Staging page

Section editor transclusions 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-specific populations. 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 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 protocols, we use "T" for paclitaxel and "D" for docetaxel; e.g., AC-T and AC-D.

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Guidelines

ASCO

• 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
• 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
• 2021: Korde et al. Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline
• 2020: Denduluri et al. Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update
• 2020: Hassett et al. Management of Male Breast Cancer: ASCO Guideline PubMed
• 2016: Burstein et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline update on ovarian suppression PubMed

Older

• 2018: Denduluri et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO clinical practice guideline focused update PubMed
• 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
• 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
• 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

ASCO/CCO

• 2022: Eisen et al. Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: ASCO-OH (CCO) Guideline Update

Older

• 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

ESMO

• 2021: Gennari et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer
• 2019: Cardoso et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Older

• 2015: Senkus et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

ESO/ESMO

• 2020: Paluch-Shimon et al. ESO–ESMO 4th International Consensus Guidelines for Breast Cancer in Young Women (BCY4)
• 2018: Cardoso et al. 4th ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4)

Older

• 2017: Cardoso et al. 3rd ESO-ESMO International consensus guidelines for advanced breast cancer (ABC3) PubMed
• 2014: Cardoso et al. ESO-ESMO 2nd International consensus guidelines for advanced breast cancer (ABC2)
• 2012: Cardoso et al. 1st International consensus guidelines for advanced breast cancer (ABC 1)

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)

Older

• 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)
• 2007: Wildiers et al. Management of breast cancer in elderly individuals: recommendations of the International Society of Geriatric Oncology

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

NCCN

• NCCN Guidelines - Breast Cancer

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

Older

• 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
• 2017: Curigliano et al. St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2017
• 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

Neoadjuvant chemotherapy, sequential protocols

AC-D

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

Regimen variant #1, 60/600/75

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Kim et al. 2020 (NEST)	2012-2014	Phase 3 (C)	Goserelin & Tamoxifen	Inconclusive whether non-inferior clinical response

Chemotherapy, AC portion

• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 4: 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 600 mg/m² IV once on day 1

Chemotherapy, T portion

• Docetaxel (Taxotere) as follows:
  • Cycles 5 to 8: 75 mg/m² IV once on day 1

21-day cycle for 8 cycles

Subsequent treatment

• Surgery

Regimen variant #2, 60/600/100

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bear et al. 2003 (NSABP B-27)	1995-2000	Phase 3 (E-esc)	1. AC	Superior pCR rate
			2. AC, then surgery, then T	Not reported
von Minckwitz et al. 2005 (GeparDuo)	1999-2001	Phase 3 (E-esc)	ddAT	Superior pCR rate

Chemotherapy, AC portion

• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 4: 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 600 mg/m² IV once on day 1

Chemotherapy, T portion

• Docetaxel (Taxotere) as follows:
  • Cycles 5 to 8: 100 mg/m² IV once on day 1

21-day cycle for 8 cycles

Subsequent treatment

• Surgery

References

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

AC-T

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

Regimen variant #1, 5 x 4

Study	Years 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

• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 5: 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 5: 600 mg/m² IV once on day 1

Chemotherapy, T portion

• Paclitaxel (Taxol) as follows:
  • Cycles 6 to 9: 80 mg/m² IV once per day on days 1, 8, 15

21-day cycle for 9 cycles

Subsequent treatment

• Surgery

References

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

D-AC

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

Regimen

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

Chemotherapy, D portion

• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 4: 75 mg/m² IV once on day 1

Chemotherapy, AC portion

• Doxorubicin (Adriamycin) as follows:
  • Cycles 5 to 8: 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 8: 600 mg/m² IV once on day 1

21-day cycle for 8 cycles

Subsequent treatment

• surgery

References

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

D-AC+Bev

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

Regimen

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

Chemotherapy, D portion

• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 4: 75 mg/m² IV once on day 1

Chemotherapy, AC portion

• Doxorubicin (Adriamycin) as follows:
  • Cycles 5 to 8: 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 8: 600 mg/m² IV once on day 1

Targeted therapy

• Bevacizumab (Avastin) as follows:
  • Cycles 1 to 6: 15 mg/kg IV once on day 1

21-day cycle for 8 cycles

Subsequent treatment

• surgery

References

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

D-FEC

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

Regimen

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

Chemotherapy, D portion

• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 3: 100 mg/m² IV once on day 1

Chemotherapy, FEC portion

• Fluorouracil (5-FU) as follows:
  • Cycles 4 to 6: 500 mg/m² IV once on day 1
• Epirubicin (Ellence) as follows:
  • Cycles 4 to 6: 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 4 to 6: 500 mg/m² IV once on day 1

21-day cycle for 6 cycles

Subsequent treatment

• Surgery

References

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

D-FEC+Bev

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Earl et al. 2015 (ARTemis)	2009-2013	Phase 3 (E-esc)	D-FEC	Seems to have superior pCR rate

Chemotherapy, D portion

• Docetaxel (Taxotere) as follows:
  • Cycles 1 to 3: 100 mg/m² IV once on day 1

Chemotherapy, FEC portion

• Fluorouracil (5-FU) as follows:
  • Cycles 4 to 6: 500 mg/m² IV once on day 1
• Epirubicin (Ellence) as follows:
  • Cycles 4 to 6: 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 4 to 6: 500 mg/m² IV once on day 1

Targeted therapy

• Bevacizumab (Avastin) as follows:
  • Cycles 1 to 4: 15 mg/kg IV once on day 1

21-day cycle for 6 cycles

Subsequent treatment

• Surgery

References

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

EC-D

EC-D: Epirubicin and Cyclophosphamide followed by Docetaxel

Regimen

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

Chemotherapy, EC portion

• Epirubicin (Ellence) as follows:
  • Cycles 1 to 4: 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 600 mg/m² IV once on day 1

Chemotherapy, D portion

• Docetaxel (Taxotere) as follows:
  • Cycles 5 to 8: 100 mg/m² IV once on day 1

21-day cycle for 8 cycles

Subsequent treatment

• Surgery

References

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

EC-T

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

Regimen

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

Chemotherapy, EC portion

• Epirubicin (Ellence) as follows:
  • Cycles 1 to 4: 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 600 mg/m² IV once on day 1

Chemotherapy, T portion

• Paclitaxel (Taxol) as follows:
  • Cycles 5 to 8: 175 mg/m² IV once on day 1

21-day cycle for 8 cycles

Subsequent treatment

• Surgery

References

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

EC-ddT

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

Regimen

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

Chemotherapy, EC portion

• Epirubicin (Ellence) as follows:
  • Cycles 1 to 4: 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 600 mg/m² IV once on day 1

Chemotherapy, T portion

• Paclitaxel (Taxol) as follows:
  • Cycles 5 to 8: 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

Subsequent treatment

• surgery

References

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

nab-Paclitaxel-EC

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Untch et al. 2016 (GeparSepto)	2012-2013	Phase 3 (E-switch-ic)	T-EC	Superior pCR rate

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

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) as follows:
  • Cycles 1 to 4: 125 mg/m² IV once per day on days 1, 8, 15

Chemotherapy, EC portion

• Epirubicin (Ellence) as follows:
  • Cycles 5 to 8: 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 8: 600 mg/m² IV once on day 1

21-day cycle for 8 cycles

Subsequent treatment

• Surgery

References

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

T-AC

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gianni et al. 2018 (ETNA)	2013-2015	Phase 3 (C)	1. nab-Paclitaxel-AC 2. nab-Paclitaxel-EC 3. nab-Paclitaxel-FEC	Did not meet primary endpoint of pCR rate

Chemotherapy, T portion

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 90 mg/m² IV once per day on days 1, 8, 15

Chemotherapy, AC portion

• Doxorubicin (Adriamycin) as follows:
  • Cycles 5 to 8: 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 8: 600 mg/m² IV once on day 1

28-day cycle for 4 cycles, then 21-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

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

T-EC

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

Regimen variant #1, 80 mg/m² paclitaxel

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Untch et al. 2016 (GeparSepto)	2012-2013	Phase 3 (C)	nab-Paclitaxel-EC	Inferior pCR rate

Chemotherapy, T portion

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 80 mg/m² IV once per day on days 1, 8, 15

Chemotherapy, EC portion

• Epirubicin (Ellence) as follows:
  • Cycles 5 to 8: 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 8: 600 mg/m² IV once on day 1

21-day cycle for 8 cycles

Subsequent treatment

• Surgery

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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gianni et al. 2018 (ETNA)	2013-2015	Phase 3 (C)	1. nab-Paclitaxel-AC 2. nab-Paclitaxel-EC 3. nab-Paclitaxel-FEC	Did not meet primary endpoint of pCR rate

Chemotherapy, T portion

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 90 mg/m² IV once per day on days 1, 8, 15

Chemotherapy, EC portion

• Epirubicin (Ellence) as follows:
  • Cycles 5 to 8: 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 8: 600 mg/m² IV once on day 1

28-day cycle for 4 cycles, then 21-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

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

ddT-EC

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

Regimen

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

Chemotherapy, T portion

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 175 mg/m² IV once on day 1

Supportive therapy, T portion

• Primary G-CSF propyhylaxis not provided

Chemotherapy, EC portion

• Epirubicin (Ellence) as follows:
  • Cycles 5 to 8: 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 8: 600 mg/m² IV once on day 1

14-day cycle for 4 cycles, then 21-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

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

T-FAC

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

Regimen variant #1, weekly paclitaxel for N0 disease

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

Chemotherapy, T portion

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 80 mg/m² IV once per day on days 1, 8, 15

Chemotherapy, FAC portion

• Fluorouracil (5-FU) as follows:
  • Cycles 5 to 8: 500 mg/m² IV once per day on days 1 & 4
• Doxorubicin (Adriamycin) as follows:
  • Cycles 5 to 8: 16.7 mg/m²/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m²)
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 8: 500 mg/m² IV once on day 1

21-day cycle for 8 cycles

Subsequent treatment

• Surgery

Regimen variant #2, weekly paclitaxel for N+ disease

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

Chemotherapy, T portion

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 150 mg/m² IV over 3 hours once per day on days 1, 8, 15

Chemotherapy, FAC portion

• Fluorouracil (5-FU) as follows:
  • Cycles 5 to 8: 500 mg/m² IV once per day on days 1 & 4
• Doxorubicin (Adriamycin) as follows:
  • Cycles 5 to 8: 16.7 mg/m²/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m²)
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 8: 500 mg/m² IV once on day 1

28-day cycle for 4 cycles, then 21-day cycle for 4 cycles

Subsequent treatment

• Surgery

Regimen variant #3, q3wk paclitaxel

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

Chemotherapy, T portion

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 225 mg/m² IV continuous infusion over 24 hours, started on day 1

Chemotherapy, FAC portion

• Fluorouracil (5-FU) as follows:
  • Cycles 5 to 8: 500 mg/m² IV once per day on days 1 & 4
• Doxorubicin (Adriamycin) as follows:
  • Cycles 5 to 8: 16.7 mg/m²/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m²)
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 8: 500 mg/m² IV once on day 1

21-day cycle for 8 cycles

Subsequent treatment

• Surgery

References

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

T-FEC

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

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

Study	Years 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

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 80 mg/m² IV once per day on days 1, 8, 15

Chemotherapy, FEC portion

• Fluorouracil (5-FU) as follows:
  • Cycles 5 to 8: 500 mg/m² IV once on day 1
• Epirubicin (Ellence) as follows:
  • Cycles 5 to 8: 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 8: 500 mg/m² IV once on day 1

21-day cycle for 8 cycles

Subsequent treatment

• Surgery

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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gianni et al. 2018 (ETNA)	2013-2015	Phase 3 (C)	1. nab-Paclitaxel-AC 2. nab-Paclitaxel-EC 3. nab-Paclitaxel-FEC	Did not meet primary endpoint of pCR rate

Chemotherapy, T portion

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 90 mg/m² IV once per day on days 1, 8, 15

Chemotherapy, FEC portion

• Fluorouracil (5-FU) as follows:
  • Cycles 5 to 8: 600 mg/m² IV once on day 1
• Epirubicin (Ellence) as follows:
  • Cycles 5 to 8: 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 8: 600 mg/m² IV once on day 1

28-day cycle for 4 cycles, then 21-day cycle for 4 cycles

Subsequent treatment

• Surgery

References

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

Neoadjuvant chemotherapy

Capecitabine & Docetaxel (TX)

TX: Taxotere (Docetaxel) & Xeloda (Capecitabine)

Regimen

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

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

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

Cyclophosphamide & Doxorubicin (AC)

AC: Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen variant #1, 4 cycles

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

Chemotherapy

• 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 TX x 4

Regimen variant #2, 6 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Smith et al. 2004 (TOPIC)	1995-1999	Phase 3 (C)	ECisF	Did not meet 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

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

Dose-dense Cyclophosphamide & Doxorubicin (ddAC)

ddAC: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide

Regimen

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

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

Chemotherapy

• 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 dose-dense paclitaxel, then surgery or surgery, then dose-dense paclitaxel; this was not a randomization

References

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

DI EC

DI EC: Dose-Intense Epirubicin & Cyclophosphamide

Regimen

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

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

21-day cycle for 4 cycles

Subsequent treatment

• Surgery, then Docetaxel & 5-FU versus no further treatment

References

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

Docetaxel & Epirubicin (DE)

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

Regimen variant #1, 3 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Chen et al. 2017 (CBCRT01)	2011-2015	Phase 3 (C)	DEE	Inferior ORR

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 3 cycles

Subsequent treatment

• Surgery

Regimen variant #2, 6 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Steger et al. 2007 (ABCSG-14)	1999-2002	Phase 3 (E-esc)	ED x 3	Superior pCR rate
Han et al. 2009	2003-2005	Phase 3 (E-esc)	ED x 4	Seems to have superior pCR rate
Steger et al. 2013 (ABCSG-24)	2004-2008	Phase 3 (C)	EDC	Seems to have inferior 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 6 cycles

Subsequent treatment

• Surgery

References

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

EDC

EDC: Epirubicin, Docetaxel, Capecitabine

Regimen

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

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

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

Epirubicin monotherapy

E: Epirubicin

Regimen

Study	Years 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

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

Epirubicin & Paclitaxel (EP)

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

Regimen

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

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

Chemotherapy

• Epirubicin (Ellence) 90 mg/m² IV once on day 1
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

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

References

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

FAC

FAC: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide

Regimen variant #1, 500/50/500

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

Chemotherapy

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m²/day 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	Years 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 FAC x 4

Regimen variant #4, 2000/50/100

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

Chemotherapy

• 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

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

FEC

FEC: Fluorouracil, Epirubicin, Cyclophosphamide

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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Baldini et al. 2003	1992-1997	Phase 3 (C)	Dose-dense FEC	Did not meet primary endpoint of 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

• 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 CEF/CMF x 3

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

Study	Years 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	Years 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

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

iddEPC

iddEPC: intense dose-dense Epirubicin, Paclitaxel, Cyclophosphamide

Protocol

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Schneeweiss et al. 2018 (GeparOcto)	2014-NR in abstract	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, part 1

• Epirubicin (Ellence) 150 mg/m² IV once on day 1

Supportive therapy

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4

14-day cycle for 3 cycles, then:

Chemotherapy, part 2

• Paclitaxel (Taxol) 225 mg/m² IV once on day 1

Supportive therapy

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4

14-day cycle for 3 cycles, then:

Chemotherapy, part 3

• Cyclophosphamide (Cytoxan) 2000 mg/m² IV once on day 1

Supportive therapy

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4

14-day cycle for 3 cycles

Subsequent treatment

• Surgery

References

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

Paclitaxel monotherapy, dose-dense (q2wk)

ddT: dose-dense Taxol (Paclitaxel)

Regimen

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

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

Preceding treatment

• Burstein et al. 2005: ddAC x 4

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

Supportive therapy

• Burstein et al. 2005: Pegfilgrastim (Neulasta) 6 mg SC once on day 2

14-day cycle for 4 cycles

Subsequent treatment

• Burstein et al. 2005: Surgery

References

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

PET

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

Regimen

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

Chemotherapy

• Cisplatin (Platinol) 30 mg/m² IV once per day on days 1, 8, 15
• Epirubicin (Ellence) 50 mg/m² IV once per day on days 1, 8, 15
• Paclitaxel (Taxol) 120 mg/m² IV once per day on days 1, 8, 15

21-day cycle for 4 cycles

Subsequent treatment

• Frasci et al. 2006: Surgery

References

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

TAC (Docetaxel)

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2008 (GeparTrio)	2002-2005	Phase 3 (E-switch-ic)	TAC x 2, then NX x 4	Non-inferior sonographic response
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

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

Neoadjuvant response criteria

Clinical response rate (cRR)

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

References

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

Miller-Payne scoring system

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

References

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

Residual cancer burden (RCB)

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

References

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

Residual disease in breast and nodes (RDBN)

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

References

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

Sataloff's classification

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

References

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

Tumor response ratio

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

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

References

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

ypTNM staging

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

Adjuvant chemotherapy, sequential protocols

A-CMF

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

Protocol variant #1, IV classical CMF

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fernando et al. 2019 (SECRAB)	1998-2004	Phase 3 (C)	1. CMF & RT 2. E-CMF & RT 3. A-CMF & RT 4. MMM & RT	Inferior LRFS

Preceding treatment

• Surgery

Chemotherapy, A portion

• Doxorubicin (Adriamycin) 75 mg/m² IV once on day 1

21-day cycle for 4 cycles, followed by:

Chemotherapy, CMF portion

• 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

Protocol variant #2, PO classical CMF

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fernando et al. 2019 (SECRAB)	1998-2004	Phase 3 (C)	1. CMF & RT 2. E-CMF & RT 3. A-CMF & RT 4. MMM & RT	Inferior LRFS

Preceding treatment

• Surgery

Chemotherapy, A portion

• Doxorubicin (Adriamycin) 75 mg/m² IV once on day 1

21-day cycle for 4 cycles, followed by:

Chemotherapy, CMF portion

• 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 4 cycles

References

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

AC-CMF

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

Regimen

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

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

Preceding treatment

• Surgery

Chemotherapy, AC portion

• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 4: 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 600 mg/m² IV once on day 1

Chemotherapy, CMF portion

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 7: 100 mg/m² PO once per day on days 1 to 14
• Methotrexate (MTX) as follows:
  • Cycles 5 to 7: 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) as follows:
  • Cycles 5 to 7: 600 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles, then 28-day cycle for 3 cycles

Subsequent treatment

• Tamoxifen x 5 y versus no further treatment

References

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

AC-D

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

Protocol variant #1, q3wk docetaxel 75 mg/m²

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

Preceding treatment

• Surgery

Chemotherapy, AC portion

• 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, followed by:

Chemotherapy, D portion

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

21-day cycle for 4 cycles

Protocol variant #2, q3wk docetaxel 100 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sparano et al. 2008 (ECOG E1199)	1999-2002	Phase 3 (E-switch-ic)	1. AC-T; q3wk paclitaxel	Seems to have superior DFS
			2. AC-T; weekly paclitaxel 3. AC-D; weekly docetaxel	Not reported
Swain et al. 2010 (NSABP B-30)	1999-2004	Phase 3 (E-switch-ic)	1. AT	Seems to have superior OS
			2. TAC	Might have superior OS
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

• 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, followed by:

Chemotherapy, D portion

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

21-day cycle for 4 cycles

Protocol variant #2, weekly docetaxel

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

Preceding treatment

• Surgery

Chemotherapy, AC portion

• 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, followed by:

Chemotherapy, D portion

• Docetaxel (Taxotere) 35 mg/m² IV over 60 minutes once on day 1

7-day cycle for 12 cycles

References

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

AC-T

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

Regimen variant #1, weekly paclitaxel

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

Note: this regimen has been studied in many trials; these may be referenced under the individual components AC or T. Over time we will migrate these studies here.

Biomarker eligibility criteria

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

Preceding treatment

• Surgery

Chemotherapy, AC portion

• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 4: 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 600 mg/m² IV once on day 1

Chemotherapy, T portion

• Paclitaxel (Taxol) as follows:
  • Cycles 5 to 8: 80 mg/m² IV once per day on days 1, 8, 15

21-day cycle for 8 cycles

Regimen variant #2, q3wk paclitaxel 175 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Citron et al. 2003 (CALGB 9741)	1997-1999	Phase 3 (C)	See link	See link
Sparano et al. 2008 (ECOG E1199)	1999-2002	Phase 3 (C)	1. AC-T; weekly paclitaxel	Inferior OS
			2. AC-D; q3wk docetaxel	Seems to have inferior DFS
			3. AC-D; weekly docetaxel	Did not meet primary endpoint of DFS
Loesch et al. 2010	2000-2002	Phase 3 (C)	See link	See link
Burnell et al. 2009 (NCIC-CTG MA.21)	2000-2005	Phase 3 (C)	See link	See link
Watanabe et al. 2017 (NSAS BC-02)	2001-2006	Phase 3 (C)	1. AC-D 2. Docetaxel x 8	Seems to have inferior OS
			3. Paclitaxel x 8	Inconclusive whether non-inferior DFS

Note: this regimen has been studied in many trials; these may be referenced under the individual components AC or T. Over time we will migrate these studies here.

Preceding treatment

• Surgery

Chemotherapy, AC portion

• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 4: 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 600 mg/m² IV once on day 1

Chemotherapy, T portion

• Paclitaxel (Taxol) as follows:
  • Cycles 5 to 8: 175 mg/m² IV over 3 hours once on day 1

21-day cycle for 8 cycles

Regimen variant #3, q3wk paclitaxel 225 mg/m²

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

Preceding treatment

• Surgery

Chemotherapy, AC portion

• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 4: 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 600 mg/m² IV once on day 1

Chemotherapy, T portion

• Paclitaxel (Taxol) as follows:
  • Cycles 5 to 8: 225 mg/m² IV over 3 hours once on day 1

21-day cycle for 8 cycles

References

1. CALGB 9741: Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. link to original article contains dosing details in manuscript PubMed NCT00003088
2. NSABP B-28: Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol. 2005 Jun 1;23(16):3686-96. Epub 2005 May 16. link to original article contains dosing details in manuscript PubMed
3. ECOG E1199: Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. link to original article link to PMC article PubMed NCT00004125
   1. Update: Sparano JA, Zhao F, Martino S, Ligibel JA, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Long-term follow-up of the E1199 phase III trial evaluating the role of taxane and schedule in operable breast cancer. J Clin Oncol. 2015 Jul 20;33(21):2353-60. Epub 2015 Jun 15. link to original article link to PMC article PubMed
4. NCIC-CTG MA.21: Burnell M, Levine MN, Chapman JA, Bramwell V, Gelmon K, Walley B, Vandenberg T, Chalchal H, Albain KS, Perez EA, Rugo H, Pritchard K, O'Brien P, Shepherd LE. Cyclophosphamide, epirubicin, and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol. 2010 Jan 1;28(1):77-82. Epub 2009 Nov 9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00014222
5. Loesch D, Greco FA, Senzer NN, Burris HA, Hainsworth JD, Jones S, Vukelja SJ, Sandbach J, Holmes F, Sedlacek S, Pippen J, Lindquist D, McIntyre K, Blum JL, Modiano MR, Boehm KA, Zhan F, Asmar L, Robert N. Phase III multicenter trial of doxorubicin plus cyclophosphamide followed by paclitaxel compared with doxorubicin plus paclitaxel followed by weekly paclitaxel as adjuvant therapy for women with high-risk breast cancer. J Clin Oncol. 2010 Jun 20;28(18):2958-65. Epub 2010 May 17. link to original article contains dosing details in manuscript PubMed
6. NSAS BC-02: Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. link to original article contains dosing details in abstract PubMed
7. NSABP B-47: Fehrenbacher L, Cecchini RS, Geyer CE Jr, Rastogi P, Costantino JP, Atkins JN, Crown JP, Polikoff J, Boileau JF, Provencher L, Stokoe C, Moore TD, Robidoux A, Flynn PJ, Borges VF, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020 Feb 10;38(5):444-453. Epub 2019 Dec 10. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01275677

Dose-dense AC-T

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

Protocol variant #1, q2wk paclitaxel

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Citron et al. 2003 (CALGB 9741)	1997-1999	Phase 3 (E-esc)	See link	See link

Preceding treatment

• Surgery

Chemotherapy, ddAC portion

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Supportive therapy

• 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 4 cycles, followed by:

Chemotherapy, T portion

• 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; 30 to 60 minutes prior to Paclitaxel (Taxol)
• One of the following H2 blockers:
  • Ranitidine (Zantac) 50 mg IV once on day 1; 30 to 60 minutes prior to Paclitaxel (Taxol)
  • Cimetidine (Tagamet) 300 mg IV once on day 1; 30 to 60 minutes prior to Paclitaxel (Taxol)
  • Famotidine (Pepcid) 20 mg IV once on day 1; 30 to 60 minutes prior to Paclitaxel (Taxol)
• One of the following dexamethasone choices:
  • Dexamethasone (Decadron) 10 mg IV once on day 1, within 60 minutes prior to Paclitaxel (Taxol)
  • Dexamethasone (Decadron) 10 mg PO once on day 1, at least 60 minutes prior to Paclitaxel (Taxol)
  • Dexamethasone (Decadron) 20 mg PO twice on day 1; 6 hours and 12 hours prior to Paclitaxel (Taxol)
• 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
    • GIM2: a mid-protocol amendment suggested giving the pegilgrastim at least 72 h after chemotherapy

14-day cycle for 4 cycles

Protocol variant #2, weekly paclitaxel

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fehrenbacher et al. 2019 (NSABP B-47)	2011-2015	Phase 3 (C)	1. AC-TH 2. ddAC-TH 3. TCH	Did not meet primary endpoint of IDFS

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

Biomarker eligibility criteria

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

Preceding treatment

• Surgery

Chemotherapy, ddAC portion

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Supportive therapy

• Filgrastim (Neupogen) 5 mcg/kg (rounded to either 300 or 480 mcg) SC once per day on days 3 to 10

14-day cycle for 4 cycles

Chemotherapy, T portion

• Paclitaxel (Taxol) 80 mg/m² IV once on day 1

7-day cycle for 12 cycles

References

1. CALGB 9741: Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. link to original article contains dosing details in manuscript PubMed NCT00003088
2. NSABP B-47: Fehrenbacher L, Cecchini RS, Geyer CE Jr, Rastogi P, Costantino JP, Atkins JN, Crown JP, Polikoff J, Boileau JF, Provencher L, Stokoe C, Moore TD, Robidoux A, Flynn PJ, Borges VF, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020 Feb 10;38(5):444-453. Epub 2019 Dec 10. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01275677

D-EC

D-EC: Docetaxel followed by Epirubicin and Cyclophosphamide

Protocol

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Polyzos et al. 2009	1995-2004	Phase 3 (E-switch-ic)	FEC	Seems to have superior DFS

Preceding treatment

• Surgery

Chemotherapy, D portion

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

21-day cycle for 4 cycles, followed by:

Chemotherapy, EC portion

• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 700 mg/m² IV once on day 1

21-day cycle for 4 cycles

References

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

D-FEC

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

Protocol

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

¹Reported efficacy is based on the 2022 update.

