Breast cancer

Back to Top
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: 
*Regimens for ER/PR positive breast cancer are here.
*Regimens for HER2 positive breast cancer are here.
**Regimens for HER2 low breast cancer are here.
*Regimens for ER/HER2 co-expressing ("double positive") breast cancer are here.
*Regimens for Triple negative breast cancer (TNBC) are here.
*Regimens for BRCA-mutated breast cancer are here.
*Regimens for PIK3CA-mutated breast cancer are here.
*Regimens for CNS metastases are here.
*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 and AC-D.
Last updated on 2024-12-02:152 regimens on this page
353 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==
*2024: Freedman et al. Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer-Cyclin-Dependent Kinase 4 and 6 Inhibitors: ASCO Guideline Rapid Recommendation Update EuroPMC
**2022: Giordano et al. Abemaciclib With Endocrine Therapy in the Treatment of High-Risk Early Breast Cancer: ASCO Optimal Adjuvant Chemotherapy and Targeted Therapy Guideline Rapid Recommendation Update EuroPMC
**2020: Denduluri et al. Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update EuroPMC
**2018: Denduluri et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO clinical practice guideline focused update EuroPMC
**2016: Harris et al. 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 EuroPMC
*2024: Al Sukhun et al. Systemic Treatment of Patients With Metastatic Breast Cancer: ASCO Resource–Stratified Guideline EuroPMC
*2023: Moy et al. Chemotherapy and Targeted Therapy for Endocrine-Pretreated or Hormone Receptor-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update EuroPMC
**2022: Moy et al. 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 EuroPMC
**2021: Moy et al. 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 EuroPMC
*2022: Henry et al. Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update EuroPMC
*2022: Eisen et al. Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: ASCO-OH (CCO) Guideline Update EuroPMC
*2021: Brackstone et al. Management of the Axilla in Early-Stage Breast Cancer: Ontario Health (Cancer Care Ontario) and ASCO Guideline EuroPMC
**2017: Lyman et al. Sentinel Lymph Node Biopsy for Patients With Early-Stage Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update EuroPMC
**2014: Lyman et al. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update EuroPMC
**2005: Lyman et al. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer EuroPMC
*2021: Burstein et al. Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Update link to PMC article EuroPMC
*2021: Korde et al. Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline link to PMC article EuroPMC
*2020: Hassett et al. Management of Male Breast Cancer: ASCO Guideline EuroPMC
*2017: Van Poznak et al. Role of bone-modifying agents in metastatic breast cancer: an American Society of Clinical Oncology–Cancer Care Ontario focused guideline update EuroPMC
*2015: van Poznak et al. Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology Clinical practice guideline EuroPMC
*2014: Partridge et al. 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 EuroPMC
==ASTRO==
*2024: Shaitelman et al. Partial breast irradiation for patients with early-stage invasive breast cancer or ductal carcinoma in situ: an ASTRO clinical practice guideline EuroPMC
==ESMO/ESO==
*2024: Park et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, treatment and follow-up of patients with early breast cancer EuroPMC
*2023: Loibl et al. Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up EuroPMC
**2019: Cardoso et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
*2023: Im et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer EuroPMC
*2022: Paluch-Simon et al. ESO–ESMO fifth international consensus guidelines for breast cancer in young women (BCY5) EuroPMC
**2020: Paluch-Shimon et al. ESO–ESMO 4th International Consensus Guidelines for Breast Cancer in Young Women (BCY4) EuroPMC
*2021: Gennari et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer EuroPMC
*2018: Cardoso et al. 4th ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4) EuroPMC
**2017: Cardoso et al. 3rd ESO-ESMO International consensus guidelines for advanced breast cancer (ABC3) EuroPMC
**2014: Cardoso et al. ESO-ESMO 2nd International consensus guidelines for advanced breast cancer (ABC2) EuroPMC
**2012: Cardoso et al. 1st International consensus guidelines for advanced breast cancer (ABC 1) EuroPMC
*2015: Senkus et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2013: Senkus et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2011: Aebi et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2010: Aebi et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2009: Kataja & Castiglione. Primary breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2008: Pestalozzi & Castiglione. Primary breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2007: Pestalozzi. Primary breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2005: Pestalozzi et al. ESMO Minimum Clinical Recommendations for diagnosis, adjuvant treatment and follow-up of primary breast cancer EuroPMC
**2001: ESMO Minimum Clinical Recommendations for diagnosis, adjuvant treatment and follow-up of primary breast cancer EuroPMC
*2012: Cardoso et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2011: Cardoso et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2010: Cardoso et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up EuroPMC
**2009: Cardoso & Castiglione. Locally recurrent or metastatic breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2008: Kataja & Castiglione. Locally recurrent or metastatic breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2007: Kataja. Recurrent or metastatic breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up EuroPMC
**2005: Kataja et al. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of locally recurrent or metastatic breast cancer (MBC) EuroPMC
==EUSOMA/SIOG==
*2021: Biganzoli et al. 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) EuroPMC
*2012: Biganzoli et al. 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) EuroPMC
*2007: Wildiers et al. Management of breast cancer in elderly individuals: recommendations of the International Society of Geriatric Oncology EuroPMC
==KSMO/ESMO==
*2020: Park et al. 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 EuroPMC
==NCCN==
*NCCN Guidelines - Breast Cancer
**2024: Gradishar et al. Breast Cancer, Version 3.2024, NCCN Clinical Practice Guidelines in Oncology EuroPMC
**2020: Gradishar et al. Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. EuroPMC
**2019: Telli et al. NCCN Guidelines Updates: Breast Cancer. EuroPMC
**2018: Giordano et al. NCCN Guidelines Updates: Breast Cancer. EuroPMC
**2018: Gradishar et al. Breast Cancer, Version 4.2017, NCCN Clinical Practice Guidelines in Oncology. EuroPMC
**2017: Salerno et al. NCCN Guidelines Update: Evolving Radiation Therapy Recommendations for Breast Cancer. EuroPMC
**2016: Gradishar et al. NCCN Guidelines Update: Breast Cancer. EuroPMC
**2016: Gradishar et al. Invasive Breast Cancer Version 1.2016, NCCN Clinical Practice Guidelines in Oncology EuroPMC
**2015: Gradishar et al. Breast Cancer Version 2.2015 EuroPMC
**2014: Gradishar et al. Breast cancer version 3.2014 EuroPMC
**2013: Theriault et al. Breast cancer, version 3.2013: featured updates to the NCCN guidelines. link to PMC article EuroPMC
**2012: Carlson et al. Metastatic breast cancer, version 1.2012: featured updates to the NCCN guidelines. link to PMC article EuroPMC
**2011: Carlson et al. Invasive breast cancer. EuroPMC
**2010: Carlson et al. Breast cancer: noninvasive and special situations. EuroPMC
**2009: Carlson et al. Breast cancer. Clinical practice guidelines in oncology. EuroPMC
**2006: Carlson et al. NCCN Task Force Report: Adjuvant Therapy for Breast Cancer. EuroPMC
**2005: Carlson et al. Breast cancer. EuroPMC
**2004: Authors not listed. NCCN Guideline update: Breast Cancer Version 1.2004. EuroPMC
**2003: Authors not listed. Breast cancer Clinical Practice Guidelines in Oncology. EuroPMC
*NCCN Guidelines - Genetic/Familial High-Risk Assessment: Breast and Ovarian
==SEOM-GEICAM-SOLTI==
*2023: Ayala de la Peña et al. SEOM-GEICAM-SOLTI clinical guidelines for early-stage breast cancer (2022) EuroPMC
==SITC==
*2021: Emens et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of breast cancer EuroPMC
== St Gallen Breast Guidelines ==
*2021: Burstein et al. Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021 link to PMC article EuroPMC
*2019: Burstein et al. 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 EuroPMC
*2017: Curigliano et al. St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2017 EuroPMC
*2015: Coates et al. Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015 EuroPMC
=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)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, D portion (cycles 5 to 8)====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycle for 8 cycles (AC x 4; T x 4)
====Subsequent treatment====
*Surgery
===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 	Higher pCR rate (secondary endpoint)Did not meet primary endpoint of clinical response rate
Bear et al. 2003 (NSABP B-27) 	1995-2000 	Phase 3 (E-esc)	2. AC, then surgery, then T	Not reported
von Minckwitz et al. 2005 (GeparDuo)	1999-2001 	Phase 3 (E-esc)	ddAT 	Higher 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)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, D portion (cycles 5 to 8)====
*Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
21-day cycle for 8 cycles (AC x 4; T x 4)
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, T portion (cycles 6 to 17)====
*Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
21-day cycle for 5 cycles, then 7-day cycle for 12 cycles (AC x 5; T x 12)
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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+Bev2. TG-AC+Bev3. TX-AC+Bev	Seems to have lower pCR rate
Bear et al. 2012 (NSABP B-40)	2007-2010 	Phase 3 (C)	4. TG-AC5. TX-AC 	Did not meet primary endpoint of pCR rate
====Chemotherapy, D portion (cycles 1 to 4)====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
====Chemotherapy, AC portion (cycles 5 to 8)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 8 cycles (D x 4; AC x 4)
====Subsequent treatment====
*surgery
===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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
==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-AC2. TG-AC3. TX-AC 	Seems to have higher pCR rate (primary endpoint)
Bear et al. 2012 (NSABP B-40)	2007-2010 	Phase 3 (E-esc)	4. TG-AC+Bev5. TX-AC+Bev	Did not meet primary endpoint of pCR rate
====Chemotherapy, D portion (cycles 1 to 4)====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
====Chemotherapy, AC portion (cycles 5 to 8)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 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)
====Subsequent treatment====
*surgery
===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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
==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 lower pCR rate
====Chemotherapy, D portion (cycles 1 to 3)====
*Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
====Chemotherapy, FEC portion (cycles 4 to 6)====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 100 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 6 cycles (D x 3; FEC x 3)
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
==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 higher pCR rate (primary endpoint)pCR rate: 22% vs 17%
====Chemotherapy, D portion (cycles 1 to 3)====
*Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
====Targeted therapy, D portion (cycles 1 to 3)====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
====Chemotherapy, FEC portion (cycles 4 to 6)====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 100 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
====Targeted therapy, FEC portion (cycles 4 to 6)====
*Bevacizumab (Avastin) as follows:
**Cycle 4: 15 mg/kg IV once on day 1
21-day cycle for 6 cycles (D x 3; FEC x 3)
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
==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 to not reported	Phase 3 (C)	1. EC-TX2. 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 lower pCR rate (primary endpoint)
====Chemotherapy, EC portion (cycles 1 to 4)====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, D portion (cycles 5 to 8)====
*Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
21-day cycle for 8 cycles (EC x 4; D x 4)
====Subsequent treatment====
*Surgery
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00288002
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 DFSDFS36: 75.8% vs 78.8%(HR 1.14, 95% CI 0.85-1.52)
====Chemotherapy, EC portion (cycles 1 to 4)====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, T portion (cycles 5 to 8)====
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycle for 8 cycles (EC x 4; T x 4)
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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 lower pCR rate
Earl et al. 2013 (Neo-tAnGo)	2005-2007 	Phase 3 (C)	2. EC-ddTG3. ddTG-EC	Did not meet primary endpoint of pCR rate
====Chemotherapy, EC portion (cycles 1 to 4)====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, ddT portion (cycles 5 to 8)====
*Paclitaxel (Taxol) 175 mg/m2 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)
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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)====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 100 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
====Chemotherapy, D portion (cycles 4 to 6)====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 6 cycles (FEC x 3; D x 3)
====Subsequent treatment====
*Surgery
===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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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 	Higher 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)====
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m2 IV once on day 1
====Chemotherapy, EC portion (cycles 13 to 16)====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (nP x 12; EC x 4)
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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 	Higher pCR rate (primary endpoint)pCR rate: 20.8% vs 12.9%
====Biomarker eligibility criteria====
*HR+ and HER2-
====Chemotherapy, nP portion (cycles 1 to 8)====
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m2 IV once on day 1
====Chemotherapy, ddEC portion (cycles 9 to 12)====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 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)
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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-AC1b. nP-EC1c. nP-FEC	Did not meet primary endpoint of pCR rate
====Chemotherapy, T portion (cycles 1 to 4)====
*Paclitaxel (Taxol) 90 mg/m2 IV once per day on days 1, 8, 15
====Chemotherapy, AC portion (cycles 5 to 8)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
28-day cycle for 4 cycles, then 21-day cycle for 4 cycles (T x 4; AC x 4)
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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 	Lower pCR rate
====Chemotherapy, T portion (cycles 1 to 12)====
*Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
====Chemotherapy, EC portion (cycles 13 to 16)====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (T x 12; EC x 4)
====Subsequent treatment====
*Surgery
===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-AC1b. nP-EC1c. nP-FEC	Did not meet primary endpoint of pCR rate
====Chemotherapy, T portion (cycles 1 to 4)====
*Paclitaxel (Taxol) 90 mg/m2 IV once per day on days 1, 8, 15
====Chemotherapy, EC portion (cycles 5 to 8)====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
28-day cycle for 4 cycles, then 21-day cycle for 4 cycles (T x 4; EC x 4)
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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 higher pCR rate (primary endpoint)
Earl et al. 2013 (Neo-tAnGo)	2005-2007 	Phase 3 (E-switch-ic)	2. EC-ddTG3. ddTG-EC	Did not meet primary endpoint of pCR rate
====Chemotherapy, ddT portion (cycles 1 to 4)====
*Paclitaxel (Taxol) 175 mg/m2 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/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
14-day cycle for 4 cycles, then 21-day cycle for 4 cycles (ddT x 4; EC x 4)
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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 	Lower 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)====
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
====Chemotherapy, ddEC portion (cycles 5 to 8)====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 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)
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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 higher pCR rate (primary endpoint)
====Chemotherapy, T portion (cycles 1 to 12)====
*Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
====Chemotherapy, FAC portion (cycles 13 to 16)====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 4
*Doxorubicin (Adriamycin) 16.7 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m2)
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (T x 12; FAC x 4)
====Subsequent treatment====
*Surgery
===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 higher pCR rate (primary endpoint)
====Chemotherapy, T portion (cycles 1 to 4)====
*Paclitaxel (Taxol) 150 mg/m2 IV over 3 hours once per day on days 1, 8, 15
====Chemotherapy, FAC portion (cycles 5 to 8)====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 4
*Doxorubicin (Adriamycin) 16.7 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m2)
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
28-day cycle for 4 cycles, then 21-day cycle for 4 cycles (T x 4; FAC x 4)
====Subsequent treatment====
*Surgery
===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 lower pCR rate
====Chemotherapy, T portion (cycles 1 to 4)====
*Paclitaxel (Taxol) 225 mg/m2 IV continuous infusion over 24 hours, started on day 1
====Chemotherapy, FAC portion (cycles 5 to 8)====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 4
*Doxorubicin (Adriamycin) 16.7 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m2)
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 8 cycles (T x 4; FAC x 4)
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==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)====
*Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
====Chemotherapy, FEC portion (cycles 13 to 16)====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 100 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (T x 12; FEC x 4)
====Subsequent treatment====
*Surgery
===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-AC1b. nP-EC1c. nP-FEC	Did not meet primary endpoint of pCR rate
====Chemotherapy, T portion (cycles 1 to 4)====
*Paclitaxel (Taxol) 90 mg/m2 IV once per day on days 1, 8, 15
====Chemotherapy, FEC portion (cycles 5 to 8)====
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
28-day cycle for 4 cycles, then 21-day cycle for 4 cycles (T x 4; FEC x 4)
====Subsequent treatment====
*Surgery
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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 higher pCR rate (primary endpoint)
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 4 cycles
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==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 	Did not meet co-primary endpoints of DFS/OS
Bear et al. 2003 (NSABP B-27) 	1995-2000 	Phase 3 (C) 	1. AC-D 	Lower pCR rate
Bear et al. 2003 (NSABP B-27) 	1995-2000 	Phase 3 (C) 	2. AC, then surgery, then T	Not reported
Lee et al. 2007 	2002-2005 	Phase 3 (C) 	TX 	Seems to have lower pCR rate
====Chemotherapy====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles
====Subsequent treatment====
*NSABP B-18 & NSABP B-27: Surgery
*Lee et al. 2007: Surgery, then adjuvant TX x 4
===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====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 6 cycles
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
## 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 EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Dose-dense Cyclophosphamide & Doxorubicin (ddAC)==
ddAC: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide
===Regimen===
Study 	Dates of enrollment	Evidence 	Efficacy
Burstein et al. 2005	2003-2004 	Non-randomized	Not reported
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====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 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
====Subsequent treatment====
*Optional neoadjuvant dose-dense paclitaxel, then surgery or surgery, then adjuvant dose-dense paclitaxel; this was not a randomization
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==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 	Lower pCR rate
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1, given second
*Doxorubicin (Adriamycin) 50 mg/m2 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
===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; 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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====
*Epirubicin (Ellence) 150 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 4000 mg/m2 IV once on day 1
====Supportive therapy====
*Autologous stem cells
21-day cycle for 4 cycles
====Subsequent treatment====
*Surgery, then adjuvant Docetaxel & 5-FU versus no further treatment
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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 	Lower pCR rate
Chen et al. 2017 (CBCRT01) 	2011-2015 	Phase 3 (C)	DEE 	Lower ORR
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given second
*Epirubicin (Ellence) 75 mg/m2 IV once on day 1, given first
====Supportive therapy====
*ABCSG-14: Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 3 to 10
*ABCSG-14: Dexamethasone (Decadron) 8 mg PO or IV twice per day on days 0 to 2
21-day cycle for 3 cycles
====Subsequent treatment====
*Surgery
===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 lower pCR rate
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
*Epirubicin (Ellence) 75 mg/m2 IV once on day 1
21-day cycle for 4 cycles
====Subsequent treatment====
*Surgery
===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 	Higher pCR rate (primary endpoint)
Han et al. 2009 	2003-2005 	Phase 3 (E-esc)	ED x 4 	Seems to have higher pCR rate (secondary endpoint)
Steger et al. 2013 (ABCSG-24)	2004-2008 	Phase 3 (C) 	EDC 	Seems to have lower pCR rate
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given second
*Epirubicin (Ellence) 75 mg/m2 IV once on day 1, given first
====Supportive therapy====
*ABCSG-14: Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 3 to 10
*ABCSG-14: Dexamethasone (Decadron) 8 mg PO or IV twice per day on days 0 to 2
21-day cycle for 6 cycles
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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 higher pCR rate (primary endpoint)
====Chemotherapy====
*Epirubicin (Ellence) 75 mg/m2 IV once on day 1
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 6 cycles
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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====
*Epirubicin (Ellence) 60 mg/m2 IV once per day on days 1 & 2
21-day cycle for 3 to 4 cycles
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==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 	Lower pCR rate (primary endpoint)pCR rate: 10% vs 18%Seems to have shorter OS (secondary endpoint)OS60: 77% vs 83%(HR 1.20, 95% CI 1.01-1.45)
Frasci et al. 2006 	1999-2004 	Phase 3 (C)	PET 	Seems to have lower 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====
*Epirubicin (Ellence) 90 mg/m2 IV bolus once on day 1, given first
*Paclitaxel (Taxol) 175 mg/m2 IV over 60 minutes once on day 1, given second
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===
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 4 cycles
====Subsequent treatment====
*Surgery
===Regimen variant #2, 600/50/600===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Baldini et al. 1997	Not reported in abstract	Phase 3 (C)	DES-CAF 	Did not meet primary endpoint of pCR rate
Note: The full manuscript was not available for review.
====Chemotherapy====
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 3 cycles
====Subsequent treatment====
*Surgery
===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====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 4
*Doxorubicin (Adriamycin) 16.7 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m2)
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 4 cycles
====Subsequent treatment====
*Surgery, then adjuvant FAC x 4
===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 longer OS (primary endpoint)OS60: 86% vs 78%(HR not reported, p=0.039)
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1, 3, 5, 8
*Doxorubicin (Adriamycin) 25 mg/m2 IV once per day on days 1 & 8
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 5
28-day cycle for 4 cycles
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC
==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====
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
*Epirubicin (Ellence) 60 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 3 cycles
====Subsequent treatment====
*Surgery, then adjuvant CEF/CMF x 3
===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====
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
*Epirubicin (Ellence) 60 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles
====Subsequent treatment====
*Surgery
===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====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
*Epirubicin (Ellence) 60 mg/m2 IV once per day on days 1 & 8
*Cyclophosphamide (Cytoxan) 75 mg/m2 PO once per day on days 1 to 14
28-day cycle for 6 cycles
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
==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)====
*Epirubicin (Ellence) 150 mg/m2 IV once on day 1
====Chemotherapy, iddP portion (cycles 4 to 6)====
*Paclitaxel (Taxol) 225 mg/m2 IV once on day 1
====Chemotherapy, iddC portion (cycles 7 to 9)====
*Cyclophosphamide (Cytoxan) 2000 mg/m2 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)
====Subsequent treatment====
*Surgery
===References===
# 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 dosing details in abstract have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
==Paclitaxel monotherapy, dose-dense (q2wk)==
ddT: dose-dense Taxol (Paclitaxel)
===Regimen===
Study 	Dates of enrollment	Evidence 	Efficacy
Burstein et al. 2005	2003-2004 	Non-randomized	Not reported
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====
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
====Supportive therapy====
*Pegfilgrastim (Neulasta) 6 mg SC once on day 2
14-day cycle for 4 cycles
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==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 higher pCR rate (primary endpoint)
====Chemotherapy====
*Cisplatin (Platinol) 30 mg/m2 IV over 30 minutes once on day 1, given third
*Epirubicin (Ellence) 50 mg/m2 IV bolus once on day 1, given first
*Paclitaxel (Taxol) 120 mg/m2 IV over 60 minutes once on day 1, given second
7-day cycle for 12 cycles
====Subsequent treatment====
*Surgery
===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. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==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-NX 	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====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 6 cycles
====Subsequent treatment====
*Surgery
===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; 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
=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.
</div>
===References===
# 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 EuroPMC
</div>
==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>
===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. link to original article EuroPMC
</div>
==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.
