Breast cancer

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

144 regimens on this page
333 variants on this page


Guidelines

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

ASCO/CCO

ESMO/ESO

EUSOMA/SIOG

KSMO/ESMO

NCCN

SITC

St Gallen Breast Guidelines

Neoadjuvant therapy, sequential regimens

AC-D

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

Regimen variant #1, 60/600/75

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

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 8)

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

Subsequent treatment


Regimen variant #2, 60/600/100

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

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

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 8)

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

Subsequent treatment

References

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

AC-T

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

Regimen

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

Chemotherapy, AC portion (cycles 1 to 5)

Chemotherapy, T portion (cycles 6 to 17)

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

Subsequent treatment

References

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

D-AC

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

Regimen

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

Chemotherapy, D portion (cycles 1 to 4)

Chemotherapy, AC portion (cycles 5 to 8)

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

Subsequent treatment

References

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

D-AC+Bev

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

Regimen

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

Chemotherapy, D portion (cycles 1 to 4)

Chemotherapy, AC portion (cycles 5 to 8)

Targeted therapy, both portions

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

Subsequent treatment

References

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

D-FEC

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

Regimen

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

Chemotherapy, D portion (cycles 1 to 3)

Chemotherapy, FEC portion (cycles 4 to 6)

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

Subsequent treatment

References

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

D-FEC+Bev

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

Regimen

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

Chemotherapy, D portion (cycles 1 to 3)

Chemotherapy, FEC portion (cycles 4 to 6)

Targeted therapy, both portions

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

Subsequent treatment

References

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

EC-D

EC-D: Epirubicin and Cyclophosphamide followed by Docetaxel

Regimen

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

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 8)

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

Subsequent treatment

References

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

EC-T

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

Regimen

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

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, T portion (cycles 5 to 8)

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

Subsequent treatment

References

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

EC-ddT

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

Regimen

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

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, ddT portion (cycles 5 to 8)

Supportive therapy, T portion

  • Primary G-CSF propyhylaxis not provided

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

Subsequent treatment

References

  1. Neo-tAnGo: Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, Iddawela M, Abraham J, Hughes-Davies L, Gounaris I, McAdam K, Houston S, Hickish T, Skene A, Chan S, Dean S, Ritchie D, Laing R, Harries M, Gallagher C, Wishart G, Dunn J, Provenzano E, Caldas C; Neo-tAnGo Investigators. Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 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

FEC-D

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

Regimen

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

Chemotherapy, FEC portion (cycles 1 to 3)

Chemotherapy, D portion (cycles 4 to 6)

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

Subsequent treatment

References

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

nP-EC

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

Regimen

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

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

Chemotherapy, nP portion (cycles 1 to 12)

Chemotherapy, EC portion (cycles 13 to 16)

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

Subsequent treatment

References

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

nP-ddEC

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

Regimen

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

Biomarker eligibility criteria

  • HR+ and HER2-

Chemotherapy, nP portion (cycles 1 to 8)

Chemotherapy, ddEC portion (cycles 9 to 12)

Supportive therapy, ddEC portion (cycles 9 to 12)

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

Subsequent treatment

References

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

T-AC

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

Regimen

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

Chemotherapy, T portion (cycles 1 to 4)

Chemotherapy, AC portion (cycles 5 to 8)

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

Subsequent treatment

References

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

T-EC

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

Regimen variant #1, 80 mg/m2 paclitaxel

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

Chemotherapy, T portion (cycles 1 to 12)

Chemotherapy, EC portion (cycles 13 to 16)

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

Subsequent treatment


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

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

Chemotherapy, T portion (cycles 1 to 4)

Chemotherapy, EC portion (cycles 5 to 8)

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

Subsequent treatment

References

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

ddT-EC

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

Regimen

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

Chemotherapy, ddT portion (cycles 1 to 4)

Supportive therapy, T portion

  • Primary G-CSF propyhylaxis not provided

Chemotherapy, EC portion (cycles 5 to 8)

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

Subsequent treatment

References

  1. Neo-tAnGo: Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, Iddawela M, Abraham J, Hughes-Davies L, Gounaris I, McAdam K, Houston S, Hickish T, Skene A, Chan S, Dean S, Ritchie D, Laing R, Harries M, Gallagher C, Wishart G, Dunn J, Provenzano E, Caldas C; Neo-tAnGo Investigators. Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 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

ddT-ddEC

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

Regimen

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

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

Biomarker eligibility criteria

  • HR+ and HER2-

Chemotherapy, ddT portion (cycles 1 to 4)

Chemotherapy, ddEC portion (cycles 5 to 8)

Supportive therapy, ddEC portion (cycles 5 to 8)

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

Subsequent treatment

References

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

T-FAC

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

Regimen variant #1, weekly paclitaxel for N0 disease

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

Chemotherapy, T portion (cycles 1 to 12)

Chemotherapy, FAC portion (cycles 13 to 16)

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

Subsequent treatment


Regimen variant #2, weekly paclitaxel for N+ disease

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

Chemotherapy, T portion (cycles 1 to 4)

Chemotherapy, FAC portion (cycles 5 to 8)

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

Subsequent treatment


Regimen variant #3, q3wk paclitaxel

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

Chemotherapy, T portion (cycles 1 to 4)

Chemotherapy, FAC portion (cycles 5 to 8)

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

Subsequent treatment

References

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

T-FEC

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

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

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

Chemotherapy, T portion (cycles 1 to 12)

Chemotherapy, FEC portion (cycles 13 to 16)

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

Subsequent treatment


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

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

Chemotherapy, T portion (cycles 1 to 4)

Chemotherapy, FEC portion (cycles 5 to 8)

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

Subsequent treatment

References

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

Neoadjuvant chemotherapy

Capecitabine & Docetaxel (TX)

TX: Taxotere (Docetaxel) & Xeloda (Capecitabine)

Regimen

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

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

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

Cyclophosphamide & Doxorubicin (AC)

AC: Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen variant #1, 4 cycles

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

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #2, 6 cycles

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

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment

References

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

Dose-dense Cyclophosphamide & Doxorubicin (ddAC)

ddAC: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide

Regimen

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

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

Chemotherapy

Supportive therapy

14-day cycle for 4 cycles

Subsequent treatment

References

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

Dose-dense Docetaxel & Doxorubicin (ddAT)

Regimen

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

Chemotherapy

Supportive therapy

14-day cycle for 4 cycles

References

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

DI EC

DI EC: Dose-Intense Epirubicin & Cyclophosphamide

Regimen

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

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

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

References

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

Docetaxel & Epirubicin (DE)

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

Regimen variant #1, 3 cycles

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

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment


Regimen variant #2, 4 cycles

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

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #3, 6 cycles

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

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment

References

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

EDC

EDC: Epirubicin, Docetaxel, Capecitabine

Regimen

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

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment

References

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

Epirubicin monotherapy

E: Epirubicin

Regimen

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

Chemotherapy

21-day cycle for 3 to 4 cycles

Subsequent treatment

References

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

Epirubicin & Paclitaxel (EP)

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

Regimen

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

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

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

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

References

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

FAC

FAC: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide

Regimen variant #1, 500/50/500

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

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #2, 600/50/600

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

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment


Regimen variant #3, 1000/50/500

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

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

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #4, 2000/50/100

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

Chemotherapy

28-day cycle for 4 cycles

Subsequent treatment

References

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

FEC

FEC: Fluorouracil, Epirubicin, Cyclophosphamide

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

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

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

Chemotherapy

21-day cycle for 3 cycles

Subsequent treatment


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

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

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment


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

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

Chemotherapy

28-day cycle for 6 cycles

Subsequent treatment

References

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

iddEPC

iddEPC: intense dose-dense Epirubicin, Paclitaxel, Cyclophosphamide

Regimen

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

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

Chemotherapy, iddE portion (cycles 1 to 3)

Chemotherapy, iddP portion (cycles 4 to 6)

Chemotherapy, iddC portion (cycles 7 to 9)

Supportive therapy, all portions (cycles 1 to 9)

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

Subsequent treatment

References

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

Paclitaxel monotherapy, dose-dense (q2wk)

ddT: dose-dense Taxol (Paclitaxel)

Regimen

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

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

Preceding treatment

  • Neoadjuvant ddAC x 4

Chemotherapy

Supportive therapy

14-day cycle for 4 cycles

Subsequent treatment

References

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

PET

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

Regimen

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

Chemotherapy

7-day cycle for 12 cycles

Subsequent treatment

References

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

TAC (Docetaxel)

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

Regimen

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

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment

References

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

Neoadjuvant response criteria

Clinical response rate (cRR)

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

References

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

Miller-Payne scoring system

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

References

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

Residual cancer burden (RCB)

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

References

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

Residual disease in breast and nodes (RDBN)

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

References

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

Sataloff's classification

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

References

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

Tumor response ratio

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

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

References

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

ypTNM staging

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

Adjuvant therapy, sequential regimens

A-CMF

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

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

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

Preceding treatment

Chemotherapy, A portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 8)

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


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

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

Preceding treatment

Chemotherapy, A portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 12)

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


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

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

Preceding treatment

Chemotherapy, A portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 12)

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


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

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

Preceding treatment

Chemotherapy, A portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 8)

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

References

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

ddA-ddT-ddC

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

Regimen variant #1, 60/175/600

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

Preceding treatment

Chemotherapy, ddA portion (cycles 1 to 4)

Chemotherapy, ddT portion (cycles 5 to 8)

Supportive therapy, ddT portion (cycles 5 to 8)

Chemotherapy, ddC portion (cycles 9 to 12)

Supportive therapy, all portions (cycles 1 to 12)

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

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


Regimen variant #2, 60/200/800

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

Preceding treatment

Chemotherapy, ddA portion (cycles 1 to 4)

Chemotherapy, ddT portion (cycles 5 to 8)

Chemotherapy, ddC portion (cycles 9 to 12)

Supportive therapy, all portions (cycles 1 to 12)

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

References

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

AC-CMF

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

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Colleoni et al. 2006 (IBCSG 13-93) 1993-1999 Non-randomized part of phase 3 RCT
Basser et al. 2006 (IBCSG 15-95) 1995-2000 Phase 3 (C) 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

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 7)

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

Subsequent treatment

References

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

AC-D

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

Regimen variant #1, q3wk docetaxel 75 mg/m2

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

Preceding treatment

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 8)

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


Regimen variant #2, q3wk docetaxel 100 mg/m2

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

Preceding treatment

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 8)

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


Regimen variant #3, weekly docetaxel

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

Preceding treatment

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 16)

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

References

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

AC-T

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

Regimen variant #1, weekly paclitaxel

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

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

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, T portion (cycles 5 to 16)

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


Regimen variant #2, q3wk paclitaxel 175 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Henderson et al. 2003 (INT 0148/CALGB 9344) 1994-1999 Phase 3 (E-RT-esc) 1. AC; standard-dose
2. AC; high-dose
3. AC; very high-dose 		Superior OS (secondary endpoint)
4. AC-T; high-dose AC
5. AC-T; very high-dose AC 		Did not meet primary endpoint of DFS
Citron et al. 2003 (CALGB 9741) 1997-1999 Phase 3 (C) 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) 1. ddEC-T
2. CEF 		Inferior RFS
Watanabe et al. 2017 (NSAS BC-02) 2001-2006 Phase 3 (C) 1. AC-D
2. Docetaxel x 8 		Seems to have inferior OS (secondary endpoint)
3. Paclitaxel x 8 Inconclusive whether non-inferior DFS (primary endpoint)
Sparano et al. 2018 (TAILORx) 2006-2010 Phase 3 (C) No chemotherapy Non-inferior IDFS (primary endpoint)