Preceding treatment

• Surgery

Chemotherapy, D portion

• Docetaxel (Taxotere) 80 mg/m² IV over 60 minutes once on day 1

21-day cycle for 3 cycles

Chemotherapy, FEC portion

• 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 3 cycles

References

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

E-CMF

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

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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Poole et al. 2006 (BR9601)	1996-2001	Phase 3 (E-esc)	CMF x 6	Superior OS1 OS60: 84% vs 78% (HR 0.76, 95% CI 0.65-0.89)
Fernando et al. 2019 (SECRAB)	1998-2004	Phase 3 (C)	1. CMF & RT 2. E-CMF & RT 3. A-CMF & RT 4. MMM & RT	Inferior LRFS
Delaloge et al. 2020 (MINDACT)	2007-2011	Phase 3 (C)	TX	Did not meet primary endpoint of DFS

¹Reported efficacy is based on the 2012 update.

Preceding treatment

• Surgery

Chemotherapy, E portion

• Epirubicin (Ellence) as follows:
  • Cycles 1 to 4: 100 mg/m² IV once on day 1

Chemotherapy, CMF portion

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 8: 750 mg/m² IV once on day 1
• Methotrexate (MTX) as follows:
  • Cycles 5 to 8: 50 mg/m² IV once on day 1
• Fluorouracil (5-FU) as follows:
  • Cycles 5 to 8: 600 mg/m² IV once on day 1

21-day cycle for 8 cycles

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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Poole et al. 2006 (NEAT)	1996-2001	Phase 3 (E-esc)	CMF x 6	Superior OS1 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 x 6	Not reported
			CMF-E	Did not meet endpoint of OS60
Fernando et al. 2019 (SECRAB)	1998-2004	Phase 3 (C)	1. CMF & RT 2. E-CMF & RT 3. A-CMF & RT 4. MMM & RT	Inferior LRFS
Ellis et al. 2009 (TACT)	2001-2003	Phase 3 (C)	FEC-D	Did not meet primary endpoint of DFS
Cameron et al. 2017 (TACT2)	2005-2008	Phase 3 (C)	See link	See link

¹Reported efficacy is based on the 2012 update.

Preceding treatment

• Surgery

Chemotherapy, E portion

• Epirubicin (Ellence) as follows:
  • Cycles 1 to 4: 100 mg/m² IV once on day 1

Chemotherapy, CMF portion

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 8: 600 mg/m² IV once per day on days 1 & 8
• Methotrexate (MTX) as follows:
  • Cycles 5 to 8: 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) as follows:
  • Cycles 5 to 8: 600 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles, then 28-day cycle for 4 cycles

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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Poole et al. 2006 (NEAT)	1996-2001	Phase 3 (E-esc)	CMF x 6	Superior OS1 OS60: 84% vs 78% (HR 0.76, 95% CI 0.65-0.89)
Fernando et al. 2019 (SECRAB)	1998-2004	Phase 3 (C)	1. CMF & RT 2. E-CMF & RT 3. A-CMF & RT 4. MMM & RT	Inferior LRFS
Cameron et al. 2017 (TACT2)	2005-2008	Phase 3 (C)	See link	See link
Delaloge et al. 2020 (MINDACT)	2007-2011	Phase 3 (C)	TX	Did not meet primary endpoint of DFS

¹Reported efficacy is based on the 2012 update.

Preceding treatment

• Surgery

Chemotherapy, E portion

• Epirubicin (Ellence) as follows:
  • Cycles 1 to 4: 100 mg/m² IV once on day 1

Chemotherapy, CMF portion

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 8: 100 mg/m² PO once per day on days 1 to 14
• Methotrexate (MTX) as follows:
  • Cycles 5 to 8: 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) as follows:
  • Cycles 5 to 8: 600 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles, then 28-day cycle for 4 cycles

References

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

E-D

E-D: Epirubicin followed by Docetaxel

Protocol variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Coombes et al. 2011 (DEVA)	1997-2005	Phase 3 (E-switch-ic)	Epirubicin	Superior OS OS60: 88.9% vs 81.8% (HR 0.66, 95% CI 0.46-0.94)

Preceding treatment

• Surgery

Chemotherapy, E portion

• Epirubicin (Ellence) 50 mg/m² IV once per day on days 1 & 8

28-day cycle for 3 cycles

Chemotherapy, D portion

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

21-day cycle for 3 cycles

Protocol variant #2

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

Preceding treatment

• Surgery

Chemotherapy, E portion

• Epirubicin (Ellence) 90 mg/m² IV over 5 to 15 minutes once on day 1

21-day cycle for 4 cycles

Chemotherapy, D portion

• Docetaxel (Taxotere) 75 mg/m² IV over 60 minutes once on day 1

21-day cycle for 4 cycles

References

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

EC-CMF

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

Regimen

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

¹Reported efficacy is based on the 2009 update.

Preceding treatment

• Surgery

Chemotherapy, EC portion

• Epirubicin (Ellence) as follows:
  • Cycles 1 to 4: 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 600 mg/m² IV once on day 1

Chemotherapy, CMF portion

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 7: 100 mg/m² PO once per day on days 1 to 14
• Methotrexate (MTX) as follows:
  • Cycles 5 to 7: 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) as follows:
  • Cycles 5 to 7: 600 mg/m² IV once per day on days 1 & 8

21-day cycle for 4 cycles, then 28-day cycle for 3 cycles

Subsequent treatment

• Tamoxifen x 5 y versus no further treatment

References

1. IBCSG 15-95: Basser RL, O'Neill A, Martinelli G, Green MD, Peccatori F, Cinieri S, Coates AS, Gelber RD, Aebi S, Castiglione-Gertsch M, Viale G, Price KN, Goldhirsch A; International Breast Cancer Study Group. Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95. J Clin Oncol. 2006 Jan 20;24(3):370-8. link to original article contains dosing details in manuscript PubMed NCT00002784
   1. Update: Colleoni M, Sun Z, Martinelli G, Basser RL, Coates AS, Gelber RD, Green MD, Peccatori F, Cinieri S, Aebi S, Viale G, Price KN, Goldhirsch A; International Breast Cancer Study Group. The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up. Ann Oncol. 2009 Aug;20(8):1344-51. Epub 2009 May 25. link to original article link to PMC article PubMed
2. IBCSG 13-93: Colleoni M, Gelber S, Goldhirsch A, Aebi S, Castiglione-Gertsch M, Price KN, Coates AS, Gelber RD; International Breast Cancer Study Group. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol. 2006 Mar 20;24(9):1332-41. Epub 2006 Feb 27. link to original article contains dosing details in manuscript PubMed

EC-D

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

Protocol variant #1, 3+3 cycles

Study	Years 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

• Epirubicin (Ellence) 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 3 cycles

Chemotherapy, D portion

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

21-day cycle for 3 cycles

Protocol variant #2, 4+4 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Martín et al. 2015 (GEICAM 2003-10)	2004-2007	Phase 3 (C)	ET-X x 4+4	Seems to have superior IDFS

Preceding treatment

• Surgery

Chemotherapy, EC portion

• Epirubicin (Ellence) 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 4 cycles

Chemotherapy, D portion

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

21-day cycle for 4 cycles

References

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

EC-T

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

Regimen variant #1, 75/600

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

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

Preceding treatment

• Surgery

Chemotherapy, EC portion

• Epirubicin (Ellence) as follows:
  • Cycles 1 to 4: 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 600 mg/m² IV once on day 1

Chemotherapy, T portion

• Paclitaxel (Taxol) as follows:
  • Cycles 5 to 8: 80 mg/m² IV once per day on days 1, 8, 15

21-day cycle for 8 cycles

Regimen variant #2, 90/600

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Earl et al. 2017 (tAnGo)	2001-2004	Phase 3 (C)	EC-TG	Did not meet primary endpoint of DFS
Del Mastro et al. 2015 (GIM2)	2003-2006	Phase 3 (C)	1. ddEC-ddT 2. ddFEC-ddT	Inferior OS
			3. FEC-P	Did not meet primary endpoint of DFS

Preceding treatment

• Surgery

Chemotherapy, EC portion

• Epirubicin (Ellence) as follows:
  • Cycles 1 to 4: 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 600 mg/m² IV once on day 1

Chemotherapy, T portion

• Paclitaxel (Taxol) as follows:
  • Cycles 5 to 8: 175 mg/m² IV over 3 hours once on day 1

21-day cycle for 8 cycles

References

1. GIM2: Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; GIM. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article contains dosing details in manuscript PubMed NCT00433420
2. tAnGo: Earl HM, Hiller L, Howard HC, Dunn JA, Young J, Bowden SJ, McDermaid M, Waterhouse AK, Wilson G, Agrawal R, O'Reilly S, Bowman A, Ritchie DM, Goodman A, Hickish T, McAdam K, Cameron D, Dodwell D, Rea DW, Caldas C, Provenzano E, Abraham JE, Canney P, Crown JP, Kennedy MJ, Coleman R, Leonard RC, Carmichael JA, Wardley AM, Poole CJ; tAnGo trial collaborators. Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Jun;18(6):755-769. Epub 2017 May 4. link to original article contains dosing details in abstract PubMed NCT00039546
3. SPECTRUM_brca: Yu KD, Ge JY, Liu XY, Mo M, He M, Shao ZM; SPECTRUM Investigators. Cyclophosphamide-Free Adjuvant Chemotherapy for Ovarian Protection in Young Women With Breast Cancer: A Randomized Phase 3 Trial. J Natl Cancer Inst. 2021 Oct 1;113(10):1352-1359. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01026116

FEC-D

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

Regimen variant #1, 3 x 3

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Roché et al. 2006 (FNCLCC PACS 01)	1997-2000	Phase 3 (E-switch-ic)	FEC x 6	Superior OS1 OS96: 83.2% vs 78% (aHR 0.75, 95% CI 0.62-0.92)
de Gregorio et al. 2020 (SUCCESS-A)	2005-2007	Phase 3 (C)	FEC-DG	Did not meet primary endpoint of DFS
Sakr et al. 2013	2006-2010	Phase 3 (E-switch-ic)	FEC; FEC 100 x 6	Seems to have superior OS
Campone et al. 2018 (UCBG 2-08)	2007-2010	Phase 3 (C)	FEC-Ixabepilone	Did not meet primary endpoint of DFS60
Foukakis et al. 2016 (PANTHER)	2007-2011	Phase 3 (C)	Dose-dense tailored chemotherapy	Did not meet primary endpoint of RFS
Delaloge et al. 2020 (MINDACT)	2007-2011	Phase 3 (C)	TX	Did not meet primary endpoint of DFS

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

Preceding treatment

• Surgery

Chemotherapy, FEC portion

• Fluorouracil (5-FU) as follows:
  • Cycles 1 to 3: 500 mg/m² IV once on day 1
• Epirubicin (Ellence) as follows:
  • Cycles 1 to 3: 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 3: 500 mg/m² IV once on day 1

Chemotherapy, D portion

• Docetaxel (Taxotere) as follows:
  • Cycles 4 to 6: 100 mg/m² IV over 60 minutes once on day 1

21-day cycle for 6 cycles

Regimen variant #2, 4 x 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ellis et al. 2009 (TACT)	2001-2003	Phase 3 (E-switch-ic)	1. E-CMF 2. FEC x 8	Did not meet primary endpoint of DFS

Note: this is 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

• Fluorouracil (5-FU) as follows:
  • Cycles 1 to 4: 600 mg/m² IV once on day 1
• Epirubicin (Ellence) as follows:
  • Cycles 1 to 4: 40 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 600 mg/m² IV once on day 1

Chemotherapy, D portion

• Docetaxel (Taxotere) as follows:
  • Cycles 5 to 8: 100 mg/m² IV over 60 minutes once on day 1

21-day cycle for 8 cycles

References

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

Dose-dense FEC-D

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
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

• 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

Supportive therapy

• Filgrastim or Pegfilgrastim (Neulasta) support (drug/dose/schedule not specified)

14-day cycle for 4 cycles

Chemotherapy, D portion

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Supportive therapy

• Filgrastim or Pegfilgrastim support (drug/dose/schedule not specified)

14-day cycle for 4 cycles

References

1. HORG CT/07.17: Mavroudis D, Matikas A, Malamos N, Papakotoulas P, Kakolyris S, Boukovinas I, Athanasiadis A, Kentepozidis N, Ziras N, Katsaounis P, Saloustros E, Georgoulias V; HORG. Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2016 Oct;27(10):1873-8. Epub 2016 Aug 8. link to original article contains dosing details in manuscript PubMed NCT01985724

FEC-P

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

Protocol

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

Preceding treatment

• Surgery

Chemotherapy, FEC portion

• 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 4 cycles, followed by:

Chemotherapy, T portion

• Paclitaxel (Taxol) 100 mg/m² IV over 60 minutes once on day 1

7-day cycle for 8 cycles

References

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

T-FEC

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

Regimen

Study	Years 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

• Paclitaxel (Taxol) as follows:
  • Cycles 1 to 4: 80 mg/m² IV once per day on days 1, 8, 15

Chemotherapy, FEC portion

• Fluorouracil (5-FU) as follows:
  • Cycles 5 to 8: 500 mg/m² IV once on day 1
• Epirubicin (Ellence) as follows:
  • Cycles 5 to 8: 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 5 to 8: 500 mg/m² IV once on day 1

21-day cycle for 8 cycles

References

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

TX-CEX

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

Protocol

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Joensuu et al. 2009 (FinXX)	2004-2007	Phase 3 (E-esc)	D-FEC	Seems to have superior OS1 OS180: 77.6% vs 73.3% (HR 0.81, 95% CI 0.66-0.99)

¹Reported efficacy is based on the 2022 update.

Preceding treatment

• Surgery

Chemotherapy, TX portion

• 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

21-day cycle for 3 cycles

Chemotherapy, CEX portion

• 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 3 cycles

References

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

Adjuvant chemotherapy

Bevacizumab monotherapy

Regimen

Study	Years 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

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

Capecitabine monotherapy

Regimen variant #1, 4 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cameron et al. 2017 (TACT2)	2005-2008	Phase 3 (E-de-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

• ddE x 4 versus Epirubicin x 4

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

21-day cycle for 4 cycles

Regimen variant #2, 6 to 8 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Muss et al. 2009 (CALGB 49907)	2001-2006	Phase 3 (E-de-esc)	Physician's choice of: 1. AC x 4 2. CMF x 6	Seems to have inferior OS
Masuda et al. 2017 (CREATE-X)	2007-2012	Phase 3 (E-esc)	Standard therapy	Superior OS OS60: 89.2% vs 83.6% (HR 0.59, 95% CI 0.39-0.90)

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

1. CALGB 49907: Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Becker HP, Kartcheske PA, Wheeler JD, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Magrinat G, Parker BA, Hart RD, Grenier D, Norton L, Hudis CA, Winer EP; CALGB. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009 May 14;360(20):2055-65. Erratum in: N Engl J Med. 2009 Oct 22;361(17):1714. Magrinat, Gutav [corrected to Magrinat, Gustav]. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00024102
2. CREATE-X: Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, Kuroi K, Im SA, Park BW, Kim SB, Yanagita Y, Ohno S, Takao S, Aogi K, Iwata H, Jeong J, Kim A, Park KH, Sasano H, Ohashi Y, Toi M. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017 Jun 1;376(22):2147-2159. link to original article contains dosing details in manuscript PubMed UMIN000000843
3. TACT2: Cameron D, Morden JP, Canney P, Velikova G, Coleman R, Bartlett J, Agrawal R, Banerji J, Bertelli G, Bloomfield D, Brunt AM, Earl H, Ellis P, Gaunt C, Gillman A, Hearfield N, Laing R, Murray N, Couper N, Stein RC, Verrill M, Wardley A, Barrett-Lee P, Bliss JM; TACT2 Investigators. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2017 Jul;18(7):929-945. Epub 2017 Jun 7. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00301925

CMF

CMF: Cyclophosphamide, Methotrexate, Fluorouracil

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

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

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 8

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Buzzoni et al. 1991 (Milan trial)	1982-1987	Phase 3 (E-switch-ic)	See link	See link
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

• Milan trial: Surgery, then A x 4
• DBCG 82b: 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 #3, 600/50/600 x 8

Study	Years 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

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, then A x 4

Chemotherapy

• 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

28-day cycle for 8 cycles

Regimen variant #4, 700/30/700 x 24

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

Preceding treatment

• 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 #5, 750/50/600 x 6-8 ("Scottish Breast Group schedule")

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

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 6 to 8 cycles

Regimen variant #6, 840/50/800

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

Preceding treatment

• 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 #7, 1000/80/1000 x 6

Study	Years 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 #8, 1000/80/1200 x 3

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

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, then EC x 4

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 3 cycles

Regimen variant #9, 1000/80/1200 x 6

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

Preceding treatment

• 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 #10, 1120/60/1000 x 12

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

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 #11, 1120/64/960 x 12

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Howell et al. 1984	1976-1983	Phase 3 (E-esc)	Observation	Superior 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 #12, 1200/80/1200 x 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gianni et al. 2009 (ECTO)	1996-2002	Phase 3 (C)	See link	See link
Perrone et al. 2014 (ELDA)	2003-2011	Phase 3 (C)	Docetaxel	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. In ELDA, this protocol was for ER/PR+ patients.

Preceding treatment

• ECTO: Surgery, then A x 4 versus AT (Taxol) x 4

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 #13, 1200/80/1200 x 6 ("Classical" IV)

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Ragaz et al. 1997	1978-1986	Phase 3 (C)	CMF & RT	Seems to have inferior OS
Coombes et al. 1996	1984-1992	Phase 3 (C)	FEC	Did not meet primary endpoints of RFS/OS
Taucher et al. 2007 (ABCSG-07)	1991-1999	Phase 3 (C)	CMF; neoadjuvant	Seems to have superior RFS
Poole et al. 2006 (NEAT)	1996-2001	Phase 3 (C)	E-CMF x 4+4	Inferior OS
Fernando et al. 2019 (SECRAB)	1998-2004	Phase 3 (C)	1. CMF & RT 2. E-CMF & RT 3. A-CMF & RT 4. MMM & RT	Inferior LRFS
Perrone et al. 2014 (ELDA)	2003-2011	Phase 3 (C)	Docetaxel	Did not meet primary endpoint of DFS

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

Preceding treatment

• 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 #14, 1400/60/1200 x 12

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

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

Preceding treatment

• 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 #15, 1400/80/1000 x 6

Study	Years 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 #16, 1400/80/1200 x 3

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

Preceding treatment

• IBCSG VI: 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

• IBCSG VI: Tamoxifen x 5 y versus no further treatment

Regimen variant #18, 1400/80/1200 x 6

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

Subsequent treatment

• NSABP B-23 and INT-0102: tamoxifen x 5 years versus placebo

Regimen variant #19, 1400/80/1200 x 12

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

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19. NSABP B-23: Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, Dimitrov NV, Atkins JN, Abramson N, Merajver S, Romond EH, Kardinal CG, Shibata HR, Margolese RG, Farrar WB. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001 Feb 15;19(4):931-42. link to original article PubMed
20. Belgian trial: Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M, Nogaret JM. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol. 2001 Jun 15;19(12):3103-10. link to original article PubMed
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32. NSAS BC-01: Watanabe T, Sano M, Takashima S, Kitaya T, Tokuda Y, Yoshimoto M, Kohno N, Nakagami K, Iwata H, Shimozuma K, Sonoo H, Tsuda H, Sakamoto G, Ohashi Y. Oral uracil and tegafur compared with classic cyclophosphamide, methotrexate, fluorouracil as postoperative chemotherapy in patients with node-negative, high-risk breast cancer: National Surgical Adjuvant Study for Breast Cancer 01 trial. J Clin Oncol. 2009 Mar 20;27(9):1368-74. Epub 2009 Feb 9. link to original article contains dosing details in manuscript PubMed NCT00152191
33. ECTO: Gianni L, Baselga J, Eiermann W, Porta VG, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Cussac AL, Bozhok A, Martinez-Agulló A, Greco M, Byakhov M, Lopez JJ, Mansutti M, Valagussa P, Bonadonna G. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. J Clin Oncol. 2009 May 20;27(15):2474-81. Epub 2009 Mar 30. link to original article contains dosing details in manuscript PubMed NCT00003013
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35. CALGB 49907: Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Becker HP, Kartcheske PA, Wheeler JD, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Magrinat G, Parker BA, Hart RD, Grenier D, Norton L, Hudis CA, Winer EP; CALGB. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009 May 14;360(20):2055-65. Erratum in: N Engl J Med. 2009 Oct 22;361(17):1714. Magrinat, Gutav [corrected to Magrinat, Gustav]. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00024102
36. Kimura M, Tominaga T, Takatsuka Y, Toi M, Abe R, Koyama H, Takashima S, Nomura Y, Miura S, Kimijima I, Tashiro H, Ohashi Y; Adjuvant CEF Research Group for Breast Cancer. Randomized trial of cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil with node-positive breast cancer in Japan. Breast Cancer. 2010 Jul;17(3):190-8. Epub 2009 Jul 3. link to original article contains dosing details in abstract PubMed
37. ELDA: Perrone F, Nuzzo F, Di Rella F, Gravina A, Iodice G, Labonia V, Landi G, Pacilio C, Rossi E, De Laurentiis M, D'Aiuto M, Botti G, Forestieri V, Lauria R, De Placido S, Tinessa V, Daniele B, Gori S, Colantuoni G, Barni S, Riccardi F, De Maio E, Montanino A, Morabito A, Daniele G, Di Maio M, Piccirillo MC, Signoriello S, Gallo C, de Matteis A. Weekly docetaxel versus CMF as adjuvant chemotherapy for older women with early breast cancer: final results of the randomized phase III ELDA trial. Ann Oncol. 2015 Apr;26(4):675-82. Epub 2014 Dec 8. link to original article contains dosing details in abstract PubMed NCT00331097
38. SECRAB: Fernando IN, Bowden SJ, Herring K, Brookes CL, Ahmed I, Marshall A, Grieve R, Churn M, Spooner D, Latief TN, Agrawal RK, Brunt AM, Stevens A, Goodman A, Canney P, Bishop J, Ritchie D, Dunn J, Poole CJ, Rea DW; SECRAB Investigators. Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial. Radiother Oncol. 2020 Jan;142:52-61. Epub 2019 Nov 27. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00003893

