Breast cancer
Section editor | |
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Gayathri Nagaraj, MD Loma Linda University Loma Linda, CA, USA |
Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
Note: this page contains regimens which were not tested in biomarker-selected populations; many of these trials do still include and stratify patients by biomarker status, however. The following links will take you to biomarker-specific subpages:
- Regimens for ER/PR positive breast cancer are here.
- Regimens for HER2 positive breast cancer are here.
- Regimens for ER/HER2 co-expressing ("double positive") breast cancer are here.
- Regimens for Triple negative breast cancer (TNBC) are here.
- Regimens for BRCA-mutated breast cancer are here.
- Regimens for PIK3CA-mutated breast cancer are here.
- Regimens for CNS metastases are here.
- Because docetaxel and paclitaxel are both often abbreviated as "T," we try to always make clear in the regimen name which agent is being used. For sequential regimens, we use "T" for paclitaxel and "D" for docetaxel; e.g., AC-T and AC-D.
143 regimens on this page
330 variants on this page
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Guidelines
Given the rapid change in evidence in many areas of hematology/oncology, readers are encouraged to consider any guideline published 5+ years ago to be for historical purposes, only.
ASCO/CCO
- 2024: Al Sukhun et al. Systemic Treatment of Patients With Metastatic Breast Cancer: ASCO Resource–Stratified Guideline PubMed
- 2023: Moy et al. Chemotherapy and Targeted Therapy for Endocrine-Pretreated or Hormone Receptor-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update PubMed
- 2022: Moy et al. Chemotherapy and Targeted Therapy for Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer That Is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Rapid Recommendation Update PubMed
- 2021: Moy et al. Chemotherapy and Targeted Therapy for Patients With Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor-Negative: ASCO Guideline Update PubMed
- 2022: Henry et al. Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update PubMed
- 2022: Eisen et al. Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: ASCO-OH (CCO) Guideline Update PubMed
- 2021: Brackstone et al. Management of the Axilla in Early-Stage Breast Cancer: Ontario Health (Cancer Care Ontario) and ASCO Guideline PubMed
- 2017: Lyman et al. Sentinel Lymph Node Biopsy for Patients With Early-Stage Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update PubMed
- 2014: Lyman et al. Sentinel lymph node biopsy for patients with early-stage breast cancer: American Society of Clinical Oncology clinical practice guideline update PubMed
- 2005: Lyman et al. American Society of Clinical Oncology guideline recommendations for sentinel lymph node biopsy in early-stage breast cancer PubMed
- 2021: Burstein et al. Endocrine Treatment and Targeted Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Update link to PMC article PubMed
- 2021: Korde et al. Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline link to PMC article PubMed
- 2020: Denduluri et al. Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update PubMed
- 2018: Denduluri et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO clinical practice guideline focused update PubMed
- 2016: Harris et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology clinical practice guideline PubMed
- 2020: Hassett et al. Management of Male Breast Cancer: ASCO Guideline PubMed
- 2017: Van Poznak et al. Role of bone-modifying agents in metastatic breast cancer: an American Society of Clinical Oncology–Cancer Care Ontario focused guideline update PubMed
- 2015: van Poznak et al. Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology Clinical practice guideline PubMed
- 2014: Partridge et al. Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Clinical Practice Guideline PubMed
ESMO/ESO
- 2023: Loibl et al. Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up PubMed
- 2023: Im et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the diagnosis, staging and treatment of patients with metastatic breast cancer PubMed
- 2022: Paluch-Simon et al. ESO–ESMO fifth international consensus guidelines for breast cancer in young women (BCY5) PubMed
- 2020: Paluch-Shimon et al. ESO–ESMO 4th International Consensus Guidelines for Breast Cancer in Young Women (BCY4) PubMed
- 2021: Gennari et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer PubMed
- 2018: Cardoso et al. 4th ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4) PubMed
- 2017: Cardoso et al. 3rd ESO-ESMO International consensus guidelines for advanced breast cancer (ABC3) PubMed
- 2014: Cardoso et al. ESO-ESMO 2nd International consensus guidelines for advanced breast cancer (ABC2) PubMed
- 2012: Cardoso et al. 1st International consensus guidelines for advanced breast cancer (ABC 1) PubMed
- 2015: Senkus et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2013: Senkus et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2011: Aebi et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2010: Aebi et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2009: Kataja & Castiglione. Primary breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2008: Pestalozzi & Castiglione. Primary breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2007: Pestalozzi. Primary breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2005: Pestalozzi et al. ESMO Minimum Clinical Recommendations for diagnosis, adjuvant treatment and follow-up of primary breast cancer PubMed
- 2001: ESMO Minimum Clinical Recommendations for diagnosis, adjuvant treatment and follow-up of primary breast cancer PubMed
- 2012: Cardoso et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2011: Cardoso et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2010: Cardoso et al. Locally recurrent or metastatic breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up PubMed
- 2009: Cardoso & Castiglione. Locally recurrent or metastatic breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2008: Kataja & Castiglione. Locally recurrent or metastatic breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2007: Kataja. Recurrent or metastatic breast cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up PubMed
- 2005: Kataja et al. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of locally recurrent or metastatic breast cancer (MBC) PubMed
EUSOMA/SIOG
- 2021: Biganzoli et al. Updated recommendations regarding the management of older patients with breast cancer: a joint paper from the European Society of Breast Cancer Specialists (EUSOMA) and the International Society of Geriatric Oncology (SIOG) PubMed
- 2012: Biganzoli et al. Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA) PubMed
- 2007: Wildiers et al. Management of breast cancer in elderly individuals: recommendations of the International Society of Geriatric Oncology PubMed
KSMO/ESMO
- 2020: Park et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with early breast cancer: a KSMO-ESMO initiative endorsed by CSCO, ISMPO, JSMO, MOS, SSO and TOS PubMed
NCCN
- NCCN Guidelines - Breast Cancer
- 2020: Gradishar et al. Breast Cancer, Version 3.2020, NCCN Clinical Practice Guidelines in Oncology. PubMed
- 2019: Telli et al. NCCN Guidelines Updates: Breast Cancer. PubMed
- 2018: Giordano et al. NCCN Guidelines Updates: Breast Cancer. PubMed
- 2018: Gradishar et al. Breast Cancer, Version 4.2017, NCCN Clinical Practice Guidelines in Oncology. PubMed
- 2017: Salerno et al. NCCN Guidelines Update: Evolving Radiation Therapy Recommendations for Breast Cancer. PubMed
- 2016: Gradishar et al. NCCN Guidelines Update: Breast Cancer. PubMed
- 2016: Gradishar et al. Invasive Breast Cancer Version 1.2016, NCCN Clinical Practice Guidelines in Oncology PubMed
- 2015: Gradishar et al. Breast Cancer Version 2.2015 PubMed
- 2014: Gradishar et al. Breast cancer version 3.2014 PubMed
- 2013: Theriault et al. Breast cancer, version 3.2013: featured updates to the NCCN guidelines. link to PMC article PubMed
- 2012: Carlson et al. Metastatic breast cancer, version 1.2012: featured updates to the NCCN guidelines. link to PMC article PubMed
- 2011: Carlson et al. Invasive breast cancer. PubMed
- 2010: Carlson et al. Breast cancer: noninvasive and special situations. PubMed
- 2009: Carlson et al. Breast cancer. Clinical practice guidelines in oncology. PubMed
- 2006: Carlson et al. NCCN Task Force Report: Adjuvant Therapy for Breast Cancer. PubMed
- 2005: Carlson et al. Breast cancer. PubMed
- 2004: Authors not listed. NCCN Guideline update: Breast Cancer Version 1.2004. PubMed
- 2003: Authors not listed. Breast cancer Clinical Practice Guidelines in Oncology. PubMed
- NCCN Guidelines - Genetic/Familial High-Risk Assessment: Breast and Ovarian
SITC
- 2021: Emens et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immunotherapy for the treatment of breast cancer PubMed
St Gallen Breast Guidelines
- 2021: Burstein et al. Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021 link to PMC article PubMed
- 2019: Burstein et al. Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019 PubMed
- 2017: Curigliano et al. St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2017 PubMed
- 2015: Coates et al. Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015 PubMed
Neoadjuvant therapy, sequential regimens
AC-D
AC-D: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Docetaxel
Regimen variant #1, 60/600/75
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kim et al. 2020 (NEST) | 2012-2014 | Phase 3 (C) | Goserelin & Tamoxifen | Inconclusive whether non-inferior clinical response |
Hwang et al. 2023 (Neo-shorter) | 2012-11 to 2015-12 | Phase 3 (C) | FEC-D; 3 x 3 | Non-inferior pCR rate (primary endpoint) |
Chemotherapy, AC portion (cycles 1 to 4)
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, D portion (cycles 5 to 8)
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycle for 8 cycles (AC x 4; T x 4)
Subsequent treatment
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)
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, D portion (cycles 5 to 8)
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
21-day cycle for 8 cycles (AC x 4; T x 4)
Subsequent treatment
References
- NSABP B-27: Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, Wolmark N; National Surgical Adjuvant Breast and Bowel Project. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003 Nov 15;21(22):4165-74. Epub 2003 Oct 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00002707
- Update: Bear HD, Anderson S, Smith RE, Geyer CE Jr, Mamounas EP, Fisher B, Brown AM, Robidoux A, Margolese R, Kahlenberg MS, Paik S, Soran A, Wickerham DL, Wolmark N. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006 May 1;24(13):2019-27. Epub 2006 Apr 10. link to original article PubMed
- Pooled update: Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008 Feb 10;26(5):778-85. Erratum in: J Clin Oncol. 2008 Jun 1;26(16):2793. link to original article PubMed
- GeparDuo: von Minckwitz G, Raab G, Caputo A, Schütte M, Hilfrich J, Blohmer JU, Gerber B, Costa SD, Merkle E, Eidtmann H, Lampe D, Jackisch C, du Bois A, Kaufmann M; GBG. Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol. 2005 Apr 20;23(12):2676-85. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00793377
- NEST: Kim HJ, Noh WC, Lee ES, Jung YS, Kim LS, Han W, Nam SJ, Gong GY, Kim HJ, Ahn SH. Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in pre-menopausal patients with oestrogen receptor-positive and HER2-negative, lymph node-positive breast cancer. Breast Cancer Res. 2020 May 27;22(1):54. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT01622361
- Neo-shorter: Hwang I, Kim JE, Jeong JH, Ahn JH, Jung KH, Son BH, Kim HH, Shin J, Lee HJ, Gong G, Kim SB. Randomized phase III trial of a neoadjuvant regimen of four cycles of adriamycin plus cyclophosphamide followed by four cycles of docetaxel (AC4-D4) versus a shorter treatment of three cycles of FEC followed by three cycles of docetaxel (FEC3-D3) in node-positive breast cancer (Neo-shorter; NCT02001506). Breast Cancer Res Treat. 2023 Sep;201(2):193-204. Epub 2023 Jun 26. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors 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)
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, T portion (cycles 6 to 17)
- Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