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, T portion (cycles 5 to 8)

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


Regimen variant #3, q3wk paclitaxel 225 mg/m2

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

Preceding treatment

Chemotherapy, AC portion (cycles 1 to 4)

Chemotherapy, T portion (cycles 5 to 8)

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

References

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

ddAC-T

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

Regimen

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

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

Biomarker eligibility criteria

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

Preceding treatment

Chemotherapy, ddAC portion (cycles 1 to 4)

Supportive therapy, ddAC portion (cycles 1 to 4)

Chemotherapy, T portion (cycles 5 to 16)

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

References

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

ddAC-ddT

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

Regimen variant #1, 4x4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Citron et al. 2003 (CALGB 9741) 1997-1999 Phase 3 (E-esc) See link See link
Swain et al. 2013 (NSABP B-38) 2004-2007 Phase 3 (C) 1. TAC x 6 Did not meet primary endpoint of DFS
2. ddAC-ddPG Did not meet primary endpoint of DFS
Sparano et al. 2018 (TAILORx) 2006-2010 Phase 3 (C) No chemotherapy Non-inferior IDFS (primary endpoint)

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy, ddAC portion (cycles 1 to 4)

Supportive therapy, ddAC portion (cycles 1 to 4)

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

Chemotherapy, ddT portion (cycles 5 to 8)

Supportive therapy, ddT portion (cycles 5 to 8)

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

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


Regimen variant #2, 6x6

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

Preceding treatment

Chemotherapy, ddAC portion (cycles 1 to 6)

Chemotherapy, ddT portion (cycles 7 to 12)

Supportive therapy, all portions (cycles 1 to 12)

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

References

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

AT-CMF

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

Regimen

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

Preceding treatment

Chemotherapy, AT portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 8)

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

References

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

CMF-E

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

Regimen

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

1Reported efficacy is based on the 2011 update.

Preceding treatment

Chemotherapy, CMF portion (cycles 1 to 6)

Chemotherapy, E portion (cycles 7 to 10)

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

References

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

D-EC

D-EC: Docetaxel followed by Epirubicin and Cyclophosphamide

Regimen

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

Preceding treatment

Chemotherapy, D portion (cycles 1 to 4)

Chemotherapy, EC portion (cycles 5 to 8)

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

References

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

D-FEC

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

Regimen variant #1

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

1Reported efficacy is based on the 2022 update.

Preceding treatment

Chemotherapy, D portion (cycles 1 to 3)

Chemotherapy, FEC portion (cycles 4 to 6)

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


Regimen variant #2

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

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

Preceding treatment

Chemotherapy, D portion (cycles 1 to 3)

Chemotherapy, FEC portion (cycles 4 to 6)

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

References

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

E-CMF

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

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

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

1Reported efficacy is based on the 2012 update.

Preceding treatment

Chemotherapy, E portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 8)

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


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

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

1Reported efficacy is based on the 2012 update.

Preceding treatment

Chemotherapy, E portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 8)

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


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

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

1Reported efficacy is based on the 2012 update.

Preceding treatment

Chemotherapy, E portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 8)

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

References

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

ddE-iddCMF

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

Regimen

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

Preceding treatment

Chemotherapy, ddE portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 7)

Supportive therapy, all portions (cycles 1 to 7)

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

References

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

E-D

E-D: Epirubicin followed by Docetaxel

Regimen variant #1

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

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

Preceding treatment

Chemotherapy, E portion (cycles 1 to 3)

Chemotherapy, D portion (cycles 4 to 6)

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


Regimen variant #2

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

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

Preceding treatment

Chemotherapy, E portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 8)

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

References

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

E-X

E-X: Epirubicin followed by Xeloda (Capecitabine)

Regimen

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

Preceding treatment

Chemotherapy, E portion (cycles 1 to 4)

Chemotherapy, X portion (cycles 5 to 8)

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

References

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

EC-CMF

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

Regimen variant #1

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

1Reported efficacy is based on the 2009 update.

Preceding treatment

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 7)

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

Subsequent treatment


Regimen variant #2

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

Preceding treatment

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 7)

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


Regimen variant #3

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

Preceding treatment

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, CMF portion (cycles 5 to 7)

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

References

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

ddEC-ddCMF

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

Regimen

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

Preceding treatment

Chemotherapy, ddEC portion (cycles 1 to 4)

Chemotherapy, ddCMF portion (cycles 5 to 7)

Supportive therapy, both portions (cycles 1 to 7)

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

References

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

ddEC-ddT

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

Regimen

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

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

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

Preceding treatment

Chemotherapy, ddEC portion (cycles 1 to 4)

Chemotherapy, ddT portion (cycles 5 to 8)

Supportive therapy, both portions (cycles 1 to 8)

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

References

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

EC-D

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

Regimen variant #1, 3+3 cycles

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

Biomarker eligibility criteria

  • TOP2A normal as determined by FISH

Preceding treatment

Chemotherapy, EC portion (cycles 1 to 3)

Chemotherapy, D portion (cycles 4 to 6)

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


Regimen variant #2, 4+4 cycles

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

Preceding treatment

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 8)

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

References

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

EC-T

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

Regimen variant #1, 75/600

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

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

Preceding treatment

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, T portion (cycles 5 to 16)

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


Regimen variant #2, 90/600

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

Preceding treatment

Chemotherapy, EC portion (cycles 1 to 4)

Chemotherapy, T portion (cycles 5 to 8)

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

References

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

ddEC-T

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

Regimen

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

Preceding treatment

Chemotherapy, ddEC portion (cycles 1 to 6)

Supportive therapy, ddEC portion (cycles 1 to 6)

Chemotherapy, T portion (cycles 7 to 10)

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

References

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

iddEnPC

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

Regimen

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

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

Preceding treatment

Chemotherapy, iddE portion (cycles 1 to 3)

Chemotherapy, iddnP portion (cycles 4 to 6)

Chemotherapy, iddC portion (cycles 7 to 9)

Supportive therapy, all portions (cycles 1 to 9)

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

References

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

iddEPC

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

Regimen

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

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

Preceding treatment

Chemotherapy, iddE portion (cycles 1 to 3)

Chemotherapy, iddP portion (cycles 4 to 6)

Chemotherapy, iddC portion (cycles 7 to 9)

Supportive therapy, all portions (cycles 1 to 9)

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

References

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

EP-ddCMF

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

Regimen

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

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

Preceding treatment

Chemotherapy, EP portion (cycles 1 to 4)

Chemotherapy, ddCMF portion (cycles 5 to 7)

Supportive therapy, ddCMF portion (cycles 5 to 7)

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

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

References

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

FAC-T

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

Regimen

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

Preceding treatment

Chemotherapy, FAC portion (cycles 1 to 4)

Chemotherapy, T portion (cycles 5 to 12)

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

References

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

FEC-D

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

Regimen variant #1, 3 x 3

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

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

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

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

Preceding treatment

Chemotherapy, FEC portion (cycles 1 to 3)

Chemotherapy, D portion (cycles 4 to 6)

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


Regimen variant #2, 4 x 4

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

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

Preceding treatment

Chemotherapy, FEC portion (cycles 1 to 4)

Chemotherapy, D portion (cycles 5 to 8)

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

References

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

ddFEC-ddD

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

Regimen

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

Preceding treatment

Chemotherapy, ddFEC portion (cycles 1 to 4)

Chemotherapy, ddD portion (cycles 5 to 8)

Supportive therapy, both portions (cycles 1 to 8)

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

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

References

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

FEC-P

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

Regimen

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

Preceding treatment

Chemotherapy, FEC portion (cycles 1 to 4)

Chemotherapy, P portion (cycles 5 to 12)

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

References

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

T-FEC

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

Regimen

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

Preceding treatment

Chemotherapy, T portion (cycles 1 to 12)

Chemotherapy, FEC portion (cycles 13 to 16)

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

References

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

TX-CEX

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

Regimen

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

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

1Reported OS efficacy is based on the 2022 update.

Preceding treatment

Chemotherapy, TX portion (cycles 1 to 3)

Chemotherapy, CEX portion (cycles 4 to 6)

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

References

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

V-FEC

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

Regimen

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

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

Preceding treatment

Chemotherapy, V portion (cycles 1 to 3)

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

Chemotherapy, FEC portion (cycles 4 to 6)

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

References

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

Adjuvant chemotherapy

Bevacizumab monotherapy

Regimen

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

Preceding treatment

Targeted therapy

21-day cycle for 10 cycles

References

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

Capecitabine monotherapy

Regimen

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

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

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

Preceding treatment

Chemotherapy

21-day cycle for 6 to 8 cycles

References

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

CMF

CMF: Cyclophosphamide, Methotrexate, Fluorouracil

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

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

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles


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

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

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy

21-day cycle for 6 to 8 cycles


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

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

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

Preceding treatment

Chemotherapy

28-day cycle for 8 cycles


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

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

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

Preceding treatment

Chemotherapy

21-day cycle for 9 cycles


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

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

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

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles


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

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

Preceding treatment

Chemotherapy

1-month cycle for 24 cycles


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

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

Preceding treatment

Chemotherapy

21-day cycle for 6 to 8 cycles


Regimen variant #8, 840/50/800

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

Preceding treatment

Chemotherapy

28-day cycle for 12 cycles


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

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

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


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

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

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


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

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

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

Preceding treatment

Chemotherapy

1-month cycle for 12 cycles


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

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

Preceding treatment

Chemotherapy

28-day cycle for 12 cycles


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

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

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

Preceding treatment

Chemotherapy

Supportive therapy

8-day course


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

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

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

Preceding treatment

Chemotherapy

28-day cycle for 4 cycles


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

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

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

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


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

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

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

Preceding treatment

Chemotherapy

28-day cycle for 12 cycles


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

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

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


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

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

Preceding treatment

Chemotherapy

28-day cycle for 3 cycles

Subsequent treatment


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

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

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

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

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

Subsequent treatment


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

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

Preceding treatment

Chemotherapy

28-day cycle for 12 cycles

References

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

CMFT

CMFT: Cyclophosphamide, Methotrexate, Fluorouracil, Tamoxifen

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

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

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

Preceding treatment

Chemotherapy

Endocrine therapy

28-day cycle for 13 cycles


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

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

Preceding treatment

Chemotherapy

Endocrine therapy

28-day cycle for 26 cycles


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

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

Preceding treatment

Chemotherapy

Endocrine therapy

28-day cycle for 12 cycles

References

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

Cyclophosphamide & Docetaxel (TC)

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

Regimen variant #1, 4 cycles

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

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

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy

Supportive therapy

21-day cycle for 4 cycles


Regimen variant #2, 6 cycles

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

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

Biomarker eligibility criteria

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

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles

References

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

Cyclophosphamide & Doxorubicin (AC)

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

Regimen variant #1, 54/1200 x 6

Study Dates 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

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #2, 60/600 x 4

Study Dates 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 co-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 Phase 3 (C) AC-EP Did not meet primary endpoint of OS
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
3. AC-T
4. AC-T; high-dose AC
5. AC-T; very high-dose AC 		Inferior OS
Mamounas et al. 2005 (NSABP B-28) 1995-1998 Phase 3 (C) AC-T Inferior DFS
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 OS1 (secondary endpoint)
RFS120: 56% vs 50%
(HR 0.80, 95% CI 0.62-0.98)