CMFT

CMFT: Cyclophosphamide, Methotrexate, Fluorouracil, Tamoxifen

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

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

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

Preceding treatment

• 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

28-day cycle for 13 cycles

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

Study	Years 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

28-day cycle for 26 cycles

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

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

Preceding treatment

• 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

1. Hubay CA, Pearson OH, Marshall JS, Rhodes RS, Debanne SM, Mansour EG, Hermann RE, Jones JC, Flynn WJ, Eckert C, McGuire WL. Antiestrogen, cytotoxic chemotherapy, and bacillus Calmette-Guerin vaccination in stage II breast cancer: a preliminary report. Surgery. 1980 May;87(5):494-501. link to original article PubMed
   1. Update: Hubay CA, Pearson OH, Marshall JS, Rhodes RS, DeBanne SM, Rosenblatt J, Mansour EG, Hermann RE, Jones JC, Flynn WJ, Eckert C, McGuire WL. Adjuvant chemotherapy, antiestrogen therapy and immunotherapy for stage II breast cancer: 45-month follow-up of a prospective, randomized clinical trial. Cancer. 1980 Dec 15;46(12 Suppl):2805-8. link to original article PubMed
2. NCIC-CTG MA.4: Pritchard KI, Paterson AH, Paul NA, Zee B, Fine S, Pater J; National Cancer Institute of Canada Clinical Trials Group. Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. J Clin Oncol. 1996 Oct;14(10):2731-7. link to original article PubMed
   1. Update: Pritchard KI, Paterson AH, Fine S, Paul NA, Zee B, Shepherd LE, Abu-Zahra H, Ragaz J, Knowling M, Levine MN, Verma S, Perrault D, Walde PL, Bramwell VH, Poljicak M, Boyd N, Warr D, Norris BD, Bowman D, Armitage GR, Weizel H, Buckman RA; NCIC-CTG. Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1997 Jun;15(6):2302-11. link to original article PubMed
3. NSABP B-20: Fisher B, Dignam J, Wolmark N, DeCillis A, Emir B, Wickerham DL, Bryant J, Dimitrov NV, Abramson N, Atkins JN, Shibata H, Deschenes L, Margolese RG. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst. 1997 Nov 19;89(22):1673-82. link to original article contains dosing details in manuscript PubMed
   1. Pooled update: Fisher B, Jeong JH, Bryant J, Anderson S, Dignam J, Fisher ER, Wolmark N; National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet. 2004 Sep 4-10;364(9437):858-68. link to original article PubMed
   2. Pooled update: Taghian AG, Jeong JH, Mamounas EP, Parda DS, Deutsch M, Costantino JP, Wolmark N. Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol. 2006 Aug 20;24(24):3927-32. link to original article PubMed
4. DBCG 82C: Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M, Kamby C, Kjaer M, Gadeberg CC, Rasmussen BB, Blichert-Toft M, Mouridsen HT. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet. 1999 May 15;353(9165):1641-8. link to original article contains dosing details in abstract PubMed
   1. Update: Ejlertsen B, Jensen MB, Elversang J, Rasmussen BB, Andersson M, Andersen J, Nielsen DL, Cold S, Mouridsen HT. One year of adjuvant tamoxifen compared with chemotherapy and tamoxifen in postmenopausal patients with stage II breast cancer. Eur J Cancer. 2013 Sep;49(14):2986-94. Epub 2013 Jun 8. link to original article contains dosing details in manuscript PubMed
5. Taiho 91023033: Park Y, Okamura K, Mitsuyama S, Saito T, Koh J, Kyono S, Higaki K, Ogita M, Asaga T, Inaji H, Komichi H, Kohno N, Yamazaki K, Tanaka F, Ito T, Nishikawa H, Osaki A, Koyama H, Suzuki T. Uracil-tegafur and tamoxifen vs cyclophosphamide, methotrexate, fluorouracil, and tamoxifen in post-operative adjuvant therapy for stage I, II, or IIIA lymph node-positive breast cancer: a comparative study. Br J Cancer. 2009 Aug 18;101(4):598-604. Epub 2009 Jul 28. Erratum in: Br J Cancer. 2009 Sep 15;101(6):1031. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00152178

Dose-dense Cyclophosphamide monotherapy

ddC: dose-dense Cyclophosphamide

Regimen variant #1, 600 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Citron et al. 2003 (CALGB 9741)	1997-1999	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

• ddT x 4

Chemotherapy

• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Supportive therapy

• 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 4 cycles

Regimen variant #2, 800 mg/m²

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

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

• ddT x 4

Chemotherapy

• Cyclophosphamide (Cytoxan) 800 mg/m² IV once on day 1

Supportive therapy

• Filgrastim (Neupogen)

14-day cycle for 4 cycles

References

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

Cyclophosphamide & Docetaxel (TC)

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

Regimen variant #1, 4 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Jones et al. 2006 (USOR 9735)	1997-1999	Phase 3 (E-switch-ic)	AC	Seems to have superior OS
Blum et al. 2017 (USOR 06-090)	2007-2009	Phase 3 (C)	TAC	Seems to have inferior IDFS
Blum et al. 2017 (NSABP-46-I/USOR 07132)	2009-2012	Phase 3 (C)	TAC	Seems to have inferior IDFS
Blum et al. 2017 (NSABP B-49)	2012-2013	Phase 3 (C)	TAC	Seems to have inferior IDFS

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.

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

• All cycles given with Filgrastim (Neupogen) support

21-day cycle for 4 cycles

Regimen variant #2, 6 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Nitz et al. 2019 (WSG PlanB)	2000-2005	Phase 3 (E-de-esc)	EC-D	Non-inferior DFS
Mavroudis et al. 2016 (HORG CT/07.17)	2007-2013	Phase 3 (E-de-esc)	ddFEC-D	Inconclusive whether non-inferior DFS36
Ejlertsen et al. 2017 (DBCG 07-READ)	2008-2012	Phase 3 (E-de-esc)	EC-D	Did not meet primary endpoint of DFS DFS60: 88.3% vs 87.9% (HR 1.00, 95% CI 0.78-1.28)
Fehrenbacher et al. 2019 (NSABP B-47)	2011-2015	Phase 3 (C)	1. AC-TH 2. ddAC-TH 3. TCH	Did not meet primary endpoint of IDFS

Biomarker eligibility criteria

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

Preceding treatment

• 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

1. USOR 9735: Jones SE, Savin MA, Holmes FA, O'Shaughnessy JA, Blum JL, Vukelja S, McIntyre KJ, Pippen JE, Bordelon JH, Kirby R, Sandbach J, Hyman WJ, Khandelwal P, Negron AG, Richards DA, Anthony SP, Mennel RG, Boehm KA, Meyer WG, Asmar L. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol. 2006 Dec 1;24(34):5381-7. Erratum in: J Clin Oncol. 2007 May 1;25(13):1819. link to original article PubMed
   1. Update: Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL, Sandbach J, Hyman WJ, Richards DA, Mennel RG, Boehm KA, Meyer WG, Asmar L, Mackey D, Riedel S, Muss H, Savin MA. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology research trial 9735. J Clin Oncol. 2009 Mar 10;27(8):1177-83. Epub 2009 Feb 9. link to original article PubMed
2. HORG CT/07.17: Mavroudis D, Matikas A, Malamos N, Papakotoulas P, Kakolyris S, Boukovinas I, Athanasiadis A, Kentepozidis N, Ziras N, Katsaounis P, Saloustros E, Georgoulias V; HORG. Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2016 Oct;27(10):1873-8. Epub 2016 Aug 8. link to original article contains dosing details in manuscript PubMed NCT01985724
3. USOR 06-090: Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00493870
4. NSABP-46-I/USOR 07132: Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00887536
5. NSABP B-49: Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01547741
6. DBCG 07-READ: Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen MB, Knoop AS, Højris I, Ewertz M, Balslev E, Danø H, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. Adjuvant cyclophosphamide and docetaxel with or without epirubicin for early TOP2A-normal breast cancer: DBCG 07-READ, an open-label, phase III, randomized trial. J Clin Oncol. 2017 Aug 10;35(23):2639-2646. Epub 2017 Jun 29. link to original article contains dosing details in manuscript PubMed NCT00689156
7. WSG PlanB: Nitz U, Gluz O, Clemens M, Malter W, Reimer T, Nuding B, Aktas B, Stefek A, Pollmanns A, Lorenz-Salehi F, Uleer C, Krabisch P, Kuemmel S, Liedtke C, Shak S, Wuerstlein R, Christgen M, Kates RE, Kreipe HH, Harbeck N; West German Study Group. West German Study PlanB trial: adjuvant four cycles of epirubicin and cyclophosphamide plus docetaxel versus six cycles of docetaxel and cyclophosphamide in HER2-negative early breast cancer. J Clin Oncol. 2019 Apr 1;37(10):799-808. Epub 2019 Feb 20. link to original article contains dosing details in abstract PubMed NCT01049425
8. NSABP B-47: Fehrenbacher L, Cecchini RS, Geyer CE Jr, Rastogi P, Costantino JP, Atkins JN, Crown JP, Polikoff J, Boileau JF, Provencher L, Stokoe C, Moore TD, Robidoux A, Flynn PJ, Borges VF, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020 Feb 10;38(5):444-453. Epub 2019 Dec 10. link to original article link to PMC article contains dosing details in manuscript PubMed NCT01275677
9. ASTER 70s: NCT01564056

Cyclophosphamide & Doxorubicin (AC)

AC: Adriamycin (Doxorubicin) and Cyclophosphamide
CA: Cyclophosphamide and Adriamycin (Doxorubicin)

Regimen variant #1, 54/1200 x 6

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Linden et al. 2007 (INT-0137)	1994-1997	Phase 3 (C)	A-C	Did not meet primary endpoint of DFS

Preceding treatment

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin) 54 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 1200 mg/m² IV once on day 1

21-day cycle for 6 cycles

Regimen variant #2, 60/600 x 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fisher et al. 1997 (NSABP B-18)	1988-1993	Phase 3 (C)	AC; neoadjuvant	Inferior resectability
Fisher et al. 1997 (NSABP B-22)	1989-1991	Phase 3 (C)	1. AC; intensified 2. AC; intensified & increased	Did not meet primary endpoints of DFS/OS
Fisher et al. 2001 (NSABP B-23)	1991-1998	Phase 3 (E-switch-ic)	CMF	Did not meet primary endpoint of OS
Içli et al. 2001	1992-1996	Non-randomized portion of RCT
Henderson et al. 2003 (INT 0148/CALGB 9344)	1994-1999	Phase 3 (C)	1. AC; high-dose 2. AC; very high dose	Did not meet primary endpoint of DFS
Mamounas et al. 2005 (NSABP B-28)	1995-1998	Phase 3 (C)	AC-T	Inferior PFS
Jones et al. 2006 (USOR 9735)	1997-1999	Phase 3 (C)	TC	Seems to have inferior OS
Goldstein et al. 2008 (ECOG E2197)	1998-2000	Phase 3 (C)	AT	Did not meet primary endpoint of DFS
Brain et al. 2005 (RAPP-01)	1999-2003	Phase 3 (C)	AT	Not reported
Muss et al. 2009 (CALGB 49907)	2001-2006	Phase 3 (C)	Capecitabine	Seems to have superior OS
Miller et al. 2018 (ECOG E5103)	2007-2011	Phase 3 (C)	See link	See link

Preceding treatment

• Most protocols: Surgery
• INT 0148/CALGB 9344: Surgery, within 84 days

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-23: Tamoxifen x 5 y versus placebo
• Içli et al. 2001: EP x 2 versus no further treatment
• INT 0148/CALGB 9344: q3wk T (Taxol) x 4 versus no further therapy
• ECOG E5103: weekly T (Taxol) x 12

Regimen variant #3, 80/600 x 4

Study	Years of enrollment	Evidence
Moore et al. 2007 (SWOG S9623)	1996-2001	Non-randomized portion 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

• Doxorubicin (Adriamycin) 80 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

• STAMP-I or STAMP-V, with auto HSCT

References

1. NSABP B-22: Fisher B, Anderson S, Wickerham DL, DeCillis A, Dimitrov N, Mamounas E, Wolmark N, Pugh R, Atkins JN, Meyers FJ, Abramson N, Wolter J, Bornstein RS, Levy L, Romond EH, Caggiano V, Grimaldi M, Jochimsen P, Deckers P. Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol. 1997 May;15(5):1858-69. link to original article contains dosing details in manuscript PubMed
   1. Pooled update: Taghian A, Jeong JH, Mamounas E, Anderson S, Bryant J, Deutsch M, Wolmark N. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol. 2004 Nov 1;22(21):4247-54. Epub 2004 Sep 27. link to original article PubMed
2. NSABP B-18: Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB Jr, Fisher ER, Wickerham DL, Wolmark N, DeCillis A, Hoehn JL, Lees AW, Dimitrov NV. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997 Jul;15(7):2483-93. link to original article contains dosing details in manuscript PubMed
   1. Update: Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, Wickerham DL, Begovic M, DeCillis A, Robidoux A, Margolese RG, Cruz AB Jr, Hoehn JL, Lees AW, Dimitrov NV, Bear HD. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998 Aug;16(8):2672-85. link to original article PubMed
   2. Update: Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst. 2001;(30):96-102. link to original article PubMed
   3. Pooled update: Taghian A, Jeong JH, Mamounas E, Anderson S, Bryant J, Deutsch M, Wolmark N. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol. 2004 Nov 1;22(21):4247-54. Epub 2004 Sep 27. link to original article PubMed
   4. Pooled update: Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008 Feb 10;26(5):778-85. Erratum in: J Clin Oncol. 2008 Jun 1;26(16):2793. link to original article PubMed
3. NSABP B-23: Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, Dimitrov NV, Atkins JN, Abramson N, Merajver S, Romond EH, Kardinal CG, Shibata HR, Margolese RG, Farrar WB. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001 Feb 15;19(4):931-42. link to original article PubMed
4. Içli F, Akbulut H, Dinçol D, Onur H, Demirkazik A, Cam R, Cay F, Demirci S, Uner A, Erekul S. A randomized trial of four cycles of adjuvant AC (adriamycin + cyclophosphamide) +/- two cycles of EP (etoposide + cisplatin) in node positive patients with breast cancer. Ann Oncol. 2001 Jul;12(7):1011-3. link to original article contains dosing details in abstract PubMed
5. INT 0148/CALGB 9344: Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003 Mar 15;21(6):976-83. link to original article contains dosing details in manuscript PubMed
6. 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 PubMed
7. RAPP-01: Brain EG, Bachelot T, Serin D, Kirscher S, Graic Y, Eymard JC, Extra JM, Combe M, Fourme E, Noguès C, Rouëssé J; RAPP-01 Trial Investigators. Life-threatening sepsis associated with adjuvant doxorubicin plus docetaxel for intermediate-risk breast cancer. JAMA. 2005 May 18;293(19):2367-71. link to original article contains dosing details in abstract PubMed
8. 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 contains dosing details in abstract PubMed
   1. Update: Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL, Sandbach J, Hyman WJ, Richards DA, Mennel RG, Boehm KA, Meyer WG, Asmar L, Mackey D, Riedel S, Muss H, Savin MA. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology research trial 9735. J Clin Oncol. 2009 Mar 10;27(8):1177-83. Epub 2009 Feb 9. link to original article PubMed
9. INT-0137: Linden HM, Haskell CM, Green SJ, Osborne CK, Sledge GW Jr, Shapiro CL, Ingle JN, Lew D, Hutchins LF, Livingston RB, Martino S. Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer: final analysis from INT-0137 (S9313). J Clin Oncol. 2007 Feb 20;25(6):656-61. link to original article contains dosing details in abstract PubMed
10. SWOG S9623: Moore HC, Green SJ, Gralow JR, Bearman SI, Lew D, Barlow WE, Hudis C, Wolff AC, Ingle JN, Chew HK, Elias AD, Livingston RB, Martino S; SWOG. Intensive dose-dense compared with high-dose adjuvant chemotherapy for high-risk operable breast cancer: Southwest Oncology Group/Intergroup study 9623. J Clin Oncol. 2007 May 1;25(13):1677-82. Epub 2007 Apr 2. link to original article contains dosing details in manuscript PubMed NCT00002772
11. ECOG E2197: Goldstein LJ, O'Neill A, Sparano JA, Perez EA, Shulman LN, Martino S, Davidson NE. Concurrent doxorubicin plus docetaxel is not more effective than concurrent doxorubicin plus cyclophosphamide in operable breast cancer with 0 to 3 positive axillary nodes: North American Breast Cancer Intergroup Trial E 2197. J Clin Oncol. 2008 Sep 1;26(25):4092-9. Epub 2008 Aug 4. link to original article link to PMC article contains dosing details in abstract PubMed NCT00003519
12. CALGB 49907: Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Becker HP, Kartcheske PA, Wheeler JD, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Magrinat G, Parker BA, Hart RD, Grenier D, Norton L, Hudis CA, Winer EP; CALGB. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009 May 14;360(20):2055-65. Erratum in: N Engl J Med. 2009 Oct 22;361(17):1714. Magrinat, Gutav [corrected to Magrinat, Gustav]. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00024102
13. ECOG E5103: Miller KD, O'Neill A, Gradishar W, Hobday TJ, Goldstein LJ, Mayer IA, Bloom S, Brufsky AM, Tevaarwerk AJ, Sparano JA, Le-Lindqwister NA, Hendricks CB, Northfelt DW, Dang CT, Sledge GW Jr. Double-blind phase III trial of adjuvant chemotherapy with and without bevacizumab in patients with lymph node-positive and high-risk lymph node-negative breast cancer (E5103). J Clin Oncol. 2018 Sep 1;36(25):2621-2629. Epub 2018 Jul 24. link to original article refers to ECOG E1199 protocol PubMed NCT00433511
14. ASTER 70s: NCT01564056

Dose-dense Cyclophosphamide & Doxorubicin (ddAC)

ddAC: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide

Regimen variant #1, 60/600 x 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Shulman et al. 2012 (CALGB 40101)	2002-2008	Phase 3 (E-de-esc)	1. ddAC x 6	Did not meet primary endpoint of RFS
			2. ddT x 4	Did not meet primary endpoint of RFS
			3. ddT x 6	Did not meet primary endpoint of RFS
Burstein et al. 2005	2003-2004	Non-randomized
Swain et al. 2013 (NSABP B-38)	2004-2007	Phase 3 (C)	See link	See link

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

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):
• Burstein et al. 2005:
  • 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
• 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

Subsequent treatment

• Burstein et al. 2005: ddT (Taxol) x 4
• NSABP B-38: ddT (Taxol) x 4 versus ddPG x 4

Regimen variant #2, 60/600 x 6

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Budd et al. 2014 (SWOG S0221)	2003-2010	Phase 3 (C)	AC; continuous	Did not meet primary endpoint of DFS
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

Subsequent treatment

• SWOG S0221: Bi-weekly paclitaxel versus weekly paclitaxel

References

1. Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. link to original article contains dosing details in manuscript PubMed
2. CALGB 40101: Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article contains dosing details in manuscript link to study protocol PDF link to PMC article PubMed NCT00041119
   1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. link to original article link to PMC article PubMed
3. NSABP B-38: Swain SM, Tang G, Geyer CE Jr, Rastogi P, Atkins JN, Donnellan PP, Fehrenbacher L, Azar CA, Robidoux A, Polikoff JA, Brufsky AM, Biggs DD, Levine EA, Zapas JL, Provencher L, Northfelt DW, Paik S, Costantino JP, Mamounas EP, Wolmark N. Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial. J Clin Oncol. 2013 Sep 10;31(26):3197-204. Epub 2013 Aug 12. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00093795
4. SWOG S0221: Budd GT, Barlow WE, Moore HC, Hobday TJ, Stewart JA, Isaacs C, Salim M, Cho JK, Rinn KJ, Albain KS, Chew HK, Burton GV, Moore TD, Srkalovic G, McGregor BA, Flaherty LE, Livingston RB, Lew DL, Gralow JR, Hortobagyi GN. SWOG S0221: a phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer. J Clin Oncol. 2015 Jan 1;33(1):58-64. Epub 2014 Nov 24. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00070564
5. ECOG E5103: Miller KD, O'Neill A, Gradishar W, Hobday TJ, Goldstein LJ, Mayer IA, Bloom S, Brufsky AM, Tevaarwerk AJ, Sparano JA, Le-Lindqwister NA, Hendricks CB, Northfelt DW, Dang CT, Sledge GW Jr. Double-blind phase III trial of adjuvant chemotherapy with and without bevacizumab in patients with lymph node-positive and high-risk lymph node-negative breast cancer (E5103). J Clin Oncol. 2018 Sep 1;36(25):2621-2629. Epub 2018 Jul 24. link to original article refers to ECOG E1199 protocol PubMed NCT00433511
6. MATADOR: van Rossum AGJ, Kok M, van Werkhoven E, Opdam M, Mandjes IAM, van Leeuwen-Stok AE, van Tinteren H, Imholz ALT, Portielje JEA, Bos MMEM, van Bochove A, Wesseling J, Rutgers EJ, Linn SC, Oosterkamp HM; MATADOR Trialists' Group. Adjuvant dose-dense doxorubicin-cyclophosphamide versus docetaxel-doxorubicin-cyclophosphamide for high-risk breast cancer: first results of the randomised MATADOR trial (BOOG 2004-04). Eur J Cancer. 2018 Oct;102:40-48. link to original article contains dosing details in abstract PubMed ISRCTN61893718

Cyclophosphamide & Epirubicin (EC)

EC: Epirubicin and Cyclophosphamide

Regimen variant #1, 60/500 x 8

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

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	Years 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

• Tamoxifen

Regimen variant #3, 90/600 x 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Zander et al. 2004	1993-2000	Non-randomized portion of phase 3 RCT
Kümmel et al. 2006	1996-2000	Phase 3 (C)	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

• Surgery

Chemotherapy

• Epirubicin (Ellence) 90 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

• Zander et al. 2004: CMF x 3 versus cyclophosphamide, mitoxantrone, thiotepa with auto HSCT

Regimen variant #4, 100/830 x 8

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

Preceding treatment

• 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 #5, 120/600 x 4 (high-dose)

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

Preceding treatment

• Papaldo et al. 2003: Surgery
• GOIM 9902: Surgery versus Surgery, then D x 4

Chemotherapy

• Epirubicin (Ellence) 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 4 cycles

References

1. Belgian trial: Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M, Nogaret JM. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol. 2001 Jun 15;19(12):3103-10. link to original article PubMed
   1. Update: de Azambuja E, Paesmans M, Beauduin M, Vindevoghel A, Cornez N, Finet C, Ries F, Closon-Dejardin MT, Kerger J, Gobert P, Focan C, Tagnon A, Dolci S, Nogaret JM, di Leo A, Piccart-Gebhart MJ. Long-term benefit of high-dose epirubicin in adjuvant chemotherapy for node-positive breast cancer: 15-year efficacy results of the Belgian multicentre study. J Clin Oncol. 2009 Feb 10;27(5):720-5. Epub 2008 Dec 22. link to original article PubMed
2. Papaldo P, Lopez M, Cortesi E, Cammilluzzi E, Antimi M, Terzoli E, Lepidini G, Vici P, Barone C, Ferretti G, Di Cosimo S, Nistico C, Carlini P, Conti F, Di Lauro L, Botti C, Vitucci C, Fabi A, Giannarelli D, Marolla P. Addition of either lonidamine or granulocyte colony-stimulating factor does not improve survival in early breast cancer patients treated with high-dose epirubicin and cyclophosphamide. J Clin Oncol. 2003 Sep 15;21(18):3462-8. link to original article contains dosing details in abstract PubMed
3. GEICAM 9401: Pico C, Martin M, Jara C, Barnadas A, Pelegri A, Balil A, Camps C, Frau A, Rodriguez-Lescure A, Lopez-Vega JM, De La Haba J, Tres A, Alvarez I, Alba E, Arcusa A, Oltra A, Batista N, Checa T, Perez-Carrion R, Curto J; GEICAM. Epirubicin-cyclophosphamide adjuvant chemotherapy plus tamoxifen administered concurrently versus sequentially: randomized phase III trial in postmenopausal node-positive breast cancer patients: a GEICAM 9401 study. Ann Oncol. 2004 Jan;15(1):79-87. link to original article contains dosing details in abstract PubMed
4. Zander AR, Kröger N, Schmoor C, Krüger W, Möbus V, Frickhofen N, Metzner B, Schultze W, Berdel WE, Koenigsmann M, Thiel E, Wandt H, Possinger K, Trümper L, Kreienberg R, Carstensen M, Schmidt EH, Jänicke F, Schumacher M, Jonat W. High-dose chemotherapy with autologous hematopoietic stem-cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: first results of a randomized trial. J Clin Oncol. 2004 Jun 15;22(12):2273-83. Epub 2004 Apr 26. link to original article contains dosing details in abstract PubMed
5. Kümmel S, Krocker J, Kohls A, Breitbach GP, Morack G, Budner M, Blohmer JU, Elling D. Randomised trial: survival benefit and safety of adjuvant dose-dense chemotherapy for node-positive breast cancer. Br J Cancer. 2006 May 8;94(9):1237-44. link to original article link to PMC article contains dosing details in abstract PubMed
   1. Update: Reinisch M, Gluz O, Ataseven B, Blohmer JU, Budner M, Dittmer-Grabowski C, Kohls A, Krocker J, Kümmel A, Hagemann F, Rüland A, Traut A, Kümmel S. Updated Survival Analysis after a Median Follow-up of 12 Years of an Anthracycline-Containing Adjuvant Prospective Multicentre, Randomised Phase III Trial on Dose-Dense Chemotherapy in Primary Node-Positive, High-Risk Breast Cancer Patients. Breast Care (Basel). 2019 Jun;14(3):159-164. Epub 2018 Sep 5. link to original article link to PMC article PubMed
6. GOIM 9902: Vici P, Brandi M, Giotta F, Foggi P, Schittulli F, Di Lauro L, Gebbia N, Massidda B, Filippelli G, Giannarelli D, Di Benedetto A, Mottolese M, Colucci G, Lopez M. A multicenter phase III prospective randomized trial of high-dose epirubicin in combination with cyclophosphamide (EC) versus docetaxel followed by EC in node-positive breast cancer: GOIM (Gruppo Oncologico Italia Meridionale) 9902 study. Ann Oncol. 2012 May;23(5):1121-9. Epub 2011 Sep 28. link to original article link to PMC article contains dosing details in abstract PubMed
7. 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 × 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article contains dosing details in manuscript PubMed NCT00433420

Dose-dense Cyclophosphamide & Epirubicin (ddEC)

ddEC: dose-dense Epirubicin and Cyclophosphamide

Regimen variant #1, 90/600

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Nitz et al. 2005 (WSG AM-01)	1995-2002	Phase 3 (C)	EC, then ECT with auto HSCT x 2	Seems to have inferior OS
Del Mastro et al. 2015 (GIM2)	2003-2006	Phase 3 (E-esc)	See link	See link

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

Preceding treatment

• Surgery

Chemotherapy

• Epirubicin (Ellence) 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Supportive therapy

• WSG AM-01: Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 5 to 12
• GIM2: Pegfilgrastim (Neulasta) 6 mg SC once on day 2

14-day cycle for 4 cycles

Subsequent treatment

• WSG AM-01: ddCMF x 3
• GIM2: Dose-dense Paclitaxel

Regimen variant #2, 120/830

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Burnell et al. 2009 (NCIC-CTG MA.21)	2000-2005	Phase 3 (E-esc)	See link	See link

Preceding treatment

• Surgery

Chemotherapy

• Epirubicin (Ellence) 120 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 830 mg/m² IV once on day 1

Supportive therapy

• 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

14-day cycle for 6 cycles

Subsequent treatment

• T (Taxol) x 4

References

1. WSG AM-01: Nitz UA, Mohrmann S, Fischer J, Lindemann W, Berdel WE, Jackisch C, Werner C, Ziske C, Kirchner H, Metzner B, Souchon R, Ruffert U, Schütt G, Pollmanns A, Schmoll HJ, Middecke C, Baltzer J, Schrader I, Wiebringhaus H, Ko Y, Rösel S, Schwenzer T, Wernet P, Hinke A, Bender HG, Frick M; West German Study Group. Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial. Lancet. 2005 Dec 3;366(9501):1935-44. Erratum in: Lancet. 2006 Mar 4;367(9512):730. link to original article contains dosing details in manuscript PubMed
2. NCIC-CTG MA.21: Burnell M, Levine MN, Chapman JA, Bramwell V, Gelmon K, Walley B, Vandenberg T, Chalchal H, Albain KS, Perez EA, Rugo H, Pritchard K, O'Brien P, Shepherd LE. Cyclophosphamide, epirubicin, and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol. 2010 Jan 1;28(1):77-82. Epub 2009 Nov 9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00014222
3. 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 × 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article contains dosing details in manuscript PubMed NCT00433420

Docetaxel monotherapy

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

Regimen variant #3, 100 mg/m² q3wk x 3

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Joensuu et al. 2006 (FinHer)	2000-2003	Phase 3 (C)	Vinorelbine	Superior RFS (HR 0.58, 95% CI 0.40-0.85)

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. Patients in FinHer without HER2/neu amplification were only randomized to this or the vinorelbine arm.