21-day cycle for 5 cycles, then 7-day cycle for 12 cycles (AC x 5; T x 12)
Subsequent treatment
References
- SWOG 0012: Ellis GK, Barlow WE, Gralow JR, Hortobagyi GN, Russell CA, Royce ME, Perez EA, Lew D, Livingston RB. Phase III comparison of standard doxorubicin and cyclophosphamide versus weekly doxorubicin and daily oral cyclophosphamide plus granulocyte colony-stimulating factor as neoadjuvant therapy for inflammatory and locally advanced breast cancer: SWOG 0012. J Clin Oncol. 2011 Mar 10;29(8):1014-21. Epub 2011 Jan 10. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article 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)
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
Chemotherapy, AC portion (cycles 5 to 8)
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 8 cycles (D x 4; AC x 4)
Subsequent treatment
References
- NSABP B-40: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00408408
- Update: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Paik S, Swain SM, Mamounas EP, Wolmark N. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1037-1048. Epub 2015 Aug 10. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. link to original article link to PMC article 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)
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
Chemotherapy, AC portion (cycles 5 to 8)
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Targeted therapy, both portions
- Bevacizumab (Avastin) as follows:
- Cycles 1 to 6: 15 mg/kg IV once on day 1
21-day cycle for 8 cycles (D x 4; AC x 4)
Subsequent treatment
References
- NSABP B-40: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00408408
- Update: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Paik S, Swain SM, Mamounas EP, Wolmark N. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1037-1048. Epub 2015 Aug 10. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. link to original article link to PMC article 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)
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
Chemotherapy, FEC portion (cycles 4 to 6)
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 6 cycles (D x 3; FEC x 3)
Subsequent treatment
References
- ARTemis: Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Abraham J, Thomas J, Provenzano E, Hughes-Davies L, Gounaris I, McAdam K, Chan S, Ahmad R, Hickish T, Houston S, Rea D, Bartlett J, Caldas C, Cameron DA, Hayward L; ARTemis Investigators. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):656-66. Epub 2015 May 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01093235
- Update: Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Gounaris I, Abraham JE, Hughes-Davies L, McAdam K, Chan S, Ahmad R, Hickish T, Rea D, Caldas C, Bartlett JMS, Cameron DA, Provenzano E, Thomas J, Hayward RL; ARTemis Investigators Group. Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin and cyclophosphamide, for women with HER2 negative early breast cancer: ARTemis Trial. Ann Oncol. 2017 Aug 1;28(8):1817-1824. link to original article link to PMC article 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)
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
Chemotherapy, FEC portion (cycles 4 to 6)
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
Targeted therapy, both portions
- Bevacizumab (Avastin) as follows:
- Cycles 1 to 4: 15 mg/kg IV once on day 1
21-day cycle for 6 cycles (D x 3; FEC x 3)
Subsequent treatment
References
- ARTemis: Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Abraham J, Thomas J, Provenzano E, Hughes-Davies L, Gounaris I, McAdam K, Chan S, Ahmad R, Hickish T, Houston S, Rea D, Bartlett J, Caldas C, Cameron DA, Hayward L; ARTemis Investigators. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):656-66. Epub 2015 May 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01093235
- Update: Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Gounaris I, Abraham JE, Hughes-Davies L, McAdam K, Chan S, Ahmad R, Hickish T, Rea D, Caldas C, Bartlett JMS, Cameron DA, Provenzano E, Thomas J, Hayward RL; ARTemis Investigators Group. Disease-free and overall survival at 3.5 years for neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin and cyclophosphamide, for women with HER2 negative early breast cancer: ARTemis Trial. Ann Oncol. 2017 Aug 1;28(8):1817-1824. link to original article link to PMC article 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 to not reported | 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)
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, D portion (cycles 5 to 8)
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
21-day cycle for 8 cycles (EC x 4; D x 4)
Subsequent treatment
References
- GeparQuattro: von Minckwitz G, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, Bauerfeind I, Hilfrich J, Eidtmann H, Gerber B, Hanusch C, Kühn T, du Bois A, Blohmer JU, Thomssen C, Dan Costa S, Jackisch C, Kaufmann M, Mehta K, Untch M. Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. J Clin Oncol. 2010 Apr 20;28(12):2015-23. Epub 2010 Mar 22. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00288002
- Update: von Minckwitz G, Rezai M, Fasching PA, Huober J, Tesch H, Bauerfeind I, Hilfrich J, Eidtmann H, Gerber B, Hanusch C, Blohmer JU, Dan Costa S, Jackisch C, Paepke S, Schneeweiss A, Kümmel S, Denkert C, Mehta K, Loibl S, Untch M. Survival after adding capecitabine and trastuzumab to neoadjuvant anthracycline-taxane-based chemotherapy for primary breast cancer (GBG 40--GeparQuattro). Ann Oncol. 2014 Jan;25(1):81-9. Epub 2013 Nov 21. link to original article PubMed
- GeparQuinto: von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Kreienberg R, Solbach C, Gerber B, Jackisch C, Kunz G, Blohmer JU, Huober J, Hauschild M, Fehm T, Müller BM, Denkert C, Loibl S, Nekljudova V, Untch M; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie–Breast Study Groups. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012 Jan 26;366(4):299-309. link to original article dosing details in manuscript have been reviewed by our editors 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)
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, T portion (cycles 5 to 8)
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycle for 8 cycles (EC x 4; T x 4)
Subsequent treatment
References
- PREPARE: Untch M, von Minckwitz G, Konecny GE, Conrad U, Fett W, Kurzeder C, Lück HJ, Stickeler E, Urbaczyk H, Liedtke B, Beckmann MW, Salat C, Harbeck N, Müller V, Schmidt M, Hasmüller S, Lenhard M, Nekljudova V, Lebeau A, Loibl S, Fasching PA; Arbeitsgemeinschaft Gynäkologische Onkologie PREPARE investigators. PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel, and CMF versus a standard-dosed epirubicin-cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer--outcome on prognosis. Ann Oncol. 2011 Sep;22(9):1999-2006. Epub 2011 Mar 7. link to original article dosing details in abstract have been reviewed by our editors 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)
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, ddT portion (cycles 5 to 8)
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
Supportive therapy, T portion
- Primary G-CSF propyhylaxis not provided
21-day cycle for 4 cycles, then 14-day cycle for 4 cycles (EC x 4; ddT x 4)
Subsequent treatment
References
- Neo-tAnGo: Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, Iddawela M, Abraham J, Hughes-Davies L, Gounaris I, McAdam K, Houston S, Hickish T, Skene A, Chan S, Dean S, Ritchie D, Laing R, Harries M, Gallagher C, Wishart G, Dunn J, Provenzano E, Caldas C; Neo-tAnGo Investigators. Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2x2 factorial randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):201-12. Epub 2013 Dec 19. link to original article dosing details in manuscript have been reviewed by our editors 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)
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
Chemotherapy, D portion (cycles 4 to 6)
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 6 cycles (FEC x 3; D x 3)
Subsequent treatment
References
- Neo-shorter: Hwang I, Kim JE, Jeong JH, Ahn JH, Jung KH, Son BH, Kim HH, Shin J, Lee HJ, Gong G, Kim SB. Randomized phase III trial of a neoadjuvant regimen of four cycles of adriamycin plus cyclophosphamide followed by four cycles of docetaxel (AC4-D4) versus a shorter treatment of three cycles of FEC followed by three cycles of docetaxel (FEC3-D3) in node-positive breast cancer (Neo-shorter; NCT02001506). Breast Cancer Res Treat. 2023 Sep;201(2):193-204. Epub 2023 Jun 26. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors 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)
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m2 IV once on day 1
Chemotherapy, EC portion (cycles 13 to 16)
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (nP x 12; EC x 4)
Subsequent treatment
References
- GeparSepto: Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Wiebringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Darb-Esfahani S, Schmitt WD, Dan Costa S, Gerber B, Engels K, Nekljudova V, Loibl S, von Minckwitz G; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie—Breast (AGO-B) Investigators. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):345-56. Epub 2016 Feb 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01583426
- Update: Furlanetto J, Jackisch C, Untch M, Schneeweiss A, Schmatloch S, Aktas B, Denkert C, Wiebringhaus H, Kümmel S, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Costa SD, Gerber B, Nekljudova V, Loibl S, von Minckwitz G. Efficacy and safety of nab-paclitaxel 125 mg/m(2) and nab-paclitaxel 150 mg/m(2) compared to paclitaxel in early high-risk breast cancer: results from the neoadjuvant randomized GeparSepto study (GBG 69). Breast Cancer Res Treat. 2017 Jun;163(3):495-506. Epub 2017 Mar 17. link to original article PubMed
- ETNA: Gianni L, Mansutti M, Anton A, Calvo L, Bisagni G, Bermejo B, Semiglazov V, Thill M, Chacon JI, Chan A, Morales S, Alvarez I, Plazaola A, Zambetti M, Redfern AD, Dittrich C, Dent RA, Magazzù D, De Fato R, Valagussa P, Tusquets I. Comparing neoadjuvant nab-paclitaxel vs paclitaxel both followed by anthracycline regimens in women with ERBB2/HER2-negative breast cancer-the Evaluating Treatment with Neoadjuvant Abraxane (ETNA) trial: a randomized phase 3 clinical trial. JAMA Oncol. 2018 Mar 1;4(3):302-308. Epub 2018 Jan 11. link to original article dosing details in manuscript have been reviewed by our editors 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)
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m2 IV once on day 1
Chemotherapy, ddEC portion (cycles 9 to 12)
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Supportive therapy, ddEC portion (cycles 9 to 12)
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2, given 24 hours after chemotherapy
7-day cycle for 8 cycles, then 14-day cycle for 4 cycles (nP x 8; ddEC x 4)
Subsequent treatment
References
- WSG-ADAPT-HR+/HER2-: Gluz O, Kuemmel S, Nitz U, Braun M, Lüdtke-Heckenkamp K, von Schumann R, Darsow M, Forstbauer H, Potenberg J, Uleer C, Grischke EM, Aktas B, Schumacher C, Zu Eulenburg C, Kates R, Jóźwiak K, Graeser M, Wuerstlein R, Baehner R, Christgen M, Kreipe HH, Harbeck N. Nab-paclitaxel weekly versus dose-dense solvent-based paclitaxel followed by dose-dense epirubicin plus cyclophosphamide in high-risk HR+/HER2- early breast cancer: results from the neoadjuvant part of the WSG-ADAPT-HR+/HER2- trial. Ann Oncol. 2023 Jun;34(6):531-542. Epub 2023 Apr 14. link to original article dosing details in manuscript have been reviewed by our editors 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)
- Paclitaxel (Taxol) 90 mg/m2 IV once per day on days 1, 8, 15
Chemotherapy, AC portion (cycles 5 to 8)
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
28-day cycle for 4 cycles, then 21-day cycle for 4 cycles (T x 4; AC x 4)
Subsequent treatment
References
- ETNA: Gianni L, Mansutti M, Anton A, Calvo L, Bisagni G, Bermejo B, Semiglazov V, Thill M, Chacon JI, Chan A, Morales S, Alvarez I, Plazaola A, Zambetti M, Redfern AD, Dittrich C, Dent RA, Magazzù D, De Fato R, Valagussa P, Tusquets I. Comparing neoadjuvant nab-paclitaxel vs paclitaxel both followed by anthracycline regimens in women with ERBB2/HER2-negative breast cancer-the Evaluating Treatment with Neoadjuvant Abraxane (ETNA) trial: a randomized phase 3 clinical trial. JAMA Oncol. 2018 Mar 1;4(3):302-308. Epub 2018 Jan 11. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article 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)
- Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
Chemotherapy, EC portion (cycles 13 to 16)
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (T x 12; EC x 4)
Subsequent treatment
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)
- Paclitaxel (Taxol) 90 mg/m2 IV once per day on days 1, 8, 15
Chemotherapy, EC portion (cycles 5 to 8)
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
28-day cycle for 4 cycles, then 21-day cycle for 4 cycles (T x 4; EC x 4)
Subsequent treatment
References
- GeparSepto: Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Wiebringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Darb-Esfahani S, Schmitt WD, Dan Costa S, Gerber B, Engels K, Nekljudova V, Loibl S, von Minckwitz G; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie—Breast (AGO-B) Investigators. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):345-56. Epub 2016 Feb 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01583426
- Update: Furlanetto J, Jackisch C, Untch M, Schneeweiss A, Schmatloch S, Aktas B, Denkert C, Wiebringhaus H, Kümmel S, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Costa SD, Gerber B, Nekljudova V, Loibl S, von Minckwitz G. Efficacy and safety of nab-paclitaxel 125 mg/m(2) and nab-paclitaxel 150 mg/m(2) compared to paclitaxel in early high-risk breast cancer: results from the neoadjuvant randomized GeparSepto study (GBG 69). Breast Cancer Res Treat. 2017 Jun;163(3):495-506. Epub 2017 Mar 17. link to original article PubMed
- ETNA: Gianni L, Mansutti M, Anton A, Calvo L, Bisagni G, Bermejo B, Semiglazov V, Thill M, Chacon JI, Chan A, Morales S, Alvarez I, Plazaola A, Zambetti M, Redfern AD, Dittrich C, Dent RA, Magazzù D, De Fato R, Valagussa P, Tusquets I. Comparing neoadjuvant nab-paclitaxel vs paclitaxel both followed by anthracycline regimens in women with ERBB2/HER2-negative breast cancer-the Evaluating Treatment with Neoadjuvant Abraxane (ETNA) trial: a randomized phase 3 clinical trial. JAMA Oncol. 2018 Mar 1;4(3):302-308. Epub 2018 Jan 11. link to original article dosing details in manuscript have been reviewed by our editors 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)
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
Supportive therapy, T portion
- Primary G-CSF propyhylaxis not provided
Chemotherapy, EC portion (cycles 5 to 8)
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
14-day cycle for 4 cycles, then 21-day cycle for 4 cycles (ddT x 4; EC x 4)
Subsequent treatment
References
- Neo-tAnGo: Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, Iddawela M, Abraham J, Hughes-Davies L, Gounaris I, McAdam K, Houston S, Hickish T, Skene A, Chan S, Dean S, Ritchie D, Laing R, Harries M, Gallagher C, Wishart G, Dunn J, Provenzano E, Caldas C; Neo-tAnGo Investigators. Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2x2 factorial randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):201-12. Epub 2013 Dec 19. link to original article dosing details in manuscript have been reviewed by our editors 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)
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
Chemotherapy, ddEC portion (cycles 5 to 8)
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Supportive therapy, ddEC portion (cycles 5 to 8)
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2, given 24 hours after chemotherapy
14-day cycle for 8 cycles (ddT x 4; ddEC x 4)
Subsequent treatment
References
- WSG-ADAPT-HR+/HER2-: Gluz O, Kuemmel S, Nitz U, Braun M, Lüdtke-Heckenkamp K, von Schumann R, Darsow M, Forstbauer H, Potenberg J, Uleer C, Grischke EM, Aktas B, Schumacher C, Zu Eulenburg C, Kates R, Jóźwiak K, Graeser M, Wuerstlein R, Baehner R, Christgen M, Kreipe HH, Harbeck N. Nab-paclitaxel weekly versus dose-dense solvent-based paclitaxel followed by dose-dense epirubicin plus cyclophosphamide in high-risk HR+/HER2- early breast cancer: results from the neoadjuvant part of the WSG-ADAPT-HR+/HER2- trial. Ann Oncol. 2023 Jun;34(6):531-542. Epub 2023 Apr 14. link to original article dosing details in manuscript have been reviewed by our editors 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)
- Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
Chemotherapy, FAC portion (cycles 13 to 16)
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 4
- Doxorubicin (Adriamycin) 16.7 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m2)
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (T x 12; FAC x 4)
Subsequent treatment
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)
- Paclitaxel (Taxol) 150 mg/m2 IV over 3 hours once per day on days 1, 8, 15
Chemotherapy, FAC portion (cycles 5 to 8)
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 4
- Doxorubicin (Adriamycin) 16.7 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m2)
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
28-day cycle for 4 cycles, then 21-day cycle for 4 cycles (T x 4; FAC x 4)
Subsequent treatment
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)
- Paclitaxel (Taxol) 225 mg/m2 IV continuous infusion over 24 hours, started on day 1
Chemotherapy, FAC portion (cycles 5 to 8)
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 4
- Doxorubicin (Adriamycin) 16.7 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m2)
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 8 cycles (T x 4; FAC x 4)
Subsequent treatment
References
- Green MC, Buzdar AU, Smith T, Ibrahim NK, Valero V, Rosales MF, Cristofanilli M, Booser DJ, Pusztai L, Rivera E, Theriault RL, Carter C, Frye D, Hunt KK, Symmans WF, Strom EA, Sahin AA, Sikov W, Hortobagyi GN. Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol. 2005 Sep 1;23(25):5983-92. Epub 2005 Aug 8. link to original article dosing details in manuscript have been reviewed by our editors 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)
- Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
Chemotherapy, FEC portion (cycles 13 to 16)
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (T x 12; FEC x 4)
Subsequent treatment
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)
- Paclitaxel (Taxol) 90 mg/m2 IV once per day on days 1, 8, 15
Chemotherapy, FEC portion (cycles 5 to 8)
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
28-day cycle for 4 cycles, then 21-day cycle for 4 cycles (T x 4; FEC x 4)
Subsequent treatment
References
- MDACC ID01-580: Kelly CM, Green MC, Broglio K, Thomas ES, Brewster AM, Valero V, Ibrahim NK, Gonzalez-Angulo AM, Booser DJ, Walters RS, Hunt KK, Hortobagyi GN, Buzdar AU. Phase III trial evaluating weekly paclitaxel versus docetaxel in combination with capecitabine in operable breast cancer. J Clin Oncol. 2012 Mar 20;30(9):930-5. Epub 2012 Feb 13. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00050167
- ETNA: Gianni L, Mansutti M, Anton A, Calvo L, Bisagni G, Bermejo B, Semiglazov V, Thill M, Chacon JI, Chan A, Morales S, Alvarez I, Plazaola A, Zambetti M, Redfern AD, Dittrich C, Dent RA, Magazzù D, De Fato R, Valagussa P, Tusquets I. Comparing neoadjuvant nab-paclitaxel vs paclitaxel both followed by anthracycline regimens in women with ERBB2/HER2-negative breast cancer-the Evaluating Treatment with Neoadjuvant Abraxane (ETNA) trial: a randomized phase 3 clinical trial. JAMA Oncol. 2018 Mar 1;4(3):302-308. Epub 2018 Jan 11. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article 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
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 4 cycles
Subsequent treatment
References
- Lee KS, Ro J, Nam BH, Lee ES, Kwon Y, Kwon HS, Chung KW, Kang HS, Kim EA, Kim SW, Shin KH, Kim SK. A randomized phase-III trial of docetaxel/capecitabine versus doxorubicin/cyclophosphamide as primary chemotherapy for patients with stage II/III breast cancer. Breast Cancer Res Treat. 2008 Jun;109(3):481-9. Epub 2007 Jul 26. link to original article dosing details in manuscript have been reviewed by our editors 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
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Regimen variant #2, 6 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Smith et al. 2004 (TOPIC) | 1995-1999 | Phase 3 (C) | ECisF | Did not meet co-primary endpoints of RFS/OS |
Chua et al. 2005 (TOPIC 2) | 1998-2002 | Phase 3 (C) | VE | Did not meet primary endpoint of RFS |
Evans et al. 2005 | 1999-2001 | Phase 3 (C) | AD | Did not meet primary endpoint of ORR |
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Subsequent treatment
References
- NSABP B-18: Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB Jr, Fisher ER, Wickerham DL, Wolmark N, DeCillis A, Hoehn JL, Lees AW, Dimitrov NV. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997 Jul;15(7):2483-93. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, Wickerham DL, Begovic M, DeCillis A, Robidoux A, Margolese RG, Cruz AB Jr, Hoehn JL, Lees AW, Dimitrov NV, Bear HD. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998 Aug;16(8):2672-85. link to original article PubMed
- Update: Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst. 2001;(30):96-102. link to original article PubMed
- Pooled update: Taghian A, Jeong JH, Mamounas E, Anderson S, Bryant J, Deutsch M, Wolmark N. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol. 2004 Nov 1;22(21):4247-54. Epub 2004 Sep 27. link to original article PubMed
- Pooled update: Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008 Feb 10;26(5):778-85. Erratum in: J Clin Oncol. 2008 Jun 1;26(16):2793. link to original article PubMed
- NSABP B-27: Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, Wolmark N; National Surgical Adjuvant Breast and Bowel Project. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003 Nov 15;21(22):4165-74. Epub 2003 Oct 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00002707
- Update: Bear HD, Anderson S, Smith RE, Geyer CE Jr, Mamounas EP, Fisher B, Brown AM, Robidoux A, Margolese R, Kahlenberg MS, Paik S, Soran A, Wickerham DL, Wolmark N. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006 May 1;24(13):2019-27. Epub 2006 Apr 10. link to original article PubMed
- Pooled update: Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008 Feb 10;26(5):778-85. Erratum in: J Clin Oncol. 2008 Jun 1;26(16):2793. link to original article PubMed
- TOPIC: Smith IE, A'Hern RP, Coombes GA, Howell A, Ebbs SR, Hickish TF, O'Brien ME, Mansi JL, Wilson CB, Robinson AC, Murray PA, Price CG, Perren TJ, Laing RW, Bliss JM; TOPIC Trial Group. A novel continuous infusional 5-fluorouracil-based chemotherapy regimen compared with conventional chemotherapy in the neo-adjuvant treatment of early breast cancer: 5 year results of the TOPIC trial. Ann Oncol. 2004 May;15(5):751-8. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Evans TR, Yellowlees A, Foster E, Earl H, Cameron DA, Hutcheon AW, Coleman RE, Perren T, Gallagher CJ, Quigley M, Crown J, Jones AL, Highley M, Leonard RC, Mansi JL; Anglo-Celtic Cooperative Oncology Group. Phase III randomized trial of doxorubicin and docetaxel versus doxorubicin and cyclophosphamide as primary medical therapy in women with breast cancer: an Anglo-Celtic Cooperative Oncology Group study. J Clin Oncol. 2005 May 1;23(13):2988-95. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Mansi JL, Yellowlees A, Lipscombe J, Earl HM, Cameron DA, Coleman RE, Perren T, Gallagher CJ, Quigley M, Crown J, Jones AL, Highley M, Leonard RC, Evans TR. Five-year outcome for women randomised in a phase III trial comparing doxorubicin and cyclophosphamide with doxorubicin and docetaxel as primary medical therapy in early breast cancer: an Anglo-Celtic Cooperative Oncology Group study. Breast Cancer Res Treat. 2010 Aug;122(3):787-94. Epub 2010 Jun 18. link to original article PubMed
- TOPIC 2: Chua S, Smith IE, A'Hern RP, Coombes GA, Hickish TF, Robinson AC, Laing RW, O'Brien ME, Ebbs SR, Hong A, Wardley A, Mughal T, Verrill M, Dubois D, Bliss JM; TOPIC Trial Group. Neoadjuvant vinorelbine/epirubicin (VE) versus standard adriamycin/cyclophosphamide (AC) in operable breast cancer: analysis of response and tolerability in a randomised phase III trial (TOPIC 2). Ann Oncol. 2005 Sep;16(9):1435-41. Epub 2005 Jun 9. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Lee KS, Ro J, Nam BH, Lee ES, Kwon Y, Kwon HS, Chung KW, Kang HS, Kim EA, Kim SW, Shin KH, Kim SK. A randomized phase-III trial of docetaxel/capecitabine versus doxorubicin/cyclophosphamide as primary chemotherapy for patients with stage II/III breast cancer. Breast Cancer Res Treat. 2008 Jun;109(3):481-9. Epub 2007 Jul 26. link to original article dosing details in manuscript have been reviewed by our editors 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