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

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

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #3, 80/600 x 4

Study Dates of enrollment Evidence
Moore et al. 2007 (SWOG S9623) 1996-2001 Non-randomized part of phase 3 RCT

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

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment

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
    1. Update: Fisher B, Jeong JH, Anderson S, Wolmark N. Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst. 2004 Dec 15;96(24):1823-31. link to original article PubMed
  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
    1. Update: Muss HB, Polley MC, Berry DA, Liu H, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Kartcheske PA, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Sutton LM, Magrinat G, Parker BA, Hart RD, Grenier D, Hurria A, Jatoi A, Norton L, Hudis CA, Winer EP, Carey L. Randomized Trial of Standard Adjuvant Chemotherapy Regimens Versus Capecitabine in Older Women With Early Breast Cancer: 10-Year Update of the CALGB 49907 Trial. J Clin Oncol. 2019 Sep 10;37(26):2338-2348. Epub 2019 Jul 24. link to original article link to PMC article PubMed
  13. TAILORx: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. link to original article link to PMC article contains dosing details in supplement PubMed NCT00310180
  14. ASTER 70s: NCT01564056

Dose-dense Cyclophosphamide & Doxorubicin (ddAC)

ddAC: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide

Regimen variant #1, 60/600 x 4

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

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

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy

Supportive therapy

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

14-day cycle for 4 cycles


Regimen variant #2, 60/600 x 6

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

Preceding treatment

Chemotherapy

Supportive therapy

14-day cycle for 6 cycles

References

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

Cyclophosphamide & Epirubicin (EC)

EC: Epirubicin and Cyclophosphamide

Regimen variant #1, 60/500 x 8

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

Preceding treatment

Chemotherapy

21-day cycle for 8 cycles


Regimen variant #2, 75/600 x 4

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

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

Subsequent treatment


Regimen variant #3, 100/830 x 8

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

Preceding treatment

Chemotherapy

21-day cycle for 8 cycles


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

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

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

References

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

Docetaxel monotherapy

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


Regimen

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

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

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles

References

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

Epirubicin & Paclitaxel (EP)

EP: Epirubicin & Paclitaxel

Regimen

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

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles

References

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

Epirubicin monotherapy

E: Epirubicin

Regimen

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

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

References

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

Dose-dense Epirubicin monotherapy

ddE: dose-dense Epirubicin

Regimen

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

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

Preceding treatment

Chemotherapy

14-day cycle for 3 cycles

Subsequent treatment

  • CMF; intensified

References

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

FAC

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

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

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

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment


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

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

Preceding treatment

Chemotherapy

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

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

Supportive therapy

21-day cycle for 6 cycles


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

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

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

Preceding treatment

Chemotherapy

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


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

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

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


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

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

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

Preceding treatment

Chemotherapy

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

Subsequent treatment

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


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

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

Preceding treatment

Chemotherapy

21-day cycle for 8 cycles

Subsequent treatment


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

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

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

Subsequent treatment


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

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

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

Preceding treatment

Chemotherapy

28-day cycle for 4 cycles


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

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

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

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


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

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

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

Preceding treatment

Chemotherapy

28-day cycle for 4 cycles

References

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

FEC

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

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

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

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

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles


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

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

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

Preceding treatment

Chemotherapy

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


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

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

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

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles


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

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

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

Preceding treatment

Chemotherapy

21-day cycle for 5 cycles


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

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

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

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles


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

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

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

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles


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

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

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

Preceding treatment

Chemotherapy

21-day cycle for 8 cycles


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

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

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

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles


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

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

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

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles


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

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

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

Preceding treatment

Chemotherapy

21-day cycle for 8 cycles


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

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

Preceding treatment

Chemotherapy

21-day cycle for 9 cycles


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

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

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

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles


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

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

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

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles


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

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

Preceding treatment

Chemotherapy


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

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

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

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


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

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

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles


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

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

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

Preceding treatment

Chemotherapy

28-day cycle for 6 cycles

References

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  31. UCBG-0106: Kerbrat P, Desmoulins I, Roca L, Levy C, Lortholary A, Marre A, Delva R, Rios M, Viens P, Brain É, Serin D, Edel M, Debled M, Campone M, Mourret-Reynier MA, Bachelot T, Foucher-Goudier MJ, Asselain B, Lemonnier J, Martin AL, Roché H. Optimal duration of adjuvant chemotherapy for high-risk node-negative (N-) breast cancer patients: 6-year results of the prospective randomised multicentre phase III UNICANCER-PACS 05 trial (UCBG-0106). Eur J Cancer. 2017 Jul;79:166-175. Epub 2017 May 11. link to original article contains dosing details in manuscript PubMed
  32. TAILORx: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. link to original article link to PMC article contains dosing details in supplement PubMed NCT00310180
  33. MINDACT: Delaloge S, Piccart M, Rutgers E, Litière S, van 't Veer LJ, van den Berkmortel F, Brain E, Dudek-Peric A, Gil-Gil M, Gomez P, Hilbers FS, Khalil Z, Knox S, Kuemmel S, Kunz G, Lesur A, Pierga JY, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Thompson AM, Viale G, Zoppoli G, Vuylsteke P, Tryfonidis K, Poncet C, Bogaerts J, Cardoso F; MINDACT investigators and the TRANSBIG Consortium. Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial. J Clin Oncol. 2020 Apr 10;38(11):1186-1197. Epub 2020 Feb 21. link to original article contains dosing details in supplement link to PMC article PubMed NCT00433589

MMM

MMM: Mitomycin-C, Mitoxantrone, Methotrexate

Regimen

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

Preceding treatment

Chemotherapy

21-day cycle for 6 cycles

References

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

Paclitaxel monotherapy, weekly

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

Regimen

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

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

Chemotherapy

7-day cycle for 12 cycles

References

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

Paclitaxel monotherapy, dose-dense (q2wk)

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

Regimen

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

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

Preceding treatment

Chemotherapy

Supportive therapy

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

14-day cycle for 4 cycles

References

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

TAC (Docetaxel)

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

Regimen variant #1, 4 cycles

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

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

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy

21-day cycle for 4 cycles


Regimen variant #2, 6 cycles

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

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

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

Eligibility criteria

  • TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

Chemotherapy

Supportive therapy

21-day cycle for 6 cycles

References

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

Metastatic disease, first-line chemotherapy

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

Cyclophosphamide & Doxorubicin (AC)

AC: Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen variant #1, 40/400

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

Chemotherapy

28-day cycles


Regimen variant #2, 40/500

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

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #3, 40/800 (PO)

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

Chemotherapy

21- to 28-day cycles


Regimen variant #4, 50/750

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

Chemotherapy

21-day cycle for up to 9 cycles


Regimen variant #5, 60/600

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

Chemotherapy

21-day cycles


Regimen variant #6, with range

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

Chemotherapy

21-day cycle for up to 8 cycles

References

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

Cyclophosphamide & Doxorubicin (AC) & Bevacizumab

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

Regimen variant #1, with range

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

Chemotherapy

Targeted therapy

21-day cycle for up to 8 cycles

Subsequent treatment

References

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

Capecitabine monotherapy

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

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

Chemotherapy

21-day cycles


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

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

Chemotherapy

21-day cycle for 8 cycles


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

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

Chemotherapy

21-day cycles


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

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

Chemotherapy

21-day cycles

References

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

Capecitabine & Bevacizumab

Regimen

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

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

Chemotherapy

Targeted therapy

21-day cycles

References

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

Capecitabine & Paclitaxel

TX: Taxol (Paclitaxel), Xeloda (Capecitabine)

Regimen

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

Chemotherapy

21-day cycles

References

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

Capecitabine & Paclitaxel, nanoparticle albumin-bound

Regimen

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

Chemotherapy

21-day cycles

References

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

CMF

CMF: Cyclophosphamide, Methotrexate, Fluorouracil

Regimen variant #1, 350/20/350

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

Chemotherapy

21-day cycles


Regimen variant #2, 600/40/600

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

Chemotherapy

21-day cycles


Regimen variant #3, 1400/80/1000

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

Chemotherapy

28-day cycles


Regimen variant #4, 1400/60/800

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

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

Chemotherapy

28-day cycles


Regimen variant #5, 1400/80/1200

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

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

Chemotherapy

28-day cycles


Regimen variant #6, 1400/120/1200

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

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

Chemotherapy

28-day cycles

References

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

CMFT

CMFT: Cyclophosphamide, Methotrexate, Fluorouracil, Tamoxifen

Regimen variant #1, lower-dose tamoxifen

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

Chemotherapy

Endocrine therapy

28-day cycles


Regimen variant #2, higher-dose tamoxifen

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

Chemotherapy

Endocrine therapy

28-day cycles

References

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

Docetaxel monotherapy

D: Docetaxel
T: Taxotere (Docetaxel)

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

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

Chemotherapy

28-day cycles


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

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

Chemotherapy

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

28-day cycles


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

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

Chemotherapy

8-week cycles


Regimen variant #4, 60 mg/m2 q3wk

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

Chemotherapy

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


Regimen variant #5, 60 mg/m2 q4wk

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

Chemotherapy

28-day cycles


Regimen variant #6, 75 mg/m2 q3wk

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

Chemotherapy

21-day cycles

Dose and schedule modifications

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


Regimen variant #7, 75 mg/m2 q4wk

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

Chemotherapy

28-day cycles


Regimen variant #8, 100 mg/m2 x 6

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

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #9, 100 mg/m2 x 8

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

Chemotherapy

21-day cycle for 8 cycles


Regimen variant #10, 100 mg/m2 x 9

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

Chemotherapy

21-day cycle for up to 9 cycles


Regimen variant #11, 100 mg/m2, indefinite

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

Chemotherapy

21-day cycles

References

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

Docetaxel & Bevacizumab

Regimen variant #1, 75/15, indefinite

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

Chemotherapy

Targeted therapy

21-day cycles


Regimen variant #2, 100/15, 9 cycles

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

Chemotherapy

Targeted therapy

21-day cycle for up to 9 cycles

Subsequent treatment


Regimen variant #3, 100/15, indefinite

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

Chemotherapy

Targeted therapy

21-day cycles

References

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

Docetaxel & Doxorubicin (AT)

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

Regimen variant #1, 50/75 x 4

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

Chemotherapy

21-day cycle for 8 cycles


Regimen variant #2, 50/75 x 6

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

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

Chemotherapy

21-day cycle for 6 cycles


Regimen variant #3, 50/75 x 8

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

Chemotherapy

21-day cycle for 8 cycles

References

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

Docetaxel & Epirubicin (DE)

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

Regimen variant #1, 8 cycles

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

Chemotherapy

21-day cycle for up to 8 cycles


Regimen variant #2, indefinite

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

Chemotherapy

21-day cycles

References

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

Docetaxel & Gemcitabine

GD: Gemcitabine & Docetaxel
GDoc: Gemcitabine & Docetaxel

Regimen

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

Chemotherapy

21-day cycles

Subsequent treatment

References

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

Doxorubicin monotherapy

Regimen variant #1, 20 mg/m2 weekly

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

Chemotherapy

7-day cycles


Regimen variant #2, 60 mg/m2 q3wk

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

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

Chemotherapy

21-day cycles (see note)


Regimen variant #3, 75 mg/m2 q3wk

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

Chemotherapy

21-day cycle for 7 cycles

References

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

Doxorubicin & Paclitaxel (AT)

AT: Adriamycin (Doxorubicin) & Taxol (Paclitaxel)

Regimen variant #1, 50/150

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

Chemotherapy

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

21-day cycles


Regimen variant #2, 50/175

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

Chemotherapy

21-day cycle for 8 cycles


Regimen variant #3, 50/220

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

1Reported efficacy is based on the 2009 update.