</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. link to original article EuroPMC
</div>
==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>
===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. link to original article EuroPMC
</div>
==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>
===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. EuroPMC
</div>
==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>
===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. link to original article EuroPMC
</div>
==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 shorter RFS
Gianni et al. 2009 (ECTO) 	1996-2002 	Phase 3 (C)	2. AT-CMF; neoadjuvant 	Not directly compared
Fernando et al. 2019 (SECRAB)	1998-2004 	Phase 3 (C)	1a. CMF & RT1b. E-CMF & RT1c. A-CMF & RT1d. MMM & RT	Higher LRR120 (co-primary endpoint)LRR120: 7.1% vs 4.6%(HR 1.61, 95% CI 1.11-2.33)
====Preceding treatment====
*Surgery
====Chemotherapy, A portion (cycles 1 to 4)====
*Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
====Chemotherapy, CMF portion (cycles 5 to 8)====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once per day on days 1 & 8
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 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)
===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	Longer OS
====Preceding treatment====
*Surgery
====Chemotherapy, A portion (cycles 1 to 4)====
*Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
====Chemotherapy, CMF portion (cycles 5 to 12)====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
*Methotrexate (MTX) 40 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
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====
*Surgery
====Chemotherapy, A portion (cycles 1 to 4)====
*Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
====Chemotherapy, CMF portion (cycles 5 to 12)====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
*Methotrexate (MTX) 50 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
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 & RT1b. E-CMF & RT1c. A-CMF & RT1d. MMM & RT	Higher LRR120 (co-primary endpoint)LRR120: 7.1% vs 4.6%(HR 1.61, 95% CI 1.11-2.33)
====Preceding treatment====
*Surgery
====Chemotherapy, A portion (cycles 1 to 4)====
*Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
====Chemotherapy, CMF portion (cycles 5 to 8)====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 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)
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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-C2. AC-T	Longer OS (secondary endpoint)OS36: 92% vs 90%(aHR 0.69, 95% CI 0.50-0.93)Longer DFS (primary endpoint)DFS48: 82% vs 75%(aHR 0.74, 95% CI 0.59-0.93)
Citron et al. 2003 (CALGB 9741)	1997-1999 	Phase 3 (E-esc)	3. ddAC-ddT 	Did not meet primary endpoint of DFS
====Preceding treatment====
*Surgery
====Chemotherapy, ddA portion (cycles 1 to 4)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
====Chemotherapy, ddT portion (cycles 5 to 8)====
*Paclitaxel (Taxol) 175 mg/m2 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, given 30 to 60 minutes prior to paclitaxel
*One of the following H2 blocker choices:
**Ranitidine (Zantac) 50 mg IV once on day 1, given 30 to 60 minutes prior to paclitaxel
**Cimetidine (Tagamet) 300 mg IV once on day 1, given 30 to 60 minutes prior to paclitaxel
**Famotidine (Pepcid) 20 mg IV once on day 1, given 30 to 60 minutes prior to paclitaxel
*One of the following dexamethasone choices:
**Dexamethasone (Decadron) 10 mg IV once on day 1, given within 60 minutes prior to paclitaxel
**Dexamethasone (Decadron) 10 mg PO once on day 1, given at least 60 minutes prior to paclitaxel
**Dexamethasone (Decadron) 20 mg PO twice on day 1, given 6 hours and 12 hours prior to paclitaxel
====Chemotherapy, ddC portion (cycles 9 to 12)====
*Cyclophosphamide (Cytoxan) 600 mg/m2 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)
===Regimen variant #2, 60/200/800===
Study 	Dates of enrollment	Evidence
Kahan et al. 2005	2000-2003 	Phase 2
====Preceding treatment====
*Surgery
====Chemotherapy, ddA portion (cycles 1 to 4)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
====Chemotherapy, ddT portion (cycles 5 to 8)====
*Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
====Chemotherapy, ddC portion (cycles 9 to 12)====
*Cyclophosphamide (Cytoxan) 800 mg/m2 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)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003088
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
## 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 EuroPMC
==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 shorter DFS1DFS96: 37% vs 47%(HR 1.32, 95% CI 1.00-1.72)
Francis et al. 2008 (BIG 02-98) 	1998-2001 	Phase 3 (C) 	1. A-CMF 	Not reported
Francis et al. 2008 (BIG 02-98) 	1998-2001 	Phase 3 (C) 	2. A-D-CMF3. AD-CMF	Might have shorter 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====
*Surgery
====Chemotherapy, AC portion (cycles 1 to 4)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, CMF portion (cycles 5 to 7)====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles, then 28-day cycle for 3 cycles (AC x 4; CMF x 3)
====Subsequent treatment====
*Adjuvant Tamoxifen x 5 y versus no further treatment
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
## 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 EuroPMC
==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-T2. Paclitaxel x 8	Seems to have longer OS (secondary endpoint)(HR 0.75, 95% CI 0.57-0.98)
Watanabe et al. 2017 (NSAS BC-02)	2001-2006 	Phase 3 (C)	3. Docetaxel x 8 	Inconclusive whether non-inferior DFS (primary endpoint)
====Preceding treatment====
*Surgery
====Chemotherapy, AC portion (cycles 1 to 4)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, D portion (cycles 5 to 8)====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
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 longer DFS (primary endpoint)
Sparano et al. 2008 (ECOG E1199)	1999-2002 	Phase 3 (E-switch-ic)	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 longer OS (primary endpoint)
Swain et al. 2010 (NSABP B-30) 	1999-2004 	Phase 3 (E-switch-ic)	2. TAC 	Might have longer 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====
*Surgery
====Chemotherapy, AC portion (cycles 1 to 4)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV over 5 to 15 minutes once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 30 to 60 minutes once on day 1
====Chemotherapy, D portion (cycles 5 to 8)====
*Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
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
Sparano et al. 2008 (ECOG E1199)	1999-2002 	Phase 3 (E-switch-ic)	2. AC-T; weekly paclitaxel 3. AC-D; q3wk docetaxel	Not reported
====Preceding treatment====
*Surgery
====Chemotherapy, AC portion (cycles 1 to 4)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV over 5 to 15 minutes once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 30 to 60 minutes once on day 1
====Chemotherapy, D portion (cycles 5 to 16)====
*Docetaxel (Taxotere) 35 mg/m2 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)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00004125
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003782
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
==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 	Longer OS (secondary endpoint)OS60: 89.7% vs 86.5%(HR 0.76, 98.3% CI 0.58-0.98)
Sparano et al. 2008 (ECOG E1199)	1999-2002 	Phase 3 (E-switch-ic)	2. AC-D; q3wk docetaxel3. AC-D; weekly docetaxel 	Not reported
Miller et al. 2018 (ECOG E5103) 	2007-2011 	Phase 3 (C) 	1a. AC-T & Bevacizumab1b. ddAC-T & Bevacizumab2a. AC-T & Bevacizumab, then Bevacizumab2b. ddAC-T & Bevacizumab, then Bevacizumab	Did not meet primary endpoint of IDFS
====Preceding treatment====
*Surgery
====Chemotherapy, AC portion (cycles 1 to 4)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV over 5 to 15 minutes once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 30 to 60 minutes once on day 1
====Chemotherapy, T portion (cycles 5 to 16)====
*Paclitaxel (Taxol) 80 mg/m2 IV over 60 minutes once on day 1
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-dose2. AC; high-dose3. AC; very high-dose	Longer OS (secondary endpoint)
Henderson et al. 2003 (INT 0148/CALGB 9344)	1994-1999 	Phase 3 (E-RT-esc)	4. AC-T; high-dose AC5. 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
Citron et al. 2003 (CALGB 9741) 	1997-1999 	Phase 3 (C) 	2. ddA-ddC-ddT3. ddAC-ddT 	Shorter OS
Sparano et al. 2008 (ECOG E1199) 	1999-2002 	Phase 3 (C) 	1. AC-T; weekly paclitaxel 	Shorter OS
Sparano et al. 2008 (ECOG E1199) 	1999-2002 	Phase 3 (C) 	2. AC-D; q3wk docetaxel 	Seems to have shorter DFS
Sparano et al. 2008 (ECOG E1199) 	1999-2002 	Phase 3 (C) 	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-T2. CEF 	Shorter RFS
Watanabe et al. 2017 (NSAS BC-02) 	2001-2006 	Phase 3 (C) 	1. AC-D2. Docetaxel x 8 	Seems to have shorter OS (secondary endpoint)
Watanabe et al. 2017 (NSAS BC-02) 	2001-2006 	Phase 3 (C) 	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====
*Surgery
====Chemotherapy, AC portion (cycles 1 to 4)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV over 5 to 15 minutes once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 30 to 60 minutes once on day 1
====Chemotherapy, T portion (cycles 5 to 8)====
*Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1 
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 	Longer DFS (co-primary endpoint)DFS60: 76% vs 72%(HR 0.83, 95% CI 0.72-0.95)
====Preceding treatment====
*Surgery
====Chemotherapy, AC portion (cycles 1 to 4)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, T portion (cycles 5 to 8)====
*Paclitaxel (Taxol) 225 mg/m2 IV over 3 hours once on day 1 
21-day cycle for 8 cycles (AC x 4; T x 4)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003088
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00004125
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# 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 dosing details in supplement have been reviewed by our editors EuroPMC 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. link to original article does not contain dosing details in manuscript; refers to ECOG E1199 protocol link to PMC article EuroPMC NCT00433511
##HRQoL analysis: Rosenberg SM, O'Neill A, Sepucha K, Miller KD, Dang CT, Northfelt DW, Sledge GW, Schneider BP, Partridge AH. Quality of Life Following Receipt of Adjuvant Chemotherapy With and Without Bevacizumab in Patients With Lymph Node-Positive and High-Risk Lymph Node-Negative Breast Cancer. JAMA Netw Open. 2022 Feb 1;5(2):e220254. link to original article link to PMC article EuroPMC
#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 & Bevacizumab1b. ddAC-T & Bevacizumab2a. AC-T & Bevacizumab, then Bevacizumab2b. ddAC-T & Bevacizumab, then Bevacizumab	Did not meet primary endpoint of IDFS
====Preceding treatment====
*Surgery
====Chemotherapy, ddAC portion (cycles 1 to 4)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====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
====Chemotherapy, T portion (cycles 5 to 16)====
*Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
14-day cycle for 4 cycles, then 7-day cycle for 12 cycles (AC x 4; T x 12)
===References===
# 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 does not contain dosing details in manuscript; refers to ECOG E1199 protocol link to PMC article EuroPMC NCT00433511
##HRQoL analysis: Rosenberg SM, O'Neill A, Sepucha K, Miller KD, Dang CT, Northfelt DW, Sledge GW, Schneider BP, Partridge AH. Quality of Life Following Receipt of Adjuvant Chemotherapy With and Without Bevacizumab in Patients With Lymph Node-Positive and High-Risk Lymph Node-Negative Breast Cancer. JAMA Netw Open. 2022 Feb 1;5(2):e220254. link to original article link to PMC article EuroPMC
==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-C2. AC-T	Longer OS (secondary endpoint)OS36: 92% vs 90%(aHR 0.69, 95% CI 0.50-0.93)Longer DFS (primary endpoint)DFS48: 82% vs 75%(aHR 0.74, 95% CI 0.59-0.93)
Citron et al. 2003 (CALGB 9741)	1997-1999 	Phase 3 (E-esc)	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
Swain et al. 2013 (NSABP B-38) 	2004-2007 	Phase 3 (C) 	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====
*Surgery
====Chemotherapy, ddAC portion (cycles 1 to 4)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====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)====
*Paclitaxel (Taxol) 175 mg/m2 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, given 30 to 60 minutes prior to paclitaxel
*One of the following H2 blockers:
**Ranitidine (Zantac) 50 mg IV once on day 1, given 30 to 60 minutes prior to paclitaxel
**Cimetidine (Tagamet) 300 mg IV once on day 1, given 30 to 60 minutes prior to paclitaxel
**Famotidine (Pepcid) 20 mg IV once on day 1, given 30 to 60 minutes prior to paclitaxel
*One of the following dexamethasone choices:
**Dexamethasone (Decadron) 10 mg IV once on day 1, given within 60 minutes prior to paclitaxel
**Dexamethasone (Decadron) 10 mg PO once on day 1, given at least 60 minutes prior to paclitaxel
**Dexamethasone (Decadron) 20 mg PO twice on day 1, given 6 hours and 12 hours prior to paclitaxel
*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 AC2. AC-T; continuous AC & weekly paclitaxel3. AC-T; weekly paclitaxel	Did not meet primary endpoint of DFS
====Preceding treatment====
*Surgery
====Chemotherapy, ddAC portion (cycles 1 to 6)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, ddT portion (cycles 7 to 12)====
*Paclitaxel (Taxol) 175 mg/m2 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)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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. link to original article link to PMC article dosing details in supplement have been reviewed by our editors EuroPMC 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 longer RFS (primary endpoint)RFS84: 76% vs 69%(HR 0.73, 95% CI 0.57-0.97)
Gianni et al. 2009 (ECTO)	1996-2002 	Phase 3 (E-esc)	2. AT-CMF; neoadjuvant	Did not meet primary endpoint of RFS
====Preceding treatment====
*Surgery
====Chemotherapy, AT portion (cycles 1 to 4)====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
====Chemotherapy, CMF portion (cycles 5 to 8)====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once per day on days 1 & 8
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 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)
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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 shorter OS1
Boccardo et al. 1990 (GROCTA-1)	1983-1987 	Phase 3 (C)	2. CMFT-ET 	Shorter OS1
1Reported efficacy is based on the 2011 update.
====Preceding treatment====
*Surgery
====Chemotherapy, CMF portion (cycles 1 to 6)====
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
*Methotrexate (MTX) 40 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
====Chemotherapy, E portion (cycles 7 to 10)====
*Epirubicin (Ellence) 75 mg/m2 IV once on day 1
21-day cycle for 10 cycles (CMF x 6; E x 4)
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
==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 higher DFS60 (primary endpoint)DFS60: 72.6% vs 67.2%
====Preceding treatment====
*Surgery
====Chemotherapy, D portion (cycles 1 to 4)====
*Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
====Chemotherapy, EC portion (cycles 5 to 8)====
*Epirubicin (Ellence) 75 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 700 mg/m2 IV once on day 1
21-day cycle for 8 cycles (D x 4; EC x 4)
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==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 	Shorter RFS (primary endpoint)RFS36: 89% vs 93%(HR 1.52, 95% CI 1.06-2.13)Seems to have shorter OS1 (secondary endpoint)OS180: 73.3% vs 77.6%(HR 1.23, 95% CI 1.01-1.52)
1Reported efficacy is based on the 2022 update.
====Preceding treatment====
*Surgery
====Chemotherapy, D portion (cycles 1 to 3)====
*Docetaxel (Taxotere) 80 mg/m2 IV over 60 minutes once on day 1
====Chemotherapy, FEC portion (cycles 4 to 6)====
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
*Epirubicin (Ellence) 75 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
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 	Longer RFS (primary endpoint)RFS36: 91% vs 86%(HR 0.58, 95% CI 0.40-0.85)
Note: this was the study design for HER2-negative patients.
====Preceding treatment====
*Surgery with axillary lymph node dissection or sentinel lymph node biopsy, within 12 weeks
====Chemotherapy, D portion (cycles 1 to 3)====
*Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
====Chemotherapy, FEC portion (cycles 4 to 6)====
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
*Epirubicin (Ellence) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 6 cycles (D x 3; FEC x 3)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
## 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 EuroPMC
==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 	Longer 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 & RT1b. E-CMF & RT1c. A-CMF & RT1d. MMM & RT	Higher LRR120 (co-primary endpoint)LRR120: 7.1% vs 4.6%(HR 1.61, 95% CI 1.11-2.33)
Delaloge et al. 2020 (MINDACT)	2007-2011 	Phase 3 (C) 	TX 	Did not meet primary endpoint of DFSDFS60: 88.8% vs 90.7%(HR 1.20, 95% CI 0.87-1.67)
1Reported efficacy for BR9601 is based on the 2012 update.
====Preceding treatment====
*Surgery
====Chemotherapy, E portion (cycles 1 to 4)====
*Epirubicin (Ellence) 100 mg/m2 IV once on day 1
====Chemotherapy, CMF portion (cycles 5 to 8)====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Methotrexate (MTX) 50 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
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 	Longer 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 & RT1b. E-CMF & RT1c. A-CMF & RT1d. MMM & RT	Higher LRR120 (co-primary endpoint)LRR120: 7.1% vs 4.6%(HR 1.61, 95% CI 1.11-2.33)
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 time to response (primary endpoint)
Cameron et al. 2017 (TACT2) 	2005-2008 	Phase 3 (C) 	2. ddE-CMF3. ddE-X 	Did not meet primary endpoint of time to response
1Reported efficacy for NEAT is based on the 2012 update.
====Preceding treatment====
*Surgery
====Chemotherapy, E portion (cycles 1 to 4)====
*Epirubicin (Ellence) 100 mg/m2 IV once on day 1
====Chemotherapy, CMF portion (cycles 5 to 8)====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once per day on days 1 & 8
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 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)
===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 	Longer 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 & RT1b. E-CMF & RT1c. A-CMF & RT1d. MMM & RT	Higher LRR120 (co-primary endpoint)LRR120: 7.1% vs 4.6%(HR 1.61, 95% CI 1.11-2.33)
Cameron et al. 2017 (TACT2) 	2005-2008 	Phase 3 (C) 	1. E-X 	Non-inferior time to response (primary endpoint)
Cameron et al. 2017 (TACT2) 	2005-2008 	Phase 3 (C) 	2. ddE-CMF3. ddE-X 	Did not meet primary endpoint of time to response
Delaloge et al. 2020 (MINDACT)	2007-2011 	Phase 3 (C) 	TX 	Did not meet primary endpoint of DFSDFS60: 88.8% vs 90.7%(HR 1.20, 95% CI 0.87-1.67)
1Reported efficacy for NEAT is based on the 2012 update.
====Preceding treatment====
*Surgery
====Chemotherapy, E portion (cycles 1 to 4)====
*Epirubicin (Ellence) 100 mg/m2 IV once on day 1
====Chemotherapy, CMF portion (cycles 5 to 8)====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 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)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC 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====
*Surgery
====Chemotherapy, ddE portion (cycles 1 to 4)====
*Epirubicin (Ellence) 110 mg/m2 IV once on day 1
====Chemotherapy, CMF portion (cycles 5 to 7)====
*Cyclophosphamide (Cytoxan) 840 mg/m2 IV once on day 1
*Methotrexate (MTX) 57 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 840 mg/m2 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)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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	Longer DFS (primary endpoint)DFS60: 79.5% vs 72.7%(HR 0.68, 95% CI 0.52-0.91)Longer OS (secondary endpoint)OS60: 88.9% vs 81.8%(HR 0.66, 95% CI 0.46-0.94)
====Preceding treatment====
*Surgery
====Chemotherapy, E portion (cycles 1 to 3)====
*Epirubicin (Ellence) 50 mg/m2 IV once per day on days 1 & 8
====Chemotherapy, D portion (cycles 4 to 6)====
*Docetaxel (Taxotere) 100 mg/m2 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)
===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 longer 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====
*Surgery
====Chemotherapy, E portion (cycles 1 to 4)====
*Epirubicin (Ellence) 90 mg/m2 IV over 5 to 15 minutes once on day 1
====Chemotherapy, D portion (cycles 5 to 8)====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 8 cycles (E x 4; D x 4)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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 time to response (primary endpoint)
Cameron et al. 2017 (TACT2)	2005-2008 	Phase 3 (E-de-esc)	2. ddE-CMF3. ddE-X	Did not meet primary endpoint of time to response
====Preceding treatment====
*Surgery
====Chemotherapy, E portion (cycles 1 to 4)====
*Epirubicin (Ellence) 100 mg/m2 IV once on day 1
====Chemotherapy, X portion (cycles 5 to 8)====
*Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 8 cycles (E x 4; X x 4)
===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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
==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 shorter DFS1DFS96: 37% vs 47%(HR 1.32, 95% CI 1.00-1.72)
1Reported efficacy is based on the 2009 update.
====Preceding treatment====
*Surgery
====Chemotherapy, EC portion (cycles 1 to 4)====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, CMF portion (cycles 5 to 7)====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 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)
====Subsequent treatment====
*Adjuvant Tamoxifen x 5 y versus no further treatment
===Regimen variant #2===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Kümmel et al. 2006	1996-2000 	Phase 3 (C)	ddEC-ddCMF	Did not meet primary endpoint of DFSDFS48: 58% vs 64%(HR 1.32, 95% CI 0.82-2.13)
====Preceding treatment====
*Surgery
====Chemotherapy, EC portion (cycles 1 to 4)====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, CMF portion (cycles 5 to 7)====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
*Methotrexate (MTX) 40 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
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 shorter EFS (primary endpoint)EFS48: 42% vs 52%(HR 1.33, 95.32% CI 0.94-1.85)
====Preceding treatment====
*Surgery
====Chemotherapy, EC portion (cycles 1 to 4)====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, CMF portion (cycles 5 to 7)====
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 8
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 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)
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
==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) 	ECT with auto HSCT x 2	Shorter EFS (primary endpoint)Median EFS: 40.6 vs 76.1 mo(HR not reported, p=0.00069)Seems to have shorter OS (secondary endpoint)Median OS: 75.9 vs NYR mo(HR not reported, p=0.02)
Kümmel et al. 2006 	1996-2000 	Phase 3 (E-esc)	EC-CMF 	Did not meet primary endpoint of DFSDFS48: 64% vs 58%(HR 0.76, 95% CI 0.47-1.22)
====Preceding treatment====
*Surgery
====Chemotherapy, ddEC portion (cycles 1 to 4)====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, ddCMF portion (cycles 5 to 7)====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 1 to 2 hours once on day 1
*Methotrexate (MTX) 40 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 600 mg/m2 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 or 13
14-day cycle for 7 cycles (ddEC x 4; ddCMF x 3)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
==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====
*Surgery
====Chemotherapy, EC portion (cycles 1 to 3)====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, D portion (cycles 4 to 6)====
*Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
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 longer IDFS (primary endpoint)IDFS60: 86% vs 82%(HR 0.77, 95% CI 0.61-0.97)
Nitz et al. 2014 (WSG-AGO EC-Doc) 	2000-2005 	Phase 3 (E-switch-ic)	1a. CMF1b. FEC	Seems to have longer EFS (primary endpoint)EFS60: 89.8% vs 87.3%(HR 0.74, 95% CI 0.57-0.97)Seems to have longer OS (secondary endpoint)OS60: 94.5% vs 92.8%(HR 0.70, 95% CI 0.49-0.99)
====Preceding treatment====
*Surgery
====Chemotherapy, EC portion (cycles 1 to 4)====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, D portion (cycles 5 to 8)====
*Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 8 cycles (EC x 4; D x 4)
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00689156
==ddEC-ddD==
ddEC-ddD: dose-dense Epirubicin & Cyclophosphamide followed by dose-dense Docetaxel
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Foukakis et al. 2016 (PANTHER)	2007-2011 	Phase 3 (E-esc)	FEC-D; 3 x 3	Seems to have longer RFS1 (primary endpoint)RFS120: 22.3% vs 18.6%(HR 0.80, 95% CI 0.65-0.98)
1Reported efficacy is based on the 2024 update.