Preceding treatment

• Surgery

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1

21-day cycle for 3 cycles

Regimen variant #4, 100 mg/m² q3wk x 4

Study	Years 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

1. NSABP B-27: Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, Wolmark N; National Surgical Adjuvant Breast and Bowel Project. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003 Nov 15;21(22):4165-74. Epub 2003 Oct 14. link to original article contains dosing details in manuscript PubMed NCT00002707
   1. Update: Bear HD, Anderson S, Smith RE, Geyer CE Jr, Mamounas EP, Fisher B, Brown AM, Robidoux A, Margolese R, Kahlenberg MS, Paik S, Soran A, Wickerham DL, Wolmark N. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006 May 1;24(13):2019-27. Epub 2006 Apr 10. link to original article PubMed
   2. Pooled update: Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008 Feb 10;26(5):778-85. Erratum in: J Clin Oncol. 2008 Jun 1;26(16):2793. link to original article PubMed
2. FinHer: Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article contains dosing details in manuscript PubMed ISRCTN76560285
   1. Update: Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. link to original article PubMed
3. NSAS BC-02: Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. link to original article contains dosing details in abstract PubMed

Dose-dense Docetaxel monotherapy

ddT: dose-dense Taxotere (Docetaxel)
ddD: dose-dense Docetaxel

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Saloustros et al. 2014 (HORG CT/04.22)	2004-2007	Phase 3 (E-switch-ic)	ddT (Taxol)	Did not meet primary endpoint of DFS36

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

• ddFEC x 4

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

Supportive therapy

• Filgrastim or Pegfilgrastim support (drug/dose/schedule not specified)

14-day cycle for 4 cycles

References

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

Doxorubicin monotherapy

A: Adriamycin (Doxorubicin)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Buzzoni et al. 1991 (Milan trial)	1982-1987	Phase 3 (E-switch-ic)	See link	See link
Leonard et al. 2004	1995-1999	Non-randomized portion of phase 3 RCT
Gianni et al. 2009 (ECTO)	1996-2002	Phase 3 (C)	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

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin) 75 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Milan trial & Leonard et al. 2004: CMF x 8
• ECTO: CMF x 4

References

1. Milan trial: Buzzoni R, Bonadonna G, Valagussa P, Zambetti M. Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes. J Clin Oncol. 1991 Dec;9(12):2134-40. link to original article PubMed
   1. Update: Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes: ten-year results. JAMA. 1995 Feb 15;273(7):542-7. link to original article PubMed
2. Leonard RC, Lind M, Twelves C, Coleman R, van Belle S, Wilson C, Ledermann J, Kennedy I, Barrett-Lee P, Perren T, Verrill M, Cameron D, Foster E, Yellowlees A, Crown J; Anglo-Celtic Cooperative Oncology Group. Conventional adjuvant chemotherapy versus single-cycle, autograft-supported, high-dose, late-intensification chemotherapy in high-risk breast cancer patients: a randomized trial. J Natl Cancer Inst. 2004 Jul 21;96(14):1076-83. link to original article contains dosing details in abstract PubMed
3. ECTO: Gianni L, Baselga J, Eiermann W, Porta VG, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Cussac AL, Bozhok A, Martinez-Agulló A, Greco M, Byakhov M, Lopez JJ, Mansutti M, Valagussa P, Bonadonna G. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. J Clin Oncol. 2009 May 20;27(15):2474-81. Epub 2009 Mar 30. link to original article contains dosing details in manuscript PubMed NCT00003013

Dose-dense Doxorubicin monotherapy

ddA: dose-dense Adriamycin (Doxorubicin)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Citron et al. 2003 (CALGB 9741)	1997-1999	Phase 3 (E-esc)	See link	See link
Kahan et al. 2005	2000-2003	Phase 2

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

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1

Supportive therapy

• Filgrastim (Neupogen)

14-day cycle for 4 cycles

Subsequent treatment

• ddT

References

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

Doxorubicin & Paclitaxel (AT)

AT: Adriamycin (Doxorubicin) & Taxol (Paclitaxel)

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gianni et al. 2009 (ECTO)	1996-2002	Phase 3 (E-esc)	See link	See link

Preceding treatment

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• CMF x 4

References

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

Epirubicin & Paclitaxel (EP)

EP: Epirubicin & Paclitaxel

Regimen

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

Preceding treatment

• Surgery

Chemotherapy

• Epirubicin (Ellence) 83 mg/m² IV once on day 1
• Paclitaxel (Taxol) 187 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• ddCMF x 3

References

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

iddEnPC

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

Protocol

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

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

Preceding treatment

• Surgery

Chemotherapy, part 1

• Epirubicin (Ellence) 150 mg/m² IV once on day 1

Supportive therapy

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4

14-day cycle for 3 cycles, then:

Chemotherapy, part 2

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 330 mg/m² IV once on day 1

Supportive therapy

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4

14-day cycle for 3 cycles, then:

Chemotherapy, part 3

• Cyclophosphamide (Cytoxan) 2000 mg/m² IV once on day 1

Supportive therapy

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4

14-day cycle for 3 cycles

References

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

iddEPC

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

Protocol

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Möbus et al. 2010 (AGO-iddEPC)	1998-2003	Phase 3 (E-esc)	EC-T	Superior OS1 OS120: 69% vs 59% (HR 0.72, 95% CI 0.60-0.87)
Möbus et al. 2017 (GAIN)	2004-2008	Phase 3 (C)	ddEC, then 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, part 1

• Epirubicin (Ellence) 150 mg/m² IV once on day 1

Supportive therapy

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4

14-day cycle for 3 cycles, then:

Chemotherapy, part 2

• Paclitaxel (Taxol) 225 mg/m² IV once on day 1

Supportive therapy

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4

14-day cycle for 3 cycles, then:

Chemotherapy, part 3

• Cyclophosphamide (Cytoxan) 2000 mg/m² IV once on day 1

Supportive therapy

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4

14-day cycle for 3 cycles

References

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

Epirubicin monotherapy

E: Epirubicin

Regimen variant #1, 75 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Boccardo et al. 1990 (GROCTA-1)	1983-1987	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

• Surgery, then CMF x 6

Chemotherapy

• Epirubicin (Ellence) 75 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• Tamoxifen x 5 y versus no further treatment

Regimen variant #4, 100 mg/m² x 6, split doses

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

Preceding treatment

• Surgery

Chemotherapy

• Epirubicin (Ellence) 50 mg/m² IV once per day on days 1 & 8

28-day cycle for 6 cycles

References

1. GROCTA-1: Boccardo F, Rubagotti A, Bruzzi P, Cappellini M, Isola G, Nenci I, Piffanelli A, Scanni A, Sismondi P, Santi L, Genta F, Saccani F, Sassi M, Malacarne P, Donati D, Farris A, Castagnetta L, Di Carlo A, Traina A, Galletto L, Smerieri F, Buzzi F; Breast Cancer Adjuvant Chemo-Hormone Therapy Cooperative Group. Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, estrogen receptor-positive breast cancer patients: results of a multicentric Italian study. J Clin Oncol. 1990 Aug;8(8):1310-20. link to original article contains dosing details in manuscript PubMed
   1. Update: Boccardo F, Guglielmini P, Parodi A, Rubagotti A. Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, oestrogen receptor-positive breast cancer patients: very late results of the 'gruppo di ricerca per la chemio-ormonoterapia adiuvante (GROCTA)' 01-Trial in early breast cancer. Breast Cancer Res Treat. 2011 Apr;126(3):653-61. Epub 2011 Feb 24. link to original article PubMed
2. DEVA: Coombes RC, Bliss JM, Espie M, Erdkamp F, Wals J, Tres A, Marty M, Coleman RE, Tubiana-Mathieu N, den Boer MO, Wardley A, Kilburn LS, Cooper D, Thomas MW, Reise JA, Wilkinson K, Hupperets P. Randomized, phase III trial of sequential epirubicin and docetaxel versus epirubicin alone in postmenopausal patients with node-positive breast cancer. J Clin Oncol. 2011 Aug 20;29(24):3247-54. Epub 2011 Jul 18. link to original article contains dosing details in abstract PubMed ISRCTN89772270

Dose-dense Epirubicin monotherapy

ddE: dose-dense Epirubicin

Regimen variant #1, 3 cycles

Study	Years of enrollment	Evidence
Fountzilas et al. 2014 (HE10/05)	2005-2008	Non-randomized portion 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

Regimen variant #2, 4 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fountzilas et al. 2005 (HE 10/97)	1997-2000	Phase 3 (C)	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

• Surgery

Chemotherapy

• Epirubicin (Ellence) 110 mg/m² IV once on day 1

Supportive therapy

• Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 3 to 10

14-day cycle for 4 cycles

Subsequent treatment

• CMF; intensified

References

1. HE 10/97: Fountzilas G, Skarlos D, Dafni U, Gogas H, Briasoulis E, Pectasides D, Papadimitriou C, Markopoulos C, Polychronis A, Kalofonos HP, Siafaka V, Kosmidis P, Timotheadou E, Tsavdaridis D, Bafaloukos D, Papakostas P, Razis E, Makrantonakis P, Aravantinos G, Christodoulou C, Dimopoulos AM; Hellenic Cooperative Oncology Group. Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol. 2005 Nov;16(11):1762-71. Epub 2005 Sep 7. link to original article contains dosing details in manuscript PubMed
2. HE10/05: Fountzilas G, Dafni U, Papadimitriou C, Timotheadou E, Gogas H, Eleftheraki AG, Xanthakis I, Christodoulou C, Koutras A, Papandreou CN, Papakostas P, Miliaras S, Markopoulos C, Dimitrakakis C, Korantzopoulos P, Karanikiotis C, Bafaloukos D, Kosmidis P, Samantas E, Varthalitis I, Pavlidis N, Pectasides D, Dimopoulos MA. Dose-dense sequential adjuvant chemotherapy followed, as indicated, by trastuzumab for one year in patients with early breast cancer: first report at 5-year median follow-up of a Hellenic Cooperative Oncology Group randomized phase III trial. BMC Cancer. 2014 Jul 15;14:515. link to original article link to PMC article contains dosing details in manuscript PubMed

FAC

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

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

Study	Years of enrollment	Evidence
Tokuda et al. 2007 (JCOG 9208)	1993-1999	Non-randomized portion 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, then tamoxifen versus tamoxifen

Regimen variant #2, 500/50/500 x 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Martín et al. 2013 (GEICAM 2003-02)	2003-2008	Phase 3 (E-switch-ic)	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

• 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 4 cycles

Subsequent treatment

• wP x 8

Regimen variant #3, 500/50/500 x 6

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

Preceding treatment

• 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 #4, 800/40/400 x 6

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Wood et al. 1994 (CALGB 8541)	1985-NR	Phase 3 (C)	1. FAC; 600/30/300 x 4	Superior OS
			2. FAC; 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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Buzdar et al. 1984	1977-1980	Phase 3 (C)	FAC + BCG	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

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	Years of enrollment	Evidence
Hortobagyi et al. 2000	1990-1997	Non-randomized portion 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 versus no further treatment

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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Davidson et al. 2005 (ECOG E5188)	1989-1994	Non-randomized portion of phase 3 RCT
Hutchins et al. 2005 (INT-0102)	1989-1993	Phase 3 (E-switch-ic)	CMF	Seems to have superior OS
Albain et al. 2009 (SWOG-8814)	1989-1995	Phase 3 (E-esc)	See link	See link
Tallman et al. 2003 (INT-0121)	1991-1998	Non-randomized portion 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 versus no further chemotherapy
• ECOG E5188: Goserelin x 5 y versus Goserelin & Tamoxifen x 5 y versus no further treatment
• SWOG-8814: Tamoxifen x 5 y

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

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

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

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

References

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

FEC

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

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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hurteloup 1988 (FESG)	1982-1984	Phase 3 (E-switch-ic)	FAC	Did not meet endpoint of OS50%
Fumoleau et al. 2003 (FASG 01)	1986-1990	Phase 3 (E-esc)	1. FEC; FEC 50 x 3	Might have superior OS
			2. FEC; FEC 75 x 3	Did not meet primary endpoint of OS120
Héry et al. 2006 (FASG 03)	1988-1994	Phase 3 (E-esc)	Observation	Did not meet primary endpoint of DFS120
Arriagada et al. 2005	1989-1996	Phase 3 (E-esc)	Observation	Superior DFS
Bonneterre 2001 (FASG 05)	1990-1993	Phase 3 (C)	FEC; FEC 100 x 6	Inferior OS
Roché et al. 2006 (FASG 06)	1990-1998	Phase 3 (C)	Goserelin & Tamoxifen x 3y	Did not meet primary endpoint of DFS60

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, 500/60/500 x 4

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

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 #3, 500/100/500 x 4 ("FEC 100")

Study	Years 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 is an experimental arm that did not meet its primary endpoint; included here because it represents a de-escalation strategy.

Preceding treatment

• UCBG-0106: 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 #4, 500/100/500 x 6 ("FEC 100")

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bonneterre 2001 (FASG 05)	1990-1993	Phase 3 (E-RT-esc)	FEC; FEC 50 x 6	Superior OS
Kerbrat et al. 2007 (FASG 09)	1993-1998	Phase 3 (C)	VE	Did not meet primary endpoint of DFS
Roché et al. 2006 (FNCLCC PACS 01)	1997-2000	Phase 3 (C)	FEC-D	Inferior OS1
Delbaldo et al. 2013 (Trial B2000)	2000-2002	Phase 3 (C)	FEC-P	Did not meet primary endpoint of DFS
Nitz et al. 2014 (WSG-AGO EC-Doc)	2000-2005	Phase 3 (C)	EC-D	Seems to have inferior OS
Spielmann et al. 2009 (FNCLCC PACS 04)	2001-2004	Phase 3 (C)	ED	Did not meet primary endpoint of DFS2
Kerbrat et al. 2017 (UCBG-0106)	2002-2006	Phase 3 (C)	FEC; FEC 100 x 4	Did not meet primary endpoint of DFS60
Sakr et al. 2013	2006-2010	Phase 3 (C)	FEC-D	Seems to have inferior OS
Delaloge et al. 2020 (MINDACT)	2007-2011	Phase 3 (C)	TX	Did not meet primary endpoint of DFS

¹Reported efficacy for FNCLCC PACS 01 is based on the 2012 update.
²Reported efficacy for FNCLCC PACS 04 is based on the 2019 update.

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 #5, 600/50/600 x 8

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Coombes et al. 1996	1984-1992	Phase 3 (E-switch-ic)	CMF	Did not meet 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 is 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 #6, 600/60/600 x 3

Study	Years of enrollment	Evidence
Joensuu et al. 2006 (FinHer)	2000-2003	Non-randomized portion 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

• Docetaxel x 3 versus Vinorelbine x 3

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

Regimen variant #7, 600/60/600 x 4

Study	Years 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

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 #8, 600/60/600 x 6

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Venturini et al. 2005 (MIG-1)	1992-1997	Phase 3 (C)	Dose-dense FEC	Did not meet primary endpoint of OS
Sirohi et al. 2010 (TRAFIC)	1995-2002	Phase 3 (C)	ECisF	Did not meet primary endpoint of RFS
del Mastro et al. 2016 (GONO-MIG5)	1996-2001	Phase 3 (C)	EP x 4	Did not meet primary endpoint of OS

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 #9, 600/60/600 x 8

Study	Years 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

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 #10, 600/60/600 x 9

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

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

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

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

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

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Levine et al. 1998 (NCIC-CTG MA.5)	1989-1993	Phase 3 (E-RT-switch-ic)	CMF	Superior RFS
Coombes et al. 2005 (ICCG HDT trial)	1993-2001	Phase 3 (C)	FEC x 3, then HDT	Did not meet primary endpoints of RFS/EFS/OS
Burnell et al. 2009 (NCIC-CTG MA.21)	2000-2005	Phase 3 (C)	1. AC-T	Superior RFS
			2. ddEC x 6, then T (Taxol); q3wk x 4	Did not meet primary endpoint of RFS
Janni et al. 2016 (ADEBAR)	2001-2005	Phase 3 (C)	EC-D	Did not meet primary endpoint of TTP
Delaloge et al. 2020 (MINDACT)	2007-2011	Phase 3 (C)	TX	Did not meet primary endpoint of DFS

Preceding treatment

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

Note: this is 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

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2. Coombes RC, Bliss JM, Wils J, Morvan F, Espié M, Amadori D, Gambrosier P, Richards M, Aapro M, Villar-Grimalt A, McArdle C, Pérez-López FR, Vassilopoulos P, Ferreira EP, Chilvers CE, Coombes G, Woods EM, Marty M; International Collaborative Cancer Group. Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. J Clin Oncol. 1996 Jan;14(1):35-45. link to original article contains dosing details in manuscript PubMed
3. NCIC-CTG MA.5: Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, Findlay B, Warr D, Bowman D, Myles J, Arnold A, Vandenberg T, MacKenzie R, Robert J, Ottaway J, Burnell M, Williams CK, Tu D; National Cancer Institute of Canada Clinical Trials Group. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol. 1998 Aug;16(8):2651-8. link to original article PubMed
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10. 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 contains dosing details in manuscript PubMed
    1. 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 PubMed
11. FinHer: Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article contains dosing details in manuscript PubMed ISRCTN76560285
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12. 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 contains dosing details in abstract PubMed
13. FASG 03: Héry M, Bonneterre J, Roché H, Luporsi E, Kerbrat P, Namer M, Fumoleau P, Monnier A, Fargeot P. Epirubicin-based chemotherapy as adjuvant treatment for poor prognosis, node-negative breast cancer: 10-year follow-up results of the French Adjuvant Study Group 03 trial. Bull Cancer. 2006 Oct;93(10):E109-14. link to original article contains dosing details in abstract PubMed
14. 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 contains dosing details in abstract PubMed
15. FNCLCC PACS 01: Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulié P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Genève J, Asselain B. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006 Dec 20;24(36):5664-71. Epub 2006 Nov 20. link to original article PubMed
    1. Update: Coudert B, Asselain B, Campone M, Spielmann M, Machiels JP, Pénault-Llorca F, Serin D, Lévy C, Romieu G, Canon JL, Orfeuvre H, Piot G, Petit T, Jerusalem G, Audhuy B, Veyret C, Beauduin M, Eymard JC, Martin AL, Roché H; UNICANCER Breast Group. Extended benefit from sequential administration of docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide regimen for node-positive breast cancer: the 8-year follow-up results of the UNICANCER-PACS01 trial. Oncologist. 2012;17(7):900-9. Epub 2012 May 18. link to original article link to PMC article PubMed
16. DBCG 89D: Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Cold S, Edlund P, Ewertz M, Jensen BB, Kamby C, Nordenskjold B, Bergh J. Improved outcome from substituting methotrexate with epirubicin: results from a randomised comparison of CMF versus CEF in patients with primary breast cancer. Eur J Cancer. 2007 Mar;43(5):877-84. Epub 2007 Feb 16. link to original article contains dosing details in manuscript PubMed
17. FASG 09: Kerbrat P, Roché H, Bonneterre J, Veyret C, Lortholary A, Monnier A, Fumoleau P, Fargeot P, Namer M, Chollet P, Goudier MJ, Audhuy B, Simon H, Montcuquet P, Eymard JC, Walter S, Clavère P, Guastalla JP; French Adjuvant Study Group. Epirubicin-vinorelbine vs FEC100 for node-positive, early breast cancer: French Adjuvant Study Group 09 trial. Br J Cancer. 2007 Jun 4;96(11):1633-8. Epub 2007 May 15. link to original article link to PMC article PubMed
18. GEICAM 9906: Martín M, Rodríguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Munárriz B, Rodríguez CA, Crespo C, de Alava E, López García-Asenjo JA, Guitián MD, Almenar S, González-Palacios JF, Vera F, Palacios J, Ramos M, Gracia Marco JM, Lluch A, Alvarez I, Seguí MA, Mayordomo JI, Antón A, Baena JM, Plazaola A, Modolell A, Pelegrí A, Mel JR, Aranda E, Adrover E, Alvarez JV, García Puche JL, Sánchez-Rovira P, Gonzalez S, López-Vega JM; GEICAM. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst. 2008 Jun 4;100(11):805-14. Epub 2008 May 27. link to original article contains dosing details in manuscript PubMed NCT00129922
19. TACT: Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. link to original article link to PMC article contains dosing details in manuscript PubMed ISRCTN79718493
20. Polyzos A, Malamos N, Boukovinas I, Adamou A, Ziras N, Kalbakis K, Kakolyris S, Syrigos K, Papakotoulas P, Kouroussis C, Karvounis N, Vamvakas L, Christophyllakis C, Athanasiadis A, Varthalitis I, Georgoulias V, Mavroudis D; Hellenic Oncology Research Group. FEC versus sequential docetaxel followed by epirubicin/cyclophosphamide as adjuvant chemotherapy in women with axillary node-positive early breast cancer: a randomized study of the Hellenic Oncology Research Group (HORG). Breast Cancer Res Treat. 2010 Jan;119(1):95-104. Epub 2009 Jul 28. link to original article contains dosing details in abstract PubMed
21. NCIC-CTG MA.21: Burnell M, Levine MN, Chapman JA, Bramwell V, Gelmon K, Walley B, Vandenberg T, Chalchal H, Albain KS, Perez EA, Rugo H, Pritchard K, O'Brien P, Shepherd LE. Cyclophosphamide, epirubicin, and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol. 2010 Jan 1;28(1):77-82. Epub 2009 Nov 9. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00014222
22. FNCLCC PACS 04: Spielmann M, Roché H, Delozier T, Canon JL, Romieu G, Bourgeois H, Extra JM, Serin D, Kerbrat P, Machiels JP, Lortholary A, Orfeuvre H, Campone M, Hardy-Bessard AC, Coudert B, Maerevoet M, Piot G, Kramar A, Martin AL, Penault-Llorca F. Trastuzumab for patients with axillary-node-positive breast cancer: results of the FNCLCC-PACS 04 trial. J Clin Oncol. 2009 Dec 20;27(36):6129-34. Epub 2009 Nov 16. link to original article PubMed NCT00054587
    1. Update: D'Hondt V, Canon JL, Roca L, Levy C, Pierga JY, Le Du F, Campone M, Desmoulins I, Goncalves A, Debled M, Rios M, Ferrero JM, Serin D, Hardy-Bessard AC, Piot G, Brain E, Dohollou N, Orfeuvre H, Lemonnier J, Roché H, Delaloge S, Dalenc F. UCBG 2-04: Long-term results of the PACS 04 trial evaluating adjuvant epirubicin plus docetaxel in node-positive breast cancer and trastuzumab in the human epidermal growth factor receptor 2-positive subgroup. Eur J Cancer. 2019 Nov;122:91-100. Epub 2019 Oct 18. link to original article contains dosing details in manuscript PubMed
23. TRAFIC: Sirohi B, A'Hern R, Coombes G, Bliss JM, Hickish T, Perren T, Crawford M, O'Brien M, Iveson T, Ebbs S, Skene A, Laing R, Smith IE. A randomised comparative trial of infusional ECisF versus conventional FEC as adjuvant chemotherapy in early breast cancer: the TRAFIC trial. Ann Oncol. 2010 Aug;21(8):1623-9. Epub 2010 Jan 21. link to original article contains dosing details in abstract PubMed ISRCTN83324925
24. Sakr H, Hamed RH, Anter AH, Yossef T. Sequential docetaxel as adjuvant chemotherapy for node-positive or/and T3 or T4 breast cancer: clinical outcome (Mansoura University). Med Oncol. 2013 Mar;30(1):457. Epub 2013 Jan 16. link to original article contains dosing details in manuscript PubMed
25. AERO-B2000: Delbaldo C, Serin D, Mousseau M, Greget S, Audhuy B, Priou F, Berdah JF, Teissier E, Laplaige P, Zelek L, Quinaux E, Buyse M, Piedbois P; Association Européenne de Recherche en Oncologie (AERO). A phase III adjuvant randomised trial of 6 cycles of 5-fluorouracil-epirubicine-cyclophosphamide (FEC100) versus 4 FEC 100 followed by 4 Taxol (FEC-T) in node positive breast cancer patients (Trial B2000). Eur J Cancer. 2014 Jan;50(1):23-30. Epub 2013 Oct 29. link to original article PubMed
26. WSG-AGO EC-Doc: Nitz U, Gluz O, Huober J, Kreipe HH, Kates RE, Hartmann A, Erber R, Moustafa Z, Scholz M, Lisboa B, Mohrmann S, Möbus V, Augustin D, Hoffmann G, Weiss E, Böhmer S, Kreienberg R, Du Bois A, Sattler D, Thomssen C, Kiechle M, Jänicke F, Wallwiener D, Harbeck N, Kuhn W. Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression. Ann Oncol. 2014 Aug;25(8):1551-7. Epub 2014 May 14. Erratum in: Ann Oncol. 2017 Nov 1;28(11):2899. link to original article contains dosing details in abstract PubMed NCT02115204
27. GIM2: Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article contains dosing details in manuscript PubMed NCT00433420
28. GONO-MIG5: Del Mastro L, Levaggi A, Michelotti A, Cavazzini G, Adami F, Scotto T, Piras M, Danese S, Garrone O, Durando A, Accortanzo V, Bighin C, Miglietta L, Pastorino S, Pronzato P, Castiglione F, Landucci E, Conte P, Bruzzi P. 5-Fluorouracil, epirubicin and cyclophosphamide versus epirubicin and paclitaxel in node-positive early breast cancer: a phase-III randomized GONO-MIG5 trial. Breast Cancer Res Treat. 2016 Jan;155(1):117-26. link to original article contains dosing details in manuscript PubMed NCT02450058
29. ADEBAR: Janni W, Harbeck N, Rack B, Augustin D, Jueckstock J, Wischnik A, Annecke K, Scholz C, Huober J, Zwingers T, Friedl TW, Kiechle M. Randomised phase III trial of FEC120 vs EC-docetaxel in patients with high-risk node-positive primary breast cancer: final survival analysis of the ADEBAR study. Br J Cancer. 2016 Apr 12;114(8):863-71. Epub 2016 Mar 31. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00047099
30. HMFEC: Coombes RC, Kilburn LS, Tubiana-Mathieu N, Olmos T, Van Bochove A, Perez-Lopez FR, Palmieri C, Stebbing J, Bliss JM. Epirubicin dose and sequential hormonal therapy-Mature results of the HMFEC randomised phase III trial in premenopausal patients with node positive early breast cancer. Eur J Cancer. 2016 Jun;60:146-53. Epub 2016 Apr 26. link to original article PubMed ISRCTN98335268
31. UCBG-0106: Kerbrat P, Desmoulins I, Roca L, Levy C, Lortholary A, Marre A, Delva R, Rios M, Viens P, Brain É, Serin D, Edel M, Debled M, Campone M, Mourret-Reynier MA, Bachelot T, Foucher-Goudier MJ, Asselain B, Lemonnier J, Martin AL, Roché H. Optimal duration of adjuvant chemotherapy for high-risk node-negative (N-) breast cancer patients: 6-year results of the prospective randomised multicentre phase III UNICANCER-PACS 05 trial (UCBG-0106). Eur J Cancer. 2017 Jul;79:166-175. Epub 2017 May 11. link to original article contains dosing details in manuscript PubMed
32. MINDACT: Delaloge S, Piccart M, Rutgers E, Litière S, van 't Veer LJ, van den Berkmortel F, Brain E, Dudek-Peric A, Gil-Gil M, Gomez P, Hilbers FS, Khalil Z, Knox S, Kuemmel S, Kunz G, Lesur A, Pierga JY, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Thompson AM, Viale G, Zoppoli G, Vuylsteke P, Tryfonidis K, Poncet C, Bogaerts J, Cardoso F; MINDACT investigators and the TRANSBIG Consortium. Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial. J Clin Oncol. 2020 Apr 10;38(11):1186-1197. Epub 2020 Feb 21. link to original article contains dosing details in supplement PubMed NCT00433589