Chemotherapy

21-day cycle for up to 8 cycles


Regimen variant #4, 60/200

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

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

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #5, with range

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

Chemotherapy

21-day cycles

References

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

Pegylated liposomal doxorubicin monotherapy

Regimen variant #1, 45 mg/m2

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

Chemotherapy

28-day cycle for 6 cycles


Regimen variant #2, 50 mg/m2

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

Chemotherapy

28-day cycles

Dose and schedule modifications

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

References

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

Cyclophosphamide & Epirubicin (EC)

EC: Epirubicin & Cyclophosphamide

Regimen variant #1, 75/600

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

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

Chemotherapy

21-day cycle for up to 6 to 8 cycles


Regimen variant #2, 90/600

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

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

Chemotherapy

21-day cycle for up to 8 cycles


Regimen variant #3, with range

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

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

Chemotherapy

21-day cycle for up to 8 cycles

References

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

Cyclophosphamide & Epirubicin (EC) & Bevacizumab

EC & Bevacizumab: Epirubicin, Cyclophosphamide, Bevacizumab

Regimen

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

Chemotherapy

Targeted therapy

21-day cycle for up to 8 cycles

Subsequent treatment

References

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

Epirubicin & Paclitaxel (EP)

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

Regimen variant #1, 60/175

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

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #2, 75/175

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

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

Chemotherapy

21-day cycles


Regimen variant #3, 75/200

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

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #4, 80/175

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

Chemotherapy

21-day cycle for up to 6 cycles


Regimen variant #5, 90/200

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

Chemotherapy

21-day cycle for 8 cycles

References

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

Epirubicin monotherapy

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

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

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

Chemotherapy

28-day cycles


Regimen variant #2, 40 mg/m2

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

Chemotherapy

21-day cycles


Regimen variant #3, 50 mg/m2

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

Chemotherapy

14-day cycles


Regimen variant #4, 60 mg/m2

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

Chemotherapy

21-day cycles


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

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

Chemotherapy

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


Regimen variant #6, 75 mg/m2

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

Chemotherapy

21-day cycles


Regimen variant #7, 90 mg/m2

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

Chemotherapy

21-day cycles


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

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

Chemotherapy

21-day cycles


Regimen variant #9, 135 mg/m2

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

Chemotherapy

21-day cycles

References

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

FAC

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

Regimen variant #1, 500/50/500

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

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

Chemotherapy

21-day cycle for up to 6 to 8 cycles

Subsequent treatment


Regimen variant #2, 600/50/600

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

Chemotherapy

21-day cycle for up to 10 cycles


Regimen variant #3, 800/40/400

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

Chemotherapy

21-day cycles


Regimen variant #4, 1000/40/500

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

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

Chemotherapy

21-day cycles


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

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

Chemotherapy

21-day cycles


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

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

Chemotherapy

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


Regimen variant #7, 1000/50/1400

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

Chemotherapy

28-day cycle for up to 9 cycles


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

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

Chemotherapy

28-day cycle for up to 6 cycles


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

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

Chemotherapy

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


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

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

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

Chemotherapy

28-day cycles

References

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

FAC & Bevacizumab

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

Regimen

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

Chemotherapy

Targeted therapy

21-day cycle for up to 8 cycles

Subsequent treatment

References

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

FEC

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

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

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

Chemotherapy

21-day cycle for 6 to 12 cycles


Regimen variant #2, 500/60/500

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

Chemotherapy

28-day cycles


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

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

Chemotherapy

21-day cycles


Regimen variant #4, 500/90/500

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

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

Chemotherapy

21-day cycle for up to 8 cycles


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

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

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

Chemotherapy

21-day cycle for 6 to 8 cycles


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

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

Chemotherapy

21-day cycle for 6 to 8 cycles


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

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

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

Chemotherapy

21-day cycle for 8 to 12 cycles


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

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

Chemotherapy

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


Regimen variant #9, 1000/60/1400

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

Chemotherapy

28-day cycles


Regimen variant #10, 1000/100/800

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

Chemotherapy

28-day cycle for 6 to 8 cycles

References

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

FEC & Bevacizumab

FEC & Bevacizumab: Fluorouracil, Epirubicin, Cyclophosphamide, Bevacizumab

Regimen

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

Chemotherapy

Targeted therapy

21-day cycle for up to 8 cycles

Subsequent treatment

References

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

Gemcitabine monotherapy

Regimen

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

Chemotherapy

28-day cycles

References

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

Gemcitabine & Paclitaxel

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

Regimen variant #1, 6 cycles

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

Chemotherapy

21-day cycle for 6 cycles

Subsequent treatment


Regimen variant #2, indefinite

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

Chemotherapy

21-day cycles

References

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

Cyclophosphamide & Non-pegylated liposomal doxorubicin (MC)

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

Regimen variant #1, 60/600

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

Chemotherapy

21-day cycles


Regimen variant #2, 75/600

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

Chemotherapy

21-day cycle for up to 8 cycles

References

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

Paclitaxel monotherapy, weekly

Regimen variant #1, 80 mg/m2 weekly

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

Chemotherapy

28-day cycles


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

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

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

Chemotherapy

28-day cycles


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

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

Chemotherapy

28-day cycles


Regimen variant #4, 100 mg/m2 weekly

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

Chemotherapy

7-day cycles


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

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

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

Chemotherapy

28-day cycles

References

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

Paclitaxel monotherapy, q3wk

Regimen variant #1, 175 mg/m2 q3wk

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

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

Chemotherapy

21-day cycles


Regimen variant #2, 175 mg/m2, CI

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

Chemotherapy

21-day cycles


Regimen variant #3, 175 mg/m2 q4wk

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

Chemotherapy

28-day cycles


Regimen variant #4, 200 mg/m2

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

Chemotherapy

21-day cycle for 7 or 8 cycles


Regimen variant #5, 250 mg/m2

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

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

Chemotherapy

21-day cycles

References

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

Paclitaxel & Bevacizumab

Regimen

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

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

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

Chemotherapy

Targeted therapy

28-day cycles

References

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

Paclitaxel & Vinorelbine

Regimen

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

Chemotherapy

28-day cycles

References

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

nab-Paclitaxel monotherapy

Example orders

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

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

Chemotherapy

28-day cycles


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

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

Chemotherapy

28-day cycles


Regimen variant #3, 260 mg/m2 q3wk

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

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

Chemotherapy

Supportive therapy

  • CA012-0: No corticosteroid or antihistamine premedication

21-day cycles


Regimen variant #4, 300 mg/m2 q3wk

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

Chemotherapy

21-day cycles

References

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

Paclitaxel, nanoparticle albumin-bound & Bevacizumab

Example orders

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

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

Chemotherapy

Targeted therapy

28-day cycles


Regimen variant #2, 260 mg/m2 q3wk

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

Chemotherapy

Targeted therapy

21-day cycles

References

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

Pemetrexed monotherapy

Regimen variant #1, 500 mg/m2

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

Eligibility criteria

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

Chemotherapy

Supportive therapy

21-day cycle for up to 3 cycles


Regimen variant #2, 600 mg/m2

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

Chemotherapy

Supportive therapy

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

14-day cycles

References

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

S-1 monotherapy

Regimen

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

Chemotherapy

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

42-day cycles

References

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

Capecitabine & Docetaxel (TX)

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

Regimen variant #1, 1900/75

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

Chemotherapy

21-day cycles


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

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

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

Chemotherapy

21-day cycles


Regimen variant #3, 2000/75, indefinite

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

Chemotherapy

21-day cycles

Subsequent treatment

References

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

Epirubicin & Vinorelbine (VE)

VE: Vinorelbine & Epirubicin

Regimen

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

Chemotherapy

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

References

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

Metastatic disease, maintenance after first-line therapy

Bevacizumab monotherapy

Regimen

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

Preceding treatment

Targeted therapy

21-day cycles

References

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

Capecitabine & Bevacizumab

Regimen

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

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

Preceding treatment

Chemotherapy

Targeted therapy

21-day cycles

References

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

Gemcitabine & Paclitaxel

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

Regimen

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

Preceding treatment

  • First-line PG x 6

Chemotherapy

21-day cycles

References

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

Metastatic disease, subsequent lines of chemotherapy

Capecitabine monotherapy

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

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

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

Prior treatment criteria

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

Biomarker eligibility criteria

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

Chemotherapy

21-day cycles


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

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

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

Prior treatment criteria

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

Biomarker eligibility criteria

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

Chemotherapy

21-day cycles

References

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

Capecitabine & Bevacizumab

Regimen variant #1, 2000/15

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

Chemotherapy

Targeted therapy

21-day cycles


Regimen variant #2, 2500/15

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Miller et al. 2005 (AVF2119g) 2000-2002 Phase 3 (E-esc) Capecitabine Did not meet primary endpoint of PFS
Median PFS: 4.86 vs 4.17 mo
(HR 0.98, 95% CI 0.77-1.25)

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

Prior treatment criteria

  • Prior therapy with both an anthracycline and a taxane, and 1 to 2 prior chemotherapy regimens for metastatic disease

Chemotherapy

Targeted therapy

21-day cycles

References

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

Capecitabine & Docetaxel (TX)

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

Regimen variant #1, 825/60

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yamamoto et al. 2016 (JO21095) 2008-2010 Phase 3 (E-esc) Docetaxel Seems to have superior PFS (primary endpoint)
Median PFS: 10.5 vs 9.8 mo
(HR 0.62, 95% CI 0.40-0.97)

Chemotherapy

21-day cycles


Regimen variant #2, 1250/75

Study Dates of enrollment Evidence Comparator Comparative Efficacy
O'Shaughnessy et al. 2002 (SO14999) NR Phase 3 (E-RT-esc) Docetaxel Superior TTP (primary endpoint)
Median TTP: 6.1 vs 4.2 mo
(HR 0.65, 95% CI 0.545-0.78)

Superior OS1 (secondary endpoint)
Median OS: 14.5 vs 11.5 mo
(HR 0.78, 95% CI 0.645-0.94)
Chan et al. 2009 (B9E-US-S188) 2002-2004 Phase 3 (C) GD Did not meet primary endpoint of PFS

1Reported efficacy for SO14999 is based on the 2004 update.

