbay JR, Noguès C; Centre René Huguenin Breast Cancer Group. A phase III randomized trial comparing adjuvant concomitant chemoradiotherapy versus standard adjuvant chemotherapy followed by radiotherapy in operable node-positive breast cancer: final results. Int J Radiat Oncol Biol Phys. 2006 Mar 15;64(4):1072-80. [https://doi.org/10.1016/j.ijrobp.2005.10.011 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16504757/ PubMed]
 +
<!-- Presented in oral format at the 27th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004. -->
 +
# '''FNCLCC PACS 01:''' Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulié P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Genève J, Asselain B. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006 Dec 20;24(36):5664-71. Epub 2006 Nov 20. [https://doi.org/10.1200/jco.2006.07.3916 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17116941/ PubMed]
 +
## '''Update:''' Coudert B, Asselain B, Campone M, Spielmann M, Machiels JP, Pénault-Llorca F, Serin D, Lévy C, Romieu G, Canon JL, Orfeuvre H, Piot G, Petit T, Jerusalem G, Audhuy B, Veyret C, Beauduin M, Eymard JC, Martin AL, Roché H; UNICANCER Breast Group. Extended benefit from sequential administration of docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide regimen for node-positive breast cancer: the 8-year follow-up results of the UNICANCER-PACS01 trial. Oncologist. 2012;17(7):900-9. Epub 2012 May 18. [https://doi.org/10.1634/theoncologist.2011-0442 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399644/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22610153/ PubMed]
 +
# '''DBCG 89D:''' Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Cold S, Edlund P, Ewertz M, Jensen BB, Kamby C, Nordenskjold B, Bergh J. Improved outcome from substituting methotrexate with epirubicin: results from a randomised comparison of CMF versus CEF in patients with primary breast cancer. Eur J Cancer. 2007 Mar;43(5):877-84. Epub 2007 Feb 16. [https://doi.org/10.1016/j.ejca.2007.01.009 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17306974/ PubMed]
 +
# '''FASG 09:''' Kerbrat P, Roché H, Bonneterre J, Veyret C, Lortholary A, Monnier A, Fumoleau P, Fargeot P, Namer M, Chollet P, Goudier MJ, Audhuy B, Simon H, Montcuquet P, Eymard JC, Walter S, Clavère P, Guastalla JP; French Adjuvant Study Group. Epirubicin-vinorelbine vs FEC100 for node-positive, early breast cancer: French Adjuvant Study Group 09 trial. Br J Cancer. 2007 Jun 4;96(11):1633-8. Epub 2007 May 15. [https://doi.org/10.1038/sj.bjc.6603773 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2359910/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/17505516/ PubMed]
 +
# '''GEICAM 9906:''' Martín M, Rodríguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Munárriz B, Rodríguez CA, Crespo C, de Alava E, López García-Asenjo JA, Guitián MD, Almenar S, González-Palacios JF, Vera F, Palacios J, Ramos M, Gracia Marco JM, Lluch A, Alvarez I, Seguí MA, Mayordomo JI, Antón A, Baena JM, Plazaola A, Modolell A, Pelegrí A, Mel JR, Aranda E, Adrover E, Alvarez JV, García Puche JL, Sánchez-Rovira P, Gonzalez S, López-Vega JM; GEICAM. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst. 2008 Jun 4;100(11):805-14. Epub 2008 May 27. [http://jnci.oxfordjournals.org/content/100/11/805.long link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18505968/ PubMed] [https://clinicaltrials.gov/study/NCT00129922 NCT00129922]
 +
# '''TACT:''' Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. [https://doi.org/10.1016/S0140-6736(09)60740-6 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2687939/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19447249/ PubMed] ISRCTN79718493
 +
# Polyzos A, Malamos N, Boukovinas I, Adamou A, Ziras N, Kalbakis K, Kakolyris S, Syrigos K, Papakotoulas P, Kouroussis C, Karvounis N, Vamvakas L, Christophyllakis C, Athanasiadis A, Varthalitis I, Georgoulias V, Mavroudis D; Hellenic Oncology Research Group. FEC versus sequential docetaxel followed by epirubicin/cyclophosphamide as adjuvant chemotherapy in women with axillary node-positive early breast cancer: a randomized study of the Hellenic Oncology Research Group (HORG). Breast Cancer Res Treat. 2010 Jan;119(1):95-104. Epub 2009 Jul 28. [https://doi.org/10.1007/s10549-009-0468-0 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19636702/ PubMed]
 +
# '''NCIC-CTG MA.21:''' Burnell M, Levine MN, Chapman JA, Bramwell V, Gelmon K, Walley B, Vandenberg T, Chalchal H, Albain KS, Perez EA, Rugo H, Pritchard K, O'Brien P, Shepherd LE. Cyclophosphamide, epirubicin, and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol. 2010 Jan 1;28(1):77-82. Epub 2009 Nov 9. [https://doi.org/10.1200/JCO.2009.22.1077 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799234/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19901117/ PubMed] [https://clinicaltrials.gov/study/NCT00014222 NCT00014222]
 +
# '''FNCLCC PACS 04:''' Spielmann M, Roché H, Delozier T, Canon JL, Romieu G, Bourgeois H, Extra JM, Serin D, Kerbrat P, Machiels JP, Lortholary A, Orfeuvre H, Campone M, Hardy-Bessard AC, Coudert B, Maerevoet M, Piot G, Kramar A, Martin AL, Penault-Llorca F. Trastuzumab for patients with axillary-node-positive breast cancer: results of the FNCLCC-PACS 04 trial. J Clin Oncol. 2009 Dec 20;27(36):6129-34. Epub 2009 Nov 16. [https://doi.org/10.1200/jco.2009.23.0946 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19917839/ PubMed] [https://clinicaltrials.gov/study/NCT00054587 NCT00054587]
 +
## '''Update:''' D'Hondt V, Canon JL, Roca L, Levy C, Pierga JY, Le Du F, Campone M, Desmoulins I, Goncalves A, Debled M, Rios M, Ferrero JM, Serin D, Hardy-Bessard AC, Piot G, Brain E, Dohollou N, Orfeuvre H, Lemonnier J, Roché H, Delaloge S, Dalenc F. UCBG 2-04: Long-term results of the PACS 04 trial evaluating adjuvant epirubicin plus docetaxel in node-positive breast cancer and trastuzumab in the human epidermal growth factor receptor 2-positive subgroup. Eur J Cancer. 2019 Nov;122:91-100. Epub 2019 Oct 18. [https://doi.org/10.1016/j.ejca.2019.09.014 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31634648/ PubMed]
 +
# '''TRAFIC:''' Sirohi B, A'Hern R, Coombes G, Bliss JM, Hickish T, Perren T, Crawford M, O'Brien M, Iveson T, Ebbs S, Skene A, Laing R, Smith IE. A randomised comparative trial of infusional ECisF versus conventional FEC as adjuvant chemotherapy in early breast cancer: the TRAFIC trial. Ann Oncol. 2010 Aug;21(8):1623-9. Epub 2010 Jan 21. [https://doi.org/10.1093/annonc/mdp602 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/20093351/ PubMed] ISRCTN83324925
 +
# Sakr H, Hamed RH, Anter AH, Yossef T. Sequential docetaxel as adjuvant chemotherapy for node-positive or/and T3 or T4 breast cancer: clinical outcome (Mansoura University). Med Oncol. 2013 Mar;30(1):457. Epub 2013 Jan 16. [https://doi.org/10.1007/s12032-013-0457-3 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23322524/ PubMed]
 +
# '''AERO-B2000:''' Delbaldo C, Serin D, Mousseau M, Greget S, Audhuy B, Priou F, Berdah JF, Teissier E, Laplaige P, Zelek L, Quinaux E, Buyse M, Piedbois P; Association Européenne de Recherche en Oncologie (AERO). A phase III adjuvant randomised trial of 6 cycles of 5-fluorouracil-epirubicine-cyclophosphamide (FEC100) versus 4 FEC 100 followed by 4 Taxol (FEC-T) in node positive breast cancer patients (Trial B2000). Eur J Cancer. 2014 Jan;50(1):23-30. Epub 2013 Oct 29. [https://doi.org/10.1016/j.ejca.2013.09.023 link to original article] [https://pubmed.ncbi.nlm.nih.gov/24183460/ PubMed]
 +
# '''WSG-AGO EC-Doc:''' Nitz U, Gluz O, Huober J, Kreipe HH, Kates RE, Hartmann A, Erber R, Moustafa Z, Scholz M, Lisboa B, Mohrmann S, Möbus V, Augustin D, Hoffmann G, Weiss E, Böhmer S, Kreienberg R, Du Bois A, Sattler D, Thomssen C, Kiechle M, Jänicke F, Wallwiener D, Harbeck N, Kuhn W. Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression. Ann Oncol. 2014 Aug;25(8):1551-7. Epub 2014 May 14. Erratum in: Ann Oncol. 2017 Nov 1;28(11):2899. [https://doi.org/10.1093/annonc/mdu186 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24827128/ PubMed] [https://clinicaltrials.gov/study/NCT02115204 NCT02115204]
 +
# '''GIM2:''' Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 x 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. [https://doi.org/10.1016/s0140-6736(14)62048-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25740286/ PubMed] [https://clinicaltrials.gov/study/NCT00433420 NCT00433420]
 +
##'''Update:''' Del Mastro L, Poggio F, Blondeaux E, De Placido S, Giuliano M, Forestieri V, De Laurentiis M, Gravina A, Bisagni G, Rimanti A, Turletti A, Nisticò C, Vaccaro A, Cognetti F, Fabi A, Gasparro S, Garrone O, Alicicco MG, Urracci Y, Mansutti M, Poletti P, Correale P, Bighin C, Puglisi F, Montemurro F, Colantuoni G, Lambertini M, Boni L; Gruppo Italiano Mammella Investigators. Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial. Lancet Oncol. 2022 Dec;23(12):1571-1582. Epub 2022 Nov 10. [https://doi.org/10.1016/s1470-2045(22)00632-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/36370716/ PubMed]
 +
# '''GONO-MIG5:''' Del Mastro L, Levaggi A, Michelotti A, Cavazzini G, Adami F, Scotto T, Piras M, Danese S, Garrone O, Durando A, Accortanzo V, Bighin C, Miglietta L, Pastorino S, Pronzato P, Castiglione F, Landucci E, Conte P, Bruzzi P. 5-Fluorouracil, epirubicin and cyclophosphamide versus epirubicin and paclitaxel in node-positive early breast cancer: a phase-III randomized GONO-MIG5 trial. Breast Cancer Res Treat. 2016 Jan;155(1):117-26. Epub 2015 Dec 10. [http://link.springer.com/article/10.1007/s10549-015-3655-1 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26661403/ PubMed] [https://clinicaltrials.gov/study/NCT02450058 NCT02450058]
 +
# '''ADEBAR:''' Janni W, Harbeck N, Rack B, Augustin D, Jueckstock J, Wischnik A, Annecke K, Scholz C, Huober J, Zwingers T, Friedl TW, Kiechle M. Randomised phase III trial of FEC120 vs EC-docetaxel in patients with high-risk node-positive primary breast cancer: final survival analysis of the ADEBAR study. Br J Cancer. 2016 Apr 12;114(8):863-71. Epub 2016 Mar 31. [https://www.nature.com/articles/bjc201682 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4984804/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27031854/ PubMed] [https://clinicaltrials.gov/study/NCT00047099 NCT00047099]
 +
# '''HMFEC:''' Coombes RC, Kilburn LS, Tubiana-Mathieu N, Olmos T, Van Bochove A, Perez-Lopez FR, Palmieri C, Stebbing J, Bliss JM. Epirubicin dose and sequential hormonal therapy-Mature results of the HMFEC randomised phase III trial in premenopausal patients with node positive early breast cancer. Eur J Cancer. 2016 Jun;60:146-53. Epub 2016 Apr 26. [https://doi.org/10.1016/j.ejca.2016.03.001 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27125966/ PubMed] ISRCTN98335268
 +
# '''UCBG-0106:''' Kerbrat P, Desmoulins I, Roca L, Levy C, Lortholary A, Marre A, Delva R, Rios M, Viens P, Brain É, Serin D, Edel M, Debled M, Campone M, Mourret-Reynier MA, Bachelot T, Foucher-Goudier MJ, Asselain B, Lemonnier J, Martin AL, Roché H. Optimal duration of adjuvant chemotherapy for high-risk node-negative (N-) breast cancer patients: 6-year results of the prospective randomised multicentre phase III UNICANCER-PACS 05 trial (UCBG-0106). Eur J Cancer. 2017 Jul;79:166-175. Epub 2017 May 11. [https://doi.org/10.1016/j.ejca.2017.03.004 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28501763/ PubMed]
 +
# '''TAILORx:''' Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. [https://doi.org/10.1056/NEJMoa1804710 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172658/ link to PMC article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/29860917/ PubMed] [https://clinicaltrials.gov/study/NCT00310180 NCT00310180]
 +
# '''MINDACT:''' Delaloge S, Piccart M, Rutgers E, Litière S, van 't Veer LJ, van den Berkmortel F, Brain E, Dudek-Peric A, Gil-Gil M, Gomez P, Hilbers FS, Khalil Z, Knox S, Kuemmel S, Kunz G, Lesur A, Pierga JY, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Thompson AM, Viale G, Zoppoli G, Vuylsteke P, Tryfonidis K, Poncet C, Bogaerts J, Cardoso F; MINDACT investigators and the TRANSBIG Consortium. Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial. J Clin Oncol. 2020 Apr 10;38(11):1186-1197. Epub 2020 Feb 21. [https://doi.org/10.1200/jco.19.01371 link to original article] '''contains dosing details in supplement''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7840116/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/32083990/ PubMed] [https://clinicaltrials.gov/study/NCT00433589 NCT00433589]
 +
#'''NSABP B-36:''' Geyer CE Jr, Bandos H, Rastogi P, Jacobs SA, Robidoux A, Fehrenbacher L, Ward PJ, Polikoff J, Brufsky AM, Provencher L, Paterson AHG, Hamm JT, Carolla RL, Baez-Diaz L, Julian TB, Swain SM, Mamounas EP, Wolmark N. Definitive results of a phase III adjuvant trial comparing six cycles of FEC-100 to four cycles of AC in women with operable node-negative breast cancer: the NSABP B-36 trial (NRG Oncology). Breast Cancer Res Treat. 2022 Jun;193(3):555-564. Epub 2022 Mar 1. Erratum in: Breast Cancer Res Treat. 2022 May 4. [https://doi.org/10.1007/s10549-021-06417-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc9194919/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35230585/ PubMed] [https://clinicaltrials.gov/study/NCT00087178 NCT00087178]
  
−
==AC -> TH (Taxotere) {{#subobject:e4e048|Regimen=1}}==
+
==MMM {{#subobject:5q18xa|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
MMM: '''<u>M</u>'''itomycin-C, '''<u>M</u>'''itoxantrone, '''<u>M</u>'''ethotrexate
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:8hgy1b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7005671/ Fernando et al. 2019 (SECRAB)]
 +
|1998-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#CMF_.26_RT_888|CMF & RT]]<br>1b. [[#E-CMF_.26_RT_888|E-CMF & RT]]<br>1c. [[#A-CMF_.26_RT_888|A-CMF & RT]]<br>1d. [[#MMM_.26_RT_888|MMM & RT]]
 +
| style="background-color:#d73027" |Inferior LRFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
AC -> TH: '''<u>A</u>'''driamycin, '''<u>C</u>'''ytoxan -> '''<u>T</u>'''axotere, '''<u>H</u>'''erceptin
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
===Regimen {{#subobject:38200a|Variant=1}}===
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
Level of Evidence:
+
</div>
−
<span
+
<div class="toccolours" style="background-color:#b3e2cd">
−
style="background:#00CD00;
+
====Chemotherapy====
−
padding:3px 6px 3px 6px;
+
*[[Mitomycin (Mutamycin)]] 8 mg/m<sup>2</sup> IV once on day 1
−
border-color:black;
+
*[[Mitoxantrone (Novantrone)]] 8 mg/m<sup>2</sup> IV once on day 1
−
border-width:2px;
+
*[[Methotrexate (MTX)]] 35 mg/m<sup>2</sup> IV once on day 1
−
border-style:solid;">Phase III</span>
+
'''21-day cycle for 6 cycles'''
−
 
+
</div></div>
−
*[[Doxorubicin (Adriamycin)]] 60 mg/m2 IV day 1
 
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV day 1
 
−
 
 
−
'''21-day cycles x 4 cycles, THEN'''
 
−
 
 
−
*[[Docetaxel (Taxotere)]] 100 mg/m2 IV day 1
 
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV on cycle 1 day 1, then 2 mg/kg IV on days 8 & 15 of cycle 1; then in cycles 2-4, [[Trastuzumab (Herceptin)]] is 2 mg/kg IV on days 1, 8, 15
 
−
 
 
−
'''21-day cycles x 4 cycles, THEN'''
 
−
 
 
−
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV day 1
 
−
 
 
−
'''3-week cycles x 14 additional cycles/weeks to complete a total of 52 weeks of therapy'''
 
−
 
 
−
===Monitoring===
 
−
*Cardiac function: echocardiogram at baseline, then every 3 months while on Trastuzumab (Herceptin)
 
−
 
 
 
===References===
 
===References===
−
# Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. [http://www.nejm.org/doi/full/10.1056/NEJMoa053028 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16495393 PubMed]
+
# '''SECRAB:''' Fernando IN, Bowden SJ, Herring K, Brookes CL, Ahmed I, Marshall A, Grieve R, Churn M, Spooner D, Latief TN, Agrawal RK, Brunt AM, Stevens A, Goodman A, Canney P, Bishop J, Ritchie D, Dunn J, Poole CJ, Rea DW; SECRAB Investigators. Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial. Radiother Oncol. 2020 Jan;142:52-61. Epub 2019 Nov 27. [https://doi.org/10.1016/j.radonc.2019.10.014 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc7005671/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31785830/ PubMed] [https://clinicaltrials.gov/study/NCT00003893 NCT00003893]
−
 
+
==Paclitaxel monotherapy, weekly {{#subobject:5218a|Regimen=1}}==
−
==Neoadjuvant Pertuzumab (Perjeta), Trastuzumab (Herceptin), Docetaxel (Taxotere) -> FEC & H (NeoSphere) {{#subobject:24b376|Regimen=1}}==
+
T: '''<u>T</u>'''axol (Paclitaxel)
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<br>P: '''<u>P</u>'''aclitaxel
 +
<br>pT: '''<u>p</u>'''acli'''<u>T</u>'''axel
 +
<br>wP: '''<u>w</u>'''eekly '''<u>P</u>'''aclitaxel
 +
<br>wT: '''<u>w</u>'''eekly '''<u>T</u>'''axol (Paclitaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:6b14dd|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="3" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494835/ Shulman et al. 2012 (CALGB 40101)]
 +
| rowspan="3" |2002-2008
 +
| rowspan="3" style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|1. [[Breast_cancer_-_historical#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]] x 4
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 +
|-
 +
|2. [[Breast_cancer_-_historical#Cyclophosphamide_.26_Doxorubicin_.28AC.29|AC]] x 6
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 +
|-
 +
|3. [[#Paclitaxel_monotherapy.2C_weekly|Paclitaxel]]; weekly x 18
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:3f1974|Variant=1}}===
+
''Note: In CALGB 40101, this is the dosing before a mid-protocol amendment in 2003. This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
−
Level of Evidence:
+
<div class="toccolours" style="background-color:#b3e2cd">
−
<span
+
====Chemotherapy====
−
style="background:#00CD00;
+
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV over 60 minutes once on day 1
−
padding:3px 6px 3px 6px;
+
'''7-day cycle for 12 cycles'''
−
border-color:black;
+
</div></div>
−
border-width:2px;
 
−
border-style:solid;">Randomized Phase II, >20 per arm</span>
 
−
 
 
−
Neoadjuvant:
 
−
*[[Pertuzumab (Perjeta)]] 840 mg IV on cycle 1 day 1, then on subsequent cycles [[Pertuzumab (Perjeta)]] is 420 mg IV on day 1
 
−
*[[Trastuzumab (Herceptin)]] 8 mg/kg IV on cycle 1 day 1, then on subsequent cycles [[Trastuzumab (Herceptin)]] is 6 mg/kg IV on day 1
 
−
*[[Docetaxel (Taxotere)]] 75 mg/m2 IV on day 1
 
−
**Based on tolerability, investigators could increase dose of [[Docetaxel (Taxotere)]] to 100 mg/m2 IV on day 1
 
−
 
 
−
'''21-day cycles x 4 cycles, then surgery'''
 
−
 
 
−
Adjuvant FEC & H:
 
−
*[[Fluorouracil (5-FU)]] 600 mg/m2 IV on day 1
 
−
*[[Epirubicin (Ellence)]] 90 mg/m2 IV on day 1
 
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV on day 1
 
−
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV on day 1
 
−
 
 
−
'''21-day cycles x 3 cycles, then'''
 
−
 
 
−
Additional Trastuzumab (Herceptin) +/- radiation and/or hormone therapy:
 
−
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV on day 1
 
−
*Radiation therapy and/or hormone therapy for ER positive patients is given "per local guidelines"
 
−
 
 
−
'''21-day cycles, to complete 1 year of total therapy with Trastuzumab (Herceptin)'''
 
−
 
 
 
===References===
 
===References===
−
# Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Jan;13(1):25-32. Epub 2011 Dec 6. [http://www.sciencedirect.com/science/article/pii/S1470204511703369 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22153890 PubMed]
+
# '''CALGB 40101:''' Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. [https://doi.org/10.1200/jco.2011.40.6405 link to original article] '''contains dosing details in manuscript''' [https://ascopubs.org/doi/suppl/10.1200/jco.2011.40.6405/suppl_file/Protocol.pdf link to study protocol PDF] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494835/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22826271/ PubMed] [https://clinicaltrials.gov/study/NCT00041119 NCT00041119]
−
 
+
## '''Update:''' Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. Epub 2014 Jun 16. [https://doi.org/10.1200/jco.2013.53.7142 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105484/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24934787/ PubMed]
−
==Neoadjuvant TCHP (TRYPHAENA) {{#subobject:24b376|Regimen=1}}==
+
==Paclitaxel monotherapy, dose-dense (q2wk) {{#subobject:8acb30|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
ddT: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>T</u>'''axol (Paclitaxel)
 +
<br>ddP: '''<u>d</u>'''ose-'''<u>d</u>'''ense '''<u>P</u>'''aclitaxel
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:d853ac|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="3" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494835/ Shulman et al. 2012 (CALGB 40101)]
 +
| rowspan="3" |2002-2008
 +
| rowspan="3" style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|1. [[#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29_2|ddAC]] x 4
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 +
|-
 +
|2. [[#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29_2|ddAC]] x 6
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 +
|-
 +
|3. [[#Paclitaxel_monotherapy.2C_dose-dense_.28q2wk.29_2|ddT]] x 6
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of RFS
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.02.8621 Burstein et al. 2005]
 +
|2003-2004
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen Schneeweiss et al. 2013 Arm C {{#subobject:3f1974|Variant=1}}===
+
''Note: in CALGB 40101, this is the dosing after a mid-protocol amendment in 2003.''
−
Level of Evidence:
+
<div class="toccolours" style="background-color:#cbd5e8">
−
<span
+
====Preceding treatment====
−
style="background:#00CD00;
+
*Burstein et al. 2005: Neoadjuvant [[#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29|ddAC]], then [[Surgery#Breast_cancer_surgery|surgery]] or [[Surgery#Breast_cancer_surgery|surgery]], then adjuvant [[#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29_2|ddAC]]
−
padding:3px 6px 3px 6px;
+
*CALGB 40101: [[Surgery#Breast_cancer_surgery|Surgery]], within 90 days
−
border-color:black;
+
</div>
−
border-width:2px;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
border-style:solid;">Randomized Phase II, >20 per arm</span>
+
====Chemotherapy====
−
 
+
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
−
Neoadjuvant:
+
====Supportive therapy====
−
*[[Docetaxel (Taxotere)]] 75 mg/m2 IV on day 1
+
*[[Diphenhydramine (Benadryl)]] 12.5 to 50 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
−
*[[Carboplatin (Paraplatin)]] AUC 6 IV on day 1
+
*One of the following H2 blockers:
−
*[[Trastuzumab (Herceptin)]] 8 mg/kg IV on cycle 1 day 1, then on subsequent cycles [[Trastuzumab (Herceptin)]] is 6 mg/kg IV on day 1
+
**[[Ranitidine (Zantac)]] 50 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
−
*[[Pertuzumab (Perjeta)]] 840 mg IV on cycle 1 day 1, then on subsequent cycles [[Pertuzumab (Perjeta)]] is 420 mg IV on day 1
+
**[[Cimetidine (Tagamet)]] 300 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
−
**No dose escalation of [[Docetaxel (Taxotere)]] in this arm
+
**[[Famotidine (Pepcid)]] 20 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
−
 
+
*One of the following dexamethasone choices:
−
'''21-day cycles x 6 cycles, then surgery'''
+
**[[Dexamethasone (Decadron)]] 10 mg IV once on day 1, within 60 minutes prior to paclitaxel
−
 
+
**[[Dexamethasone (Decadron)]] 10 mg PO once on day 1, at least 60 minutes prior to paclitaxel
−
Additional Trastuzumab (Herceptin) +/- radiation and/or hormone therapy:
+
**[[Dexamethasone (Decadron)]] 20 mg PO twice on day 1; 6 hours and 12 hours prior to paclitaxel
−
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV on day 1
+
*Recommended growth factor support with one of the following:
−
*Radiation therapy and/or hormone therapy for ER positive patients is given "per local guidelines"
+
**[[Filgrastim (Neupogen)]] 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
−
 
+
**[[Sargramostim (Leukine)]] 250 to 500 mcg/m<sup>2</sup> SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
−
'''21-day cycles, to complete 1 year of total therapy with Trastuzumab (Herceptin)'''
+
**[[Pegfilgrastim (Neulasta)]] 6 mg SC once, given 24 to 36 hours after chemotherapy
−
 
+
'''14-day cycle for 4 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortés J. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013 Sep;24(9):2278-84. [http://annonc.oxfordjournals.org/content/24/9/2278.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/23704196 PubMed]
+
# Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. [https://doi.org/10.1200/jco.2005.02.8621 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16293865/ PubMed]
 +
# '''CALGB 40101:''' Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. [https://doi.org/10.1200/jco.2011.40.6405 link to original article] '''contains dosing details in manuscript''' [https://ascopubs.org/doi/suppl/10.1200/jco.2011.40.6405/suppl_file/Protocol.pdf link to study protocol PDF] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3494835/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22826271/ PubMed] [https://clinicaltrials.gov/study/NCT00041119 NCT00041119]
 +
## '''Update:''' Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. Epub 2014 Jun 16. [https://doi.org/10.1200/jco.2013.53.7142 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105484/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24934787/ PubMed]
  
−
==Neoadjuvant weekly TH (Taxol) -> FEC & H {{#subobject:feab4a|Regimen=1}}==
+
==TAC (Docetaxel) {{#subobject:ed77a6|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
TAC: '''<u>T</u>'''axotere (Docetaxel), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide
 +
<br>ACT: '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''axotere (Docetaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 4 cycles {{#subobject:36e78d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935316/ Swain et al. 2010 (NSABP B-30)]
 +
|rowspan=2|1999-2004
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#AC-D_2|AC-D]]
 +
| style="background-color:#fee08b" |Might have inferior OS
 +
|-
 +
|2. [[#Docetaxel_.26_Doxorubicin_.28AT.29_999|AT]]
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172658/ Sparano et al. 2018 (TAILORx)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer,_ER-positive_-_null_regimens#Observation|No chemotherapy]]
 +
| style="background-color:#eeee01" |Non-inferior IDFS (primary endpoint)
 +
|-
 +
|}
 +
''Note: this was a mid-protocol dosing amendment for NSABP B-30. This was the lower bound of cycles in TAILORx.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Eligibility criteria====
 +
*TAILORx: Oncotype DX score of 11 to 25
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e8">
 +
====Preceding treatment====
 +
*[[Surgery#Breast_cancer_surgery|Surgery]]
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV over 15 minutes once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV over 1 to 5 minutes once on day 1
 +
'''21-day cycle for 4 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 6 cycles {{#subobject:9660e9|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa043681 Martin et al. 2005 (BCIRG 001)]
 +
|1997-1999
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
 +
|[[#FAC_2|FAC]]
 +
| style="background-color:#1a9850" |Superior OS<sup>1</sup> (secondary endpoint)<br>OS120: 76% vs 69%<br>(HR 0.74, 95% CI 0.61-0.90)<br><br>Superior DFS (primary endpoint)<br>DFS60: 75% vs 68%
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa0910320 Martín et al. 2010 (GEICAM 9805)]
 +
|1999-2003
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#FAC_2|FAC]]
 +
| style="background-color:#1a9850" |Superior DFS (primary endpoint)<br>(HR 0.68, 95% CI 0.49-0.93)
 +
|-
 +
|[https://doi.org/10.1200/jco.2010.28.5437 Eiermann et al. 2011 (BCIRG-005)]
 +
|2000-2003
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#AC-D_2|AC-D]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS60
 +
|-
 +
| rowspan="2" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757290/ Swain et al. 2013 (NSABP B-38)]
 +
| rowspan="2" |2004-2007
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#ddAC-ddT|ddAC-ddT]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|2. [[#ddAC-ddPG_999|ddAC-ddPG]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2018.07.013 van Rossum et al. 2018 (MATADOR)]
 +
|2004-2012
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Dose-dense_Cyclophosphamide_.26_Doxorubicin_.28ddAC.29_2|ddAC]]
 +
| style="background-color:#ffffbf" |Did not meet secondary endpoints of RFS/OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172658/ Sparano et al. 2018 (TAILORx)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer,_ER-positive_-_null_regimens#Observation|No chemotherapy]]
 +
| style="background-color:#eeee01" |Non-inferior IDFS (primary endpoint)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549453/ Blum et al. 2017 (USOR 06-090)]
 +
|2007-2009
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cyclophosphamide_.26_Docetaxel_.28TC.29|TC]]
 +
| style="background-color:#91cf60" |Seems to have superior IDFS (primary endpoint)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549453/ Blum et al. 2017 (NSABP-46-I/USOR 07132)]
 +
|2009-2012
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cyclophosphamide_.26_Docetaxel_.28TC.29|TC]]
 +
| style="background-color:#91cf60" |Seems to have superior IDFS (primary endpoint)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549453/ Blum et al. 2017 (NSABP B-49)]
 +
|2012-04-04 to 2013-11-21
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cyclophosphamide_.26_Docetaxel_.28TC.29|TC]]
 +
| style="background-color:#91cf60" |Seems to have superior IDFS (primary endpoint)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
weekly TH -> FEC & H: weekly '''<u>T</u>'''axol, '''<u>H</u>'''erceptin -> '''<u>F</u>'''ive-FU, '''<u>E</u>'''pirubicin, '''<u>C</u>'''ytoxan, '''<u>H</u>'''erceptin
+
''<sup>1</sup>Reported efficacy is based on the 2012 update.''<br>
−
 
+
''Note: Blum et al. 2017 is a pooled analysis of three RCTs, some of which had arms other than TAC and TC. Refer to the paper for further details. This was the upper bound of cycles in TAILORx.''
−
===Regimen {{#subobject:7341d2|Variant=1}}===
+
<div class="toccolours" style="background-color:#fdcdac">
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV on cycle 1 day 1 prior to first dose of paclitaxel, then 2 mg/kg on days 8 & 15 of cycle 1; then in cycles 2-4, [[Trastuzumab (Herceptin)]] is 2 mg/kg IV on days 1, 8, 15
+
====Eligibility criteria====
−
*[[Paclitaxel (Taxol)]] 80 mg/m2 IV over 1 hour on days 1, 8, 15
+
*TAILORx: Oncotype DX score of 11 to 25
−
 
+
</div>
−
'''21-day cycles x 4 cycles, THEN'''
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
*[[Fluorouracil (5-FU)]] 500 mg/m2 IV on days 1 & 4
+
*[[Surgery#Breast_cancer_surgery|Surgery]]
−
*[[Epirubicin (Ellence)]] 75 mg/m2 IV on day 1
+
</div>
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m2 IV on day 1
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Trastuzumab (Herceptin)]] 2 mg/kg IV on days 1, 8, 15
+
====Chemotherapy====
−
 
+
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given third, one hour after cyclophosphamide'''
−
'''21-day cycles x 4 cycles'''
+
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV over 15 minutes once on day 1, '''given first'''
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV over 1 to 5 minutes once on day 1, '''given second'''
 +
====Supportive therapy====
 +
*[[Dexamethasone (Decadron)]] 8 mg PO every 12 hours for 6 total doses, starting the day before treatment
 +
*[[Ciprofloxacin (Cipro)]] 500 mg PO twice per day on days 5 to 14
 +
*G-CSF not originally routinely administered unless patients had febrile neutropenia, but some guidelines recommend one of the following:
 +
**[[Filgrastim (Neupogen)]] 5 mcg/kg SC once per day on days 4 to 11
 +
**[[Lenograstim (Granocyte)]] 150 mcg/m<sup>2</sup> SC once per day on days 4 to 11
 +
'''21-day cycle for 6 cycles'''
 +
</div></div>
  
 
===References===
 
===References===
 +
<!-- no pre-pub disclosed -->
 +
# '''BCIRG 001:''' Martín M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C; Breast Cancer International Research Group. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med. 2005 Jun 2;352(22):2302-13. [https://doi.org/10.1056/NEJMoa043681 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15930421/ PubMed] [https://clinicaltrials.gov/study/NCT00688740 NCT00688740]
 +
## '''Update:''' Mackey JR, Martín M, Pienkowski T, Rolski J, Guastalla JP, Sami A, Glaspy J, Juhos E, Wardley A, Fornander T, Hainsworth J, Coleman R, Modiano MR, Vinholes J, Pinter T, Rodríguez-Lescure A, Colwell B, Whitlock P, Provencher L, Laing K, Walde D, Price C, Hugh JC, Childs BH, Bassi K, Lindsay MA, Wilson V, Rupin M, Houé V, Vogel C; TRIO/BCIRG 001 investigators. Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial. Lancet Oncol. 2013 Jan;14(1):72-80. Epub 2012 Dec 12. [https://doi.org/10.1016/S1470-2045(12)70525-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23246022/ PubMed]
 +
# '''NSABP B-30:''' Swain SM, Jeong JH, Geyer CE Jr, Costantino JP, Pajon ER, Fehrenbacher L, Atkins JN, Polikoff J, Vogel VG, Erban JK, Rastogi P, Livingston RB, Perez EA, Mamounas EP, Land SR, Ganz PA, Wolmark N. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med. 2010 Jun 3;362(22):2053-65. [https://doi.org/10.1056/NEJMoa0909638 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935316/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20519679/ PubMed] [https://clinicaltrials.gov/study/NCT00003782 NCT00003782]
 +
<!-- no pre-pub disclosed -->
 +
# '''GEICAM 9805:''' Martín M, Seguí MA, Antón A, Ruiz A, Ramos M, Adrover E, Aranda I, Rodríguez-Lescure A, Grosse R, Calvo L, Barnadas A, Isla D, Martinez del Prado P, Ruiz Borrego M, Zaluski J, Arcusa A, Muñoz M, López Vega JM, Mel JR, Munarriz B, Llorca C, Jara C, Alba E, Florián J, Li J, López García-Asenjo JA, Sáez A, Rios MJ, Almenar S, Peiró G, Lluch A; GEICAM. Adjuvant docetaxel for high-risk, node-negative breast cancer. N Engl J Med. 2010 Dec 2;363(23):2200-10. [https://doi.org/10.1056/NEJMoa0910320 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21121833/ PubMed] [https://clinicaltrials.gov/study/NCT00121992 NCT00121992]
 +
<!-- Presented in part at the 28th Annual San Antonio Breast Cancer Symposia, December 8-11, 2005, San Antonio, TX, and at the 31st Annual San Antonio Breast Cancer Symposia, December 10-14, 2008, San Antonio, TX. -->
 +
# '''BCIRG-005:''' Eiermann W, Pienkowski T, Crown J, Sadeghi S, Martín M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press M, Sauter G, Lindsay MA, Riva A, Buyse M, Drevot P, Taupin H, Mackey JR. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol. 2011 Oct 10;29(29):3877-84. Epub 2011 Sep 12. [https://doi.org/10.1200/jco.2010.28.5437 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21911726/ PubMed] [https://clinicaltrials.gov/study/NCT00312208 NCT00312208]
 +
## '''Update:''' Mackey JR, Pieńkowski T, Crown J, Sadeghi S, Martín M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press MF, Sauter G, Lindsay M, Houé V, Buyse M, Drevot P, Hitier S, Bensfia S, Eiermann W; Translational Research In Oncology (TRIO)/ Breast Cancer International Research Group (BCIRG)-005 investigators. Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial. Ann Oncol. 2016 Jun;27(6):1041-7. Epub 2016 Mar 2. [https://doi.org/10.1093/annonc/mdw098 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26940688/ PubMed]
 +
# '''NSABP B-38:''' Swain SM, Tang G, Geyer CE Jr, Rastogi P, Atkins JN, Donnellan PP, Fehrenbacher L, Azar CA, Robidoux A, Polikoff JA, Brufsky AM, Biggs DD, Levine EA, Zapas JL, Provencher L, Northfelt DW, Paik S, Costantino JP, Mamounas EP, Wolmark N. Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial. J Clin Oncol. 2013 Sep 10;31(26):3197-204. Epub 2013 Aug 12. [https://doi.org/10.1200/JCO.2012.48.1275 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757290/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23940225/ PubMed] [https://clinicaltrials.gov/study/NCT00093795 NCT00093795]
 +
# '''USOR 06-090:''' Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. [https://doi.org/10.1200/JCO.2016.71.4147 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549453/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28398846/ PubMed] [https://clinicaltrials.gov/study/NCT00493870 NCT00493870]
 +
##'''Pooled update:''' Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. [https://doi.org/10.1200/jco.23.01428 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11095853/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/38335467/ PubMed]
 +
# '''NSABP-46-I/USOR 07132:''' Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. [https://doi.org/10.1200/JCO.2016.71.4147 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549453/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28398846/ PubMed] [https://clinicaltrials.gov/study/NCT00887536 NCT00887536]
 +
##'''Pooled update:''' Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. [https://doi.org/10.1200/jco.23.01428 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11095853/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/38335467/ PubMed]
 +
# '''NSABP B-49:''' Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. [https://doi.org/10.1200/JCO.2016.71.4147 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549453/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28398846/ PubMed] [https://clinicaltrials.gov/study/NCT01547741 NCT01547741]
 +
##'''Pooled update:''' Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. [https://doi.org/10.1200/jco.23.01428 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11095853/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/38335467/ PubMed]
 +
# '''TAILORx:''' Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. [https://doi.org/10.1056/NEJMoa1804710 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172658/ link to PMC article] '''contains dosing details in supplement''' [https://pubmed.ncbi.nlm.nih.gov/29860917/ PubMed] [https://clinicaltrials.gov/study/NCT00310180 NCT00310180]
 +
# '''MATADOR:''' van Rossum AGJ, Kok M, van Werkhoven E, Opdam M, Mandjes IAM, van Leeuwen-Stok AE, van Tinteren H, Imholz ALT, Portielje JEA, Bos MMEM, van Bochove A, Wesseling J, Rutgers EJ, Linn SC, Oosterkamp HM; MATADOR Trialists' Group. Adjuvant dose-dense doxorubicin-cyclophosphamide versus docetaxel-doxorubicin-cyclophosphamide for high-risk breast cancer: first results of the randomised MATADOR trial (BOOG 2004-04). Eur J Cancer. 2018 Oct;102:40-48. [https://doi.org/10.1016/j.ejca.2018.07.013 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30125761/ PubMed] ISRCTN61893718
 +
#'''PUMCH-Breast-TCX:''' [https://clinicaltrials.gov/study/NCT01354522 NCT01354522]
  
−
==Neoadjuvant TH (Taxol) -> FEC & H {{#subobject:d2476f|Regimen=1}}==
+
=Metastatic disease, first-line chemotherapy=
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
''Note: in many of these regimens, patients were allowed to have received (neo)adjuvant chemotherapy and hormonal therapy (when applicable). These are first-line regimens in the metastatic setting, with a few being specifically for the locally advanced but unresectable setting.''
 +
==Cyclophosphamide & Doxorubicin (AC) {{#subobject:843320|Regimen=1}}==
 +
AC: '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 40/400 {{#subobject:2e4988|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(19870301)59:5%3C874::AID-CNCR2820590503%3E3.0.CO;2-O Rosner et al. 1987]
 +
|1981-1985
 +
| style="background-color:#1a9851" |Randomized (E-de-esc)
 +
|1. [[Breast_cancer_-_historical#CFP_2|CFP]]<br>2. [[Breast_cancer_-_historical#CMFVP_2|CMFVP]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup> IV once on day 1
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 40/500 {{#subobject:2e4988|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdn781 Katsumata et al. 2009 (JCOG9802)]
 +
|1999-2003
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#AC.2FD_999|AC/D]]<br>2. [[#Docetaxel_monotherapy_2|Docetaxel]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTF
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 40/800 (PO) {{#subobject:136e1b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(197507)36:1%3C90::AID-CNCR2820360104%3E3.0.CO;2-H Jones et al. 1975]
 +
|1973-1974
 +
| style="background-color:#91cf61" |Non-randomized
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(19820301)49:5%3C835::AID-CNCR2820490502%3E3.0.CO;2-Z Tranum et al. 1982 (SWOG-7405B)]
 +
|1974-1977
 +
|style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|1. [[#FAC_3|FAC]]<br>2. [[#A-CMFVP_999|A-CMFVP]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 200 mg/m<sup>2</sup>/day PO in divided doses on days 3 to 6
 +
'''21- to 28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 50/750 {{#subobject:2e4755|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1986.4.2.186 Forbes 1986]
 +
|1978-1981
 +
| style="background-color:#1a9851" |Randomized (C)
 +
|1. [[Breast_cancer_-_historical#ACT|ACT]]<br>2. [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_4|Tamoxifen]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 750 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 9 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, 60/600 {{#subobject:2e4988|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2002.11.005 Biganzoli et al. 2002 (EORTC 10961)]
 +
|1996-1999
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Doxorubicin_.26_Paclitaxel_.28AT.29_2|AT (Taxol)]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|[https://doi.org/10.1200/jco.2003.04.040 Nabholtz et al. 2003 (TAX 306)]
 +
|NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Doxorubicin_.28AT.29|AT (Taxotere)]]
 +
| style="background-color:#fc8d59" |Seems to have inferior TTP
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
TH -> FEC & H: '''<u>T</u>'''axol, '''<u>H</u>'''erceptin -> '''<u>F</u>'''ive-FU, '''<u>E</u>'''pirubicin, '''<u>C</u>'''ytoxan, '''<u>H</u>'''erceptin
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
===Regimen {{#subobject:8e388e|Variant=1}}===
+
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
−
Level of Evidence:
+
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
−
<span
+
'''21-day cycles'''
−
style="background:#00CD00;
+
</div></div><br>
−
padding:3px 6px 3px 6px;
+
<div class="toccolours" style="background-color:#eeeeee">
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV on cycle 1 day 1 prior to first dose of paclitaxel, then 2 mg/kg on days 8 & 15 of cycle 1; then in cycles 2-4, [[Trastuzumab (Herceptin)]] is 2 mg/kg IV on days 1, 8, 15
 
−
*[[Paclitaxel (Taxol)]] 225 mg/m2 IV over 24 hours on day 1
 
−
 
 
−
'''21-day cycles x 4 cycles, THEN'''
 
−
 
 
−
*[[Fluorouracil (5-FU)]] 500 mg/m2 IV on days 1 & 4
 
−
*[[Epirubicin (Ellence)]] 75 mg/m2 IV on day 1
 
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m2 IV on day 1
 
−
*[[Trastuzumab (Herceptin)]] 2 mg/kg IV on days 1, 8, 15
 
−
 
 
−
'''21-day cycles x 4 cycles'''
 
  
 +
===Regimen variant #6, with range {{#subobject:900e58|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_.26_Bevacizumab|AC & Bevacizumab]]<br>1b. [[#Capecitabine_.26_Bevacizumab|Capecitabine & Bevacizumab]]<br>1c. [[#Docetaxel_.26_Bevacizumab|Docetaxel & Bevacizumab]]<br>1d. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_.26_Bevacizumab|EC & Bevacizumab]]<br>1e. [[#FAC_.26_Bevacizumab|FAC & Bevacizumab]]<br>1f. [[#FEC_.26_Bevacizumab|FEC & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 50 to 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 to 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 8 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005 Jun 1;23(16):3676-85. Epub 2005 Feb 28. [http://jco.ascopubs.org/content/23/16/3676.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/15738535 PubMed]
+
# Jones SE, Durie BG, Salmon SE. Combination chemotherapy with adriamycin and cyclophosphamide for advanced breast cancer. Cancer. 1975 Jul;36(1):90-7. [https://doi.org/10.1002/1097-0142(197507)36:1%3C90::AID-CNCR2820360104%3E3.0.CO;2-H link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/1203853/ PubMed]
−
 
+
# '''SWOG-7405B:''' Tranum BL, McDonald B, Thigpen T, Vaughn C, Wilson H, Maloney T, Costanzi J, Bickers J, el Mawli NG, Palmer R, Hoogstraten B, Heilburn L, Rasmusen S; [[Study_Groups#SWOG|SWOG]]. Adriamycin combinations in advanced breast cancer: a Southwest Oncology Group Study. Cancer. 1982 Mar 1;49(5):835-9. [https://doi.org/10.1002/1097-0142(19820301)49:5%3C835::AID-CNCR2820490502%3E3.0.CO;2-Z link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/7037152/ PubMed]
−
==Trastuzumab (Herceptin) monotherapy after adjuvant chemotherapy (HERA) {{#subobject:e585d5|Regimen=1}}==
+
# Forbes JF; Australian and New Zealand Breast Cancer Trials Group, Clinical Oncological Society of Australia. A randomized trial in postmenopausal patients with advanced breast cancer comparing endocrine and cytotoxic therapy given sequentially or in combination. J Clin Oncol. 1986 Feb;4(2):186-93. [https://doi.org/10.1200/JCO.1986.4.2.186 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2868074/ PubMed]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
# Rosner D, Nemoto T, Lane WW. A randomized study of intensive versus moderate chemotherapy programs in metastatic breast cancer. Cancer. 1987 Mar 1;59(5):874-83. [https://doi.org/10.1002/1097-0142(19870301)59:5%3C874::AID-CNCR2820590503%3E3.0.CO;2-O link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3815266/ PubMed]
 +
# '''EORTC 10961:''' Biganzoli L, Cufer T, Bruning P, Coleman R, Duchateau L, Calvert AH, Gamucci T, Twelves C, Fargeot P, Epelbaum R, Lohrisch C, Piccart MJ. Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organisation for Research and Treatment of Cancer 10961 multicenter phase III trial. J Clin Oncol. 2002 Jul 15;20(14):3114-21. [https://doi.org/10.1200/JCO.2002.11.005 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/12118025/ PubMed]
 +
# '''TAX 306:''' Nabholtz JM, Falkson C, Campos D, Szanto J, Martín M, Chan S, Pienkowski T, Zaluski J, Pinter T, Krzakowski M, Vorobiof D, Leonard R, Kennedy I, Azli N, Murawsky M, Riva A, Pouillart P; TAX 306 Study Group. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol. 2003 Mar 15;21(6):968-75. [https://doi.org/10.1200/jco.2003.04.040 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12637459/ PubMed]
 +
# '''JCOG9802:''' Katsumata N, Watanabe T, Minami H, Aogi K, Tabei T, Sano M, Masuda N, Andoh J, Ikeda T, Shibata T, Takashima S. Phase III trial of doxorubicin plus cyclophosphamide (AC), docetaxel, and alternating AC and docetaxel as front-line chemotherapy for metastatic breast cancer: Japan Clinical Oncology Group trial (JCOG9802). Ann Oncol. 2009 Jul;20(7):1210-5. Epub 2009 Mar 2. [https://doi.org/10.1093/annonc/mdn781 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19254942/ PubMed]
 +
<!-- Presented in part at the 45th Annual Meeting of the American Society for Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and at the 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology Multidisciplinary Congress, September 20-24, 2009, Berlin, Germany. -->
 +
# '''RIBBON-1:''' Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.28.0982 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21383283/ PubMed] [https://clinicaltrials.gov/study/NCT00262067 NCT00262067]
 +
==Cyclophosphamide & Doxorubicin (AC) & Bevacizumab {{#subobject:843320|Regimen=1}}==
 +
AC & Bevacizumab: '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, Bevacizumab
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, with range {{#subobject:900e58|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-363-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 +
|-
 +
|} -->
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]]<br>1b. [[#Capecitabine_monotherapy_2|Capecitabine]]<br>1c. [[#Docetaxel_monotherapy_2|Docetaxel]]<br>1d. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]]<br>1e. [[#FAC_3|FAC]]<br>1f. [[#FEC_3|FEC]]<br>1g. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>(HR 0.64, 95% CI 0.52-0.80)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:857980|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Doxorubicin (Adriamycin)]] 50 to 60 mg/m<sup>2</sup> IV once on day 1
−
style="background:#00CD00;
+
*[[Cyclophosphamide (Cytoxan)]] 500 to 600 mg/m<sup>2</sup> IV once on day 1
−
padding:3px 6px 3px 6px;
+
====Targeted therapy====
−
border-color:black;
+
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
−
border-width:2px;
+
'''21-day cycle for up to 8 cycles'''
−
border-style:solid;">Phase III</span>
+
</div>
−
 
+
<div class="toccolours" style="background-color:#cbd5e7">
−
''Participants in the study had already received at least four courses of adjuvant and/or neoadjuvant chemotherapy''
+
====Subsequent treatment====
−
*[[Trastuzumab (Herceptin)]] 8 mg/kg IV over 90 minutes on cycle 1 day 1, then on subsequent cycles Trastuzumab (Herceptin) is 6 mg/kg IV over 90 minutes on day 1
+
*RIBBON-1, SD or better: [[#Bevacizumab_monotherapy_2|Bevacizumab]] maintenance
−
 
+
</div></div>
−
'''3-week cycles x 1 to 2 years'''
 
−
 
 
 
===References===
 
===References===
−
# Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Láng I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Rüschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1659-72. [http://www.nejm.org/doi/full/10.1056/NEJMoa052306 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16236737 PubMed]
+
<!-- Presented in part at the 45th Annual Meeting of the American Society for Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and at the 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology Multidisciplinary Congress, September 20-24, 2009, Berlin, Germany. -->
−
# Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J, Kaufmann M, Cameron D, Bell R, Bergh J, Coleman R, Wardley A, Harbeck N, Lopez RI, Mallmann P, Gelmon K, Wilcken N, Wist E, Sánchez Rovira P, Piccart-Gebhart MJ; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007 Jan 6;369(9555):29-36. [http://www.sciencedirect.com/science/article/pii/S0140673607600282 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17208639 PubMed]
+
# '''RIBBON-1:''' Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.28.0982 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21383283/ PubMed] [https://clinicaltrials.gov/study/NCT00262067 NCT00262067]
−
# Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, Untch M, Smith I, Baselga J, Jackisch C, Cameron D, Mano M, Pedrini JL, Veronesi A, Mendiola C, Pluzanska A, Semiglazov V, Vrdoljak E, Eckart MJ, Shen Z, Skiadopoulos G, Procter M, Pritchard KI, Piccart-Gebhart MJ, Bell R; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol. 2011 Mar;12(3):236-44. doi: 10.1016/S1470-2045(11)70033-X. Epub 2011 Feb 25. [http://www.sciencedirect.com/science/article/pii/S147020451170033X link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21354370 PubMed]
+
==Capecitabine monotherapy {{#subobject:842c42|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
=Metastatic disease, single agent therapy=
+
===Regimen variant #1, 650 mg/m<sup>2</sup> PO twice per day, continuous {{#subobject:45bb7c|Variant=1}}===
−
 
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
==Capecitabine (Xeloda) {{#subobject:842c42|Regimen=1}}==
+
!style="width: 20%"|Study
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1200/jco.2010.33.9101 Stockler et al. 2011 (ANZ 0001)]
 +
|rowspan=2|2001-2005
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|1. [[#CMF_2|CMF]]
 +
| style="background-color:#91cf60" |Seems to have superior OS
 +
|-
 +
|2. [[#Capecitabine_monotherapy_2|Capecitabine]]; intermittent
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of quality-adjusted PFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen #1, Bajetta et al. 2005; Geyer et al. 2006; von Minckwitz et al. 2009 (GBG 26/BIG 3-05); Sparano et al. 2010; von Minckwitz et al. 2011 (GBG 26/BIG 3-05); Crown et al. 2013 (Intermittent) {{#subobject:fb2810|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Capecitabine (Xeloda)]] 650 mg/m<sup>2</sup> PO twice per day
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Capecitabine (Xeloda)]] 1250 mg/m2 PO BID on days 1 to 14
 
−
 
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div><br>
−
===Regimen #2, Bajetta et al. 2005 & Stockler et al. 2011 (Intermittent) {{#subobject:674c2d|Variant=1}}===
+
<div class="toccolours" style="background-color:#eeeeee">
−
Level of Evidence:
+
===Regimen variant #2, 1000 mg/m<sup>2</sup> PO twice per day, limited duration {{#subobject:698b2d|Variant=1}}===
−
<span
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
style="background:#00CD00;
+
!style="width: 20%"|Study
−
padding:3px 6px 3px 6px;
+
!style="width: 20%"|Dates of enrollment
−
border-color:black;
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
border-width:2px;
+
!style="width: 20%"|Comparator
−
border-style:solid;">Phase III</span>
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
 
+
|-
−
*[[Capecitabine (Xeloda)]] 1000 mg/m2 PO BID on days 1 to 14
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433520/ Smorenburg et al. 2014 (OMEGA)]
−
 
+
|2007-2011
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Pegylated_liposomal_doxorubicin_monotherapy|PLD]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 +
'''21-day cycle for 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 1000 mg/m<sup>2</sup> PO twice per day, indefinite {{#subobject:674c2d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.02.167 Bajetta et al. 2005]
 +
|1999-2003
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1200/jco.2010.33.9101 Stockler et al. 2011 (ANZ 0001)]
 +
|rowspan=2|2001-2005
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|1. [[#CMF_2|CMF]]
 +
| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)
 +
|-
 +
|2. [[#Capecitabine_monotherapy_2|Capecitabine]]; continuous
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of quality-adjusted PFS
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_.26_Bevacizumab|AC & Bevacizumab]]<br>1b. [[#Capecitabine_.26_Bevacizumab|Capecitabine & Bevacizumab]]<br>1c. [[#Docetaxel_.26_Bevacizumab|Docetaxel & Bevacizumab]]<br>1d. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_.26_Bevacizumab|EC & Bevacizumab]]<br>1e. [[#FAC_.26_Bevacizumab|FAC & Bevacizumab]]<br>1f. [[#FEC_.26_Bevacizumab|FEC & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div><br>
−
===Regimen #3, Stockler et al. 2011 (Continuous) {{#subobject:45bb7c|Variant=1}}===
+
<div class="toccolours" style="background-color:#eeeeee">
−
Level of Evidence:
+
===Regimen variant #4, 1250 mg/m<sup>2</sup> PO twice per day {{#subobject:fb2810|Variant=1}}===
−
<span
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
style="background:#00CD00;
+
!style="width: 20%"|Study
−
padding:3px 6px 3px 6px;
+
!style="width: 20%"|Dates of enrollment
−
border-color:black;
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
border-width:2px;
+
!style="width: 20%"|Comparator
−
border-style:solid;">Phase III</span>
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
 
+
|-
−
*[[Capecitabine (Xeloda)]] 650 mg/m2 PO BID on days 1 to 21
+
|[https://doi.org/10.1200/jco.2005.02.167 Bajetta et al. 2005]
−
 
+
|1999-2003
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5222915/ Harbeck et al. 2016 (PELICAN)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Pegylated_liposomal_doxorubicin_monotherapy|PLD]]
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior TTP (primary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
−
# Bajetta E, Procopio G, Celio L, Gattinoni L, Della Torre S, Mariani L, Catena L, Ricotta R, Longarini R, Zilembo N, Buzzoni R. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol. 2005 Apr 1;23(10):2155-61. Epub 2005 Feb 14. [http://jco.ascopubs.org/content/23/10/2155.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15710946 PubMed]
+
# Bajetta E, Procopio G, Celio L, Gattinoni L, Della Torre S, Mariani L, Catena L, Ricotta R, Longarini R, Zilembo N, Buzzoni R. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol. 2005 Apr 1;23(10):2155-61. Epub 2005 Feb 14. [https://doi.org/10.1200/jco.2005.02.167 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15710946/ PubMed]
−
# Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006 Dec 28;355(26):2733-43. [http://www.nejm.org/doi/full/10.1056/NEJMoa064320 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17192538 PubMed]
+
<!-- Presented in part at the 45th Annual Meeting of the American Society for Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and at the 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology Multidisciplinary Congress, September 20-24, 2009, Berlin, Germany. -->
−
# Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. [http://jco.ascopubs.org/content/25/33/5210.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17968020 PubMed]
+
# '''RIBBON-1:''' Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.28.0982 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21383283/ PubMed] [https://clinicaltrials.gov/study/NCT00262067 NCT00262067]
−
# von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer W, Baumann KH, Clemens MR, Duerr R, Uleer C, Andersson M, Stein RC, Nekljudova V, Loibl S. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study. J Clin Oncol. 2009 Apr 20;27(12):1999-2006. Epub 2009 Mar 16. [http://jco.ascopubs.org/content/27/12/1999.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19289619 PubMed]
+
<!-- Presented in part at the 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, TX, and 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. -->
−
## '''Update:''' von Minckwitz G, Schwedler K, Schmidt M, Barinoff J, Mundhenke C, Cufer T, Maartense E, de Jongh FE, Baumann KH, Bischoff J, Harbeck N, Lück HJ, Maass N, Zielinski C, Andersson M, Stein RC, Nekljudova V, Loibl S; GBG 26/BIG 03-05 study group and participating investigators. Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. Eur J Cancer. 2011 Oct;47(15):2273-81. Epub 2011 Jul 7. [http://www.ejcancer.info/article/S0959-8049%2811%2900425-4/abstract link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21741829 PubMed]
+
# '''ANZ 0001:''' Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B, Van Hazel G, Wilcken NR, Grimison PS, Nowak AK, Gainford MC, Fong A, Paksec L, Sourjina T, Zannino D, Gebski V, Simes RJ, Forbes JF, Coates AS. Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4498-504. Epub 2011 Oct 24. [https://doi.org/10.1200/jco.2010.33.9101 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22025143/ PubMed]
−
# Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane.  J Clin Oncol. 2010 Jul 10;28(20):3256-63.[http://jco.ascopubs.org/content/28/20/3256.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20530276 PubMed]
+
# '''OMEGA:''' Smorenburg CH, de Groot SM, van Leeuwen-Stok AE, Hamaker ME, Wymenga AN, de Graaf H, de Jongh FE, Braun JJ, Los M, Maartense E, van Tinteren H, Nortier JW, Seynaeve C; Dutch Breast Cancer Research Group. A randomized phase III study comparing pegylated liposomal doxorubicin with capecitabine as first-line chemotherapy in elderly patients with metastatic breast cancer: results of the OMEGA study of the Dutch Breast Cancer Research Group BOOG. Ann Oncol. 2014 Mar;25(3):599-605. Epub 2014 Feb 6. [https://doi.org/10.1093/annonc/mdt588 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433520/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24504445/ PubMed] ISRCTN11114726
−
# Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B, Van Hazel G, Wilcken NR, Grimison PS, Nowak AK, Gainford MC, Fong A, Paksec L, Sourjina T, Zannino D, Gebski V, Simes RJ, Forbes JF, Coates AS. Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4498-504. doi: 10.1200/JCO.2010.33.9101. Epub 2011 Oct 24. [http://jco.ascopubs.org/content/29/34/4498.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22025143 PubMed]
+
# '''PELICAN:''' Harbeck N, Saupe S, Jäger E, Schmidt M, Kreienberg R, Müller L, Otremba BJ, Waldenmaier D, Dorn J, Warm M, Scholz M, Untch M, de Wit M, Barinoff J, Lück HJ, Harter P, Augustin D, Harnett P, Beckmann MW, Al-Batran SE; PELICAN Investigators. A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study. Breast Cancer Res Treat. 2017 Jan;161(1):63-72. Epub 2016 Oct 31. [https://doi.org/10.1007/s10549-016-4033-3 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5222915/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27798749/ PubMed] [https://clinicaltrials.gov/study/NCT00266799 NCT00266799]
−
# Crown JP, Diéras V, Staroslawska E, Yardley DA, Bachelot T, Davidson N, Wildiers H, Fasching PA, Capitain O, Ramos M, Greil R, Cognetti F, Fountzilas G, Blasinska-Morawiec M, Liedtke C, Kreienberg R, Miller WH Jr, Tassell V, Huang X, Paolini J, Kern KA, Romieu G. Phase III Trial of Sunitinib in Combination With Capecitabine Versus Capecitabine Monotherapy for the Treatment of Patients With Pretreated Metastatic Breast Cancer. J Clin Oncol. 2013 Aug 10;31(23):2870-8. doi: 10.1200/JCO.2012.43.3391. Epub 2013 Jul 15. [http://jco.ascopubs.org/content/31/23/2870.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23857972 PubMed]
+
# '''CONTESSA:''' [https://clinicaltrials.gov/study/NCT03326674 NCT03326674]
−
 
+
==Capecitabine & Bevacizumab {{#subobject:14a8f1|Regimen=1}}==
−
==Docetaxel (Taxotere) {{#subobject:47db8e|Regimen=1}}==
+
<div class="toccolours" style="background-color:#eeeeee">
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
===Regimen {{#subobject:b1de3e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-363-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 +
|-
 +
|} -->
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]]<br>1b. [[#Capecitabine_monotherapy_2|Capecitabine]]<br>1c. [[#Docetaxel_monotherapy_2|Docetaxel]]<br>1d. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]]<br>1e. [[#FAC_3|FAC]]<br>1f. [[#FEC_3|FEC]]<br>1g. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>(HR 0.69, 95% CI 0.56-0.84)
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(12)70566-1 Lang et al. 2013 (TURANDOT)]
 +
|2008-2010
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Paclitaxel_.26_Bevacizumab|Paclitaxel & Bevacizumab]]
 +
| style="background-color:#eeee01" |Non-inferior OS<sup>1</sup> (primary endpoint)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788680/ Welt et al. 2016 (CARIN)]
 +
|2009-2012
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine.2C_Vinorelbine.2C_Bevacizumab_333|Capecitabine, Vinorelbine, Bevacizumab]]
 +
| style="background-color:#fee08b" |Might have inferior PFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:f1d457|Variant=1}}===
+
''<sup>1</sup>Reported efficacy for TURANDOT is based on the 2016 update.''
−
Level of Evidence:
+
<div class="toccolours" style="background-color:#b3e2cd">
−
<span
+
====Chemotherapy====
−
style="background:#00CD00;
+
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
−
padding:3px 6px 3px 6px;
+
====Targeted therapy====
−
border-color:black;
+
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Docetaxel (Taxotere)]] 60, 75, or 100 mg/m2 IV once on day 1
 
−
 
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div>
−
Alternate schedule:
 
−
*[[Docetaxel (Taxotere)]] 40 mg/m2 IV weekly for weeks 1 to 6, then off for weeks 7 & 8
 
−
 
 
−
'''8-week cycles'''
 
−
 
 
 
===References===
 
===References===
−
# '''Review:''' Burris HA 3rd. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin Oncol. 1999 Jun;26(3 Suppl 9):1-6. [http://www.ncbi.nlm.nih.gov/pubmed/10426452 PubMed]
+
<!-- Presented in part at the 45th Annual Meeting of the American Society for Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and at the 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology Multidisciplinary Congress, September 20-24, 2009, Berlin, Germany. -->
−
# Chan S, Friedrichs K, Noel D, Pintér T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, González Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J; 303 Study Group. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2341-54. [http://jco.ascopubs.org/content/17/8/2341.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/10561296 PubMed]
+
# '''RIBBON-1:''' Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.28.0982 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21383283/ PubMed] [https://clinicaltrials.gov/study/NCT00262067 NCT00262067]
−
# Alexandre J, Bleuzen P, Bonneterre J, Sutherland W, Misset JL, Guastalla J, Viens P, Faivre S, Chahine A, Spielman M, Bensmaïne A, Marty M, Mahjoubi M, Cvitkovic E. Factors predicting for efficacy and safety of docetaxel in a compassionate-use cohort of 825 heavily pretreated advanced breast cancer patients. J Clin Oncol. 2000 Feb;18(3):562-73. [http://jco.ascopubs.org/content/18/3/562.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/10653871 PubMed]
+
# '''TURANDOT:''' Lang I, Brodowicz T, Ryvo L, Kahan Z, Greil R, Beslija S, Stemmer SM, Kaufman B, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Messinger D, Zielinski C; Central European Cooperative Oncology Group. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial. Lancet Oncol. 2013 Feb;14(2):125-33. Epub 2013 Jan 10. [https://doi.org/10.1016/S1470-2045(12)70566-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23312888/ PubMed] [https://clinicaltrials.gov/study/NCT00600340 NCT00600340]
−
# Burstein HJ, Manola J, Younger J, Parker LM, Bunnell CA, Scheib R, Matulonis UA, Garber JE, Clarke KD, Shulman LN, Winer EP. Docetaxel administered on a weekly basis for metastatic breast cancer. [http://jco.ascopubs.org/content/18/6/1212.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/10715290 PubMed] content property of [http://hemonc.org HemOnc.org]
+
## '''Update:''' Zielinski C, Láng I, Inbar M, Kahán Z, Greil R, Beslija S, Stemmer SM, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Petruzelka L, Eniu A, Nisenbaum B, Dank M, Anghel R, Messinger D, Brodowicz T; TURANDOT investigators. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1230-9. Epub 2016 Aug 5. [https://doi.org/10.1016/S1470-2045(16)30154-1 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27501767/ PubMed]
−
# O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. [http://jco.ascopubs.org/content/20/12/2812.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/12065558 PubMed]
+
# '''CARIN:''' Welt A, Marschner N, Lerchenmueller C, Decker T, Steffens CC, Koehler A, Depenbusch R, Busies S, Hegewisch-Becker S. Capecitabine and bevacizumab with or without vinorelbine in first-line treatment of HER2/neu-negative metastatic or locally advanced breast cancer: final efficacy and safety data of the randomised, open-label superiority phase 3 CARIN trial. Breast Cancer Res Treat. 2016 Feb;156(1):97-107. Epub 2016 Feb 29. [https://doi.org/10.1007/s10549-016-3727-x link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4788680/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26927446/ PubMed] [https://clinicaltrials.gov/study/NCT00868634 NCT00868634]
−
# Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Antón A, Lluch A, Kennedy J, O'Byrne K, Conte P, Green M, Ward C, Mayne K, Extra JM. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005 Jul 1;23(19):4265-74. Epub 2005 May 23. [http://jco.ascopubs.org/content/23/19/4265.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15911866 PubMed]
 
−
# Harvey V, Mouridsen H, Semiglazov V, Jakobsen E, Voznyi E, Robinson BA, Groult V, Murawsky M, Cold S. Phase III trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol. 2006 Nov 1;24(31):4963-70. Epub 2006 Oct 10. [http://jco.ascopubs.org/content/24/31/4963.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/17033039 PubMed]
 
−
# Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009 Aug 1;27(22):3611-9. doi: 10.1200/JCO.2008.18.5397. Epub 2009 May 26. Erratum in: J Clin Oncol. 2011 Jul 1;29(19):2739. [http://jco.ascopubs.org/content/27/22/3611.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19470941 PubMed]
 
  
−
==Doxorubicin (Adriamycin) {{#subobject:8a2b88|Regimen=1}}==
+
==Capecitabine & Paclitaxel {{#subobject:bd0f63|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
TX: '''<u>T</u>'''axol (Paclitaxel), '''<u>X</u>'''eloda (Capecitabine)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:74e9d|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.05.1383 Blum et al. 2006]
 +
|2003
 +
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:96cac2|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Capecitabine (Xeloda)]] 825 mg/m<sup>2</sup> (rounded to nearest 500 mg) PO twice per day on days 1 to 14
−
style="background:#00CD00;
+
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Doxorubicin (Adriamycin)]] 60-75 mg/m2 IV day 1
 
−
 
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div>
−
Alternate schedule:
 
−
*[[Doxorubicin (Adriamycin)]] 20 mg/m2 IV weekly
 
−
 
 
 
===References===
 
===References===
−
# Gundersen S, Kvinnsland S, Klepp O, Kvaløy S, Lund E, Høst H. Weekly adriamycin versus VAC in advanced breast cancer. A randomized trial. Eur J Cancer Clin Oncol. 1986 Dec;22(12):1431-4. [http://www.ncbi.nlm.nih.gov/pubmed/3595668 PubMed]
+
# Blum JL, Dees EC, Chacko A, Doane L, Ethirajan S, Hopkins J, McMahon R, Merten S, Negron A, Neubauer M, Ilegbodu D, Boehm KA, Asmar L, O'Shaughnessy JA. Phase II trial of capecitabine and weekly paclitaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2006 Sep 20;24(27):4384-90. Epub 2006 Aug 22. [https://doi.org/10.1200/jco.2005.05.1383 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16926223/ PubMed]
−
# Chan S, Friedrichs K, Noel D, Pintér T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, González Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J; 303 Study Group. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2341-54. [http://jco.ascopubs.org/content/17/8/2341.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/10561296 PubMed]
+
==Capecitabine & Paclitaxel, nanoparticle albumin-bound {{#subobject:821a8e|Regimen=1}}==
−
# O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C; CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004 Mar;15(3):440-9. [http://annonc.oxfordjournals.org/content/15/3/440.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/14998846 PubMed]
+
<div class="toccolours" style="background-color:#eeeeee">
−
 
+
===Regimen {{#subobject:e2b0d2|Variant=1}}===
−
==Doxorubicin liposomal (Doxil) {{#subobject:2b08a6|Regimen=1}}==
+
{| class="wikitable" style="width: 60%; text-align:center;"  
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1016/j.clbc.2011.10.004 Schwartzberg et al. 2011]
 +
|NR
 +
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:6ebaf9|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Capecitabine (Xeloda)]] 825 mg/m<sup>2</sup> (rounded to nearest 500 mg) PO twice per day on days 1 to 15
−
style="background:#00CD00;
+
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 125 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
padding:3px 6px 3px 6px;
+
'''21-day cycles'''
−
border-color:black;
+
</div></div>
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Doxorubicin liposomal (Doxil)]] 50 mg/m2 IV day 1
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
 
===References===
 
===References===
−
# O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C; CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004 Mar;15(3):440-9. [http://annonc.oxfordjournals.org/content/15/3/440.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/14998846 PubMed]
+
# Schwartzberg LS, Arena FP, Mintzer DM, Epperson AL, Walker MS. Phase II multicenter trial of albumin-bound paclitaxel and capecitabine in first-line treatment of patients with metastatic breast cancer. Clin Breast Cancer. 2012 Apr;12(2):87-93. Epub 2011 Dec 6. [https://doi.org/10.1016/j.clbc.2011.10.004 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22154117/ PubMed]
−
 
+
==CMF {{#subobject:9c9c1d|Regimen=1}}==
−
==Epirubicin (Ellence) {{#subobject:e941f2|Regimen=1}}==
+
CMF: '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 350/20/350 {{#subobject:4a33d3|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(19821201)50:11%3C2269::aid-cncr2820501107%3E3.0.co;2-l Muss et al. 1982]
 +
|1979-1981
 +
|style="background-color:#1a9851"|Randomized (C)
 +
|[[Breast_cancer_-_historical#CAV|CAV]]
 +
| style="background-color:#fc8d59" |Seems to have inferior ORR
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:740b22|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Cyclophosphamide (Cytoxan)]] 350 mg/m<sup>2</sup> IV once on day 1
−
style="background:#00CD00;
+
*[[Methotrexate (MTX)]] 20 mg/m<sup>2</sup> IV once on day 1
−
padding:3px 6px 3px 6px;
+
*[[Fluorouracil (5-FU)]] 350 mg/m<sup>2</sup> IV once on day 1
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Epirubicin (Ellence)]] 40, 60, 90, or 135 mg/m2 IV day 1
 
−
 
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div><br>
−
===References===
+
<div class="toccolours" style="background-color:#eeeeee">
−
# Bastholt L, Dalmark M, Gjedde SB, Pfeiffer P, Pedersen D, Sandberg E, Kjaer M, Mouridsen HT, Rose C, Nielsen OS, Jakobsen P, Bentzen SM. Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 1996 Apr;14(4):1146-55. [http://jco.ascopubs.org/content/14/4/1146.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/8648369 PubMed]
+
===Regimen variant #2, 600/40/600 {{#subobject:4a66d3|Variant=1}}===
−
 
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
==Eribulin (Halaven) {{#subobject:ef2415|Regimen=1}}==
+
!style="width: 20%"|Study
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1988.6.9.1377 Tannock et al. 1988]
 +
|1981-1986
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#CMF_2|CMF]]; lower-dose
 +
| style="background-color:#d9ef8b" |Might have superior OS
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(19940501)73:9%3C2337::AID-CNCR2820730916%3E3.0.CO;2-Q Ingle et al. 1994 (NCCTG 87-32-52)]
 +
|1987-1991
 +
| style="background-color:#1a9851" |Randomized (C)
 +
|[[#DES-CEF_333|DES-CEF]]
 +
| style="background-color:#fee08b" |Might have inferior ORR
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:25ef0|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
−
style="background:#00CD00;
+
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once on day 1
−
padding:3px 6px 3px 6px;
+
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Eribulin (Halaven)]] 1.4 mg/m2 IV over 2 to 5 minutes on days 1 & 8
 
−
 
 
 
'''21-day cycles'''
 
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 1400/80/1000 {{#subobject:d3cef4|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1200/JCO.1987.5.10.1523 Aisner et al. 1987 (CALGB 7682)]
 +
|rowspan=2|1976-1980
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#FAC_3|CAF]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|2. [[Breast_cancer_-_historical#CAFVP|CAFVP]]
 +
| style="background-color:#d73027" |Inferior ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 1400/60/800 {{#subobject:4a44d3|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(197611)38:5%3C1882::AID-CNCR2820380503%3E3.0.CO;2-H Canellos et al. 1976]
 +
|NR
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Breast_cancer_-_historical#Melphalan_monotherapy_2|Melphalan]]
 +
| style="background-color:#91cf60" |Seems to have superior OS
 +
|-
 +
|}
 +
''Note: this was the dose used for patients older than 60 in the revised protocol of Canellos et al. 1976.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, 1400/80/1200 {{#subobject:4a77d3|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1639498/ Brambilla et al. 1976]
 +
|1973-1974
 +
| style="background-color:#1a9851" |Randomized (C)
 +
|[[#Doxorubicin_.26_Vincristine_.28AV.29_999|AV]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(197611)38:5%3C1882::AID-CNCR2820380503%3E3.0.CO;2-H Canellos et al. 1976]
 +
|NR
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Breast_cancer_-_historical#Melphalan_monotherapy_2|Melphalan]]
 +
| style="background-color:#91cf60" |Seems to have superior OS
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(197805)41:5%3C1649::AID-CNCR2820410501%3E3.0.CO;2-J Bull et al. 1978]
 +
|NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FAC_3|CAF]]
 +
| style="background-color:#fee08b" |Might have inferior ORR
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(19821001)50:7%3C1235::AID-CNCR2820500703%3E3.0.CO;2-L Tormey et al. 1982 (ECOG E2173)]
 +
|1973-1974
 +
| style="background-color:#1a9851" |Randomized (C)
 +
|1. [[#Doxorubicin_.26_Vincristine_.28AV.29_999|AV]]<br>2. [[Breast_cancer_-_historical#CMFP_2|CMFP]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(19830215)51:4%3C581::AID-CNCR2820510404%3E3.0.CO;2-G Cocconi et al. 1983]
 +
|NR
 +
| style="background-color:#1a9851" |Randomized (C)
 +
|[[#CMFT_2|CMFT]]
 +
| style="background-color:#fee08b" |Might have inferior TTF
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(19851215)56:12%3C2745::AID-CNCR2820561204%3E3.0.CO;2-G Viladiu et al. 1985]
 +
|1978-1981
 +
|style="background-color:#1a9851" |Randomized (C)
 +
|1. [[#CMFT_2|CMFT]]<br>2. [[#CMF_.26_MPA_888|CMF & MPA]]
 +
| style="background-color:#fc8d59" |Seems to have inferior ORR
 +
|-
 +
|[https://doi.org/10.1016/0277-5379(91)90259-g Engelsman et al. 1991 (EORTC 10808)]
 +
|1981-1984
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#CMF_2|CMF]]; 600/40/600 (IV)
 +
| style="background-color:#91cf60" |Seems to have superior OS
 +
|-
 +
|[https://doi.org/10.1093/oxfordjournals.annonc.a057671 Cocconi et al. 1990]
 +
|1981-1985
 +
| style="background-color:#1a9851" |Randomized (C)
 +
|[[#CMF_2|CMF]] x 6, then intensification
 +
| style="background-color:#ffffbf" |Did not meet endpoints of TTP/OS
 +
|-
 +
|[https://doi.org/10.1016/s0959-8049(05)80296-5 Yosef et al. 1993]
 +
|1983-1987
 +
| style="background-color:#1a9851" |Randomized (C)
 +
|[[#SMF_999|SMF]]
 +
| style="background-color:#ffffbf" |Did not meet endpoints of TTF/OS
 +
|-
 +
|[https://doi.org/10.1200/JCO.1991.9.4.664 Cocconi et al. 1991]
 +
|1985-1988
 +
| style="background-color:#1a9851" |Randomized (C)
 +
|[[#Cisplatin_.26_Etoposide_.28EP.29_333|PE]]
 +
| style="background-color:#fee08b" |Might have inferior ORR
 +
|-
 +
|[https://doi.org/10.1200/jco.2001.19.4.943 Ackland et al. 2001 (HEPI 013)]
 +
|1990-1992
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC_3|CEF]]
 +
| style="background-color:#d73027" |Inferior TTP
 +
|-
 +
|[https://doi.org/10.1056/NEJM200004133421501 Stadtmauer et al. 2000]
 +
|1990-1997
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#CMF_2|CMF]] x 4-6, then [[Breast_cancer_-_historical#CTCb.2C_then_auto_HSCT_2|HDT]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|[https://doi.org/10.1097/01.cad.0000175587.31940.19 von Minckwitz et al. 2005]
 +
|1996-2001
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#BMF_888|BMF]]
 +
| style="background-color:#d73027" |Inferior TTP
 +
|-
 +
|[https://doi.org/10.1200/jco.2010.33.9101 Stockler et al. 2011 (ANZ 0001)]
 +
|2001-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Capecitabine_monotherapy_2|Capecitabine]]; continuous<br>2. [[#Capecitabine_monotherapy_2|Capecitabine]]; intermittent
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|}
 +
''Note: this was the dose used for patients younger than 60 in the revised protocol of Canellos et al. 1976.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
 +
===Regimen variant #6, 1400/120/1200 {{#subobject:5b33d3|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(197611)38:5%3C1882::AID-CNCR2820380503%3E3.0.CO;2-H Canellos et al. 1976]
 +
|NR
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Breast_cancer_-_historical#Melphalan_monotherapy_2|Melphalan]]
 +
| style="background-color:#91cf60" |Seems to have superior OS
 +
|-
 +
|}
 +
''Note: this was the dose used for patients in the original protocol of Canellos et al. 1976 and was deemed too myelotoxic.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] 60 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Diéras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389) investigators. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011 Mar 12;377(9769):914-23. Epub 2011 Mar 2. [http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960070-6/fulltext link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21376385 PubMed]
+
# Brambilla C, De Lena M, Rossi A, Valagussa P, Bonadonna G. Response and survival in advanced breast cancer after two non-cross-resistant combinations. Br Med J. 1976 Apr 3;1(6013):801-4. [https://doi.org/10.1136/bmj.1.6013.801 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1639498/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/1260337/ PubMed]
−
# [http://www.halaven.com/sites/default/files/HALAVEN_full_Prescribing_Information.pdf Eribulin (Halaven) package insert]
+
# Canellos GP, Pocock SJ, Taylor SG 3rd, Sears ME, Klaasen DJ, Band PR; [[Study_Groups#ECOG|ECOG]]. Combination chemotherapy for metastatic breast carcinoma: prospective comparison of multiple drug therapy with L-phenylalanine mustard. Cancer. 1976 Nov;38(5):1882-6. [https://doi.org/10.1002/1097-0142(197611)38:5%3C1882::AID-CNCR2820380503%3E3.0.CO;2-H link to original article] [https://pubmed.ncbi.nlm.nih.gov/991103/ PubMed]
 +
# Bull JM, Tormey DC, Li SH, Carbone PP, Falkson G, Blom J, Perlin E, Simon R. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978 May;41(5):1649-57. [https://doi.org/10.1002/1097-0142(197805)41:5%3C1649::AID-CNCR2820410501%3E3.0.CO;2-J link to original article] [https://pubmed.ncbi.nlm.nih.gov/348293/ PubMed]
 +
# '''ECOG E2173:''' Tormey DC, Gelman R, Band PR, Sears M, Rosenthal SN, DeWys W, Perlia C, Rice MA. Comparison of induction chemotherapies for metastatic breast cancer: an Eastern Cooperative Oncology Group Trial. Cancer. 1982 Oct 1;50(7):1235-44. [https://doi.org/10.1002/1097-0142(19821001)50:7%3C1235::AID-CNCR2820500703%3E3.0.CO;2-L link to original article] [https://pubmed.ncbi.nlm.nih.gov/7049347/ PubMed]
 +
# Muss HB, Richards F 2nd, Jackson DV, Cooper MR, White DR, Stuart JJ, Ramseur W, Christian RM, Wells HB, Pope E, Spurr CL; Piedmont Oncology Association. Vincristine, doxorubicin, and cyclophosphamide versus low-dose intravenous cyclophosphamide, methotrexate, and 5-fluorouracil in advanced breast cancer: a randomized trial of the Piedmont Oncology Association. Cancer. 1982 Dec 1;50(11):2269-74. [https://doi.org/10.1002/1097-0142(19821201)50:11%3C2269::aid-cncr2820501107%3E3.0.co;2-l link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/6754062/ PubMed]
 +
# Cocconi G, De Lisi V, Boni C, Mori P, Malacarne P, Amadori D, Giovanelli E. Chemotherapy versus combination of chemotherapy and endocrine therapy in advanced breast cancer: a prospective randomized study. Cancer. 1983 Feb 15;51(4):581-8. [https://doi.org/10.1002/1097-0142(19830215)51:4%3C581::AID-CNCR2820510404%3E3.0.CO;2-G link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/6336981/ PubMed]
 +
# Viladiu P, Alonso MC, Avella A, Beltrán M, Borrás J, Ojeda B, Bosch FX. Chemotherapy versus chemotherapy plus hormonotherapy in postmenopausal advanced breast cancer patients: a randomized trial. Cancer. 1985 Dec 15;56(12):2745-50. [https://doi.org/10.1002/1097-0142(19851215)56:12%3C2745::AID-CNCR2820561204%3E3.0.CO;2-G link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3902200/ PubMed]
 +
# '''CALGB 7682:''' Aisner J, Weinberg V, Perloff M, Weiss R, Perry M, Korzun A, Ginsberg S, Holland JF; [[Study_Groups#CALGB|CALGB]]. Chemotherapy versus chemoimmunotherapy (CAF v CAFVP v CMF each +/- MER) for metastatic carcinoma of the breast: a CALGB study. J Clin Oncol. 1987 Oct;5(10):1523-33. [https://doi.org/10.1200/JCO.1987.5.10.1523 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/3655855/ PubMed]
 +
# Tannock IF, Boyd NF, DeBoer G, Erlichman C, Fine S, Larocque G, Mayers C, Perrault D, Sutherland H. A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer. J Clin Oncol. 1988 Sep;6(9):1377-87. [https://doi.org/10.1200/JCO.1988.6.9.1377 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2458438/ PubMed]
 +
# Cocconi G, Bisagni G, Bacchi M, Buzzi F, Canaletti R, Carpi A, Ceci G, Colozza A, De Lisi V, Lottici R, Passalacqua R, Peracchia G; GOIRC. A comparison of continuation versus late intensification followed by discontinuation of chemotherapy in advanced breast cancer: a prospective randomized trial of the Italian Oncology Group for Clinical Research (GOIRC). Ann Oncol. 1990;1(1):36-44. [https://doi.org/10.1093/oxfordjournals.annonc.a057671 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2078484/ PubMed]
 +
# '''EORTC 10808:''' Engelsman E, Klijn JC, Rubens RD, Wildiers J, Beex LV, Nooij MA, Rotmensz N, Sylvester R. "Classical" CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer: an EORTC Breast Cancer Co-operative Group Phase III Trial (10808). Eur J Cancer. 1991;27(8):966-70. [https://doi.org/10.1016/0277-5379(91)90259-g link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1832904/ PubMed]
 +
# Cocconi G, Bisagni G, Bacchi M, Boni C, Bartolucci R, Ceci G, Colozza MA, De Lisi V, Lottici R, Mosconi AM, Passalacqua R, Tonato M; Italian Oncology Group for Clinical Research. Cisplatin and etoposide as first-line chemotherapy for metastatic breast carcinoma: a prospective randomized trial of the Italian Oncology Group for Clinical Research. J Clin Oncol. 1991 Apr;9(4):664-9. [https://doi.org/10.1200/JCO.1991.9.4.664 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2066763/ PubMed]
 +
# Yosef H, Slater A, Keen CW, Bunting JS, Hope-Stone H, Parmar H, Roberts JT, Termander B, Nilsson B. Prednimustine (Sterecyt) versus cyclophosphamide both in combination with methotrexate and 5-fluorouracil in the treatment of advanced breast cancer. Eur J Cancer. 1993;29A(8):1100-5. [https://doi.org/10.1016/s0959-8049(05)80296-5 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8518020/ PubMed]
 +
# '''NCCTG 87-32-52:''' Ingle JN, Foley JF, Mailliard JA, Krook JE, Hartmann LC, Jung SH, Veeder MH, Gesme DH Jr, Hatfield AK, Goldberg RM. Randomized trial of cyclophosphamide, methotrexate, and 5-fluorouracil with or without estrogenic recruitment in women with metastatic breast cancer. Cancer. 1994 May 1;73(9):2337-43. [https://doi.org/10.1002/1097-0142(19940501)73:9%3C2337::AID-CNCR2820730916%3E3.0.CO;2-Q link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8168039/ PubMed]
 +
# Stadtmauer EA, O'Neill A, Goldstein LJ, Crilley PA, Mangan KF, Ingle JN, Brodsky I, Martino S, Lazarus HM, Erban JK, Sickles C, Glick JH; Philadelphia Bone Marrow Transplant Group. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J Med. 2000 Apr 13;342(15):1069-76. [https://doi.org/10.1056/NEJM200004133421501 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10760307/ PubMed]
 +
# '''HEPI 013:''' Ackland SP, Anton A, Breitbach GP, Colajori E, Tursi JM, Delfino C, Efremidis A, Ezzat A, Fittipaldo A, Kolaric K, Lopez M, Viaro D; HEPI 013 study group. Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study. J Clin Oncol. 2001 Feb 15;19(4):943-53. [https://doi.org/10.1200/jco.2001.19.4.943 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11181656/ PubMed]
 +
# von Minckwitz G, Chernozemsky I, Sirakova L, Chilingirov P, Souchon R, Marschner N, Kleeberg U, Tsekov C, Fritze D, Thomssen C, Stuart N, Vermorken JB, Loibl S, Merkle Kh, Kaufmann M. Bendamustine prolongs progression-free survival in metastatic breast cancer (MBC): a phase III prospective, randomized, multicenter trial of bendamustine hydrochloride, methotrexate and 5-fluorouracil (BMF) versus cyclophosphamide, methotrexate and 5-fluorouracil (CMF) as first-line treatment of MBC. Anticancer Drugs. 2005 Sep;16(8):871-7. [https://doi.org/10.1097/01.cad.0000175587.31940.19 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16096436/ PubMed]
 +
<!-- Presented in part at the 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, TX, and 43rd Annual Meeting of the American Society of Clinical Oncology, June 1-5, 2007, Chicago, IL. -->
 +
# '''ANZ 0001:''' Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B, Van Hazel G, Wilcken NR, Grimison PS, Nowak AK, Gainford MC, Fong A, Paksec L, Sourjina T, Zannino D, Gebski V, Simes RJ, Forbes JF, Coates AS. Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4498-504. Epub 2011 Oct 24. [https://doi.org/10.1200/jco.2010.33.9101 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22025143/ PubMed]
  
−
==Gemcitabine (Gemzar) {{#subobject:af0915|Regimen=1}}==
+
==CMFT {{#subobject:9c9c1d|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
CMFT: '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil, '''<u>T</u>'''amoxifen
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, lower-dose tamoxifen {{#subobject:ab14d5|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(19830215)51:4%3C581::AID-CNCR2820510404%3E3.0.CO;2-G Cocconi et al. 1983]
 +
|NR
 +
| style="background-color:#1a9851" |Randomized (E-esc)
 +
|[[#CMF_2|CMF]]
 +
| style="background-color:#d9ef8b" |Might have superior TTF
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
====Endocrine therapy====
 +
*[[Tamoxifen (Nolvadex)]] 10 mg PO twice per day on days 1 to 28
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, higher-dose tamoxifen {{#subobject:ajgu35|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(19851215)56:12%3C2745::AID-CNCR2820561204%3E3.0.CO;2-G Viladiu et al. 1985]
 +
|1978-1981
 +
|style="background-color:#1a9851" |Randomized (E-esc)
 +
|1. [[#CMF_2|CMF]]<br>2. [[#CMF_.26_MPA_999|CMF & MPA]]
 +
| style="background-color:#91cf60" |Seems to have superior ORR
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:4db8d|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
−
style="background:#EEEE00;
+
*[[Methotrexate (MTX)]] 40 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
padding:3px 6px 3px 6px;
+
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
border-color:black;
+
====Endocrine therapy====
−
border-width:2px;
+
*[[Tamoxifen (Nolvadex)]] 20 mg PO twice per day on days 1 to 28
−
border-style:solid;">Phase II</span>
 
−
 
 
−
*[[Gemcitabine (Gemzar)]] 800-1200 mg/m2 IV days 1, 8, 15
 
−
 
 
 
'''28-day cycles'''
 
'''28-day cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
−
# Carmichael J, Possinger K, Phillip P, Beykirch M, Kerr H, Walling J, Harris AL. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol. 1995 Nov;13(11):2731-6. [http://jco.ascopubs.org/content/13/11/2731.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/7595731 PubMed]
+
# Cocconi G, De Lisi V, Boni C, Mori P, Malacarne P, Amadori D, Giovanelli E. Chemotherapy versus combination of chemotherapy and endocrine therapy in advanced breast cancer: a prospective randomized study. Cancer. 1983 Feb 15;51(4):581-8. [https://doi.org/10.1002/1097-0142(19830215)51:4%3C581::AID-CNCR2820510404%3E3.0.CO;2-G link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/6336981/ PubMed]
−
# '''Review:''' Seidman AD. Gemcitabine as single-agent therapy in the management of advanced breast cancer. Oncology (Williston Park). 2001 Feb;15(2 Suppl 3):11-4. [http://www.ncbi.nlm.nih.gov/pubmed/11252882 PubMed]
+
# Viladiu P, Alonso MC, Avella A, Beltrán M, Borrás J, Ojeda B, Bosch FX. Chemotherapy versus chemotherapy plus hormonotherapy in postmenopausal advanced breast cancer patients: a randomized trial. Cancer. 1985 Dec 15;56(12):2745-50. [https://doi.org/10.1002/1097-0142(19851215)56:12%3C2745::AID-CNCR2820561204%3E3.0.CO;2-G link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3902200/ PubMed]
  
−
==Paclitaxel (Taxol) {{#subobject:3e5448|Regimen=1}}==
+
==Docetaxel monotherapy {{#subobject:47db8e|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
D: '''<u>D</u>'''ocetaxel
 +
<br>T: '''<u>T</u>'''axotere (Docetaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 30 mg/m<sup>2</sup> 3 weeks out of 4 {{#subobject:09ffcd|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://www.karger.com/Article/FullText/320640 Stemmler et al. 2011 (D2)]
 +
|2001-2008
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Docetaxel_monotherapy_2|Docetaxel]]; q3wk
 +
| style="background-color:#fc8d59" |Seems to have inferior ORR (secondary endpoint)
 +
| style="background-color:#1a9850" |Superior hematotoxicity (primary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 30 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 40 mg/m<sup>2</sup> 3 weeks out of 4 {{#subobject:09eecd|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1002/cncr.23321 Rivera et al. 2008]
 +
|2001-2004
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Docetaxel_monotherapy_2|Docetaxel]]; q3wk
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
| style="background-color:#1a9850" |Superior toxicity
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] as follows:
 +
**Cycle 1: 35 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15
 +
**Cycle 2 onwards: 40 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 40 mg/m<sup>2</sup> 6 weeks out of 8 {{#subobject:6ed28b|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2000.18.6.1212 Burstein et al. 2000]
 +
|1998
 +
| style="background-color:#91cf61" |Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
 +
'''8-week cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 60 mg/m<sup>2</sup> q3wk {{#subobject:cf6000|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdn781 Katsumata et al. 2009 (JCOG9802)]
 +
|1999-2003
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|1. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]]<br>2. [[#AC.2FD_999|AC/D]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTF
 +
|
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(15)00411-8 Takashima et al. 2015 (SELECT BC)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#S-1_monotherapy|S-1]]
 +
| style="background-color:#eeee01" |Seems to have non-inferior OS
 +
| style="background-color:#d73027" |Inferior EQ-5D score
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 6 cycles (JCOG9802) or indefinitely (SELECT BC)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, 60 mg/m<sup>2</sup> q4wk {{#subobject:c5cf8d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(15)00411-8 Takashima et al. 2015 (SELECT BC)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#S-1_monotherapy|S-1]]
 +
| style="background-color:#eeee01" |Seems to have non-inferior OS
 +
| style="background-color:#d73027" |Inferior EQ-5D score
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:1a1adf|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1
−
style="background:#00CD00;
+
'''28-day cycles'''
−
padding:3px 6px 3px 6px;
+
</div></div><br>
−
border-color:black;
+
<div class="toccolours" style="background-color:#eeeeee">
−
border-width:2px;
+
===Regimen variant #6, 75 mg/m<sup>2</sup> q3wk {{#subobject:32c5e5|Variant=1}}===
−
border-style:solid;">Phase III</span>
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
 
+
!style="width: 17%"|Study
−
*[[Paclitaxel (Taxol)]] 175 mg/m2 IV day 1
+
!style="width: 15%"|Dates of enrollment
−
 
+
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1002/cncr.23321 Rivera et al. 2008]
 +
|2001-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_monotherapy_2|Docetaxel]]; weekly
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
| style="background-color:#d73027" |Inferior toxicity
 +
|-
 +
|[https://www.karger.com/Article/FullText/320640 Stemmler et al. 2011 (D2)]
 +
|2001-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_monotherapy_2|Docetaxel]]; weekly
 +
| style="background-color:#91cf60" |Seems to have superior ORR
 +
| style="background-color:#d73027" |Inferior hematotoxicity
 +
|-
 +
|[https://doi.org/10.1200/JCO.2008.20.5013 Sparano et al. 2009 (DOXIL-BCA-3001)]
 +
|2004-2006
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Pegylated_liposomal_doxorubicin_888|Docetaxel & PLD]]
 +
| style="background-color:#d73027" |Inferior TTP
 +
| style="background-color:#1a9850" |Less toxic
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_.26_Bevacizumab|AC & Bevacizumab]]<br>1b. [[#Capecitabine_.26_Bevacizumab|Capecitabine & Bevacizumab]]<br>1c. [[#Docetaxel_.26_Bevacizumab|Docetaxel & Bevacizumab]]<br>1d. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_.26_Bevacizumab|EC & Bevacizumab]]<br>1e. [[#FAC_.26_Bevacizumab|FAC & Bevacizumab]]<br>1f. [[#FEC_.26_Bevacizumab|FEC & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(15)00411-8 Takashima et al. 2015 (SELECT BC)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#S-1_monotherapy|S-1]]
 +
| style="background-color:#eeee01" |Seems to have non-inferior OS
 +
| style="background-color:#d73027" |Inferior EQ-5D score
 +
|-
 +
|[https://doi.org/10.1200/JCO.2014.57.1513 Mackey et al. 2014 (ROSE/TRIO-12)]
 +
|2008-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Ramucirumab_333|Docetaxel & Ramucirumab]]
 +
| style="background-color:#fee08b" |Might have inferior PFS
 +
|
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#fff2ae">
 +
====Dose and schedule modifications====
 +
*Rivera et al. 2008 gave 75 mg/m<sup>2</sup> in cycle 1, with escalation to 100 mg/m<sup>2</sup> depending on toxicity
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #7, 75 mg/m<sup>2</sup> q4wk {{#subobject:79ac92|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(15)00411-8 Takashima et al. 2015 (SELECT BC)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#S-1_monotherapy|S-1]]
 +
| style="background-color:#eeee01" |Seems to have non-inferior OS
 +
| style="background-color:#d73027" |Inferior EQ-5D score
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #8, 100 mg/m<sup>2</sup> x 6 {{#subobject:79aj8c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361414/ Pacilio et al. 2006]
 +
|2000-2003
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Epirubicin_.28DE.29_999|Docetaxel & Epirubicin]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #9, 100 mg/m<sup>2</sup> x 8 {{#subobject:fajga1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2007.11.8851 Crump et al. 2007 (NCIC-CTG MA.16)]
 +
|1997-2000
 +
|style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#FAC_3|FAC]] x 4, then HDCT with auto HSCT<br>2. [[#FEC_3|FEC]] x 4, then HDCT with auto HSCT<br> 3. [[#Paclitaxel_monotherapy_999|Paclitaxel]] x 4, , then HDCT with auto HSCT<br> 4. [[#Docetaxel_monotherapy_2|Docetaxel]] x 4, then HDCT with auto HSCT
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #10, 100 mg/m<sup>2</sup> x 9 {{#subobject:fa8j8c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1200/JCO.2008.21.6457 Miles et al. 2010 (AVADO)]
 +
|rowspan=2|2006-03 to 2007-04
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Docetaxel_.26_Bevacizumab|Docetaxel & Bevacizumab]]; 100/7.5
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|2. [[#Docetaxel_.26_Bevacizumab|Docetaxel & Bevacizumab]]; 100/15
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 9 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #11, 100 mg/m<sup>2</sup>, indefinite {{#subobject:bf6578|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1996.14.2.422 Trudeau et al. 1996]
 +
|1992-1993
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.33.9507 Nielsen et al. 2011]
 +
|2001-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Gemcitabine|Docetaxel & Gemcitabine]]
 +
| style="background-color:#fee08b" |Might have inferior TTP
 +
|
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860103/ Joensuu et al. 2009 (B9E-MC-S241)]
 +
|2002-2006
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#D.2FG_999|D/G]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTF
 +
| style="background-color:#d73027" |More toxic
 +
|-
 +
|[https://doi.org/10.1200/jco.2008.18.5397 Gradishar et al. 2009]
 +
|2005-2006
 +
| style="background-color:#1a9851" |Randomized Phase 2 (C)
 +
|1. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]; higher-dose weekly<br>2. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]; lower-dose weekly<br> 3. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]; q3wk
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_.26_Bevacizumab|AC & Bevacizumab]]<br>1b. [[#Capecitabine_.26_Bevacizumab|Capecitabine & Bevacizumab]]<br>1c. [[#Docetaxel_.26_Bevacizumab|Docetaxel & Bevacizumab]]<br>1d. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_.26_Bevacizumab|EC & Bevacizumab]]<br>1e. [[#FAC_.26_Bevacizumab|FAC & Bevacizumab]]<br>1f. [[#FEC_.26_Bevacizumab|FEC & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|
 +
|-
 +
|[https://doi.org/10.1200/JCO.2011.35.7376 Bergh et al. 2012 (SUN 1064)]
 +
|2007-2009
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Sunitinib_999|Docetaxel & Sunitinib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div>
−
Alternate schedule:
 
−
*[[Paclitaxel (Taxol)]] 80 mg/m2 IV weekly
 
−
 
 
 
===References===
 
===References===
−
# Seidman AD, Tiersten A, Hudis C, Gollub M, Barrett S, Yao TJ, Lepore J, Gilewski T, Currie V, Crown J et al. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2575-81. [http://jco.ascopubs.org/content/13/10/2575.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/7595709 PubMed]
+
# Trudeau ME, Eisenhauer EA, Higgins BP, Letendre F, Lofters WS, Norris BD, Vandenberg TA, Delorme F, Muldal AM; National Cancer Institute of Canada-Clinical Trials Group. Docetaxel in patients with metastatic breast cancer: a phase II study of the National Cancer Institute of Canada-Clinical Trials Group. J Clin Oncol. 1996 Feb;14(2):422-8. [https://doi.org/10.1200/JCO.1996.14.2.422 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8636752/ PubMed]
−
# Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. [http://www.nejm.org/doi/full/10.1056/NEJM200103153441101 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/11248153 PubMed]
+
# '''Review:''' Burris HA 3rd. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin Oncol. 1999 Jun;26(3 Suppl 9):1-6. [https://pubmed.ncbi.nlm.nih.gov/10426452/ PubMed]
−
# Perez EA, Vogel CL, Irwin DH, Kirshner JJ, Patel R. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2001 Nov 15;19(22):4216-23. [http://jco.ascopubs.org/content/19/22/4216.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/11709565 PubMed]
+
# Burstein HJ, Manola J, Younger J, Parker LM, Bunnell CA, Scheib R, Matulonis UA, Garber JE, Clarke KD, Shulman LN, Winer EP. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol. 2000 Mar;18(6):1212-9. [https://doi.org/10.1200/jco.2000.18.6.1212 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10715290/ PubMed] content property of [https://hemonc.org HemOnc.org]
−
# Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. [http://jco.ascopubs.org/content/23/31/7794.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16172456 PubMed]
+
# Pacilio C, Morabito A, Nuzzo F, Gravina A, Labonia V, Landi G, Rossi E, De Maio E, Di Maio M, D'Aiuto G, Botti G, Normanno N, Chiodini P, Gallo C, Perrone F, de Matteis A; NCI-Naples Breast Cancer Group. Is epirubicin effective in first-line chemotherapy of metastatic breast cancer (MBC) after an epirubicin-containing adjuvant treatment? A single centre phase III trial. Br J Cancer. 2006 May 8;94(9):1233-6. [https://doi.org/10.1038/sj.bjc.6603096 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361414/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16622454/ PubMed]
−
# Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76. [http://www.nejm.org/doi/full/10.1056/NEJMoa072113 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18160686 PubMed]
+
#'''NCIC-CTG MA.16:''' Crump M, Gluck S, Tu D, Stewart D, Levine M, Kirkbride P, Dancey J, O'Reilly S, Shore T, Couban S, Girouard C, Marlin S, Shepherd L, Pritchard KI. Randomized trial of high-dose chemotherapy with autologous peripheral-blood stem-cell support compared with standard-dose chemotherapy in women with metastatic breast cancer: NCIC MA.16. J Clin Oncol. 2008 Jan 1;26(1):37-43. Epub 2007 Nov 19. [https://doi.org/10.1200/jco.2007.11.8851 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18025439/ PubMed] [https://clinicaltrials.gov/study/NCT00003032 NCT00003032]
−
# Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. [http://jco.ascopubs.org/content/26/10/1642.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18375893 PubMed]
+
# Rivera E, Mejia JA, Arun BK, Adinin RB, Walters RS, Brewster A, Broglio KR, Yin G, Esmaeli B, Hortobagyi GN, Valero V. Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic breast cancer. Cancer. 2008 Apr 1;112(7):1455-61. [https://doi.org/10.1002/cncr.23321 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18300256/ PubMed]
−
# Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, Rolski J, Melemed AS, Reyes-Vidal JM, Sekhon JS, Simms L, O'Shaughnessy J. Gemcitabine plus Paclitaxel versus Paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008 Aug 20;26(24):3950-7. [http://jco.ascopubs.org/content/26/24/3950.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18711184 PubMed]
+
# '''JCOG9802:''' Katsumata N, Watanabe T, Minami H, Aogi K, Tabei T, Sano M, Masuda N, Andoh J, Ikeda T, Shibata T, Takashima S. Phase III trial of doxorubicin plus cyclophosphamide (AC), docetaxel, and alternating AC and docetaxel as front-line chemotherapy for metastatic breast cancer: Japan Clinical Oncology Group trial (JCOG9802). Ann Oncol. 2009 Jul;20(7):1210-5. Epub 2009 Mar 2. [https://doi.org/10.1093/annonc/mdn781 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19254942/ PubMed]
−
 
+
<!-- Presented in part at the 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, TX; the 43rd Annual Meeting of the American Society for Clinical Oncology, June 1-5, 2007, Chicago, IL; the 14th European Cancer Conference, September 23-27, 2007, Barcelona, Spain; and the 6th European Breast Cancer Conference, April 15-19, 2008, Berlin, Germany. -->
−
==Paclitaxel, nanoparticle albumin-bound (Abraxane) {{#subobject:5dc417|Regimen=1}}==
+
# Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009 Aug 1;27(22):3611-9. Epub 2009 May 26. Erratum in: J Clin Oncol. 2011 Jul 1;29(19):2739. [https://doi.org/10.1200/jco.2008.18.5397 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19470941/ PubMed]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
# '''DOXIL-BCA-3001:''' Sparano JA, Makhson AN, Semiglazov VF, Tjulandin SA, Balashova OI, Bondarenko IN, Bogdanova NV, Manikhas GM, Oliynychenko GP, Chatikhine VA, Zhuang SH, Xiu L, Yuan Z, Rackoff WR. Pegylated liposomal doxorubicin plus docetaxel significantly improves time to progression without additive cardiotoxicity compared with docetaxel monotherapy in patients with advanced breast cancer previously treated with neoadjuvant-adjuvant anthracycline therapy: results from a randomized phase III study. J Clin Oncol. 2009 Sep 20;27(27):4522-9. Epub 2009 Aug 17. [https://doi.org/10.1200/JCO.2008.20.5013 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19687336/ PubMed] [https://clinicaltrials.gov/study/NCT00091442 NCT00091442]
 +
# '''B9E-MC-S241:''' Joensuu H, Sailas L, Alanko T, Sunela K, Huuhtanen R, Utriainen M, Kokko R, Bono P, Wigren T, Pyrhönen S, Turpeenniemi-Hujanen T, Asola R, Leinonen M, Hahka-Kemppinen M, Kellokumpu-Lehtinen P. Docetaxel versus docetaxel alternating with gemcitabine as treatments of advanced breast cancer: final analysis of a randomised trial. Ann Oncol. 2010 May;21(5):968-73. Epub 2009 Oct 9. [https://doi.org/10.1093/annonc/mdp397 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860103/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19819914/ PubMed] [https://clinicaltrials.gov/study/NCT00191243 NCT00191243]
 +
# '''AVADO:''' Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010 Jul 10;28(20):3239-47. Epub 2010 May 24. [https://doi.org/10.1200/JCO.2008.21.6457 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20498403/ PubMed] [https://clinicaltrials.gov/study/NCT00333775 NCT00333775]
 +
# '''D2:''' Stemmler HJ, Harbeck N, Gröll de Rivera I, Vehling Kaiser U, Rauthe G, Abenhardt W, Artmann A, Sommer H, Meerpohl HG, Kiechle M, Heinemann V. Prospective multicenter randomized phase III study of weekly versus standard docetaxel (D2) for first-line treatment of metastatic breast cancer. Oncology. 2010;79(3-4):197-203. Epub 2011 Mar 1. [https://www.karger.com/Article/FullText/320640 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21358207/ PubMed]
 +
<!-- Presented in part at the 45th Annual Meeting of the American Society for Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and at the 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology Multidisciplinary Congress, September 20-24, 2009, Berlin, Germany. -->
 +
# '''RIBBON-1:''' Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.28.0982 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21383283/ PubMed] [https://clinicaltrials.gov/study/NCT00262067 NCT00262067]
 +
# Nielsen DL, Bjerre KD, Jakobsen EH, Cold S, Stenbygaard L, Sørensen PG, Kamby C, Møller S, Jørgensen CL, Andersson M; Danish Breast Cancer Cooperative Group. Gemcitabine plus docetaxel versus docetaxel in patients with predominantly human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: a randomized, phase III study by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 2011 Dec 20;29(36):4748-54. Epub 2011 Nov 14. [https://doi.org/10.1200/JCO.2010.33.9507 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22084374/ PubMed]
 +
<!-- Presented, in part, at the 46th Annual Meeting of the American Society of Clinical Oncology, June 4-8, 2010, Chicago, IL. -->
 +
# '''SUN 1064:''' Bergh J, Bondarenko IM, Lichinitser MR, Liljegren A, Greil R, Voytko NL, Makhson AN, Cortes J, Lortholary A, Bischoff J, Chan A, Delaloge S, Huang X, Kern KA, Giorgetti C. First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study. J Clin Oncol. 2012 Mar 20;30(9):921-9. Epub 2012 Feb 13. [https://doi.org/10.1200/JCO.2011.35.7376 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22331954/ PubMed] [https://clinicaltrials.gov/study/NCT00393939 NCT00393939]
 +
# '''ROSE/TRIO-12:''' Mackey JR, Ramos-Vazquez M, Lipatov O, McCarthy N, Krasnozhon D, Semiglazov V, Manikhas A, Gelmon KA, Konecny GE, Webster M, Hegg R, Verma S, Gorbunova V, Abi Gerges D, Thireau F, Fung H, Simms L, Buyse M, Ibrahim A, Martín M. Primary results of ROSE/TRIO-12, a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer. J Clin Oncol. 2015 Jan 10;33(2):141-8. Epub 2014 Sep 2. [https://doi.org/10.1200/JCO.2014.57.1513 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25185099/ PubMed] [https://clinicaltrials.gov/study/NCT00703326 NCT00703326]
 +
# '''SELECT BC:''' Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T, Hozumi Y, Tsurutani J, Imoto S, Watanabe T, Sagara Y, Nishimura R, Shimozuma K, Ohashi Y; SELECT BC Study Group. Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2016 Jan;17(1):90-8. Epub 2015 Nov 27. [https://doi.org/10.1016/S1470-2045(15)00411-8 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26617202/ PubMed] UMIN C000000416
 +
## '''HRQoL analysis:''' Shiroiwa T, Fukuda T, Shimozuma K, Mouri M, Hagiwara Y, Doihara H, Akabane H, Kashiwaba M, Watanabe T, Ohashi Y, Mukai H. Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial. Qual Life Res. 2017 Feb;26(2):445-453. Epub 2016 Aug 12. [https://doi.org/10.1007/s11136-016-1388-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288429/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27517267/ PubMed]
 +
==Docetaxel & Bevacizumab {{#subobject:65222f|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 75/15, indefinite {{#subobject:4040c4|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-363-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 +
|-
 +
|} -->
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]]<br>1b. [[#Capecitabine_monotherapy_2|Capecitabine]]<br>1c. [[#Docetaxel_monotherapy_2|Docetaxel]]<br>1d. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]]<br>1e. [[#FAC_3|FAC]]<br>1f. [[#FEC_3|FEC]]<br>1g. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>(HR 0.64, 95% CI 0.52-0.80)
 +
|-
 +
|[https://doi.org/10.1007/s10549-014-3217-y Lück et al. 2014 (TABEA)]
 +
|2009-2012
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Docetaxel_.28TX.29_.26_Bevacizumab_999|TX & Bevacizumab]]<br>1b. [[#Capecitabine.2C_Paclitaxel.2C_Bevacizumab_999|Capecitabine, Paclitaxel, Bevacizumab]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdw077 Trédan et al. 2016 (GINECO-BR107)]
 +
|2010-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Bevacizumab|Docetaxel & Bevacizumab]], then [[#Exemestane_.26_Bevacizumab_999|Exemestane & Bevacizumab]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Example orders===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Example orders for Paclitaxel, nanoparticle albumin-bound (Abraxane) in breast cancer]]
+
====Chemotherapy====
−
 
+
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
−
===Regimen #1, Gradishar et al. 2009 {{#subobject:f0096c|Variant=1}}===
+
====Targeted therapy====
−
Level of Evidence:
+
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
−
<span
 
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Randomized Phase II, >20 per arm</span>
 
−
 
 
−
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 or 150 mg/m2 IV once per day on days 1, 8, 15
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===Regimen #2, Gradishar et al. 2005 {{#subobject:bf6371|Variant=1}}===
 
−
Level of Evidence:
 
−
<span
 
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 260 mg/m2 IV over 30 minutes once on day 1
 
−
 
 
 
'''21-day cycles'''
 
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
Supportive medications:
+
===Regimen variant #2, 100/15, 9 cycles {{#subobject:48a438|Variant=1}}===
−
*No corticosteroid or antihistamine premedication
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
 
+
!style="width: 20%"|Study
−
===Regimen #3, Gradishar et al. 2009 {{#subobject:11b87e|Variant=1}}===
+
!style="width: 20%"|Dates of enrollment
−
Level of Evidence:
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
<span
+
!style="width: 20%"|Comparator
−
style="background:#00CD00;
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
padding:3px 6px 3px 6px;
+
|-
−
border-color:black;
+
|rowspan=2|[https://doi.org/10.1200/JCO.2008.21.6457 Miles et al. 2010 (AVADO)]
−
border-width:2px;
+
|rowspan=2|2006-03 to 2007-04
−
border-style:solid;">Randomized Phase II, >20 per arm</span>
+
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-esc)
−
 
+
|1. [[#Docetaxel_monotherapy_2|Docetaxel]]
−
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 300 mg/m2 IV over 30 minutes once on day 1
+
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 10.1 vs 8.2 mo<br>(HR 0.77, 95% CI 0.64-0.93)
−
 
+
|-
 +
|2. [[#Docetaxel_.26_Bevacizumab|Docetaxel & Bevacizumab]]; 100/7.5
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
 +
'''21-day cycle for up to 9 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Bevacizumab_monotherapy_2|Bevacizumab]] maintenance
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 100/15, indefinite {{#subobject:8bn438|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-363-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 +
|-
 +
|} -->
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]]<br>1b. [[#Capecitabine_monotherapy_2|Capecitabine]]<br>1c. [[#Docetaxel_monotherapy_2|Docetaxel]]<br>1d. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]]<br>1e. [[#FAC_3|FAC]]<br>1f. [[#FEC_3|FEC]]<br>1g. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>(HR 0.64, 95% CI 0.52-0.80)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
−
# Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. [http://jco.ascopubs.org/content/23/31/7794.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16172456 PubMed]
+
# '''AVADO:''' Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010 Jul 10;28(20):3239-47. Epub 2010 May 24. [https://doi.org/10.1200/JCO.2008.21.6457 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20498403/ PubMed] [https://clinicaltrials.gov/study/NCT00333775 NCT00333775]
−
# Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009 Aug 1;27(22):3611-9. doi: 10.1200/JCO.2008.18.5397. Epub 2009 May 26. Erratum in: J Clin Oncol. 2011 Jul 1;29(19):2739. [http://jco.ascopubs.org/content/27/22/3611.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19470941 PubMed]
+
<!-- Presented in part at the 45th Annual Meeting of the American Society for Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and at the 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology Multidisciplinary Congress, September 20-24, 2009, Berlin, Germany. -->
 +
# '''RIBBON-1:''' Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.28.0982 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21383283/ PubMed] [https://clinicaltrials.gov/study/NCT00262067 NCT00262067]
 +
# '''TABEA:''' Lück HJ, Lübbe K, Reinisch M, Maass N, Feisel-Schwickardi G, Tomé O, Janni W, Aydogdu M, Neunhöffer T, Ober A, Aktas B, Park-Simon TW, Schumacher C, Höffkes HG, Illmer T, Wagner H, Mehta K, von Minckwitz G, Nekljudova V, Loibl S. Phase III study on efficacy of taxanes plus bevacizumab with or without capecitabine as first-line chemotherapy in metastatic breast cancer. Breast Cancer Res Treat. 2015 Jan;149(1):141-9. Epub 2014 Dec 18. [https://doi.org/10.1007/s10549-014-3217-y link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25519041/ PubMed]
 +
# '''GINECO-BR107:''' Trédan O, Follana P, Moullet I, Cropet C, Trager-Maury S, Dauba J, Lavau-Denes S, Diéras V, Béal-Ardisson D, Gouttebel M, Orfeuvre H, Stefani L, Jouannaud C, Bürki F, Petit T, Guardiola E, Becuwe C, Blot E, Pujade-Lauraine E, Bachelot T. A phase III trial of exemestane plus bevacizumab maintenance therapy in patients with metastatic breast cancer after first-line taxane and bevacizumab: a GINECO group study. Ann Oncol. 2016 Jun;27(6):1020-9. Epub 2016 Feb 24. [https://doi.org/10.1093/annonc/mdw077 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26916095/ PubMed] [https://clinicaltrials.gov/study/NCT01303679 NCT01303679]
 +
==Docetaxel & Doxorubicin (AT) {{#subobject:145802|Regimen=1}}==
 +
AT: '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>T</u>'''axotere (Docetaxel)
 +
<br>AD: '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>D</u>'''ocetaxel
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 50/75 x 4 {{#subobject:9cca82|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1007/s10549-007-9651-3 Cassier et al. 2007 (ERASME 3)]
 +
|2000-2004
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Doxorubicin_.26_Paclitaxel_.28AT.29_2|AT (Taxol)]]
 +
| style="background-color:#fee08b" |Might have inferior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] as follows:
 +
**Cycles 1 to 4: 50 mg/m<sup>2</sup> IV over 15 minutes once on day 1, '''given first'''
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1, '''given second'''
 +
'''21-day cycle for 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 50/75 x 6 {{#subobject:9c6b82|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.06.236 Bontenbal et al. 2005]
 +
|1997-2002
 +
| style="background-color:#1a9851" |Phase 2/3 (E-de-esc)
 +
|[[#FAC_3|FAC]]
 +
| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br><br>Superior TTP (primary endpoint)
 +
|
 +
|-
 +
|[https://doi.org/10.1200/JCO.2004.08.125 Alba et al. 2004 (GEICAM-9903)]
 +
|1999-2001
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#A-D_888|A-D]]
 +
|
 +
| style="background-color:#d73027" |More toxic
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
==Pemetrexed (Alimta) {{#subobject:93e4ed|Regimen=1}}==
+
===Regimen variant #3, 50/75 x 8 {{#subobject:9cba382|Variant=1}}===
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2003.04.040 Nabholtz et al. 2003 (TAX 306)]
 +
|NR
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]]
 +
| style="background-color:#91cf60" |Seems to have superior TTP
 +
|
 +
|-
 +
|[https://www.karger.com/Article/Abstract/320625 Stemmler et al. 2010 (D4)]
 +
|2001-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Doxorubicin_.28AT.29|AT (Taxotere)]]; weekly docetaxel
 +
| style="background-color:#ffffbf" |Did not meet secondary endpoint of TTP
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of hematotoxicity
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen #1, Robert et al. 2011 {{#subobject:a2f6d|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
−
style="background:#EEEE00;
+
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
−
padding:3px 6px 3px 6px;
+
'''21-day cycle for 8 cycles'''
−
border-color:black;
+
</div></div>
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
−
 
 
−
*[[Pemetrexed (Alimta)]] 600 mg/m2 IV on day 1
 
−
 
 
−
'''14-day cycles, given until progression of disease or unacceptable toxicity'''
 
−
 
 
−
Supportive medications:
 
−
*[[Dexamethasone (Decadron)]] 4 mg PO BID the day before, day of, and day after chemotherapy
 
−
*Folic acid 350-1000 mcg PO daily, to start at least 5 days prior to start of pemetrexed therapy, to continue throughout therapy with pemetrexed, and until 3 weeks after the last dose of pemetrexed
 
−
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM every 8-10 weeks, the first dose given at least 1 week prior to start of pemetrexed therapy, to continue throughout therapy with pemetrexed, and until 3 weeks after the last dose of pemetrexed
 
−
 
 
−
===Regimen #2, Gomez et al. 2006 {{#subobject:b49e6b|Variant=1}}===
 
−
Level of Evidence:
 
−
<span
 
−
style="background:#EEEE00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
−
 
 
−
''Patients in the study were "chemotherapy-naïve, with advanced (T4 and N0-N2, M0, M1) breast cancer."''
 