====Preceding treatment====
*Surgery
====Chemotherapy, ddEC portion (cycles 1 to 4)====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, ddD portion (cycles 5 to 8)====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
====Supportive therapy, both portions (cycles 1 to 8)====
*ONE of the following:
**Filgrastim (Neupogen) (dose not specified) SC once per day on days 4 to 11
**Pegfilgrastim (Neulasta) 6 mg SC once on day 2
14-day cycle for 8 cycles (ddEC x 4; ddD x 4)
====Dose and schedule modifications====
*Epirubicin dose adjusted from 38 mg/m2 to 120 mg/m2 based on prior cycle nadirs; see paper for details
*Cyclophosphamide dose adjusted from 450 mg/m2 to 1200 mg/m2 based on prior cycle nadirs; see paper for details
*Docetaxel dose adjusted from 60 mg/m2 to 100 mg/m2 based on prior cycle nadirs; see paper for details
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00798070
##HRQoL analysis: Brandberg Y, Johansson H, Hellström M, Gnant M, Möbus V, Greil R, Foukakis T, Bergh J; Swedish Breast Cancer Group, the Austrian Breast, Colorectal Cancer Study Group, the German Breast Cancer Group. Long-term (up to 16 months) health-related quality of life after adjuvant tailored dose-dense chemotherapy vs standard three-weekly chemotherapy in women with high-risk early breast cancer. Breast Cancer Res Treat. 2020 May;181(1):87-96. Epub 2020 Mar 31. link to original article link to PMC article EuroPMC
##Update: Matikas A, Möbus V, Greil R, Andersson A, Steger GG, Untch M, Fornander T, Malmström P, Schmatloch S, Johansson H, Hellström M, Brandberg Y, Gnant M, Loibl S, Foukakis T, Bergh J; SweBCG, ABCSG and GBG. Tailored Dose-Dense Versus Standard Adjuvant Chemotherapy for High-Risk Early Breast Cancer: End-of-Study Results of the Randomized PANTHER Trial. J Clin Oncol. 2024 Sep 10;42(26):3077-3082. Epub 2024 Jul 17. link to original article link to PMC article EuroPMC
==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-wP 	Might have lower DFS60 (co-primary endpoint)DFS60: 78.3% vs 84.7%(sHR 1.47, 95% CI 0.96-2.22)
Note: this trial should not be confused with the one by the same name in head & neck cancer.
====Preceding treatment====
*Surgery
====Chemotherapy, EC portion (cycles 1 to 4)====
*Epirubicin (Ellence) 75 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, T portion (cycles 5 to 16)====
*Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
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 DFSDFS120: 65% vs 65%(aHR 1.03, 95% CI 0.91-1.16)
Del Mastro et al. 2015 (GIM2)	2003-2006 	Phase 3 (C)	1. ddEC-ddT2. ddFEC-ddT	Shorter OS
Del Mastro et al. 2015 (GIM2)	2003-2006 	Phase 3 (C)	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 DFSDFS60: 80.6% vs 86%(HR 1.22, 95% CI 0.91-1.64)
====Preceding treatment====
*Surgery
====Chemotherapy, EC portion (cycles 1 to 4)====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, T portion (cycles 5 to 8)====
*Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
21-day cycle for 8 cycles (EC x 4; T x 4)
===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; 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC NCT00039546
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01026116
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01134523
#CH-BC-012: NCT01378533
#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 	Longer RFS (primary endpoint)RFS36: 89.5% vs 85%(HR 0.60, 95% CI 0.44-0.80)
Burnell et al. 2009 (NCIC-CTG MA.21)	2000-2005 	Phase 3 (E-esc)	2. FEC 	Did not meet primary endpoint of RFSRFS36: 89.5% vs 90.1%(HR 0.89, 95% CI 0.64-1.22)
====Preceding treatment====
*Surgery
====Chemotherapy, ddEC portion (cycles 1 to 6)====
*Epirubicin (Ellence) 120 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 830 mg/m2 IV once on day 1
====Supportive therapy, ddEC portion (cycles 1 to 6)====
*Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 2 to 13
*Epoetin alfa (Procrit) 40,000 units SC once per day on days 1 & 8
====Chemotherapy, T portion (cycles 7 to 10)====
*Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
14-day cycle for 6 cycles, then 21-day cycle for 4 cycles (ddEC x 6; T x 4)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00014222
==ddEC-ddT==
ddEC-ddT: dose-dense Epirubicin & Cyclophosphamide followed by dose-dense Taxol (Paclitaxel)
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Del Mastro et al. 2015 (GIM2)	2003-2006 	Phase 3 (E-esc)	1. EC-T2. FEC-P	Longer OS (secondary endpoint)OS60: 94% vs 89%(HR 0.65, 95% CI 0.51-0.84)Longer DFS (primary endpoint)DFS60: 81% vs 76%(HR 0.77, 95% CI 0.65-0.92)
Del Mastro et al. 2015 (GIM2)	2003-2006 	Phase 3 (E-esc)	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====
*Surgery
====Chemotherapy, ddEC portion (cycles 1 to 4)====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, ddT portion (cycles 5 to 8)====
*Paclitaxel (Taxol) 175 mg/m2 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)
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
==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 iDFSiDFS48: 84.3% vs 84.3%
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====
*Surgery
====Chemotherapy, iddE portion (cycles 1 to 3)====
*Epirubicin (Ellence) 150 mg/m2 IV once on day 1 
====Chemotherapy, iddnP portion (cycles 4 to 6)====
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 330 mg/m2 IV once on day 1 
====Chemotherapy, iddC portion (cycles 7 to 9)====
*Cyclophosphamide (Cytoxan) 2000 mg/m2 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; iddnP x 3; iddC x 3)
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 	Longer 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====
*Surgery
====Chemotherapy, iddE portion (cycles 1 to 3)====
*Epirubicin (Ellence) 150 mg/m2 IV once on day 1 
====Chemotherapy, iddP portion (cycles 4 to 6)====
*Paclitaxel (Taxol) 225 mg/m2 IV once on day 1
====Chemotherapy, iddC portion (cycles 7 to 9)====
*Cyclophosphamide (Cytoxan) 2000 mg/m2 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)
===References===
# 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 EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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====
*Surgery
====Chemotherapy, EP portion (cycles 1 to 4)====
*Epirubicin (Ellence) 83 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 187 mg/m2 IV once on day 1
====Chemotherapy, ddCMF portion (cycles 5 to 7)====
*Cyclophosphamide (Cytoxan) 840 mg/m2 IV once on day 1
*Methotrexate (MTX) 57 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 840 mg/m2 IV once on day 1
====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===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
==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 longer DFS (primary endpoint)DFS60: 93% vs 90.3%(HR 0.73, 95% CI 0.54-0.99)
====Preceding treatment====
*Surgery
====Chemotherapy, FAC portion (cycles 1 to 4)====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
====Chemotherapy, T portion (cycles 5 to 12)====
*Paclitaxel (Taxol) 100 mg/m2 IV once on day 1
21-day cycle for 4 cycles, then 7-day cycle for 8 cycles (FAC x 4; T x 8)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 	Longer OS1 (secondary endpoint)OS96: 83.2% vs 78%(aHR 0.75, 95% CI 0.62-0.92)Seems to have higher DFS60 (primary endpoint)
de Gregorio et al. 2020 (SUCCESS-A) 	2005-2007 	Phase 3 (C) 	FEC-DG 	Did not meet primary endpoint of DFSDFS60: 86.6% vs 87.2%(HR 1.08, 95% CI 0.89-1.28)
Sakr et al. 2013 	2006-2010 	Phase 3 (E-switch-ic)	FEC; FEC 100 x 6	Seems to have longer OS (secondary endpoint)OS60: 89.4% vs 85%(HR 0.73, 95% CI 0.56-0.94)Seems to have higher DFS60 (primary endpoint)DFS60: 78% vs 74%
Campone et al. 2018 (UCBG 2-08) 	2007-2010 	Phase 3 (C) 	FEC-Ixabepilone 	Did not meet primary endpoint of DFS60DFS60: 76% vs 79%(HR 1.25, 95% CI 0.91-1.72)
Foukakis et al. 2016 (PANTHER) 	2007-2011 	Phase 3 (C) 	ddEC-ddD; 4 x 4 	Seems to have shorter RFS2 (primary endpoint)RFS120: 18.6% vs 22.3%(HR 1.25, 95% CI 1.02-1.54)
Delaloge et al. 2020 (MINDACT) 	2007-2011 	Phase 3 (C) 	TX 	Did not meet primary endpoint of DFSDFS60: 88.8% vs 90.7%(HR 1.20, 95% CI 0.87-1.67)
de Gregorio et al. 2022 (LMU Success C)	2008-2011 	Phase 3 (C) 	TC 	Inconclusive whether non-inferior DFS3 (primary endpoint)
1Reported efficacy for FNCLCC PACS 01 is based on the 2012 update.
2Reported efficacy for PANTHER is based on the 2024 update; note that this is a change from previously borderline statistically significant findings.
3LMU Success C was designed as a non-inferiority trial but was reported using a superiority design post-hoc analysis.
====Preceding treatment====
*Surgery
====Chemotherapy, FEC portion (cycles 1 to 3)====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 100 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
====Chemotherapy, D portion (cycles 4 to 6)====
*Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
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-CMF1b. 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====
*Surgery
====Chemotherapy, FEC portion (cycles 1 to 4)====
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
*Epirubicin (Ellence) 40 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, D portion (cycles 5 to 8)====
*Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 8 cycles (FEC x 4; D x 4)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00798070
##HRQoL analysis: Brandberg Y, Johansson H, Hellström M, Gnant M, Möbus V, Greil R, Foukakis T, Bergh J; Swedish Breast Cancer Group, the Austrian Breast, Colorectal Cancer Study Group, the German Breast Cancer Group. Long-term (up to 16 months) health-related quality of life after adjuvant tailored dose-dense chemotherapy vs standard three-weekly chemotherapy in women with high-risk early breast cancer. Breast Cancer Res Treat. 2020 May;181(1):87-96. Epub 2020 Mar 31. link to original article link to PMC article EuroPMC
##Update: Matikas A, Möbus V, Greil R, Andersson A, Steger GG, Untch M, Fornander T, Malmström P, Schmatloch S, Johansson H, Hellström M, Brandberg Y, Gnant M, Loibl S, Foukakis T, Bergh J; SweBCG, ABCSG and GBG. Tailored Dose-Dense Versus Standard Adjuvant Chemotherapy for High-Risk Early Breast Cancer: End-of-Study Results of the Randomized PANTHER Trial. J Clin Oncol. 2024 Sep 10;42(26):3077-3082. Epub 2024 Jul 17. link to original article link to PMC article EuroPMC
# 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 EuroPMC 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. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT02181101
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00847444
==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====
*Surgery
====Chemotherapy, ddFEC portion (cycles 1 to 4)====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1 
*Epirubicin (Ellence) 75 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
====Chemotherapy, ddD portion (cycles 5 to 8)====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
====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===
# 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 dosing details in abstract have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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 	Longer DFS60 (primary endpoint)DFS60: 78.5% vs 72.1%(HR 0.77, 95% CI 0.62-0.95)
====Preceding treatment====
*Surgery
====Chemotherapy, FEC portion (cycles 1 to 4)====
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Chemotherapy, P portion (cycles 5 to 12)====
*Paclitaxel (Taxol) 100 mg/m2 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)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
==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====
*Surgery
====Chemotherapy, T portion (cycles 1 to 12)====
*Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
====Chemotherapy, FEC portion (cycles 13 to 16)====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 100 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (T x 12; FEC x 4)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 	Longer RFS (primary endpoint)RFS36: 93% vs 89%(HR 0.66, 95% CI 0.47-0.94)Seems to have longer 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====
*Surgery
====Chemotherapy, TX portion (cycles 1 to 3)====
*Docetaxel (Taxotere) 60 mg/m2 IV over 60 minutes once on day 1
*Capecitabine (Xeloda) 900 mg/m2 PO twice per day on days 1 to 15
====Chemotherapy, CEX portion (cycles 4 to 6)====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
*Epirubicin (Ellence) 75 mg/m2 IV once on day 1
*Capecitabine (Xeloda) 900 mg/m2 PO twice per day on days 1 to 15
21-day cycle for 6 cycles (TX x 3; CEX x 3)
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
## 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 EuroPMC
==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 	Shorter RFS (primary endpoint)RFS36: 86% vs 91%(HR 1.72, 95% CI 1.18-2.50)
Note: this is the study design for patients with HER2-negative disease.
====Preceding treatment====
*Surgery
====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)====
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
*Epirubicin (Ellence) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 6 cycles (V x 3; FEC x 3)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
=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====
*Neoadjuvant AC+Bev x 4, then surgery
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for 10 cycles
===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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
==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 41b. CMF x 6	Seems to have shorter RFS1 (primary endpoint)RFS120: 50% vs 56%(HR 1.25, 95% CI 1.02-1.61)
Masuda et al. 2017 (CREATE-X) 	2007-2012 	Phase 3 (E-esc) 	Standard therapy 	Longer DFS (primary endpoint)DFS60: 74.1% vs 67.6%(HR 0.70, 95% CI 0.53-0.92)Longer 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====
*CALGB 49907: Surgery
*CREATE-X: Neoadjuvant chemotherapy containing anthracycline, taxane, or both, then surgery
====Chemotherapy====
*Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 6 to 8 cycles
===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]. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 shorter DFSMedian DFS: 2.7 vs 4.4 years(HR not reported, p=0.04)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
*Methotrexate (MTX) 40 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
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====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
*Methotrexate (MTX) 40 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
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====
*Mastectomy
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
*Methotrexate (MTX) 40 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
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 	Seems to have shorter DFS (primary endpoint)(HR 1.19, 95% CI 1.01-1.41)Shorter OS (secondary endpoint)(HR 1.27, 95% CI 1.06-1.52)
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====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
*Methotrexate (MTX) 40 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
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 lower DFS60 (primary endpoint)DFS60: 50% vs 58%
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====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
*Methotrexate (MTX) 60 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
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 longer OS
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 50 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 15 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 350 mg/m2 IV once per day on days 1 & 8
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. CMFP2. Bilateral oophorectomy3. Oophorectomy & Prednisolone	Did not meet primary endpoint of EFS
Poole et al. 2006 (BR9601) 	1996-2001 	Phase 3 (C)	E-CMF x 4+4 	Shorter OS1 (co-primary endpoint)OS60: 78% vs 84%(HR 1.32, 95% CI 1.12-1.54)
Fernando et al. 2019 (SECRAB)	1998-2004 	Phase 3 (C)	1a. CMF & RT1b. E-CMF & RT1c. A-CMF & RT1d. MMM & RT 	Higher LRR120 (co-primary endpoint)LRR120: 7.1% vs 4.6%(HR 1.61, 95% CI 1.11-2.33)
1Reported efficacy for BR9601 is based on the 2012 update.
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
*Methotrexate (MTX) 50 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
21-day cycle for varying durations: 6 cycles (SECRAB); 8 cycles (BR9601, Stewart et al. 1993)
===Regimen variant #8, 840/50/800===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hubay et al. 1980	Not reported 	Randomized (C)	1. CMFT 	Seems to have shorter RFS
Hubay et al. 1980	Not reported 	Randomized (C)	2. CMFT & BCG	Did not meet endpoints of RFS/OS
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 30 mg/m2 PO twice per day on days 1 to 14
*Methotrexate (MTX) 25 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 & 8
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====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 8
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
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 	Shorter OS
====Preceding treatment====
*Surgery, within 6 weeks
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 8
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
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
Brincker et al. 1983 (DBCG 77B)	1977-1983 	Phase 3 (E-esc)	2. Levamisole 	Not reported
Brincker et al. 1983 (DBCG 77B)	1977-1983 	Phase 3 (E-esc)	3. No chemotherapy 	Seems to have longer OS1 (secondary endpoint)
1Reported efficacy versus no chemotherapy is based on the 2010 update.
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 80 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 30 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
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	Longer RFS
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 80 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 32 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 4800 mg/m2 IV once per day on days 1 & 8
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 longer DFS
Note: leucovorin was not used for antineoplastic effect in this regimen.
====Preceding treatment====
*Mastectomy
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 400 mg/m2 IV once per day on days 1 & 8
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 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
===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====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once per day on days 1 & 8
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
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 shorter 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 longer RFS(HR 0.70, 95% CI 0.52-0.96)
Poole et al. 2006 (NEAT) 	1996-2001 	Phase 3 (C)	E-CMF x 4+4 	Shorter OS1 (co-primary endpoint)OS60: 78% vs 84%(HR 1.32, 95% CI 1.12-1.54)
Fernando et al. 2019 (SECRAB) 	1998-2004 	Phase 3 (C)	1a. CMF & RT1b. E-CMF & RT1c. A-CMF & RT1d. MMM & RT	Higher LRR120 (co-primary endpoint)LRR120: 7.1% vs 4.6%(HR 1.61, 95% CI 1.11-2.33)
Perrone et al. 2014 (ELDA) 	2003-2011 	Phase 3 (C)	Docetaxel 	Did not meet primary endpoint of DFS
1Reported efficacy for NEAT is based on the 2012 update.
Note: In ELDA, this protocol was for ER/PR- patients.
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once per day on days 1 & 8
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
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
Rubens et al. 1989 (EORTC 10792)	1979-1985 	Phase 3 (E-esc)	2. Tamoxifen3. CMFT	Not reported
Note: this trial had a complex efficacy analysis; see paper for details.
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 30 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
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====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
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 shorter DFS
Castiglione-Gertsch et al. 1996 (IBCSG VI)	1986-1993 	Phase 3 (E-de-esc)	2. CMF x 3, with re-introduction3. CMF x 6, with re-introduction	Might have shorter DFS
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 3 cycles
====Subsequent treatment====
*Adjuvant Tamoxifen x 5 y versus no further treatment
===Regimen variant #19, 1400/80/1200 x 6===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Tancini et al. 1979 (CALGB 7581) 	1975 to not reported	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 longer DFS
Castiglione-Gertsch et al. 1996 (IBCSG VI) 	1986-1993 	Phase 3 (C) 	2. CMF x 3, with re-introduction 3. CMF x 6, with re-introduction	Might have shorter DFS
Piccart et al. 2001 (Belgian trial) 	1988-1996 	Phase 3 (C) 	1. EC; full-dose 	Did not meet primary endpoint of EFS
Piccart et al. 2001 (Belgian trial) 	1988-1996 	Phase 3 (C) 	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 	Seems to have shorter RFS (primary endpoint)RFS60: 53% vs 63%(aHR 1.30, 95% CI 1.04-1.64)
Amadori et al. 2000 	1989-1993 	Phase 3 (E-esc) 	Observation 	Longer DFS (primary endpoint)DFS60: 83% vs 72%(HR 0.59, 95% CI 0.36-0.95)
Hutchins et al. 2005 (INT-0102) 	1989-1993 	Phase 3 (C) 	CAF 	Did not meet primary endpoint of DFSDFS120: 75% vs 77%(HR 0.92, 95% CI 0.79-1.06)
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 longer 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 	Shorter OS1 (co-primary endpoint)OS60: 78% vs 84%(HR 1.32, 95% CI 1.12-1.54)
Fernando et al. 2019 (SECRAB) 	1998-2004 	Phase 3 (C) 	1a. CMF & RT1b. E-CMF & RT1c. A-CMF & RT1d. MMM & RT 	Higher LRR120 (co-primary endpoint)LRR120: 7.1% vs 4.6%(HR 1.61, 95% CI 1.11-2.33)
Muss et al. 2009 (CALGB 49907) 	2001-2006 	Phase 3 (C) 	Capecitabine 	Seems to have longer RFS1 (primary endpoint)RFS120: 56% vs 50%(HR 0.80, 95% CI 0.62-0.98)
Sparano et al. 2018 (TAILORx) 	2006-2010 	Phase 3 (C) 	No chemotherapy 	Non-inferior IDFS (primary endpoint)
1Reported efficacy for NEAT is based on the 2012 update.
2Reported efficacy for CALGB 49907 is based on the 2019 update.
====Eligibility criteria====
*TAILORx: Oncotype DX score of 11 to 25
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 cycles
====Subsequent treatment====
*NSABP B-23 and INT-0102: Adjuvant tamoxifen x 5 years versus placebo
===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 	Longer RFS
Tancini et al. 1979 (CALGB 7581)	1975 to not reported	Phase 3 (C) 	CMF x 6 	Did not meet primary endpoint of RFS
Misset et al. 1996 (OncoFrance) 	1978-1981 	Phase 3 (C) 	AVCF 	Shorter OS
Tormey et al. 1990 (ECOG E5177) 	1978-1982 	Phase 3 (C) 	1. CMFP2. CMFPT	Did not meet co-primary endpoints of time to response/OS
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 12 cycles
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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. EuroPMC
## 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 EuroPMC
# 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 EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
#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 EuroPMC
##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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002582
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article dosing details in abstract have been reviewed by our editors EuroPMC 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]. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC 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. link to original article link to PMC article dosing details in supplement have been reviewed by our editors EuroPMC 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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 	Longer DFS1
Overgaard et al. 1999 (DBCG 82C)	1982-1990 	Phase 3 (E-esc)	2. Tamoxifen & RT	Not reported
1Reported efficacy for this arm versus tamoxifen monotherapy is based on the 2013 update.