MMM

MMM: Mitomycin-C, Mitoxantrone, Methotrexate

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Fernando et al. 2019 (SECRAB)	1998-2004	Phase 3 (C)	1. CMF & RT 2. E-CMF & RT 3. A-CMF & RT 4. MMM & RT	Inferior LRFS

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

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

Paclitaxel monotherapy, weekly

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

Regimen variant #1, 80 mg/m² x 12

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Shulman et al. 2012 (CALGB 40101)	2002-2008	Phase 3 (E-de-esc)	1. AC x 4	Did not meet primary endpoint of RFS
			2. AC x 6	Did not meet primary endpoint of RFS
			3. Paclitaxel; weekly x 18	Did not meet primary endpoint of RFS
Budd et al. 2014 (SWOG S0221)	2003-2010	Phase 3 (C)	ddT x 6	Did not meet primary endpoint of DFS
Miller et al. 2018 (ECOG E5103)	2007-2011	Phase 3 (C)	See link	See link

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.

Preceding treatment

• SWOG S0221: Surgery, then ddAC x 6 versus continuous AC
• ECOG E5103: Surgery, then AC x 4 or ddAC x 4

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV over 60 minutes once per day on days 1, 8, 15

21-day cycle for 4 cycles

Regimen variant #2, 100 mg/m² x 8

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Martín et al. 2013 (GEICAM 2003-02)	2003-2008	Phase 3 (E-switch-ic)	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

• GEICAM 2003-02: Surgery, then FAC x 4

Chemotherapy

• Paclitaxel (Taxol) 100 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycle for 2 cycles

References

1. CALGB 40101: Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article contains dosing details in manuscript link to study protocol PDF link to PMC article PubMed NCT00041119
   1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. link to original article link to PMC article PubMed
2. GEICAM 2003-02: Martín M, Ruiz A, Ruiz Borrego M, Barnadas A, González S, Calvo L, Margelí Vila M, Antón A, Rodríguez-Lescure A, Seguí-Palmer MA, Muñoz-Mateu M, Dorca Ribugent J, López-Vega JM, Jara C, Espinosa E, Mendiola Fernández C, Andrés R, Ribelles N, Plazaola A, Sánchez-Rovira P, Salvador Bofill J, Crespo C, Carabantes FJ, Servitja S, Chacón JI, Rodríguez CA, Hernando B, Álvarez I, Carrasco E, Lluch A. Fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus FAC followed by weekly paclitaxel as adjuvant therapy for high-risk, node-negative breast cancer: results from the GEICAM/2003-02 study. J Clin Oncol. 2013 Jul 10;31(20):2593-9. Epub 2013 Jun 3. link to original article contains dosing details in manuscript PubMed NCT00129389
3. SWOG S0221: Budd GT, Barlow WE, Moore HC, Hobday TJ, Stewart JA, Isaacs C, Salim M, Cho JK, Rinn KJ, Albain KS, Chew HK, Burton GV, Moore TD, Srkalovic G, McGregor BA, Flaherty LE, Livingston RB, Lew DL, Gralow JR, Hortobagyi GN. SWOG S0221: a phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer. J Clin Oncol. 2015 Jan 1;33(1):58-64. Epub 2014 Nov 24. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00070564
4. ECOG E5103: Miller KD, O'Neill A, Gradishar W, Hobday TJ, Goldstein LJ, Mayer IA, Bloom S, Brufsky AM, Tevaarwerk AJ, Sparano JA, Le-Lindqwister NA, Hendricks CB, Northfelt DW, Dang CT, Sledge GW Jr. Double-blind phase III trial of adjuvant chemotherapy with and without bevacizumab in patients with lymph node-positive and high-risk lymph node-negative breast cancer (E5103). J Clin Oncol. 2018 Sep 1;36(25):2621-2629. Epub 2018 Jul 24. link to original article refers to ECOG E1199 protocol PubMed NCT00433511

Paclitaxel monotherapy, dose-dense (q2wk)

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

Regimen variant #1, 175 mg/m² x 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Citron et al. 2003 (CALGB 9741)	1997-1999	Phase 3 (E-esc)	See link	See link
Shulman et al. 2012 (CALGB 40101)	2002-2008	Phase 3 (E-de-esc)	1. ddAC x 4	Did not meet primary endpoint of RFS
			2. ddAC x 6	Did not meet primary endpoint of RFS
			3. ddT x 6	Did not meet primary endpoint of RFS
Burstein et al. 2005	2003-2004	Non-randomized
Del Mastro et al. 2015 (GIM2)	2003-2006	Phase 3 (E-esc)	See link	See link
Swain et al. 2013 (NSABP B-38)	2004-2007	Phase 3 (C)	See link	See link

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

Preceding treatment

• CALGB 9741: ddA x 4
• Burstein et al. 2005: Neoadjuvant ddAC, then surgery or surgery, then adjuvant ddAC
• CALGB 40101: Surgery, within 90 days
• NSABP B-38: ddAC x 4
• GIM2: ddEC x 4 versus ddFEC x 4

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; 30 to 60 minutes prior to Paclitaxel (Taxol)
• One of the following H2 blockers:
  • Ranitidine (Zantac) 50 mg IV once on day 1; 30 to 60 minutes prior to Paclitaxel (Taxol)
  • Cimetidine (Tagamet) 300 mg IV once on day 1; 30 to 60 minutes prior to Paclitaxel (Taxol)
  • Famotidine (Pepcid) 20 mg IV once on day 1; 30 to 60 minutes prior to Paclitaxel (Taxol)
• One of the following dexamethasone choices:
  • Dexamethasone (Decadron) 10 mg IV once on day 1, within 60 minutes prior to Paclitaxel (Taxol)
  • Dexamethasone (Decadron) 10 mg PO once on day 1, at least 60 minutes prior to Paclitaxel (Taxol)
  • Dexamethasone (Decadron) 20 mg PO twice on day 1; 6 hours and 12 hours prior to Paclitaxel (Taxol)
• 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
    • GIM2: a mid-protocol amendment suggested giving the pegilgrastim at least 72 h after chemotherapy

14-day cycle for 4 cycles

Subsequent treatment

• CALGB 9741: ddC x 4

Regimen variant #2, 175 mg/m² x 6

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Budd et al. 2014 (SWOG S0221)	2003-2010	Phase 3 (E-switch-ic)	Paclitaxel; weekly	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.

Preceding treatment

• ddAC x 6 versus continuous AC

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

Supportive therapy

• Pegfilgrastim (Neulasta) 6 mg SC once on day 2

14-day cycle for 6 cycles

Regimen variant #3, 200 mg/m² x 4

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

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

• ddA x 4

Chemotherapy

• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1

Supportive therapy

• Filgrastim (Neupogen)

14-day cycle for 4 cycles

Subsequent treatment

• ddC

References

1. CALGB 9741: Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. link to original article contains dosing details in manuscript PubMed NCT00003088
2. Kahan Z, Uhercsak G, Hajnal-Papp R, Boda K, Thurzo L. Dose-dense sequential adriamycin-paclitaxel-cyclophosphamide chemotherapy is well tolerated and safe in high-risk early breast cancer. Oncology. 2005;68(4-6):446-53. Epub 2005 Jul 13. link to original article PubMed
   1. Update: Kelemen G, Uhercsák G, Ormándi K, Eller J, Thurzó L, Kahán Z. Long-term efficiency and toxicity of adjuvant dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy in high-risk breast cancer. Oncology. 2010;78(3-4):271-3. Epub 2010 Jun 7. link to original article PubMed
3. Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. link to original article contains dosing details in manuscript PubMed
4. CALGB 40101: Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article contains dosing details in manuscript link to study protocol PDF link to PMC article PubMed NCT00041119
   1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. link to original article link to PMC article PubMed
5. NSABP B-38: Swain SM, Tang G, Geyer CE Jr, Rastogi P, Atkins JN, Donnellan PP, Fehrenbacher L, Azar CA, Robidoux A, Polikoff JA, Brufsky AM, Biggs DD, Levine EA, Zapas JL, Provencher L, Northfelt DW, Paik S, Costantino JP, Mamounas EP, Wolmark N. Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial. J Clin Oncol. 2013 Sep 10;31(26):3197-204. Epub 2013 Aug 12. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00093795
6. SWOG S0221: Budd GT, Barlow WE, Moore HC, Hobday TJ, Stewart JA, Isaacs C, Salim M, Cho JK, Rinn KJ, Albain KS, Chew HK, Burton GV, Moore TD, Srkalovic G, McGregor BA, Flaherty LE, Livingston RB, Lew DL, Gralow JR, Hortobagyi GN. SWOG S0221: a phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer. J Clin Oncol. 2015 Jan 1;33(1):58-64. Epub 2014 Nov 24. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00070564
7. 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 × 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article contains dosing details in manuscript PubMed NCT00433420

TAC (Docetaxel)

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

Regimen variant #1, 4 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Swain et al. 2010 (NSABP B-30)	1999-2004	Phase 3 (C)	1. AC-D	Might have inferior OS
			2. AT	Not reported

Note: this was a mid-protocol dosing amendment.

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Martin et al. 2005 (BCIRG 001)	1997-1999	Phase 3 (E-RT-switch-ic)	FAC	Superior OS1 OS120: 76% vs 69% (HR 0.74, 95% CI 0.61-0.90)
Martín et al. 2010 (GEICAM 9805)	1999-2003	Phase 3 (E-switch-ic)	FAC	Superior DFS (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, then ddP	Did not meet primary endpoint of DFS
			2. ddAC, then 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
Blum et al. 2017 (USOR 06-090)	2007-2009	Phase 3 (C)	TC	Seems to have superior IDFS
Blum et al. 2017 (NSABP-46-I/USOR 07132)	2009-2012	Phase 3 (C)	TC	Seems to have superior IDFS
Blum et al. 2017 (NSABP B-49)	2012-2013	Phase 3 (C)	TC	Seems to have superior IDFS

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

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

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

Vinorelbine monotherapy

V: Vinorelbine

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Joensuu et al. 2006 (FinHer)	2000-2003	Phase 3 (E-switch-ic)	Docetaxel	Inferior DDFS

Note: Patients without HER2/neu amplification were only randomized to this arm verus the docetaxel arm.

Preceding treatment

• Surgery

Chemotherapy

• 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

21-day cycle for 3 cycles

Subsequent treatment

• FEC

References

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

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

Chemotherapy

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

Chemotherapy

• 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Jones et al. 1975	1973-1974	Non-randomized
Tranum et al. 1982 (SWOG-7405B)	1974-1977	Phase 3 (E-de-esc)	1. FAC 2. A, then 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Forbes 1986	1978-1981	Randomized (C)	1. ACT 2. 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Biganzoli et al. 2002 (EORTC 10961)	1996-1999	Phase 3 (C)	AT (Taxol)	Did not meet primary endpoint of PFS
Nabholtz et al. 2003 (TAX 306)	NR	Phase 3 (C)	AT (Taxotere)	Seems to have inferior TTP

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycles (see note)

Regimen variant #6, with range

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robert et al. 2011 (RIBBON-1)	2005-2007	Phase 3 (C)	AC & Bevacizumab	Inferior PFS

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

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

Cyclophosphamide & Doxorubicin (AC) & Bevacizumab

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

Regimen variant #1, with range

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robert et al. 2011 (RIBBON-1)	2005-2007	Phase 3 (E-esc)	AC	Superior PFS (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

• Bevacizumab maintenance, if no PD

References

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

Capecitabine monotherapy

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

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

Chemotherapy

• 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	Years 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bajetta et al. 2005	1999-2003	Phase 2
Stockler et al. 2011 (ANZ 0001)	2001-2005	Phase 3 (E-de-esc)	1. CMF	Seems to have superior OS
			2. Capecitabine; continuous	Did not meet primary endpoint of quality-adjusted PFS
Robert et al. 2011 (RIBBON-1)	2005-2007	Phase 3 (C)	Capecitabine & Bevacizumab	Inferior PFS

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

Preceding treatment

• JO21095: Docetaxel, with progression

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

21-day cycles

References

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

Capecitabine & Bevacizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robert et al. 2011 (RIBBON-1)	2005-2007	Phase 3 (E-esc)	Capecitabine	Superior PFS (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
Welt et al. 2016 (CARIN)	2009-2012	Phase 3 (C)	Capecitabine, Vinorelbine, Bevacizumab	Might have inferior PFS

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

Chemotherapy

• 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

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

Capecitabine & Paclitaxel

TX: Taxol (Paclitaxel), Xeloda (Capecitabine)

Regimen

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

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

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

Capecitabine & Paclitaxel, nanoparticle albumin-bound

Regimen

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

Chemotherapy

• Capecitabine (Xeloda) 825 mg/m² (rounded to nearest 500 mg) PO twice per day on days 1 to 15
• Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m² IV once per day on days 1 & 8

21-day cycles

References

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

CMF

CMF: Cyclophosphamide, Methotrexate, Fluorouracil

Regimen variant #1, 600/40/600

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

Chemotherapy

• 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 #2, 1400/80/1000

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Aisner et al. 1987	1976-1980	Phase 3 (C)	1. CAF	Seems to have inferior OS
			2. CAFVP	Inferior 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 #3, 1400/60/800

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

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

Chemotherapy

• 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 #4, 1400/80/1200

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

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

Chemotherapy

• 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 #5, 1400/120/1200

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

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

Chemotherapy

• 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

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

CMFT

CMFT: Cyclophosphamide, Methotrexate, Fluorouracil, Tamoxifen

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cocconi et al. 1983	NR	Randomized (E-esc)	CMF	Might have superior TTF
Viladiu et al. 1985	1978-1981	Randomized (E-esc)	1. CMF 2. CMF & MPA	Seems to have superior ORR

Chemotherapy

• Cyclophosphamide (Cytoxan)
• Methotrexate (MTX)
• Fluorouracil (5-FU)

Endocrine therapy

• Tamoxifen (Nolvadex)

References

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

Docetaxel monotherapy

D: Docetaxel
T: Taxotere (Docetaxel)

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

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

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

Chemotherapy

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

28-day cycles

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

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

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

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1

21-day cycle for up to 6 cycles

Regimen variant #5, 60 mg/m² q4wk

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

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1

28-day cycles

Regimen variant #6, 75 mg/m² q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Stemmler et al. 2011 (D2)	2001-2008	Phase 3 (C)	Docetaxel; weekly	Seems to have superior ORR	Inferior hematotoxicity
Sparano et al. 2009 (DOXIL-BCA-3001)	2004-2006	Phase 3 (C)	Docetaxel & PLD	Inferior TTP	Less toxic
Robert et al. 2011 (RIBBON-1)	2005-2007	Phase 3 (C)	Docetaxel & Bevacizumab	Inferior PFS
Takashima et al. 2015 (SELECT BC)	2006-2010	Phase 3 (C)	S-1	Seems to have non-inferior OS	Inferior EQ-5D score
Mackey et al. 2014 (ROSE/TRIO-12)	2008-2011	Phase 3 (C)	Docetaxel & Ramucirumab	Might have inferior PFS

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycles

Regimen variant #7, 75 mg/m² q4wk

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

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

28-day cycles

Regimen variant #8, 100 mg/m² x 6

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

Chemotherapy

• 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Miles et al. 2010 (AVADO)	2006-2007	Phase 3 (C)	1. Docetaxel & Bevacizumab; 100/7.5	Did not meet primary endpoint of PFS
			2. Docetaxel & Bevacizumab; 100/15	Inferior 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Trudeau et al. 1996	1992-1993	Phase 2
Rivera et al. 2008	2001-2004	Phase 3 (C)	Docetaxel; weekly	Did not meet primary endpoint of ORR	Inferior toxicity
Nielsen et al. 2011	2001-2005	Phase 3 (C)	Docetaxel & Gemcitabine	Might have inferior TTP
Joensuu et al. 2009 (B9E-MC-S241)	2002-2006	Phase 3 (C)	D/G	Did not meet primary endpoint of TTF	More toxic
Gradishar et al. 2009	2005-2006	Randomized Phase 2 (C)	1. nab-Paclitaxel; higher-dose weekly 2. nab-Paclitaxel; lower-dose weekly 3. nab-Paclitaxel; q3wk	Did not meet primary endpoint of ORR
Robert et al. 2011 (RIBBON-1)	2005-2007	Phase 3 (C)	Docetaxel & Bevacizumab	Inferior PFS
Bergh et al. 2012 (SUN 1064)	2007-2009	Phase 3 (C)	Docetaxel & Sunitinib	Did not meet primary endpoint of PFS

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV over 60 minutes once on day 1
  • Note: Rivera et al. 2008 gave 75 mg/m² in cycle 1, with escalation to 100 mg/m² depending on toxicity

21-day cycles

References

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

Docetaxel & Bevacizumab

Regimen variant #1, 75/15, indefinite

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robert et al. 2011 (RIBBON-1)	2005-2007	Phase 3 (E-esc)	Docetaxel	Superior PFS (HR 0.64, 95% CI 0.52-0.80)
Lück et al. 2014 (TABEA)	2009-2012	Phase 3 (C)	1. TX & Bevacizumab 2. Capecitabine, Paclitaxel, Bevacizumab	Did not meet primary endpoint of PFS
Trédan et al. 2016 (GINECO-BR107)	2010-2013	Phase 3 (C)	Docetaxel & Bevacizumab, then Exemestane & Bevacizumab	Did not meet primary endpoint of PFS

Chemotherapy

• 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Miles et al. 2010 (AVADO)	2006-2007	Phase 3 (C)	1. Docetaxel	Superior PFS
			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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robert et al. 2011 (RIBBON-1)	2005-2007	Phase 3 (E-esc)	Docetaxel	Superior PFS (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

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

Docetaxel & Doxorubicin (AT)

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

Regimen variant #1, 50/75 x 4

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

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

21-day cycle for 4 cycles

Subsequent treatment

• Docetaxel x 4

Regimen variant #2, 50/75 x 6

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Bontenbal et al. 2005	1997-2002	Phase 3 (E-de-esc)	FAC	Seems to have superior OS
Alba et al. 2004 (GEICAM-9903)	1999-2001	Phase 3 (C)	A, then T (Taxotere)		More toxic

Chemotherapy

• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycle for 6 cycles

Regimen variant #3, 50/75 x 8

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

Chemotherapy

• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

21-day cycle for 8 cycles

References

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

Docetaxel & Epirubicin (DE)

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

Regimen variant #1, 8 cycles

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bonneterre et al. 2004	1998-2000	Randomized Phase 2 (E-de-esc)	FEC	Superior ORR
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 once on day 1
• Epirubicin (Ellence) 75 mg/m² IV once on day 1

21-day cycle for up to 8 cycles

Regimen variant #2, indefinite

Study	Years 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

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

Docetaxel & Gemcitabine

GD: Gemcitabine & Docetaxel
GDoc: Gemcitabine & Docetaxel

Regimen

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

Chemotherapy

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
  • 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 cycles

Subsequent treatment

• B9E-MC-S273, upon progression: Capecitabine

References

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

Doxorubicin monotherapy

Regimen variant #1, 20 mg/m² weekly

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

Chemotherapy

• Doxorubicin (Adriamycin) 20 mg/m² IV once on day 1

7-day cycles

Regimen variant #2, 60 mg/m² q3wk

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

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

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1

21-day cycles (see note)

Regimen variant #3, 75 mg/m² q3wk

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

Chemotherapy

• Doxorubicin (Adriamycin) 75 mg/m² IV once on day 1

21-day cycle for 7 cycles

References

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

Doxorubicin & Paclitaxel (AT)

AT: Adriamycin (Doxorubicin) & Taxol (Paclitaxel)

Regimen variant #1, 50/150

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

Chemotherapy

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

21-day cycles

Regimen variant #2, 50/175

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

Chemotherapy

• Doxorubicin (Adriamycin) 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 4 cycles

Subsequent treatment

• Paclitaxel x 4

Regimen variant #3, 50/220

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

¹Reported efficacy is based on the 2009 update.