−
*[[Pemetrexed (Alimta)]] 500 mg/m2 IV over 10 minutes on day 1
 
−
 
 
−
'''21-day cycles x up to 3 cycles'''
 
−
 
 
−
Supportive medications:
 
−
*[[Dexamethasone (Decadron)]] 4 mg PO BID the day before, day of, and day after chemotherapy
 
−
*Folic acid 350-1000 mcg PO daily, to start 5-7 days prior to start of pemetrexed therapy, to continue throughout therapy with pemetrexed
 
−
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM every 9 weeks, the first dose given before the study's pretreatment biopsy, to continue throughout therapy with pemetrexed
 
−
 
 
 
===References===
 
===References===
−
# Gomez HL, Santillana SL, Vallejos CS, Velarde R, Sanchez J, Wang X, Bauer NL, Hockett RD, Chen VJ, Niyikiza C, Hanauske AR. A phase II trial of pemetrexed in advanced breast cancer: clinical response and association with molecular target expression. Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):832-8. [http://clincancerres.aacrjournals.org/content/12/3/832.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16467096 PubMed]
+
# '''TAX 306:''' Nabholtz JM, Falkson C, Campos D, Szanto J, Martín M, Chan S, Pienkowski T, Zaluski J, Pinter T, Krzakowski M, Vorobiof D, Leonard R, Kennedy I, Azli N, Murawsky M, Riva A, Pouillart P; TAX 306 Study Group. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol. 2003 Mar 15;21(6):968-75. [https://doi.org/10.1200/jco.2003.04.040 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12637459/ PubMed]
−
# Robert NJ, Conkling PR, O'Rourke MA, Kuefler PR, McIntyre KJ, Zhan F, Asmar L, Wang Y, Shonukan OO, O'Shaughnessy JA. Results of a phase II study of pemetrexed as first-line chemotherapy in patients with advanced or metastatic breast cancer. Breast Cancer Res Treat. 2011 Feb;126(1):101-8. Epub 2010 Dec 25. [http://www.springerlink.com/content/b1354n1r36631118 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21188632 PubMed]
+
# '''GEICAM-9903:''' Alba E, Martín M, Ramos M, Adrover E, Balil A, Jara C, Barnadas A, Fernández-Aramburo A, Sánchez-Rovira P, Amenedo M, Casado A; GEICAM. Multicenter randomized trial comparing sequential with concomitant administration of doxorubicin and docetaxel as first-line treatment of metastatic breast cancer: a Spanish Breast Cancer Research Group (GEICAM-9903) phase III study. J Clin Oncol. 2004 Jul 1;22(13):2587-93. [https://doi.org/10.1200/JCO.2004.08.125 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15226326/ PubMed]
−
 
+
# Bontenbal M, Creemers GJ, Braun HJ, de Boer AC, Janssen JT, Leys RB, Ruit JB, Goey SH, van der Velden PC, Kerkhofs LG, Schothorst KL, Schmitz PI, Bokma HJ, Verweij J, Seynaeve C; Dutch Community Setting Trial for the Clinical Trial Group. Phase II to III study comparing doxorubicin and docetaxel with fluorouracil, doxorubicin, and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer: results of a Dutch Community Setting Trial for the Clinical Trial Group of the Comprehensive Cancer Centre. J Clin Oncol. 2005 Oct 1;23(28):7081-8. [https://doi.org/10.1200/JCO.2005.06.236 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16192591/ PubMed]
−
==Vinorelbine (Navelbine) {{#subobject:5c104c|Regimen=1}}==
+
# '''ERASME 3:''' Cassier PA, Chabaud S, Trillet-Lenoir V, Peaud PY, Tigaud JD, Cure H, Orfeuvre H, Salles B, Martin C, Jacquin JP, Agostini C, Guastalla JP, Pérol D, Bachelot T. A phase-III trial of doxorubicin and docetaxel versus doxorubicin and paclitaxel in metastatic breast cancer: results of the ERASME 3 study. Breast Cancer Res Treat. 2008 May;109(2):343-50. Epub 2007 Jul 5. [https://doi.org/10.1007/s10549-007-9651-3 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17611792/ PubMed]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
# '''D4:''' Stemmler HJ, Harbeck N, Gröll de Rivera I, Vehling Kaiser U, Rauthe G, Abenhardt W, Artmann A, Sommer H, Meerpohl HG, Kiechle M, Heinemann V. Prospective multicenter randomized phase III study of weekly versus standard docetaxel plus doxorubicin (D4) for first-line treatment of metastatic breast cancer. Oncology. 2010;79(3-4):204-10. Epub 2011 Mar 1. [https://www.karger.com/Article/Abstract/320625 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21358208/ PubMed]
 +
==Docetaxel & Epirubicin (DE) {{#subobject:8039af|Regimen=1}}==
 +
DE: '''<u>D</u>'''ocetaxel & '''<u>E</u>'''pirubicin
 +
<br>ED: '''<u>E</u>'''pirubicin & '''<u>D</u>'''ocetaxel
 +
<br>ET: '''<u>E</u>'''pirubicin & '''<u>T</u>'''axotere (Docetaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 8 cycles {{#subobject:ab14d5|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409942/ Bonneterre et al. 2004]
 +
|1998-2000
 +
| style="background-color:#1a9851" |Randomized Phase 2 (E-de-esc)
 +
|[[#FEC_3|FEC]]
 +
| style="background-color:#1a9850" |Superior ORR (primary endpoint)
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdp585 Blohmer et al. 2010]
 +
|2000-2003
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, indefinite {{#subobject:bu13d5|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdp498 Mavroudis et al. 2009 (HORG CT/02.09)]
 +
|2002-2007
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Docetaxel_.28TX.29_2|TX]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:c0c952|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
−
style="background:#EEEE00;
+
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
−
padding:3px 6px 3px 6px;
+
'''21-day cycles'''
−
border-color:black;
+
</div></div>
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
−
 
 
−
*[[Vinorelbine (Navelbine)]] 25 mg/m2 IV weekly
 
−
 
 
 
===References===
 
===References===
−
# Gasparini G, Caffo O, Barni S, Frontini L, Testolin A, Guglielmi RB, Ambrosini G. Vinorelbine is an active antiproliferative agent in pretreated advanced breast cancer patients: a phase II study. J Clin Oncol. 1994 Oct;12(10):2094-101. [http://jco.ascopubs.org/content/12/10/2094.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/7931479 PubMed]
+
# Bonneterre J, Dieras V, Tubiana-Hulin M, Bougnoux P, Bonneterre ME, Delozier T, Mayer F, Culine S, Dohoulou N, Bendahmane B. Phase II multicentre randomised study of docetaxel plus epirubicin vs 5-fluorouracil plus epirubicin and cyclophosphamide in metastatic breast cancer. Br J Cancer. 2004 Oct 18;91(8):1466-71. [https://doi.org/10.1038/sj.bjc.6602179 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409942/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15381937/ PubMed]
−
# Zelek L, Barthier S, Riofrio M, Fizazi K, Rixe O, Delord JP, Le Cesne A, Spielmann M. Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer. 2001 Nov 1;92(9):2267-72. [http://www.ncbi.nlm.nih.gov/pubmed/11745280 PubMed]
+
# '''HORG CT/02.09:''' Mavroudis D, Papakotoulas P, Ardavanis A, Syrigos K, Kakolyris S, Ziras N, Kouroussis C, Malamos N, Polyzos A, Christophyllakis C, Kentepozidis N, Georgoulias V; Hellenic Oncology Research Group. Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer. Ann Oncol. 2010 Jan;21(1):48-54. Epub 2009 Nov 11. [https://doi.org/10.1093/annonc/mdp498 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19906761/ PubMed] [https://clinicaltrials.gov/study/NCT00429871 NCT00429871]
−
 
+
# Blohmer JU, Schmid P, Hilfrich J, Friese K, Kleine-Tebbe A, Koelbl H, Sommer H, Morack G, Wischnewsky MB, Lichtenegger W, Kuemmel S. Epirubicin and cyclophosphamide versus epirubicin and docetaxel as first-line therapy for women with metastatic breast cancer: final results of a randomised phase III trial. Ann Oncol. 2010 Jul;21(7):1430-5. Epub 2010 Jan 20. [https://doi.org/10.1093/annonc/mdp585 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20089562/ PubMed]
−
=Metastatic disease, combination chemotherapy=
+
==Docetaxel & Gemcitabine {{#subobject:031a92|Regimen=1}}==
−
==AC {{#subobject:843320|Regimen=1}}==
+
GD: '''<u>G</u>'''emcitabine & '''<u>D</u>'''ocetaxel
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<br>GDoc: '''<u>G</u>'''emcitabine & '''<u>Doc</u>'''etaxel
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:c95bcd|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.33.9507 Nielsen et al. 2011]
 +
|2001-2005
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Docetaxel_monotherapy_2|Docetaxel]]
 +
| style="background-color:#d9ef8b" |Might have superior TTP (primary endpoint)
 +
|-
 +
|rowspan=2|[https://doi.org/10.1007/s10549-008-0047-9 Fountzilas et al. 2008]
 +
|rowspan=2|2002-2006
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_999|Carboplatin & Paclitaxel]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|2. [[#Paclitaxel_monotherapy.2C_weekly_2|Paclitaxel]]; weekly
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdq578 Seidman et al. 2010 (B9E-MC-S273)]
 +
|2002-2008
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Capecitabine_.26_Docetaxel_.28TX.29_2|TX]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3621657/ Del Mastro et al. 2013 (B9E-IT-S376)]
 +
|2005-2010
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|1. [[#Docetaxel_.26_Gemcitabine|GD]]; weekly<br>2. [[#Gemcitabine_.26_Paclitaxel|GT]]; q3wk<br> 3. [[#Gemcitabine_.26_Paclitaxel|GT]]; weekly
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
AC: '''<u>A</u>'''driamycin, '''<u>C</u>'''yclophosphamide
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
===Regimen {{#subobject:2e4988|Variant=1}}===
+
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
−
Level of Evidence:
+
**Nielsen et al. 2011 gave docetaxel on day 8
−
<span
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Doxorubicin (Adriamycin)]] 60 mg/m2 IV day 1
 
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV day 1
 
−
 
 
 
'''21-day cycles'''
 
'''21-day cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*B9E-MC-S273, upon progression: Second-line [[#Capecitabine_monotherapy_3|Capecitabine]]
 +
</div></div>
 +
===References===
 +
# Fountzilas G, Dafni U, Dimopoulos MA, Koutras A, Skarlos D, Papakostas P, Gogas H, Bafaloukos D, Kalogera-Fountzila A, Samantas E, Briasoulis E, Pectasides D, Maniadakis N, Matsiakou F, Aravantinos G, Papadimitriou C, Karina M, Christodoulou C, Kosmidis P, Kalofonos HP; Hellenic Cooperative Oncology Group. A randomized phase III study comparing three anthracycline-free taxane-based regimens, as first line chemotherapy, in metastatic breast cancer: a Hellenic Cooperative Oncology Group study. Breast Cancer Res Treat. 2009 May;115(1):87-99. Epub 2008 May 16. [https://doi.org/10.1007/s10549-008-0047-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18483853/ PubMed]
 +
# '''B9E-MC-S273:''' Seidman AD, Brufsky A, Ansari RH, Hart LL, Stein RS, Schwartzberg LS, Stewart JF, Russell CA, Chen SC, Fein LE, De La Cruz Vargas JA, Kim SB, Cavalheiro J, Zhao L, Gill JF, Obasaju CK, Orlando M, Tai DF. Phase III trial of gemcitabine plus docetaxel versus capecitabine plus docetaxel with planned crossover to the alternate single agent in metastatic breast cancer. Ann Oncol. 2011 May;22(5):1094-101. Epub 2010 Nov 17. [https://doi.org/10.1093/annonc/mdq578 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21084429/ PubMed] [https://clinicaltrials.gov/study/NCT00191438 NCT00191438]
 +
## '''Pooled update:''' Seidman AD, Chan S, Wang J, Zhu C, Xu C, Xu B. A pooled analysis of gemcitabine plus docetaxel versus capecitabine plus docetaxel in metastatic breast cancer. Oncologist. 2014 May;19(5):443-52. Epub 2014 Apr 4. [https://doi.org/10.1634/theoncologist.2013-0428 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4012969/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24705980/ PubMed]
 +
# Nielsen DL, Bjerre KD, Jakobsen EH, Cold S, Stenbygaard L, Sørensen PG, Kamby C, Møller S, Jørgensen CL, Andersson M; Danish Breast Cancer Cooperative Group. Gemcitabine plus docetaxel versus docetaxel in patients with predominantly human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: a randomized, phase III study by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 2011 Dec 20;29(36):4748-54. Epub 2011 Nov 14. [https://doi.org/10.1200/JCO.2010.33.9507 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/22084374/ PubMed]
 +
# '''B9E-IT-S376:''' Del Mastro L, Fabi A, Mansutti M, De Laurentiis M, Durando A, Merlo DF, Bruzzi P, La Torre I, Ceccarelli M, Kazeem G, Marchi P, Boy D, Venturini M, De Placido S, Cognetti F. Randomised phase 3 open-label trial of first-line treatment with gemcitabine in association with docetaxel or paclitaxel in women with metastatic breast cancer: a comparison of different schedules and treatments. BMC Cancer. 2013 Mar 28;13:164. [https://doi.org/10.1186/1471-2407-13-164 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3621657/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/23537313/ PubMed] [https://clinicaltrials.gov/study/NCT00236899 NCT00236899]
 +
==Doxorubicin monotherapy {{#subobject:8a2b88|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 20 mg/m<sup>2</sup> weekly {{#subobject:96cac2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/0277-5379(86)90075-1 Gundersen et al. 1986]
 +
|1982-06 to 1983-12
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[Breast_cancer_-_historical#CAV|VAC]]
 +
| style="background-color:#ffffbf" |Did not meet endpoint of OS
 +
|-
 +
|[https://doi.org/10.1016/0277-5379(90)90255-r Gundersen et al. 1990]
 +
|1984-1986
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Epirubicin_monotherapy_2|Epirubicin]]
 +
| style="background-color:#ffffbf" |Did not meet endpoints of ORR/OS
 +
|-
 +
|[https://doi.org/10.1016/0959-8049(94)00213-o Gundersen et al. 1994]
 +
|1987-1990
 +
| style="background-color:#1a9851" |Randomized (C)
 +
|[[#Doxorubicin_.26_MPA_333|Doxorubicin & MPA]]
 +
| style="background-color:#fee08b" |Might have inferior ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 20 mg/m<sup>2</sup> IV once on day 1
 +
'''7-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 60 mg/m<sup>2</sup> q3wk {{#subobject:cf8189|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(197402)33:2%3C519::AID-CNCR2820330229%3E3.0.CO;2-X Gottlieb et al. 1974 (SWG02)]
 +
|1972-01 to 1972-10
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|1. [[#Lomustine_monotherapy_999|Lomustine]]<br>2. [[#Semustine_monotherapy_999|Semustine]]
 +
| style="background-color:#1a9850" |Superior OS
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(197607)38:1%3C13::AID-CNCR2820380104%3E3.0.CO;2-5 Hoogstraten et al. 1976]
 +
|1972-1974
 +
|style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer_-_historical_#CMFVP_2|CMFVP]]
 +
| style="background-color:#fc8d59" |Seems to have inferior ORR
 +
|-
 +
|[https://doi.org/10.1002/mpo.2950160505 Vaughn et al. 1988 (SWOG S8020)]
 +
|1980-1982
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Doxorubicin_.26_Etoposide_888|Doxorubicin & Etoposide]]
 +
| style="background-color:#fc8d59" |Seems to have inferior TTP
 +
|-
 +
|[https://doi.org/10.1097/00000421-198912000-00003 Ingle et al. 1989]
 +
|1982-11 to 1987-02
 +
| style="background-color:#1a9851" |Randomized (C)
 +
|[[#DVM_888|DVM]]
 +
| style="background-color:#fc8d59" |Seems to have inferior TTP
 +
|-
 +
|[https://doi.org/10.1200/JCO.1991.9.12.2148 Perez et al. 1991]
 +
|1985-1988
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Epirubicin_monotherapy_2|Epirubicin]]
 +
| style="background-color:#ffffbf" |Did not meet endpoints of ORR/OS
 +
|-
 +
|[https://doi.org/10.1200/JCO.2000.18.12.2385 Norris et al. 2000 (NCIC-CTG MA.8)]
 +
|1992-1995
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Doxorubicin_.26_Vinorelbine_.28NA.29_999|NA]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|rowspan=2|[https://doi.org/10.1200/JCO.2003.08.013 Sledge et al. 2003 (ECOG E1193)]
 +
|rowspan=2|1993-1995
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Doxorubicin_.26_Paclitaxel_.28AT.29_2|AT (Taxol)]]
 +
| style="background-color:#d73027" |Inferior TTF
 +
|-
 +
|2. [[#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdh097 O'Brien et al. 2004]
 +
|1998-06 to 2000-08
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Pegylated_liposomal_doxorubicin_monotherapy|PLD]]
 +
| style="background-color:#eeee01" |Seems to have non-inferior PFS (co-primary endpoint)
 +
|-
 +
|}
 +
''Note: in NCIC-CTG MA.8, this dose was after a mid-protocol amendment. Treatment in NCIC-CTG MA.8 was given until a cumulative dose of 450 mg/m<sup>2</sup>. Treatment in Ingle et al. 1989 was given until a cumulative dose of 500 mg/m<sup>2</sup>.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles (see note)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
 +
===Regimen variant #3, 75 mg/m<sup>2</sup> q3wk {{#subobject:1982c0|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2000.18.4.724 Paridaens et al. 2000 (EORTC 10923)]
 +
|1993-1996
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 7 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, Bowman D, Wolmark N, Wickerham DL, Kardinal CG et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol. 1990 Sep;8(9):1483-96. [http://jco.ascopubs.org/content/8/9/1483.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/2202791 PubMed]
+
# '''SWG02:''' Gottlieb JA, Rivkin SE, Spigel SC, Hoogstraten B, O'Bryan RM, Delaney FC, Singhakowinta A; [[Study_Groups#SWOG|SWOG]]. Proceedings: Superiority of adriamycin over oral nitrosoureas in patients with advanced breast carcinoma: a Southwest Cancer Chemotherapy study Group study. Cancer. 1974 Feb;33(2):519-26. [https://doi.org/10.1002/1097-0142(197402)33:2%3C519::AID-CNCR2820330229%3E3.0.CO;2-X link to original article] [https://pubmed.ncbi.nlm.nih.gov/4812769/ PubMed]
−
# Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. [http://www.nejm.org/doi/full/10.1056/NEJM200103153441101 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/11248153 PubMed]
+
# Hoogstraten B, George SL, Samal B, Rivkin SE, Costanzi JJ, Bonnet JD, Thigpen T, Braine H; [[Study_Groups#SWOG|SWOG]]. Combination chemotherapy and adriamycin in patients with advanced breast cancer: a Southwest Oncology Group study. Cancer. 1976 Jul;38(1):13-20. [https://doi.org/10.1002/1097-0142(197607)38:1%3C13::AID-CNCR2820380104%3E3.0.CO;2-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/947510/ PubMed]
−
# Nabholtz JM, Falkson C, Campos D, Szanto J, Martin M, Chan S, Pienkowski T, Zaluski J, Pinter T, Krzakowski M, Vorobiof D, Leonard R, Kennedy I, Azli N, Murawsky M, Riva A, Pouillart P; TAX 306 Study Group. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol. 2003 Mar 15;21(6):968-75. [http://jco.ascopubs.org/content/21/6/968.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/12637459 PubMed]
+
# Gundersen S, Kvinnsland S, Klepp O, Kvaløy S, Lund E, Høst H. Weekly adriamycin versus VAC in advanced breast cancer: a randomized trial. Eur J Cancer Clin Oncol. 1986 Dec;22(12):1431-4. [https://doi.org/10.1016/0277-5379(86)90075-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3595668/ PubMed]
 +
# '''SWOG S8020:''' Vaughn CB, Green SJ, O'Bryan R, Reed M, Grozea PN, Fletcher WS, Green JB, Metch B, Oishi N. VP-16 + adriamycin vs adriamycin alone in advanced adenocarcinoma of the breast, phase II, a randomized trial: a Southwest Oncology Group Study. Med Pediatr Oncol. 1988;16(5):312-9. [https://doi.org/10.1002/mpo.2950160505 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/3054453/ PubMed]
 +
# Ingle JN, Mailliard JA, Schaid DJ, Krook JE, Gerstner JB, Pfeifle DM, Marschke RF Jr, Long HJ, McCormack GW, Foley JF; NCCTG. Randomized trial of doxorubicin alone or combined with vincristine and mitomycin C in women with metastatic breast cancer. Am J Clin Oncol. 1989 Dec;12(6):474-80. [https://doi.org/10.1097/00000421-198912000-00003 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/2686393/ PubMed]
 +
# Gundersen S, Kvinnsland S, Klepp O, Lund E, Høst H; Norwegian Breast Cancer Group. Weekly Adriamycin vs 4-epidoxorubicin every second week in advanced breast cancer: a randomized trial. Eur J Cancer. 1990 Jan;26(1):45-8. [https://doi.org/10.1016/0277-5379(90)90255-r link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/2138477/ PubMed]
 +
# Perez DJ, Harvey VJ, Robinson BA, Atkinson CH, Dady PJ, Kirk AR, Evans BD, Chapman PJ. A randomized comparison of single-agent doxorubicin and epirubicin as first-line cytotoxic therapy in advanced breast cancer. J Clin Oncol. 1991 Dec;9(12):2148-52. [https://doi.org/10.1200/JCO.1991.9.12.2148 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/1960557/ PubMed]
 +
# Gundersen S, Hannisdal E, Lundgren S, Wist E; Norwegian Breast Cancer Group. Weekly doxorubicin with or without high-dose medroxyprogesterone acetate in hormone-resistant advanced breast cancer: a randomised study. Eur J Cancer. 1994;30A(12):1775-8. [https://doi.org/10.1016/0959-8049(94)00213-o link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7880604/ PubMed]
 +
# '''EORTC 10923:''' Paridaens R, Biganzoli L, Bruning P, Klijn JG, Gamucci T, Houston S, Coleman R, Schachter J, Van Vreckem A, Sylvester R, Awada A, Wildiers J, Piccart M. Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European Organisation for Research and Treatment of Cancer Randomized Study with cross-over. J Clin Oncol. 2000 Feb;18(4):724-33. [https://doi.org/10.1200/JCO.2000.18.4.724 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10673513/ PubMed]
 +
## '''HRQoL analysis:''' Kramer JA, Curran D, Piccart M, de Haes JC, Bruning PF, Klijn JG, Bontenbal M, van Pottelsberghe C, Groenvold M, Paridaens R. Randomised trial of paclitaxel versus doxorubicin as first-line chemotherapy for advanced breast cancer: quality of life evaluation using the EORTC QLQ-C30 and the Rotterdam symptom checklist. Eur J Cancer. 2000 Aug;36(12):1488-97. [https://doi.org/10.1016/s0959-8049(00)00134-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10930796/ PubMed]
 +
# '''NCIC-CTG MA.8:''' Norris B, Pritchard KI, James K, Myles J, Bennett K, Marlin S, Skillings J, Findlay B, Vandenberg T, Goss P, Latreille J, Rudinskas L, Lofters W, Trudeau M, Osoba D, Rodgers A. Phase III comparative study of vinorelbine combined with doxorubicin versus doxorubicin alone in disseminated metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group study MA8. J Clin Oncol. 2000 Jun;18(12):2385-94. [https://doi.org/10.1200/JCO.2000.18.12.2385 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10856098/ PubMed]
 +
# '''ECOG E1193:''' Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, Wood WC. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol. 2003 Feb 15;21(4):588-92. [https://doi.org/10.1200/JCO.2003.08.013 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12586793/ PubMed]
 +
# O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C; CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004 Mar;15(3):440-9. [https://doi.org/10.1093/annonc/mdh097 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14998846/ PubMed]
  
−
 
+
==Doxorubicin & Paclitaxel (AT) {{#subobject:86ac2d|Regimen=1}}==
−
==AT (Taxol) {{#subobject:86ac2d|Regimen=1}}==
+
AT: '''<u>A</u>'''driamycin (Doxorubicin) & '''<u>T</u>'''axol (Paclitaxel)
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 50/150 {{#subobject:bf9bd0|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2003.08.013 Sledge et al. 2003 (ECOG E1193)]
 +
|1993-1995
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[#Doxorubicin_monotherapy|Doxorubicin]]<br>2. [[#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel]]; q3wk
 +
| style="background-color:#1a9850" |Superior TTF
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] as follows, '''given first''':
 +
**Cycles 1 to 8: 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Paclitaxel (Taxol)]] 150 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1, '''given second, 3 hours after doxorubicin'''
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 50/175 {{#subobject:9cfac2|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1007/s10549-007-9651-3 Cassier et al. 2007 (ERASME 3)]
 +
|2000-2004
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Docetaxel_.26_Doxorubicin_.28AT.29|AT (Taxotere)]]
 +
| style="background-color:#d9ef8b" |Might have superior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] as follows:
 +
**Cycles 1 to 4: 50 mg/m<sup>2</sup> IV over 15 minutes once on day 1, '''given first'''
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given second'''
 +
'''21-day cycle for 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 50/220 {{#subobject:adad22|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2001.19.6.1707 Jassem et al. 2001]
 +
|1996-1998
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[#FAC_3|FAC]]
 +
| style="background-color:#1a9850" |Superior OS<sup>1</sup><br>Median OS: 23 vs 18.3 mo
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy is based on the 2009 update.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Paclitaxel (Taxol)]] 220 mg/m<sup>2</sup> IV over 3 hours once on day 2
 +
'''21-day cycle for up to 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 60/200 {{#subobject:91549a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2002.11.005 Biganzoli et al. 2002 (EORTC 10961)]
 +
|1996-1999
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.06.072 Schmid et al. 2005]
 +
|1998-2002
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|Tandem auto HSCT
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of CR rate
 +
|-
 +
|}
 +
''Note: in EORTC 10961, first cycle of paclitaxel was 175 mg/m<sup>2</sup>.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV over 15 minutes once on day 1
 +
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1
 +
'''21-day cycle for up to 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, with range {{#subobject:1f6e13|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.1995.13.11.2688 Gianni et al. 1995]
 +
|1993-1994
 +
| style="background-color:#91cf61" |Non-randomized
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
AT: '''<u>A</u>'''driamycin, '''<u>T</u>'''axol
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
===Regimen {{#subobject:1f6e13|Variant=1}}===
+
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
−
Level of Evidence:
+
*[[Paclitaxel (Taxol)]] 125 to 200 mg/m<sup>2</sup> IV once on day 1
−
<span
 
−
style="background:#EEEE00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Non-randomized</span>
 
−
 
 
−
*[[Doxorubicin (Adriamycin)]] 60 mg/m2 IV day 1
 
−
*[[Paclitaxel (Taxol)]] 125-200 mg/m2 IV day 1
 
−
 
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div>
 +
===References===
 +
# Gianni L, Munzone E, Capri G, Fulfaro F, Tarenzi E, Villani F, Spreafico C, Laffranchi A, Caraceni A, Martini C, Stefanelli M, Valagussa P, Bonadonna G. Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol. 1995 Nov;13(11):2688-99. [https://doi.org/10.1200/jco.1995.13.11.2688 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7595726/ PubMed]
 +
# Jassem J, Pieńkowski T, Płuzańska A, Jelic S, Gorbunova V, Mrsic-Krmpotic Z, Berzins J, Nagykalnai T, Wigler N, Renard J, Munier S, Weil C; Central & Eastern Europe and Israel Pacitaxel Breast Cancer Study Group. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J Clin Oncol. 2001 Mar 15;19(6):1707-15. [https://doi.org/10.1200/JCO.2001.19.6.1707 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/11251000/ PubMed]
 +
##'''Update:''' Jassem J, Pienkowski T, Pluzanska A, Jelic S, Gorbunova V, Berzins J, Nagykalnai T, Biganzoli L, Aloe A, Astier L, Munier S. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin and cyclophosphamide as first-line therapy for women with advanced breast cancer: long-term analysis of the previously published trial. Onkologie. 2009 Sep;32(8-9):468-72. Epub 2009 Jul 20. [https://doi.org/10.1159/000226210 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19745590/ PubMed]
 +
# '''EORTC 10961:''' Biganzoli L, Cufer T, Bruning P, Coleman R, Duchateau L, Calvert AH, Gamucci T, Twelves C, Fargeot P, Epelbaum R, Lohrisch C, Piccart MJ. Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organisation for Research and Treatment of Cancer 10961 multicenter phase III trial. J Clin Oncol. 2002 Jul 15;20(14):3114-21. [https://doi.org/10.1200/JCO.2002.11.005 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/12118025/ PubMed]
 +
# '''ECOG E1193:''' Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, Wood WC. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol. 2003 Feb 15;21(4):588-92. [https://doi.org/10.1200/JCO.2003.08.013 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12586793/ PubMed]
 +
# Schmid P, Schippinger W, Nitsch T, Huebner G, Heilmann V, Schultze W, Hausmaninger H, Wischnewsky M, Possinger K. Up-front tandem high-dose chemotherapy compared with standard chemotherapy with doxorubicin and paclitaxel in metastatic breast cancer: results of a randomized trial. J Clin Oncol. 2005 Jan 20;23(3):432-40. [https://doi.org/10.1200/JCO.2005.06.072 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/15659490/ PubMed]
 +
# '''ERASME 3:''' Cassier PA, Chabaud S, Trillet-Lenoir V, Peaud PY, Tigaud JD, Cure H, Orfeuvre H, Salles B, Martin C, Jacquin JP, Agostini C, Guastalla JP, Pérol D, Bachelot T. A phase-III trial of doxorubicin and docetaxel versus doxorubicin and paclitaxel in metastatic breast cancer: results of the ERASME 3 study. Breast Cancer Res Treat. 2008 May;109(2):343-50. Epub 2007 Jul 5. [https://doi.org/10.1007/s10549-007-9651-3 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17611792/ PubMed]
 +
==Pegylated liposomal doxorubicin monotherapy {{#subobject:2b08a6|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 45 mg/m<sup>2</sup> {{#subobject:c2baf3|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433520/ Smorenburg et al. 2014 (OMEGA)]
 +
|2007-2011
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Capecitabine_monotherapy_2|Capecitabine]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Pegylated liposomal doxorubicin (Doxil)]] 45 mg/m<sup>2</sup> IV once on day 1
 +
'''28-day cycle for 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 50 mg/m<sup>2</sup> {{#subobject:6ebaf9|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdh097 O'Brien et al. 2004]
 +
|1998-06 to 2000-08
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Doxorubicin_monotherapy|Doxorubicin]]
 +
| style="background-color:#eeee01" |Seems to have non-inferior PFS (co-primary endpoint)<br>Median PFS: 6.9 vs 7.8 mo<br>(HR 1.00, 95% CI 0.82-1.22)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5222915/ Harbeck et al. 2016 (PELICAN)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Capecitabine_monotherapy_2|Capecitabine]]
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior TTP (primary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Pegylated liposomal doxorubicin (Doxil)]] 50 mg/m<sup>2</sup> IV over up to 60 minutes once on day 1
 +
'''28-day cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#fff2ae">
 +
====Dose and schedule modifications====
 +
*If infusion reactions occurred, infusion could be given over up to 90 minutes
 +
</div></div>
 +
===References===
 +
# O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C; CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004 Mar;15(3):440-9. [https://doi.org/10.1093/annonc/mdh097 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/14998846/ PubMed]
 +
# '''OMEGA:''' Smorenburg CH, de Groot SM, van Leeuwen-Stok AE, Hamaker ME, Wymenga AN, de Graaf H, de Jongh FE, Braun JJ, Los M, Maartense E, van Tinteren H, Nortier JW, Seynaeve C; Dutch Breast Cancer Research Group. A randomized phase III study comparing pegylated liposomal doxorubicin with capecitabine as first-line chemotherapy in elderly patients with metastatic breast cancer: results of the OMEGA study of the Dutch Breast Cancer Research Group BOOG. Ann Oncol. 2014 Mar;25(3):599-605. Epub 2014 Feb 6. [https://doi.org/10.1093/annonc/mdt588 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4433520/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/24504445/ PubMed] ISRCTN11114726
 +
# '''PELICAN:''' Harbeck N, Saupe S, Jäger E, Schmidt M, Kreienberg R, Müller L, Otremba BJ, Waldenmaier D, Dorn J, Warm M, Scholz M, Untch M, de Wit M, Barinoff J, Lück HJ, Harter P, Augustin D, Harnett P, Beckmann MW, Al-Batran SE; PELICAN Investigators. A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study. Breast Cancer Res Treat. 2017 Jan;161(1):63-72. Epub 2016 Oct 31. [https://doi.org/10.1007/s10549-016-4033-3 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5222915/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27798749/ PubMed] [https://clinicaltrials.gov/study/NCT00266799 NCT00266799]
 +
==Cyclophosphamide & Epirubicin (EC) {{#subobject:b81844|Regimen=1}}==
 +
EC: '''<u>E</u>'''pirubicin & '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 75/600 {{#subobject:8466d6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdh393 Chan et al. 2004]
 +
|1996-05 to 1997-08
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cyclophosphamide_.26_Non-pegylated_liposomal_doxorubicin_.28MC.29|MC]]
 +
| style="background-color:#d73027" |Inferior TTP
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.01.1817 Langley et al. 2005 (UKNCRI AB01)]
 +
|1996-1999
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Epirubicin_.26_Paclitaxel_.28EP.29_3|EP]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|}
 +
''Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 6 to 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 90/600 {{#subobject:6079b8|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdp585 Blohmer et al. 2010]
 +
|2000-2003
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Epirubicin_.28DE.29_2|ED]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
''Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, with range {{#subobject:21d6fa|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_.26_Bevacizumab|AC & Bevacizumab]]<br>1b. [[#Capecitabine_.26_Bevacizumab|Capecitabine & Bevacizumab]]<br>1c. [[#Docetaxel_.26_Bevacizumab|Docetaxel & Bevacizumab]]<br>1d. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_.26_Bevacizumab|EC & Bevacizumab]]<br>1e. [[#FAC_.26_Bevacizumab|FAC & Bevacizumab]]<br>1f. [[#FEC_.26_Bevacizumab|FEC & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
''Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 90 to 100 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 to 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 8 cycles'''
 +
</div></div>
 +
===References===
 +
# Chan S, Davidson N, Juozaityte E, Erdkamp F, Pluzanska A, Azarnia N, Lee LW. Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer. Ann Oncol. 2004 Oct;15(10):1527-34. [https://doi.org/10.1093/annonc/mdh393 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15367414/ PubMed]
 +
<!-- Presented at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001. -->
 +
# '''UKNCRI AB01:''' Langley RE, Carmichael J, Jones AL, Cameron DA, Qian W, Uscinska B, Howell A, Parmar M. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute trial AB01. J Clin Oncol. 2005 Nov 20;23(33):8322-30. [https://doi.org/10.1200/jco.2005.01.1817 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16293863/ PubMed]
 +
# Blohmer JU, Schmid P, Hilfrich J, Friese K, Kleine-Tebbe A, Koelbl H, Sommer H, Morack G, Wischnewsky MB, Lichtenegger W, Kuemmel S. Epirubicin and cyclophosphamide versus epirubicin and docetaxel as first-line therapy for women with metastatic breast cancer: final results of a randomised phase III trial. Ann Oncol. 2010 Jul;21(7):1430-5. Epub 2010 Jan 20. [https://doi.org/10.1093/annonc/mdp585 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/20089562/ PubMed]
 +
<!-- Presented in part at the 45th Annual Meeting of the American Society for Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and at the 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology Multidisciplinary Congress, September 20-24, 2009, Berlin, Germany. -->
 +
# '''RIBBON-1:''' Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.28.0982 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21383283/ PubMed] [https://clinicaltrials.gov/study/NCT00262067 NCT00262067]
 +
==Cyclophosphamide & Epirubicin (EC) & Bevacizumab {{#subobject:3e6b59|Regimen=1}}==
 +
EC & Bevacizumab: '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide, Bevacizumab
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:56e1be|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-363-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 +
|-
 +
|} -->
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]]<br>1b. [[#Capecitabine_monotherapy_2|Capecitabine]]<br>1c. [[#Docetaxel_monotherapy_2|Docetaxel]]<br>1d. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]]<br>1e. [[#FAC_3|FAC]]<br>1f. [[#FEC_3|FEC]]<br>1g. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>(HR 0.64, 95% CI 0.52-0.80)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 90 to 100 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 to 600 mg/m<sup>2</sup> IV once on day 1
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
 +
'''21-day cycle for up to 8 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*RIBBON-1, SD or better: [[#Bevacizumab_monotherapy_2|Bevacizumab]] maintenance
 +
</div></div>
 
===References===
 
===References===
−
# Gianni L, Munzone E, Capri G, Fulfaro F, Tarenzi E, Villani F, Spreafico C, Laffranchi A, Caraceni A, Martini C et al. Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol. 1995 Nov;13(11):2688-99. [http://jco.ascopubs.org/content/13/11/2688.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/7595726 PubMed]
+
<!-- Presented in part at the 45th Annual Meeting of the American Society for Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and at the 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology Multidisciplinary Congress, September 20-24, 2009, Berlin, Germany. -->
−
 
+
# '''RIBBON-1:''' Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.28.0982 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21383283/ PubMed] [https://clinicaltrials.gov/study/NCT00262067 NCT00262067]
−
==AT (Taxotere) {{#subobject:145802|Regimen=1}}==
+
==Epirubicin & Paclitaxel (EP) {{#subobject:e10567|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
EP: '''<u>E</u>'''pirubicin & '''<u>P</u>'''aclitaxel
 +
<br>ET: '''<u>E</u>'''pirubicin & '''<u>T</u>'''axol (Paclitaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 60/175 {{#subobject:1a480a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1007/s10549-013-2589-8 Lück et al. 2013]
 +
|2002-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Paclitaxel_.28XP.29_999|XP]]
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 75/175 {{#subobject:d6aabd|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1007/s10549-011-1880-9 Hatschek et al. 2011 (TEX trial)]
 +
|2002-2007
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#TEX_999|TEX]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
AT: '''<u>A</u>'''driamycin, '''<u>T</u>'''axotere
+
''Note: the doses of this regimen were individually adjusted after cycle 1; see paper for details.''
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen {{#subobject:9c6b82|Variant=1}}===
+
====Chemotherapy====
−
Level of Evidence:
+
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
−
<span
+
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Doxorubicin (Adriamycin)]] 50 mg/m2 IV day 1
 
−
*[[Docetaxel (Taxotere)]] 75 mg/m2 IV day 1
 
−
 
 
 
'''21-day cycles'''
 
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 75/200 {{#subobject:f9fb8b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.01.1817 Langley et al. 2005 (UKNCRI AB01)]
 +
|1996-1999
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 80/175 {{#subobject:2bee43|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdh395 Fountzilas et al. 2004]
 +
|1999-2002
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Carboplatin_.26_Paclitaxel_.28CP.29_999|CP]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 80 mg/m<sup>2</sup> IV once on day 1, '''given second'''
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
 +
'''21-day cycle for up to 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, 90/200 {{#subobject:cabbcf|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1002/cncr.20400 Conte et al. 2004]
 +
|1996-2001
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#E-T_888|E-T]]
 +
| style="background-color:#eeee01" |Seems to have non-inferior ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 8 cycles'''
 +
</div></div>
  
 
===References===
 
===References===
−
# Nabholtz JM, Falkson C, Campos D, Szanto J, Martin M, Chan S, Pienkowski T, Zaluski J, Pinter T, Krzakowski M, Vorobiof D, Leonard R, Kennedy I, Azli N, Murawsky M, Riva A, Pouillart P; TAX 306 Study Group. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol. 2003 Mar 15;21(6):968-75. [http://jco.ascopubs.org/content/21/6/968.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/12637459 PubMed]
+
# Conte PF, Guarneri V, Bruzzi P, Prochilo T, Salvadori B, Bolognesi A, Aldrighetti D, Venturini M, Rosso R, Mammoliti S, Carnino F, Giannessi P, Costantini M, Moyano A, Baldini E; GONO. Concomitant versus sequential administration of epirubicin and paclitaxel as first-line therapy in metastatic breast carcinoma: results for the Gruppo Oncologico Nord Ovest randomized trial. Cancer. 2004 Aug 15;101(4):704-12. [https://doi.org/10.1002/cncr.20400 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15305399/ PubMed]
−
 
+
# Fountzilas G, Kalofonos HP, Dafni U, Papadimitriou C, Bafaloukos D, Papakostas P, Kalogera-Fountzila A, Gogas H, Aravantinos G, Moulopoulos LA, Economopoulos T, Pectasides D, Maniadakis N, Siafaka V, Briasoulis E, Christodoulou C, Tsavdaridis D, Makrantonakis P, Razis E, Kosmidis P, Skarlos D, Dimopoulos MA; Hellenic Cooperative Oncology Group. Paclitaxel and epirubicin versus paclitaxel and carboplatin as first-line chemotherapy in patients with advanced breast cancer: a phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol. 2004 Oct;15(10):1517-26. [https://doi.org/10.1093/annonc/mdh395 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15367413/ PubMed]
−
==CAF {{#subobject:35e2d5|Regimen=1}}==
+
<!-- Presented at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001. -->
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
# '''UKNCRI AB01:''' Langley RE, Carmichael J, Jones AL, Cameron DA, Qian W, Uscinska B, Howell A, Parmar M. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute trial AB01. J Clin Oncol. 2005 Nov 20;23(33):8322-30. [https://doi.org/10.1200/jco.2005.01.1817 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16293863/ PubMed]
 +
# '''TEX trial:''' Hatschek T, Carlsson L, Einbeigi Z, Lidbrink E, Linderholm B, Lindh B, Loman N, Malmberg M, Rotstein S, Söderberg M, Sundquist M, Walz TM, Hellström M, Svensson H, Aström G, Brandberg Y, Carstensen J, Fernö M, Bergh J. Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in metastatic breast cancer: a randomized multicenter trial. Breast Cancer Res Treat. 2012 Feb;131(3):939-47. Epub 2011 Nov 18. [https://doi.org/10.1007/s10549-011-1880-9 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22094937/ PubMed] [https://clinicaltrials.gov/study/NCT01433614 NCT01433614]
 +
# Lück HJ, Du Bois A, Loibl S, Schrader I, Huober J, Heilmann V, Beckmann M, Stähler A, Jackisch C, Hubalek M, Richter B, Stickeler E, Eidtmann H, Thomssen C, Untch M, Wollschläger K, Schuster T, von Minckwitz G; AGO Breast Cancer Study Group. Capecitabine plus paclitaxel versus epirubicin plus paclitaxel as first-line treatment for metastatic breast cancer: efficacy and safety results of a randomized, phase III trial by the AGO Breast Cancer Study Group. Breast Cancer Res Treat. 2013 Jun;139(3):779-87. Epub 2013 Jun 15. [https://doi.org/10.1007/s10549-013-2589-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/23771714/ PubMed]
 +
==Epirubicin monotherapy {{#subobject:e941f2|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 35 mg/m<sup>2</sup>, 3 out of 4 weeks {{#subobject:e75cc8|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdi181 Feher et al. 2005]
 +
|1996-1999
 +
|style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Gemcitabine_monotherapy|Gemcitabine]]
 +
| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>Median OS: 19.1 vs 11.8 mo<br><br>Superior TTP (primary endpoint)<br>Median TTP: 6.1 vs 3.4 mo
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
CAF: '''<u>C</u>'''ytoxan, '''<u>A</u>'''driamycin, '''<u>F</u>'''ive-FU
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
===Regimen {{#subobject:b89f0f|Variant=1}}===
+
*[[Epirubicin (Ellence)]] 35 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
−
Level of Evidence:
 
−
<span
 
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m2 PO once per day on days 1 to 14
 
−
*[[Doxorubicin (Adriamycin)]] 30 mg/m2 IV on days 1 & 8
 
−
*[[Fluorouracil (5-FU)]] 500 mg/m2 IV on days 1 & 8
 
−
 
 
 
'''28-day cycles'''
 
'''28-day cycles'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 40 mg/m<sup>2</sup> {{#subobject:740b22|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| rowspan="3" |[https://doi.org/10.1200/jco.1996.14.4.1146 Bastholt et al. 1996]
 +
|rowspan=3|1987-1991
 +
| rowspan="3" style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|1. [[#Epirubicin_monotherapy_2|Epirubicin]]; 60 mg/m<sup>2</sup>
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 +
|-
 +
|2. [[#Epirubicin_monotherapy_2|Epirubicin]]; 90 mg/m<sup>2</sup>
 +
| style="background-color:#d73027" |Inferior TTP
 +
|-
 +
|3. [[#Epirubicin_monotherapy_2|Epirubicin]]; 135 mg/m<sup>2</sup>
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 50 mg/m<sup>2</sup> {{#subobject:7408cc|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/0277-5379(90)90255-r Gundersen et al. 1990]
 +
|1984-1986
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Doxorubicin_monotherapy|Doxorubicin]]
 +
| style="background-color:#ffffbf" |Did not meet endpoints of ORR/OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
'''14-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 60 mg/m<sup>2</sup> {{#subobject:5b43d9|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/oxfordjournals.annonc.a057748 Nielsen et al. 1990]
 +
|1983-1986
 +
|style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Epirubicin_.26_Vindesine_999|Epirubicin & Vindesine]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
| [https://doi.org/10.1200/jco.1996.14.4.1146 Bastholt et al. 1996]
 +
|1987-1991
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|1. [[#Epirubicin_monotherapy_2|Epirubicin]]; 40 mg/m<sup>2</sup><br>2. [[#Epirubicin_monotherapy_2|Epirubicin]]; 90 mg/m<sup>2</sup><br> 3. [[#Epirubicin_monotherapy_2|Epirubicin]]; 135 mg/m<sup>2</sup>
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, 70 mg/m<sup>2</sup>, 2 out of 4 weeks {{#subobject:03c8f3|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1007/s002800000178 Nielsen et al. 2000]
 +
|1987-1990
 +
|style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Cisplatin_.26_Epirubicin_888|Cisplatin & Epirubicin]]
 +
| style="background-color:#fc8d59" |Seems to have inferior TTP
 +
| style="background-color:#1a9850" |Superior toxicity
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 70 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycles until maximum dose of epirubicin reached (1000 mg/m<sup>2</sup>)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #6, 75 mg/m<sup>2</sup> {{#subobject:e8gaa6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1200/JCO.1991.9.2.305 Bonneterre & Hurteloup 1991]
 +
|rowspan=2|NR
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|1. [[#FEC_3|FEC]]; FEC 50
 +
| style="background-color:#fc8d59" |Seems to have inferior ORR
 +
|-
 +
|2. [[#FEC_3|FEC]]; FEC 75
 +
| style="background-color:#d73027" |Inferior ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #7, 90 mg/m<sup>2</sup> {{#subobject:e56ea6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1991.9.12.2148 Perez et al. 1991]
 +
|1985-1988
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Doxorubicin_monotherapy|Doxorubicin]]
 +
| style="background-color:#ffffbf" |Did not meet endpoints of ORR/OS
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1200/jco.1996.14.4.1146 Bastholt et al. 1996]
 +
|rowspan=2|1987-1991
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Epirubicin_monotherapy_2|Epirubicin]]; 40 mg/m<sup>2</sup>
 +
| style="background-color:#1a9850" |Superior TTP
 +
|-
 +
|2. [[#Epirubicin_monotherapy_2|Epirubicin]]; 60 mg/m<sup>2</sup><br> 3. [[#Epirubicin_monotherapy_2|Epirubicin]]; 135 mg/m<sup>2</sup>
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 +
|-
 +
|[https://doi.org/10.1200/JCO.2004.11.503 Ejlertsen et al. 2004 (SBG 9403)]
 +
|1995-1999
 +
|style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Epirubicin_.26_Vinorelbine_.28VE.29|VE]]
 +
| style="background-color:#fc8d59" |Seems to have inferior PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #8, 120 mg/m<sup>2</sup>, split doses {{#subobject:45c4d9|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1996.14.4.1165 Dogliotti et al. 1996]
 +
|1991-1993
 +
|style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Epirubicin_.26_Lonidamine_777|Epirubicin & Lonidamine]]
 +
| style="background-color:#d73027" |Inferior ORR
 +
|-
 +
|[https://doi.org/10.1200/JCO.2002.08.012 Berruti et al. 2002]
 +
|1995-1999
 +
|style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Cisplatin_.26_Epirubicin_999|Cisplatin & Epirubicin]]<br>2. [[#Cisplatin.2C_Epirubicin.2C_Lonidamine_999|Cisplatin, Epirubicin, Lonidamine]]<br>3. [[#Epirubicin_.26_Lonidamine_999|Epirubicin & Lonidamine]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once per day on days 1 & 2
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #9, 135 mg/m<sup>2</sup> {{#subobject:e0a80d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
| [https://doi.org/10.1200/jco.1996.14.4.1146 Bastholt et al. 1996]
 +
|1987-1991
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[#Epirubicin_monotherapy_2|Epirubicin]]; 40 mg/m<sup>2</sup><br>2. [[#Epirubicin_monotherapy_2|Epirubicin]]; 60 mg/m<sup>2</sup><br> 3. [[#Epirubicin_monotherapy_2|Epirubicin]]; 90 mg/m<sup>2</sup>
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Epirubicin (Ellence)]] 135 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Bull JM, Tormey DC, Li SH, Carbone PP, Falkson G, Blom J, Perlin E, Simon R. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978 May;41(5):1649-57. [http://www.ncbi.nlm.nih.gov/pubmed/348293 PubMed]
+
# Gundersen S, Kvinnsland S, Klepp O, Lund E, Høst H; Norwegian Breast Cancer Group. Weekly Adriamycin vs 4-epidoxorubicin every second week in advanced breast cancer: a randomized trial. Eur J Cancer. 1990 Jan;26(1):45-8. [https://doi.org/10.1016/0277-5379(90)90255-r link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/2138477/ PubMed]
 +
# Nielsen D, Dombernowsky P, Skovsgaard T, Jensen J, Andersen E, Engelholm SA, Hansen M. Epirubicin or epirubicin and vindesine in advanced breast cancer: a phase III study. Ann Oncol. 1990 Jul;1(4):275-80. [https://doi.org/10.1093/oxfordjournals.annonc.a057748 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/2265137/ PubMed]
 +
# Bonneterre J, Hurteloup P; French Epirubicin Study Group. A prospective randomized trial comparing epirubicin monochemotherapy to two fluorouracil, cyclophosphamide, and epirubicin regimens differing in epirubicin dose in advanced breast cancer patients. J Clin Oncol. 1991 Feb;9(2):305-12. [https://doi.org/10.1200/JCO.1991.9.2.305 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1988577/ PubMed]
 +
# Perez DJ, Harvey VJ, Robinson BA, Atkinson CH, Dady PJ, Kirk AR, Evans BD, Chapman PJ. A randomized comparison of single-agent doxorubicin and epirubicin as first-line cytotoxic therapy in advanced breast cancer. J Clin Oncol. 1991 Dec;9(12):2148-52. [https://doi.org/10.1200/JCO.1991.9.12.2148 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/1960557/ PubMed]
 +
# Bastholt L, Dalmark M, Gjedde SB, Pfeiffer P, Pedersen D, Sandberg E, Kjaer M, Mouridsen HT, Rose C, Nielsen OS, Jakobsen P, Bentzen SM; Danish Breast Cancer Cooperative Group. Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 1996 Apr;14(4):1146-55. [https://doi.org/10.1200/jco.1996.14.4.1146 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/8648369/ PubMed]
 +
# Dogliotti L, Berruti A, Buniva T, Zola P, Baù MG, Farris A, Sarobba MG, Bottini A, Alquati P, Deltetto F, Gosso P, Monzeglio C, Moro G, Sussio M, Perroni D. Lonidamine significantly increases the activity of epirubicin in patients with advanced breast cancer: results from a multicenter prospective randomized trial. J Clin Oncol. 1996 Apr;14(4):1165-72. [https://doi.org/10.1200/JCO.1996.14.4.1165 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8648371/ PubMed]
 +
# Nielsen D, Dombernowsky P, Larsen SK, Hansen OP, Skovsgaard T. Epirubicin or epirubicin and cisplatin as first-line therapy in advanced breast cancer: a phase III study. Cancer Chemother Pharmacol. 2000;46(6):459-66. [https://doi.org/10.1007/s002800000178 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/11138459/ PubMed]
 +
# Berruti A, Bitossi R, Gorzegno G, Bottini A, Alquati P, De Matteis A, Nuzzo F, Giardina G, Danese S, De Lena M, Lorusso V, Farris A, Sarobba MG, DeFabiani E, Bonazzi G, Castiglione F, Bumma C, Moro G, Bruzzi P, Dogliotti L; Epirubicin-Lonidamine Group. Time to progression in metastatic breast cancer patients treated with epirubicin is not improved by the addition of either cisplatin or lonidamine: final results of a phase III study with a factorial design. J Clin Oncol. 2002 Oct 15;20(20):4150-9. [https://doi.org/10.1200/JCO.2002.08.012 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/12377958/ PubMed]
 +
# '''SBG 9403:''' Ejlertsen B, Mouridsen HT, Langkjer ST, Andersen J, Sjöström J, Kjaer M; Scandinavian Breast Group. Phase III study of intravenous vinorelbine in combination with epirubicin versus epirubicin alone in patients with advanced breast cancer: a Scandinavian Breast Group Trial (SBG9403). J Clin Oncol. 2004 Jun 15;22(12):2313-20. [https://doi.org/10.1200/JCO.2004.11.503 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15197192/ PubMed]
 +
# Feher O, Vodvarka P, Jassem J, Morack G, Advani SH, Khoo KS, Doval DC, Ermisch S, Roychowdhury D, Miller MA, von Minckwitz G. First-line gemcitabine versus epirubicin in postmenopausal women aged 60 or older with metastatic breast cancer: a multicenter, randomized, phase III study. Ann Oncol. 2005 Jun;16(6):899-908. Epub 2005 Apr 8. [https://doi.org/10.1093/annonc/mdi181 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15821120/ PubMed]
 +
==FAC {{#subobject:b0cb|Regimen=1}}==
 +
FAC: '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide
 +
<br>CAF: '''<u>C</u>'''yclophosphamide, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>F</u>'''luorouracil
 +
<br>AFC: '''<u>A</u>'''driamycin (Doxorubicin), '''<u>F</u>'''luorouracil, '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 500/50/500 {{#subobject:c92289|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(197708)40:2%3C625::AID-CNCR2820400206%3E3.0.CO;2-M Smalley et al. 1977]
 +
|1974-04-01 to 1975-07-01
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[Breast_cancer_-_historical#CMFVP_2|CMFVP]]
 +
| style="background-color:#d9ef8b" |Might have superior OS<sup>1</sup>
 +
|-
 +
|[https://doi.org/10.1200/JCO.1988.6.10.1611 Bennett et al. 1988]
 +
|1983-1985
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#CNF_999|CNF]]
 +
| style="background-color:#ffffbf" |Did not meet endpoints of TTF/OS
 +
|-
 +
|[https://doi.org/10.1056/NEJM199111073251904 Muss et al. 1991]
 +
|1984-1989
 +
| style="background-color:#91cf61" |Non-randomized part of RCT
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1002/(SICI)1097-0142(19990301)85:5%3C1091::AID-CNCR12%3E3.0.CO;2-A Blajman et al. 1999]
 +
|1991-1994
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Doxorubicin_.26_Vinorelbine_.28NA.29_999|NA]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|[https://doi.org/10.1016/s0959-8049(01)00093-4 Namer et al. 2001]
 +
|1993-04 to 1995-12
 +
|style="background-color:#1a9851"|Phase 3 (C)
 +
|[[Breast_cancer_-_historical#Mitoxantrone_.26_Vinorelbine_.28MV.29|MV]]
 +
| style="background-color:#eeee01" |Equivalent ORR
 +
|-
 +
|[https://doi.org/10.1200/JCO.2001.19.6.1707 Jassem et al. 2001]
 +
|1996-1998
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Doxorubicin_.26_Paclitaxel_.28AT.29_2|AT (Taxol)]]
 +
| style="background-color:#d73027" |Inferior OS<sup>2</sup>
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.06.236 Bontenbal et al. 2005]
 +
|1997-2002
 +
| style="background-color:#1a9851" |Phase 2/3 (C)
 +
|[[#Docetaxel_.26_Doxorubicin_.28AT.29|AT (Taxotere)]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_.26_Bevacizumab|AC & Bevacizumab]]<br>1b. [[#Capecitabine_.26_Bevacizumab|Capecitabine & Bevacizumab]]<br>1c. [[#Docetaxel_.26_Bevacizumab|Docetaxel & Bevacizumab]]<br>1d. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_.26_Bevacizumab|EC & Bevacizumab]]<br>1e. [[#FAC_.26_Bevacizumab|FAC & Bevacizumab]]<br>1f. [[#FEC_.26_Bevacizumab|FEC & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy for Smalley et al. 1977 is based on the 1983 update.''<br>
 +
''<sup>2</sup>Reported efficacy for Jassem et al. 2001 is based on the 2009 update.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 6 to 8 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*Muss et al. 1991: [[Breast_cancer_-_historical#CMFP|CMFP]] continuation versus [[Breast_cancer_-_null_regimens#Observation_2|observation]] followed by second-line [[Breast_cancer_-_historical#CMFP|CMFP]] at progression
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
==CEF, FEC {{#subobject:ed96e7|Regimen=1}}==
+
===Regimen variant #2, 600/50/600 {{#subobject:dbd450|Variant=1}}===
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1007/BF00666487 Alonso et al. 1995]
 +
|1988-1991
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#CNF_999|CNF]]
 +
| style="background-color:#ffffbf" |Did not meet endpoints of ORR/OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 10 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 800/40/400 {{#subobject:dajb20|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(197806)41:6%3C2078::AID-CNCR2820410602%3E3.0.CO;2-Q Tranum et al. 1978]
 +
|NR
 +
| style="background-color:#1a9851" |Randomized (E-esc)
 +
|1. [[#Doxorubicin_.26_Fluorouracil_.28FA.29_999|AF]]<br>2. [[Breast_cancer_-_historical#CAMF|AFCM]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 400 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 1000/40/500 {{#subobject:d56b20|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1995.13.6.1443 Aisner et al. 1995 (CALGB 8281)]
 +
|1982-1987
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#VATH_999|VATH]]<br>2. [[#VATH.2FCMFVP_999|VATH/CMFVP]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|[https://doi.org/10.1200/JCO.2003.05.119 Parnes et al. 2003 (CALGB 9140)]
 +
|1991-1995
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FAC_.26_Folinic_acid_999|FAC & Leucovorin]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
''Note: Aisner et al. 1995 does not describe dosing; included here because it is a CALGB study.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 200 mg/m<sup>2</sup> IV once per day on days 1 to 5
 +
*[[Doxorubicin (Adriamycin)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, 1000/50/500, indefinite {{#subobject:ed75b0|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(197911)44:5%3C1955::AID-CNCR2820440559%3E3.0.CO;2-P Hortobagyi et al. 1979]
 +
|1974-NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FAC-BCG_999|FAC-BCG]]
 +
| style="background-color:#d73027" |Inferior OS in responders
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
CEF: '''<u>C</u>'''ytoxan, '''<u>E</u>'''pirubicin, '''<u>F</u>'''ive-FU
+
<div class="toccolours" style="background-color:#b3e2cd">
−
FEC: '''<u>F</u>'''ive-FU, '''<u>E</u>'''pirubicin, '''<u>C</u>'''ytoxan
+
====Chemotherapy====
−
 
+
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8 or days 1 & 4
−
===Regimen {{#subobject:830d7f|Variant=1}}===
+
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
−
Level of Evidence:
+
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
−
<span
+
'''21-day cycles'''
−
style="background:#00CD00;
+
</div></div><br>
−
padding:3px 6px 3px 6px;
+
<div class="toccolours" style="background-color:#eeeeee">
−
border-color:black;
+
===Regimen variant #6, 1000/50/500 until max anthracycline {{#subobject:cefa41|Variant=1}}===
−
border-width:2px;
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
border-style:solid;">Phase III</span>
+
!style="width: 17%"|Study
−
 
+
!style="width: 15%"|Dates of enrollment
−
*[[Fluorouracil (5-FU)]] 500 mg/m2 IV days 1 & 8
+
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
*[[Epirubicin (Ellence)]] 50 mg/m2 IV days 1 & 8  
+
!style="width: 17%"|Comparator
−
*[[Cyclophosphamide (Cytoxan)]] 400 mg/m2 IV days 1 & 8
+
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
 
+
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1988.6.6.976 Ambrosini et al. 1988]
 +
|1983-1985
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC_3|FEC]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint
 +
| style="background-color:#d73027" |More toxic
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 11 cycles (maximum of 550 mg/m<sup>2</sup> doxorubicin)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #7, 1000/50/1400 {{#subobject:b25f0f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1200/JCO.1987.5.10.1523 Aisner et al. 1987 (CALGB 7682)]
 +
|rowspan=2|1976-1980
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|1. [[Breast_cancer_-_historical#CAFVP|CAFVP]]
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|2. [[#CMF_2|CMF]]
 +
| style="background-color:#1a9850" |Superior ORR
 +
|-
 +
|[https://doi.org/10.1007/BF01807589 Kardinal et al. 1983 (CALGB 8081)]
 +
|1980-1982
 +
| style="background-color:#1a9851" |Randomized (C)
 +
|[[#CAFT_999|CAFT]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
'''28-day cycle for up to 9 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #8, 1000/60/1400 x 6 {{#subobject:b89f0f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2000.18.2.262 Sledge et al. 2000 (ECOG E3186)]
 +
|1988-1992
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#CAFTH_333|CAFTH]]
 +
| style="background-color:#fee08b" |Might have inferior TTF
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
'''28-day cycle for up to 6 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #9, 1000/60/1400, maximum doxorubicin of 500 mg/m<sup>2</sup> {{#subobject:b93f0f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1985.3.7.932 Cummings et al. 1985]
 +
|1978-1979
 +
| style="background-color:#1a9851" |Randomized (E-de-esc)
 +
|[[Breast_cancer_-_historical#CMFP_2|CMFP]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|[https://doi.org/10.1200/JCO.1987.5.6.881 Falkson et al. 1987 (ECOG E2177)]
 +
|NR-1983
 +
| style="background-color:#1a9851" |Randomized (C)
 +
|[[#O.2BCAF_999|O+CAF]]
 +
| style="background-color:#ffffbf" |Did not meet co-primary endpoints of ORR/TTF/OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 +
'''28-day cycles until maximum cumulative dose of doxorubicin of 500 mg/m<sup>2</sup>'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #10, 1000/60/1400, indefinite {{#subobject:b89f0f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(197805)41:5%3C1649::AID-CNCR2820410501%3E3.0.CO;2-J Bull et al. 1978]
 +
|NR
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#CMF_2|CMF]]
 +
| style="background-color:#d9ef8b" |Might have superior ORR
 +
|-
 +
|[https://doi.org/10.1016/0959-8049(94)90123-6 Tominaga et al. 1994]
 +
|NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer_-_historical#CAF_.26_MPA|CAF & MPA]]
 +
| style="background-color:#fc8d59" |Seems to have inferior ORR
 +
|-
 +
|}
 +
''Note: the dosing details of Tominaga et al. 1994 are not described in the abstract.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Doxorubicin (Adriamycin)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
 
'''28-day cycles'''
 
'''28-day cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
−
# Ackland SP, Anton A, Breitbach GP, Colajori E, Tursi JM, Delfino C, Efremidis A, Ezzat A, Fittipaldo A, Kolaric K, Lopez M, Viaro D; HEPI 013 study group. Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study. J Clin Oncol. 2001 Feb 15;19(4):943-53. [http://jco.ascopubs.org/content/19/4/943.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/11181656 PubMed]
+
# Smalley RV, Carpenter J, Bartolucci A, Vogel C, Krauss S; Southeastern Cancer Study Group. A comparison of cyclophosphamide, adriamycin, 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisone (CMFVP) in patients with metastatic breast cancer: a Southeastern Cancer Study Group project. Cancer. 1977 Aug;40(2):625-32. [https://doi.org/10.1002/1097-0142(197708)40:2%3C625::AID-CNCR2820400206%3E3.0.CO;2-M link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/329975/ PubMed]
 +
## '''Update:''' Smalley RV, Lefante J, Bartolucci A, Carpenter J, Vogel C, Krauss S. A comparison of cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone (CMFVP) in patients with advanced breast cancer. Breast Cancer Res Treat. 1983;3(2):209-20. [https://doi.org/10.1007/BF01803563 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6688538/ PubMed]
 +
# Bull JM, Tormey DC, Li SH, Carbone PP, Falkson G, Blom J, Perlin E, Simon R. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978 May;41(5):1649-57. [https://doi.org/10.1002/1097-0142(197805)41:5%3C1649::AID-CNCR2820410501%3E3.0.CO;2-J link to original article] [https://pubmed.ncbi.nlm.nih.gov/348293/ PubMed]
 +
# Tranum B, Hoogstraten B, Kennedy A, Vaughn CB, Samal B, Thigpen T, Rivkin S, Smith F, Palmer RL, Costanzi J, Tucker WG, Wilson H, Maloney TR; [[Study_Groups#SWOG|SWOG]]. Adriamycin in combination for the treatment of breast cancer: a Southwest Oncology Group study. Cancer. 1978 Jun;41(6):2078-83. [https://doi.org/10.1002/1097-0142(197806)41:6%3C2078::AID-CNCR2820410602%3E3.0.CO;2-Q link to original article] [https://pubmed.ncbi.nlm.nih.gov/657081/ PubMed]
 +
# Hortobagyi GN, Gutterman JU, Blumenschein GR, Tashima CK, Burgess MA, Einhorn L, Buzdar AU, Richman SP, Hersh EM. Combination chemoimmunotherapy of metastatic breast cancer with 5-fluorouracil, adriamycin, cyclophosphamide, and BCG. Cancer. 1979 Nov;44(5):1955-62. [https://doi.org/10.1002/1097-0142(197911)44:5%3C1955::AID-CNCR2820440559%3E3.0.CO;2-P link to original article] [https://pubmed.ncbi.nlm.nih.gov/387212/ PubMed]
 +
# '''CALGB 8081:''' Kardinal CG, Perry MC, Weinberg V, Wood W, Ginsberg S, Raju RN. Chemoendocrine therapy vs chemotherapy alone for advanced breast cancer in postmenopausal women: preliminary report of a randomized study. Breast Cancer Res Treat. 1983;3(4):365-71. [https://doi.org/10.1007/BF01807589 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6365209/ PubMed]
 +
## '''Update:''' Perry MC, Kardinal CG, Korzun AH, Ginsberg SJ, Raich PC, Holland JF, Ellison RR, Kopel S, Schilling A, Aisner J, Schulman P, Weinberg V, Rice MA, Wood W. Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081. J Clin Oncol. 1987 Oct;5(10):1534-45. [https://doi.org/10.1200/JCO.1987.5.10.1534 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3655856/ PubMed]
 +
# Cummings FJ, Gelman R, Horton J. Comparison of CAF versus CMFP in metastatic breast cancer: analysis of prognostic factors. J Clin Oncol. 1985 Jul;3(7):932-40. [https://doi.org/10.1200/JCO.1985.3.7.932 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3894587/ PubMed]
 +
# '''ECOG E2177:''' Falkson G, Gelman RS, Tormey DC, Falkson CI, Wolter JM, Cummings FJ. Treatment of metastatic breast cancer in premenopausal women using CAF with or without oophorectomy: an Eastern Cooperative Oncology Group Study. J Clin Oncol. 1987 Jun;5(6):881-9. [https://doi.org/10.1200/JCO.1987.5.6.881 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/3585444/ PubMed]
 +
## '''Update:''' Falkson G, Holcroft C, Gelman RS, Tormey DC, Wolter JM, Cummings FJ. Ten-year follow-up study of premenopausal women with metastatic breast cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol. 1995 Jun;13(6):1453-8. [https://doi.org/10.1200/JCO.1995.13.6.1453 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7751892/ PubMed]
 +
# '''CALGB 7682:''' Aisner J, Weinberg V, Perloff M, Weiss R, Perry M, Korzun A, Ginsberg S, Holland JF; [[Study_Groups#CALGB|CALGB]]. Chemotherapy versus chemoimmunotherapy (CAF v CAFVP v CMF each +/- MER) for metastatic carcinoma of the breast: a CALGB study. J Clin Oncol. 1987 Oct;5(10):1523-33. [https://doi.org/10.1200/JCO.1987.5.10.1523 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/3655855/ PubMed]
 +
# Ambrosini G, Balli M, Garusi G, Demicheli R, Jirillo A, Bonciarelli G, Bruscagnin G, Fila G, Bumma C, Lacroix F, Buzzi F, Di Costanzo F, Padalino D, Brugia M, Calabresi F, Natali M, Cartei G, Chiesa G, Blasina B, Ciambellotti E, Moro G, D'Aquino S, Altavilla G, Adamo V, De Maria D, Falchi AM, Bertoncelli P, Farris A, Fiorentino M, Fornasiero A, Fosser V, Daniele O, Foggi CM, Speranza GB, Sartori S, Camilluzzi E, Gallo L, Poggio R, Secondo V, Gambi A, Grignani F, Capodicasa E, Lopez M, Papaldo P, Di Lauro L, Vici P, Marenco G, Folco U, Bonanni F, Marsilio P, Palazzotto G, Di Carlo A, Cusimano MP, Pastorino G, Puccetti C, Giusto M, Rausa L, Gebbia N, Palmeri S, D'Alessandro N, Saccani F, Becchi G, Schieppati G, Spinelli I, Tagliagambe A, Tonato M, Minotti V, Ardia A, Viaro D, De Micheli P, Zingali G, Sacchetti G, Intini C; Italian Multicentre Breast Study with Epirubicin. Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: an Italian multicentre trial. J Clin Oncol. 1988 Jun;6(6):976-82. [https://doi.org/10.1200/JCO.1988.6.6.976 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/2897433/ PubMed]
 +
# Bennett JM, Muss HB, Doroshow JH, Wolff S, Krementz ET, Cartwright K, Dukart G, Reisman A, Schoch I. A randomized multicenter trial comparing mitoxantrone, cyclophosphamide, and fluorouracil with doxorubicin, cyclophosphamide, and fluorouracil in the therapy of metastatic breast carcinoma. J Clin Oncol. 1988 Oct;6(10):1611-20. [https://doi.org/10.1200/JCO.1988.6.10.1611 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/3049953/ PubMed]
 +
# Muss HB, Case LD, Richards F 2nd, White DR, Cooper MR, Cruz JM, Powell BL, Spurr CL, Capizzi RL; Piedmont Oncology Association. Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. N Engl J Med. 1991 Nov 7;325(19):1342-8. [https://doi.org/10.1056/NEJM199111073251904 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1922236/ PubMed]
 +
# Tominaga T, Abe O, Ohshima A, Hayasaka H, Uchino J, Abe R, Enomoto K, Izuo M, Watanabe H, Takatani O, Yoshida M, Sakai K, Koyama H, Hattori T, Senoo T, Monden Y, Nomura Y. Comparison of chemotherapy with or without medroxyprogesterone acetate for advanced or recurrent breast cancer. Eur J Cancer. 1994;30A(7):959-64. [https://doi.org/10.1016/0959-8049(94)90123-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7946592/ PubMed]
 +
# Alonso MC, Tabernero JM, Ojeda B, Llanos M, Solà C, Climent MA, Seguí MA, López JJ. A phase III randomized trial of cyclophosphamide, mitoxantrone, and 5-fluorouracil (CNF) versus cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) in patients with metastatic breast cancer. Breast Cancer Res Treat. 1995 Apr;34(1):15-24. [https://doi.org/10.1007/BF00666487 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7749156/ PubMed]
 +
# '''CALGB 8281:''' Aisner J, Cirrincione C, Perloff M, Perry M, Budman D, Abrams J, Panasci L, Muss H, Citron M, Holland J, Wood W, Henderson IC. Combination chemotherapy for metastatic or recurrent carcinoma of the breast--a randomized phase III trial comparing CAF versus VATH versus VATH alternating with CMFVP: Cancer and Leukemia Group B Study 8281. J Clin Oncol. 1995 Jun;13(6):1443-52. [https://doi.org/10.1200/JCO.1995.13.6.1443 link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/7751891/ PubMed]
 +
# Blajman C, Balbiani L, Block J, Coppola F, Chacon R, Fein L, Bonicatto S, Alvarez A, Schmilovich A, Delgado FM. A prospective, randomized Phase III trial comparing combination chemotherapy with cyclophosphamide, doxorubicin, and 5-fluorouracil with vinorelbine plus doxorubicin in the treatment of advanced breast carcinoma. Cancer. 1999 Mar 1;85(5):1091-7. [https://doi.org/10.1002/(SICI)1097-0142(19990301)85:5%3C1091::AID-CNCR12%3E3.0.CO;2-A link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10091793/ PubMed]
 +
# '''ECOG E3186:''' Sledge GW Jr, Hu P, Falkson G, Tormey D, Abeloff M. Comparison of chemotherapy with chemohormonal therapy as first-line therapy for metastatic, hormone-sensitive breast cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol. 2000 Jan;18(2):262-6. [https://doi.org/10.1200/JCO.2000.18.2.262 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/10637238/ PubMed]
 +
# Jassem J, Pieńkowski T, Płuzańska A, Jelic S, Gorbunova V, Mrsic-Krmpotic Z, Berzins J, Nagykalnai T, Wigler N, Renard J, Munier S, Weil C; Central & Eastern Europe and Israel Pacitaxel Breast Cancer Study Group. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J Clin Oncol. 2001 Mar 15;19(6):1707-15. [https://doi.org/10.1200/JCO.2001.19.6.1707 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/11251000/ PubMed]
 +
##'''Update:''' Jassem J, Pienkowski T, Pluzanska A, Jelic S, Gorbunova V, Berzins J, Nagykalnai T, Biganzoli L, Aloe A, Astier L, Munier S. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin and cyclophosphamide as first-line therapy for women with advanced breast cancer: long-term analysis of the previously published trial. Onkologie. 2009 Sep;32(8-9):468-72. Epub 2009 Jul 20. [https://doi.org/10.1159/000226210 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19745590/ PubMed]
 +
#Namer M, Soler-Michel P, Turpin F, Chinet-Charrot P, de Gislain C, Pouillart P, Delozier T, Luporsi E, Etienne PL, Schraub S, Eymard JC, Serin D, Ganem G, Calais G, Maillart P, Colin P, Trillet-Lenoir V, Prevost G, Tigaud D, Clavère P, Marti P, Romieu G, Wendling JL. Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer. Eur J Cancer. 2001 Jun;37(9):1132-40. [https://doi.org/10.1016/s0959-8049(01)00093-4 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11378344/ PubMed]
 +
# '''CALGB 9140:''' Parnes HL, Cirrincione C, Aisner J, Berry DA, Allen SL, Abrams J, Chuang E, Cooper MR, Perry MC, Duggan DB, Szatrowski TP, Henderson IC, Norton L; [[Study_Groups#CALGB|CALGB]]. Phase III study of cyclophosphamide, doxorubicin, and fluorouracil (CAF) plus leucovorin versus CAF for metastatic breast cancer: Cancer and Leukemia Group B 9140. J Clin Oncol. 2003 May 1;21(9):1819-24. [https://doi.org/10.1200/JCO.2003.05.119 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/12721259/ PubMed]
 +
# Bontenbal M, Creemers GJ, Braun HJ, de Boer AC, Janssen JT, Leys RB, Ruit JB, Goey SH, van der Velden PC, Kerkhofs LG, Schothorst KL, Schmitz PI, Bokma HJ, Verweij J, Seynaeve C; Dutch Community Setting Trial for the Clinical Trial Group. Phase II to III study comparing doxorubicin and docetaxel with fluorouracil, doxorubicin, and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer: results of a Dutch Community Setting Trial for the Clinical Trial Group of the Comprehensive Cancer Centre. J Clin Oncol. 2005 Oct 1;23(28):7081-8. [https://doi.org/10.1200/JCO.2005.06.236 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16192591/ PubMed]
 +
<!-- Presented in part at the 45th Annual Meeting of the American Society for Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and at the 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology Multidisciplinary Congress, September 20-24, 2009, Berlin, Germany. -->
 +
# '''RIBBON-1:''' Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.28.0982 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21383283/ PubMed] [https://clinicaltrials.gov/study/NCT00262067 NCT00262067]
  
−
==Cisplatin & Vinorelbine {{#subobject:c1c866|Regimen=1}}==
+
==FAC & Bevacizumab {{#subobject:4e04d9|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
FAC & Bevacizumab: '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, Bevacizumab
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:961016|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-363-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 +
|-
 +
|} -->
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]]<br>1b. [[#Capecitabine_monotherapy_2|Capecitabine]]<br>1c. [[#Docetaxel_monotherapy_2|Docetaxel]]<br>1d. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]]<br>1e. [[#FAC_3|FAC]]<br>1f. [[#FEC_3|FEC]]<br>1g. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>(HR 0.64, 95% CI 0.52-0.80)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:9caba1|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
−
style="background:#EEEE00;
+
*[[Doxorubicin (Adriamycin)]] 50 mg/m<sup>2</sup> IV once on day 1
−
padding:3px 6px 3px 6px;
+
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
−
border-color:black;
+
====Targeted therapy====
−
border-width:2px;
+
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
−
border-style:solid;">Phase II</span>
+
'''21-day cycle for up to 8 cycles'''
−
 
+
</div>
−
*[[Cisplatin (Platinol)]] 75 mg/m2 IV over 1 hour once on day 1
+
<div class="toccolours" style="background-color:#cbd5e7">
−
*[[Vinorelbine (Navelbine)]] 25 mg/m2 IV over 5 to 10 minutes once per day on days 1 & 8
+
====Subsequent treatment====
−
 
+
*RIBBON-1, SD or better: [[#Bevacizumab_monotherapy_2|Bevacizumab]] maintenance
−
'''21-day cycles x up to 6 cycles or progression of disease'''
+
</div></div>
−
 
 
−
Supportive medications:
 
−
*Normal saline 200 mL bolus after vinorelbine to prevent phlebitis
 
−
*Normal saline 2000 mL with KCl (unspecified amount of KCl) IV over 4 hours (infusion rate: 500 mL/H) once prior to cisplatin
 
−
*Furosemide (Lasix) 40 mg IV once 20 minutes prior to cisplatin
 
−
*Normal saline 1000 mL and D5W 1000 mL IV over 4 hours (overall infusion rate: 500 mL/H; paper did not say whether fluids were given sequentially or concurrently) once after cisplatin
 
−
*[[Antiemesis|5-HT3 antagonists]] used
 
−
 
 
 
===References===
 
===References===
−
# Vassilomanolakis M, Koumakis G, Barbounis V, Demiri M, Pateras H, Efremidis AP. Vinorelbine and cisplatin in metastatic breast cancer patients previously treated with anthracyclines. Ann Oncol. 2000 Sep;11(9):1155-60. [http://annonc.oxfordjournals.org/content/11/9/1155.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/11061611 Pubmed]
+
<!-- Presented in part at the 45th Annual Meeting of the American Society for Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and at the 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology Multidisciplinary Congress, September 20-24, 2009, Berlin, Germany. -->
−
 
+
# '''RIBBON-1:''' Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.28.0982 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21383283/ PubMed] [https://clinicaltrials.gov/study/NCT00262067 NCT00262067]
−
==CMF {{#subobject:9c9c1d|Regimen=1}}==
+
==FEC {{#subobject:ed96e7|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
FEC: '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide
 +
<br>CEF: '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''pirubicin, '''<u>F</u>'''luorouracil
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 500/50/500 ("FEC 50") {{#subobject:d92480|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1200/JCO.1991.9.2.305 Bonneterre & Hurteloup 1991]
 +
|rowspan=2|NR
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Epirubicin_monotherapy_2|Epirubicin]]
 +
| style="background-color:#91cf60" |Seems to have superior ORR
 +
|-
 +
|2. [[#FEC_3|FEC]]; FEC 75
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|[https://doi.org/10.1200/JCO.1993.11.7.1253 Focan et al. 1993]
 +
|1985-1990
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC_3|FEC]]; FEC 100
 +
| style="background-color:#fc8d59" |Seems to have inferior TTP
 +
|-
 +
|[https://doi.org/10.1023/a:1008295427877 Brufman et al. 1997 (HEPI 010)]
 +
|1989-1992
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC_3|FEC]]; FEC 100
 +
| style="background-color:#d73027" |Inferior ORR
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdf306 Heidemann et al. 2002 (GER-AIO-01/92)]
 +
|1992-1997
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Mitoxantrone_monotherapy_999|Mitoxantrone]]
 +
| style="background-color:#ffffbf" |Did not meet efficacy endpoints
 +
|-
 +
|[https://doi.org/10.1016/s0959-8049(01)00093-4 Namer et al. 2001]
 +
|1993-04 to 1995-12
 +
|style="background-color:#1a9851"|Phase 3 (C)
 +
|[[Breast_cancer_-_historical#Mitoxantrone_.26_Vinorelbine_.28MV.29|MV]]
 +
| style="background-color:#eeee01" |Equivalent ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 to 12 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 500/60/500 {{#subobject:eb63d8|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1993.11.3.467 Blomqvist et al. 1993]
 +
|1987-1991
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC_3|FEC]]; weekly
 +
| style="background-color:#1a9850" |Superior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 500/75/500 ("FEC 75") {{#subobject:0df196|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1200/JCO.1991.9.2.305 Bonneterre & Hurteloup 1991]
 +
|rowspan=2|NR
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1. [[#Epirubicin_monotherapy_2|Epirubicin]]
 +
| style="background-color:#1a9850" |Superior ORR
 +
|-
 +
|2. [[#FEC_3|FEC]]; FEC 50
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|[https://doi.org/10.1016/s0959-8049(00)00068-x Pacini et al. 2000]
 +
|1991-1996
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Epirubicin_.26_Mitomycin_.28EM.29_888|EM]]<br>2. [[#Epirubicin_.26_Mitomycin_.28EM.29_.26_Lonidamine_777|EM & Lonidamine]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|rowspan=2|[https://doi.org/10.1179/joc.2003.15.2.184 Capotorto et al. 2003]
 +
|rowspan=2|1995-1998
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#ddFEC_888|ddFEC]]
 +
| style="background-color:#d73027" |Inferior ORR
 +
|-
 +
|2. [[#Dose-dense_MMM_999|ddMMM]]
 +
| style="background-color:#ffffbf" |Did not meet endpoint of ORR
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409942/ Bonneterre et al. 2004]
 +
|1998-2000
 +
| style="background-color:#1a9851" |Randomized Phase 2 (C)
 +
|[[#Docetaxel_.26_Epirubicin_.28DE.29_2|DE]]
 +
| style="background-color:#d73027" |Inferior ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 500/90/500 {{#subobject:8aa343|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.12.106 Zielinksi et al. 2005 (CECOG BM1)]
 +
|1999-2002
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#GET_999|GET]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_.26_Bevacizumab|AC & Bevacizumab]]<br>1b. [[#Capecitabine_.26_Bevacizumab|Capecitabine & Bevacizumab]]<br>1c. [[#Docetaxel_.26_Bevacizumab|Docetaxel & Bevacizumab]]<br>1d. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_.26_Bevacizumab|EC & Bevacizumab]]<br>1e. [[#FAC_.26_Bevacizumab|FAC & Bevacizumab]]<br>1f. [[#FEC_.26_Bevacizumab|FEC & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
''Note: this is the lower bound of the dosing range allowed in RIBBON-1.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, 500/100/500 ("FEC 100") {{#subobject:33c356|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1023/a:1008295427877 Brufman et al. 1997 (HEPI 010)]
 +
|1989-1992
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#FEC_3|FEC]]; FEC 50
 +
| style="background-color:#1a9850" |Superior ORR
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_.26_Bevacizumab|AC & Bevacizumab]]<br>1b. [[#Capecitabine_.26_Bevacizumab|Capecitabine & Bevacizumab]]<br>1c. [[#Docetaxel_.26_Bevacizumab|Docetaxel & Bevacizumab]]<br>1d. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_.26_Bevacizumab|EC & Bevacizumab]]<br>1e. [[#FAC_.26_Bevacizumab|FAC & Bevacizumab]]<br>1f. [[#FEC_.26_Bevacizumab|FEC & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
''Note: this is the upper bound of the dosing range allowed in RIBBON-1.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 to 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #6, 500/100/500, split epirubicin ("FEC 100") {{#subobject:3spl56|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1993.11.7.1253 Focan et al. 1993]
 +
|1985-1990
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#FEC_3|FEC]]; FEC 50
 +
| style="background-color:#91cf60" |Seems to have superior TTP
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 6 to 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #7, 600/60/600 ("CEF21") {{#subobject:80e015|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1987.5.3.339 Conte et al. 1987]
 +
|1983-1985
 +
| style="background-color:#1a9851" |Randomized (C)
 +
|[[#DES-CEF_999|DES-CEF]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|[https://doi.org/10.1093/oxfordjournals.annonc.a010637 Conte et al. 1996]
 +
|1985-1990
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#DES-CEF_999|DES-CEF]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|[https://doi.org/10.1016/s0959-8049(05)80145-5 Ejlertsen et al. 1993]
 +
|1986-1989
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#FEC_3|FEC]] x 18 mo
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|[https://doi.org/10.1200/JCO.2001.19.8.2213 Del Mastro et al. 2001]
 +
|1994-1997
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#HD-CEF14_999|HD-CEF14]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
''Note: dosing information was not available in the abstract of Ejlertsen et al. 1993; this dosing has been used in other studies by this group.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for 8 to 12 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #8, 1000/50/500 until max anthracycline {{#subobject:caf441|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1988.6.6.976 Ambrosini et al. 1988]
 +
|1983-1985
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#FAC_3|FAC]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint
 +
| style="background-color:#1a9850" |Less toxic
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 14 cycles (maximum of 700 mg/m<sup>2</sup> epirubicin)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #9, 1000/60/1400 {{#subobject:8505fe|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1023/a:1006387801960 Esteban et al. 1999]
 +
|1987-1993
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#CNF_999|CNF]]
 +
| style="background-color:#91cf60" |Seems to have superior OS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
CMF: '''<u>C</u>'''ytoxan, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''ive-FU
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
===Regimen {{#subobject:4a77d3|Variant=1}}===
+
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
Level of Evidence:
+
*[[Epirubicin (Ellence)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8  
−
<span
+
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m<sup>2</sup> PO once per day on days 1 to 14
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Cyclophosphamide (Cytoxan)]] 100 mg/m2 PO once per day on days 1 to 14
 
−
*[[Methotrexate (MTX)]] 40 mg/m2 IV on days 1 & 8
 
−
*[[Fluorouracil (5-FU)]] 600 mg/m2 IV on days 1 & 8
 
−
 
 
 
'''28-day cycles'''
 
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #10, 1000/100/800 {{#subobject:830d7f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2001.19.4.943 Ackland et al. 2001 (HEPI 013)]
 +
|1990-1992
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#CMF_2|CMF]]
 +
| style="background-color:#1a9850" |Superior TTP
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Epirubicin (Ellence)]] 50 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Cyclophosphamide (Cytoxan)]] 400 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''28-day cycle for 6 to 8 cycles'''
 +
</div></div>
 +
===References===
 +
# Conte PF, Pronzato P, Rubagotti A, Alama A, Amadori D, Demicheli R, Gardin G, Gentilini P, Jacomuzzi A, Lionetto R, Monzeglio C, Nicolin A, Rosso R, Sismondi P, Sussio M, Santi L. Conventional versus cytokinetic polychemotherapy with estrogenic recruitment in metastatic breast cancer: results of a randomized cooperative trial. J Clin Oncol. 1987 Mar;5(3):339-47. [https://doi.org/10.1200/JCO.1987.5.3.339 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/3546611/ PubMed]
 +
# Ambrosini G, Balli M, Garusi G, Demicheli R, Jirillo A, Bonciarelli G, Bruscagnin G, Fila G, Bumma C, Lacroix F, Buzzi F, Di Costanzo F, Padalino D, Brugia M, Calabresi F, Natali M, Cartei G, Chiesa G, Blasina B, Ciambellotti E, Moro G, D'Aquino S, Altavilla G, Adamo V, De Maria D, Falchi AM, Bertoncelli P, Farris A, Fiorentino M, Fornasiero A, Fosser V, Daniele O, Foggi CM, Speranza GB, Sartori S, Camilluzzi E, Gallo L, Poggio R, Secondo V, Gambi A, Grignani F, Capodicasa E, Lopez M, Papaldo P, Di Lauro L, Vici P, Marenco G, Folco U, Bonanni F, Marsilio P, Palazzotto G, Di Carlo A, Cusimano MP, Pastorino G, Puccetti C, Giusto M, Rausa L, Gebbia N, Palmeri S, D'Alessandro N, Saccani F, Becchi G, Schieppati G, Spinelli I, Tagliagambe A, Tonato M, Minotti V, Ardia A, Viaro D, De Micheli P, Zingali G, Sacchetti G, Intini C; Italian Multicentre Breast Study with Epirubicin. Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: an Italian multicentre trial. J Clin Oncol. 1988 Jun;6(6):976-82. [https://doi.org/10.1200/JCO.1988.6.6.976 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/2897433/ PubMed]
 +
# Bonneterre J, Hurteloup P; French Epirubicin Study Group. A prospective randomized trial comparing epirubicin monochemotherapy to two fluorouracil, cyclophosphamide, and epirubicin regimens differing in epirubicin dose in advanced breast cancer patients. J Clin Oncol. 1991 Feb;9(2):305-12. [https://doi.org/10.1200/JCO.1991.9.2.305 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/1988577/ PubMed]
 +
# Ejlertsen B, Pfeiffer P, Pedersen D, Mouridsen HT, Rose C, Overgaard M, Sandberg E, Kristensen B. Decreased efficacy of cyclophosphamide, epirubicin and 5-fluorouracil in metastatic breast cancer when reducing treatment duration from 18 to 6 months. Eur J Cancer. 1993;29A(4):527-31. [https://doi.org/10.1016/s0959-8049(05)80145-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8435205/ PubMed]
 +
# Blomqvist C, Elomaa I, Rissanen P, Hietanen P, Nevasaari K, Helle L. Influence of treatment schedule on toxicity and efficacy of cyclophosphamide, epirubicin, and fluorouracil in metastatic breast cancer: a randomized trial comparing weekly and every-4-week administration. J Clin Oncol. 1993 Mar;11(3):467-73. [https://doi.org/10.1200/JCO.1993.11.3.467 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8445422/ PubMed]
 +
# Focan C, Andrien JM, Closon MT, Dicato M, Driesschaert P, Focan-Henrard D, Lemaire M, Lobelle JP, Longree L, Ries F. Dose-response relationship of epirubicin-based first-line chemotherapy for advanced breast cancer: a prospective randomized trial. J Clin Oncol. 1993 Jul;11(7):1253-63. [https://doi.org/10.1200/JCO.1993.11.7.1253 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8315422/ PubMed]
 +
# Conte PF, Baldini E, Gardin G, Pronzato P, Amadori D, Carnino F, Monzeglio C, Gentilini P, Gallotti P, DeMicheli R, Venturini M, Rubagotti A, Rosso R; GONO. Chemotherapy with or without estrogenic recruitment in metastatic breast cancer: a randomized trial of the Gruppo Oncologico Nord Ovest (GONO). Ann Oncol. 1996 Jul;7(5):487-90. [https://doi.org/10.1093/oxfordjournals.annonc.a010637 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8839903/ PubMed]
 +
# '''HEPI 010:''' Brufman G, Colajori E, Ghilezan N, Lassus M, Martoni A, Perevodchikova N, Tosello C, Viaro D, Zielinski C; Epirubicin High Dose (HEPI 010) Study Group. Doubling epirubicin dose intensity (100 mg/m<sup>2</sup> versus 50 mg/m<sup>2</sup>) in the FEC regimen significantly increases response rates: an international randomised phase III study in metastatic breast cancer. Ann Oncol. 1997 Feb;8(2):155-62. [https://doi.org/10.1023/a:1008295427877 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/9093724/ PubMed]
 +
# Esteban E, Lacave AJ, Fernández JL, Corral N, Buesa JM, Estrada E, Palacio I, Vieitez JM, Muñiz I, Alvarez E. Phase III trial of cyclophosphamide, epirubicin, fluorouracil (CEF) versus cyclophosphamide, mitoxantrone, fluorouracil (CNF) in women with metastatic breast cancer. Breast Cancer Res Treat. 1999 Nov;58(2):141-50. [https://doi.org/10.1023/a:1006387801960 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10674879/ PubMed]
 +
# Pacini P, Rinaldini M, Algeri R, Guarneri A, Tucci E, Barsanti G, Neri B, Bastiani P, Marzano S, Fallai C. FEC (5-fluorouracil, epidoxorubicin and cyclophosphamide) versus EM (epidoxorubicin and mitomycin-C) with or without lonidamine as first-line treatment for advanced breast cancer, a multicentric randomised study: final results. Eur J Cancer. 2000 May;36(8):966-75. [https://doi.org/10.1016/s0959-8049(00)00068-x link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10885599/ PubMed]
 +
# '''HEPI 013:''' Ackland SP, Anton A, Breitbach GP, Colajori E, Tursi JM, Delfino C, Efremidis A, Ezzat A, Fittipaldo A, Kolaric K, Lopez M, Viaro D; HEPI 013 study group. Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study. J Clin Oncol. 2001 Feb 15;19(4):943-53. [https://doi.org/10.1200/jco.2001.19.4.943 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/11181656/ PubMed]
 +
# Del Mastro L, Venturini M, Lionetto R, Carnino F, Guarneri D, Gallo L, Contu A, Pronzato P, Vesentini L, Bergaglio M, Comis S, Rosso R; GONO; MIG. Accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) compared with standard CEF in metastatic breast cancer patients: results of a multicenter, randomized phase III study of the Italian Gruppo Oncologico Nord-Ouest-Mammella Inter Gruppo Group. J Clin Oncol. 2001 Apr 15;19(8):2213-21. [https://doi.org/10.1200/JCO.2001.19.8.2213 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11304774/ PubMed]
 +
#Namer M, Soler-Michel P, Turpin F, Chinet-Charrot P, de Gislain C, Pouillart P, Delozier T, Luporsi E, Etienne PL, Schraub S, Eymard JC, Serin D, Ganem G, Calais G, Maillart P, Colin P, Trillet-Lenoir V, Prevost G, Tigaud D, Clavère P, Marti P, Romieu G, Wendling JL. Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer. Eur J Cancer. 2001 Jun;37(9):1132-40. [https://doi.org/10.1016/s0959-8049(01)00093-4 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11378344/ PubMed]
 +
# '''GER-AIO-01/92:''' Heidemann E, Stoeger H, Souchon R, Hirschmann WD, Bodenstein H, Oberhoff C, Fischer JT, Schulze M, Clemens M, Andreesen R, Mahlke M, König M, Scharl A, Fehnle K, Kaufmann M. Is first-line single-agent mitoxantrone in the treatment of high-risk metastatic breast cancer patients as effective as combination chemotherapy? No difference in survival but higher quality of life were found in a multicenter randomized trial. Ann Oncol. 2002 Nov;13(11):1717-29. [https://doi.org/10.1093/annonc/mdf306 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/12419743/ PubMed] [https://clinicaltrials.gov/study/NCT00002544 NCT00002544]
 +
# Capotorto AM, Pavesi L, Pedrazzoli P, Da Prada GA, Zamagni C, Massidda B, Farris A, Martoni A, Lelli G, Robustelli della Cuna G. Randomized, controlled, multicenter phase III trial of standard-dose fluorouracil-epirubicin-cyclophosphamide (FEC), compared with time-intensive FEC (FEC-G) and mitoxantrone-methotrexate-mitomycin C (MMM-G) in metastatic breast carcinoma. J Chemother. 2003 Apr;15(2):184-91. [https://doi.org/10.1179/joc.2003.15.2.184 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/12797397/ PubMed]
 +
# Bonneterre J, Dieras V, Tubiana-Hulin M, Bougnoux P, Bonneterre ME, Delozier T, Mayer F, Culine S, Dohoulou N, Bendahmane B. Phase II multicentre randomised study of docetaxel plus epirubicin vs 5-fluorouracil plus epirubicin and cyclophosphamide in metastatic breast cancer. Br J Cancer. 2004 Oct 18;91(8):1466-71. [https://doi.org/10.1038/sj.bjc.6602179 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2409942/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15381937/ PubMed]
 +
# '''CECOG BM1:''' Zielinski C, Beslija S, Mrsic-Krmpotic Z, Welnicka-Jaskiewicz M, Wiltschke C, Kahan Z, Grgic M, Tzekova V, Inbar M, Cervek J, Chernozemsky I, Szanto J, Spanik S, Wagnerova M, Ghilezan N, Pawlega J, Vrbanec D, Khamtsov D, Soldatenkova V, Brodowicz T. Gemcitabine, epirubicin, and paclitaxel versus fluorouracil, epirubicin, and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: a Central European Cooperative Oncology Group International, multicenter, prospective, randomized phase III trial. J Clin Oncol. 2005 Mar 1;23(7):1401-8. [https://doi.org/10.1200/JCO.2005.12.106 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15735116/ PubMed]
 +
<!-- Presented in part at the 45th Annual Meeting of the American Society for Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and at the 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology Multidisciplinary Congress, September 20-24, 2009, Berlin, Germany. -->
 +
# '''RIBBON-1:''' Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.28.0982 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21383283/ PubMed] [https://clinicaltrials.gov/study/NCT00262067 NCT00262067]
  
 +
==FEC & Bevacizumab {{#subobject:72fe69|Regimen=1}}==
 +
FEC & Bevacizumab: '''<u>F</u>'''luorouracil, '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide, Bevacizumab
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:cb9b3a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-363-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 +
|-
 +
|} -->
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]]<br>1b. [[#Capecitabine_monotherapy_2|Capecitabine]]<br>1c. [[#Docetaxel_monotherapy_2|Docetaxel]]<br>1d. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]]<br>1e. [[#FAC_3|FAC]]<br>1f. [[#FEC_3|FEC]]<br>1g. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>(HR 0.64, 95% CI 0.52-0.80)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Fluorouracil (5-FU)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
*[[Epirubicin (Ellence)]] 90 to 100 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m<sup>2</sup> IV once on day 1
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
 +
'''21-day cycle for up to 8 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*RIBBON-1, SD or better: [[#Bevacizumab_monotherapy_2|Bevacizumab]] maintenance
 +
</div></div>
 
===References===
 
===References===
−
# Hortobagyi GN, Gutterman JU, Blumenschein GR, Tashima CK, Burgess MA, Einhorn L, Buzdar AU, Richman SP, Hersh EM. Combination chemoimmunotherapy of metastatic breast cancer with 5-fluorouracil, adriamycin, cyclophosphamide, and BCG. Cancer. 1979 Nov;44(5):1955-62. [http://www.ncbi.nlm.nih.gov/pubmed/387212 PubMed]
+
<!-- Presented in part at the 45th Annual Meeting of the American Society for Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and at the 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology Multidisciplinary Congress, September 20-24, 2009, Berlin, Germany. -->
−
# Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, Bowman D, Wolmark N, Wickerham DL, Kardinal CG et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol. 1990 Sep;8(9):1483-96. [http://jco.ascopubs.org/content/8/9/1483.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/2202791 PubMed]
+
# '''RIBBON-1:''' Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.28.0982 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21383283/ PubMed] [https://clinicaltrials.gov/study/NCT00262067 NCT00262067]
−
# Ackland SP, Anton A, Breitbach GP, Colajori E, Tursi JM, Delfino C, Efremidis A, Ezzat A, Fittipaldo A, Kolaric K, Lopez M, Viaro D; HEPI 013 study group. Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study. J Clin Oncol. 2001 Feb 15;19(4):943-53. [http://jco.ascopubs.org/content/19/4/943.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/11181656 PubMed]
+
==Gemcitabine monotherapy {{#subobject:b240d6|Regimen=1}}==
−
# Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B, Van Hazel G, Wilcken NR, Grimison PS, Nowak AK, Gainford MC, Fong A, Paksec L, Sourjina T, Zannino D, Gebski V, Simes RJ, Forbes JF, Coates AS. Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4498-504. doi: 10.1200/JCO.2010.33.9101. Epub 2011 Oct 24. [http://jco.ascopubs.org/content/29/34/4498.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/22025143 PubMed]
+
<div class="toccolours" style="background-color:#eeeeee">
−
 
+
===Regimen {{#subobject:7ea6c2|Variant=1}}===
−
==EC {{#subobject:b81844|Regimen=1}}==
+
{| class="wikitable" style="width: 60%; text-align:center;"  
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.1995.13.11.2731 Carmichael et al. 1995]
 +
|NR
 +
| style="background-color:#ffffbe" |Phase 2, less than 20 pts in this subgroup
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
EC: '''<u>E</u>'''pirubicin, '''<u>C</u>'''ytoxan
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
===Regimen {{#subobject:8466d6|Variant=1}}===
+
*[[Gemcitabine (Gemzar)]] 800 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15
−
Level of Evidence:
+
'''28-day cycles'''
−
<span
+
</div></div>
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Epirubicin (Ellence)]] 75 mg/m2 IV day 1
 
−
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m2 IV day 1
 
−
 
 
−
'''21-day cycles up to 6 cycles'''
 
−
 
 
 