Chemotherapy

21-day cycles

References

  1. SO14999: O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. link to original article contains dosing details in manuscript PubMed
    1. Update: Miles D, Vukelja S, Moiseyenko V, Cervantes G, Mauriac L, Van Hazel G, Lui WY, Ayoub JP, O'Shaughnessy JA. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Clin Breast Cancer. 2004 Oct;5(4):273-8. link to original article PubMed
  2. B9E-US-S188: Chan S, Romieu G, Huober J, Delozier T, Tubiana-Hulin M, Schneeweiss A, Lluch A, Llombart A, du Bois A, Kreienberg R, Mayordomo JI, Antón A, Harrison M, Jones A, Carrasco E, Vaury AT, Frimodt-Moller B, Fumoleau P. Phase III study of gemcitabine plus docetaxel compared with capecitabine plus docetaxel for anthracycline-pretreated patients with metastatic breast cancer. J Clin Oncol. 2009 Apr 10;27(11):1753-60. Epub 2009 Mar 9. link to original article contains dosing details in abstract PubMed NCT00191152
    1. Pooled update: Seidman AD, Chan S, Wang J, Zhu C, Xu C, Xu B. A pooled analysis of gemcitabine plus docetaxel versus capecitabine plus docetaxel in metastatic breast cancer. Oncologist. 2014 May;19(5):443-52. Epub 2014 Apr 4. link to original article link to PMC article PubMed
  3. JO21095: Yamamoto D, Sato N, Rai Y, Yamamoto Y, Saito M, Iwata H, Masuda N, Oura S, Watanabe J, Hattori S, Matsuura Y, Kuroi K. Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. Breast Cancer Res Treat. 2017 Feb;161(3):473-482. Epub 2016 Dec 22. link to original article contains dosing details in manuscript PubMed

Capecitabine & Ixabepilone

XI: Xeloda (Capecitabine) & Ixabepilone

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Thomas et al. 2007 (CA163-046) 2003-2006 Phase 3 (E-RT-esc) Capecitabine Superior PFS (primary endpoint)
Median PFS: 5.8 vs 4.2 mo
(HR 0.75, 95% CI 0.64-0.88)
Sparano et al. 2010 (CA163-048) 2003-2006 Phase 3 (E-RT-esc) Capecitabine Might have superior OS (primary endpoint)
Median OS: 16.4 vs 15.6 mo
(HR 0.90, 95% CI 0.78-1.03)

Chemotherapy

21-day cycles

References

  1. CA163-046: Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. Epub 2007 Oct 29. link to original article contains dosing details in manuscript PubMed NCT00080301
    1. Update: Hortobagyi GN, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Lerzo GL, Pivot XB, Hurtado de Mendoza F, Xu B, Vahdat LT, Peck RA, Mukhopadhyay P, Roché HH. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes. Breast Cancer Res Treat. 2010 Jul;122(2):409-18. Epub 2010 May 8. link to original article PubMed
  2. CA163-048: Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010 Jul 10;28(20):3256-63. Epub 2010 Jun 7. link to original article contains dosing details in manuscript link to PMC article PubMed NCT00082433

Capecitabine & Vinflunine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Martin et al. 2018 (L00070 IN 305 B0) 2009-2011 Phase 3 (E-esc) Capecitabine Seems to have superior PFS (primary endpoint)
Median PFS: 5.6 vs 4.3 mo
(HR 0.84, 95% CI 0.71-0.99)

Chemotherapy

21-day cycles

References

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

Carboplatin & Gemcitabine (GCb)

Regimen

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

Chemotherapy

21-day cycles until CR or indefinitely

References

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

Cisplatin & Vinorelbine (CVb)

CVb: Cisplatin & Vinorelbine

Regimen

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

Chemotherapy

Supportive therapy

  • Normal saline 200 mL bolus after vinorelbine to prevent phlebitis
  • Normal saline 2000 mL with KCl (unspecified amount of KCl) IV over 4 hours once on day 1, prior to cisplatin
  • Furosemide (Lasix) 40 mg IV once on day 1; 20 minutes prior to cisplatin
  • Normal saline 1000 mL and D5W 1000 mL IV over 4 hours once on day 1, after cisplatin
    • Paper did not say whether fluids were given sequentially or concurrently
  • 5-HT3 antagonists used

21-day cycle for up to 6 cycles

References

  1. Ray-Coquard I, Biron P, Bachelot T, Guastalla JP, Catimel G, Merrouche Y, Droz JP, Chauvin F, Blay JY. Vinorelbine and cisplatin (CIVIC regimen) for the treatment of metastatic breast carcinoma after failure of anthracycline- and/or paclitaxel-containing regimens. Cancer. 1998 Jan 1;82(1):134-40. link to original article PubMed
  2. Vassilomanolakis M, Koumakis G, Barbounis V, Demiri M, Pateras H, Efremidis AP. Vinorelbine and cisplatin in metastatic breast cancer patients previously treated with anthracyclines. Ann Oncol. 2000 Sep;11(9):1155-60. link to original article contains dosing details in manuscript PubMed

Cyclophosphamide & Methotrexate (CM)

CM: Cyclophosphamide & Methotrexate

Regimen variant #1

Study Dates of enrollment Evidence
Colleoni et al. 2002 1997-2000 Non-randomized

Chemotherapy

7-day cycles


Regimen variant #2, metronomic

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Colleoni et al. 2005 2000-2003 Randomized (C) CM & Thalidomide Did not meet primary endpoint of percent reduction in VEGF after 2 months of treatment

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

7-day cycles

References

  1. Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nolè F, Peruzzotti G, Robertson C, Orlando L, Cinieri S, de Braud F, Viale G, Goldhirsch A. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol. 2002 Jan;13(1):73-80. link to original article contains dosing details in manuscript PubMed
  2. Colleoni M, Orlando L, Sanna G, Rocca A, Maisonneuve P, Peruzzotti G, Ghisini R, Sandri MT, Zorzino L, Nolè F, Viale G, Goldhirsch A. Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann Oncol. 2006 Feb;17(2):232-8. Epub 2005 Dec 1. link to original article contains dosing details in abstract PubMed

Cyclophosphamide monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cortes et al. 2018 (L00070 IN 308 B0) 2009-2011 Phase 3 (C) Vinflunine Did not meet primary endpoint of OS
Median OS: 9.3 vs 9.1 mo
(HR 0.96)

Note: this was the most commonly used comparator arm; doses were not provided in the manuscript.

Chemotherapy

References

  1. L00070 IN 308 B0: Cortes J, Perez-Garcia J, Levy C, Gómez Pardo P, Bourgeois H, Spazzapan S, Martínez-Jañez N, Chao TC, Espié M, Nabholtz JM, Gonzàlez Farré X, Beliakouski V, Román García J, Holgado E, Campone M. Open-label randomised phase III trial of vinflunine versus an alkylating agent in patients with heavily pretreated metastatic breast cancer. Ann Oncol. 2018 Apr 1;29(4):881-887. link to original article does not contain dosing details PubMed NCT01091168

Docetaxel monotherapy

D: Docetaxel
T: Taxotere (Docetaxel)

Regimen variant #1, 40 mg/m2 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Rivera et al. 2008 2001-2004 Phase 3 (E-switch-ic), less than 20 pts in this subgroup Docetaxel; q3wk Did not meet primary endpoint of ORR Superior toxicity

Chemotherapy

  • Docetaxel (Taxotere) as follows:
    • Cycle 1: 35 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
    • Cycle 2 onwards: 40 mg/m2 IV over 30 minutes once per day on days 1, 8, 15

28-day cycles


Regimen variant #2, 40 mg/m2 6 weeks out of 8

Study Dates of enrollment Evidence
Burstein et al. 2000 1998 Phase 2

Chemotherapy

8-week cycles


Regimen variant #3, 60 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Adachi et al. 1996 1993 Phase 2
Harvey et al. 2006 (TAX 313) 1995-2001 Phase 3 (E-RT-de-esc) 1. Docetaxel; 75 mg/m2 q3wk Might have inferior TTP (secondary endpoint)
2. Docetaxel; 100 mg/m2 q3wk Might have inferior TTP (secondary endpoint)
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: this is the dosage used for Japanese patients; Adachi et al. 1996 reported 21- to 28-day cycles

Chemotherapy

21-day cycles


Regimen variant #4, 70 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Yamamoto et al. 2016 (JO21095) 2008-2010 Phase 3 (C) TX Seems to have inferior OS

Chemotherapy

21-day cycles

Subsequent treatment


Regimen variant #5, 75 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Harvey et al. 2006 (TAX 313) 1995-2001 Phase 3 (E-RT-esc) 1. Docetaxel; 60 mg/m2 q3wk Might have superior TTP (secondary endpoint)

Superior ORR (primary endpoint)
2. Docetaxel; 100 mg/m2 q3wk Might have inferior TTP (secondary endpoint)
Rivera et al. 2008 2001-2004 Phase 3 (C), less than 20 pts in this subgroup Docetaxel; weekly Did not meet primary endpoint of ORR Inferior toxicity
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Gemcitabine & Bevacizumab
1d. Paclitaxel & Bevacizumab
1e. nab-Paclitaxel & Bevacizumab
1f. Vinorelbine & Bevacizumab 		Inferior PFS
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: This is the lower end of the range of docetaxel dosing described in TANIA.

Chemotherapy

21-day cycles

Dose and schedule modifications

  • Rivera et al. 2008 gave 75 mg/m2 in cycle 1, with escalation to 100 mg/m2 depending on toxicity


Regimen variant #6, 100 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
ten Bokkel Huinink et al. 1994 NR Phase 2
Nabholtz et al. 1999 (TAX 304) NR Phase 3 (E-RT-de-esc) Mitomycin & Vinblastine (MV) Superior OS
Chan et al. 1999 (TAX 303) 1994-1997 Phase 3 (E-RT-switch-ic) Doxorubicin Did not meet primary endpoint of TTP50%

Superior ORR (secondary endpoint)
Sjöström et al. 1999 1994-1997 Phase 3 (E-de-esc) MF Superior TTP
O'Shaughnessy et al. 2002 (SO14999) NR Phase 3 (C) TX Inferior OS1
Jones et al. 2005 (TAX 311) 1994-2001 Phase 3 (E-switch-ic) Paclitaxel Superior OS (secondary endpoint)
Median OS: 15.4 vs 12.7 mo
(HR 0.71, 95% CI 0.58-0.87)
Bonneterre et al. 2002 1995-1997 Phase 3 (E-de-esc) 5-FU & Vinorelbine Did not meet primary endpoint of TTP Less toxic
Harvey et al. 2006 (TAX 313) 1995-2001 Phase 3 (E-RT-esc) 1. Docetaxel; 60 mg/m2 q3wk Might have superior TTP (secondary endpoint)

Superior ORR (primary endpoint)
2. Docetaxel; 75 mg/m2 q3wk Might have superior TTP (secondary endpoint)

Superior ORR (primary endpoint)
Nielsen et al. 2011 2001-2005 Phase 3 (C) Docetaxel & Gemcitabine Might have inferior TTP
Schröder et al. 2011 2001-2006 Phase 3 (C) Docetaxel; weekly Seems to have superior OS
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Gemcitabine & Bevacizumab
1d. Paclitaxel & Bevacizumab
1e. nab-Paclitaxel & Bevacizumab
1f. Vinorelbine & Bevacizumab 		Inferior PFS
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

1Reported efficacy for SO14999 is based on the 2004 update.
Note: this was the upper end of the range of docetaxel dosing described in TANIA. TAX 304 stopped treatment after 10 cycles. TAX 303 stopped treatment after 7 cycles.