Chemotherapy

• 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, 60/200

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

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

Chemotherapy

• 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 #5, with range

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

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

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

Pegylated liposomal doxorubicin monotherapy

Regimen variant #1, 45 mg/m²

Study	Years 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
O'Brien et al. 2004	1998-2000	Phase 3 (E-switch-ic)	Doxorubicin	Seems to have non-inferior PFS
Harbeck et al. 2016 (PELICAN)	2006-2010	Phase 3 (E-switch-ic)	Capecitabine	Inconclusive whether non-inferior TTP

Chemotherapy

• Pegylated liposomal doxorubicin (Doxil) 50 mg/m² IV over up to 60 minutes once on day 1
  • If infusion reactions occurred, infusion could be given over up to 90 minutes

28-day cycles

References

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

Cyclophosphamide & Epirubicin (EC)

EC: Epirubicin & Cyclophosphamide

Regimen variant #1, 75/600

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

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

Chemotherapy

• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for up to 6 to 8 cycles

Regimen variant #2, 90/600

Study	Years 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 once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for up to 8 cycles

Regimen variant #3, with range

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robert et al. 2011 (RIBBON-1)	2005-2007	Phase 3 (C)	EC & Bevacizumab	Inferior PFS

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

Chemotherapy

• 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

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

Cyclophosphamide & Epirubicin (EC) & Bevacizumab

EC & Bevacizumab: Epirubicin, Cyclophosphamide, Bevacizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robert et al. 2011 (RIBBON-1)	2005-2007	Phase 3 (E-esc)	EC	Superior PFS (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

• Bevacizumab maintenance, if no PD

References

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

Epirubicin & Paclitaxel (EP)

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

Regimen variant #1, 60/175

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

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

Chemotherapy

• 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	Years 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 once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV once on day 1

21-day cycle for up to 6 cycles

Regimen variant #4, 80/175

Study	Years 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Conte et al. 2004	1996-2001	Phase 3 (C)	E, then P	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

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

Epirubicin monotherapy

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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Feher et al. 2005	1996-1999	Phase 3 (C)	Gemcitabine	Superior OS

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

Chemotherapy

• Epirubicin (Ellence) 40 mg/m² IV once on day 1

21-day cycles

Regimen variant #3, 50 mg/m²

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

Chemotherapy

• Epirubicin (Ellence) 50 mg/m² IV once on day 1

14-day cycles

Regimen variant #4, 60 mg/m²

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

Chemotherapy

• Epirubicin (Ellence) 60 mg/m² IV once on day 1

21-day cycles

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

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

Chemotherapy

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

Chemotherapy

• Epirubicin (Ellence) 75 mg/m² IV once on day 1

21-day cycles

Regimen variant #7, 90 mg/m²

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

Chemotherapy

• Epirubicin (Ellence) 90 mg/m² IV once on day 1

21-day cycles

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

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

Chemotherapy

• Epirubicin (Ellence) 60 mg/m² IV once per day on days 1 & 2

21-day cycles

Regimen variant #9, 135 mg/m²

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

Chemotherapy

• Epirubicin (Ellence) 135 mg/m² IV once on day 1

21-day cycles

References

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

FAC

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

Regimen variant #1, 500/50/500

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Smalley et al. 1977	1974-1975	Phase 3 (E-de-esc)	CMFVP	Might have superior OS1
Bennett et al. 1988	1983-1985	Phase 3 (C)	CNF	Did not meet endpoints of TTF/OS
Muss et al. 1991	1984-1989	Non-randomized portion of RCT
Blajman et al. 1999	1991-1994	Phase 3 (C)	NA	Did not meet primary endpoint of ORR
Jassem et al. 2001	1996-1998	Phase 3 (C)	AT (Taxol)	Inferior OS2
Bontenbal et al. 2005	1997-2002	Phase 3 (C)	AT (Taxotere)	Seems to have inferior OS
Robert et al. 2011 (RIBBON-1)	2005-2007	Phase 3 (C)	FAC & Bevacizumab	Inferior PFS

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

Chemotherapy

• 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 6 to 8 cycles

Subsequent treatment

• Muss et al. 1991: CMFP versus observation, then CMFP at progression

Regimen variant #2, 600/50/600

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

Chemotherapy

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

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

Chemotherapy

• 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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Hortobagyi et al. 1979	1974-NR	Phase 3 (C)	FAC-BCG	Inferior 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, 1000/50/1400

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

Chemotherapy

• 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 #7, 1000/60/1400 x 6

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

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 up to 6 cycles

Regimen variant #8, 1000/60/1400, maximum doxorubicin of 500 mg/m²

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

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 cycles until maximum cumulative dose of doxorubicin of 500 mg/m²

Regimen variant #9, 1000/60/1400, indefinite

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

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

Chemotherapy

• 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 cycles

References

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

FAC & Bevacizumab

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

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robert et al. 2011 (RIBBON-1)	2005-2007	Phase 3 (E-esc)	FAC	Superior PFS (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

• Bevacizumab maintenance, if no PD

References

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

FEC

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

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

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

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 to 12 cycles

Regimen variant #2, 500/60/500

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

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

Chemotherapy

• 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

21-day cycles

Regimen variant #4, 500/90/500

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Zielinksi et al. 2005 (CECOG BM1)	1999-2002	Phase 3 (C)	GET	Did not meet primary endpoint of TTP
Robert et al. 2011 (RIBBON-1)	2005-2007	Phase 3 (C)	FEC & Bevacizumab	Inferior PFS

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Focan et al. 1993	1985-1990	Phase 3 (E-esc)	FEC; FEC 50	Seems to have superior TTP
Brufman et al. 1997 (HEPI 010)	1989-1992	Phase 3 (E-esc)	FEC; FEC 50	Superior ORR
Robert et al. 2011 (RIBBON-1)	2005-2007	Phase 3 (C)	FEC & Bevacizumab	Inferior PFS

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
  • Note: in Focan et al. 1993, dose was split: 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 6 to 8 cycles

Regimen variant #6, 600/60/600 ("CEF21")

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

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

Chemotherapy

• 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 to 12 cycles

Regimen variant #7, 1000/50/500 until max anthracycline

Study	Years 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 #8, 1000/60/1400

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

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 #9, 1000/100/800

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

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 8 cycles

References

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

FEC & Bevacizumab

FEC & Bevacizumab: Fluorouracil, Epirubicin, Cyclophosphamide, Bevacizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robert et al. 2011 (RIBBON-1)	2005-2007	Phase 3 (E-esc)	FEC	Superior PFS (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

• Bevacizumab maintenance, if no PD

References

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

Gemcitabine monotherapy

Regimen

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

Chemotherapy

• Gemcitabine (Gemzar) 800 mg/m² IV over 30 minutes once per day on days 1, 8, 15

28-day cycles

References

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

Gemcitabine & Paclitaxel

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

Regimen variant #1, 6 cycles

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

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 cycle for 6 cycles

Subsequent treatment

• PG maintenance versus Observation

Regimen variant #2, indefinite

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

Chemotherapy

• 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 cycles

References

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

Cyclophosphamide & Non-pegylated liposomal doxorubicin (MC)

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

Regimen variant #1, 60/600

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

Chemotherapy

• Non-pegylated liposomal doxorubicin (Myocet) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for up to 8 cycles

References

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

Paclitaxel monotherapy, weekly

Regimen variant #1, 80 mg/m² weekly

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

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycles

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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Takashima et al. 2015 (SELECT BC)	2006-2010	Phase 3 (C)	S-1	Seems to have non-inferior OS	Inferior EQ-5D score
Fujiwara et al. 2019 (A3105301)	2012-2014	Phase 3 (C)	NK105	Inconclusive whether non-inferior PFS	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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Miller et al. 2007 (ECOG E2100)	2001-2004	Phase 3 (C)	Paclitaxel & Bevacizumab	Inferior PFS
Miles et al. 2016 (MERiDiAN)	2012-2013	Phase 3 (C)	Paclitaxel & Bevacizumab	Inferior PFS

Chemotherapy

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

Chemotherapy

• Paclitaxel (Taxol) 100 mg/m² IV over 60 minutes once per day on days 1, 8, 15

21-day cycles

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

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

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

Chemotherapy

• Paclitaxel (Taxol) 100 mg/m² IV once per day on days 1, 8, 15

28-day cycles

References

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

Paclitaxel monotherapy, q3wk

Regimen variant #1, 175 mg/m² q3wk

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

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

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

21-day cycles

Regimen variant #2, 175 mg/m², CI

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Sledge et al. 2003 (ECOG E1193)	1993-1995	Phase 3 (C)	1. AT (Taxol)	Inferior TTF
			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	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Takashima et al. 2015 (SELECT BC)	2006-2010	Phase 3 (C)	S-1	Seems to have non-inferior OS	Inferior EQ-5D score

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

28-day cycles

Regimen variant #4, 200 mg/m²

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

Chemotherapy

• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours once on day 1

21-day cycle for 7 or 8 cycles

Regimen variant #5, 250 mg/m²

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

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

Chemotherapy

• Paclitaxel (Taxol) 250 mg/m² IV continuous infusion over 24 hours, started on day 1

21-day cycles

References

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

Paclitaxel & Bevacizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Miller et al. 2007 (ECOG E2100)	2001-2004	Phase 3 (E-RT-esc)	Paclitaxel	Superior PFS Median PFS: 11.8 vs 5.9 mo (HR 0.60)
Robert et al. 2011 (SUN 1094)	2006-2009	Phase 3 (C)	Paclitaxel & Sunitinib	Did not meet primary endpoint of PFS
Lang et al. 2013 (TURANDOT)	2008-2010	Phase 3 (E-switch-ic)	Capecitabine & Bevacizumab	Non-inferior OS1
Rugo et al. 2015 (CALGB 40502/NCCTG N063H)	2008-2011	Phase 3 (C)	1. Ixabepilone & Bevacizumab	Superior PFS
			2. nab-Paclitaxel & Bevacizumab	Might have superior PFS
Rochlitz et al. 2016 (SAKK 24/09)	2010-2012	Phase 3 (C)	Capecitabine, Cyclophosphamide, Bevacizumab	Did not meet secondary endpoint of PFS
Miles et al. 2016 (MERiDiAN)	2012-2013	Phase 3 (E-esc)	Paclitaxel	Superior PFS 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

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

Paclitaxel & Vinorelbine

Regimen

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

Chemotherapy

• Paclitaxel (Taxol) 135 mg/m² IV over 3 hours once on day 1, given second
• Vinorelbine (Navelbine) 30 mg/m² IV over 20 minutes once per day on days 1 & 8

28-day cycles

References

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

nab-Paclitaxel monotherapy

Example orders

• Example orders for Paclitaxel, nanoparticle albumin-bound (Abraxane) in breast cancer

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

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

Chemotherapy

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

Chemotherapy

• 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gradishar et al. 2005 (CA012-0)	2001-2002	Phase 3 (E-switch-ic)	Paclitaxel; q3wk	Superior TTP
Robert et al. 2011 (RIBBON-1)	2005-2007	Phase 3 (C)	nab-Paclitaxel & Bevacizumab	Inferior PFS

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

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 300 mg/m² IV over 30 minutes once on day 1

21-day cycles

References

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

Paclitaxel, nanoparticle albumin-bound & Bevacizumab

Example orders

• Example orders for Paclitaxel, nanoparticle albumin-bound & Bevacizumab in breast cancer

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

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

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Robert et al. 2011 (RIBBON-1)	2005-2007	Phase 3 (E-esc)	nab-Paclitaxel	Superior PFS (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

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

Pemetrexed monotherapy

Regimen variant #1, 500 mg/m²

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

Patients in the study were "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 start of Pemetrexed (Alimta), 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	Years of enrollment	Evidence
Robert et al. 2011	2005-2006	Phase 2

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 start of Pemetrexed (Alimta), 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 start of Pemetrexed (Alimta), to continue throughout therapy, and until 3 weeks after the last dose of pemetrexed

14-day cycles

References

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

S-1 monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Takashima et al. 2015 (SELECT BC)	2006-2010	Phase 3 (E-switch-ic)	1. Docetaxel 2. Paclitaxel	Seems to have non-inferior OS	Superior EQ-5D score
Mukai et al. 2021 (SELECT BC-CONFIRM)	2011-2013	Phase 3 (E-switch-ic)	1. AC 2. FAC 3. EC 4. FEC	Non-inferior OS

Chemotherapy

• Tegafur, gimeracil, oteracil (S-1) by the following criteria:
  • BSA less than 1.25 m²: 40 mg PO twice per day on days 1 to 28
  • BSA at least 1.25 m² and less than 1.5 m²: 50 mg PO twice per day on days 1 to 28
  • BSA 1.5 m² or more: 60 mg PO twice per day on days 1 to 28

42-day cycles

References

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

Capecitabine & Docetaxel (TX)

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

Regimen variant #1, 1900/75

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

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

Chemotherapy

• 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Seidman et al. 2010 (B9E-MC-S273)	2002-2008	Phase 3 (C)	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 once on day 1

21-day cycles

Subsequent treatment

• Upon progression: Gemcitabine

References

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

Epirubicin & Vinorelbine (VE)

VE: Vinorelbine & Epirubicin

Regimen

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

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8
• Epirubicin (Ellence) 90 mg/m² IV once on day 1

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

References

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

Metastatic disease, maintenance after first-line therapy

Bevacizumab monotherapy

Regimen

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

Preceding treatment

• AVADO: Docetaxel & Bev x 9
• RIBBON-1: AC & Bev x 8 or EC & Bev x 8 or FAC & Bev x 8 or FEC & Bev x 8
• IMELDA: Docetaxel & Bev x 3 to 6

Targeted therapy

• Bevacizumab (Avastin) 15 mg/kg IV once on day 1

21-day cycles

References

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

Capecitabine & Bevacizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gligorov et al. 2014 (IMELDA)	2009-2011	Phase 3 (E-esc)	Bevacizumab	Superior OS Median OS: 39 vs 23.7 mo (HR 0.43, 95% CI 0.26-0.69)

Preceding treatment

• 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

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

Gemcitabine & Paclitaxel

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

Regimen

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

Preceding treatment

• 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

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

Metastatic disease, subsequent lines of chemotherapy

Capecitabine monotherapy

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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Brufsky et al. 2011 (RIBBON-2)	2006-2008	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Gemcitabine & Bevacizumab 4. Paclitaxel & Bevacizumab 5. nab-Paclitaxel & Bevacizumab 6. Vinorelbine & Bevacizumab	Inferior PFS
Barrios et al. 2010 (SUN 1107)	2006-2009	Phase 3 (C)	Sunitinib	Superior PFS Median PFS: 4.2 vs 2.8 mo (HR 0.68, 95% CI 0.53-0.86)
Baselga et al. 2017 (RESILIENCE)	2010-NR	Phase 3 (C)	Capecitabine & Sorafenib	Did not meet primary endpoint of PFS Median PFS: 5.4 vs 5.5 mo (HR 1.03, 95% CI 0.82-1.28)
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab	Inferior PFS
Modi et al. 2022 (DESTINY-Breast04)	2018-2021	Phase 3 (C)	Trastuzumab deruxtecan	Inferior OS
Awaiting publication (TROPiCS-02)	2019-2024	Phase 3 (C)	Sacituzumab govitecan	Seems to have inferior OS	Faster deterioration of global QoL

Note: in SUN 1107, this dosage was used for patients older than 65 years. This was the lower bound of dosing in DESTINY-Breast04 & TROPiCS-02.

Prior treatment criteria

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

Biomarker eligibility criteria

• DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative
• TROPiCS-02: HR+

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Blum et al. 1999	1996	Phase 2 (RT)
Reichardt et al. 2003	1999-2000	Phase 2
Miller et al. 2005 (AVF2119g)	2000-2002	Phase 3 (C)	Capecitabine & Bevacizumab	Did not meet primary endpoint of PFS
Pallis et al. 2011 (HORG CT/02.11)	2002-2008	Phase 3 (C)	Gemcitabine & Vinorelbine	Did not meet primary endpoint of PFS Median PFS: 5.2 vs 5.4 mo
Thomas et al. 2007 (CA163-046)	2003-2006	Phase 3 (C)	Capecitabine & Ixabepilone	Inferior PFS
Sparano et al. 2010 (CA163-048)	2003-2006	Phase 3 (C)	Capecitabine & Ixabepilone	Might have inferior OS
Barrios et al. 2010 (SUN 1107)	2006-2009	Phase 3 (C)	Sunitinib	Superior PFS Median PFS: 4.2 vs 2.8 mo (HR 0.68, 95% CI 0.53-0.86)
Kaufman et al. 2015 (E7389-G000-301)	2006-2009	Phase 3 (C)	Eribulin	Might have inferior OS
Crown et al. 2013 (A6181099)	2007-2009 (C)	Phase 3 (C)	Capecitabine & Sunitinib	Might have superior PFS 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 portion of phase 3 RCT
Martin et al. 2018 (L00070 IN 305 B0)	2009-2011 (C)	Phase 3 (C)	Capecitabine & Vinflunine	Seems to have inferior PFS
Park et al. 2018 (PROCEED)	2011-2016 (C)	Phase 3 (C)	IX	Did not meet primary endpoint of PFS Median PFS: 4.7 vs 6.4 mo
Zhang et al. 2017 (BG01-1323L)	2014-2015	Phase 3 (C)	Capecitabine & Utidelone	Seems to have inferior OS1
Modi et al. 2022 (DESTINY-Breast04)	2018-2021	Phase 3 (C)	Trastuzumab deruxtecan	Inferior OS
Awaiting publication (TROPiCS-02)	2019-2024	Phase 3 (C)	Sacituzumab govitecan	Seems to have inferior OS	Faster deterioration of global QoL

¹Reported efficacy for BG01-1323L is based on the 2020 update.
Note: To our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm in this context. This was the upper bound of dosing in DESTINY-Breast04 & TROPiCS-02.

Prior treatment criteria

• Blum et al. 1999: Exposure to paclitaxel and an anthracycline
• Reichardt et al. 2003: Exposure to a taxane-containing regimen
• AVF2119g, HORG CT/02.11, CA163-046, CA163-048, SUN 1107, E7389-G000-301, A6181099, L00070 IN 305 B0, PROCEED, BG01-1323L: Exposure to a taxane and an anthracycline
• JO21095: Exposure to an anthracycline-containing regimen and docetaxel, with PD
• DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

• DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative
• TROPiCS-02: HR+

Chemotherapy

• Capecitabine (Xeloda) 1250 mg/m² PO twice per day on days 1 to 14

21-day cycles

References

1. Blum JL, Jones SE, Buzdar AU, Mucci LoRusso P, Kuter I, Vogel C, Osterwalder B, Burger HU, Stoner Brown C, Griffin T. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol. 1999 Feb;17(2):485-93. link to original article contains dosing details in abstract PubMed
2. Reichardt P, Von Minckwitz G, Thuss-Patience PC, Jonat W, Kölbl H, Jänicke F, Kieback DG, Kuhn W, Schindler AE, Mohrmann S, Kaufmann M, Lück HJ. Multicenter phase II study of oral capecitabine (Xeloda) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy. Ann Oncol. 2003 Aug;14(8):1227-33. link to original article contains dosing details in abstract PubMed
3. AVF2119g: Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005 Feb 1;23(4):792-9. link to original article contains dosing details in abstract PubMed NCT00109239
4. CA163-046: Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. link to original article contains dosing details in manuscript PubMed NCT00080301
   1. Update: Hortobagyi GN, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Lerzo GL, Pivot XB, Hurtado de Mendoza F, Xu B, Vahdat LT, Peck RA, Mukhopadhyay P, Roché HH. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes. Breast Cancer Res Treat. 2010 Jul;122(2):409-18. Epub 2010 May 8. link to original article PubMed
5. SUN 1107: Barrios CH, Liu MC, Lee SC, Vanlemmens L, Ferrero JM, Tabei T, Pivot X, Iwata H, Aogi K, Lugo-Quintana R, Harbeck N, Brickman MJ, Zhang K, Kern KA, Martin M. Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer. Breast Cancer Res Treat. 2010 May;121(1):121-31. Epub 2010 Mar 26. link to original article link to PMC article contains dosing details in abstract PubMed
6. CA163-048: Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010 Jul 10;28(20):3256-63. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00082433
7. HORG CT/02.11: Pallis AG, Boukovinas I, Ardavanis A, Varthalitis I, Malamos N, Georgoulias V, Mavroudis D; Hellenic Oncology Research Group. A multicenter randomized phase III trial of vinorelbine/gemcitabine doublet versus capecitabine monotherapy in anthracycline- and taxane-pretreated women with metastatic breast cancer. Ann Oncol. 2012 May;23(5):1164-9. Epub 2011 Sep 21. link to original article contains dosing details in abstract PubMed NCT00431106
8. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
9. A6181099: Crown JP, Diéras V, Staroslawska E, Yardley DA, Bachelot T, Davidson N, Wildiers H, Fasching PA, Capitain O, Ramos M, Greil R, Cognetti F, Fountzilas G, Blasinska-Morawiec M, Liedtke C, Kreienberg R, Miller WH Jr, Tassell V, Huang X, Paolini J, Kern KA, Romieu G. Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer. J Clin Oncol. 2013 Aug 10;31(23):2870-8. Epub 2013 Jul 15. link to original article contains dosing details in manuscript PubMed NCT00435409
10. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed
11. E7389-G000-301: Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, Olivo MS, He Y, Dutcus CE, Cortes J. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015 Feb 20;33(6):594-601. Epub 2015 Jan 20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00337103
12. JO21095: Yamamoto D, Sato N, Rai Y, Yamamoto Y, Saito M, Iwata H, Masuda N, Oura S, Watanabe J, Hattori S, Matsuura Y, Kuroi K. Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. Breast Cancer Res Treat. 2017 Feb;161(3):473-482. Epub 2016 Dec 22. link to original article contains dosing details in manuscript PubMed
13. BG01-1323L: Zhang P, Sun T, Zhang Q, Yuan Z, Jiang Z, Wang XJ, Cui S, Teng Y, Hu XC, Yang J, Pan H, Tong Z, Li H, Yao Q, Wang Y, Yin Y, Sun P, Zheng H, Cheng J, Lu J, Zhang B, Geng C, Liu J, Peng R, Yan M, Zhang S, Huang J, Tang L, Qiu R, Xu B; BG01-1323L study group. Utidelone plus capecitabine versus capecitabine alone for heavily pretreated metastatic breast cancer refractory to anthracyclines and taxanes: a multicentre, open-label, superiority, phase 3, randomised controlled trial. Lancet Oncol. 2017 Mar;18(3):371-383. Epub 2017 Feb 11. link to original article contains dosing details in abstract PubMed NCT02253459
    1. Update: Xu B, Sun T, Zhang Q, Zhang P, Yuan Z, Jiang Z, Wang X, Cui S, Teng Y, Hu XC, Yang J, Pan H, Tong Z, Li H, Yao Q, Wang Y, Yin Y, Sun P, Zheng H, Cheng J, Lu J, Zhang B, Geng C, Liu J, Shen K, Yu S, Li H, Tang L, Qiu R; study group of BG01-1323L. Efficacy of utidelone plus capecitabine versus capecitabine for heavily pretreated, anthracycline- and taxane-refractory metastatic breast cancer: final analysis of overall survival in a phase III randomised controlled trial. Ann Oncol. 2021 Feb;32(2):218-228. Epub 2020 Nov 11. link to original article PubMed
14. RESILIENCE: Baselga J, Zamagni C, Gómez P, Bermejo B, Nagai SE, Melichar B, Chan A, Mángel L, Bergh J, Costa F, Gómez HL, Gradishar WJ, Hudis CA, Rapoport BL, Roché H, Maeda P, Huang L, Meinhardt G, Zhang J, Schwartzberg LS. RESILIENCE: phase III randomized, double-blind trial comparing sorafenib with capecitabine versus placebo with capecitabine in locally advanced or metastatic HER2-negative breast cancer. Clin Breast Cancer. 2017 Dec;17(8):585-594.e4. Epub 2017 May 22. link to original article contains dosing details in abstract PubMed NCT01234337
15. PROCEED: Park IH, Im SA, Jung KH, Sohn JH, Park YH, Lee KS, Sim SH, Park KH, Kim JH, Nam BH, Kim HJ, Kim TY, Lee KH, Kim SB, Ahn JH, Lee S, Ro J. Randomized open label phase III trial of irinotecan plus capecitabine versus capecitabine monotherapy in patients with metastatic breast cancer previously treated with anthracycline and taxane: PROCEED trial (KCSG BR 11-01). Cancer Res Treat. 2019 Jan;51(1):43-52. Epub 2018 Feb 14. link to original article contains dosing details in abstract link to PMC article PubMed NCT01501669
16. L00070 IN 305 B0: Martin M, Campone M, Bondarenko I, Sakaeva D, Krishnamurthy S, Roman L, Lebedeva L, Vedovato JC, Aapro M. Randomised phase III trial of vinflunine plus capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with an anthracycline and resistant to taxane. Ann Oncol. 2018 May 1;29(5):1195-1202. link to original article contains dosing details in abstract PubMed NCT01095003
17. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029
18. EVER-132-002: NCT04639986
19. TROPiCS-02: NCT03901339