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 1 to 9: 600 mg/m2 IV once on day 1
*Methotrexate (MTX) as follows:
**Cycles 1 to 9: 40 mg/m2 IV once on day 1
*Fluorouracil (5-FU) as follows:
**Cycles 1 to 9: 600 mg/m2 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
===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====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) as follows:
**Cycles 1 to 6: 65 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) as follows:
**Cycles 1 to 6: 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) as follows:
**Cycles 1 to 6: 500 mg/m2 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
===Regimen variant #3, 840/50/800/40 x 12===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Hubay et al. 1980	Not reported 	Randomized (E-RT-esc)	1. CMF 	Seems to have longer RFS
Hubay et al. 1980	Not reported 	Randomized (E-RT-esc)	2. CMFT & BCG	Did not meet endpoints of RFS/OS
====Preceding treatment====
*Surgery
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 30 mg/m2 PO twice per day on days 1 to 14
*Methotrexate (MTX) 25 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 & 8
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO twice per day
28-day cycle for 12 cycles
===References===
# 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 EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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 does not contain dosing details in manuscript EuroPMC
## 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 	Longer DFS (primary endpoint)DFS60: 86% vs 80%(HR 0.67, 95% CI 0.50-0.94)
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 	Inconclusive whether non-inferior IDFS (primary endpoint)IDFS48: 88.2% vs 90.7%(HR 1.20, 95% CI 0.97-1.49)
Blum et al. 2017 (NSABP-46-I/USOR 07132)	2009-2012 	Phase 3 (C) 	TAC 	Inconclusive whether non-inferior IDFS (primary endpoint)IDFS48: 88.2% vs 90.7%(HR 1.20, 95% CI 0.97-1.49)
Blum et al. 2017 (NSABP B-49) 	2012-04-04 to 2013-11-21	Phase 3 (E-de-esc) 	TAC 	Inconclusive whether non-inferior IDFS (primary endpoint)IDFS48: 88.2% vs 90.7%(HR 1.20, 95% CI 0.97-1.49)
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====
*Surgery
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Supportive therapy====
*Most protocols: all cycles given with Filgrastim (Neupogen) support
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 DFSDFS60: 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)
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
====Preceding treatment====
*Surgery
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 6 cycles
===References===
# 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 EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article dosing details in supplement have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00847444
#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
Shulman et al. 2012 (CALGB 40101)	2002-2008 	Phase 3 (E-de-esc)	2. ddT x 4 	Did not meet primary endpoint of RFS
Shulman et al. 2012 (CALGB 40101)	2002-2008 	Phase 3 (E-de-esc)	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====
*Surgery
====Chemotherapy====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====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====
*Surgery
====Chemotherapy====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
====Supportive therapy====
*Pegfilgrastim (Neulasta) 6 mg SC once on day 2
14-day cycle for 6 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors link to study protocol PDF link to PMC article EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in supplement have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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
Piccart et al. 2001 (Belgian trial)	1988-1996 	Phase 3 (E-de-esc)	2. EC; high-dose	Seems to have shorter EFS (primary endpoint)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Epirubicin (Ellence) 60 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
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====
*Surgery
====Chemotherapy====
*Epirubicin (Ellence) 75 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles
====Subsequent treatment====
*Adjuvant tamoxifen
===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
Piccart et al. 2001 (Belgian trial)	1988-1996 	Phase 3 (E-esc)	2. EC; moderate-dose	Seems to have longer EFS
====Preceding treatment====
*Surgery
====Chemotherapy====
*Epirubicin (Ellence) 100 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 830 mg/m2 IV once on day 1
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)	1. EC & Lonidamine2. EC & G-CSF3. EC, G-CSF, 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 DFS60DFS60: 73.4% vs 73.4%(HR 1.01, 95% CI 0.76-1.33)
====Preceding treatment====
*Papaldo et al. 2003: Surgery
*GOIM 9902: Surgery
====Chemotherapy====
*Epirubicin (Ellence) 120 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV push once on day 1
21-day cycle for 4 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
==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====
*NSABP B-27: Neoadjuvant AC x 4, then surgery
====Chemotherapy====
*Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 4 cycles
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
## 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 EuroPMC
# 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 link to PMC article EuroPMC
==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====
*Surgery
====Chemotherapy====
*Epirubicin (Ellence) 75 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycle for 6 cycles
===References===
#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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 	Shorter DFS (primary endpoint)DFS60: 72.7% vs 79.5%(HR 1.47, 95% CI 1.10-1.92)Shorter OS (secondary endpoint)OS60: 81.8% vs 88.9%(HR 1.52, 95% CI 1.06-2.17)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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====
*Surgery
====Chemotherapy====
*Epirubicin (Ellence) 110 mg/m2 IV once on day 1
14-day cycle for 3 cycles
====Subsequent treatment====
*CMF; intensified
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 6 cycles
====Subsequent treatment====
*Cyclophosphamide & Thiotepa, then auto HSCT consolidation followed by adjuvant tamoxifen versus adjuvant tamoxifen
===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 higher DFS60 (primary endpoint)DFS60: 58% vs 50%
Martin et al. 2005 (BCIRG 001) 	1997-1999 	Phase 3 (C) 	TAC 	Shorter OS1 (secondary endpoint)OS120: 69% vs 76%(HR 1.35, 95% CI 1.11-1.64)Shorter DFS (primary endpoint)DFS60: 68% vs 75%(aHR 1.39, 95% CI 1.14-1.69)
Martín et al. 2010 (GEICAM 9805) 	1999-2003 	Phase 3 (C) 	TAC 	Shorter DFS (primary endpoint)DFS60: 85.3% vs 90.1%(HR 1.47, 95% CI 1.08-2.04)
Martín et al. 2013 (GEICAM 2003-02)	2003-2008 	Phase 3 (C) 	FAC-T 	Seems to have shorter DFS (primary endpoint)DFS60: 90.3% vs 93%(HR 1.37, 95% CI 1.01-1.85)
Delaloge et al. 2020 (MINDACT) 	2007-2011 	Phase 3 (C) 	TX 	Did not meet primary endpoint of DFSDFS60: 88.8% vs 90.7%(HR 1.20, 95% CI 0.87-1.67)
1Reported efficacy for BCIRG 001 is based on the 2012 update.
====Preceding treatment====
*Surgery
====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====
*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/m2 SC once per day on days 4 to 11
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
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 to not reported	Phase 3 (E-de-esc)	1. FAC; 600/30/300 x 4 	Longer OS
Wood et al. 1994 (CALGB 8541)	1985 to not reported	Phase 3 (E-de-esc)	2. FAC; 1200/60/600 x 4	Did not meet primary endpoint of DFS
====Preceding treatment====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 & 8
*Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 & 8
*Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 4
*Doxorubicin (Adriamycin) 16.7 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m2)
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 8 cycles
====Subsequent treatment====
*CEP with auto HSCT consolidation versus no further 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 	Did not meet primary endpoint of DFSDFS120: 77% vs 75%(HR 1.09, 95% CI 0.94-1.27)
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
*Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 1 & 8
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
28-day cycle for 6 cycles
====Subsequent treatment====
*INT-0121: Cyclophosphamide & thiotepa, then auto HSCT consolidation versus no further chemotherapy
*ECOG E5188: Adjuvant Goserelin x 5 y versus Goserelin & Tamoxifen x 5 y versus no further treatment
*SWOG-8814: Adjuvant Tamoxifen x 5 y
===Regimen variant #8, 1200/60/600 x 4===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Wood et al. 1994 (CALGB 8541)	1985 to not reported	Phase 3 (C)	1. FAC; 600/30/300 x 4	Longer OS
Wood et al. 1994 (CALGB 8541)	1985 to not reported	Phase 3 (C)	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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
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 DFSDFS60: 88.8% vs 90.7%(HR 1.20, 95% CI 0.87-1.67)
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
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 shorter OS (primary endpoint)OS60: 78% vs 86%(HR not reported, p=0.039)
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1, 3, 5, 8
*Doxorubicin (Adriamycin) 25 mg/m2 IV once per day on days 1 & 8
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 5
28-day cycle for 4 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00929591
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00121992
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC 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 longer OS
Fumoleau et al. 2003 (FASG 01)	1986-1990 	Phase 3 (C) 	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 	Longer DFS
Bonneterre 2001 (FASG 05) 	1990-1993 	Phase 3 (C) 	FEC; FEC 100 x 6 	Shorter OSOS60: 65.3% vs 77.4%(aHR 1.54, 95% CI 1.14-2.08)
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 60 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 100 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
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 	Longer OSOS60: 77.4% vs 65.3%(aHR 0.65, 95% CI 0.48-0.88)
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 	Shorter OS1 (secondary endpoint)OS96: 78% vs 83.2%(aHR 1.33, 95% CI 1.09-1.61)Seems to have lower DFS60 (primary endpoint)
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 shorter EFSEFS60: 87.3% vs 89.8%(HR 1.35, 95% CI 1.03-1.75)Seems to have shorter OSOS60: 92.8% vs 94.5%(HR 1.43, 95% CI 1.01-2.04)
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
Thomssen et al. 2023 (NNBC 3-Europe) 	2002-2009 	Phase 3 (C) 	FEC-D 	Did not meet primary endpoint of DFSDFS60: 93.7% vs 93.2%(HR 0.95, 95% CI 0.68-1.35)
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 DFSDFS9y: 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 shorter OS (secondary endpoint)OS60: 85% vs 89.4%(HR 1.37, 95% CI 1.06-1.79)Seems to have lower DFS60 (primary endpoint)DFS60: 74% vs 78%
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 DFSDFS60: 88.8% vs 90.7%(HR 1.20, 95% CI 0.87-1.67)
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 100 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
*Epirubicin (Ellence) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
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 OSOS120: 78% vs 80%(HR 1.15, 95% CI 0.88-1.49)
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
*Epirubicin (Ellence) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
*Epirubicin (Ellence) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
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 	Seems to have longer DFS (primary endpoint)(HR 0.84, 95% CI 0.71-0.99)Longer OS (secondary endpoint)(HR 0.79, 95% CI 0.66-0.94)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
*Epirubicin (Ellence) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
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 	Lower DFS60 (primary endpoint)DFS60: 72.1% vs 78.5%(HR 1.30, 95% CI 1.05-1.61)
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
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 lower DFS60 (primary endpoint)DFS60: 67.2% vs 72.6%
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 700 mg/m2 IV once on day 1
*Epirubicin (Ellence) 75 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 700 mg/m2 IV once on day 1
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	Longer DFS (primary endpoint)DFS60: 81% vs 69%(HR 0.58, 95% CI 0.30-0.94)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
===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 DFSDFS60: 88.8% vs 90.7%(HR 1.20, 95% CI 0.87-1.67)
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
*Epirubicin (Ellence) 60 mg/m2 IV once per day on days 1 & 8
*Cyclophosphamide (Cytoxan) 370 mg/m2 IV once per day on days 1 & 8
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 	Seems to have longer RFS (primary endpoint)RFS60: 63% vs 53%(aHR 0.77, 95% CI 0.61-0.96)
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 	Longer RFS (primary endpoint)RFS36: 90.1% vs 85%(HR 0.67, 95% CI 0.50-0.89)
Burnell et al. 2009 (NCIC-CTG MA.21)	2000-2005 	Phase 3 (C) 	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 DFSDFS60: 88.8% vs 90.7%(HR 1.20, 95% CI 0.87-1.67)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
*Epirubicin (Ellence) 60 mg/m2 IV once per day on days 1 & 8
*Cyclophosphamide (Cytoxan) 75 mg/m2 PO once per day on days 1 to 14
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====
*Surgery
====Chemotherapy====
*Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
## 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 EuroPMC
# 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## 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. link to original article EuroPMC
# 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 
## 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 EuroPMC
# 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. link to original article EuroPMC
# 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. link to original article EuroPMC 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. link to original article EuroPMC
## 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. link to original article link to PMC article EuroPMC
# 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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. link to original article EuroPMC
# 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
## 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. link to original article link to PMC article EuroPMC
# 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. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in supplement have been reviewed by our editors EuroPMC 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. link to original article dosing details in supplement have been reviewed by our editors link to PMC article EuroPMC 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00087178
#NNBC 3-Europe: Thomssen C, Vetter M, Kantelhardt EJ, Meisner C, Schmidt M, Martin PM, Clatot F, Augustin D, Hanf V, Paepke D, Meinerz W, Hoffmann G, Wiest W, Sweep FCGJ, Schmitt M, Jänicke F, Loibl S, Minckwitz GV, Harbeck N; NNBC 3-Europe Study Group. Adjuvant Docetaxel in Node-Negative Breast Cancer Patients: A Randomized Trial of AGO-Breast Study Group, German Breast Group, and EORTC-Pathobiology Group. Cancers (Basel). 2023 Mar 3;15(5):1580. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC
==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 & RT1b. E-CMF & RT1c. A-CMF & RT1d. MMM & RT	Higher LRR120 (co-primary endpoint)LRR120: 7.1% vs 4.6%(HR 1.61, 95% CI 1.11-2.33)
====Preceding treatment====
*Surgery
====Chemotherapy====
*Mitomycin (Mutamycin) 8 mg/m2 IV once on day 1
*Mitoxantrone (Novantrone) 8 mg/m2 IV once on day 1
*Methotrexate (MTX) 35 mg/m2 IV once on day 1
21-day cycle for 6 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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
Shulman et al. 2012 (CALGB 40101)	2002-2008 	Phase 3 (E-de-esc)	2. AC x 6 	Did not meet primary endpoint of RFS
Shulman et al. 2012 (CALGB 40101)	2002-2008 	Phase 3 (E-de-esc)	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====
*Paclitaxel (Taxol) 80 mg/m2 IV over 60 minutes once on day 1
7-day cycle for 12 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors link to study protocol PDF link to PMC article EuroPMC 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. link to original article link to PMC article EuroPMC
==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
Shulman et al. 2012 (CALGB 40101)	2002-2008 	Phase 3 (E-de-esc)	2. ddAC x 6	Did not meet primary endpoint of RFS
Shulman et al. 2012 (CALGB 40101)	2002-2008 	Phase 3 (E-de-esc)	3. ddT x 6 	Did not meet primary endpoint of RFS
Burstein et al. 2005 	2003-2004 	Non-randomized 	 	Not reported
Note: in CALGB 40101, this is the dosing after a mid-protocol amendment in 2003.
====Preceding treatment====
*Burstein et al. 2005: Neoadjuvant ddAC, then surgery or surgery, then adjuvant ddAC
*CALGB 40101: Surgery, within 90 days
====Chemotherapy====
*Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
====Supportive therapy====
*Diphenhydramine (Benadryl) 12.5 to 50 mg IV once on day 1, given 30 to 60 minutes prior to paclitaxel
*One of the following H2 blockers:
**Ranitidine (Zantac) 50 mg IV once on day 1, given 30 to 60 minutes prior to paclitaxel
**Cimetidine (Tagamet) 300 mg IV once on day 1, given 30 to 60 minutes prior to paclitaxel
**Famotidine (Pepcid) 20 mg IV once on day 1, given 30 to 60 minutes prior to paclitaxel
*One of the following dexamethasone choices:
**Dexamethasone (Decadron) 10 mg IV once on day 1, given within 60 minutes prior to paclitaxel
**Dexamethasone (Decadron) 10 mg PO once on day 1, given at least 60 minutes prior to paclitaxel
**Dexamethasone (Decadron) 20 mg PO twice on day 1, given 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 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===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to study protocol PDF link to PMC article EuroPMC 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. link to original article link to PMC article EuroPMC
==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 shorter OS
Swain et al. 2010 (NSABP B-30)	1999-2004 	Phase 3 (C)	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====
*Surgery
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV over 15 minutes once on day 1
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV over 1 to 5 minutes once on day 1
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 	Longer OS1 (secondary endpoint)OS120: 76% vs 69%(HR 0.74, 95% CI 0.61-0.90)Longer DFS (primary endpoint)DFS60: 75% vs 68%(aHR 0.72, 95% CI 0.59-0.88)
Martín et al. 2010 (GEICAM 9805) 	1999-2003 	Phase 3 (E-switch-ic) 	FAC 	Longer DFS (primary endpoint)DFS60: 90.1% vs 85.3%(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
Swain et al. 2013 (NSABP B-38) 	2004-2007 	Phase 3 (C) 	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 	Inconclusive whether non-inferior IDFS (primary endpoint)IDFS48: 90.7% vs 88.2%(HR 0.83, 95% CI 0.67-1.03)
Blum et al. 2017 (NSABP-46-I/USOR 07132)	2009-2012 	Phase 3 (C) 	TC 	Inconclusive whether non-inferior IDFS (primary endpoint)IDFS48: 90.7% vs 88.2%(HR 0.83, 95% CI 0.67-1.03)
Blum et al. 2017 (NSABP B-49) 	2012-04-04 to 2013-11-21	Phase 3 (C) 	TC 	Inconclusive whether non-inferior IDFS (primary endpoint)IDFS48: 90.7% vs 88.2%(HR 0.83, 95% CI 0.67-1.03)
1Reported efficacy for BCIRG 001 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====
*Surgery
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given third, one hour after cyclophosphamide
*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 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/m2 SC once per day on days 4 to 11
21-day cycle for 6 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003782
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00121992
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in supplement have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC ISRCTN61893718
#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. CFP2. CMFVP	Did not meet primary endpoint of OS
====Chemotherapy====
*Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
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/D2. Docetaxel	Did not meet primary endpoint of TTF
====Chemotherapy====
*Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
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 	 	ORR: 80%
Tranum et al. 1982 (SWOG-7405B)	1974-1977 	Phase 3 (E-de-esc)	1. FAC2. A-CMFVP	Did not meet primary endpoint of ORR
====Chemotherapy====
*Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 200 mg/m2/day PO in divided doses on days 3 to 6
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. ACT2. Tamoxifen	Did not meet primary endpoint of OS
====Chemotherapy====
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
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) 	Not reported 	Phase 3 (C)	AT (Taxotere)	Shorter TTP (primary endpoint)Median TTP: 31.9 vs 37.3 weeks(aHR 1.32, 95% CI 1.06-1.67)
====Chemotherapy====
*Doxorubicin (Adriamycin) 60 mg/m2 IV over 15 minutes once on day 1, given first
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 15 minutes once on day 1, given second
21-day cycle of varying durations: 6 cycles (EORTC 10961); 8 cycles (TAX 306)
===Regimen variant #6, with range===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Robert et al. 2011 (RIBBON-1 Tax/Anthra cohort)	2005-2007 	Phase 3 (C)	1a. AC & Bevacizumab1b. Docetaxel & Bevacizumab1c. EC & Bevacizumab1d. FAC & Bevacizumab1e. FEC & Bevacizumab1f. nab-Paclitaxel & Bevacizumab	Shorter PFS (primary endpoint)Median PFS: 8 vs 9.2 mo(HR 1.56, 95% CI 1.25-1.92)
====Chemotherapy====
*Doxorubicin (Adriamycin) 50 to 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 500 to 600 mg/m2 IV once on day 1
21-day cycle for up to 8 cycles
===References===
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# RIBBON-1 Tax/Anthra cohort: 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 Tax/Anthra cohort)	2005-2007 	Phase 3 (E-esc)	1a. AC1b. Docetaxel1c. EC1d. FAC1e. FEC1f. nab-Paclitaxel	Longer PFS (primary endpoint)Median PFS: 9.2 vs 8 mo(HR 0.64, 95% CI 0.52-0.80)
====Chemotherapy====
*Doxorubicin (Adriamycin) 50 to 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 500 to 600 mg/m2 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
====Subsequent treatment====
*RIBBON-1, SD or better: Bevacizumab maintenance
===References===
# RIBBON-1 Tax/Anthra cohort: 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 longer OS
Stockler et al. 2011 (ANZ 0001)	2001-2005 	Phase 3 (E-de-esc)	2. Capecitabine; intermittent	Did not meet primary endpoint of quality-adjusted PFS
====Chemotherapy====
*Capecitabine (Xeloda) 650 mg/m2 PO twice per day
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====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
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 	 	ORR: 34.9%, 95% CI 21-50.9
Stockler et al. 2011 (ANZ 0001) 	2001-2005 	Phase 3 (E-de-esc)	1. CMF 	Seems to have longer OS (secondary endpoint)
Stockler et al. 2011 (ANZ 0001) 	2001-2005 	Phase 3 (E-de-esc)	2. Capecitabine; continuous	Did not meet primary endpoint of quality-adjusted PFS
Robert et al. 2011 (RIBBON-1 Cape cohort)	2005-2007 	Phase 3 (C) 	Capecitabine & Bevacizumab 	Shorter PFS (primary endpoint)Median PFS: 5.7 vs 8.6 mo(HR 1.45, 95% CI 1.19-1.79)
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
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 	 	ORR: 36.7%, 95% CI 19.9-56.1
Harbeck et al. 2016 (PELICAN)	2006-2010 	Phase 3 (E-switch-ic)	PLD 	Inconclusive whether non-inferior TTP (primary endpoint)
====Chemotherapy====
*Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
21-day cycles
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# RIBBON-1 Cape cohort: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00262067
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00266799
# CONTESSA: NCT03326674
==Capecitabine & Bevacizumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Robert et al. 2011 (RIBBON-1 Cape cohort)	2005-2007 	Phase 3 (E-esc) 	Capecitabine 	Longer PFS (primary endpoint)Median PFS: 8.6 vs 5.7 mo(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 shorter PFS (primary endpoint)Median PFS: 8.8 vs 9.6 mo(HR 1.19, 95% CI 0.99-1.43)
1Reported efficacy for TURANDOT is based on the 2016 update.
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===References===
# RIBBON-1 Cape cohort: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00262067
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00868634
==Capecitabine & Paclitaxel==
TX: Taxol (Paclitaxel), Xeloda (Capecitabine)
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Blum et al. 2006	2003 	Phase 2 	ORR (primary endpoint): 55%, 95% CI 40-69
====Chemotherapy====
*Capecitabine (Xeloda) 825 mg/m2 (rounded to nearest 500 mg) PO twice per day on days 1 to 14
*Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1 & 8
21-day cycles
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Capecitabine & Paclitaxel, nanoparticle albumin-bound==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Schwartzberg et al. 2011	Not reported 	Phase 2 	ORR: 61%
====Chemotherapy====
*Capecitabine (Xeloda) 825 mg/m2 PO twice per day on days 1 to 15 (28 doses total)
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m2 IV once per day on days 1 & 8
21-day cycles
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==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 lower ORR
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 350 mg/m2 IV once on day 1
*Methotrexate (MTX) 20 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 350 mg/m2 IV once on day 1
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 longer OS
Ingle et al. 1994 (NCCTG 87-32-52)	1987-1991 	Randomized (C)	DES-CEF 	Might have lower ORR
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
*Methotrexate (MTX) 40 mg/m2 IV once on day 1
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #3, 1000/80/1200===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Ackland et al. 2001 (HEPI 013)	1990-1992 	Phase 3 (C)	CEF 	Shorter TTP (primary endpoint)Median TTP: 6.3 vs 8.7 mo(HR 1.37, 95% CI 1.09-1.69)
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 8
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
21- to 28-day cycle for 6 to 9 cycles
===Regimen variant #4, 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 shorter OS
Aisner et al. 1987 (CALGB 7682)	1976-1980 	Phase 3 (C)	2. CAFVP 	Lower ORR
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
28-day cycles
===Regimen variant #5, 1400/60/800===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Canellos et al. 1976	Not reported 	Phase 3 (E-esc)	Melphalan 	Seems to have longer OS
Note: this was the dose used for patients older than 60 in the revised protocol of Canellos et al. 1976.