Chemotherapy

21-day cycles (see note)

References

  1. ten Bokkel Huinink WW, Prove AM, Piccart M, Steward W, Tursz T, Wanders J, Franklin H, Clavel M, Verweij J, Alakl M, Bayssas M, Kaye SB; EORTC Early Clinical Trials Group. A phase II trial with docetaxel (Taxotere) in second line treatment with chemotherapy for advanced breast cancer: a study of the EORTC Early Clinical Trials Group. Ann Oncol. 1994 Jul;5(6):527-32. link to original article contains dosing details in abstract PubMed
  2. Adachi I, Watanabe T, Takashima S, Narabayashi M, Horikoshi N, Aoyama H, Taguchi T. A late phase II study of RP56976 (docetaxel) in patients with advanced or recurrent breast cancer. Br J Cancer. 1996 Jan;73(2):210-6. link to original article link to PMC article contains dosing details in abstract PubMed
  3. TAX 304: Nabholtz JM, Senn HJ, Bezwoda WR, Melnychuk D, Deschênes L, Douma J, Vandenberg TA, Rapoport B, Rosso R, Trillet-Lenoir V, Drbal J, Molino A, Nortier JW, Richel DJ, Nagykalnai T, Siedlecki P, Wilking N, Genot JY, Hupperets PS, Pannuti F, Skarlos D, Tomiak EM, Murawsky M, Alakl M, Aapro M; 304 Study Group. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. J Clin Oncol. 1999 May;17(5):1413-24. link to original article contains dosing details in abstract PubMed
  4. Review: Burris HA 3rd. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin Oncol. 1999 Jun;26(3 Suppl 9):1-6. PubMed
  5. TAX 303: Chan S, Friedrichs K, Noel D, Pintér T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, González Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J; 303 Study Group. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2341-54. link to original article PubMed
  6. Sjöström J, Blomqvist C, Mouridsen H, Pluzanska A, Ottosson-Lönn S, Bengtsson NO, Ostenstad B, Mjaaland I, Palm-Sjövall M, Wist E, Valvere V, Anderson H, Bergh J; Scandinavian Breast Group. Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: a randomised phase III study with crossover on progression by the Scandinavian Breast Group. Eur J Cancer. 1999 Aug;35(8):1194-201. link to original article contains dosing details in abstract PubMed
  7. SO14999: O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. link to original article contains dosing details in manuscript PubMed
    1. Update: Miles D, Vukelja S, Moiseyenko V, Cervantes G, Mauriac L, Van Hazel G, Lui WY, Ayoub JP, O'Shaughnessy JA. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Clin Breast Cancer. 2004 Oct;5(4):273-8. link to original article PubMed
  8. Bonneterre J, Roché H, Monnier A, Guastalla JP, Namer M, Fargeot P, Assadourian S. Docetaxel vs 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure. Br J Cancer. 2002 Nov 18;87(11):1210-5. link to original article contains dosing details in abstract link to PMC article PubMed
  9. TAX 311: Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, Laufman L, Sundaram S, Urba WJ, Pritchard KI, Mennel R, Richards D, Olsen S, Meyers ML, Ravdin PM. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005 Aug 20;23(24):5542-51. link to original article contains dosing details in abstract PubMed NCT00002662
  10. TAX 313: Harvey V, Mouridsen H, Semiglazov V, Jakobsen E, Voznyi E, Robinson BA, Groult V, Murawsky M, Cold S. Phase III trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol. 2006 Nov 1;24(31):4963-70. Epub 2006 Oct 10. link to original article PubMed
  11. Rivera E, Mejia JA, Arun BK, Adinin RB, Walters RS, Brewster A, Broglio KR, Yin G, Esmaeli B, Hortobagyi GN, Valero V. Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic breast cancer. Cancer. 2008 Apr 1;112(7):1455-61. link to original article contains dosing details in manuscript PubMed
  12. Schröder CP, de Munck L, Westermann AM, Smit WM, Creemers GJ, de Graaf H, Stouthard JM, van Deijk G, Erjavec Z, van Bochove A, Vader W, Willemse PH. Weekly docetaxel in metastatic breast cancer patients: no superior benefits compared to three-weekly docetaxel. Eur J Cancer. 2011 Jun;47(9):1355-62. Epub 2011 Jan 19. link to original article PubMed
  13. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  14. Nielsen DL, Bjerre KD, Jakobsen EH, Cold S, Stenbygaard L, Sørensen PG, Kamby C, Møller S, Jørgensen CL, Andersson M; Danish Breast Cancer Cooperative Group. Gemcitabine plus docetaxel versus docetaxel in patients with predominantly human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: a randomized, phase III study by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 2011 Dec 20;29(36):4748-54. Epub 2011 Nov 14. link to original article contains dosing details in abstract PubMed
  15. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed
  16. JO21095: Yamamoto D, Sato N, Rai Y, Yamamoto Y, Saito M, Iwata H, Masuda N, Oura S, Watanabe J, Hattori S, Matsuura Y, Kuroi K. Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. Breast Cancer Res Treat. 2017 Feb;161(3):473-482. Epub 2016 Dec 22. link to original article contains dosing details in manuscript PubMed

Docetaxel & Bevacizumab

Regimen variant #1, docetaxel 60 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the dosage used for Japanese patients.

Chemotherapy

Targeted therapy

21-day cycles


Regimen variant #2, docetaxel 75 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Gemcitabine
1d. Paclitaxel
1e. nab-Paclitaxel
1f. Vinorelbine 		Superior PFS (primary endpoint)
Median PFS: 7.2 vs 5.1 mo
(HR 0.78, 95% CI 0.64-0.93)
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the lower end of the range of docetaxel dosing described in TANIA.

Chemotherapy

Targeted therapy

21-day cycles


Regimen variant #3, docetaxel 100 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Gemcitabine
1d. Paclitaxel
1e. nab-Paclitaxel
1f. Vinorelbine 		Superior PFS (primary endpoint)
Median PFS: 7.2 vs 5.1 mo
(HR 0.78, 95% CI 0.64-0.93)
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the upper end of the range of docetaxel dosing described in TANIA.

Chemotherapy

Targeted therapy

21-day cycles

References

  1. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  2. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Docetaxel & Gemcitabine

DG: Docetaxel & Gemcitabine

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tomova et al. 2010 2002-09 to 2006-03 Phase 3 (C) D-G Did not meet primary endpoint of TTP

Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

21-day cycle for 8 cycles

References

  1. Tomova A, Bartsch R, Brodowicz T, Tzekova V, Timcheva C, Wiltschke C, Gerges DA, Pawlega J, Spanik S, Inbar M, Zielinski CC. Concomitant docetaxel plus gemcitabine versus sequential docetaxel followed by gemcitabine in anthracycline-pretreated metastatic or locally recurrent inoperable breast cancer patients: a prospective multicentre trial of the Central European Cooperative Oncology Group (CECOG). Breast Cancer Res Treat. 2010 Jan;119(1):169-76. link to original article contains dosing details in abstract PubMed

Doxorubicin monotherapy

Regimen variant #1, 20 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: this is the lower end of the range of weekly doxorubicin dosing described in TANIA.

Chemotherapy

7-day cycles


Regimen variant #2, 25 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: this is the higher end of the range of weekly doxorubicin dosing described in TANIA.

Chemotherapy

7-day cycles


Regimen variant #3, 60 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cowan et al. 1991 (SWOG S8203) 1983-1986 Phase 3 (E-switch-ic) 1. Bisantrene
2. Mitoxantrone 		Seems to have superior OS
Norris et al. 2000 (NCIC-CTG MA.8) 1992-1995 Phase 3 (C) NA Did not meet primary endpoint of OS
Reyno et al. 2004 (NCIC CT MA.19) 1998-1999 Phase 3 (C) Doxorubicin & Tesmilifene Did not meet primary endpoint of PFS
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: in NCIC-CTG MA.8, this dose was after a mid-protocol amendment. Treatment in NCIC-CTG MA.8 & MA.19 was given until a cumulative dose of 450 mg/m2. This is the lower end of the range of q3wk doxorubicin dosing described in TANIA.

Chemotherapy

21-day cycles (see note)


Regimen variant #4, 75 mg/m2 q3wk, limited duration

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Chan et al. 1999 (TAX 303) 1994-1997 Phase 3 (C) Docetaxel Did not meet primary endpoint of TTP50%

Chemotherapy

21-day cycle for up to 7 cycles


Regimen variant #5, 75 mg/m2 q3wk, indefinite

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Bontenbal et al. 1998 (EORTC 10811) 1982-1986 Phase 3 (C) Epirubicin Did not meet primary endpoint of ORR
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: this is the higher end of the range of q3wk doxorubicin dosing described in TANIA.

Chemotherapy

21-day cycles

References

  1. SWOG S8203: Cowan JD, Neidhart J, McClure S, Coltman CA Jr, Gumbart C, Martino S, Hutchins LF, Stephens RL, Vaughan CB, Osborne CK. Randomized trial of doxorubicin, bisantrene, and mitoxantrone in advanced breast cancer: a Southwest Oncology Group study. J Natl Cancer Inst. 1991 Aug 7;83(15):1077-84. link to original article contains dosing details in abstract PubMed
  2. EORTC 10811: Bontenbal M, Andersson M, Wildiers J, Cocconi G, Jassem J, Paridaens R, Rotmensz N, Sylvester R, Mouridsen HT, Klijn JG, van Oosterom AT; EORTC Breast Cancer Cooperative Group. Doxorubicin vs epirubicin, report of a second-line randomized phase II/III study in advanced breast cancer. Br J Cancer. 1998 Jun;77(12):2257-63. link to original article link to PMC article contains dosing details in abstract PubMed
  3. TAX 303: Chan S, Friedrichs K, Noel D, Pintér T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, González Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J; 303 Study Group. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2341-54. link to original article PubMed
  4. NCIC-CTG MA.8: Norris B, Pritchard KI, James K, Myles J, Bennett K, Marlin S, Skillings J, Findlay B, Vandenberg T, Goss P, Latreille J, Rudinskas L, Lofters W, Trudeau M, Osoba D, Rodgers A. Phase III comparative study of vinorelbine combined with doxorubicin versus doxorubicin alone in disseminated metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group study MA8. J Clin Oncol. 2000 Jun;18(12):2385-94. link to original article contains dosing details in abstract PubMed
  5. NCIC CT MA.19: Reyno L, Seymour L, Tu D, Dent S, Gelmon K, Walley B, Pluzanska A, Gorbunova V, Garin A, Jassem J, Pienkowski T, Dancey J, Pearce L, MacNeil M, Marlin S, Lebwohl D, Voi M, Pritchard K; National Cancer Institute of Canada Clinical Trials Group. Phase III study of N,N-diethyl-2-[4-(phenylmethyl) phenoxy]ethanamine (BMS-217380-01) combined with doxorubicin versus doxorubicin alone in metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group Study MA.19. J Clin Oncol. 2004 Jan 15;22(2):269-76. link to original article PubMed
  6. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Doxorubicin & Bevacizumab

Regimen variant #1, doxorubicin 20 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the lower end of the range of weekly doxorubicin dosing described in TANIA.

Chemotherapy

Targeted therapy

28-day cycles


Regimen variant #2, doxorubicin 25 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the higher end of the range of weekly doxorubicin dosing described in TANIA.

Chemotherapy

Targeted therapy

28-day cycles


Regimen variant #3, doxorubicin 60 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the lower end of the range of q3wk doxorubicin dosing described in TANIA.

Chemotherapy

Targeted therapy

21-day cycles


Regimen variant #4, doxorubicin 75 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the higher end of the range of q3wk doxorubicin dosing described in TANIA.

Chemotherapy

Targeted therapy

21-day cycles

References

  1. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Eribulin monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Cortes et al. 2011 (EMBRACE) 2006-2008 Phase 3 (E-RT-switch-ic) Investigator's choice Seems to have superior OS (primary endpoint)
Median OS: 13.1 vs 10.6 mo
(HR 0.81, 95% CI 0.66-0.99)
Kaufman et al. 2015 (E7389-G000-301) 2006-2009 Phase 3 (E-switch-ic) Capecitabine Seems to have superior OS (co-primary endpoint)
Median OS: 15.9 vs 14.5 mo
(HR 0.88, 95% CI 0.77-1.00)
Perez et al. 2015 (BEACONbrca) 2011-2013 Phase 3 (C) Etirinotecan pegol Might have inferior OS
Yuan et al. 2019 (E7389-C086-304) 2013-2015 Phase 3 (E-switch-ic) Vinorelbine Seems to have superior PFS (primary endpoint)
Median PFS: 2.8 vs 2.8 mo
(HR 0.80, 95% CI 0.65-0.98)
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

Note: BEACON should not be confused for the trial by the same name in several other cancer types. This dosing is the one commonly used in North America.