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Supportive therapy
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2, given 24 hours after chemotherapy
- Burstein et al. 2005, for patients with Hb 10 to 12 g/dL:
- Darbepoetin alfa (Aranesp) 200 mcg SC once on day 1
- See Burstein et al. 2005 for additional dose adjustments
- Darbepoetin alfa (Aranesp) 200 mcg SC once on day 1
14-day cycle for 4 cycles
Subsequent treatment
- Optional neoadjuvant dose-dense paclitaxel, then surgery or surgery, then adjuvant dose-dense paclitaxel; this was not a randomization
References
- Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. link to original article dosing details in manuscript have been reviewed by our editors 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
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1, given second
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1, given first
Supportive therapy
- Filgrastim (Neupogen) (route/dose not specified) once per day on days 5 to 10
14-day cycle for 4 cycles
References
- GeparDuo: von Minckwitz G, Raab G, Caputo A, Schütte M, Hilfrich J, Blohmer JU, Gerber B, Costa SD, Merkle E, Eidtmann H, Lampe D, Jackisch C, du Bois A, Kaufmann M; GBG. Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol. 2005 Apr 20;23(12):2676-85. link to original article dosing details in manuscript have been reviewed by our editors 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
- Epirubicin (Ellence) 150 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 4000 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- Surgery, then adjuvant Docetaxel & 5-FU versus no further treatment
References
- UNICANCER PEGASE 07: Gonçalves A, Pierga JY, Ferrero JM, Mouret-Reynier MA, Bachelot T, Delva R, Fabbro M, Lerebours F, Lotz JP, Linassier C, Dohollou N, Eymard JC, Leduc B, Lemonnier J, Martin AL, Boher JM, Viens P, Roché H. UNICANCER-PEGASE 07 study: a randomized phase III trial evaluating postoperative docetaxel-5FU regimen after neoadjuvant dose-intense chemotherapy for treatment of inflammatory breast cancer. Ann Oncol. 2015 Aug;26(8):1692-7. Epub 2015 May 5. link to original article dosing details in abstract have been reviewed by our editors 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
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
21-day cycle for 3 cycles
Subsequent treatment
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
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
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
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Subsequent treatment
References
- ABCSG-14: Steger GG, Galid A, Gnant M, Mlineritsch B, Lang A, Tausch C, Rudas M, Greil R, Wenzel C, Singer CF, Haid A, Pöstlberger S, Samonigg H, Luschin-Ebengreuth G, Kwasny W, Klug E, Kubista E, Menzel C, Jakesz R; ABCSG. Pathologic complete response with six compared with three cycles of neoadjuvant epirubicin plus docetaxel and granulocyte colony-stimulating factor in operable breast cancer: results of ABCSG-14. J Clin Oncol. 2007 May 20;25(15):2012-8. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Han S, Kim J, Lee J, Chang E, Gwak G, Cho H, Yang KH, Park S, Park K. Comparison of 6 cycles versus 4 cycles of neoadjuvant epirubicin plus docetaxel chemotherapy in stages II and III breast cancer. Eur J Surg Oncol. 2009 Jun;35(6):583-7. Epub 2009 Feb 5. link to original article dosing details in abstract have been reviewed by our editors PubMed
- ABCSG-24: Steger GG, Greil R, Lang A, Rudas M, Fitzal F, Mlineritsch B, Hartmann BL, Bartsch R, Melbinger E, Hubalek M, Stoeger H, Dubsky P, Ressler S, Petzer AL, Singer CF, Muss C, Jakesz R, Gampenrieder SP, Zielinski CC, Fesl C, Gnant M; ABCSG. Epirubicin and docetaxel with or without capecitabine as neoadjuvant treatment for early breast cancer: final results of a randomized phase III study (ABCSG-24). Ann Oncol. 2014 Feb;25(2):366-71. Epub 2013 Dec 16. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00309556
- CBCRT01: Chen J, Yao Q, Huang M, Wang B, Zhang J, Wang T, Ming Y, Zhou X, Jia Q, Huan Y, Wang J, Wang L. A randomized Phase III trial of neoadjuvant recombinant human endostatin, docetaxel and epirubicin as first-line therapy for patients with breast cancer (CBCRT01). Int J Cancer. 2018 May 15;142(10):2130-2138. Epub 2017 Dec 23. link to original article dosing details in manuscript have been reviewed by our editors 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
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 6 cycles
Subsequent treatment
References
- ABCSG-24: Steger GG, Greil R, Lang A, Rudas M, Fitzal F, Mlineritsch B, Hartmann BL, Bartsch R, Melbinger E, Hubalek M, Stoeger H, Dubsky P, Ressler S, Petzer AL, Singer CF, Muss C, Jakesz R, Gampenrieder SP, Zielinski CC, Fesl C, Gnant M; ABCSG. Epirubicin and docetaxel with or without capecitabine as neoadjuvant treatment for early breast cancer: final results of a randomized phase III study (ABCSG-24). Ann Oncol. 2014 Feb;25(2):366-71. Epub 2013 Dec 16. link to original article dosing details in manuscript have been reviewed by our editors 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
- Epirubicin (Ellence) 60 mg/m2 IV once per day on days 1 & 2
21-day cycle for 3 to 4 cycles
Subsequent treatment
References
- Bottini A, Berruti A, Brizzi MP, Bersiga A, Generali D, Allevi G, Aguggini S, Bolsi G, Bonardi S, Tondelli B, Vana F, Tampellini M, Alquati P, Dogliotti L. Cytotoxic and antiproliferative activity of the single agent epirubicin versus epirubicin plus tamoxifen as primary chemotherapy in human breast cancer: a single-institution phase III trial. Endocr Relat Cancer. 2005 Jun;12(2):383-92. link to original article dosing details in manuscript have been reviewed by our editors 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
- Epirubicin (Ellence) 90 mg/m2 IV bolus once on day 1, given first
- Paclitaxel (Taxol) 175 mg/m2 IV over 60 minutes once on day 1, given second
21-day cycle for 4 cycles
References
- Frasci G, D'Aiuto G, Comella P, Thomas R, Botti G, Di Bonito M, De Rosa V, Iodice G, Rubulotta MR, Comella G; Southern Italy Cooperative Oncology Group. Weekly cisplatin, epirubicin, and paclitaxel with granulocyte colony-stimulating factor support vs triweekly epirubicin and paclitaxel in locally advanced breast cancer: final analysis of a SICOG phase III study. Br J Cancer. 2006 Oct 23;95(8):1005-12. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed
- TECHNO: Untch M, Möbus V, Kuhn W, Muck BR, Thomssen C, Bauerfeind I, Harbeck N, Werner C, Lebeau A, Schneeweiss A, Kahlert S, von Koch F, Petry KU, Wallwiener D, Kreienberg R, Albert US, Lück HJ, Hinke A, Jänicke F, Konecny GE. Intensive dose-dense compared with conventionally scheduled preoperative chemotherapy for high-risk primary breast cancer. J Clin Oncol. 2009 Jun 20;27(18):2938-45. Epub 2009 Apr 13. link to original article dosing details in manuscript have been reviewed by our editors 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
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
Regimen variant #2, 600/50/600
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Baldini et al. 1997 | Not reported in abstract | Phase 3 (C) | DES-CAF | Did not meet primary endpoint of pCR rate |
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 3 cycles
Subsequent treatment
Regimen variant #3, 1000/50/500
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Buzdar et al. 1999 | 1994-1998 | Phase 3 (C) | Paclitaxel; q3wk x 4 | Did not meet primary endpoint of DFS |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 4
- Doxorubicin (Adriamycin) 16.7 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m2)
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 4 cycles
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
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1, 3, 5, 8
- Doxorubicin (Adriamycin) 25 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 5
28-day cycle for 4 cycles
Subsequent treatment
References
- S6: Scholl SM, Fourquet A, Asselain B, Pierga JY, Vilcoq JR, Durand JC, Dorval T, Palangié T, Jouve M, Beuzeboc P, Garcio-Giralt E, Salmon RJ, de la Rochefordiere A, Campana F, Pouillart P. Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: preliminary results of a randomised trial: S6. Eur J Cancer. 1994;30A(5):645-52. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Baldini E, Gardin G, Giannessi P, Brema F, Camorriano A, Carnino F, Naso C, Pastorino G, Pronzato P, Rosso R, Rubagotti A, Torretta G, Conte PF; North-West Oncology Group. A randomized trial of chemotherapy with or without estrogenic recruitment in locally advanced breast cancer. Tumori. 1997 Sep-Oct;83(5):829-33. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Buzdar AU, Singletary SE, Theriault RL, Booser DJ, Valero V, Ibrahim N, Smith TL, Asmar L, Frye D, Manuel N, Kau SW, McNeese M, Strom E, Hunt K, Ames F, Hortobagyi GN. Prospective evaluation of paclitaxel versus combination chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide as neoadjuvant therapy in patients with operable breast cancer. J Clin Oncol. 1999 Nov;17(11):3412-7. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- MDACC 91-0156: Arun BK, Dhinghra K, Valero V, Kau SW, Broglio K, Booser D, Guerra L, Yin G, Walters R, Sahin A, Ibrahim N, Buzdar AU, Frye D, Sneige N, Strom E, Ross M, Theriault RL, Vadhan-Raj S, Hortobagyi GN. Phase III randomized trial of dose intensive neoadjuvant chemotherapy with or without G-CSF in locally advanced breast cancer: long-term results. Oncologist. 2011;16(11):1527-34. Epub 2011 Oct 31. link to original article dosing details in abstract have been reviewed by our editors 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
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 3 cycles
Regimen variant #2, 600/60/600 x 4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
van der Hage et al. 2001 (EORTC 10902) | 1991-1999 | Phase 3 (E-switch-ic) | FEC; adjuvant | Did not meet primary endpoint of OS |
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
Regimen variant #3, 1000/120/1050 x 6
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Therasse et al. 2003 (EORTC 10921) | 1993-1996 | Phase 3 (C) | ddEC | Did not meet primary endpoint of PFS |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Epirubicin (Ellence) 60 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 75 mg/m2 PO once per day on days 1 to 14
28-day cycle for 6 cycles
Subsequent treatment
References
- EORTC 10902: van der Hage JA, van de Velde CJ, Julien JP, Tubiana-Hulin M, Vandervelden C, Duchateau L. Preoperative chemotherapy in primary operable breast cancer: results from the European Organisation for Research and Treatment of Cancer trial 10902. J Clin Oncol. 2001 Nov 15;19(22):4224-37. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: van Nes JG, Putter H, Julien JP, Tubiana-Hulin M, van de Vijver M, Bogaerts J, de Vos M, van de Velde CJ; Cooperating Investigators of the EORTC. Preoperative chemotherapy is safe in early breast cancer, even after 10 years of follow-up; clinical and translational results from the EORTC trial 10902. Breast Cancer Res Treat. 2009 May;115(1):101-13. Epub 2008 May 18. link to original article PubMed
- Baldini E, Gardin G, Giannessi PG, Evangelista G, Roncella M, Prochilo T, Collecchi P, Rosso R, Lionetto R, Bruzzi P, Mosca F, Conte PF. Accelerated versus standard cyclophosphamide, epirubicin and 5-fluorouracil or cyclophosphamide, methotrexate and 5-fluorouracil: a randomized phase III trial in locally advanced breast cancer. Ann Oncol. 2003 Feb;14(2):227-32. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- EORTC 10921: Therasse P, Mauriac L, Welnicka-Jaskiewicz M, Bruning P, Cufer T, Bonnefoi H, Tomiak E, Pritchard KI, Hamilton A, Piccart MJ; EORTC. Final results of a randomized phase III trial comparing cyclophosphamide, epirubicin, and fluorouracil with a dose-intensified epirubicin and cyclophosphamide + filgrastim as neoadjuvant treatment in locally advanced breast cancer: an EORTC-NCIC-SAKK multicenter study. J Clin Oncol. 2003 Mar 1;21(5):843-50. link to original article dosing details in abstract have been reviewed by our editors 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)