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 30 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 & 8
28-day cycles
===Regimen variant #6, 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 	Not reported 	Phase 3 (E-esc)	Melphalan 	Seems to have longer OS
Bull et al. 1978 	Not reported 	Phase 3 (C) 	CAF 	Might have lower ORR
Tormey et al. 1982 (ECOG E2173) 	1973-1974 	Randomized (C) 	1. AV2. CMFP 	Seems to have shorter OS
Cocconi et al. 1983 	Not reported 	Randomized (C) 	CMFT 	Might have shorter TTF
Viladiu et al. 1985 	1978-1981 	Randomized (C) 	1. CMFT2. CMF & MPA 	Seems to have lower ORR
Engelsman et al. 1991 (EORTC 10808)	1981-1984 	Phase 3 (C) 	CMF; 600/40/600 (IV) 	Seems to have longer 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 lower ORR
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 	Shorter TTP (primary endpoint)Median TTP: 6.7 vs 8.2 mo(HR not reported, p=0.0071)
Stockler et al. 2011 (ANZ 0001) 	2001-2005 	Phase 3 (C) 	1. Capecitabine; continuous2. Capecitabine; intermittent	Seems to have shorter OS
Note: this was the dose used for patients younger than 60 in the revised protocol of Canellos et al. 1976.
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycles
===Regimen variant #7, 1400/120/1200===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Canellos et al. 1976	Not reported 	Phase 3 (E-esc)	Melphalan 	Seems to have longer OS
Note: this was the dose used for patients in the original protocol of Canellos et al. 1976 and was deemed too myelotoxic.
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 60 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycles
===References===
# Brambilla C, De Lena M, Rossi A, Valagussa P, Bonadonna G. Response and survival in advanced breast cancer after two non-cross-resistant combinations. BMJ. 1976 Apr 3;1(6013):801-4. link to original article link to PMC article EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==CMFT==
CMFT: Cyclophosphamide, Methotrexate, Fluorouracil, Tamoxifen
===Regimen variant #1, lower-dose tamoxifen===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
Cocconi et al. 1983	Not reported 	Randomized (E-esc)	CMF 	Might have longer TTF
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 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
===Regimen variant #2, higher-dose tamoxifen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Viladiu et al. 1985	1978-1981 	Randomized (E-esc)	1. CMF2. CMF & MPA	Seems to have higher ORR
====Chemotherapy====
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
*Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
*Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
====Endocrine therapy====
*Tamoxifen (Nolvadex) 20 mg PO twice per day on days 1 to 28
28-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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 lower ORR (secondary endpoint)	Less hematotoxicity (primary endpoint)
====Chemotherapy====
*Docetaxel (Taxotere) 30 mg/m2 IV once per day on days 1, 8, 15
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	Less 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	Efficacy
Burstein et al. 2000	1998 	Phase 2 	ORR: 41%, 95% CI 24-61
====Chemotherapy====
*Docetaxel (Taxotere) 40 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
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. AC2. 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 	Worse EQ-5D score
====Chemotherapy====
*Docetaxel (Taxotere) 60 mg/m2 IV over 60 minutes once on day 1
21-day cycle for varying durations: 6 cycles (JCOG9802); 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	Worse EQ-5D score
====Chemotherapy====
*Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
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 	More toxicity
Stemmler et al. 2011 (D2) 	2001-2008 	Phase 3 (C)	Docetaxel; weekly 	Seems to have higher ORR 	More hematotoxicity
Sparano et al. 2009 (DOXIL-BCA-3001) 	2004-2006 	Phase 3 (C)	Docetaxel & PLD 	Shorter TTP (primary endpoint)Median TTP: 7 vs 9.8 mo(HR 1.54, 95% CI 1.30-1.82) 	Less toxic
Robert et al. 2011 (RIBBON-1 Tax/Anthra cohort)	2005-2007 	Phase 3 (C)	1a. AC & Bevacizumab1b. Docetaxel & Bevacizumab1c. EC & Bevacizumab1d. FAC & Bevacizumab1e. FEC & Bevacizumab1f. nab-Paclitaxel & Bevacizumab	Shorter PFS (primary endpoint)Median PFS: 8 vs 9.2 mo(HR 1.56, 95% CI 1.25-1.92) 	
Takashima et al. 2015 (SELECT BC) 	2006-2010 	Phase 3 (C)	S-1 	Seems to have non-inferior OS 	Worse EQ-5D score
Mackey et al. 2014 (ROSE/TRIO-12) 	2008-2011 	Phase 3 (C)	Docetaxel & Ramucirumab 	Might have shorter PFS (primary endpoint)Median PFS: 8.2 vs 9.5 mo(HR 1.14, 95% CI 0.99-1.33)	
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
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	Worse EQ-5D score
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
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====
*Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
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 HSCT2. 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====
*Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
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
Miles et al. 2010 (AVADO)	2006-03 to 2007-04 	Phase 3 (C)	2. Docetaxel & Bevacizumab; 100/15 	Shorter PFS
====Chemotherapy====
*Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
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 	 	ORR: 55%, 95% CI 40-69 	
Nielsen et al. 2011 	2001-2005 	Phase 3 (C) 	Docetaxel & Gemcitabine 	Might have shorter TTP (primary endpoint)Median TTP: 8.3 vs 10.3 mo(HR 1.30, 95% CI 0.99-1.69)	
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 weekly2. nab-Paclitaxel; lower-dose weekly 3. nab-Paclitaxel; q3wk 	Did not meet primary endpoint of ORR 	
Robert et al. 2011 (RIBBON-1 Tax/Anthra cohort)	2005-2007 	Phase 3 (C) 	1a. AC & Bevacizumab1b. Docetaxel & Bevacizumab1c. EC & Bevacizumab1d. FAC & Bevacizumab1e. FEC & Bevacizumab1f. nab-Paclitaxel & Bevacizumab	Shorter PFS (primary endpoint)Median PFS: 8 vs 9.2 mo(HR 1.56, 95% CI 1.25-1.92) 	
Bergh et al. 2012 (SUN 1064) 	2007-2009 	Phase 3 (C) 	Docetaxel & Sunitinib 	Did not meet primary endpoint of PFSMedian PFS: 8.3 vs 8.6 mo(HR 1.09, 95% CI 0.84-1.39) 	
====Chemotherapy====
*Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycles
===References===
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# Review: Burris HA 3rd. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin Oncol. 1999 Jun;26(3 Suppl 9):1-6. EuroPMC
# 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 EuroPMC content property of HemOnc.org
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00003032
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# RIBBON-1 Tax/Anthra cohort: 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in abstract have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
==Docetaxel & Bevacizumab==
===Regimen variant #1, 75/15, indefinite===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Robert et al. 2011 (RIBBON-1 Tax/Anthra cohort)	2005-2007 	Phase 3 (E-esc)	1a. AC1b. Docetaxel1c. EC1d. FAC1e. FEC1f. nab-Paclitaxel 	Longer PFS (primary endpoint)Median PFS: 9.2 vs 8 mo(HR 0.64, 95% CI 0.52-0.80)
Lück et al. 2014 (TABEA) 	2009-2012 	Phase 3 (C) 	1a. TX & Bevacizumab1b. Capecitabine, Paclitaxel, Bevacizumab	Did not meet primary endpoint of PFSMedian PFS: 11.3 vs 9.9 mo(HR 0.91, 95% CI 0.63-1.24)
Trédan et al. 2016 (GINECO-BR107) 	2010-2013 	Phase 3 (C) 	Docetaxel & Bevacizumab, then Exemestane & Bevacizumab 	Did not meet primary endpoint of PFS
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
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 	Longer PFS (primary endpoint)Median PFS: 10.1 vs 8.2 mo(HR 0.77, 95% CI 0.64-0.93)
Miles et al. 2010 (AVADO)	2006-03 to 2007-04 	Phase 3 (E-esc)	2. Docetaxel & Bevacizumab; 100/7.5	Not reported
====Chemotherapy====
*Docetaxel (Taxotere) 100 mg/m2 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
====Subsequent treatment====
*Bevacizumab maintenance
===Regimen variant #3, 100/15, indefinite===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Robert et al. 2011 (RIBBON-1 Tax/Anthra cohort)	2005-2007 	Phase 3 (E-esc)	1a. AC1b. Docetaxel1c. EC1d. FAC1e. FEC1f. nab-Paclitaxel	Longer PFS (primary endpoint)Median PFS: 9.2 vs 8 mo(HR 0.64, 95% CI 0.52-0.80)
====Chemotherapy====
*Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00333775
# RIBBON-1 Tax/Anthra cohort: 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 	Comparative Toxicity
Cassier et al. 2007 (ERASME 3)	2000-2004 	Phase 3 (E-switch-ic)	AT (Taxol)	Might have shorter OS (secondary endpont)Median OS: 21.4 vs 27.3 mo(HR not reported, p=0.081)	Did not meet primary endpoint of QoL
====Chemotherapy====
*Doxorubicin (Adriamycin) as follows:
**Cycles 1 to 4: 50 mg/m2 IV over 15 minutes once on day 1, given first
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given second
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 longer OS (secondary endpoint)Median OS: 22.6 vs 16.2 mo(HR 0.70, 95% CI 0.52-0.94)Longer TTP (primary endpoint)Median TTP: 8 vs 6.6 mo(HR 0.67, 95% CI 0.51-0.88)	
Alba et al. 2004 (GEICAM-9903)	1999-2001 	Phase 3 (C) 	A-D 	 	More toxic
====Chemotherapy====
*Doxorubicin (Adriamycin) 50 mg/m2 IV bolus once on day 1, given first
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given second, 1 hour after doxorubicin
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)	Not reported 	Phase 3 (E-switch-ic)	AC 	Longer TTP (primary endpoint)Median TTP: 37.3 vs 31.9 weeks(aHR 0.76, 95% CI 0.60-0.94)	
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====
*Doxorubicin (Adriamycin) 50 mg/m2 IV over 15 minutes once on day 1, given first
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given second, 60 minutes after doxorubicin
21-day cycle for 8 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
==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 	Higher ORR (primary endpoint)
Blohmer et al. 2010 	2000-2003 	Phase 3 (E-switch-ic) 	EC 	Did not meet primary endpoint of ORR
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
*Epirubicin (Ellence) 75 mg/m2 IV over 10 minutes once on day 1
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====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
*Epirubicin (Ellence) 75 mg/m2 IV once on day 1
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==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 longer TTP (primary endpoint)Median TTP: 10.3 vs 8.3 mo(HR 0.77, 95% CI 0.59-1.01)
Fountzilas et al. 2008 	2002-2006 	Phase 3 (E-esc) 	1. Carboplatin & Paclitaxel 	Did not meet primary endpoint of OS
Fountzilas et al. 2008 	2002-2006 	Phase 3 (E-esc) 	2. Paclitaxel; weekly 	Seems to have shorter 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; weekly2. GT; q3wk 3. GT; weekly	Did not meet primary endpoint of TTP
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given first
**Nielsen et al. 2011 gave docetaxel on day 8
*Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 minutes once per day on days 1 & 8
21-day cycle of varying durations: 6 cycles (Fountzilas et al. 2008); 6 to 10 cycles (B9E-IT-S376); indefinitely (B9E-MC-S273, Nielsen et al. 2011)
====Subsequent treatment====
*B9E-MC-S273, upon progression: Second-line Capecitabine
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 lower ORR
Note: Maximum cumulative dose in these trials was 750 mg/m2.
====Chemotherapy====
*Doxorubicin (Adriamycin) 20 mg/m2 IV over 5 to 10 minutes once on day 1
7-day cycle for 37 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. Lomustine2. Semustine	Longer OS
Hoogstraten et al. 1976 	1972-1974 	Phase 3 (C) 	CMFVP 	Seems to have lower ORR
Vaughn et al. 1988 (SWOG S8020) 	1980-1982 	Phase 3 (C) 	Doxorubicin & Etoposide 	Seems to have shorter TTP
Ingle et al. 1989 	1982-11 to 1987-02 	Randomized (C) 	DVM 	Seems to have shorter 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) 	Shorter TTF
Sledge et al. 2003 (ECOG E1193) 	1993-1995 	Phase 3 (C) 	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)Median PFS: 7.8 vs 6.9 mo(HR 1.00, 95% CI 0.82-1.22)
Note: in NCIC-CTG MA.8, this dose was after a mid-protocol amendment.
====Chemotherapy====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
21-day cycle of varying durations: until a cumulative dose of 450 mg/m2 (NCIC-CTG MA.8, SWOG S8020); 8 cycles (ECOG E1193); until a cumulative dose of 500 mg/m2 (Ingle et al. 1989); until a cumulative dose of 550 mg/m2 (Perez et al. 1991); indefinitely (O'Brien et al. 2004)
===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	Longer PFS (co-primary endpoint)Median PFS: 7.5 vs 3.9 mo(HR not reported, p=0.0001)
====Chemotherapy====
*Doxorubicin (Adriamycin) 75 mg/m2 IV over 5 to 15 minutes once on day 1
21-day cycle for up to 7 cycles
===References===
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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. Doxorubicin2. Paclitaxel; q3wk	Longer 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 	Comparative Toxicity
Cassier et al. 2007 (ERASME 3)	2000-2004 	Phase 3 (E-switch-ic)	AT (Taxotere)	Might have longer OS (secondary endpont)Median OS: 27.3 vs 21.4 mo(HR not reported, p=0.081)	Did not meet primary endpoint of QoL
====Chemotherapy====
*Doxorubicin (Adriamycin) as follows:
**Cycles 1 to 4: 50 mg/m2 IV over 15 minutes once on day 1, given first
*Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1, given second
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 	Longer OS (secondary endpoint)Median OS: 23.3 vs 18.3 mo(HR 0.68, 95% CI 0.51-0.93)
====Chemotherapy====
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 220 mg/m2 IV over 3 hours once on day 2
21-day cycle for up to 8 cycles
===Regimen variant #4, 60/175->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
====Chemotherapy====
*Doxorubicin (Adriamycin) 60 mg/m2 IV over 15 minutes once on day 1, given first
*Paclitaxel (Taxol) as follows:
**Cycle 1: 175 mg/m2 IV over 3 hours once on day 1, given second, 30 minutes after end of doxorubicin
**Cycles 2 to 5: 200 mg/m2 IV over 3 hours once on day 1, given second, 30 minutes after end of doxorubicin
21-day cycle for up to 6 cycles
===Regimen variant #5, 60/200===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Schmid et al. 2005	1998-2002 	Phase 3 (C)	Tandem auto HSCT	Did not meet primary endpoint of CR rate
====Chemotherapy====
*Doxorubicin (Adriamycin) 60 mg/m2 IV over 15 minutes once on day 1
*Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
21-day cycle for up to 6 cycles
===Regimen variant #6, with range===
Study 	Dates of enrollment	Evidence 	Efficacy
Gianni et al. 1995	1993-1994 	Non-randomized	ORR: 94%, 95% CI 79-99
====Chemotherapy====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 125 to 200 mg/m2 IV once on day 1
21-day cycles
===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. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
##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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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====
*Pegylated liposomal doxorubicin (Doxil) 45 mg/m2 IV once on day 1
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====
*Pegylated liposomal doxorubicin (Doxil) 50 mg/m2 IV over up to 60 minutes once on day 1
28-day cycles
====Dose and schedule modifications====
*If infusion reactions occurred, infusion could be given over up to 90 minutes
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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 	Shorter TTPMedian TTP: 5.6 vs 7.7 mo(HR 1.52, 95% CI 1.06-2.22)
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. Infusion and sequencing instructions are as per Chan et al. 2004.
====Chemotherapy====
*Epirubicin (Ellence) 75 mg/m2 IV over 60 minutes once on day 1, given second
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 15 minutes once on day 1, given first
21-day cycle for varying durations: 6 cycles (UKNCRI AB01); 8 cycles (Chan et al. 2004)
===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====
*Epirubicin (Ellence) 90 mg/m2 IV bolus once on day 1, given first
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 30 minutes once on day 1, given second
21-day cycle for 6 to 8 cycles
===Regimen variant #3, with range===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Robert et al. 2011 (RIBBON-1 Tax/Anthra cohort)	2005-2007 	Phase 3 (C)	1a. AC & Bevacizumab1b. Docetaxel & Bevacizumab1c. EC & Bevacizumab1d. FAC & Bevacizumab1e. FEC & Bevacizumab1f. nab-Paclitaxel & Bevacizumab	Shorter PFS (primary endpoint)Median PFS: 8 vs 9.2 mo(HR 1.56, 95% CI 1.25-1.92)
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====
*Epirubicin (Ellence) 90 to 100 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 to 600 mg/m2 IV once on day 1
21-day cycle for up to 8 cycles
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# RIBBON-1 Tax/Anthra cohort: 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 Tax/Anthra cohort)	2005-2007 	Phase 3 (E-esc)	1a. AC1b. Docetaxel1c. EC1d. FAC1e. FEC1f. nab-Paclitaxel	Longer PFS (primary endpoint)Median PFS: 9.2 vs 8 mo(HR 0.64, 95% CI 0.52-0.80)
====Chemotherapy====
*Epirubicin (Ellence) 90 to 100 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 to 600 mg/m2 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
====Subsequent treatment====
*RIBBON-1, SD or better: Bevacizumab maintenance
===References===
# RIBBON-1 Tax/Anthra cohort: 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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====
*Epirubicin (Ellence) 60 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
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 PFSMedian PFS: 10.8 vs 12.4 mo(HR 1.19, 95% CI 0.93-1.54)
Note: the doses of this regimen were individually adjusted after cycle 1; see paper for details.
====Chemotherapy====
*Epirubicin (Ellence) 75 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
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====
*Epirubicin (Ellence) 75 mg/m2 IV bolus once on day 1, given first
*Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given second
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====
*Epirubicin (Ellence) 80 mg/m2 IV once on day 1, given second
*Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1, given first
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====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
*Paclitaxel (Taxol) 200 mg/m2 IV once on day 1
21-day cycle for 8 cycles
===References===
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC 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. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
==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	Longer OS (secondary endpoint)Median OS: 19.1 vs 11.8 mo(HR not reported, p=0.0004)Longer TTP (primary endpoint)Median TTP: 6.1 vs 3.4 mo(HR 0.60, 95% CI 0.48-0.74)
====Chemotherapy====
*Epirubicin (Ellence) 35 mg/m2 IV once per day on days 1, 8, 15
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
Bastholt et al. 1996	1987-1991 	Phase 3 (E-de-esc)	2. Epirubicin; 90 mg/m2 	Shorter TTP
Bastholt et al. 1996	1987-1991 	Phase 3 (E-de-esc)	3. Epirubicin; 135 mg/m2	Did not meet primary endpoint of TTP
Note: In Bastholt et al. 1996, the maximum cumulative dose was 1000 mg/m2.
====Chemotherapy====
*Epirubicin (Ellence) 40 mg/m2 IV once on day 1
21-day cycle for 25 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
Note: Maximum cumulative dose in Gundersen et al. 1990 was 750 mg/m2.
====Chemotherapy====
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1
14-day cycle for 15 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/m22. Epirubicin; 90 mg/m2 3. Epirubicin; 135 mg/m2	Did not meet primary endpoint of TTP
Note: In Bastholt et al. 1996, the maximum cumulative dose was 1000 mg/m2; this was also the case for Nielsen et al. 1990 after a mid-protocol amendment.
====Chemotherapy====
*Epirubicin (Ellence) 60 mg/m2 IV once on day 1
21-day cycle for 16 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 shorter TTPMedian TTP: 8.4 vs 15.3 mo(HR not reported, p=0.045)	Less toxicity
====Chemotherapy====
*Epirubicin (Ellence) 70 mg/m2 IV once per day on days 1 & 8
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	Not reported 	Phase 3 (E-de-esc)	1. FEC; FEC 50	Seems to have lower ORR
Bonneterre & Hurteloup 1991	Not reported 	Phase 3 (E-de-esc)	2. FEC; FEC 75	Lower ORR
====Chemotherapy====
*Epirubicin (Ellence) 75 mg/m2 IV once on day 1
21-day cycle for 11 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 	Longer TTP
Bastholt et al. 1996 	1987-1991 	Phase 3 (C) 	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 	Shorter PFS (primary endpoint)Median PFS: 8.2 vs 10.1 mo(aHR 1.33, 95% CI 1.09-1.64)
Note: In SBG 9403, epirubicin was discontinued once the cumulative dose exceeded 900 mg/m2 but before it exceeded 950 mg/m2, after a mid-protocol amendment. In Bastholt et al. 1996, the maximum cumulative dose was 1000 mg/m2.
====Chemotherapy====
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1
21-day cycle of varying durations: 6 or more cycles (Perez et al. 1991); 10 cycles (SBG 9403); 11 cycles (Bastholt et al. 1996)
===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 	Lower ORR
Berruti et al. 2002 	1995-1999 	Phase 3 (C)	1. Cisplatin & Epirubicin2. Cisplatin, Epirubicin, Lonidamine3. Epirubicin & Lonidamine	Did not meet primary endpoint of TTP
====Chemotherapy====
*Epirubicin (Ellence) 60 mg/m2 IV once per day on days 1 & 2
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/m22. Epirubicin; 60 mg/m2 3. Epirubicin; 90 mg/m2	Did not meet primary endpoint of TTP
Note: In Bastholt et al. 1996, the maximum cumulative dose was 1000 mg/m2.