Prior treatment criteria

  • EMBRACE: Exposure to between two and five lines of chemotherapy (two or more for advanced disease), including an anthracycline and a taxane, unless these were contraindicated
  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

21-day cycles

References

  1. EMBRACE: Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Diéras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389) investigators. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011 Mar 12;377(9769):914-23. Epub 2011 Mar 2. link to original article contains dosing details in abstract PubMed NCT00388726
  2. E7389-G000-301: Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, Olivo MS, He Y, Dutcus CE, Cortes J. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015 Feb 20;33(6):594-601. Epub 2015 Jan 20. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00337103
  3. BEACONbrca: Perez EA, Awada A, O'Shaughnessy J, Rugo HS, Twelves C, Im SA, Gómez-Pardo P, Schwartzberg LS, Diéras V, Yardley DA, Potter DA, Mailliez A, Moreno-Aspitia A, Ahn JS, Zhao C, Hoch U, Tagliaferri M, Hannah AL, Cortes J. Etirinotecan pegol (NKTR-102) versus treatment of physician's choice in women with advanced breast cancer previously treated with an anthracycline, a taxane, and capecitabine (BEACON): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 2015 Nov;16(15):1556-1568. Epub 2015 Oct 22. link to original article PubMed NCT01492101
  4. E7389-C086-304: Yuan P, Hu X, Sun T, Li W, Zhang Q, Cui S, Cheng Y, Ouyang Q, Wang X, Chen Z, Hiraiwa M, Saito K, Funasaka S, Xu B. Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial. Eur J Cancer. 2019 May;112:57-65. Epub 2019 Mar 29. link to original article contains dosing details in abstract PubMed NCT02225470
  5. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029
  6. EVER-132-002: NCT04639986

Gemcitabine monotherapy

Regimen variant #1, 800 mg/m2 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Carmichael et al. 1995 NR Phase 2
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

Note: this was the lower bound of dosing in DESTINY-Breast04.

Prior treatment criteria

  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

28-day cycles


Regimen variant #2, 1000 mg/m2 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Chemotherapy

28-day cycles


Regimen variant #3, 1200 mg/m2 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Spielmann et al. 2001 NR Phase 2
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

Note: this was the upper bound of dosing in DESTINY-Breast04.

Prior treatment criteria

  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

28-day cycles


Regimen variant #4, 1250 mg/m2 2 weeks out of 3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Gemcitabine & Bevacizumab
1d. Paclitaxel & Bevacizumab
1e. nab-Paclitaxel & Bevacizumab
1f. Vinorelbine & Bevacizumab 		Inferior PFS
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Chemotherapy

21-day cycles

References

  1. Carmichael J, Possinger K, Philip P, Beykirch M, Kerr H, Walling J, Harris AL. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol. 1995 Nov;13(11):2731-6. link to original article contains dosing details in abstract PubMed
  2. Spielmann M, Llombart-Cussac A, Kalla S, Espié M, Namer M, Ferrero JM, Diéras V, Fumoleau P, Cuvier C, Perrocheau G, Ponzio A, Kayitalire L, Pouillart P. Single-agent gemcitabine is active in previously treated metastatic breast cancer. Oncology. 2001;60(4):303-7. link to original article PubMed
  3. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  4. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed
  5. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029
  6. EVER-132-002: NCT04639986

Gemcitabine & Bevacizumab

Regimen variant #1, 1000 mg/m2, 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Chemotherapy

Targeted therapy

28-day cycles


Regimen variant #2, 1250 mg/m2, 2 weeks out of 3

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Gemcitabine
1d. Paclitaxel
1e. nab-Paclitaxel
1f. Vinorelbine 		Superior PFS (primary endpoint)
Median PFS: 7.2 vs 5.1 mo
(HR 0.78, 95% CI 0.64-0.93)
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Chemotherapy

Targeted therapy

21-day cycles

References

  1. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  2. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Ixabepilone monotherapy

Regimen

Study Dates of enrollment Evidence
Perez et al. 2007 (CA163-081) 2004-2005 Phase 2 (RT)

Chemotherapy

21-day cycle for up to 18 cycles

References

  1. CA163-081: Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, Viens P, Cai C, Mullaney B, Peck R, Hortobagyi GN. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007 Aug 10;25(23):3407-14. Epub 2007 Jul 2. link to original article contains dosing details in manuscript PubMed NCT00080262

Non-pegylated liposomal doxorubicin monotherapy

NPLD: Non-Pegylated Liposomal Doxorubicin

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Chemotherapy

21-day cycles

References

  1. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Non-pegylated liposomal doxorubicin & Bevacizumab

NPLD & Bev: Non-Pegylated Liposomal Doxorubicin & Bevacizumab

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Chemotherapy

Targeted therapy

21-day cycles

References

  1. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Paclitaxel monotherapy, weekly

Regimen variant #1, 80 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Perez et al. 2001 NR Phase 2
Seidman et al. 2008 (CALGB 9840) 1998-NR Phase 3 (E-switch-ic) Paclitaxel; q3wk Superior OS (secondary endpoint)
Median OS: 24 vs 12 mo
(HR 0.78, 95% CI 0.65-0.94)
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

Prior treatment criteria

  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

28-day cycles


Regimen variant #2, 90 mg/m2 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Gemcitabine & Bevacizumab
1d. Paclitaxel & Bevacizumab
1e. nab-Paclitaxel & Bevacizumab
1f. Vinorelbine & Bevacizumab 		Inferior PFS

Chemotherapy

28-day cycles

References

  1. Perez EA, Vogel CL, Irwin DH, Kirshner JJ, Patel R. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2001 Nov 15;19(22):4216-23. link to original article PubMed
  2. CALGB 9840: Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. link to original article PubMed NCT00003440
  3. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  4. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029

Paclitaxel monotherapy, q3wk

Regimen variant #1, 135 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Nabholtz et al. 1996 1992-03 to 1992-08 Phase 3 (E-RT-de-esc) Paclitaxel; 175 mg/m2 q3wk Did not meet primary endpoint of ORR1

1Although Nabholtz et al. 1996 did not meet its primary endpoint, there seemed to be a TTP disadvantage in the lower-dose arm.

Chemotherapy

21-day cycles


Regimen variant #2, 175 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Seidman et al. 1995 NR Phase 2
Nabholtz et al. 1996 1992-03 to 1992-08 Phase 3 (E-RT-esc) Paclitaxel; 135 mg/m2 q3wk Did not meet primary endpoint of ORR1
Winer et al. 2004 (CALGB 9342) 1994-1997 Phase 3 (C) 1. Paclitaxel; 210 mg/m2 q3wk
2. Paclitaxel; 250 mg/m2 q3wk 		Did not meet primary endpoint of ORR
Jones et al. 2005 (TAX 311) 1994-2001 Phase 3 (E-switch-ic) Docetaxel Inferior OS (secondary endpoint)
Icli et al. 2005 1997-2002 Phase 3 (C) EoP Seems to have inferior OS
Seidman et al. 2008 (CALGB 9840) 1998-NR Phase 3 (C) Paclitaxel; weekly Inferior OS
Gradishar et al. 2005 (CA012-0) 2001-11 to 2002-11 Phase 3 (C) nab-Paclitaxel Inferior TTP
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Gemcitabine & Bevacizumab
1d. Paclitaxel & Bevacizumab
1e. nab-Paclitaxel & Bevacizumab
1f. Vinorelbine & Bevacizumab 		Inferior PFS
Rugo et al. 2023 (KX-ORAX-001) 2015-12 to 2019-02 Phase 3 (C) Oral paclitaxel and encequidar Might have inferior OS
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

1Although Nabholtz et al. 1996 did not meet its primary endpoint, there seemed to be a TTP advantage in the higher-dose arm, which subsequently led to its adoption as the standard-of-care.

Prior treatment criteria

  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

21-day cycles

References

  1. Seidman AD, Tiersten A, Hudis C, Gollub M, Barrett S, Yao TJ, Lepore J, Gilewski T, Currie V, Crown J, Hakes T, Baselga J, Sklarin N, Moynihan ME, Tong W, Egorin M, Kearns C, Spriggs D, Norton L. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2575-81. link to original article PubMed
  2. Nabholtz JM, Gelmon K, Bontenbal M, Spielmann M, Catimel G, Conte P, Klaassen U, Namer M, Bonneterre J, Fumoleau P, Winograd B. Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol. 1996 Jun;14(6):1858-67. link to original article contains dosing details in abstract PubMed
  3. CALGB 9342: Winer EP, Berry DA, Woolf S, Duggan D, Kornblith A, Harris LN, Michaelson RA, Kirshner JA, Fleming GF, Perry MC, Graham ML, Sharp SA, Keresztes R, Henderson IC, Hudis C, Muss H, Norton L. Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: Cancer and Leukemia Group B trial 9342. J Clin Oncol. 2004 Jun 1;22(11):2061-8. link to original article contains dosing details in abstract PubMed
  4. Icli F, Akbulut H, Uner A, Yalcin B, Baltali E, Altinbas M, Coşkun S, Komurcu S, Erkisi M, Demirkazik A, Senler FC, Sencan O, Büyükcelik A, Boruban C, Onur H, Zengin N, Sak SD; Turkish Oncology Group. Cisplatin plus oral etoposide (EoP) combination is more effective than paclitaxel in patients with advanced breast cancer pretreated with anthracyclines: a randomised phase III trial of Turkish Oncology Group. Br J Cancer. 2005 Feb 28;92(4):639-44. link to original article link to PMC article contains dosing details in abstract PubMed
  5. TAX 311: Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, Laufman L, Sundaram S, Urba WJ, Pritchard KI, Mennel R, Richards D, Olsen S, Meyers ML, Ravdin PM. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005 Aug 20;23(24):5542-51. link to original article contains dosing details in abstract PubMed NCT00002662
  6. CA012-0: Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. link to original article contains dosing details in manuscript PubMed NCT00046527
  7. CALGB 9840: Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. link to original article PubMed NCT00003440
  8. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  9. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029
  10. KX-ORAX-001: Rugo HS, Umanzor GA, Barrios FJ, Vasallo RH, Chivalan MA, Bejarano S, Ramirez JR, Fein L, Kowalyszyn RD, Kramer ED, Wang H, Kwan MR, Cutler DL. Open-Label, Randomized, Multicenter, Phase III Study Comparing Oral Paclitaxel Plus Encequidar Versus Intravenous Paclitaxel in Patients With Metastatic Breast Cancer. J Clin Oncol. 2023 Jan 1;41(1):65-74. Epub 2022 Jul 20. link to original article link to PMC article PubMed NCT02594371

Paclitaxel & Bevacizumab

Regimen variant #1, 90 mg/m2 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Gemcitabine
1d. Paclitaxel
1e. nab-Paclitaxel
1f. Vinorelbine 		Superior PFS (primary endpoint)
Median PFS: 7.2 vs 5.1 mo
(HR 0.78, 95% CI 0.64-0.93)

Chemotherapy

Targeted therapy

28-day cycles


Regimen variant #2, 175 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Gemcitabine
1d. Paclitaxel
1e. nab-Paclitaxel
1f. Vinorelbine 		Superior PFS (primary endpoint)
Median PFS: 7.2 vs 5.1 mo
(HR 0.78, 95% CI 0.64-0.93)

Chemotherapy

Targeted therapy

21-day cycles

References

  1. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697

nab-Paclitaxel monotherapy

Example orders

Regimen variant #1, 100 mg/m2, 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

Note: the details of this regimen are unclear in von Minckwitz et al. 2014.