- Epirubicin (Ellence) 150 mg/m2 IV once on day 1
Chemotherapy, iddP portion (cycles 4 to 6)
- Paclitaxel (Taxol) 225 mg/m2 IV once on day 1
Chemotherapy, iddC portion (cycles 7 to 9)
- Cyclophosphamide (Cytoxan) 2000 mg/m2 IV once on day 1
Supportive therapy, all portions (cycles 1 to 9)
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4
14-day cycle for 9 cycles (iddE x 3; iddP x 3; iddC x 3)
Subsequent treatment
References
- GeparOcto: Schneeweiss A, Möbus V, Tesch H, Hanusch C, Denkert C, Lübbe K, Huober J, Klare P, Kümmel S, Untch M, Kast K, Jackisch C, Thomalla J, Ingold-Heppner B, Blohmer JU, Rezai M, Frank M, Engels K, Rhiem K, Fasching PA, Nekljudova V, von Minckwitz G, Loibl S. Intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for neoadjuvant treatment of high-risk early breast cancer (GeparOcto-GBG 84): A randomised phase III trial. Eur J Cancer. 2019 Jan;106:181-192. Epub 2018 Dec 5. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT02125344
- Update: Schneeweiss A, Michel LL, Möbus V, Tesch H, Klare P, Hahnen E, Denkert C, Kast K, Pohl-Rescigno E, Hanusch C, Link T, Untch M, Jackisch C, Blohmer JU, Fasching PA, Solbach C, Schmutzler RK, Huober J, Rhiem K, Nekljudova V, Lübbe K, Loibl S; GBG and AGO-B. Survival analysis of the randomised phase III GeparOcto trial comparing neoadjuvant chemotherapy of intense dose-dense epirubicin, paclitaxel, cyclophosphamide versus weekly paclitaxel, liposomal doxorubicin (plus carboplatin in triple-negative breast cancer) for patients with high-risk early breast cancer. Eur J Cancer. 2022 Jan;160:100-111. Epub 2021 Nov 17. link to original article 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
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
Supportive therapy
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2
14-day cycle for 4 cycles
Subsequent treatment
References
- Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. link to original article dosing details in manuscript have been reviewed by our editors 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
- Cisplatin (Platinol) 30 mg/m2 IV over 30 minutes once on day 1, given third
- Epirubicin (Ellence) 50 mg/m2 IV bolus once on day 1, given first
- Paclitaxel (Taxol) 120 mg/m2 IV over 60 minutes once on day 1, given second
7-day cycle for 12 cycles
Subsequent treatment
References
- Frasci G, D'Aiuto G, Comella P, Thomas R, Botti G, Di Bonito M, De Rosa V, Iodice G, Rubulotta MR, Comella G; Southern Italy Cooperative Oncology Group. Weekly cisplatin, epirubicin, and paclitaxel with granulocyte colony-stimulating factor support vs triweekly epirubicin and paclitaxel in locally advanced breast cancer: final analysis of a SICOG phase III study. Br J Cancer. 2006 Oct 23;95(8):1005-12. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article 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
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Subsequent treatment
References
- GeparTrio: von Minckwitz G, Kümmel S, Vogel P, Hanusch C, Eidtmann H, Hilfrich J, Gerber B, Huober J, Costa SD, Jackisch C, Loibl S, Mehta K, Kaufmann M; GBG. Neoadjuvant vinorelbine-capecitabine versus docetaxel-doxorubicin-cyclophosphamide in early nonresponsive breast cancer: phase III randomized GeparTrio trial. J Natl Cancer Inst. 2008 Apr 16;100(8):542-51. Epub 2008 Apr 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00544765
- Update: von Minckwitz G, Kümmel S, Vogel P, Hanusch C, Eidtmann H, Hilfrich J, Gerber B, Huober J, Costa SD, Jackisch C, Loibl S, Mehta K, Kaufmann M; German Breast Group. Intensified neoadjuvant chemotherapy in early-responding breast cancer: phase III randomized GeparTrio study. J Natl Cancer Inst. 2008 Apr 16;100(8):552-62. Epub 2008 Apr 8. link to original article PubMed
- INTENS: Vriens BE, Aarts MJ, de Vries B, van Gastel SM, Wals J, Smilde TJ, van Warmerdam LJ, de Boer M, van Spronsen DJ, Borm GF, Tjan-Heijnen VC; BOOG. Doxorubicin/cyclophosphamide with concurrent versus sequential docetaxel as neoadjuvant treatment in patients with breast cancer. Eur J Cancer. 2013 Oct;49(15):3102-10. Epub 2013 Jul 10. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00314977
- Update: Vriens BEPJ, Vriens IJH, Aarts MJB, van Gastel SM, van den Berkmortel FWPJ, Smilde TJ, van Warmerdam LJC, van Spronsen DJ, Peer PGM, de Boer M, Tjan-Heijnen VCG; BOOG. Improved survival for sequentially as opposed to concurrently delivered neoadjuvant chemotherapy in non-metastatic breast cancer. Breast Cancer Res Treat. 2017 Oct;165(3):593-600. Epub 2017 Jul 3. link to original article link to PMC article 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
- 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
- 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
- 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
- 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
- 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
- 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)
- Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
Chemotherapy, CMF portion (cycles 5 to 8)
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once per day on days 1 & 8
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (A x 4; CMF x 4)
Regimen variant #2, 75 x 4 --> 600/40/600 x 8
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Buzzoni et al. 1991 (Milan trial) | 1982-1987 | Phase 3 (E-switch-ic) | A/CMF x 12 | Superior OS |
Preceding treatment
Chemotherapy, A portion (cycles 1 to 4)
- Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
Chemotherapy, CMF portion (cycles 5 to 12)
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
- Methotrexate (MTX) 40 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
21-day cycle for 12 cycles (A x 4; CMF x 8)
Regimen variant #3, 75 x 4 --> 600/50/600 x 8
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Leonard et al. 2004 | 1995-1999 | Phase 3 (C) | Cyclophosphamide & Thiotepa with auto HSCT | Did not meet primary endpoint of RFS |
Preceding treatment
Chemotherapy, A portion (cycles 1 to 4)
- Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
Chemotherapy, CMF portion (cycles 5 to 12)
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
- Methotrexate (MTX) 50 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles, then 28-day cycle for 8 cycles (A x 4; CMF x 8)
Regimen variant #4, 75 x 4 --> 1400/80/1200 x 4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fernando et al. 2019 (SECRAB) | 1998-2004 | Phase 3 (C) | 1a. CMF & RT 1b. E-CMF & RT 1c. A-CMF & RT 1d. MMM & RT |
Inferior LRFS |
Preceding treatment
Chemotherapy, A portion (cycles 1 to 4)
- Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
Chemotherapy, CMF portion (cycles 5 to 8)
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (A x 4; CMF x 4)
References
- Milan trial: Buzzoni R, Bonadonna G, Valagussa P, Zambetti M. Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes. J Clin Oncol. 1991 Dec;9(12):2134-40. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes: ten-year results. JAMA. 1995 Feb 15;273(7):542-7. link to original article PubMed
- Leonard RC, Lind M, Twelves C, Coleman R, van Belle S, Wilson C, Ledermann J, Kennedy I, Barrett-Lee P, Perren T, Verrill M, Cameron D, Foster E, Yellowlees A, Crown J; Anglo-Celtic Cooperative Oncology Group. Conventional adjuvant chemotherapy versus single-cycle, autograft-supported, high-dose, late-intensification chemotherapy in high-risk breast cancer patients: a randomized trial. J Natl Cancer Inst. 2004 Jul 21;96(14):1076-83. link to original article dosing details in abstract have been reviewed by our editors PubMed
- ECTO: Gianni L, Baselga J, Eiermann W, Porta VG, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Cussac AL, Bozhok A, Martinez-Agulló A, Greco M, Byakhov M, Lopez JJ, Mansutti M, Valagussa P, Bonadonna G. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. J Clin Oncol. 2009 May 20;27(15):2474-81. Epub 2009 Mar 30. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00003013
- SECRAB: Fernando IN, Bowden SJ, Herring K, Brookes CL, Ahmed I, Marshall A, Grieve R, Churn M, Spooner D, Latief TN, Agrawal RK, Brunt AM, Stevens A, Goodman A, Canney P, Bishop J, Ritchie D, Dunn J, Poole CJ, Rea DW; SECRAB Investigators. Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial. Radiother Oncol. 2020 Jan;142:52-61. Epub 2019 Nov 27. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00003893
ddA-ddT-ddC
ddA-ddT-ddC: dose-dense Adriamycin (Doxorubicin), followed by dose-dense Taxol (Paclitaxel), followed by dose-dense Cyclophosphamide
Regimen variant #1, 60/175/600
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Citron et al. 2003 (CALGB 9741) | 1997-1999 | Phase 3 (E-esc) | 1. A-T-C 2. AC-T |
Seems to have superior OS (secondary endpoint) Superior DFS (primary endpoint) |
3. ddAC-ddT | Did not meet primary endpoint of DFS |
Preceding treatment
Chemotherapy, ddA portion (cycles 1 to 4)
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
Chemotherapy, ddT portion (cycles 5 to 8)
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
Supportive therapy, ddT portion (cycles 5 to 8)
- Diphenhydramine (Benadryl) 12.5 to 50 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
- One of the following H2 blocker choices:
- Ranitidine (Zantac) 50 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
- Cimetidine (Tagamet) 300 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
- Famotidine (Pepcid) 20 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
- One of the following dexamethasone choices:
- Dexamethasone (Decadron) 10 mg IV once on day 1, within 60 minutes prior to paclitaxel
- Dexamethasone (Decadron) 10 mg PO once on day 1, at least 60 minutes prior to paclitaxel
- Dexamethasone (Decadron) 20 mg PO twice on day 1; 6 hours and 12 hours prior to paclitaxel
Chemotherapy, ddC portion (cycles 9 to 12)
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Supportive therapy, all portions (cycles 1 to 12)
- Filgrastim (Neupogen) 5 mcg/kg (rounded to either 300 or 480 mcg) SC once per day on days 3 to 10
- Note: Citron et al. 2003 says the schedule was "filgrastim days 3 to 10 of each cycle (a total of seven doses)," so it is unclear whether 7 or 8 doses was actually used).
14-day cycle for 12 cycles (ddA x 4; ddT x 4; ddC x 4)
Regimen variant #2, 60/200/800
Study | Dates of enrollment | Evidence |
---|---|---|
Kahan et al. 2005 | 2000-2003 | Phase 2 |
Preceding treatment
Chemotherapy, ddA portion (cycles 1 to 4)
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
Chemotherapy, ddT portion (cycles 5 to 8)
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
Chemotherapy, ddC portion (cycles 9 to 12)
- Cyclophosphamide (Cytoxan) 800 mg/m2 IV once on day 1
Supportive therapy, all portions (cycles 1 to 12)
14-day cycle for 12 cycles (ddA x 4; ddT x 4; ddC x 4)
References
- CALGB 9741: Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00003088
- Kahan Z, Uhercsak G, Hajnal-Papp R, Boda K, Thurzo L. Dose-dense sequential adriamycin-paclitaxel-cyclophosphamide chemotherapy is well tolerated and safe in high-risk early breast cancer. Oncology. 2005;68(4-6):446-53. Epub 2005 Jul 13. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Update: Kelemen G, Uhercsák G, Ormándi K, Eller J, Thurzó L, Kahán Z. Long-term efficiency and toxicity of adjuvant dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy in high-risk breast cancer. Oncology. 2010;78(3-4):271-3. Epub 2010 Jun 7. link to original article PubMed
AC-CMF
AC-CMF: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Cyclophosphamide, Methotrexate, Fluorouracil
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Colleoni et al. 2006 (IBCSG 13-93) | 1993-1999 | Non-randomized part of phase 3 RCT | ||
Basser et al. 2006 (IBCSG 15-95) | 1995-2000 | Phase 3 (C) | EC; dose-intense | Seems to have inferior DFS1 |
Francis et al. 2008 (BIG 02-98) | 1998-2001 | Phase 3 (C) | 1. A-CMF | Not reported |
2. A-D-CMF 3. AD-CMF |
Might have inferior DFS2 |
1Reported efficacy for IBCSG 15-95 is based on the 2009 update.
2Reported efficacy for BIG 02-98 is based on the 2015 update.