====Chemotherapy====
*Epirubicin (Ellence) 135 mg/m2 IV once on day 1
21-day cycle for 7 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
==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 longer 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) 	Shorter OS (secondary endpoint)Median OS: 18.3 vs 23.3 mo(HR 1.47, 95% CI 1.08-1.96)
Bontenbal et al. 2005 	1997-2002 	Phase 2/3 (C) 	AT (Taxotere) 	Seems to have shorter OS (secondary endpoint)Median OS: 16.2 vs 22.6 mo(HR 1.43, 95% CI 1.06-1.92)Shorter TTP (primary endpoint)Median TTP: 6.6 vs 8 mo(HR 1.49, 95% CI 1.14-1.96)
Robert et al. 2011 (RIBBON-1 Tax/Anthra cohort)	2005-2007 	Phase 3 (C) 	1a. AC & Bevacizumab1b. Docetaxel & Bevacizumab1c. EC & Bevacizumab1d. FAC & Bevacizumab1e. FEC & Bevacizumab1f. nab-Paclitaxel & Bevacizumab	Shorter PFS (primary endpoint)Median PFS: 8 vs 9.2 mo(HR 1.56, 95% CI 1.25-1.92)
1Reported efficacy for Smalley et al. 1977 is based on the 1983 update.
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV bolus once on day 1, given second
*Doxorubicin (Adriamycin) 50 mg/m2 IV bolus once on day 1, given first
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV over 15 minutes once on day 1, given third
21-day cycle for varying durations: 6 cycles (Muss et al. 1991, Bontenbal et al. 2005); 6 or more cycles (Namer et al. 2001); 8 cycles (Jassem et al. 2001, RIBBON-1); 9 cycles (Bennett et al. 1988); 10 cycles (Smalley et al. 1977); 11 cycles (Blajman et al. 1999)
====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====
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
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	Not reported 	Randomized (E-esc)	1. AF2. AFCM	Did not meet primary endpoint of ORR
====Chemotherapy====
*Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 & 8
*Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
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. VATH2. 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====
*Fluorouracil (5-FU) 200 mg/m2 IV once per day on days 1 to 5
*Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #5, 1000/50/500, indefinite===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Hortobagyi et al. 1979	1974 to not reported	Phase 3 (C)	FAC-BCG 	Shorter OS in responders
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8 or days 1 & 4
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
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====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
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
Aisner et al. 1987 (CALGB 7682) 	1976-1980 	Phase 3 (E-switch-ic)	2. CMF 	Higher ORR
Kardinal et al. 1983 (CALGB 8081)	1980-1982 	Randomized (C) 	CAFT 	Did not meet primary endpoint of ORR
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
*Doxorubicin (Adriamycin) 25 mg/m2 IV once per day on days 1 & 8
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
28-day cycle for up to 9 cycles
===Regimen variant #8, 1000/60/1400===
Study 	Dates of enrollment 	Evidence 	Comparator	Comparative Efficacy
Bull et al. 1978 	Not reported 	Phase 3 (E-switch-ic)	CMF 	Might have higher ORR
Cummings et al. 1985 	1978-1979 	Randomized (E-de-esc)	CMFP 	Did not meet primary endpoint of ORR
Falkson et al. 1987 (ECOG E2177)	Not reported to 1983	Randomized (C) 	O+CAF 	Did not meet co-primary endpoints of ORR/TTF/OS
Tominaga et al. 1994 	Not reported 	Phase 3 (C) 	CAF & MPA 	Seems to have lower ORR
Sledge et al. 2000 (ECOG E3186) 	1988-1992 	Phase 3 (C) 	CAFTH 	Might have shorter TTF (primary endpoint)Median TTF: 10.3 vs 13.4 mo(HR not reported, p=0.087)
Note: Doxorubicin was stopped once a cumulative dose of 450 mg/m2 was reached (Bull et al. 1978) or 500 mg/m2 was reached (Cummings et al. 1985, ECOG E2177).
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
*Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 1 & 8
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
28-day cycle for varying durations: 3 cycles (Tominaga et al. 1994); 6 cycles (ECOG E3186); 7 cycles (Bull et al. 1978); 8 cycles (Cummings et al. 1985, ECOG E2177)
====Subsequent treatment====
*Tominaga et al. 1994: 5-FU maintenance
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 EuroPMC
# 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 EuroPMC
## 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
##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 EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC 
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# RIBBON-1 Tax/Anthra cohort: 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 Tax/Anthra cohort)	2005-2007 	Phase 3 (E-esc)	1a. AC1b. Docetaxel1c. EC1d. FAC1e. FEC1f. nab-Paclitaxel	Longer PFS (primary endpoint)Median PFS: 9.2 vs 8 mo(HR 0.64, 95% CI 0.52-0.80)
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 500 mg/m2 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
====Subsequent treatment====
*RIBBON-1, SD or better: Bevacizumab maintenance
===References===
# RIBBON-1 Tax/Anthra cohort: 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 	Not reported 	Phase 3 (C)	1. Epirubicin 	Seems to have higher ORR
Bonneterre & Hurteloup 1991 	Not reported 	Phase 3 (C)	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 shorter TTPMedian TTP: 8 vs 19 mo(HR not reported, p<0.02)
Brufman et al. 1997 (HEPI 010) 	1989-1992 	Phase 3 (C)	FEC; FEC 100 	Lower 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
Note: Bonneterre & Hurteloup 1991 allowed a total cumulative epirubicin dose of 825 mg/m2. Focan et al. 1993 allowed a total cumulative epirubicin dose of 1000 mg/m2.
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for varying durations: 6 or more cycles (Namer et al. 2001); 8 cycles (HEPI 010); 12 cycles (GER-AIO-01/92); 16 cycles (Bonneterre & Hurteloup 1991); 20 cycles (Focan et al. 1993)
===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	Longer OS (secondary endpoint)Median OS: 21.2 vs 11.8 mo(HR not reported, p=0.01)
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 60 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
28-day cycles
===Regimen variant #3, 500/75/500 ("FEC 75")===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Bonneterre & Hurteloup 1991	Not reported 	Phase 3 (E-esc) 	1. Epirubicin 	Higher ORR
Bonneterre & Hurteloup 1991	Not reported 	Phase 3 (E-esc) 	2. FEC; FEC 50 	Did not meet primary endpoint of ORR
Pacini et al. 2000 	1991-1996 	Phase 3 (C) 	1. EM2. EM & Lonidamine	Shorter OS
Capotorto et al. 2003 	1995-1998 	Phase 3 (C) 	1. ddFEC 	Lower ORR
Capotorto et al. 2003 	1995-1998 	Phase 3 (C) 	2. ddMMM 	Did not meet endpoint of ORR
Bonneterre et al. 2004 	1998-2000 	Randomized Phase 2 (C)	DE 	Lower ORR
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV over 60 minutes once on day 1
*Epirubicin (Ellence) 75 mg/m2 IV over 10 minutes once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV over 30 minutes once on day 1
21-day cycle for varying durations: 6 or more cycles (Capotorto et al. 2003); 8 cycles (Bonneterre et al. 2004, Pacini et al. 2000); 11 cycles (Bonneterre & Hurteloup 1991)
===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 Tax/Anthra cohort)	2005-2007 	Phase 3 (C)	1a. AC & Bevacizumab1b. Docetaxel & Bevacizumab1c. EC & Bevacizumab1d. FAC & Bevacizumab1e. FEC & Bevacizumab1f. nab-Paclitaxel & Bevacizumab	Shorter PFS (primary endpoint)Median PFS: 8 vs 9.2 mo(HR 1.56, 95% CI 1.25-1.92)
Note: this is the lower bound of the dosing range allowed in RIBBON-1.
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 90 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
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 	Higher ORR
Robert et al. 2011 (RIBBON-1 Tax/Anthra cohort)	2005-2007 	Phase 3 (C) 	1a. AC & Bevacizumab1b. Docetaxel & Bevacizumab1c. EC & Bevacizumab1d. FAC & Bevacizumab1e. FEC & Bevacizumab1f. nab-Paclitaxel & Bevacizumab	Shorter PFS (primary endpoint)Median PFS: 8 vs 9.2 mo(HR 1.56, 95% CI 1.25-1.92)
Note: this is the upper bound of the dosing range allowed in RIBBON-1.
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 100 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 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 longer TTPMedian TTP: 19 vs 8 mo(HR not reported, p<0.02)
Note: Focan et al. 1993 allowed a total cumulative epirubicin dose of 1000 mg/m2.
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 50 mg/m2 IV once per day on days 1 & 8
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 10 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
Del Mastro et al. 2001	1994-1997 	Phase 3 (C) 	HD-CEF14 	Did not meet primary endpoint of ORR
====Chemotherapy====
*Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
*Epirubicin (Ellence) 60 mg/m2 IV once on day 1 
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle of varying durations: 8 to 12 cycles (Del Mastro et al. 2001); 10 cycles (Conte et al. 1996); 11 cycles (Conte et al. 1987)
===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====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
*Epirubicin (Ellence) 50 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
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 longer OS (secondary endpoint)Median OS: 74.4 vs 51.4 weeks(HR not reported, p=0.015)
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
*Epirubicin (Ellence) 30 mg/m2 IV once per day on days 1 & 8 
*Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
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 	Longer TTP (primary endpoint)Median TTP: 8.7 vs 6.3 mo(HR 0.73, 95% CI 0.59-0.92)
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
*Epirubicin (Ellence) 50 mg/m2 IV once per day on days 1 & 8 
*Cyclophosphamide (Cytoxan) 400 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 to 9 cycles
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
#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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# RIBBON-1 Tax/Anthra cohort: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00262067
==FEC & Bevacizumab==
FEC & Bevacizumab: Fluorouracil, Epirubicin, Cyclophosphamide, Bevacizumab
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Robert et al. 2011 (RIBBON-1 Tax/Anthra cohort)	2005-2007 	Phase 3 (E-esc)	1a. AC1b. Docetaxel1c. EC1d. FAC1e. FEC1f. nab-Paclitaxel	Longer PFS (primary endpoint)Median PFS: 9.2 vs 8 mo(HR 0.64, 95% CI 0.52-0.80)
====Chemotherapy====
*Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
*Epirubicin (Ellence) 90 to 100 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 500 mg/m2 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
====Subsequent treatment====
*RIBBON-1, SD or better: Bevacizumab maintenance
===References===
# RIBBON-1 Tax/Anthra cohort: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00262067
==Gemcitabine monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Efficacy
Carmichael et al. 1995	Not reported 	Phase 2, less than 20 pts in this subgroup	ORR: 25%, 95% CI 12.7-41.2
====Chemotherapy====
*Gemcitabine (Gemzar) 800 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
28-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Gemcitabine & Paclitaxel==
GT: Gemcitabine & Taxol (Paclitaxel)
PG: Paclitaxel & Gemcitabine
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Albain et al. 2008 	1999-2002 	Phase 3 (E-RT-esc) 	Paclitaxel 	Seems to have longer 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; weekly2. GD; q3wk 3. GT; weekly	Did not meet primary endpoint of TTP
Park et al. 2013 (KCSG-BR07-02) 	2007-2010 	Non-randomized part of phase 3 RCT	 	
====Chemotherapy====
*Gemcitabine (Gemzar) 1250 mg/m2 IV over 30 to 60 minutes once per day on days 1 & 8, given second on day 1
*Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1, given first
21-day cycle for varying durations: 6 cycles (KCSG-BR07-02); 6 to 10 cycles (B9E-IT-S376); indefintely (Albain et al. 2008)
====Subsequent treatment====
*KCSG-BR07-02: PG maintenance versus Observation
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00236899
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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====
*Non-pegylated liposomal doxorubicin (Myocet) 60 mg/m2 IV once on day 1
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
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 	Longer TTPMedian TTP: 7.7 vs 5.6 mo(HR 0.66, 95% CI 0.45-0.94)
====Chemotherapy====
*Non-pegylated liposomal doxorubicin (Myocet) 75 mg/m2 IV over 60 minutes once on day 1, given second
*Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 15 minutes once on day 1, given first
21-day cycle for up to 8 cycles
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
==Paclitaxel monotherapy, weekly==
===Regimen variant #1, 80 mg/m2 weekly===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Perez et al. 2001 	Not reported 	Phase 2 	 	ORR: 21.5%, 95% CI 15.4-27.5
Seidman et al. 2008 (CALGB 9840)	1998 to not reported	Phase 3 (E-switch-ic)	Paclitaxel; q3wk 	Longer OS (secondary endpoint)Median OS: 24 vs 12 mo(HR 0.78, 95% CI 0.65-0.94)Higher RR (primary endpoint)RR: 42% vs 29%
Fountzilas et al. 2008 	2002-2006 	Phase 3 (E-de-esc) 	1. Carboplatin & Paclitaxel2. Docetaxel & Gemcitabine	Seems to have longer OS (primary endpoint)
Martin et al. 2017 (BELLE-4) 	2012-2014 	Phase 3 (C) 	Buparlisib & Paclitaxel 	Did not meet primary endpoint of PFSMedian PFS: 9.2 vs 8 mo(HR 0.85, 95% CI 0.60-1.22)
====Chemotherapy====
*Paclitaxel (Taxol) 80 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22
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 	Worse EQ-5D score
Fujiwara et al. 2019 (A3105301) 	2012-2014 	Phase 3 (C)	NK-105 	Inconclusive whether non-inferior PFS (primary endpoint)Median PFS: 8.5 vs 8.4 mo(aHR 0.80, 95% CI 0.63-1.01)	Higher rate of CIPN
Note: this is the lower limit of dosing allowed in SELECT BC.
====Chemotherapy====
*Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1, 8, 15
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	Shorter PFS (primary endpoint)Median PFS: 5.9 vs 11.8 mo(HR 1.67, 95% CI 1.23-2.27)Might have shorter OS (secondary endpoint)Median OS: 25.2 vs 26.7 mo(HR 1.14, 95% CI 0.95-1.37)
Miles et al. 2016 (MERiDiAN) 	2012-2013 	Phase 3 (C)	Paclitaxel & Bevacizumab	Shorter PFSMedian PFS: 8.8 vs 11 mo(HR 1.47, 99% 1.10-1.96)
====Chemotherapy====
*Paclitaxel (Taxol) 90 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
===Regimen variant #4, 100 mg/m2 weekly===
Study 	Dates of enrollment	Evidence 	Efficacy
Seidman et al. 1998	Not reported 	Phase 2, less than 20 pts in this subgroup	ORR: 53%, 95% CI 34-72
====Chemotherapy====
*Paclitaxel (Taxol) 100 mg/m2 IV over 60 minutes once on day 1
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	Worse EQ-5D score
Note: this is the upper limit of dosing allowed in SELECT BC.
====Chemotherapy====
*Paclitaxel (Taxol) 100 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
===References===
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00028990
##HRQoL analysis: Cella D, Wang M, Wagner L, Miller K. Survival-adjusted health-related quality of life (HRQL) among patients with metastatic breast cancer receiving paclitaxel plus bevacizumab versus paclitaxel alone: results from Eastern Cooperative Oncology Group Study 2100 (E2100). Breast Cancer Res Treat. 2011 Dec;130(3):855-861. link to original article link to EuroPMC
# 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 EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC 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 	Not reported 	Phase 2 	 	ORR: 32%, 95% CI 15-53 	
Winer et al. 2004 (CALGB 9342) 	1994-1997 	Phase 3 (C)	1. Paclitaxel; 210 mg/m2 q3wk2. Paclitaxel; 250 mg/m2 q3wk	Did not meet primary endpoint of ORR 	
Seidman et al. 2008 (CALGB 9840) 	1998 to not reported	Phase 3 (C)	Paclitaxel; weekly 	Shorter OS (secondary endpoint)Median OS: 12 vs 24 mo(HR 1.28, 95% CI 1.06-1.54)Lower RR (primary endpoint)RR: 29% vs 42% 	
Albain et al. 2008 	1999-2002 	Phase 3 (C)	GT 	Seems to have shorter OSMedian OS: 15.8 vs 18.6 mo(HR 1.28, 95% CI 1.04-1.56) 	
Gradishar et al. 2005 (CA012-0) 	2001-11 to 2002-11 	Phase 3 (C)	nab-Paclitaxel 	Lower ORR (primary endpoint)ORR: 19% vs 33%Shorter TTP (secondary endpoint)Median TTP: 16.9 vs 23 weeks(HR 1.33, 95% CI 1.09-1.64)	
Di Leo et al. 2008 (EGF30001) 	2004-01 to 2005-07 	Phase 3 (C)	Lapatinib & Paclitaxel 	Might have shorter TTP (primary endpoint)Median TTP: 22.9 vs 29 weeks(HR 1.15, 95% CI 0.95-1.39) 	Less toxic
Takashima et al. 2015 (SELECT BC)	2006-2010 	Phase 3 (C)	S-1 	Seems to have non-inferior OS 	Worse 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====
*Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
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) 	Shorter TTF
Sledge et al. 2003 (ECOG E1193)	1993-1995 	Phase 3 (E-switch-ooc)	2. Doxorubicin	Did not meet primary endpoint of ORR
====Chemotherapy====
*Paclitaxel (Taxol) 175 mg/m2 IV continuous infusion over 24 hours, started on day 1
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	Worse EQ-5D score
====Chemotherapy====
*Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
28-day cycles
===Regimen variant #4, 200 mg/m2===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Bishop et al. 1999 	1993 to not reported	Phase 3 (E-de-esc) 	CMFP 	Seems to have longer OSMedian OS: 17.3 vs 13.9 mo(aHR 0.70, 95% CI 0.50-1.00)
Paridaens et al. 2000 (EORTC 10923)	1993-1996 	Phase 3 (E-switch-ic)	Doxorubicin	Shorter PFS (co-primary endpoint)Median PFS: 3.9 vs 7.5 mo(HR not reported, p=0.0001)
====Chemotherapy====
*Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
21-day cycle for 7 (EORTC 10923) or 8 (Bishop et al. 1999) cycles
===Regimen variant #5, 250 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Holmes et al. 1991 	1990 	Phase 2 	 	ORR: 56%, 95% CI 35-76
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====
*Paclitaxel (Taxol) 250 mg/m2 IV continuous infusion over 24 hours, started on day 1
21-day cycles
===References===
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00046527
# 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 EuroPMC NCT00003440
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00075270
##HRQoL analysis: Sherrill B, Di Leo A, Amonkar MM, Wu Y, Zvirbule Z, Aziz Z, Bines J, Gomez HL. Quality-of-life and quality-adjusted survival (Q-TWiST) in patients receiving lapatinib in combination with paclitaxel as first-line treatment for metastatic breast cancer. Curr Med Res Opin. 2010 Apr;26(4):767-75. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC 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 	Longer PFS (primary endpoint)Median PFS: 11.8 vs 5.9 mo(HR 0.60, 95% CI 0.44-0.81)Might have longer OS (secondary endpoint)Median OS: 26.7 vs 25.2 mo(HR 0.88, 95% CI 0.74-1.05)
Robert et al. 2011 (SUN 1094) 	2006-2009 	Phase 3 (C) 	Paclitaxel & Sunitinib 	Longer PFS (primary endpoint)Median PFS: 9.2 vs 7.4 mo(HR 0.61, 95% CI 0.44-0.85)
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 	Longer PFS (primary endpoint)Median PFS: 11 vs 7.4 mo(HR 0.63, 95% CI 0.52-0.76)
Rugo et al. 2015 (CALGB 40502/NCCTG N063H)	2008-2011 	Phase 3 (C) 	2. nab-Paclitaxel & Bevacizumab 	Seems to have longer PFS (primary endpoint)Median PFS: 11 vs 9.3 mo(HR 0.83, 95% CI 0.69-1.00)
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 	Longer 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====
*Paclitaxel (Taxol) 90 mg/m2 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
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00028990
##HRQoL analysis: Cella D, Wang M, Wagner L, Miller K. Survival-adjusted health-related quality of life (HRQL) among patients with metastatic breast cancer receiving paclitaxel plus bevacizumab versus paclitaxel alone: results from Eastern Cooperative Oncology Group Study 2100 (E2100). Breast Cancer Res Treat. 2011 Dec;130(3):855-861. link to original article link to EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
==Paclitaxel & Vinorelbine==
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Romero Acuña et al. 1999	1995-1997 	Phase 2 	ORR: 60%, 95% CI 46-74
====Chemotherapy====
*Paclitaxel (Taxol) 135 mg/m2 IV over 3 hours once on day 1, given second, 1 hour after vinorelbine infusion
*Vinorelbine (Navelbine) 30 mg/m2 IV over 20 minutes once per day on days 1 & 8, given first
====Supportive therapy====
*Dexamethasone (Decadron) 20 mg PO twice on day 1, taken 12 hours and 6 hours prior to paclitaxel
*Diphenhydramine (Benadryl) 50 mg IV once on day 1, given 30 minutes prior to paclitaxel
*Ranitidine (Zantac) 50 mg IV once on day 1, given 30 minutes prior to paclitaxel
28-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==nab-Paclitaxel monotherapy==
===Example orders===
*Example orders for Paclitaxel, nanoparticle albumin-bound (Abraxane) in breast cancer
===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. Docetaxel2. nab-Paclitaxel; weekly, 150 mg/m2 3. nab-Paclitaxel; q3wk	Did not meet primary endpoint of ORR
====Chemotherapy====
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV once per day on days 1, 8, 15
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. Docetaxel2. nab-Paclitaxel; weekly, 100 mg/m2 3. nab-Paclitaxel; q3wk	Did not meet primary endpoint of ORR
====Chemotherapy====
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 150 mg/m2 IV once per day on days 1, 8, 15
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 	Higher ORR (primary endpoint)ORR: 33% vs 19%Longer TTP (secondary endpoint)Median TTP: 23 vs 16.9 weeks(HR 0.75, 95% CI 0.61-0.92)
Robert et al. 2011 (RIBBON-1 Tax/Anthra cohort)	2005-2007 	Phase 3 (C) 	1a. AC & Bevacizumab1b. Docetaxel & Bevacizumab1c. EC & Bevacizumab1d. FAC & Bevacizumab1e. FEC & Bevacizumab1f. nab-Paclitaxel & Bevacizumab	Shorter PFS (primary endpoint)Median PFS: 8 vs 9.2 mo(HR 1.56, 95% CI 1.25-1.92)
====Chemotherapy====
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m2 IV over 30 minutes once on day 1
====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. Docetaxel2. nab-Paclitaxel; weekly, 100 mg/m2 3. nab-Paclitaxel; weekly, 150 mg/m2	Did not meet primary endpoint of ORR
====Chemotherapy====
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 300 mg/m2 IV over 30 minutes once on day 1
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00046527
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# RIBBON-1 Tax/Anthra cohort: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00262067
==Paclitaxel, nanoparticle albumin-bound & Bevacizumab==
===Example orders===
*Example orders for Paclitaxel, nanoparticle albumin-bound & Bevacizumab in breast cancer
===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
Rugo et al. 2015 (CALGB 40502/NCCTG N063H)	2008-2011 	Phase 3 (E-switch-ic)	2. Paclitaxel & Bevacizumab 	Seems to have shorter PFS (primary endpoint)Median PFS: 9.3 vs 11 mo(HR 1.20, 95% CI 1.00-1.45)
====Chemotherapy====
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 150 mg/m2 IV 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
===Regimen variant #2, 260 mg/m2 q3wk===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Robert et al. 2011 (RIBBON-1 Tax/Anthra cohort)	2005-2007 	Phase 3 (E-esc)	1a. AC1b. Docetaxel1c. EC1d. FAC1e. FEC1f. nab-Paclitaxel	Longer PFS (primary endpoint)Median PFS: 9.2 vs 8 mo(HR 0.64, 95% CI 0.52-0.80)
====Chemotherapy====
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===References===
# RIBBON-1 Tax/Anthra cohort: 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors EuroPMC NCT00785291
==Pemetrexed monotherapy==
===Regimen variant #1, 500 mg/m2===
Study 	Dates of enrollment	Evidence	Efficacy
Gomez et al. 2006	2001-2002 	Phase 2 	ORR: 31%
====Eligibility criteria====
*Chemotherapy-naïve, with advanced (T4 and N0-N2, M0, M1) breast cancer
====Chemotherapy====
*Pemetrexed (Alimta) 500 mg/m2 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
===Regimen variant #2, 600 mg/m2===
Study 	Dates of enrollment	Evidence	Efficacy
Robert et al. 2011	2005-2006 	Phase 2 	ORR: 26%
====Chemotherapy====
*Pemetrexed (Alimta) 600 mg/m2 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
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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. Docetaxel1b. Paclitaxel	Seems to have non-inferior OS (primary endpoint)	Better EQ-5D score
Mukai et al. 2021 (SELECT BC-CONFIRM)	2011-2013 	Phase 3 (E-switch-ic)	1a. AC1b. FAC1c. EC1d. 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===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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====
*Capecitabine (Xeloda) 950 mg/m2 PO twice per day on days 1 to 14
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
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 (primary endpoint)Median PFS: 8.4 vs 7.1 mo(HR 0.61, 95% CI 0.43-0.85)
Note: only patients without progression proceeded to the capecitabine maintenance phase.