===References===
 
===References===
−
# Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. [http://www.nejm.org/doi/full/10.1056/NEJM200103153441101 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/11248153 PubMed]
+
# Carmichael J, Possinger K, Philip P, Beykirch M, Kerr H, Walling J, Harris AL. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol. 1995 Nov;13(11):2731-6. [https://doi.org/10.1200/jco.1995.13.11.2731 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7595731/ PubMed]
−
# Langley RE, Carmichael J, Jones AL, Cameron DA, Qian W, Uscinska B, Howell A, Parmar M. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute trial AB01. J Clin Oncol. 2005 Nov 20;23(33):8322-30. [http://jco.ascopubs.org/content/23/33/8322.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16293863 PubMed]
+
==Gemcitabine & Paclitaxel {{#subobject:1285e|Regimen=1}}==
−
 
+
GT: '''<u>G</u>'''emcitabine & '''<u>T</u>'''axol (Paclitaxel)
−
==EP {{#subobject:e10567|Regimen=1}}==
+
<br>PG: '''<u>P</u>'''aclitaxel & '''<u>G</u>'''emcitabine
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 6 cycles {{#subobject:5e5f66|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2012.45.2490 Park et al. 2013 (KCSG-BR07-02)]
 +
|2007-2010
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8, '''given second on day 1'''
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1, '''given first'''
 +
'''21-day cycle for 6 cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*[[#Gemcitabine_.26_Paclitaxel_2|PG]] maintenance versus [[Breast_cancer_-_null_regimens#Observation_2|Observation]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, indefinite {{#subobject:7a28ec|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2007.11.9362 Albain et al. 2008]
 +
|1999-2002
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel]]
 +
| style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)<br>Median OS: 18.6 vs 15.8 mo<br>(HR 0.78, 95% CI 0.64-0.96)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3621657/ Del Mastro et al. 2013 (B9E-IT-S376)]
 +
|2005-2010
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|1. [[#Docetaxel_.26_Gemcitabine|GD]]; weekly<br>2. [[#Docetaxel_.26_Gemcitabine|GD]]; q3wk<br> 3. [[#Gemcitabine_.26_Paclitaxel|GT]]; weekly
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
EP: '''<u>E</u>'''pirubicin, '''<u>P</u>'''aclitaxel
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
===Regimen {{#subobject:f9fb8b|Variant=1}}===
+
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 30 to 60 minutes once per day on days 1 & 8, '''given second on day 1'''
−
Level of Evidence:
+
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given first'''
−
<span
+
'''21-day cycles'''
−
style="background:#00CD00;
+
</div></div>
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Epirubicin (Ellence)]] 75 mg/m2 IV day 1  
 
−
*[[Paclitaxel (Taxol)]] 200 mg/m2 IV day 1
 
−
 
 
−
'''21-day cycles up to 6 cycles'''
 
−
 
 
 
===References===
 
===References===
−
# Langley RE, Carmichael J, Jones AL, Cameron DA, Qian W, Uscinska B, Howell A, Parmar M. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute trial AB01. J Clin Oncol. 2005 Nov 20;23(33):8322-30. [http://jco.ascopubs.org/content/23/33/8322.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16293863 PubMed]
+
<!-- Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003, and the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. -->
−
 
+
# Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, Rolski J, Melemed AS, Reyes-Vidal JM, Sekhon JS, Simms L, O'Shaughnessy J. Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008 Aug 20;26(24):3950-7. [https://doi.org/10.1200/jco.2007.11.9362 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18711184/ PubMed]
−
==FAC {{#subobject:b0cb|Regimen=1}}==
+
# '''B9E-IT-S376:''' Del Mastro L, Fabi A, Mansutti M, De Laurentiis M, Durando A, Merlo DF, Bruzzi P, La Torre I, Ceccarelli M, Kazeem G, Marchi P, Boy D, Venturini M, De Placido S, Cognetti F. Randomised phase 3 open-label trial of first-line treatment with gemcitabine in association with docetaxel or paclitaxel in women with metastatic breast cancer: a comparison of different schedules and treatments. BMC Cancer. 2013 Mar 28;13:164. [https://doi.org/10.1186/1471-2407-13-164 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3621657/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/23537313/ PubMed] [https://clinicaltrials.gov/study/NCT00236899 NCT00236899]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
# '''KCSG-BR07-02:''' Park YH, Jung KH, Im SA, Sohn JH, Ro J, Ahn JH, Kim SB, Nam BH, Oh DY, Han SW, Lee S, Park IH, Lee KS, Kim JH, Kang SY, Lee MH, Park HS, Ahn JS, Im YH. Phase III, multicenter, randomized trial of maintenance chemotherapy versus observation in patients with metastatic breast cancer after achieving disease control with six cycles of gemcitabine plus paclitaxel as first-line chemotherapy: KCSG-BR07-02. J Clin Oncol. 2013 May 10;31(14):1732-9. Epub 2013 Apr 8. [https://doi.org/10.1200/JCO.2012.45.2490 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23569309/ PubMed] [https://clinicaltrials.gov/study/NCT00561119 NCT00561119]
 +
==Cyclophosphamide & Non-pegylated liposomal doxorubicin (MC) {{#subobject:7ac8f8|Regimen=1}}==
 +
MC: '''<u>M</u>'''yocet (non-pegylated liposomal doxorubicin) & '''<u>C</u>'''yclophosphamide
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 60/600 {{#subobject:57bc79|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.spandidos-publications.com/ijo/45/5/2137 Lorusso et al. 2014]
 +
|2006-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Non-pegylated_liposomal_doxorubicin_.26_Vinorelbine_999|NPLD & Vinorelbine]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
Level of Evidence:
+
<div class="toccolours" style="background-color:#b3e2cd">
−
<span
+
====Chemotherapy====
−
style="background:#EEEE00;
+
*[[Non-pegylated liposomal doxorubicin (Myocet)]] 60 mg/m<sup>2</sup> IV once on day 1
−
padding:3px 6px 3px 6px;
+
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
−
 
 
−
FAC: '''<u>F</u>'''ive-FU, '''<u>A</u>'''driamycin, '''<u>C</u>'''ytoxan
 
−
 
 
−
===Regimen {{#subobject:ed75b0|Variant=1}}===
 
−
*[[Fluorouracil (5-FU)]] 500 mg/m2 IV on days 1 & 8 or days 1 & 4
 
−
*[[Doxorubicin (Adriamycin)]] 50 mg/m2 IV on day 1
 
−
*[[Cyclophosphamide (Cytoxan)]] 500 mg/m2 IV on day 1
 
−
 
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 75/600 {{#subobject:57bc80|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdh393 Chan et al. 2004]
 +
|1996-05 to 1997-08
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]]
 +
| style="background-color:#1a9850" |Superior TTP<br>Median TTP: 7.7 vs 5.6 mo<br>(HR 0.66, 95% CI 0.45-0.94)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Non-pegylated liposomal doxorubicin (Myocet)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
*[[Cyclophosphamide (Cytoxan)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 8 cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Hortobagyi GN, Gutterman JU, Blumenschein GR, Tashima CK, Burgess MA, Einhorn L, Buzdar AU, Richman SP, Hersh EM. Combination chemoimmunotherapy of metastatic breast cancer with 5-fluorouracil, adriamycin, cyclophosphamide, and BCG. Cancer. 1979 Nov;44(5):1955-62. [http://www.ncbi.nlm.nih.gov/pubmed/387212 PubMed]
+
# Chan S, Davidson N, Juozaityte E, Erdkamp F, Pluzanska A, Azarnia N, Lee LW. Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer. Ann Oncol. 2004 Oct;15(10):1527-34. [https://doi.org/10.1093/annonc/mdh393 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15367414/ PubMed]
−
 
+
# Lorusso V, Giotta F, Bordonaro R, Maiello E, Del Prete S, Gebbia V, Filippelli G, Pisconti S, Cinieri S, Romito S, Riccardi F, Forcignanò R, Ciccarese M, Petrucelli L, Saracino V, Lupo LI, Gambino A, Leo S, Colucci G; Gruppo Oncologico Dell'Italia Meridionale. Non-pegylated liposome-encapsulated doxorubicin citrate plus cyclophosphamide or vinorelbine in metastatic breast cancer not previously treated with chemotherapy:a multicenter phase III study. Int J Oncol. 2014 Nov;45(5):2137-42. Epub 2014 Aug 18. [https://www.spandidos-publications.com/ijo/45/5/2137 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25176223/ PubMed]
−
==Gemcitabine & Carboplatin {{#subobject:83a5ee|Regimen=1}}==
+
==Paclitaxel monotherapy, weekly {{#subobject:3e5448|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 80 mg/m<sup>2</sup> weekly {{#subobject:718d5b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2001.19.22.4216 Perez et al. 2001]
 +
|NR
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/jco.2007.11.6699 Seidman et al. 2008 (CALGB 9840)]
 +
|1998-NR
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel]]; q3wk
 +
| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>Median OS: 24 vs 12 mo<br>(HR 0.78, 95% CI 0.65-0.94)
 +
|-
 +
|[https://doi.org/10.1007/s10549-008-0047-9 Fountzilas et al. 2008]
 +
|2002-2006
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|1. [[#Carboplatin_.26_Paclitaxel_.28CP.29_999|Carboplatin & Paclitaxel]]<br>2. [[#Docetaxel_.26_Gemcitabine|Docetaxel & Gemcitabine]]
 +
| style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdw562 Martin et al. 2017 (BELLE-4)]
 +
|2012-2014
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Buparlisib_.26_Paclitaxel_999|Buparlisib & Paclitaxel]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 80 mg/m<sup>2</sup> 3 weeks out of 4 {{#subobject:b70577|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(15)00411-8 Takashima et al. 2015 (SELECT BC)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#S-1_monotherapy|S-1]]
 +
| style="background-color:#eeee01" |Seems to have non-inferior OS
 +
| style="background-color:#d73027" |Inferior EQ-5D score
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6461876/ Fujiwara et al. 2019 (A3105301)]
 +
|2012-2014
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#NK-105_monotherapy_999|NK-105]]
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS (primary endpoint)
 +
| style="background-color:#d73027" |Higher rate of CIPN
 +
|-
 +
|}
 +
''Note: this is the lower limit of dosing allowed in SELECT BC.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 90 mg/m<sup>2</sup> 3 weeks out of 4 {{#subobject:1a1adf|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa072113 Miller et al. 2007 (ECOG E2100)]
 +
|2001-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Paclitaxel_.26_Bevacizumab|Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2016.09.024 Miles et al. 2016 (MERiDiAN)]
 +
|2012-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Paclitaxel_.26_Bevacizumab|Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel (Taxol)]] 90 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 100 mg/m<sup>2</sup> weekly {{#subobject:f8eb25|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1998.16.10.3353 Seidman et al. 1998]
 +
|NR
 +
| style="background-color:#ffffbe" |Phase 2, less than 20 pts in this subgroup
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel (Taxol)]] 100 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
'''7-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, 100 mg/m<sup>2</sup> 3 weeks out of 4 {{#subobject:1a1adf|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(15)00411-8 Takashima et al. 2015 (SELECT BC)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#S-1_monotherapy|S-1]]
 +
| style="background-color:#eeee01" |Seems to have non-inferior OS
 +
| style="background-color:#d73027" |Inferior EQ-5D score
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen, Nagourney et al. 2008 {{#subobject:e571d|Variant=1}}===
+
''Note: this is the upper limit of dosing allowed in SELECT BC.''
−
Level of Evidence:
+
<div class="toccolours" style="background-color:#b3e2cd">
−
<span
+
====Chemotherapy====
−
style="background:#ff0000;
+
*[[Paclitaxel (Taxol)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
−
padding:3px 6px 3px 6px;
+
'''28-day cycles'''
−
border-color:black;
+
</div></div>
−
border-width:2px;
 
−
border-style:solid;">Pilot, <20 patients reported</span>
 
−
 
 
−
*[[Gemcitabine (Gemzar)]] 800 mg/m2 IV over 1 hour once per day on days 1 & 8
 
−
*[[Carboplatin (Paraplatin)]] AUC 2 IV over 1 hour once per day on days 1 & 8
 
−
 
 
−
'''21-day cycles, given until complete remission, progression of disease, or unacceptable toxicity'''
 
−
 
 
 
===References===
 
===References===
−
# Nagourney RA, Flam M, Link J, Hager S, Blitzer J, Lyons W, Sommers BL, Evans S. Carboplatin plus gemcitabine repeating doublet therapy in recurrent breast cancer. Clin Breast Cancer. 2008 Oct;8(5):432-5. doi: 10.3816/CBC.2008.n.052. [http://www.sciencedirect.com/science/article/pii/S1526820911705407 link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/18952557 PubMed]
+
# Seidman AD, Hudis CA, Albanell J, Tong W, Tepler I, Currie V, Moynahan ME, Theodoulou M, Gollub M, Baselga J, Norton L. Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol. 1998 Oct;16(10):3353-61. Erratum in: J Clin Oncol. 2006 May 10;24(14):2220. Albanel, J [corrected to Albanell, J ]. [https://doi.org/10.1200/JCO.1998.16.10.3353 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/9779712/ PubMed]
 +
# Perez EA, Vogel CL, Irwin DH, Kirshner JJ, Patel R. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2001 Nov 15;19(22):4216-23. [https://doi.org/10.1200/jco.2001.19.22.4216 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11709565/ PubMed]
 +
# '''ECOG E2100:''' Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76. [https://doi.org/10.1056/NEJMoa072113 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18160686/ PubMed] [https://clinicaltrials.gov/study/NCT00028990 NCT00028990]
 +
<!-- Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA. -->
 +
# '''CALGB 9840:''' Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. [https://doi.org/10.1200/jco.2007.11.6699 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18375893/ PubMed] [https://clinicaltrials.gov/study/NCT00003440 NCT00003440]
 +
# Fountzilas G, Dafni U, Dimopoulos MA, Koutras A, Skarlos D, Papakostas P, Gogas H, Bafaloukos D, Kalogera-Fountzila A, Samantas E, Briasoulis E, Pectasides D, Maniadakis N, Matsiakou F, Aravantinos G, Papadimitriou C, Karina M, Christodoulou C, Kosmidis P, Kalofonos HP; Hellenic Cooperative Oncology Group. A randomized phase III study comparing three anthracycline-free taxane-based regimens, as first line chemotherapy, in metastatic breast cancer: a Hellenic Cooperative Oncology Group study. Breast Cancer Res Treat. 2009 May;115(1):87-99. Epub 2008 May 16. [https://doi.org/10.1007/s10549-008-0047-9 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18483853/ PubMed]
 +
# '''SELECT BC:''' Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T, Hozumi Y, Tsurutani J, Imoto S, Watanabe T, Sagara Y, Nishimura R, Shimozuma K, Ohashi Y; SELECT BC Study Group. Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2016 Jan;17(1):90-8. Epub 2015 Nov 27. [https://doi.org/10.1016/S1470-2045(15)00411-8 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26617202/ PubMed] UMIN C000000416
 +
## '''HRQoL analysis:''' Shiroiwa T, Fukuda T, Shimozuma K, Mouri M, Hagiwara Y, Doihara H, Akabane H, Kashiwaba M, Watanabe T, Ohashi Y, Mukai H. Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial. Qual Life Res. 2017 Feb;26(2):445-453. Epub 2016 Aug 12. [https://doi.org/10.1007/s11136-016-1388-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288429/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27517267/ PubMed]
 +
# '''MERiDiAN:''' Miles D, Cameron D, Bondarenko I, Manzyuk L, Alcedo JC, Lopez RI, Im SA, Canon JL, Shparyk Y, Yardley DA, Masuda N, Ro J, Denduluri N, Hubeaux S, Quah C, Bais C, O'Shaughnessy J. Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation. Eur J Cancer. 2017 Jan;70:146-155. Epub 2016 Nov 4. [https://doi.org/10.1016/j.ejca.2016.09.024 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27817944/ PubMed] [https://clinicaltrials.gov/study/NCT01663727 NCT01663727]
 +
## '''Update:''' Miles D, Cameron D, Hilton M, Garcia J, O'Shaughnessy J. Overall survival in MERiDiAN, a double-blind placebo-controlled randomised phase III trial evaluating first-line bevacizumab plus paclitaxel for HER2-negative metastatic breast cancer. Eur J Cancer. 2018 Feb;90:153-155. Epub 2017 Nov 23. [https://doi.org/10.1016/j.ejca.2017.10.018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29174181/ PubMed]
 +
# '''BELLE-4:''' Martín M, Chan A, Dirix L, O'Shaughnessy J, Hegg R, Manikhas A, Shtivelband M, Krivorotko P, Batista López N, Campone M, Ruiz Borrego M, Khan QJ, Beck JT, Ramos Vázquez M, Urban P, Goteti S, Di Tomaso E, Massacesi C, Delaloge S. A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4). Ann Oncol. 2017 Feb 1;28(2):313-320. [https://doi.org/10.1093/annonc/mdw562 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27803006/ PubMed] [https://clinicaltrials.gov/study/NCT01572727 NCT01572727]
 +
# '''A3105301:''' Fujiwara Y, Mukai H, Saeki T, Ro J, Lin YC, Nagai SE, Lee KS, Watanabe J, Ohtani S, Kim SB, Kuroi K, Tsugawa K, Tokuda Y, Iwata H, Park YH, Yang Y, Nambu Y. A multi-national, randomised, open-label, parallel, phase III non-inferiority study comparing NK105 and paclitaxel in metastatic or recurrent breast cancer patients. Br J Cancer. 2019 Mar;120(5):475-480. Epub 2019 Feb 12. [https://doi.org/10.1038/s41416-019-0391-z link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc6461876/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/30745582/ PubMed] [https://clinicaltrials.gov/study/NCT01644890 NCT01644890]
 +
==Paclitaxel monotherapy, q3wk {{#subobject:3e5448|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 175 mg/m<sup>2</sup> q3wk {{#subobject:72389a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1200/jco.1995.13.10.2575 Seidman et al. 1995]
 +
|NR
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/JCO.2004.08.048 Winer et al. 2004 (CALGB 9342)]
 +
|1994-1997
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel]]; 210 mg/m<sup>2</sup> q3wk<br>2. [[#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel]]; 250 mg/m<sup>2</sup> q3wk
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/jco.2007.11.6699 Seidman et al. 2008 (CALGB 9840)]
 +
|1998-NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Paclitaxel_monotherapy.2C_weekly_2|Paclitaxel]]; weekly
 +
| style="background-color:#d73027" |Inferior OS
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/jco.2007.11.9362 Albain et al. 2008]
 +
|1999-2002
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Gemcitabine_.26_Paclitaxel|GT]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.04.937 Gradishar et al. 2005 (CA012-0)]
 +
|2001-11 to 2002-11
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]
 +
| style="background-color:#d73027" |Inferior TTP
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651098/ Di Leo et al. 2008 (EGF30001)]
 +
|2004-01 to 2005-07
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Lapatinib_.26_Paclitaxel_999|Lapatinib & Paclitaxel]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 +
| style="background-color:#1a9850" |Less toxic
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(15)00411-8 Takashima et al. 2015 (SELECT BC)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#S-1_monotherapy|S-1]]
 +
| style="background-color:#eeee01" |Seems to have non-inferior OS
 +
| style="background-color:#d73027" |Inferior EQ-5D score
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512366/ Park et al. 2016 (GPMBC301)]
 +
|2008-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Paclitaxel_polymeric_micelle_formulation_monotherapy_888|Genexol-PM]]
 +
| style="background-color:#eeee01" |Seems to have non-inferior ORR
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|}
 +
''Note: patients in EGF30001 were NOT required to be HER2-positive.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
==GT {{#subobject:1285e|Regimen=1}}==
+
===Regimen variant #2, 175 mg/m<sup>2</sup>, CI {{#subobject:e67gb7|Variant=1}}===
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|rowspan=2|[https://doi.org/10.1200/JCO.2003.08.013 Sledge et al. 2003 (ECOG E1193)]
 +
|rowspan=2|1993-1995
 +
|rowspan=2 style="background-color:#1a9851" |Phase 3 (E-switch-ooc)
 +
|1. [[#Doxorubicin_.26_Paclitaxel_.28AT.29_2|AT (Taxol)]]
 +
| style="background-color:#d73027" |Inferior TTF
 +
|-
 +
|2. [[#Doxorubicin_monotherapy|Doxorubicin]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
GT: '''<u>G</u>'''emcitabine, '''<u>T</u>'''axol
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
===Regimen {{#subobject:5e5f66|Variant=1}}===
+
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
−
Level of Evidence:
+
'''21-day cycles'''
−
<span
+
</div></div><br>
−
style="background:#00CD00;
+
<div class="toccolours" style="background-color:#eeeeee">
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Gemcitabine (Gemzar)]] 1250 mg/m2 IV on days 1 & 8; on day 1, administer after paclitaxel
 
−
*[[Paclitaxel (Taxol)]] 175 mg/m2 IV day 1
 
  
 +
===Regimen variant #3, 175 mg/m<sup>2</sup> q4wk {{#subobject:42c791|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(15)00411-8 Takashima et al. 2015 (SELECT BC)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#S-1_monotherapy|S-1]]
 +
| style="background-color:#eeee01" |Seems to have non-inferior OS
 +
| style="background-color:#d73027" |Inferior EQ-5D score
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 200 mg/m<sup>2</sup> {{#subobject:2e25d1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1999.17.8.2355 Bishop et al. 1999]
 +
|1993-NR
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[Breast_cancer_-_historical#CMFP_2|CMFP]]
 +
| style="background-color:#91cf60" |Seems to have superior OS
 +
|-
 +
|[https://doi.org/10.1200/JCO.2000.18.4.724 Paridaens et al. 2000 (EORTC 10923)]
 +
|1993-1996
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Doxorubicin_monotherapy|Doxorubicin]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel (Taxol)]] 200 mg/m<sup>2</sup> IV over 3 hours once on day 1
 +
'''21-day cycle for 7 or 8 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, 250 mg/m<sup>2</sup> {{#subobject:e60257|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/jnci/83.24.1797-a Holmes et al. 1991]
 +
|1990
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/JCO.1999.17.11.3403 Smith et al. 1996 (NSABP B-26)]
 +
|1994-1996
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel]]; 250 mg/m<sup>2</sup> over 3 hours
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
''Note: Holmes et al. 1991 is of historic interest, being the first phase II trial of a taxane in breast cancer.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel (Taxol)]] 250 mg/m<sup>2</sup> IV continuous infusion over 24 hours, started on day 1
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
−
# Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, Rolski J, Melemed AS, Reyes-Vidal JM, Sekhon JS, Simms L, O'Shaughnessy J. Gemcitabine plus Paclitaxel versus Paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008 Aug 20;26(24):3950-7. [http://jco.ascopubs.org/content/26/24/3950.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18711184 PubMed]
+
# Holmes FA, Walters RS, Theriault RL, Forman AD, Newton LK, Raber MN, Buzdar AU, Frye DK, Hortobagyi GN. Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst. 1991 Dec 18;83(24):1797-805. [https://doi.org/10.1093/jnci/83.24.1797-a link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/1683908/ PubMed]
−
 
+
# Seidman AD, Tiersten A, Hudis C, Gollub M, Barrett S, Yao TJ, Lepore J, Gilewski T, Currie V, Crown J, Hakes T, Baselga J, Sklarin N, Moynihan ME, Tong W, Egorin M, Kearns C, Spriggs D, Norton L. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2575-81. [https://doi.org/10.1200/jco.1995.13.10.2575 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7595709/ PubMed]
−
==Ixabepilone (Ixempra) & Capecitabine (Xeloda) {{#subobject:9ce286|Regimen=1}}==
+
# Bishop JF, Dewar J, Toner GC, Smith J, Tattersall MH, Olver IN, Ackland S, Kennedy I, Goldstein D, Gurney H, Walpole E, Levi J, Stephenson J, Canetta R. Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2355-64. [https://doi.org/10.1200/JCO.1999.17.8.2355 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10561297/ PubMed]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
# '''NSABP B-26:''' Smith RE, Brown AM, Mamounas EP, Anderson SJ, Lembersky BC, Atkins JH, Shibata HR, Baez L, DeFusco PA, Davila E, Tipping SJ, Bearden JD, Thirlwell MP. Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-26. J Clin Oncol. 1999 Nov;17(11):3403-11. [https://doi.org/10.1200/JCO.1999.17.11.3403 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10550134/ PubMed]
 +
# '''EORTC 10923:''' Paridaens R, Biganzoli L, Bruning P, Klijn JG, Gamucci T, Houston S, Coleman R, Schachter J, Van Vreckem A, Sylvester R, Awada A, Wildiers J, Piccart M. Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European Organisation for Research and Treatment of Cancer Randomized Study with cross-over. J Clin Oncol. 2000 Feb;18(4):724-33. [https://doi.org/10.1200/JCO.2000.18.4.724 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10673513/ PubMed]
 +
## '''HRQoL analysis:''' Kramer JA, Curran D, Piccart M, de Haes JC, Bruning PF, Klijn JG, Bontenbal M, van Pottelsberghe C, Groenvold M, Paridaens R. Randomised trial of paclitaxel versus doxorubicin as first-line chemotherapy for advanced breast cancer: quality of life evaluation using the EORTC QLQ-C30 and the Rotterdam symptom checklist. Eur J Cancer. 2000 Aug;36(12):1488-97. [https://doi.org/10.1016/s0959-8049(00)00134-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10930796/ PubMed]
 +
# '''ECOG E1193:''' Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, Wood WC. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol. 2003 Feb 15;21(4):588-92. [https://doi.org/10.1200/JCO.2003.08.013 link to original article] [https://pubmed.ncbi.nlm.nih.gov/12586793/ PubMed]
 +
# '''CALGB 9342:''' Winer EP, Berry DA, Woolf S, Duggan D, Kornblith A, Harris LN, Michaelson RA, Kirshner JA, Fleming GF, Perry MC, Graham ML, Sharp SA, Keresztes R, Henderson IC, Hudis C, Muss H, Norton L. Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: Cancer and Leukemia Group B trial 9342. J Clin Oncol. 2004 Jun 1;22(11):2061-8. [https://doi.org/10.1200/JCO.2004.08.048 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15169793/ PubMed]
 +
<!-- Presented in part at the 26th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 3-6, 2003. -->
 +
# '''CA012-0:''' Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. [https://doi.org/10.1200/jco.2005.04.937 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16172456/ PubMed] [https://clinicaltrials.gov/study/NCT00046527 NCT00046527]
 +
<!-- Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA. -->
 +
# '''CALGB 9840:''' Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. [https://doi.org/10.1200/jco.2007.11.6699 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18375893/ PubMed] [https://clinicaltrials.gov/study/NCT00003440 NCT00003440]
 +
<!-- Presented in part at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003, and the 40th Annual Meeting of the American Society of Clinical Oncology, New Orleans, LA, June 5-8, 2004. -->
 +
# Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, Rolski J, Melemed AS, Reyes-Vidal JM, Sekhon JS, Simms L, O'Shaughnessy J. Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008 Aug 20;26(24):3950-7. [https://doi.org/10.1200/jco.2007.11.9362 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18711184/ PubMed]
 +
# '''EGF30001:''' Di Leo A, Gomez HL, Aziz Z, Zvirbule Z, Bines J, Arbushites MC, Guerrera SF, Koehler M, Oliva C, Stein SH, Williams LS, Dering J, Finn RS, Press MF. Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol. 2008 Dec 1;26(34):5544-52. Epub 2008 Oct 27. Erratum in: J Clin Oncol. 2009 Apr 10;27(11):1923. [https://doi.org/10.1200/JCO.2008.16.2578 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2651098/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/18955454/ PubMed] [https://clinicaltrials.gov/study/NCT00075270 NCT00075270]
 +
# '''SELECT BC:''' Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T, Hozumi Y, Tsurutani J, Imoto S, Watanabe T, Sagara Y, Nishimura R, Shimozuma K, Ohashi Y; SELECT BC Study Group. Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2016 Jan;17(1):90-8. Epub 2015 Nov 27. [https://doi.org/10.1016/S1470-2045(15)00411-8 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26617202/ PubMed] UMIN C000000416
 +
## '''HRQoL analysis:''' Shiroiwa T, Fukuda T, Shimozuma K, Mouri M, Hagiwara Y, Doihara H, Akabane H, Kashiwaba M, Watanabe T, Ohashi Y, Mukai H. Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial. Qual Life Res. 2017 Feb;26(2):445-453. Epub 2016 Aug 12. [https://doi.org/10.1007/s11136-016-1388-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288429/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27517267/ PubMed]
 +
# '''GPMBC301:''' Park IH, Sohn JH, Kim SB, Lee KS, Chung JS, Lee SH, Kim TY, Jung KH, Cho EK, Kim YS, Song HS, Seo JH, Ryoo HM, Lee SA, Yoon SY, Kim CS, Kim YT, Kim SY, Jin MR, Ro J. An Open-Label, Randomized, Parallel, Phase III Trial Evaluating the Efficacy and Safety of Polymeric Micelle-Formulated Paclitaxel Compared to Conventional Cremophor EL-Based Paclitaxel for Recurrent or Metastatic HER2-Negative Breast Cancer. Cancer Res Treat. 2017 Jul;49(3):569-577. Epub 2016 Sep 12. [https://doi.org/10.4143/crt.2016.289 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512366/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27618821/ PubMed] [https://clinicaltrials.gov/study/NCT00876486 NCT00876486]
 +
==Paclitaxel & Bevacizumab {{#subobject:ab5252|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:1c2f5c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/NEJMoa072113 Miller et al. 2007 (ECOG E2100)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-11-1 <span style="color:white;">ESMO-MCBS (2)</span>]'''
 +
|-
 +
|} -->
 +
|2001-2004
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[#Paclitaxel_monotherapy.2C_weekly_2|Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 11.8 vs 5.9 mo<br>(HR 0.60)<br><br>Did not meet secondary endpoint of OS<br>Median OS: 26.7 vs 25.2 mo<br>(HR 0.88)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617186/ Robert et al. 2011 (SUN 1094)]
 +
|2006-2009
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Paclitaxel_.26_Sunitinib_999|Paclitaxel & Sunitinib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(12)70566-1 Lang et al. 2013 (TURANDOT)]
 +
|2008-2010
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Capecitabine_.26_Bevacizumab|Capecitabine & Bevacizumab]]
 +
| style="background-color:#eeee01" |Non-inferior OS<sup>1</sup> (primary endpoint)
 +
|-
 +
|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500830/ Rugo et al. 2015 (CALGB 40502/NCCTG N063H)]
 +
|rowspan=2|2008-2011
 +
| rowspan=2 style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[Stub#Ixabepilone_.26_Bevacizumab|Ixabepilone & Bevacizumab]]
 +
| style="background-color:#1a9850" |Superior PFS
 +
|-
 +
|2. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d9ef8b" |Might have superior PFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5057418/ Rochlitz et al. 2016 (SAKK 24/09)]
 +
|2010-2012
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine.2C_Cyclophosphamide.2C_Bevacizumab_999|Capecitabine, Cyclophosphamide, Bevacizumab]]
 +
| style="background-color:#ffffbf" |Did not meet secondary endpoint of PFS
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2016.09.024 Miles et al. 2016 (MERiDiAN)]
 +
|2012-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Paclitaxel_monotherapy.2C_weekly_2|Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 11 vs 8.8 mo<br>(HR 0.68, 99% CI 0.51-0.91)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:f5cae3|Variant=1}}===
+
''<sup>1</sup>Reported efficacy for TURANDOT is based on the 2016 update.''<br>
−
Level of Evidence:
+
''Note: ECOG E2100 was the basis for accelerated approval of bevacizumab in breast cancer.''
−
<span
+
<div class="toccolours" style="background-color:#b3e2cd">
−
style="background:#00CD00;
+
====Chemotherapy====
−
padding:3px 6px 3px 6px;
+
*[[Paclitaxel (Taxol)]] 90 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15
−
border-color:black;
+
====Targeted therapy====
−
border-width:2px;
+
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
−
border-style:solid;">Phase III</span>
+
'''28-day cycles'''
−
 
+
</div></div>
−
*[[Ixabepilone (Ixempra)]] 40 mg/m2 IV once on day 1
 
−
*[[Capecitabine (Xeloda)]] 2000 mg/m2 PO once per day on days 1 to 14
 
−
 
 
−
'''21-day cycles'''
 
−
 
 
 
===References===
 
===References===
−
# Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. [http://jco.ascopubs.org/content/25/33/5210.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/17968020 PubMed]
+
# '''ECOG E2100:''' Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76. [https://doi.org/10.1056/NEJMoa072113 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18160686/ PubMed] [https://clinicaltrials.gov/study/NCT00028990 NCT00028990]
−
# Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010 Jul 10;28(20):3256-63. [http://www.ncbi.nlm.nih.gov/pmc/articles/pmid/20530276/?tool=pubmed link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20530276 PubMed]
+
# '''SUN 1094:''' Robert NJ, Saleh MN, Paul D, Generali D, Gressot L, Copur MS, Brufsky AM, Minton SE, Giguere JK, Smith JW 2nd, Richards PD, Gernhardt D, Huang X, Liau KF, Kern KA, Davis J. Sunitinib plus paclitaxel versus bevacizumab plus paclitaxel for first-line treatment of patients with advanced breast cancer: a phase III, randomized, open-label trial. Clin Breast Cancer. 2011 Apr;11(2):82-92. Epub 2011 Apr 11. Erratum in: Clin Breast Cancer. 2011 Aug;11(4):273. [https://doi.org/10.1016/j.clbc.2011.03.005 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4617186/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21569994/ PubMed] [https://clinicaltrials.gov/study/NCT00373256 NCT00373256]
 +
# '''TURANDOT:''' Lang I, Brodowicz T, Ryvo L, Kahan Z, Greil R, Beslija S, Stemmer SM, Kaufman B, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Messinger D, Zielinski C; Central European Cooperative Oncology Group. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial. Lancet Oncol. 2013 Feb;14(2):125-33. Epub 2013 Jan 10. [https://doi.org/10.1016/S1470-2045(12)70566-1 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23312888/ PubMed] [https://clinicaltrials.gov/study/NCT00600340 NCT00600340]
 +
## '''Update:''' Zielinski C, Láng I, Inbar M, Kahán Z, Greil R, Beslija S, Stemmer SM, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Petruzelka L, Eniu A, Nisenbaum B, Dank M, Anghel R, Messinger D, Brodowicz T; TURANDOT investigators. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1230-9. Epub 2016 Aug 5. [https://doi.org/10.1016/S1470-2045(16)30154-1 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27501767/ PubMed]
 +
# '''CALGB 40502/NCCTG N063H:''' Rugo HS, Barry WT, Moreno-Aspitia A, Lyss AP, Cirrincione C, Leung E, Mayer EL, Naughton M, Toppmeyer D, Carey LA, Perez EA, Hudis C, Winer EP. Randomized phase III trial of paclitaxel once per week compared with nanoparticle albumin-bound nab-paclitaxel once per week or ixabepilone with bevacizumab as first-line chemotherapy for locally recurrent or metastatic breast cancer: CALGB 40502/NCCTG N063H (Alliance). J Clin Oncol. 2015 Jul 20;33(21):2361-9. Epub 2015 Jun 8. [https://doi.org/10.1200/JCO.2014.59.5298 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500830/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26056183/ PubMed] [https://clinicaltrials.gov/study/NCT00785291 NCT00785291]
 +
# '''SAKK 24/09:''' Rochlitz C, Bigler M, von Moos R, Bernhard J, Matter-Walstra K, Wicki A, Zaman K, Anchisi S, Küng M, Na KJ, Bärtschi D, Borner M, Rordorf T, Rauch D, Müller A, Ruhstaller T, Vetter M, Trojan A, Hasler-Strub U, Cathomas R, Winterhalder R; Swiss Group for Clinical Cancer Research (SAKK). SAKK 24/09: safety and tolerability of bevacizumab plus paclitaxel vs bevacizumab plus metronomic cyclophosphamide and capecitabine as first-line therapy in patients with HER2-negative advanced stage breast cancer - a multicenter, randomized phase III trial. BMC Cancer. 2016 Oct 10;16(1):780. [https://doi.org/10.1186/s12885-016-2823-y link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5057418/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/27724870/ PubMed] [https://clinicaltrials.gov/study/NCT01131195 NCT01131195]
 +
# '''MERiDiAN:''' Miles D, Cameron D, Bondarenko I, Manzyuk L, Alcedo JC, Lopez RI, Im SA, Canon JL, Shparyk Y, Yardley DA, Masuda N, Ro J, Denduluri N, Hubeaux S, Quah C, Bais C, O'Shaughnessy J. Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation. Eur J Cancer. 2017 Jan;70:146-155. Epub 2016 Nov 4. [https://doi.org/10.1016/j.ejca.2016.09.024 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/27817944/ PubMed] [https://clinicaltrials.gov/study/NCT01663727 NCT01663727]
 +
## '''Update:''' Miles D, Cameron D, Hilton M, Garcia J, O'Shaughnessy J. Overall survival in MERiDiAN, a double-blind placebo-controlled randomised phase III trial evaluating first-line bevacizumab plus paclitaxel for HER2-negative metastatic breast cancer. Eur J Cancer. 2018 Feb;90:153-155. Epub 2017 Nov 23. [https://doi.org/10.1016/j.ejca.2017.10.018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29174181/ PubMed]
  
−
==Paclitaxel (Taxol) & Bevacizumab (Avastin) {{#subobject:1d634b|Regimen=1}}==
+
==Paclitaxel & Vinorelbine {{#subobject:ab6465|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:1c8hcc|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1999.17.1.74 Romero Acuña et al. 1999]
 +
|1995-1997
 +
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:ba68f9|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Paclitaxel (Taxol)]] 135 mg/m<sup>2</sup> IV over 3 hours once on day 1, '''given second'''
−
style="background:#00CD00;
+
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV over 20 minutes once per day on days 1 & 8
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Paclitaxel (Taxol)]] 90 mg/m2 IV over 1 hour on days 1, 8, 15
 
−
*[[Bevacizumab (Avastin)]] 10 mg/kg IV on days 1, 15
 
−
 
 
 
'''28-day cycles'''
 
'''28-day cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
−
# Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76. [http://www.nejm.org/doi/full/10.1056/NEJMoa072113 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18160686 PubMed]
+
# Romero Acuña L, Langhi M, Pérez J, Romero Acuña J, Machiavelli M, Lacava J, Vallejo C, Romero A, Fasce H, Ortiz E, Grasso S, Amato S, Rodríguez R, Barbieri M, Leone B. Vinorelbine and paclitaxel as first-line chemotherapy in metastatic breast cancer. J Clin Oncol. 1999 Jan;17(1):74-81. [https://doi.org/10.1200/JCO.1999.17.1.74 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10458220/ PubMed]
−
 
+
==nab-Paclitaxel monotherapy {{#subobject:5dc417|Regimen=1}}==
−
==Paclitaxel, nanoparticle albumin-bound & Bevacizumab {{#subobject:17e71f|Regimen=1}}==
+
===Example orders===
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
*[[Example orders for Paclitaxel, nanoparticle albumin-bound (Abraxane) in breast cancer]]
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 100 mg/m<sup>2</sup>, 3 weeks out of 4 {{#subobject:f0096c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2008.18.5397 Gradishar et al. 2009]
 +
|2005-2006
 +
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 +
|1. [[#Docetaxel_monotherapy_2|Docetaxel]]<br>2. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]; weekly, 150 mg/m<sup>2</sup><br> 3. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]; q3wk
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 150 mg/m<sup>2</sup> weekly, 3 weeks out of 4 {{#subobject:f0096c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2008.18.5397 Gradishar et al. 2009]
 +
|2005-2006
 +
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 +
|1. [[#Docetaxel_monotherapy_2|Docetaxel]]<br>2. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]; weekly, 100 mg/m<sup>2</sup><br> 3. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]; q3wk
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 150 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 260 mg/m<sup>2</sup> q3wk {{#subobject:bf6371|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.04.937 Gradishar et al. 2005 (CA012-0)]
 +
|2001-11 to 2002-11
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel]]; q3wk
 +
| style="background-color:#1a9850" |Superior ORR (primary endpoint)<br>ORR: 33% vs 19%<br><br>Superior TTP (secondary endpoint)<br>Median TTP: 23 vs 16.9 weeks<br>(HR 0.75)
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_.26_Bevacizumab|AC & Bevacizumab]]<br>1b. [[#Capecitabine_.26_Bevacizumab|Capecitabine & Bevacizumab]]<br>1c. [[#Docetaxel_.26_Bevacizumab|Docetaxel & Bevacizumab]]<br>1d. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_.26_Bevacizumab|EC & Bevacizumab]]<br>1e. [[#FAC_.26_Bevacizumab|FAC & Bevacizumab]]<br>1f. [[#FEC_.26_Bevacizumab|FEC & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 260 mg/m<sup>2</sup> IV over 30 minutes once on day 1
 +
====Supportive therapy====
 +
*CA012-0: No corticosteroid or antihistamine premedication
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 300 mg/m<sup>2</sup> q3wk {{#subobject:11b87e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2008.18.5397 Gradishar et al. 2009]
 +
|2005-2006
 +
| style="background-color:#1a9851" |Randomized Phase 2 (E-switch-ic)
 +
|1. [[#Docetaxel_monotherapy_2|Docetaxel]]<br>2. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]; weekly, 100 mg/m<sup>2</sup><br> 3. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]; weekly, 150 mg/m<sup>2</sup>
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 300 mg/m<sup>2</sup> IV over 30 minutes once on day 1
 +
'''21-day cycles'''
 +
</div></div>
 +
===References===
 +
<!-- Presented in part at the 26th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 3-6, 2003. -->
 +
# '''CA012-0:''' Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. [https://doi.org/10.1200/jco.2005.04.937 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16172456/ PubMed] [https://clinicaltrials.gov/study/NCT00046527 NCT00046527]
 +
<!-- Presented in part at the 29th Annual San Antonio Breast Cancer Symposium, December 14-17, 2006, San Antonio, TX; the 43rd Annual Meeting of the American Society for Clinical Oncology, June 1-5, 2007, Chicago, IL; the 14th European Cancer Conference, September 23-27, 2007, Barcelona, Spain; and the 6th European Breast Cancer Conference, April 15-19, 2008, Berlin, Germany. -->
 +
# Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009 Aug 1;27(22):3611-9. Epub 2009 May 26. Erratum in: J Clin Oncol. 2011 Jul 1;29(19):2739. [https://doi.org/10.1200/jco.2008.18.5397 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19470941/ PubMed]
 +
<!-- Presented in part at the 45th Annual Meeting of the American Society for Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and at the 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology Multidisciplinary Congress, September 20-24, 2009, Berlin, Germany. -->
 +
# '''RIBBON-1:''' Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.28.0982 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21383283/ PubMed] [https://clinicaltrials.gov/study/NCT00262067 NCT00262067]
 +
==Paclitaxel, nanoparticle albumin-bound & Bevacizumab {{#subobject:17e71f|Regimen=1}}==
 
===Example orders===
 
===Example orders===
 
*[[Example orders for Paclitaxel, nanoparticle albumin-bound & Bevacizumab in breast cancer]]
 
*[[Example orders for Paclitaxel, nanoparticle albumin-bound & Bevacizumab in breast cancer]]
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
===Regimen, Danso et al. 2008 {{#subobject:8ded2a|Variant=1}}===
+
===Regimen variant #1, 150 mg/m<sup>2</sup>, 3 weeks out of 4 {{#subobject:1fce34|Variant=1}}===
−
Level of Evidence:
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
<span
+
!style="width: 20%"|Study
−
style="background:#EEEE00;
+
!style="width: 20%"|Dates of enrollment
−
padding:3px 6px 3px 6px;
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
border-color:black;
+
!style="width: 20%"|Comparator
−
border-width:2px;
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
border-style:solid;">Phase II</span>
+
|-
−
 
+
|rowspan=2|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500830/ Rugo et al. 2015 (CALGB 40502/NCCTG N063H)]
−
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 90 mg/m2 IV over 1 hour once per day on days 1, 8, 15
+
|rowspan=2|2008-2011
 +
| rowspan=2 style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|1. [[Stub#Ixabepilone_.26_Bevacizumab|Ixabepilone & Bevacizumab]]
 +
| style="background-color:#d3d3d3" |Not reported
 +
|-
 +
|2. [[#Paclitaxel_.26_Bevacizumab|Paclitaxel & Bevacizumab]]
 +
| style="background-color:#fee08b" |Might have inferior PFS (primary endpoint)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 150 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 +
====Targeted therapy====
 
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
 
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
−
 
 
'''28-day cycles'''
 
'''28-day cycles'''
−
 
+
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 260 mg/m<sup>2</sup> q3wk {{#subobject:8ded2a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-363-1 <span style="color:white;">ESMO-MCBS (3)</span>]'''
 +
|-
 +
|} -->
 +
|2005-2007
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]]<br>1b. [[#Capecitabine_monotherapy_2|Capecitabine]]<br>1c. [[#Docetaxel_monotherapy_2|Docetaxel]]<br>1d. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]]<br>1e. [[#FAC_3|FAC]]<br>1f. [[#FEC_3|FEC]]<br>1g. [[#nab-Paclitaxel_monotherapy|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>(HR 0.64, 95% CI 0.52-0.80)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 260 mg/m<sup>2</sup> IV once on day 1
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
 +
'''21-day cycles'''
 +
</div></div>
 +
===References===
 +
<!-- # '''Abstract:''' M. A. Danso, J. L. Blum, N. J. Robert, L. Krekow, R. Rotche, D. A. Smith, P. Richards, T. Anderson, D. A. Richards and J. O'Shaughnessy. Phase II trial of weekly nab-paclitaxel in combination with bevacizumab as first-line treatment in metastatic breast cancer. 2008 ASCO Annual Meeting abstract 1075. [http://meeting.ascopubs.org/cgi/content/abstract/26/15_suppl/1075 link to abstract] -->
 +
<!-- Presented in part at the 45th Annual Meeting of the American Society for Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and at the 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology Multidisciplinary Congress, September 20-24, 2009, Berlin, Germany. -->
 +
# '''RIBBON-1:''' Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.28.0982 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21383283/ PubMed] [https://clinicaltrials.gov/study/NCT00262067 NCT00262067]
 +
# '''CALGB 40502/NCCTG N063H:''' Rugo HS, Barry WT, Moreno-Aspitia A, Lyss AP, Cirrincione C, Leung E, Mayer EL, Naughton M, Toppmeyer D, Carey LA, Perez EA, Hudis C, Winer EP. Randomized phase III trial of paclitaxel once per week compared with nanoparticle albumin-bound nab-paclitaxel once per week or ixabepilone with bevacizumab as first-line chemotherapy for locally recurrent or metastatic breast cancer: CALGB 40502/NCCTG N063H (Alliance). J Clin Oncol. 2015 Jul 20;33(21):2361-9. Epub 2015 Jun 8. [https://doi.org/10.1200/JCO.2014.59.5298 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500830/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26056183/ PubMed] [https://clinicaltrials.gov/study/NCT00785291 NCT00785291]
 +
==Pemetrexed monotherapy {{#subobject:93e4ed|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 500 mg/m<sup>2</sup> {{#subobject:b49e6b|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1158/1078-0432.CCR-05-0295 Gomez et al. 2006]
 +
|2001-2002
 +
| style="background-color:#91cf61" |Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Eligibility criteria====
 +
*Chemotherapy-naïve, with advanced (T4 and N0-N2, M0, M1) breast cancer
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Pemetrexed (Alimta)]] 500 mg/m<sup>2</sup> IV over 10 minutes once on day 1
 +
====Supportive therapy====
 +
*[[Dexamethasone (Decadron)]] 4 mg PO twice per day on days -1 to 2 (3 days)
 +
*[[Folic acid (Folate)]] 350 to 1000 mcg PO once per day, to start 5 to 7 days prior to pemetrexed, to continue throughout therapy
 +
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM every 9 weeks, the first dose given before the study's pretreatment biopsy, to continue throughout therapy
 +
'''21-day cycle for up to 3 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 600 mg/m<sup>2</sup> {{#subobject:a2f6d|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1007/s10549-010-1286-0 Robert et al. 2011]
 +
|2005-2006
 +
| style="background-color:#91cf61" |Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Pemetrexed (Alimta)]] 600 mg/m<sup>2</sup> IV once on day 1
 +
====Supportive therapy====
 +
*[[Dexamethasone (Decadron)]] 4 mg PO twice per day on days -1 to 2 (3 days)
 +
*[[Folic acid (Folate)]] 350 to 1000 mcg PO once per day, to start at least 5 days prior to pemetrexed, to continue throughout therapy, and until 3 weeks after the last dose of pemetrexed
 +
*[[Cyanocobalamin (Vitamin B12)]] 1000 mcg IM every 8 to 10 weeks, the first dose given at least 1 week prior to pemetrexed, to continue throughout therapy, and until 3 weeks after the last dose of pemetrexed
 +
'''14-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# M. A. Danso, J. L. Blum, N. J. Robert, L. Krekow, R. Rotche, D. A. Smith, P. Richards, T. Anderson, D. A. Richards and J. O'Shaughnessy. Phase II trial of weekly nab-paclitaxel in combination with bevacizumab as first-line treatment in metastatic breast cancer. 2008 ASCO Annual Meeting abstract 1075. [http://meeting.ascopubs.org/cgi/content/abstract/26/15_suppl/1075 link to abstract]
+
# Gomez HL, Santillana SL, Vallejos CS, Velarde R, Sanchez J, Wang X, Bauer NL, Hockett RD, Chen VJ, Niyikiza C, Hanauske AR. A phase II trial of pemetrexed in advanced breast cancer: clinical response and association with molecular target expression. Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):832-8. [https://doi.org/10.1158/1078-0432.CCR-05-0295 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16467096/ PubMed]
 +
# Robert NJ, Conkling PR, O'Rourke MA, Kuefler PR, McIntyre KJ, Zhan F, Asmar L, Wang Y, Shonukan OO, O'Shaughnessy JA. Results of a phase II study of pemetrexed as first-line chemotherapy in patients with advanced or metastatic breast cancer. Breast Cancer Res Treat. 2011 Feb;126(1):101-8. Epub 2010 Dec 25. [https://doi.org/10.1007/s10549-010-1286-0 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21188632/ PubMed]
  
−
==Paclitaxel, nanoparticle albumin-bound & Capecitabine {{#subobject:821a8e|Regimen=1}}==
+
==S-1 monotherapy {{#subobject:7702f2|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:48e547|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(15)00411-8 Takashima et al. 2015 (SELECT BC)]
 +
|2006-2010
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|1a. [[#Docetaxel_monotherapy_2|Docetaxel]]<br>1b. [[#Paclitaxel_monotherapy.2C_weekly_2|Paclitaxel]]
 +
| style="background-color:#eeee01" |Seems to have non-inferior OS (primary endpoint)
 +
| style="background-color:#1a9850" |Superior EQ-5D score
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548517/ Mukai et al. 2021 (SELECT BC-CONFIRM)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|1a. [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]]<br>1b. [[#FAC_3|FAC]]<br>1c. [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]]<br>1d. [[#FEC_3|FEC]]
 +
| style="background-color:#eeee01" |Non-inferior OS (primary endpoint)
 +
|
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:e2b0d2|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Tegafur, gimeracil, oteracil (S-1)]] by the following BSA-based criteria:
−
style="background:#EEEE00;
+
**Less than 1.25 m<sup>2</sup>: 40 mg PO twice per day on days 1 to 28
−
padding:3px 6px 3px 6px;
+
**1.25 up to 1.50 m<sup>2</sup>: 50 mg PO twice per day on days 1 to 28
−
border-color:black;
+
**1.50 m<sup>2</sup> or more: 60 mg PO twice per day on days 1 to 28
−
border-width:2px;
+
'''42-day cycles'''
−
border-style:solid;">Phase II</span>
+
</div></div>
−
 
 
−
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 125 mg/m2 IV once per day on days 1 & 8
 
−
*[[Capecitabine (Xeloda)]] 825 mg/m2 (rounded to nearest 500 mg) PO BID on days 1 to 15
 
−
 
 
−
'''21-day cycles, given until progression of disease or unacceptable toxicity'''
 
  
 
===References===
 
===References===
−
# Schwartzberg LS, Arena FP, Mintzer DM, Epperson AL, Walker MS. Phase II multicenter trial of albumin-bound paclitaxel and capecitabine in first-line treatment of patients with metastatic breast cancer. Clin Breast Cancer. 2012 Apr;12(2):87-93. Epub 2011 Dec 6. [http://www.sciencedirect.com/science/article/pii/S1526820911002060 link to original article] '''contains protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22154117 PubMed]
+
# '''SELECT BC:''' Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T, Hozumi Y, Tsurutani J, Imoto S, Watanabe T, Sagara Y, Nishimura R, Shimozuma K, Ohashi Y; SELECT BC Study Group. Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2016 Jan;17(1):90-8. Epub 2015 Nov 27. [https://doi.org/10.1016/S1470-2045(15)00411-8 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26617202/ PubMed] UMIN C000000416
 +
## '''HRQoL analysis:''' Shiroiwa T, Fukuda T, Shimozuma K, Mouri M, Hagiwara Y, Doihara H, Akabane H, Kashiwaba M, Watanabe T, Ohashi Y, Mukai H. Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial. Qual Life Res. 2017 Feb;26(2):445-453. Epub 2016 Aug 12. [https://doi.org/10.1007/s11136-016-1388-1 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5288429/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27517267/ PubMed]
 +
# '''SELECT BC-CONFIRM:''' Mukai H, Uemura Y, Akabane H, Watanabe T, Park Y, Takahashi M, Sagara Y, Nishimura R, Takashima T, Fujisawa T, Hozumi Y, Kawahara T. Anthracycline-containing regimens or taxane versus S-1 as first-line chemotherapy for metastatic breast cancer. Br J Cancer. 2021 Oct;125(9):1217-1225. Epub 2021 Sep 3. [https://doi.org/10.1038/s41416-021-01531-6 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8548517/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34480096/ PubMed] UMIN000005449
 +
==Capecitabine & Docetaxel (TX) {{#subobject:9d5b30|Regimen=1}}==
 +
TX: '''<u>T</u>'''axotere (Docetaxel) & '''<u>X</u>'''eloda (Capecitabine)
 +
<br>CD: '''<u>C</u>'''apecitabine & '''<u>D</u>'''ocetaxel
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 1900/75 {{#subobject:acuqib|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdp498 Mavroudis et al. 2009 (HORG CT/02.09)]
 +
|2002-2007
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Docetaxel_.26_Epirubicin_.28DE.29_2|DE]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Capecitabine (Xeloda)]] 950 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 2000/75, limited duration of docetaxel {{#subobject:acd1c7|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1002/cncr.29492 Wang et al. 2015 (ML25241)]
 +
|2010-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Stub#Capecitabine_.26_Vinorelbine|NX]]
 +
| style="background-color:#ffffbf" |Inconclusive whether non-inferior PFS
 +
|-
 +
|}
 +
''Note: only patients without progression proceeded to the capecitabine maintenance phase.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 +
*[[Docetaxel (Taxotere)]] as follows:
 +
**Cycles 1 to 6 up to 8: 75 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 2000/75, indefinite {{#subobject:ad8cc7|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdq578 Seidman et al. 2010 (B9E-MC-S273)]
 +
|2002-2008
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Docetaxel_.26_Gemcitabine|GD]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*B9E-MC-S273, upon progression: second-line [[#Gemcitabine_monotherapy_2|Gemcitabine]]
 +
</div></div>
 +
===References===
 +
# '''HORG CT/02.09:''' Mavroudis D, Papakotoulas P, Ardavanis A, Syrigos K, Kakolyris S, Ziras N, Kouroussis C, Malamos N, Polyzos A, Christophyllakis C, Kentepozidis N, Georgoulias V; Hellenic Oncology Research Group. Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer. Ann Oncol. 2010 Jan;21(1):48-54. Epub 2009 Nov 11. [https://doi.org/10.1093/annonc/mdp498 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19906761/ PubMed] [https://clinicaltrials.gov/study/NCT00429871 NCT00429871]
 +
# '''B9E-MC-S273:''' Seidman AD, Brufsky A, Ansari RH, Hart LL, Stein RS, Schwartzberg LS, Stewart JF, Russell CA, Chen SC, Fein LE, De La Cruz Vargas JA, Kim SB, Cavalheiro J, Zhao L, Gill JF, Obasaju CK, Orlando M, Tai DF. Phase III trial of gemcitabine plus docetaxel versus capecitabine plus docetaxel with planned crossover to the alternate single agent in metastatic breast cancer. Ann Oncol. 2011 May;22(5):1094-101. Epub 2010 Nov 17. [https://doi.org/10.1093/annonc/mdq578 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21084429/ PubMed] [https://clinicaltrials.gov/study/NCT00191438 NCT00191438]
 +
## '''Pooled update:''' Seidman AD, Chan S, Wang J, Zhu C, Xu C, Xu B. A pooled analysis of gemcitabine plus docetaxel versus capecitabine plus docetaxel in metastatic breast cancer. Oncologist. 2014 May;19(5):443-52. Epub 2014 Apr 4. [https://doi.org/10.1634/theoncologist.2013-0428 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4012969/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24705980/ PubMed]
 +
# '''ML25241:''' Wang J, Xu B, Yuan P, Ma F, Li Q, Zhang P, Cai R, Fan Y, Luo Y, Li Q. Capecitabine combined with docetaxel versus vinorelbine followed by capecitabine maintenance medication for first-line treatment of patients with advanced breast cancer: phase 3 randomized trial. Cancer. 2015 Oct 1;121(19):3412-21. Epub 2015 Jun 19. [https://doi.org/10.1002/cncr.29492 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/26096296/ PubMed] [https://clinicaltrials.gov/study/NCT01126138 NCT01126138]
 +
==Epirubicin & Vinorelbine (VE) {{#subobject:e329f2|Regimen=1}}==
 +
VE: '''<u>V</u>'''inorelbine & '''<u>E</u>'''pirubicin
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:ea3na6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2004.11.503 Ejlertsen et al. 2004 (SBG 9403)]
 +
|1995-1999
 +
|style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Epirubicin_monotherapy_2|Epirubicin]]
 +
| style="background-color:#91cf60" |Seems to have superior PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
*[[Epirubicin (Ellence)]] 90 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 18 cycles (1 year)'''
 +
</div></div>
 +
===References===
 +
# '''SBG 9403:''' Ejlertsen B, Mouridsen HT, Langkjer ST, Andersen J, Sjöström J, Kjaer M; Scandinavian Breast Group. Phase III study of intravenous vinorelbine in combination with epirubicin versus epirubicin alone in patients with advanced breast cancer: a Scandinavian Breast Group Trial (SBG9403). J Clin Oncol. 2004 Jun 15;22(12):2313-20. [https://doi.org/10.1200/JCO.2004.11.503 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15197192/ PubMed]
  
−
==TX (Taxotere) - Docetaxel (Taxotere) & Capecitabine (Xeloda) {{#subobject:a11c57|Regimen=1}}==
+
=Metastatic disease, maintenance after first-line therapy=
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
==Bevacizumab monotherapy {{#subobject:0e6349|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:f64795|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.28.0982 Robert et al. 2011 (RIBBON-1)]
 +
|2005-2007
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/JCO.2008.21.6457 Miles et al. 2010 (AVADO)]
 +
|2006-03 to 2007-04
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70444-9 Gligorov et al. 2014 (IMELDA)]
 +
|2009-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Bevacizumab_2|Capecitabine & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior OS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
TX: '''<u>T</u>'''axotere, '''<u>X</u>'''eloda
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
===Regimen {{#subobject:6c7dba|Variant=1}}===
+
*AVADO: First-line [[#Docetaxel_.26_Bevacizumab|Docetaxel & Bev]] x 9
−
Level of Evidence:
+
*RIBBON-1: First-line [[#Cyclophosphamide_.26_Doxorubicin_.28AC.29_.26_Bevacizumab_2|AC & Bev]] x 8 or [[#Cyclophosphamide_.26_Epirubicin_.28EC.29_.26_Bevacizumab|EC & Bev]] x 8 or [[#FAC_.26_Bevacizumab|FAC & Bev]] x 8 or [[#FEC_.26_Bevacizumab|FEC & Bev]] x 8
−
<span
+
*IMELDA: First-line [[#Docetaxel_.26_Bevacizumab|Docetaxel & Bev]] x 3 to 6
−
style="background:#00CD00;
+
</div>
−
padding:3px 6px 3px 6px;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
border-color:black;
+
====Targeted therapy====
−
border-width:2px;
+
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Docetaxel (Taxotere)]] 75 mg/m2 IV day 1
 
−
*[[Capecitabine (Xeloda)]] 950-1250 mg/m2 PO BID days 1 to 14
 
−
 
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
−
# O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. [http://jco.ascopubs.org/content/20/12/2812.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/12065558 PubMed]
+
# '''AVADO:''' Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010 Jul 10;28(20):3239-47. Epub 2010 May 24. [https://doi.org/10.1200/JCO.2008.21.6457 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/20498403/ PubMed] [https://clinicaltrials.gov/study/NCT00333775 NCT00333775]
−
 
+
<!-- Presented in part at the 45th Annual Meeting of the American Society for Clinical Oncology, May 29-June 2, 2009, Orlando, FL, and at the 15th Congress of the European Cancer Organisation and 34th Congress of the European Society for Medical Oncology Multidisciplinary Congress, September 20-24, 2009, Berlin, Germany. -->
−
==TX (Taxol) - Paclitaxel (Taxol) & Capecitabine (Xeloda) {{#subobject:bd0f63|Regimen=1}}==
+
# '''RIBBON-1:''' Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. [https://doi.org/10.1200/JCO.2010.28.0982 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21383283/ PubMed] [https://clinicaltrials.gov/study/NCT00262067 NCT00262067]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
# '''IMELDA:''' Gligorov J, Doval D, Bines J, Alba E, Cortes P, Pierga JY, Gupta V, Costa R, Srock S, de Ducla S, Freudensprung U, Mustacchi G. Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1351-60. Epub 2014 Sep 28. [https://doi.org/10.1016/S1470-2045(14)70444-9 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25273343/ PubMed] [https://clinicaltrials.gov/study/NCT00929240 NCT00929240]
 +
==Capecitabine & Bevacizumab {{#subobject:hca349|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:f67gcjc|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70444-9 Gligorov et al. 2014 (IMELDA)]
 +
|2009-2011
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Bevacizumab_monotherapy_2|Bevacizumab]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 11.9 vs 4.3 mo<br>(sHR 0.38, 95% CI 0.27-0.55)<br><br>Superior OS (secondary endpoint)<br>Median OS: 39 vs 23.7 mo<br>(HR 0.43, 95% CI 0.26-0.69)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
TX: '''<u>T</u>'''axol, '''<u>X</u>'''eloda
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
===Regimen {{#subobject:74e9d|Variant=1}}===
+
*First-line [[#Docetaxel_.26_Bevacizumab|Docetaxel & Bev]] x 3 to 6
−
Level of Evidence:
+
</div>
−
<span
+
<div class="toccolours" style="background-color:#b3e2cd">
−
style="background:#EEEE00;
+
====Chemotherapy====
−
padding:3px 6px 3px 6px;
+
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
−
border-color:black;
+
====Targeted therapy====
−
border-width:2px;
+
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
−
border-style:solid;">Phase II</span>
+
'''21-day cycles'''
−
 
+
</div></div>
−
*[[Paclitaxel (Taxol)]] 80 mg/m2 IV on days 1 & 8
 
−
*[[Capecitabine (Xeloda)]] 825 mg/m2 (rounded to nearest 500 mg) PO BID on days 1 to 14
 
−
 
 
−
'''21-day cycles, given until progression of disease or unacceptable toxicity'''
 
−
 
 
 
===References===
 
===References===
−
# Blum JL, Dees EC, Chacko A, Doane L, Ethirajan S, Hopkins J, McMahon R, Merten S, Negron A, Neubauer M, Ilegbodu D, Boehm KA, Asmar L, O'Shaughnessy JA. Phase II trial of capecitabine and weekly paclitaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2006 Sep 20;24(27):4384-90. Epub 2006 Aug 22. [http://jco.ascopubs.org/content/24/27/4384.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/16926223 PubMed]
+
# '''IMELDA:''' Gligorov J, Doval D, Bines J, Alba E, Cortes P, Pierga JY, Gupta V, Costa R, Srock S, de Ducla S, Freudensprung U, Mustacchi G. Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1351-60. Epub 2014 Sep 28. [https://doi.org/10.1016/S1470-2045(14)70444-9 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/25273343/ PubMed] [https://clinicaltrials.gov/study/NCT00929240 NCT00929240]
−
 
+
==Gemcitabine & Paclitaxel {{#subobject:a86e9e|Regimen=1}}==
−
==VAC {{#subobject:90f8d0|Regimen=1}}==
+
GT: '''<u>G</u>'''emcitabine & '''<u>T</u>'''axol (Paclitaxel)
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<br>PG: '''<u>P</u>'''aclitaxel & '''<u>G</u>'''emcitabine
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:19fc21|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2012.45.2490 Park et al. 2013 (KCSG-BR07-02)]
 +
|2007-2010
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[Breast_cancer_-_null_regimens#Observation_2|Observation]]
 +
| style="background-color:#91cf60" |Seems to have superior OS (secondary endpoint)<br>Median OS: 32.3 vs 23.5 mo<br>(HR 0.65, 95% CI 0.42-0.99)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
VAC: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin, '''<u>C</u>'''yclophosphamide
+
<div class="toccolours" style="background-color:#cbd5e8">
−
 
+
====Preceding treatment====
−
===Regimen {{#subobject:4da860|Variant=1}}===
+
*First-line [[#Gemcitabine_.26_Paclitaxel|PG]] x 6
−
Level of Evidence:
+
</div>
−
<span
+
<div class="toccolours" style="background-color:#b3e2cd">
−
style="background:#00CD00;
+
====Chemotherapy====
−
padding:3px 6px 3px 6px;
+
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV once per day on days 1 & 8, '''given second on day 1'''
−
border-color:black;
+
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1, '''given first'''
−
border-width:2px;
+
'''21-day cycles'''
−
border-style:solid;">Phase III</span>
+
</div></div>
−
 
 
−
''Used as a comparator arm in older trials; here for reference purposes only.''
 
−
 
 
−
*[[Vincristine (Oncovin)]]
 
−
*[[Doxorubicin (Adriamycin)]]
 
−
*[[Cyclophosphamide (Cytoxan)]]
 
−
 
 
 
===References===
 
===References===
−
# Gundersen S, Kvinnsland S, Klepp O, Kvaløy S, Lund E, Høst H. Weekly adriamycin versus VAC in advanced breast cancer. A randomized trial. Eur J Cancer Clin Oncol. 1986 Dec;22(12):1431-4. [http://www.ncbi.nlm.nih.gov/pubmed/3595668 PubMed]
+
# '''KCSG-BR07-02:''' Park YH, Jung KH, Im SA, Sohn JH, Ro J, Ahn JH, Kim SB, Nam BH, Oh DY, Han SW, Lee S, Park IH, Lee KS, Kim JH, Kang SY, Lee MH, Park HS, Ahn JS, Im YH. Phase III, multicenter, randomized trial of maintenance chemotherapy versus observation in patients with metastatic breast cancer after achieving disease control with six cycles of gemcitabine plus paclitaxel as first-line chemotherapy: KCSG-BR07-02. J Clin Oncol. 2013 May 10;31(14):1732-9. Epub 2013 Apr 8. [https://doi.org/10.1200/JCO.2012.45.2490 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23569309/ PubMed] [https://clinicaltrials.gov/study/NCT00561119 NCT00561119]
−
 
+
=Metastatic disease, subsequent lines of chemotherapy=
−
==Vinorelbine & Bevacizumab {{#subobject:f3046|Regimen=1}}==
+
==Capecitabine monotherapy {{#subobject:bd9beb|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 1000 mg/m<sup>2</sup> PO twice per day {{#subobject:4eb6c8|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.34.1255 Brufsky et al. 2011 (RIBBON-2)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1d. [[#Paclitaxel_.26_Bevacizumab_2|Paclitaxel & Bevacizumab]]<br>1e. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]<br>1f. [[#Vinorelbine_.26_Bevacizumab|Vinorelbine & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855860/ Barrios et al. 2010 (SUN 1107)]
 +
|2006-2009
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Sunitinib_monotherapy_999|Sunitinib]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 4.2 vs 2.8 mo<br>(HR 0.68, 95% CI 0.53-0.86)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5699974/ Baselga et al. 2017 (RESILIENCE)]
 +
|2010-NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Sorafenib_999|Capecitabine & Sorafenib]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br>Median PFS: 5.4 vs 5.5 mo<br>(HR 1.03, 95% CI 0.82-1.28)
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Doxorubicin_.26_Bevacizumab|Doxorubicin & Bevacizumab]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_.26_Bevacizumab|NPLD & Bevacizumab]]<br>1e. [[#Pegylated_liposomal_doxorubicin_.26_Bevacizumab|PLD & Bevacizumab]]<br>1f. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2203690 Modi et al. 2022 (DESTINY-Breast04)]
 +
|2018-2021
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Trastuzumab_deruxtecan_monotherapy|Trastuzumab deruxtecan]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|}
 +
''Note: in SUN 1107, this dosage was used for patients older than 65 years. This was the lower bound of dosing in DESTINY-Breast04.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Prior treatment criteria====
 +
*DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease
 +
====Biomarker eligibility criteria====
 +
*DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 1250 mg/m<sup>2</sup> PO twice per day {{#subobject:f3e92c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1999.17.2.485 Blum et al. 1999 (SO14697)]
 +
|1996
 +
| style="background-color:#91cf61" |Phase 2 (RT)
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdg346 Reichardt et al. 2003]
 +
|1999-2000
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.05.098 Miller et al. 2005 (AVF2119g)]
 +
|2000-2002
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdr405 Pallis et al. 2011 (HORG CT/02.11)]
 +
|2002-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Gemcitabine_.26_Vinorelbine_999|Gemcitabine & Vinorelbine]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br>Median PFS: 5.2 vs 5.4 mo
 +
|-
 +
|[https://doi.org/10.1200/jco.2007.12.6557 Thomas et al. 2007 (CA163-046)]
 +
|2003-2006
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Ixabepilone|Capecitabine & Ixabepilone]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903325/ Sparano et al. 2010 (CA163-048)]
 +
|2003-2006
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Ixabepilone|Capecitabine & Ixabepilone]]
 +
| style="background-color:#fee08b" |Might have inferior OS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855860/ Barrios et al. 2010 (SUN 1107)]
 +
|2006-2009
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Sunitinib_monotherapy_999|Sunitinib]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 4.2 vs 2.8 mo<br>(HR 0.68, 95% CI 0.53-0.86)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463422/ Kaufman et al. 2015 (E7389-G000-301)]
 +
|2006-2009
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Eribulin_monotherapy|Eribulin]]
 +
| style="background-color:#fee08b" |Might have inferior OS
 +
|-
 +
|[https://doi.org/10.1200/jco.2012.43.3391 Crown et al. 2013 (A6181099)]
 +
|2007-2009
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Sunitinib_999|Capecitabine & Sunitinib]]
 +
| style="background-color:#d9ef8b" |Might have superior PFS (primary endpoint)<br>Median PFS: 5.9 vs 5.5 mo<br>(HR 0.82, 95% CI 0.63-1.05)
 +
|-
 +
|[https://doi.org/10.1007/s10549-016-4075-6 Yamamoto et al. 2016 (JO21095)]
 +
|2008-2010
 +
| style="background-color:#91cf61" |Non-randomized part of phase 3 RCT
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdy063 Martin et al. 2018 (L00070 IN 305 B0)]
 +
|2009-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Vinflunine|Capecitabine & Vinflunine]]
 +
| style="background-color:#fc8d59" |Seems to have inferior PFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333992/ Park et al. 2018 (PROCEED)]
 +
|2011-2016
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#CAPIRI_999|IX]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br>Median PFS: 4.7 vs 6.4 mo
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(17)30088-8 Zhang et al. 2017 (BG01-1323L)]
 +
|2014-08-08 to 2015-12-14
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Utidelone_777|Capecitabine & Utidelone]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS<sup>1</sup>
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2203690 Modi et al. 2022 (DESTINY-Breast04)]
 +
|2018-2021
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Trastuzumab_deruxtecan_monotherapy|Trastuzumab deruxtecan]]
 +
| style="background-color:#d73027" |Inferior OS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Example orders===
+
''<sup>1</sup>Reported efficacy for BG01-1323L is based on the 2020 update.''<br>
−
*[[Example orders for Vinorelbine and Bevacizumab in breast cancer]]
+
''Note: To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm in this context. This was the upper bound of dosing in DESTINY-Breast04.''
−
 
+
<div class="toccolours" style="background-color:#fdcdac">
−
===Regimen, Burstein et al. 2008 {{#subobject:82cbe7|Variant=1}}===
+
====Prior treatment criteria====
−
Level of Evidence:
+
*SO14697: Exposure to paclitaxel and an anthracycline
−
<span
+
*Reichardt et al. 2003: Exposure to a [[Regimen_classes#Taxane-based_regimen|taxane-containing regimen]]
−
style="background:#EEEE00;
+
*AVF2119g, HORG CT/02.11, CA163-046, CA163-048, SUN 1107, E7389-G000-301, A6181099, L00070 IN 305 B0, PROCEED, BG01-1323L: Exposure to a taxane and an anthracycline
−
padding:3px 6px 3px 6px;
+
*JO21095: Exposure to an [[Regimen_classes#Anthracycline-based_regimen|anthracycline-containing regimen]] and [[#Docetaxel_monotherapy_3|docetaxel]], with PD
−
border-color:black;
+
*DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease
−
border-width:2px;
+
====Biomarker eligibility criteria====
−
border-style:solid;">Phase II</span>
+
*DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative
−
 
+
</div>
−
*[[Vinorelbine (Navelbine)]] 25 mg/m2 IV once per week
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once every other week
+
====Chemotherapy====
−
 
+
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
−
'''given until progression of disease or unacceptable toxicity'''
+
'''21-day cycles'''
 +
</div></div>
  
 
===References===
 
===References===
−
# Burstein HJ, Chen YH, Parker LM, Savoie J, Younger J, Kuter I, Ryan PD, Garber JE, Chen H, Campos SM, Shulman LN, Harris LN, Gelman R, Winer EP. VEGF as a marker for outcome among advanced breast cancer patients receiving anti-VEGF therapy with bevacizumab and vinorelbine chemotherapy. Clin Cancer Res. 2008 Dec 1;14(23):7871-7. doi: 10.1158/1078-0432.CCR-08-0593. [http://clincancerres.aacrjournals.org/content/14/23/7871.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/19047116 PubMed]
+
# '''SO14697:''' Blum JL, Jones SE, Buzdar AU, Mucci LoRusso P, Kuter I, Vogel C, Osterwalder B, Burger HU, Stoner Brown C, Griffin T. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol. 1999 Feb;17(2):485-93. [https://doi.org/10.1200/JCO.1999.17.2.485 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10080589/ PubMed]
 +
# Reichardt P, Von Minckwitz G, Thuss-Patience PC, Jonat W, Kölbl H, Jänicke F, Kieback DG, Kuhn W, Schindler AE, Mohrmann S, Kaufmann M, Lück HJ. Multicenter phase II study of oral capecitabine (Xeloda) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy. Ann Oncol. 2003 Aug;14(8):1227-33. [https://doi.org/10.1093/annonc/mdg346 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/12881384/ PubMed]
 +
# '''AVF2119g:''' Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005 Feb 1;23(4):792-9. [https://doi.org/10.1200/JCO.2005.05.098 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15681523/ PubMed] [https://clinicaltrials.gov/study/NCT00109239 NCT00109239]
 +
<!-- Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 3, 2007, Chicago, IL. -->
 +
# '''CA163-046:''' Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. Epub 2007 Oct 29. [https://doi.org/10.1200/jco.2007.12.6557 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17968020/ PubMed] [https://clinicaltrials.gov/study/NCT00080301 NCT00080301]
 +
## '''Update:''' Hortobagyi GN, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Lerzo GL, Pivot XB, Hurtado de Mendoza F, Xu B, Vahdat LT, Peck RA, Mukhopadhyay P, Roché HH. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes. Breast Cancer Res Treat. 2010 Jul;122(2):409-18. Epub 2010 May 8. [https://doi.org/10.1007/s10549-010-0901-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20454927/ PubMed]
 +
# '''SUN 1107:''' Barrios CH, Liu MC, Lee SC, Vanlemmens L, Ferrero JM, Tabei T, Pivot X, Iwata H, Aogi K, Lugo-Quintana R, Harbeck N, Brickman MJ, Zhang K, Kern KA, Martin M. Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer. Breast Cancer Res Treat. 2010 May;121(1):121-31. Epub 2010 Mar 26. [https://doi.org/10.1007/s10549-010-0788-0 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2855860/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/20339913/ PubMed]
 +
<!-- Presented in part at the American Society of Clinical Oncology Breast Cancer Symposium, September 5-7, 2008, Washington, DC (abstr 186). -->
 +
# '''CA163-048:''' Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010 Jul 10;28(20):3256-63. Epub 2010 Jun 7. [https://doi.org/10.1200/jco.2009.24.4244 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903325/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20530276/ PubMed] [https://clinicaltrials.gov/study/NCT00082433 NCT00082433]
 +
# '''HORG CT/02.11:''' Pallis AG, Boukovinas I, Ardavanis A, Varthalitis I, Malamos N, Georgoulias V, Mavroudis D; Hellenic Oncology Research Group. A multicenter randomized phase III trial of vinorelbine/gemcitabine doublet versus capecitabine monotherapy in anthracycline- and taxane-pretreated women with metastatic breast cancer. Ann Oncol. 2012 May;23(5):1164-9. Epub 2011 Sep 21. [https://doi.org/10.1093/annonc/mdr405 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21937705/ PubMed] [https://clinicaltrials.gov/study/NCT00431106 NCT00431106]
 +
<!-- Presented at the 32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-13, 2009, and at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. -->
 +
# '''RIBBON-2:''' Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. [https://doi.org/10.1200/JCO.2010.34.1255 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21990397/ PubMed] [https://clinicaltrials.gov/study/NCT00281697 NCT00281697]
 +
<!-- Presented in part at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. -->
 +
# '''A6181099:''' Crown JP, Diéras V, Staroslawska E, Yardley DA, Bachelot T, Davidson N, Wildiers H, Fasching PA, Capitain O, Ramos M, Greil R, Cognetti F, Fountzilas G, Blasinska-Morawiec M, Liedtke C, Kreienberg R, Miller WH Jr, Tassell V, Huang X, Paolini J, Kern KA, Romieu G. Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer. J Clin Oncol. 2013 Aug 10;31(23):2870-8. Epub 2013 Jul 15. [https://doi.org/10.1200/jco.2012.43.3391 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/23857972/ PubMed] [https://clinicaltrials.gov/study/NCT00435409 NCT00435409]
 +
# '''TANIA:''' von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. [https://doi.org/10.1016/S1470-2045(14)70439-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25273342/ PubMed] [https://clinicaltrials.gov/study/NCT01250379 NCT01250379]
 +
## '''Update:''' Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. [https://doi.org/10.1093/annonc/mdw316 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27502725/ PubMed]
 +
# '''E7389-G000-301:''' Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, Olivo MS, He Y, Dutcus CE, Cortes J. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015 Feb 20;33(6):594-601. Epub 2015 Jan 20. [https://doi.org/10.1200/JCO.2013.52.4892 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463422/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25605862/ PubMed] [https://clinicaltrials.gov/study/NCT00337103 NCT00337103]
 +
# '''JO21095:''' Yamamoto D, Sato N, Rai Y, Yamamoto Y, Saito M, Iwata H, Masuda N, Oura S, Watanabe J, Hattori S, Matsuura Y, Kuroi K. Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. Breast Cancer Res Treat. 2017 Feb;161(3):473-482. Epub 2016 Dec 22. [https://doi.org/10.1007/s10549-016-4075-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28005247/ PubMed]
 +
# '''BG01-1323L:''' Zhang P, Sun T, Zhang Q, Yuan Z, Jiang Z, Wang XJ, Cui S, Teng Y, Hu XC, Yang J, Pan H, Tong Z, Li H, Yao Q, Wang Y, Yin Y, Sun P, Zheng H, Cheng J, Lu J, Zhang B, Geng C, Liu J, Peng R, Yan M, Zhang S, Huang J, Tang L, Qiu R, Xu B; BG01-1323L study group. Utidelone plus capecitabine versus capecitabine alone for heavily pretreated metastatic breast cancer refractory to anthracyclines and taxanes: a multicentre, open-label, superiority, phase 3, randomised controlled trial. Lancet Oncol. 2017 Mar;18(3):371-383. Epub 2017 Feb 11. [https://doi.org/10.1016/S1470-2045(17)30088-8 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/28209298/ PubMed] [https://clinicaltrials.gov/study/NCT02253459 NCT02253459]
 +
## '''Update:''' Xu B, Sun T, Zhang Q, Zhang P, Yuan Z, Jiang Z, Wang X, Cui S, Teng Y, Hu XC, Yang J, Pan H, Tong Z, Li H, Yao Q, Wang Y, Yin Y, Sun P, Zheng H, Cheng J, Lu J, Zhang B, Geng C, Liu J, Shen K, Yu S, Li H, Tang L, Qiu R; study group of BG01-1323L. Efficacy of utidelone plus capecitabine versus capecitabine for heavily pretreated, anthracycline- and taxane-refractory metastatic breast cancer: final analysis of overall survival in a phase III randomised controlled trial. Ann Oncol. 2021 Feb;32(2):218-228. Epub 2020 Nov 11. [https://doi.org/10.1016/j.annonc.2020.10.600 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33188874/ PubMed]
 +
# '''RESILIENCE:''' Baselga J, Zamagni C, Gómez P, Bermejo B, Nagai SE, Melichar B, Chan A, Mángel L, Bergh J, Costa F, Gómez HL, Gradishar WJ, Hudis CA, Rapoport BL, Roché H, Maeda P, Huang L, Meinhardt G, Zhang J, Schwartzberg LS. RESILIENCE: phase III randomized, double-blind trial comparing sorafenib with capecitabine versus placebo with capecitabine in locally advanced or metastatic HER2-negative breast cancer. Clin Breast Cancer. 2017 Dec;17(8):585-594.e4. Epub 2017 May 22. [https://doi.org/10.1016/j.clbc.2017.05.006 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5699974/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/28830796/ PubMed] [https://clinicaltrials.gov/study/NCT01234337 NCT01234337]
 +
# '''PROCEED:''' Park IH, Im SA, Jung KH, Sohn JH, Park YH, Lee KS, Sim SH, Park KH, Kim JH, Nam BH, Kim HJ, Kim TY, Lee KH, Kim SB, Ahn JH, Lee S, Ro J. Randomized open label phase III trial of irinotecan plus capecitabine versus capecitabine monotherapy in patients with metastatic breast cancer previously treated with anthracycline and taxane: PROCEED trial (KCSG BR 11-01). Cancer Res Treat. 2019 Jan;51(1):43-52. Epub 2018 Feb 14. [https://doi.org/10.4143/crt.2017.562 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333992/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29458237/ PubMed] [https://clinicaltrials.gov/study/NCT01501669 NCT01501669]
 +
# '''L00070 IN 305 B0:''' Martin M, Campone M, Bondarenko I, Sakaeva D, Krishnamurthy S, Roman L, Lebedeva L, Vedovato JC, Aapro M. Randomised phase III trial of vinflunine plus capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with an anthracycline and resistant to taxane. Ann Oncol. 2018 May 1;29(5):1195-1202. [https://doi.org/10.1093/annonc/mdy063 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/29447329/ PubMed] [https://clinicaltrials.gov/study/NCT01095003 NCT01095003]
 +
# '''DESTINY-Breast04:''' Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. [https://doi.org/10.1056/nejmoa2203690 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35665782/ PubMed] [https://clinicaltrials.gov/study/NCT03734029 NCT03734029]
 +
# '''EVER-132-002:''' [https://clinicaltrials.gov/study/NCT04639986 NCT04639986]
  
−
=Metastatic disease, endocrine therapy=
+
==Capecitabine & Bevacizumab {{#subobject:16ed34|Regimen=1}}==
−
==Anastrozole (Arimidex) {{#subobject:796bb|Regimen=1}}==
+
<div class="toccolours" style="background-color:#eeeeee">
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
===Regimen variant #1, 2000/15 {{#subobject:a7ad32|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.34.1255 Brufsky et al. 2011 (RIBBON-2)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1d. [[#Paclitaxel_monotherapy.2C_weekly_3|Paclitaxel]]<br>1e. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]<br>1f. [[#Vinorelbine_monotherapy|Vinorelbine]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 7.2 vs 5.1 mo<br>(HR 0.78, 95% CI 0.64-0.93)
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Doxorubicin_monotherapy_2|Doxorubicin]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_monotherapy|NPLD]]<br>1e. [[#Pegylated_liposomal_doxorubicin_monotherapy_2|PLD]]<br>1f. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1g. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 6.3 vs 4.2 mo<br>(HR 0.75, 95% CI 0.61-0.93)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 2500/15 {{#subobject:f3e77b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.05.098 Miller et al. 2005 (AVF2119g)]
 +
|2000-2002
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Capecitabine_monotherapy_3|Capecitabine]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS<br>Median PFS: 4.86 vs 4.17 mo<br>(HR 0.98, 95% CI 0.77-1.25)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
''Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.''
−
===Regimen {{#subobject:bd033c|Variant=1}}===
+
<div class="toccolours" style="background-color:#fdcdac">
−
Level of Evidence:
+
====Prior treatment criteria====
−
<span
+
*Prior therapy with both an anthracycline and a taxane, and 1 to 2 prior chemotherapy regimens for metastatic disease
−
style="background:#00CD00;
+
</div>
−
padding:3px 6px 3px 6px;
+
<div class="toccolours" style="background-color:#b3e2cd">
−
border-color:black;
+
====Chemotherapy====
−
border-width:2px;
+
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
−
border-style:solid;">Phase III</span>
+
====Targeted therapy====
−
 
+
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
−
*[[Anastrozole (Arimidex)]] 1 mg PO daily
+
'''21-day cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
−
# Howell A, Robertson JF, Quaresma Albano J, Aschermannova A, Mauriac L, Kleeberg UR, Vergote I, Erikstein B, Webster A, Morris C. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002 Aug 15;20(16):3396-403. [http://jco.ascopubs.org/content/20/16/3396.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/12177099 PubMed]
+
# '''AVF2119g:''' Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005 Feb 1;23(4):792-9. [https://doi.org/10.1200/JCO.2005.05.098 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15681523/ PubMed] [https://clinicaltrials.gov/study/NCT00109239 NCT00109239]
−
# Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Livingston RB, Hortobagyi GN. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012 Aug 2;367(5):435-44. doi: 10.1056/NEJMoa1201622. [http://www.nejm.org/doi/full/10.1056/NEJMoa1201622 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22853014 PubMed]
+
<!-- Presented at the 32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-13, 2009, and at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. -->
−
 
+
# '''RIBBON-2:''' Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. [https://doi.org/10.1200/JCO.2010.34.1255 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21990397/ PubMed] [https://clinicaltrials.gov/study/NCT00281697 NCT00281697]
−
See [[#Anastrozole_.28Arimidex.29|references for Anastrozole (Arimidex)]]
+
# '''TANIA:''' von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. [https://doi.org/10.1016/S1470-2045(14)70439-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25273342/ PubMed] [https://clinicaltrials.gov/study/NCT01250379 NCT01250379]
−
 
+
## '''Update:''' Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. [https://doi.org/10.1093/annonc/mdw316 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27502725/ PubMed]
−
==Anastrozole & Fulvestrant {{#subobject:c3bc6e|Regimen=1}}==
+
==Capecitabine & Docetaxel (TX) {{#subobject:a11c57|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
TX: '''<u>T</u>'''axotere (Docetaxel) & '''<u>X</u>'''eloda (Capecitabine)
 +
<br>XT: '''<u>X</u>'''eloda (Capecitabine) & '''<u>T</u>'''axotere (Docetaxel)
 +
<br>DC: '''<u>D</u>'''ocetaxel & '''<u>C</u>'''apecitabine
 +
<br>CD: '''<u>C</u>'''apecitabine & '''<u>D</u>'''ocetaxel
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 825/60 {{#subobject:5bcf6a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1007/s10549-016-4075-6 Yamamoto et al. 2016 (JO21095)]
 +
|2008-2010
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Docetaxel_monotherapy_3|Docetaxel]]
 +
| style="background-color:#91cf60" |Seems to have superior PFS (primary endpoint)<br>Median PFS: 10.5 vs 9.8 mo<br>(HR 0.62, 95% CI 0.40-0.97)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Capecitabine (Xeloda)]] 825 mg/m<sup>2</sup> PO twice per day on days 1 to 14
 +
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 1250/75 {{#subobject:6c7dba|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2002.09.002 O'Shaughnessy et al. 2002 (SO14999)]
 +
|NR
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[#Docetaxel_monotherapy_3|Docetaxel]]
 +
| style="background-color:#1a9850" |Superior TTP (primary endpoint)<br>Median TTP: 6.1 vs 4.2 mo<br>(HR 0.65, 95% CI 0.545-0.78)<br><br>Superior OS<sup>1</sup> (secondary endpoint)<br>Median OS: 14.5 vs 11.5 mo<br>(HR 0.78, 95% CI 0.645-0.94)
 +
|-
 +
|[https://doi.org/10.1200/JCO.2007.15.8485 Chan et al. 2009 (B9E-US-S188)]
 +
|2002-2004
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Gemcitabine_999|GD]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen, Mehta et al. 2012 (SWOG S0226) {{#subobject:7ef8ed|Variant=1}}===
+
''<sup>1</sup>Reported efficacy for SO14999 is based on the 2004 update.''
−
Level of Evidence:
+
<div class="toccolours" style="background-color:#b3e2cd">
−
<span
+
====Chemotherapy====
−
style="background:#00CD00;
+
*[[Capecitabine (Xeloda)]] 1250 mg/m<sup>2</sup> PO twice per day on days 1 to 14
−
padding:3px 6px 3px 6px;
+
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
−
border-color:black;
+
'''21-day cycles'''
−
border-width:2px;
+
</div></div>
−
border-style:solid;">Phase III</span>
 
−
 
 
−
====Initial therapy====
 
−
*[[Anastrozole (Arimidex)]] 1 mg PO once per day on days 1 to 56
 
−
*[[Fulvestrant (Faslodex)]] 500 mg IM once on day 1; then [[Fulvestrant (Faslodex)]] 250 mg IM once daily on days 14 & 28
 
−
 
 
−
'''56-day course, then proceed to subsequent therapy'''
 
−
 
 
−
====Subsequent therapy====
 
−
*[[Anastrozole (Arimidex)]] 1 mg PO once daily on days 1 to 28
 
−
*[[Fulvestrant (Faslodex)]] 250 mg IM once on day 1
 
−
**Patients who progressed on this therapy were allowed to receive a higher dose, [[Fulvestrant (Faslodex)]] 500 mg IM once on day 1
 
−
 
 
−
'''28-day cycles, given until progression of disease or unacceptable toxicity'''
 
  
 
===References===
 
===References===
−
# Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Livingston RB, Hortobagyi GN. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012 Aug 2;367(5):435-44. doi: 10.1056/NEJMoa1201622. [http://www.nejm.org/doi/full/10.1056/NEJMoa1201622 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22853014 PubMed]
+
# '''SO14999:''' O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. [https://doi.org/10.1200/jco.2002.09.002 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12065558/ PubMed]
−
 
+
## '''Update:''' Miles D, Vukelja S, Moiseyenko V, Cervantes G, Mauriac L, Van Hazel G, Lui WY, Ayoub JP, O'Shaughnessy JA. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Clin Breast Cancer. 2004 Oct;5(4):273-8. [https://doi.org/10.3816/cbc.2004.n.030 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15507172/ PubMed]
−
==Exemestane (Aromasin) {{#subobject:a3d882|Regimen=1}}==
+
# '''B9E-US-S188:''' Chan S, Romieu G, Huober J, Delozier T, Tubiana-Hulin M, Schneeweiss A, Lluch A, Llombart A, du Bois A, Kreienberg R, Mayordomo JI, Antón A, Harrison M, Jones A, Carrasco E, Vaury AT, Frimodt-Moller B, Fumoleau P. Phase III study of gemcitabine plus docetaxel compared with capecitabine plus docetaxel for anthracycline-pretreated patients with metastatic breast cancer. J Clin Oncol. 2009 Apr 10;27(11):1753-60. Epub 2009 Mar 9. [https://doi.org/10.1200/JCO.2007.15.8485 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19273714/ PubMed] [https://clinicaltrials.gov/study/NCT00191152 NCT00191152]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
## '''Pooled update:''' Seidman AD, Chan S, Wang J, Zhu C, Xu C, Xu B. A pooled analysis of gemcitabine plus docetaxel versus capecitabine plus docetaxel in metastatic breast cancer. Oncologist. 2014 May;19(5):443-52. Epub 2014 Apr 4. [https://doi.org/10.1634/theoncologist.2013-0428 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4012969/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24705980/ PubMed]
 +
# '''JO21095:''' Yamamoto D, Sato N, Rai Y, Yamamoto Y, Saito M, Iwata H, Masuda N, Oura S, Watanabe J, Hattori S, Matsuura Y, Kuroi K. Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. Breast Cancer Res Treat. 2017 Feb;161(3):473-482. Epub 2016 Dec 22. [https://doi.org/10.1007/s10549-016-4075-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28005247/ PubMed]
 +
==Capecitabine & Ixabepilone {{#subobject:9ce286|Regimen=1}}==
 +
XI: '''<u>X</u>'''eloda (Capecitabine) & '''<u>I</u>'''xabepilone
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:f5cae3|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2007.12.6557 Thomas et al. 2007 (CA163-046)]
 +
|2003-2006
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[#Capecitabine_monotherapy_3|Capecitabine]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 5.8 vs 4.2 mo<br>(HR 0.75, 95% CI 0.64-0.88)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903325/ Sparano et al. 2010 (CA163-048)]
 +
|2003-2006
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[#Capecitabine_monotherapy_3|Capecitabine]]
 +
| style="background-color:#d9ef8b" |Might have superior OS (primary endpoint)<br>Median OS: 16.4 vs 15.6 mo<br>(HR 0.90, 95% CI 0.78-1.03)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen {{#subobject:49119f|Variant=1}}===
+
====Chemotherapy====
−
Level of Evidence:
+
*[[Capecitabine (Xeloda)]] 1000 mg/m<sup>2</sup> PO twice per day on days 1 to 14
−
<span
+
*[[Ixabepilone (Ixempra)]] 40 mg/m<sup>2</sup> IV once on day 1
−
style="background:#00CD00;
+
'''21-day cycles'''
−
padding:3px 6px 3px 6px;
+
</div></div>
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Exemestane (Aromasin)]] 25 mg PO daily
 
−
 
 
 
===References===
 
===References===
−
# Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, Fein L, Romieu G, Buzdar A, Robertson JF, Brufsky A, Possinger K, Rennie P, Sapunar F, Lowe E, Piccart M. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008 Apr 1;26(10):1664-70. Epub 2008 Mar 3. [http://jco.ascopubs.org/content/26/10/1664.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18316794 PubMed]
+
<!-- Presented in part at the 43rd Annual Meeting of the American Society of Clinical Oncology, June 3, 2007, Chicago, IL. -->
−
# Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012 Feb 9;366(6):520-9. Epub 2011 Dec 7. [http://www.nejm.org/doi/full/10.1056/NEJMoa1109653 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22149876 PubMed]
+
# '''CA163-046:''' Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. Epub 2007 Oct 29. [https://doi.org/10.1200/jco.2007.12.6557 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17968020/ PubMed] [https://clinicaltrials.gov/study/NCT00080301 NCT00080301]
−
 
+
## '''Update:''' Hortobagyi GN, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Lerzo GL, Pivot XB, Hurtado de Mendoza F, Xu B, Vahdat LT, Peck RA, Mukhopadhyay P, Roché HH. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes. Breast Cancer Res Treat. 2010 Jul;122(2):409-18. Epub 2010 May 8. [https://doi.org/10.1007/s10549-010-0901-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20454927/ PubMed]
−
See [[#Exemestane_.28Aromasin.29|references for Exemestane (Aromasin)]]
+
<!-- Presented in part at the American Society of Clinical Oncology Breast Cancer Symposium, September 5-7, 2008, Washington, DC (abstr 186). -->
−
 
+
# '''CA163-048:''' Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010 Jul 10;28(20):3256-63. Epub 2010 Jun 7. [https://doi.org/10.1200/jco.2009.24.4244 link to original article] '''contains dosing details in manuscript''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2903325/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/20530276/ PubMed] [https://clinicaltrials.gov/study/NCT00082433 NCT00082433]
−
==Exemestane & Everolimus {{#subobject:c6aadc|Regimen=1}}==
+
==Capecitabine & Vinflunine {{#subobject:bd9hg1|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:f3e92c|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdy063 Martin et al. 2018 (L00070 IN 305 B0)]
 +
|2009-2011
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|[[#Capecitabine_monotherapy_3|Capecitabine]]
 +
| style="background-color:#91cf60" |Seems to have superior PFS (primary endpoint)<br>Median PFS: 5.6 vs 4.3 mo<br>(HR 0.84, 95% CI 0.71-0.99)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen, Baselga et al. 2012 (BOLERO-2) {{#subobject:fdbaa3|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Capecitabine (Xeloda)]] 825 mg/m<sup>2</sup> PO twice per day on days 1 to 14
−
style="background:#00CD00;
+
*[[Vinflunine (Javlor)]] 280 mg/m<sup>2</sup> IV once on day 1
−
padding:3px 6px 3px 6px;
+
'''21-day cycles'''
−
border-color:black;
+
</div></div>
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Everolimus (Afinitor)]] 10 mg PO once per day
 
−
*[[Exemestane (Aromasin)]] 25 mg PO once per day
 
−
 
 
−
'''given until progression of disease or unacceptable toxicity'''
 
−
 
 
 
===References===
 
===References===
−
# Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012 Feb 9;366(6):520-9. Epub 2011 Dec 7. [http://www.nejm.org/doi/full/10.1056/NEJMoa1109653 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22149876 PubMed]
+
# '''L00070 IN 305 B0:''' Martin M, Campone M, Bondarenko I, Sakaeva D, Krishnamurthy S, Roman L, Lebedeva L, Vedovato JC, Aapro M. Randomised phase III trial of vinflunine plus capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with an anthracycline and resistant to taxane. Ann Oncol. 2018 May 1;29(5):1195-1202. [https://doi.org/10.1093/annonc/mdy063 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/29447329/ PubMed] [https://clinicaltrials.gov/study/NCT01095003 NCT01095003]
−
 
+
==Carboplatin & Gemcitabine (GCb) {{#subobject:83a5ee|Regimen=1}}==
−
==Fulvestrant (Faslodex) {{#subobject:c91702|Regimen=1}}==
+
<div class="toccolours" style="background-color:#eeeeee">
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
===Regimen {{#subobject:e571d|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.3816/CBC.2008.n.052 Nagourney et al. 2008]
 +
|2002-2005
 +
| style="background-color:#ffffbe" |Pilot, less than 20 pts
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
Level of Evidence:
+
<div class="toccolours" style="background-color:#b3e2cd">
−
<span
+
====Chemotherapy====
−
style="background:#00CD00;
+
*[[Carboplatin (Paraplatin)]] AUC 2 IV over 60 minutes once per day on days 1 & 8
−
padding:3px 6px 3px 6px;
+
*[[Gemcitabine (Gemzar)]] 800 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1 & 8
−
border-color:black;
+
'''21-day cycles until CR or indefinitely'''
−
border-width:2px;
+
</div></div>
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Fulvestrant (Faslodex)]] 500 mg IM every 2 weeks x 3 doses, and then every 4 weeks thereafter
 
−
 
 
 
===References===
 
===References===
−
# Howell A, Robertson JF, Quaresma Albano J, Aschermannova A, Mauriac L, Kleeberg UR, Vergote I, Erikstein B, Webster A, Morris C. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002 Aug 15;20(16):3396-403. [http://jco.ascopubs.org/content/20/16/3396.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/12177099 PubMed]
+
# Nagourney RA, Flam M, Link J, Hager S, Blitzer J, Lyons W, Sommers BL, Evans S. Carboplatin plus gemcitabine repeating doublet therapy in recurrent breast cancer. Clin Breast Cancer. 2008 Oct;8(5):432-5. [https://doi.org/10.3816/CBC.2008.n.052 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/18952557/ PubMed]
−
# Perey L, Paridaens R, Hawle H, Zaman K, Nolé F, Wildiers H, Fiche M, Dietrich D, Clément P, Köberle D, Goldhirsch A, Thürlimann B. Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00). Ann Oncol. 2007 Jan;18(1):64-9. Epub 2006 Oct 9. [http://annonc.oxfordjournals.org/content/18/1/64.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/17030543 PubMed]
+
==Cisplatin & Vinorelbine (CVb) {{#subobject:c1c866|Regimen=1}}==
−
# Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, Fein L, Romieu G, Buzdar A, Robertson JF, Brufsky A, Possinger K, Rennie P, Sapunar F, Lowe E, Piccart M. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008 Apr 1;26(10):1664-70. Epub 2008 Mar 3. [http://jco.ascopubs.org/content/26/10/1664.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18316794 PubMed]
+
CVb: '''<u>C</u>'''isplatin & '''<u>V</u>'''inorel'''<u>b</u>'''ine
−
# [http://www1.astrazeneca-us.com/pi/faslodex.pdf Fulvestrant (Faslodex) package insert]
+
<div class="toccolours" style="background-color:#eeeeee">
−
 
+
===Regimen {{#subobject:9caba1|Variant=1}}===
−
==Letrozole (Femara) {{#subobject:75d541|Regimen=1}}==
+
{| class="wikitable" style="width: 60%; text-align:center;"
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1002/(SICI)1097-0142(19980101)82:1%3C134::AID-CNCR16%3E3.0.CO;2-3 Ray-Coquard et al. 1998]
 +
|1992-1994
 +
| style="background-color:#91cf61" |Phase 2
 +
|-
 +
|[https://doi.org/10.1023/a:1008377724931 Vassilomanolakis et al. 2000]
 +
|NR
 +
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen {{#subobject:d7ef99|Variant=1}}===
+
====Chemotherapy====
−
*[[Letrozole (Femara)]] 2.5 mg PO daily
+
*[[Cisplatin (Platinol)]] 75 mg/m<sup>2</sup> IV over 60 minutes once on day 1
 +
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV over 5 to 10 minutes once per day on days 1 & 8
 +
====Supportive therapy====
 +
*[[Normal saline]] 200 mL bolus after vinorelbine to prevent phlebitis
 +
*[[Normal saline]] 2000 mL with KCl (unspecified amount of KCl) IV over 4 hours once on day 1, prior to cisplatin
 +
*[[Furosemide (Lasix)]] 40 mg IV once on day 1; 20 minutes prior to cisplatin
 +
*[[Normal saline]] 1000 mL and D5W 1000 mL IV over 4 hours once on day 1, after cisplatin
 +
**Paper did not say whether fluids were given sequentially or concurrently
 +
*[[:Category:Serotonin_5-HT3_antagonists|5-HT3 antagonists]] used
 +
'''21-day cycle for up to 6 cycles'''
 +
</div></div>
  
 
===References===
 
===References===
−
See [[#Letrozole_.28Femara.29|references for Letrozole (Femara)]]
+
# Ray-Coquard I, Biron P, Bachelot T, Guastalla JP, Catimel G, Merrouche Y, Droz JP, Chauvin F, Blay JY. Vinorelbine and cisplatin (CIVIC regimen) for the treatment of metastatic breast carcinoma after failure of anthracycline- and/or paclitaxel-containing regimens. Cancer. 1998 Jan 1;82(1):134-40. [https://doi.org/10.1002/(SICI)1097-0142(19980101)82:1%3C134::AID-CNCR16%3E3.0.CO;2-3 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9428489/ PubMed]
−
# Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2971159-3/abstract link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/25524798 PubMed]
+
# Vassilomanolakis M, Koumakis G, Barbounis V, Demiri M, Pateras H, Efremidis AP. Vinorelbine and cisplatin in metastatic breast cancer patients previously treated with anthracyclines. Ann Oncol. 2000 Sep;11(9):1155-60. [https://doi.org/10.1023/a:1008377724931 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11061611/ PubMed]
−
 
+
==Cyclophosphamide & Methotrexate (CM) {{#subobject:fb8chd|Regimen=1}}==
−
==Letrozole & Palbociclib {{#subobject:da6f2|Regimen=1}}==
+
CM: '''<u>C</u>'''yclophosphamide & '''<u>M</u>'''ethotrexate
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1 {{#subobject:fc3ubz|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdf013 Colleoni et al. 2002]
 +
|1997-2000
 +
| style="background-color:#91cf61" |Non-randomized
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Cyclophosphamide (Cytoxan)]] 50 mg PO once per day on days 1 to 7
 +
*[[Methotrexate (MTX)]] 2.5 mg PO twice per day on days 1 & 2
 +
'''7-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, metronomic {{#subobject:fcdhb1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdj066 Colleoni et al. 2005]
 +
|2000-2003
 +
| style="background-color:#1a9851" |Randomized (C)
 +
|[[#Cyclophosphamide_.26_Methotrexate_.28CM.29_.26_Thalidomide_999|CM & Thalidomide]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of percent reduction in VEGF after 2 months of treatment
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
−
===Regimen, Finn et al. 2015 (PALOMA-1/TRIO-18) {{#subobject:d4d90|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of evidence: <span style="background:#EEEE00; padding:3px 6px 3px 6px; border-color:black; border-width:2px; border-style:solid;">Phase II</span>
+
====Chemotherapy====
−
*[[Letrozole (Femara)]] 2.5 mg PO once per day on days 1 to 28
+
*[[Cyclophosphamide (Cytoxan)]] 50 mg PO once per day on days 1 to 7
−
*[[Palbociclib (Ibrance)]] 125 mg PO once per day on days 1 to 21
+
*[[Methotrexate (MTX)]] 2.5 mg PO twice per day on days 1 & 4
−
 
+
'''7-day cycles'''
−
'''28-day cycles, given until progression of disease or unacceptable toxicity'''
+
</div></div>
  
 
===References===
 
===References===
−
# Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35. [http://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2814%2971159-3/abstract link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/25524798 PubMed]
+
# Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nolè F, Peruzzotti G, Robertson C, Orlando L, Cinieri S, de Braud F, Viale G, Goldhirsch A. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol. 2002 Jan;13(1):73-80. [https://doi.org/10.1093/annonc/mdf013 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/11863115/ PubMed]
−
 
+
# Colleoni M, Orlando L, Sanna G, Rocca A, Maisonneuve P, Peruzzotti G, Ghisini R, Sandri MT, Zorzino L, Nolè F, Viale G, Goldhirsch A. Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann Oncol. 2006 Feb;17(2):232-8. Epub 2005 Dec 1. [https://doi.org/10.1093/annonc/mdj066 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16322118/ PubMed]
−
==Tamoxifen (Nolvadex) {{#subobject:dffabd|Regimen=1}}==
+
==Cyclophosphamide monotherapy {{#subobject:fb7cyd|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:fc71g9|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1093/annonc/mdy051 Cortes et al. 2018 (L00070 IN 308 B0)]
 +
|2009-2011
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Vinflunine_monotherapy_999|Vinflunine]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS<br>Median OS: 9.3 vs 9.1 mo<br>(HR 0.96)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
''Note: this was the most commonly used comparator arm; doses were not provided in the manuscript or CT.gov.''
−
===Regimen {{#subobject:497965|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Cyclophosphamide (Cytoxan)]]
−
style="background:#00CD00;
+
</div></div>
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Randomized Phase II, >20 per arm</span>
 
−
 
 
−
*[[Tamoxifen (Nolvadex)]] 20 mg PO daily
 
−
 
 
 
===References===
 
===References===
−
# Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaëth D, Legouffe E, Allouache D, El Kouri C, Pujade-Lauraine E. Randomized Phase II Trial of Everolimus in Combination With Tamoxifen in Patients With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer With Prior Exposure to Aromatase Inhibitors: A GINECO Study. J Clin Oncol. 2012 May 7. [Epub ahead of print] [http://jco.ascopubs.org/content/early/2012/05/03/JCO.2011.39.0708.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22565002 PubMed]
+
# '''L00070 IN 308 B0:''' Cortes J, Perez-Garcia J, Levy C, Gómez Pardo P, Bourgeois H, Spazzapan S, Martínez-Jañez N, Chao TC, Espié M, Nabholtz JM, Gonzàlez Farré X, Beliakouski V, Román García J, Holgado E, Campone M. Open-label randomised phase III trial of vinflunine versus an alkylating agent in patients with heavily pretreated metastatic breast cancer. Ann Oncol. 2018 Apr 1;29(4):881-887. [https://doi.org/10.1093/annonc/mdy051 link to original article] '''does not contain dosing details''' [https://pubmed.ncbi.nlm.nih.gov/29481630/ PubMed] [https://clinicaltrials.gov/study/NCT01091168 NCT01091168]
  
−
See [[#Tamoxifen_.28Nolvadex.29|references for Tamoxifen (Nolvadex)]]
+
==Docetaxel monotherapy {{#subobject:fb8c8d|Regimen=1}}==
 +
D: '''<u>D</u>'''ocetaxel
 +
<br>T: '''<u>T</u>'''axotere (Docetaxel)
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 40 mg/m<sup>2</sup> 3 weeks out of 4 {{#subobject:f1b265|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1002/cncr.23321 Rivera et al. 2008]
 +
|2001-2004
 +
| style="background-color:#91cf61" |Phase 3 (E-switch-ic), less than 20 pts in this subgroup
 +
|[[#Docetaxel_monotherapy_3|Docetaxel]]; q3wk
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
| style="background-color:#1a9850" |Superior toxicity
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] as follows:
 +
**Cycle 1: 35 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15
 +
**Cycle 2 onwards: 40 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
==Tamoxifen (Nolvadex) & Everolimus (Afinitor) (GINECO) {{#subobject:2abaa9|Regimen=1}}==
+
===Regimen variant #2, 40 mg/m<sup>2</sup> 6 weeks out of 8 {{#subobject:b23d7b|Variant=1}}===
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
{| class="wikitable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2000.18.6.1212 Burstein et al. 2000]
 +
|1998
 +
| style="background-color:#91cf61" |Phase 2
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen {{#subobject:dd6395|Variant=1}}===
+
====Chemotherapy====
−
Level of Evidence:
+
*[[Docetaxel (Taxotere)]] 40 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22, 29, 36
−
<span
+
'''8-week cycles'''
−
style="background:#00CD00;
+
</div></div><br>
−
padding:3px 6px 3px 6px;
+
<div class="toccolours" style="background-color:#eeeeee">
−
border-color:black;
+
===Regimen variant #3, 60 mg/m<sup>2</sup> {{#subobject:f90ee9|Variant=1}}===
−
border-width:2px;
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
border-style:solid;">Randomized Phase II, >20 per arm</span>
+
!style="width: 20%"|Study
−
 