Preceding treatment
Chemotherapy, AC portion (cycles 1 to 4)
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, CMF portion (cycles 5 to 7)
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles, then 28-day cycle for 3 cycles (AC x 4; CMF x 3)
Subsequent treatment
- Adjuvant Tamoxifen x 5 y versus no further treatment
References
- IBCSG 15-95: Basser RL, O'Neill A, Martinelli G, Green MD, Peccatori F, Cinieri S, Coates AS, Gelber RD, Aebi S, Castiglione-Gertsch M, Viale G, Price KN, Goldhirsch A; International Breast Cancer Study Group. Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95. J Clin Oncol. 2006 Jan 20;24(3):370-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00002784
- Update: Colleoni M, Sun Z, Martinelli G, Basser RL, Coates AS, Gelber RD, Green MD, Peccatori F, Cinieri S, Aebi S, Viale G, Price KN, Goldhirsch A; International Breast Cancer Study Group. The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up. Ann Oncol. 2009 Aug;20(8):1344-51. Epub 2009 May 25. link to original article link to PMC article PubMed
- IBCSG 13-93: Colleoni M, Gelber S, Goldhirsch A, Aebi S, Castiglione-Gertsch M, Price KN, Coates AS, Gelber RD; International Breast Cancer Study Group. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol. 2006 Mar 20;24(9):1332-41. Epub 2006 Feb 27. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- BIG 02-98: Francis P, Crown J, Di Leo A, Buyse M, Balil A, Andersson M, Nordenskjöld B, Lang I, Jakesz R, Vorobiof D, Gutiérrez J, van Hazel G, Dolci S, Jamin S, Bendahmane B, Gelber RD, Goldhirsch A, Castiglione-Gertsch M, Piccart-Gebhart M; BIG. Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial. J Natl Cancer Inst. 2008 Jan 16;100(2):121-33. Epub 2008 Jan 8. Erratum in: J Natl Cancer Inst. 2008 Nov 19;100(22):1655. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00174655
- Update: Oakman C, Francis PA, Crown J, Quinaux E, Buyse M, De Azambuja E, Margeli Vila M, Andersson M, Nordenskjöld B, Jakesz R, Thürlimann B, Gutiérrez J, Harvey V, Punzalan L, Dell'orto P, Larsimont D, Steinberg I, Gelber RD, Piccart-Gebhart M, Viale G, Di Leo A. Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trial. Ann Oncol. 2013 May;24(5):1203-11. Epub 2013 Jan 4. link to original article PubMed
- Update: Sonnenblick A, Francis PA, Azim HA Jr, de Azambuja E, Nordenskjöld B, Gutiérez J, Quinaux E, Mastropasqua MG, Ameye L, Anderson M, Lluch A, Gnant M, Goldhirsch A, Di Leo A, Barnadas A, Cortes-Funes H, Piccart M, Crown J. Final 10-year results of the Breast International Group 2-98 phase III trial and the role of Ki67 in predicting benefit of adjuvant docetaxel in patients with oestrogen receptor positive breast cancer. Eur J Cancer. 2015 Aug;51(12):1481-9. Epub 2015 Jun 11. 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)
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, D portion (cycles 5 to 8)
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 8 cycles (AC x 4; D x 4)
Regimen variant #2, q3wk docetaxel 100 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sparano et al. 2008 (ECOG E1199) | 1999-2002 | Phase 3 (E-switch-ic) | 1. AC-T; q3wk paclitaxel | Seems to have 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)
- Doxorubicin (Adriamycin) 60 mg/m2 IV over 5 to 15 minutes once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 30 to 60 minutes once on day 1
Chemotherapy, D portion (cycles 5 to 8)
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 8 cycles (AC x 4; D x 4)
Regimen variant #3, weekly docetaxel
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sparano et al. 2008 (ECOG E1199) | 1999-2002 | Phase 3 (E-switch-ic) | 1. AC-T; q3wk paclitaxel | Did not meet primary endpoint of DFS |
2. AC-T; weekly paclitaxel 3. AC-D; q3wk docetaxel |
Not reported |
Preceding treatment
Chemotherapy, AC portion (cycles 1 to 4)
- Doxorubicin (Adriamycin) 60 mg/m2 IV over 5 to 15 minutes once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 30 to 60 minutes once on day 1
Chemotherapy, D portion (cycles 5 to 16)
- Docetaxel (Taxotere) 35 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 4 cycles, then 7-day cycle for 12 cycles (AC x 4; D x 12)
References
- ECOG E1199: Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00004125
- Update: Sparano JA, Zhao F, Martino S, Ligibel JA, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Long-term follow-up of the E1199 phase III trial evaluating the role of taxane and schedule in operable breast cancer. J Clin Oncol. 2015 Jul 20;33(21):2353-60. Epub 2015 Jun 15. link to original article link to PMC article PubMed
- NSABP B-30: Swain SM, Jeong JH, Geyer CE Jr, Costantino JP, Pajon ER, Fehrenbacher L, Atkins JN, Polikoff J, Vogel VG, Erban JK, Rastogi P, Livingston RB, Perez EA, Mamounas EP, Land SR, Ganz PA, Wolmark N. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med. 2010 Jun 3;362(22):2053-65. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00003782
- BCIRG-005: Eiermann W, Pienkowski T, Crown J, Sadeghi S, Martín M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press M, Sauter G, Lindsay MA, Riva A, Buyse M, Drevot P, Taupin H, Mackey JR. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol. 2011 Oct 10;29(29):3877-84. Epub 2011 Sep 12. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00312208
- Update: Mackey JR, Pieńkowski T, Crown J, Sadeghi S, Martín M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press MF, Sauter G, Lindsay M, Houé V, Buyse M, Drevot P, Hitier S, Bensfia S, Eiermann W; Translational Research In Oncology (TRIO)/ Breast Cancer International Research Group (BCIRG)-005 investigators. Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial. Ann Oncol. 2016 Jun;27(6):1041-7. Epub 2016 Mar 2. link to original article PubMed
- NSAS BC-02: Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed
AC-T
AC-T: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel)
Regimen variant #1, weekly paclitaxel
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sparano et al. 2008 (ECOG E1199) | 1999-2002 | Phase 3 (E-switch-ic) | 1. AC-T; q3wk paclitaxel | Superior OS (secondary endpoint) OS60: 89.7% vs 86.5% (HR 0.76, 98.3% CI 0.58-0.98) |
2. AC-D; q3wk docetaxel 3. AC-D; weekly docetaxel |
Not reported | |||
Miller et al. 2018 (ECOG E5103) | 2007-2011 | Phase 3 (C) | 1a. AC-T & Bevacizumab 1b. ddAC-T & Bevacizumab 2a. AC-T & Bevacizumab, then Bevacizumab 2b. ddAC-T & Bevacizumab, then Bevacizumab |
Did not meet primary endpoint of IDFS |
Fehrenbacher et al. 2019 (NSABP B-47) | 2011-2015 | Phase 3 (C) | 1a. AC-TH 1b. ddAC-TH 1c. TCH |
Did not meet primary endpoint of IDFS |
Biomarker eligibility criteria
- NSABP B-47: HER2 IHC of 1+ or 2+ with FISH ratio less than 2 or HER2 gene copy number less than 4
Preceding treatment
Chemotherapy, AC portion (cycles 1 to 4)
- Doxorubicin (Adriamycin) 60 mg/m2 IV over 5 to 15 minutes once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 30 to 60 minutes once on day 1
Chemotherapy, T portion (cycles 5 to 16)
- Paclitaxel (Taxol) 80 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 4 cycles, then 7-day cycle for 12 cycles (AC x 4; T x 12)
Regimen variant #2, q3wk paclitaxel 175 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Henderson et al. 2003 (INT 0148/CALGB 9344) | 1994-1999 | Phase 3 (E-RT-esc) | 1. AC; standard-dose 2. AC; high-dose 3. AC; very high-dose |
Superior OS (secondary endpoint) |
4. AC-T; high-dose AC 5. AC-T; very high-dose AC |
Did not meet primary endpoint of DFS | |||
Citron et al. 2003 (CALGB 9741) | 1997-1999 | Phase 3 (C) | 1. A-T-C | Did not meet primary endpoint of DFS |
2. ddA-ddC-ddT 3. ddAC-ddT |
Seems to have inferior OS | |||
Sparano et al. 2008 (ECOG E1199) | 1999-2002 | Phase 3 (C) | 1. AC-T; weekly paclitaxel | Inferior OS |
2. AC-D; q3wk docetaxel | Seems to have inferior DFS | |||
3. AC-D; weekly docetaxel | Did not meet primary endpoint of DFS | |||
Loesch et al. 2010 | 2000-2002 | Phase 3 (C) | See link | See link |
Burnell et al. 2009 (NCIC-CTG MA.21) | 2000-2005 | Phase 3 (C) | 1. ddEC-T 2. CEF |
Inferior RFS |
Watanabe et al. 2017 (NSAS BC-02) | 2001-2006 | Phase 3 (C) | 1. AC-D 2. Docetaxel x 8 |
Seems to have inferior OS (secondary endpoint) |
3. Paclitaxel x 8 | Inconclusive whether non-inferior DFS (primary endpoint) | |||
Sparano et al. 2018 (TAILORx) | 2006-2010 | Phase 3 (C) | No chemotherapy | Non-inferior IDFS (primary endpoint) |
Eligibility criteria
- TAILORx: Oncotype DX score of 11 to 25
Preceding treatment
Chemotherapy, AC portion (cycles 1 to 4)
- Doxorubicin (Adriamycin) 60 mg/m2 IV over 5 to 15 minutes once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 30 to 60 minutes once on day 1
Chemotherapy, T portion (cycles 5 to 8)
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
21-day cycle for 8 cycles (AC x 4; T x 4)
Regimen variant #3, q3wk paclitaxel 225 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Mamounas et al. 2005 (NSABP B-28) | 1995-1998 | Phase 3 (E-esc) | AC x 4 | Superior DFS (co-primary endpoint) |
Preceding treatment
Chemotherapy, AC portion (cycles 1 to 4)
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, T portion (cycles 5 to 8)
- Paclitaxel (Taxol) 225 mg/m2 IV over 3 hours once on day 1
21-day cycle for 8 cycles (AC x 4; T x 4)
References
- INT 0148/CALGB 9344: Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003 Mar 15;21(6):976-83. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- CALGB 9741: Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00003088
- NSABP B-28: Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol. 2005 Jun 1;23(16):3686-96. Epub 2005 May 16. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- ECOG E1199: Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00004125
- Update: Sparano JA, Zhao F, Martino S, Ligibel JA, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Long-term follow-up of the E1199 phase III trial evaluating the role of taxane and schedule in operable breast cancer. J Clin Oncol. 2015 Jul 20;33(21):2353-60. Epub 2015 Jun 15. link to original article link to PMC article PubMed
- NCIC-CTG MA.21: Burnell M, Levine MN, Chapman JA, Bramwell V, Gelmon K, Walley B, Vandenberg T, Chalchal H, Albain KS, Perez EA, Rugo H, Pritchard K, O'Brien P, Shepherd LE. Cyclophosphamide, epirubicin, and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol. 2010 Jan 1;28(1):77-82. Epub 2009 Nov 9. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00014222
- Loesch D, Greco FA, Senzer NN, Burris HA, Hainsworth JD, Jones S, Vukelja SJ, Sandbach J, Holmes F, Sedlacek S, Pippen J, Lindquist D, McIntyre K, Blum JL, Modiano MR, Boehm KA, Zhan F, Asmar L, Robert N. Phase III multicenter trial of doxorubicin plus cyclophosphamide followed by paclitaxel compared with doxorubicin plus paclitaxel followed by weekly paclitaxel as adjuvant therapy for women with high-risk breast cancer. J Clin Oncol. 2010 Jun 20;28(18):2958-65. Epub 2010 May 17. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- NSAS BC-02: Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed
- TAILORx: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. link to original article link to PMC article contains dosing details in supplement PubMed NCT00310180
- ECOG E5103: Miller KD, O'Neill A, Gradishar W, Hobday TJ, Goldstein LJ, Mayer IA, Bloom S, Brufsky AM, Tevaarwerk AJ, Sparano JA, Le-Lindqwister NA, Hendricks CB, Northfelt DW, Dang CT, Sledge GW Jr. Double-blind phase III trial of adjuvant chemotherapy with and without bevacizumab in patients with lymph node-positive and high-risk lymph node-negative breast cancer (E5103). J Clin Oncol. 2018 Sep 1;36(25):2621-2629. Epub 2018 Jul 24. link to original article does not contain dosing details in manuscript; refers to ECOG E1199 protocol link to PMC article PubMed NCT00433511
- NSABP B-47: Fehrenbacher L, Cecchini RS, Geyer CE Jr, Rastogi P, Costantino JP, Atkins JN, Crown JP, Polikoff J, Boileau JF, Provencher L, Stokoe C, Moore TD, Robidoux A, Flynn PJ, Borges VF, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020 Feb 10;38(5):444-453. Epub 2019 Dec 10. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT01275677
- USON 01062: NCT00089479
ddAC-T
ddAC-T: dose-dense Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel)
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Miller et al. 2018 (ECOG E5103) | 2007-2011 | Phase 3 (C) | 1a. AC-T & Bevacizumab 1b. ddAC-T & Bevacizumab 2a. AC-T & Bevacizumab, then Bevacizumab 2b. ddAC-T & Bevacizumab, then Bevacizumab |
Did not meet primary endpoint of IDFS |
Fehrenbacher et al. 2019 (NSABP B-47) | 2011-2015 | Phase 3 (C) | 1a. AC-TH 1b. ddAC-TH 1c. TCH |
Did not meet primary endpoint of IDFS |
Note: Fehrenbacher et al. 2019 does not explicitly describe the use of filgrastim, but it is typically used for the dose-dense portion of this regimen.
Biomarker eligibility criteria
- NSABP B-47: HER2 IHC of 1+ or 2+ with FISH ratio less than 2 or HER2 gene copy number less than 4
Preceding treatment
Chemotherapy, ddAC portion (cycles 1 to 4)
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Supportive therapy, ddAC portion (cycles 1 to 4)
- Filgrastim (Neupogen) 5 mcg/kg (rounded to either 300 or 480 mcg) SC once per day on days 3 to 10
Chemotherapy, T portion (cycles 5 to 16)
- Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
14-day cycle for 4 cycles, then 7-day cycle for 12 cycles (AC x 4; T x 12)
References
- ECOG E5103: Miller KD, O'Neill A, Gradishar W, Hobday TJ, Goldstein LJ, Mayer IA, Bloom S, Brufsky AM, Tevaarwerk AJ, Sparano JA, Le-Lindqwister NA, Hendricks CB, Northfelt DW, Dang CT, Sledge GW Jr. Double-blind phase III trial of adjuvant chemotherapy with and without bevacizumab in patients with lymph node-positive and high-risk lymph node-negative breast cancer (E5103). J Clin Oncol. 2018 Sep 1;36(25):2621-2629. Epub 2018 Jul 24. link to original article does not contain dosing details in manuscript; refers to ECOG E1199 protocol link to PMC article PubMed NCT00433511
- NSABP B-47: Fehrenbacher L, Cecchini RS, Geyer CE Jr, Rastogi P, Costantino JP, Atkins JN, Crown JP, Polikoff J, Boileau JF, Provencher L, Stokoe C, Moore TD, Robidoux A, Flynn PJ, Borges VF, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020 Feb 10;38(5):444-453. Epub 2019 Dec 10. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT01275677
ddAC-ddT
ddAC-ddT: dose-dense Adriamycin (Doxorubicin) & Cyclophosphamide followed by dose-dense Taxol (Paclitaxel)
Regimen variant #1, 4x4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Citron et al. 2003 (CALGB 9741) | 1997-1999 | Phase 3 (E-esc) | 1. A-T-C 2. AC-T |
Seems to have superior OS (secondary endpoint) Superior DFS (primary endpoint) |
3. ddA-ddC-ddT | Did not meet primary endpoint of DFS | |||
Swain et al. 2013 (NSABP B-38) | 2004-2007 | Phase 3 (C) | 1. TAC x 6 | Did not meet primary endpoint of DFS |
2. ddAC-ddPG | Did not meet primary endpoint of DFS | |||
Sparano et al. 2018 (TAILORx) | 2006-2010 | Phase 3 (C) | No chemotherapy | Non-inferior IDFS (primary endpoint) |
Eligibility criteria
- TAILORx: Oncotype DX score of 11 to 25
Preceding treatment
Chemotherapy, ddAC portion (cycles 1 to 4)
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Supportive therapy, ddAC portion (cycles 1 to 4)
- Filgrastim (Neupogen) 5 mcg/kg (rounded to either 300 or 480 mcg) SC once per day on days 3 to 10
- Note: Citron et al. 2003 says the schedule was "filgrastim days 3 to 10 of each cycle (a total of seven doses)," so it is unclear whether 7 or 8 doses was actually used).