Capecitabine & Bevacizumab

Regimen variant #1, 2000/15

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2)	2006-2008	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Gemcitabine 4. Paclitaxel 5. nab-Paclitaxel 6. Vinorelbine	Superior PFS 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)	1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel	Superior PFS 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Miller et al. 2005 (AVF2119g)	2000-2002	Phase 3 (E-esc)	Capecitabine	Did not meet primary endpoint of PFS Median PFS: 4.86 vs 4.17 mo (HR 0.98, 95% CI 0.77-1.25)

Note: this is 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

1. AVF2119g: Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005 Feb 1;23(4):792-9. link to original article contains dosing details in abstract PubMed NCT00109239
2. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
3. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
   1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Capecitabine & Docetaxel (TX)

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

Regimen variant #1, 825/60

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2016 (JO21095)	2008-2010	Phase 3 (E-esc)	Docetaxel	Seems to have superior PFS 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
O'Shaughnessy et al. 2002	NR	Phase 3 (E-RT-esc)	Docetaxel	Superior OS1 Median OS: 14.5 vs 11.5 mo (HR 0.78, 95% CI 0.645-0.94)
Chan et al. 2009 (B9E-US-S188)	2002-2004	Phase 3 (C)	GD	Did not meet primary endpoint of PFS

¹Reported efficacy for O'Shaughnessy et al. 2002 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

1. O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. link to original article contains dosing details in manuscript PubMed
   1. Update: Miles D, Vukelja S, Moiseyenko V, Cervantes G, Mauriac L, Van Hazel G, Liu WY, Ayoub JP, O'Shaughnessy JA. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Clin Breast Cancer. 2004 Oct;5(4):273-8. link to original article PubMed
2. B9E-US-S188: Chan S, Romieu G, Huober J, Delozier T, Tubiana-Hulin M, Schneeweiss A, Lluch A, Llombart A, du Bois A, Kreienberg R, Mayordomo JI, Antón A, Harrison M, Jones A, Carrasco E, Vaury AT, Frimodt-Moller B, Fumoleau P. Phase III study of gemcitabine plus docetaxel compared with capecitabine plus docetaxel for anthracycline-pretreated patients with metastatic breast cancer. J Clin Oncol. 2009 Apr 10;27(11):1753-60. Epub 2009 Mar 9. link to original article contains dosing details in abstract PubMed NCT00191152
   1. Pooled update: Seidman AD, Chan S, Wang J, Zhu C, Xu C, Xu B. A pooled analysis of gemcitabine plus docetaxel versus capecitabine plus docetaxel in metastatic breast cancer. Oncologist. 2014 May;19(5):443-52. Epub 2014 Apr 4. link to original article link to PMC article PubMed
3. JO21095: Yamamoto D, Sato N, Rai Y, Yamamoto Y, Saito M, Iwata H, Masuda N, Oura S, Watanabe J, Hattori S, Matsuura Y, Kuroi K. Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. Breast Cancer Res Treat. 2017 Feb;161(3):473-482. Epub 2016 Dec 22. link to original article contains dosing details in manuscript PubMed

Capecitabine & Ixabepilone

XI: Xeloda (Capecitabine) & Ixabepilone

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Thomas et al. 2007 (CA163-046)	2003-2006	Phase 3 (E-RT-esc)	Capecitabine	Superior PFS Median PFS: 5.8 vs 4.2 mo (HR 0.75, 95% CI 0.64-0.88)
Sparano et al. 2010 (CA163-048)	2003-2006	Phase 3 (E-RT-esc)	Capecitabine	Might have superior OS 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

1. CA163-046: Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. link to original article contains dosing details in manuscript PubMed NCT00080301
   1. Update: Hortobagyi GN, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Lerzo GL, Pivot XB, Hurtado de Mendoza F, Xu B, Vahdat LT, Peck RA, Mukhopadhyay P, Roché HH. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes. Breast Cancer Res Treat. 2010 Jul;122(2):409-18. Epub 2010 May 8. link to original article PubMed
2. CA163-048: Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010 Jul 10;28(20):3256-63. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00082433

Capecitabine & Vinflunine

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Martin et al. 2018 (L00070 IN 305 B0)	2009-2011	Phase 3 (E-esc)	Capecitabine	Seems to have superior PFS 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

1. L00070 IN 305 B0: Martin M, Campone M, Bondarenko I, Sakaeva D, Krishnamurthy S, Roman L, Lebedeva L, Vedovato JC, Aapro M. Randomised phase III trial of vinflunine plus capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with an anthracycline and resistant to taxane. Ann Oncol. 2018 May 1;29(5):1195-1202. link to original article contains dosing details in manuscript PubMed NCT01095003

Carboplatin & Gemcitabine (GCb)

Regimen

Study	Years of enrollment	Evidence
Nagourney et al. 2008	2002-2005	Pilot, less than 20 pts

Chemotherapy

• Carboplatin (Paraplatin) AUC 2 IV over 60 minutes once per day on days 1 & 8
• Gemcitabine (Gemzar) 800 mg/m² IV over 60 minutes once per day on days 1 & 8

21-day cycles until CR or indefinitely

References

1. Nagourney RA, Flam M, Link J, Hager S, Blitzer J, Lyons W, Sommers BL, Evans S. Carboplatin plus gemcitabine repeating doublet therapy in recurrent breast cancer. Clin Breast Cancer. 2008 Oct;8(5):432-5. link to original article contains dosing details in abstract PubMed

Cisplatin & Vinorelbine (CVb)

CVb: Cisplatin & Vinorelbine

Regimen

Study	Years of enrollment	Evidence
Ray-Coquard et al. 1998	1992-1994	Phase 2
Vassilomanolakis et al. 2000	NR	Phase 2

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 bolus after Vinorelbine (Navelbine) to prevent phlebitis
• Normal saline 2000 mL with KCl (unspecified amount of KCl) IV over 4 hours once on day 1, prior to Cisplatin (Platinol)
• Furosemide (Lasix) 40 mg IV once on day 1; 20 minutes prior to Cisplatin (Platinol)
• Normal saline 1000 mL and D5W 1000 mL IV over 4 hours once on day 1, after Cisplatin (Platinol)
  • Paper did not say whether fluids were given sequentially or concurrently
• 5-HT3 antagonists used

21-day cycle for up to 6 cycles

References

1. Ray-Coquard I, Biron P, Bachelot T, Guastalla JP, Catimel G, Merrouche Y, Droz JP, Chauvin F, Blay JY. Vinorelbine and cisplatin (CIVIC regimen) for the treatment of metastatic breast carcinoma after failure of anthracycline- and/or paclitaxel-containing regimens. Cancer. 1998 Jan 1;82(1):134-40. link to original article PubMed
2. Vassilomanolakis M, Koumakis G, Barbounis V, Demiri M, Pateras H, Efremidis AP. Vinorelbine and cisplatin in metastatic breast cancer patients previously treated with anthracyclines. Ann Oncol. 2000 Sep;11(9):1155-60. link to original article contains dosing details in manuscript Pubmed

Cyclophosphamide & Methotrexate (CM)

CM: Cyclophosphamide & Methotrexate

Regimen variant #1

Study	Years of enrollment	Evidence
Colleoni et al. 2002	1997-2000	Non-randomized

Chemotherapy

• Cyclophosphamide (Cytoxan) 50 mg PO once per day
• Methotrexate (MTX) 2.5 mg PO twice per day on days 1 & 2

7-day cycles

Regimen variant #2, metronomic

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Colleoni et al. 2005	2000-2003	Randomized (C)	CM & Thalidomide	Did not meet primary endpoint of % 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
• Methotrexate (MTX) 2.5 mg PO twice per day on days 1 & 4

7-day cycles

References

1. Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nolè F, Peruzzotti G, Robertson C, Orlando L, Cinieri S, de Braud F, Viale G, Goldhirsch A. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol. 2002 Jan;13(1):73-80. link to original article contains dosing details in manuscript PubMed
2. Colleoni M, Orlando L, Sanna G, Rocca A, Maisonneuve P, Peruzzotti G, Ghisini R, Sandri MT, Zorzino L, Nolè F, Viale G, Goldhirsch A. Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann Oncol. 2006 Feb;17(2):232-8. Epub 2005 Dec 1. link to original article contains dosing details in abstract PubMed

Cyclophosphamide monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cortes et al. 2018 (L00070 IN 308 B0)	2009-2011 (C)	Phase 3 (C)	Vinflunine	Did not meet primary endpoint of OS Median OS: 9.3 vs 9.1 mo (HR 0.96)

Note: this was the most commonly used comparator arm; doses were not provided in the manuscript.

Chemotherapy

• Cyclophosphamide (Cytoxan)

References

1. L00070 IN 308 B0: Cortes J, Perez-Garcia J, Levy C, Gómez Pardo P, Bourgeois H, Spazzapan S, Martínez-Jañez N, Chao TC, Espié M, Nabholtz JM, Gonzàlez Farré X, Beliakouski V, Román García J, Holgado E, Campone M. Open-label randomised phase III trial of vinflunine versus an alkylating agent in patients with heavily pretreated metastatic breast cancer. Ann Oncol. 2018 Apr 1;29(4):881-887. link to original article PubMed NCT01091168

Docetaxel monotherapy

D: Docetaxel
T: Taxotere (Docetaxel)

Regimen variant #1, 40 mg/m² 3 weeks out of 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Rivera et al. 2008	2001-2004	Phase 3 (C), less than 20 pts in this subgroup	Docetaxel; q3wk	Did not meet primary endpoint of ORR	Superior toxicity

Chemotherapy

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

28-day cycles

Regimen variant #2, 40 mg/m² 6 weeks out of 8

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

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Adachi et al. 1996	1993	Phase 2
Harvey et al. 2006 (TAX 313)	1995-2001	Phase 3 (E-RT-de-esc)	1. Docetaxel; 75 mg/m2 q3wk	Might have inferior TTP
			2. Docetaxel; 100 mg/m2 q3wk	Might have inferior TTP
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab	Inferior PFS

Note: this is the dosage used for Japanese patients; Adachi et al. 1996 reported 21- to 28-day cycles

Chemotherapy

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1

21-day cycles

Regimen variant #4, 70 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Yamamoto et al. 2016 (JO21095)	2008-2010	Phase 3 (C)	TX	Seems to have inferior OS

Chemotherapy

• Docetaxel (Taxotere) 70 mg/m² IV once on day 1

21-day cycles

Subsequent treatment

• Upon progression: Capecitabine

Regimen variant #5, 75 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Harvey et al. 2006 (TAX 313)	1995-2001	Phase 3 (E-RT-esc)	1. Docetaxel; 60 mg/m2 q3wk	Might have superior TTP
			2. Docetaxel; 100 mg/m2 q3wk	Might have inferior TTP
Brufsky et al. 2011 (RIBBON-2)	2006-2008	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Gemcitabine & Bevacizumab 4. Paclitaxel & Bevacizumab 5. nab-Paclitaxel & Bevacizumab 6. Vinorelbine & Bevacizumab	Inferior PFS
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab	Inferior PFS

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

Regimen variant #6, 100 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
ten Bokkel Huinink et al. 1994	NR	Phase 2
Nabholtz et al. 1999 (TAX 304)	NR	Phase 3 (E-RT-de-esc)	Mitomycin & Vinblastine (MV)	Superior OS
Chan et al. 1999 (TAX 303)	1994-1997	Phase 3 (E-RT-switch-ic)	Doxorubicin	Superior ORR
Sjöström et al. 1999	1994-1997	Phase 3 (E-de-esc)	MF	Superior TTP
O'Shaughnessy et al. 2002	NR	Phase 3 (C)	TX	Inferior OS1
Jones et al. 2005 (TAX 311)	1994-2001	Phase 3 (E-switch-ic)	Paclitaxel	Superior OS Median OS: 15.4 vs 12.7 mo (HR 0.71, 95% CI 0.58-0.87)
Bonneterre et al. 2002	1995-1997	Phase 3 (E-de-esc)	5-FU & Vinorelbine	Did not meet primary endpoint of TTP	Less toxic
Harvey et al. 2006 (TAX 313)	1995-2001	Phase 3 (E-RT-esc)	1. Docetaxel; 60 mg/m2 q3wk	Might have superior TTP
			2. Docetaxel; 75 mg/m2 q3wk	Might have superior TTP
Rivera et al. 2008	2001-2004	Phase 3 (C), less than 20 pts in this subgroup	Docetaxel; weekly	Did not meet primary endpoint of ORR	Inferior toxicity
Nielsen et al. 2011	2001-2005	Phase 3 (C)	Docetaxel & Gemcitabine	Might have inferior TTP
Schröder et al. 2011	2001-2006	Phase 3 (C)	Docetaxel; weekly	Seems to have superior OS
Brufsky et al. 2011 (RIBBON-2)	2006-2008	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Gemcitabine & Bevacizumab 4. Paclitaxel & Bevacizumab 5. nab-Paclitaxel & Bevacizumab 6. Vinorelbine & Bevacizumab	Inferior PFS
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab	Inferior PFS

¹Reported efficacy for O'Shaughnessy et al. 2002 is based on the 2004 update.
Note: this is the upper end of the range of docetaxel dosing described in TANIA. TAX 304 stopped treatment after 10 cycles. TAX 303 stopped treatment after 7 cycles.

Chemotherapy

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1
  • Note: Rivera et al. 2008 gave 75 mg/m² in cycle 1, with escalation to 100 mg/m² depending on toxicity

21-day cycles (see note)

References

1. ten Bokkel Huinink WW, Prove AM, Piccart M, Steward W, Tursz T, Wanders J, Franklin H, Clavel M, Verweij J, Alakl M, Bayssas M, Kaye SB; EORTC Early Clinical Trials Group. A phase II trial with docetaxel (Taxotere) in second line treatment with chemotherapy for advanced breast cancer: a study of the EORTC Early Clinical Trials Group. Ann Oncol. 1994 Jul;5(6):527-32. link to original article contains dosing details in abstract PubMed
2. Adachi I, Watanabe T, Takashima S, Narabayashi M, Horikoshi N, Aoyama H, Taguchi T. A late phase II study of RP56976 (docetaxel) in patients with advanced or recurrent breast cancer. Br J Cancer. 1996 Jan;73(2):210-6. link to original article link to PMC article contains dosing details in abstract PubMed
3. TAX 304: Nabholtz JM, Senn HJ, Bezwoda WR, Melnychuk D, Deschênes L, Douma J, Vandenberg TA, Rapoport B, Rosso R, Trillet-Lenoir V, Drbal J, Molino A, Nortier JW, Richel DJ, Nagykalnai T, Siedlecki P, Wilking N, Genot JY, Hupperets PS, Pannuti F, Skarlos D, Tomiak EM, Murawsky M, Alakl M, Aapro M; 304 Study Group. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. J Clin Oncol. 1999 May;17(5):1413-24. link to original article contains dosing details in abstract PubMed
4. Review: Burris HA 3rd. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin Oncol. 1999 Jun;26(3 Suppl 9):1-6. PubMed
5. TAX 303: Chan S, Friedrichs K, Noel D, Pintér T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, González Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J; 303 Study Group. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2341-54. link to original article PubMed
6. Sjöström J, Blomqvist C, Mouridsen H, Pluzanska A, Ottosson-Lönn S, Bengtsson NO, Ostenstad B, Mjaaland I, Palm-Sjövall M, Wist E, Valvere V, Anderson H, Bergh J; Scandinavian Breast Group. Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: a randomised phase III study with crossover on progression by the Scandinavian Breast Group. Eur J Cancer. 1999 Aug;35(8):1194-201. link to original article contains dosing details in abstract PubMed
7. O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. link to original article contains dosing details in manuscript PubMed
   1. Update: Miles D, Vukelja S, Moiseyenko V, Cervantes G, Mauriac L, Van Hazel G, Liu WY, Ayoub JP, O'Shaughnessy JA. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Clin Breast Cancer. 2004 Oct;5(4):273-8. link to original article PubMed
8. Bonneterre J, Roché H, Monnier A, Guastalla JP, Namer M, Fargeot P, Assadourian S. Docetaxel vs 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure. Br J Cancer. 2002 Nov 18;87(11):1210-5. link to original article contains dosing details in abstract link to PMC article PubMed
9. TAX 311: Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, Laufman L, Sundaram S, Urba WJ, Pritchard KI, Mennel R, Richards D, Olsen S, Meyers ML, Ravdin PM. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005 Aug 20;23(24):5542-51. link to original article contains dosing details in abstract PubMed NCT00002662
10. TAX 313: Harvey V, Mouridsen H, Semiglazov V, Jakobsen E, Voznyi E, Robinson BA, Groult V, Murawsky M, Cold S. Phase III trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol. 2006 Nov 1;24(31):4963-70. Epub 2006 Oct 10. link to original article PubMed
11. Rivera E, Mejia JA, Arun BK, Adinin RB, Walters RS, Brewster A, Broglio KR, Yin G, Esmaeli B, Hortobagyi GN, Valero V. Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic breast cancer. Cancer. 2008 Apr 1;112(7):1455-61. link to original article contains dosing details in manuscript PubMed
12. Schröder CP, de Munck L, Westermann AM, Smit WM, Creemers GJ, de Graaf H, Stouthard JM, van Deijk G, Erjavec Z, van Bochove A, Vader W, Willemse PH. Weekly docetaxel in metastatic breast cancer patients: no superior benefits compared to three-weekly docetaxel. Eur J Cancer. 2011 Jun;47(9):1355-62. Epub 2011 Jan 19. link to original article PubMed
13. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
14. Nielsen DL, Bjerre KD, Jakobsen EH, Cold S, Stenbygaard L, Sørensen PG, Kamby C, Møller S, Jørgensen CL, Andersson M; Danish Breast Cancer Cooperative Group. Gemcitabine plus docetaxel versus docetaxel in patients with predominantly human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: a randomized, phase III study by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 2011 Dec 20;29(36):4748-54. Epub 2011 Nov 14. link to original article contains dosing details in abstract PubMed
15. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed
16. JO21095: Yamamoto D, Sato N, Rai Y, Yamamoto Y, Saito M, Iwata H, Masuda N, Oura S, Watanabe J, Hattori S, Matsuura Y, Kuroi K. Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. Breast Cancer Res Treat. 2017 Feb;161(3):473-482. Epub 2016 Dec 22. link to original article contains dosing details in manuscript PubMed
17. ATTAIN: Tripathy D, Tolaney SM, Seidman AD, Anders CK, Ibrahim N, Rugo HS, Twelves C, Diéras V, Müller V, Du Y, Currie SL, Hoch U, Tagliaferri M, Hannah AL, Cortés J; ATTAIN Investigators. Treatment With Etirinotecan Pegol for Patients With Metastatic Breast Cancer and Brain Metastases: Final Results From the Phase 3 ATTAIN Randomized Clinical Trial. JAMA Oncol. 2022 Jul 1;8(7):1047-1052. link to original article link to PMC article PubMed NCT02915744

Docetaxel & Bevacizumab

Regimen variant #1, docetaxel 60 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel	Superior PFS 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2)	2006-2008	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Gemcitabine 4. Paclitaxel 5. nab-Paclitaxel 6. Vinorelbine	Superior PFS 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)	1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel	Superior PFS 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2)	2006-2008	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Gemcitabine 4. Paclitaxel 5. nab-Paclitaxel 6. Vinorelbine	Superior PFS 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)	1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel	Superior PFS 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

1. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
2. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
   1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Docetaxel & Gemcitabine

DG: Docetaxel & Gemcitabine

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Tomova et al. 2010	NR in abstract	Phase 3 (C)	Docetaxel, then Gemcitabine	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 8 cycles

References

1. Tomova A, Bartsch R, Brodowicz T, Tzekova V, Timcheva C, Wiltschke C, Gerges DA, Pawlega J, Spanik S, Inbar M, Zielinski CC. Concomitant docetaxel plus gemcitabine versus sequential docetaxel followed by gemcitabine in anthracycline-pretreated metastatic or locally recurrent inoperable breast cancer patients: a prospective multicentre trial of the Central European Cooperative Oncology Group (CECOG). Breast Cancer Res Treat. 2010 Jan;119(1):169-76. link to original article contains dosing details in abstract PubMed

Doxorubicin monotherapy

Regimen variant #1, 20 mg/m² weekly

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab	Inferior PFS

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab	Inferior PFS

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Cowan et al. 1991 (SWOG S8203)	1983-1986	Phase 3 (E-switch-ic)	1. Bisantrene 2. Mitoxantrone	Seems to have superior OS
Norris et al. 2000 (NCIC-CTG MA.8)	1992-1995	Phase 3 (C)	NA	Did not meet primary endpoint of OS
Reyno et al. 2004 (NCIC CT MA.19)	1998-1999	Phase 3 (C)	Doxorubicin & Tesmilifene	Did not meet primary endpoint of PFS
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab	Inferior PFS

Note: in NCIC-CTG MA.8, this dose was after a mid-protocol amendment. Treatment in NCIC-CTG MA.8 & MA.19 was given until a cumulative dose of 450 mg/m². This is the lower end of the range of q3wk doxorubicin dosing described in TANIA.

Chemotherapy

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1

21-day cycles (see note)

Regimen variant #4, 75 mg/m² q3wk, limited duration

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Chan et al. 1999 (TAX 303)	1994-1997	Phase 3 (C)	Docetaxel	Inferior ORR

Chemotherapy

• Doxorubicin (Adriamycin) 75 mg/m² IV once on day 1

21-day cycle for up to 7 cycles

Regimen variant #5, 75 mg/m² q3wk, indefinite

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Bontenbal et al. 1998 (EORTC 10811)	1982-1986	Phase 3 (C)	Epirubicin	Did not meet primary endpoint of ORR
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab	Inferior PFS

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

21-day cycles

References

1. SWOG S8203: Cowan JD, Neidhart J, McClure S, Coltman CA Jr, Gumbart C, Martino S, Hutchins LF, Stephens RL, Vaughan CB, Osborne CK. Randomized trial of doxorubicin, bisantrene, and mitoxantrone in advanced breast cancer: a Southwest Oncology Group study. J Natl Cancer Inst. 1991 Aug 7;83(15):1077-84. link to original article contains dosing details in abstract PubMed
2. EORTC 10811: Bontenbal M, Andersson M, Wildiers J, Cocconi G, Jassem J, Paridaens R, Rotmensz N, Sylvester R, Mouridsen HT, Klijn JG, van Oosterom AT; EORTC Breast Cancer Cooperative Group. Doxorubicin vs epirubicin, report of a second-line randomized phase II/III study in advanced breast cancer. Br J Cancer. 1998 Jun;77(12):2257-63. link to original article link to PMC article contains dosing details in abstract PubMed
3. TAX 303: Chan S, Friedrichs K, Noel D, Pintér T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, González Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J; 303 Study Group. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2341-54. link to original article PubMed
4. NCIC-CTG MA.8: Norris B, Pritchard KI, James K, Myles J, Bennett K, Marlin S, Skillings J, Findlay B, Vandenberg T, Goss P, Latreille J, Rudinskas L, Lofters W, Trudeau M, Osoba D, Rodgers A. Phase III comparative study of vinorelbine combined with doxorubicin versus doxorubicin alone in disseminated metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group study MA8. J Clin Oncol. 2000 Jun;18(12):2385-94. link to original article contains dosing details in abstract PubMed
5. NCIC CT MA.19: Reyno L, Seymour L, Tu D, Dent S, Gelmon K, Walley B, Pluzanska A, Gorbunova V, Garin A, Jassem J, Pienkowski T, Dancey J, Pearce L, MacNeil M, Marlin S, Lebwohl D, Voi M, Pritchard K; National Cancer Institute of Canada Clinical Trials Group. Phase III study of N,N-diethyl-2-[4-(phenylmethyl) phenoxy]ethanamine (BMS-217380-01) combined with doxorubicin versus doxorubicin alone in metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group Study MA.19. J Clin Oncol. 2004 Jan 15;22(2):269-76. link to original article PubMed
6. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
   1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Doxorubicin & Bevacizumab

Regimen variant #1, doxorubicin 20 mg/m² weekly

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel	Superior PFS 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel	Superior PFS 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel	Superior PFS 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel	Superior PFS 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

1. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
   1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Eribulin monotherapy

Regimen variant #1

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Awaiting publication (TROPiCS-02)	2019-2024	Phase 3 (C)	Sacituzumab govitecan	Seems to have inferior OS	Faster deterioration of global QoL

Note: This dosing is the one commonly used in Europe. 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

• TROPiCS-02: HR+

Chemotherapy

• Eribulin (Halaven) 1.23 mg/m² IV once per day on days 1 & 8

21-day cycles

Regimen variant #2

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Cortes et al. 2011 (EMBRACE)	2006-2008	Phase 3 (E-RT-switch-ic)	Investigator's choice	Seems to have superior OS Median OS: 13.1 vs 10.6 mo (HR 0.81, 95% CI 0.66-0.99)
Kaufman et al. 2015 (E7389-G000-301)	2006-2009	Phase 3 (E-switch-ic)	Capecitabine	Seems to have superior OS Median OS: 15.9 vs 14.5 mo (HR 0.88, 95% CI 0.77-1.00)
Perez et al. 2015 (BEACONbrca)	2011-2013	Phase 3 (C)	Etirinotecan pegol	Might have inferior OS
Yuan et al. 2019 (E7389-C086-304)	2013-2015	Phase 3 (E-switch-ic)	Vinorelbine	Seems to have superior PFS Median PFS: 2.8 vs 2.8 mo (HR 0.80, 95% CI 0.65-0.98)
Tripathy et al. 2022 (ATTAIN)	2017-2019	Phase 3 (C)	Etirinotecan pegol	Did not meet primary endpoint of OS
Modi et al. 2022 (DESTINY-Breast04)	2018-2021	Phase 3 (C)	Trastuzumab deruxtecan	Inferior OS
Awaiting publication (TROPiCS-02)	2019-2024	Phase 3 (C)	Sacituzumab govitecan	Seems to have inferior OS	Faster deterioration of global QoL

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

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

Biomarker eligibility criteria

• DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative
• TROPiCS-02: HR+

Chemotherapy

• Eribulin (Halaven) 1.4 mg/m² IV over 2 to 5 minutes once per day on days 1 & 8

21-day cycles

References

1. EMBRACE: Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Diéras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389) investigators. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011 Mar 12;377(9769):914-23. Epub 2011 Mar 2. link to original article contains dosing details in abstract PubMed NCT00388726
2. E7389-G000-301: Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, Olivo MS, He Y, Dutcus CE, Cortes J. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015 Feb 20;33(6):594-601. Epub 2015 Jan 20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00337103
3. BEACON_brca: Perez EA, Awada A, O'Shaughnessy J, Rugo HS, Twelves C, Im SA, Gómez-Pardo P, Schwartzberg LS, Diéras V, Yardley DA, Potter DA, Mailliez A, Moreno-Aspitia A, Ahn JS, Zhao C, Hoch U, Tagliaferri M, Hannah AL, Cortes J. Etirinotecan pegol (NKTR-102) versus treatment of physician's choice in women with advanced breast cancer previously treated with an anthracycline, a taxane, and capecitabine (BEACON): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1556-1568. Epub 2015 Oct 22. link to original article PubMed NCT01492101
4. E7389-C086-304: Yuan P, Hu X, Sun T, Li W, Zhang Q, Cui S, Cheng Y, Ouyang Q, Wang X, Chen Z, Hiraiwa M, Saito K, Funasaka S, Xu B. Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial. Eur J Cancer. 2019 May;112:57-65. Epub 2019 Mar 29. link to original article contains dosing details in abstract PubMed NCT02225470
5. ATTAIN: Tripathy D, Tolaney SM, Seidman AD, Anders CK, Ibrahim N, Rugo HS, Twelves C, Diéras V, Müller V, Du Y, Currie SL, Hoch U, Tagliaferri M, Hannah AL, Cortés J; ATTAIN Investigators. Treatment With Etirinotecan Pegol for Patients With Metastatic Breast Cancer and Brain Metastases: Final Results From the Phase 3 ATTAIN Randomized Clinical Trial. JAMA Oncol. 2022 Jul 1;8(7):1047-1052. link to original article link to PMC article PubMed NCT02915744
6. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029
7. EVER-132-002: NCT04639986
8. TROPiCS-02: NCT03901339

Gemcitabine monotherapy

Regimen variant #1, 800 mg/m² 3 weeks out of 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Carmichael et al. 1995	NR	Phase 2
Modi et al. 2022 (DESTINY-Breast04)	2018-2021	Phase 3 (C)	Trastuzumab deruxtecan	Inferior OS
Awaiting publication (TROPiCS-02)	2019-2024	Phase 3 (C)	Sacituzumab govitecan	Seems to have inferior OS	Faster deterioration of global QoL

Note: this was the lower bound of dosing in DESTINY-Breast04 & TROPiCS-02.