+
!style="width: 20%"|Dates of enrollment
−
*[[Tamoxifen (Nolvadex)]] 20 mg PO daily
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
*[[Everolimus (Afinitor)]] 10 mg PO daily
+
!style="width: 20%"|Comparator
−
 
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
'''given until progression of disease or unacceptable toxicity'''
+
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2074308/ Adachi et al. 1996]
 +
|1993
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1200/jco.2005.05.0294 Harvey et al. 2006 (TAX 313)]
 +
| rowspan="2" |1995-2001
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-de-esc)
 +
|1. [[#Docetaxel_monotherapy_3|Docetaxel]]; 75 mg/m<sup>2</sup> q3wk
 +
| style="background-color:#fee08b" |Might have inferior TTP (secondary endpoint)
 +
|-
 +
|2. [[#Docetaxel_monotherapy_3|Docetaxel]]; 100 mg/m<sup>2</sup> q3wk
 +
| style="background-color:#fee08b" |Might have inferior TTP (secondary endpoint)
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Doxorubicin_.26_Bevacizumab|Doxorubicin & Bevacizumab]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_.26_Bevacizumab|NPLD & Bevacizumab]]<br>1e. [[#Pegylated_liposomal_doxorubicin_.26_Bevacizumab|PLD & Bevacizumab]]<br>1f. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
''Note: this is the dosage used for Japanese patients; Adachi et al. 1996 reported 21- to 28-day cycles''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 70 mg/m<sup>2</sup> {{#subobject:a74e46|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1007/s10549-016-4075-6 Yamamoto et al. 2016 (JO21095)]
 +
|2008-2010
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Docetaxel_.28TX.29_3|TX]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 70 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#cbd5e7">
 +
====Subsequent treatment====
 +
*JO21095, upon progression: Subsequent-line [[#Capecitabine_monotherapy_2|Capecitabine]]
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, 75 mg/m<sup>2</sup> {{#subobject:81b82f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1200/jco.2005.05.0294 Harvey et al. 2006 (TAX 313)]
 +
| rowspan="2" |1995-2001
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|1. [[#Docetaxel_monotherapy_3|Docetaxel]]; 60 mg/m<sup>2</sup> q3wk
 +
| style="background-color:#d9ef8b" |Might have superior TTP (secondary endpoint)<br><br>Superior ORR (primary endpoint)
 +
|
 +
|-
 +
|2. [[#Docetaxel_monotherapy_3|Docetaxel]]; 100 mg/m<sup>2</sup> q3wk
 +
| style="background-color:#fee08b" |Might have inferior TTP (secondary endpoint)
 +
|
 +
|-
 +
|[https://doi.org/10.1002/cncr.23321 Rivera et al. 2008]
 +
|2001-2004
 +
| style="background-color:#91cf61" |Phase 3 (C), less than 20 pts in this subgroup
 +
|[[#Docetaxel_monotherapy_3|Docetaxel]]; weekly
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
| style="background-color:#d73027" |Inferior toxicity
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.34.1255 Brufsky et al. 2011 (RIBBON-2)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1d. [[#Paclitaxel_.26_Bevacizumab_2|Paclitaxel & Bevacizumab]]<br>1e. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]<br>1f. [[#Vinorelbine_.26_Bevacizumab|Vinorelbine & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Doxorubicin_.26_Bevacizumab|Doxorubicin & Bevacizumab]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_.26_Bevacizumab|NPLD & Bevacizumab]]<br>1e. [[#Pegylated_liposomal_doxorubicin_.26_Bevacizumab|PLD & Bevacizumab]]<br>1f. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|
 +
|-
 +
|}
 +
''Note: This is the lower end of the range of docetaxel dosing described in TANIA.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div>
 +
<div class="toccolours" style="background-color:#fff2ae">
 +
====Dose and schedule modifications====
 +
*Rivera et al. 2008 gave 75 mg/m<sup>2</sup> in cycle 1, with escalation to 100 mg/m<sup>2</sup> depending on toxicity
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #6, 100 mg/m<sup>2</sup> {{#subobject:67c50d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://www.annalsofoncology.org/article/S0923-7534(19)63147-9 ten Bokkel Huinink et al. 1994]
 +
|NR
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/JCO.1999.17.5.1413 Nabholtz et al. 1999 (TAX 304)]
 +
|NR
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-de-esc)
 +
|[[Breast_cancer_-_historical#Mitomycin_.26_Vinblastine_.28MV.29|Mitomycin & Vinblastine (MV)]]
 +
| style="background-color:#1a9850" |Superior OS
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/jco.1999.17.8.2341 Chan et al. 1999 (TAX 303)]
 +
|1994-1997
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
 +
|[[#Doxorubicin_monotherapy_2|Doxorubicin]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP50%<br><br>Superior ORR (secondary endpoint)
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1016/s0959-8049(99)00122-7 Sjöström et al. 1999]
 +
|1994-1997
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[Breast_cancer_-_historical#Fluorouracil_.26_Methotrexate_.28MF.29_2|MF]]
 +
| style="background-color:#1a9850" |Superior TTP
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/jco.2002.09.002 O'Shaughnessy et al. 2002 (SO14999)]
 +
|NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Capecitabine_.26_Docetaxel_.28TX.29_3|TX]]
 +
| style="background-color:#d73027" |Inferior OS<sup>1</sup>
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.02.027 Jones et al. 2005 (TAX 311)]
 +
|1994-2001
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Paclitaxel_monotherapy.2C_q3wk_2|Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>Median OS: 15.4 vs 12.7 mo<br>(HR 0.71, 95% CI 0.58-0.87)
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2408916/ Bonneterre et al. 2002]
 +
|1995-1997
 +
| style="background-color:#1a9851" |Phase 3 (E-de-esc)
 +
|[[#Fluorouracil_.26_Vinorelbine_888|5-FU & Vinorelbine]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 +
| style="background-color:#1a9850" |Less toxic
 +
|-
 +
| rowspan="2" |[https://doi.org/10.1200/jco.2005.05.0294 Harvey et al. 2006 (TAX 313)]
 +
|rowspan=2|1995-2001
 +
| rowspan="2" style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|1. [[#Docetaxel_monotherapy_3|Docetaxel]]; 60 mg/m<sup>2</sup> q3wk
 +
| style="background-color:#d9ef8b" |Might have superior TTP (secondary endpoint)<br><br>Superior ORR (primary endpoint)
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|2. [[#Docetaxel_monotherapy_3|Docetaxel]]; 75 mg/m<sup>2</sup> q3wk
 +
| style="background-color:#d9ef8b" |Might have superior TTP (secondary endpoint)<br><br>Superior ORR (primary endpoint)
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.33.9507 Nielsen et al. 2011]
 +
|2001-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_.26_Gemcitabine_333|Docetaxel & Gemcitabine]]
 +
| style="background-color:#fee08b" |Might have inferior TTP
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2010.12.018 Schröder et al. 2011]
 +
|2001-2006
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_monotherapy_3|Docetaxel]]; weekly
 +
| style="background-color:#91cf60" |Seems to have superior OS
 +
|
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.34.1255 Brufsky et al. 2011 (RIBBON-2)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1d. [[#Paclitaxel_.26_Bevacizumab_2|Paclitaxel & Bevacizumab]]<br>1e. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]<br>1f. [[#Vinorelbine_.26_Bevacizumab|Vinorelbine & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Doxorubicin_.26_Bevacizumab|Doxorubicin & Bevacizumab]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_.26_Bevacizumab|NPLD & Bevacizumab]]<br>1e. [[#Pegylated_liposomal_doxorubicin_.26_Bevacizumab|PLD & Bevacizumab]]<br>1f. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|}
 +
''<sup>1</sup>Reported efficacy for SO14999 is based on the 2004 update.''<br>
 +
''Note: this was the upper end of the range of docetaxel dosing described in TANIA. TAX 304 stopped treatment after 10 cycles. TAX 303 stopped treatment after 7 cycles.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles (see note)'''
 +
</div></div>
  
 
===References===
 
===References===
−
# Hayes DF, Van Zyl JA, Hacking A, Goedhals L, Bezwoda WR, Mailliard JA, Jones SE, Vogel CL, Berris RF, Shemano I et al. Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2556-66. [http://jco.ascopubs.org/content/13/10/2556.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/7595707 PubMed]
+
# ten Bokkel Huinink WW, Prove AM, Piccart M, Steward W, Tursz T, Wanders J, Franklin H, Clavel M, Verweij J, Alakl M, Bayssas M, Kaye SB; [[Study_Groups#EORTC|EORTC]] Early Clinical Trials Group. A phase II trial with docetaxel (Taxotere) in second line treatment with chemotherapy for advanced breast cancer: a study of the EORTC Early Clinical Trials Group. Ann Oncol. 1994 Jul;5(6):527-32. [https://www.annalsofoncology.org/article/S0923-7534(19)63147-9 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7918124/ PubMed]
−
# Gershanovich M, Garin A, Baltina D, Kurvet A, Kangas L, Ellmén J. A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer. Eastern European Study Group. Breast Cancer Res Treat. 1997 Sep;45(3):251-62. [http://www.springerlink.com/content/pg25l5346057212u/ link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/9386869 PubMed]
+
# Adachi I, Watanabe T, Takashima S, Narabayashi M, Horikoshi N, Aoyama H, Taguchi T. A late phase II study of RP56976 (docetaxel) in patients with advanced or recurrent breast cancer. Br J Cancer. 1996 Jan;73(2):210-6. [https://doi.org/10.1038/bjc.1996.37 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2074308/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8546908/ PubMed]
−
# Pyrhönen S, Valavaara R, Modig H, Pawlicki M, Pienkowski T, Gundersen S, Bauer J, Westman G, Lundgren S, Blanco G, Mella O, Nilsson I, Hietanen T, Hindy I, Vuorinen J, Hajba A. Comparison of toremifene and tamoxifen in post-menopausal patients with advanced breast cancer: a randomized double-blind, the 'nordic' phase III study. Br J Cancer. 1997;76(2):270-7. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2223944/ link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/9231932 PubMed]
+
# '''TAX 304:''' Nabholtz JM, Senn HJ, Bezwoda WR, Melnychuk D, Deschênes L, Douma J, Vandenberg TA, Rapoport B, Rosso R, Trillet-Lenoir V, Drbal J, Molino A, Nortier JW, Richel DJ, Nagykalnai T, Siedlecki P, Wilking N, Genot JY, Hupperets PS, Pannuti F, Skarlos D, Tomiak EM, Murawsky M, Alakl M, Aapro M; 304 Study Group. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. J Clin Oncol. 1999 May;17(5):1413-24. [https://doi.org/10.1200/JCO.1999.17.5.1413 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10334526/ PubMed]
−
# Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaëth D, Legouffe E, Allouache D, El Kouri C, Pujade-Lauraine E. Randomized Phase II Trial of Everolimus in Combination With Tamoxifen in Patients With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer With Prior Exposure to Aromatase Inhibitors: A GINECO Study. J Clin Oncol. 2012 May 7. [Epub ahead of print] [http://jco.ascopubs.org/content/early/2012/05/03/JCO.2011.39.0708.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22565002 PubMed]
+
# '''Review:''' Burris HA 3rd. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin Oncol. 1999 Jun;26(3 Suppl 9):1-6. [https://pubmed.ncbi.nlm.nih.gov/10426452/ PubMed]
 +
# '''TAX 303:''' Chan S, Friedrichs K, Noel D, Pintér T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, González Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J; 303 Study Group. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2341-54. [https://doi.org/10.1200/jco.1999.17.8.2341 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10561296/ PubMed]
 +
# Sjöström J, Blomqvist C, Mouridsen H, Pluzanska A, Ottosson-Lönn S, Bengtsson NO, Ostenstad B, Mjaaland I, Palm-Sjövall M, Wist E, Valvere V, Anderson H, Bergh J; Scandinavian Breast Group. Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: a randomised phase III study with crossover on progression by the Scandinavian Breast Group. Eur J Cancer. 1999 Aug;35(8):1194-201. [https://doi.org/10.1016/s0959-8049(99)00122-7 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10615229/ PubMed]
 +
# '''SO14999:''' O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. [https://doi.org/10.1200/jco.2002.09.002 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/12065558/ PubMed]
 +
## '''Update:''' Miles D, Vukelja S, Moiseyenko V, Cervantes G, Mauriac L, Van Hazel G, Lui WY, Ayoub JP, O'Shaughnessy JA. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Clin Breast Cancer. 2004 Oct;5(4):273-8. [https://doi.org/10.3816/cbc.2004.n.030 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15507172/ PubMed]
 +
# Bonneterre J, Roché H, Monnier A, Guastalla JP, Namer M, Fargeot P, Assadourian S. Docetaxel vs 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure. Br J Cancer. 2002 Nov 18;87(11):1210-5. [https://doi.org/10.1038/sj.bjc.6600645 link to original article] '''contains dosing details in abstract''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2408916/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/12439707/ PubMed]
 +
# '''TAX 311:''' Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, Laufman L, Sundaram S, Urba WJ, Pritchard KI, Mennel R, Richards D, Olsen S, Meyers ML, Ravdin PM. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005 Aug 20;23(24):5542-51. [https://doi.org/10.1200/JCO.2005.02.027 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16110015/ PubMed] [https://clinicaltrials.gov/study/NCT00002662 NCT00002662]
 +
# '''TAX 313:''' Harvey V, Mouridsen H, Semiglazov V, Jakobsen E, Voznyi E, Robinson BA, Groult V, Murawsky M, Cold S. Phase III trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol. 2006 Nov 1;24(31):4963-70. Epub 2006 Oct 10. [https://doi.org/10.1200/jco.2005.05.0294 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17033039/ PubMed]
 +
# Rivera E, Mejia JA, Arun BK, Adinin RB, Walters RS, Brewster A, Broglio KR, Yin G, Esmaeli B, Hortobagyi GN, Valero V. Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic breast cancer. Cancer. 2008 Apr 1;112(7):1455-61. [https://doi.org/10.1002/cncr.23321 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/18300256/ PubMed]
 +
# Schröder CP, de Munck L, Westermann AM, Smit WM, Creemers GJ, de Graaf H, Stouthard JM, van Deijk G, Erjavec Z, van Bochove A, Vader W, Willemse PH. Weekly docetaxel in metastatic breast cancer patients: no superior benefits compared to three-weekly docetaxel. Eur J Cancer. 2011 Jun;47(9):1355-62. Epub 2011 Jan 19. [https://doi.org/10.1016/j.ejca.2010.12.018 link to original article] [https://pubmed.ncbi.nlm.nih.gov/21251813/ PubMed]
 +
<!-- Presented at the 32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-13, 2009, and at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. -->
 +
# '''RIBBON-2:''' Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. [https://doi.org/10.1200/JCO.2010.34.1255 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21990397/ PubMed] [https://clinicaltrials.gov/study/NCT00281697 NCT00281697]
 +
# Nielsen DL, Bjerre KD, Jakobsen EH, Cold S, Stenbygaard L, Sørensen PG, Kamby C, Møller S, Jørgensen CL, Andersson M; Danish Breast Cancer Cooperative Group. Gemcitabine plus docetaxel versus docetaxel in patients with predominantly human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: a randomized, phase III study by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 2011 Dec 20;29(36):4748-54. Epub 2011 Nov 14. [https://doi.org/10.1200/JCO.2010.33.9507 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/22084374/ PubMed]
 +
# '''TANIA:''' von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. [https://doi.org/10.1016/S1470-2045(14)70439-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25273342/ PubMed] [https://clinicaltrials.gov/study/NCT01250379 NCT01250379]
 +
## '''Update:''' Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. [https://doi.org/10.1093/annonc/mdw316 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27502725/ PubMed]
 +
# '''JO21095:''' Yamamoto D, Sato N, Rai Y, Yamamoto Y, Saito M, Iwata H, Masuda N, Oura S, Watanabe J, Hattori S, Matsuura Y, Kuroi K. Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. Breast Cancer Res Treat. 2017 Feb;161(3):473-482. Epub 2016 Dec 22. [https://doi.org/10.1007/s10549-016-4075-6 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/28005247/ PubMed]
  
−
==Toremifene (Fareston) {{#subobject:eeba1|Regimen=1}}==
+
==Docetaxel & Bevacizumab {{#subobject:481e73|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, docetaxel 60 mg/m<sup>2</sup> {{#subobject:f90ee9|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Doxorubicin_monotherapy_2|Doxorubicin]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_monotherapy|NPLD]]<br>1e. [[#Pegylated_liposomal_doxorubicin_monotherapy_2|PLD]]<br>1f. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1g. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 6.3 vs 4.2 mo<br>(HR 0.75, 95% CI 0.61-0.93)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
Level of Evidence:
+
''Note: this is the dosage used for Japanese patients.''
−
<span
+
<div class="toccolours" style="background-color:#b3e2cd">
−
style="background:#00CD00;
+
====Chemotherapy====
−
padding:3px 6px 3px 6px;
+
*[[Docetaxel (Taxotere)]] 60 mg/m<sup>2</sup> IV once on day 1
−
border-color:black;
+
====Targeted therapy====
−
border-width:2px;
+
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
−
border-style:solid;">Phase III</span>
+
'''21-day cycles'''
−
 
+
</div></div><br>
−
*[[Toremifene (Fareston)]] 60 mg PO daily
+
<div class="toccolours" style="background-color:#eeeeee">
−
 
+
===Regimen variant #2, docetaxel 75 mg/m<sup>2</sup> {{#subobject:81b82f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.34.1255 Brufsky et al. 2011 (RIBBON-2)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1d. [[#Paclitaxel_monotherapy.2C_weekly_3|Paclitaxel]]<br>1e. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]<br>1f. [[#Vinorelbine_monotherapy|Vinorelbine]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 7.2 vs 5.1 mo<br>(HR 0.78, 95% CI 0.64-0.93)
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Doxorubicin_monotherapy_2|Doxorubicin]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_monotherapy|NPLD]]<br>1e. [[#Pegylated_liposomal_doxorubicin_monotherapy_2|PLD]]<br>1f. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1g. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 6.3 vs 4.2 mo<br>(HR 0.75, 95% CI 0.61-0.93)
 +
|-
 +
|}
 +
''Note: this is the lower end of the range of docetaxel dosing described in TANIA.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, docetaxel 100 mg/m<sup>2</sup> {{#subobject:67c50d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.34.1255 Brufsky et al. 2011 (RIBBON-2)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1d. [[#Paclitaxel_monotherapy.2C_weekly_3|Paclitaxel]]<br>1e. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]<br>1f. [[#Vinorelbine_monotherapy|Vinorelbine]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 7.2 vs 5.1 mo<br>(HR 0.78, 95% CI 0.64-0.93)
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Doxorubicin_monotherapy_2|Doxorubicin]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_monotherapy|NPLD]]<br>1e. [[#Pegylated_liposomal_doxorubicin_monotherapy_2|PLD]]<br>1f. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1g. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 6.3 vs 4.2 mo<br>(HR 0.75, 95% CI 0.61-0.93)
 +
|-
 +
|}
 +
''Note: this is the upper end of the range of docetaxel dosing described in TANIA.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Docetaxel (Taxotere)]] 100 mg/m<sup>2</sup> IV once on day 1
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
 +
'''21-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Hayes DF, Van Zyl JA, Hacking A, Goedhals L, Bezwoda WR, Mailliard JA, Jones SE, Vogel CL, Berris RF, Shemano I et al. Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2556-66. [http://jco.ascopubs.org/content/13/10/2556.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/7595707 PubMed]
+
<!-- Presented at the 32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-13, 2009, and at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. -->
−
# Gershanovich M, Garin A, Baltina D, Kurvet A, Kangas L, Ellmén J. A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer. Eastern European Study Group. Breast Cancer Res Treat. 1997 Sep;45(3):251-62. [http://www.springerlink.com/content/pg25l5346057212u/ link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/9386869 PubMed]
+
# '''RIBBON-2:''' Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. [https://doi.org/10.1200/JCO.2010.34.1255 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21990397/ PubMed] [https://clinicaltrials.gov/study/NCT00281697 NCT00281697]
−
# Pyrhönen S, Valavaara R, Modig H, Pawlicki M, Pienkowski T, Gundersen S, Bauer J, Westman G, Lundgren S, Blanco G, Mella O, Nilsson I, Hietanen T, Hindy I, Vuorinen J, Hajba A. Comparison of toremifene and tamoxifen in post-menopausal patients with advanced breast cancer: a randomized double-blind, the 'nordic' phase III study. Br J Cancer. 1997;76(2):270-7. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2223944/ link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/9231932 PubMed]
+
# '''TANIA:''' von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. [https://doi.org/10.1016/S1470-2045(14)70439-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25273342/ PubMed] [https://clinicaltrials.gov/study/NCT01250379 NCT01250379]
−
# [http://www.fareston.com/docs/GTX-Prescribing-Information.pdf Toremifene (Fareston) package insert]
+
## '''Update:''' Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. [https://doi.org/10.1093/annonc/mdw316 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27502725/ PubMed]
−
 
+
==Docetaxel & Gemcitabine {{#subobject:80fe2|Regimen=1}}==
−
=Metastatic disease, HER-2 positive=
+
DG: '''<u>D</u>'''ocetaxel & '''<u>G</u>'''emcitabine
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
==ACH {{#subobject:92e436|Regimen=1}}==
+
===Regimen {{#subobject:2d16cd|Variant=1}}===
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1007/s10549-009-0553-4 Tomova et al. 2010]
 +
|2002-09 to 2006-03
 +
|style="background-color:#1a9851"|Phase 3 (C)
 +
|[[#D-G_999|D-G]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
ACH: '''<u>A</u>'''driamycin, '''<u>C</u>'''yclophosphamide, '''<u>H</u>'''erceptin
+
''Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.''
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
===Regimen {{#subobject:67e482|Variant=1}}===
+
====Chemotherapy====
−
Level of Evidence:
+
*[[Docetaxel (Taxotere)]] 75 mg/m<sup>2</sup> IV once on day 8
−
<span
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1 & 8
−
style="background:#00CD00;
+
'''21-day cycle for 8 cycles'''
−
padding:3px 6px 3px 6px;
+
</div></div>
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
''Not commonly used; here for reference purposes only.''
 
−
 
 
−
*[[Doxorubicin (Adriamycin)]]  
 
−
*[[Cyclophosphamide (Cytoxan)]]  
 
−
*[[Trastuzumab (Herceptin)]]
 
  
 
===References===
 
===References===
−
# Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. [http://www.nejm.org/doi/full/10.1056/NEJM200103153441101 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/11248153 PubMed]
+
# Tomova A, Bartsch R, Brodowicz T, Tzekova V, Timcheva C, Wiltschke C, Gerges DA, Pawlega J, Spanik S, Inbar M, Zielinski CC. Concomitant docetaxel plus gemcitabine versus sequential docetaxel followed by gemcitabine in anthracycline-pretreated metastatic or locally recurrent inoperable breast cancer patients: a prospective multicentre trial of the Central European Cooperative Oncology Group (CECOG). Breast Cancer Res Treat. 2010 Jan;119(1):169-76. [https://doi.org/10.1007/s10549-009-0553-4 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/19768533/ PubMed]
−
 
+
==Doxorubicin monotherapy {{#subobject:4f9e89|Regimen=1}}==
−
==Ado-trastuzumab emtansine (Kadcyla) {{#subobject:d320be|Regimen=1}}==
+
<div class="toccolours" style="background-color:#eeeeee">
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
===Regimen variant #1, 20 mg/m<sup>2</sup> weekly {{#subobject:39a14f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Doxorubicin_.26_Bevacizumab|Doxorubicin & Bevacizumab]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_.26_Bevacizumab|NPLD & Bevacizumab]]<br>1e. [[#Pegylated_liposomal_doxorubicin_.26_Bevacizumab|PLD & Bevacizumab]]<br>1f. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
''Note: this is the lower end of the range of weekly doxorubicin dosing described in TANIA.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 20 mg/m<sup>2</sup> IV once on day 1
 +
'''7-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 25 mg/m<sup>2</sup> weekly {{#subobject:903e76|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Doxorubicin_.26_Bevacizumab|Doxorubicin & Bevacizumab]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_.26_Bevacizumab|NPLD & Bevacizumab]]<br>1e. [[#Pegylated_liposomal_doxorubicin_.26_Bevacizumab|PLD & Bevacizumab]]<br>1f. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
''Note: this is the higher end of the range of weekly doxorubicin dosing described in TANIA.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV once on day 1
 +
'''7-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 60 mg/m<sup>2</sup> q3wk {{#subobject:fdff75|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://academic.oup.com/jnci/article-abstract/83/15/1077/882648 Cowan et al. 1991 (SWOG S8203)]
 +
|1983-1986
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|1. [[#Bisantrene_monotherapy_999|Bisantrene]]<br>2. [[Breast_cancer_-_historical#Mitoxantrone_monotherapy|Mitoxantrone]]
 +
| style="background-color:#91cf60" |Seems to have superior OS
 +
|-
 +
|[https://doi.org/10.1200/JCO.2000.18.12.2385 Norris et al. 2000 (NCIC-CTG MA.8)]
 +
|1992-1995
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Doxorubicin_.26_Vinorelbine_.28NA.29_999|NA]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 +
|-
 +
|[https://doi.org/10.1200/JCO.2003.04.075 Reyno et al. 2004 (NCIC CT MA.19)]
 +
|1998-1999
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Doxorubicin_.26_Tesmilifene_999|Doxorubicin & Tesmilifene]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Doxorubicin_.26_Bevacizumab|Doxorubicin & Bevacizumab]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_.26_Bevacizumab|NPLD & Bevacizumab]]<br>1e. [[#Pegylated_liposomal_doxorubicin_.26_Bevacizumab|PLD & Bevacizumab]]<br>1f. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
''Note: in NCIC-CTG MA.8, this dose was after a mid-protocol amendment. Treatment in NCIC-CTG MA.8 & MA.19 was given until a cumulative dose of 450 mg/m<sup>2</sup>. This is the lower end of the range of q3wk doxorubicin dosing described in TANIA.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles (see note)'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 75 mg/m<sup>2</sup> q3wk, limited duration {{#subobject:ccbd9e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.1999.17.8.2341 Chan et al. 1999 (TAX 303)]
 +
|1994-1997
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Docetaxel_monotherapy_3|Docetaxel]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTP50%
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycle for up to 7 cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #5, 75 mg/m<sup>2</sup> q3wk, indefinite {{#subobject:a3529b|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2150384/ Bontenbal et al. 1998 (EORTC 10811)]
 +
|1982-1986
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Epirubicin_monotherapy_999|Epirubicin]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Doxorubicin_.26_Bevacizumab|Doxorubicin & Bevacizumab]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_.26_Bevacizumab|NPLD & Bevacizumab]]<br>1e. [[#Pegylated_liposomal_doxorubicin_.26_Bevacizumab|PLD & Bevacizumab]]<br>1f. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Example orders===
+
''Note: this is the higher end of the range of q3wk doxorubicin dosing described in TANIA.''
−
*[[Example orders for Ado-trastuzumab emtansine (Kadcyla) in breast cancer]]
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
===Regimen {{#subobject:63b7de|Variant=1}}===
+
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV once on day 1
−
Level of Evidence:
+
'''21-day cycles'''
−
<span
+
</div></div>
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Ado-trastuzumab emtansine (Kadcyla)]] 3.6 mg/kg IV once on day 1
 
−
 
 
−
'''21-day cycles, given until progression of disease or unacceptable toxicity'''
 
−
 
 
 
===References===
 
===References===
−
# Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012 Nov 8;367(19):1783-91. doi: 10.1056/NEJMoa1209124. Epub 2012 Oct 1. [http://www.nejm.org/doi/full/10.1056/NEJMoa1209124 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23020162 PubMed]
+
# '''SWOG S8203:''' Cowan JD, Neidhart J, McClure S, Coltman CA Jr, Gumbart C, Martino S, Hutchins LF, Stephens RL, Vaughan CB, Osborne CK. Randomized trial of doxorubicin, bisantrene, and mitoxantrone in advanced breast cancer: a Southwest Oncology Group study. J Natl Cancer Inst. 1991 Aug 7;83(15):1077-84. [https://academic.oup.com/jnci/article-abstract/83/15/1077/882648 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/1875415/ PubMed]
−
# Hurvitz SA, Dirix L, Kocsis J, Bianchi GV, Lu J, Vinholes J, Guardino E, Song C, Tong B, Ng V, Chu YW, Perez EA. Phase II Randomized Study of Trastuzumab Emtansine Versus Trastuzumab Plus Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer. J Clin Oncol. 2013 Feb 11. [Epub ahead of print] [http://jco.ascopubs.org/content/early/2013/02/08/JCO.2012.44.9694.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23382472 PubMed]
+
# '''EORTC 10811:''' Bontenbal M, Andersson M, Wildiers J, Cocconi G, Jassem J, Paridaens R, Rotmensz N, Sylvester R, Mouridsen HT, Klijn JG, van Oosterom AT; [[Study_Groups#EORTC|EORTC]] Breast Cancer Cooperative Group. Doxorubicin vs epirubicin, report of a second-line randomized phase II/III study in advanced breast cancer. Br J Cancer. 1998 Jun;77(12):2257-63. [https://www.nature.com/articles/bjc1998375 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2150384/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/9649142/ PubMed]
−
 
+
# '''TAX 303:''' Chan S, Friedrichs K, Noel D, Pintér T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, González Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J; 303 Study Group. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2341-54. [https://doi.org/10.1200/jco.1999.17.8.2341 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10561296/ PubMed]
−
==Capecitabine (Xeloda) & Lapatinib (Tykerb) {{#subobject:800fde|Regimen=1}}==
+
# '''NCIC-CTG MA.8:''' Norris B, Pritchard KI, James K, Myles J, Bennett K, Marlin S, Skillings J, Findlay B, Vandenberg T, Goss P, Latreille J, Rudinskas L, Lofters W, Trudeau M, Osoba D, Rodgers A. Phase III comparative study of vinorelbine combined with doxorubicin versus doxorubicin alone in disseminated metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group study MA8. J Clin Oncol. 2000 Jun;18(12):2385-94. [https://doi.org/10.1200/JCO.2000.18.12.2385 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/10856098/ PubMed]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
# '''NCIC CT MA.19:''' Reyno L, Seymour L, Tu D, Dent S, Gelmon K, Walley B, Pluzanska A, Gorbunova V, Garin A, Jassem J, Pienkowski T, Dancey J, Pearce L, MacNeil M, Marlin S, Lebwohl D, Voi M, Pritchard K; National Cancer Institute of Canada Clinical Trials Group. Phase III study of N,N-diethyl-2-[4-(phenylmethyl) phenoxy]ethanamine (BMS-217380-01) combined with doxorubicin versus doxorubicin alone in metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group Study MA.19. J Clin Oncol. 2004 Jan 15;22(2):269-76. [https://doi.org/10.1200/JCO.2003.04.075 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14722035/ PubMed]
 +
# '''TANIA:''' von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. [https://doi.org/10.1016/S1470-2045(14)70439-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25273342/ PubMed] [https://clinicaltrials.gov/study/NCT01250379 NCT01250379]
 +
## '''Update:''' Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. [https://doi.org/10.1093/annonc/mdw316 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27502725/ PubMed]
 +
==Doxorubicin & Bevacizumab {{#subobject:b345a5|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, doxorubicin 20 mg/m<sup>2</sup> weekly {{#subobject:d9cf13|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Doxorubicin_monotherapy_2|Doxorubicin]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_monotherapy|NPLD]]<br>1e. [[#Pegylated_liposomal_doxorubicin_monotherapy_2|PLD]]<br>1f. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1g. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 6.3 vs 4.2 mo<br>(HR 0.75, 95% CI 0.61-0.93)
 +
|-
 +
|}
 +
''Note: this is the lower end of the range of weekly doxorubicin dosing described in TANIA.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 20 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, doxorubicin 25 mg/m<sup>2</sup> weekly {{#subobject:bb2f9f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Doxorubicin_monotherapy_2|Doxorubicin]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_monotherapy|NPLD]]<br>1e. [[#Pegylated_liposomal_doxorubicin_monotherapy_2|PLD]]<br>1f. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1g. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 6.3 vs 4.2 mo<br>(HR 0.75, 95% CI 0.61-0.93)
 +
|-
 +
|}
 +
''Note: this is the higher end of the range of weekly doxorubicin dosing described in TANIA.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 25 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, doxorubicin 60 mg/m<sup>2</sup> q3wk {{#subobject:e69410|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Doxorubicin_monotherapy_2|Doxorubicin]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_monotherapy|NPLD]]<br>1e. [[#Pegylated_liposomal_doxorubicin_monotherapy_2|PLD]]<br>1f. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1g. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 6.3 vs 4.2 mo<br>(HR 0.75, 95% CI 0.61-0.93)
 +
|-
 +
|}
 +
''Note: this is the lower end of the range of q3wk doxorubicin dosing described in TANIA.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Doxorubicin (Adriamycin)]] 60 mg/m<sup>2</sup> IV once on day 1
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, doxorubicin 75 mg/m<sup>2</sup> q3wk {{#subobject:1effcd|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Doxorubicin_monotherapy_2|Doxorubicin]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_monotherapy|NPLD]]<br>1e. [[#Pegylated_liposomal_doxorubicin_monotherapy_2|PLD]]<br>1f. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1g. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 6.3 vs 4.2 mo<br>(HR 0.75, 95% CI 0.61-0.93)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:653bef|Variant=1}}===
+
''Note: this is the higher end of the range of q3wk doxorubicin dosing described in TANIA.''
−
Level of Evidence:
+
<div class="toccolours" style="background-color:#b3e2cd">
−
<span
+
====Chemotherapy====
−
style="background:#00CD00;
+
*[[Doxorubicin (Adriamycin)]] 75 mg/m<sup>2</sup> IV once on day 1
−
padding:3px 6px 3px 6px;
+
====Targeted therapy====
−
border-color:black;
+
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Capecitabine (Xeloda)]] 1000 mg/m2 PO BID days 1 to 14
 
−
*[[Lapatinib (Tykerb)]] 1250 mg PO daily days 1 to 21
 
−
 
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
−
# Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006 Dec 28;355(26):2733-43. [http://www.nejm.org/doi/full/10.1056/NEJMoa064320 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/17192538 PubMed]
+
# '''TANIA:''' von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. [https://doi.org/10.1016/S1470-2045(14)70439-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25273342/ PubMed] [https://clinicaltrials.gov/study/NCT01250379 NCT01250379]
−
# Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012 Nov 8;367(19):1783-91. doi: 10.1056/NEJMoa1209124. Epub 2012 Oct 1. [http://www.nejm.org/doi/full/10.1056/NEJMoa1209124 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23020162 PubMed]
+
## '''Update:''' Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. [https://doi.org/10.1093/annonc/mdw316 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27502725/ PubMed]
−
 
+
==Eribulin monotherapy {{#subobject:ef2415|Regimen=1}}==
−
==Capecitabine (Xeloda), Trastuzumab (Herceptin), Bevacizumab (Avastin) {{#subobject:b68b8e|Regimen=1}}==
+
<div class="toccolours" style="background-color:#eeeeee">
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
===Regimen {{#subobject:25ef0|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/s0140-6736(11)60070-6 Cortes et al. 2011 (EMBRACE)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-13-1 <span style="color:white;">ESMO-MCBS (2)</span>]'''
 +
|-
 +
|} -->
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
 +
|Investigator's choice
 +
| style="background-color:#91cf60" |Seems to have superior OS (primary endpoint)<br>Median OS: 13.1 vs 10.6 mo<br>(HR 0.81, 95% CI 0.66-0.99)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463422/ Kaufman et al. 2015 (E7389-G000-301)]
 +
|2006-2009
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Capecitabine_monotherapy_3|Capecitabine]]
 +
| style="background-color:#91cf60" |Seems to have superior OS (co-primary endpoint)<br>Median OS: 15.9 vs 14.5 mo<br>(HR 0.88, 95% CI 0.77-1.00)
 +
|-
 +
|[https://doi.org/10.1016/s1470-2045(15)00332-0 Perez et al. 2015 (BEACON<sub>brca</sub>)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Etirinotecan_pegol_monotherapy_777|Etirinotecan pegol]]
 +
| style="background-color:#fee08b" |Might have inferior OS
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2019.02.002 Yuan et al. 2019 (E7389-C086-304)]
 +
|2013-2015
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Vinorelbine_monotherapy|Vinorelbine]]
 +
| style="background-color:#91cf60" |Seems to have superior PFS (primary endpoint)<br>Median PFS: 2.8 vs 2.8 mo<br>(HR 0.80, 95% CI 0.65-0.98)
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2203690 Modi et al. 2022 (DESTINY-Breast04)]
 +
|2018-2021
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Trastuzumab_deruxtecan_monotherapy|Trastuzumab deruxtecan]]
 +
| style="background-color:#d73027" |Inferior OS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:d76d98|Variant=1}}===
+
''Note: BEACON should not be confused for the trial by the same name in several other cancer types. This dosing is the one commonly used in North America.''
−
Level of Evidence:
+
<div class="toccolours" style="background-color:#fdcdac">
−
<span
+
====Prior treatment criteria====
−
style="background:#EEEE00;
+
*EMBRACE: Exposure to between two and five lines of chemotherapy (two or more for advanced disease), including an anthracycline and a taxane, unless these were contraindicated
−
padding:3px 6px 3px 6px;
+
*DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease
−
border-color:black;
+
====Biomarker eligibility criteria====
−
border-width:2px;
+
*DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative
−
border-style:solid;">Phase II</span>
+
</div>
−
 
+
<div class="toccolours" style="background-color:#b3e2cd">
−
*[[Capecitabine (Xeloda)]] 1000 mg/m2 PO BID on days 1 to 14
+
====Chemotherapy====
−
*[[Trastuzumab (Herceptin)]] 8 mg/kg IV on cycle 1 day 1, then on subsequent cycles [[Trastuzumab (Herceptin)]] is 6 mg/kg IV on day 1
+
*[[Eribulin (Halaven)]] 1.4 mg/m<sup>2</sup> IV over 2 to 5 minutes once per day on days 1 & 8
−
*[[Bevacizumab (Avastin)]] 15 mg/kg IV on day 1
+
'''21-day cycles'''
−
 
+
</div></div>
−
'''21-day cycles, given until progression of disease or unacceptable toxicity'''
 
  
 
===References===
 
===References===
−
# Martín M, Makhson A, Gligorov J, Lichinitser M, Lluch A, Semiglazov V, Scotto N, Mitchell L, Tjulandin S. Phase II study of bevacizumab in combination with trastuzumab and capecitabine as first-line treatment for HER-2-positive locally recurrent or metastatic breast cancer. Oncologist. 2012;17(4):469-75. Epub 2012 Mar 30. [http://theoncologist.alphamedpress.org/content/17/4/469.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22467666]
+
# '''EMBRACE:''' Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Diéras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389) investigators. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011 Mar 12;377(9769):914-23. Epub 2011 Mar 2. [https://doi.org/10.1016/s0140-6736(11)60070-6 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/21376385/ PubMed] [https://clinicaltrials.gov/study/NCT00388726 NCT00388726]
−
# [http://clinicaltrials.gov/ct2/show/NCT00811135 A Study of Avastin (Bevacizumab) in Combination With Herceptin (Trastuzumab) and Xeloda (Capecitabine) in Patients With HER2-Positive Breast Cancer at ClinicalTrials.gov, NCT00811135]
+
# '''E7389-G000-301:''' Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, Olivo MS, He Y, Dutcus CE, Cortes J. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015 Feb 20;33(6):594-601. Epub 2015 Jan 20. [https://doi.org/10.1200/JCO.2013.52.4892 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4463422/ link to PMC article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25605862/ PubMed] [https://clinicaltrials.gov/study/NCT00337103 NCT00337103]
−
 
+
# '''BEACON<sub>brca</sub>:''' Perez EA, Awada A, O'Shaughnessy J, Rugo HS, Twelves C, Im SA, Gómez-Pardo P, Schwartzberg LS, Diéras V, Yardley DA, Potter DA, Mailliez A, Moreno-Aspitia A, Ahn JS, Zhao C, Hoch U, Tagliaferri M, Hannah AL, Cortes J. Etirinotecan pegol (NKTR-102) versus treatment of physician's choice in women with advanced breast cancer previously treated with an anthracycline, a taxane, and capecitabine (BEACON): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1556-1568. Epub 2015 Oct 22. [https://doi.org/10.1016/s1470-2045(15)00332-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26482278/ PubMed] [https://clinicaltrials.gov/study/NCT01492101 NCT01492101]
−
==ECH {{#subobject:fd17f7|Regimen=1}}==
+
# '''E7389-C086-304:''' Yuan P, Hu X, Sun T, Li W, Zhang Q, Cui S, Cheng Y, Ouyang Q, Wang X, Chen Z, Hiraiwa M, Saito K, Funasaka S, Xu B. Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial. Eur J Cancer. 2019 May;112:57-65. Epub 2019 Mar 29. [https://doi.org/10.1016/j.ejca.2019.02.002 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30928806/ PubMed] [https://clinicaltrials.gov/study/NCT02225470 NCT02225470]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
# '''DESTINY-Breast04:''' Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. [https://doi.org/10.1056/nejmoa2203690 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35665782/ PubMed] [https://clinicaltrials.gov/study/NCT03734029 NCT03734029]
 +
# '''EVER-132-002:''' [https://clinicaltrials.gov/study/NCT04639986 NCT04639986]
 +
==Gemcitabine monotherapy {{#subobject:af0915|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 800 mg/m<sup>2</sup> 3 weeks out of 4 {{#subobject:4db8d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.1995.13.11.2731 Carmichael et al. 1995]
 +
|NR
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2203690 Modi et al. 2022 (DESTINY-Breast04)]
 +
|2018-2021
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Trastuzumab_deruxtecan_monotherapy|Trastuzumab deruxtecan]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|}
 +
''Note: this was the lower bound of dosing in DESTINY-Breast04.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Prior treatment criteria====
 +
*DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease
 +
====Biomarker eligibility criteria====
 +
*DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Gemcitabine (Gemzar)]] 800 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 1000 mg/m<sup>2</sup> 3 weeks out of 4 {{#subobject:b0f55d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Doxorubicin_.26_Bevacizumab|Doxorubicin & Bevacizumab]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_.26_Bevacizumab|NPLD & Bevacizumab]]<br>1e. [[#Pegylated_liposomal_doxorubicin_.26_Bevacizumab|PLD & Bevacizumab]]<br>1f. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 1200 mg/m<sup>2</sup> 3 weeks out of 4 {{#subobject:3bbee6|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[http://www.karger.com/Article/Abstract/58524 Spielmann et al. 2001]
 +
|NR
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2203690 Modi et al. 2022 (DESTINY-Breast04)]
 +
|2018-2021
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Trastuzumab_deruxtecan_monotherapy|Trastuzumab deruxtecan]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|}
 +
''Note: this was the upper bound of dosing in DESTINY-Breast04.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Prior treatment criteria====
 +
*DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease
 +
====Biomarker eligibility criteria====
 +
*DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Gemcitabine (Gemzar)]] 1200 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1, 8, 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 1250 mg/m<sup>2</sup> 2 weeks out of 3 {{#subobject:11b425|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.34.1255 Brufsky et al. 2011 (RIBBON-2)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1d. [[#Paclitaxel_.26_Bevacizumab_2|Paclitaxel & Bevacizumab]]<br>1e. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]<br>1f. [[#Vinorelbine_.26_Bevacizumab|Vinorelbine & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Doxorubicin_.26_Bevacizumab|Doxorubicin & Bevacizumab]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_.26_Bevacizumab|NPLD & Bevacizumab]]<br>1e. [[#Pegylated_liposomal_doxorubicin_.26_Bevacizumab|PLD & Bevacizumab]]<br>1f. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
ECH: '''<u>E</u>'''pirubicin, '''<u>C</u>'''ytoxan, '''<u>H</u>'''erceptin
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
===Regimen {{#subobject:959eb9|Variant=1}}===
+
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8
−
Level of Evidence:
+
'''21-day cycles'''
−
<span
+
</div></div>
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
''Not commonly used; here for reference purposes only.''
 
−
 
 
−
*[[Epirubicin (Ellence)]] 
 
−
*[[Cyclophosphamide (Cytoxan)]]
 
−
*[[Trastuzumab (Herceptin)]]
 
−
 
 
 
===References===
 
===References===
−
# Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. [http://www.nejm.org/doi/full/10.1056/NEJM200103153441101 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/11248153 PubMed]
+
# Carmichael J, Possinger K, Philip P, Beykirch M, Kerr H, Walling J, Harris AL. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol. 1995 Nov;13(11):2731-6. [https://doi.org/10.1200/jco.1995.13.11.2731 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7595731/ PubMed]
 +
# Spielmann M, Llombart-Cussac A, Kalla S, Espié M, Namer M, Ferrero JM, Diéras V, Fumoleau P, Cuvier C, Perrocheau G, Ponzio A, Kayitalire L, Pouillart P. Single-agent gemcitabine is active in previously treated metastatic breast cancer. Oncology. 2001;60(4):303-7. [http://www.karger.com/Article/Abstract/58524 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11408796/ PubMed]
 +
<!-- Presented at the 32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-13, 2009, and at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. -->
 +
# '''RIBBON-2:''' Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. [https://doi.org/10.1200/JCO.2010.34.1255 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21990397/ PubMed] [https://clinicaltrials.gov/study/NCT00281697 NCT00281697]
 +
# '''TANIA:''' von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. [https://doi.org/10.1016/S1470-2045(14)70439-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25273342/ PubMed] [https://clinicaltrials.gov/study/NCT01250379 NCT01250379]
 +
## '''Update:''' Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. [https://doi.org/10.1093/annonc/mdw316 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27502725/ PubMed]
 +
# '''DESTINY-Breast04:''' Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. [https://doi.org/10.1056/nejmoa2203690 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35665782/ PubMed] [https://clinicaltrials.gov/study/NCT03734029 NCT03734029]
 +
# '''EVER-132-002:''' [https://clinicaltrials.gov/study/NCT04639986 NCT04639986]
  
−
==Lapatinib (Tykerb) {{#subobject:cb3a19|Regimen=1}}==
+
==Gemcitabine & Bevacizumab {{#subobject:134dbe|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 1000 mg/m<sup>2</sup>, 3 weeks out of 4 {{#subobject:ccfb9a|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Doxorubicin_monotherapy_2|Doxorubicin]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_monotherapy|NPLD]]<br>1e. [[#Pegylated_liposomal_doxorubicin_monotherapy_2|PLD]]<br>1f. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1g. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 6.3 vs 4.2 mo<br>(HR 0.75, 95% CI 0.61-0.93)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:a84697|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Gemcitabine (Gemzar)]] 1000 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
−
style="background:#00CD00;
+
====Targeted therapy====
−
padding:3px 6px 3px 6px;
+
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
−
border-color:black;
+
'''28-day cycles'''
−
border-width:2px;
+
</div></div><br>
−
border-style:solid;">Phase III</span>
+
<div class="toccolours" style="background-color:#eeeeee">
−
 
+
===Regimen variant #2, 1250 mg/m<sup>2</sup>, 2 weeks out of 3 {{#subobject:15445c|Variant=1}}===
−
*[[Lapatinib (Tykerb)]] 1250 mg PO daily days 1 to 21
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
 
+
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.34.1255 Brufsky et al. 2011 (RIBBON-2)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1d. [[#Paclitaxel_monotherapy.2C_weekly_3|Paclitaxel]]<br>1e. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]<br>1f. [[#Vinorelbine_monotherapy|Vinorelbine]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 7.2 vs 5.1 mo<br>(HR 0.78, 95% CI 0.64-0.93)
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Doxorubicin_monotherapy_2|Doxorubicin]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_monotherapy|NPLD]]<br>1e. [[#Pegylated_liposomal_doxorubicin_monotherapy_2|PLD]]<br>1f. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1g. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 6.3 vs 4.2 mo<br>(HR 0.75, 95% CI 0.61-0.93)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Gemcitabine (Gemzar)]] 1250 mg/m<sup>2</sup> IV over 30 minutes once per day on days 1 & 8
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
−
# Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010 Mar 1;28(7):1124-30. doi: 10.1200/JCO.2008.21.4437. Epub 2010 Feb 1. [http://jco.ascopubs.org/content/28/7/1124.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/20124187 PubMed]
+
<!-- Presented at the 32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-13, 2009, and at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. -->
−
## '''Update:''' Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, Ellis C, Florance A, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012 Jul 20;30(21):2585-92. doi: 10.1200/JCO.2011.35.6725. Epub 2012 Jun 11. [http://jco.ascopubs.org/content/30/21/2585.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/22689807 PubMed]
+
# '''RIBBON-2:''' Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. [https://doi.org/10.1200/JCO.2010.34.1255 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21990397/ PubMed] [https://clinicaltrials.gov/study/NCT00281697 NCT00281697]
−
 
+
# '''TANIA:''' von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. [https://doi.org/10.1016/S1470-2045(14)70439-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25273342/ PubMed] [https://clinicaltrials.gov/study/NCT01250379 NCT01250379]
−
==TCH - Docetaxel, Carboplatin, Trastuzumab {{#subobject:cb6592|Regimen=1}}==
+
## '''Update:''' Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. [https://doi.org/10.1093/annonc/mdw316 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27502725/ PubMed]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
==Ixabepilone monotherapy {{#subobject:9df286|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:f4ab33|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2006.09.3849 Perez et al. 2007 (CA163-081)]
 +
|2004-2005
 +
| style="background-color:#91cf61" |Phase 2 (RT)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
TCH: '''<u>T</u>'''axotere, '''<u>C</u>'''arboplatin, '''<u>H</u>'''erceptin
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
===Regimen, Valero et al. 2011 (BCIRG 007) {{#subobject:570bd5|Variant=1}}===
+
*[[Ixabepilone (Ixempra)]] 40 mg/m<sup>2</sup> IV over 3 hours once on day 1
−
Level of Evidence:
+
'''21-day cycle for up to 18 cycles'''
−
<span
+
</div></div>
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Docetaxel (Taxotere)]] 75 mg/m2 IV day 1
 
−
*[[Carboplatin (Paraplatin)]] AUC 6 IV day 1
 
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV on cycle 1 day 1, then 2 mg/kg IV weekly during chemotherapy
 
−
 
 
−
'''21-day cycles x 8 cycles, followed by:'''
 
−
 
 
−
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV every 3 weeks until progression
 
−
 
 
 
===References===
 
===References===
−
# Valero V, Forbes J, Pegram MD, Pienkowski T, Eiermann W, von Minckwitz G, Roche H, Martin M, Crown J, Mackey JR, Fumoleau P, Rolski J, Mrsic-Krmpotic Z, Jagiello-Gruszfeld A, Riva A, Buyse M, Taupin H, Sauter G, Press MF, Slamon DJ. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol. 2011 Jan 10;29(2):149-56. Epub 2010 Nov 29. [http://jco.ascopubs.org/content/29/2/149.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21115860 PubMed]
+
# '''CA163-081:''' Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, Viens P, Cai C, Mullaney B, Peck R, Hortobagyi GN. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007 Aug 10;25(23):3407-14. Epub 2007 Jul 2. [https://doi.org/10.1200/JCO.2006.09.3849 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/17606974/ PubMed] [https://clinicaltrials.gov/study/NCT00080262 NCT00080262]
  
−
==TCH - Paclitaxel, Carboplatin, Trastuzumab {{#subobject:dc581d|Regimen=1}}==
+
==Non-pegylated liposomal doxorubicin monotherapy {{#subobject:06760b|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
NPLD: '''<u>N</u>'''on-'''<u>P</u>'''egylated '''<u>L</u>'''iposomal '''<u>D</u>'''oxorubicin
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:2ed37f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Doxorubicin_.26_Bevacizumab|Doxorubicin & Bevacizumab]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_.26_Bevacizumab|NPLD & Bevacizumab]]<br>1e. [[#Pegylated_liposomal_doxorubicin_.26_Bevacizumab|PLD & Bevacizumab]]<br>1f. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
TCH: '''<u>T</u>'''axol, '''<u>C</u>'''arboplatin, '''<u>H</u>'''erceptin
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
===Regimen {{#subobject:573aed|Variant=1}}===
+
*[[Non-pegylated liposomal doxorubicin (Myocet)]] 60 mg/m<sup>2</sup> IV once on day 1
−
Level of Evidence:
 
−
<span
 
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Paclitaxel (Taxol)]] 175 mg/m2 IV day 1
 
−
*[[Carboplatin (Paraplatin)]] AUC 6 IV day 1
 
−
*EITHER [[Trastuzumab (Herceptin)]] 4 mg/kg IV on cycle 1 day 1, then 2 mg/kg IV on day 8 & 15 of cycle 1; then on subsequent cycles, [[Trastuzumab (Herceptin)]] is 2 mg/kg IV on days 1, 8, 15
 
−
*OR [[Trastuzumab (Herceptin)]] 8 mg/kg IV on cycle 1 day 1, then on subsequent cycles [[Trastuzumab (Herceptin)]] is 6 mg/kg IV on day 1
 
−
 
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div>
−
Alternate schedule:
 
−
*[[Paclitaxel (Taxol)]] 80 mg/m2 IV on days 1, 8, 15
 
−
*[[Carboplatin (Paraplatin)]] AUC 2 IV on days 1, 8, 15
 
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV on cycle 1 day 1, then 2 mg/kg IV on days 8, 15, 22 of cycle 1; then on subsequent cycles, [[Trastuzumab (Herceptin)]] is 2 mg/kg IV on days 1, 8, 15, 22
 
−
 
 
−
'''28-day cycles'''
 
−
 
 
−
===Monitoring===
 
−
*Cardiac function: echocardiogram at baseline, then every 3 months while on Trastuzumab (Herceptin)
 
−
 
 
 
===References===
 
===References===
−
# Perez EA, Suman VJ, Rowland KM, Ingle JN, Salim M, Loprinzi CL, Flynn PJ, Mailliard JA, Kardinal CG, Krook JE, Thrower AR, Visscher DW, Jenkins RB. Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer. 2005 Dec;6(5):425-32. [http://www.sciencedirect.com/science/article/pii/S152682091170461X link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16381626 PubMed]
+
# '''TANIA:''' von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. [https://doi.org/10.1016/S1470-2045(14)70439-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25273342/ PubMed] [https://clinicaltrials.gov/study/NCT01250379 NCT01250379]
−
# Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre R, Cobleigh M, Albain K, McCullough C, Fuchs L, Slamon D. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006 Jun 20;24(18):2786-92. [http://jco.ascopubs.org/content/24/18/2786.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16782917 PubMed]
+
## '''Update:''' Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. [https://doi.org/10.1093/annonc/mdw316 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27502725/ PubMed]
−
 
+
==Non-pegylated liposomal doxorubicin & Bevacizumab {{#subobject:2e10a5|Regimen=1}}==
−
==TH (Taxol) - Paclitaxel & Trastuzumab {{#subobject:aa22dd|Regimen=1}}==
+
NPLD & Bev: '''<u>N</u>'''on-'''<u>P</u>'''egylated '''<u>L</u>'''iposomal '''<u>D</u>'''oxorubicin & '''<u>Bev</u>'''acizumab
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:88281d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Doxorubicin_monotherapy_2|Doxorubicin]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_monotherapy|NPLD]]<br>1e. [[#Pegylated_liposomal_doxorubicin_monotherapy_2|PLD]]<br>1f. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1g. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 6.3 vs 4.2 mo<br>(HR 0.75, 95% CI 0.61-0.93)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:31e4b6|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Non-pegylated liposomal doxorubicin (Myocet)]] 60 mg/m<sup>2</sup> IV once on day 1
−
style="background:#00CD00;
+
====Targeted therapy====
−
padding:3px 6px 3px 6px;
+
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*[[Paclitaxel (Taxol)]] 175 mg/m2 IV day 1
 
−
*EITHER [[Trastuzumab (Herceptin)]] 4 mg/kg IV on cycle 1 day 1, then 2 mg/kg IV on day 8 & 15 of cycle 1; then on subsequent cycles, [[Trastuzumab (Herceptin)]] is 2 mg/kg IV on days 1, 8, 15
 
−
*OR [[Trastuzumab (Herceptin)]] 8 mg/kg IV on cycle 1 day 1, then on subsequent cycles [[Trastuzumab (Herceptin)]] is 6 mg/kg IV on day 1
 
−
 
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div>
−
Alternate schedule:
 
−
*[[Paclitaxel (Taxol)]] 80 to 90 mg/m2 IV weekly
 
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV on day 1, then 2 mg/kg IV weekly with paclitaxel
 
−
 
 
 
===References===
 
===References===
−
# Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. [http://www.nejm.org/doi/full/10.1056/NEJM200103153441101 link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/11248153 PubMed]
+
# '''TANIA:''' von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. [https://doi.org/10.1016/S1470-2045(14)70439-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25273342/ PubMed] [https://clinicaltrials.gov/study/NCT01250379 NCT01250379]
−
# Seidman AD, Fornier MN, Esteva FJ, Tan L, Kaptain S, Bach A, Panageas KS, Arroyo C, Valero V, Currie V, Gilewski T, Theodoulou M, Moynahan ME, Moasser M, Sklarin N, Dickler M, D'Andrea G, Cristofanilli M, Rivera E, Hortobagyi GN, Norton L, Hudis CA. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol. 2001 May 15;19(10):2587-95. [http://jco.ascopubs.org/content/19/10/2587.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/11352950 PubMed]
+
## '''Update:''' Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. [https://doi.org/10.1093/annonc/mdw316 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27502725/ PubMed]
−
# Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre R, Cobleigh M, Albain K, McCullough C, Fuchs L, Slamon D. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006 Jun 20;24(18):2786-92. [http://jco.ascopubs.org/content/24/18/2786.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/16782917 PubMed]
+
==Paclitaxel monotherapy, weekly {{#subobject:b55e07|Regimen=1}}==
−
# Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.22885/abstract link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/17614302 PubMed]
+
<div class="toccolours" style="background-color:#eeeeee">
−
# Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. [http://jco.ascopubs.org/content/26/10/1642.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/18375893 PubMed]
+
===Regimen variant #1, 80 mg/m<sup>2</sup> weekly {{#subobject:686fc8|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2001.19.22.4216 Perez et al. 2001]
 +
|NR
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/jco.2007.11.6699 Seidman et al. 2008 (CALGB 9840)]
 +
|1998-NR
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Paclitaxel_monotherapy.2C_q3wk_2|Paclitaxel]]; q3wk
 +
| style="background-color:#1a9850" |Superior OS (secondary endpoint)<br>Median OS: 24 vs 12 mo<br>(HR 0.78, 95% CI 0.65-0.94)
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2203690 Modi et al. 2022 (DESTINY-Breast04)]
 +
|2018-2021
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Trastuzumab_deruxtecan_monotherapy|Trastuzumab deruxtecan]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Prior treatment criteria====
 +
*DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease
 +
====Biomarker eligibility criteria====
 +
*DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel (Taxol)]] 80 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
==TH (Taxotere) - Docetaxel & Trastuzumab {{#subobject:c99645|Regimen=1}}==
+
===Regimen variant #2, 90 mg/m<sup>2</sup> 3 weeks out of 4 {{#subobject:55b062|Variant=1}}===
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.34.1255 Brufsky et al. 2011 (RIBBON-2)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1d. [[#Paclitaxel_.26_Bevacizumab_2|Paclitaxel & Bevacizumab]]<br>1e. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]<br>1f. [[#Vinorelbine_.26_Bevacizumab|Vinorelbine & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen #1, Esteva et al. 2002 (weekly treatment) {{#subobject:f2e79b|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Paclitaxel (Taxol)]] 90 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
−
style="background:#EEEE00;
+
'''28-day cycles'''
−
padding:3px 6px 3px 6px;
+
</div></div>
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
−
 
 
−
''Esteva et al. 2002 described the day before the start of a cycle as "day 0," which is not the typical convention, so day -1 is being used instead.''
 
−
*[[Docetaxel (Taxotere)]] 35 mg/m2 IV over 30 minutes once per day on days 1, 8, 15, given first
 
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV over 90 minutes once on cycle 1 day -1; then [[Trastuzumab (Herceptin)]] 2 mg/kg IV over 30 minutes once per day on cycle 1 days 8 & 15; then [[Trastuzumab (Herceptin)]] 2 mg/kg IV over 30 minutes once per day on days 1, 8, 15 of subsequent cycles, given second
 
−
 
 
−
'''28-day cycles, given until progression of disease or unacceptable toxicity'''
 
−
 
 
−
Supportive medications:
 
−
*[[Dexamethasone (Decadron)]] 4 mg PO every 12 hours x 3 doses on cycles 1 & 2, starting the night before docetaxel.  Patients who did not have "hypersensitivity reactions and no significant fluid retention during the first 8 weeks" received [[Dexamethasone (Decadron)]] 4 mg PO BID on day 1 for at least the next two cycles.  Patients who "remained free of fluid retention after 8 additional weeks" then received [[Dexamethasone (Decadron)]] 4 mg PO once on day 1 prior to docetaxel in subsequent cycles.
 
−
 
 
−
===Regimen #2, Marty et al. 2005 (M77001) {{#subobject:e03cec|Variant=1}}===
 
−
Level of Evidence:
 
−
<span
 
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Randomized Phase II, >20 per arm</span>
 
−
 
 
−
''Marty et al. 2005 did not exactly specify days of therapy; this is the best guess for what was used based on the description.''
 
−
====Induction therapy====
 
−
*[[Docetaxel (Taxotere)]] 100 mg/m2 IV once on day 1
 
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV once on cycle 1 day 1; then [[Trastuzumab (Herceptin)]] 2 mg/kg IV once per day on cycle 1 days 8 & 15; then [[Trastuzumab (Herceptin)]] 2 mg/kg IV once per day on days 1, 8, 15 of subsequent cycles
 
−
 
 
−
'''21-day cycles x 6 cycles, given until progression of disease or unacceptable toxicity.''' Patients could receive docetaxel beyond six cycles at the discretion of the investigator.  Otherwise, patients proceeded to maintenance trastuzumab therapy.
 
−
 
 
−
Supportive medications:
 
−
*Corticosteroids prior to docetaxel, "which could include [[Dexamethasone (Decadron)|dexamethasone]], [[Methylprednisolone (Solumedrol)|methylprednisolone]], or [[Prednisolone (Millipred)|prednisolone]]" (no doses/routes/schedule specified).
 
−
 
 
−
====Maintenance trastuzumab====
 
−
*[[Trastuzumab (Herceptin)]] 2 mg/kg IV once per week
 
−
 
 
−
'''given until progression of disease or unacceptable toxicity'''
 
−
 
 
−
===Regimen #3, Valero et al. 2011 (BCIRG 007) {{#subobject:31786c|Variant=1}}===
 
−
Level of Evidence:
 
−
<span
 
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
====Induction therapy====
 
−
*[[Docetaxel (Taxotere)]] 100 mg/m2 IV once on day 1
 
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV over 90 minutes once on cycle 1 day 1; then [[Trastuzumab (Herceptin)]] 2 mg/kg IV over 30 minutes once per day on cycle 1 days 8 & 15; then [[Trastuzumab (Herceptin)]] 2 mg/kg IV over 30 minutes once per day on days 1, 8, 15 of subsequent cycles
 
−
 
 
−
'''21-day cycles x 8 cycles;''' patients then proceeded to maintenance trastuzumab therapy.
 
−
 
 
−
Supportive medications:
 
−
*[[Dexamethasone (Decadron)]] 8 mg (or equivalent) PO BID x 6 doses, starting the night before docetaxel
 
−
*"Antiemetic premedication was mandatory" (no additional details given).
 
−
 
 
−
====Maintenance trastuzumab====
 
−
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV once every 3 weeks
 
−
 
 
−
'''given until progression of disease or unacceptable toxicity'''
 
−
 
 
−
===Regimen #4, Baselga et al. 2012 (CLEOPATRA) {{#subobject:d6d8da|Variant=1}}===
 
−
Level of Evidence:
 
−
<span
 
−
style="background:#00CD00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
''This unusual schedule with both medications being given on day 2 of cycle 1 is due to this regimen being the control arm of Baselga et al. 2012 & Swain et al. 2013, in which patients in one arm received a placebo instead of pertuzumab on day 1.  It is reasonable to assume that in practice, drugs in this regimen will be given on day 1 from the beginning.''
 
−
*[[Docetaxel (Taxotere)]] 75 mg/m2 IV once on cycle 1 day 2; then [[Docetaxel (Taxotere)]] 75 mg/m2 IV once on day 1 of subsequent cycles
 
−
*[[Trastuzumab (Herceptin)]] 8 mg/kg IV once on cycle 1 day 2; then [[Trastuzumab (Herceptin)]] 6 mg/kg IV once on day 1 of subsequent cycles
 
−
 
 
−
'''21-day cycles x at least 6 cycles, given until progression of disease or unacceptable toxicity'''
 
−
 
 
−
If it is decided to no longer administer Docetaxel (Taxotere) with this regimen, then patients could continue to receive:
 
−
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV once on day 1
 
−
 
 
−
'''21-day cycles, given until progression of disease or unacceptable toxicity'''
 
−
 
 
 
===References===
 
===References===
−
# Esteva FJ, Valero V, Booser D, Guerra LT, Murray JL, Pusztai L, Cristofanilli M, Arun B, Esmaeli B, Fritsche HA, Sneige N, Smith TL, Hortobagyi GN. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2002 Apr 1;20(7):1800-8. [http://jco.ascopubs.org/content/20/7/1800.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/11919237 PubMed]
+
# Perez EA, Vogel CL, Irwin DH, Kirshner JJ, Patel R. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2001 Nov 15;19(22):4216-23. [https://doi.org/10.1200/jco.2001.19.22.4216 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11709565/ PubMed]
−
# Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Antón A, Lluch A, Kennedy J, O'Byrne K, Conte P, Green M, Ward C, Mayne K, Extra JM. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005 Jul 1;23(19):4265-74. Epub 2005 May 23. [http://jco.ascopubs.org/content/23/19/4265.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/15911866 PubMed]
+
<!-- Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA. -->
−
# Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.22885/abstract link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/17614302 PubMed]
+
# '''CALGB 9840:''' Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. [https://doi.org/10.1200/jco.2007.11.6699 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18375893/ PubMed] [https://clinicaltrials.gov/study/NCT00003440 NCT00003440]
−
# Valero V, Forbes J, Pegram MD, Pienkowski T, Eiermann W, von Minckwitz G, Roche H, Martin M, Crown J, Mackey JR, Fumoleau P, Rolski J, Mrsic-Krmpotic Z, Jagiello-Gruszfeld A, Riva A, Buyse M, Taupin H, Sauter G, Press MF, Slamon DJ. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol. 2011 Jan 10;29(2):149-56. Epub 2010 Nov 29. [http://jco.ascopubs.org/content/29/2/149.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/21115860 PubMed]
+
<!-- Presented at the 32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-13, 2009, and at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. -->
−
# Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. Epub 2011 Dec 7. [http://www.nejm.org/doi/full/10.1056/NEJMoa1113216 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22149875 PubMed]
+
# '''RIBBON-2:''' Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. [https://doi.org/10.1200/JCO.2010.34.1255 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21990397/ PubMed] [https://clinicaltrials.gov/study/NCT00281697 NCT00281697]
−
## '''Update:''' Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. doi: 10.1016/S1470-2045(13)70130-X. Epub 2013 Apr 18. [http://www.sciencedirect.com/science/article/pii/S147020451370130X link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23602601 PubMed]
+
# '''DESTINY-Breast04:''' Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. [https://doi.org/10.1056/nejmoa2203690 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35665782/ PubMed] [https://clinicaltrials.gov/study/NCT03734029 NCT03734029]
−
# Hurvitz SA, Dirix L, Kocsis J, Bianchi GV, Lu J, Vinholes J, Guardino E, Song C, Tong B, Ng V, Chu YW, Perez EA. Phase II Randomized Study of Trastuzumab Emtansine Versus Trastuzumab Plus Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer. J Clin Oncol. 2013 Feb 11. [Epub ahead of print] [http://jco.ascopubs.org/content/early/2013/02/08/JCO.2012.44.9694.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23382472 PubMed]
+
==Paclitaxel monotherapy, q3wk {{#subobject:b90e58|Regimen=1}}==
−
 
+
<div class="toccolours" style="background-color:#eeeeee">
−
==THP - Docetaxel, Trastuzumab, Pertuzumab {{#subobject:938b69|Regimen=1}}==
+
===Regimen variant #1, 135 mg/m<sup>2</sup> {{#subobject:430acf|Variant=1}}===
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.1996.14.6.1858 Nabholtz et al. 1996]
 +
|1992-03 to 1992-08
 +
|style="background-color:#1a9851" |Phase 3 (E-RT-de-esc)
 +
|[[#Paclitaxel_monotherapy.2C_q3wk_2|Paclitaxel]]; 175 mg/m<sup>2</sup> q3wk
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<sup>1</sup>
 +
|-
 +
|}
 +
''<sup>1</sup>Although Nabholtz et al. 1996 did not meet its primary endpoint, there seemed to be a TTP disadvantage in the lower-dose arm.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel (Taxol)]] 135 mg/m<sup>2</sup> IV over 3 hours once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 175 mg/m<sup>2</sup> {{#subobject:f2e948|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.1995.13.10.2575 Seidman et al. 1995]
 +
|NR
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1200/JCO.1996.14.6.1858 Nabholtz et al. 1996]
 +
|1992-03 to 1992-08
 +
|style="background-color:#1a9851" |Phase 3 (E-RT-esc)
 +
|[[#Paclitaxel_monotherapy.2C_q3wk_2|Paclitaxel]]; 135 mg/m<sup>2</sup> q3wk
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR<sup>1</sup>
 +
|-
 +
|[https://doi.org/10.1200/JCO.2004.08.048 Winer et al. 2004 (CALGB 9342)]
 +
|1994-1997
 +
|style="background-color:#1a9851" |Phase 3 (C)
 +
|1. [[#Paclitaxel_monotherapy.2C_q3wk_2|Paclitaxel]]; 210 mg/m<sup>2</sup> q3wk<br>2. [[#Paclitaxel_monotherapy.2C_q3wk_2|Paclitaxel]]; 250 mg/m<sup>2</sup> q3wk
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.02.027 Jones et al. 2005 (TAX 311)]
 +
|1994-2001
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|[[#Docetaxel_monotherapy_3|Docetaxel]]
 +
| style="background-color:#d73027" |Inferior OS (secondary endpoint)
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361864/ Icli et al. 2005]
 +
|1997-2002
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#EoP_888|EoP]]
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 +
|-
 +
|[https://doi.org/10.1200/jco.2007.11.6699 Seidman et al. 2008 (CALGB 9840)]
 +
|1998-NR
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Paclitaxel_monotherapy.2C_weekly_3|Paclitaxel]]; weekly
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.04.937 Gradishar et al. 2005 (CA012-0)]
 +
|2001-11 to 2002-11
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]
 +
| style="background-color:#d73027" |Inferior TTP
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.34.1255 Brufsky et al. 2011 (RIBBON-2)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1d. [[#Paclitaxel_.26_Bevacizumab_2|Paclitaxel & Bevacizumab]]<br>1e. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]<br>1f. [[#Vinorelbine_.26_Bevacizumab|Vinorelbine & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9788977/ Rugo et al. 2023 (KX-ORAX-001)]
 +
|2015-12 to 2019-02
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Oral_paclitaxel_and_encequidar_monotherapy_777|Oral paclitaxel and encequidar]]
 +
| style="background-color:#fee08b" |Might have inferior OS
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2203690 Modi et al. 2022 (DESTINY-Breast04)]
 +
|2018-2021
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Trastuzumab_deruxtecan_monotherapy|Trastuzumab deruxtecan]]
 +
| style="background-color:#d73027" |Inferior OS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen, Baselga et al. 2012 (CLEOPATRA) {{#subobject:37f3dc|Variant=1}}===
+
''<sup>1</sup>Although Nabholtz et al. 1996 did not meet its primary endpoint, there seemed to be a TTP advantage in the higher-dose arm, which subsequently led to its adoption as the standard-of-care.''
−
Level of Evidence:
+
<div class="toccolours" style="background-color:#fdcdac">
−
<span
+
====Prior treatment criteria====
−
style="background:#00CD00;
+
*DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease
−
padding:3px 6px 3px 6px;
+
====Biomarker eligibility criteria====
−
border-color:black;
+
*DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative
−
border-width:2px;
+
</div>
−
border-style:solid;">Phase III</span>
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
*[[Docetaxel (Taxotere)]] 75 mg/m2 IV once on cycle 1 day 2; then [[Docetaxel (Taxotere)]] 75 mg/m2 IV once on day 1 of subsequent cycles
+
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
−
*[[Trastuzumab (Herceptin)]] 8 mg/kg IV once on cycle 1 day 2; then [[Trastuzumab (Herceptin)]] 6 mg/kg IV once on day 1 of subsequent cycles
+
'''21-day cycles'''
−
*[[Pertuzumab (Perjeta)]] 840 mg IV once on cycle 1 day 1; then [[Pertuzumab (Perjeta)]] 420 mg IV once on day 1 of subsequent cycles
+
</div></div>
−
 
 
−
'''21-day cycles x at least 6 cycles, given until progression of disease or unacceptable toxicity'''
 
−
 
 
−
If it is decided to no longer administer Docetaxel (Taxotere) with this regimen, then patients could continue to receive:
 
−
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV once on day 1
 
−
*[[Pertuzumab (Perjeta)]] 420 mg IV once on day 1
 
−
 
 
−
'''21-day cycles, given until progression of disease or unacceptable toxicity'''
 
  
 
===References===
 
===References===
−
# Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. Epub 2011 Dec 7. [http://www.nejm.org/doi/full/10.1056/NEJMoa1113216 link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/22149875 PubMed]
+
# Seidman AD, Tiersten A, Hudis C, Gollub M, Barrett S, Yao TJ, Lepore J, Gilewski T, Currie V, Crown J, Hakes T, Baselga J, Sklarin N, Moynihan ME, Tong W, Egorin M, Kearns C, Spriggs D, Norton L. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2575-81. [https://doi.org/10.1200/jco.1995.13.10.2575 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7595709/ PubMed]
−
## '''Update:''' Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. doi: 10.1016/S1470-2045(13)70130-X. Epub 2013 Apr 18. [http://www.sciencedirect.com/science/article/pii/S147020451370130X link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/23602601 PubMed]
+
# Nabholtz JM, Gelmon K, Bontenbal M, Spielmann M, Catimel G, Conte P, Klaassen U, Namer M, Bonneterre J, Fumoleau P, Winograd B. Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol. 1996 Jun;14(6):1858-67. [https://doi.org/10.1200/JCO.1996.14.6.1858 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/8656254/ PubMed]
 +
# '''CALGB 9342:''' Winer EP, Berry DA, Woolf S, Duggan D, Kornblith A, Harris LN, Michaelson RA, Kirshner JA, Fleming GF, Perry MC, Graham ML, Sharp SA, Keresztes R, Henderson IC, Hudis C, Muss H, Norton L. Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: Cancer and Leukemia Group B trial 9342. J Clin Oncol. 2004 Jun 1;22(11):2061-8. [https://doi.org/10.1200/JCO.2004.08.048 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15169793/ PubMed]
 +
# Icli F, Akbulut H, Uner A, Yalcin B, Baltali E, Altinbas M, Coşkun S, Komurcu S, Erkisi M, Demirkazik A, Senler FC, Sencan O, Büyükcelik A, Boruban C, Onur H, Zengin N, Sak SD; Turkish Oncology Group. Cisplatin plus oral etoposide (EoP) combination is more effective than paclitaxel in patients with advanced breast cancer pretreated with anthracyclines: a randomised phase III trial of Turkish Oncology Group. Br J Cancer. 2005 Feb 28;92(4):639-44. [https://doi.org/10.1038/sj.bjc.6602388 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361864/ link to PMC article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15726120/ PubMed]
 +
# '''TAX 311:''' Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, Laufman L, Sundaram S, Urba WJ, Pritchard KI, Mennel R, Richards D, Olsen S, Meyers ML, Ravdin PM. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005 Aug 20;23(24):5542-51. [https://doi.org/10.1200/JCO.2005.02.027 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16110015/ PubMed] [https://clinicaltrials.gov/study/NCT00002662 NCT00002662]
 +
<!-- Presented in part at the 26th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 3-6, 2003. -->
 +
# '''CA012-0:''' Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. [https://doi.org/10.1200/jco.2005.04.937 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16172456/ PubMed] [https://clinicaltrials.gov/study/NCT00046527 NCT00046527]
 +
<!-- Presented at the 40th Annual Meeting of the American Society of Clinical Oncology, June 5-8, 2004, New Orleans, LA. -->
 +
# '''CALGB 9840:''' Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. [https://doi.org/10.1200/jco.2007.11.6699 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18375893/ PubMed] [https://clinicaltrials.gov/study/NCT00003440 NCT00003440]
 +
<!-- Presented at the 32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-13, 2009, and at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. -->
 +
# '''RIBBON-2:''' Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. [https://doi.org/10.1200/JCO.2010.34.1255 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21990397/ PubMed] [https://clinicaltrials.gov/study/NCT00281697 NCT00281697]
 +
# '''DESTINY-Breast04:''' Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. [https://doi.org/10.1056/nejmoa2203690 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35665782/ PubMed] [https://clinicaltrials.gov/study/NCT03734029 NCT03734029]
 +
#'''KX-ORAX-001:''' Rugo HS, Umanzor GA, Barrios FJ, Vasallo RH, Chivalan MA, Bejarano S, Ramirez JR, Fein L, Kowalyszyn RD, Kramer ED, Wang H, Kwan MR, Cutler DL. Open-Label, Randomized, Multicenter, Phase III Study Comparing Oral Paclitaxel Plus Encequidar Versus Intravenous Paclitaxel in Patients With Metastatic Breast Cancer. J Clin Oncol. 2023 Jan 1;41(1):65-74. Epub 2022 Jul 20. [https://doi.org/10.1200/JCO.21.02953 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9788977/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35858154/ PubMed] [https://clinicaltrials.gov/study/NCT02594371 NCT02594371]
  
−
==Trastuzumab (Herceptin) & Lapatinib (Tykerb) {{#subobject:9be4d2|Regimen=1}}==
+
==Paclitaxel & Bevacizumab {{#subobject:1d634b|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 90 mg/m<sup>2</sup> 3 weeks out of 4 {{#subobject:ba68f9|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.34.1255 Brufsky et al. 2011 (RIBBON-2)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1d. [[#Paclitaxel_monotherapy.2C_weekly_3|Paclitaxel]]<br>1e. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]<br>1f. [[#Vinorelbine_monotherapy|Vinorelbine]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 7.2 vs 5.1 mo<br>(HR 0.78, 95% CI 0.64-0.93)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel (Taxol)]] 90 mg/m<sup>2</sup> IV over 60 minutes once per day on days 1, 8, 15
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 175 mg/m<sup>2</sup> q3wk {{#subobject:8820d1|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.34.1255 Brufsky et al. 2011 (RIBBON-2)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1d. [[#Paclitaxel_monotherapy.2C_weekly_3|Paclitaxel]]<br>1e. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]<br>1f. [[#Vinorelbine_monotherapy|Vinorelbine]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 7.2 vs 5.1 mo<br>(HR 0.78, 95% CI 0.64-0.93)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:e892bb|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV once on day 1
−
style="background:#00CD00;
+
====Targeted therapy====
−
padding:3px 6px 3px 6px;
+
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase III</span>
 
−
 
 
−
*EITHER [[Trastuzumab (Herceptin)]] 4 mg/kg IV on cycle 1 day 1, then 2 mg/kg IV on day 8 & 15 of cycle 1; then on subsequent cycles, [[Trastuzumab (Herceptin)]] is 2 mg/kg IV on days 1, 8, 15
 
−
*OR [[Trastuzumab (Herceptin)]] 8 mg/kg IV on cycle 1 day 1, then on subsequent cycles [[Trastuzumab (Herceptin)]] is 6 mg/kg IV on day 1
 
−
*[[Lapatinib (Tykerb)]] 1250 mg PO daily days 1 to 21
 
−
 
 
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
−
# Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010 Mar 1;28(7):1124-30. doi: 10.1200/JCO.2008.21.4437. Epub 2010 Feb 1. [http://jco.ascopubs.org/content/28/7/1124.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/20124187 PubMed]
+
<!-- Presented at the 32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-13, 2009, and at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. -->
−
## '''Update:''' Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, Ellis C, Florance A, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012 Jul 20;30(21):2585-92. doi: 10.1200/JCO.2011.35.6725. Epub 2012 Jun 11. [http://jco.ascopubs.org/content/30/21/2585.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/22689807 PubMed]
+
# '''RIBBON-2:''' Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. [https://doi.org/10.1200/JCO.2010.34.1255 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21990397/ PubMed] [https://clinicaltrials.gov/study/NCT00281697 NCT00281697]
 +
==nab-Paclitaxel monotherapy {{#subobject:7592da|Regimen=1}}==
 +
===Example orders===
 +
*[[Example orders for Paclitaxel, nanoparticle albumin-bound (Abraxane) in breast cancer]]
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 100 mg/m<sup>2</sup>, 3 weeks out of 4 {{#subobject:4d1f30|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Doxorubicin_.26_Bevacizumab|Doxorubicin & Bevacizumab]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_.26_Bevacizumab|NPLD & Bevacizumab]]<br>1e. [[#Pegylated_liposomal_doxorubicin_.26_Bevacizumab|PLD & Bevacizumab]]<br>1f. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2203690 Modi et al. 2022 (DESTINY-Breast04)]
 +
|2018-2021
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Trastuzumab_deruxtecan_monotherapy|Trastuzumab deruxtecan]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|}
 +
''Note: the details of this regimen are unclear in von Minckwitz et al. 2014.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Prior treatment criteria====
 +
*DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease
 +
====Biomarker eligibility criteria====
 +
*DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 125 mg/m<sup>2</sup>, 3 weeks out of 4 {{#subobject:4dhha0|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2203690 Modi et al. 2022 (DESTINY-Breast04)]
 +
|2018-2021
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Trastuzumab_deruxtecan_monotherapy|Trastuzumab deruxtecan]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Prior treatment criteria====
 +
*DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease
 +
====Biomarker eligibility criteria====
 +
*DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 125 mg/m<sup>2</sup> IV once per day on days 1, 8, 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #3, 260 mg/m<sup>2</sup> q3wk {{#subobject:7d9620|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.2005.04.937 Gradishar et al. 2005 (CA012-0)]
 +
|2001-11 to 2002-11
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ic)
 +
|[[#Paclitaxel_monotherapy.2C_q3wk_2|Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior ORR (primary endpoint)<br>ORR: 33% vs 19%<br><br>Superior TTP (secondary endpoint)<br>Median TTP: 23 vs 16.9 weeks<br>(HR 0.75)
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.34.1255 Brufsky et al. 2011 (RIBBON-2)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1d. [[#Paclitaxel_.26_Bevacizumab_2|Paclitaxel & Bevacizumab]]<br>1e. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]<br>1f. [[#Vinorelbine_.26_Bevacizumab|Vinorelbine & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Doxorubicin_.26_Bevacizumab|Doxorubicin & Bevacizumab]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_.26_Bevacizumab|NPLD & Bevacizumab]]<br>1e. [[#Pegylated_liposomal_doxorubicin_.26_Bevacizumab|PLD & Bevacizumab]]<br>1f. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2203690 Modi et al. 2022 (DESTINY-Breast04)]
 +
|2018-2021
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Trastuzumab_deruxtecan_monotherapy|Trastuzumab deruxtecan]]
 +
| style="background-color:#d73027" |Inferior OS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Prior treatment criteria====
 +
*DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease
 +
====Biomarker eligibility criteria====
 +
*DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 260 mg/m<sup>2</sup> IV over 30 minutes once on day 1
 +
====Supportive therapy====
 +
*CA012-0: No corticosteroid or antihistamine premedication
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
−
==XH {{#subobject:677608|Regimen=1}}==
+
===Regimen variant #4, 300 mg/m<sup>2</sup> q3wk {{#subobject:7d7ym0|Variant=1}}===
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
{| class="wikitable" style="width: 60%; text-align:center;"  
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2005.11.013 Ibrahim et al. 2005]
 +
|1999-2001
 +
| style="background-color:#91cf61" |Phase 2 (RT)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
XH: '''<u>X</u>'''eloda, '''<u>H</u>'''erceptin
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
===Regimen #1, Bartsch et al. 2007 {{#subobject:32c470|Variant=1}}===
+
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 300 mg/m<sup>2</sup> IV over 30 minutes once on day 1
−
Level of Evidence:
 
−
<span
 
−
style="background:#EEEE00;
 
−
padding:3px 6px 3px 6px;
 
−
border-color:black;
 
−
border-width:2px;
 
−
border-style:solid;">Phase II</span>
 
−
 
 
−
*[[Capecitabine (Xeloda)]] 1000-1250 mg/m2 PO BID days 1 to 14
 
−
*EITHER [[Trastuzumab (Herceptin)]] 4 mg/kg IV on cycle 1 day 1, then 2 mg/kg IV on day 8 & 15 of cycle 1; then on subsequent cycles, [[Trastuzumab (Herceptin)]] is 2 mg/kg IV on days 1, 8, 15
 
−
*OR [[Trastuzumab (Herceptin)]] 8 mg/kg IV on cycle 1 day 1, then on subsequent cycles [[Trastuzumab (Herceptin)]] is 6 mg/kg IV on day 1
 
−
 
 
 
'''21-day cycles'''
 
'''21-day cycles'''
 +
</div></div>
 +
===References===
 +
# Ibrahim NK, Samuels B, Page R, Doval D, Patel KM, Rao SC, Nair MK, Bhar P, Desai N, Hortobagyi GN. Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer. J Clin Oncol. 2005 Sep 1;23(25):6019-26. [https://doi.org/10.1200/JCO.2005.11.013 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/16135470/ PubMed]
 +
<!-- Presented in part at the 26th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 3-6, 2003. -->
 +
# '''CA012-0:''' Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. [https://doi.org/10.1200/jco.2005.04.937 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/16172456/ PubMed] [https://clinicaltrials.gov/study/NCT00046527 NCT00046527]
 +
<!-- Presented at the 32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-13, 2009, and at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. -->
 +
# '''RIBBON-2:''' Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. [https://doi.org/10.1200/JCO.2010.34.1255 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21990397/ PubMed] [https://clinicaltrials.gov/study/NCT00281697 NCT00281697]
 +
# '''TANIA:''' von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. [https://doi.org/10.1016/S1470-2045(14)70439-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25273342/ PubMed] [https://clinicaltrials.gov/study/NCT01250379 NCT01250379]
 +
## '''Update:''' Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. [https://doi.org/10.1093/annonc/mdw316 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27502725/ PubMed]
 +
# '''DESTINY-Breast04:''' Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. [https://doi.org/10.1056/nejmoa2203690 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35665782/ PubMed] [https://clinicaltrials.gov/study/NCT03734029 NCT03734029]
  
−
===Regimen #2, von Minckwitz et al. 2009 (GBG 26/BIG 3-05) {{#subobject:e38ff|Variant=1}}===
+
==Paclitaxel, nanoparticle albumin-bound & Bevacizumab {{#subobject:645e02|Regimen=1}}==
−
Level of Evidence:
+
===Example orders===
−
<span
+
*[[Example orders for Paclitaxel, nanoparticle albumin-bound & Bevacizumab in breast cancer]]
−
style="background:#00CD00;
+
<div class="toccolours" style="background-color:#eeeeee">
−
padding:3px 6px 3px 6px;
+
===Regimen variant #1, 100 mg/m<sup>2</sup> weekly {{#subobject:63e270|Variant=1}}===
−
border-color:black;
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
border-width:2px;
+
!style="width: 20%"|Study
−
border-style:solid;">Phase III</span>
+
!style="width: 20%"|Dates of enrollment
−
 
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
*[[Capecitabine (Xeloda)]] 1250 mg/m2 PO BID days 1 to 14
+
!style="width: 20%"|Comparator
−
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV once on day 1
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
 
+
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Doxorubicin_monotherapy_2|Doxorubicin]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_monotherapy|NPLD]]<br>1e. [[#Pegylated_liposomal_doxorubicin_monotherapy_2|PLD]]<br>1f. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1g. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 6.3 vs 4.2 mo<br>(HR 0.75, 95% CI 0.61-0.93)
 +
|-
 +
|}
 +
''Note: the schedule of bevacizumab is inferred, as there was insufficient detail in the description in the manuscript.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 100 mg/m<sup>2</sup> IV once per day on days 1, 8, 15, 22
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 260 mg/m<sup>2</sup> q3wk {{#subobject:b2c00e|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.34.1255 Brufsky et al. 2011 (RIBBON-2)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1d. [[#Paclitaxel_monotherapy.2C_weekly_3|Paclitaxel]]<br>1e. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]<br>1f. [[#Vinorelbine_monotherapy|Vinorelbine]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 7.2 vs 5.1 mo<br>(HR 0.78, 95% CI 0.64-0.93)
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Doxorubicin_monotherapy_2|Doxorubicin]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_monotherapy|NPLD]]<br>1e. [[#Pegylated_liposomal_doxorubicin_monotherapy_2|PLD]]<br>1f. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1g. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 6.3 vs 4.2 mo<br>(HR 0.75, 95% CI 0.61-0.93)
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Paclitaxel, nanoparticle albumin-bound (Abraxane)]] 260 mg/m<sup>2</sup> IV once on day 1
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
 
'''21-day cycles'''
 
'''21-day cycles'''
 +
</div></div>
 +
===References===
 +
<!-- Presented at the 32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-13, 2009, and at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. -->
 +
# '''RIBBON-2:''' Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. [https://doi.org/10.1200/JCO.2010.34.1255 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21990397/ PubMed] [https://clinicaltrials.gov/study/NCT00281697 NCT00281697]
 +
# '''TANIA:''' von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. [https://doi.org/10.1016/S1470-2045(14)70439-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25273342/ PubMed] [https://clinicaltrials.gov/study/NCT01250379 NCT01250379]
 +
## '''Update:''' Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. [https://doi.org/10.1093/annonc/mdw316 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27502725/ PubMed]
 +
==Pegylated liposomal doxorubicin monotherapy {{#subobject:06760b|Regimen=1}}==
 +
PLD: '''<u>P</u>'''egylated '''<u>L</u>'''iposomal '''<u>D</u>'''oxorubicin
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 40 mg/m<sup>2</sup> {{#subobject:2ed37f|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Doxorubicin_.26_Bevacizumab|Doxorubicin & Bevacizumab]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_.26_Bevacizumab|NPLD & Bevacizumab]]<br>1e. [[#Pegylated_liposomal_doxorubicin_.26_Bevacizumab|PLD & Bevacizumab]]<br>1f. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
''Note: this is the lower end of the range of pegylated liposomal doxorubicin dosing described in TANIA.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Pegylated liposomal doxorubicin (Doxil)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 50 mg/m<sup>2</sup> {{#subobject:f033fb|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2004.08.157 Keller et al. 2004]
 +
|NR
 +
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
 +
|1. [[#Mitomycin_.26_Vinblastine_888|Mitomycin & Vinblastine]]<br>2. [[#Vinorelbine_monotherapy|Vinorelbine]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Doxorubicin_.26_Bevacizumab|Doxorubicin & Bevacizumab]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_.26_Bevacizumab|NPLD & Bevacizumab]]<br>1e. [[#Pegylated_liposomal_doxorubicin_.26_Bevacizumab|PLD & Bevacizumab]]<br>1f. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1g. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
''Note: this was the higher end of the range of pegylated liposomal doxorubicin dosing described in TANIA.''
 +
<div class="toccolours" style="background-color:#fdcdac">
 +
====Prior treatment criteria====
 +
*Keller et al. 2004: Taxane exposure
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Pegylated liposomal doxorubicin (Doxil)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
'''28-day cycles'''
 +
</div></div>
  
 
===References===
 
===References===
−
# Bartsch R, Wenzel C, Altorjai G, Pluschnig U, Rudas M, Mader RM, Gnant M, Zielinski CC, Steger GG. Capecitabine and trastuzumab in heavily pretreated metastatic breast cancer. J Clin Oncol. 2007 Sep 1;25(25):3853-8. Epub 2007 Aug 6. [http://jco.ascopubs.org/content/25/25/3853.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/17679724 PubMed]
+
# Keller AM, Mennel RG, Georgoulias VA, Nabholtz JM, Erazo A, Lluch A, Vogel CL, Kaufmann M, von Minckwitz G, Henderson IC, Mellars L, Alland L, Tendler C. Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol. 2004 Oct 1;22(19):3893-901. [https://doi.org/10.1200/JCO.2004.08.157 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15459210/ PubMed]
−
# von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer W, Baumann KH, Clemens MR, Duerr R, Uleer C, Andersson M, Stein RC, Nekljudova V, Loibl S. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study. J Clin Oncol. 2009 Apr 20;27(12):1999-2006. Epub 2009 Mar 16. [http://jco.ascopubs.org/content/27/12/1999.long link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/19289619 PubMed]
+
# '''TANIA:''' von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. [https://doi.org/10.1016/S1470-2045(14)70439-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25273342/ PubMed] [https://clinicaltrials.gov/study/NCT01250379 NCT01250379]
−
## '''Update:''' von Minckwitz G, Schwedler K, Schmidt M, Barinoff J, Mundhenke C, Cufer T, Maartense E, de Jongh FE, Baumann KH, Bischoff J, Harbeck N, Lück HJ, Maass N, Zielinski C, Andersson M, Stein RC, Nekljudova V, Loibl S; GBG 26/BIG 03-05 study group and participating investigators. Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. Eur J Cancer. 2011 Oct;47(15):2273-81. Epub 2011 Jul 7. [http://www.ejcancer.info/article/S0959-8049%2811%2900425-4/abstract link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/21741829 PubMed]
+
## '''Update:''' Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. [https://doi.org/10.1093/annonc/mdw316 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27502725/ PubMed]
−
 
+
==Pegylated liposomal doxorubicin & Bevacizumab {{#subobject:2e10a5|Regimen=1}}==
−
==Trastuzumab (Herceptin) & other single agent chemotherapy {{#subobject:ceb3cd|Regimen=1}}==
+
PLD & Bev: '''<u>P</u>'''egylated '''<u>L</u>'''iposomal '''<u>D</u>'''oxorubicin & '''<u>Bev</u>'''acizumab
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 40 mg/m<sup>2</sup> {{#subobject:88281d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Doxorubicin_monotherapy_2|Doxorubicin]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_monotherapy|NPLD]]<br>1e. [[#Pegylated_liposomal_doxorubicin_monotherapy_2|PLD]]<br>1f. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1g. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 6.3 vs 4.2 mo<br>(HR 0.75, 95% CI 0.61-0.93)
 +
|-
 +
|}
 +
''Note: this is the lower end of the range of pegylated liposomal doxorubicin dosing described in TANIA.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Pegylated liposomal doxorubicin (Doxil)]] 40 mg/m<sup>2</sup> IV once on day 1
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
 +
'''28-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, 50 mg/m<sup>2</sup> {{#subobject:9feb98|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(14)70439-5 von Minckwitz et al. 2014 (TANIA)]
 +
|2011-2013
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Doxorubicin_monotherapy_2|Doxorubicin]]<br>1d. [[#Non-pegylated_liposomal_doxorubicin_monotherapy|NPLD]]<br>1e. [[#Pegylated_liposomal_doxorubicin_monotherapy_2|PLD]]<br>1f. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1g. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 6.3 vs 4.2 mo<br>(HR 0.75, 95% CI 0.61-0.93)
 +
|-
 +
|}
 +
''Note: this is the higher end of the range of pegylated liposomal doxorubicin dosing described in TANIA.''
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Pegylated liposomal doxorubicin (Doxil)]] 50 mg/m<sup>2</sup> IV once on day 1
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once per day on days 1 & 15
 +
'''28-day cycles'''
 +
</div></div>
 +
===References===
 +
# '''TANIA:''' von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. [https://doi.org/10.1016/S1470-2045(14)70439-5 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/25273342/ PubMed] [https://clinicaltrials.gov/study/NCT01250379 NCT01250379]
 +
## '''Update:''' Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. [https://doi.org/10.1093/annonc/mdw316 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27502725/ PubMed]
 +
==Trastuzumab deruxtecan monotherapy {{#subobject:afhy8w|Regimen=1}}==
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen {{#subobject:4cczw1d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 17%"|Study
 +
!style="width: 15%"|Dates of enrollment
 +
!style="width: 17%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 17%"|Comparator
 +
!style="width: 17%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
!style="width: 17%"|[[Levels_of_Evidence#Toxicity|Comparative Toxicity]]
 +
|-
 +
|[https://doi.org/10.1056/nejmoa2203690 Modi et al. 2022 (DESTINY-Breast04)]
 +
<!-- {| class="wikitable" style="margin:auto; color:white; background-color:#1B4F26"
 +
|'''[https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-scorecards/scorecard-351-1 <span style="color:white;">ESMO-MCBS (4)</span>]'''
 +
|-
 +
|} -->
 +
|2018-2021
 +
| style="background-color:#1a9851" |Phase 3 (E-RT-switch-ooc)
 +
|Investigator's choice of:<br>1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Eribulin_monotherapy|Eribulin]]<br>1c. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1d. [[#Paclitaxel_monotherapy.2C_weekly_3|Paclitaxel]]; weekly<br>1e. [[#Paclitaxel_monotherapy.2C_q3wk_2|Paclitaxel]]; q3wk<br>1f. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]
 +
| style="background-color:#1a9850" |Superior PFS<sup>1</sup> (primary endpoint)<br>Median PFS: 10.1 vs 5.4 mo<br>(HR 0.51, 95% CI 0.40-0.64)<br><br>Superior OS<sup>2</sup> (secondary endpoint)<br>Median OS: 23.4 vs 16.8 mo<br>(HR 0.64, 95% CI 0.49-0.84)
 +
| style="background-color:#d73027" |Higher rate of pneumonitis
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen {{#subobject:b601ee|Variant=1}}===
+
''<sup>1</sup>Reported efficacy is for the hormone-receptor positive subgroup.''<br>
−
*EITHER [[Trastuzumab (Herceptin)]] 4 mg/kg IV on cycle 1 day 1, then 2 mg/kg IV on day 8 & 15 of cycle 1; then on subsequent cycles, [[Trastuzumab (Herceptin)]] is 2 mg/kg IV on days 1, 8, 15
+
''<sup>2</sup>Reported efficacy is for all enrolled patients.''<br>
−
*OR [[Trastuzumab (Herceptin)]] 8 mg/kg IV on cycle 1 day 1, then on subsequent cycles [[Trastuzumab (Herceptin)]] is 6 mg/kg IV on day 1
+
''Note: eribulin was the most commonly used comparator regimen.
−
*A [[#Metastatic_disease.2C_single_agent_therapy|single agent chemotherapy regimen]] described above
+
<div class="toccolours" style="background-color:#fdcdac">
−
 
+
====Prior treatment criteria====
 +
*DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease
 +
====Biomarker eligibility criteria====
 +
*DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative
 +
</div>
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Antibody-drug conjugate therapy====
 +
*[[Trastuzumab deruxtecan (Enhertu)]] 5.4 mg/kg IV once on day 1
 
'''21-day cycles'''
 
'''21-day cycles'''
−
 
+
</div></div>
 
===References===
 
===References===
−
See [[#Metastatic_disease.2C_single_agent_therapy|single agent chemotherapy regimens]]
+
# '''DESTINY-Breast04:''' Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. [https://doi.org/10.1056/nejmoa2203690 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/35665782/ PubMed] [https://clinicaltrials.gov/study/NCT03734029 NCT03734029]
  
−
==Trastuzumab (Herceptin) & Pertuzumab (Perjeta) {{#subobject:b1d7b1|Regimen=1}}==
+
==Vinorelbine monotherapy {{#subobject:5c104c|Regimen=1}}==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, 25 mg/m<sup>2</sup> weekly {{#subobject:c0c952|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/jco.1994.12.10.2094 Gasparini et al. 1994]
 +
|1991-1993
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1002/1097-0142(20011101)92:9%3C2267::aid-cncr1572%3E3.0.co;2-q Zelek et al. 2001]
 +
|1997-1999
 +
| style="background-color:#91cf61" |Phase 2
 +
| style="background-color:#d3d3d3" |
 +
| style="background-color:#d3d3d3" |
 +
|-
 +
|[https://doi.org/10.1007/s10549-019-05280-2 Decker et al. 2019 (VicTORia)]
 +
|2011-2016
 +
| style="background-color:#1a9851" |Randomized Phase 2 (C)
 +
|[[Stub#Everolimus_.26_Vinorelbine|Everolimus & Vinorelbine]]
 +
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 +
|-
 +
|[https://doi.org/10.1016/j.ejca.2019.02.002 Yuan et al. 2019 (E7389-C086-304)]
 +
|2013-2015
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Eribulin_monotherapy|Eribulin]]
 +
| style="background-color:#fc8d59" |Seems to have inferior PFS
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen #1, Baselga et al. 2010 - trastuzumab every 3 weeks {{#subobject:4f5a4d|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once on day 1
−
style="background:#EEEE00;
+
'''7-day cycles'''
−
padding:3px 6px 3px 6px;
+
</div></div><br>
−
border-color:black;
+
<div class="toccolours" style="background-color:#eeeeee">
−
border-width:2px;
+
===Regimen variant #2, 30 mg/m<sup>2</sup> weekly {{#subobject:1b6c25|Variant=1}}===
−
border-style:solid;">Phase II</span>
+
{| class="wikitable sortable" style="width: 100%; text-align:center;"
−
 
+
!style="width: 20%"|Study
−
Loading dose:
+
!style="width: 20%"|Dates of enrollment
−
*[[Trastuzumab (Herceptin)]] 8 mg/kg IV on day -28 (that is, 28 days before the start of cycle 1)
+
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
−
 
+
!style="width: 20%"|Comparator
−
Cycles 1 to 8:
+
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
−
*[[Trastuzumab (Herceptin)]] 6 mg/kg IV on day 1, given first
+
|-
−
*[[Pertuzumab (Perjeta)]] 840 mg IV on cycle 1 day 2, then on subsequent cycles [[Pertuzumab (Perjeta)]] is 420 mg IV on day 1, given second
+
|[https://doi.org/10.1200/JCO.1995.13.10.2567 Jones et al. 1995a]
−
 
+
|1990-1992
−
'''21-day cycles x 8 cycles'''; treatment can be continued if there is no progressive disease
+
| style="background-color:#1a9851" |Phase 3 (E-switch-ic)
−
 
+
|[[Breast_cancer_-_historical#Melphalan_monotherapy_2|Melphalan]]
−
===Regimen #2, Baselga et al. 2010 - weekly trastuzumab {{#subobject:ecb953|Variant=1}}===
+
| style="background-color:#91cf60" |Seems to have superior OS
−
Level of Evidence:
+
|-
−
<span
+
|[https://doi.org/10.1200/JCO.2004.08.157 Keller et al. 2004]
−
style="background:#EEEE00;
+
|NR
−
padding:3px 6px 3px 6px;
+
| style="background-color:#1a9851" |Phase 3 (C)
−
border-color:black;
+
|1. [[#Mitomycin_.26_Vinblastine_999|Mitomycin & Vinblastine]]<br>2. [[#Pegylated_liposomal_doxorubicin_monotherapy_2|PLD]]
−
border-width:2px;
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
−
border-style:solid;">Phase II</span>
+
|-
−
 
+
|}
−
Loading dose:
+
<div class="toccolours" style="background-color:#fdcdac">
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV on day -28 (that is, 28 days before the start of cycle 1)
+
====Prior treatment criteria====
−
 
+
*Jones et al. 1995a: Anthracycline exposure
−
Cycles 1 to 8:
+
*Keller et al. 2004: Taxane exposure
−
*[[Trastuzumab (Herceptin)]] 2 mg/kg IV on days 1, 8, 15, given first
+
</div>
−
*[[Pertuzumab (Perjeta)]] 840 mg IV on cycle 1 day 2, then on subsequent cycles [[Pertuzumab (Perjeta)]] is 420 mg IV on day 1, given second
+
<div class="toccolours" style="background-color:#b3e2cd">
−
 
+
====Chemotherapy====
−
'''21-day cycles x 8 cycles'''; treatment can be continued if there is no progressive disease
+
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once on day 1
 +
'''7-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
  
 +
===Regimen variant #3, 30 mg/m<sup>2</sup> q3wk {{#subobject:c63b68|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.34.1255 Brufsky et al. 2011 (RIBBON-2)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|1a. [[#Capecitabine_.26_Bevacizumab_3|Capecitabine & Bevacizumab]]<br>1b. [[#Docetaxel_.26_Bevacizumab_2|Docetaxel & Bevacizumab]]<br>1c. [[#Gemcitabine_.26_Bevacizumab|Gemcitabine & Bevacizumab]]<br>1d. [[#Paclitaxel_.26_Bevacizumab_2|Paclitaxel & Bevacizumab]]<br>1e. [[#Paclitaxel.2C_nanoparticle_albumin-bound_.26_Bevacizumab_2|nab-Paclitaxel & Bevacizumab]]<br>1f. [[#Vinorelbine_.26_Bevacizumab|Vinorelbine & Bevacizumab]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once on day 1
 +
'''21-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #4, 30 mg/m<sup>2</sup> 2 out of 3 weeks {{#subobject:7321fd|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1016/S1470-2045(07)70041-4 Martín et al. 2007 (GEICAM 2000-04)]
 +
|2001-2005
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Gemcitabine_.26_Vinorelbine_888|Gemcitabine & Vinorelbine]]
 +
| style="background-color:#d73027" |Inferior PFS
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
'''21-day cycles'''
 +
</div></div>
 
===References===
 
===References===
−
# Baselga J, Gelmon KA, Verma S, Wardley A, Conte P, Miles D, Bianchi G, Cortes J, McNally VA, Ross GA, Fumoleau P, Gianni L. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 2010 Mar 1;28(7):1138-44. Epub 2010 Feb 1. [http://jco.ascopubs.org/content/28/7/1138.long link to original article] '''contains verified protocol''' [http://www.ncbi.nlm.nih.gov/pubmed/20124182 PubMed]
+
# Gasparini G, Caffo O, Barni S, Frontini L, Testolin A, Guglielmi RB, Ambrosini G. Vinorelbine is an active antiproliferative agent in pretreated advanced breast cancer patients: a phase II study. J Clin Oncol. 1994 Oct;12(10):2094-101. [https://doi.org/10.1200/jco.1994.12.10.2094 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7931479/ PubMed]
−
 
+
# Jones S, Winer E, Vogel C, Laufman L, Hutchins L, O'Rourke M, Lembersky B, Budman D, Bigley J, Hohneker J. Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. J Clin Oncol. 1995 Oct;13(10):2567-74. [https://doi.org/10.1200/JCO.1995.13.10.2567 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/7595708/ PubMed]
−
==Vinorelbine (Navelbine) & Trastuzumab (Herceptin) {{#subobject:59edc1|Regimen=1}}==
+
# Zelek L, Barthier S, Riofrio M, Fizazi K, Rixe O, Delord JP, Le Cesne A, Spielmann M. Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer. 2001 Nov 1;92(9):2267-72. [https://doi.org/10.1002/1097-0142(20011101)92:9%3C2267::aid-cncr1572%3E3.0.co;2-q link to original article] [https://pubmed.ncbi.nlm.nih.gov/11745280/ PubMed]
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
# Keller AM, Mennel RG, Georgoulias VA, Nabholtz JM, Erazo A, Lluch A, Vogel CL, Kaufmann M, von Minckwitz G, Henderson IC, Mellars L, Alland L, Tendler C. Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol. 2004 Oct 1;22(19):3893-901. [https://doi.org/10.1200/JCO.2004.08.157 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/15459210/ PubMed]
 +
# '''GEICAM 2000-04:''' Martín M, Ruiz A, Muñoz M, Balil A, García-Mata J, Calvo L, Carrasco E, Mahillo E, Casado A, García-Saenz JA, Escudero MJ, Guillem V, Jara C, Ribelles N, Salas F, Soto C, Morales-Vasquez F, Rodríguez CA, Adrover E, Mel JR; GEICAM. Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. Lancet Oncol. 2007 Mar;8(3):219-25. [https://doi.org/10.1016/S1470-2045(07)70041-4 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/17329192/ PubMed] [https://clinicaltrials.gov/study/NCT00128310 NCT00128310]
 +
<!-- Presented at the 32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-13, 2009, and at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. -->
 +
# '''RIBBON-2:''' Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. [https://doi.org/10.1200/JCO.2010.34.1255 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21990397/ PubMed] [https://clinicaltrials.gov/study/NCT00281697 NCT00281697]
 +
# '''E7389-C086-304:''' Yuan P, Hu X, Sun T, Li W, Zhang Q, Cui S, Cheng Y, Ouyang Q, Wang X, Chen Z, Hiraiwa M, Saito K, Funasaka S, Xu B. Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial. Eur J Cancer. 2019 May;112:57-65. Epub 2019 Mar 29. [https://doi.org/10.1016/j.ejca.2019.02.002 link to original article] '''contains dosing details in abstract''' [https://pubmed.ncbi.nlm.nih.gov/30928806/ PubMed] [https://clinicaltrials.gov/study/NCT02225470 NCT02225470]
 +
# '''VicTORia:''' Decker T, Marschner N, Muendlein A, Welt A, Hagen V, Rauh J, Schröder H, Jaehnig P, Potthoff K, Lerchenmüller C. VicTORia: a randomised phase II study to compare vinorelbine in combination with the mTOR inhibitor everolimus versus vinorelbine monotherapy for second-line chemotherapy in advanced HER2-negative breast cancer. Breast Cancer Res Treat. 2019 Aug;176(3):637-647. Epub 2019 May 21. [https://doi.org/10.1007/s10549-019-05280-2 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/31115844/ PubMed] [https://clinicaltrials.gov/study/NCT01520103 NCT01520103]
 +
# '''EVER-132-002:''' [https://clinicaltrials.gov/study/NCT04639986 NCT04639986]
 +
==Vinorelbine & Bevacizumab {{#subobject:f3046|Regimen=1}}==
 +
===Example orders===
 +
*[[Example orders for Vinorelbine and Bevacizumab in breast cancer]]
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #1, vinorelbine 25 mg/m<sup>2</sup> weekly {{#subobject:82cbe7|Variant=1}}===
 +
{| class="wikitable" style="width: 60%; text-align:center;"
 +
!style="width: 33%"|Study
 +
!style="width: 33%"|Dates of enrollment
 +
!style="width: 33%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
|-
 +
|[https://doi.org/10.1158/1078-0432.CCR-08-0593 Burstein et al. 2008]
 +
|2001-2002
 +
| style="background-color:#91cf61" |Phase 2
 +
|-
 +
|}
 +
<div class="toccolours" style="background-color:#b3e2cd">
 +
====Chemotherapy====
 +
*[[Vinorelbine (Navelbine)]] 25 mg/m<sup>2</sup> IV once per day on days 1 & 8
 +
====Targeted therapy====
 +
*[[Bevacizumab (Avastin)]] 10 mg/kg IV once on day 1
 +
'''14-day cycles'''
 +
</div></div><br>
 +
<div class="toccolours" style="background-color:#eeeeee">
 +
===Regimen variant #2, vinorelbine 30 mg/m<sup>2</sup> q3wk {{#subobject:2b0f5d|Variant=1}}===
 +
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 +
!style="width: 20%"|Study
 +
!style="width: 20%"|Dates of enrollment
 +
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 +
!style="width: 20%"|Comparator
 +
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 +
|-
 +
|[https://doi.org/10.1200/JCO.2010.34.1255 Brufsky et al. 2011 (RIBBON-2)]
 +
|2006-2008
 +
| style="background-color:#1a9851" |Phase 3 (E-esc)
 +
|1a. [[#Capecitabine_monotherapy_3|Capecitabine]]<br>1b. [[#Docetaxel_monotherapy_3|Docetaxel]]<br>1c. [[#Gemcitabine_monotherapy_2|Gemcitabine]]<br>1d. [[#Paclitaxel_monotherapy.2C_weekly_3|Paclitaxel]]<br>1e. [[#nab-Paclitaxel_monotherapy_3|nab-Paclitaxel]]<br>1f. [[#Vinorelbine_monotherapy|Vinorelbine]]
 +
| style="background-color:#1a9850" |Superior PFS (primary endpoint)<br>Median PFS: 7.2 vs 5.1 mo<br>(HR 0.78, 95% CI 0.64-0.93)
 
|-
 
|-
−
|[[#toc|back to top]]
 
 
|}
 
|}
−
===Regimen, Burstein et al. 2007 (TRAVIOTA) {{#subobject:947c3a|Variant=1}}===
+
<div class="toccolours" style="background-color:#b3e2cd">
−
Level of Evidence:
+
====Chemotherapy====
−
<span
+
*[[Vinorelbine (Navelbine)]] 30 mg/m<sup>2</sup> IV once on day 1
−
style="background:#00CD00;
+
====Targeted therapy====
−
padding:3px 6px 3px 6px;
+
*[[Bevacizumab (Avastin)]] 15 mg/kg IV once on day 1
−
border-color:black;
+
'''21-day cycles'''
−
border-width:2px;
+
</div></div>
−
border-style:solid;">Randomized Phase II, >20 per arm</span>
 
−
 
 
−
*[[Vinorelbine (Navelbine)]] 25 mg/m2 IV weekly
 
−
*[[Trastuzumab (Herceptin)]] 4 mg/kg IV on day 1, then 2 mg/kg IV weekly with paclitaxel
 
−
 
 
 
===References===
 
===References===
−
# Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. [http://onlinelibrary.wiley.com/doi/10.1002/cncr.22885/abstract link to original article] [http://www.ncbi.nlm.nih.gov/pubmed/17614302 PubMed]
+
# Burstein HJ, Chen YH, Parker LM, Savoie J, Younger J, Kuter I, Ryan PD, Garber JE, Chen H, Campos SM, Shulman LN, Harris LN, Gelman R, Winer EP. VEGF as a marker for outcome among advanced breast cancer patients receiving anti-VEGF therapy with bevacizumab and vinorelbine chemotherapy. Clin Cancer Res. 2008 Dec 1;14(23):7871-7. [https://doi.org/10.1158/1078-0432.CCR-08-0593 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/19047116/ PubMed]
 +
<!-- Presented at the 32nd Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-13, 2009, and at the 46th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, June 4-8, 2010. -->
 +
# '''RIBBON-2:''' Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. [https://doi.org/10.1200/JCO.2010.34.1255 link to original article] '''contains dosing details in manuscript''' [https://pubmed.ncbi.nlm.nih.gov/21990397/ PubMed] [https://clinicaltrials.gov/study/NCT00281697 NCT00281697]
  
 
=Additional resources=
 
=Additional resources=
 
*[http://www.cancer.gov/bcrisktool/ Gail model Breast Cancer Risk Assessment Tool]
 
*[http://www.cancer.gov/bcrisktool/ Gail model Breast Cancer Risk Assessment Tool]
 
**[[Gail model breast cancer risk factors]]
 
**[[Gail model breast cancer risk factors]]
−
*[[Breast cancer BRCA1/BRCA2 genetic testing]]
+
*[[Breast cancer BRCA1 & BRCA2 genetic testing]]
 
*[http://www.adjuvantonline.com/index.jsp/ Adjuvant! Online (requires login)]
 
*[http://www.adjuvantonline.com/index.jsp/ Adjuvant! Online (requires login)]
 
*[http://www.mycancergenome.org/content/disease/breast-cancer/ My Cancer Genome]
 
*[http://www.mycancergenome.org/content/disease/breast-cancer/ My Cancer Genome]
−
 
+
*[http://www.predict.nhs.uk/ PREDICT]
 
=Patient information=
 
=Patient information=
 
*[http://www.lakeviewhealth.com/alcohol-increase-breast-cancer-risk-factors-infographic.php Alcohol and risk of breast cancer infographic]
 
*[http://www.lakeviewhealth.com/alcohol-increase-breast-cancer-risk-factors-infographic.php Alcohol and risk of breast cancer infographic]
−
 
+
[[Category:Breast cancer regimens]]
−
[[Category:Chemotherapy regimens]]
+
[[Category:Disease-specific pages]]
−
[[Category:Solid oncology regimens]]
+
[[Category:Malignant breast neoplasm]]

Latest revision as of 19:31, 23 June 2024

Back to Top

Section editor
TBA

Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
Note: this page contains regimens which were not tested in biomarker-selected populations; many of these trials do still include and stratify patients by biomarker status, however. The following links will take you to biomarker-specific subpages:

143 regimens on this page
330 variants on this page


Guidelines

Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.