Chemotherapy, ddT portion (cycles 5 to 8)
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
Supportive therapy, ddT portion (cycles 5 to 8)
- Diphenhydramine (Benadryl) 12.5 to 50 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
- One of the following H2 blockers:
- Ranitidine (Zantac) 50 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
- Cimetidine (Tagamet) 300 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
- Famotidine (Pepcid) 20 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
- One of the following dexamethasone choices:
- Dexamethasone (Decadron) 10 mg IV once on day 1, within 60 minutes prior to paclitaxel
- Dexamethasone (Decadron) 10 mg PO once on day 1, at least 60 minutes prior to paclitaxel
- Dexamethasone (Decadron) 20 mg PO twice on day 1; 6 hours and 12 hours prior to paclitaxel
- 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)
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, ddT portion (cycles 7 to 12)
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
Supportive therapy, all portions (cycles 1 to 12)
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2
14-day cycle for 12 cycles (ddAC x 6; ddT x 6)
References
- CALGB 9741: Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00003088
- NSABP B-38: Swain SM, Tang G, Geyer CE Jr, Rastogi P, Atkins JN, Donnellan PP, Fehrenbacher L, Azar CA, Robidoux A, Polikoff JA, Brufsky AM, Biggs DD, Levine EA, Zapas JL, Provencher L, Northfelt DW, Paik S, Costantino JP, Mamounas EP, Wolmark N. Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial. J Clin Oncol. 2013 Sep 10;31(26):3197-204. Epub 2013 Aug 12. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00093795
- SWOG S0221: Budd GT, Barlow WE, Moore HC, Hobday TJ, Stewart JA, Isaacs C, Salim M, Cho JK, Rinn KJ, Albain KS, Chew HK, Burton GV, Moore TD, Srkalovic G, McGregor BA, Flaherty LE, Livingston RB, Lew DL, Gralow JR, Hortobagyi GN. SWOG S0221: a phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer. J Clin Oncol. 2015 Jan 1;33(1):58-64. Epub 2014 Nov 24. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00070564
- TAILORx: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. link to original article link to PMC article 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)
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
Chemotherapy, CMF portion (cycles 5 to 8)
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once per day on days 1 & 8
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (AT x 4; CMF x 4)
References
- ECTO: Gianni L, Baselga J, Eiermann W, Porta VG, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Cussac AL, Bozhok A, Martinez-Agulló A, Greco M, Byakhov M, Lopez JJ, Mansutti M, Valagussa P, Bonadonna G. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. J Clin Oncol. 2009 May 20;27(15):2474-81. Epub 2009 Mar 30. link to original article dosing details in manuscript have been reviewed by our editors 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)
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
- Methotrexate (MTX) 40 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
Chemotherapy, E portion (cycles 7 to 10)
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
21-day cycle for 10 cycles (CMF x 6; E x 4)
References
- GROCTA-1: Boccardo F, Rubagotti A, Bruzzi P, Cappellini M, Isola G, Nenci I, Piffanelli A, Scanni A, Sismondi P, Santi L, Genta F, Saccani F, Sassi M, Malacarne P, Donati D, Farris A, Castagnetta L, Di Carlo A, Traina A, Galletto L, Smerieri F, Buzzi F; Breast Cancer Adjuvant Chemo-Hormone Therapy Cooperative Group. Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, estrogen receptor-positive breast cancer patients: results of a multicentric Italian study. J Clin Oncol. 1990 Aug;8(8):1310-20. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Boccardo F, Guglielmini P, Parodi A, Rubagotti A. Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, oestrogen receptor-positive breast cancer patients: very late results of the 'gruppo di ricerca per la chemio-ormonoterapia adiuvante (GROCTA)' 01-Trial in early breast cancer. Breast Cancer Res Treat. 2011 Apr;126(3):653-61. Epub 2011 Feb 24. 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)
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
Chemotherapy, EC portion (cycles 5 to 8)
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 700 mg/m2 IV once on day 1
21-day cycle for 8 cycles (D x 4; EC x 4)
References
- Polyzos A, Malamos N, Boukovinas I, Adamou A, Ziras N, Kalbakis K, Kakolyris S, Syrigos K, Papakotoulas P, Kouroussis C, Karvounis N, Vamvakas L, Christophyllakis C, Athanasiadis A, Varthalitis I, Georgoulias V, Mavroudis D; Hellenic Oncology Research Group. FEC versus sequential docetaxel followed by epirubicin/cyclophosphamide as adjuvant chemotherapy in women with axillary node-positive early breast cancer: a randomized study of the Hellenic Oncology Research Group (HORG). Breast Cancer Res Treat. 2010 Jan;119(1):95-104. Epub 2009 Jul 28. link to original article dosing details in manuscript have been reviewed by our editors 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)
- Docetaxel (Taxotere) 80 mg/m2 IV over 60 minutes once on day 1
Chemotherapy, FEC portion (cycles 4 to 6)
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 6 cycles (D x 3; FEC x 3)
Regimen variant #2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Joensuu et al. 2006 (FinHer) | 2000-2003 | Phase 3 (E-switch-ic) | V-FEC | Superior DDFS (secondary endpoint) |
Note: this was the study design for HER2-negative patients.
Preceding treatment
- Surgery with axillary lymph node dissection or sentinel lymph node biopsy, within 12 weeks
Chemotherapy, D portion (cycles 1 to 3)
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
Chemotherapy, FEC portion (cycles 4 to 6)
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 6 cycles (D x 3; FEC x 3)
References
- FinHer: Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article dosing details in manuscript have been reviewed by our editors PubMed ISRCTN76560285
- Update: Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. Epub 2009 Nov 2. link to original article PubMed
- FinXX: Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Asola R, Kokko R, Ahlgren J, Auvinen P, Hemminki A, Paija O, Helle L, Nuortio L, Villman K, Nilsson G, Lahtela SL, Lehtiö K, Pajunen M, Poikonen P, Nyandoto P, Kataja V, Bono P, Leinonen M, Lindman H; FinXX Study Investigators. Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer: an open-label, randomised controlled trial. Lancet Oncol. 2009 Dec;10(12):1145-51. Epub 2009 Nov 10. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00114816
- Update: Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Kokko R, Ahlgren J, Auvinen P, Paija O, Helle L, Villman K, Nyandoto P, Nilsson G, Pajunen M, Asola R, Poikonen P, Leinonen M, Kataja V, Bono P, Lindman H. Adjuvant capecitabine, docetaxel, cyclophosphamide, and epirubicin for early breast cancer: final analysis of the randomized FinXX trial. J Clin Oncol. 2012 Jan 1;30(1):11-8. Epub 2011 Nov 21. link to original article PubMed
- Update: Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola A, Tanner M, Ahlgren J, Auvinen P, Lahdenperä O, Villman K, Nyandoto P, Nilsson G, Poikonen-Saksela P, Kataja V, Bono P, Junnila J, Lindman H. Adjuvant Capecitabine for Early Breast Cancer: 15-Year Overall Survival Results From a Randomized Trial. J Clin Oncol. 2022 Apr 1;40(10):1051-1058. Epub 2022 Jan 12. 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)
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
Chemotherapy, CMF portion (cycles 5 to 8)
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Methotrexate (MTX) 50 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
21-day cycle for 8 cycles (E x 4; CMF x 4)
Regimen variant #2, 100/1200/80/1200
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Poole et al. 2006 (NEAT) | 1996-2001 | Phase 3 (E-esc) | CMF x 6 | 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)
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
Chemotherapy, CMF portion (cycles 5 to 8)
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once per day on days 1 & 8
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (E x 4; CMF x 4)
Regimen variant #3, 100/1400/80/1200 ("classic CMF")
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Poole et al. 2006 (NEAT) | 1996-2001 | Phase 3 (E-esc) | CMF x 6 | 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)
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
Chemotherapy, CMF portion (cycles 5 to 8)
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles, then 28-day cycle for 4 cycles (E x 4; CMF x 4)
References
- NEAT: Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00003577
- Update: Earl HM, Hiller L, Dunn JA, Vallier AL, Bowden SJ, Jordan SD, Blows F, Munro A, Bathers S, Grieve R, Spooner DA, Agrawal R, Fernando I, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, McAdam K, Foster L, Leonard RC, Twelves CJ, Cameron D, Bartlett JM, Pharoah P, Provenzano E, Caldas C, Poole CJ; NEAT Investigators and the SCTBG. Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials. Br J Cancer. 2012 Oct 9;107(8):1257-67. Epub 2012 Sep 11. link to original article link to PMC article PubMed
- BR9601: Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00003012
- Update: Earl HM, Hiller L, Dunn JA, Vallier AL, Bowden SJ, Jordan SD, Blows F, Munro A, Bathers S, Grieve R, Spooner DA, Agrawal R, Fernando I, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, McAdam K, Foster L, Leonard RC, Twelves CJ, Cameron D, Bartlett JM, Pharoah P, Provenzano E, Caldas C, Poole CJ; NEAT Investigators and the SCTBG. Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials. Br J Cancer. 2012 Oct 9;107(8):1257-67. Epub 2012 Sep 11. link to original article link to PMC article PubMed
- TACT: Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed ISRCTN79718493
- Boccardo F, Amadori D, Guglielmini P, Sismondi P, Farris A, Agostara B, Gambi A, Catalano G, Faedi M, Rubagotti A. Epirubicin followed by cyclophosphamide, methotrexate and 5-fluorouracil versus paclitaxel followed by epirubicin and vinorelbine in patients with high-risk operable breast cancer. Oncology. 2010;78(3-4):274-81. Epub 2010 Jun 8. link to original article dosing details in abstract have been reviewed by our editors PubMed
- IRST-IBIS-03: Amadori D, Silvestrini R, De Lena M, Boccardo F, Rocca A, Scarpi E, Schittulli F, Brandi M, Maltoni R, Serra P, Ponzone R, Biglia N, Gianni L, Tienghi A, Valerio MR, Bonginelli P, Amaducci L, Faedi M, Baldini E, Paradiso A. Randomized phase III trial of adjuvant epirubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) versus CMF followed by epirubicin in patients with node-negative or 1-3 node-positive rapidly proliferating breast cancer. Breast Cancer Res Treat. 2011 Feb;125(3):775-84. Epub 2010 Dec 4. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01031030
- TACT2: Cameron D, Morden JP, Canney P, Velikova G, Coleman R, Bartlett J, Agrawal R, Banerji J, Bertelli G, Bloomfield D, Brunt AM, Earl H, Ellis P, Gaunt C, Gillman A, Hearfield N, Laing R, Murray N, Couper N, Stein RC, Verrill M, Wardley A, Barrett-Lee P, Bliss JM; TACT2 Investigators. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2017 Jul;18(7):929-945. Epub 2017 Jun 7. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00301925
- HRQoL analysis: Velikova G, Morden JP, Haviland JS, Emery C, Barrett-Lee P, Earl H, Bloomfield D, Brunt AM, Canney P, Coleman R, Verrill M, Wardley A, Bertelli G, Ellis P, Stein R, Bliss JM, Cameron D; TACT2 Trial Management Group. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer (UK TACT2; CRUK/05/19): quality of life results from a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2023 Dec;24(12):1359-1374. Epub 2023 Nov 2. Erratum in: Lancet Oncol. 2023 Dec;24(12):e459. link to original article PubMed