Prior treatment criteria

  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

28-day cycles


Regimen variant #2, 125 mg/m2, 3 weeks out of 4

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

Prior treatment criteria

  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

28-day cycles


Regimen variant #3, 260 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gradishar et al. 2005 (CA012-0) 2001-11 to 2002-11 Phase 3 (E-RT-switch-ic) Paclitaxel Superior ORR (primary endpoint)
ORR: 33% vs 19%

Superior TTP (secondary endpoint)
Median TTP: 23 vs 16.9 weeks
(HR 0.75)
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Gemcitabine & Bevacizumab
1d. Paclitaxel & Bevacizumab
1e. nab-Paclitaxel & Bevacizumab
1f. Vinorelbine & Bevacizumab 		Inferior PFS
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (C) Trastuzumab deruxtecan Inferior OS

Prior treatment criteria

  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Chemotherapy

Supportive therapy

  • CA012-0: No corticosteroid or antihistamine premedication

21-day cycles


Regimen variant #4, 300 mg/m2 q3wk

Study Dates of enrollment Evidence
Ibrahim et al. 2005 1999-2001 Phase 2 (RT)

Chemotherapy

21-day cycles

References

  1. Ibrahim NK, Samuels B, Page R, Doval D, Patel KM, Rao SC, Nair MK, Bhar P, Desai N, Hortobagyi GN. Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer. J Clin Oncol. 2005 Sep 1;23(25):6019-26. link to original article contains dosing details in abstract PubMed
  2. CA012-0: Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. link to original article contains dosing details in manuscript PubMed NCT00046527
  3. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  4. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed
  5. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029

Paclitaxel, nanoparticle albumin-bound & Bevacizumab

Example orders

Regimen variant #1, 100 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: the schedule of bevacizumab is inferred, as there was insufficient detail in the description in the manuscript.

Chemotherapy

Targeted therapy

28-day cycles


Regimen variant #2, 260 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Gemcitabine
1d. Paclitaxel
1e. nab-Paclitaxel
1f. Vinorelbine 		Superior PFS (primary endpoint)
Median PFS: 7.2 vs 5.1 mo
(HR 0.78, 95% CI 0.64-0.93)
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Chemotherapy

Targeted therapy

21-day cycles

References

  1. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  2. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Pegylated liposomal doxorubicin monotherapy

PLD: Pegylated Liposomal Doxorubicin

Regimen variant #1, 40 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: this is the lower end of the range of pegylated liposomal doxorubicin dosing described in TANIA.

Chemotherapy

28-day cycles


Regimen variant #2, 50 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Keller et al. 2004 NR Phase 3 (E-switch-ic) 1. Mitomycin & Vinblastine
2. Vinorelbine 		Did not meet primary endpoint of PFS
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Doxorubicin & Bevacizumab
1d. NPLD & Bevacizumab
1e. PLD & Bevacizumab
1f. Gemcitabine & Bevacizumab
1g. nab-Paclitaxel & Bevacizumab 		Inferior PFS

Note: this is the higher end of the range of pegylated liposomal doxorubicin dosing described in TANIA.

Chemotherapy

28-day cycles

References

  1. Keller AM, Mennel RG, Georgoulias VA, Nabholtz JM, Erazo A, Lluch A, Vogel CL, Kaufmann M, von Minckwitz G, Henderson IC, Mellars L, Alland L, Tendler C. Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol. 2004 Oct 1;22(19):3893-901. link to original article contains dosing details in abstract PubMed
  2. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Pegylated liposomal doxorubicin & Bevacizumab

PLD & Bev: Pegylated Liposomal Doxorubicin & Bevacizumab

Regimen variant #1, 40 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the lower end of the range of pegylated liposomal doxorubicin dosing described in TANIA.

Chemotherapy

Targeted therapy

28-day cycles


Regimen variant #2, 50 mg/m2

Study Dates of enrollment Evidence Comparator Comparative Efficacy
von Minckwitz et al. 2014 (TANIA) 2011-2013 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Doxorubicin
1d. NPLD
1e. PLD
1f. Gemcitabine
1g. nab-Paclitaxel 		Superior PFS (primary endpoint)
Median PFS: 6.3 vs 4.2 mo
(HR 0.75, 95% CI 0.61-0.93)

Note: this is the higher end of the range of pegylated liposomal doxorubicin dosing described in TANIA.

Chemotherapy

Targeted therapy

28-day cycles

References

  1. TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains dosing details in manuscript PubMed NCT01250379
    1. Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed

Trastuzumab deruxtecan monotherapy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy Comparative Toxicity
Modi et al. 2022 (DESTINY-Breast04) 2018-2021 Phase 3 (E-RT-switch-ooc) Investigator's choice of:
1a. Capecitabine
1b. Eribulin
1c. Gemcitabine
1d. Paclitaxel; weekly
1e. Paclitaxel; q3wk
1f. nab-Paclitaxel 		Superior PFS1 (primary endpoint)
Median PFS: 10.1 vs 5.4 mo
(HR 0.51, 95% CI 0.40-0.64)

Superior OS2 (secondary endpoint)
Median OS: 23.4 vs 16.8 mo
(HR 0.64, 95% CI 0.49-0.84) 		Higher rate of pneumonitis

1Reported efficacy is for the hormone-receptor positive subgroup.
2Reported efficacy is for all enrolled patients.
Note: eribulin was the most commonly used comparator regimen.

Prior treatment criteria

  • DESTINY-Breast04: Exposure to 1 to 2 lines of chemotherapy for metastatic disease

Biomarker eligibility criteria

  • DESTINY-Breast04: HER2 IHC 1+ or HER2 IHC 2+ and FISH negative

Antibody-drug conjugate therapy

21-day cycles

References

  1. DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article contains dosing details in manuscript PubMed NCT03734029

Vinorelbine monotherapy

Regimen variant #1, 25 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Gasparini et al. 1994 1991-1993 Phase 2
Zelek et al. 2001 1997-1999 Phase 2
Decker et al. 2019 (VicTORia) 2011-2016 Randomized Phase 2 (C) Everolimus & Vinorelbine Did not meet primary endpoint of PFS
Yuan et al. 2019 (E7389-C086-304) 2013-2015 Phase 3 (C) Eribulin Seems to have inferior PFS

Chemotherapy

7-day cycles


Regimen variant #2, 30 mg/m2 weekly

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Jones et al. 1995a 1990-1992 Phase 3 (E-switch-ic) Melphalan Seems to have superior OS
Keller et al. 2004 NR Phase 3 (C) 1. Mitomycin & Vinblastine
2. PLD 		Did not meet primary endpoint of PFS

Chemotherapy

7-day cycles


Regimen variant #3, 30 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (C) 1a. Capecitabine & Bevacizumab
1b. Docetaxel & Bevacizumab
1c. Gemcitabine & Bevacizumab
1d. Paclitaxel & Bevacizumab
1e. nab-Paclitaxel & Bevacizumab
1f. Vinorelbine & Bevacizumab 		Inferior PFS

Chemotherapy

21-day cycles


Regimen variant #4, 30 mg/m2 2 out of 3 weeks

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Martín et al. 2007 (GEICAM 2000-04) 2001-2005 Phase 3 (C) Gemcitabine & Vinorelbine Inferior PFS

Chemotherapy

21-day cycles

References

  1. Gasparini G, Caffo O, Barni S, Frontini L, Testolin A, Guglielmi RB, Ambrosini G. Vinorelbine is an active antiproliferative agent in pretreated advanced breast cancer patients: a phase II study. J Clin Oncol. 1994 Oct;12(10):2094-101. link to original article PubMed
  2. Jones S, Winer E, Vogel C, Laufman L, Hutchins L, O'Rourke M, Lembersky B, Budman D, Bigley J, Hohneker J. Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. J Clin Oncol. 1995 Oct;13(10):2567-74. link to original article contains dosing details in abstract PubMed
  3. Zelek L, Barthier S, Riofrio M, Fizazi K, Rixe O, Delord JP, Le Cesne A, Spielmann M. Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer. 2001 Nov 1;92(9):2267-72. link to original article PubMed
  4. Keller AM, Mennel RG, Georgoulias VA, Nabholtz JM, Erazo A, Lluch A, Vogel CL, Kaufmann M, von Minckwitz G, Henderson IC, Mellars L, Alland L, Tendler C. Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol. 2004 Oct 1;22(19):3893-901. link to original article contains dosing details in abstract PubMed
  5. GEICAM 2000-04: Martín M, Ruiz A, Muñoz M, Balil A, García-Mata J, Calvo L, Carrasco E, Mahillo E, Casado A, García-Saenz JA, Escudero MJ, Guillem V, Jara C, Ribelles N, Salas F, Soto C, Morales-Vasquez F, Rodríguez CA, Adrover E, Mel JR; GEICAM. Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. Lancet Oncol. 2007 Mar;8(3):219-25. link to original article contains dosing details in abstract PubMed NCT00128310
  6. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697
  7. E7389-C086-304: Yuan P, Hu X, Sun T, Li W, Zhang Q, Cui S, Cheng Y, Ouyang Q, Wang X, Chen Z, Hiraiwa M, Saito K, Funasaka S, Xu B. Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial. Eur J Cancer. 2019 May;112:57-65. Epub 2019 Mar 29. link to original article contains dosing details in abstract PubMed NCT02225470
  8. VicTORia: Decker T, Marschner N, Muendlein A, Welt A, Hagen V, Rauh J, Schröder H, Jaehnig P, Potthoff K, Lerchenmüller C. VicTORia: a randomised phase II study to compare vinorelbine in combination with the mTOR inhibitor everolimus versus vinorelbine monotherapy for second-line chemotherapy in advanced HER2-negative breast cancer. Breast Cancer Res Treat. 2019 Aug;176(3):637-647. Epub 2019 May 21. link to original article contains dosing details in manuscript PubMed NCT01520103
  9. EVER-132-002: NCT04639986

Vinorelbine & Bevacizumab

Example orders

Regimen variant #1, vinorelbine 25 mg/m2 weekly

Study Dates of enrollment Evidence
Burstein et al. 2008 2001-2002 Phase 2

Chemotherapy

Targeted therapy

14-day cycles


Regimen variant #2, vinorelbine 30 mg/m2 q3wk

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Brufsky et al. 2011 (RIBBON-2) 2006-2008 Phase 3 (E-esc) 1a. Capecitabine
1b. Docetaxel
1c. Gemcitabine
1d. Paclitaxel
1e. nab-Paclitaxel
1f. Vinorelbine 		Superior PFS (primary endpoint)
Median PFS: 7.2 vs 5.1 mo
(HR 0.78, 95% CI 0.64-0.93)

Chemotherapy

Targeted therapy

21-day cycles

References

  1. Burstein HJ, Chen YH, Parker LM, Savoie J, Younger J, Kuter I, Ryan PD, Garber JE, Chen H, Campos SM, Shulman LN, Harris LN, Gelman R, Winer EP. VEGF as a marker for outcome among advanced breast cancer patients receiving anti-VEGF therapy with bevacizumab and vinorelbine chemotherapy. Clin Cancer Res. 2008 Dec 1;14(23):7871-7. link to original article contains dosing details in manuscript PubMed
  2. RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains dosing details in manuscript PubMed NCT00281697

Additional resources

Patient information

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