ASCO/CCO

ESMO/ESO

EUSOMA/SIOG

KSMO/ESMO

NCCN

SITC

St Gallen Breast Guidelines

Neoadjuvant therapy, sequential regimens

AC-D

AC-D: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Docetaxel

Regimen variant #1, 60/600/75

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kim et al. 2020 (NEST) 2012-2014 Phase 3 (C) Goserelin & Tamoxifen Inconclusive whether non-inferior clinical response
Hwang et al. 2023 (Neo-shorter) 2012-11 to 2015-12 Phase 3 (C) FEC-D; 3 x 3 Non-inferior pCR rate (primary endpoint)

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 8)

21-day cycle for 8 cycles (AC x 4; T x 4)

Subsequent treatment


Regimen variant #2, 60/600/100

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bear et al. 2003 (NSABP B-27) 1995-2000 Phase 3 (E-esc) 1. AC Superior pCR rate (secondary endpoint)

Did not meet primary endpoint of clinical response rate
2. AC, then surgery, then T Not reported
von Minckwitz et al. 2005 (GeparDuo) 1999-2001 Phase 3 (E-esc) ddAT Superior pCR rate (primary endpoint)
pCR rate: 14.3% vs 7%
(OR 2.22, 90% CI 1.52-3.24)

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 8)

21-day cycle for 8 cycles (AC x 4; T x 4)

Subsequent treatment

References

  1. NSABP B-27: Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, Wolmark N; National Surgical Adjuvant Breast and Bowel Project. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003 Nov 15;21(22):4165-74. Epub 2003 Oct 14. link to original article contains dosing details in manuscript PubMed NCT00002707
    1. Update: Bear HD, Anderson S, Smith RE, Geyer CE Jr, Mamounas EP, Fisher B, Brown AM, Robidoux A, Margolese R, Kahlenberg MS, Paik S, Soran A, Wickerham DL, Wolmark N. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006 May 1;24(13):2019-27. Epub 2006 Apr 10. link to original article PubMed
    2. Pooled update: Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008 Feb 10;26(5):778-85. Erratum in: J Clin Oncol. 2008 Jun 1;26(16):2793. link to original article PubMed
  2. GeparDuo: von Minckwitz G, Raab G, Caputo A, Schütte M, Hilfrich J, Blohmer JU, Gerber B, Costa SD, Merkle E, Eidtmann H, Lampe D, Jackisch C, du Bois A, Kaufmann M; GBG. Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol. 2005 Apr 20;23(12):2676-85. link to original article contains dosing details in manuscript PubMed NCT00793377
  3. NEST: Kim HJ, Noh WC, Lee ES, Jung YS, Kim LS, Han W, Nam SJ, Gong GY, Kim HJ, Ahn SH. Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in pre-menopausal patients with oestrogen receptor-positive and HER2-negative, lymph node-positive breast cancer. Breast Cancer Res. 2020 May 27;22(1):54. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01622361
  4. Neo-shorter: Hwang I, Kim JE, Jeong JH, Ahn JH, Jung KH, Son BH, Kim HH, Shin J, Lee HJ, Gong G, Kim SB. Randomized phase III trial of a neoadjuvant regimen of four cycles of adriamycin plus cyclophosphamide followed by four cycles of docetaxel (AC4-D4) versus a shorter treatment of three cycles of FEC followed by three cycles of docetaxel (FEC3-D3) in node-positive breast cancer (Neo-shorter; NCT02001506). Breast Cancer Res Treat. 2023 Sep;201(2):193-204. Epub 2023 Jun 26. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02001506

AC-T

AC-T: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ellis et al. 2011 (SWOG 0012) 2001-2005 Phase 3 (C) AC-T; daily cyclophosphamide Did not meet primary endpoint of pCR rate

Chemotherapy, AC portion (cycles 1 to 5)

Chemotherapy, T portion (cycles 6 to 17)

21-day cycle for 5 cycles, then 7-day cycle for 12 cycles (AC x 5; T x 12)

Subsequent treatment

References

  1. SWOG 0012: Ellis GK, Barlow WE, Gralow JR, Hortobagyi GN, Russell CA, Royce ME, Perez EA, Lew D, Livingston RB. Phase III comparison of standard doxorubicin and cyclophosphamide versus weekly doxorubicin and daily oral cyclophosphamide plus granulocyte colony-stimulating factor as neoadjuvant therapy for inflammatory and locally advanced breast cancer: SWOG 0012. J Clin Oncol. 2011 Mar 10;29(8):1014-21. Epub 2011 Jan 10. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00016406

D-AC

D-AC: Docetaxel followed by Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bear et al. 2012 (NSABP B-40) 2007-2010 Phase 3 (C) 1. D-AC+Bev
2. TG-AC+Bev
3. TX-AC+Bev 		Seems to have inferior pCR rate
4. TG-AC
5. TX-AC 		Did not meet primary endpoint of pCR rate

Chemotherapy, D portion (cycles 1 to 4)

Chemotherapy, AC portion (cycles 5 to 8)

21-day cycle for 8 cycles (D x 4; AC x 4)

Subsequent treatment

References

  1. NSABP B-40: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00408408
    1. Update: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Paik S, Swain SM, Mamounas EP, Wolmark N. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1037-1048. Epub 2015 Aug 10. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. link to original article link to PMC article PubMed

D-AC+Bev

D-AC+Bev: Docetaxel followed by Adriamycin (Doxorubicin) & Cyclophosphamide, with Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bear et al. 2012 (NSABP B-40) 2007-2010 Phase 3 (E-esc) 1. D-AC
2. TG-AC
3. TX-AC 		Seems to have superior pCR rate (primary endpoint)
4. TG-AC+Bev
5. TX-AC+Bev 		Did not meet primary endpoint of pCR rate

Chemotherapy, D portion (cycles 1 to 4)

Chemotherapy, AC portion (cycles 5 to 8)

Targeted therapy, both portions

21-day cycle for 8 cycles (D x 4; AC x 4)

Subsequent treatment

References

  1. NSABP B-40: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00408408
    1. Update: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Paik S, Swain SM, Mamounas EP, Wolmark N. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1037-1048. Epub 2015 Aug 10. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. link to original article link to PMC article PubMed

D-FEC

D-FEC: Docetaxel followed by Fluorouracil, Epirubicin, Cyclophosphamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Earl et al. 2015 (ARTemis) 2009-2013 Phase 3 (C) D-FEC+Bev Seems to have inferior pCR rate

Chemotherapy, D portion (cycles 1 to 3)

Chemotherapy, FEC portion (cycles 4 to 6)

21-day cycle for 6 cycles (D x 3; FEC x 3)

Subsequent treatment

References

  1. ARTemis: Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Abraham J, Thomas J, Provenzano E, Hughes-Davies L, Gounaris I, McAdam K, Chan S, Ahmad R, Hickish T, Houston S, Rea D, Bartlett J, Caldas C, Cameron DA, Hayward L; ARTemis Investigators. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):656-66. Epub 2015 May 11. link to original article contains dosing details in manuscript PubMed NCT01093235
    1. Update: Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Gounaris I, Abraham JE, Hughes-Davies L, McAdam K, Chan S, Ahmad R, Hickish T, Rea D, Caldas C, Bartlett JMS, Cameron DA, Provenzano E, Thomas J, Hayward RL; ARTemis Investigators Group. Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin and cyclophosphamide, for women with HER2 negative early breast cancer: ARTemis Trial. Ann Oncol. 2017 Aug 1;28(8):1817-1824. link to original article link to PMC article PubMed

D-FEC+Bev

D-FEC+Bev: Docetaxel followed by Fluorouracil, Epirubicin, Cyclophosphamide, with Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Earl et al. 2015 (ARTemis) 2009-2013 Phase 3 (E-esc) D-FEC Seems to have superior pCR rate (primary endpoint)
pCR rate: 22% vs 17%

Chemotherapy, D portion (cycles 1 to 3)

Chemotherapy, FEC portion (cycles 4 to 6)

Targeted therapy, both portions

21-day cycle for 6 cycles (D x 3; FEC x 3)

Subsequent treatment

References

  1. ARTemis: Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Abraham J, Thomas J, Provenzano E, Hughes-Davies L, Gounaris I, McAdam K, Chan S, Ahmad R, Hickish T, Houston S, Rea D, Bartlett J, Caldas C, Cameron DA, Hayward L; ARTemis Investigators. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):656-66. Epub 2015 May 11. link to original article contains dosing details in manuscript PubMed NCT01093235
    1. Update: Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Gounaris I, Abraham JE, Hughes-Davies L, McAdam K, Chan S, Ahmad R, Hickish T, Rea D, Caldas C, Bartlett JMS, Cameron DA, Provenzano E, Thomas J, Hayward RL; ARTemis Investigators Group. Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin and cyclophosphamide, for women with HER2 negative early breast cancer: ARTemis Trial. Ann Oncol. 2017 Aug 1;28(8):1817-1824. link to original article link to PMC article PubMed

EC-D

EC-D: Epirubicin and Cyclophosphamide followed by Docetaxel

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2010 (GeparQuattro) 2005-NR Phase 3 (C) 1. EC-TX
2. EC-T-X 		Did not meet primary endpoint of pCR rate
von Minckwitz et al. 2012 (GeparQuinto) 2007-2010 Phase 3 (C) EC-D+Bev Seems to have inferior pCR rate (primary endpoint)

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 8)

21-day cycle for 8 cycles (EC x 4; D x 4)

Subsequent treatment

References

  1. GeparQuattro: von Minckwitz G, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, Bauerfeind I, Hilfrich J, Eidtmann H, Gerber B, Hanusch C, Kühn T, du Bois A, Blohmer JU, Thomssen C, Dan Costa S, Jackisch C, Kaufmann M, Mehta K, Untch M. Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. J Clin Oncol. 2010 Apr 20;28(12):2015-23. Epub 2010 Mar 22. link to original article contains dosing details in abstract PubMed NCT00288002
    1. Update: von Minckwitz G, Rezai M, Fasching PA, Huober J, Tesch H, Bauerfeind I, Hilfrich J, Eidtmann H, Gerber B, Hanusch C, Blohmer JU, Dan Costa S, Jackisch C, Paepke S, Schneeweiss A, Kümmel S, Denkert C, Mehta K, Loibl S, Untch M. Survival after adding capecitabine and trastuzumab to neoadjuvant anthracycline-taxane-based chemotherapy for primary breast cancer (GBG 40--GeparQuattro). Ann Oncol. 2014 Jan;25(1):81-9. Epub 2013 Nov 21. link to original article PubMed
  2. GeparQuinto: von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Kreienberg R, Solbach C, Gerber B, Jackisch C, Kunz G, Blohmer JU, Huober J, Hauschild M, Fehm T, Müller BM, Denkert C, Loibl S, Nekljudova V, Untch M; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie–Breast Study Groups. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012 Jan 26;366(4):299-309. link to original article contains dosing details in manuscript PubMed NCT00567554

EC-T

EC-T: Epirubicin and Cyclophosphamide followed by Taxol (Paclitaxel)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Untch et al. 2011 (PREPARE) 2002-2005 Phase 3 (C) ddE-ddT-CMF Did not meet primary endpoint of DFS

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, T portion (cycles 5 to 8)

21-day cycle for 8 cycles (EC x 4; T x 4)

Subsequent treatment

References

  1. PREPARE: Untch M, von Minckwitz G, Konecny GE, Conrad U, Fett W, Kurzeder C, Lück HJ, Stickeler E, Urbaczyk H, Liedtke B, Beckmann MW, Salat C, Harbeck N, Müller V, Schmidt M, Hasmüller S, Lenhard M, Nekljudova V, Lebeau A, Loibl S, Fasching PA; Arbeitsgemeinschaft Gynäkologische Onkologie PREPARE investigators. PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel, and CMF versus a standard-dosed epirubicin-cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer--outcome on prognosis. Ann Oncol. 2011 Sep;22(9):1999-2006. Epub 2011 Mar 7. link to original article contains dosing details in abstract PubMed NCT00544232

EC-ddT

EC-ddT: Epirubicin & Cyclophosphamide, followed by dose-dense Taxol (Paclitaxel)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Earl et al. 2013 (Neo-tAnGo) 2005-2007 Phase 3 (C) 1. ddT-EC Seems to have inferior pCR rate
2. EC-ddTG
3. ddTG-EC 		Did not meet primary endpoint of pCR rate

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, ddT portion (cycles 5 to 8)

Supportive therapy, T portion

  • Primary G-CSF propyhylaxis not provided

21-day cycle for 4 cycles, then 14-day cycle for 4 cycles (EC x 4; ddT x 4)

Subsequent treatment

References

  1. Neo-tAnGo: Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, Iddawela M, Abraham J, Hughes-Davies L, Gounaris I, McAdam K, Houston S, Hickish T, Skene A, Chan S, Dean S, Ritchie D, Laing R, Harries M, Gallagher C, Wishart G, Dunn J, Provenzano E, Caldas C; Neo-tAnGo Investigators. Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2x2 factorial randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):201-12. Epub 2013 Dec 19. link to original article contains dosing details in manuscript PubMed NCT00070278

FEC-D

FEC-D: Fluorouracil, Epirubicin, Cyclophosphamide followed by Docetaxel

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hwang et al. 2023 (Neo-shorter) 2012-11 to 2015-12 Phase 3 (E-de-esc) AC-D; 4 x 4 Non-inferior pCR rate (primary endpoint)

Chemotherapy, FEC portion (cycles 1 to 3)

Chemotherapy, D portion (cycles 4 to 6)

21-day cycle for 6 cycles (FEC x 3; D x 3)

Subsequent treatment

References

  1. Neo-shorter: Hwang I, Kim JE, Jeong JH, Ahn JH, Jung KH, Son BH, Kim HH, Shin J, Lee HJ, Gong G, Kim SB. Randomized phase III trial of a neoadjuvant regimen of four cycles of adriamycin plus cyclophosphamide followed by four cycles of docetaxel (AC4-D4) versus a shorter treatment of three cycles of FEC followed by three cycles of docetaxel (FEC3-D3) in node-positive breast cancer (Neo-shorter; NCT02001506). Breast Cancer Res Treat. 2023 Sep;201(2):193-204. Epub 2023 Jun 26. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02001506

nP-EC

nP-EC: nab-Paclitaxel followed by Epirubicin & Cyclophosphamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Untch et al. 2016 (GeparSepto) 2012-07-30 to 2013-12-23 Phase 3 (E-switch-ic) T-EC Superior pCR rate (primary endpoint)
pCR rate: 38% vs 29%
(OR 1.53, 95% CI 1.20-1.95)

Note: this is the dose after study amendment due to increased treatment discontinuation and sensory neuropathy.

Chemotherapy, nP portion (cycles 1 to 12)

Chemotherapy, EC portion (cycles 13 to 16)

7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (nP x 12; EC x 4)

Subsequent treatment

References

  1. GeparSepto: Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Wiebringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Darb-Esfahani S, Schmitt WD, Dan Costa S, Gerber B, Engels K, Nekljudova V, Loibl S, von Minckwitz G; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie—Breast (AGO-B) Investigators. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):345-56. Epub 2016 Feb 8. link to original article contains dosing details in manuscript PubMed NCT01583426
    1. Update: Furlanetto J, Jackisch C, Untch M, Schneeweiss A, Schmatloch S, Aktas B, Denkert C, Wiebringhaus H, Kümmel S, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Costa SD, Gerber B, Nekljudova V, Loibl S, von Minckwitz G. Efficacy and safety of nab-paclitaxel 125 mg/m(2) and nab-paclitaxel 150 mg/m(2) compared to paclitaxel in early high-risk breast cancer: results from the neoadjuvant randomized GeparSepto study (GBG 69). Breast Cancer Res Treat. 2017 Jun;163(3):495-506. Epub 2017 Mar 17. link to original article PubMed
  2. ETNA: Gianni L, Mansutti M, Anton A, Calvo L, Bisagni G, Bermejo B, Semiglazov V, Thill M, Chacon JI, Chan A, Morales S, Alvarez I, Plazaola A, Zambetti M, Redfern AD, Dittrich C, Dent RA, Magazzù D, De Fato R, Valagussa P, Tusquets I. Comparing neoadjuvant nab-paclitaxel vs paclitaxel both followed by anthracycline regimens in women with ERBB2/HER2-negative breast cancer-the Evaluating Treatment with Neoadjuvant Abraxane (ETNA) trial: a randomized phase 3 clinical trial. JAMA Oncol. 2018 Mar 1;4(3):302-308. Epub 2018 Jan 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01822314

nP-ddEC

nP-ddEC: nab-Paclitaxel followed by dose-dense Epirubicin & Cyclophosphamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gluz et al. 2023 (WSG-ADAPT-HR+/HER2-) 2013-05 to 2019-09 Phase 3 (E-switch-ic) ddT-ddEC Superior pCR rate (primary endpoint)
pCR rate: 20.8% vs 12.9%

Biomarker eligibility criteria

  • HR+ and HER2-

Chemotherapy, nP portion (cycles 1 to 8)

Chemotherapy, ddEC portion (cycles 9 to 12)

Supportive therapy, ddEC portion (cycles 9 to 12)

7-day cycle for 8 cycles, then 14-day cycle for 4 cycles (nP x 8; ddEC x 4)

Subsequent treatment

References

  1. WSG-ADAPT-HR+/HER2-: Gluz O, Kuemmel S, Nitz U, Braun M, Lüdtke-Heckenkamp K, von Schumann R, Darsow M, Forstbauer H, Potenberg J, Uleer C, Grischke EM, Aktas B, Schumacher C, Zu Eulenburg C, Kates R, Jóźwiak K, Graeser M, Wuerstlein R, Baehner R, Christgen M, Kreipe HH, Harbeck N. Nab-paclitaxel weekly versus dose-dense solvent-based paclitaxel followed by dose-dense epirubicin plus cyclophosphamide in high-risk HR+/HER2- early breast cancer: results from the neoadjuvant part of the WSG-ADAPT-HR+/HER2- trial. Ann Oncol. 2023 Jun;34(6):531-542. Epub 2023 Apr 14. link to original article contains dosing details in manuscript PubMed NCT01779206

T-AC

T-AC: Taxol (Paclitaxel), followed by Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gianni et al. 2018 (ETNA) 2013-2015 Phase 3 (C) 1a. nab-Paclitaxel-AC
1b. nP-EC
1c. nP-FEC 		Did not meet primary endpoint of pCR rate

Chemotherapy, T portion (cycles 1 to 4)

Chemotherapy, AC portion (cycles 5 to 8)

28-day cycle for 4 cycles, then 21-day cycle for 4 cycles (T x 4; AC x 4)

Subsequent treatment

References

  1. ETNA: Gianni L, Mansutti M, Anton A, Calvo L, Bisagni G, Bermejo B, Semiglazov V, Thill M, Chacon JI, Chan A, Morales S, Alvarez I, Plazaola A, Zambetti M, Redfern AD, Dittrich C, Dent RA, Magazzù D, De Fato R, Valagussa P, Tusquets I. Comparing neoadjuvant nab-paclitaxel vs paclitaxel both followed by anthracycline regimens in women with ERBB2/HER2-negative breast cancer-the Evaluating Treatment with Neoadjuvant Abraxane (ETNA) trial: a randomized phase 3 clinical trial. JAMA Oncol. 2018 Mar 1;4(3):302-308. Epub 2018 Jan 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01822314

T-EC

T-EC: Taxol (Paclitaxel), followed by Epirubicin & Cyclophosphamide

Regimen variant #1, 80 mg/m2 paclitaxel

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Untch et al. 2016 (GeparSepto) 2012-07-30 to 2013-12-23 Phase 3 (C) nP-EC Inferior pCR rate

Chemotherapy, T portion (cycles 1 to 12)

Chemotherapy, EC portion (cycles 13 to 16)

7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (T x 12; EC x 4)

Subsequent treatment


Regimen variant #2, 90 mg/m2, 3 out of 4 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gianni et al. 2018 (ETNA) 2013-2015 Phase 3 (C) 1a. nP-AC
1b. nP-EC
1c. nP-FEC 		Did not meet primary endpoint of pCR rate

Chemotherapy, T portion (cycles 1 to 4)

Chemotherapy, EC portion (cycles 5 to 8)

28-day cycle for 4 cycles, then 21-day cycle for 4 cycles (T x 4; EC x 4)

Subsequent treatment

References

  1. GeparSepto: Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Wiebringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Darb-Esfahani S, Schmitt WD, Dan Costa S, Gerber B, Engels K, Nekljudova V, Loibl S, von Minckwitz G; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie—Breast (AGO-B) Investigators. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):345-56. Epub 2016 Feb 8. link to original article contains dosing details in manuscript PubMed NCT01583426
    1. Update: Furlanetto J, Jackisch C, Untch M, Schneeweiss A, Schmatloch S, Aktas B, Denkert C, Wiebringhaus H, Kümmel S, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Costa SD, Gerber B, Nekljudova V, Loibl S, von Minckwitz G. Efficacy and safety of nab-paclitaxel 125 mg/m(2) and nab-paclitaxel 150 mg/m(2) compared to paclitaxel in early high-risk breast cancer: results from the neoadjuvant randomized GeparSepto study (GBG 69). Breast Cancer Res Treat. 2017 Jun;163(3):495-506. Epub 2017 Mar 17. link to original article PubMed
  2. ETNA: Gianni L, Mansutti M, Anton A, Calvo L, Bisagni G, Bermejo B, Semiglazov V, Thill M, Chacon JI, Chan A, Morales S, Alvarez I, Plazaola A, Zambetti M, Redfern AD, Dittrich C, Dent RA, Magazzù D, De Fato R, Valagussa P, Tusquets I. Comparing neoadjuvant nab-paclitaxel vs paclitaxel both followed by anthracycline regimens in women with ERBB2/HER2-negative breast cancer-the Evaluating Treatment with Neoadjuvant Abraxane (ETNA) trial: a randomized phase 3 clinical trial. JAMA Oncol. 2018 Mar 1;4(3):302-308. Epub 2018 Jan 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01822314

ddT-EC

ddT-EC: dose-dense Taxol (Paclitaxel), followed by Epirubicin & Cyclophosphamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Earl et al. 2013 (Neo-tAnGo) 2005-2007 Phase 3 (E-switch-ic) 1. EC-ddT Seems to have superior pCR rate (primary endpoint)
2. EC-ddTG
3. ddTG-EC 		Did not meet primary endpoint of pCR rate

Chemotherapy, ddT portion (cycles 1 to 4)

Supportive therapy, T portion

  • Primary G-CSF propyhylaxis not provided

Chemotherapy, EC portion (cycles 5 to 8)

14-day cycle for 4 cycles, then 21-day cycle for 4 cycles (ddT x 4; EC x 4)

Subsequent treatment

References

  1. Neo-tAnGo: Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, Iddawela M, Abraham J, Hughes-Davies L, Gounaris I, McAdam K, Houston S, Hickish T, Skene A, Chan S, Dean S, Ritchie D, Laing R, Harries M, Gallagher C, Wishart G, Dunn J, Provenzano E, Caldas C; Neo-tAnGo Investigators. Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2x2 factorial randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):201-12. Epub 2013 Dec 19. link to original article contains dosing details in manuscript PubMed NCT00070278

ddT-ddEC

ddT-ddEC: dose-dense Taxol (Paclitaxel), followed by dose-dense Epirubicin & Cyclophosphamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gluz et al. 2023 (WSG-ADAPT-HR+/HER2-) 2013-05 to 2019-09 Phase 3 (C) nP-ddEC Inferior pCR rate (primary endpoint)

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Biomarker eligibility criteria

  • HR+ and HER2-

Chemotherapy, ddT portion (cycles 1 to 4)

Chemotherapy, ddEC portion (cycles 5 to 8)

Supportive therapy, ddEC portion (cycles 5 to 8)

14-day cycle for 8 cycles (ddT x 4; ddEC x 4)

Subsequent treatment

References

  1. WSG-ADAPT-HR+/HER2-: Gluz O, Kuemmel S, Nitz U, Braun M, Lüdtke-Heckenkamp K, von Schumann R, Darsow M, Forstbauer H, Potenberg J, Uleer C, Grischke EM, Aktas B, Schumacher C, Zu Eulenburg C, Kates R, Jóźwiak K, Graeser M, Wuerstlein R, Baehner R, Christgen M, Kreipe HH, Harbeck N. Nab-paclitaxel weekly versus dose-dense solvent-based paclitaxel followed by dose-dense epirubicin plus cyclophosphamide in high-risk HR+/HER2- early breast cancer: results from the neoadjuvant part of the WSG-ADAPT-HR+/HER2- trial. Ann Oncol. 2023 Jun;34(6):531-542. Epub 2023 Apr 14. link to original article contains dosing details in manuscript PubMed NCT01779206

T-FAC

T-FAC: Taxol (Paclitaxel), followed by Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide

Regimen variant #1, weekly paclitaxel for N0 disease

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Green et al. 2005 1998-2001 Phase 3 (E-switch-ic) T-FAC; q3wk paclitaxel Seems to have superior pCR rate (primary endpoint)

Chemotherapy, T portion (cycles 1 to 12)

Chemotherapy, FAC portion (cycles 13 to 16)

7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (T x 12; FAC x 4)

Subsequent treatment


Regimen variant #2, weekly paclitaxel for N+ disease

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Green et al. 2005 1998-2001 Phase 3 (E-switch-ic) T-FAC; q3wk paclitaxel Seems to have superior pCR rate (primary endpoint)

Chemotherapy, T portion (cycles 1 to 4)

Chemotherapy, FAC portion (cycles 5 to 8)

28-day cycle for 4 cycles, then 21-day cycle for 4 cycles (T x 4; FAC x 4)

Subsequent treatment


Regimen variant #3, q3wk paclitaxel

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Green et al. 2005 1998-2001 Phase 3 (C) T-FAC; weekly paclitaxel Seems to have inferior pCR rate

Chemotherapy, T portion (cycles 1 to 4)

Chemotherapy, FAC portion (cycles 5 to 8)

21-day cycle for 8 cycles (T x 4; FAC x 4)

Subsequent treatment

References

  1. Green MC, Buzdar AU, Smith T, Ibrahim NK, Valero V, Rosales MF, Cristofanilli M, Booser DJ, Pusztai L, Rivera E, Theriault RL, Carter C, Frye D, Hunt KK, Symmans WF, Strom EA, Sahin AA, Sikov W, Hortobagyi GN. Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol. 2005 Sep 1;23(25):5983-92. Epub 2005 Aug 8. link to original article contains dosing details in manuscript PubMed

T-FEC

T-FEC: Taxol (Paclitaxel), followed by Epirubicin & Cyclophosphamide

Regimen variant #1, 80/500/100/500

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kelly et al. 2012 (MDACC ID01-580) 2002-2008 Phase 3 (C) TX-FEC Did not meet primary endpoint of RFS

Chemotherapy, T portion (cycles 1 to 12)

Chemotherapy, FEC portion (cycles 13 to 16)

7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (T x 12; FEC x 4)

Subsequent treatment


Regimen variant #2, 90/600/90/600

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gianni et al. 2018 (ETNA) 2013-2015 Phase 3 (C) 1a. nP-AC
1b. nP-EC
1c. nP-FEC 		Did not meet primary endpoint of pCR rate

Chemotherapy, T portion (cycles 1 to 4)

Chemotherapy, FEC portion (cycles 5 to 8)

28-day cycle for 4 cycles, then 21-day cycle for 4 cycles (T x 4; FEC x 4)

Subsequent treatment

References

  1. MDACC ID01-580: Kelly CM, Green MC, Broglio K, Thomas ES, Brewster AM, Valero V, Ibrahim NK, Gonzalez-Angulo AM, Booser DJ, Walters RS, Hunt KK, Hortobagyi GN, Buzdar AU. Phase III trial evaluating weekly paclitaxel versus docetaxel in combination with capecitabine in operable breast cancer. J Clin Oncol. 2012 Mar 20;30(9):930-5. Epub 2012 Feb 13. link to original article contains dosing details in manuscript PubMed NCT00050167
  2. ETNA: Gianni L, Mansutti M, Anton A, Calvo L, Bisagni G, Bermejo B, Semiglazov V, Thill M, Chacon JI, Chan A, Morales S, Alvarez I, Plazaola A, Zambetti M, Redfern AD, Dittrich C, Dent RA, Magazzù D, De Fato R, Valagussa P, Tusquets I. Comparing neoadjuvant nab-paclitaxel vs paclitaxel both followed by anthracycline regimens in women with ERBB2/HER2-negative breast cancer-the Evaluating Treatment with Neoadjuvant Abraxane (ETNA) trial: a randomized phase 3 clinical trial. JAMA Oncol. 2018 Mar 1;4(3):302-308. Epub 2018 Jan 11. link to original article contains dosing details in manuscript link to PMC article PubMed NCT01822314

Neoadjuvant chemotherapy

Capecitabine & Docetaxel (TX)

TX: Taxotere (Docetaxel) & Xeloda (Capecitabine)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lee et al. 2007 2002-2005 Phase 3 (E-switch-ic) AC Seems to have superior pCR rate (primary endpoint)

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. Lee KS, Ro J, Nam BH, Lee ES, Kwon Y, Kwon HS, Chung KW, Kang HS, Kim EA, Kim SW, Shin KH, Kim SK. A randomized phase-III trial of docetaxel/capecitabine versus doxorubicin/cyclophosphamide as primary chemotherapy for patients with stage II/III breast cancer. Breast Cancer Res Treat. 2008 Jun;109(3):481-9. Epub 2007 Jul 26. link to original article contains dosing details in manuscript PubMed

Cyclophosphamide & Doxorubicin (AC)

AC: Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen variant #1, 4 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fisher et al. 1997 (NSABP B-18) 1988-1993 Phase 3 (E-switch-ic) Adjuvant AC Superior resectability
Bear et al. 2003 (NSABP B-27) 1995-2000 Phase 3 (C) 1. AC-D Inferior pCR rate
2. AC, then surgery, then T Not reported
Lee et al. 2007 2002-2005 Phase 3 (C) TX Seems to have inferior pCR rate

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #2, 6 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Smith et al. 2004 (TOPIC) 1995-1999 Phase 3 (C) ECisF Did not meet co-primary endpoints of RFS/OS
Chua et al. 2005 (TOPIC 2) 1998-2002 Phase 3 (C) VE Did not meet primary endpoint of RFS
Evans et al. 2005 1999-2001 Phase 3 (C) AD Did not meet primary endpoint of ORR

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment

References

  1. NSABP B-18: Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB Jr, Fisher ER, Wickerham DL, Wolmark N, DeCillis A, Hoehn JL, Lees AW, Dimitrov NV. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997 Jul;15(7):2483-93. link to original article contains dosing details in manuscript PubMed
    1. Update: Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, Wickerham DL, Begovic M, DeCillis A, Robidoux A, Margolese RG, Cruz AB Jr, Hoehn JL, Lees AW, Dimitrov NV, Bear HD. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998 Aug;16(8):2672-85. link to original article PubMed
    2. Update: Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst. 2001;(30):96-102. link to original article PubMed
    3. Pooled update: Taghian A, Jeong JH, Mamounas E, Anderson S, Bryant J, Deutsch M, Wolmark N. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol. 2004 Nov 1;22(21):4247-54. Epub 2004 Sep 27. link to original article PubMed
    4. Pooled update: Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008 Feb 10;26(5):778-85. Erratum in: J Clin Oncol. 2008 Jun 1;26(16):2793. link to original article PubMed
  2. NSABP B-27: Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, Wolmark N; National Surgical Adjuvant Breast and Bowel Project. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003 Nov 15;21(22):4165-74. Epub 2003 Oct 14. link to original article contains dosing details in manuscript PubMed NCT00002707
    1. Update: Bear HD, Anderson S, Smith RE, Geyer CE Jr, Mamounas EP, Fisher B, Brown AM, Robidoux A, Margolese R, Kahlenberg MS, Paik S, Soran A, Wickerham DL, Wolmark N. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006 May 1;24(13):2019-27. Epub 2006 Apr 10. link to original article PubMed
    2. Pooled update: Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008 Feb 10;26(5):778-85. Erratum in: J Clin Oncol. 2008 Jun 1;26(16):2793. link to original article PubMed
  3. TOPIC: Smith IE, A'Hern RP, Coombes GA, Howell A, Ebbs SR, Hickish TF, O'Brien ME, Mansi JL, Wilson CB, Robinson AC, Murray PA, Price CG, Perren TJ, Laing RW, Bliss JM; TOPIC Trial Group. A novel continuous infusional 5-fluorouracil-based chemotherapy regimen compared with conventional chemotherapy in the neo-adjuvant treatment of early breast cancer: 5 year results of the TOPIC trial. Ann Oncol. 2004 May;15(5):751-8. link to original article contains dosing details in abstract PubMed
  4. Evans TR, Yellowlees A, Foster E, Earl H, Cameron DA, Hutcheon AW, Coleman RE, Perren T, Gallagher CJ, Quigley M, Crown J, Jones AL, Highley M, Leonard RC, Mansi JL; Anglo-Celtic Cooperative Oncology Group. Phase III randomized trial of doxorubicin and docetaxel versus doxorubicin and cyclophosphamide as primary medical therapy in women with breast cancer: an Anglo-Celtic Cooperative Oncology Group study. J Clin Oncol. 2005 May 1;23(13):2988-95. link to original article contains dosing details in manuscript PubMed
    1. Update: Mansi JL, Yellowlees A, Lipscombe J, Earl HM, Cameron DA, Coleman RE, Perren T, Gallagher CJ, Quigley M, Crown J, Jones AL, Highley M, Leonard RC, Evans TR. Five-year outcome for women randomised in a phase III trial comparing doxorubicin and cyclophosphamide with doxorubicin and docetaxel as primary medical therapy in early breast cancer: an Anglo-Celtic Cooperative Oncology Group study. Breast Cancer Res Treat. 2010 Aug;122(3):787-94. Epub 2010 Jun 18. link to original article PubMed
  5. TOPIC 2: Chua S, Smith IE, A'Hern RP, Coombes GA, Hickish TF, Robinson AC, Laing RW, O'Brien ME, Ebbs SR, Hong A, Wardley A, Mughal T, Verrill M, Dubois D, Bliss JM; TOPIC Trial Group. Neoadjuvant vinorelbine/epirubicin (VE) versus standard adriamycin/cyclophosphamide (AC) in operable breast cancer: analysis of response and tolerability in a randomised phase III trial (TOPIC 2). Ann Oncol. 2005 Sep;16(9):1435-41. Epub 2005 Jun 9. link to original article contains dosing details in manuscript PubMed
  6. Lee KS, Ro J, Nam BH, Lee ES, Kwon Y, Kwon HS, Chung KW, Kang HS, Kim EA, Kim SW, Shin KH, Kim SK. A randomized phase-III trial of docetaxel/capecitabine versus doxorubicin/cyclophosphamide as primary chemotherapy for patients with stage II/III breast cancer. Breast Cancer Res Treat. 2008 Jun;109(3):481-9. Epub 2007 Jul 26. link to original article contains dosing details in abstract PubMed

Dose-dense Cyclophosphamide & Doxorubicin (ddAC)

ddAC: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide

Regimen

Study Dates of enrollment Evidence
Burstein et al. 2005 2003-2004 Non-randomized

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

Supportive therapy

14-day cycle for 4 cycles

Subsequent treatment

References

  1. Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. link to original article contains dosing details in manuscript PubMed

Dose-dense Docetaxel & Doxorubicin (ddAT)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2005 (GeparDuo) 1999-2001 Phase 3 (C) AC-D Inferior pCR rate

Chemotherapy

Supportive therapy

14-day cycle for 4 cycles

References

  1. GeparDuo: von Minckwitz G, Raab G, Caputo A, Schütte M, Hilfrich J, Blohmer JU, Gerber B, Costa SD, Merkle E, Eidtmann H, Lampe D, Jackisch C, du Bois A, Kaufmann M; GBG. Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol. 2005 Apr 20;23(12):2676-85. link to original article contains dosing details in manuscript PubMed NCT00793377

DI EC

DI EC: Dose-Intense Epirubicin & Cyclophosphamide

Regimen

Study Dates of enrollment Evidence
Gonçalves et al. 2015 (UNICANCER PEGASE 07) 2001-2005 Non-randomized part of phase 3 RCT

Note: This regimen required hematopoeitic stem cell support; see paper for details.

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

  1. UNICANCER PEGASE 07: Gonçalves A, Pierga JY, Ferrero JM, Mouret-Reynier MA, Bachelot T, Delva R, Fabbro M, Lerebours F, Lotz JP, Linassier C, Dohollou N, Eymard JC, Leduc B, Lemonnier J, Martin AL, Boher JM, Viens P, Roché H. UNICANCER-PEGASE 07 study: a randomized phase III trial evaluating postoperative docetaxel-5FU regimen after neoadjuvant dose-intense chemotherapy for treatment of inflammatory breast cancer. Ann Oncol. 2015 Aug;26(8):1692-7. Epub 2015 May 5. link to original article contains dosing details in abstract PubMed NCT02324088

Docetaxel & Epirubicin (DE)

DE: Docetaxel & Epirubicin
ED: Epirubicin & Docetaxel
ET: Epirubicin & Taxotere (Docetaxel)

Regimen variant #1, 3 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Steger et al. 2007 (ABCSG-14) 1999-2002 Phase 3 (C) ED x 6 Inferior pCR rate
Chen et al. 2017 (CBCRT01) 2011-2015 Phase 3 (C) DEE Inferior ORR

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment


Regimen variant #2, 4 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Han et al. 2009 2003-2005 Phase 3 (C) ED x 6 Seems to have inferior pCR rate

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #3, 6 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Steger et al. 2007 (ABCSG-14) 1999-2002 Phase 3 (E-esc) ED x 3 Superior pCR rate (primary endpoint)
Han et al. 2009 2003-2005 Phase 3 (E-esc) ED x 4 Seems to have superior pCR rate (secondary endpoint)
Steger et al. 2013 (ABCSG-24) 2004-2008 Phase 3 (C) EDC Seems to have inferior pCR rate

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment

References

  1. ABCSG-14: Steger GG, Galid A, Gnant M, Mlineritsch B, Lang A, Tausch C, Rudas M, Greil R, Wenzel C, Singer CF, Haid A, Pöstlberger S, Samonigg H, Luschin-Ebengreuth G, Kwasny W, Klug E, Kubista E, Menzel C, Jakesz R; ABCSG. Pathologic complete response with six compared with three cycles of neoadjuvant epirubicin plus docetaxel and granulocyte colony-stimulating factor in operable breast cancer: results of ABCSG-14. J Clin Oncol. 2007 May 20;25(15):2012-8. link to original article contains dosing details in abstract PubMed
  2. Han S, Kim J, Lee J, Chang E, Gwak G, Cho H, Yang KH, Park S, Park K. Comparison of 6 cycles versus 4 cycles of neoadjuvant epirubicin plus docetaxel chemotherapy in stages II and III breast cancer. Eur J Surg Oncol. 2009 Jun;35(6):583-7. Epub 2009 Feb 5. link to original article contains dosing details in abstract PubMed
  3. ABCSG-24: Steger GG, Greil R, Lang A, Rudas M, Fitzal F, Mlineritsch B, Hartmann BL, Bartsch R, Melbinger E, Hubalek M, Stoeger H, Dubsky P, Ressler S, Petzer AL, Singer CF, Muss C, Jakesz R, Gampenrieder SP, Zielinski CC, Fesl C, Gnant M; ABCSG. Epirubicin and docetaxel with or without capecitabine as neoadjuvant treatment for early breast cancer: final results of a randomized phase III study (ABCSG-24). Ann Oncol. 2014 Feb;25(2):366-71. Epub 2013 Dec 16. link to original article contains dosing details in abstract PubMed NCT00309556
  4. CBCRT01: Chen J, Yao Q, Huang M, Wang B, Zhang J, Wang T, Ming Y, Zhou X, Jia Q, Huan Y, Wang J, Wang L. A randomized Phase III trial of neoadjuvant recombinant human endostatin, docetaxel and epirubicin as first-line therapy for patients with breast cancer (CBCRT01). Int J Cancer. 2018 May 15;142(10):2130-2138. Epub 2017 Dec 23. link to original article contains dosing details in manuscript PubMed NCT01479036

EDC

EDC: Epirubicin, Docetaxel, Capecitabine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Steger et al. 2013 (ABCSG-24) 2004-2008 Phase 3 (E-esc) ED Seems to have superior pCR rate (primary endpoint)

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment

References

  1. ABCSG-24: Steger GG, Greil R, Lang A, Rudas M, Fitzal F, Mlineritsch B, Hartmann BL, Bartsch R, Melbinger E, Hubalek M, Stoeger H, Dubsky P, Ressler S, Petzer AL, Singer CF, Muss C, Jakesz R, Gampenrieder SP, Zielinski CC, Fesl C, Gnant M; ABCSG. Epirubicin and docetaxel with or without capecitabine as neoadjuvant treatment for early breast cancer: final results of a randomized phase III study (ABCSG-24). Ann Oncol. 2014 Feb;25(2):366-71. Epub 2013 Dec 16. link to original article contains dosing details in abstract PubMed NCT00309556

Epirubicin monotherapy

E: Epirubicin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bottini et al. 2005 1997-2002 Phase 3 (C) Epirubicin & Tamoxifen Did not meet primary endpoint of clinical RR

Chemotherapy

21-day cycle for 3 to 4 cycles

Subsequent treatment

References

  1. Bottini A, Berruti A, Brizzi MP, Bersiga A, Generali D, Allevi G, Aguggini S, Bolsi G, Bonardi S, Tondelli B, Vana F, Tampellini M, Alquati P, Dogliotti L. Cytotoxic and antiproliferative activity of the single agent epirubicin versus epirubicin plus tamoxifen as primary chemotherapy in human breast cancer: a single-institution phase III trial. Endocr Relat Cancer. 2005 Jun;12(2):383-92. link to original article contains dosing details in manuscript PubMed

Epirubicin & Paclitaxel (EP)

EP: Epirubicin & Paclitaxel
ET: Epirubicin & Taxol (Paclitaxel)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Untch et al. 2009 (TECHNO) 1998-2002 Phase 3 (C) ddE-P Seems to have inferior OS
Frasci et al. 2006 1999-2004 Phase 3 (C) PET Seems to have inferior pCR rate

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

  • Frasci et al. 2006: Surgery, then adjuvant CMF x 4 or FEC x 4, depending on number of involved lymph nodes
  • TECHNO: Surgery, then adjuvant CMF x 3

References

  1. Frasci G, D'Aiuto G, Comella P, Thomas R, Botti G, Di Bonito M, De Rosa V, Iodice G, Rubulotta MR, Comella G; Southern Italy Cooperative Oncology Group. Weekly cisplatin, epirubicin, and paclitaxel with granulocyte colony-stimulating factor support vs triweekly epirubicin and paclitaxel in locally advanced breast cancer: final analysis of a SICOG phase III study. Br J Cancer. 2006 Oct 23;95(8):1005-12. link to original article contains dosing details in abstract link to PMC article PubMed
  2. TECHNO: Untch M, Möbus V, Kuhn W, Muck BR, Thomssen C, Bauerfeind I, Harbeck N, Werner C, Lebeau A, Schneeweiss A, Kahlert S, von Koch F, Petry KU, Wallwiener D, Kreienberg R, Albert US, Lück HJ, Hinke A, Jänicke F, Konecny GE. Intensive dose-dense compared with conventionally scheduled preoperative chemotherapy for high-risk primary breast cancer. J Clin Oncol. 2009 Jun 20;27(18):2938-45. Epub 2009 Apr 13. link to original article contains dosing details in manuscript PubMed

FAC

FAC: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide

Regimen variant #1, 500/50/500

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Arun et al. 2011 (MDACC 91-0156) 1992-1997 Phase 3 (C) DI FAC Did not meet primary endpoint of pCR rate

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #2, 600/50/600

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Baldini et al. 1997 NR in abstract Phase 3 (C) DES-CAF Did not meet primary endpoint of pCR rate

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment


Regimen variant #3, 1000/50/500

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Buzdar et al. 1999 1994-1998 Phase 3 (C) Paclitaxel; q3wk x 4 Did not meet primary endpoint of DFS

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #4, 2000/50/100

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Scholl et al. 1994 (S6) 1986-1990 Phase 3 (E-switch-ic) Adjuvant FAC Seems to have superior OS

Chemotherapy

28-day cycle for 4 cycles

Subsequent treatment

References

  1. S6: Scholl SM, Fourquet A, Asselain B, Pierga JY, Vilcoq JR, Durand JC, Dorval T, Palangié T, Jouve M, Beuzeboc P, Garcio-Giralt E, Salmon RJ, de la Rochefordiere A, Campana F, Pouillart P. Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: preliminary results of a randomised trial: S6. Eur J Cancer. 1994;30A(5):645-52. link to original article contains dosing details in manuscript PubMed
  2. Baldini E, Gardin G, Giannessi P, Brema F, Camorriano A, Carnino F, Naso C, Pastorino G, Pronzato P, Rosso R, Rubagotti A, Torretta G, Conte PF; North-West Oncology Group. A randomized trial of chemotherapy with or without estrogenic recruitment in locally advanced breast cancer. Tumori. 1997 Sep-Oct;83(5):829-33. link to original article contains dosing details in abstract PubMed
  3. Buzdar AU, Singletary SE, Theriault RL, Booser DJ, Valero V, Ibrahim N, Smith TL, Asmar L, Frye D, Manuel N, Kau SW, McNeese M, Strom E, Hunt K, Ames F, Hortobagyi GN. Prospective evaluation of paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer. J Clin Oncol. 1999 Nov;17(11):3412-7. link to original article contains dosing details in manuscript PubMed
  4. MDACC 91-0156: Arun BK, Dhinghra K, Valero V, Kau SW, Broglio K, Booser D, Guerra L, Yin G, Walters R, Sahin A, Ibrahim N, Buzdar AU, Frye D, Sneige N, Strom E, Ross M, Theriault RL, Vadhan-Raj S, Hortobagyi GN. Phase III randomized trial of dose intensive neoadjuvant chemotherapy with or without G-CSF in locally advanced breast cancer: long-term results. Oncologist. 2011;16(11):1527-34. Epub 2011 Oct 31. link to original article contains dosing details in abstract link to PMC article PubMed

FEC

FEC: Fluorouracil, Epirubicin, Cyclophosphamide

Regimen variant #1, 600/60/600 x 3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Baldini et al. 2003 1992-1997 Phase 3 (C) ddFEC Did not meet primary endpoint of pCR rate

Note: This was a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment


Regimen variant #2, 600/60/600 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
van der Hage et al. 2001 (EORTC 10902) 1991-1999 Phase 3 (E-switch-ic) FEC; adjuvant Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #3, 1000/120/1050 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Therasse et al. 2003 (EORTC 10921) 1993-1996 Phase 3 (C) ddEC Did not meet primary endpoint of PFS

Chemotherapy

28-day cycle for 6 cycles

Subsequent treatment

References

  1. EORTC 10902: van der Hage JA, van de Velde CJ, Julien JP, Tubiana-Hulin M, Vandervelden C, Duchateau L. Preoperative chemotherapy in primary operable breast cancer: results from the European Organisation for Research and Treatment of Cancer trial 10902. J Clin Oncol. 2001 Nov 15;19(22):4224-37. link to original article contains dosing details in manuscript PubMed
    1. Update: van Nes JG, Putter H, Julien JP, Tubiana-Hulin M, van de Vijver M, Bogaerts J, de Vos M, van de Velde CJ; Cooperating Investigators of the EORTC. Preoperative chemotherapy is safe in early breast cancer, even after 10 years of follow-up; clinical and translational results from the EORTC trial 10902. Breast Cancer Res Treat. 2009 May;115(1):101-13. Epub 2008 May 18. link to original article PubMed
  2. Baldini E, Gardin G, Giannessi PG, Evangelista G, Roncella M, Prochilo T, Collecchi P, Rosso R, Lionetto R, Bruzzi P, Mosca F, Conte PF. Accelerated versus standard cyclophosphamide, epirubicin and 5-fluorouracil or cyclophosphamide, methotrexate and 5-fluorouracil: a randomized phase III trial in locally advanced breast cancer. Ann Oncol. 2003 Feb;14(2):227-32. link to original article contains dosing details in manuscript PubMed
  3. EORTC 10921: Therasse P, Mauriac L, Welnicka-Jaskiewicz M, Bruning P, Cufer T, Bonnefoi H, Tomiak E, Pritchard KI, Hamilton A, Piccart MJ; EORTC. Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study. J Clin Oncol. 2003 Mar 1;21(5):843-50. link to original article contains dosing details in abstract PubMed

iddEPC

iddEPC: intense dose-dense Epirubicin, Paclitaxel, Cyclophosphamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Schneeweiss et al. 2018 (GeparOcto) 2014-12 to 2016-06 Phase 3 (C) NPLD & Paclitaxel Did not meet primary endpoint of pCR rate

Note: G-CSF details are from the adjuvant trial; see paper for exact details.

Chemotherapy, iddE portion (cycles 1 to 3)

Chemotherapy, iddP portion (cycles 4 to 6)

Chemotherapy, iddC portion (cycles 7 to 9)

Supportive therapy, all portions (cycles 1 to 9)

14-day cycle for 9 cycles (iddE x 3; iddP x 3; iddC x 3)

Subsequent treatment

References

  1. GeparOcto: Schneeweiss A, Möbus V, Tesch H, Hanusch C, Denkert C, Lübbe K, Huober J, Klare P, Kümmel S, Untch M, Kast K, Jackisch C, Thomalla J, Ingold-Heppner B, Blohmer JU, Rezai M, Frank M, Engels K, Rhiem K, Fasching PA, Nekljudova V, von Minckwitz G, Loibl S. Intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for neoadjuvant treatment of high-risk early breast cancer (GeparOcto-GBG 84): A randomised phase III trial. Eur J Cancer. 2019 Jan;106:181-192. Epub 2018 Dec 5. link to original article contains dosing details in abstract PubMed NCT02125344
    1. Update: Schneeweiss A, Michel LL, Möbus V, Tesch H, Klare P, Hahnen E, Denkert C, Kast K, Pohl-Rescigno E, Hanusch C, Link T, Untch M, Jackisch C, Blohmer JU, Fasching PA, Solbach C, Schmutzler RK, Huober J, Rhiem K, Nekljudova V, Lübbe K, Loibl S; GBG and AGO-B. Survival analysis of the randomised phase III GeparOcto trial comparing neoadjuvant chemotherapy of intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for patients with high-risk early breast cancer. Eur J Cancer. 2022 Jan;160:100-111. Epub 2021 Nov 17. link to original article PubMed

Paclitaxel monotherapy, dose-dense (q2wk)

ddT: dose-dense Taxol (Paclitaxel)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Burstein et al. 2005 2003-2004 Non-randomized

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

  • Neoadjuvant ddAC x 4

Chemotherapy

Supportive therapy

14-day cycle for 4 cycles

Subsequent treatment

References

  1. Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. link to original article contains dosing details in manuscript PubMed

PET

PET: Platinol (Cisplatin), Epirubicin, Taxol (Paclitaxel)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Frasci et al. 2006 1999-2004 Phase 3 (E-esc) EP Seems to have superior pCR rate (primary endpoint)

Chemotherapy

7-day cycle for 12 cycles

Subsequent treatment

References

  1. Frasci G, D'Aiuto G, Comella P, Thomas R, Botti G, Di Bonito M, De Rosa V, Iodice G, Rubulotta MR, Comella G; Southern Italy Cooperative Oncology Group. Weekly cisplatin, epirubicin, and paclitaxel with granulocyte colony-stimulating factor support vs triweekly epirubicin and paclitaxel in locally advanced breast cancer: final analysis of a SICOG phase III study. Br J Cancer. 2006 Oct 23;95(8):1005-12. link to original article contains dosing details in abstract link to PMC article PubMed

TAC (Docetaxel)

TAC: Taxotere (Docetaxel), Adriamycin (Doxorubicin), Cyclophosphamide
ATC: Adriamycin (Doxorubicin), Taxotere (Docetaxel), Cyclophosphamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2008 (GeparTrio) 2002-2005 Phase 3 (E-switch-ic) TAC x 2, then NX x 4 Non-inferior sonographic response (primary endpoint)
Vriens et al. 2013 (INTENS) 2006-2009 Phase 3 (E-switch-ic) AC-D Did not meet primary endpoint of pCR rate

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment

References

  1. GeparTrio: von Minckwitz G, Kümmel S, Vogel P, Hanusch C, Eidtmann H, Hilfrich J, Gerber B, Huober J, Costa SD, Jackisch C, Loibl S, Mehta K, Kaufmann M; GBG. Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial. J Natl Cancer Inst. 2008 Apr 16;100(8):542-51. Epub 2008 Apr 8. link to original article contains dosing details in manuscript PubMed NCT00544765
    1. Update: von Minckwitz G, Kümmel S, Vogel P, Hanusch C, Eidtmann H, Hilfrich J, Gerber B, Huober J, Costa SD, Jackisch C, Loibl S, Mehta K, Kaufmann M; German Breast Group. Intensified neoadjuvant chemotherapy in early-responding breast cancer: phase III randomized GeparTrio study. J Natl Cancer Inst. 2008 Apr 16;100(8):552-62. Epub 2008 Apr 8. link to original article PubMed
  2. INTENS: Vriens BE, Aarts MJ, de Vries B, van Gastel SM, Wals J, Smilde TJ, van Warmerdam LJ, de Boer M, van Spronsen DJ, Borm GF, Tjan-Heijnen VC; BOOG. Doxorubicin/cyclophosphamide with concurrent versus sequential docetaxel as neoadjuvant treatment in patients with breast cancer. Eur J Cancer. 2013 Oct;49(15):3102-10. Epub 2013 Jul 10. link to original article contains dosing details in abstract PubMed NCT00314977
    1. Update: Vriens BEPJ, Vriens IJH, Aarts MJB, van Gastel SM, van den Berkmortel FWPJ, Smilde TJ, van Warmerdam LJC, van Spronsen DJ, Peer PGM, de Boer M, Tjan-Heijnen VCG; BOOG. Improved survival for sequentially as opposed to concurrently delivered neoadjuvant chemotherapy in non-metastatic breast cancer. Breast Cancer Res Treat. 2017 Oct;165(3):593-600. Epub 2017 Jul 3. link to original article link to PMC article PubMed

Neoadjuvant response criteria

Clinical response rate (cRR)

Although fairly dated, some trials such as ACOSOG Z1031 make use of the WHO criteria for response to neoadjuvant therapy. Included here primarily for historical purposes.

References

  1. Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer. 1981 Jan 1;47(1):207-14. link to original article PubMed

Miller-Payne scoring system

  • Grade 1: No change or some changes to individual malignant cells, but no reduction in overall cellularity
  • Grade 2: Minor loss of tumor cells (up to 30%), but overall cellularity still high
  • Grade 3: An estimated 30 to 90% reduction in the number of tumor cells
  • Grade 4: Marked disappearance of tumor cells such that only small clusters or widely dispersed individual cells remain (loss of greater than 90% of tumor cells)
  • Grade 5: No invasive cancer cells identifiable in sections from the site of the tumor (carcinoma in situ may be present)

References

  1. Ogston KN, Miller ID, Payne S, Hutcheon AW, Sarkar TK, Smith I, Schofield A, Heys SD. A new histological grading system to assess response of breast cancers to primary chemotherapy: prognostic significance and survival. Breast. 2003 Oct;12(5):320-7. link to original article PubMed

Residual cancer burden (RCB)

  • The RCB is calculated as follows: RCB = 1.4 (finv*dprim)0.17 + [4(1 - 0.75LN)dmet]0.17
    • where dprim is derived from the bidimensional diameters of the primary tumor bed in the resected specimen, finv is the proportion of the primary tumor bed that contains invasive carcinoma, LN is the number of axillary lymph nodes containing metastatic carcinoma, and dmet is the diameter of the largest metastasis in an axillary lymph node.
    • The cut-off points are 1.36 and 3.28.

References

  1. Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, Pusztai L. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol. 2007 Oct 1;25(28):4414-22. Epub 2007 Sep 4. link to original article PubMed

Residual disease in breast and nodes (RDBN)

  • Level 1: pCR in breast and nodes with or without in situ carcinoma
  • Levels 2 to 4: Residual disease, calculated as 0.2 (residual breast tumor size in cm) + index of involved nodes (0 for no positive nodes, 1 for 1 to 4 positive nodes, 2 for 5 to 7 positive nodes, and 3 for 8 positive nodes) + the Scarff–Bloom–Richardson grade (1, 2, or 3). The cut-off points are 3 and 4.3.

References

  1. Chollet P, Abrial C, Durando X, Thivat E, Tacca O, Mouret-Reynier MA, Leheurteur M, Kwiatkowski F, Dauplat J, Penault-Llorca F. A new prognostic classification after primary chemotherapy for breast cancer: residual disease in breast and nodes (RDBN). Cancer J. 2008 Mar-Apr;14(2):128-32. link to original article PubMed

Sataloff's classification

  • Breast:
    • T-A: Total or nearly total therapeutic effect
    • T-B: Greater than 50% therapeutic effect
    • T-C: Less than 50% therapeutic effect
    • T-D: No therapeutic effect
  • Lymph node:
    • N-A: Therapeutic effect but no metastasis
    • N-B: No metastasis, no therapeutic effect
    • N-C: Therapeutic effect but metastasis
    • N-D: Metastasis, no therapeutic effect

References

  1. Sataloff DM, Mason BA, Prestipino AJ, Seinige UL, Lieber CP, Baloch Z. Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome. J Am Coll Surg. 1995 Mar;180(3):297-306. PubMed

Tumor response ratio

Calculated as follows: Residual breast disease observed upon pathologic examination divided by the size of the tumor on the pre-neoadjuvant therapy image.

  • TRR = 0: pathologic complete response (pCR)
  • TRR greater than 0 up to 0.4: strong partial response
  • TRR greater than 0.4 up to 1.0: weak partial response (WPR)
  • TRR greater than 1.0: tumor growth

References

  1. Miller M, Ottesen RA, Niland JC, Kruper L, Chen SL, Vito C. Tumor response ratio predicts overall survival in breast cancer patients treated with neoadjuvant chemotherapy. Ann Surg Oncol. 2014 Oct;21(10):3317-23. Epub 2014 Jul 25. link to original article PubMed

ypTNM staging

This system is proprietary to the AJCC. Please visit their site or consult the AJCC Manual for further details.

Adjuvant therapy, sequential regimens

A-CMF

A-CMF: Adriamycin (Doxorubicin) followed by Cyclophosphamide, Methotrexate, Fluorouracil

Regimen variant #1, 75 x 4 --> 600/40/600 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gianni et al. 2009 (ECTO) 1996-2002 Phase 3 (C) 1. AT-CMF; adjuvant Seems to have inferior RFS
2. AT-CMF; neoadjuvant Not directly compared
Fernando et al. 2019 (SECRAB) 1998-2004 Phase 3 (C) 1a. CMF & RT
1b. E-CMF & RT
1c. A-CMF & RT
1d. MMM & RT 		Inferior LRFS

Preceding treatment

Chemotherapy, A portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 8)

21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (A x 4; CMF x 4)


Regimen variant #2, 75 x 4 --> 600/40/600 x 8

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Buzzoni et al. 1991 (Milan trial) 1982-1987 Phase 3 (E-switch-ic) A/CMF x 12 Superior OS

Preceding treatment

Chemotherapy, A portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 12)

21-day cycle for 12 cycles (A x 4; CMF x 8)


Regimen variant #3, 75 x 4 --> 600/50/600 x 8

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Leonard et al. 2004 1995-1999 Phase 3 (C) Cyclophosphamide & Thiotepa with auto HSCT Did not meet primary endpoint of RFS

Preceding treatment

Chemotherapy, A portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 12)

21-day cycle for 4 cycles, then 28-day cycle for 8 cycles (A x 4; CMF x 8)


Regimen variant #4, 75 x 4 --> 1400/80/1200 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fernando et al. 2019 (SECRAB) 1998-2004 Phase 3 (C) 1a. CMF & RT
1b. E-CMF & RT
1c. A-CMF & RT
1d. MMM & RT 		Inferior LRFS

Preceding treatment

Chemotherapy, A portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 8)

21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (A x 4; CMF x 4)

References

  1. Milan trial: Buzzoni R, Bonadonna G, Valagussa P, Zambetti M. Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes. J Clin Oncol. 1991 Dec;9(12):2134-40. link to original article contains dosing details in manuscript PubMed
    1. Update: Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes: ten-year results. JAMA. 1995 Feb 15;273(7):542-7. link to original article PubMed
  2. Leonard RC, Lind M, Twelves C, Coleman R, van Belle S, Wilson C, Ledermann J, Kennedy I, Barrett-Lee P, Perren T, Verrill M, Cameron D, Foster E, Yellowlees A, Crown J; Anglo-Celtic Cooperative Oncology Group. Conventional adjuvant chemotherapy versus single-cycle, autograft-supported, high-dose, late-intensification chemotherapy in high-risk breast cancer patients: a randomized trial. J Natl Cancer Inst. 2004 Jul 21;96(14):1076-83. link to original article contains dosing details in abstract PubMed
  3. ECTO: Gianni L, Baselga J, Eiermann W, Porta VG, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Cussac AL, Bozhok A, Martinez-Agulló A, Greco M, Byakhov M, Lopez JJ, Mansutti M, Valagussa P, Bonadonna G. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. J Clin Oncol. 2009 May 20;27(15):2474-81. Epub 2009 Mar 30. link to original article contains dosing details in manuscript PubMed NCT00003013
  4. SECRAB: Fernando IN, Bowden SJ, Herring K, Brookes CL, Ahmed I, Marshall A, Grieve R, Churn M, Spooner D, Latief TN, Agrawal RK, Brunt AM, Stevens A, Goodman A, Canney P, Bishop J, Ritchie D, Dunn J, Poole CJ, Rea DW; SECRAB Investigators. Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial. Radiother Oncol. 2020 Jan;142:52-61. Epub 2019 Nov 27. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00003893

ddA-ddT-ddC

ddA-ddT-ddC: dose-dense Adriamycin (Doxorubicin), followed by dose-dense Taxol (Paclitaxel), followed by dose-dense Cyclophosphamide

Regimen variant #1, 60/175/600

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Citron et al. 2003 (CALGB 9741) 1997-1999 Phase 3 (E-esc) 1. A-T-C
2. AC-T 		Seems to have superior OS (secondary endpoint)

Superior DFS (primary endpoint)
3. ddAC-ddT Did not meet primary endpoint of DFS

Preceding treatment

Chemotherapy, ddA portion (cycles 1 to 4)

Chemotherapy, ddT portion (cycles 5 to 8)

Supportive therapy, ddT portion (cycles 5 to 8)

Chemotherapy, ddC portion (cycles 9 to 12)

Supportive therapy, all portions (cycles 1 to 12)

  • Filgrastim (Neupogen) 5 mcg/kg (rounded to either 300 or 480 mcg) SC once per day on days 3 to 10
    • Note: Citron et al. 2003 says the schedule was "filgrastim days 3 to 10 of each cycle (a total of seven doses)," so it is unclear whether 7 or 8 doses was actually used).

14-day cycle for 12 cycles (ddA x 4; ddT x 4; ddC x 4)


Regimen variant #2, 60/200/800

Study Dates of enrollment Evidence
Kahan et al. 2005 2000-2003 Phase 2

Preceding treatment

Chemotherapy, ddA portion (cycles 1 to 4)

Chemotherapy, ddT portion (cycles 5 to 8)

Chemotherapy, ddC portion (cycles 9 to 12)

Supportive therapy, all portions (cycles 1 to 12)

14-day cycle for 12 cycles (ddA x 4; ddT x 4; ddC x 4)

References

  1. CALGB 9741: Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. link to original article contains dosing details in manuscript PubMed NCT00003088
  2. Kahan Z, Uhercsak G, Hajnal-Papp R, Boda K, Thurzo L. Dose-dense sequential adriamycin-paclitaxel-cyclophosphamide chemotherapy is well tolerated and safe in high-risk early breast cancer. Oncology. 2005;68(4-6):446-53. Epub 2005 Jul 13. link to original article contains dosing details in abstract PubMed
    1. Update: Kelemen G, Uhercsák G, Ormándi K, Eller J, Thurzó L, Kahán Z. Long-term efficiency and toxicity of adjuvant dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy in high-risk breast cancer. Oncology. 2010;78(3-4):271-3. Epub 2010 Jun 7. link to original article PubMed

AC-CMF

AC-CMF: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Cyclophosphamide, Methotrexate, Fluorouracil

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Colleoni et al. 2006 (IBCSG 13-93) 1993-1999 Non-randomized part of phase 3 RCT
Basser et al. 2006 (IBCSG 15-95) 1995-2000 Phase 3 (C) EC; dose-intense Seems to have inferior DFS1
Francis et al. 2008 (BIG 02-98) 1998-2001 Phase 3 (C) 1. A-CMF Not reported
2. A-D-CMF
3. AD-CMF 		Might have inferior DFS2

1Reported efficacy for IBCSG 15-95 is based on the 2009 update.
2Reported efficacy for BIG 02-98 is based on the 2015 update.

Preceding treatment

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 7)

21-day cycle for 4 cycles, then 28-day cycle for 3 cycles (AC x 4; CMF x 3)

Subsequent treatment

References

  1. IBCSG 15-95: Basser RL, O'Neill A, Martinelli G, Green MD, Peccatori F, Cinieri S, Coates AS, Gelber RD, Aebi S, Castiglione-Gertsch M, Viale G, Price KN, Goldhirsch A; International Breast Cancer Study Group. Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95. J Clin Oncol. 2006 Jan 20;24(3):370-8. link to original article contains dosing details in manuscript PubMed NCT00002784
    1. Update: Colleoni M, Sun Z, Martinelli G, Basser RL, Coates AS, Gelber RD, Green MD, Peccatori F, Cinieri S, Aebi S, Viale G, Price KN, Goldhirsch A; International Breast Cancer Study Group. The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up. Ann Oncol. 2009 Aug;20(8):1344-51. Epub 2009 May 25. link to original article link to PMC article PubMed
  2. IBCSG 13-93: Colleoni M, Gelber S, Goldhirsch A, Aebi S, Castiglione-Gertsch M, Price KN, Coates AS, Gelber RD; International Breast Cancer Study Group. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol. 2006 Mar 20;24(9):1332-41. Epub 2006 Feb 27. link to original article contains dosing details in manuscript PubMed
  3. BIG 02-98: Francis P, Crown J, Di Leo A, Buyse M, Balil A, Andersson M, Nordenskjöld B, Lang I, Jakesz R, Vorobiof D, Gutiérrez J, van Hazel G, Dolci S, Jamin S, Bendahmane B, Gelber RD, Goldhirsch A, Castiglione-Gertsch M, Piccart-Gebhart M; BIG. Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial. J Natl Cancer Inst. 2008 Jan 16;100(2):121-33. Epub 2008 Jan 8. Erratum in: J Natl Cancer Inst. 2008 Nov 19;100(22):1655. link to original article contains dosing details in abstract PubMed NCT00174655
    1. Update: Oakman C, Francis PA, Crown J, Quinaux E, Buyse M, De Azambuja E, Margeli Vila M, Andersson M, Nordenskjöld B, Jakesz R, Thürlimann B, Gutiérrez J, Harvey V, Punzalan L, Dell'orto P, Larsimont D, Steinberg I, Gelber RD, Piccart-Gebhart M, Viale G, Di Leo A. Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trial. Ann Oncol. 2013 May;24(5):1203-11. Epub 2013 Jan 4. link to original article PubMed
    2. Update: Sonnenblick A, Francis PA, Azim HA Jr, de Azambuja E, Nordenskjöld B, Gutiérez J, Quinaux E, Mastropasqua MG, Ameye L, Anderson M, Lluch A, Gnant M, Goldhirsch A, Di Leo A, Barnadas A, Cortes-Funes H, Piccart M, Crown J. Final 10-year results of the Breast International Group 2-98 phase III trial and the role of Ki67 in predicting benefit of adjuvant docetaxel in patients with oestrogen receptor positive breast cancer. Eur J Cancer. 2015 Aug;51(12):1481-9. Epub 2015 Jun 11. link to original article PubMed

AC-D

AC-D: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Docetaxel

Regimen variant #1, q3wk docetaxel 75 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Watanabe et al. 2017 (NSAS BC-02) 2001-2006 Phase 3 (C) 1. AC-T
2. Paclitaxel x 8 		Seems to have superior OS (secondary endpoint)
(HR 0.75, 95% CI 0.57-0.98)
3. Docetaxel x 8 Inconclusive whether non-inferior DFS (primary endpoint)

Preceding treatment

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 8)

21-day cycle for 8 cycles (AC x 4; D x 4)


Regimen variant #2, q3wk docetaxel 100 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sparano et al. 2008 (ECOG E1199) 1999-2002 Phase 3 (E-switch-ic) 1. AC-T; q3wk paclitaxel Seems to have superior DFS (primary endpoint)
2. AC-T; weekly paclitaxel
3. AC-D; weekly docetaxel 		Not reported
Swain et al. 2010 (NSABP B-30) 1999-2004 Phase 3 (E-switch-ic) 1. AT Seems to have superior OS (primary endpoint)
2. TAC Might have superior OS (primary endpoint)
Eiermann et al. 2011 (BCIRG-005) 2000-2003 Phase 3 (E-switch-ic) TAC Did not meet primary endpoint of DFS60

Preceding treatment

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 8)

21-day cycle for 8 cycles (AC x 4; D x 4)


Regimen variant #3, weekly docetaxel

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sparano et al. 2008 (ECOG E1199) 1999-2002 Phase 3 (E-switch-ic) 1. AC-T; q3wk paclitaxel Did not meet primary endpoint of DFS
2. AC-T; weekly paclitaxel
3. AC-D; q3wk docetaxel 		Not reported

Preceding treatment

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 16)

21-day cycle for 4 cycles, then 7-day cycle for 12 cycles (AC x 4; D x 12)

References

  1. ECOG E1199: Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. link to original article link to PMC article PubMed NCT00004125
    1. Update: Sparano JA, Zhao F, Martino S, Ligibel JA, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Long-term follow-up of the E1199 phase III trial evaluating the role of taxane and schedule in operable breast cancer. J Clin Oncol. 2015 Jul 20;33(21):2353-60. Epub 2015 Jun 15. link to original article link to PMC article PubMed
  2. NSABP B-30: Swain SM, Jeong JH, Geyer CE Jr, Costantino JP, Pajon ER, Fehrenbacher L, Atkins JN, Polikoff J, Vogel VG, Erban JK, Rastogi P, Livingston RB, Perez EA, Mamounas EP, Land SR, Ganz PA, Wolmark N. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med. 2010 Jun 3;362(22):2053-65. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00003782
  3. BCIRG-005: Eiermann W, Pienkowski T, Crown J, Sadeghi S, Martín M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press M, Sauter G, Lindsay MA, Riva A, Buyse M, Drevot P, Taupin H, Mackey JR. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol. 2011 Oct 10;29(29):3877-84. Epub 2011 Sep 12. link to original article contains dosing details in manuscript PubMed NCT00312208
    1. Update: Mackey JR, Pieńkowski T, Crown J, Sadeghi S, Martín M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press MF, Sauter G, Lindsay M, Houé V, Buyse M, Drevot P, Hitier S, Bensfia S, Eiermann W; Translational Research In Oncology (TRIO)/ Breast Cancer International Research Group (BCIRG)-005 investigators. Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial. Ann Oncol. 2016 Jun;27(6):1041-7. Epub 2016 Mar 2. link to original article PubMed
  4. NSAS BC-02: Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. link to original article contains dosing details in abstract link to PMC article PubMed

AC-T

AC-T: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel)

Regimen variant #1, weekly paclitaxel

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sparano et al. 2008 (ECOG E1199) 1999-2002 Phase 3 (E-switch-ic) 1. AC-T; q3wk paclitaxel Superior OS (secondary endpoint)
OS60: 89.7% vs 86.5%
(HR 0.76, 98.3% CI 0.58-0.98)
2. AC-D; q3wk docetaxel
3. AC-D; weekly docetaxel 		Not reported
Miller et al. 2018 (ECOG E5103) 2007-2011 Phase 3 (C) 1a. AC-T & Bevacizumab
1b. ddAC-T & Bevacizumab
2a. AC-T & Bevacizumab, then Bevacizumab
2b. ddAC-T & Bevacizumab, then Bevacizumab 		Did not meet primary endpoint of IDFS
Fehrenbacher et al. 2019 (NSABP B-47) 2011-2015 Phase 3 (C) 1a. AC-TH
1b. ddAC-TH
1c. TCH 		Did not meet primary endpoint of IDFS

Biomarker eligibility criteria

  • NSABP B-47: HER2 IHC of 1+ or 2+ with FISH ratio less than 2 or HER2 gene copy number less than 4

Preceding treatment

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, T portion (cycles 5 to 16)

21-day cycle for 4 cycles, then 7-day cycle for 12 cycles (AC x 4; T x 12)


Regimen variant #2, q3wk paclitaxel 175 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Henderson et al. 2003 (INT 0148/CALGB 9344) 1994-1999 Phase 3 (E-RT-esc) 1. AC; standard-dose
2. AC; high-dose
3. AC; very high-dose 		Superior OS (secondary endpoint)
4. AC-T; high-dose AC
5. AC-T; very high-dose AC 		Did not meet primary endpoint of DFS
Citron et al. 2003 (CALGB 9741) 1997-1999 Phase 3 (C) 1. A-T-C Did not meet primary endpoint of DFS
2. ddA-ddC-ddT
3. ddAC-ddT 		Seems to have inferior OS
Sparano et al. 2008 (ECOG E1199) 1999-2002 Phase 3 (C) 1. AC-T; weekly paclitaxel Inferior OS
2. AC-D; q3wk docetaxel Seems to have inferior DFS
3. AC-D; weekly docetaxel Did not meet primary endpoint of DFS
Loesch et al. 2010 2000-2002 Phase 3 (C) See link See link
Burnell et al. 2009 (NCIC-CTG MA.21) 2000-2005 Phase 3 (C) 1. ddEC-T
2. CEF 		Inferior RFS
Watanabe et al. 2017 (NSAS BC-02) 2001-2006 Phase 3 (C) 1. AC-D
2. Docetaxel x 8 		Seems to have inferior OS (secondary endpoint)
3. Paclitaxel x 8 Inconclusive whether non-inferior DFS (primary endpoint)
Sparano et al. 2018 (TAILORx) 2006-2010 Phase 3 (C) No chemotherapy Non-inferior IDFS (primary endpoint)

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, T portion (cycles 5 to 8)

21-day cycle for 8 cycles (AC x 4; T x 4)


Regimen variant #3, q3wk paclitaxel 225 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mamounas et al. 2005 (NSABP B-28) 1995-1998 Phase 3 (E-esc) AC x 4 Superior DFS (co-primary endpoint)

Preceding treatment

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, T portion (cycles 5 to 8)

21-day cycle for 8 cycles (AC x 4; T x 4)

References

  1. INT 0148/CALGB 9344: Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003 Mar 15;21(6):976-83. link to original article contains dosing details in manuscript PubMed
  2. CALGB 9741: Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. link to original article contains dosing details in manuscript PubMed NCT00003088
  3. NSABP B-28: Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol. 2005 Jun 1;23(16):3686-96. Epub 2005 May 16. link to original article contains dosing details in manuscript PubMed
  4. ECOG E1199: Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. link to original article link to PMC article PubMed NCT00004125
    1. Update: Sparano JA, Zhao F, Martino S, Ligibel JA, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Long-term follow-up of the E1199 phase III trial evaluating the role of taxane and schedule in operable breast cancer. J Clin Oncol. 2015 Jul 20;33(21):2353-60. Epub 2015 Jun 15. link to original article link to PMC article PubMed
  5. NCIC-CTG MA.21: Burnell M, Levine MN, Chapman JA, Bramwell V, Gelmon K, Walley B, Vandenberg T, Chalchal H, Albain KS, Perez EA, Rugo H, Pritchard K, O'Brien P, Shepherd LE. Cyclophosphamide, epirubicin, and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol. 2010 Jan 1;28(1):77-82. Epub 2009 Nov 9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00014222
  6. Loesch D, Greco FA, Senzer NN, Burris HA, Hainsworth JD, Jones S, Vukelja SJ, Sandbach J, Holmes F, Sedlacek S, Pippen J, Lindquist D, McIntyre K, Blum JL, Modiano MR, Boehm KA, Zhan F, Asmar L, Robert N. Phase III multicenter trial of doxorubicin plus cyclophosphamide followed by paclitaxel compared with doxorubicin plus paclitaxel followed by weekly paclitaxel as adjuvant therapy for women with high-risk breast cancer. J Clin Oncol. 2010 Jun 20;28(18):2958-65. Epub 2010 May 17. link to original article contains dosing details in manuscript PubMed
  7. NSAS BC-02: Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. link to original article contains dosing details in abstract link to PMC article PubMed
  8. TAILORx: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. link to original article link to PMC article contains dosing details in supplement PubMed NCT00310180
  9. ECOG E5103: Miller KD, O'Neill A, Gradishar W, Hobday TJ, Goldstein LJ, Mayer IA, Bloom S, Brufsky AM, Tevaarwerk AJ, Sparano JA, Le-Lindqwister NA, Hendricks CB, Northfelt DW, Dang CT, Sledge GW Jr. Double-blind phase III trial of adjuvant chemotherapy with and without bevacizumab in patients with lymph node-positive and high-risk lymph node-negative breast cancer (E5103). J Clin Oncol. 2018 Sep 1;36(25):2621-2629. Epub 2018 Jul 24. link to original article refers to ECOG E1199 protocol link to PMC article PubMed NCT00433511
  10. NSABP B-47: Fehrenbacher L, Cecchini RS, Geyer CE Jr, Rastogi P, Costantino JP, Atkins JN, Crown JP, Polikoff J, Boileau JF, Provencher L, Stokoe C, Moore TD, Robidoux A, Flynn PJ, Borges VF, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020 Feb 10;38(5):444-453. Epub 2019 Dec 10. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01275677
  11. USON 01062: NCT00089479

ddAC-T

ddAC-T: dose-dense Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Miller et al. 2018 (ECOG E5103) 2007-2011 Phase 3 (C) 1a. AC-T & Bevacizumab
1b. ddAC-T & Bevacizumab
2a. AC-T & Bevacizumab, then Bevacizumab
2b. ddAC-T & Bevacizumab, then Bevacizumab 		Did not meet primary endpoint of IDFS
Fehrenbacher et al. 2019 (NSABP B-47) 2011-2015 Phase 3 (C) 1a. AC-TH
1b. ddAC-TH
1c. TCH 		Did not meet primary endpoint of IDFS

Note: Fehrenbacher et al. 2019 does not explicitly describe the use of filgrastim, but it is typically used for the dose-dense portion of this regimen.

Biomarker eligibility criteria

  • NSABP B-47: HER2 IHC of 1+ or 2+ with FISH ratio less than 2 or HER2 gene copy number less than 4

Preceding treatment

Chemotherapy, ddAC portion (cycles 1 to 4)

Supportive therapy, ddAC portion (cycles 1 to 4)

Chemotherapy, T portion (cycles 5 to 16)

14-day cycle for 4 cycles, then 7-day cycle for 12 cycles (AC x 4; T x 12)

References

  1. ECOG E5103: Miller KD, O'Neill A, Gradishar W, Hobday TJ, Goldstein LJ, Mayer IA, Bloom S, Brufsky AM, Tevaarwerk AJ, Sparano JA, Le-Lindqwister NA, Hendricks CB, Northfelt DW, Dang CT, Sledge GW Jr. Double-blind phase III trial of adjuvant chemotherapy with and without bevacizumab in patients with lymph node-positive and high-risk lymph node-negative breast cancer (E5103). J Clin Oncol. 2018 Sep 1;36(25):2621-2629. Epub 2018 Jul 24. link to original article refers to ECOG E1199 protocol link to PMC article PubMed NCT00433511
  2. NSABP B-47: Fehrenbacher L, Cecchini RS, Geyer CE Jr, Rastogi P, Costantino JP, Atkins JN, Crown JP, Polikoff J, Boileau JF, Provencher L, Stokoe C, Moore TD, Robidoux A, Flynn PJ, Borges VF, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020 Feb 10;38(5):444-453. Epub 2019 Dec 10. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01275677

ddAC-ddT

ddAC-ddT: dose-dense Adriamycin (Doxorubicin) & Cyclophosphamide followed by dose-dense Taxol (Paclitaxel)

Regimen variant #1, 4x4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Citron et al. 2003 (CALGB 9741) 1997-1999 Phase 3 (E-esc) 1. A-T-C
2. AC-T 		Seems to have superior OS (secondary endpoint)

Superior DFS (primary endpoint)
3. ddA-ddC-ddT Did not meet primary endpoint of DFS
Swain et al. 2013 (NSABP B-38) 2004-2007 Phase 3 (C) 1. TAC x 6 Did not meet primary endpoint of DFS
2. ddAC-ddPG Did not meet primary endpoint of DFS
Sparano et al. 2018 (TAILORx) 2006-2010 Phase 3 (C) No chemotherapy Non-inferior IDFS (primary endpoint)

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy, ddAC portion (cycles 1 to 4)

Supportive therapy, ddAC portion (cycles 1 to 4)

  • Filgrastim (Neupogen) 5 mcg/kg (rounded to either 300 or 480 mcg) SC once per day on days 3 to 10
    • Note: Citron et al. 2003 says the schedule was "filgrastim days 3 to 10 of each cycle (a total of seven doses)," so it is unclear whether 7 or 8 doses was actually used).

Chemotherapy, ddT portion (cycles 5 to 8)

Supportive therapy, ddT portion (cycles 5 to 8)

  • Diphenhydramine (Benadryl) 12.5 to 50 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
  • One of the following H2 blockers:
  • One of the following dexamethasone choices:
  • Recommended growth factor support with one of the following choices:
    • Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Sargramostim (Leukine) 250 to 500 mcg/m2 SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Pegfilgrastim (Neulasta) 6 mg SC once, given 24 to 36 hours after chemotherapy
      • GIM2: a mid-protocol amendment suggested giving the pegilgrastim at least 72 h after chemotherapy

14-day cycle for 8 cycles (ddAC x 4; ddT x 4)


Regimen variant #2, 6x6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Budd et al. 2014 (SWOG S0221) 2003-2010 Phase 3 (C) 1. AC-ddT; continuous AC
2. AC-T; continuous AC & weekly paclitaxel
3. AC-T; weekly paclitaxel 		Did not meet primary endpoint of DFS

Preceding treatment

Chemotherapy, ddAC portion (cycles 1 to 6)

Chemotherapy, ddT portion (cycles 7 to 12)

Supportive therapy, all portions (cycles 1 to 12)

14-day cycle for 12 cycles (ddAC x 6; ddT x 6)

References

  1. CALGB 9741: Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. link to original article contains dosing details in manuscript PubMed NCT00003088
  2. NSABP B-38: Swain SM, Tang G, Geyer CE Jr, Rastogi P, Atkins JN, Donnellan PP, Fehrenbacher L, Azar CA, Robidoux A, Polikoff JA, Brufsky AM, Biggs DD, Levine EA, Zapas JL, Provencher L, Northfelt DW, Paik S, Costantino JP, Mamounas EP, Wolmark N. Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial. J Clin Oncol. 2013 Sep 10;31(26):3197-204. Epub 2013 Aug 12. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00093795
  3. SWOG S0221: Budd GT, Barlow WE, Moore HC, Hobday TJ, Stewart JA, Isaacs C, Salim M, Cho JK, Rinn KJ, Albain KS, Chew HK, Burton GV, Moore TD, Srkalovic G, McGregor BA, Flaherty LE, Livingston RB, Lew DL, Gralow JR, Hortobagyi GN. SWOG S0221: a phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer. J Clin Oncol. 2015 Jan 1;33(1):58-64. Epub 2014 Nov 24. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00070564
  4. TAILORx: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. link to original article link to PMC article contains dosing details in supplement PubMed NCT00310180

AT-CMF

AT-CMF: Adriamycin (Doxorubicin) & Taxol (Paclitaxel) followed by Cyclophosphamide, Methotrexate, Fluorouracil

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gianni et al. 2009 (ECTO) 1996-2002 Phase 3 (E-esc) 1. A-CMF Seems to have superior RFS (primary endpoint)
RFS84: 76% vs 69%
(HR 0.73, 95% CI 0.57-0.97)
2. AT-CMF; neoadjuvant Did not meet primary endpoint of RFS

Preceding treatment

Chemotherapy, AT portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 8)

21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (AT x 4; CMF x 4)

References

  1. ECTO: Gianni L, Baselga J, Eiermann W, Porta VG, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Cussac AL, Bozhok A, Martinez-Agulló A, Greco M, Byakhov M, Lopez JJ, Mansutti M, Valagussa P, Bonadonna G. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. J Clin Oncol. 2009 May 20;27(15):2474-81. Epub 2009 Mar 30. link to original article contains dosing details in manuscript PubMed NCT00003013

CMF-E

CMF-E: Cyclophosphamide, Methotrexate, Fluorouracil, followed by Epirubicin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Boccardo et al. 1990 (GROCTA-1) 1983-1987 Phase 3 (C) 1. Tamoxifen x 5 y Seems to have inferior OS1
2. CMFT-ET Inferior OS1

1Reported efficacy is based on the 2011 update.

Preceding treatment

Chemotherapy, CMF portion (cycles 1 to 6)

Chemotherapy, E portion (cycles 7 to 10)

21-day cycle for 10 cycles (CMF x 6; E x 4)

References

  1. GROCTA-1: Boccardo F, Rubagotti A, Bruzzi P, Cappellini M, Isola G, Nenci I, Piffanelli A, Scanni A, Sismondi P, Santi L, Genta F, Saccani F, Sassi M, Malacarne P, Donati D, Farris A, Castagnetta L, Di Carlo A, Traina A, Galletto L, Smerieri F, Buzzi F; Breast Cancer Adjuvant Chemo-Hormone Therapy Cooperative Group. Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, estrogen receptor-positive breast cancer patients: results of a multicentric Italian study. J Clin Oncol. 1990 Aug;8(8):1310-20. link to original article contains dosing details in manuscript PubMed
    1. Update: Boccardo F, Guglielmini P, Parodi A, Rubagotti A. Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, oestrogen receptor-positive breast cancer patients: very late results of the 'gruppo di ricerca per la chemio-ormonoterapia adiuvante (GROCTA)' 01-Trial in early breast cancer. Breast Cancer Res Treat. 2011 Apr;126(3):653-61. Epub 2011 Feb 24. link to original article PubMed

D-EC

D-EC: Docetaxel followed by Epirubicin and Cyclophosphamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Polyzos et al. 2009 1995-2004 Phase 3 (E-switch-ic) FEC Seems to have superior DFS60 (primary endpoint)
DFS60: 72.6% vs 67.2%

Preceding treatment

Chemotherapy, D portion (cycles 1 to 4)

Chemotherapy, EC portion (cycles 5 to 8)

21-day cycle for 8 cycles (D x 4; EC x 4)

References

  1. Polyzos A, Malamos N, Boukovinas I, Adamou A, Ziras N, Kalbakis K, Kakolyris S, Syrigos K, Papakotoulas P, Kouroussis C, Karvounis N, Vamvakas L, Christophyllakis C, Athanasiadis A, Varthalitis I, Georgoulias V, Mavroudis D; Hellenic Oncology Research Group. FEC versus sequential docetaxel followed by epirubicin/cyclophosphamide as adjuvant chemotherapy in women with axillary node-positive early breast cancer: a randomized study of the Hellenic Oncology Research Group (HORG). Breast Cancer Res Treat. 2010 Jan;119(1):95-104. Epub 2009 Jul 28. link to original article contains dosing details in abstract PubMed

D-FEC

D-FEC: Docetaxel followed by Fluorouracil, Epirubicin, Cyclophosphamide
T-CEF: Taxotere (Docetaxel) followed by Cyclophosphamide, Epirubicin, Fluorouracil

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Joensuu et al. 2009 (FinXX) 2004-2007 Phase 3 (C) TX-CEX Seems to have inferior OS1

1Reported efficacy is based on the 2022 update.

Preceding treatment

Chemotherapy, D portion (cycles 1 to 3)

Chemotherapy, FEC portion (cycles 4 to 6)

21-day cycle for 6 cycles (D x 3; FEC x 3)


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Joensuu et al. 2006 (FinHer) 2000-2003 Phase 3 (E-switch-ic) V-FEC Superior DDFS (secondary endpoint)

Note: this was the study design for HER2-negative patients.

Preceding treatment

Chemotherapy, D portion (cycles 1 to 3)

Chemotherapy, FEC portion (cycles 4 to 6)

21-day cycle for 6 cycles (D x 3; FEC x 3)

References

  1. FinHer: Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article contains dosing details in manuscript PubMed ISRCTN76560285
    1. Update: Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. Epub 2009 Nov 2. link to original article PubMed
  2. FinXX: Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Asola R, Kokko R, Ahlgren J, Auvinen P, Hemminki A, Paija O, Helle L, Nuortio L, Villman K, Nilsson G, Lahtela SL, Lehtiö K, Pajunen M, Poikonen P, Nyandoto P, Kataja V, Bono P, Leinonen M, Lindman H; FinXX Study Investigators. Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer: an open-label, randomised controlled trial. Lancet Oncol. 2009 Dec;10(12):1145-51. Epub 2009 Nov 10. link to original article PubMed NCT00114816
    1. Update: Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Kokko R, Ahlgren J, Auvinen P, Paija O, Helle L, Villman K, Nyandoto P, Nilsson G, Pajunen M, Asola R, Poikonen P, Leinonen M, Kataja V, Bono P, Lindman H. Adjuvant capecitabine, docetaxel, cyclophosphamide, and epirubicin for early breast cancer: final analysis of the randomized FinXX trial. J Clin Oncol. 2012 Jan 1;30(1):11-8. Epub 2011 Nov 21. link to original article PubMed
    2. Update: Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola A, Tanner M, Ahlgren J, Auvinen P, Lahdenperä O, Villman K, Nyandoto P, Nilsson G, Poikonen-Saksela P, Kataja V, Bono P, Junnila J, Lindman H. Adjuvant Capecitabine for Early Breast Cancer: 15-Year Overall Survival Results From a Randomized Trial. J Clin Oncol. 2022 Apr 1;40(10):1051-1058. Epub 2022 Jan 12. link to original article link to PMC article PubMed

E-CMF

E-CMF: Epirubicin followed by Cyclophosphamide, Methotrexate, Fluorouracil

Regimen variant #1, 100/750/50/600

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Poole et al. 2006 (BR9601) 1996-2001 Phase 3 (E-esc) CMF x 6 Superior OS1 (co-primary endpoint)
OS60: 84% vs 78%
(HR 0.76, 95% CI 0.65-0.89)
Fernando et al. 2019 (SECRAB) 1998-2004 Phase 3 (C) 1a. CMF & RT
1b. E-CMF & RT
1c. A-CMF & RT
1d. MMM & RT 		Inferior LRFS
Delaloge et al. 2020 (MINDACT) 2007-2011 Phase 3 (C) TX Did not meet primary endpoint of DFS

1Reported efficacy is based on the 2012 update.

Preceding treatment

Chemotherapy, E portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 8)

21-day cycle for 8 cycles (E x 4; CMF x 4)


Regimen variant #2, 100/1200/80/1200

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Poole et al. 2006 (NEAT) 1996-2001 Phase 3 (E-esc) CMF x 6 Superior OS1 (co-primary endpoint)
OS60: 84% vs 78%
(HR 0.76, 95% CI 0.65-0.89)
Boccardo et al. 2010 1997-2004 Phase 3 (C) T-EV Did not meet primary endpoint of OS
Amadori et al. 2010 (IRST-IBIS-03) 1997-2004 Phase 3 (E-switch-ic) CMF-E Did not meet endpoint of OS60
Fernando et al. 2019 (SECRAB) 1998-2004 Phase 3 (C) 1a. CMF & RT
1b. E-CMF & RT
1c. A-CMF & RT
1d. MMM & RT 		Inferior LRFS
Ellis et al. 2009 (TACT) 2001-2003 Phase 3 (C) FEC-D Did not meet primary endpoint of DFS
Cameron et al. 2017 (TACT2) 2005-2008 Phase 3 (C) 1. E-X Non-inferior TTR (primary endpoint)
2. ddE-CMF
3. ddE-X 		Did not meet primary endpoint of TTR

1Reported efficacy is based on the 2012 update.

Preceding treatment

Chemotherapy, E portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 8)

21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (E x 4; CMF x 4)


Regimen variant #3, 100/1400/80/1200 ("classic CMF")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Poole et al. 2006 (NEAT) 1996-2001 Phase 3 (E-esc) CMF x 6 Superior OS1 (co-primary endpoint)
OS60: 84% vs 78%
(HR 0.76, 95% CI 0.65-0.89)
Fernando et al. 2019 (SECRAB) 1998-2004 Phase 3 (C) 1a. CMF & RT
1b. E-CMF & RT
1c. A-CMF & RT
1d. MMM & RT 		Inferior LRFS
Cameron et al. 2017 (TACT2) 2005-2008 Phase 3 (C) 1. E-X Non-inferior TTR (primary endpoint)
2. ddE-CMF
3. ddE-X 		Did not meet primary endpoint of TTR
Delaloge et al. 2020 (MINDACT) 2007-2011 Phase 3 (C) TX Did not meet primary endpoint of DFS

1Reported efficacy is based on the 2012 update.

Preceding treatment

Chemotherapy, E portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 8)

21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (E x 4; CMF x 4)

References

  1. NEAT: Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. link to original article PubMed NCT00003577
    1. Update: Earl HM, Hiller L, Dunn JA, Vallier AL, Bowden SJ, Jordan SD, Blows F, Munro A, Bathers S, Grieve R, Spooner DA, Agrawal R, Fernando I, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, McAdam K, Foster L, Leonard RC, Twelves CJ, Cameron D, Bartlett JM, Pharoah P, Provenzano E, Caldas C, Poole CJ; NEAT Investigators and the SCTBG. Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials. Br J Cancer. 2012 Oct 9;107(8):1257-67. Epub 2012 Sep 11. link to original article link to PMC article PubMed
  2. BR9601: Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. link to original article PubMed NCT00003012
    1. Update: Earl HM, Hiller L, Dunn JA, Vallier AL, Bowden SJ, Jordan SD, Blows F, Munro A, Bathers S, Grieve R, Spooner DA, Agrawal R, Fernando I, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, McAdam K, Foster L, Leonard RC, Twelves CJ, Cameron D, Bartlett JM, Pharoah P, Provenzano E, Caldas C, Poole CJ; NEAT Investigators and the SCTBG. Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials. Br J Cancer. 2012 Oct 9;107(8):1257-67. Epub 2012 Sep 11. link to original article link to PMC article PubMed
  3. TACT: Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. link to original article link to PMC article contains dosing details in manuscript PubMed ISRCTN79718493
  4. Boccardo F, Amadori D, Guglielmini P, Sismondi P, Farris A, Agostara B, Gambi A, Catalano G, Faedi M, Rubagotti A. Epirubicin followed by cyclophosphamide, methotrexate and 5-fluorouracil versus paclitaxel followed by epirubicin and vinorelbine in patients with high-risk operable breast cancer. Oncology. 2010;78(3-4):274-81. Epub 2010 Jun 8. link to original article contains dosing details in abstract PubMed
  5. IRST-IBIS-03: Amadori D, Silvestrini R, De Lena M, Boccardo F, Rocca A, Scarpi E, Schittulli F, Brandi M, Maltoni R, Serra P, Ponzone R, Biglia N, Gianni L, Tienghi A, Valerio MR, Bonginelli P, Amaducci L, Faedi M, Baldini E, Paradiso A. Randomized phase III trial of adjuvant epirubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) versus CMF followed by epirubicin in patients with node-negative or 1-3 node-positive rapidly proliferating breast cancer. Breast Cancer Res Treat. 2011 Feb;125(3):775-84. Epub 2010 Dec 4. link to original article contains dosing details in manuscript PubMed NCT01031030
  6. TACT2: Cameron D, Morden JP, Canney P, Velikova G, Coleman R, Bartlett J, Agrawal R, Banerji J, Bertelli G, Bloomfield D, Brunt AM, Earl H, Ellis P, Gaunt C, Gillman A, Hearfield N, Laing R, Murray N, Couper N, Stein RC, Verrill M, Wardley A, Barrett-Lee P, Bliss JM; TACT2 Investigators. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2017 Jul;18(7):929-945. Epub 2017 Jun 7. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00301925
    1. HRQoL analysis: Velikova G, Morden JP, Haviland JS, Emery C, Barrett-Lee P, Earl H, Bloomfield D, Brunt AM, Canney P, Coleman R, Verrill M, Wardley A, Bertelli G, Ellis P, Stein R, Bliss JM, Cameron D; TACT2 Trial Management Group. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer (UK TACT2; CRUK/05/19): quality of life results from a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2023 Dec;24(12):1359-1374. Epub 2023 Nov 2. Erratum in: Lancet Oncol. 2023 Dec;24(12):e459. link to original article PubMed
  7. SECRAB: Fernando IN, Bowden SJ, Herring K, Brookes CL, Ahmed I, Marshall A, Grieve R, Churn M, Spooner D, Latief TN, Agrawal RK, Brunt AM, Stevens A, Goodman A, Canney P, Bishop J, Ritchie D, Dunn J, Poole CJ, Rea DW; SECRAB Investigators. Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial. Radiother Oncol. 2020 Jan;142:52-61. Epub 2019 Nov 27. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00003893
  8. MINDACT: Delaloge S, Piccart M, Rutgers E, Litière S, van 't Veer LJ, van den Berkmortel F, Brain E, Dudek-Peric A, Gil-Gil M, Gomez P, Hilbers FS, Khalil Z, Knox S, Kuemmel S, Kunz G, Lesur A, Pierga JY, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Thompson AM, Viale G, Zoppoli G, Vuylsteke P, Tryfonidis K, Poncet C, Bogaerts J, Cardoso F; MINDACT investigators and the TRANSBIG Consortium. Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial. J Clin Oncol. 2020 Apr 10;38(11):1186-1197. Epub 2020 Feb 21. link to original article contains dosing details in supplement link to PMC article PubMed NCT00433589

ddE-iddCMF

ddE-iddCMF: dose-dense Epirubicin, followed by intense dose-dense Cyclophosphamide, Methotrexate, Fluorouracil

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fountzilas et al. 2005 (HE 10/97) 1997-2000 Phase 3 (C) ddE-T-iddCMF Did not meet primary endpoint of DFS

Preceding treatment

Chemotherapy, ddE portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 7)

Supportive therapy, all portions (cycles 1 to 7)

14-day cycle for 7 cycles (ddE x 4; iddCMF x 3)

References

  1. HE 10/97: Fountzilas G, Skarlos D, Dafni U, Gogas H, Briasoulis E, Pectasides D, Papadimitriou C, Markopoulos C, Polychronis A, Kalofonos HP, Siafaka V, Kosmidis P, Timotheadou E, Tsavdaridis D, Bafaloukos D, Papakostas P, Razis E, Makrantonakis P, Aravantinos G, Christodoulou C, Dimopoulos AM; Hellenic Cooperative Oncology Group. Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol. 2005 Nov;16(11):1762-71. Epub 2005 Sep 7. link to original article contains dosing details in manuscript PubMed

E-D

E-D: Epirubicin followed by Docetaxel

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Coombes et al. 2011 (DEVA) 1997-2005 Phase 3 (E-switch-ic) Epirubicin Superior DFS (primary endpoint)
DFS60: 79.5% vs 72.7%
(HR 0.68, 95% CI 0.52-0.91)

Superior OS (secondary endpoint)
OS60: 88.9% vs 81.8%
(HR 0.66, 95% CI 0.46-0.94)

Preceding treatment

Chemotherapy, E portion (cycles 1 to 3)

Chemotherapy, D portion (cycles 4 to 6)

28-day cycle for 3 cycles, then 21-day cycle for 3 cycles (E x 3; D x 3)


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mavroudis et al. 2017 (HORG CT/01.04) 2001-2013 Phase 3 (C) Docetaxel & Epirubicin Might have superior DFS (primary endpoint)
DFS60: 92.6% vs 88.2%
(HR 0.63, 95% CI 0.39-1.01)

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

Chemotherapy, E portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 8)

21-day cycle for 8 cycles (E x 4; D x 4)

References

  1. DEVA: Coombes RC, Bliss JM, Espie M, Erdkamp F, Wals J, Tres A, Marty M, Coleman RE, Tubiana-Mathieu N, den Boer MO, Wardley A, Kilburn LS, Cooper D, Thomas MW, Reise JA, Wilkinson K, Hupperets P. Randomized, phase III trial of sequential epirubicin and docetaxel versus epirubicin alone in postmenopausal patients with node-positive breast cancer. J Clin Oncol. 2011 Aug 20;29(24):3247-54. Epub 2011 Jul 18. link to original article contains dosing details in abstract PubMed ISRCTN89772270
  2. HORG CT/01.04: Mavroudis D, Saloustros E, Boukovinas I, Papakotoulas P, Kakolyris S, Ziras N, Christophylakis C, Kentepozidis N, Fountzilas G, Rigas G, Varthalitis I, Kalbakis K, Agelaki S, Hatzidaki D, Georgoulias V; Hellenic Oncology Research Group. Sequential vs concurrent epirubicin and docetaxel as adjuvant chemotherapy for high-risk, node-negative, early breast cancer: an interim analysis of a randomised phase III study from the Hellenic Oncology Research Group. Br J Cancer. 2017 Jul 11;117(2):164-170. Epub 2017 Jun 22. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00424606

E-X

E-X: Epirubicin followed by Xeloda (Capecitabine)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cameron et al. 2017 (TACT2) 2005-2008 Phase 3 (E-de-esc) 1. E-CMF Non-inferior TTR (primary endpoint)
2. ddE-CMF
3. ddE-X 		Did not meet primary endpoint of TTR

Preceding treatment

Chemotherapy, E portion (cycles 1 to 4)

Chemotherapy, X portion (cycles 5 to 8)

21-day cycle for 8 cycles (E x 4; X x 4)

References

  1. TACT2: Cameron D, Morden JP, Canney P, Velikova G, Coleman R, Bartlett J, Agrawal R, Banerji J, Bertelli G, Bloomfield D, Brunt AM, Earl H, Ellis P, Gaunt C, Gillman A, Hearfield N, Laing R, Murray N, Couper N, Stein RC, Verrill M, Wardley A, Barrett-Lee P, Bliss JM; TACT2 Investigators. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2017 Jul;18(7):929-945. Epub 2017 Jun 7. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00301925
    1. HRQoL analysis: Velikova G, Morden JP, Haviland JS, Emery C, Barrett-Lee P, Earl H, Bloomfield D, Brunt AM, Canney P, Coleman R, Verrill M, Wardley A, Bertelli G, Ellis P, Stein R, Bliss JM, Cameron D; TACT2 Trial Management Group. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer (UK TACT2; CRUK/05/19): quality of life results from a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2023 Dec;24(12):1359-1374. Epub 2023 Nov 2. Erratum in: Lancet Oncol. 2023 Dec;24(12):e459. link to original article PubMed

EC-CMF

EC-CMF: Epirubicin & Cyclophosphamide followed by Cyclophosphamide, Methotrexate, Fluorouracil

Regimen variant #1

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Colleoni et al. 2006 (IBCSG 13-93) 1993-1999 Non-randomized part of phase 3 RCT
Basser et al. 2006 (IBCSG 15-95) 1995-2000 Phase 3 (C) EC; dose-intense Seems to have inferior DFS1

1Reported efficacy is based on the 2009 update.