Prior treatment criteria

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

Biomarker eligibility criteria

• DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative
• TROPiCS-02: HR+

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab	Inferior PFS

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Spielmann et al. 2001	NR	Phase 2
Modi et al. 2022 (DESTINY-Breast04)	2018-2021	Phase 3 (C)	Trastuzumab deruxtecan	Inferior OS
Awaiting publication (TROPiCS-02)	2019-2024	Phase 3 (C)	Sacituzumab govitecan	Seems to have inferior OS	Faster deterioration of global QoL

Note: this was the upper bound of dosing in DESTINY-Breast04 & TROPiCS-02.

Prior treatment criteria

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

Biomarker eligibility criteria

• DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative
• TROPiCS-02: HR+

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2)	2006-2008	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Gemcitabine & Bevacizumab 4. Paclitaxel & Bevacizumab 5. nab-Paclitaxel & Bevacizumab 6. Vinorelbine & Bevacizumab	Inferior PFS
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab	Inferior PFS

Chemotherapy

• Gemcitabine (Gemzar) 1250 mg/m² IV over 30 minutes once per day on days 1 & 8

21-day cycles

References

1. Carmichael J, Possinger K, Phillip P, Beykirch M, Kerr H, Walling J, Harris AL. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol. 1995 Nov;13(11):2731-6. link to original article contains dosing details in abstract PubMed
2. Spielmann M, Llombart-Cussac A, Kalla S, Espié M, Namer M, Ferrero JM, Diéras V, Fumoleau P, Cuvier C, Perrocheau G, Ponzio A, Kayitalire L, Pouillart P. Single-agent gemcitabine is active in previously treated metastatic breast cancer. Oncology. 2001;60(4):303-7. link to original article PubMed
3. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
4. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
   1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed
5. ATTAIN: Tripathy D, Tolaney SM, Seidman AD, Anders CK, Ibrahim N, Rugo HS, Twelves C, Diéras V, Müller V, Du Y, Currie SL, Hoch U, Tagliaferri M, Hannah AL, Cortés J; ATTAIN Investigators. Treatment With Etirinotecan Pegol for Patients With Metastatic Breast Cancer and Brain Metastases: Final Results From the Phase 3 ATTAIN Randomized Clinical Trial. JAMA Oncol. 2022 Jul 1;8(7):1047-1052. link to original article link to PMC article PubMed NCT02915744
6. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029
7. EVER-132-002: NCT04639986
8. TROPiCS-02: NCT03901339

Gemcitabine & Bevacizumab

Regimen variant #1, 1000 mg/m², 3 weeks out of 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel	Superior PFS 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2)	2006-2008	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Gemcitabine 4. Paclitaxel 5. nab-Paclitaxel 6. Vinorelbine	Superior PFS 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)	1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel	Superior PFS 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

1. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
2. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
   1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Ixabepilone monotherapy

Regimen

Study	Years of enrollment	Evidence
Perez et al. 2007	2004-2005	Phase 2 (RT)

Chemotherapy

• Ixabepilone (Ixempra) 40 mg/m² IV over 3 hours once on day 1

21-day cycles

References

1. 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 PubMed
2. ATTAIN: Tripathy D, Tolaney SM, Seidman AD, Anders CK, Ibrahim N, Rugo HS, Twelves C, Diéras V, Müller V, Du Y, Currie SL, Hoch U, Tagliaferri M, Hannah AL, Cortés J; ATTAIN Investigators. Treatment With Etirinotecan Pegol for Patients With Metastatic Breast Cancer and Brain Metastases: Final Results From the Phase 3 ATTAIN Randomized Clinical Trial. JAMA Oncol. 2022 Jul 1;8(7):1047-1052. link to original article link to PMC article PubMed NCT02915744

Non-pegylated liposomal doxorubicin monotherapy

NPLD: Non-Pegylated Liposomal Doxorubicin

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab	Inferior PFS

Chemotherapy

• Non-pegylated liposomal doxorubicin (Myocet) 60 mg/m² IV once on day 1

21-day cycles

References

1. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
   1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Non-pegylated liposomal doxorubicin & Bevacizumab

NPLD & Bev: Non-Pegylated Liposomal Doxorubicin & Bevacizumab

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel	Superior PFS 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

1. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
   1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Paclitaxel monotherapy, weekly

Regimen variant #1, 80 mg/m² weekly

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Perez et al. 2001	NR	Phase 2
Seidman et al. 2008 (CALGB 9840)	1998-NR	Phase 3 (E-switch-ic)	Paclitaxel; q3wk	Superior OS Median OS: 24 vs 12 mo (HR 0.78, 95% CI 0.65-0.94)
Modi et al. 2022 (DESTINY-Breast04)	2018-2021	Phase 3 (C)	Trastuzumab deruxtecan	Inferior OS

Prior treatment criteria

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

Biomarker eligibility criteria

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

Chemotherapy

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15, 22

28-day cycles

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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2)	2006-2008	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Gemcitabine & Bevacizumab 4. Paclitaxel & Bevacizumab 5. nab-Paclitaxel & Bevacizumab 6. Vinorelbine & Bevacizumab	Inferior PFS

Chemotherapy

• Paclitaxel (Taxol) 90 mg/m² IV once per day on days 1, 8, 15

28-day cycles

References

1. Perez EA, Vogel CL, Irwin DH, Kirshner JJ, Patel R. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2001 Nov 15;19(22):4216-23. link to original article PubMed
2. CALGB 9840: Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. link to original article PubMed NCT00003440
3. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
4. ATTAIN: Tripathy D, Tolaney SM, Seidman AD, Anders CK, Ibrahim N, Rugo HS, Twelves C, Diéras V, Müller V, Du Y, Currie SL, Hoch U, Tagliaferri M, Hannah AL, Cortés J; ATTAIN Investigators. Treatment With Etirinotecan Pegol for Patients With Metastatic Breast Cancer and Brain Metastases: Final Results From the Phase 3 ATTAIN Randomized Clinical Trial. JAMA Oncol. 2022 Jul 1;8(7):1047-1052. link to original article link to PMC article PubMed NCT02915744
5. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029

Paclitaxel monotherapy, q3wk

Regimen variant #1, 135 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Nabholtz et al. 1996	1992	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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Seidman et al. 1995	NR	Phase 2
Nabholtz et al. 1996	1992	Phase 3 (E-RT-esc)	Paclitaxel; 135 mg/m2 q3wk	Did not meet primary endpoint of ORR1
Winer et al. 2004 (CALGB 9342)	1994-1997	Phase 3 (C)	1. Paclitaxel; 210 mg/m2 q3wk 2. Paclitaxel; 250 mg/m2 q3wk	Did not meet primary endpoint of ORR
Jones et al. 2005 (TAX 311)	1994-2001	Phase 3 (E-switch-ic)	Docetaxel	Inferior OS
Icli et al. 2005	1997-2002	Phase 3 (C)	EoP	Seems to have inferior OS
Seidman et al. 2008 (CALGB 9840)	1998-NR	Phase 3 (C)	Paclitaxel; weekly	Inferior OS
Gradishar et al. 2005 (CA012-0)	2001-2002	Phase 3 (C)	nab-Paclitaxel	Inferior TTP
Brufsky et al. 2011 (RIBBON-2)	2006-2008	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Gemcitabine & Bevacizumab 4. Paclitaxel & Bevacizumab 5. nab-Paclitaxel & Bevacizumab 6. Vinorelbine & Bevacizumab	Inferior PFS
Modi et al. 2022 (DESTINY-Breast04)	2018-2021	Phase 3 (C)	Trastuzumab deruxtecan	Inferior OS

¹Although Nabholtz et al. 1996 did not meet its primary endpoint, there seemed to be a TTP advantage in the higher-dose arm, which subsequently led to its adoption as the standard-of-care.

Prior treatment criteria

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

Biomarker eligibility criteria

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

Chemotherapy

• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

21-day cycles

References

1. Seidman AD, Tiersten A, Hudis C, Gollub M, Barrett S, Yao TJ, Lepore J, Gilewski T, Currie V, Crown J, Hakes T, Baselga J, Sklarin N, Moynihan ME, Tong W, Egorin M, Kearns C, Spriggs D, Norton L. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2575-81. link to original article PubMed
2. Nabholtz JM, Gelmon K, Bontenbal M, Spielmann M, Catimel G, Conte P, Klaassen U, Namer M, Bonneterre J, Fumoleau P, Winograd B. Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol. 1996 Jun;14(6):1858-67. link to original article contains dosing details in abstract PubMed
3. CALGB 9342: Winer EP, Berry DA, Woolf S, Duggan D, Kornblith A, Harris LN, Michaelson RA, Kirshner JA, Fleming GF, Perry MC, Graham ML, Sharp SA, Keresztes R, Henderson IC, Hudis C, Muss H, Norton L. Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: Cancer and Leukemia Group B trial 9342. J Clin Oncol. 2004 Jun 1;22(11):2061-8. link to original article contains dosing details in abstract PubMed
4. Icli F, Akbulut H, Uner A, Yalcin B, Baltali E, Altinbas M, Coşkun S, Komurcu S, Erkisi M, Demirkazik A, Senler FC, Sencan O, Büyükcelik A, Boruban C, Onur H, Zengin N, Sak SD; Turkish Oncology Group. Cisplatin plus oral etoposide (EoP) combination is more effective than paclitaxel in patients with advanced breast cancer pretreated with anthracyclines: a randomised phase III trial of Turkish Oncology Group. Br J Cancer. 2005 Feb 28;92(4):639-44. link to original article link to PMC article contains dosing details in abstract PubMed
5. TAX 311: Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, Laufman L, Sundaram S, Urba WJ, Pritchard KI, Mennel R, Richards D, Olsen S, Meyers ML, Ravdin PM. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005 Aug 20;23(24):5542-51. link to original article contains dosing details in abstract PubMed NCT00002662
6. CA012-0: Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. link to original article contains dosing details in manuscript PubMed NCT00046527
7. CALGB 9840: Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. link to original article PubMed NCT00003440
8. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
9. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029

Paclitaxel & Bevacizumab

Regimen variant #1, 90 mg/m² 3 weeks out of 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2)	2006-2008	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Gemcitabine 4. Paclitaxel; weekly 5. nab-Paclitaxel 6. Vinorelbine	Superior PFS 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2)	2006-2008	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Gemcitabine 4. Paclitaxel; weekly 5. nab-Paclitaxel 6. Vinorelbine	Superior PFS 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

1. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697

nab-Paclitaxel monotherapy

Example orders

• Example orders for Paclitaxel, nanoparticle albumin-bound (Abraxane) in breast cancer

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

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab	Inferior PFS
Modi et al. 2022 (DESTINY-Breast04)	2018-2021	Phase 3 (C)	Trastuzumab deruxtecan	Inferior OS

Note: the details of this regimen are unclear in von Minckwitz et al. 2014.

Prior treatment criteria

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

Biomarker eligibility criteria

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

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #2, 125 mg/m², 3 weeks out of 4

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Modi et al. 2022 (DESTINY-Breast04)	2018-2021	Phase 3 (C)	Trastuzumab deruxtecan	Inferior OS

Prior treatment criteria

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

Biomarker eligibility criteria

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

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m² IV once per day on days 1, 8, 15

28-day cycles

Regimen variant #3, 260 mg/m² q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Gradishar et al. 2005 (CA012-0)	2001-2002	Phase 3 (E-RT-switch-ic)	Paclitaxel	Superior TTP Median TTP: 23 vs 16.9 weeks (HR 0.75)
Brufsky et al. 2011 (RIBBON-2)	2006-2008	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Gemcitabine & Bevacizumab 4. Paclitaxel & Bevacizumab 5. nab-Paclitaxel & Bevacizumab 6. Vinorelbine & Bevacizumab	Inferior PFS
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab	Inferior PFS
Modi et al. 2022 (DESTINY-Breast04)	2018-2021	Phase 3 (C)	Trastuzumab deruxtecan	Inferior OS

Prior treatment criteria

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

Biomarker eligibility criteria

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

Chemotherapy

• 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	Years of enrollment	Evidence
Ibrahim et al. 2005	1999-2001	Phase 2 (RT)

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 300 mg/m² IV over 30 minutes once on day 1

21-day cycles

References

1. Ibrahim NK, Samuels B, Page R, Doval D, Patel KM, Rao SC, Nair MK, Bhar P, Desai N, Hortobagyi GN. Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer. J Clin Oncol. 2005 Sep 1;23(25):6019-26. link to original article contains dosing details in abstract PubMed
2. CA012-0: Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. link to original article contains dosing details in manuscript PubMed NCT00046527
3. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
4. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
   1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed
5. ATTAIN: Tripathy D, Tolaney SM, Seidman AD, Anders CK, Ibrahim N, Rugo HS, Twelves C, Diéras V, Müller V, Du Y, Currie SL, Hoch U, Tagliaferri M, Hannah AL, Cortés J; ATTAIN Investigators. Treatment With Etirinotecan Pegol for Patients With Metastatic Breast Cancer and Brain Metastases: Final Results From the Phase 3 ATTAIN Randomized Clinical Trial. JAMA Oncol. 2022 Jul 1;8(7):1047-1052. link to original article link to PMC article PubMed NCT02915744
6. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029

Paclitaxel, nanoparticle albumin-bound & Bevacizumab

Example orders

• Example orders for Paclitaxel, nanoparticle albumin-bound & Bevacizumab in breast cancer

Regimen variant #1, 100 mg/m² weekly

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel	Superior PFS 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2)	2006-2008	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Gemcitabine 4. Paclitaxel; weekly 5. nab-Paclitaxel 6. Vinorelbine	Superior PFS 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)	1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel	Superior PFS 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

1. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
2. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
   1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Pegylated liposomal doxorubicin monotherapy

PLD: Pegylated Liposomal Doxorubicin

Regimen variant #1, 40 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab	Inferior PFS

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Keller et al. 2004	NR	Phase 3 (E-switch-ic)	1. Mitomycin & Vinblastine 2. Vinorelbine	Did not meet primary endpoint of PFS
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab	Inferior PFS

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

28-day cycles

References

1. Keller AM, Mennel RG, Georgoulias VA, Nabholtz JM, Erazo A, Lluch A, Vogel CL, Kaufmann M, von Minckwitz G, Henderson IC, Mellars L, Alland L, Tendler C. Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol. 2004 Oct 1;22(19):3893-901. link to original article contains dosing details in abstract PubMed
2. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
   1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Pegylated liposomal doxorubicin & Bevacizumab

PLD & Bev: Pegylated Liposomal Doxorubicin & Bevacizumab

Regimen variant #1, 40 mg/m²

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel	Superior PFS 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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
von Minckwitz et al. 2014 (TANIA)	2011-2013	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel	Superior PFS 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

1. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
   1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Trastuzumab deruxtecan monotherapy

Regimen

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Modi et al. 2022 (DESTINY-Breast04)	2018-2021	Phase 3 (E-switch-ooc)	Physician's choice of: 1. Capecitabine 2. Eribulin 3. Gemcitabine 4. Paclitaxel; weekly 5. Paclitaxel; q3wk 6. nab-Paclitaxel	Superior OS Median OS: 23.9 vs 17.5 mo (HR 0.64, 95% CI 0.48-0.86)	Higher rate of pneumonitis

Note: eribulin was the most commonly used comparator regimen.

Prior treatment criteria

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

Biomarker eligibility criteria

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

Antibody-drug conjugate therapy

• Trastuzumab deruxtecan (Enhertu) 5.4 mg/kg IV once on day 1

21-day cycles

References

1. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029

Vinorelbine monotherapy

Regimen variant #1, 25 mg/m² weekly

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy	Comparative Toxicity
Gasparini et al. 1994	1991-1993	Phase 2
Zelek et al. 2001	1997-1999	Phase 2
Decker et al. 2019 (VicTORia)	2011-2016	Randomized Phase 2 (C)	Everolimus & Vinorelbine	Did not meet primary endpoint of PFS
Yuan et al. 2019 (E7389-C086-304)	2013-2015	Phase 3 (C)	Eribulin	Seems to have inferior PFS
Awaiting publication (TROPiCS-02)	2019-2024	Phase 3 (C)	Sacituzumab govitecan	Seems to have inferior OS	Faster deterioration of global QoL

Biomarker eligibility criteria

• TROPiCS-02: HR+

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1, 8, 15

21-day cycles

Regimen variant #2, 30 mg/m² weekly

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Jones et al. 1995a	1990-1992	Phase 3 (E-switch-ic)	Melphalan	Seems to have superior OS
Keller et al. 2004	NR	Phase 3 (C)	1. Mitomycin & Vinblastine 2. PLD	Did not meet primary endpoint of PFS

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1, 8, 15

21-day cycles

Regimen variant #3, 30 mg/m² q3wk

Study	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2)	2006-2008	Phase 3 (C)	1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Gemcitabine & Bevacizumab 4. Paclitaxel & Bevacizumab 5. nab-Paclitaxel & Bevacizumab 6. Vinorelbine & Bevacizumab	Inferior PFS

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Martín et al. 2007 (GEICAM 2000-04)	2001-2005	Phase 3 (C)	Gemcitabine & Vinorelbine	Inferior PFS

Chemotherapy

• Vinorelbine (Navelbine) 30 mg/m² IV once per day on days 1 & 8

21-day cycles

References

1. Gasparini G, Caffo O, Barni S, Frontini L, Testolin A, Guglielmi RB, Ambrosini G. Vinorelbine is an active antiproliferative agent in pretreated advanced breast cancer patients: a phase II study. J Clin Oncol. 1994 Oct;12(10):2094-101. link to original article PubMed
2. Jones S, Winer E, Vogel C, Laufman L, Hutchins L, O'Rourke M, Lembersky B, Budman D, Bigley J, Hohneker J. Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. J Clin Oncol. 1995 Oct;13(10):2567-74. link to original article contains dosing details in abstract PubMed
3. Zelek L, Barthier S, Riofrio M, Fizazi K, Rixe O, Delord JP, Le Cesne A, Spielmann M. Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer. 2001 Nov 1;92(9):2267-72. link to original article PubMed
4. Keller AM, Mennel RG, Georgoulias VA, Nabholtz JM, Erazo A, Lluch A, Vogel CL, Kaufmann M, von Minckwitz G, Henderson IC, Mellars L, Alland L, Tendler C. Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol. 2004 Oct 1;22(19):3893-901. link to original article contains dosing details in abstract PubMed
5. GEICAM 2000-04: Martín M, Ruiz A, Muñoz M, Balil A, García-Mata J, Calvo L, Carrasco E, Mahillo E, Casado A, García-Saenz JA, Escudero MJ, Guillem V, Jara C, Ribelles N, Salas F, Soto C, Morales-Vasquez F, Rodríguez CA, Adrover E, Mel JR; GEICAM. Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. Lancet Oncol. 2007 Mar;8(3):219-25. link to original article contains dosing details in abstract PubMed NCT00128310
6. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
7. E7389-C086-304: Yuan P, Hu X, Sun T, Li W, Zhang Q, Cui S, Cheng Y, Ouyang Q, Wang X, Chen Z, Hiraiwa M, Saito K, Funasaka S, Xu B. Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial. Eur J Cancer. 2019 May;112:57-65. Epub 2019 Mar 29. link to original article contains dosing details in abstract PubMed NCT02225470
8. VicTORia: Decker T, Marschner N, Muendlein A, Welt A, Hagen V, Rauh J, Schröder H, Jaehnig P, Potthoff K, Lerchenmüller C. VicTORia: a randomised phase II study to compare vinorelbine in combination with the mTOR inhibitor everolimus versus vinorelbine monotherapy for second-line chemotherapy in advanced HER2-negative breast cancer. Breast Cancer Res Treat. 2019 Aug;176(3):637-647. Epub 2019 May 21. link to original article contains dosing details in manuscript PubMed NCT01520103
9. ATTAIN: Tripathy D, Tolaney SM, Seidman AD, Anders CK, Ibrahim N, Rugo HS, Twelves C, Diéras V, Müller V, Du Y, Currie SL, Hoch U, Tagliaferri M, Hannah AL, Cortés J; ATTAIN Investigators. Treatment With Etirinotecan Pegol for Patients With Metastatic Breast Cancer and Brain Metastases: Final Results From the Phase 3 ATTAIN Randomized Clinical Trial. JAMA Oncol. 2022 Jul 1;8(7):1047-1052. link to original article link to PMC article PubMed NCT02915744
10. EVER-132-002: NCT04639986
11. TROPiCS-02: NCT03901339

Vinorelbine & Bevacizumab

Example orders

• Example orders for Vinorelbine and Bevacizumab in breast cancer

Regimen variant #1, vinorelbine 25 mg/m² weekly

Study	Years of enrollment	Evidence
Burstein et al. 2008	2001-2002	Phase 2

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	Years of enrollment	Evidence	Comparator	Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2)	2006-2008	Phase 3 (E-esc)	1. Capecitabine 2. Docetaxel 3. Gemcitabine 4. Paclitaxel; weekly 5. nab-Paclitaxel 6. Vinorelbine	Superior PFS 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

1. Burstein HJ, Chen YH, Parker LM, Savoie J, Younger J, Kuter I, Ryan PD, Garber JE, Chen H, Campos SM, Shulman LN, Harris LN, Gelman R, Winer EP. VEGF as a marker for outcome among advanced breast cancer patients receiving anti-VEGF therapy with bevacizumab and vinorelbine chemotherapy. Clin Cancer Res. 2008 Dec 1;14(23):7871-7. link to original article contains dosing details in manuscript PubMed
2. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697

Additional resources

• Gail model Breast Cancer Risk Assessment Tool
  • Gail model breast cancer risk factors
• Breast cancer BRCA1 & BRCA2 genetic testing
• Adjuvant! Online (requires login)
• My Cancer Genome
• PREDICT

Patient information

• Alcohol and risk of breast cancer infographic