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Docetaxel (Taxotere) as follows: 
**Cycles 1 to 6 up to 8: 75 mg/m2 IV once on day 1
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====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycles
====Subsequent treatment====
*B9E-MC-S273, upon progression: second-line Gemcitabine
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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	Longer PFS (primary endpoint)Median PFS: 10.1 vs 8.2 mo(aHR 0.75, 95% CI 0.61-0.92)
Note: Epirubicin was discontinued once the cumulative dose exceeded 900 mg/m2 but before it exceeded 950 mg/m2, after a mid-protocol amendment.
====Chemotherapy====
*Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 8
*Epirubicin (Ellence) as follows (see note):
**Cycles 1 to 10: 90 mg/m2 IV once on day 1
21-day cycle for up to 18 cycles (1 year)
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
=Metastatic disease, maintenance after first-line therapy=
==Bevacizumab monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Robert et al. 2011 (RIBBON-1 Tax/Anthra cohort)	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	Shorter PFS (primary endpoint)Median PFS: 4.3 vs 11.9 mo(sHR 2.63, 95% CI 1.82-3.70)Shorter OS (secondary endpoint)Median OS: 23.7 vs 39 mo(HR 2.33, 95% CI 1.45-3.85)
====Preceding treatment====
*AVADO: First-line Docetaxel & Bev x 9
*RIBBON-1 Tax/Anthra cohort: First-line AC & Bev x 8 or EC & Bev x 8 or FAC & Bev x 8 or FEC & Bev x 8
*IMELDA: First-line Docetaxel & Bev x 3 to 6
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00333775
# RIBBON-1 Tax/Anthra cohort: 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00262067
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00929240
==Capecitabine & Bevacizumab==
===Regimen===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Gligorov et al. 2014 (IMELDA)	2009-2011 	Phase 3 (E-esc)	Bevacizumab	Longer PFS (primary endpoint)Median PFS: 11.9 vs 4.3 mo(sHR 0.38, 95% CI 0.27-0.55)Longer OS (secondary endpoint)Median OS: 39 vs 23.7 mo(HR 0.43, 95% CI 0.26-0.69)
====Preceding treatment====
*First-line Docetaxel & Bev x 3 to 6
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 longer 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====
*Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8, given second on day 1
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1, given first
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 & Bevacizumab1b. Docetaxel & Bevacizumab1c. Gemcitabine & Bevacizumab1d. Paclitaxel & Bevacizumab1e. nab-Paclitaxel & Bevacizumab1f. Vinorelbine & Bevacizumab 	Shorter PFSMedian PFS: 5.1 vs 7.2 mo(HR 1.28, 95% CI 1.08-1.56)
Barrios et al. 2010 (SUN 1107) 	2006-2009 	Phase 3 (C)	Sunitinib 	Longer 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 to not reported	Phase 3 (C)	Capecitabine & Sorafenib 	Did not meet primary endpoint of PFSMedian 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 & Bevacizumab1b. Docetaxel & Bevacizumab1c. Doxorubicin & Bevacizumab1d. NPLD & Bevacizumab1e. PLD & Bevacizumab1f. Gemcitabine & Bevacizumab1g. nab-Paclitaxel & Bevacizumab	Shorter PFSMedian PFS: 4.2 vs 6.3 mo(HR 1.33, 95% CI 1.08-1.64)
Note: in SUN 1107, this dosage was used for patients older than 65 years.
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
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) 	 	ORR: 20%, 95% CI 14-28
Reichardt et al. 2003 	1999-2000 	Phase 2 	 	ORR: 15%, 95% CI 10-23
Miller et al. 2005 (AVF2119g) 	2000-2002 	Phase 3 (C) 	Capecitabine & Bevacizumab	Did not meet primary endpoint of PFSMedian PFS: 4.17 vs 4.86 mo(HR 1.02, 95% CI 0.80-1.30)
Pallis et al. 2011 (HORG CT/02.11) 	2002-2008 	Phase 3 (C) 	Gemcitabine & Vinorelbine 	Did not meet primary endpoint of PFSMedian PFS: 5.2 vs 5.4 mo
Thomas et al. 2007 (CA163-046) 	2003-2006 	Phase 3 (C) 	Capecitabine & Ixabepilone	Shorter PFS (primary endpoint)Median PFS: 4.2 vs 5.8 mo(HR 1.33, 95% CI 1.14-1.56)
Sparano et al. 2010 (CA163-048) 	2003-2006 	Phase 3 (C) 	Capecitabine & Ixabepilone	Might have shorter OS (primary endpoint)Median OS: 15.6 vs 16.4 mo(HR 1.11, 95% CI 0.97-1.28)
Barrios et al. 2010 (SUN 1107) 	2006-2009 	Phase 3 (C) 	Sunitinib 	Longer 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 	Seems to have shorter OS (co-primary endpoint)Median OS: 14.5 vs 15.9 mo(HR 1.14, 95% CI 1.00-1.30)
Crown et al. 2013 (A6181099) 	2007-2009 	Phase 3 (C) 	Capecitabine & Sunitinib 	Might have longer 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 shorter PFSMedian PFS: 4.3 vs 5.6 mo(HR 1.19, 95% CI 1.01-1.41)
Park et al. 2018 (PROCEED) 	2011-2016 	Phase 3 (C) 	IX 	Did not meet primary endpoint of PFSMedian PFS: 4.7 vs 6.4 mo(HR 1.19, 95% CI 0.90-1.59)
Zhang et al. 2017 (BG01-1323L) 	2014-08-08 to 2015-12-14	Phase 3 (C) 	Capecitabine & Utidelone 	Shorter PFS (primary endpoint)Median PFS: 4.27 vs 8.44 mo(HR 2.17, 95% CI 1.69-2.78)Shorter OS1 (secondary endpoint)Median OS: 16 vs 19.8 mo(HR 1.33, 95% CI 1.06-1.69)
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.
====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
====Chemotherapy====
*Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
21-day cycles
===References===
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00109239
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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. link to original article dosing details in abstract have been reviewed by our editors EuroPMC NCT00431106
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00281697
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00337103
##HRQoL analysis: Cortes J, Hudgens S, Twelves C, Perez EA, Awada A, Yelle L, McCutcheon S, Kaufman PA, Forsythe A, Velikova G. Health-related quality of life in patients with locally advanced or metastatic breast cancer treated with eribulin mesylate or capecitabine in an open-label randomized phase 3 trial. Breast Cancer Res Treat. 2015 Dec;154(3):509-20. Epub 2015 Nov 14. link to original article link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC 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. link to original article dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01095003
# 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. Capecitabine1b. Docetaxel1c. Gemcitabine1d. Paclitaxel1e. nab-Paclitaxel1f. Vinorelbine 	Longer 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. Capecitabine1b. Docetaxel1c. Doxorubicin1d. NPLD1e. PLD1f. Gemcitabine1g. nab-Paclitaxel	Longer PFS (primary endpoint)Median PFS: 6.3 vs 4.2 mo(HR 0.75, 95% CI 0.61-0.93)
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
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 PFSMedian 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====
*Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00109239
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
==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 longer PFS (primary endpoint)Median PFS: 10.5 vs 9.8 mo(HR 0.62, 95% CI 0.40-0.97)
====Chemotherapy====
*Capecitabine (Xeloda) 825 mg/m2 PO twice per day on days 1 to 14
*Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
21-day cycles
===Regimen variant #2, 1250/75===
Study 	Dates of enrollment	Evidence 	Comparator	Comparative Efficacy
O'Shaughnessy et al. 2002 (SO14999)	Not reported 	Phase 3 (E-RT-esc)	Docetaxel 	Longer TTP (primary endpoint)Median TTP: 6.1 vs 4.2 mo(HR 0.65, 95% CI 0.545-0.78)Longer 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 PFSMedian PFS: 7.98 vs 8.05 mo
1Reported efficacy for SO14999 is based on the 2004 update.
====Chemotherapy====
*Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
*Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC NCT00191152
## 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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	Longer 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 longer OS (primary endpoint)Median OS: 16.4 vs 15.6 mo(HR 0.90, 95% CI 0.78-1.03)
====Chemotherapy====
*Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
*Ixabepilone (Ixempra) 40 mg/m2 IV once on day 1
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors link to PMC article EuroPMC 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 longer PFS (primary endpoint)Median PFS: 5.6 vs 4.3 mo(HR 0.84, 95% CI 0.71-0.99)
====Chemotherapy====
*Capecitabine (Xeloda) 825 mg/m2 PO twice per day on days 1 to 14
*Vinflunine (Javlor) 280 mg/m2 IV once on day 1
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT01095003
==Carboplatin & Gemcitabine (GCb)==
===Regimen===
Study 	Dates of enrollment	Evidence 	Efficacy
Nagourney et al. 2008	2002-2005 	Pilot, less than 20 pts	ORR: 53.3%, 95% CI 28-82
====Chemotherapy====
*Carboplatin (Paraplatin) AUC 2 IV over 60 minutes once per day on days 1 & 8, given first
*Gemcitabine (Gemzar) 800 mg/m2 IV over 60 minutes once per day on days 1 & 8, given second
====Supportive therapy====
*Granisetron (Kytril) 1 mg IV once per day on days 1 & 8, given prior to chemotherapy
*Dexamethasone (Decadron) 10 mg IV once per day on days 1 & 8, given prior to chemotherapy
21-day cycles
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
==Cisplatin & Vinorelbine (CVb)==
CVb: Cisplatin & Vinorelbine
===Regimen===
Study 	Dates of enrollment	Evidence	Efficacy
Ray-Coquard et al. 1998 	1992-1994 	Phase 2 	ORR: 41%, 95% CI 28-54
Vassilomanolakis et al. 2000	Not reported 	Phase 2 	ORR: 49%, 95% CI 35-63
====Chemotherapy====
*Cisplatin (Platinol) 75 mg/m2 IV over 60 minutes once on day 1
*Vinorelbine (Navelbine) 25 mg/m2 IV over 5 to 10 minutes once per day on days 1 & 8
====Supportive therapy====
*Normal saline 200 mL IV bolus, given after vinorelbine to prevent phlebitis 
*Normal saline 2000 mL with KCl (unspecified amount of KCl) IV over 4 hours once on day 1, given prior to cisplatin
*Furosemide (Lasix) 40 mg IV once on day 1, given 20 minutes prior to cisplatin
*Normal saline 1000 mL and D5W 1000 mL IV over 4 hours once on day 1, given 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===
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==Cyclophosphamide & Methotrexate (CM)==
CM: Cyclophosphamide & Methotrexate
===Regimen variant #1===
Study 	Dates of enrollment	Evidence 	Efficacy
Colleoni et al. 2002	1997-2000 	Non-randomized	ORR: 19%, 95% CI 10.2-30.9
====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
===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====
*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 & 4
7-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
==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 OSMedian 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====
*Cyclophosphamide (Cytoxan)
===References===
# 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 EuroPMC 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	Less 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	Efficacy
Burstein et al. 2000	1998 	Phase 2 	ORR: 41%, 95% CI 24-61
====Chemotherapy====
*Docetaxel (Taxotere) 40 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
8-week cycles
===Regimen variant #3, 60 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Adachi et al. 1996 	1993 	Phase 2 	 	ORR: 44.4%, 95% CI 32.7-56.6
Harvey et al. 2006 (TAX 313) 	1995-2001 	Phase 3 (E-RT-de-esc)	1. Docetaxel; 75 mg/m2 q3wk 	Might have shorter TTP (secondary endpoint)
Harvey et al. 2006 (TAX 313) 	1995-2001 	Phase 3 (E-RT-de-esc)	2. Docetaxel; 100 mg/m2 q3wk 	Might have shorter TTP (secondary endpoint)
von Minckwitz et al. 2014 (TANIA)	2011-2013 	Phase 3 (C) 	1a. Capecitabine & Bevacizumab1b. Docetaxel & Bevacizumab1c. Doxorubicin & Bevacizumab1d. NPLD & Bevacizumab1e. PLD & Bevacizumab1f. Gemcitabine & Bevacizumab1g. nab-Paclitaxel & Bevacizumab	Shorter PFSMedian PFS: 4.2 vs 6.3 mo(HR 1.33, 95% CI 1.08-1.64)
Note: this is the dosage used for Japanese patients; Adachi et al. 1996 reported 21- to 28-day cycles
====Chemotherapy====
*Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
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 shorter OSMedian PFS: 9.8 vs 10.5 mo(HR 1.61, 95% CI 1.03-2.50)
====Chemotherapy====
*Docetaxel (Taxotere) 70 mg/m2 IV once on day 1
21-day cycles
====Subsequent treatment====
*JO21095, upon progression: Subsequent-line Capecitabine
===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 longer TTP (secondary endpoint)Higher ORR (primary endpoint)	
Harvey et al. 2006 (TAX 313) 	1995-2001 	Phase 3 (E-RT-esc) 	2. Docetaxel; 100 mg/m2 q3wk 	Might have shorter 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 	Less toxicity
Brufsky et al. 2011 (RIBBON-2) 	2006-2008 	Phase 3 (C) 	1a. Capecitabine & Bevacizumab1b. Docetaxel & Bevacizumab1c. Gemcitabine & Bevacizumab1d. Paclitaxel & Bevacizumab1e. nab-Paclitaxel & Bevacizumab1f. Vinorelbine & Bevacizumab 	Shorter PFSMedian PFS: 5.1 vs 7.2 mo(HR 1.28, 95% CI 1.08-1.56) 	
von Minckwitz et al. 2014 (TANIA)	2011-2013 	Phase 3 (C) 	1a. Capecitabine & Bevacizumab1b. Docetaxel & Bevacizumab1c. Doxorubicin & Bevacizumab1d. NPLD & Bevacizumab1e. PLD & Bevacizumab1f. Gemcitabine & Bevacizumab1g. nab-Paclitaxel & Bevacizumab	Shorter PFSMedian PFS: 4.2 vs 6.3 mo(HR 1.33, 95% CI 1.08-1.64) 	
Note: This is the lower end of the range of docetaxel dosing described in TANIA.
====Chemotherapy====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
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 	Not reported 	Phase 2 	 	ORR: 58%, 95% CI 37-78 	
Chan et al. 1999 (TAX 303) 	1994-1997 	Phase 3 (E-RT-switch-ic)	Doxorubicin 	Did not meet primary endpoint of TTP50%Higher ORR (secondary endpoint) 	
Nabholtz et al. 1999 (TAX 304) 	Not reported 	Phase 3 (E-RT-de-esc) 	Mitomycin & Vinblastine (MV) 	Longer TTP (primary endpoint)Median TTP: 19 vs 11 weeks(aHR 0.67, 95% CI 0.53-0.83)Longer OS (secondary endpoint)Median OS: 11.4 vs 8.7 mo(aHR 0.71, 95% CI 0.56-0.91) 	
Sjöström et al. 1999 	1994-1997 	Phase 3 (E-de-esc) 	MF 	Longer TTP (primary endpoint)Median TTP: 6.3 vs 3 mo(aHR 0.63, 95% CI 0.46-0.85) 	
O'Shaughnessy et al. 2002 (SO14999)	Not reported 	Phase 3 (C) 	TX 	Shorter TTP (primary endpoint)Median TTP: 4.2 vs 6.1 mo(HR 1.54, 95% CI 1.28-1.83)Shorter OS1 (secondary endpoint)Median OS: 11.5 vs 14.5 mo(HR 1.28, 95% CI 1.06-1.55)	
Jones et al. 2005 (TAX 311) 	1994-2001 	Phase 3 (E-switch-ic) 	Paclitaxel 	Longer 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 longer TTP (secondary endpoint)Higher ORR (primary endpoint) 	
Harvey et al. 2006 (TAX 313) 	1995-2001 	Phase 3 (E-RT-esc) 	2. Docetaxel; 75 mg/m2 q3wk 	Might have longer TTP (secondary endpoint)Higher ORR (primary endpoint) 	
Nielsen et al. 2011 	2001-2005 	Phase 3 (C) 	Docetaxel & Gemcitabine 	Might have shorter TTP (primary endpoint)Median TTP: 8.3 vs 10.3 mo(HR 1.30, 95% CI 0.99-1.69) 	
Schröder et al. 2011 	2001-2006 	Phase 3 (C) 	Docetaxel; weekly 	Seems to have longer OS (secondary endpoint)Median OS: 42.6 vs 33.7 weeks(aHR 0.70, 95% CI 0.50-0.98) 	
Brufsky et al. 2011 (RIBBON-2) 	2006-2008 	Phase 3 (C) 	1a. Capecitabine & Bevacizumab1b. Docetaxel & Bevacizumab1c. Gemcitabine & Bevacizumab1d. Paclitaxel & Bevacizumab1e. nab-Paclitaxel & Bevacizumab1f. Vinorelbine & Bevacizumab 	Shorter PFSMedian PFS: 5.1 vs 7.2 mo(HR 1.28, 95% CI 1.08-1.56) 	
von Minckwitz et al. 2014 (TANIA) 	2011-2013 	Phase 3 (C) 	1a. Capecitabine & Bevacizumab1b. Docetaxel & Bevacizumab1c. Doxorubicin & Bevacizumab1d. NPLD & Bevacizumab1e. PLD & Bevacizumab1f. Gemcitabine & Bevacizumab1g. nab-Paclitaxel & Bevacizumab	Shorter PFSMedian PFS: 4.2 vs 6.3 mo(HR 1.33, 95% CI 1.08-1.64) 	
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.
====Chemotherapy====
*Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle of varying durations: 6 to 8 cycles (Schröder et al. 2011); at least 6 cycles (Sjöström et al. 1999, TAX 313); 7 cycles (TAX 303); 9 cycles (Bonneterre et al. 2002); 10 cycles (TAX 304); indefinitely (Nielsen et al. 2011, RIBBON-2, SO14999, TANIA, TAX 311, ten Bokkel Huinink et al. 1994)
===References===
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# Review: Burris HA 3rd. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin Oncol. 1999 Jun;26(3 Suppl 9):1-6. EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
## 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 EuroPMC
# 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 dosing details in abstract have been reviewed by our editors link to PMC article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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. Capecitabine1b. Docetaxel1c. Doxorubicin1d. NPLD1e. PLD1f. Gemcitabine1g. nab-Paclitaxel	Longer 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====
*Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
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. Capecitabine1b. Docetaxel1c. Gemcitabine1d. Paclitaxel1e. nab-Paclitaxel1f. Vinorelbine 	Longer 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. Capecitabine1b. Docetaxel1c. Doxorubicin1d. NPLD1e. PLD1f. Gemcitabine1g. nab-Paclitaxel	Longer 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====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
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. Capecitabine1b. Docetaxel1c. Gemcitabine1d. Paclitaxel1e. nab-Paclitaxel1f. Vinorelbine 	Longer 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. Capecitabine1b. Docetaxel1c. Doxorubicin1d. NPLD1e. PLD1f. Gemcitabine1g. nab-Paclitaxel	Longer 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====
*Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
==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====
*Docetaxel (Taxotere) 75 mg/m2 IV once on day 8
*Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
21-day cycle for up to 8 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
==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 & Bevacizumab1b. Docetaxel & Bevacizumab1c. Doxorubicin & Bevacizumab1d. NPLD & Bevacizumab1e. PLD & Bevacizumab1f. Gemcitabine & Bevacizumab1g. nab-Paclitaxel & Bevacizumab	Shorter PFSMedian PFS: 4.2 vs 6.3 mo(HR 1.33, 95% CI 1.08-1.64)
Note: this is the lower end of the range of weekly doxorubicin dosing described in TANIA.
====Chemotherapy====
*Doxorubicin (Adriamycin) 20 mg/m2 IV once on day 1
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 & Bevacizumab1b. Docetaxel & Bevacizumab1c. Doxorubicin & Bevacizumab1d. NPLD & Bevacizumab1e. PLD & Bevacizumab1f. Gemcitabine & Bevacizumab1g. nab-Paclitaxel & Bevacizumab	Shorter PFSMedian PFS: 4.2 vs 6.3 mo(HR 1.33, 95% CI 1.08-1.64)
Note: this is the higher end of the range of weekly doxorubicin dosing described in TANIA.