Preceding treatment

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 7)

21-day cycle for 4 cycles, then 28-day cycle for 3 cycles (EC x 4; CMF x 3)

Subsequent treatment


Regimen variant #2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kümmel et al. 2006 1996-2000 Phase 3 (C) ddEC-ddCMF Might have inferior OS

Preceding treatment

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 7)

21-day cycle for 7 cycles (EC x 4; CMF x 3)


Regimen variant #3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zander et al. 2004 1993-2000 Phase 3 (C) Cyclophosphamide, Mitoxantrone, Thiotepa with auto HSCT Might have inferior EFS

Preceding treatment

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 7)

21-day cycle for 4 cycles, then 28-day cycle for 3 cycles (EC x 4; CMF x 3)

References

  1. Zander AR, Kröger N, Schmoor C, Krüger W, Möbus V, Frickhofen N, Metzner B, Schultze W, Berdel WE, Koenigsmann M, Thiel E, Wandt H, Possinger K, Trümper L, Kreienberg R, Carstensen M, Schmidt EH, Jänicke F, Schumacher M, Jonat W. High-dose chemotherapy with autologous hematopoietic stem-cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: first results of a randomized trial. J Clin Oncol. 2004 Jun 15;22(12):2273-83. Epub 2004 Apr 26. link to original article contains dosing details in abstract PubMed
  2. IBCSG 15-95: Basser RL, O'Neill A, Martinelli G, Green MD, Peccatori F, Cinieri S, Coates AS, Gelber RD, Aebi S, Castiglione-Gertsch M, Viale G, Price KN, Goldhirsch A; International Breast Cancer Study Group. Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95. J Clin Oncol. 2006 Jan 20;24(3):370-8. link to original article contains dosing details in manuscript PubMed NCT00002784
    1. Update: Colleoni M, Sun Z, Martinelli G, Basser RL, Coates AS, Gelber RD, Green MD, Peccatori F, Cinieri S, Aebi S, Viale G, Price KN, Goldhirsch A; International Breast Cancer Study Group. The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up. Ann Oncol. 2009 Aug;20(8):1344-51. Epub 2009 May 25. link to original article link to PMC article PubMed
  3. IBCSG 13-93: Colleoni M, Gelber S, Goldhirsch A, Aebi S, Castiglione-Gertsch M, Price KN, Coates AS, Gelber RD; International Breast Cancer Study Group. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol. 2006 Mar 20;24(9):1332-41. Epub 2006 Feb 27. link to original article contains dosing details in manuscript PubMed
  4. Kümmel S, Krocker J, Kohls A, Breitbach GP, Morack G, Budner M, Blohmer JU, Elling D. Randomised trial: survival benefit and safety of adjuvant dose-dense chemotherapy for node-positive breast cancer. Br J Cancer. 2006 May 8;94(9):1237-44. link to original article link to PMC article contains dosing details in abstract PubMed
    1. Update: Reinisch M, Gluz O, Ataseven B, Blohmer JU, Budner M, Dittmer-Grabowski C, Kohls A, Krocker J, Kümmel A, Hagemann F, Rüland A, Traut A, Kümmel S. Updated Survival Analysis after a Median Follow-up of 12 Years of an Anthracycline-Containing Adjuvant Prospective Multicentre, Randomised Phase III Trial on Dose-Dense Chemotherapy in Primary Node-Positive, High-Risk Breast Cancer Patients. Breast Care (Basel). 2019 Jun;14(3):159-164. Epub 2018 Sep 5. link to original article link to PMC article PubMed

ddEC-ddCMF

ddEC-ddCMF: dose-dense Epirubicin & Cyclophosphamide followed by dose-dense Cyclophosphamide, Methotrexate, Fluorouracil

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Nitz et al. 2005 (WSG AM-01) 1995-2002 Phase 3 (C) EC, then ECT with auto HSCT x 2 Seems to have inferior OS
Kümmel et al. 2006 1996-2000 Phase 3 (E-esc) EC-CMF Might have superior OS (secondary endpoint)

Preceding treatment

Chemotherapy, ddEC portion (cycles 1 to 4)

Chemotherapy, ddCMF portion (cycles 5 to 7)

Supportive therapy, both portions (cycles 1 to 7)

14-day cycle for 7 cycles (ddEC x 4; ddCMF x 3)

References

  1. WSG AM-01: Nitz UA, Mohrmann S, Fischer J, Lindemann W, Berdel WE, Jackisch C, Werner C, Ziske C, Kirchner H, Metzner B, Souchon R, Ruffert U, Schütt G, Pollmanns A, Schmoll HJ, Middecke C, Baltzer J, Schrader I, Wiebringhaus H, Ko Y, Rösel S, Schwenzer T, Wernet P, Hinke A, Bender HG, Frick M; West German Study Group. Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial. Lancet. 2005 Dec 3;366(9501):1935-44. Erratum in: Lancet. 2006 Mar 4;367(9512):730. link to original article contains dosing details in manuscript PubMed
  2. Kümmel S, Krocker J, Kohls A, Breitbach GP, Morack G, Budner M, Blohmer JU, Elling D. Randomised trial: survival benefit and safety of adjuvant dose-dense chemotherapy for node-positive breast cancer. Br J Cancer. 2006 May 8;94(9):1237-44. link to original article link to PMC article contains dosing details in abstract PubMed
    1. Update: Reinisch M, Gluz O, Ataseven B, Blohmer JU, Budner M, Dittmer-Grabowski C, Kohls A, Krocker J, Kümmel A, Hagemann F, Rüland A, Traut A, Kümmel S. Updated Survival Analysis after a Median Follow-up of 12 Years of an Anthracycline-Containing Adjuvant Prospective Multicentre, Randomised Phase III Trial on Dose-Dense Chemotherapy in Primary Node-Positive, High-Risk Breast Cancer Patients. Breast Care (Basel). 2019 Jun;14(3):159-164. Epub 2018 Sep 5. link to original article link to PMC article PubMed

ddEC-ddT

ddEC-ddCMF: dose-dense Epirubicin & Cyclophosphamide followed by dose-dense Cyclophosphamide, Methotrexate, Fluorouracil

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Del Mastro et al. 2015 (GIM2) 2003-2006 Phase 3 (E-esc) 1. EC-T
2. FEC-P 		Superior OS (secondary endpoint)
OS60: 94% vs 89%
(HR 0.65, 95% CI 0.51-0.84)

Superior DFS (primary endpoint)
DFS60: 81% vs 76%
(HR 0.77, 95% CI 0.65-0.92)
3. ddFEC-ddT Did not meet primary endpoint of DFS

Note: a mid-protocol amendment of GIM2 suggested giving the pegfilgrastim at least 72 h after chemotherapy.

Preceding treatment

Chemotherapy, ddEC portion (cycles 1 to 4)

Chemotherapy, ddT portion (cycles 5 to 8)

Supportive therapy, both portions (cycles 1 to 8)

14-day cycle for 8 cycles (ddEC x 4; ddT x 4)

References

  1. GIM2: Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 x 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article contains dosing details in manuscript PubMed NCT00433420
    1. Update: Del Mastro L, Poggio F, Blondeaux E, De Placido S, Giuliano M, Forestieri V, De Laurentiis M, Gravina A, Bisagni G, Rimanti A, Turletti A, Nisticò C, Vaccaro A, Cognetti F, Fabi A, Gasparro S, Garrone O, Alicicco MG, Urracci Y, Mansutti M, Poletti P, Correale P, Bighin C, Puglisi F, Montemurro F, Colantuoni G, Lambertini M, Boni L; Gruppo Italiano Mammella Investigators. Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial. Lancet Oncol. 2022 Dec;23(12):1571-1582. Epub 2022 Nov 10. link to original article PubMed

EC-D

EC-D: Epirubicin and Cyclophosphamide followed by Docetaxel
EC-T: Epirubicin and Cyclophosphamide followed by Taxotere (Docetaxel)

Regimen variant #1, 3+3 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ejlertsen et al. 2017 (DBCG 07-READ) 2008-2012 Phase 3 (C) TC x 6 Did not meet primary endpoint of DFS

Biomarker eligibility criteria

  • TOP2A normal as determined by FISH

Preceding treatment

Chemotherapy, EC portion (cycles 1 to 3)

Chemotherapy, D portion (cycles 4 to 6)

21-day cycle for 6 cycles (EC x 3; D x 3)


Regimen variant #2, 4+4 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Martín et al. 2015 (GEICAM 2003-10) 2004-2007 Phase 3 (C) ET-X x 4+4 Seems to have superior IDFS (primary endpoint)
IDFS60: 86% vs 82%
(HR 0.77, 95% CI 0.61-0.97)

Preceding treatment

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 8)

21-day cycle for 8 cycles (EC x 4; D x 4)

References

  1. WSG-AGO EC-Doc: Nitz U, Gluz O, Huober J, Kreipe HH, Kates RE, Hartmann A, Erber R, Moustafa Z, Scholz M, Lisboa B, Mohrmann S, Möbus V, Augustin D, Hoffmann G, Weiss E, Böhmer S, Kreienberg R, Du Bois A, Sattler D, Thomssen C, Kiechle M, Jänicke F, Wallwiener D, Harbeck N, Kuhn W. Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression. Ann Oncol. 2014 Aug;25(8):1551-7. Epub 2014 May 14. Erratum in: Ann Oncol. 2017 Nov 1;28(11):2899. link to original article contains dosing details in abstract PubMed NCT02115204
  2. GEICAM 2003-10: Martín M, Ruiz Simón A, Ruiz Borrego M, Ribelles N, Rodríguez-Lescure A, Muñoz-Mateu M, González S, Margelí Vila M, Barnadas A, Ramos M, Del Barco Berron S, Jara C, Calvo L, Martínez-Jáñez N, Mendiola Fernández C, Rodríguez CA, Martínez de Dueñas E, Andrés R, Plazaola A, de la Haba-Rodríguez J, López-Vega JM, Adrover E, Ballesteros AI, Santaballa A, Sánchez-Rovira P, Baena-Cañada JM, Casas M, del Carmen Cámara M, Carrasco EM, Lluch A. Epirubicin plus cyclophosphamide followed by docetaxel versus epirubicin plus docetaxel followed by capecitabine as adjuvant therapy for node-positive early breast cancer: results from the GEICAM/2003-10 study. J Clin Oncol. 2015 Nov 10;33(32):3788-95. Epub 2015 Sep 28. link to original article contains dosing details in manuscript PubMed NCT00129935
  3. DBCG 07-READ: Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen MB, Knoop AS, Højris I, Ewertz M, Balslev E, Danø H, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. Adjuvant cyclophosphamide and docetaxel with or without epirubicin for early TOP2A-normal breast cancer: DBCG 07-READ, an open-label, phase III, randomized trial. J Clin Oncol. 2017 Aug 10;35(23):2639-2646. Epub 2017 Jun 29. link to original article contains dosing details in manuscript PubMed NCT00689156

EC-T

EC-T: Epirubicin and Cyclophosphamide followed by Taxol (Paclitaxel)
EC-P: Epirubicin and Cyclophosphamide followed by Paclitaxel

Regimen variant #1, 75/600

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yu et al. 2021 (SPECTRUMbrca) 2011-2016 Phase 3 (C) EP-T Might have inferior DFS60

Note: this trial should not be confused with the one by the same name in head & neck cancer.

Preceding treatment

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, T portion (cycles 5 to 16)

21-day cycle for 4 cycles, then 7-day cycle for 12 cycles (EC x 4; T x 12)


Regimen variant #2, 90/600

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Earl et al. 2017 (tAnGo) 2001-2004 Phase 3 (C) EC-TG Did not meet primary endpoint of DFS
Del Mastro et al. 2015 (GIM2) 2003-2006 Phase 3 (C) 1. ddEC-ddT
2. ddFEC-ddT 		Inferior OS
3. FEC-P Did not meet primary endpoint of DFS
Yuan et al. 2023 (CH-BC-006) 2010-06-01 to 2016-06-30 Phase 3 (C) EP Non-inferior DFS

Preceding treatment

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, T portion (cycles 5 to 8)

21-day cycle for 8 cycles (EC x 4; T x 4)

References

  1. GIM2: Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; GIM. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 x 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article contains dosing details in manuscript PubMed NCT00433420
    1. Update: Del Mastro L, Poggio F, Blondeaux E, De Placido S, Giuliano M, Forestieri V, De Laurentiis M, Gravina A, Bisagni G, Rimanti A, Turletti A, Nisticò C, Vaccaro A, Cognetti F, Fabi A, Gasparro S, Garrone O, Alicicco MG, Urracci Y, Mansutti M, Poletti P, Correale P, Bighin C, Puglisi F, Montemurro F, Colantuoni G, Lambertini M, Boni L; Gruppo Italiano Mammella Investigators. Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial. Lancet Oncol. 2022 Dec;23(12):1571-1582. Epub 2022 Nov 10. link to original article PubMed
  2. tAnGo: Earl HM, Hiller L, Howard HC, Dunn JA, Young J, Bowden SJ, McDermaid M, Waterhouse AK, Wilson G, Agrawal R, O'Reilly S, Bowman A, Ritchie DM, Goodman A, Hickish T, McAdam K, Cameron D, Dodwell D, Rea DW, Caldas C, Provenzano E, Abraham JE, Canney P, Crown JP, Kennedy MJ, Coleman R, Leonard RC, Carmichael JA, Wardley AM, Poole CJ; tAnGo trial collaborators. Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Jun;18(6):755-769. Epub 2017 May 4. link to original article contains dosing details in abstract PubMed NCT00039546
  3. SPECTRUMbrca: Yu KD, Ge JY, Liu XY, Mo M, He M, Shao ZM; SPECTRUM Investigators. Cyclophosphamide-Free Adjuvant Chemotherapy for Ovarian Protection in Young Women With Breast Cancer: A Randomized Phase 3 Trial. J Natl Cancer Inst. 2021 Oct 1;113(10):1352-1359. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01026116
  4. CH-BC-006: Yuan P, Kang Y, Ma F, Fan Y, Wang J, Wang X, Yue J, Luo Y, Zhang P, Li Q, Xu B. Effect of Epirubicin Plus Paclitaxel vs Epirubicin and Cyclophosphamide Followed by Paclitaxel on Disease-Free Survival Among Patients With Operable ERBB2-Negative and Lymph Node-Positive Breast Cancer: A Randomized Clinical Trial. JAMA Netw Open. 2023 Feb 1;6(2):e230122. link to original article link to PMC article contains dosing details in abstract PubMed NCT01134523
  5. CH-BC-012: NCT01378533
  6. Fudan BC MASTER: NCT01314833

ddEC-T

ddEC-T: dose-dense Epirubicin and Cyclophosphamide, followed by Taxol (Paclitaxel)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Burnell et al. 2009 (NCIC-CTG MA.21) 2000-2005 Phase 3 (E-esc) 1. AC-T Superior RFS (primary endpoint)
RFS36: 89.5% vs 85%
(HR 0.60, 95% CI 0.44-0.80)
2. FEC Did not meet primary endpoint of RFS
RFS36: 89.5% vs 90.1%
(HR 0.89, 95% CI 0.64-1.22)

Preceding treatment

Chemotherapy, ddEC portion (cycles 1 to 6)

Supportive therapy, ddEC portion (cycles 1 to 6)

Chemotherapy, T portion (cycles 7 to 10)

14-day cycle for 6 cycles, then 21-day cycle for 4 cycles (ddEC x 6; T x 4)

References

  1. NCIC-CTG MA.21: Burnell M, Levine MN, Chapman JA, Bramwell V, Gelmon K, Walley B, Vandenberg T, Chalchal H, Albain KS, Perez EA, Rugo H, Pritchard K, O'Brien P, Shepherd LE. Cyclophosphamide, epirubicin, and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol. 2010 Jan 1;28(1):77-82. Epub 2009 Nov 9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00014222

iddEnPC

iddEnPC: intense dose-dense Epirubicin, nab-Paclitaxel, Cyclophosphamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Möbus et al. 2021 (GAIN-2) 2012-2017 Phase 3 (C) dtEC-dtD Did not meet primary endpoint of iDFS

Note: growth factor support is not specifically mentioned in the manuscript. The details below for pegfilgrastim are based on the GAIN trial of iddEPC.

Preceding treatment

Chemotherapy, iddE portion (cycles 1 to 3)

Chemotherapy, iddnP portion (cycles 4 to 6)

Chemotherapy, iddC portion (cycles 7 to 9)

Supportive therapy, all portions (cycles 1 to 9)

14-day cycle for 9 cycles (iddE x 3; iddnP x 3; iddC x 3)

References

  1. GAIN-2: Möbus V, Lück HJ, Ladda E, Klare P, Schmidt M, Schneeweiss A, Grischke EM, Wachsmann G, Forstbauer H, Untch M, Marmé F, Blohmer JU, Jackisch C, Huober J, Stickeler E, Reinisch M, Link T, Sinn BV, Janni W, Denkert C, Furlanetto J, Engels K, Solbach C, Schmatloch S, Rey J, Burchardi N, Loibl S; GBG and AGO-B. Phase III randomised trial comparing intense dose-dense chemotherapy to tailored dose-dense chemotherapy in high-risk early breast cancer (GAIN-2). Eur J Cancer. 2021 Oct;156:138-148. Epub 2021 Aug 24. link to original article contains dosing details in manuscript PubMed NCT01690702

iddEPC

iddEPC: intense dose-dense Epirubicin, Paclitaxel, Cyclophosphamide
IDD-ETC: Intense Dose-Dense Epirubicin, Taxol (Paclitaxel), Cyclophosphamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Möbus et al. 2010 (AGO-iddEPC) 1998-2003 Phase 3 (E-esc) EC-T Superior OS1 (secondary endpoint)
OS120: 69% vs 59%
(HR 0.72, 95% CI 0.60-0.87)
Möbus et al. 2017 (GAIN) 2004-2008 Phase 3 (C) ddEC-XP Did not meet primary endpoint of DFS

1Reported efficacy for AGO-iddEPC is based on the 2018 update.
Note: this dosing of cyclophosphamide was after a mid-protocol amendment of GAIN.

Preceding treatment

Chemotherapy, iddE portion (cycles 1 to 3)

Chemotherapy, iddP portion (cycles 4 to 6)

Chemotherapy, iddC portion (cycles 7 to 9)

Supportive therapy, all portions (cycles 1 to 9)

14-day cycle for 9 cycles (iddE x 3; iddP x 3; iddC x 3)

References

  1. AGO-iddEPC: Moebus V, Jackisch C, Lueck HJ, du Bois A, Thomssen C, Kurbacher C, Kuhn W, Nitz U, Schneeweiss A, Huober J, Harbeck N, von Minckwitz G, Runnebaum IB, Hinke A, Kreienberg R, Konecny GE, Untch M. Intense dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide compared with conventionally scheduled chemotherapy in high-risk primary breast cancer: mature results of an AGO phase III study. J Clin Oncol. 2010 Jun 10;28(17):2874-80. Epub 2010 May 10. link to original article PubMed
    1. Update: Möbus V, Jackisch C, Lück HJ, du Bois A, Thomssen C, Kuhn W, Nitz U, Schneeweiss A, Huober J, Harbeck N, von Minckwitz G, Runnebaum IB, Hinke A, Konecny GE, Untch M, Kurbacher C; AGO Breast Study Group (AGO-B). Ten-year results of intense dose-dense chemotherapy show superior survival compared with a conventional schedule in high-risk primary breast cancer: final results of AGO phase III iddEPC trial. Ann Oncol. 2018 Jan 1;29(1):178-185. link to original article PubMed
  2. GAIN: Möbus V, von Minckwitz G, Jackisch C, Lück HJ, Schneeweiss A, Tesch H, Elling D, Harbeck N, Conrad B, Fehm T, Huober J, Müller V, Bauerfeind I, du Bois A, Loibl S, Nekljudova V, Untch M, Thomssen C; German Breast Group; AGO Breast Study Group (AGO-B); NOGGO. German Adjuvant Intergroup Node-positive Study (GAIN): a phase III trial comparing two dose-dense regimens (iddEPC versus ddEC-PwX) in high-risk early breast cancer patients. Ann Oncol. 2017 Aug 1;28(8):1803-1810. link to original article contains dosing details in manuscript PubMed NCT00196872

EP-ddCMF

EP-ddCMF: Epirubicin & Paclitaxel followed by dose-dense Cyclophosphamide, Methotrexate, Fluorouracil

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fountzilas et al. 2007 (HE 10/00) 2000-2005 Phase 3 (C) ddE-ddP-ddCMF Did not meet primary endpoint of DFS36

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT, prior to becoming a standard comparator arm.

Preceding treatment

Chemotherapy, EP portion (cycles 1 to 4)

Chemotherapy, ddCMF portion (cycles 5 to 7)

Supportive therapy, ddCMF portion (cycles 5 to 7)

  • G-CSF (dose not specified) SC once per day on days 2 to 10

21-day cycle for 4 cycles, then 14-day cycle for 3 cycles (EP x 4; ddCMF x 3)

References

  1. HE 10/00: Fountzilas G, Dafni U, Gogas H, Linardou H, Kalofonos HP, Briasoulis E, Pectasides D, Samantas E, Bafaloukos D, Stathopoulos GP, Karina M, Papadimitriou C, Skarlos D, Pisanidis N, Papakostas P, Markopoulos C, Tzorakoeleftherakis E, Dimitrakakis K, Makrantonakis P, Xiros N, Polichronis A, Varthalitis I, Karanikiotis C, Dimopoulos AM; Hellenic Cooperative Oncology Group. Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: safety analysis of the Hellenic Cooperative Oncology Group randomized phase III trial HE 10/00. Ann Oncol. 2008 May;19(5):853-60. Epub 2007 Nov 27. link to original article contains dosing details in manuscript PubMed
    1. Update: Gogas H, Dafni U, Karina M, Papadimitriou C, Batistatou A, Bobos M, Kalofonos HP, Eleftheraki AG, Timotheadou E, Bafaloukos D, Christodoulou C, Markopoulos C, Briasoulis E, Papakostas P, Samantas E, Kosmidis P, Stathopoulos GP, Karanikiotis C, Pectasides D, Dimopoulos MA, Fountzilas G. Postoperative dose-dense sequential versus concomitant administration of epirubicin and paclitaxel in patients with node-positive breast cancer: 5-year results of the Hellenic Cooperative Oncology Group HE 10/00 phase III Trial. Breast Cancer Res Treat. 2012 Apr;132(2):609-19. Epub 2011 Dec 21. link to original article PubMed

FAC-T

FAC-T: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide followed by Taxol (Paclitaxel)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Martín et al. 2013 (GEICAM 2003-02) 2003-2008 Phase 3 (E-switch-ic) FAC x 6 Seems to have superior DFS (primary endpoint)
(HR 0.73, 95% CI 0.54-0.99)

Preceding treatment

Chemotherapy, FAC portion (cycles 1 to 4)

Chemotherapy, T portion (cycles 5 to 12)

21-day cycle for 4 cycles, then 7-day cycle for 8 cycles (FAC x 4; T x 8)

References

  1. GEICAM 2003-02: Martín M, Ruiz A, Ruiz Borrego M, Barnadas A, González S, Calvo L, Margelí Vila M, Antón A, Rodríguez-Lescure A, Seguí-Palmer MA, Muñoz-Mateu M, Dorca Ribugent J, López-Vega JM, Jara C, Espinosa E, Mendiola Fernández C, Andrés R, Ribelles N, Plazaola A, Sánchez-Rovira P, Salvador Bofill J, Crespo C, Carabantes FJ, Servitja S, Chacón JI, Rodríguez CA, Hernando B, Álvarez I, Carrasco E, Lluch A. Fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus FAC followed by weekly paclitaxel as adjuvant therapy for high-risk, node-negative breast cancer: results from the GEICAM/2003-02 study. J Clin Oncol. 2013 Jul 10;31(20):2593-9. Epub 2013 Jun 3. link to original article contains dosing details in manuscript PubMed NCT00129389

FEC-D

FEC-D: Fluorouracil, Epirubicin, Cyclophosphamide followed by Docetaxel

Regimen variant #1, 3 x 3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Roché et al. 2006 (FNCLCC PACS 01) 1997-2000 Phase 3 (E-switch-ic) FEC x 6 Superior OS1 (secondary endpoint)
OS96: 83.2% vs 78%
(aHR 0.75, 95% CI 0.62-0.92)

Seems to have superior DFS60 (primary endpoint)
de Gregorio et al. 2020 (SUCCESS-A) 2005-2007 Phase 3 (C) FEC-DG Did not meet primary endpoint of DFS
Sakr et al. 2013 2006-2010 Phase 3 (E-switch-ic) FEC; FEC 100 x 6 Seems to have superior OS (secondary endpoint)

Seems to have superior DFS60 (primary endpoint)
Campone et al. 2018 (UCBG 2-08) 2007-2010 Phase 3 (C) FEC-Ixabepilone Did not meet primary endpoint of DFS60
Foukakis et al. 2016 (PANTHER) 2007-2011 Phase 3 (C) Dose-dense tailored chemotherapy Did not meet primary endpoint of RFS
Delaloge et al. 2020 (MINDACT) 2007-2011 Phase 3 (C) TX Did not meet primary endpoint of DFS

1Reported efficacy for FNCLCC PACS 01 is based on the 2012 update.

Preceding treatment

Chemotherapy, FEC portion (cycles 1 to 3)

Chemotherapy, D portion (cycles 4 to 6)

21-day cycle for 6 cycles (FEC x 3; D x 3)


Regimen variant #2, 4 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ellis et al. 2009 (TACT) 2001-2003 Phase 3 (E-switch-ic) 1a. E-CMF
1b. FEC x 8 		Did not meet primary endpoint of DFS

Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Preceding treatment

Chemotherapy, FEC portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 8)

21-day cycle for 8 cycles (FEC x 4; D x 4)

References

  1. FNCLCC PACS 01: Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulié P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Genève J, Asselain B. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006 Dec 20;24(36):5664-71. Epub 2006 Nov 20. link to original article PubMed
    1. Update: Coudert B, Asselain B, Campone M, Spielmann M, Machiels JP, Pénault-Llorca F, Serin D, Lévy C, Romieu G, Canon JL, Orfeuvre H, Piot G, Petit T, Jerusalem G, Audhuy B, Veyret C, Beauduin M, Eymard JC, Martin AL, Roché H; UNICANCER Breast Group. Extended benefit from sequential administration of docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide regimen for node-positive breast cancer: the 8-year follow-up results of the UNICANCER-PACS01 trial. Oncologist. 2012;17(7):900-9. Epub 2012 May 18. link to original article link to PMC article PubMed
  2. TACT: Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. link to original article link to PMC article contains dosing details in manuscript PubMed ISRCTN79718493
  3. Sakr H, Hamed RH, Anter AH, Yossef T. Sequential docetaxel as adjuvant chemotherapy for node-positive or/and T3 or T4 breast cancer: clinical outcome (Mansoura University). Med Oncol. 2013 Mar;30(1):457. Epub 2013 Jan 16. link to original article contains dosing details in manuscript PubMed
  4. PANTHER: Foukakis T, von Minckwitz G, Bengtsson NO, Brandberg Y, Wallberg B, Fornander T, Mlineritsch B, Schmatloch S, Singer CF, Steger G, Egle D, Karlsson E, Carlsson L, Loibl S, Untch M, Hellström M, Johansson H, Anderson H, Malmström P, Gnant M, Greil R, Möbus V, Bergh J; Swedish Breast Cancer Group; German Breast Group; Austrian Breast & Colorectal Cancer Study Group. Effect of tailored dose-dense chemotherapy vs standard 3-weekly adjuvant chemotherapy on recurrence-free survival among women with high-risk early breast cancer: a randomized clinical trial. JAMA. 2016 Nov 8;316(18):1888-1896. link to original article contains dosing details in manuscript PubMed NCT00798070
  5. UCBG 2-08: Campone M, Lacroix-Triki M, Roca L, Spielmann M, Wildiers H, Cottu P, Kerbrat P, Levy C, Desmoulins I, Bachelot T, Winston T, Eymard JC, Uwer L, Duhoux FP, Verhoeven D, Jaubert D, Coeffic D, Orfeuvre H, Canon JL, Asselain B, Martin AL, Lemonnier J, Roché H. UCBG 2-08: 5-year efficacy results from the UNICANCER-PACS08 randomised phase III trial of adjuvant treatment with FEC100 and then either docetaxel or ixabepilone in patients with early-stage, poor prognosis breast cancer. Eur J Cancer. 2018 Nov;103:184-194. Epub 2018 Sep 26. link to original article PubMed NCT00630032
  6. MINDACT: Delaloge S, Piccart M, Rutgers E, Litière S, van 't Veer LJ, van den Berkmortel F, Brain E, Dudek-Peric A, Gil-Gil M, Gomez P, Hilbers FS, Khalil Z, Knox S, Kuemmel S, Kunz G, Lesur A, Pierga JY, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Thompson AM, Viale G, Zoppoli G, Vuylsteke P, Tryfonidis K, Poncet C, Bogaerts J, Cardoso F; MINDACT investigators and the TRANSBIG Consortium. Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial. J Clin Oncol. 2020 Apr 10;38(11):1186-1197. Epub 2020 Feb 21. link to original article contains dosing details in supplement link to PMC article PubMed NCT00433589
  7. SUCCESS-A: de Gregorio A, Häberle L, Fasching PA, Müller V, Schrader I, Lorenz R, Forstbauer H, Friedl TWP, Bauer E, de Gregorio N, Deniz M, Fink V, Bekes I, Andergassen U, Schneeweiss A, Tesch H, Mahner S, Brucker SY, Blohmer JU, Fehm TN, Heinrich G, Lato K, Beckmann MW, Rack B, Janni W. Gemcitabine as adjuvant chemotherapy in patients with high-risk early breast cancer-results from the randomized phase III SUCCESS-A trial. Breast Cancer Res. 2020 Oct 23;22(1):111. link to original article link to PMC article contains dosing details in manuscript PubMed NCT02181101

ddFEC-ddD

ddFEC-D: dose-dense Fluorouracil, Epirubicin, Cyclophosphamide followed by dose-dense Docetaxel

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Saloustros et al. 2014 (HORG CT/04.22) 2004-2007 Phase 3 (E-switch-ic) ddFEC-T Did not meet primary endpoint of DFS36
Mavroudis et al. 2016 (HORG CT/07.17) 2007-2013 Phase 3 (C) TC Inconclusive whether non-inferior DFS36

Preceding treatment

Chemotherapy, ddFEC portion (cycles 1 to 4)

Chemotherapy, ddD portion (cycles 5 to 8)

Supportive therapy, both portions (cycles 1 to 8)

  • G-CSF support (drug/dose/schedule not specified)

14-day cycle for 8 cycles (ddFEC x 4; ddD x 4)

References

  1. HORG CT/04.22: Saloustros E, Malamos N, Boukovinas I, Kakolyris S, Kouroussis C, Athanasiadis A, Ziras N, Kentepozidis N, Makrantonakis P, Polyzos A, Christophyllakis C, Georgoulias V, Mavroudis D. Dose-dense paclitaxel versus docetaxel following FEC as adjuvant chemotherapy in axillary node-positive early breast cancer: a multicenter randomized study of the Hellenic Oncology Research Group (HORG). Breast Cancer Res Treat. 2014 Dec;148(3):591-7. Epub 2014 Nov 16. link to original article contains dosing details in abstract PubMed NCT00431080
  2. HORG CT/07.17: Mavroudis D, Matikas A, Malamos N, Papakotoulas P, Kakolyris S, Boukovinas I, Athanasiadis A, Kentepozidis N, Ziras N, Katsaounis P, Saloustros E, Georgoulias V; HORG. Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2016 Oct;27(10):1873-8. Epub 2016 Aug 8. link to original article contains dosing details in manuscript PubMed NCT01985724

FEC-P

FEC-P: Fluorouracil, Epirubicin, Cyclophosphamide followed by Paclitaxel
FEC-T: Fluorouracil, Epirubicin, Cyclophosphamide followed by Taxol (Paclitaxel)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Martín et al. 2008 (GEICAM 9906) 1999-2002 Phase 3 (E-switch-ic) FEC x 6 Superior DFS60 (primary endpoint)
DFS60: 78.5% vs 72.1%
(HR 0.77, 95% CI 0.62-0.95)

Preceding treatment

Chemotherapy, FEC portion (cycles 1 to 4)

Chemotherapy, P portion (cycles 5 to 12)

21-day cycle for 4 cycles, then 7-day cycle for 8 cycles (FEC x 4; P x 8)

References

  1. GEICAM 9906: Martín M, Rodríguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Munárriz B, Rodríguez CA, Crespo C, de Alava E, López García-Asenjo JA, Guitián MD, Almenar S, González-Palacios JF, Vera F, Palacios J, Ramos M, Gracia Marco JM, Lluch A, Alvarez I, Seguí MA, Mayordomo JI, Antón A, Baena JM, Plazaola A, Modolell A, Pelegrí A, Mel JR, Aranda E, Adrover E, Alvarez JV, García Puche JL, Sánchez-Rovira P, Gonzalez S, López-Vega JM; GEICAM. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst. 2008 Jun 4;100(11):805-14. Epub 2008 May 27. link to original article contains dosing details in manuscript PubMed NCT00129922
  2. GIM2: Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; GIM. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 x 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article contains dosing details in manuscript PubMed NCT00433420
    1. Update: Del Mastro L, Poggio F, Blondeaux E, De Placido S, Giuliano M, Forestieri V, De Laurentiis M, Gravina A, Bisagni G, Rimanti A, Turletti A, Nisticò C, Vaccaro A, Cognetti F, Fabi A, Gasparro S, Garrone O, Alicicco MG, Urracci Y, Mansutti M, Poletti P, Correale P, Bighin C, Puglisi F, Montemurro F, Colantuoni G, Lambertini M, Boni L; Gruppo Italiano Mammella Investigators. Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial. Lancet Oncol. 2022 Dec;23(12):1571-1582. Epub 2022 Nov 10. link to original article PubMed

T-FEC

T-FEC: Taxol (Paclitaxel), followed by Epirubicin & Cyclophosphamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kelly et al. 2012 (MDACC ID01-580) 2002-2008 Phase 3 (C) TX-FEC Did not meet primary endpoint of RFS

Preceding treatment

Chemotherapy, T portion (cycles 1 to 12)

Chemotherapy, FEC portion (cycles 13 to 16)

7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (T x 12; FEC x 4)

References

  1. MDACC ID01-580: Kelly CM, Green MC, Broglio K, Thomas ES, Brewster AM, Valero V, Ibrahim NK, Gonzalez-Angulo AM, Booser DJ, Walters RS, Hunt KK, Hortobagyi GN, Buzdar AU. Phase III trial evaluating weekly paclitaxel versus docetaxel in combination with capecitabine in operable breast cancer. J Clin Oncol. 2012 Mar 20;30(9):930-5. Epub 2012 Feb 13. link to original article contains dosing details in manuscript PubMed NCT00050167

TX-CEX

TX-CEX: Taxotere (Docetaxel) & Xeloda (Capecitabine) followed by Cyclophosphamide, Epirubicin, Xeloda (Capecitabine)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Joensuu et al. 2009 (FinXX) 2004-2007 Phase 3 (E-esc) D-FEC Superior RFS (primary endpoint)
RFS36: 93% vs 89%
(HR 0.66, 95% CI 0.47-0.94)

Seems to have superior OS1 (secondary endpoint)
OS180: 77.6% vs 73.3%
(HR 0.81, 95% CI 0.66-0.99)

1Reported OS efficacy is based on the 2022 update.

Preceding treatment

Chemotherapy, TX portion (cycles 1 to 3)

Chemotherapy, CEX portion (cycles 4 to 6)

21-day cycle for 6 cycles (TX x 3; CEX x 3)

References

  1. FinXX: Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Asola R, Kokko R, Ahlgren J, Auvinen P, Hemminki A, Paija O, Helle L, Nuortio L, Villman K, Nilsson G, Lahtela SL, Lehtiö K, Pajunen M, Poikonen P, Nyandoto P, Kataja V, Bono P, Leinonen M, Lindman H; FinXX Study Investigators. Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer: an open-label, randomised controlled trial. Lancet Oncol. 2009 Dec;10(12):1145-51. Epub 2009 Nov 10. link to original article contains dosing details in manuscript PubMed NCT00114816
    1. Update: Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Kokko R, Ahlgren J, Auvinen P, Paija O, Helle L, Villman K, Nyandoto P, Nilsson G, Pajunen M, Asola R, Poikonen P, Leinonen M, Kataja V, Bono P, Lindman H. Adjuvant capecitabine, docetaxel, cyclophosphamide, and epirubicin for early breast cancer: final analysis of the randomized FinXX trial. J Clin Oncol. 2012 Jan 1;30(1):11-8. Epub 2011 Nov 21. link to original article PubMed
    2. Update: Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola A, Tanner M, Ahlgren J, Auvinen P, Lahdenperä O, Villman K, Nyandoto P, Nilsson G, Poikonen-Saksela P, Kataja V, Bono P, Junnila J, Lindman H. Adjuvant Capecitabine for Early Breast Cancer: 15-Year Overall Survival Results From a Randomized Trial. J Clin Oncol. 2022 Apr 1;40(10):1051-1058. Epub 2022 Jan 12. link to original article link to PMC article PubMed

V-FEC

V-FEC: Vinorelbine followed by Fluorouracil, Epirubicin, Cyclophosphamide

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Joensuu et al. 2006 (FinHer) 2000-2003 Phase 3 (C) D-FEC Inferior DDFS

Note: this is the study design for patients with HER2-negative disease.

Preceding treatment

Chemotherapy, V portion (cycles 1 to 3)

  • Vinorelbine (Navelbine) as follows:
    • Cycles 1 & 2: 25 mg/m2 IV over 5 to 10 minutes once per day on days 1, 8, 15
    • Cycle 3: 25 mg/m2 IV over 5 to 10 minutes once per day on days 1 & 8

Chemotherapy, FEC portion (cycles 4 to 6)

21-day cycle for 6 cycles (V x 3; FEC x 3)

References

  1. FinHer: Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article contains dosing details in manuscript PubMed ISRCTN76560285
    1. Update: Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. Epub 2009 Nov 2. link to original article PubMed

Adjuvant chemotherapy

Bevacizumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bear et al. 2012 (NSABP B-40) 2007-2010 Phase 3 (E-esc) See link See link

Preceding treatment

Targeted therapy

21-day cycle for 10 cycles

References

  1. NSABP B-40: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00408408
    1. Update: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Paik S, Swain SM, Mamounas EP, Wolmark N. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1037-1048. Epub 2015 Aug 10. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. link to original article link to PMC article PubMed

Capecitabine monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Muss et al. 2009 (CALGB 49907) 2001-2006 Phase 3 (E-de-esc) Investigator's choice of:
1a. AC x 4
1b. CMF x 6 		Seems to have inferior RFS1 (primary endpoint)
Masuda et al. 2017 (CREATE-X) 2007-2012 Phase 3 (E-esc) Standard therapy Superior DFS (primary endpoint)
DFS60: 74.1% vs 67.6%
(HR 0.70, 95% CI 0.53-0.92)

Superior OS (secondary endpoint)
OS60: 89.2% vs 83.6%
(HR 0.59, 95% CI 0.39-0.90)

1Reported efficacy for CALGB 49907 is based on the 2019 update.
Note: patients in CALGB 49907 received a maximum of 6 cycles. All patients in CREATE-X had residual disease at time of surgical resection. Concomitant endocrine therapy was allowed.

Preceding treatment

Chemotherapy

21-day cycle for 6 to 8 cycles

References

  1. CALGB 49907: Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Becker HP, Kartcheske PA, Wheeler JD, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Magrinat G, Parker BA, Hart RD, Grenier D, Norton L, Hudis CA, Winer EP; CALGB. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009 May 14;360(20):2055-65. Erratum in: N Engl J Med. 2009 Oct 22;361(17):1714. Magrinat, Gutav [corrected to Magrinat, Gustav]. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00024102
    1. Update: Muss HB, Polley MC, Berry DA, Liu H, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Kartcheske PA, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Sutton LM, Magrinat G, Parker BA, Hart RD, Grenier D, Hurria A, Jatoi A, Norton L, Hudis CA, Winer EP, Carey L. Randomized Trial of Standard Adjuvant Chemotherapy Regimens Versus Capecitabine in Older Women With Early Breast Cancer: 10-Year Update of the CALGB 49907 Trial. J Clin Oncol. 2019 Sep 10;37(26):2338-2348. Epub 2019 Jul 24. link to original article link to PMC article PubMed
  2. CREATE-X: Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, Kuroi K, Im SA, Park BW, Kim SB, Yanagita Y, Ohno S, Takao S, Aogi K, Iwata H, Jeong J, Kim A, Park KH, Sasano H, Ohashi Y, Toi M; Japan Breast Cancer Research Group; Korean Breast Cancer Study Group; Korean Cancer Study Group. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017 Jun 1;376(22):2147-2159. link to original article contains dosing details in manuscript PubMed UMIN000000843

CMF

CMF: Cyclophosphamide, Methotrexate, Fluorouracil

Regimen variant #1, 600/40/600 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ron et al. 2001 1988-1992 Phase 3 (C) CNF Seems to have inferior DFS

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #2, 600/40/600 x 6 to 8

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sparano et al. 2018 (TAILORx) 2006-2010 Phase 3 (C) No chemotherapy Non-inferior IDFS (primary endpoint)

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy

21-day cycle for 6 to 8 cycles


Regimen variant #3, 600/40/600 x 8, q4wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Overgaard et al. 1997 (DBCG 82b) 1982-1989 Phase 3 (E-switch-ooc) See link See link

Note: in DBCG 82b, radiotherapy was given between cycles 1 & 2.

Preceding treatment

Chemotherapy

28-day cycle for 8 cycles


Regimen variant #4, 600/40/600 x 9

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ejlertsen et al. 2007 (DBCG 89D) 1990-1998 Phase 3 (C) FEC x 9 Inferior OS

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

Chemotherapy

21-day cycle for 9 cycles


Regimen variant #5, 600/60/600 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Martin et al. 2003 (GEICAM 8701) 1987-1991 Phase 3 (C) FAC; 500/50/500 x 6 Might have inferior DFS

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #6, 700/30/700 x 24

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Clahsen et al. 1995 (EORTC 09771) 1976-1980 Phase 3 (E-esc) Observation Seems to have superior OS

Preceding treatment

Chemotherapy

1-month cycle for 24 cycles


Regimen variant #7, 750/50/600 x 6-8 ("Scottish Breast Group schedule")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Stewart et al. 1993 1980-1990 Phase 3 (C) 1. CMFP
2. Bilateral oophorectomy
3. Oophorectomy & Prednisolone 		Did not meet primary endpoint of EFS
Poole et al. 2006 (BR9601) 1996-2001 Phase 3 (C) E-CMF x 4+4 Inferior OS
Fernando et al. 2019 (SECRAB) 1998-2004 Phase 3 (C) 1a. CMF & RT
1b. E-CMF & RT
1c. A-CMF & RT
1d. MMM & RT 		Inferior LRFS

Preceding treatment

Chemotherapy

21-day cycle for 6 to 8 cycles


Regimen variant #8, 840/50/800

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hubay et al. 1980 NR Randomized (C) 1. CMFT Seems to have inferior RFS
2. CMFT & BCG Did not meet endpoints of RFS/OS

Preceding treatment

Chemotherapy

28-day cycle for 12 cycles


Regimen variant #9, 1000/80/1000 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kimura et al. 2009 1996-2000 Phase 3 (C) FEC Did not meet primary endpoint of DFS

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


Regimen variant #10, 1000/80/1200 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jonat et al. 2002 (ZEBRA) 1990-1996 Phase 3 (C) Goserelin x 2 y Did not meet primary endpoint of DFS
Schmid et al. 2007 (TABLE) 1995-1998 Phase 3 (C) Leuprolide Inferior OS

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


Regimen variant #11, 1120/60/1000 x 12

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brincker et al. 1983 (DBCG 77B) 1977-1983 Phase 3 (E-esc) 1. Cyclophosphamide Did not meet primary endpoint of RFS
2. Levamisole Not reported
3. No chemotherapy Seems to have superior OS1 (secondary endpoint)

1Reported efficacy versus no chemotherapy is based on the 2010 update.

Preceding treatment

Chemotherapy

1-month cycle for 12 cycles


Regimen variant #12, 1120/64/960 x 12

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Howell et al. 1984 1976-1983 Phase 3 (E-esc) Observation Superior RFS

Preceding treatment

Chemotherapy

28-day cycle for 12 cycles


Regimen variant #13, 1200/80/1200 x 1

Historic variant
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Goldhirsch et al. 1989 (LCBS V) 1981-1985 Phase 3 (E-esc) No further treatment Seems to have superior DFS

Note: leucovorin was not used for antineoplastic effect in this regimen.

Preceding treatment

Chemotherapy

Supportive therapy

8-day course


Regimen variant #14, 1200/80/1200 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Perrone et al. 2014 (ELDA) 2003-2011 Phase 3 (C) Docetaxel Did not meet primary endpoint of DFS

Note: In ELDA, this protocol was for ER/PR+ patients.

Preceding treatment

Chemotherapy

28-day cycle for 4 cycles


Regimen variant #15, 1200/80/1200 x 6 ("Classical" IV)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ragaz et al. 1997 1978-1986 Phase 3 (C) CMF & RT Seems to have inferior OS
Coombes et al. 1996 1984-1992 Phase 3 (C) FEC Did not meet co-primary endpoints of RFS/OS
Taucher et al. 2007 (ABCSG-07) 1991-1999 Phase 3 (C) CMF; neoadjuvant Seems to have superior RFS
Poole et al. 2006 (NEAT) 1996-2001 Phase 3 (C) E-CMF x 4+4 Inferior OS
Fernando et al. 2019 (SECRAB) 1998-2004 Phase 3 (C) 1a. CMF & RT
1b. E-CMF & RT
1c. A-CMF & RT
1d. MMM & RT 		Inferior LRFS
Perrone et al. 2014 (ELDA) 2003-2011 Phase 3 (C) Docetaxel Did not meet primary endpoint of DFS

Note: In ELDA, this protocol was for ER/PR- patients.

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


Regimen variant #16, 1400/60/1200 x 12

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rubens et al. 1989 (EORTC 10792) 1979-1985 Phase 3 (E-esc) 1. Observation Did not meet endpoint of OS
2. Tamoxifen
3. CMFT 		Not reported

Note: this trial had a complex efficacy analysis; see paper for details.

Preceding treatment

Chemotherapy

28-day cycle for 12 cycles


Regimen variant #17, 1400/80/1000 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Watanabe et al. 2009 (NSAS BC-01) 1996-2001 Phase 3 (C) UFT Inconclusive whether non-inferior RFS

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


Regimen variant #18, 1400/80/1200 x 3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Castiglione-Gertsch et al. 1996 (IBCSG VI) 1986-1993 Phase 3 (E-de-esc) 1. CMF x 6 Seems to have inferior DFS
2. CMF x 3, with re-introduction
3. CMF x 6, with re-introduction 		Might have inferior DFS

Preceding treatment

Chemotherapy

28-day cycle for 3 cycles

Subsequent treatment


Regimen variant #19, 1400/80/1200 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tancini et al. 1979 (CALGB 7581) 1975-NR Phase 3 (E-de-esc) CMF x 12 Did not meet primary endpoint of RFS
Coombes et al. 1996 1984-1992 Phase 3 (C) FEC Did not meet co-primary endpoints of RFS/OS
Castiglione-Gertsch et al. 1996 (IBCSG VI) 1986-1993 Phase 3 (C) 1. CMF x 3 Seems to have superior DFS
2. CMF x 3, with re-introduction
3. CMF x 6, with re-introduction 		Might have inferior DFS
Piccart et al. 2001 (Belgian trial) 1988-1996 Phase 3 (C) 1. EC; full-dose Did not meet primary endpoint of EFS
2. EC; moderate-dose Did not meet primary endpoint of EFS
Levine et al. 1998 (NCIC-CTG MA.5) 1989-1993 Phase 3 (C) CEF Inferior RFS
Amadori et al. 2000 1989-1993 Phase 3 (E-esc) Observation Seems to have superior DFS
Hutchins et al. 2005 (INT-0102) 1989-1993 Phase 3 (C) CAF Seems to have inferior OS
Jonat et al. 2002 (ZEBRA) 1990-1996 Phase 3 (C) Goserelin x 2 y Did not meet primary endpoint of DFS
Fisher et al. 2001 (NSABP B-23) 1991-1998 Phase 3 (C) AC Did not meet primary endpoint of OS
Adjuvant Breast Cancer Trials Collaborative Group 2007 (NCRI ABC-CT) 1992-2000 Phase 3 (E-esc) Observation Seems to have superior OS (primary endpoint)
(aHR 0.83, 95% CI 0.70-0.99)
Poole et al. 2006 (NEAT) 1996-2001 Phase 3 (C) E-CMF x 4+4 Inferior OS
Fernando et al. 2019 (SECRAB) 1998-2004 Phase 3 (C) 1a. CMF & RT
1b. E-CMF & RT
1c. A-CMF & RT
1d. MMM & RT 		Inferior LRFS
Muss et al. 2009 (CALGB 49907) 2001-2006 Phase 3 (C) Capecitabine Seems to have superior OS1 (secondary endpoint)
RFS120: 56% vs 50%
(HR 0.80, 95% CI 0.62-0.98)

Seems to have superior RFS (primary endpoint)
Sparano et al. 2018 (TAILORx) 2006-2010 Phase 3 (C) No chemotherapy Non-inferior IDFS (primary endpoint)

1Reported efficacy for CALGB 49907 is based on the 2019 update.

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

Subsequent treatment


Regimen variant #20, 1400/80/1200 x 12

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bonadonna et al. 1976 1973-1975 Phase 3 (E-esc) Observation Superior RFS
Tancini et al. 1979 (CALGB 7581) 1975-NR Phase 3 (C) CMF x 6 Did not meet primary endpoint of RFS
Misset et al. 1996 (OncoFrance) 1978-1981 Phase 3 (C) AVCF Inferior OS
Tormey et al. 1990 (ECOG E5177) 1978-1982 Phase 3 (C) 1. CMFP
2. CMFPT 		Did not meet co-primary endpoints of TTR/OS

Preceding treatment

Chemotherapy

28-day cycle for 12 cycles

References

  1. Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, De Lena M, Tancini G, Bajetta E, Musumeci R, Veronesi U. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976 Feb 19;294(8):405-10. link to original article contains dosing details in manuscript PubMed
    1. Update: Bonadonna G, Rossi A, Valagussa P, Banfi A, Veronesi U. The CMF program for operable breast cancer with positive axillary nodes: updated analysis on the disease-free interval, site of relapse and drug tolerance. Cancer. 1977 Jun;39(6 Suppl):2904-15. link to original article PubMed
    2. Update: Bonadonna G, Valagussa P, Rossi A, Tancini G, Brambilla C, Zambetti M, Veronesi U. Ten-year experience with CMF-based adjuvant chemotherapy in resectable breast cancer. Breast Cancer Res Treat. 1985;5(2):95-115. link to original article PubMed
    3. Update: Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995 Apr 6;332(14):901-6. link to original article PubMed
  2. CALGB 7581: Tancini G, Bajetta E, Marchini S, Valagussa P, Bonadonna G, Veronesi U. Preliminary 3-year results of 12 versus 6 cycles of surgical adjuvant CMF in premenopausal breast cancer. Cancer Clin Trials. 1979 Winter;2(4):285-92. PubMed
    1. Update: Tancini G, Bonadonna G, Valagussa P, Marchini S, Veronesi U. Adjuvant CMF in breast cancer: comparative 5-year results of 12 versus 6 cycles. J Clin Oncol. 1983 Jan;1(1):2-10. link to original article PubMed
  3. Hubay CA, Pearson OH, Marshall JS, Rhodes RS, Debanne SM, Mansour EG, Hermann RE, Jones JC, Flynn WJ, Eckert C, McGuire WL. Antiestrogen, cytotoxic chemotherapy, and bacillus Calmette-Guerin vaccination in stage II breast cancer: a preliminary report. Surgery. 1980 May;87(5):494-501. link to original article PubMed
    1. Update: Hubay CA, Pearson OH, Marshall JS, Rhodes RS, DeBanne SM, Rosenblatt J, Mansour EG, Hermann RE, Jones JC, Flynn WJ, Eckert C, McGuire WL. Adjuvant chemotherapy, antiestrogen therapy and immunotherapy for stage II breast cancer: 45-month follow-up of a prospective, randomized clinical trial. Cancer. 1980 Dec 15;46(12 Suppl):2805-8. link to original article PubMed
  4. DBCG 77B: Brincker H, Mouridsen HT, Andersen KW. Adjuvant chemotherapy with cyclophosphamide or CMF in premenopausal women with stage II breast cancer. Breast Cancer Res Treat. 1983;3(1):91-5. link to original article contains dosing details in manuscript PubMed
    1. Update: Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Andersson M, Kamby C, Knoop AS; Danish Breast Cancer Cooperative Group. Cyclophosphamide, methotrexate, and fluorouracil; oral cyclophosphamide; levamisole; or no adjuvant therapy for patients with high-risk, premenopausal breast cancer. Cancer. 2010 May 1;116(9):2081-9. link to original article PubMed
  5. Howell A, Bush H, George WD, Howat JM, Crowther D, Sellwood RA, Rubens RD, Hayward JL, Bulbrook RD, Fentiman IS, Chaudary M. Controlled trial of adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil for breast cancer. Lancet. 1984 Aug 11;2(8398):307-11. link to original article PubMed
  6. LCBS V: Goldhirsch A, Gelber RD; Ludwig Breast Cancer Study Group. Prolonged disease-free survival after one course of perioperative adjuvant chemotherapy for node-negative breast cancer. N Engl J Med. 1989 Feb 23;320(8):491-6. link to original article PubMed
  7. ECOG E5177: Tormey DC, Gray R, Gilchrist K, Grage T, Carbone PP, Wolter J, Woll JE, Cummings FJ. Adjuvant chemohormonal therapy with cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen compared with CMF for premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial. Cancer. 1990 Jan 15;65(2):200-6. link to original article contains dosing details in manuscript PubMed
  8. Stewart HJ, Forrest APM, Hawkins RA, Prescott RJ, Smith DC, Everington D, Richards MA, George WD; Scottish Cancer Trials Breast Group and ICRF Breast Unit Guy's Hospital London. Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast carcinoma: the Scottish trial. Lancet. 1993 May 22;341(8856):1293-8. link to original article contains dosing details in manuscript PubMed
  9. EORTC 09771: Clahsen PC, van de Velde CJ, Welvaart K, Repelaer van Driel OJ, Sylvester RJ; Cooperating Investigators. Ten-year results of a randomized trial evaluating prolonged low-dose adjuvant chemotherapy in node-positive breast cancer: a joint European Organisation for Research and Treatment of Cancer-Dutch Breast Cancer Working Party Study. J Clin Oncol. 1995 Jan;13(1):33-41. link to original article contains dosing details in abstract PubMed
  10. Coombes RC, Bliss JM, Wils J, Morvan F, Espié M, Amadori D, Gambrosier P, Richards M, Aapro M, Villar-Grimalt A, McArdle C, Pérez-López FR, Vassilopoulos P, Ferreira EP, Chilvers CE, Coombes G, Woods EM, Marty M; International Collaborative Cancer Group. Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. J Clin Oncol. 1996 Jan;14(1):35-45. link to original article contains dosing details in manuscript PubMed
  11. OncoFrance: Misset JL, di Palma M, Delgado M, Plagne R, Chollet P, Fumoleau P, Le Mevel B, Belpomme D, Guerrin J, Fargeot P, Metz R, Ithzaki M, Hill C, Mathé G. Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: final report after a 16-year median follow-up duration. J Clin Oncol. 1996 Apr;14(4):1136-45. link to original article contains dosing details in manuscript PubMed
  12. IBCSG VI: Castiglione-Gertsch M, Goldhirsch A; International Breast Cancer Study Group. Duration and reintroduction of adjuvant chemotherapy for node-positive premenopausal breast cancer patients. J Clin Oncol. 1996 Jun;14(6):1885-94. link to original article contains dosing details in manuscript PubMed
    1. Pooled QoL analysis: Hürny C, Bernhard J, Coates AS, Castiglione-Gertsch M, Peterson HF, Gelber RD, Forbes JF, Rudenstam CM, Simoncini E, Crivellari D, Goldhirsch A, Senn HJ; International Breast Cancer Study Group. Impact of adjuvant therapy on quality of life in women with node-positive operable breast cancer. Lancet. 1996 May 11;347(9011):1279-84. Erratum in: Lancet 1997 Jul 26;350(9073):298. link to original article PubMed
  13. EORTC 10792: Rubens RD, Bartelink H, Engelsman E, Hayward JL, Rotmensz N, Sylvester R, van der Schueren E, Papadiamantis J, Vassilaros SD, Wildiers J, Winter PJ. Locally advanced breast cancer: the contribution of cytotoxic and endocrine treatment to radiotherapy - an EORTC Breast Cancer Co-operative Group Trial (10792). Eur J Cancer Clin Oncol. 1989 Apr;25(4):667-78. link to original article PubMed
    1. Update: Bartelink H, Rubens RD, van der Schueren E, Sylvester R. Hormonal therapy prolongs survival in irradiated locally advanced breast cancer: a European Organization for Research and Treatment of Cancer Randomized Phase III Trial. J Clin Oncol. 1997 Jan;15(1):207-15. link to original article contains dosing details in manuscript PubMed
  14. DBCG 82b: Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, Kjaer M, Gadeberg CC, Mouridsen HT, Jensen MB, Zedeler K. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy: Danish Breast Cancer Cooperative Group 82b trial. N Engl J Med. 1997 Oct 2;337(14):949-55. link to original article contains dosing details in manuscript PubMed
  15. Ragaz J, Jackson SM, Le N, Plenderleith IH, Spinelli JJ, Basco VE, Wilson KS, Knowling MA, Coppin CM, Paradis M, Coldman AJ, Olivotto IA. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med. 1997 Oct 2;337(14):956-62. link to original article contains dosing details in abstract PubMed
  16. Review: Goldhirsch A, Colleoni M, Coates AS, Castiglione-Gertsch M, Gelber RD; International Breast Cancer Study Group. Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: are all CMFs alike?. Ann Oncol. 1998 May;9(5):489-93. link to original article contains dosing details in abstract PubMed
  17. NCIC-CTG MA.5: Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, Findlay B, Warr D, Bowman D, Myles J, Arnold A, Vandenberg T, MacKenzie R, Robert J, Ottaway J, Burnell M, Williams CK, Tu D; National Cancer Institute of Canada Clinical Trials Group. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol. 1998 Aug;16(8):2651-8. link to original article PubMed
    1. Update: Levine MN, Pritchard KI, Bramwell VH, Shepherd LE, Tu D, Paul N; National Cancer Institute of Canada Clinical Trials Group. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol. 2005 Aug 1;23(22):5166-70. link to original article PubMed
    2. Subgroup analysis: Pritchard KI, Shepherd LE, O'Malley FP, Andrulis IL, Tu D, Bramwell VH, Levine MN; National Cancer Institute of Canada Clinical Trials Group. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med. 2006 May 18;354(20):2103-11. link to original article PubMed
  18. Amadori D, Nanni O, Marangolo M, Pacini P, Ravaioli A, Rossi A, Gambi A, Catalano G, Perroni D, Scarpi E, Giunchi DC, Tienghi A, Becciolini A, Volpi A. Disease-free survival advantage of adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with node-negative, rapidly proliferating breast cancer: a randomized multicenter study. J Clin Oncol. 2000 Sep;18(17):3125-34. link to original article contains dosing details in manuscript PubMed
    1. Update: Amadori D, Nanni O, Volpi A, Casadei Giunchi D, Marangolo M, Livi L, Ravaioli A, Rossi AP, Gambi A, Luzi Fedeli S, Perroni D, Scarpi E, Becciolini A, Silvestrini R. Phase III randomized multicenter study on the effects of adjuvant CMF in patients with node-negative, rapidly proliferating breast cancer: twelve-year results and retrospective subgroup analysis. Breast Cancer Res Treat. 2008 Mar;108(2):259-64. Epub 2007 May 26. link to original article PubMed
  19. NSABP B-23: Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, Dimitrov NV, Atkins JN, Abramson N, Merajver S, Romond EH, Kardinal CG, Shibata HR, Margolese RG, Farrar WB. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001 Feb 15;19(4):931-42. link to original article PubMed
    1. Update: Fisher B, Jeong JH, Anderson S, Wolmark N. Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst. 2004 Dec 15;96(24):1823-31. link to original article PubMed
  20. Belgian trial: Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M, Nogaret JM. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol. 2001 Jun 15;19(12):3103-10. link to original article PubMed
    1. Update: de Azambuja E, Paesmans M, Beauduin M, Vindevoghel A, Cornez N, Finet C, Ries F, Closon-Dejardin MT, Kerger J, Gobert P, Focan C, Tagnon A, Dolci S, Nogaret JM, di Leo A, Piccart-Gebhart MJ. Long-term benefit of high-dose epirubicin in adjuvant chemotherapy for node-positive breast cancer: 15-year efficacy results of the Belgian multicentre study. J Clin Oncol. 2009 Feb 10;27(5):720-5. Epub 2008 Dec 22. link to original article PubMed
  21. Ron IG, Wigler N, Borovik R, Brufman G, Rizel S, Shani A, Brenner J, Farbstein H, Dale A, Inbar MJ, Brenner HJ, Chaitchik S, Catane R. CMF (cyclophosphamide, methotrexate, 5-fluorouracil) versus CNF (cyclophosphamide, mitoxantrone, 5-fluorouracil) as adjuvant chemotherapy for stage II lymph-node positive breast cancer: a phase III randomized multicenter study. Am J Clin Oncol. 2001 Aug;24(4):323-7. link to original article PubMed
  22. ZEBRA: Jonat W, Kaufmann M, Sauerbrei W, Blamey R, Cuzick J, Namer M, Fogelman I, de Haes JC, de Matteis A, Stewart A, Eiermann W, Szakolczai I, Palmer M, Schumacher M, Geberth M, Lisboa B; Zoladex Early Breast Cancer Research Association Study. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: the Zoladex Early Breast Cancer Research Association study. J Clin Oncol. 2002 Dec 15;20(24):4628-35. link to original article contains dosing details in manuscript PubMed
  23. GEICAM 8701: Martin M, Villar A, Sole-Calvo A, Gonzalez R, Massuti B, Lizon J, Camps C, Carrato A, Casado A, Candel MT, Albanell J, Aranda J, Munarriz B, Campbell J, Diaz-Rubio E; GEICAM. Doxorubicin in combination with fluorouracil and cyclophosphamide (iv FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (iv CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Ann Oncol. 2003 Jun;14(6):833-42. link to original article contains dosing details in abstract PubMed
  24. INT-0102: Hutchins LF, Green SJ, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of intergroup protocol INT-0102. J Clin Oncol. 2005 Nov 20;23(33):8313-21. link to original article PubMed
  25. NEAT: Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. link to original article PubMed NCT00003577
    1. Update: Earl HM, Hiller L, Dunn JA, Vallier AL, Bowden SJ, Jordan SD, Blows F, Munro A, Bathers S, Grieve R, Spooner DA, Agrawal R, Fernando I, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, McAdam K, Foster L, Leonard RC, Twelves CJ, Cameron D, Bartlett JM, Pharoah P, Provenzano E, Caldas C, Poole CJ; NEAT Investigators and the SCTBG. Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials. Br J Cancer. 2012 Oct 9;107(8):1257-67. Epub 2012 Sep 11. link to original article link to PMC article PubMed
  26. BR9601: Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. link to original article PubMed NCT00003012
    1. Update: Earl HM, Hiller L, Dunn JA, Vallier AL, Bowden SJ, Jordan SD, Blows F, Munro A, Bathers S, Grieve R, Spooner DA, Agrawal R, Fernando I, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, McAdam K, Foster L, Leonard RC, Twelves CJ, Cameron D, Bartlett JM, Pharoah P, Provenzano E, Caldas C, Poole CJ; NEAT Investigators and the SCTBG. Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials. Br J Cancer. 2012 Oct 9;107(8):1257-67. Epub 2012 Sep 11. link to original article link to PMC article PubMed
  27. DBCG 89D: Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Cold S, Edlund P, Ewertz M, Jensen BB, Kamby C, Nordenskjold B, Bergh J. Improved outcome from substituting methotrexate with epirubicin: results from a randomised comparison of CMF versus CEF in patients with primary breast cancer. Eur J Cancer. 2007 Mar;43(5):877-84. Epub 2007 Feb 16. link to original article contains dosing details in manuscript PubMed
  28. NCRI ABC-CT: Adjuvant Breast Cancer Trials Collaborative Group. Polychemotherapy for early breast cancer: results from the international adjuvant breast cancer chemotherapy randomized trial. J Natl Cancer Inst. 2007 Apr 4;99(7):506-15. link to original article contains dosing details in manuscript PubMed NCT00002582
  29. TABLE: Schmid P, Untch M, Kossé V, Bondar G, Vassiljev L, Tarutinov V, Lehmann U, Maubach L, Meurer J, Wallwiener D, Possinger K. Leuprorelin acetate every-3-months depot versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in premenopausal patients with node-positive breast cancer: the TABLE study. J Clin Oncol. 2007 Jun 20;25(18):2509-15. link to original article contains dosing details in manuscript PubMed
  30. ABCSG-07: Taucher S, Steger GG, Jakesz R, Tausch C, Wette V, Schippinger W, Kwasny W, Reiner G, Greil R, Dubsky P, Poestlberger S, Tschmelitsch J, Samonigg H, Gnant M; ABCSG. The potential risk of neoadjuvant chemotherapy in breast cancer patients--results from a prospective randomized trial of the Austrian Breast and Colorectal Cancer Study Group (ABCSG-07). Breast Cancer Res Treat. 2008 Nov;112(2):309-16. Epub 2007 Dec 14. link to original article contains dosing details in abstract PubMed
  31. NSAS BC-01: Watanabe T, Sano M, Takashima S, Kitaya T, Tokuda Y, Yoshimoto M, Kohno N, Nakagami K, Iwata H, Shimozuma K, Sonoo H, Tsuda H, Sakamoto G, Ohashi Y. Oral uracil and tegafur compared with classic cyclophosphamide, methotrexate, fluorouracil as postoperative chemotherapy in patients with node-negative, high-risk breast cancer: National Surgical Adjuvant Study for Breast Cancer 01 trial. J Clin Oncol. 2009 Mar 20;27(9):1368-74. Epub 2009 Feb 9. link to original article contains dosing details in manuscript PubMed NCT00152191
  32. TACT: Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. link to original article link to PMC article contains dosing details in abstract PubMed ISRCTN79718493
  33. CALGB 49907: Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Becker HP, Kartcheske PA, Wheeler JD, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Magrinat G, Parker BA, Hart RD, Grenier D, Norton L, Hudis CA, Winer EP; CALGB. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009 May 14;360(20):2055-65. Erratum in: N Engl J Med. 2009 Oct 22;361(17):1714. Magrinat, Gutav [corrected to Magrinat, Gustav]. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00024102
    1. Update: Muss HB, Polley MC, Berry DA, Liu H, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Kartcheske PA, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Sutton LM, Magrinat G, Parker BA, Hart RD, Grenier D, Hurria A, Jatoi A, Norton L, Hudis CA, Winer EP, Carey L. Randomized Trial of Standard Adjuvant Chemotherapy Regimens Versus Capecitabine in Older Women With Early Breast Cancer: 10-Year Update of the CALGB 49907 Trial. J Clin Oncol. 2019 Sep 10;37(26):2338-2348. Epub 2019 Jul 24. link to original article link to PMC article PubMed
  34. Kimura M, Tominaga T, Takatsuka Y, Toi M, Abe R, Koyama H, Takashima S, Nomura Y, Miura S, Kimijima I, Tashiro H, Ohashi Y; Adjuvant CEF Research Group for Breast Cancer. Randomized trial of cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil with node-positive breast cancer in Japan. Breast Cancer. 2010 Jul;17(3):190-8. Epub 2009 Jul 3. link to original article contains dosing details in abstract PubMed
  35. ELDA: Perrone F, Nuzzo F, Di Rella F, Gravina A, Iodice G, Labonia V, Landi G, Pacilio C, Rossi E, De Laurentiis M, D'Aiuto M, Botti G, Forestieri V, Lauria R, De Placido S, Tinessa V, Daniele B, Gori S, Colantuoni G, Barni S, Riccardi F, De Maio E, Montanino A, Morabito A, Daniele G, Di Maio M, Piccirillo MC, Signoriello S, Gallo C, de Matteis A. Weekly docetaxel versus CMF as adjuvant chemotherapy for older women with early breast cancer: final results of the randomized phase III ELDA trial. Ann Oncol. 2015 Apr;26(4):675-82. Epub 2014 Dec 8. link to original article contains dosing details in abstract PubMed NCT00331097
  36. TAILORx: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. link to original article link to PMC article contains dosing details in supplement PubMed NCT00310180
  37. SECRAB: Fernando IN, Bowden SJ, Herring K, Brookes CL, Ahmed I, Marshall A, Grieve R, Churn M, Spooner D, Latief TN, Agrawal RK, Brunt AM, Stevens A, Goodman A, Canney P, Bishop J, Ritchie D, Dunn J, Poole CJ, Rea DW; SECRAB Investigators. Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial. Radiother Oncol. 2020 Jan;142:52-61. Epub 2019 Nov 27. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00003893

CMFT

CMFT: Cyclophosphamide, Methotrexate, Fluorouracil, Tamoxifen

Regimen variant #1, 600/40/600 x 9, 30 x 12 mo

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Overgaard et al. 1999 (DBCG 82C) 1982-1990 Phase 3 (E-esc) 1. Tamoxifen Superior DFS1
2. Tamoxifen & RT Not reported

1Reported efficacy for this arm versus tamoxifen monotherapy is based on the 2013 update.

Preceding treatment

Chemotherapy

Endocrine therapy

28-day cycle for 13 cycles


Regimen variant #2, 780/80/1000 x 6, 20 x 2 yr

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Park et al. 2009 (Taiho 91023033) 1996-2000 Phase 3 (C) UFT & Tamoxifen Non-inferior RFS60

Preceding treatment

Chemotherapy

Endocrine therapy

28-day cycle for 26 cycles


Regimen variant #3, 840/50/800/40 x 12

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hubay et al. 1980 NR Randomized (E-RT-esc) 1. CMF Seems to have superior RFS
2. CMFT & BCG Did not meet endpoints of RFS/OS

Preceding treatment

Chemotherapy

Endocrine therapy

28-day cycle for 12 cycles

References

  1. Hubay CA, Pearson OH, Marshall JS, Rhodes RS, Debanne SM, Mansour EG, Hermann RE, Jones JC, Flynn WJ, Eckert C, McGuire WL. Antiestrogen, cytotoxic chemotherapy, and bacillus Calmette-Guerin vaccination in stage II breast cancer: a preliminary report. Surgery. 1980 May;87(5):494-501. link to original article PubMed
    1. Update: Hubay CA, Pearson OH, Marshall JS, Rhodes RS, DeBanne SM, Rosenblatt J, Mansour EG, Hermann RE, Jones JC, Flynn WJ, Eckert C, McGuire WL. Adjuvant chemotherapy, antiestrogen therapy and immunotherapy for stage II breast cancer: 45-month follow-up of a prospective, randomized clinical trial. Cancer. 1980 Dec 15;46(12 Suppl):2805-8. link to original article PubMed
  2. NSABP B-20: Fisher B, Dignam J, Wolmark N, DeCillis A, Emir B, Wickerham DL, Bryant J, Dimitrov NV, Abramson N, Atkins JN, Shibata H, Deschenes L, Margolese RG. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst. 1997 Nov 19;89(22):1673-82. link to original article contains dosing details in manuscript PubMed
    1. Pooled update: Fisher B, Jeong JH, Bryant J, Anderson S, Dignam J, Fisher ER, Wolmark N; National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet. 2004 Sep 4-10;364(9437):858-68. link to original article PubMed
    2. Pooled update: Taghian AG, Jeong JH, Mamounas EP, Parda DS, Deutsch M, Costantino JP, Wolmark N. Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol. 2006 Aug 20;24(24):3927-32. link to original article PubMed
  3. DBCG 82C: Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M, Kamby C, Kjaer M, Gadeberg CC, Rasmussen BB, Blichert-Toft M, Mouridsen HT. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet. 1999 May 15;353(9165):1641-8. link to original article contains dosing details in abstract PubMed
    1. Update: Ejlertsen B, Jensen MB, Elversang J, Rasmussen BB, Andersson M, Andersen J, Nielsen DL, Cold S, Mouridsen HT. One year of adjuvant tamoxifen compared with chemotherapy and tamoxifen in postmenopausal patients with stage II breast cancer. Eur J Cancer. 2013 Sep;49(14):2986-94. Epub 2013 Jun 8. link to original article contains dosing details in manuscript PubMed
  4. Taiho 91023033: Park Y, Okamura K, Mitsuyama S, Saito T, Koh J, Kyono S, Higaki K, Ogita M, Asaga T, Inaji H, Komichi H, Kohno N, Yamazaki K, Tanaka F, Ito T, Nishikawa H, Osaki A, Koyama H, Suzuki T. Uracil-tegafur and tamoxifen vs cyclophosphamide, methotrexate, fluorouracil, and tamoxifen in post-operative adjuvant therapy for stage I, II, or IIIA lymph node-positive breast cancer: a comparative study. Br J Cancer. 2009 Aug 18;101(4):598-604. Epub 2009 Jul 28. Erratum in: Br J Cancer. 2009 Sep 15;101(6):1031. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00152178

Cyclophosphamide & Docetaxel (TC)

TC: Taxotere (Docetaxel) & Cyclophosphamide
DC: Docetaxel & Cyclophosphamide

Regimen variant #1, 4 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jones et al. 2006 (USOR 9735) 1997-1999 Phase 3 (E-switch-ic) AC Seems to have superior OS
Sparano et al. 2018 (TAILORx) 2006-2010 Phase 3 (C) No chemotherapy Non-inferior IDFS (primary endpoint)
Blum et al. 2017 (USOR 06-090) 2007-2009 Phase 3 (E-de-esc) TAC Seems to have inferior IDFS
Blum et al. 2017 (NSABP-46-I/USOR 07132) 2009-2012 Phase 3 (C) TAC Seems to have inferior IDFS
Blum et al. 2017 (NSABP B-49) 2012-04-04 to 2013-11-21 Phase 3 (E-de-esc) TAC Seems to have inferior IDFS (primary endpoint)

Note: Blum et al. 2017 is a pooled analysis of three RCTs, some of which had arms other than TAC and TC. Refer to the paper for further details.

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy

Supportive therapy

21-day cycle for 4 cycles


Regimen variant #2, 6 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mavroudis et al. 2016 (HORG CT/07.17) 2007-2013 Phase 3 (E-de-esc) ddFEC-D Inconclusive whether non-inferior DFS36 (primary endpoint)
de Gregorio et al. 2022 (LMU Success C) 2008-2011 Phase 3 (E-de-esc) FEC-D Inconclusive whether non-inferior DFS1 (primary endpoint)
Ejlertsen et al. 2017 (DBCG 07-READ) 2008-2012 Phase 3 (E-de-esc) EC-D Did not meet primary endpoint of DFS
DFS60: 88.3% vs 87.9%
(HR 1.00, 95% CI 0.78-1.28)
Nitz et al. 2019 (WSG PlanB) 2009-02 to 2011-12 Phase 3 (E-de-esc) EC-D Non-inferior DFS (primary endpoint)
Fehrenbacher et al. 2019 (NSABP B-47) 2011-2015 Phase 3 (C) 1a. AC-TH
1b. ddAC-TH
1c. TCH 		Did not meet primary endpoint of IDFS

1LMU Success C was designed as a non-inferiority trial but was reported using a superiority design post-hoc analysis.
Note: de Gregorio et al. 2022 was a pooled update and also the first report of LMU Success C.

Biomarker eligibility criteria

  • DBCG 07-READ: TOP2A normal as determined by FISH
  • NSABP B-47: HER2 IHC of 1+ or 2+ with FISH ratio less than 2 or HER2 gene copy number less than 4

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles

References

  1. USOR 9735: Jones SE, Savin MA, Holmes FA, O'Shaughnessy JA, Blum JL, Vukelja S, McIntyre KJ, Pippen JE, Bordelon JH, Kirby R, Sandbach J, Hyman WJ, Khandelwal P, Negron AG, Richards DA, Anthony SP, Mennel RG, Boehm KA, Meyer WG, Asmar L. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol. 2006 Dec 1;24(34):5381-7. Erratum in: J Clin Oncol. 2007 May 1;25(13):1819. link to original article PubMed
    1. Update: Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL, Sandbach J, Hyman WJ, Richards DA, Mennel RG, Boehm KA, Meyer WG, Asmar L, Mackey D, Riedel S, Muss H, Savin MA. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology research trial 9735. J Clin Oncol. 2009 Mar 10;27(8):1177-83. Epub 2009 Feb 9. link to original article PubMed
  2. HORG CT/07.17: Mavroudis D, Matikas A, Malamos N, Papakotoulas P, Kakolyris S, Boukovinas I, Athanasiadis A, Kentepozidis N, Ziras N, Katsaounis P, Saloustros E, Georgoulias V; HORG. Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2016 Oct;27(10):1873-8. Epub 2016 Aug 8. link to original article contains dosing details in manuscript PubMed NCT01985724
  3. USOR 06-090: Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00493870
    1. Pooled update: Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. link to original article link to PMC article PubMed
  4. NSABP-46-I/USOR 07132: Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00887536
    1. Pooled update: Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. link to original article link to PMC article PubMed
  5. NSABP B-49: Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01547741
    1. Pooled update: Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. link to original article link to PMC article PubMed
  6. DBCG 07-READ: Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen MB, Knoop AS, Højris I, Ewertz M, Balslev E, Danø H, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. Adjuvant cyclophosphamide and docetaxel with or without epirubicin for early TOP2A-normal breast cancer: DBCG 07-READ, an open-label, phase III, randomized trial. J Clin Oncol. 2017 Aug 10;35(23):2639-2646. Epub 2017 Jun 29. link to original article contains dosing details in manuscript PubMed NCT00689156
  7. TAILORx: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. link to original article link to PMC article contains dosing details in supplement PubMed NCT00310180
  8. WSG PlanB: Nitz U, Gluz O, Clemens M, Malter W, Reimer T, Nuding B, Aktas B, Stefek A, Pollmanns A, Lorenz-Salehi F, Uleer C, Krabisch P, Kuemmel S, Liedtke C, Shak S, Wuerstlein R, Christgen M, Kates RE, Kreipe HH, Harbeck N; West German Study Group. West German Study PlanB trial: adjuvant four cycles of epirubicin and cyclophosphamide plus docetaxel versus six cycles of docetaxel and cyclophosphamide in HER2-negative early breast cancer. J Clin Oncol. 2019 Apr 1;37(10):799-808. Epub 2019 Feb 20. link to original article contains dosing details in abstract PubMed NCT01049425
    1. Pooled update: de Gregorio A, Janni W, Friedl TWP, Nitz U, Rack B, Schneeweiss A, Kates R, Fehm T, Kreipe H, Christgen M, Kuemmel S, Trapp E, Wuerstlein R, Hartkopf A, Clemens M, Reimer T, Haberle L, Fasching PA, Gluz O, Harbeck N. The impact of anthracyclines in intermediate and high-risk HER2-negative early breast cancer-a pooled analysis of the randomised clinical trials PlanB and SUCCESS C. Br J Cancer. 2022 Jun;126(12):1715-1724. Epub 2022 Feb 22. link to original article link to PMC article PubMed
  9. NSABP B-47: Fehrenbacher L, Cecchini RS, Geyer CE Jr, Rastogi P, Costantino JP, Atkins JN, Crown JP, Polikoff J, Boileau JF, Provencher L, Stokoe C, Moore TD, Robidoux A, Flynn PJ, Borges VF, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020 Feb 10;38(5):444-453. Epub 2019 Dec 10. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01275677
  10. LMU Success C: de Gregorio A, Janni W, Friedl TWP, Nitz U, Rack B, Schneeweiss A, Kates R, Fehm T, Kreipe H, Christgen M, Kuemmel S, Trapp E, Wuerstlein R, Hartkopf A, Clemens M, Reimer T, Haberle L, Fasching PA, Gluz O, Harbeck N. The impact of anthracyclines in intermediate and high-risk HER2-negative early breast cancer-a pooled analysis of the randomised clinical trials PlanB and SUCCESS C. Br J Cancer. 2022 Jun;126(12):1715-1724. Epub 2022 Feb 22. link to original article link to PMC article PubMed NCT00847444
  11. ASTER 70s: NCT01564056

Dose-dense Cyclophosphamide & Doxorubicin (ddAC)

ddAC: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide

Regimen variant #1, 60/600 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shulman et al. 2012 (CALGB 40101) 2002-2008 Phase 3 (E-de-esc) 1. ddAC x 6 Did not meet primary endpoint of RFS
2. ddT x 4 Did not meet primary endpoint of RFS
3. ddT x 6 Did not meet primary endpoint of RFS
Sparano et al. 2018 (TAILORx) 2006-2010 Phase 3 (C) No chemotherapy Non-inferior IDFS (primary endpoint)

Note: CALGB 40101 originally specified 21-day cycles but was amended to 14-day cycles after results of CALGB 9741 were available.

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy

Supportive therapy

  • (varies depending on reference):
  • CALGB 40101: one of the following:
    • Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Sargramostim (Leukine) 250 to 500 mcg/m2 SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Pegfilgrastim (Neulasta) 6 mg SC once, given 24 to 36 hours after chemotherapy

14-day cycle for 4 cycles


Regimen variant #2, 60/600 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
van Rossum et al. 2018 (MATADOR) 2004-2012 Phase 3 (E-switch-ic) TAC Did not meet secondary endpoints of RFS/OS

Preceding treatment

Chemotherapy

Supportive therapy

14-day cycle for 6 cycles

References

  1. CALGB 40101: Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article contains dosing details in manuscript link to study protocol PDF link to PMC article PubMed NCT00041119
    1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. Epub 2014 Jun 16. link to original article link to PMC article PubMed
  2. TAILORx: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. link to original article link to PMC article contains dosing details in supplement PubMed NCT00310180
  3. MATADOR: van Rossum AGJ, Kok M, van Werkhoven E, Opdam M, Mandjes IAM, van Leeuwen-Stok AE, van Tinteren H, Imholz ALT, Portielje JEA, Bos MMEM, van Bochove A, Wesseling J, Rutgers EJ, Linn SC, Oosterkamp HM; MATADOR Trialists' Group. Adjuvant dose-dense doxorubicin-cyclophosphamide versus docetaxel-doxorubicin-cyclophosphamide for high-risk breast cancer: first results of the randomised MATADOR trial (BOOG 2004-04). Eur J Cancer. 2018 Oct;102:40-48. link to original article contains dosing details in abstract PubMed ISRCTN61893718

Cyclophosphamide & Epirubicin (EC)

EC: Epirubicin and Cyclophosphamide

Regimen variant #1, 60/500 x 8

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Piccart et al. 2001 (Belgian trial) 1988-1996 Phase 3 (E-de-esc) 1. CMF Did not meet primary endpoint of EFS
2. EC; high-dose Seems to have inferior EFS (primary endpoint)

Preceding treatment

Chemotherapy

21-day cycle for 8 cycles


Regimen variant #2, 75/600 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pico et al. 2004 (GEICAM 9401) 1995-2000 Phase 3 (E-de-esc) ECT (Tamoxifen) Did not meet primary endpoint of DFS60

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #3, 100/830 x 8

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Piccart et al. 2001 (Belgian trial) 1988-1996 Phase 3 (E-esc) 1. CMF Did not meet primary endpoint of EFS
2. EC; moderate-dose Seems to have superior EFS

Preceding treatment

Chemotherapy

21-day cycle for 8 cycles


Regimen variant #4, 120/600 x 4 (high-dose)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Papaldo et al. 2003 1991-1994 Phase 3 (C) EC & Lonidamine Did not meet primary endpoint of DFS60
Vici et al. 2011 (GOIM 9902) 1999-2005 Phase 3 (C) D-EC Did not meet primary endpoint of DFS60

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

References

  1. Belgian trial: Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M, Nogaret JM. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol. 2001 Jun 15;19(12):3103-10. link to original article PubMed
    1. Update: de Azambuja E, Paesmans M, Beauduin M, Vindevoghel A, Cornez N, Finet C, Ries F, Closon-Dejardin MT, Kerger J, Gobert P, Focan C, Tagnon A, Dolci S, Nogaret JM, di Leo A, Piccart-Gebhart MJ. Long-term benefit of high-dose epirubicin in adjuvant chemotherapy for node-positive breast cancer: 15-year efficacy results of the Belgian multicentre study. J Clin Oncol. 2009 Feb 10;27(5):720-5. Epub 2008 Dec 22. link to original article PubMed
  2. Papaldo P, Lopez M, Cortesi E, Cammilluzzi E, Antimi M, Terzoli E, Lepidini G, Vici P, Barone C, Ferretti G, Di Cosimo S, Nistico C, Carlini P, Conti F, Di Lauro L, Botti C, Vitucci C, Fabi A, Giannarelli D, Marolla P. Addition of either lonidamine or granulocyte colony-stimulating factor does not improve survival in early breast cancer patients treated with high-dose epirubicin and cyclophosphamide. J Clin Oncol. 2003 Sep 15;21(18):3462-8. link to original article contains dosing details in abstract PubMed
  3. GEICAM 9401: Pico C, Martin M, Jara C, Barnadas A, Pelegri A, Balil A, Camps C, Frau A, Rodriguez-Lescure A, Lopez-Vega JM, De La Haba J, Tres A, Alvarez I, Alba E, Arcusa A, Oltra A, Batista N, Checa T, Perez-Carrion R, Curto J; GEICAM. Epirubicin-cyclophosphamide adjuvant chemotherapy plus tamoxifen administered concurrently versus sequentially: randomized phase III trial in postmenopausal node-positive breast cancer patients: a GEICAM 9401 study. Ann Oncol. 2004 Jan;15(1):79-87. link to original article contains dosing details in abstract PubMed
  4. GOIM 9902: Vici P, Brandi M, Giotta F, Foggi P, Schittulli F, Di Lauro L, Gebbia N, Massidda B, Filippelli G, Giannarelli D, Di Benedetto A, Mottolese M, Colucci G, Lopez M. A multicenter phase III prospective randomized trial of high-dose epirubicin in combination with cyclophosphamide (EC) versus docetaxel followed by EC in node-positive breast cancer: GOIM (Gruppo Oncologico Italia Meridionale) 9902 study. Ann Oncol. 2012 May;23(5):1121-9. Epub 2011 Sep 28. link to original article link to PMC article contains dosing details in abstract PubMed
  5. GIM2: Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 x 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article contains dosing details in manuscript PubMed NCT00433420
    1. Update: Del Mastro L, Poggio F, Blondeaux E, De Placido S, Giuliano M, Forestieri V, De Laurentiis M, Gravina A, Bisagni G, Rimanti A, Turletti A, Nisticò C, Vaccaro A, Cognetti F, Fabi A, Gasparro S, Garrone O, Alicicco MG, Urracci Y, Mansutti M, Poletti P, Correale P, Bighin C, Puglisi F, Montemurro F, Colantuoni G, Lambertini M, Boni L; Gruppo Italiano Mammella Investigators. Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial. Lancet Oncol. 2022 Dec;23(12):1571-1582. Epub 2022 Nov 10. link to original article PubMed

Docetaxel monotherapy

D: Docetaxel
T: Taxotere (Docetaxel)
dT: doceTaxel


Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bear et al. 2003 (NSABP B-27) 1995-2000 Phase 3 (E-esc) See link See link

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

References

  1. NSABP B-27: Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, Wolmark N; National Surgical Adjuvant Breast and Bowel Project. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003 Nov 15;21(22):4165-74. Epub 2003 Oct 14. link to original article contains dosing details in manuscript PubMed NCT00002707
    1. Update: Bear HD, Anderson S, Smith RE, Geyer CE Jr, Mamounas EP, Fisher B, Brown AM, Robidoux A, Margolese R, Kahlenberg MS, Paik S, Soran A, Wickerham DL, Wolmark N. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006 May 1;24(13):2019-27. Epub 2006 Apr 10. link to original article PubMed
    2. Pooled update: Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008 Feb 10;26(5):778-85. Erratum in: J Clin Oncol. 2008 Jun 1;26(16):2793. link to original article PubMed
  2. NSAS BC-02: Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. link to original article contains dosing details in abstract link to PMC article PubMed

Epirubicin & Paclitaxel (EP)

EP: Epirubicin & Paclitaxel

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yuan et al. 2023 (CH-BC-006) 2010-06-01 to 2016-06-30 Phase 3 (E-de-esc) EC-P Non-inferior DFS (primary endpoint)
DFS60: 86% vs 80.6%
(HR 0.82, 95% CI 0.61-1.10)

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles

References

  1. CH-BC-006: Yuan P, Kang Y, Ma F, Fan Y, Wang J, Wang X, Yue J, Luo Y, Zhang P, Li Q, Xu B. Effect of Epirubicin Plus Paclitaxel vs Epirubicin and Cyclophosphamide Followed by Paclitaxel on Disease-Free Survival Among Patients With Operable ERBB2-Negative and Lymph Node-Positive Breast Cancer: A Randomized Clinical Trial. JAMA Netw Open. 2023 Feb 1;6(2):e230122. link to original article link to PMC article contains dosing details in abstract PubMed NCT01134523

Epirubicin monotherapy

E: Epirubicin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Coombes et al. 2011 (DEVA) 1997-2005 Phase 3 (C) E-D Inferior OS

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

References

  1. DEVA: Coombes RC, Bliss JM, Espie M, Erdkamp F, Wals J, Tres A, Marty M, Coleman RE, Tubiana-Mathieu N, den Boer MO, Wardley A, Kilburn LS, Cooper D, Thomas MW, Reise JA, Wilkinson K, Hupperets P. Randomized, phase III trial of sequential epirubicin and docetaxel versus epirubicin alone in postmenopausal patients with node-positive breast cancer. J Clin Oncol. 2011 Aug 20;29(24):3247-54. Epub 2011 Jul 18. link to original article contains dosing details in abstract PubMed ISRCTN89772270

Dose-dense Epirubicin monotherapy

ddE: dose-dense Epirubicin

Regimen

Study Dates of enrollment Evidence
Fountzilas et al. 2014 (HE10/05) 2005-2008 Non-randomized part of phase 3 RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

Chemotherapy

14-day cycle for 3 cycles

Subsequent treatment

  • CMF; intensified

References

  1. HE10/05: Fountzilas G, Dafni U, Papadimitriou C, Timotheadou E, Gogas H, Eleftheraki AG, Xanthakis I, Christodoulou C, Koutras A, Papandreou CN, Papakostas P, Miliaras S, Markopoulos C, Dimitrakakis C, Korantzopoulos P, Karanikiotis C, Bafaloukos D, Kosmidis P, Samantas E, Varthalitis I, Pavlidis N, Pectasides D, Dimopoulos MA. Dose-dense sequential adjuvant chemotherapy followed, as indicated, by trastuzumab for one year in patients with early breast cancer: first report at 5-year median follow-up of a Hellenic Cooperative Oncology Group randomized phase III trial. BMC Cancer. 2014 Jul 15;14:515. link to original article link to PMC article contains dosing details in manuscript PubMed

FAC

FAC: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide
CAF: Cyclophosphamide, Adriamycin (Doxorubicin), Fluorouracil

Regimen variant #1, 500/40/500 x 6

Study Dates of enrollment Evidence
Tokuda et al. 2007 (JCOG 9208) 1993-1999 Non-randomized part of phase 3 RCT

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment


Regimen variant #2, 500/50/500 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Martin et al. 2003 (GEICAM 8701) 1987-1991 Phase 3 (E-switch-ic) CMF Might have superior DFS
Martin et al. 2005 (BCIRG 001) 1997-1999 Phase 3 (C) TAC Inferior OS
Martín et al. 2010 (GEICAM 9805) 1999-2003 Phase 3 (C) TAC Inferior DFS
Martín et al. 2013 (GEICAM 2003-02) 2003-2008 Phase 3 (C) FAC-T Seems to have inferior DFS
Delaloge et al. 2020 (MINDACT) 2007-2011 Phase 3 (C) TX Did not meet primary endpoint of DFS

Preceding treatment

Chemotherapy

Infusion times per Martin et al. 2005 (BCIRG 001).

  • Fluorouracil (5-FU) 500 mg/m2 IV over 15 minutes once on day 1, given second
  • Doxorubicin (Adriamycin) 50 mg/m2 IV over 15 minutes once on day 1, given first
  • Cyclophosphamide (Cytoxan) 500 mg/m2 IV over 1 to 5 minutes once on day 1, given third
    • A HemOnc.org user reached out to us and said their institutional practice is to infuse cyclophosphamide over 20 to 30 minutes to decrease the likelihood of head and sinus pain.

Supportive therapy

21-day cycle for 6 cycles


Regimen variant #3, 500/50/500 until max anthracycline

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hurteloup 1988 (FESG) 1982-1984 Phase 3 (C) FEC Did not meet endpoint of OS50%

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

Chemotherapy

21-day cycle for up to 11 cycles (maximum cumulative doxorubicin dose of 550 mg/m2)


Regimen variant #4, 800/40/400 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wood et al. 1994 (CALGB 8541) 1985-NR Phase 3 (E-de-esc) 1. FAC; 600/30/300 x 4 Superior OS
2. FAC; 1200/60/600 x 4 Did not meet primary endpoint of DFS

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


Regimen variant #5, 800/40/400 until max doxorubicin

Historic variant
Study Dates of enrollment Evidence Comparator Comparative Efficacy
Buzdar et al. 1984 1977-1980 Phase 3 (C) FAC + BCG Did not meet primary endpoint of DFS

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

Chemotherapy

21-day cycles until cumulative doxorubicin dose of 300 mg/m2 reached.

Subsequent treatment

  • After reaching cumulative maximum doxorubicin, patients would go on to receive: maintenance CMF. This is now obsolete.


Regimen variant #6, 1000/50/500 x 8

Study Dates of enrollment Evidence
Hortobagyi et al. 2000 1990-1997 Non-randomized part of RCT

Preceding treatment

Chemotherapy

21-day cycle for 8 cycles

Subsequent treatment


Regimen variant #7, 1000/60/1400 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Davidson et al. 2005 (ECOG E5188) 1989-1994 Non-randomized part of phase 3 RCT
Hutchins et al. 2005 (INT-0102) 1989-1993 Phase 3 (E-switch-ic) CMF Seems to have superior OS
Albain et al. 2009 (SWOG-8814) 1989-1995 Phase 3 (E-esc) See link See link
Tallman et al. 2003 (INT-0121) 1991-1998 Non-randomized part of RCT

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

Subsequent treatment


Regimen variant #8, 1200/60/600 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wood et al. 1994 (CALGB 8541) 1985-NR Phase 3 (C) 1. FAC; 600/30/300 x 4 Superior OS
2. FAC; 800/40/400 x 6 Did not meet primary endpoint of DFS

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

Chemotherapy

28-day cycle for 4 cycles


Regimen variant #9, 1200/60/600 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Delaloge et al. 2020 (MINDACT) 2007-2011 Phase 3 (C) TX Did not meet primary endpoint of DFS

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


Regimen variant #10, 2000/50/100 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Scholl et al. 1994 (S6) 1986-1990 Phase 3 (C) Neoadjuvant FAC Seems to have inferior OS

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

Chemotherapy

28-day cycle for 4 cycles

References

  1. Buzdar AU, Blumenschein GR, Smith TL, Powell KC, Hortobagyi GN, Yap HY, Schell FC, Barnes BC, Ames FC, Martin RG, Hersh EM. Adjuvant chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide, with or without Bacillus Calmette-Guérin and with or without irradiation in operable breast cancer: a prospective randomized trial. Cancer. 1984 Feb 1;53(3):384-9. link to original article contains dosing details in manuscript PubMed
    1. Update: Buzdar AU, Kau SW, Smith TL, Hortobagyi GN. Ten-year results of FAC adjuvant chemotherapy trial in breast cancer. Am J Clin Oncol. 1989 Apr;12(2):123-8. link to original article PubMed
  2. FESG: Hurteloup P; French Epirubicin Study Group. A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol. 1988 Apr;6(4):679-88. link to original article contains dosing details in abstract PubMed
  3. CALGB 8541: Wood WC, Budman DR, Korzun AH, Cooper MR, Younger J, Hart RD, Moore A, Ellerton JA, Norton L, Ferree CR, Colangelo Ballow A, Frei E, Henderson IC. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994 May 5;330(18):1253-9. Erratum in: N Engl J Med 1994 Jul 14;331(2):139. link to original article contains dosing details in manuscript PubMed
    1. Subgroup analysis: Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Koerner F, Cirrincione CT, Budman DR, Wood WC, Barcos M, Henderson IC. c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med. 1994 May 5;330(18):1260-6. Erratum in: N Engl J Med 1994 Jul 21;331(3):211. link to original article PubMed
  4. S6: Scholl SM, Fourquet A, Asselain B, Pierga JY, Vilcoq JR, Durand JC, Dorval T, Palangié T, Jouve M, Beuzeboc P, Garcio-Giralt E, Salmon RJ, de la Rochefordiere A, Campana F, Pouillart P. Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: preliminary results of a randomised trial: S6. Eur J Cancer. 1994;30A(5):645-52. link to original article contains dosing details in manuscript PubMed
  5. Hortobagyi GN, Buzdar AU, Theriault RL, Valero V, Frye D, Booser DJ, Holmes FA, Giralt S, Khouri I, Andersson B, Gajewski JL, Rondon G, Smith TL, Singletary SE, Ames FC, Sneige N, Strom EA, McNeese MD, Deisseroth AB, Champlin RE. Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst. 2000 Feb 2;92(3):225-33. link to original article contains dosing details in manuscript PubMed
  6. GEICAM 8701: Martin M, Villar A, Sole-Calvo A, Gonzalez R, Massuti B, Lizon J, Camps C, Carrato A, Casado A, Candel MT, Albanell J, Aranda J, Munarriz B, Campbell J, Diaz-Rubio E; GEICAM. Doxorubicin in combination with fluorouracil and cyclophosphamide (iv FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (iv CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Ann Oncol. 2003 Jun;14(6):833-42. link to original article contains dosing details in abstract PubMed
  7. INT-0121: Tallman MS, Gray R, Robert NJ, LeMaistre CF, Osborne CK, Vaughan WP, Gradishar WJ, Pisansky TM, Fetting J, Paietta E, Lazarus HM. Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med. 2003 Jul 3;349(1):17-26. link to original article PubMed
  8. BCIRG 001: Martín M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C; Breast Cancer International Research Group. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med. 2005 Jun 2;352(22):2302-13. link to original article contains dosing details in abstract PubMed NCT00688740
    1. Update: Mackey JR, Martín M, Pienkowski T, Rolski J, Guastalla JP, Sami A, Glaspy J, Juhos E, Wardley A, Fornander T, Hainsworth J, Coleman R, Modiano MR, Vinholes J, Pinter T, Rodríguez-Lescure A, Colwell B, Whitlock P, Provencher L, Laing K, Walde D, Price C, Hugh JC, Childs BH, Bassi K, Lindsay MA, Wilson V, Rupin M, Houé V, Vogel C; TRIO/BCIRG 001 investigators. Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial. Lancet Oncol. 2013 Jan;14(1):72-80. Epub 2012 Dec 12. link to original article PubMed
  9. ECOG E5188: Davidson NE, O'Neill AM, Vukov AM, Osborne CK, Martino S, White DR, Abeloff MD. Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: results from INT 0101 (E5188). J Clin Oncol. 2005 Sep 1;23(25):5973-82. Epub 2005 Aug 8. link to original article contains dosing details in manuscript PubMed
  10. INT-0102: Hutchins LF, Green SJ, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of intergroup protocol INT-0102. J Clin Oncol. 2005 Nov 20;23(33):8313-21. link to original article PubMed
  11. JCOG 9208: Tokuda Y, Tajima T, Narabayashi M, Takeyama K, Watanabe T, Fukutomi T, Chou T, Sano M, Igarashi T, Sasaki Y, Ogura M, Miura S, Okamoto S, Ogita M, Kasai M, Kobayashi T, Fukuda H, Takashima S, Tobinai K; Autologous Bone Marrow Transplantation Study Group; Breast Cancer Study Group of the Japan Clinical Oncology Group (JCOG). Phase III study to evaluate the use of high-dose chemotherapy as consolidation of treatment for high-risk postoperative breast cancer: Japan Clinical Oncology Group study, JCOG 9208. Cancer Sci. 2008 Jan;99(1):145-51. Epub 2007 Oct 25. link to original article contains dosing details in manuscript PubMed
  12. SWOG-8814: Albain KS, Barlow WE, Ravdin PM, Farrar WB, Burton GV, Ketchel SJ, Cobau CD, Levine EG, Ingle JN, Pritchard KI, Lichter AS, Schneider DJ, Abeloff MD, Henderson IC, Muss HB, Green SJ, Lew D, Livingston RB, Martino S, Osborne CK; Breast Cancer Intergroup of North America. Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009 Dec 19;374(9707):2055-2063. Epub 2009 Dec 10. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00929591
  13. GEICAM 9805: Martín M, Seguí MA, Antón A, Ruiz A, Ramos M, Adrover E, Aranda I, Rodríguez-Lescure A, Grosse R, Calvo L, Barnadas A, Isla D, Martinez del Prado P, Ruiz Borrego M, Zaluski J, Arcusa A, Muñoz M, López Vega JM, Mel JR, Munarriz B, Llorca C, Jara C, Alba E, Florián J, Li J, López García-Asenjo JA, Sáez A, Rios MJ, Almenar S, Peiró G, Lluch A; GEICAM. Adjuvant docetaxel for high-risk, node-negative breast cancer. N Engl J Med. 2010 Dec 2;363(23):2200-10. link to original article PubMed NCT00121992
  14. GEICAM 2003-02: Martín M, Ruiz A, Ruiz Borrego M, Barnadas A, González S, Calvo L, Margelí Vila M, Antón A, Rodríguez-Lescure A, Seguí-Palmer MA, Muñoz-Mateu M, Dorca Ribugent J, López-Vega JM, Jara C, Espinosa E, Mendiola Fernández C, Andrés R, Ribelles N, Plazaola A, Sánchez-Rovira P, Salvador Bofill J, Crespo C, Carabantes FJ, Servitja S, Chacón JI, Rodríguez CA, Hernando B, Álvarez I, Carrasco E, Lluch A. Fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus FAC followed by weekly paclitaxel as adjuvant therapy for high-risk, node-negative breast cancer: results from the GEICAM/2003-02 study. J Clin Oncol. 2013 Jul 10;31(20):2593-9. Epub 2013 Jun 3. link to original article contains dosing details in manuscript PubMed NCT00129389
  15. MINDACT: Delaloge S, Piccart M, Rutgers E, Litière S, van 't Veer LJ, van den Berkmortel F, Brain E, Dudek-Peric A, Gil-Gil M, Gomez P, Hilbers FS, Khalil Z, Knox S, Kuemmel S, Kunz G, Lesur A, Pierga JY, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Thompson AM, Viale G, Zoppoli G, Vuylsteke P, Tryfonidis K, Poncet C, Bogaerts J, Cardoso F; MINDACT investigators and the TRANSBIG Consortium. Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial. J Clin Oncol. 2020 Apr 10;38(11):1186-1197. Epub 2020 Feb 21. link to original article contains dosing details in supplement link to PMC article PubMed NCT00433589

FEC

FEC: Fluorouracil, Epirubicin, Cyclophosphamide
CEF: Cyclophosphamide, Epirubicin, Fluorouracil

Regimen variant #1, 500/50/500 x 6 ("FEC 50")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fumoleau et al. 2003 (FASG 01) 1986-1990 Phase 3 (C) 1. FEC; FEC 50 x 3 Might have superior OS
2. FEC; FEC 75 x 3 Did not meet primary endpoint of OS120
Héry et al. 2006 (FASG 03) 1988-1994 Phase 3 (E-esc) Observation Did not meet primary endpoint of DFS120
Arriagada et al. 2005 1989-1996 Phase 3 (E-esc) Observation Superior DFS
Bonneterre 2001 (FASG 05) 1990-1993 Phase 3 (C) FEC; FEC 100 x 6 Inferior OS
Roché et al. 2006 (FASG 06) 1990-1998 Phase 3 (C) Goserelin & Tamoxifen x 3y Did not meet primary endpoint of DFS60
Sparano et al. 2018 (TAILORx) 2006-2010 Phase 3 (C) No chemotherapy Non-inferior IDFS (primary endpoint)

Note: This was the lower bound of epirubicin dosing for TAILORx.

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #2, 500/50/500 until max anthracycline

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hurteloup 1988 (FESG) 1982-1984 Phase 3 (E-switch-ic) FAC Did not meet endpoint of OS50%

Note: While this was a negative study, this arm was better tolerated in the treated population and this study likely established the popularity of epirubicin-based regimens in Europe.

Preceding treatment

Chemotherapy

21-day cycle for up to 15 cycles (maximum cumulative epirubicin dose of 720 mg/m2)


Regimen variant #3, 500/60/500 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rouëssé et al. 2006 1994-1999 Phase 3 (C) FNC & RT Did not meet primary endpoint of DFS

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles


Regimen variant #4, 500/90/500 x 5

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rodenhuis et al. 2003 (Dutch National Study) 1993-1999 Phase 3 (C) FEC x 4, then CTCb with auto HSCT Did not meet primary endpoint of OS1

1Reported efficacy for the Dutch National Study is based on the 2020 update.
Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

Chemotherapy

21-day cycle for 5 cycles


Regimen variant #5, 500/100/500 x 4 ("FEC 100")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Kerbrat et al. 2017 (UCBG-0106) 2002-2006 Phase 3 (E-de-esc) FEC; FEC 100 x 6 Did not meet primary endpoint of DFS60

Note: This was an experimental arm that did not meet its primary endpoint; included here because it represents a de-escalation strategy.

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles


Regimen variant #6, 500/100/500 x 6 ("FEC 100")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bonneterre 2001 (FASG 05) 1990-1993 Phase 3 (E-RT-esc) FEC; FEC 50 x 6 Superior OS
Kerbrat et al. 2007 (FASG 09) 1993-1998 Phase 3 (C) VE Did not meet primary endpoint of DFS
Roché et al. 2006 (FNCLCC PACS 01) 1997-2000 Phase 3 (C) FEC-D Inferior OS1
Delbaldo et al. 2013 (Trial B2000) 2000-2002 Phase 3 (C) FEC-P Did not meet primary endpoint of DFS
Nitz et al. 2014 (WSG-AGO EC-Doc) 2000-2005 Phase 3 (C) EC-D Seems to have inferior OS
Spielmann et al. 2009 (FNCLCC PACS 04) 2001-2004 Phase 3 (C) ED Did not meet primary endpoint of DFS2
Kerbrat et al. 2017 (UCBG-0106) 2002-2006 Phase 3 (C) FEC; FEC 100 x 4 Did not meet primary endpoint of DFS60
Geyer et al. 2022 (NSABP B-36) 2004-05-20 to 2008-07-25 Phase 3 (E-esc) AC x 4 Did not meet primary endpoint of DFS
DFS9y: 79.4% vs 80.1%
(HR 1.09, 95% CI 0.92-1.29)
Sakr et al. 2013 2006-2010 Phase 3 (C) FEC-D Seems to have inferior OS
Sparano et al. 2018 (TAILORx) 2006-2010 Phase 3 (C) No chemotherapy Non-inferior IDFS (primary endpoint)
Delaloge et al. 2020 (MINDACT) 2007-2011 Phase 3 (C) TX Did not meet primary endpoint of DFS

1Reported efficacy for FNCLCC PACS 01 is based on the 2012 update.
2Reported efficacy for FNCLCC PACS 04 is based on the 2019 update.
Note: This was the upper bound of epirubicin dosing in TAILORx.

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #7, 600/50/600 x 8

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Coombes et al. 1996 1984-1992 Phase 3 (E-switch-ic) CMF Did not meet co-primary endpoints of RFS/OS
Coombes et al. 2016 (HMFEC) 1992-2000 Phase 3 (C) FEC; FEC 75 Did not meet primary endpoint of DFS

Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Preceding treatment

Chemotherapy

21-day cycle for 8 cycles


Regimen variant #8, 600/60/600 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
van der Hage et al. 2001 (EORTC 10902) 1991-1999 Phase 3 (C) FEC; neoadjuvant Did not meet primary endpoint of OS

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles


Regimen variant #9, 600/60/600 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Venturini et al. 2005 (MIG-1) 1992-1997 Phase 3 (C) ddFEC Did not meet primary endpoint of OS
Sirohi et al. 2010 (TRAFIC) 1995-2002 Phase 3 (C) ECisF Did not meet primary endpoint of RFS
del Mastro et al. 2015 (GONO-MIG5) 1996-2001 Phase 3 (C) EP x 4 Did not meet primary endpoint of OS

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #10, 600/60/600 x 8

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ellis et al. 2009 (TACT) 2001-2003 Phase 3 (C) FEC-D Did not meet primary endpoint of DFS

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

Chemotherapy

21-day cycle for 8 cycles


Regimen variant #11, 600/60/600 x 9

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ejlertsen et al. 2007 (DBCG 89D) 1990-1998 Phase 3 (E-switch-ic) CMF Superior OS

Preceding treatment

Chemotherapy

21-day cycle for 9 cycles


Regimen variant #12, 600/90/600 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Martín et al. 2008 (GEICAM 9906) 1999-2002 Phase 3 (C) FEC-P Inferior DFS60

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #13, 700/75/700 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Polyzos et al. 2009 1995-2004 Phase 3 (C) D-EC Seems to have inferior DFS60

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #14, 1000/50/500 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Paradiso et al. 2001 1989-1994 Phase 3 (E-esc) Observation Seems to have superior DFS

Preceding treatment

Chemotherapy


Regimen variant #15, 1000/120/740 x 6 ("Canadian CEF (IV)")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Delaloge et al. 2020 (MINDACT) 2007-2011 Phase 3 (C) TX Did not meet primary endpoint of DFS

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


Regimen variant #16, 1000/120/1050 x 6 ("FEC 120"; "Canadian CEF")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Levine et al. 1998 (NCIC-CTG MA.5) 1989-1993 Phase 3 (E-RT-switch-ic) CMF Superior RFS
Coombes et al. 2005 (ICCG HDT trial) 1993-2001 Phase 3 (C) FEC x 3, then HDT Did not meet co-primary endpoints of RFS/EFS/OS
Burnell et al. 2009 (NCIC-CTG MA.21) 2000-2005 Phase 3 (C) 1. AC-T Superior RFS (primary endpoint)
RFS36: 90.1% vs 85%
(HR 0.67, 95% CI 0.50-0.89)
2. ddEC-T Did not meet primary endpoint of RFS
Janni et al. 2016 (ADEBAR) 2001-2005 Phase 3 (C) EC-D Did not meet primary endpoint of TTP
Delaloge et al. 2020 (MINDACT) 2007-2011 Phase 3 (C) TX Did not meet primary endpoint of DFS

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


Regimen variant #17, 1200/50/1200 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Coombes et al. 1996 1984-1992 Phase 3 (E-switch-ic) CMF Did not meet co-primary endpoints of RFS/OS

Note: This was an experimental arm that did not meet its primary endpoint; however, based on a subgroup analysis, it became a preferred regimen.

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

References

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  2. Coombes RC, Bliss JM, Wils J, Morvan F, Espié M, Amadori D, Gambrosier P, Richards M, Aapro M, Villar-Grimalt A, McArdle C, Pérez-López FR, Vassilopoulos P, Ferreira EP, Chilvers CE, Coombes G, Woods EM, Marty M; International Collaborative Cancer Group. Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. J Clin Oncol. 1996 Jan;14(1):35-45. link to original article contains dosing details in manuscript PubMed
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  13. FASG 03: Héry M, Bonneterre J, Roché H, Luporsi E, Kerbrat P, Namer M, Fumoleau P, Monnier A, Fargeot P. Epirubicin-based chemotherapy as adjuvant treatment for poor prognosis, node-negative breast cancer: 10-year follow-up results of the French Adjuvant Study Group 03 trial. Bull Cancer. 2006 Oct;93(10):E109-14. link to original article contains dosing details in abstract PubMed
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  15. FNCLCC PACS 01: Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulié P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Genève J, Asselain B. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006 Dec 20;24(36):5664-71. Epub 2006 Nov 20. link to original article PubMed
    1. Update: Coudert B, Asselain B, Campone M, Spielmann M, Machiels JP, Pénault-Llorca F, Serin D, Lévy C, Romieu G, Canon JL, Orfeuvre H, Piot G, Petit T, Jerusalem G, Audhuy B, Veyret C, Beauduin M, Eymard JC, Martin AL, Roché H; UNICANCER Breast Group. Extended benefit from sequential administration of docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide regimen for node-positive breast cancer: the 8-year follow-up results of the UNICANCER-PACS01 trial. Oncologist. 2012;17(7):900-9. Epub 2012 May 18. link to original article link to PMC article PubMed
  16. DBCG 89D: Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Cold S, Edlund P, Ewertz M, Jensen BB, Kamby C, Nordenskjold B, Bergh J. Improved outcome from substituting methotrexate with epirubicin: results from a randomised comparison of CMF versus CEF in patients with primary breast cancer. Eur J Cancer. 2007 Mar;43(5):877-84. Epub 2007 Feb 16. link to original article contains dosing details in manuscript PubMed
  17. FASG 09: Kerbrat P, Roché H, Bonneterre J, Veyret C, Lortholary A, Monnier A, Fumoleau P, Fargeot P, Namer M, Chollet P, Goudier MJ, Audhuy B, Simon H, Montcuquet P, Eymard JC, Walter S, Clavère P, Guastalla JP; French Adjuvant Study Group. Epirubicin-vinorelbine vs FEC100 for node-positive, early breast cancer: French Adjuvant Study Group 09 trial. Br J Cancer. 2007 Jun 4;96(11):1633-8. Epub 2007 May 15. link to original article link to PMC article PubMed
  18. GEICAM 9906: Martín M, Rodríguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Munárriz B, Rodríguez CA, Crespo C, de Alava E, López García-Asenjo JA, Guitián MD, Almenar S, González-Palacios JF, Vera F, Palacios J, Ramos M, Gracia Marco JM, Lluch A, Alvarez I, Seguí MA, Mayordomo JI, Antón A, Baena JM, Plazaola A, Modolell A, Pelegrí A, Mel JR, Aranda E, Adrover E, Alvarez JV, García Puche JL, Sánchez-Rovira P, Gonzalez S, López-Vega JM; GEICAM. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst. 2008 Jun 4;100(11):805-14. Epub 2008 May 27. link to original article contains dosing details in manuscript PubMed NCT00129922
  19. TACT: Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. link to original article link to PMC article contains dosing details in manuscript PubMed ISRCTN79718493
  20. Polyzos A, Malamos N, Boukovinas I, Adamou A, Ziras N, Kalbakis K, Kakolyris S, Syrigos K, Papakotoulas P, Kouroussis C, Karvounis N, Vamvakas L, Christophyllakis C, Athanasiadis A, Varthalitis I, Georgoulias V, Mavroudis D; Hellenic Oncology Research Group. FEC versus sequential docetaxel followed by epirubicin/cyclophosphamide as adjuvant chemotherapy in women with axillary node-positive early breast cancer: a randomized study of the Hellenic Oncology Research Group (HORG). Breast Cancer Res Treat. 2010 Jan;119(1):95-104. Epub 2009 Jul 28. link to original article contains dosing details in abstract PubMed
  21. NCIC-CTG MA.21: Burnell M, Levine MN, Chapman JA, Bramwell V, Gelmon K, Walley B, Vandenberg T, Chalchal H, Albain KS, Perez EA, Rugo H, Pritchard K, O'Brien P, Shepherd LE. Cyclophosphamide, epirubicin, and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol. 2010 Jan 1;28(1):77-82. Epub 2009 Nov 9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00014222
  22. FNCLCC PACS 04: Spielmann M, Roché H, Delozier T, Canon JL, Romieu G, Bourgeois H, Extra JM, Serin D, Kerbrat P, Machiels JP, Lortholary A, Orfeuvre H, Campone M, Hardy-Bessard AC, Coudert B, Maerevoet M, Piot G, Kramar A, Martin AL, Penault-Llorca F. Trastuzumab for patients with axillary-node-positive breast cancer: results of the FNCLCC-PACS 04 trial. J Clin Oncol. 2009 Dec 20;27(36):6129-34. Epub 2009 Nov 16. link to original article PubMed NCT00054587
    1. Update: D'Hondt V, Canon JL, Roca L, Levy C, Pierga JY, Le Du F, Campone M, Desmoulins I, Goncalves A, Debled M, Rios M, Ferrero JM, Serin D, Hardy-Bessard AC, Piot G, Brain E, Dohollou N, Orfeuvre H, Lemonnier J, Roché H, Delaloge S, Dalenc F. UCBG 2-04: Long-term results of the PACS 04 trial evaluating adjuvant epirubicin plus docetaxel in node-positive breast cancer and trastuzumab in the human epidermal growth factor receptor 2-positive subgroup. Eur J Cancer. 2019 Nov;122:91-100. Epub 2019 Oct 18. link to original article contains dosing details in manuscript PubMed
  23. TRAFIC: Sirohi B, A'Hern R, Coombes G, Bliss JM, Hickish T, Perren T, Crawford M, O'Brien M, Iveson T, Ebbs S, Skene A, Laing R, Smith IE. A randomised comparative trial of infusional ECisF versus conventional FEC as adjuvant chemotherapy in early breast cancer: the TRAFIC trial. Ann Oncol. 2010 Aug;21(8):1623-9. Epub 2010 Jan 21. link to original article contains dosing details in abstract PubMed ISRCTN83324925
  24. Sakr H, Hamed RH, Anter AH, Yossef T. Sequential docetaxel as adjuvant chemotherapy for node-positive or/and T3 or T4 breast cancer: clinical outcome (Mansoura University). Med Oncol. 2013 Mar;30(1):457. Epub 2013 Jan 16. link to original article contains dosing details in manuscript PubMed
  25. AERO-B2000: Delbaldo C, Serin D, Mousseau M, Greget S, Audhuy B, Priou F, Berdah JF, Teissier E, Laplaige P, Zelek L, Quinaux E, Buyse M, Piedbois P; Association Européenne de Recherche en Oncologie (AERO). A phase III adjuvant randomised trial of 6 cycles of 5-fluorouracil-epirubicine-cyclophosphamide (FEC100) versus 4 FEC 100 followed by 4 Taxol (FEC-T) in node positive breast cancer patients (Trial B2000). Eur J Cancer. 2014 Jan;50(1):23-30. Epub 2013 Oct 29. link to original article PubMed
  26. WSG-AGO EC-Doc: Nitz U, Gluz O, Huober J, Kreipe HH, Kates RE, Hartmann A, Erber R, Moustafa Z, Scholz M, Lisboa B, Mohrmann S, Möbus V, Augustin D, Hoffmann G, Weiss E, Böhmer S, Kreienberg R, Du Bois A, Sattler D, Thomssen C, Kiechle M, Jänicke F, Wallwiener D, Harbeck N, Kuhn W. Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression. Ann Oncol. 2014 Aug;25(8):1551-7. Epub 2014 May 14. Erratum in: Ann Oncol. 2017 Nov 1;28(11):2899. link to original article contains dosing details in abstract PubMed NCT02115204
  27. GIM2: Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 x 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article contains dosing details in manuscript PubMed NCT00433420
    1. Update: Del Mastro L, Poggio F, Blondeaux E, De Placido S, Giuliano M, Forestieri V, De Laurentiis M, Gravina A, Bisagni G, Rimanti A, Turletti A, Nisticò C, Vaccaro A, Cognetti F, Fabi A, Gasparro S, Garrone O, Alicicco MG, Urracci Y, Mansutti M, Poletti P, Correale P, Bighin C, Puglisi F, Montemurro F, Colantuoni G, Lambertini M, Boni L; Gruppo Italiano Mammella Investigators. Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial. Lancet Oncol. 2022 Dec;23(12):1571-1582. Epub 2022 Nov 10. link to original article PubMed
  28. GONO-MIG5: Del Mastro L, Levaggi A, Michelotti A, Cavazzini G, Adami F, Scotto T, Piras M, Danese S, Garrone O, Durando A, Accortanzo V, Bighin C, Miglietta L, Pastorino S, Pronzato P, Castiglione F, Landucci E, Conte P, Bruzzi P. 5-Fluorouracil, epirubicin and cyclophosphamide versus epirubicin and paclitaxel in node-positive early breast cancer: a phase-III randomized GONO-MIG5 trial. Breast Cancer Res Treat. 2016 Jan;155(1):117-26. Epub 2015 Dec 10. link to original article contains dosing details in manuscript PubMed NCT02450058
  29. ADEBAR: Janni W, Harbeck N, Rack B, Augustin D, Jueckstock J, Wischnik A, Annecke K, Scholz C, Huober J, Zwingers T, Friedl TW, Kiechle M. Randomised phase III trial of FEC120 vs EC-docetaxel in patients with high-risk node-positive primary breast cancer: final survival analysis of the ADEBAR study. Br J Cancer. 2016 Apr 12;114(8):863-71. Epub 2016 Mar 31. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00047099
  30. HMFEC: Coombes RC, Kilburn LS, Tubiana-Mathieu N, Olmos T, Van Bochove A, Perez-Lopez FR, Palmieri C, Stebbing J, Bliss JM. Epirubicin dose and sequential hormonal therapy-Mature results of the HMFEC randomised phase III trial in premenopausal patients with node positive early breast cancer. Eur J Cancer. 2016 Jun;60:146-53. Epub 2016 Apr 26. link to original article PubMed ISRCTN98335268
  31. UCBG-0106: Kerbrat P, Desmoulins I, Roca L, Levy C, Lortholary A, Marre A, Delva R, Rios M, Viens P, Brain É, Serin D, Edel M, Debled M, Campone M, Mourret-Reynier MA, Bachelot T, Foucher-Goudier MJ, Asselain B, Lemonnier J, Martin AL, Roché H. Optimal duration of adjuvant chemotherapy for high-risk node-negative (N-) breast cancer patients: 6-year results of the prospective randomised multicentre phase III UNICANCER-PACS 05 trial (UCBG-0106). Eur J Cancer. 2017 Jul;79:166-175. Epub 2017 May 11. link to original article contains dosing details in manuscript PubMed
  32. TAILORx: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. link to original article link to PMC article contains dosing details in supplement PubMed NCT00310180
  33. MINDACT: Delaloge S, Piccart M, Rutgers E, Litière S, van 't Veer LJ, van den Berkmortel F, Brain E, Dudek-Peric A, Gil-Gil M, Gomez P, Hilbers FS, Khalil Z, Knox S, Kuemmel S, Kunz G, Lesur A, Pierga JY, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Thompson AM, Viale G, Zoppoli G, Vuylsteke P, Tryfonidis K, Poncet C, Bogaerts J, Cardoso F; MINDACT investigators and the TRANSBIG Consortium. Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial. J Clin Oncol. 2020 Apr 10;38(11):1186-1197. Epub 2020 Feb 21. link to original article contains dosing details in supplement link to PMC article PubMed NCT00433589
  34. NSABP B-36: Geyer CE Jr, Bandos H, Rastogi P, Jacobs SA, Robidoux A, Fehrenbacher L, Ward PJ, Polikoff J, Brufsky AM, Provencher L, Paterson AHG, Hamm JT, Carolla RL, Baez-Diaz L, Julian TB, Swain SM, Mamounas EP, Wolmark N. Definitive results of a phase III adjuvant trial comparing six cycles of FEC-100 to four cycles of AC in women with operable node-negative breast cancer: the NSABP B-36 trial (NRG Oncology). Breast Cancer Res Treat. 2022 Jun;193(3):555-564. Epub 2022 Mar 1. Erratum in: Breast Cancer Res Treat. 2022 May 4. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00087178

MMM

MMM: Mitomycin-C, Mitoxantrone, Methotrexate

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fernando et al. 2019 (SECRAB) 1998-2004 Phase 3 (C) 1a. CMF & RT
1b. E-CMF & RT
1c. A-CMF & RT
1d. MMM & RT 		Inferior LRFS

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles

References

  1. SECRAB: Fernando IN, Bowden SJ, Herring K, Brookes CL, Ahmed I, Marshall A, Grieve R, Churn M, Spooner D, Latief TN, Agrawal RK, Brunt AM, Stevens A, Goodman A, Canney P, Bishop J, Ritchie D, Dunn J, Poole CJ, Rea DW; SECRAB Investigators. Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial. Radiother Oncol. 2020 Jan;142:52-61. Epub 2019 Nov 27. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00003893

Paclitaxel monotherapy, weekly

T: Taxol (Paclitaxel)
P: Paclitaxel
pT: pacliTaxel
wP: weekly Paclitaxel
wT: weekly Taxol (Paclitaxel)

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shulman et al. 2012 (CALGB 40101) 2002-2008 Phase 3 (E-de-esc) 1. AC x 4 Did not meet primary endpoint of RFS
2. AC x 6 Did not meet primary endpoint of RFS
3. Paclitaxel; weekly x 18 Did not meet primary endpoint of RFS

Note: In CALGB 40101, this is the dosing before a mid-protocol amendment in 2003. This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Chemotherapy

7-day cycle for 12 cycles

References

  1. CALGB 40101: Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article contains dosing details in manuscript link to study protocol PDF link to PMC article PubMed NCT00041119
    1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. Epub 2014 Jun 16. link to original article link to PMC article PubMed

Paclitaxel monotherapy, dose-dense (q2wk)

ddT: dose-dense Taxol (Paclitaxel)
ddP: dose-dense Paclitaxel

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Shulman et al. 2012 (CALGB 40101) 2002-2008 Phase 3 (E-de-esc) 1. ddAC x 4 Did not meet primary endpoint of RFS
2. ddAC x 6 Did not meet primary endpoint of RFS
3. ddT x 6 Did not meet primary endpoint of RFS
Burstein et al. 2005 2003-2004 Non-randomized

Note: in CALGB 40101, this is the dosing after a mid-protocol amendment in 2003.

Preceding treatment

Chemotherapy

Supportive therapy

  • Diphenhydramine (Benadryl) 12.5 to 50 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
  • One of the following H2 blockers:
  • One of the following dexamethasone choices:
  • Recommended growth factor support with one of the following:
    • Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Sargramostim (Leukine) 250 to 500 mcg/m2 SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Pegfilgrastim (Neulasta) 6 mg SC once, given 24 to 36 hours after chemotherapy

14-day cycle for 4 cycles

References

  1. Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. link to original article contains dosing details in manuscript PubMed
  2. CALGB 40101: Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article contains dosing details in manuscript link to study protocol PDF link to PMC article PubMed NCT00041119
    1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. Epub 2014 Jun 16. link to original article link to PMC article PubMed

TAC (Docetaxel)

TAC: Taxotere (Docetaxel), Adriamycin (Doxorubicin), Cyclophosphamide
ACT: Adriamycin (Doxorubicin), Cyclophosphamide, Taxotere (Docetaxel)

Regimen variant #1, 4 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Swain et al. 2010 (NSABP B-30) 1999-2004 Phase 3 (C) 1. AC-D Might have inferior OS
2. AT Not reported
Sparano et al. 2018 (TAILORx) 2006-2010 Phase 3 (C) No chemotherapy Non-inferior IDFS (primary endpoint)

Note: this was a mid-protocol dosing amendment for NSABP B-30. This was the lower bound of cycles in TAILORx.

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles


Regimen variant #2, 6 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Martin et al. 2005 (BCIRG 001) 1997-1999 Phase 3 (E-RT-switch-ic) FAC Superior OS1 (secondary endpoint)
OS120: 76% vs 69%
(HR 0.74, 95% CI 0.61-0.90)

Superior DFS (primary endpoint)
DFS60: 75% vs 68%
Martín et al. 2010 (GEICAM 9805) 1999-2003 Phase 3 (E-switch-ic) FAC Superior DFS (primary endpoint)
(HR 0.68, 95% CI 0.49-0.93)
Eiermann et al. 2011 (BCIRG-005) 2000-2003 Phase 3 (C) AC-D Did not meet primary endpoint of DFS60
Swain et al. 2013 (NSABP B-38) 2004-2007 Phase 3 (C) 1. ddAC-ddT Did not meet primary endpoint of DFS
2. ddAC-ddPG Did not meet primary endpoint of DFS
van Rossum et al. 2018 (MATADOR) 2004-2012 Phase 3 (E-switch-ic) ddAC Did not meet secondary endpoints of RFS/OS
Sparano et al. 2018 (TAILORx) 2006-2010 Phase 3 (C) No chemotherapy Non-inferior IDFS (primary endpoint)
Blum et al. 2017 (USOR 06-090) 2007-2009 Phase 3 (C) TC Seems to have superior IDFS (primary endpoint)
Blum et al. 2017 (NSABP-46-I/USOR 07132) 2009-2012 Phase 3 (C) TC Seems to have superior IDFS (primary endpoint)
Blum et al. 2017 (NSABP B-49) 2012-04-04 to 2013-11-21 Phase 3 (C) TC Seems to have superior IDFS (primary endpoint)

1Reported efficacy is based on the 2012 update.
Note: Blum et al. 2017 is a pooled analysis of three RCTs, some of which had arms other than TAC and TC. Refer to the paper for further details. This was the upper bound of cycles in TAILORx.

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy

Supportive therapy

21-day cycle for 6 cycles

References

  1. BCIRG 001: Martín M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C; Breast Cancer International Research Group. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med. 2005 Jun 2;352(22):2302-13. link to original article contains dosing details in abstract PubMed NCT00688740
    1. Update: Mackey JR, Martín M, Pienkowski T, Rolski J, Guastalla JP, Sami A, Glaspy J, Juhos E, Wardley A, Fornander T, Hainsworth J, Coleman R, Modiano MR, Vinholes J, Pinter T, Rodríguez-Lescure A, Colwell B, Whitlock P, Provencher L, Laing K, Walde D, Price C, Hugh JC, Childs BH, Bassi K, Lindsay MA, Wilson V, Rupin M, Houé V, Vogel C; TRIO/BCIRG 001 investigators. Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial. Lancet Oncol. 2013 Jan;14(1):72-80. Epub 2012 Dec 12. link to original article PubMed
  2. NSABP B-30: Swain SM, Jeong JH, Geyer CE Jr, Costantino JP, Pajon ER, Fehrenbacher L, Atkins JN, Polikoff J, Vogel VG, Erban JK, Rastogi P, Livingston RB, Perez EA, Mamounas EP, Land SR, Ganz PA, Wolmark N. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med. 2010 Jun 3;362(22):2053-65. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00003782
  3. GEICAM 9805: Martín M, Seguí MA, Antón A, Ruiz A, Ramos M, Adrover E, Aranda I, Rodríguez-Lescure A, Grosse R, Calvo L, Barnadas A, Isla D, Martinez del Prado P, Ruiz Borrego M, Zaluski J, Arcusa A, Muñoz M, López Vega JM, Mel JR, Munarriz B, Llorca C, Jara C, Alba E, Florián J, Li J, López García-Asenjo JA, Sáez A, Rios MJ, Almenar S, Peiró G, Lluch A; GEICAM. Adjuvant docetaxel for high-risk, node-negative breast cancer. N Engl J Med. 2010 Dec 2;363(23):2200-10. link to original article PubMed NCT00121992
  4. BCIRG-005: Eiermann W, Pienkowski T, Crown J, Sadeghi S, Martín M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press M, Sauter G, Lindsay MA, Riva A, Buyse M, Drevot P, Taupin H, Mackey JR. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol. 2011 Oct 10;29(29):3877-84. Epub 2011 Sep 12. link to original article contains dosing details in manuscript PubMed NCT00312208
    1. Update: Mackey JR, Pieńkowski T, Crown J, Sadeghi S, Martín M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press MF, Sauter G, Lindsay M, Houé V, Buyse M, Drevot P, Hitier S, Bensfia S, Eiermann W; Translational Research In Oncology (TRIO)/ Breast Cancer International Research Group (BCIRG)-005 investigators. Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial. Ann Oncol. 2016 Jun;27(6):1041-7. Epub 2016 Mar 2. link to original article PubMed
  5. NSABP B-38: Swain SM, Tang G, Geyer CE Jr, Rastogi P, Atkins JN, Donnellan PP, Fehrenbacher L, Azar CA, Robidoux A, Polikoff JA, Brufsky AM, Biggs DD, Levine EA, Zapas JL, Provencher L, Northfelt DW, Paik S, Costantino JP, Mamounas EP, Wolmark N. Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial. J Clin Oncol. 2013 Sep 10;31(26):3197-204. Epub 2013 Aug 12. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00093795
  6. USOR 06-090: Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00493870
    1. Pooled update: Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. link to original article link to PMC article PubMed
  7. NSABP-46-I/USOR 07132: Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00887536
    1. Pooled update: Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. link to original article link to PMC article PubMed
  8. NSABP B-49: Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01547741
    1. Pooled update: Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. link to original article link to PMC article PubMed
  9. TAILORx: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. link to original article link to PMC article contains dosing details in supplement PubMed NCT00310180
  10. MATADOR: van Rossum AGJ, Kok M, van Werkhoven E, Opdam M, Mandjes IAM, van Leeuwen-Stok AE, van Tinteren H, Imholz ALT, Portielje JEA, Bos MMEM, van Bochove A, Wesseling J, Rutgers EJ, Linn SC, Oosterkamp HM; MATADOR Trialists' Group. Adjuvant dose-dense doxorubicin-cyclophosphamide versus docetaxel-doxorubicin-cyclophosphamide for high-risk breast cancer: first results of the randomised MATADOR trial (BOOG 2004-04). Eur J Cancer. 2018 Oct;102:40-48. link to original article contains dosing details in abstract PubMed ISRCTN61893718
  11. PUMCH-Breast-TCX: NCT01354522

Metastatic disease, first-line chemotherapy

Note: in many of these regimens, patients were allowed to have received (neo)adjuvant chemotherapy and hormonal therapy (when applicable). These are first-line regimens in the metastatic setting, with a few being specifically for the locally advanced but unresectable setting.

Cyclophosphamide & Doxorubicin (AC)

AC: Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen variant #1, 40/400

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rosner et al. 1987 1981-1985 Randomized (E-de-esc) 1. CFP
2. CMFVP 		Did not meet primary endpoint of OS

Chemotherapy

28-day cycles


Regimen variant #2, 40/500

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Katsumata et al. 2009 (JCOG9802) 1999-2003 Phase 3 (C) 1. AC/D
2. Docetaxel 		Did not meet primary endpoint of TTF

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #3, 40/800 (PO)

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jones et al. 1975 1973-1974 Non-randomized
Tranum et al. 1982 (SWOG-7405B) 1974-1977 Phase 3 (E-de-esc) 1. FAC
2. A-CMFVP 		Did not meet primary endpoint of ORR

Chemotherapy

21- to 28-day cycles


Regimen variant #4, 50/750

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Forbes 1986 1978-1981 Randomized (C) 1. ACT
2. Tamoxifen 		Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 9 cycles


Regimen variant #5, 60/600

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Biganzoli et al. 2002 (EORTC 10961) 1996-1999 Phase 3 (C) AT (Taxol) Did not meet primary endpoint of PFS
Nabholtz et al. 2003 (TAX 306) NR Phase 3 (C) AT (Taxotere) Seems to have inferior TTP

Chemotherapy

21-day cycles


Regimen variant #6, with range

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Robert et al. 2011 (RIBBON-1) 2005-2007 Phase 3 (C) 1a. AC & Bevacizumab
1b. Capecitabine & Bevacizumab
1c. Docetaxel & Bevacizumab
1d. EC & Bevacizumab
1e. FAC & Bevacizumab
1f. FEC & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Chemotherapy

21-day cycle for up to 8 cycles

References

  1. Jones SE, Durie BG, Salmon SE. Combination chemotherapy with adriamycin and cyclophosphamide for advanced breast cancer. Cancer. 1975 Jul;36(1):90-7. link to original article contains dosing details in abstract PubMed
  2. SWOG-7405B: Tranum BL, McDonald B, Thigpen T, Vaughn C, Wilson H, Maloney T, Costanzi J, Bickers J, el Mawli NG, Palmer R, Hoogstraten B, Heilburn L, Rasmusen S; SWOG. Adriamycin combinations in advanced breast cancer: a Southwest Oncology Group Study. Cancer. 1982 Mar 1;49(5):835-9. link to original article contains dosing details in manuscript PubMed
  3. Forbes JF; Australian and New Zealand Breast Cancer Trials Group, Clinical Oncological Society of Australia. A randomized trial in postmenopausal patients with advanced breast cancer comparing endocrine and cytotoxic therapy given sequentially or in combination. J Clin Oncol. 1986 Feb;4(2):186-93. link to original article contains dosing details in manuscript PubMed
  4. Rosner D, Nemoto T, Lane WW. A randomized study of intensive versus moderate chemotherapy programs in metastatic breast cancer. Cancer. 1987 Mar 1;59(5):874-83. link to original article contains dosing details in manuscript PubMed
  5. EORTC 10961: Biganzoli L, Cufer T, Bruning P, Coleman R, Duchateau L, Calvert AH, Gamucci T, Twelves C, Fargeot P, Epelbaum R, Lohrisch C, Piccart MJ. Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organisation for Research and Treatment of Cancer 10961 multicenter phase III trial. J Clin Oncol. 2002 Jul 15;20(14):3114-21. link to original article contains dosing details in abstract PubMed
  6. TAX 306: Nabholtz JM, Falkson C, Campos D, Szanto J, Martín M, Chan S, Pienkowski T, Zaluski J, Pinter T, Krzakowski M, Vorobiof D, Leonard R, Kennedy I, Azli N, Murawsky M, Riva A, Pouillart P; TAX 306 Study Group. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol. 2003 Mar 15;21(6):968-75. link to original article PubMed
  7. JCOG9802: Katsumata N, Watanabe T, Minami H, Aogi K, Tabei T, Sano M, Masuda N, Andoh J, Ikeda T, Shibata T, Takashima S. Phase III trial of doxorubicin plus cyclophosphamide (AC), docetaxel, and alternating AC and docetaxel as front-line chemotherapy for metastatic breast cancer: Japan Clinical Oncology Group trial (JCOG9802). Ann Oncol. 2009 Jul;20(7):1210-5. Epub 2009 Mar 2. link to original article contains dosing details in abstract PubMed
  8. RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains dosing details in manuscript PubMed NCT00262067

Cyclophosphamide & Doxorubicin (AC) & Bevacizumab

AC & Bevacizumab: Adriamycin (Doxorubicin), Cyclophosphamide, Bevacizumab

Regimen variant #1, with range

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Robert et al. 2011 (RIBBON-1) 2005-2007 Phase 3 (E-esc) 1a. AC
1b. Capecitabine
1c. Docetaxel
1d. EC
1e. FAC
1f. FEC
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
(HR 0.64, 95% CI 0.52-0.80)

Chemotherapy

Targeted therapy

21-day cycle for up to 8 cycles

Subsequent treatment

References

  1. RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains dosing details in manuscript PubMed NCT00262067

Capecitabine monotherapy

Regimen variant #1, 650 mg/m2 PO twice per day, continuous

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Stockler et al. 2011 (ANZ 0001) 2001-2005 Phase 3 (E-de-esc) 1. CMF Seems to have superior OS
2. Capecitabine; intermittent Did not meet primary endpoint of quality-adjusted PFS

Chemotherapy

21-day cycles


Regimen variant #2, 1000 mg/m2 PO twice per day, limited duration

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Smorenburg et al. 2014 (OMEGA) 2007-2011 Phase 3 (E-switch-ic) PLD Did not meet primary endpoint of PFS

Chemotherapy

21-day cycle for 8 cycles


Regimen variant #3, 1000 mg/m2 PO twice per day, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bajetta et al. 2005 1999-2003 Phase 2
Stockler et al. 2011 (ANZ 0001) 2001-2005 Phase 3 (E-de-esc) 1. CMF Seems to have superior OS (secondary endpoint)
2. Capecitabine; continuous Did not meet primary endpoint of quality-adjusted PFS
Robert et al. 2011 (RIBBON-1) 2005-2007 Phase 3 (C) 1a. AC & Bevacizumab
1b. Capecitabine & Bevacizumab
1c. Docetaxel & Bevacizumab
1d. EC & Bevacizumab
1e. FAC & Bevacizumab
1f. FEC & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Chemotherapy

21-day cycles


Regimen variant #4, 1250 mg/m2 PO twice per day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bajetta et al. 2005 1999-2003 Phase 2
Harbeck et al. 2016 (PELICAN) 2006-2010 Phase 3 (E-switch-ic) PLD Inconclusive whether non-inferior TTP (primary endpoint)

Chemotherapy

21-day cycles

References

  1. Bajetta E, Procopio G, Celio L, Gattinoni L, Della Torre S, Mariani L, Catena L, Ricotta R, Longarini R, Zilembo N, Buzzoni R. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol. 2005 Apr 1;23(10):2155-61. Epub 2005 Feb 14. link to original article contains dosing details in manuscript PubMed
  2. RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains dosing details in manuscript PubMed NCT00262067
  3. ANZ 0001: Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B, Van Hazel G, Wilcken NR, Grimison PS, Nowak AK, Gainford MC, Fong A, Paksec L, Sourjina T, Zannino D, Gebski V, Simes RJ, Forbes JF, Coates AS. Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4498-504. Epub 2011 Oct 24. link to original article contains dosing details in manuscript PubMed
  4. OMEGA: Smorenburg CH, de Groot SM, van Leeuwen-Stok AE, Hamaker ME, Wymenga AN, de Graaf H, de Jongh FE, Braun JJ, Los M, Maartense E, van Tinteren H, Nortier JW, Seynaeve C; Dutch Breast Cancer Research Group. A randomized phase III study comparing pegylated liposomal doxorubicin with capecitabine as first-line chemotherapy in elderly patients with metastatic breast cancer: results of the OMEGA study of the Dutch Breast Cancer Research Group BOOG. Ann Oncol. 2014 Mar;25(3):599-605. Epub 2014 Feb 6. link to original article link to PMC article contains dosing details in abstract PubMed ISRCTN11114726
  5. PELICAN: Harbeck N, Saupe S, Jäger E, Schmidt M, Kreienberg R, Müller L, Otremba BJ, Waldenmaier D, Dorn J, Warm M, Scholz M, Untch M, de Wit M, Barinoff J, Lück HJ, Harter P, Augustin D, Harnett P, Beckmann MW, Al-Batran SE; PELICAN Investigators. A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study. Breast Cancer Res Treat. 2017 Jan;161(1):63-72. Epub 2016 Oct 31. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00266799
  6. CONTESSA: NCT03326674

Capecitabine & Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Robert et al. 2011 (RIBBON-1) 2005-2007 Phase 3 (E-esc) 1a. AC
1b. Capecitabine
1c. Docetaxel
1d. EC
1e. FAC
1f. FEC
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
(HR 0.69, 95% CI 0.56-0.84)
Lang et al. 2013 (TURANDOT) 2008-2010 Phase 3 (E-switch-ic) Paclitaxel & Bevacizumab Non-inferior OS1 (primary endpoint)
Welt et al. 2016 (CARIN) 2009-2012 Phase 3 (C) Capecitabine, Vinorelbine, Bevacizumab Might have inferior PFS

1Reported efficacy for TURANDOT is based on the 2016 update.

Chemotherapy

Targeted therapy

21-day cycles

References

  1. RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains dosing details in manuscript PubMed NCT00262067
  2. TURANDOT: Lang I, Brodowicz T, Ryvo L, Kahan Z, Greil R, Beslija S, Stemmer SM, Kaufman B, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Messinger D, Zielinski C; Central European Cooperative Oncology Group. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial. Lancet Oncol. 2013 Feb;14(2):125-33. Epub 2013 Jan 10. link to original article PubMed NCT00600340
    1. Update: Zielinski C, Láng I, Inbar M, Kahán Z, Greil R, Beslija S, Stemmer SM, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Petruzelka L, Eniu A, Nisenbaum B, Dank M, Anghel R, Messinger D, Brodowicz T; TURANDOT investigators. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1230-9. Epub 2016 Aug 5. link to original article contains dosing details in abstract PubMed
  3. CARIN: Welt A, Marschner N, Lerchenmueller C, Decker T, Steffens CC, Koehler A, Depenbusch R, Busies S, Hegewisch-Becker S. Capecitabine and bevacizumab with or without vinorelbine in first-line treatment of HER2/neu-negative metastatic or locally advanced breast cancer: final efficacy and safety data of the randomised, open-label superiority phase 3 CARIN trial. Breast Cancer Res Treat. 2016 Feb;156(1):97-107. Epub 2016 Feb 29. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00868634

Capecitabine & Paclitaxel

TX: Taxol (Paclitaxel), Xeloda (Capecitabine)

Regimen

Study Dates of enrollment Evidence
Blum et al. 2006 2003 Phase 2

Chemotherapy

21-day cycles

References

  1. Blum JL, Dees EC, Chacko A, Doane L, Ethirajan S, Hopkins J, McMahon R, Merten S, Negron A, Neubauer M, Ilegbodu D, Boehm KA, Asmar L, O'Shaughnessy JA. Phase II trial of capecitabine and weekly paclitaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2006 Sep 20;24(27):4384-90. Epub 2006 Aug 22. link to original article contains dosing details in manuscript PubMed

Capecitabine & Paclitaxel, nanoparticle albumin-bound

Regimen

Study Dates of enrollment Evidence
Schwartzberg et al. 2011 NR Phase 2

Chemotherapy

21-day cycles

References

  1. Schwartzberg LS, Arena FP, Mintzer DM, Epperson AL, Walker MS. Phase II multicenter trial of albumin-bound paclitaxel and capecitabine in first-line treatment of patients with metastatic breast cancer. Clin Breast Cancer. 2012 Apr;12(2):87-93. Epub 2011 Dec 6. link to original article contains dosing details in abstract PubMed

CMF

CMF: Cyclophosphamide, Methotrexate, Fluorouracil

Regimen variant #1, 350/20/350

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Muss et al. 1982 1979-1981 Randomized (C) CAV Seems to have inferior ORR

Chemotherapy

21-day cycles


Regimen variant #2, 600/40/600

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tannock et al. 1988 1981-1986 Phase 3 (C) CMF; lower-dose Might have superior OS
Ingle et al. 1994 (NCCTG 87-32-52) 1987-1991 Randomized (C) DES-CEF Might have inferior ORR

Chemotherapy

21-day cycles


Regimen variant #3, 1400/80/1000

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Aisner et al. 1987 (CALGB 7682) 1976-1980 Phase 3 (C) 1. CAF Seems to have inferior OS
2. CAFVP Inferior ORR

Chemotherapy

28-day cycles


Regimen variant #4, 1400/60/800

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Canellos et al. 1976 NR Phase 3 (E-esc) Melphalan Seems to have superior OS

Note: this was the dose used for patients older than 60 in the revised protocol of Canellos et al. 1976.

Chemotherapy

28-day cycles


Regimen variant #5, 1400/80/1200

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brambilla et al. 1976 1973-1974 Randomized (C) AV Did not meet primary endpoint of ORR
Canellos et al. 1976 NR Phase 3 (E-esc) Melphalan Seems to have superior OS
Bull et al. 1978 NR Phase 3 (C) CAF Might have inferior ORR
Tormey et al. 1982 (ECOG E2173) 1973-1974 Randomized (C) 1. AV
2. CMFP 		Seems to have inferior OS
Cocconi et al. 1983 NR Randomized (C) CMFT Might have inferior TTF
Viladiu et al. 1985 1978-1981 Randomized (C) 1. CMFT
2. CMF & MPA 		Seems to have inferior ORR
Engelsman et al. 1991 (EORTC 10808) 1981-1984 Phase 3 (C) CMF; 600/40/600 (IV) Seems to have superior OS
Cocconi et al. 1990 1981-1985 Randomized (C) CMF x 6, then intensification Did not meet endpoints of TTP/OS
Yosef et al. 1993 1983-1987 Randomized (C) SMF Did not meet endpoints of TTF/OS
Cocconi et al. 1991 1985-1988 Randomized (C) PE Might have inferior ORR
Ackland et al. 2001 (HEPI 013) 1990-1992 Phase 3 (C) CEF Inferior TTP
Stadtmauer et al. 2000 1990-1997 Phase 3 (C) CMF x 4-6, then HDT Did not meet primary endpoint of OS
von Minckwitz et al. 2005 1996-2001 Phase 3 (C) BMF Inferior TTP
Stockler et al. 2011 (ANZ 0001) 2001-2005 Phase 3 (C) 1. Capecitabine; continuous
2. Capecitabine; intermittent 		Seems to have inferior OS

Note: this was the dose used for patients younger than 60 in the revised protocol of Canellos et al. 1976.

Chemotherapy

28-day cycles


Regimen variant #6, 1400/120/1200

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Canellos et al. 1976 NR Phase 3 (E-esc) Melphalan Seems to have superior OS

Note: this was the dose used for patients in the original protocol of Canellos et al. 1976 and was deemed too myelotoxic.

Chemotherapy

28-day cycles

References

  1. Brambilla C, De Lena M, Rossi A, Valagussa P, Bonadonna G. Response and survival in advanced breast cancer after two non-cross-resistant combinations. Br Med J. 1976 Apr 3;1(6013):801-4. link to original article link to PMC article PubMed
  2. Canellos GP, Pocock SJ, Taylor SG 3rd, Sears ME, Klaasen DJ, Band PR; ECOG. Combination chemotherapy for metastatic breast carcinoma: prospective comparison of multiple drug therapy with L-phenylalanine mustard. Cancer. 1976 Nov;38(5):1882-6. link to original article PubMed
  3. Bull JM, Tormey DC, Li SH, Carbone PP, Falkson G, Blom J, Perlin E, Simon R. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978 May;41(5):1649-57. link to original article PubMed
  4. ECOG E2173: Tormey DC, Gelman R, Band PR, Sears M, Rosenthal SN, DeWys W, Perlia C, Rice MA. Comparison of induction chemotherapies for metastatic breast cancer: an Eastern Cooperative Oncology Group Trial. Cancer. 1982 Oct 1;50(7):1235-44. link to original article PubMed
  5. Muss HB, Richards F 2nd, Jackson DV, Cooper MR, White DR, Stuart JJ, Ramseur W, Christian RM, Wells HB, Pope E, Spurr CL; Piedmont Oncology Association. Vincristine, doxorubicin, and cyclophosphamide versus low-dose intravenous cyclophosphamide, methotrexate, and 5-fluorouracil in advanced breast cancer: a randomized trial of the Piedmont Oncology Association. Cancer. 1982 Dec 1;50(11):2269-74. link to original article contains dosing details in abstract PubMed
  6. Cocconi G, De Lisi V, Boni C, Mori P, Malacarne P, Amadori D, Giovanelli E. Chemotherapy versus combination of chemotherapy and endocrine therapy in advanced breast cancer: a prospective randomized study. Cancer. 1983 Feb 15;51(4):581-8. link to original article contains dosing details in manuscript PubMed
  7. Viladiu P, Alonso MC, Avella A, Beltrán M, Borrás J, Ojeda B, Bosch FX. Chemotherapy versus chemotherapy plus hormonotherapy in postmenopausal advanced breast cancer patients: a randomized trial. Cancer. 1985 Dec 15;56(12):2745-50. link to original article contains dosing details in manuscript PubMed
  8. CALGB 7682: Aisner J, Weinberg V, Perloff M, Weiss R, Perry M, Korzun A, Ginsberg S, Holland JF; CALGB. Chemotherapy versus chemoimmunotherapy (CAF v CAFVP v CMF each +/- MER) for metastatic carcinoma of the breast: a CALGB study. J Clin Oncol. 1987 Oct;5(10):1523-33. link to original article contains dosing details in abstract PubMed
  9. Tannock IF, Boyd NF, DeBoer G, Erlichman C, Fine S, Larocque G, Mayers C, Perrault D, Sutherland H. A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer. J Clin Oncol. 1988 Sep;6(9):1377-87. link to original article PubMed
  10. Cocconi G, Bisagni G, Bacchi M, Buzzi F, Canaletti R, Carpi A, Ceci G, Colozza A, De Lisi V, Lottici R, Passalacqua R, Peracchia G; GOIRC. A comparison of continuation versus late intensification followed by discontinuation of chemotherapy in advanced breast cancer: a prospective randomized trial of the Italian Oncology Group for Clinical Research (GOIRC). Ann Oncol. 1990;1(1):36-44. link to original article PubMed
  11. EORTC 10808: Engelsman E, Klijn JC, Rubens RD, Wildiers J, Beex LV, Nooij MA, Rotmensz N, Sylvester R. "Classical" CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer: an EORTC Breast Cancer Co-operative Group Phase III Trial (10808). Eur J Cancer. 1991;27(8):966-70. link to original article contains dosing details in manuscript PubMed
  12. Cocconi G, Bisagni G, Bacchi M, Boni C, Bartolucci R, Ceci G, Colozza MA, De Lisi V, Lottici R, Mosconi AM, Passalacqua R, Tonato M; Italian Oncology Group for Clinical Research. Cisplatin and etoposide as first-line chemotherapy for metastatic breast carcinoma: a prospective randomized trial of the Italian Oncology Group for Clinical Research. J Clin Oncol. 1991 Apr;9(4):664-9. link to original article PubMed
  13. Yosef H, Slater A, Keen CW, Bunting JS, Hope-Stone H, Parmar H, Roberts JT, Termander B, Nilsson B. Prednimustine (Sterecyt) versus cyclophosphamide both in combination with methotrexate and 5-fluorouracil in the treatment of advanced breast cancer. Eur J Cancer. 1993;29A(8):1100-5. link to original article contains dosing details in abstract PubMed
  14. NCCTG 87-32-52: Ingle JN, Foley JF, Mailliard JA, Krook JE, Hartmann LC, Jung SH, Veeder MH, Gesme DH Jr, Hatfield AK, Goldberg RM. Randomized trial of cyclophosphamide, methotrexate, and 5-fluorouracil with or without estrogenic recruitment in women with metastatic breast cancer. Cancer. 1994 May 1;73(9):2337-43. link to original article contains dosing details in abstract PubMed
  15. Stadtmauer EA, O'Neill A, Goldstein LJ, Crilley PA, Mangan KF, Ingle JN, Brodsky I, Martino S, Lazarus HM, Erban JK, Sickles C, Glick JH; Philadelphia Bone Marrow Transplant Group. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J Med. 2000 Apr 13;342(15):1069-76. link to original article PubMed
  16. HEPI 013: Ackland SP, Anton A, Breitbach GP, Colajori E, Tursi JM, Delfino C, Efremidis A, Ezzat A, Fittipaldo A, Kolaric K, Lopez M, Viaro D; HEPI 013 study group. Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study. J Clin Oncol. 2001 Feb 15;19(4):943-53. link to original article PubMed
  17. von Minckwitz G, Chernozemsky I, Sirakova L, Chilingirov P, Souchon R, Marschner N, Kleeberg U, Tsekov C, Fritze D, Thomssen C, Stuart N, Vermorken JB, Loibl S, Merkle Kh, Kaufmann M. Bendamustine prolongs progression-free survival in metastatic breast cancer (MBC): a phase III prospective, randomized, multicenter trial of bendamustine hydrochloride, methotrexate and 5-fluorouracil (BMF) versus cyclophosphamide, methotrexate and 5-fluorouracil (CMF) as first-line treatment of MBC. Anticancer Drugs. 2005 Sep;16(8):871-7. link to original article PubMed
  18. ANZ 0001: Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B, Van Hazel G, Wilcken NR, Grimison PS, Nowak AK, Gainford MC, Fong A, Paksec L, Sourjina T, Zannino D, Gebski V, Simes RJ, Forbes JF, Coates AS. Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4498-504. Epub 2011 Oct 24. link to original article PubMed

CMFT

CMFT: Cyclophosphamide, Methotrexate, Fluorouracil, Tamoxifen

Regimen variant #1, lower-dose tamoxifen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cocconi et al. 1983 NR Randomized (E-esc) CMF Might have superior TTF

Chemotherapy

Endocrine therapy

28-day cycles


Regimen variant #2, higher-dose tamoxifen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Viladiu et al. 1985 1978-1981 Randomized (E-esc) 1. CMF
2. CMF & MPA 		Seems to have superior ORR

Chemotherapy

Endocrine therapy

28-day cycles

References

  1. Cocconi G, De Lisi V, Boni C, Mori P, Malacarne P, Amadori D, Giovanelli E. Chemotherapy versus combination of chemotherapy and endocrine therapy in advanced breast cancer: a prospective randomized study. Cancer. 1983 Feb 15;51(4):581-8. link to original article contains dosing details in manuscript PubMed
  2. Viladiu P, Alonso MC, Avella A, Beltrán M, Borrás J, Ojeda B, Bosch FX. Chemotherapy versus chemotherapy plus hormonotherapy in postmenopausal advanced breast cancer patients: a randomized trial. Cancer. 1985 Dec 15;56(12):2745-50. link to original article contains dosing details in manuscript PubMed

Docetaxel monotherapy

D: Docetaxel
T: Taxotere (Docetaxel)

Regimen variant #1, 30 mg/m2 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Stemmler et al. 2011 (D2) 2001-2008 Phase 3 (E-switch-ic) Docetaxel; q3wk Seems to have inferior ORR (secondary endpoint) Superior hematotoxicity (primary endpoint)

Chemotherapy

28-day cycles


Regimen variant #2, 40 mg/m2 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Rivera et al. 2008 2001-2004 Phase 3 (E-switch-ic) Docetaxel; q3wk Did not meet primary endpoint of ORR Superior toxicity

Chemotherapy

  • Docetaxel (Taxotere) as follows:
    • Cycle 1: 35 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
    • Cycle 2 onwards: 40 mg/m2 IV over 30 minutes once per day on days 1, 8, 15

28-day cycles


Regimen variant #3, 40 mg/m2 6 weeks out of 8

Study Dates of enrollment Evidence
Burstein et al. 2000 1998 Phase 2

Chemotherapy

8-week cycles


Regimen variant #4, 60 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Katsumata et al. 2009 (JCOG9802) 1999-2003 Phase 3 (E-de-esc) 1. AC
2. AC/D 		Did not meet primary endpoint of TTF
Takashima et al. 2015 (SELECT BC) 2006-2010 Phase 3 (C) S-1 Seems to have non-inferior OS Inferior EQ-5D score

Chemotherapy

21-day cycle for up to 6 cycles (JCOG9802) or indefinitely (SELECT BC)


Regimen variant #5, 60 mg/m2 q4wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Takashima et al. 2015 (SELECT BC) 2006-2010 Phase 3 (C) S-1 Seems to have non-inferior OS Inferior EQ-5D score

Chemotherapy

28-day cycles


Regimen variant #6, 75 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Rivera et al. 2008 2001-2004 Phase 3 (C) Docetaxel; weekly Did not meet primary endpoint of ORR Inferior toxicity
Stemmler et al. 2011 (D2) 2001-2008 Phase 3 (C) Docetaxel; weekly Seems to have superior ORR Inferior hematotoxicity
Sparano et al. 2009 (DOXIL-BCA-3001) 2004-2006 Phase 3 (C) Docetaxel & PLD Inferior TTP Less toxic
Robert et al. 2011 (RIBBON-1) 2005-2007 Phase 3 (C) 1a. AC & Bevacizumab
1b. Capecitabine & Bevacizumab
1c. Docetaxel & Bevacizumab
1d. EC & Bevacizumab
1e. FAC & Bevacizumab
1f. FEC & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS
Takashima et al. 2015 (SELECT BC) 2006-2010 Phase 3 (C) S-1 Seems to have non-inferior OS Inferior EQ-5D score
Mackey et al. 2014 (ROSE/TRIO-12) 2008-2011 Phase 3 (C) Docetaxel & Ramucirumab Might have inferior PFS

Chemotherapy

21-day cycles

Dose and schedule modifications

  • Rivera et al. 2008 gave 75 mg/m2 in cycle 1, with escalation to 100 mg/m2 depending on toxicity


Regimen variant #7, 75 mg/m2 q4wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Takashima et al. 2015 (SELECT BC) 2006-2010 Phase 3 (C) S-1 Seems to have non-inferior OS Inferior EQ-5D score

Chemotherapy

28-day cycles


Regimen variant #8, 100 mg/m2 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pacilio et al. 2006 2000-2003 Phase 3 (C) Docetaxel & Epirubicin Did not meet primary endpoint of ORR

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #9, 100 mg/m2 x 8

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Crump et al. 2007 (NCIC-CTG MA.16) 1997-2000 Phase 3 (C) 1. FAC x 4, then HDCT with auto HSCT
2. FEC x 4, then HDCT with auto HSCT
3. Paclitaxel x 4, , then HDCT with auto HSCT
4. Docetaxel x 4, then HDCT with auto HSCT 		Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for 8 cycles


Regimen variant #10, 100 mg/m2 x 9

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Miles et al. 2010 (AVADO) 2006-03 to 2007-04 Phase 3 (C) 1. Docetaxel & Bevacizumab; 100/7.5 Did not meet primary endpoint of PFS
2. Docetaxel & Bevacizumab; 100/15 Inferior PFS

Chemotherapy

21-day cycle for up to 9 cycles


Regimen variant #11, 100 mg/m2, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Trudeau et al. 1996 1992-1993 Phase 2
Nielsen et al. 2011 2001-2005 Phase 3 (C) Docetaxel & Gemcitabine Might have inferior TTP
Joensuu et al. 2009 (B9E-MC-S241) 2002-2006 Phase 3 (C) D/G Did not meet primary endpoint of TTF More toxic
Gradishar et al. 2009 2005-2006 Randomized Phase 2 (C) 1. nab-Paclitaxel; higher-dose weekly
2. nab-Paclitaxel; lower-dose weekly
3. nab-Paclitaxel; q3wk 		Did not meet primary endpoint of ORR
Robert et al. 2011 (RIBBON-1) 2005-2007 Phase 3 (C) 1a. AC & Bevacizumab
1b. Capecitabine & Bevacizumab
1c. Docetaxel & Bevacizumab
1d. EC & Bevacizumab
1e. FAC & Bevacizumab
1f. FEC & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS
Bergh et al. 2012 (SUN 1064) 2007-2009 Phase 3 (C) Docetaxel & Sunitinib Did not meet primary endpoint of PFS

Chemotherapy

21-day cycles

References

  1. Trudeau ME, Eisenhauer EA, Higgins BP, Letendre F, Lofters WS, Norris BD, Vandenberg TA, Delorme F, Muldal AM; National Cancer Institute of Canada-Clinical Trials Group. Docetaxel in patients with metastatic breast cancer: a phase II study of the National Cancer Institute of Canada-Clinical Trials Group. J Clin Oncol. 1996 Feb;14(2):422-8. link to original article contains dosing details in abstract PubMed
  2. Review: Burris HA 3rd. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin Oncol. 1999 Jun;26(3 Suppl 9):1-6. PubMed
  3. Burstein HJ, Manola J, Younger J, Parker LM, Bunnell CA, Scheib R, Matulonis UA, Garber JE, Clarke KD, Shulman LN, Winer EP. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol. 2000 Mar;18(6):1212-9. link to original article PubMed content property of HemOnc.org
  4. Pacilio C, Morabito A, Nuzzo F, Gravina A, Labonia V, Landi G, Rossi E, De Maio E, Di Maio M, D'Aiuto G, Botti G, Normanno N, Chiodini P, Gallo C, Perrone F, de Matteis A; NCI-Naples Breast Cancer Group. Is epirubicin effective in first-line chemotherapy of metastatic breast cancer (MBC) after an epirubicin-containing adjuvant treatment? A single centre phase III trial. Br J Cancer. 2006 May 8;94(9):1233-6. link to original article link to PMC article contains dosing details in manuscript PubMed
  5. NCIC-CTG MA.16: Crump M, Gluck S, Tu D, Stewart D, Levine M, Kirkbride P, Dancey J, O'Reilly S, Shore T, Couban S, Girouard C, Marlin S, Shepherd L, Pritchard KI. Randomized trial of high-dose chemotherapy with autologous peripheral-blood stem-cell support compared with standard-dose chemotherapy in women with metastatic breast cancer: NCIC MA.16. J Clin Oncol. 2008 Jan 1;26(1):37-43. Epub 2007 Nov 19. link to original article contains dosing details in manuscript PubMed NCT00003032
  6. Rivera E, Mejia JA, Arun BK, Adinin RB, Walters RS, Brewster A, Broglio KR, Yin G, Esmaeli B, Hortobagyi GN, Valero V. Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic breast cancer. Cancer. 2008 Apr 1;112(7):1455-61. link to original article contains dosing details in manuscript PubMed
  7. JCOG9802: Katsumata N, Watanabe T, Minami H, Aogi K, Tabei T, Sano M, Masuda N, Andoh J, Ikeda T, Shibata T, Takashima S. Phase III trial of doxorubicin plus cyclophosphamide (AC), docetaxel, and alternating AC and docetaxel as front-line chemotherapy for metastatic breast cancer: Japan Clinical Oncology Group trial (JCOG9802). Ann Oncol. 2009 Jul;20(7):1210-5. Epub 2009 Mar 2. link to original article contains dosing details in abstract PubMed
  8. Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009 Aug 1;27(22):3611-9. Epub 2009 May 26. Erratum in: J Clin Oncol. 2011 Jul 1;29(19):2739. link to original article contains dosing details in manuscript PubMed
  9. DOXIL-BCA-3001: Sparano JA, Makhson AN, Semiglazov VF, Tjulandin SA, Balashova OI, Bondarenko IN, Bogdanova NV, Manikhas GM, Oliynychenko GP, Chatikhine VA, Zhuang SH, Xiu L, Yuan Z, Rackoff WR. Pegylated liposomal doxorubicin plus docetaxel significantly improves time to progression without additive cardiotoxicity compared with docetaxel monotherapy in patients with advanced breast cancer previously treated with neoadjuvant-adjuvant anthracycline therapy: results from a randomized phase III study. J Clin Oncol. 2009 Sep 20;27(27):4522-9. Epub 2009 Aug 17. link to original article contains dosing details in manuscript PubMed NCT00091442
  10. B9E-MC-S241: Joensuu H, Sailas L, Alanko T, Sunela K, Huuhtanen R, Utriainen M, Kokko R, Bono P, Wigren T, Pyrhönen S, Turpeenniemi-Hujanen T, Asola R, Leinonen M, Hahka-Kemppinen M, Kellokumpu-Lehtinen P. Docetaxel versus docetaxel alternating with gemcitabine as treatments of advanced breast cancer: final analysis of a randomised trial. Ann Oncol. 2010 May;21(5):968-73. Epub 2009 Oct 9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00191243
  11. AVADO: Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010 Jul 10;28(20):3239-47. Epub 2010 May 24. link to original article contains dosing details in manuscript PubMed NCT00333775
  12. D2: Stemmler HJ, Harbeck N, Gröll de Rivera I, Vehling Kaiser U, Rauthe G, Abenhardt W, Artmann A, Sommer H, Meerpohl HG, Kiechle M, Heinemann V. Prospective multicenter randomized phase III study of weekly versus standard docetaxel (D2) for first-line treatment of metastatic breast cancer. Oncology. 2010;79(3-4):197-203. Epub 2011 Mar 1. link to original article contains dosing details in abstract PubMed
  13. RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains dosing details in manuscript PubMed NCT00262067
  14. Nielsen DL, Bjerre KD, Jakobsen EH, Cold S, Stenbygaard L, Sørensen PG, Kamby C, Møller S, Jørgensen CL, Andersson M; Danish Breast Cancer Cooperative Group. Gemcitabine plus docetaxel versus docetaxel in patients with predominantly human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: a randomized, phase III study by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 2011 Dec 20;29(36):4748-54. Epub 2011 Nov 14. link to original article contains dosing details in abstract PubMed
  15. SUN 1064: Bergh J, Bondarenko IM, Lichinitser MR, Liljegren A, Greil R, Voytko NL, Makhson AN, Cortes J, Lortholary A, Bischoff J, Chan A, Delaloge S, Huang X, Kern KA, Giorgetti C. First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study. J Clin Oncol. 2012 Mar 20;30(9):921-9. Epub 2012 Feb 13. link to original article contains dosing details in manuscript PubMed NCT00393939
  16. ROSE/TRIO-12: Mackey JR, Ramos-Vazquez M, Lipatov O, McCarthy N, Krasnozhon D, Semiglazov V, Manikhas A, Gelmon KA, Konecny GE, Webster M, Hegg R, Verma S, Gorbunova V, Abi Gerges D, Thireau F, Fung H, Simms L, Buyse M, Ibrahim A, Martín M. Primary results of ROSE/TRIO-12, a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer. J Clin Oncol. 2015 Jan 10;33(2):141-8. Epub 2014 Sep 2. link to original article contains dosing details in abstract PubMed NCT00703326
  17. SELECT BC: Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T, Hozumi Y, Tsurutani J, Imoto S, Watanabe T, Sagara Y, Nishimura R, Shimozuma K, Ohashi Y; SELECT BC Study Group. Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2016 Jan;17(1):90-8. Epub 2015 Nov 27. link to original article contains dosing details in manuscript PubMed UMIN C000000416
    1. HRQoL analysis: Shiroiwa T, Fukuda T, Shimozuma K, Mouri M, Hagiwara Y, Doihara H, Akabane H, Kashiwaba M, Watanabe T, Ohashi Y, Mukai H. Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial. Qual Life Res. 2017 Feb;26(2):445-453. Epub 2016 Aug 12. link to original article link to PMC article PubMed

Docetaxel & Bevacizumab

Regimen variant #1, 75/15, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Robert et al. 2011 (RIBBON-1) 2005-2007 Phase 3 (E-esc) 1a. AC
1b. Capecitabine
1c. Docetaxel
1d. EC
1e. FAC
1f. FEC
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
(HR 0.64, 95% CI 0.52-0.80)
Lück et al. 2014 (TABEA) 2009-2012 Phase 3 (C) 1a. TX & Bevacizumab
1b. Capecitabine, Paclitaxel, Bevacizumab 		Did not meet primary endpoint of PFS
Trédan et al. 2016 (GINECO-BR107) 2010-2013 Phase 3 (C) Docetaxel & Bevacizumab, then Exemestane & Bevacizumab Did not meet primary endpoint of PFS

Chemotherapy

Targeted therapy

21-day cycles


Regimen variant #2, 100/15, 9 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Miles et al. 2010 (AVADO) 2006-03 to 2007-04 Phase 3 (E-esc) 1. Docetaxel Superior PFS (primary endpoint)
Median PFS: 10.1 vs 8.2 mo
(HR 0.77, 95% CI 0.64-0.93)
2. Docetaxel & Bevacizumab; 100/7.5 Not reported

Chemotherapy

Targeted therapy

21-day cycle for up to 9 cycles

Subsequent treatment


Regimen variant #3, 100/15, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Robert et al. 2011 (RIBBON-1) 2005-2007 Phase 3 (E-esc) 1a. AC
1b. Capecitabine
1c. Docetaxel
1d. EC
1e. FAC
1f. FEC
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
(HR 0.64, 95% CI 0.52-0.80)

Chemotherapy

Targeted therapy

21-day cycles

References

  1. AVADO: Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010 Jul 10;28(20):3239-47. Epub 2010 May 24. link to original article contains dosing details in manuscript PubMed NCT00333775
  2. RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains dosing details in manuscript PubMed NCT00262067
  3. TABEA: Lück HJ, Lübbe K, Reinisch M, Maass N, Feisel-Schwickardi G, Tomé O, Janni W, Aydogdu M, Neunhöffer T, Ober A, Aktas B, Park-Simon TW, Schumacher C, Höffkes HG, Illmer T, Wagner H, Mehta K, von Minckwitz G, Nekljudova V, Loibl S. Phase III study on efficacy of taxanes plus bevacizumab with or without capecitabine as first-line chemotherapy in metastatic breast cancer. Breast Cancer Res Treat. 2015 Jan;149(1):141-9. Epub 2014 Dec 18. link to original article contains dosing details in abstract PubMed
  4. GINECO-BR107: Trédan O, Follana P, Moullet I, Cropet C, Trager-Maury S, Dauba J, Lavau-Denes S, Diéras V, Béal-Ardisson D, Gouttebel M, Orfeuvre H, Stefani L, Jouannaud C, Bürki F, Petit T, Guardiola E, Becuwe C, Blot E, Pujade-Lauraine E, Bachelot T. A phase III trial of exemestane plus bevacizumab maintenance therapy in patients with metastatic breast cancer after first-line taxane and bevacizumab: a GINECO group study. Ann Oncol. 2016 Jun;27(6):1020-9. Epub 2016 Feb 24. link to original article contains dosing details in manuscript PubMed NCT01303679

Docetaxel & Doxorubicin (AT)

AT: Adriamycin (Doxorubicin) & Taxotere (Docetaxel)
AD: Adriamycin (Doxorubicin) & Docetaxel

Regimen variant #1, 50/75 x 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cassier et al. 2007 (ERASME 3) 2000-2004 Phase 3 (E-switch-ic) AT (Taxol) Might have inferior OS

Chemotherapy

21-day cycle for 8 cycles


Regimen variant #2, 50/75 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Bontenbal et al. 2005 1997-2002 Phase 2/3 (E-de-esc) FAC Seems to have superior OS (secondary endpoint)

Superior TTP (primary endpoint)
Alba et al. 2004 (GEICAM-9903) 1999-2001 Phase 3 (C) A-D More toxic

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #3, 50/75 x 8

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Nabholtz et al. 2003 (TAX 306) NR Phase 3 (E-switch-ic) AC Seems to have superior TTP
Stemmler et al. 2010 (D4) 2001-2008 Phase 3 (C) AT (Taxotere); weekly docetaxel Did not meet secondary endpoint of TTP Did not meet primary endpoint of hematotoxicity

Chemotherapy

21-day cycle for 8 cycles

References

  1. TAX 306: Nabholtz JM, Falkson C, Campos D, Szanto J, Martín M, Chan S, Pienkowski T, Zaluski J, Pinter T, Krzakowski M, Vorobiof D, Leonard R, Kennedy I, Azli N, Murawsky M, Riva A, Pouillart P; TAX 306 Study Group. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol. 2003 Mar 15;21(6):968-75. link to original article PubMed
  2. GEICAM-9903: Alba E, Martín M, Ramos M, Adrover E, Balil A, Jara C, Barnadas A, Fernández-Aramburo A, Sánchez-Rovira P, Amenedo M, Casado A; GEICAM. Multicenter randomized trial comparing sequential with concomitant administration of doxorubicin and docetaxel as first-line treatment of metastatic breast cancer: a Spanish Breast Cancer Research Group (GEICAM-9903) phase III study. J Clin Oncol. 2004 Jul 1;22(13):2587-93. link to original article contains dosing details in abstract PubMed
  3. Bontenbal M, Creemers GJ, Braun HJ, de Boer AC, Janssen JT, Leys RB, Ruit JB, Goey SH, van der Velden PC, Kerkhofs LG, Schothorst KL, Schmitz PI, Bokma HJ, Verweij J, Seynaeve C; Dutch Community Setting Trial for the Clinical Trial Group. Phase II to III study comparing doxorubicin and docetaxel with fluorouracil, doxorubicin, and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer: results of a Dutch Community Setting Trial for the Clinical Trial Group of the Comprehensive Cancer Centre. J Clin Oncol. 2005 Oct 1;23(28):7081-8. link to original article contains dosing details in abstract PubMed
  4. ERASME 3: Cassier PA, Chabaud S, Trillet-Lenoir V, Peaud PY, Tigaud JD, Cure H, Orfeuvre H, Salles B, Martin C, Jacquin JP, Agostini C, Guastalla JP, Pérol D, Bachelot T. A phase-III trial of doxorubicin and docetaxel versus doxorubicin and paclitaxel in metastatic breast cancer: results of the ERASME 3 study. Breast Cancer Res Treat. 2008 May;109(2):343-50. Epub 2007 Jul 5. link to original article contains dosing details in manuscript PubMed
  5. D4: Stemmler HJ, Harbeck N, Gröll de Rivera I, Vehling Kaiser U, Rauthe G, Abenhardt W, Artmann A, Sommer H, Meerpohl HG, Kiechle M, Heinemann V. Prospective multicenter randomized phase III study of weekly versus standard docetaxel plus doxorubicin (D4) for first-line treatment of metastatic breast cancer. Oncology. 2010;79(3-4):204-10. Epub 2011 Mar 1. link to original article contains dosing details in abstract PubMed

Docetaxel & Epirubicin (DE)

DE: Docetaxel & Epirubicin
ED: Epirubicin & Docetaxel
ET: Epirubicin & Taxotere (Docetaxel)

Regimen variant #1, 8 cycles

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bonneterre et al. 2004 1998-2000 Randomized Phase 2 (E-de-esc) FEC Superior ORR (primary endpoint)
Blohmer et al. 2010 2000-2003 Phase 3 (E-switch-ic) EC Did not meet primary endpoint of ORR

Chemotherapy

21-day cycle for up to 8 cycles


Regimen variant #2, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mavroudis et al. 2009 (HORG CT/02.09) 2002-2007 Phase 3 (C) TX Did not meet primary endpoint of TTP

Chemotherapy

21-day cycles

References

  1. Bonneterre J, Dieras V, Tubiana-Hulin M, Bougnoux P, Bonneterre ME, Delozier T, Mayer F, Culine S, Dohoulou N, Bendahmane B. Phase II multicentre randomised study of docetaxel plus epirubicin vs 5-fluorouracil plus epirubicin and cyclophosphamide in metastatic breast cancer. Br J Cancer. 2004 Oct 18;91(8):1466-71. link to original article link to PMC article contains dosing details in abstract PubMed
  2. HORG CT/02.09: Mavroudis D, Papakotoulas P, Ardavanis A, Syrigos K, Kakolyris S, Ziras N, Kouroussis C, Malamos N, Polyzos A, Christophyllakis C, Kentepozidis N, Georgoulias V; Hellenic Oncology Research Group. Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer. Ann Oncol. 2010 Jan;21(1):48-54. Epub 2009 Nov 11. link to original article contains dosing details in manuscript PubMed NCT00429871
  3. Blohmer JU, Schmid P, Hilfrich J, Friese K, Kleine-Tebbe A, Koelbl H, Sommer H, Morack G, Wischnewsky MB, Lichtenegger W, Kuemmel S. Epirubicin and cyclophosphamide versus epirubicin and docetaxel as first-line therapy for women with metastatic breast cancer: final results of a randomised phase III trial. Ann Oncol. 2010 Jul;21(7):1430-5. Epub 2010 Jan 20. link to original article contains dosing details in manuscript PubMed

Docetaxel & Gemcitabine

GD: Gemcitabine & Docetaxel
GDoc: Gemcitabine & Docetaxel

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Nielsen et al. 2011 2001-2005 Phase 3 (E-esc) Docetaxel Might have superior TTP (primary endpoint)
Fountzilas et al. 2008 2002-2006 Phase 3 (E-esc) 1. Carboplatin & Paclitaxel Did not meet primary endpoint of OS
2. Paclitaxel; weekly Seems to have inferior OS
Seidman et al. 2010 (B9E-MC-S273) 2002-2008 Phase 3 (E-switch-ic) TX Did not meet primary endpoint of TTP
Del Mastro et al. 2013 (B9E-IT-S376) 2005-2010 Phase 3 (E-switch-ic) 1. GD; weekly
2. GT; q3wk
3. GT; weekly 		Did not meet primary endpoint of TTP

Chemotherapy

21-day cycles

Subsequent treatment

References

  1. Fountzilas G, Dafni U, Dimopoulos MA, Koutras A, Skarlos D, Papakostas P, Gogas H, Bafaloukos D, Kalogera-Fountzila A, Samantas E, Briasoulis E, Pectasides D, Maniadakis N, Matsiakou F, Aravantinos G, Papadimitriou C, Karina M, Christodoulou C, Kosmidis P, Kalofonos HP; Hellenic Cooperative Oncology Group. A randomized phase III study comparing three anthracycline-free taxane-based regimens, as first line chemotherapy, in metastatic breast cancer: a Hellenic Cooperative Oncology Group study. Breast Cancer Res Treat. 2009 May;115(1):87-99. Epub 2008 May 16. link to original article contains dosing details in manuscript PubMed
  2. B9E-MC-S273: Seidman AD, Brufsky A, Ansari RH, Hart LL, Stein RS, Schwartzberg LS, Stewart JF, Russell CA, Chen SC, Fein LE, De La Cruz Vargas JA, Kim SB, Cavalheiro J, Zhao L, Gill JF, Obasaju CK, Orlando M, Tai DF. Phase III trial of gemcitabine plus docetaxel versus capecitabine plus docetaxel with planned crossover to the alternate single agent in metastatic breast cancer. Ann Oncol. 2011 May;22(5):1094-101. Epub 2010 Nov 17. link to original article contains dosing details in abstract PubMed NCT00191438
    1. Pooled update: Seidman AD, Chan S, Wang J, Zhu C, Xu C, Xu B. A pooled analysis of gemcitabine plus docetaxel versus capecitabine plus docetaxel in metastatic breast cancer. Oncologist. 2014 May;19(5):443-52. Epub 2014 Apr 4. link to original article link to PMC article PubMed
  3. Nielsen DL, Bjerre KD, Jakobsen EH, Cold S, Stenbygaard L, Sørensen PG, Kamby C, Møller S, Jørgensen CL, Andersson M; Danish Breast Cancer Cooperative Group. Gemcitabine plus docetaxel versus docetaxel in patients with predominantly human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: a randomized, phase III study by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 2011 Dec 20;29(36):4748-54. Epub 2011 Nov 14. link to original article contains dosing details in manuscript PubMed
  4. B9E-IT-S376: Del Mastro L, Fabi A, Mansutti M, De Laurentiis M, Durando A, Merlo DF, Bruzzi P, La Torre I, Ceccarelli M, Kazeem G, Marchi P, Boy D, Venturini M, De Placido S, Cognetti F. Randomised phase 3 open-label trial of first-line treatment with gemcitabine in association with docetaxel or paclitaxel in women with metastatic breast cancer: a comparison of different schedules and treatments. BMC Cancer. 2013 Mar 28;13:164. link to original article link to PMC article contains dosing details in abstract PubMed NCT00236899

Doxorubicin monotherapy

Regimen variant #1, 20 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gundersen et al. 1986 1982-06 to 1983-12 Phase 3 (E-de-esc) VAC Did not meet endpoint of OS
Gundersen et al. 1990 1984-1986 Phase 3 (C) Epirubicin Did not meet endpoints of ORR/OS
Gundersen et al. 1994 1987-1990 Randomized (C) Doxorubicin & MPA Might have inferior ORR

Chemotherapy

7-day cycles


Regimen variant #2, 60 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gottlieb et al. 1974 (SWG02) 1972-01 to 1972-10 Phase 3 (E-switch-ic) 1. Lomustine
2. Semustine 		Superior OS
Hoogstraten et al. 1976 1972-1974 Phase 3 (C) CMFVP Seems to have inferior ORR
Vaughn et al. 1988 (SWOG S8020) 1980-1982 Phase 3 (C) Doxorubicin & Etoposide Seems to have inferior TTP
Ingle et al. 1989 1982-11 to 1987-02 Randomized (C) DVM Seems to have inferior TTP
Perez et al. 1991 1985-1988 Phase 3 (C) Epirubicin Did not meet endpoints of ORR/OS
Norris et al. 2000 (NCIC-CTG MA.8) 1992-1995 Phase 3 (C) NA Did not meet primary endpoint of OS
Sledge et al. 2003 (ECOG E1193) 1993-1995 Phase 3 (C) 1. AT (Taxol) Inferior TTF
2. Paclitaxel Did not meet primary endpoint of ORR
O'Brien et al. 2004 1998-06 to 2000-08 Phase 3 (C) PLD Seems to have non-inferior PFS (co-primary endpoint)

Note: in NCIC-CTG MA.8, this dose was after a mid-protocol amendment. Treatment in NCIC-CTG MA.8 was given until a cumulative dose of 450 mg/m2. Treatment in Ingle et al. 1989 was given until a cumulative dose of 500 mg/m2.

Chemotherapy

21-day cycles (see note)


Regimen variant #3, 75 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Paridaens et al. 2000 (EORTC 10923) 1993-1996 Phase 3 (C) Paclitaxel Superior PFS

Chemotherapy

21-day cycle for 7 cycles

References

  1. SWG02: Gottlieb JA, Rivkin SE, Spigel SC, Hoogstraten B, O'Bryan RM, Delaney FC, Singhakowinta A; SWOG. Proceedings: Superiority of adriamycin over oral nitrosoureas in patients with advanced breast carcinoma: a Southwest Cancer Chemotherapy study Group study. Cancer. 1974 Feb;33(2):519-26. link to original article PubMed
  2. Hoogstraten B, George SL, Samal B, Rivkin SE, Costanzi JJ, Bonnet JD, Thigpen T, Braine H; SWOG. Combination chemotherapy and adriamycin in patients with advanced breast cancer: a Southwest Oncology Group study. Cancer. 1976 Jul;38(1):13-20. link to original article contains dosing details in manuscript PubMed
  3. Gundersen S, Kvinnsland S, Klepp O, Kvaløy S, Lund E, Høst H. Weekly adriamycin versus VAC in advanced breast cancer: a randomized trial. Eur J Cancer Clin Oncol. 1986 Dec;22(12):1431-4. link to original article PubMed
  4. SWOG S8020: Vaughn CB, Green SJ, O'Bryan R, Reed M, Grozea PN, Fletcher WS, Green JB, Metch B, Oishi N. VP-16 + adriamycin vs adriamycin alone in advanced adenocarcinoma of the breast, phase II, a randomized trial: a Southwest Oncology Group Study. Med Pediatr Oncol. 1988;16(5):312-9. link to original article contains dosing details in abstract PubMed
  5. Ingle JN, Mailliard JA, Schaid DJ, Krook JE, Gerstner JB, Pfeifle DM, Marschke RF Jr, Long HJ, McCormack GW, Foley JF; NCCTG. Randomized trial of doxorubicin alone or combined with vincristine and mitomycin C in women with metastatic breast cancer. Am J Clin Oncol. 1989 Dec;12(6):474-80. link to original article contains dosing details in abstract PubMed
  6. Gundersen S, Kvinnsland S, Klepp O, Lund E, Høst H; Norwegian Breast Cancer Group. Weekly Adriamycin vs 4-epidoxorubicin every second week in advanced breast cancer: a randomized trial. Eur J Cancer. 1990 Jan;26(1):45-8. link to original article contains dosing details in abstract PubMed
  7. Perez DJ, Harvey VJ, Robinson BA, Atkinson CH, Dady PJ, Kirk AR, Evans BD, Chapman PJ. A randomized comparison of single-agent doxorubicin and epirubicin as first-line cytotoxic therapy in advanced breast cancer. J Clin Oncol. 1991 Dec;9(12):2148-52. link to original article contains dosing details in abstract PubMed
  8. Gundersen S, Hannisdal E, Lundgren S, Wist E; Norwegian Breast Cancer Group. Weekly doxorubicin with or without high-dose medroxyprogesterone acetate in hormone-resistant advanced breast cancer: a randomised study. Eur J Cancer. 1994;30A(12):1775-8. link to original article contains dosing details in abstract PubMed
  9. EORTC 10923: Paridaens R, Biganzoli L, Bruning P, Klijn JG, Gamucci T, Houston S, Coleman R, Schachter J, Van Vreckem A, Sylvester R, Awada A, Wildiers J, Piccart M. Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European Organisation for Research and Treatment of Cancer Randomized Study with cross-over. J Clin Oncol. 2000 Feb;18(4):724-33. link to original article contains dosing details in abstract PubMed
    1. HRQoL analysis: Kramer JA, Curran D, Piccart M, de Haes JC, Bruning PF, Klijn JG, Bontenbal M, van Pottelsberghe C, Groenvold M, Paridaens R. Randomised trial of paclitaxel versus doxorubicin as first-line chemotherapy for advanced breast cancer: quality of life evaluation using the EORTC QLQ-C30 and the Rotterdam symptom checklist. Eur J Cancer. 2000 Aug;36(12):1488-97. link to original article PubMed
  10. NCIC-CTG MA.8: Norris B, Pritchard KI, James K, Myles J, Bennett K, Marlin S, Skillings J, Findlay B, Vandenberg T, Goss P, Latreille J, Rudinskas L, Lofters W, Trudeau M, Osoba D, Rodgers A. Phase III comparative study of vinorelbine combined with doxorubicin versus doxorubicin alone in disseminated metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group study MA8. J Clin Oncol. 2000 Jun;18(12):2385-94. link to original article contains dosing details in abstract PubMed
  11. ECOG E1193: Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, Wood WC. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol. 2003 Feb 15;21(4):588-92. link to original article PubMed
  12. O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C; CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004 Mar;15(3):440-9. link to original article PubMed

Doxorubicin & Paclitaxel (AT)

AT: Adriamycin (Doxorubicin) & Taxol (Paclitaxel)

Regimen variant #1, 50/150

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sledge et al. 2003 (ECOG E1193) 1993-1995 Phase 3 (E-esc) 1. Doxorubicin
2. Paclitaxel; q3wk 		Superior TTF

Chemotherapy

  • Doxorubicin (Adriamycin) as follows, given first:
    • Cycles 1 to 8: 50 mg/m2 IV once on day 1
  • Paclitaxel (Taxol) 150 mg/m2 IV continuous infusion over 24 hours, started on day 1, given second, 3 hours after doxorubicin

21-day cycles


Regimen variant #2, 50/175

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cassier et al. 2007 (ERASME 3) 2000-2004 Phase 3 (E-switch-ic) AT (Taxotere) Might have superior OS

Chemotherapy

21-day cycle for 8 cycles


Regimen variant #3, 50/220

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jassem et al. 2001 1996-1998 Phase 3 (E-de-esc) FAC Superior OS1
Median OS: 23 vs 18.3 mo

1Reported efficacy is based on the 2009 update.

Chemotherapy

21-day cycle for up to 8 cycles


Regimen variant #4, 60/200

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Biganzoli et al. 2002 (EORTC 10961) 1996-1999 Phase 3 (E-switch-ic) AC Did not meet primary endpoint of PFS
Schmid et al. 2005 1998-2002 Phase 3 (C) Tandem auto HSCT Did not meet primary endpoint of CR rate

Note: in EORTC 10961, first cycle of paclitaxel was 175 mg/m2.

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #5, with range

Study Dates of enrollment Evidence
Gianni et al. 1995 1993-1994 Non-randomized

Chemotherapy

21-day cycles

References

  1. Gianni L, Munzone E, Capri G, Fulfaro F, Tarenzi E, Villani F, Spreafico C, Laffranchi A, Caraceni A, Martini C, Stefanelli M, Valagussa P, Bonadonna G. Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol. 1995 Nov;13(11):2688-99. link to original article PubMed
  2. Jassem J, Pieńkowski T, Płuzańska A, Jelic S, Gorbunova V, Mrsic-Krmpotic Z, Berzins J, Nagykalnai T, Wigler N, Renard J, Munier S, Weil C; Central & Eastern Europe and Israel Pacitaxel Breast Cancer Study Group. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J Clin Oncol. 2001 Mar 15;19(6):1707-15. link to original article contains dosing details in abstract PubMed
    1. Update: Jassem J, Pienkowski T, Pluzanska A, Jelic S, Gorbunova V, Berzins J, Nagykalnai T, Biganzoli L, Aloe A, Astier L, Munier S. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin and cyclophosphamide as first-line therapy for women with advanced breast cancer: long-term analysis of the previously published trial. Onkologie. 2009 Sep;32(8-9):468-72. Epub 2009 Jul 20. link to original article PubMed
  3. EORTC 10961: Biganzoli L, Cufer T, Bruning P, Coleman R, Duchateau L, Calvert AH, Gamucci T, Twelves C, Fargeot P, Epelbaum R, Lohrisch C, Piccart MJ. Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organisation for Research and Treatment of Cancer 10961 multicenter phase III trial. J Clin Oncol. 2002 Jul 15;20(14):3114-21. link to original article contains dosing details in abstract PubMed
  4. ECOG E1193: Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, Wood WC. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol. 2003 Feb 15;21(4):588-92. link to original article PubMed
  5. Schmid P, Schippinger W, Nitsch T, Huebner G, Heilmann V, Schultze W, Hausmaninger H, Wischnewsky M, Possinger K. Up-front tandem high-dose chemotherapy compared with standard chemotherapy with doxorubicin and paclitaxel in metastatic breast cancer: results of a randomized trial. J Clin Oncol. 2005 Jan 20;23(3):432-40. link to original article contains dosing details in manuscript PubMed
  6. ERASME 3: Cassier PA, Chabaud S, Trillet-Lenoir V, Peaud PY, Tigaud JD, Cure H, Orfeuvre H, Salles B, Martin C, Jacquin JP, Agostini C, Guastalla JP, Pérol D, Bachelot T. A phase-III trial of doxorubicin and docetaxel versus doxorubicin and paclitaxel in metastatic breast cancer: results of the ERASME 3 study. Breast Cancer Res Treat. 2008 May;109(2):343-50. Epub 2007 Jul 5. link to original article contains dosing details in manuscript PubMed

Pegylated liposomal doxorubicin monotherapy

Regimen variant #1, 45 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Smorenburg et al. 2014 (OMEGA) 2007-2011 Phase 3 (E-switch-ic) Capecitabine Did not meet primary endpoint of PFS

Chemotherapy

28-day cycle for 6 cycles


Regimen variant #2, 50 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
O'Brien et al. 2004 1998-06 to 2000-08 Phase 3 (E-switch-ic) Doxorubicin Seems to have non-inferior PFS (co-primary endpoint)
Median PFS: 6.9 vs 7.8 mo
(HR 1.00, 95% CI 0.82-1.22)
Harbeck et al. 2016 (PELICAN) 2006-2010 Phase 3 (E-switch-ic) Capecitabine Inconclusive whether non-inferior TTP (primary endpoint)

Chemotherapy

28-day cycles

Dose and schedule modifications

  • If infusion reactions occurred, infusion could be given over up to 90 minutes

References

  1. O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C; CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004 Mar;15(3):440-9. link to original article contains dosing details in manuscript PubMed
  2. OMEGA: Smorenburg CH, de Groot SM, van Leeuwen-Stok AE, Hamaker ME, Wymenga AN, de Graaf H, de Jongh FE, Braun JJ, Los M, Maartense E, van Tinteren H, Nortier JW, Seynaeve C; Dutch Breast Cancer Research Group. A randomized phase III study comparing pegylated liposomal doxorubicin with capecitabine as first-line chemotherapy in elderly patients with metastatic breast cancer: results of the OMEGA study of the Dutch Breast Cancer Research Group BOOG. Ann Oncol. 2014 Mar;25(3):599-605. Epub 2014 Feb 6. link to original article link to PMC article contains dosing details in abstract PubMed ISRCTN11114726
  3. PELICAN: Harbeck N, Saupe S, Jäger E, Schmidt M, Kreienberg R, Müller L, Otremba BJ, Waldenmaier D, Dorn J, Warm M, Scholz M, Untch M, de Wit M, Barinoff J, Lück HJ, Harter P, Augustin D, Harnett P, Beckmann MW, Al-Batran SE; PELICAN Investigators. A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study. Breast Cancer Res Treat. 2017 Jan;161(1):63-72. Epub 2016 Oct 31. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00266799

Cyclophosphamide & Epirubicin (EC)

EC: Epirubicin & Cyclophosphamide

Regimen variant #1, 75/600

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Chan et al. 2004 1996-05 to 1997-08 Phase 3 (C) MC Inferior TTP
Langley et al. 2005 (UKNCRI AB01) 1996-1999 Phase 3 (C) EP Did not meet primary endpoint of PFS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

21-day cycle for up to 6 to 8 cycles


Regimen variant #2, 90/600

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Blohmer et al. 2010 2000-2003 Phase 3 (C) ED Did not meet primary endpoint of ORR

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

21-day cycle for up to 8 cycles


Regimen variant #3, with range

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Robert et al. 2011 (RIBBON-1) 2005-2007 Phase 3 (C) 1a. AC & Bevacizumab
1b. Capecitabine & Bevacizumab
1c. Docetaxel & Bevacizumab
1d. EC & Bevacizumab
1e. FAC & Bevacizumab
1f. FEC & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

21-day cycle for up to 8 cycles

References

  1. Chan S, Davidson N, Juozaityte E, Erdkamp F, Pluzanska A, Azarnia N, Lee LW. Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer. Ann Oncol. 2004 Oct;15(10):1527-34. link to original article contains dosing details in abstract PubMed
  2. UKNCRI AB01: Langley RE, Carmichael J, Jones AL, Cameron DA, Qian W, Uscinska B, Howell A, Parmar M. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute trial AB01. J Clin Oncol. 2005 Nov 20;23(33):8322-30. link to original article PubMed
  3. Blohmer JU, Schmid P, Hilfrich J, Friese K, Kleine-Tebbe A, Koelbl H, Sommer H, Morack G, Wischnewsky MB, Lichtenegger W, Kuemmel S. Epirubicin and cyclophosphamide versus epirubicin and docetaxel as first-line therapy for women with metastatic breast cancer: final results of a randomised phase III trial. Ann Oncol. 2010 Jul;21(7):1430-5. Epub 2010 Jan 20. link to original article contains dosing details in abstract PubMed
  4. RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains dosing details in manuscript PubMed NCT00262067

Cyclophosphamide & Epirubicin (EC) & Bevacizumab

EC & Bevacizumab: Epirubicin, Cyclophosphamide, Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Robert et al. 2011 (RIBBON-1) 2005-2007 Phase 3 (E-esc) 1a. AC
1b. Capecitabine
1c. Docetaxel
1d. EC
1e. FAC
1f. FEC
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
(HR 0.64, 95% CI 0.52-0.80)

Chemotherapy

Targeted therapy

21-day cycle for up to 8 cycles

Subsequent treatment

References

  1. RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains dosing details in manuscript PubMed NCT00262067

Epirubicin & Paclitaxel (EP)

EP: Epirubicin & Paclitaxel
ET: Epirubicin & Taxol (Paclitaxel)

Regimen variant #1, 60/175

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lück et al. 2013 2002-2005 Phase 3 (C) XP Inconclusive whether non-inferior PFS

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #2, 75/175

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hatschek et al. 2011 (TEX trial) 2002-2007 Phase 3 (C) TEX Did not meet primary endpoint of PFS

Note: the doses of this regimen were individually adjusted after cycle 1; see paper for details.

Chemotherapy

21-day cycles


Regimen variant #3, 75/200

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Langley et al. 2005 (UKNCRI AB01) 1996-1999 Phase 3 (E-switch-ic) EC Did not meet primary endpoint of PFS

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #4, 80/175

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fountzilas et al. 2004 1999-2002 Phase 3 (C) CP Did not meet primary endpoint of OS

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #5, 90/200

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Conte et al. 2004 1996-2001 Phase 3 (C) E-T Seems to have non-inferior ORR

Chemotherapy

21-day cycle for 8 cycles

References

  1. Conte PF, Guarneri V, Bruzzi P, Prochilo T, Salvadori B, Bolognesi A, Aldrighetti D, Venturini M, Rosso R, Mammoliti S, Carnino F, Giannessi P, Costantini M, Moyano A, Baldini E; GONO. Concomitant versus sequential administration of epirubicin and paclitaxel as first-line therapy in metastatic breast carcinoma: results for the Gruppo Oncologico Nord Ovest randomized trial. Cancer. 2004 Aug 15;101(4):704-12. link to original article contains dosing details in abstract PubMed
  2. Fountzilas G, Kalofonos HP, Dafni U, Papadimitriou C, Bafaloukos D, Papakostas P, Kalogera-Fountzila A, Gogas H, Aravantinos G, Moulopoulos LA, Economopoulos T, Pectasides D, Maniadakis N, Siafaka V, Briasoulis E, Christodoulou C, Tsavdaridis D, Makrantonakis P, Razis E, Kosmidis P, Skarlos D, Dimopoulos MA; Hellenic Cooperative Oncology Group. Paclitaxel and epirubicin versus paclitaxel and carboplatin as first-line chemotherapy in patients with advanced breast cancer: a phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol. 2004 Oct;15(10):1517-26. link to original article contains dosing details in abstract PubMed
  3. UKNCRI AB01: Langley RE, Carmichael J, Jones AL, Cameron DA, Qian W, Uscinska B, Howell A, Parmar M. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute trial AB01. J Clin Oncol. 2005 Nov 20;23(33):8322-30. link to original article PubMed
  4. TEX trial: Hatschek T, Carlsson L, Einbeigi Z, Lidbrink E, Linderholm B, Lindh B, Loman N, Malmberg M, Rotstein S, Söderberg M, Sundquist M, Walz TM, Hellström M, Svensson H, Aström G, Brandberg Y, Carstensen J, Fernö M, Bergh J. Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in metastatic breast cancer: a randomized multicenter trial. Breast Cancer Res Treat. 2012 Feb;131(3):939-47. Epub 2011 Nov 18. link to original article contains dosing details in abstract PubMed NCT01433614
  5. Lück HJ, Du Bois A, Loibl S, Schrader I, Huober J, Heilmann V, Beckmann M, Stähler A, Jackisch C, Hubalek M, Richter B, Stickeler E, Eidtmann H, Thomssen C, Untch M, Wollschläger K, Schuster T, von Minckwitz G; AGO Breast Cancer Study Group. Capecitabine plus paclitaxel versus epirubicin plus paclitaxel as first-line treatment for metastatic breast cancer: efficacy and safety results of a randomized, phase III trial by the AGO Breast Cancer Study Group. Breast Cancer Res Treat. 2013 Jun;139(3):779-87. Epub 2013 Jun 15. link to original article contains dosing details in abstract PubMed

Epirubicin monotherapy

Regimen variant #1, 35 mg/m2, 3 out of 4 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Feher et al. 2005 1996-1999 Phase 3 (C) Gemcitabine Superior OS (secondary endpoint)
Median OS: 19.1 vs 11.8 mo

Superior TTP (primary endpoint)
Median TTP: 6.1 vs 3.4 mo

Chemotherapy

28-day cycles


Regimen variant #2, 40 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bastholt et al. 1996 1987-1991 Phase 3 (E-de-esc) 1. Epirubicin; 60 mg/m2 Did not meet primary endpoint of TTP
2. Epirubicin; 90 mg/m2 Inferior TTP
3. Epirubicin; 135 mg/m2 Did not meet primary endpoint of TTP

Chemotherapy

21-day cycles


Regimen variant #3, 50 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gundersen et al. 1990 1984-1986 Phase 3 (E-switch-ic) Doxorubicin Did not meet endpoints of ORR/OS

Chemotherapy

14-day cycles


Regimen variant #4, 60 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Nielsen et al. 1990 1983-1986 Phase 3 (C) Epirubicin & Vindesine Did not meet primary endpoint of ORR
Bastholt et al. 1996 1987-1991 Phase 3 (E-de-esc) 1. Epirubicin; 40 mg/m2
2. Epirubicin; 90 mg/m2
3. Epirubicin; 135 mg/m2 		Did not meet primary endpoint of TTP

Chemotherapy

21-day cycles


Regimen variant #5, 70 mg/m2, 2 out of 4 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Nielsen et al. 2000 1987-1990 Phase 3 (C) Cisplatin & Epirubicin Seems to have inferior TTP Superior toxicity

Chemotherapy

28-day cycles until maximum dose of epirubicin reached (1000 mg/m2)


Regimen variant #6, 75 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bonneterre & Hurteloup 1991 NR Phase 3 (E-de-esc) 1. FEC; FEC 50 Seems to have inferior ORR
2. FEC; FEC 75 Inferior ORR

Chemotherapy

21-day cycles


Regimen variant #7, 90 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Perez et al. 1991 1985-1988 Phase 3 (E-switch-ic) Doxorubicin Did not meet endpoints of ORR/OS
Bastholt et al. 1996 1987-1991 Phase 3 (C) 1. Epirubicin; 40 mg/m2 Superior TTP
2. Epirubicin; 60 mg/m2
3. Epirubicin; 135 mg/m2 		Did not meet primary endpoint of TTP
Ejlertsen et al. 2004 (SBG 9403) 1995-1999 Phase 3 (C) VE Seems to have inferior PFS

Chemotherapy

21-day cycles


Regimen variant #8, 120 mg/m2, split doses

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Dogliotti et al. 1996 1991-1993 Phase 3 (C) Epirubicin & Lonidamine Inferior ORR
Berruti et al. 2002 1995-1999 Phase 3 (C) 1. Cisplatin & Epirubicin
2. Cisplatin, Epirubicin, Lonidamine
3. Epirubicin & Lonidamine 		Did not meet primary endpoint of TTP

Chemotherapy

21-day cycles


Regimen variant #9, 135 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bastholt et al. 1996 1987-1991 Phase 3 (E-esc) 1. Epirubicin; 40 mg/m2
2. Epirubicin; 60 mg/m2
3. Epirubicin; 90 mg/m2 		Did not meet primary endpoint of TTP

Chemotherapy

21-day cycles

References

  1. Gundersen S, Kvinnsland S, Klepp O, Lund E, Høst H; Norwegian Breast Cancer Group. Weekly Adriamycin vs 4-epidoxorubicin every second week in advanced breast cancer: a randomized trial. Eur J Cancer. 1990 Jan;26(1):45-8. link to original article contains dosing details in abstract PubMed
  2. Nielsen D, Dombernowsky P, Skovsgaard T, Jensen J, Andersen E, Engelholm SA, Hansen M. Epirubicin or epirubicin and vindesine in advanced breast cancer: a phase III study. Ann Oncol. 1990 Jul;1(4):275-80. link to original article contains dosing details in abstract PubMed
  3. Bonneterre J, Hurteloup P; French Epirubicin Study Group. A prospective randomized trial comparing epirubicin monochemotherapy to two fluorouracil, cyclophosphamide, and epirubicin regimens differing in epirubicin dose in advanced breast cancer patients. J Clin Oncol. 1991 Feb;9(2):305-12. link to original article contains dosing details in manuscript PubMed
  4. Perez DJ, Harvey VJ, Robinson BA, Atkinson CH, Dady PJ, Kirk AR, Evans BD, Chapman PJ. A randomized comparison of single-agent doxorubicin and epirubicin as first-line cytotoxic therapy in advanced breast cancer. J Clin Oncol. 1991 Dec;9(12):2148-52. link to original article contains dosing details in abstract PubMed
  5. Bastholt L, Dalmark M, Gjedde SB, Pfeiffer P, Pedersen D, Sandberg E, Kjaer M, Mouridsen HT, Rose C, Nielsen OS, Jakobsen P, Bentzen SM; Danish Breast Cancer Cooperative Group. Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 1996 Apr;14(4):1146-55. link to original article contains dosing details in manuscript PubMed
  6. Dogliotti L, Berruti A, Buniva T, Zola P, Baù MG, Farris A, Sarobba MG, Bottini A, Alquati P, Deltetto F, Gosso P, Monzeglio C, Moro G, Sussio M, Perroni D. Lonidamine significantly increases the activity of epirubicin in patients with advanced breast cancer: results from a multicenter prospective randomized trial. J Clin Oncol. 1996 Apr;14(4):1165-72. link to original article contains dosing details in abstract PubMed
  7. Nielsen D, Dombernowsky P, Larsen SK, Hansen OP, Skovsgaard T. Epirubicin or epirubicin and cisplatin as first-line therapy in advanced breast cancer: a phase III study. Cancer Chemother Pharmacol. 2000;46(6):459-66. link to original article contains dosing details in abstract PubMed
  8. Berruti A, Bitossi R, Gorzegno G, Bottini A, Alquati P, De Matteis A, Nuzzo F, Giardina G, Danese S, De Lena M, Lorusso V, Farris A, Sarobba MG, DeFabiani E, Bonazzi G, Castiglione F, Bumma C, Moro G, Bruzzi P, Dogliotti L; Epirubicin-Lonidamine Group. Time to progression in metastatic breast cancer patients treated with epirubicin is not improved by the addition of either cisplatin or lonidamine: final results of a phase III study with a factorial design. J Clin Oncol. 2002 Oct 15;20(20):4150-9. link to original article contains dosing details in abstract PubMed
  9. SBG 9403: Ejlertsen B, Mouridsen HT, Langkjer ST, Andersen J, Sjöström J, Kjaer M; Scandinavian Breast Group. Phase III study of intravenous vinorelbine in combination with epirubicin versus epirubicin alone in patients with advanced breast cancer: a Scandinavian Breast Group Trial (SBG9403). J Clin Oncol. 2004 Jun 15;22(12):2313-20. link to original article contains dosing details in abstract PubMed
  10. Feher O, Vodvarka P, Jassem J, Morack G, Advani SH, Khoo KS, Doval DC, Ermisch S, Roychowdhury D, Miller MA, von Minckwitz G. First-line gemcitabine versus epirubicin in postmenopausal women aged 60 or older with metastatic breast cancer: a multicenter, randomized, phase III study. Ann Oncol. 2005 Jun;16(6):899-908. Epub 2005 Apr 8. link to original article contains dosing details in abstract PubMed

FAC

FAC: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide
CAF: Cyclophosphamide, Adriamycin (Doxorubicin), Fluorouracil
AFC: Adriamycin (Doxorubicin), Fluorouracil, Cyclophosphamide

Regimen variant #1, 500/50/500

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Smalley et al. 1977 1974-04-01 to 1975-07-01 Phase 3 (E-de-esc) CMFVP Might have superior OS1
Bennett et al. 1988 1983-1985 Phase 3 (C) CNF Did not meet endpoints of TTF/OS
Muss et al. 1991 1984-1989 Non-randomized part of RCT
Blajman et al. 1999 1991-1994 Phase 3 (C) NA Did not meet primary endpoint of ORR
Namer et al. 2001 1993-04 to 1995-12 Phase 3 (C) MV Equivalent ORR
Jassem et al. 2001 1996-1998 Phase 3 (C) AT (Taxol) Inferior OS2
Bontenbal et al. 2005 1997-2002 Phase 2/3 (C) AT (Taxotere) Seems to have inferior OS
Robert et al. 2011 (RIBBON-1) 2005-2007 Phase 3 (C) 1a. AC & Bevacizumab
1b. Capecitabine & Bevacizumab
1c. Docetaxel & Bevacizumab
1d. EC & Bevacizumab
1e. FAC & Bevacizumab
1f. FEC & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

1Reported efficacy for Smalley et al. 1977 is based on the 1983 update.
2Reported efficacy for Jassem et al. 2001 is based on the 2009 update.

Chemotherapy

21-day cycle for up to 6 to 8 cycles

Subsequent treatment

  • Muss et al. 1991: CMFP continuation versus observation followed by second-line CMFP at progression


Regimen variant #2, 600/50/600

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Alonso et al. 1995 1988-1991 Phase 3 (C) CNF Did not meet endpoints of ORR/OS

Chemotherapy

21-day cycle for up to 10 cycles


Regimen variant #3, 800/40/400

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tranum et al. 1978 NR Randomized (E-esc) 1. AF
2. AFCM 		Did not meet primary endpoint of ORR

Chemotherapy

21-day cycles


Regimen variant #4, 1000/40/500

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Aisner et al. 1995 (CALGB 8281) 1982-1987 Phase 3 (C) 1. VATH
2. VATH/CMFVP 		Did not meet primary endpoint of ORR
Parnes et al. 2003 (CALGB 9140) 1991-1995 Phase 3 (C) FAC & Leucovorin Did not meet primary endpoint of ORR

Note: Aisner et al. 1995 does not describe dosing; included here because it is a CALGB study.

Chemotherapy

21-day cycles


Regimen variant #5, 1000/50/500, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Hortobagyi et al. 1979 1974-NR Phase 3 (C) FAC-BCG Inferior OS in responders

Chemotherapy

21-day cycles


Regimen variant #6, 1000/50/500 until max anthracycline

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Ambrosini et al. 1988 1983-1985 Phase 3 (C) FEC Did not meet primary endpoint More toxic

Chemotherapy

21-day cycle for up to 11 cycles (maximum of 550 mg/m2 doxorubicin)


Regimen variant #7, 1000/50/1400

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Aisner et al. 1987 (CALGB 7682) 1976-1980 Phase 3 (E-switch-ic) 1. CAFVP Not reported
2. CMF Superior ORR
Kardinal et al. 1983 (CALGB 8081) 1980-1982 Randomized (C) CAFT Did not meet primary endpoint of ORR

Chemotherapy

28-day cycle for up to 9 cycles


Regimen variant #8, 1000/60/1400 x 6

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sledge et al. 2000 (ECOG E3186) 1988-1992 Phase 3 (C) CAFTH Might have inferior TTF

Chemotherapy

28-day cycle for up to 6 cycles


Regimen variant #9, 1000/60/1400, maximum doxorubicin of 500 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cummings et al. 1985 1978-1979 Randomized (E-de-esc) CMFP Did not meet primary endpoint of ORR
Falkson et al. 1987 (ECOG E2177) NR-1983 Randomized (C) O+CAF Did not meet co-primary endpoints of ORR/TTF/OS

Chemotherapy

28-day cycles until maximum cumulative dose of doxorubicin of 500 mg/m2


Regimen variant #10, 1000/60/1400, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bull et al. 1978 NR Phase 3 (E-switch-ic) CMF Might have superior ORR
Tominaga et al. 1994 NR Phase 3 (C) CAF & MPA Seems to have inferior ORR

Note: the dosing details of Tominaga et al. 1994 are not described in the abstract.

Chemotherapy

28-day cycles

References

  1. Smalley RV, Carpenter J, Bartolucci A, Vogel C, Krauss S; Southeastern Cancer Study Group. A comparison of cyclophosphamide, adriamycin, 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisone (CMFVP) in patients with metastatic breast cancer: a Southeastern Cancer Study Group project. Cancer. 1977 Aug;40(2):625-32. link to original article contains dosing details in manuscript PubMed
    1. Update: Smalley RV, Lefante J, Bartolucci A, Carpenter J, Vogel C, Krauss S. A comparison of cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone (CMFVP) in patients with advanced breast cancer. Breast Cancer Res Treat. 1983;3(2):209-20. link to original article PubMed
  2. Bull JM, Tormey DC, Li SH, Carbone PP, Falkson G, Blom J, Perlin E, Simon R. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978 May;41(5):1649-57. link to original article PubMed
  3. Tranum B, Hoogstraten B, Kennedy A, Vaughn CB, Samal B, Thigpen T, Rivkin S, Smith F, Palmer RL, Costanzi J, Tucker WG, Wilson H, Maloney TR; SWOG. Adriamycin in combination for the treatment of breast cancer: a Southwest Oncology Group study. Cancer. 1978 Jun;41(6):2078-83. link to original article PubMed
  4. Hortobagyi GN, Gutterman JU, Blumenschein GR, Tashima CK, Burgess MA, Einhorn L, Buzdar AU, Richman SP, Hersh EM. Combination chemoimmunotherapy of metastatic breast cancer with 5-fluorouracil, adriamycin, cyclophosphamide, and BCG. Cancer. 1979 Nov;44(5):1955-62. link to original article PubMed
  5. CALGB 8081: Kardinal CG, Perry MC, Weinberg V, Wood W, Ginsberg S, Raju RN. Chemoendocrine therapy vs chemotherapy alone for advanced breast cancer in postmenopausal women: preliminary report of a randomized study. Breast Cancer Res Treat. 1983;3(4):365-71. link to original article PubMed
    1. Update: Perry MC, Kardinal CG, Korzun AH, Ginsberg SJ, Raich PC, Holland JF, Ellison RR, Kopel S, Schilling A, Aisner J, Schulman P, Weinberg V, Rice MA, Wood W. Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081. J Clin Oncol. 1987 Oct;5(10):1534-45. link to original article contains dosing details in manuscript PubMed
  6. Cummings FJ, Gelman R, Horton J. Comparison of CAF versus CMFP in metastatic breast cancer: analysis of prognostic factors. J Clin Oncol. 1985 Jul;3(7):932-40. link to original article PubMed
  7. ECOG E2177: Falkson G, Gelman RS, Tormey DC, Falkson CI, Wolter JM, Cummings FJ. Treatment of metastatic breast cancer in premenopausal women using CAF with or without oophorectomy: an Eastern Cooperative Oncology Group Study. J Clin Oncol. 1987 Jun;5(6):881-9. link to original article contains dosing details in manuscript PubMed
    1. Update: Falkson G, Holcroft C, Gelman RS, Tormey DC, Wolter JM, Cummings FJ. Ten-year follow-up study of premenopausal women with metastatic breast cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol. 1995 Jun;13(6):1453-8. link to original article PubMed
  8. CALGB 7682: Aisner J, Weinberg V, Perloff M, Weiss R, Perry M, Korzun A, Ginsberg S, Holland JF; CALGB. Chemotherapy versus chemoimmunotherapy (CAF v CAFVP v CMF each +/- MER) for metastatic carcinoma of the breast: a CALGB study. J Clin Oncol. 1987 Oct;5(10):1523-33. link to original article contains dosing details in abstract PubMed
  9. Ambrosini G, Balli M, Garusi G, Demicheli R, Jirillo A, Bonciarelli G, Bruscagnin G, Fila G, Bumma C, Lacroix F, Buzzi F, Di Costanzo F, Padalino D, Brugia M, Calabresi F, Natali M, Cartei G, Chiesa G, Blasina B, Ciambellotti E, Moro G, D'Aquino S, Altavilla G, Adamo V, De Maria D, Falchi AM, Bertoncelli P, Farris A, Fiorentino M, Fornasiero A, Fosser V, Daniele O, Foggi CM, Speranza GB, Sartori S, Camilluzzi E, Gallo L, Poggio R, Secondo V, Gambi A, Grignani F, Capodicasa E, Lopez M, Papaldo P, Di Lauro L, Vici P, Marenco G, Folco U, Bonanni F, Marsilio P, Palazzotto G, Di Carlo A, Cusimano MP, Pastorino G, Puccetti C, Giusto M, Rausa L, Gebbia N, Palmeri S, D'Alessandro N, Saccani F, Becchi G, Schieppati G, Spinelli I, Tagliagambe A, Tonato M, Minotti V, Ardia A, Viaro D, De Micheli P, Zingali G, Sacchetti G, Intini C; Italian Multicentre Breast Study with Epirubicin. Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: an Italian multicentre trial. J Clin Oncol. 1988 Jun;6(6):976-82. link to original article contains dosing details in manuscript PubMed
  10. Bennett JM, Muss HB, Doroshow JH, Wolff S, Krementz ET, Cartwright K, Dukart G, Reisman A, Schoch I. A randomized multicenter trial comparing mitoxantrone, cyclophosphamide, and fluorouracil with doxorubicin, cyclophosphamide, and fluorouracil in the therapy of metastatic breast carcinoma. J Clin Oncol. 1988 Oct;6(10):1611-20. link to original article contains dosing details in abstract PubMed
  11. Muss HB, Case LD, Richards F 2nd, White DR, Cooper MR, Cruz JM, Powell BL, Spurr CL, Capizzi RL; Piedmont Oncology Association. Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. N Engl J Med. 1991 Nov 7;325(19):1342-8. link to original article contains dosing details in manuscript PubMed
  12. Tominaga T, Abe O, Ohshima A, Hayasaka H, Uchino J, Abe R, Enomoto K, Izuo M, Watanabe H, Takatani O, Yoshida M, Sakai K, Koyama H, Hattori T, Senoo T, Monden Y, Nomura Y. Comparison of chemotherapy with or without medroxyprogesterone acetate for advanced or recurrent breast cancer. Eur J Cancer. 1994;30A(7):959-64. link to original article contains dosing details in abstract PubMed
  13. Alonso MC, Tabernero JM, Ojeda B, Llanos M, Solà C, Climent MA, Seguí MA, López JJ. A phase III randomized trial of cyclophosphamide, mitoxantrone, and 5-fluorouracil (CNF) versus cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) in patients with metastatic breast cancer. Breast Cancer Res Treat. 1995 Apr;34(1):15-24. link to original article contains dosing details in abstract PubMed
  14. CALGB 8281: Aisner J, Cirrincione C, Perloff M, Perry M, Budman D, Abrams J, Panasci L, Muss H, Citron M, Holland J, Wood W, Henderson IC. Combination chemotherapy for metastatic or recurrent carcinoma of the breast--a randomized phase III trial comparing CAF versus VATH versus VATH alternating with CMFVP: Cancer and Leukemia Group B Study 8281. J Clin Oncol. 1995 Jun;13(6):1443-52. link to original article does not contain dosing details PubMed
  15. Blajman C, Balbiani L, Block J, Coppola F, Chacon R, Fein L, Bonicatto S, Alvarez A, Schmilovich A, Delgado FM. A prospective, randomized Phase III trial comparing combination chemotherapy with cyclophosphamide, doxorubicin, and 5-fluorouracil with vinorelbine plus doxorubicin in the treatment of advanced breast carcinoma. Cancer. 1999 Mar 1;85(5):1091-7. link to original article contains dosing details in manuscript PubMed
  16. ECOG E3186: Sledge GW Jr, Hu P, Falkson G, Tormey D, Abeloff M. Comparison of chemotherapy with chemohormonal therapy as first-line therapy for metastatic, hormone-sensitive breast cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol. 2000 Jan;18(2):262-6. link to original article contains dosing details in manuscript PubMed
  17. Jassem J, Pieńkowski T, Płuzańska A, Jelic S, Gorbunova V, Mrsic-Krmpotic Z, Berzins J, Nagykalnai T, Wigler N, Renard J, Munier S, Weil C; Central & Eastern Europe and Israel Pacitaxel Breast Cancer Study Group. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J Clin Oncol. 2001 Mar 15;19(6):1707-15. link to original article contains dosing details in abstract PubMed
    1. Update: Jassem J, Pienkowski T, Pluzanska A, Jelic S, Gorbunova V, Berzins J, Nagykalnai T, Biganzoli L, Aloe A, Astier L, Munier S. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin and cyclophosphamide as first-line therapy for women with advanced breast cancer: long-term analysis of the previously published trial. Onkologie. 2009 Sep;32(8-9):468-72. Epub 2009 Jul 20. link to original article PubMed
  18. Namer M, Soler-Michel P, Turpin F, Chinet-Charrot P, de Gislain C, Pouillart P, Delozier T, Luporsi E, Etienne PL, Schraub S, Eymard JC, Serin D, Ganem G, Calais G, Maillart P, Colin P, Trillet-Lenoir V, Prevost G, Tigaud D, Clavère P, Marti P, Romieu G, Wendling JL. Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer. Eur J Cancer. 2001 Jun;37(9):1132-40. link to original article contains dosing details in manuscript PubMed
  19. CALGB 9140: Parnes HL, Cirrincione C, Aisner J, Berry DA, Allen SL, Abrams J, Chuang E, Cooper MR, Perry MC, Duggan DB, Szatrowski TP, Henderson IC, Norton L; CALGB. Phase III study of cyclophosphamide, doxorubicin, and fluorouracil (CAF) plus leucovorin versus CAF for metastatic breast cancer: Cancer and Leukemia Group B 9140. J Clin Oncol. 2003 May 1;21(9):1819-24. link to original article contains dosing details in abstract PubMed
  20. Bontenbal M, Creemers GJ, Braun HJ, de Boer AC, Janssen JT, Leys RB, Ruit JB, Goey SH, van der Velden PC, Kerkhofs LG, Schothorst KL, Schmitz PI, Bokma HJ, Verweij J, Seynaeve C; Dutch Community Setting Trial for the Clinical Trial Group. Phase II to III study comparing doxorubicin and docetaxel with fluorouracil, doxorubicin, and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer: results of a Dutch Community Setting Trial for the Clinical Trial Group of the Comprehensive Cancer Centre. J Clin Oncol. 2005 Oct 1;23(28):7081-8. link to original article contains dosing details in abstract PubMed
  21. RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains dosing details in manuscript PubMed NCT00262067

FAC & Bevacizumab

FAC & Bevacizumab: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide, Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Robert et al. 2011 (RIBBON-1) 2005-2007 Phase 3 (E-esc) 1a. AC
1b. Capecitabine
1c. Docetaxel
1d. EC
1e. FAC
1f. FEC
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
(HR 0.64, 95% CI 0.52-0.80)

Chemotherapy

Targeted therapy

21-day cycle for up to 8 cycles

Subsequent treatment

References

  1. RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains dosing details in manuscript PubMed NCT00262067

FEC

FEC: Fluorouracil, Epirubicin, Cyclophosphamide
CEF: Cyclophosphamide, Epirubicin, Fluorouracil

Regimen variant #1, 500/50/500 ("FEC 50")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bonneterre & Hurteloup 1991 NR Phase 3 (C) 1. Epirubicin Seems to have superior ORR
2. FEC; FEC 75 Did not meet primary endpoint of ORR
Focan et al. 1993 1985-1990 Phase 3 (C) FEC; FEC 100 Seems to have inferior TTP
Brufman et al. 1997 (HEPI 010) 1989-1992 Phase 3 (C) FEC; FEC 100 Inferior ORR
Heidemann et al. 2002 (GER-AIO-01/92) 1992-1997 Phase 3 (C) Mitoxantrone Did not meet efficacy endpoints
Namer et al. 2001 1993-04 to 1995-12 Phase 3 (C) MV Equivalent ORR

Chemotherapy

21-day cycle for 6 to 12 cycles


Regimen variant #2, 500/60/500

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Blomqvist et al. 1993 1987-1991 Phase 3 (C) FEC; weekly Superior OS

Chemotherapy

28-day cycles


Regimen variant #3, 500/75/500 ("FEC 75")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bonneterre & Hurteloup 1991 NR Phase 3 (E-esc) 1. Epirubicin Superior ORR
2. FEC; FEC 50 Did not meet primary endpoint of ORR
Pacini et al. 2000 1991-1996 Phase 3 (C) 1. EM
2. EM & Lonidamine 		Inferior OS
Capotorto et al. 2003 1995-1998 Phase 3 (C) 1. ddFEC Inferior ORR
2. ddMMM Did not meet endpoint of ORR
Bonneterre et al. 2004 1998-2000 Randomized Phase 2 (C) DE Inferior ORR

Chemotherapy

21-day cycles


Regimen variant #4, 500/90/500

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Zielinksi et al. 2005 (CECOG BM1) 1999-2002 Phase 3 (C) GET Did not meet primary endpoint of TTP
Robert et al. 2011 (RIBBON-1) 2005-2007 Phase 3 (C) 1a. AC & Bevacizumab
1b. Capecitabine & Bevacizumab
1c. Docetaxel & Bevacizumab
1d. EC & Bevacizumab
1e. FAC & Bevacizumab
1f. FEC & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: this is the lower bound of the dosing range allowed in RIBBON-1.