====Chemotherapy====
*Doxorubicin (Adriamycin) 25 mg/m2 IV once on day 1
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. Bisantrene2. Mitoxantrone 	Seems to have longer 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 PFSMedian PFS: 6 vs 5.9 mo(HR 1.18, 95% CI 0.92-1.49)
von Minckwitz et al. 2014 (TANIA) 	2011-2013 	Phase 3 (C) 	1a. Capecitabine & Bevacizumab1b. Docetaxel & Bevacizumab1c. Doxorubicin & Bevacizumab1d. NPLD & Bevacizumab1e. PLD & Bevacizumab1f. Gemcitabine & Bevacizumab1g. nab-Paclitaxel & Bevacizumab	Shorter PFSMedian PFS: 4.2 vs 6.3 mo(HR 1.33, 95% CI 1.08-1.64)
Note: in NCIC-CTG MA.8, this dose was after a mid-protocol amendment. This was the lower end of the range of q3wk doxorubicin dosing described in TANIA.
====Chemotherapy====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
21-day cycle for varying durations: until a cumulative dose of 450 mg/m2 (NCIC-CTG MA.8, NCIC CT MA.19); indefinitely (SWOG S8203, TANIA)
===Regimen variant #4, 75 mg/m2 q3wk===
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
Chan et al. 1999 (TAX 303) 	1994-1997 	Phase 3 (C)	Docetaxel 	Did not meet primary endpoint of TTP50%
von Minckwitz et al. 2014 (TANIA) 	2011-2013 	Phase 3 (C)	1a. Capecitabine & Bevacizumab1b. Docetaxel & Bevacizumab1c. Doxorubicin & Bevacizumab1d. NPLD & Bevacizumab1e. PLD & Bevacizumab1f. Gemcitabine & Bevacizumab1g. nab-Paclitaxel & Bevacizumab	Shorter PFSMedian PFS: 4.2 vs 6.3 mo(HR 1.33, 95% CI 1.08-1.64)
Note: this is the higher end of the range of q3wk doxorubicin dosing described in TANIA.
====Chemotherapy====
*Doxorubicin (Adriamycin) 75 mg/m2 IV over 15 to 20 minutes once on day 1
21-day cycle for varying durations: 7 cycles (TAX 303); until a cumulative dose of 550 mg/m2 (EORTC 10811); indefinitely (TANIA)
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
==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. Capecitabine1b. Docetaxel1c. Doxorubicin1d. NPLD1e. PLD1f. Gemcitabine1g. nab-Paclitaxel	Longer 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====
*Doxorubicin (Adriamycin) 20 mg/m2 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
===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. Capecitabine1b. Docetaxel1c. Doxorubicin1d. NPLD1e. PLD1f. Gemcitabine1g. nab-Paclitaxel	Longer 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====
*Doxorubicin (Adriamycin) 25 mg/m2 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
===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. Capecitabine1b. Docetaxel1c. Doxorubicin1d. NPLD1e. PLD1f. Gemcitabine1g. nab-Paclitaxel	Longer 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====
*Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
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. Capecitabine1b. Docetaxel1c. Doxorubicin1d. NPLD1e. PLD1f. Gemcitabine1g. nab-Paclitaxel	Longer 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====
*Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
==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 longer 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 longer 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 shorter OS (primary endpoint)Median OS: 10.3 vs 12.4 mo(HR 1.15, 95% CI 0.98-1.33)
Yuan et al. 2019 (E7389-C086-304) 	2013-2015 	Phase 3 (E-switch-ic) 	Vinorelbine 	Seems to have longer PFS (primary endpoint)Median PFS: 2.8 vs 2.8 mo(HR 0.80, 95% CI 0.65-0.98)
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
====Chemotherapy====
*Eribulin (Halaven) 1.4 mg/m2 IV over 2 to 5 minutes once per day on days 1 & 8
21-day cycles
===References===
# 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 dosing details in abstract have been reviewed by our editors EuroPMC NCT00388726
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00337103
##HRQoL analysis: Cortes J, Hudgens S, Twelves C, Perez EA, Awada A, Yelle L, McCutcheon S, Kaufman PA, Forsythe A, Velikova G. Health-related quality of life in patients with locally advanced or metastatic breast cancer treated with eribulin mesylate or capecitabine in an open-label randomized phase 3 trial. Breast Cancer Res Treat. 2015 Dec;154(3):509-20. Epub 2015 Nov 14. link to original article link to PMC article EuroPMC
# 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 EuroPMC NCT01492101
##HRQoL analysis: Twelves C, Cortés J, O'Shaughnessy J, Awada A, Perez EA, 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, Rugo HS. Health-related quality of life in patients with locally recurrent or metastatic breast cancer treated with etirinotecan pegol versus treatment of physician's choice: Results from the randomised phase III BEACON trial. Eur J Cancer. 2017 May;76:205-215. link to original article link to EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT02225470
# EVER-132-002: NCT04639986
==Gemcitabine monotherapy==
===Regimen variant #1, 800 mg/m2 3 weeks out of 4===
Study 	Dates of enrollment	Evidence	Efficacy
Carmichael et al. 1995	Not reported 	Phase 2 	ORR: 25%, 95% CI 12.7-41.2
====Chemotherapy====
*Gemcitabine (Gemzar) 800 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
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 & Bevacizumab1b. Docetaxel & Bevacizumab1c. Doxorubicin & Bevacizumab1d. NPLD & Bevacizumab1e. PLD & Bevacizumab1f. Gemcitabine & Bevacizumab1g. nab-Paclitaxel & Bevacizumab	Shorter PFSMedian PFS: 4.2 vs 6.3 mo(HR 1.33, 95% CI 1.08-1.64)
====Chemotherapy====
*Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
===Regimen variant #3, 1200 mg/m2 3 weeks out of 4===
Study 	Dates of enrollment	Evidence	Efficacy
Spielmann et al. 2001	Not reported 	Phase 2 	ORR: 29%, 95% CI 16-46
====Chemotherapy====
*Gemcitabine (Gemzar) 1200 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
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 & Bevacizumab1b. Docetaxel & Bevacizumab1c. Gemcitabine & Bevacizumab1d. Paclitaxel & Bevacizumab1e. nab-Paclitaxel & Bevacizumab1f. Vinorelbine & Bevacizumab 	Shorter PFSMedian PFS: 5.1 vs 7.2 mo(HR 1.28, 95% CI 1.08-1.56)
von Minckwitz et al. 2014 (TANIA)	2011-2013 	Phase 3 (C)	1a. Capecitabine & Bevacizumab1b. Docetaxel & Bevacizumab1c. Doxorubicin & Bevacizumab1d. NPLD & Bevacizumab1e. PLD & Bevacizumab1f. Gemcitabine & Bevacizumab1g. nab-Paclitaxel & Bevacizumab	Shorter PFSMedian PFS: 4.2 vs 6.3 mo(HR 1.33, 95% CI 1.08-1.64)
====Chemotherapy====
*Gemcitabine (Gemzar) 1250 mg/m2 IV over 30 minutes once per day on days 1 & 8
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
# 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. Capecitabine1b. Docetaxel1c. Doxorubicin1d. NPLD1e. PLD1f. Gemcitabine1g. nab-Paclitaxel	Longer PFS (primary endpoint)Median PFS: 6.3 vs 4.2 mo(HR 0.75, 95% CI 0.61-0.93)
====Chemotherapy====
*Gemcitabine (Gemzar) 1000 mg/m2 IV 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
===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. Capecitabine1b. Docetaxel1c. Gemcitabine1d. Paclitaxel1e. nab-Paclitaxel1f. Vinorelbine 	Longer 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. Capecitabine1b. Docetaxel1c. Doxorubicin1d. NPLD1e. PLD1f. Gemcitabine1g. nab-Paclitaxel	Longer PFS (primary endpoint)Median PFS: 6.3 vs 4.2 mo(HR 0.75, 95% CI 0.61-0.93)
====Chemotherapy====
*Gemcitabine (Gemzar) 1250 mg/m2 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
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
==Ixabepilone monotherapy==
===Regimen===
Study 	Dates of enrollment	Evidence 	Efficacy
Perez et al. 2007 (CA163-081)	2004-2005 	Phase 2 (RT)	ORR (primary endpoint): 11.5%, 95% CI 6.3-18.9
====Chemotherapy====
*Ixabepilone (Ixempra) 40 mg/m2 IV over 3 hours once on day 1
21-day cycle for up to 18 cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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 & Bevacizumab1b. Docetaxel & Bevacizumab1c. Doxorubicin & Bevacizumab1d. NPLD & Bevacizumab1e. PLD & Bevacizumab1f. Gemcitabine & Bevacizumab1g. nab-Paclitaxel & Bevacizumab	Shorter PFSMedian PFS: 4.2 vs 6.3 mo(HR 1.33, 95% CI 1.08-1.64)
====Chemotherapy====
*Non-pegylated liposomal doxorubicin (Myocet) 60 mg/m2 IV once on day 1
21-day cycles
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
==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. Capecitabine1b. Docetaxel1c. Doxorubicin1d. NPLD1e. PLD1f. Gemcitabine1g. nab-Paclitaxel	Longer PFS (primary endpoint)Median PFS: 6.3 vs 4.2 mo(HR 0.75, 95% CI 0.61-0.93)
====Chemotherapy====
*Non-pegylated liposomal doxorubicin (Myocet) 60 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
==Paclitaxel monotherapy, weekly==
===Regimen variant #1, 80 mg/m2 weekly===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Perez et al. 2001 	Not reported 	Phase 2 	 	ORR: 21.5%, 95% CI 15.4-27.5
Seidman et al. 2008 (CALGB 9840)	1998 to not reported	Phase 3 (E-switch-ic)	Paclitaxel; q3wk	Longer OS (secondary endpoint)Median OS: 24 vs 12 mo(HR 0.78, 95% CI 0.65-0.94)Higher RR (primary endpoint)RR: 42% vs 29%
====Chemotherapy====
*Paclitaxel (Taxol) 80 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22
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 & Bevacizumab1b. Docetaxel & Bevacizumab1c. Gemcitabine & Bevacizumab1d. Paclitaxel & Bevacizumab1e. nab-Paclitaxel & Bevacizumab1f. Vinorelbine & Bevacizumab	Shorter PFSMedian PFS: 5.1 vs 7.2 mo(HR 1.28, 95% CI 1.08-1.56)
====Chemotherapy====
*Paclitaxel (Taxol) 90 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 EuroPMC NCT00003440
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00281697
==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====
*Paclitaxel (Taxol) 135 mg/m2 IV over 3 hours once on day 1
21-day cycles
===Regimen variant #2, 175 mg/m2===
Study 	Dates of enrollment 	Evidence 	Comparator 	Comparative Efficacy
Seidman et al. 1995 	Not reported 	Phase 2 	 	ORR: 32%, 95% CI 15-53
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 q3wk2. 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 	Shorter OS (secondary endpoint)Median OS: 12.7 vs 15.4 mo(HR 1.41, 95% CI 1.15-1.72)
Icli et al. 2005 	1997-2002 	Phase 3 (C) 	EoP 	Shorter TTP (primary endpoint)Median TTP: 3.9 vs 5.5 mo(HR not reported, p=0.003)Seems to have shorter OS (secondary endpoint)Median OS: 9.5 vs 14 mo(HR not reported, p=0.039)
Seidman et al. 2008 (CALGB 9840)	1998 to not reported	Phase 3 (C) 	Paclitaxel; weekly 	Shorter OS (secondary endpoint)Median OS: 12 vs 24 mo(HR 1.28, 95% CI 1.06-1.54)Lower RR (primary endpoint)RR: 29% vs 42%
Gradishar et al. 2005 (CA012-0) 	2001-11 to 2002-11 	Phase 3 (C) 	nab-Paclitaxel 	Lower ORR (primary endpoint)ORR: 19% vs 33%Shorter TTP (secondary endpoint)Median TTP: 16.9 vs 23 weeks(HR 1.33, 95% CI 1.09-1.64)
Brufsky et al. 2011 (RIBBON-2) 	2006-2008 	Phase 3 (C) 	1a. Capecitabine & Bevacizumab1b. Docetaxel & Bevacizumab1c. Gemcitabine & Bevacizumab1d. Paclitaxel & Bevacizumab1e. nab-Paclitaxel & Bevacizumab1f. Vinorelbine & Bevacizumab	Shorter PFSMedian PFS: 5.1 vs 7.2 mo(HR 1.28, 95% CI 1.08-1.56)
Rugo et al. 2023 (KX-ORAX-001) 	2015-12 to 2019-02 	Phase 3 (C) 	Oral paclitaxel and encequidar 	Lower ORR (primary endpoint)ORR: 23% vs 36%Might have shorter OS (secondary endpoint)Median OS: 16.5 vs 22.7 mo(HR 1.26, 95.5% CI 0.96-1.65)
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.
====Chemotherapy====
*Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00002662
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00046527
# 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 EuroPMC NCT00003440
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00281697
#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 EuroPMC 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. Capecitabine1b. Docetaxel1c. Gemcitabine1d. Paclitaxel1e. nab-Paclitaxel1f. Vinorelbine	Longer PFS (primary endpoint)Median PFS: 7.2 vs 5.1 mo(HR 0.78, 95% CI 0.64-0.93)
====Chemotherapy====
*Paclitaxel (Taxol) 90 mg/m2 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
===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. Capecitabine1b. Docetaxel1c. Gemcitabine1d. Paclitaxel1e. nab-Paclitaxel1f. Vinorelbine	Longer PFS (primary endpoint)Median PFS: 7.2 vs 5.1 mo(HR 0.78, 95% CI 0.64-0.93)
====Chemotherapy====
*Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00281697
==nab-Paclitaxel monotherapy==
===Example orders===
*Example orders for Paclitaxel, nanoparticle albumin-bound (Abraxane) in breast cancer
===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 & Bevacizumab1b. Docetaxel & Bevacizumab1c. Doxorubicin & Bevacizumab1d. NPLD & Bevacizumab1e. PLD & Bevacizumab1f. Gemcitabine & Bevacizumab1g. nab-Paclitaxel & Bevacizumab	Shorter PFSMedian PFS: 4.2 vs 6.3 mo(HR 1.33, 95% CI 1.08-1.64)
Note: the details of this regimen were unclear in von Minckwitz et al. 2014.
====Chemotherapy====
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
===Regimen variant #2, 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 	Higher ORR (primary endpoint)ORR: 33% vs 19%Longer 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 & Bevacizumab1b. Docetaxel & Bevacizumab1c. Gemcitabine & Bevacizumab1d. Paclitaxel & Bevacizumab1e. nab-Paclitaxel & Bevacizumab1f. Vinorelbine & Bevacizumab 	Shorter PFSMedian PFS: 5.1 vs 7.2 mo(HR 1.28, 95% CI 1.08-1.56)
von Minckwitz et al. 2014 (TANIA)	2011-2013 	Phase 3 (C) 	1a. Capecitabine & Bevacizumab1b. Docetaxel & Bevacizumab1c. Doxorubicin & Bevacizumab1d. NPLD & Bevacizumab1e. PLD & Bevacizumab1f. Gemcitabine & Bevacizumab1g. nab-Paclitaxel & Bevacizumab	Shorter PFSMedian PFS: 4.2 vs 6.3 mo(HR 1.33, 95% CI 1.08-1.64)
====Chemotherapy====
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m2 IV over 30 minutes once on day 1
====Supportive therapy====
*CA012-0: No corticosteroid or antihistamine premedication
21-day cycles
===Regimen variant #3, 300 mg/m2 q3wk===
Study 	Dates of enrollment	Evidence 	Efficacy
Ibrahim et al. 2005	1999-2001 	Phase 2 (RT)	ORR: 48%, 95% CI 35.3-60
====Chemotherapy====
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 300 mg/m2 IV over 30 minutes once on day 1
21-day cycles
===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. link to original article dosing details in abstract have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00046527
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
==Paclitaxel, nanoparticle albumin-bound & Bevacizumab==
===Example orders===
*Example orders for Paclitaxel, nanoparticle albumin-bound & Bevacizumab in breast cancer
===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. Capecitabine1b. Docetaxel1c. Doxorubicin1d. NPLD1e. PLD1f. Gemcitabine1g. nab-Paclitaxel	Longer 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====
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 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
===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. Capecitabine1b. Docetaxel1c. Gemcitabine1d. Paclitaxel1e. nab-Paclitaxel1f. Vinorelbine 	Longer 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. Capecitabine1b. Docetaxel1c. Doxorubicin1d. NPLD1e. PLD1f. Gemcitabine1g. nab-Paclitaxel	Longer PFS (primary endpoint)Median PFS: 6.3 vs 4.2 mo(HR 0.75, 95% CI 0.61-0.93)
====Chemotherapy====
*Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
==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 & Bevacizumab1b. Docetaxel & Bevacizumab1c. Doxorubicin & Bevacizumab1d. NPLD & Bevacizumab1e. PLD & Bevacizumab1f. Gemcitabine & Bevacizumab1g. nab-Paclitaxel & Bevacizumab	Shorter PFSMedian PFS: 4.2 vs 6.3 mo(HR 1.33, 95% CI 1.08-1.64)
Note: this is the lower end of the range of pegylated liposomal doxorubicin dosing described in TANIA.
====Chemotherapy====
*Pegylated liposomal doxorubicin (Doxil) 40 mg/m2 IV once on day 1
28-day cycles
===Regimen variant #2, 50 mg/m2===
Study 	Dates of enrollment	Evidence 	Comparator 	Comparative Efficacy
Keller et al. 2004 	Not reported 	Phase 3 (E-switch-ic)	1a. MV1b. Vinorelbine 	Might have longer PFS (primary endpoint)Median PFS: 2.9 vs 2.5 mo(HR 0.79, 95% CI 0.62-1.02)
von Minckwitz et al. 2014 (TANIA)	2011-2013 	Phase 3 (C) 	1a. Capecitabine & Bevacizumab1b. Docetaxel & Bevacizumab1c. Doxorubicin & Bevacizumab1d. NPLD & Bevacizumab1e. PLD & Bevacizumab1f. Gemcitabine & Bevacizumab1g. nab-Paclitaxel & Bevacizumab	Shorter PFSMedian PFS: 4.2 vs 6.3 mo(HR 1.33, 95% CI 1.08-1.64)
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====
*Pegylated liposomal doxorubicin (Doxil) 50 mg/m2 IV over 60 minutes once on day 1
28-day cycles
===References===
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
==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. Capecitabine1b. Docetaxel1c. Doxorubicin1d. NPLD1e. PLD1f. Gemcitabine1g. nab-Paclitaxel	Longer 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====
*Pegylated liposomal doxorubicin (Doxil) 40 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
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. Capecitabine1b. Docetaxel1c. Doxorubicin1d. NPLD1e. PLD1f. Gemcitabine1g. nab-Paclitaxel	Longer 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====
*Pegylated liposomal doxorubicin (Doxil) 50 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article EuroPMC
==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 	 	ORR: 36%, 95% CI 24-47
Zelek et al. 2001 	1997-1999 	Phase 2 	 	ORR: 25%, 95% CI 13-41
Decker et al. 2019 (VicTORia) 	2011-2016 	Randomized Phase 2 (C)	Everolimus & Vinorelbine	Did not meet primary endpoint of PFSMedian PFS: 4.21 vs 4.08 mo(HR 0.95, 95% CI 0.66-1.37)
Yuan et al. 2019 (E7389-C086-304)	2013-2015 	Phase 3 (C) 	Eribulin 	Seems to have shorter PFSMedian PFS: 2.8 vs 2.8 mo(HR 1.25, 95% CI 1.02-1.54)
====Chemotherapy====
*Vinorelbine (Navelbine) 25 mg/m2 IV once on day 1
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 longer OS (secondary endpoint)Median OS: 35 vs 31 weeks(HR not reported, p=0.034)
Keller et al. 2004	Not reported 	Phase 3 (C) 	PLD 	Might have shorter PFS (primary endpoint)Median PFS: 2.5 vs 2.9 mo(HR 1.27, 95% CI 0.98-1.61)
====Prior treatment criteria====
*Jones et al. 1995a: Anthracycline exposure
*Keller et al. 2004: Taxane exposure
====Chemotherapy====
*Vinorelbine (Navelbine) 30 mg/m2 IV over 6 to 10 minutes once on day 1
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 & Bevacizumab1b. Docetaxel & Bevacizumab1c. Gemcitabine & Bevacizumab1d. Paclitaxel & Bevacizumab1e. nab-Paclitaxel & Bevacizumab1f. Vinorelbine & Bevacizumab	Shorter PFSMedian PFS: 5.1 vs 7.2 mo(HR 1.28, 95% CI 1.08-1.56)
====Chemotherapy====
*Vinorelbine (Navelbine) 30 mg/m2 IV once on day 1
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	Shorter PFS (primary endpoint)Median PFS: 4 vs 6 mo(HR 1.52, 95% CI 1.14-2.00)
====Chemotherapy====
*Vinorelbine (Navelbine) 30 mg/m2 IV once per day on days 1 & 8
21-day cycles
===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. link to original article EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC
# 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 EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in abstract have been reviewed by our editors EuroPMC NCT00128310
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC 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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC NCT01520103
# EVER-132-002: NCT04639986
==Vinorelbine & Bevacizumab==
===Example orders===
*Example orders for Vinorelbine and Bevacizumab in breast cancer
===Regimen variant #1, vinorelbine 25 mg/m2 weekly===
Study 	Dates of enrollment	Evidence	Efficacy
Burstein et al. 2008	2001-2002 	Phase 2 	ORR: 34%, 95% CI 22-48
====Chemotherapy====
*Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 8
====Targeted therapy====
*Bevacizumab (Avastin) 10 mg/kg IV once on day 1
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. Capecitabine1b. Docetaxel1c. Gemcitabine1d. Paclitaxel1e. nab-Paclitaxel1f. Vinorelbine	Longer PFS (primary endpoint)Median PFS: 7.2 vs 5.1 mo(HR 0.78, 95% CI 0.64-0.93)
====Chemotherapy====
*Vinorelbine (Navelbine) 30 mg/m2 IV once on day 1
====Targeted therapy====
*Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
===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. link to original article dosing details in manuscript have been reviewed by our editors EuroPMC
# 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 dosing details in manuscript have been reviewed by our editors EuroPMC NCT00281697
=Additional resources=
*Gail model Breast Cancer Risk Assessment Tool
**Gail model breast cancer risk factors
*Breast cancer BRCA1 & BRCA2 genetic testing
*My Cancer Genome
*PREDICT
Category:Breast cancer regimens
Category:Disease-specific pages
Category:Malignant breast neoplasm