Chemotherapy

21-day cycle for up to 8 cycles


Regimen variant #5, 500/100/500 ("FEC 100")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufman et al. 1997 (HEPI 010) 1989-1992 Phase 3 (E-esc) FEC; FEC 50 Superior ORR
Robert et al. 2011 (RIBBON-1) 2005-2007 Phase 3 (C) 1a. AC & Bevacizumab
1b. Capecitabine & Bevacizumab
1c. Docetaxel & Bevacizumab
1d. EC & Bevacizumab
1e. FAC & Bevacizumab
1f. FEC & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: this is the upper bound of the dosing range allowed in RIBBON-1.

Chemotherapy

21-day cycle for 6 to 8 cycles


Regimen variant #6, 500/100/500, split epirubicin ("FEC 100")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Focan et al. 1993 1985-1990 Phase 3 (E-esc) FEC; FEC 50 Seems to have superior TTP

Chemotherapy

21-day cycle for 6 to 8 cycles


Regimen variant #7, 600/60/600 ("CEF21")

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Conte et al. 1987 1983-1985 Randomized (C) DES-CEF Did not meet primary endpoint of ORR
Conte et al. 1996 1985-1990 Phase 3 (C) DES-CEF Did not meet primary endpoint of ORR
Ejlertsen et al. 1993 1986-1989 Phase 3 (C) FEC x 18 mo Inferior OS
Del Mastro et al. 2001 1994-1997 Phase 3 (C) HD-CEF14 Did not meet primary endpoint of ORR

Note: dosing information was not available in the abstract of Ejlertsen et al. 1993; this dosing has been used in other studies by this group.

Chemotherapy

21-day cycle for 8 to 12 cycles


Regimen variant #8, 1000/50/500 until max anthracycline

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Ambrosini et al. 1988 1983-1985 Phase 3 (E-switch-ic) FAC Did not meet primary endpoint Less toxic

Chemotherapy

21-day cycle for up to 14 cycles (maximum of 700 mg/m2 epirubicin)


Regimen variant #9, 1000/60/1400

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Esteban et al. 1999 1987-1993 Phase 3 (C) CNF Seems to have superior OS

Chemotherapy

28-day cycles


Regimen variant #10, 1000/100/800

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ackland et al. 2001 (HEPI 013) 1990-1992 Phase 3 (E-switch-ic) CMF Superior TTP

Chemotherapy

28-day cycle for 6 to 8 cycles

References

  1. Conte PF, Pronzato P, Rubagotti A, Alama A, Amadori D, Demicheli R, Gardin G, Gentilini P, Jacomuzzi A, Lionetto R, Monzeglio C, Nicolin A, Rosso R, Sismondi P, Sussio M, Santi L. Conventional versus cytokinetic polychemotherapy with estrogenic recruitment in metastatic breast cancer: results of a randomized cooperative trial. J Clin Oncol. 1987 Mar;5(3):339-47. link to original article contains dosing details in abstract PubMed
  2. Ambrosini G, Balli M, Garusi G, Demicheli R, Jirillo A, Bonciarelli G, Bruscagnin G, Fila G, Bumma C, Lacroix F, Buzzi F, Di Costanzo F, Padalino D, Brugia M, Calabresi F, Natali M, Cartei G, Chiesa G, Blasina B, Ciambellotti E, Moro G, D'Aquino S, Altavilla G, Adamo V, De Maria D, Falchi AM, Bertoncelli P, Farris A, Fiorentino M, Fornasiero A, Fosser V, Daniele O, Foggi CM, Speranza GB, Sartori S, Camilluzzi E, Gallo L, Poggio R, Secondo V, Gambi A, Grignani F, Capodicasa E, Lopez M, Papaldo P, Di Lauro L, Vici P, Marenco G, Folco U, Bonanni F, Marsilio P, Palazzotto G, Di Carlo A, Cusimano MP, Pastorino G, Puccetti C, Giusto M, Rausa L, Gebbia N, Palmeri S, D'Alessandro N, Saccani F, Becchi G, Schieppati G, Spinelli I, Tagliagambe A, Tonato M, Minotti V, Ardia A, Viaro D, De Micheli P, Zingali G, Sacchetti G, Intini C; Italian Multicentre Breast Study with Epirubicin. Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: an Italian multicentre trial. J Clin Oncol. 1988 Jun;6(6):976-82. link to original article contains dosing details in abstract PubMed
  3. Bonneterre J, Hurteloup P; French Epirubicin Study Group. A prospective randomized trial comparing epirubicin monochemotherapy to two fluorouracil, cyclophosphamide, and epirubicin regimens differing in epirubicin dose in advanced breast cancer patients. J Clin Oncol. 1991 Feb;9(2):305-12. link to original article contains dosing details in manuscript PubMed
  4. Ejlertsen B, Pfeiffer P, Pedersen D, Mouridsen HT, Rose C, Overgaard M, Sandberg E, Kristensen B. Decreased efficacy of cyclophosphamide, epirubicin and 5-fluorouracil in metastatic breast cancer when reducing treatment duration from 18 to 6 months. Eur J Cancer. 1993;29A(4):527-31. link to original article PubMed
  5. Blomqvist C, Elomaa I, Rissanen P, Hietanen P, Nevasaari K, Helle L. Influence of treatment schedule on toxicity and efficacy of cyclophosphamide, epirubicin, and fluorouracil in metastatic breast cancer: a randomized trial comparing weekly and every-4-week administration. J Clin Oncol. 1993 Mar;11(3):467-73. link to original article contains dosing details in abstract PubMed
  6. Focan C, Andrien JM, Closon MT, Dicato M, Driesschaert P, Focan-Henrard D, Lemaire M, Lobelle JP, Longree L, Ries F. Dose-response relationship of epirubicin-based first-line chemotherapy for advanced breast cancer: a prospective randomized trial. J Clin Oncol. 1993 Jul;11(7):1253-63. link to original article contains dosing details in abstract PubMed
  7. Conte PF, Baldini E, Gardin G, Pronzato P, Amadori D, Carnino F, Monzeglio C, Gentilini P, Gallotti P, DeMicheli R, Venturini M, Rubagotti A, Rosso R; GONO. Chemotherapy with or without estrogenic recruitment in metastatic breast cancer: a randomized trial of the Gruppo Oncologico Nord Ovest (GONO). Ann Oncol. 1996 Jul;7(5):487-90. link to original article contains dosing details in abstract PubMed
  8. HEPI 010: Brufman G, Colajori E, Ghilezan N, Lassus M, Martoni A, Perevodchikova N, Tosello C, Viaro D, Zielinski C; Epirubicin High Dose (HEPI 010) Study Group. Doubling epirubicin dose intensity (100 mg/m2 versus 50 mg/m2) in the FEC regimen significantly increases response rates: an international randomised phase III study in metastatic breast cancer. Ann Oncol. 1997 Feb;8(2):155-62. link to original article contains dosing details in manuscript PubMed
  9. Esteban E, Lacave AJ, Fernández JL, Corral N, Buesa JM, Estrada E, Palacio I, Vieitez JM, Muñiz I, Alvarez E. Phase III trial of cyclophosphamide, epirubicin, fluorouracil (CEF) versus cyclophosphamide, mitoxantrone, fluorouracil (CNF) in women with metastatic breast cancer. Breast Cancer Res Treat. 1999 Nov;58(2):141-50. link to original article contains dosing details in abstract PubMed
  10. Pacini P, Rinaldini M, Algeri R, Guarneri A, Tucci E, Barsanti G, Neri B, Bastiani P, Marzano S, Fallai C. FEC (5-fluorouracil, epidoxorubicin and cyclophosphamide) versus EM (epidoxorubicin and mitomycin-C) with or without lonidamine as first-line treatment for advanced breast cancer, a multicentric randomised study: final results. Eur J Cancer. 2000 May;36(8):966-75. link to original article contains dosing details in abstract PubMed
  11. HEPI 013: Ackland SP, Anton A, Breitbach GP, Colajori E, Tursi JM, Delfino C, Efremidis A, Ezzat A, Fittipaldo A, Kolaric K, Lopez M, Viaro D; HEPI 013 study group. Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study. J Clin Oncol. 2001 Feb 15;19(4):943-53. link to original article contains dosing details in abstract PubMed
  12. Del Mastro L, Venturini M, Lionetto R, Carnino F, Guarneri D, Gallo L, Contu A, Pronzato P, Vesentini L, Bergaglio M, Comis S, Rosso R; GONO; MIG. Accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) compared with standard CEF in metastatic breast cancer patients: results of a multicenter, randomized phase III study of the Italian Gruppo Oncologico Nord-Ouest-Mammella Inter Gruppo Group. J Clin Oncol. 2001 Apr 15;19(8):2213-21. link to original article contains dosing details in manuscript PubMed
  13. Namer M, Soler-Michel P, Turpin F, Chinet-Charrot P, de Gislain C, Pouillart P, Delozier T, Luporsi E, Etienne PL, Schraub S, Eymard JC, Serin D, Ganem G, Calais G, Maillart P, Colin P, Trillet-Lenoir V, Prevost G, Tigaud D, Clavère P, Marti P, Romieu G, Wendling JL. Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer. Eur J Cancer. 2001 Jun;37(9):1132-40. link to original article contains dosing details in manuscript PubMed
  14. GER-AIO-01/92: Heidemann E, Stoeger H, Souchon R, Hirschmann WD, Bodenstein H, Oberhoff C, Fischer JT, Schulze M, Clemens M, Andreesen R, Mahlke M, König M, Scharl A, Fehnle K, Kaufmann M. Is first-line single-agent mitoxantrone in the treatment of high-risk metastatic breast cancer patients as effective as combination chemotherapy? No difference in survival but higher quality of life were found in a multicenter randomized trial. Ann Oncol. 2002 Nov;13(11):1717-29. link to original article contains dosing details in abstract PubMed NCT00002544
  15. Capotorto AM, Pavesi L, Pedrazzoli P, Da Prada GA, Zamagni C, Massidda B, Farris A, Martoni A, Lelli G, Robustelli della Cuna G. Randomized, controlled, multicenter phase III trial of standard-dose fluorouracil-epirubicin-cyclophosphamide (FEC), compared with time-intensive FEC (FEC-G) and mitoxantrone-methotrexate-mitomycin C (MMM-G) in metastatic breast carcinoma. J Chemother. 2003 Apr;15(2):184-91. link to original article contains dosing details in abstract PubMed
  16. Bonneterre J, Dieras V, Tubiana-Hulin M, Bougnoux P, Bonneterre ME, Delozier T, Mayer F, Culine S, Dohoulou N, Bendahmane B. Phase II multicentre randomised study of docetaxel plus epirubicin vs 5-fluorouracil plus epirubicin and cyclophosphamide in metastatic breast cancer. Br J Cancer. 2004 Oct 18;91(8):1466-71. link to original article link to PMC article contains dosing details in abstract PubMed
  17. CECOG BM1: Zielinski C, Beslija S, Mrsic-Krmpotic Z, Welnicka-Jaskiewicz M, Wiltschke C, Kahan Z, Grgic M, Tzekova V, Inbar M, Cervek J, Chernozemsky I, Szanto J, Spanik S, Wagnerova M, Ghilezan N, Pawlega J, Vrbanec D, Khamtsov D, Soldatenkova V, Brodowicz T. Gemcitabine, epirubicin, and paclitaxel versus fluorouracil, epirubicin, and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: a Central European Cooperative Oncology Group International, multicenter, prospective, randomized phase III trial. J Clin Oncol. 2005 Mar 1;23(7):1401-8. link to original article contains dosing details in abstract PubMed
  18. RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains dosing details in manuscript PubMed NCT00262067

FEC & Bevacizumab

FEC & Bevacizumab: Fluorouracil, Epirubicin, Cyclophosphamide, Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Robert et al. 2011 (RIBBON-1) 2005-2007 Phase 3 (E-esc) 1a. AC
1b. Capecitabine
1c. Docetaxel
1d. EC
1e. FAC
1f. FEC
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
(HR 0.64, 95% CI 0.52-0.80)

Chemotherapy

Targeted therapy

21-day cycle for up to 8 cycles

Subsequent treatment

References

  1. RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains dosing details in manuscript PubMed NCT00262067

Gemcitabine monotherapy

Regimen

Study Dates of enrollment Evidence
Carmichael et al. 1995 NR Phase 2, less than 20 pts in this subgroup

Chemotherapy

28-day cycles

References

  1. Carmichael J, Possinger K, Philip P, Beykirch M, Kerr H, Walling J, Harris AL. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol. 1995 Nov;13(11):2731-6. link to original article contains dosing details in abstract PubMed

Gemcitabine & Paclitaxel

GT: Gemcitabine & Taxol (Paclitaxel)
PG: Paclitaxel & Gemcitabine

Regimen variant #1, 6 cycles

Study Dates of enrollment Evidence
Park et al. 2013 (KCSG-BR07-02) 2007-2010 Non-randomized part of phase 3 RCT

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment


Regimen variant #2, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Albain et al. 2008 1999-2002 Phase 3 (E-RT-esc) Paclitaxel Seems to have superior OS (primary endpoint)
Median OS: 18.6 vs 15.8 mo
(HR 0.78, 95% CI 0.64-0.96)
Del Mastro et al. 2013 (B9E-IT-S376) 2005-2010 Phase 3 (E-switch-ic) 1. GD; weekly
2. GD; q3wk
3. GT; weekly 		Did not meet primary endpoint of TTP

Chemotherapy

21-day cycles

References

  1. Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, Rolski J, Melemed AS, Reyes-Vidal JM, Sekhon JS, Simms L, O'Shaughnessy J. Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008 Aug 20;26(24):3950-7. link to original article contains dosing details in manuscript PubMed
  2. B9E-IT-S376: Del Mastro L, Fabi A, Mansutti M, De Laurentiis M, Durando A, Merlo DF, Bruzzi P, La Torre I, Ceccarelli M, Kazeem G, Marchi P, Boy D, Venturini M, De Placido S, Cognetti F. Randomised phase 3 open-label trial of first-line treatment with gemcitabine in association with docetaxel or paclitaxel in women with metastatic breast cancer: a comparison of different schedules and treatments. BMC Cancer. 2013 Mar 28;13:164. link to original article link to PMC article contains dosing details in abstract PubMed NCT00236899
  3. KCSG-BR07-02: Park YH, Jung KH, Im SA, Sohn JH, Ro J, Ahn JH, Kim SB, Nam BH, Oh DY, Han SW, Lee S, Park IH, Lee KS, Kim JH, Kang SY, Lee MH, Park HS, Ahn JS, Im YH. Phase III, multicenter, randomized trial of maintenance chemotherapy versus observation in patients with metastatic breast cancer after achieving disease control with six cycles of gemcitabine plus paclitaxel as first-line chemotherapy: KCSG-BR07-02. J Clin Oncol. 2013 May 10;31(14):1732-9. Epub 2013 Apr 8. link to original article contains dosing details in manuscript PubMed NCT00561119

Cyclophosphamide & Non-pegylated liposomal doxorubicin (MC)

MC: Myocet (non-pegylated liposomal doxorubicin) & Cyclophosphamide

Regimen variant #1, 60/600

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lorusso et al. 2014 2006-2011 Phase 3 (C) NPLD & Vinorelbine Did not meet primary endpoint of TTP

Chemotherapy

21-day cycles


Regimen variant #2, 75/600

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Chan et al. 2004 1996-05 to 1997-08 Phase 3 (E-switch-ic) EC Superior TTP
Median TTP: 7.7 vs 5.6 mo
(HR 0.66, 95% CI 0.45-0.94)

Chemotherapy

21-day cycle for up to 8 cycles

References

  1. Chan S, Davidson N, Juozaityte E, Erdkamp F, Pluzanska A, Azarnia N, Lee LW. Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer. Ann Oncol. 2004 Oct;15(10):1527-34. link to original article contains dosing details in abstract PubMed
  2. Lorusso V, Giotta F, Bordonaro R, Maiello E, Del Prete S, Gebbia V, Filippelli G, Pisconti S, Cinieri S, Romito S, Riccardi F, Forcignanò R, Ciccarese M, Petrucelli L, Saracino V, Lupo LI, Gambino A, Leo S, Colucci G; Gruppo Oncologico Dell'Italia Meridionale. Non-pegylated liposome-encapsulated doxorubicin citrate plus cyclophosphamide or vinorelbine in metastatic breast cancer not previously treated with chemotherapy:a multicenter phase III study. Int J Oncol. 2014 Nov;45(5):2137-42. Epub 2014 Aug 18. link to original article contains dosing details in abstract PubMed

Paclitaxel monotherapy, weekly

Regimen variant #1, 80 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Perez et al. 2001 NR Phase 2
Seidman et al. 2008 (CALGB 9840) 1998-NR Phase 3 (E-switch-ic) Paclitaxel; q3wk Superior OS (secondary endpoint)
Median OS: 24 vs 12 mo
(HR 0.78, 95% CI 0.65-0.94)
Fountzilas et al. 2008 2002-2006 Phase 3 (E-de-esc) 1. Carboplatin & Paclitaxel
2. Docetaxel & Gemcitabine 		Seems to have superior OS (primary endpoint)
Martin et al. 2017 (BELLE-4) 2012-2014 Phase 3 (C) Buparlisib & Paclitaxel Did not meet primary endpoint of PFS

Chemotherapy

28-day cycles


Regimen variant #2, 80 mg/m2 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Takashima et al. 2015 (SELECT BC) 2006-2010 Phase 3 (C) S-1 Seems to have non-inferior OS Inferior EQ-5D score
Fujiwara et al. 2019 (A3105301) 2012-2014 Phase 3 (C) NK-105 Inconclusive whether non-inferior PFS (primary endpoint) Higher rate of CIPN

Note: this is the lower limit of dosing allowed in SELECT BC.

Chemotherapy

28-day cycles


Regimen variant #3, 90 mg/m2 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Miller et al. 2007 (ECOG E2100) 2001-2004 Phase 3 (C) Paclitaxel & Bevacizumab Inferior PFS
Miles et al. 2016 (MERiDiAN) 2012-2013 Phase 3 (C) Paclitaxel & Bevacizumab Inferior PFS

Chemotherapy

28-day cycles


Regimen variant #4, 100 mg/m2 weekly

Study Dates of enrollment Evidence
Seidman et al. 1998 NR Phase 2, less than 20 pts in this subgroup

Chemotherapy

7-day cycles


Regimen variant #5, 100 mg/m2 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Takashima et al. 2015 (SELECT BC) 2006-2010 Phase 3 (C) S-1 Seems to have non-inferior OS Inferior EQ-5D score

Note: this is the upper limit of dosing allowed in SELECT BC.

Chemotherapy

28-day cycles

References

  1. Seidman AD, Hudis CA, Albanell J, Tong W, Tepler I, Currie V, Moynahan ME, Theodoulou M, Gollub M, Baselga J, Norton L. Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol. 1998 Oct;16(10):3353-61. Erratum in: J Clin Oncol. 2006 May 10;24(14):2220. Albanel, J [corrected to Albanell, J ]. link to original article contains dosing details in abstract PubMed
  2. Perez EA, Vogel CL, Irwin DH, Kirshner JJ, Patel R. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2001 Nov 15;19(22):4216-23. link to original article PubMed
  3. ECOG E2100: Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76. link to original article PubMed NCT00028990
  4. CALGB 9840: Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. link to original article PubMed NCT00003440
  5. Fountzilas G, Dafni U, Dimopoulos MA, Koutras A, Skarlos D, Papakostas P, Gogas H, Bafaloukos D, Kalogera-Fountzila A, Samantas E, Briasoulis E, Pectasides D, Maniadakis N, Matsiakou F, Aravantinos G, Papadimitriou C, Karina M, Christodoulou C, Kosmidis P, Kalofonos HP; Hellenic Cooperative Oncology Group. A randomized phase III study comparing three anthracycline-free taxane-based regimens, as first line chemotherapy, in metastatic breast cancer: a Hellenic Cooperative Oncology Group study. Breast Cancer Res Treat. 2009 May;115(1):87-99. Epub 2008 May 16. link to original article contains dosing details in manuscript PubMed
  6. SELECT BC: Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T, Hozumi Y, Tsurutani J, Imoto S, Watanabe T, Sagara Y, Nishimura R, Shimozuma K, Ohashi Y; SELECT BC Study Group. Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2016 Jan;17(1):90-8. Epub 2015 Nov 27. link to original article contains dosing details in manuscript PubMed UMIN C000000416
    1. HRQoL analysis: Shiroiwa T, Fukuda T, Shimozuma K, Mouri M, Hagiwara Y, Doihara H, Akabane H, Kashiwaba M, Watanabe T, Ohashi Y, Mukai H. Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial. Qual Life Res. 2017 Feb;26(2):445-453. Epub 2016 Aug 12. link to original article link to PMC article PubMed
  7. MERiDiAN: Miles D, Cameron D, Bondarenko I, Manzyuk L, Alcedo JC, Lopez RI, Im SA, Canon JL, Shparyk Y, Yardley DA, Masuda N, Ro J, Denduluri N, Hubeaux S, Quah C, Bais C, O'Shaughnessy J. Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation. Eur J Cancer. 2017 Jan;70:146-155. Epub 2016 Nov 4. link to original article contains dosing details in abstract PubMed NCT01663727
    1. Update: Miles D, Cameron D, Hilton M, Garcia J, O'Shaughnessy J. Overall survival in MERiDiAN, a double-blind placebo-controlled randomised phase III trial evaluating first-line bevacizumab plus paclitaxel for HER2-negative metastatic breast cancer. Eur J Cancer. 2018 Feb;90:153-155. Epub 2017 Nov 23. link to original article PubMed
  8. BELLE-4: Martín M, Chan A, Dirix L, O'Shaughnessy J, Hegg R, Manikhas A, Shtivelband M, Krivorotko P, Batista López N, Campone M, Ruiz Borrego M, Khan QJ, Beck JT, Ramos Vázquez M, Urban P, Goteti S, Di Tomaso E, Massacesi C, Delaloge S. A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4). Ann Oncol. 2017 Feb 1;28(2):313-320. link to original article contains dosing details in manuscript PubMed NCT01572727
  9. A3105301: Fujiwara Y, Mukai H, Saeki T, Ro J, Lin YC, Nagai SE, Lee KS, Watanabe J, Ohtani S, Kim SB, Kuroi K, Tsugawa K, Tokuda Y, Iwata H, Park YH, Yang Y, Nambu Y. A multi-national, randomised, open-label, parallel, phase III non-inferiority study comparing NK105 and paclitaxel in metastatic or recurrent breast cancer patients. Br J Cancer. 2019 Mar;120(5):475-480. Epub 2019 Feb 12. link to original article contains dosing details in abstract link to PMC article PubMed NCT01644890

Paclitaxel monotherapy, q3wk

Regimen variant #1, 175 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Seidman et al. 1995 NR Phase 2
Winer et al. 2004 (CALGB 9342) 1994-1997 Phase 3 (C) 1. Paclitaxel; 210 mg/m2 q3wk
2. Paclitaxel; 250 mg/m2 q3wk 		Did not meet primary endpoint of ORR
Seidman et al. 2008 (CALGB 9840) 1998-NR Phase 3 (C) Paclitaxel; weekly Inferior OS
Albain et al. 2008 1999-2002 Phase 3 (C) GT Seems to have inferior OS
Gradishar et al. 2005 (CA012-0) 2001-11 to 2002-11 Phase 3 (C) nab-Paclitaxel Inferior TTP
Di Leo et al. 2008 (EGF30001) 2004-01 to 2005-07 Phase 3 (C) Lapatinib & Paclitaxel Did not meet primary endpoint of TTP Less toxic
Takashima et al. 2015 (SELECT BC) 2006-2010 Phase 3 (C) S-1 Seems to have non-inferior OS Inferior EQ-5D score
Park et al. 2016 (GPMBC301) 2008-2013 Phase 3 (C) Genexol-PM Seems to have non-inferior ORR

Note: patients in EGF30001 were NOT required to be HER2-positive.

Chemotherapy

21-day cycles


Regimen variant #2, 175 mg/m2, CI

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Sledge et al. 2003 (ECOG E1193) 1993-1995 Phase 3 (E-switch-ooc) 1. AT (Taxol) Inferior TTF
2. Doxorubicin Did not meet primary endpoint of ORR

Chemotherapy

21-day cycles


Regimen variant #3, 175 mg/m2 q4wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Takashima et al. 2015 (SELECT BC) 2006-2010 Phase 3 (C) S-1 Seems to have non-inferior OS Inferior EQ-5D score

Chemotherapy

28-day cycles


Regimen variant #4, 200 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bishop et al. 1999 1993-NR Phase 3 (E-de-esc) CMFP Seems to have superior OS
Paridaens et al. 2000 (EORTC 10923) 1993-1996 Phase 3 (E-switch-ic) Doxorubicin Inferior PFS

Chemotherapy

21-day cycle for 7 or 8 cycles


Regimen variant #5, 250 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Holmes et al. 1991 1990 Phase 2
Smith et al. 1996 (NSABP B-26) 1994-1996 Phase 3 (C) Paclitaxel; 250 mg/m2 over 3 hours Did not meet primary endpoint of ORR

Note: Holmes et al. 1991 is of historic interest, being the first phase II trial of a taxane in breast cancer.

Chemotherapy

21-day cycles

References

  1. Holmes FA, Walters RS, Theriault RL, Forman AD, Newton LK, Raber MN, Buzdar AU, Frye DK, Hortobagyi GN. Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst. 1991 Dec 18;83(24):1797-805. link to original article contains dosing details in abstract PubMed
  2. Seidman AD, Tiersten A, Hudis C, Gollub M, Barrett S, Yao TJ, Lepore J, Gilewski T, Currie V, Crown J, Hakes T, Baselga J, Sklarin N, Moynihan ME, Tong W, Egorin M, Kearns C, Spriggs D, Norton L. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2575-81. link to original article PubMed
  3. Bishop JF, Dewar J, Toner GC, Smith J, Tattersall MH, Olver IN, Ackland S, Kennedy I, Goldstein D, Gurney H, Walpole E, Levi J, Stephenson J, Canetta R. Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2355-64. link to original article contains dosing details in abstract PubMed
  4. NSABP B-26: Smith RE, Brown AM, Mamounas EP, Anderson SJ, Lembersky BC, Atkins JH, Shibata HR, Baez L, DeFusco PA, Davila E, Tipping SJ, Bearden JD, Thirlwell MP. Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-26. J Clin Oncol. 1999 Nov;17(11):3403-11. link to original article contains dosing details in abstract PubMed
  5. EORTC 10923: Paridaens R, Biganzoli L, Bruning P, Klijn JG, Gamucci T, Houston S, Coleman R, Schachter J, Van Vreckem A, Sylvester R, Awada A, Wildiers J, Piccart M. Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European Organisation for Research and Treatment of Cancer Randomized Study with cross-over. J Clin Oncol. 2000 Feb;18(4):724-33. link to original article contains dosing details in abstract PubMed
    1. HRQoL analysis: Kramer JA, Curran D, Piccart M, de Haes JC, Bruning PF, Klijn JG, Bontenbal M, van Pottelsberghe C, Groenvold M, Paridaens R. Randomised trial of paclitaxel versus doxorubicin as first-line chemotherapy for advanced breast cancer: quality of life evaluation using the EORTC QLQ-C30 and the Rotterdam symptom checklist. Eur J Cancer. 2000 Aug;36(12):1488-97. link to original article PubMed
  6. ECOG E1193: Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, Wood WC. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol. 2003 Feb 15;21(4):588-92. link to original article PubMed
  7. CALGB 9342: Winer EP, Berry DA, Woolf S, Duggan D, Kornblith A, Harris LN, Michaelson RA, Kirshner JA, Fleming GF, Perry MC, Graham ML, Sharp SA, Keresztes R, Henderson IC, Hudis C, Muss H, Norton L. Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: Cancer and Leukemia Group B trial 9342. J Clin Oncol. 2004 Jun 1;22(11):2061-8. link to original article contains dosing details in abstract PubMed
  8. CA012-0: Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. link to original article contains dosing details in manuscript PubMed NCT00046527
  9. CALGB 9840: Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. link to original article PubMed NCT00003440
  10. Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, Rolski J, Melemed AS, Reyes-Vidal JM, Sekhon JS, Simms L, O'Shaughnessy J. Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008 Aug 20;26(24):3950-7. link to original article PubMed
  11. EGF30001: Di Leo A, Gomez HL, Aziz Z, Zvirbule Z, Bines J, Arbushites MC, Guerrera SF, Koehler M, Oliva C, Stein SH, Williams LS, Dering J, Finn RS, Press MF. Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol. 2008 Dec 1;26(34):5544-52. Epub 2008 Oct 27. Erratum in: J Clin Oncol. 2009 Apr 10;27(11):1923. link to original article link to PMC article contains dosing details in abstract PubMed NCT00075270
  12. SELECT BC: Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T, Hozumi Y, Tsurutani J, Imoto S, Watanabe T, Sagara Y, Nishimura R, Shimozuma K, Ohashi Y; SELECT BC Study Group. Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2016 Jan;17(1):90-8. Epub 2015 Nov 27. link to original article contains dosing details in manuscript PubMed UMIN C000000416
    1. HRQoL analysis: Shiroiwa T, Fukuda T, Shimozuma K, Mouri M, Hagiwara Y, Doihara H, Akabane H, Kashiwaba M, Watanabe T, Ohashi Y, Mukai H. Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial. Qual Life Res. 2017 Feb;26(2):445-453. Epub 2016 Aug 12. link to original article link to PMC article PubMed
  13. GPMBC301: Park IH, Sohn JH, Kim SB, Lee KS, Chung JS, Lee SH, Kim TY, Jung KH, Cho EK, Kim YS, Song HS, Seo JH, Ryoo HM, Lee SA, Yoon SY, Kim CS, Kim YT, Kim SY, Jin MR, Ro J. An Open-Label, Randomized, Parallel, Phase III Trial Evaluating the Efficacy and Safety of Polymeric Micelle-Formulated Paclitaxel Compared to Conventional Cremophor EL-Based Paclitaxel for Recurrent or Metastatic HER2-Negative Breast Cancer. Cancer Res Treat. 2017 Jul;49(3):569-577. Epub 2016 Sep 12. link to original article link to PMC article contains dosing details in abstract PubMed NCT00876486

Paclitaxel & Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Miller et al. 2007 (ECOG E2100) 2001-2004 Phase 3 (E-RT-esc) Paclitaxel Superior PFS (primary endpoint)
Median PFS: 11.8 vs 5.9 mo
(HR 0.60)

Did not meet secondary endpoint of OS
Median OS: 26.7 vs 25.2 mo
(HR 0.88)
Robert et al. 2011 (SUN 1094) 2006-2009 Phase 3 (C) Paclitaxel & Sunitinib Did not meet primary endpoint of PFS
Lang et al. 2013 (TURANDOT) 2008-2010 Phase 3 (E-switch-ic) Capecitabine & Bevacizumab Non-inferior OS1 (primary endpoint)
Rugo et al. 2015 (CALGB 40502/NCCTG N063H) 2008-2011 Phase 3 (C) 1. Ixabepilone & Bevacizumab Superior PFS
2. nab-Paclitaxel & Bevacizumab Might have superior PFS
Rochlitz et al. 2016 (SAKK 24/09) 2010-2012 Phase 3 (C) Capecitabine, Cyclophosphamide, Bevacizumab Did not meet secondary endpoint of PFS
Miles et al. 2016 (MERiDiAN) 2012-2013 Phase 3 (E-esc) Paclitaxel Superior PFS (primary endpoint)
Median PFS: 11 vs 8.8 mo
(HR 0.68, 99% CI 0.51-0.91)

1Reported efficacy for TURANDOT is based on the 2016 update.
Note: ECOG E2100 was the basis for accelerated approval of bevacizumab in breast cancer.

Chemotherapy

Targeted therapy

28-day cycles

References

  1. ECOG E2100: Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76. link to original article PubMed NCT00028990
  2. SUN 1094: Robert NJ, Saleh MN, Paul D, Generali D, Gressot L, Copur MS, Brufsky AM, Minton SE, Giguere JK, Smith JW 2nd, Richards PD, Gernhardt D, Huang X, Liau KF, Kern KA, Davis J. Sunitinib plus paclitaxel versus bevacizumab plus paclitaxel for first-line treatment of patients with advanced breast cancer: a phase III, randomized, open-label trial. Clin Breast Cancer. 2011 Apr;11(2):82-92. Epub 2011 Apr 11. Erratum in: Clin Breast Cancer. 2011 Aug;11(4):273. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00373256
  3. TURANDOT: Lang I, Brodowicz T, Ryvo L, Kahan Z, Greil R, Beslija S, Stemmer SM, Kaufman B, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Messinger D, Zielinski C; Central European Cooperative Oncology Group. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial. Lancet Oncol. 2013 Feb;14(2):125-33. Epub 2013 Jan 10. link to original article PubMed NCT00600340
    1. Update: Zielinski C, Láng I, Inbar M, Kahán Z, Greil R, Beslija S, Stemmer SM, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Petruzelka L, Eniu A, Nisenbaum B, Dank M, Anghel R, Messinger D, Brodowicz T; TURANDOT investigators. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1230-9. Epub 2016 Aug 5. link to original article contains dosing details in abstract PubMed
  4. CALGB 40502/NCCTG N063H: Rugo HS, Barry WT, Moreno-Aspitia A, Lyss AP, Cirrincione C, Leung E, Mayer EL, Naughton M, Toppmeyer D, Carey LA, Perez EA, Hudis C, Winer EP. Randomized phase III trial of paclitaxel once per week compared with nanoparticle albumin-bound nab-paclitaxel once per week or ixabepilone with bevacizumab as first-line chemotherapy for locally recurrent or metastatic breast cancer: CALGB 40502/NCCTG N063H (Alliance). J Clin Oncol. 2015 Jul 20;33(21):2361-9. Epub 2015 Jun 8. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00785291
  5. SAKK 24/09: Rochlitz C, Bigler M, von Moos R, Bernhard J, Matter-Walstra K, Wicki A, Zaman K, Anchisi S, Küng M, Na KJ, Bärtschi D, Borner M, Rordorf T, Rauch D, Müller A, Ruhstaller T, Vetter M, Trojan A, Hasler-Strub U, Cathomas R, Winterhalder R; Swiss Group for Clinical Cancer Research (SAKK). SAKK 24/09: safety and tolerability of bevacizumab plus paclitaxel vs bevacizumab plus metronomic cyclophosphamide and capecitabine as first-line therapy in patients with HER2-negative advanced stage breast cancer - a multicenter, randomized phase III trial. BMC Cancer. 2016 Oct 10;16(1):780. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01131195
  6. MERiDiAN: Miles D, Cameron D, Bondarenko I, Manzyuk L, Alcedo JC, Lopez RI, Im SA, Canon JL, Shparyk Y, Yardley DA, Masuda N, Ro J, Denduluri N, Hubeaux S, Quah C, Bais C, O'Shaughnessy J. Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation. Eur J Cancer. 2017 Jan;70:146-155. Epub 2016 Nov 4. link to original article contains dosing details in abstract PubMed NCT01663727
    1. Update: Miles D, Cameron D, Hilton M, Garcia J, O'Shaughnessy J. Overall survival in MERiDiAN, a double-blind placebo-controlled randomised phase III trial evaluating first-line bevacizumab plus paclitaxel for HER2-negative metastatic breast cancer. Eur J Cancer. 2018 Feb;90:153-155. Epub 2017 Nov 23. link to original article PubMed

Paclitaxel & Vinorelbine

Regimen

Study Dates of enrollment Evidence
Romero Acuña et al. 1999 1995-1997 Phase 2

Chemotherapy

28-day cycles

References

  1. Romero Acuña L, Langhi M, Pérez J, Romero Acuña J, Machiavelli M, Lacava J, Vallejo C, Romero A, Fasce H, Ortiz E, Grasso S, Amato S, Rodríguez R, Barbieri M, Leone B. Vinorelbine and paclitaxel as first-line chemotherapy in metastatic breast cancer. J Clin Oncol. 1999 Jan;17(1):74-81. link to original article contains dosing details in abstract PubMed

nab-Paclitaxel monotherapy

Example orders

Regimen variant #1, 100 mg/m2, 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gradishar et al. 2009 2005-2006 Randomized Phase 2 (E-switch-ic) 1. Docetaxel
2. nab-Paclitaxel; weekly, 150 mg/m2
3. nab-Paclitaxel; q3wk 		Did not meet primary endpoint of ORR

Chemotherapy

28-day cycles


Regimen variant #2, 150 mg/m2 weekly, 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gradishar et al. 2009 2005-2006 Randomized Phase 2 (E-switch-ic) 1. Docetaxel
2. nab-Paclitaxel; weekly, 100 mg/m2
3. nab-Paclitaxel; q3wk 		Did not meet primary endpoint of ORR

Chemotherapy

28-day cycles


Regimen variant #3, 260 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gradishar et al. 2005 (CA012-0) 2001-11 to 2002-11 Phase 3 (E-switch-ic) Paclitaxel; q3wk Superior ORR (primary endpoint)
ORR: 33% vs 19%

Superior TTP (secondary endpoint)
Median TTP: 23 vs 16.9 weeks
(HR 0.75)
Robert et al. 2011 (RIBBON-1) 2005-2007 Phase 3 (C) 1a. AC & Bevacizumab
1b. Capecitabine & Bevacizumab
1c. Docetaxel & Bevacizumab
1d. EC & Bevacizumab
1e. FAC & Bevacizumab
1f. FEC & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Chemotherapy

Supportive therapy

  • CA012-0: No corticosteroid or antihistamine premedication

21-day cycles


Regimen variant #4, 300 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gradishar et al. 2009 2005-2006 Randomized Phase 2 (E-switch-ic) 1. Docetaxel
2. nab-Paclitaxel; weekly, 100 mg/m2
3. nab-Paclitaxel; weekly, 150 mg/m2 		Did not meet primary endpoint of ORR

Chemotherapy

21-day cycles

References

  1. CA012-0: Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. link to original article contains dosing details in manuscript PubMed NCT00046527
  2. Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009 Aug 1;27(22):3611-9. Epub 2009 May 26. Erratum in: J Clin Oncol. 2011 Jul 1;29(19):2739. link to original article contains dosing details in manuscript PubMed
  3. RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains dosing details in manuscript PubMed NCT00262067

Paclitaxel, nanoparticle albumin-bound & Bevacizumab

Example orders

Regimen variant #1, 150 mg/m2, 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Rugo et al. 2015 (CALGB 40502/NCCTG N063H) 2008-2011 Phase 3 (E-switch-ic) 1. Ixabepilone & Bevacizumab Not reported
2. Paclitaxel & Bevacizumab Might have inferior PFS (primary endpoint)

Chemotherapy

Targeted therapy

28-day cycles


Regimen variant #2, 260 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Robert et al. 2011 (RIBBON-1) 2005-2007 Phase 3 (E-esc) 1a. AC
1b. Capecitabine
1c. Docetaxel
1d. EC
1e. FAC
1f. FEC
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
(HR 0.64, 95% CI 0.52-0.80)

Chemotherapy

Targeted therapy

21-day cycles

References

  1. RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains dosing details in manuscript PubMed NCT00262067
  2. CALGB 40502/NCCTG N063H: Rugo HS, Barry WT, Moreno-Aspitia A, Lyss AP, Cirrincione C, Leung E, Mayer EL, Naughton M, Toppmeyer D, Carey LA, Perez EA, Hudis C, Winer EP. Randomized phase III trial of paclitaxel once per week compared with nanoparticle albumin-bound nab-paclitaxel once per week or ixabepilone with bevacizumab as first-line chemotherapy for locally recurrent or metastatic breast cancer: CALGB 40502/NCCTG N063H (Alliance). J Clin Oncol. 2015 Jul 20;33(21):2361-9. Epub 2015 Jun 8. link to original article link to PMC article PubMed NCT00785291

Pemetrexed monotherapy

Regimen variant #1, 500 mg/m2

Study Dates of enrollment Evidence
Gomez et al. 2006 2001-2002 Phase 2

Eligibility criteria

  • Chemotherapy-naïve, with advanced (T4 and N0-N2, M0, M1) breast cancer

Chemotherapy

Supportive therapy

21-day cycle for up to 3 cycles


Regimen variant #2, 600 mg/m2

Study Dates of enrollment Evidence
Robert et al. 2011 2005-2006 Phase 2

Chemotherapy

Supportive therapy

  • Dexamethasone (Decadron) 4 mg PO twice per day on days -1 to 2 (3 days)
  • Folic acid (Folate) 350 to 1000 mcg PO once per day, to start at least 5 days prior to pemetrexed, to continue throughout therapy, and until 3 weeks after the last dose of pemetrexed
  • Cyanocobalamin (Vitamin B12) 1000 mcg IM every 8 to 10 weeks, the first dose given at least 1 week prior to pemetrexed, to continue throughout therapy, and until 3 weeks after the last dose of pemetrexed

14-day cycles

References

  1. Gomez HL, Santillana SL, Vallejos CS, Velarde R, Sanchez J, Wang X, Bauer NL, Hockett RD, Chen VJ, Niyikiza C, Hanauske AR. A phase II trial of pemetrexed in advanced breast cancer: clinical response and association with molecular target expression. Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):832-8. link to original article contains dosing details in manuscript PubMed
  2. Robert NJ, Conkling PR, O'Rourke MA, Kuefler PR, McIntyre KJ, Zhan F, Asmar L, Wang Y, Shonukan OO, O'Shaughnessy JA. Results of a phase II study of pemetrexed as first-line chemotherapy in patients with advanced or metastatic breast cancer. Breast Cancer Res Treat. 2011 Feb;126(1):101-8. Epub 2010 Dec 25. link to original article contains dosing details in manuscript PubMed

S-1 monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Takashima et al. 2015 (SELECT BC) 2006-2010 Phase 3 (E-switch-ic) 1a. Docetaxel
1b. Paclitaxel 		Seems to have non-inferior OS (primary endpoint) Superior EQ-5D score
Mukai et al. 2021 (SELECT BC-CONFIRM) 2011-2013 Phase 3 (E-switch-ic) 1a. AC
1b. FAC
1c. EC
1d. FEC 		Non-inferior OS (primary endpoint)

Chemotherapy

  • Tegafur, gimeracil, oteracil (S-1) by the following BSA-based criteria:
    • Less than 1.25 m2: 40 mg PO twice per day on days 1 to 28
    • 1.25 up to 1.50 m2: 50 mg PO twice per day on days 1 to 28
    • 1.50 m2 or more: 60 mg PO twice per day on days 1 to 28

42-day cycles

References

  1. SELECT BC: Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T, Hozumi Y, Tsurutani J, Imoto S, Watanabe T, Sagara Y, Nishimura R, Shimozuma K, Ohashi Y; SELECT BC Study Group. Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2016 Jan;17(1):90-8. Epub 2015 Nov 27. link to original article contains dosing details in manuscript PubMed UMIN C000000416
    1. HRQoL analysis: Shiroiwa T, Fukuda T, Shimozuma K, Mouri M, Hagiwara Y, Doihara H, Akabane H, Kashiwaba M, Watanabe T, Ohashi Y, Mukai H. Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial. Qual Life Res. 2017 Feb;26(2):445-453. Epub 2016 Aug 12. link to original article link to PMC article PubMed
  2. SELECT BC-CONFIRM: Mukai H, Uemura Y, Akabane H, Watanabe T, Park Y, Takahashi M, Sagara Y, Nishimura R, Takashima T, Fujisawa T, Hozumi Y, Kawahara T. Anthracycline-containing regimens or taxane versus S-1 as first-line chemotherapy for metastatic breast cancer. Br J Cancer. 2021 Oct;125(9):1217-1225. Epub 2021 Sep 3. link to original article contains dosing details in manuscript link to PMC article PubMed UMIN000005449

Capecitabine & Docetaxel (TX)

TX: Taxotere (Docetaxel) & Xeloda (Capecitabine)
CD: Capecitabine & Docetaxel

Regimen variant #1, 1900/75

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Mavroudis et al. 2009 (HORG CT/02.09) 2002-2007 Phase 3 (E-switch-ic) DE Did not meet primary endpoint of TTP

Chemotherapy

21-day cycles


Regimen variant #2, 2000/75, limited duration of docetaxel

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Wang et al. 2015 (ML25241) 2010-2013 Phase 3 (C) NX Inconclusive whether non-inferior PFS

Note: only patients without progression proceeded to the capecitabine maintenance phase.

Chemotherapy

21-day cycles


Regimen variant #3, 2000/75, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Seidman et al. 2010 (B9E-MC-S273) 2002-2008 Phase 3 (E-switch-ic) GD Did not meet primary endpoint of TTP

Chemotherapy

21-day cycles

Subsequent treatment

References

  1. HORG CT/02.09: Mavroudis D, Papakotoulas P, Ardavanis A, Syrigos K, Kakolyris S, Ziras N, Kouroussis C, Malamos N, Polyzos A, Christophyllakis C, Kentepozidis N, Georgoulias V; Hellenic Oncology Research Group. Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer. Ann Oncol. 2010 Jan;21(1):48-54. Epub 2009 Nov 11. link to original article contains dosing details in abstract PubMed NCT00429871
  2. B9E-MC-S273: Seidman AD, Brufsky A, Ansari RH, Hart LL, Stein RS, Schwartzberg LS, Stewart JF, Russell CA, Chen SC, Fein LE, De La Cruz Vargas JA, Kim SB, Cavalheiro J, Zhao L, Gill JF, Obasaju CK, Orlando M, Tai DF. Phase III trial of gemcitabine plus docetaxel versus capecitabine plus docetaxel with planned crossover to the alternate single agent in metastatic breast cancer. Ann Oncol. 2011 May;22(5):1094-101. Epub 2010 Nov 17. link to original article contains dosing details in abstract PubMed NCT00191438
    1. Pooled update: Seidman AD, Chan S, Wang J, Zhu C, Xu C, Xu B. A pooled analysis of gemcitabine plus docetaxel versus capecitabine plus docetaxel in metastatic breast cancer. Oncologist. 2014 May;19(5):443-52. Epub 2014 Apr 4. link to original article link to PMC article PubMed
  3. ML25241: Wang J, Xu B, Yuan P, Ma F, Li Q, Zhang P, Cai R, Fan Y, Luo Y, Li Q. Capecitabine combined with docetaxel versus vinorelbine followed by capecitabine maintenance medication for first-line treatment of patients with advanced breast cancer: phase 3 randomized trial. Cancer. 2015 Oct 1;121(19):3412-21. Epub 2015 Jun 19. link to original article contains dosing details in manuscript PubMed NCT01126138

Epirubicin & Vinorelbine (VE)

VE: Vinorelbine & Epirubicin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ejlertsen et al. 2004 (SBG 9403) 1995-1999 Phase 3 (E-esc) Epirubicin Seems to have superior PFS

Chemotherapy

21-day cycle for up to 18 cycles (1 year)

References

  1. SBG 9403: Ejlertsen B, Mouridsen HT, Langkjer ST, Andersen J, Sjöström J, Kjaer M; Scandinavian Breast Group. Phase III study of intravenous vinorelbine in combination with epirubicin versus epirubicin alone in patients with advanced breast cancer: a Scandinavian Breast Group Trial (SBG9403). J Clin Oncol. 2004 Jun 15;22(12):2313-20. link to original article contains dosing details in abstract PubMed

Metastatic disease, maintenance after first-line therapy

Bevacizumab monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Robert et al. 2011 (RIBBON-1) 2005-2007 Non-randomized part of phase 3 RCT
Miles et al. 2010 (AVADO) 2006-03 to 2007-04 Non-randomized part of phase 3 RCT
Gligorov et al. 2014 (IMELDA) 2009-2011 Phase 3 (C) Capecitabine & Bevacizumab Inferior OS

Preceding treatment

Targeted therapy

21-day cycles

References

  1. AVADO: Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010 Jul 10;28(20):3239-47. Epub 2010 May 24. link to original article contains dosing details in manuscript PubMed NCT00333775
  2. RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains dosing details in manuscript PubMed NCT00262067
  3. IMELDA: Gligorov J, Doval D, Bines J, Alba E, Cortes P, Pierga JY, Gupta V, Costa R, Srock S, de Ducla S, Freudensprung U, Mustacchi G. Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1351-60. Epub 2014 Sep 28. link to original article contains dosing details in abstract PubMed NCT00929240

Capecitabine & Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gligorov et al. 2014 (IMELDA) 2009-2011 Phase 3 (E-esc) Bevacizumab Superior PFS (primary endpoint)
Median PFS: 11.9 vs 4.3 mo
(sHR 0.38, 95% CI 0.27-0.55)

Superior OS (secondary endpoint)
Median OS: 39 vs 23.7 mo
(HR 0.43, 95% CI 0.26-0.69)

Preceding treatment

Chemotherapy

Targeted therapy

21-day cycles

References

  1. IMELDA: Gligorov J, Doval D, Bines J, Alba E, Cortes P, Pierga JY, Gupta V, Costa R, Srock S, de Ducla S, Freudensprung U, Mustacchi G. Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1351-60. Epub 2014 Sep 28. link to original article contains dosing details in abstract PubMed NCT00929240

Gemcitabine & Paclitaxel

GT: Gemcitabine & Taxol (Paclitaxel)
PG: Paclitaxel & Gemcitabine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Park et al. 2013 (KCSG-BR07-02) 2007-2010 Phase 3 (E-esc) Observation Seems to have superior OS (secondary endpoint)
Median OS: 32.3 vs 23.5 mo
(HR 0.65, 95% CI 0.42-0.99)

Preceding treatment

  • First-line PG x 6

Chemotherapy

21-day cycles

References

  1. KCSG-BR07-02: Park YH, Jung KH, Im SA, Sohn JH, Ro J, Ahn JH, Kim SB, Nam BH, Oh DY, Han SW, Lee S, Park IH, Lee KS, Kim JH, Kang SY, Lee MH, Park HS, Ahn JS, Im YH. Phase III, multicenter, randomized trial of maintenance chemotherapy versus observation in patients with metastatic breast cancer after achieving disease control with six cycles of gemcitabine plus paclitaxel as first-line chemotherapy: KCSG-BR07-02. J Clin Oncol. 2013 May 10;31(14):1732-9. Epub 2013 Apr 8. link to original article contains dosing details in manuscript PubMed NCT00561119

Metastatic disease, subsequent lines of chemotherapy

Capecitabine monotherapy

Regimen variant #1, 1000 mg/m2 PO twice per day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Gemcitabine & Bevacizumab
1d. Paclitaxel & Bevacizumab
1e. nab-Paclitaxel & Bevacizumab
1f. Vinorelbine & Bevacizumab 		Inferior PFS
Barrios et al. 2010 (SUN 1107) 2006-2009 Phase 3 (C) Sunitinib Superior PFS (primary endpoint)
Median PFS: 4.2 vs 2.8 mo
(HR 0.68, 95% CI 0.53-0.86)
Baselga et al. 2017 (RESILIENCE) 2010-NR Phase 3 (C) Capecitabine & Sorafenib Did not meet primary endpoint of PFS
Median PFS: 5.4 vs 5.5 mo
(HR 1.03, 95% CI 0.82-1.28)
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

Note: in SUN 1107, this dosage was used for patients older than 65 years. This was the lower bound of dosing in DESTINY-Breast04.

Prior treatment criteria

  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

21-day cycles


Regimen variant #2, 1250 mg/m2 PO twice per day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Blum et al. 1999 (SO14697) 1996 Phase 2 (RT)
Reichardt et al. 2003 1999-2000 Phase 2
Miller et al. 2005 (AVF2119g) 2000-2002 Phase 3 (C) Capecitabine & Bevacizumab Did not meet primary endpoint of PFS
Pallis et al. 2011 (HORG CT/02.11) 2002-2008 Phase 3 (C) Gemcitabine & Vinorelbine Did not meet primary endpoint of PFS
Median PFS: 5.2 vs 5.4 mo
Thomas et al. 2007 (CA163-046) 2003-2006 Phase 3 (C) Capecitabine & Ixabepilone Inferior PFS
Sparano et al. 2010 (CA163-048) 2003-2006 Phase 3 (C) Capecitabine & Ixabepilone Might have inferior OS
Barrios et al. 2010 (SUN 1107) 2006-2009 Phase 3 (C) Sunitinib Superior PFS (primary endpoint)
Median PFS: 4.2 vs 2.8 mo
(HR 0.68, 95% CI 0.53-0.86)
Kaufman et al. 2015 (E7389-G000-301) 2006-2009 Phase 3 (C) Eribulin Might have inferior OS
Crown et al. 2013 (A6181099) 2007-2009 Phase 3 (C) Capecitabine & Sunitinib Might have superior PFS (primary endpoint)
Median PFS: 5.9 vs 5.5 mo
(HR 0.82, 95% CI 0.63-1.05)
Yamamoto et al. 2016 (JO21095) 2008-2010 Non-randomized part of phase 3 RCT
Martin et al. 2018 (L00070 IN 305 B0) 2009-2011 Phase 3 (C) Capecitabine & Vinflunine Seems to have inferior PFS
Park et al. 2018 (PROCEED) 2011-2016 Phase 3 (C) IX Did not meet primary endpoint of PFS
Median PFS: 4.7 vs 6.4 mo
Zhang et al. 2017 (BG01-1323L) 2014-08-08 to 2015-12-14 Phase 3 (C) Capecitabine & Utidelone Seems to have inferior OS1
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

1Reported efficacy for BG01-1323L is based on the 2020 update.
Note: To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm in this context. This was the upper bound of dosing in DESTINY-Breast04.

Prior treatment criteria

  • SO14697: Exposure to paclitaxel and an anthracycline
  • Reichardt et al. 2003: Exposure to a taxane-containing regimen
  • AVF2119g, HORG CT/02.11, CA163-046, CA163-048, SUN 1107, E7389-G000-301, A6181099, L00070 IN 305 B0, PROCEED, BG01-1323L: Exposure to a taxane and an anthracycline
  • JO21095: Exposure to an anthracycline-containing regimen and docetaxel, with PD
  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

21-day cycles

References

  1. SO14697: Blum JL, Jones SE, Buzdar AU, Mucci LoRusso P, Kuter I, Vogel C, Osterwalder B, Burger HU, Stoner Brown C, Griffin T. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol. 1999 Feb;17(2):485-93. link to original article contains dosing details in abstract PubMed
  2. Reichardt P, Von Minckwitz G, Thuss-Patience PC, Jonat W, Kölbl H, Jänicke F, Kieback DG, Kuhn W, Schindler AE, Mohrmann S, Kaufmann M, Lück HJ. Multicenter phase II study of oral capecitabine (Xeloda) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy. Ann Oncol. 2003 Aug;14(8):1227-33. link to original article contains dosing details in abstract PubMed
  3. AVF2119g: Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005 Feb 1;23(4):792-9. link to original article contains dosing details in abstract PubMed NCT00109239
  4. CA163-046: Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. Epub 2007 Oct 29. link to original article contains dosing details in manuscript PubMed NCT00080301
    1. Update: Hortobagyi GN, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Lerzo GL, Pivot XB, Hurtado de Mendoza F, Xu B, Vahdat LT, Peck RA, Mukhopadhyay P, Roché HH. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes. Breast Cancer Res Treat. 2010 Jul;122(2):409-18. Epub 2010 May 8. link to original article PubMed
  5. SUN 1107: Barrios CH, Liu MC, Lee SC, Vanlemmens L, Ferrero JM, Tabei T, Pivot X, Iwata H, Aogi K, Lugo-Quintana R, Harbeck N, Brickman MJ, Zhang K, Kern KA, Martin M. Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer. Breast Cancer Res Treat. 2010 May;121(1):121-31. Epub 2010 Mar 26. link to original article link to PMC article contains dosing details in abstract PubMed
  6. CA163-048: Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010 Jul 10;28(20):3256-63. Epub 2010 Jun 7. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00082433
  7. HORG CT/02.11: Pallis AG, Boukovinas I, Ardavanis A, Varthalitis I, Malamos N, Georgoulias V, Mavroudis D; Hellenic Oncology Research Group. A multicenter randomized phase III trial of vinorelbine/gemcitabine doublet versus capecitabine monotherapy in anthracycline- and taxane-pretreated women with metastatic breast cancer. Ann Oncol. 2012 May;23(5):1164-9. Epub 2011 Sep 21. link to original article contains dosing details in abstract PubMed NCT00431106
  8. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  9. A6181099: Crown JP, Diéras V, Staroslawska E, Yardley DA, Bachelot T, Davidson N, Wildiers H, Fasching PA, Capitain O, Ramos M, Greil R, Cognetti F, Fountzilas G, Blasinska-Morawiec M, Liedtke C, Kreienberg R, Miller WH Jr, Tassell V, Huang X, Paolini J, Kern KA, Romieu G. Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer. J Clin Oncol. 2013 Aug 10;31(23):2870-8. Epub 2013 Jul 15. link to original article contains dosing details in manuscript PubMed NCT00435409
  10. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed
  11. E7389-G000-301: Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, Olivo MS, He Y, Dutcus CE, Cortes J. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015 Feb 20;33(6):594-601. Epub 2015 Jan 20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00337103
  12. JO21095: Yamamoto D, Sato N, Rai Y, Yamamoto Y, Saito M, Iwata H, Masuda N, Oura S, Watanabe J, Hattori S, Matsuura Y, Kuroi K. Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. Breast Cancer Res Treat. 2017 Feb;161(3):473-482. Epub 2016 Dec 22. link to original article contains dosing details in manuscript PubMed
  13. BG01-1323L: Zhang P, Sun T, Zhang Q, Yuan Z, Jiang Z, Wang XJ, Cui S, Teng Y, Hu XC, Yang J, Pan H, Tong Z, Li H, Yao Q, Wang Y, Yin Y, Sun P, Zheng H, Cheng J, Lu J, Zhang B, Geng C, Liu J, Peng R, Yan M, Zhang S, Huang J, Tang L, Qiu R, Xu B; BG01-1323L study group. Utidelone plus capecitabine versus capecitabine alone for heavily pretreated metastatic breast cancer refractory to anthracyclines and taxanes: a multicentre, open-label, superiority, phase 3, randomised controlled trial. Lancet Oncol. 2017 Mar;18(3):371-383. Epub 2017 Feb 11. link to original article contains dosing details in abstract PubMed NCT02253459
    1. Update: Xu B, Sun T, Zhang Q, Zhang P, Yuan Z, Jiang Z, Wang X, Cui S, Teng Y, Hu XC, Yang J, Pan H, Tong Z, Li H, Yao Q, Wang Y, Yin Y, Sun P, Zheng H, Cheng J, Lu J, Zhang B, Geng C, Liu J, Shen K, Yu S, Li H, Tang L, Qiu R; study group of BG01-1323L. Efficacy of utidelone plus capecitabine versus capecitabine for heavily pretreated, anthracycline- and taxane-refractory metastatic breast cancer: final analysis of overall survival in a phase III randomised controlled trial. Ann Oncol. 2021 Feb;32(2):218-228. Epub 2020 Nov 11. link to original article PubMed
  14. RESILIENCE: Baselga J, Zamagni C, Gómez P, Bermejo B, Nagai SE, Melichar B, Chan A, Mángel L, Bergh J, Costa F, Gómez HL, Gradishar WJ, Hudis CA, Rapoport BL, Roché H, Maeda P, Huang L, Meinhardt G, Zhang J, Schwartzberg LS. RESILIENCE: phase III randomized, double-blind trial comparing sorafenib with capecitabine versus placebo with capecitabine in locally advanced or metastatic HER2-negative breast cancer. Clin Breast Cancer. 2017 Dec;17(8):585-594.e4. Epub 2017 May 22. link to original article contains dosing details in abstract link to PMC article PubMed NCT01234337
  15. PROCEED: Park IH, Im SA, Jung KH, Sohn JH, Park YH, Lee KS, Sim SH, Park KH, Kim JH, Nam BH, Kim HJ, Kim TY, Lee KH, Kim SB, Ahn JH, Lee S, Ro J. Randomized open label phase III trial of irinotecan plus capecitabine versus capecitabine monotherapy in patients with metastatic breast cancer previously treated with anthracycline and taxane: PROCEED trial (KCSG BR 11-01). Cancer Res Treat. 2019 Jan;51(1):43-52. Epub 2018 Feb 14. link to original article contains dosing details in abstract link to PMC article PubMed NCT01501669
  16. L00070 IN 305 B0: Martin M, Campone M, Bondarenko I, Sakaeva D, Krishnamurthy S, Roman L, Lebedeva L, Vedovato JC, Aapro M. Randomised phase III trial of vinflunine plus capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with an anthracycline and resistant to taxane. Ann Oncol. 2018 May 1;29(5):1195-1202. link to original article contains dosing details in abstract PubMed NCT01095003
  17. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029
  18. EVER-132-002: NCT04639986

Capecitabine & Bevacizumab

Regimen variant #1, 2000/15

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Gemcitabine
1d. Paclitaxel
1e. nab-Paclitaxel
1f. Vinorelbine 		Superior PFS (primary endpoint)
Median PFS: 7.2 vs 5.1 mo
(HR 0.78, 95% CI 0.64-0.93)
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Chemotherapy

Targeted therapy

21-day cycles


Regimen variant #2, 2500/15

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Miller et al. 2005 (AVF2119g) 2000-2002 Phase 3 (E-esc) Capecitabine Did not meet primary endpoint of PFS
Median PFS: 4.86 vs 4.17 mo
(HR 0.98, 95% CI 0.77-1.25)

Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.

Prior treatment criteria

  • Prior therapy with both an anthracycline and a taxane, and 1 to 2 prior chemotherapy regimens for metastatic disease

Chemotherapy

Targeted therapy

21-day cycles

References

  1. AVF2119g: Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005 Feb 1;23(4):792-9. link to original article contains dosing details in abstract PubMed NCT00109239
  2. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  3. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Capecitabine & Docetaxel (TX)

TX: Taxotere (Docetaxel) & Xeloda (Capecitabine)
XT: Xeloda (Capecitabine) & Taxotere (Docetaxel)
DC: Docetaxel & Capecitabine
CD: Capecitabine & Docetaxel

Regimen variant #1, 825/60

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yamamoto et al. 2016 (JO21095) 2008-2010 Phase 3 (E-esc) Docetaxel Seems to have superior PFS (primary endpoint)
Median PFS: 10.5 vs 9.8 mo
(HR 0.62, 95% CI 0.40-0.97)

Chemotherapy

21-day cycles


Regimen variant #2, 1250/75

Study Dates of enrollment Evidence Comparator Comparative Efficacy
O'Shaughnessy et al. 2002 (SO14999) NR Phase 3 (E-RT-esc) Docetaxel Superior TTP (primary endpoint)
Median TTP: 6.1 vs 4.2 mo
(HR 0.65, 95% CI 0.545-0.78)

Superior OS1 (secondary endpoint)
Median OS: 14.5 vs 11.5 mo
(HR 0.78, 95% CI 0.645-0.94)
Chan et al. 2009 (B9E-US-S188) 2002-2004 Phase 3 (C) GD Did not meet primary endpoint of PFS

1Reported efficacy for SO14999 is based on the 2004 update.

Chemotherapy

21-day cycles

References

  1. SO14999: O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. link to original article contains dosing details in manuscript PubMed
    1. Update: Miles D, Vukelja S, Moiseyenko V, Cervantes G, Mauriac L, Van Hazel G, Lui WY, Ayoub JP, O'Shaughnessy JA. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Clin Breast Cancer. 2004 Oct;5(4):273-8. link to original article PubMed
  2. B9E-US-S188: Chan S, Romieu G, Huober J, Delozier T, Tubiana-Hulin M, Schneeweiss A, Lluch A, Llombart A, du Bois A, Kreienberg R, Mayordomo JI, Antón A, Harrison M, Jones A, Carrasco E, Vaury AT, Frimodt-Moller B, Fumoleau P. Phase III study of gemcitabine plus docetaxel compared with capecitabine plus docetaxel for anthracycline-pretreated patients with metastatic breast cancer. J Clin Oncol. 2009 Apr 10;27(11):1753-60. Epub 2009 Mar 9. link to original article contains dosing details in abstract PubMed NCT00191152
    1. Pooled update: Seidman AD, Chan S, Wang J, Zhu C, Xu C, Xu B. A pooled analysis of gemcitabine plus docetaxel versus capecitabine plus docetaxel in metastatic breast cancer. Oncologist. 2014 May;19(5):443-52. Epub 2014 Apr 4. link to original article link to PMC article PubMed
  3. JO21095: Yamamoto D, Sato N, Rai Y, Yamamoto Y, Saito M, Iwata H, Masuda N, Oura S, Watanabe J, Hattori S, Matsuura Y, Kuroi K. Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. Breast Cancer Res Treat. 2017 Feb;161(3):473-482. Epub 2016 Dec 22. link to original article contains dosing details in manuscript PubMed

Capecitabine & Ixabepilone

XI: Xeloda (Capecitabine) & Ixabepilone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Thomas et al. 2007 (CA163-046) 2003-2006 Phase 3 (E-RT-esc) Capecitabine Superior PFS (primary endpoint)
Median PFS: 5.8 vs 4.2 mo
(HR 0.75, 95% CI 0.64-0.88)
Sparano et al. 2010 (CA163-048) 2003-2006 Phase 3 (E-RT-esc) Capecitabine Might have superior OS (primary endpoint)
Median OS: 16.4 vs 15.6 mo
(HR 0.90, 95% CI 0.78-1.03)

Chemotherapy

21-day cycles

References

  1. CA163-046: Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. Epub 2007 Oct 29. link to original article contains dosing details in manuscript PubMed NCT00080301
    1. Update: Hortobagyi GN, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Lerzo GL, Pivot XB, Hurtado de Mendoza F, Xu B, Vahdat LT, Peck RA, Mukhopadhyay P, Roché HH. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes. Breast Cancer Res Treat. 2010 Jul;122(2):409-18. Epub 2010 May 8. link to original article PubMed
  2. CA163-048: Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010 Jul 10;28(20):3256-63. Epub 2010 Jun 7. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00082433

Capecitabine & Vinflunine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Martin et al. 2018 (L00070 IN 305 B0) 2009-2011 Phase 3 (E-esc) Capecitabine Seems to have superior PFS (primary endpoint)
Median PFS: 5.6 vs 4.3 mo
(HR 0.84, 95% CI 0.71-0.99)

Chemotherapy

21-day cycles

References

  1. L00070 IN 305 B0: Martin M, Campone M, Bondarenko I, Sakaeva D, Krishnamurthy S, Roman L, Lebedeva L, Vedovato JC, Aapro M. Randomised phase III trial of vinflunine plus capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with an anthracycline and resistant to taxane. Ann Oncol. 2018 May 1;29(5):1195-1202. link to original article contains dosing details in manuscript PubMed NCT01095003

Carboplatin & Gemcitabine (GCb)

Regimen

Study Dates of enrollment Evidence
Nagourney et al. 2008 2002-2005 Pilot, less than 20 pts

Chemotherapy

21-day cycles until CR or indefinitely

References

  1. Nagourney RA, Flam M, Link J, Hager S, Blitzer J, Lyons W, Sommers BL, Evans S. Carboplatin plus gemcitabine repeating doublet therapy in recurrent breast cancer. Clin Breast Cancer. 2008 Oct;8(5):432-5. link to original article contains dosing details in abstract PubMed

Cisplatin & Vinorelbine (CVb)

CVb: Cisplatin & Vinorelbine

Regimen

Study Dates of enrollment Evidence
Ray-Coquard et al. 1998 1992-1994 Phase 2
Vassilomanolakis et al. 2000 NR Phase 2

Chemotherapy

Supportive therapy

  • Normal saline 200 mL bolus after vinorelbine to prevent phlebitis
  • Normal saline 2000 mL with KCl (unspecified amount of KCl) IV over 4 hours once on day 1, prior to cisplatin
  • Furosemide (Lasix) 40 mg IV once on day 1; 20 minutes prior to cisplatin
  • Normal saline 1000 mL and D5W 1000 mL IV over 4 hours once on day 1, after cisplatin
    • Paper did not say whether fluids were given sequentially or concurrently
  • 5-HT3 antagonists used

21-day cycle for up to 6 cycles

References

  1. Ray-Coquard I, Biron P, Bachelot T, Guastalla JP, Catimel G, Merrouche Y, Droz JP, Chauvin F, Blay JY. Vinorelbine and cisplatin (CIVIC regimen) for the treatment of metastatic breast carcinoma after failure of anthracycline- and/or paclitaxel-containing regimens. Cancer. 1998 Jan 1;82(1):134-40. link to original article PubMed
  2. Vassilomanolakis M, Koumakis G, Barbounis V, Demiri M, Pateras H, Efremidis AP. Vinorelbine and cisplatin in metastatic breast cancer patients previously treated with anthracyclines. Ann Oncol. 2000 Sep;11(9):1155-60. link to original article contains dosing details in manuscript PubMed

Cyclophosphamide & Methotrexate (CM)

CM: Cyclophosphamide & Methotrexate

Regimen variant #1

Study Dates of enrollment Evidence
Colleoni et al. 2002 1997-2000 Non-randomized

Chemotherapy

7-day cycles


Regimen variant #2, metronomic

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Colleoni et al. 2005 2000-2003 Randomized (C) CM & Thalidomide Did not meet primary endpoint of percent reduction in VEGF after 2 months of treatment

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

7-day cycles

References

  1. Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nolè F, Peruzzotti G, Robertson C, Orlando L, Cinieri S, de Braud F, Viale G, Goldhirsch A. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol. 2002 Jan;13(1):73-80. link to original article contains dosing details in manuscript PubMed
  2. Colleoni M, Orlando L, Sanna G, Rocca A, Maisonneuve P, Peruzzotti G, Ghisini R, Sandri MT, Zorzino L, Nolè F, Viale G, Goldhirsch A. Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann Oncol. 2006 Feb;17(2):232-8. Epub 2005 Dec 1. link to original article contains dosing details in abstract PubMed

Cyclophosphamide monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cortes et al. 2018 (L00070 IN 308 B0) 2009-2011 Phase 3 (C) Vinflunine Did not meet primary endpoint of OS
Median OS: 9.3 vs 9.1 mo
(HR 0.96)

Note: this was the most commonly used comparator arm; doses were not provided in the manuscript or CT.gov.

Chemotherapy

References

  1. L00070 IN 308 B0: Cortes J, Perez-Garcia J, Levy C, Gómez Pardo P, Bourgeois H, Spazzapan S, Martínez-Jañez N, Chao TC, Espié M, Nabholtz JM, Gonzàlez Farré X, Beliakouski V, Román García J, Holgado E, Campone M. Open-label randomised phase III trial of vinflunine versus an alkylating agent in patients with heavily pretreated metastatic breast cancer. Ann Oncol. 2018 Apr 1;29(4):881-887. link to original article does not contain dosing details PubMed NCT01091168

Docetaxel monotherapy

D: Docetaxel
T: Taxotere (Docetaxel)

Regimen variant #1, 40 mg/m2 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Rivera et al. 2008 2001-2004 Phase 3 (E-switch-ic), less than 20 pts in this subgroup Docetaxel; q3wk Did not meet primary endpoint of ORR Superior toxicity

Chemotherapy

  • Docetaxel (Taxotere) as follows:
    • Cycle 1: 35 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
    • Cycle 2 onwards: 40 mg/m2 IV over 30 minutes once per day on days 1, 8, 15

28-day cycles


Regimen variant #2, 40 mg/m2 6 weeks out of 8

Study Dates of enrollment Evidence
Burstein et al. 2000 1998 Phase 2

Chemotherapy

8-week cycles


Regimen variant #3, 60 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Adachi et al. 1996 1993 Phase 2
Harvey et al. 2006 (TAX 313) 1995-2001 Phase 3 (E-RT-de-esc) 1. Docetaxel; 75 mg/m2 q3wk Might have inferior TTP (secondary endpoint)
2. Docetaxel; 100 mg/m2 q3wk Might have inferior TTP (secondary endpoint)
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: this is the dosage used for Japanese patients; Adachi et al. 1996 reported 21- to 28-day cycles

Chemotherapy

21-day cycles


Regimen variant #4, 70 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yamamoto et al. 2016 (JO21095) 2008-2010 Phase 3 (C) TX Seems to have inferior OS

Chemotherapy

21-day cycles

Subsequent treatment


Regimen variant #5, 75 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Harvey et al. 2006 (TAX 313) 1995-2001 Phase 3 (E-RT-esc) 1. Docetaxel; 60 mg/m2 q3wk Might have superior TTP (secondary endpoint)

Superior ORR (primary endpoint)
2. Docetaxel; 100 mg/m2 q3wk Might have inferior TTP (secondary endpoint)
Rivera et al. 2008 2001-2004 Phase 3 (C), less than 20 pts in this subgroup Docetaxel; weekly Did not meet primary endpoint of ORR Inferior toxicity
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Gemcitabine & Bevacizumab
1d. Paclitaxel & Bevacizumab
1e. nab-Paclitaxel & Bevacizumab
1f. Vinorelbine & Bevacizumab 		Inferior PFS
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: This is the lower end of the range of docetaxel dosing described in TANIA.

Chemotherapy

21-day cycles

Dose and schedule modifications

  • Rivera et al. 2008 gave 75 mg/m2 in cycle 1, with escalation to 100 mg/m2 depending on toxicity


Regimen variant #6, 100 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
ten Bokkel Huinink et al. 1994 NR Phase 2
Nabholtz et al. 1999 (TAX 304) NR Phase 3 (E-RT-de-esc) Mitomycin & Vinblastine (MV) Superior OS
Chan et al. 1999 (TAX 303) 1994-1997 Phase 3 (E-RT-switch-ic) Doxorubicin Did not meet primary endpoint of TTP50%

Superior ORR (secondary endpoint)
Sjöström et al. 1999 1994-1997 Phase 3 (E-de-esc) MF Superior TTP
O'Shaughnessy et al. 2002 (SO14999) NR Phase 3 (C) TX Inferior OS1
Jones et al. 2005 (TAX 311) 1994-2001 Phase 3 (E-switch-ic) Paclitaxel Superior OS (secondary endpoint)
Median OS: 15.4 vs 12.7 mo
(HR 0.71, 95% CI 0.58-0.87)
Bonneterre et al. 2002 1995-1997 Phase 3 (E-de-esc) 5-FU & Vinorelbine Did not meet primary endpoint of TTP Less toxic
Harvey et al. 2006 (TAX 313) 1995-2001 Phase 3 (E-RT-esc) 1. Docetaxel; 60 mg/m2 q3wk Might have superior TTP (secondary endpoint)

Superior ORR (primary endpoint)
2. Docetaxel; 75 mg/m2 q3wk Might have superior TTP (secondary endpoint)

Superior ORR (primary endpoint)
Nielsen et al. 2011 2001-2005 Phase 3 (C) Docetaxel & Gemcitabine Might have inferior TTP
Schröder et al. 2011 2001-2006 Phase 3 (C) Docetaxel; weekly Seems to have superior OS
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Gemcitabine & Bevacizumab
1d. Paclitaxel & Bevacizumab
1e. nab-Paclitaxel & Bevacizumab
1f. Vinorelbine & Bevacizumab 		Inferior PFS
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

1Reported efficacy for SO14999 is based on the 2004 update.
Note: this was the upper end of the range of docetaxel dosing described in TANIA. TAX 304 stopped treatment after 10 cycles. TAX 303 stopped treatment after 7 cycles.

Chemotherapy

21-day cycles (see note)

References

  1. ten Bokkel Huinink WW, Prove AM, Piccart M, Steward W, Tursz T, Wanders J, Franklin H, Clavel M, Verweij J, Alakl M, Bayssas M, Kaye SB; EORTC Early Clinical Trials Group. A phase II trial with docetaxel (Taxotere) in second line treatment with chemotherapy for advanced breast cancer: a study of the EORTC Early Clinical Trials Group. Ann Oncol. 1994 Jul;5(6):527-32. link to original article contains dosing details in abstract PubMed
  2. Adachi I, Watanabe T, Takashima S, Narabayashi M, Horikoshi N, Aoyama H, Taguchi T. A late phase II study of RP56976 (docetaxel) in patients with advanced or recurrent breast cancer. Br J Cancer. 1996 Jan;73(2):210-6. link to original article link to PMC article contains dosing details in abstract PubMed
  3. TAX 304: Nabholtz JM, Senn HJ, Bezwoda WR, Melnychuk D, Deschênes L, Douma J, Vandenberg TA, Rapoport B, Rosso R, Trillet-Lenoir V, Drbal J, Molino A, Nortier JW, Richel DJ, Nagykalnai T, Siedlecki P, Wilking N, Genot JY, Hupperets PS, Pannuti F, Skarlos D, Tomiak EM, Murawsky M, Alakl M, Aapro M; 304 Study Group. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. J Clin Oncol. 1999 May;17(5):1413-24. link to original article contains dosing details in abstract PubMed
  4. Review: Burris HA 3rd. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin Oncol. 1999 Jun;26(3 Suppl 9):1-6. PubMed
  5. TAX 303: Chan S, Friedrichs K, Noel D, Pintér T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, González Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J; 303 Study Group. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2341-54. link to original article PubMed
  6. Sjöström J, Blomqvist C, Mouridsen H, Pluzanska A, Ottosson-Lönn S, Bengtsson NO, Ostenstad B, Mjaaland I, Palm-Sjövall M, Wist E, Valvere V, Anderson H, Bergh J; Scandinavian Breast Group. Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: a randomised phase III study with crossover on progression by the Scandinavian Breast Group. Eur J Cancer. 1999 Aug;35(8):1194-201. link to original article contains dosing details in abstract PubMed
  7. SO14999: O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. link to original article contains dosing details in manuscript PubMed
    1. Update: Miles D, Vukelja S, Moiseyenko V, Cervantes G, Mauriac L, Van Hazel G, Lui WY, Ayoub JP, O'Shaughnessy JA. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Clin Breast Cancer. 2004 Oct;5(4):273-8. link to original article PubMed
  8. Bonneterre J, Roché H, Monnier A, Guastalla JP, Namer M, Fargeot P, Assadourian S. Docetaxel vs 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure. Br J Cancer. 2002 Nov 18;87(11):1210-5. link to original article contains dosing details in abstract link to PMC article PubMed
  9. TAX 311: Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, Laufman L, Sundaram S, Urba WJ, Pritchard KI, Mennel R, Richards D, Olsen S, Meyers ML, Ravdin PM. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005 Aug 20;23(24):5542-51. link to original article contains dosing details in abstract PubMed NCT00002662
  10. TAX 313: Harvey V, Mouridsen H, Semiglazov V, Jakobsen E, Voznyi E, Robinson BA, Groult V, Murawsky M, Cold S. Phase III trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol. 2006 Nov 1;24(31):4963-70. Epub 2006 Oct 10. link to original article PubMed
  11. Rivera E, Mejia JA, Arun BK, Adinin RB, Walters RS, Brewster A, Broglio KR, Yin G, Esmaeli B, Hortobagyi GN, Valero V. Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic breast cancer. Cancer. 2008 Apr 1;112(7):1455-61. link to original article contains dosing details in manuscript PubMed
  12. Schröder CP, de Munck L, Westermann AM, Smit WM, Creemers GJ, de Graaf H, Stouthard JM, van Deijk G, Erjavec Z, van Bochove A, Vader W, Willemse PH. Weekly docetaxel in metastatic breast cancer patients: no superior benefits compared to three-weekly docetaxel. Eur J Cancer. 2011 Jun;47(9):1355-62. Epub 2011 Jan 19. link to original article PubMed
  13. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  14. Nielsen DL, Bjerre KD, Jakobsen EH, Cold S, Stenbygaard L, Sørensen PG, Kamby C, Møller S, Jørgensen CL, Andersson M; Danish Breast Cancer Cooperative Group. Gemcitabine plus docetaxel versus docetaxel in patients with predominantly human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: a randomized, phase III study by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 2011 Dec 20;29(36):4748-54. Epub 2011 Nov 14. link to original article contains dosing details in abstract PubMed
  15. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed
  16. JO21095: Yamamoto D, Sato N, Rai Y, Yamamoto Y, Saito M, Iwata H, Masuda N, Oura S, Watanabe J, Hattori S, Matsuura Y, Kuroi K. Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. Breast Cancer Res Treat. 2017 Feb;161(3):473-482. Epub 2016 Dec 22. link to original article contains dosing details in manuscript PubMed

Docetaxel & Bevacizumab

Regimen variant #1, docetaxel 60 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the dosage used for Japanese patients.

Chemotherapy

Targeted therapy

21-day cycles


Regimen variant #2, docetaxel 75 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Gemcitabine
1d. Paclitaxel
1e. nab-Paclitaxel
1f. Vinorelbine 		Superior PFS (primary endpoint)
Median PFS: 7.2 vs 5.1 mo
(HR 0.78, 95% CI 0.64-0.93)
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the lower end of the range of docetaxel dosing described in TANIA.

Chemotherapy

Targeted therapy

21-day cycles


Regimen variant #3, docetaxel 100 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Gemcitabine
1d. Paclitaxel
1e. nab-Paclitaxel
1f. Vinorelbine 		Superior PFS (primary endpoint)
Median PFS: 7.2 vs 5.1 mo
(HR 0.78, 95% CI 0.64-0.93)
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the upper end of the range of docetaxel dosing described in TANIA.

Chemotherapy

Targeted therapy

21-day cycles

References

  1. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  2. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Docetaxel & Gemcitabine

DG: Docetaxel & Gemcitabine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tomova et al. 2010 2002-09 to 2006-03 Phase 3 (C) D-G Did not meet primary endpoint of TTP

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

21-day cycle for 8 cycles

References

  1. Tomova A, Bartsch R, Brodowicz T, Tzekova V, Timcheva C, Wiltschke C, Gerges DA, Pawlega J, Spanik S, Inbar M, Zielinski CC. Concomitant docetaxel plus gemcitabine versus sequential docetaxel followed by gemcitabine in anthracycline-pretreated metastatic or locally recurrent inoperable breast cancer patients: a prospective multicentre trial of the Central European Cooperative Oncology Group (CECOG). Breast Cancer Res Treat. 2010 Jan;119(1):169-76. link to original article contains dosing details in abstract PubMed

Doxorubicin monotherapy

Regimen variant #1, 20 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: this is the lower end of the range of weekly doxorubicin dosing described in TANIA.

Chemotherapy

7-day cycles


Regimen variant #2, 25 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: this is the higher end of the range of weekly doxorubicin dosing described in TANIA.

Chemotherapy

7-day cycles


Regimen variant #3, 60 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cowan et al. 1991 (SWOG S8203) 1983-1986 Phase 3 (E-switch-ic) 1. Bisantrene
2. Mitoxantrone 		Seems to have superior OS
Norris et al. 2000 (NCIC-CTG MA.8) 1992-1995 Phase 3 (C) NA Did not meet primary endpoint of OS
Reyno et al. 2004 (NCIC CT MA.19) 1998-1999 Phase 3 (C) Doxorubicin & Tesmilifene Did not meet primary endpoint of PFS
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: in NCIC-CTG MA.8, this dose was after a mid-protocol amendment. Treatment in NCIC-CTG MA.8 & MA.19 was given until a cumulative dose of 450 mg/m2. This is the lower end of the range of q3wk doxorubicin dosing described in TANIA.

Chemotherapy

21-day cycles (see note)


Regimen variant #4, 75 mg/m2 q3wk, limited duration

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Chan et al. 1999 (TAX 303) 1994-1997 Phase 3 (C) Docetaxel Did not meet primary endpoint of TTP50%

Chemotherapy

21-day cycle for up to 7 cycles


Regimen variant #5, 75 mg/m2 q3wk, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bontenbal et al. 1998 (EORTC 10811) 1982-1986 Phase 3 (C) Epirubicin Did not meet primary endpoint of ORR
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: this is the higher end of the range of q3wk doxorubicin dosing described in TANIA.

Chemotherapy

21-day cycles

References

  1. SWOG S8203: Cowan JD, Neidhart J, McClure S, Coltman CA Jr, Gumbart C, Martino S, Hutchins LF, Stephens RL, Vaughan CB, Osborne CK. Randomized trial of doxorubicin, bisantrene, and mitoxantrone in advanced breast cancer: a Southwest Oncology Group study. J Natl Cancer Inst. 1991 Aug 7;83(15):1077-84. link to original article contains dosing details in abstract PubMed
  2. EORTC 10811: Bontenbal M, Andersson M, Wildiers J, Cocconi G, Jassem J, Paridaens R, Rotmensz N, Sylvester R, Mouridsen HT, Klijn JG, van Oosterom AT; EORTC Breast Cancer Cooperative Group. Doxorubicin vs epirubicin, report of a second-line randomized phase II/III study in advanced breast cancer. Br J Cancer. 1998 Jun;77(12):2257-63. link to original article link to PMC article contains dosing details in abstract PubMed
  3. TAX 303: Chan S, Friedrichs K, Noel D, Pintér T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, González Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J; 303 Study Group. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2341-54. link to original article PubMed
  4. NCIC-CTG MA.8: Norris B, Pritchard KI, James K, Myles J, Bennett K, Marlin S, Skillings J, Findlay B, Vandenberg T, Goss P, Latreille J, Rudinskas L, Lofters W, Trudeau M, Osoba D, Rodgers A. Phase III comparative study of vinorelbine combined with doxorubicin versus doxorubicin alone in disseminated metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group study MA8. J Clin Oncol. 2000 Jun;18(12):2385-94. link to original article contains dosing details in abstract PubMed
  5. NCIC CT MA.19: Reyno L, Seymour L, Tu D, Dent S, Gelmon K, Walley B, Pluzanska A, Gorbunova V, Garin A, Jassem J, Pienkowski T, Dancey J, Pearce L, MacNeil M, Marlin S, Lebwohl D, Voi M, Pritchard K; National Cancer Institute of Canada Clinical Trials Group. Phase III study of N,N-diethyl-2-[4-(phenylmethyl) phenoxy]ethanamine (BMS-217380-01) combined with doxorubicin versus doxorubicin alone in metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group Study MA.19. J Clin Oncol. 2004 Jan 15;22(2):269-76. link to original article PubMed
  6. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Doxorubicin & Bevacizumab

Regimen variant #1, doxorubicin 20 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the lower end of the range of weekly doxorubicin dosing described in TANIA.

Chemotherapy

Targeted therapy

28-day cycles


Regimen variant #2, doxorubicin 25 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the higher end of the range of weekly doxorubicin dosing described in TANIA.

Chemotherapy

Targeted therapy

28-day cycles


Regimen variant #3, doxorubicin 60 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the lower end of the range of q3wk doxorubicin dosing described in TANIA.

Chemotherapy

Targeted therapy

21-day cycles


Regimen variant #4, doxorubicin 75 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the higher end of the range of q3wk doxorubicin dosing described in TANIA.

Chemotherapy

Targeted therapy

21-day cycles

References

  1. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Eribulin monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cortes et al. 2011 (EMBRACE) 2006-2008 Phase 3 (E-RT-switch-ic) Investigator's choice Seems to have superior OS (primary endpoint)
Median OS: 13.1 vs 10.6 mo
(HR 0.81, 95% CI 0.66-0.99)
Kaufman et al. 2015 (E7389-G000-301) 2006-2009 Phase 3 (E-switch-ic) Capecitabine Seems to have superior OS (co-primary endpoint)
Median OS: 15.9 vs 14.5 mo
(HR 0.88, 95% CI 0.77-1.00)
Perez et al. 2015 (BEACONbrca) 2011-2013 Phase 3 (C) Etirinotecan pegol Might have inferior OS
Yuan et al. 2019 (E7389-C086-304) 2013-2015 Phase 3 (E-switch-ic) Vinorelbine Seems to have superior PFS (primary endpoint)
Median PFS: 2.8 vs 2.8 mo
(HR 0.80, 95% CI 0.65-0.98)
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

Note: BEACON should not be confused for the trial by the same name in several other cancer types. This dosing is the one commonly used in North America.

Prior treatment criteria

  • EMBRACE: Exposure to between two and five lines of chemotherapy (two or more for advanced disease), including an anthracycline and a taxane, unless these were contraindicated
  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

21-day cycles

References

  1. EMBRACE: Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Diéras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389) investigators. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011 Mar 12;377(9769):914-23. Epub 2011 Mar 2. link to original article contains dosing details in abstract PubMed NCT00388726
  2. E7389-G000-301: Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, Olivo MS, He Y, Dutcus CE, Cortes J. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015 Feb 20;33(6):594-601. Epub 2015 Jan 20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00337103
  3. BEACONbrca: Perez EA, Awada A, O'Shaughnessy J, Rugo HS, Twelves C, Im SA, Gómez-Pardo P, Schwartzberg LS, Diéras V, Yardley DA, Potter DA, Mailliez A, Moreno-Aspitia A, Ahn JS, Zhao C, Hoch U, Tagliaferri M, Hannah AL, Cortes J. Etirinotecan pegol (NKTR-102) versus treatment of physician's choice in women with advanced breast cancer previously treated with an anthracycline, a taxane, and capecitabine (BEACON): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1556-1568. Epub 2015 Oct 22. link to original article PubMed NCT01492101
  4. E7389-C086-304: Yuan P, Hu X, Sun T, Li W, Zhang Q, Cui S, Cheng Y, Ouyang Q, Wang X, Chen Z, Hiraiwa M, Saito K, Funasaka S, Xu B. Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial. Eur J Cancer. 2019 May;112:57-65. Epub 2019 Mar 29. link to original article contains dosing details in abstract PubMed NCT02225470
  5. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029
  6. EVER-132-002: NCT04639986

Gemcitabine monotherapy

Regimen variant #1, 800 mg/m2 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Carmichael et al. 1995 NR Phase 2
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

Note: this was the lower bound of dosing in DESTINY-Breast04.

Prior treatment criteria

  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

28-day cycles


Regimen variant #2, 1000 mg/m2 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Chemotherapy

28-day cycles


Regimen variant #3, 1200 mg/m2 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Spielmann et al. 2001 NR Phase 2
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

Note: this was the upper bound of dosing in DESTINY-Breast04.

Prior treatment criteria

  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

28-day cycles


Regimen variant #4, 1250 mg/m2 2 weeks out of 3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Gemcitabine & Bevacizumab
1d. Paclitaxel & Bevacizumab
1e. nab-Paclitaxel & Bevacizumab
1f. Vinorelbine & Bevacizumab 		Inferior PFS
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Chemotherapy

21-day cycles

References

  1. Carmichael J, Possinger K, Philip P, Beykirch M, Kerr H, Walling J, Harris AL. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol. 1995 Nov;13(11):2731-6. link to original article contains dosing details in abstract PubMed
  2. Spielmann M, Llombart-Cussac A, Kalla S, Espié M, Namer M, Ferrero JM, Diéras V, Fumoleau P, Cuvier C, Perrocheau G, Ponzio A, Kayitalire L, Pouillart P. Single-agent gemcitabine is active in previously treated metastatic breast cancer. Oncology. 2001;60(4):303-7. link to original article PubMed
  3. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  4. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed
  5. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029
  6. EVER-132-002: NCT04639986

Gemcitabine & Bevacizumab

Regimen variant #1, 1000 mg/m2, 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Chemotherapy

Targeted therapy

28-day cycles


Regimen variant #2, 1250 mg/m2, 2 weeks out of 3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Gemcitabine
1d. Paclitaxel
1e. nab-Paclitaxel
1f. Vinorelbine 		Superior PFS (primary endpoint)
Median PFS: 7.2 vs 5.1 mo
(HR 0.78, 95% CI 0.64-0.93)
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Chemotherapy

Targeted therapy

21-day cycles

References

  1. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  2. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Ixabepilone monotherapy

Regimen

Study Dates of enrollment Evidence
Perez et al. 2007 (CA163-081) 2004-2005 Phase 2 (RT)

Chemotherapy

21-day cycle for up to 18 cycles

References

  1. CA163-081: Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, Viens P, Cai C, Mullaney B, Peck R, Hortobagyi GN. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007 Aug 10;25(23):3407-14. Epub 2007 Jul 2. link to original article contains dosing details in manuscript PubMed NCT00080262

Non-pegylated liposomal doxorubicin monotherapy

NPLD: Non-Pegylated Liposomal Doxorubicin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Chemotherapy

21-day cycles

References

  1. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Non-pegylated liposomal doxorubicin & Bevacizumab

NPLD & Bev: Non-Pegylated Liposomal Doxorubicin & Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Chemotherapy

Targeted therapy

21-day cycles

References

  1. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Paclitaxel monotherapy, weekly

Regimen variant #1, 80 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Perez et al. 2001 NR Phase 2
Seidman et al. 2008 (CALGB 9840) 1998-NR Phase 3 (E-switch-ic) Paclitaxel; q3wk Superior OS (secondary endpoint)
Median OS: 24 vs 12 mo
(HR 0.78, 95% CI 0.65-0.94)
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

Prior treatment criteria

  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

28-day cycles


Regimen variant #2, 90 mg/m2 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Gemcitabine & Bevacizumab
1d. Paclitaxel & Bevacizumab
1e. nab-Paclitaxel & Bevacizumab
1f. Vinorelbine & Bevacizumab 		Inferior PFS

Chemotherapy

28-day cycles

References

  1. Perez EA, Vogel CL, Irwin DH, Kirshner JJ, Patel R. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2001 Nov 15;19(22):4216-23. link to original article PubMed
  2. CALGB 9840: Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. link to original article PubMed NCT00003440
  3. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  4. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029

Paclitaxel monotherapy, q3wk

Regimen variant #1, 135 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Nabholtz et al. 1996 1992-03 to 1992-08 Phase 3 (E-RT-de-esc) Paclitaxel; 175 mg/m2 q3wk Did not meet primary endpoint of ORR1

1Although Nabholtz et al. 1996 did not meet its primary endpoint, there seemed to be a TTP disadvantage in the lower-dose arm.

Chemotherapy

21-day cycles


Regimen variant #2, 175 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Seidman et al. 1995 NR Phase 2
Nabholtz et al. 1996 1992-03 to 1992-08 Phase 3 (E-RT-esc) Paclitaxel; 135 mg/m2 q3wk Did not meet primary endpoint of ORR1
Winer et al. 2004 (CALGB 9342) 1994-1997 Phase 3 (C) 1. Paclitaxel; 210 mg/m2 q3wk
2. Paclitaxel; 250 mg/m2 q3wk 		Did not meet primary endpoint of ORR
Jones et al. 2005 (TAX 311) 1994-2001 Phase 3 (E-switch-ic) Docetaxel Inferior OS (secondary endpoint)
Icli et al. 2005 1997-2002 Phase 3 (C) EoP Seems to have inferior OS
Seidman et al. 2008 (CALGB 9840) 1998-NR Phase 3 (C) Paclitaxel; weekly Inferior OS
Gradishar et al. 2005 (CA012-0) 2001-11 to 2002-11 Phase 3 (C) nab-Paclitaxel Inferior TTP
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Gemcitabine & Bevacizumab
1d. Paclitaxel & Bevacizumab
1e. nab-Paclitaxel & Bevacizumab
1f. Vinorelbine & Bevacizumab 		Inferior PFS
Rugo et al. 2023 (KX-ORAX-001) 2015-12 to 2019-02 Phase 3 (C) Oral paclitaxel and encequidar Might have inferior OS
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

1Although Nabholtz et al. 1996 did not meet its primary endpoint, there seemed to be a TTP advantage in the higher-dose arm, which subsequently led to its adoption as the standard-of-care.

Prior treatment criteria

  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

21-day cycles

References

  1. Seidman AD, Tiersten A, Hudis C, Gollub M, Barrett S, Yao TJ, Lepore J, Gilewski T, Currie V, Crown J, Hakes T, Baselga J, Sklarin N, Moynihan ME, Tong W, Egorin M, Kearns C, Spriggs D, Norton L. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2575-81. link to original article PubMed
  2. Nabholtz JM, Gelmon K, Bontenbal M, Spielmann M, Catimel G, Conte P, Klaassen U, Namer M, Bonneterre J, Fumoleau P, Winograd B. Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol. 1996 Jun;14(6):1858-67. link to original article contains dosing details in abstract PubMed
  3. CALGB 9342: Winer EP, Berry DA, Woolf S, Duggan D, Kornblith A, Harris LN, Michaelson RA, Kirshner JA, Fleming GF, Perry MC, Graham ML, Sharp SA, Keresztes R, Henderson IC, Hudis C, Muss H, Norton L. Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: Cancer and Leukemia Group B trial 9342. J Clin Oncol. 2004 Jun 1;22(11):2061-8. link to original article contains dosing details in abstract PubMed
  4. Icli F, Akbulut H, Uner A, Yalcin B, Baltali E, Altinbas M, Coşkun S, Komurcu S, Erkisi M, Demirkazik A, Senler FC, Sencan O, Büyükcelik A, Boruban C, Onur H, Zengin N, Sak SD; Turkish Oncology Group. Cisplatin plus oral etoposide (EoP) combination is more effective than paclitaxel in patients with advanced breast cancer pretreated with anthracyclines: a randomised phase III trial of Turkish Oncology Group. Br J Cancer. 2005 Feb 28;92(4):639-44. link to original article link to PMC article contains dosing details in abstract PubMed
  5. TAX 311: Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, Laufman L, Sundaram S, Urba WJ, Pritchard KI, Mennel R, Richards D, Olsen S, Meyers ML, Ravdin PM. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005 Aug 20;23(24):5542-51. link to original article contains dosing details in abstract PubMed NCT00002662
  6. CA012-0: Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. link to original article contains dosing details in manuscript PubMed NCT00046527
  7. CALGB 9840: Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. link to original article PubMed NCT00003440
  8. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  9. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029
  10. KX-ORAX-001: Rugo HS, Umanzor GA, Barrios FJ, Vasallo RH, Chivalan MA, Bejarano S, Ramirez JR, Fein L, Kowalyszyn RD, Kramer ED, Wang H, Kwan MR, Cutler DL. Open-Label, Randomized, Multicenter, Phase III Study Comparing Oral Paclitaxel Plus Encequidar Versus Intravenous Paclitaxel in Patients With Metastatic Breast Cancer. J Clin Oncol. 2023 Jan 1;41(1):65-74. Epub 2022 Jul 20. link to original article link to PMC article PubMed NCT02594371

Paclitaxel & Bevacizumab

Regimen variant #1, 90 mg/m2 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Gemcitabine
1d. Paclitaxel
1e. nab-Paclitaxel
1f. Vinorelbine 		Superior PFS (primary endpoint)
Median PFS: 7.2 vs 5.1 mo
(HR 0.78, 95% CI 0.64-0.93)

Chemotherapy

Targeted therapy

28-day cycles


Regimen variant #2, 175 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Gemcitabine
1d. Paclitaxel
1e. nab-Paclitaxel
1f. Vinorelbine 		Superior PFS (primary endpoint)
Median PFS: 7.2 vs 5.1 mo
(HR 0.78, 95% CI 0.64-0.93)

Chemotherapy

Targeted therapy

21-day cycles

References

  1. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697

nab-Paclitaxel monotherapy

Example orders

Regimen variant #1, 100 mg/m2, 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

Note: the details of this regimen are unclear in von Minckwitz et al. 2014.

Prior treatment criteria

  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

28-day cycles


Regimen variant #2, 125 mg/m2, 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

Prior treatment criteria

  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

28-day cycles


Regimen variant #3, 260 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gradishar et al. 2005 (CA012-0) 2001-11 to 2002-11 Phase 3 (E-RT-switch-ic) Paclitaxel Superior ORR (primary endpoint)
ORR: 33% vs 19%

Superior TTP (secondary endpoint)
Median TTP: 23 vs 16.9 weeks
(HR 0.75)
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Gemcitabine & Bevacizumab
1d. Paclitaxel & Bevacizumab
1e. nab-Paclitaxel & Bevacizumab
1f. Vinorelbine & Bevacizumab 		Inferior PFS
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

Prior treatment criteria

  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

Supportive therapy

  • CA012-0: No corticosteroid or antihistamine premedication

21-day cycles


Regimen variant #4, 300 mg/m2 q3wk

Study Dates of enrollment Evidence
Ibrahim et al. 2005 1999-2001 Phase 2 (RT)

Chemotherapy

21-day cycles

References

  1. Ibrahim NK, Samuels B, Page R, Doval D, Patel KM, Rao SC, Nair MK, Bhar P, Desai N, Hortobagyi GN. Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer. J Clin Oncol. 2005 Sep 1;23(25):6019-26. link to original article contains dosing details in abstract PubMed
  2. CA012-0: Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. link to original article contains dosing details in manuscript PubMed NCT00046527
  3. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  4. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed
  5. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029

Paclitaxel, nanoparticle albumin-bound & Bevacizumab

Example orders

Regimen variant #1, 100 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: the schedule of bevacizumab is inferred, as there was insufficient detail in the description in the manuscript.

Chemotherapy

Targeted therapy

28-day cycles


Regimen variant #2, 260 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Gemcitabine
1d. Paclitaxel
1e. nab-Paclitaxel
1f. Vinorelbine 		Superior PFS (primary endpoint)
Median PFS: 7.2 vs 5.1 mo
(HR 0.78, 95% CI 0.64-0.93)
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Chemotherapy

Targeted therapy

21-day cycles

References

  1. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  2. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Pegylated liposomal doxorubicin monotherapy

PLD: Pegylated Liposomal Doxorubicin

Regimen variant #1, 40 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: this is the lower end of the range of pegylated liposomal doxorubicin dosing described in TANIA.

Chemotherapy

28-day cycles


Regimen variant #2, 50 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Keller et al. 2004 NR Phase 3 (E-switch-ic) 1. Mitomycin & Vinblastine
2. Vinorelbine 		Did not meet primary endpoint of PFS
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: this was the higher end of the range of pegylated liposomal doxorubicin dosing described in TANIA.

Prior treatment criteria

  • Keller et al. 2004: Taxane exposure

Chemotherapy

28-day cycles

References

  1. Keller AM, Mennel RG, Georgoulias VA, Nabholtz JM, Erazo A, Lluch A, Vogel CL, Kaufmann M, von Minckwitz G, Henderson IC, Mellars L, Alland L, Tendler C. Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol. 2004 Oct 1;22(19):3893-901. link to original article contains dosing details in abstract PubMed
  2. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Pegylated liposomal doxorubicin & Bevacizumab

PLD & Bev: Pegylated Liposomal Doxorubicin & Bevacizumab

Regimen variant #1, 40 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the lower end of the range of pegylated liposomal doxorubicin dosing described in TANIA.

Chemotherapy

Targeted therapy

28-day cycles


Regimen variant #2, 50 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the higher end of the range of pegylated liposomal doxorubicin dosing described in TANIA.

Chemotherapy

Targeted therapy

28-day cycles

References

  1. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Trastuzumab deruxtecan monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (E-RT-switch-ooc) Investigator's choice of:
1a. Capecitabine
1b. Eribulin
1c. Gemcitabine
1d. Paclitaxel; weekly
1e. Paclitaxel; q3wk
1f. nab-Paclitaxel 		Superior PFS1 (primary endpoint)
Median PFS: 10.1 vs 5.4 mo
(HR 0.51, 95% CI 0.40-0.64)

Superior OS2 (secondary endpoint)
Median OS: 23.4 vs 16.8 mo
(HR 0.64, 95% CI 0.49-0.84) 		Higher rate of pneumonitis

1Reported efficacy is for the hormone-receptor positive subgroup.
2Reported efficacy is for all enrolled patients.
Note: eribulin was the most commonly used comparator regimen.

Prior treatment criteria

  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Antibody-drug conjugate therapy

21-day cycles

References

  1. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029

Vinorelbine monotherapy

Regimen variant #1, 25 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gasparini et al. 1994 1991-1993 Phase 2
Zelek et al. 2001 1997-1999 Phase 2
Decker et al. 2019 (VicTORia) 2011-2016 Randomized Phase 2 (C) Everolimus & Vinorelbine Did not meet primary endpoint of PFS
Yuan et al. 2019 (E7389-C086-304) 2013-2015 Phase 3 (C) Eribulin Seems to have inferior PFS

Chemotherapy

7-day cycles


Regimen variant #2, 30 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jones et al. 1995a 1990-1992 Phase 3 (E-switch-ic) Melphalan Seems to have superior OS
Keller et al. 2004 NR Phase 3 (C) 1. Mitomycin & Vinblastine
2. PLD 		Did not meet primary endpoint of PFS

Prior treatment criteria

  • Jones et al. 1995a: Anthracycline exposure
  • Keller et al. 2004: Taxane exposure

Chemotherapy

7-day cycles


Regimen variant #3, 30 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Gemcitabine & Bevacizumab
1d. Paclitaxel & Bevacizumab
1e. nab-Paclitaxel & Bevacizumab
1f. Vinorelbine & Bevacizumab 		Inferior PFS

Chemotherapy

21-day cycles


Regimen variant #4, 30 mg/m2 2 out of 3 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Martín et al. 2007 (GEICAM 2000-04) 2001-2005 Phase 3 (C) Gemcitabine & Vinorelbine Inferior PFS

Chemotherapy

21-day cycles

References

  1. Gasparini G, Caffo O, Barni S, Frontini L, Testolin A, Guglielmi RB, Ambrosini G. Vinorelbine is an active antiproliferative agent in pretreated advanced breast cancer patients: a phase II study. J Clin Oncol. 1994 Oct;12(10):2094-101. link to original article PubMed
  2. Jones S, Winer E, Vogel C, Laufman L, Hutchins L, O'Rourke M, Lembersky B, Budman D, Bigley J, Hohneker J. Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. J Clin Oncol. 1995 Oct;13(10):2567-74. link to original article contains dosing details in abstract PubMed
  3. Zelek L, Barthier S, Riofrio M, Fizazi K, Rixe O, Delord JP, Le Cesne A, Spielmann M. Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer. 2001 Nov 1;92(9):2267-72. link to original article PubMed
  4. Keller AM, Mennel RG, Georgoulias VA, Nabholtz JM, Erazo A, Lluch A, Vogel CL, Kaufmann M, von Minckwitz G, Henderson IC, Mellars L, Alland L, Tendler C. Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol. 2004 Oct 1;22(19):3893-901. link to original article contains dosing details in abstract PubMed
  5. GEICAM 2000-04: Martín M, Ruiz A, Muñoz M, Balil A, García-Mata J, Calvo L, Carrasco E, Mahillo E, Casado A, García-Saenz JA, Escudero MJ, Guillem V, Jara C, Ribelles N, Salas F, Soto C, Morales-Vasquez F, Rodríguez CA, Adrover E, Mel JR; GEICAM. Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. Lancet Oncol. 2007 Mar;8(3):219-25. link to original article contains dosing details in abstract PubMed NCT00128310
  6. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  7. E7389-C086-304: Yuan P, Hu X, Sun T, Li W, Zhang Q, Cui S, Cheng Y, Ouyang Q, Wang X, Chen Z, Hiraiwa M, Saito K, Funasaka S, Xu B. Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial. Eur J Cancer. 2019 May;112:57-65. Epub 2019 Mar 29. link to original article contains dosing details in abstract PubMed NCT02225470
  8. VicTORia: Decker T, Marschner N, Muendlein A, Welt A, Hagen V, Rauh J, Schröder H, Jaehnig P, Potthoff K, Lerchenmüller C. VicTORia: a randomised phase II study to compare vinorelbine in combination with the mTOR inhibitor everolimus versus vinorelbine monotherapy for second-line chemotherapy in advanced HER2-negative breast cancer. Breast Cancer Res Treat. 2019 Aug;176(3):637-647. Epub 2019 May 21. link to original article contains dosing details in manuscript PubMed NCT01520103
  9. EVER-132-002: NCT04639986

Vinorelbine & Bevacizumab

Example orders

Regimen variant #1, vinorelbine 25 mg/m2 weekly

Study Dates of enrollment Evidence
Burstein et al. 2008 2001-2002 Phase 2

Chemotherapy

Targeted therapy

14-day cycles


Regimen variant #2, vinorelbine 30 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Gemcitabine
1d. Paclitaxel
1e. nab-Paclitaxel
1f. Vinorelbine 		Superior PFS (primary endpoint)
Median PFS: 7.2 vs 5.1 mo
(HR 0.78, 95% CI 0.64-0.93)

Chemotherapy

Targeted therapy

21-day cycles

References

  1. Burstein HJ, Chen YH, Parker LM, Savoie J, Younger J, Kuter I, Ryan PD, Garber JE, Chen H, Campos SM, Shulman LN, Harris LN, Gelman R, Winer EP. VEGF as a marker for outcome among advanced breast cancer patients receiving anti-VEGF therapy with bevacizumab and vinorelbine chemotherapy. Clin Cancer Res. 2008 Dec 1;14(23):7871-7. link to original article contains dosing details in manuscript PubMed
  2. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697

Additional resources

Patient information

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