- SECRAB: Fernando IN, Bowden SJ, Herring K, Brookes CL, Ahmed I, Marshall A, Grieve R, Churn M, Spooner D, Latief TN, Agrawal RK, Brunt AM, Stevens A, Goodman A, Canney P, Bishop J, Ritchie D, Dunn J, Poole CJ, Rea DW; SECRAB Investigators. Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial. Radiother Oncol. 2020 Jan;142:52-61. Epub 2019 Nov 27. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00003893
- MINDACT: Delaloge S, Piccart M, Rutgers E, Litière S, van 't Veer LJ, van den Berkmortel F, Brain E, Dudek-Peric A, Gil-Gil M, Gomez P, Hilbers FS, Khalil Z, Knox S, Kuemmel S, Kunz G, Lesur A, Pierga JY, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Thompson AM, Viale G, Zoppoli G, Vuylsteke P, Tryfonidis K, Poncet C, Bogaerts J, Cardoso F; MINDACT investigators and the TRANSBIG Consortium. Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial. J Clin Oncol. 2020 Apr 10;38(11):1186-1197. Epub 2020 Feb 21. link to original article 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)
- Epirubicin (Ellence) 110 mg/m2 IV once on day 1
Chemotherapy, CMF portion (cycles 5 to 7)
- Cyclophosphamide (Cytoxan) 840 mg/m2 IV once on day 1
- Methotrexate (MTX) 57 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 840 mg/m2 IV once on day 1
Supportive therapy, all portions (cycles 1 to 7)
14-day cycle for 7 cycles (ddE x 4; iddCMF x 3)
References
- HE 10/97: Fountzilas G, Skarlos D, Dafni U, Gogas H, Briasoulis E, Pectasides D, Papadimitriou C, Markopoulos C, Polychronis A, Kalofonos HP, Siafaka V, Kosmidis P, Timotheadou E, Tsavdaridis D, Bafaloukos D, Papakostas P, Razis E, Makrantonakis P, Aravantinos G, Christodoulou C, Dimopoulos AM; Hellenic Cooperative Oncology Group. Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol. 2005 Nov;16(11):1762-71. Epub 2005 Sep 7. link to original article dosing details in manuscript have been reviewed by our editors 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)
- Epirubicin (Ellence) 50 mg/m2 IV once per day on days 1 & 8
Chemotherapy, D portion (cycles 4 to 6)
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
28-day cycle for 3 cycles, then 21-day cycle for 3 cycles (E x 3; D x 3)
Regimen variant #2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Mavroudis et al. 2017 (HORG CT/01.04) | 2001-2013 | Phase 3 (C) | Docetaxel & Epirubicin | Might have 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)
- Epirubicin (Ellence) 90 mg/m2 IV over 5 to 15 minutes once on day 1
Chemotherapy, D portion (cycles 5 to 8)
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 8 cycles (E x 4; D x 4)
References
- DEVA: Coombes RC, Bliss JM, Espie M, Erdkamp F, Wals J, Tres A, Marty M, Coleman RE, Tubiana-Mathieu N, den Boer MO, Wardley A, Kilburn LS, Cooper D, Thomas MW, Reise JA, Wilkinson K, Hupperets P. Randomized, phase III trial of sequential epirubicin and docetaxel versus epirubicin alone in postmenopausal patients with node-positive breast cancer. J Clin Oncol. 2011 Aug 20;29(24):3247-54. Epub 2011 Jul 18. link to original article dosing details in manuscript have been reviewed by our editors PubMed ISRCTN89772270
- HORG CT/01.04: Mavroudis D, Saloustros E, Boukovinas I, Papakotoulas P, Kakolyris S, Ziras N, Christophylakis C, Kentepozidis N, Fountzilas G, Rigas G, Varthalitis I, Kalbakis K, Agelaki S, Hatzidaki D, Georgoulias V; Hellenic Oncology Research Group. Sequential vs concurrent epirubicin and docetaxel as adjuvant chemotherapy for high-risk, node-negative, early breast cancer: an interim analysis of a randomised phase III study from the Hellenic Oncology Research Group. Br J Cancer. 2017 Jul 11;117(2):164-170. Epub 2017 Jun 22. link to original article dosing details in manuscript have been reviewed by our editors 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)
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
Chemotherapy, X portion (cycles 5 to 8)
- Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 8 cycles (E x 4; X x 4)
References
- TACT2: Cameron D, Morden JP, Canney P, Velikova G, Coleman R, Bartlett J, Agrawal R, Banerji J, Bertelli G, Bloomfield D, Brunt AM, Earl H, Ellis P, Gaunt C, Gillman A, Hearfield N, Laing R, Murray N, Couper N, Stein RC, Verrill M, Wardley A, Barrett-Lee P, Bliss JM; TACT2 Investigators. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2017 Jul;18(7):929-945. Epub 2017 Jun 7. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00301925
- HRQoL analysis: Velikova G, Morden JP, Haviland JS, Emery C, Barrett-Lee P, Earl H, Bloomfield D, Brunt AM, Canney P, Coleman R, Verrill M, Wardley A, Bertelli G, Ellis P, Stein R, Bliss JM, Cameron D; TACT2 Trial Management Group. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer (UK TACT2; CRUK/05/19): quality of life results from a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2023 Dec;24(12):1359-1374. Epub 2023 Nov 2. Erratum in: Lancet Oncol. 2023 Dec;24(12):e459. link to original article PubMed
EC-CMF
EC-CMF: Epirubicin & Cyclophosphamide followed by Cyclophosphamide, Methotrexate, Fluorouracil
Regimen variant #1
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Colleoni et al. 2006 (IBCSG 13-93) | 1993-1999 | Non-randomized part of phase 3 RCT | ||
Basser et al. 2006 (IBCSG 15-95) | 1995-2000 | Phase 3 (C) | EC; dose-intense | Seems to have inferior DFS1 |
1Reported efficacy is based on the 2009 update.
Preceding treatment
Chemotherapy, EC portion (cycles 1 to 4)
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, CMF portion (cycles 5 to 7)
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles, then 28-day cycle for 3 cycles (EC x 4; CMF x 3)
Subsequent treatment
- Adjuvant Tamoxifen x 5 y versus no further treatment
Regimen variant #2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kümmel et al. 2006 | 1996-2000 | Phase 3 (C) | ddEC-ddCMF | Might have inferior OS |
Preceding treatment
Chemotherapy, EC portion (cycles 1 to 4)
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, CMF portion (cycles 5 to 7)
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
- Methotrexate (MTX) 40 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
21-day cycle for 7 cycles (EC x 4; CMF x 3)
Regimen variant #3
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Zander et al. 2004 | 1993-2000 | Phase 3 (C) | Cyclophosphamide, Mitoxantrone, Thiotepa with auto HSCT | Might have inferior EFS |
Preceding treatment
Chemotherapy, EC portion (cycles 1 to 4)
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, CMF portion (cycles 5 to 7)
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 8
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
21-day cycle for 4 cycles, then 28-day cycle for 3 cycles (EC x 4; CMF x 3)
References
- Zander AR, Kröger N, Schmoor C, Krüger W, Möbus V, Frickhofen N, Metzner B, Schultze W, Berdel WE, Koenigsmann M, Thiel E, Wandt H, Possinger K, Trümper L, Kreienberg R, Carstensen M, Schmidt EH, Jänicke F, Schumacher M, Jonat W. High-dose chemotherapy with autologous hematopoietic stem-cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: first results of a randomized trial. J Clin Oncol. 2004 Jun 15;22(12):2273-83. Epub 2004 Apr 26. link to original article dosing details in abstract have been reviewed by our editors PubMed
- IBCSG 15-95: Basser RL, O'Neill A, Martinelli G, Green MD, Peccatori F, Cinieri S, Coates AS, Gelber RD, Aebi S, Castiglione-Gertsch M, Viale G, Price KN, Goldhirsch A; International Breast Cancer Study Group. Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95. J Clin Oncol. 2006 Jan 20;24(3):370-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00002784
- Update: Colleoni M, Sun Z, Martinelli G, Basser RL, Coates AS, Gelber RD, Green MD, Peccatori F, Cinieri S, Aebi S, Viale G, Price KN, Goldhirsch A; International Breast Cancer Study Group. The effect of endocrine responsiveness on high-risk breast cancer treated with dose-intensive chemotherapy: results of International Breast Cancer Study Group Trial 15-95 after prolonged follow-up. Ann Oncol. 2009 Aug;20(8):1344-51. Epub 2009 May 25. link to original article link to PMC article PubMed
- IBCSG 13-93: Colleoni M, Gelber S, Goldhirsch A, Aebi S, Castiglione-Gertsch M, Price KN, Coates AS, Gelber RD; International Breast Cancer Study Group. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol. 2006 Mar 20;24(9):1332-41. Epub 2006 Feb 27. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Kümmel S, Krocker J, Kohls A, Breitbach GP, Morack G, Budner M, Blohmer JU, Elling D. Randomised trial: survival benefit and safety of adjuvant dose-dense chemotherapy for node-positive breast cancer. Br J Cancer. 2006 May 8;94(9):1237-44. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Reinisch M, Gluz O, Ataseven B, Blohmer JU, Budner M, Dittmer-Grabowski C, Kohls A, Krocker J, Kümmel A, Hagemann F, Rüland A, Traut A, Kümmel S. Updated Survival Analysis after a Median Follow-up of 12 Years of an Anthracycline-Containing Adjuvant Prospective Multicentre, Randomised Phase III Trial on Dose-Dense Chemotherapy in Primary Node-Positive, High-Risk Breast Cancer Patients. Breast Care (Basel). 2019 Jun;14(3):159-164. Epub 2018 Sep 5. 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)
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, ddCMF portion (cycles 5 to 7)
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 1 to 2 hours once on day 1
- Methotrexate (MTX) 40 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 600 mg/m2 IV over 60 minutes once on day 1
Supportive therapy, both portions (cycles 1 to 7)
- Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 5 to 12 or 13
14-day cycle for 7 cycles (ddEC x 4; ddCMF x 3)
References
- WSG AM-01: Nitz UA, Mohrmann S, Fischer J, Lindemann W, Berdel WE, Jackisch C, Werner C, Ziske C, Kirchner H, Metzner B, Souchon R, Ruffert U, Schütt G, Pollmanns A, Schmoll HJ, Middecke C, Baltzer J, Schrader I, Wiebringhaus H, Ko Y, Rösel S, Schwenzer T, Wernet P, Hinke A, Bender HG, Frick M; West German Study Group. Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial. Lancet. 2005 Dec 3;366(9501):1935-44. Erratum in: Lancet. 2006 Mar 4;367(9512):730. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Kümmel S, Krocker J, Kohls A, Breitbach GP, Morack G, Budner M, Blohmer JU, Elling D. Randomised trial: survival benefit and safety of adjuvant dose-dense chemotherapy for node-positive breast cancer. Br J Cancer. 2006 May 8;94(9):1237-44. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Reinisch M, Gluz O, Ataseven B, Blohmer JU, Budner M, Dittmer-Grabowski C, Kohls A, Krocker J, Kümmel A, Hagemann F, Rüland A, Traut A, Kümmel S. Updated Survival Analysis after a Median Follow-up of 12 Years of an Anthracycline-Containing Adjuvant Prospective Multicentre, Randomised Phase III Trial on Dose-Dense Chemotherapy in Primary Node-Positive, High-Risk Breast Cancer Patients. Breast Care (Basel). 2019 Jun;14(3):159-164. Epub 2018 Sep 5. 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)
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, ddT portion (cycles 5 to 8)
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
Supportive therapy, both portions (cycles 1 to 8)
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2
14-day cycle for 8 cycles (ddEC x 4; ddT x 4)
References
- GIM2: Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 x 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00433420
- Update: Del Mastro L, Poggio F, Blondeaux E, De Placido S, Giuliano M, Forestieri V, De Laurentiis M, Gravina A, Bisagni G, Rimanti A, Turletti A, Nisticò C, Vaccaro A, Cognetti F, Fabi A, Gasparro S, Garrone O, Alicicco MG, Urracci Y, Mansutti M, Poletti P, Correale P, Bighin C, Puglisi F, Montemurro F, Colantuoni G, Lambertini M, Boni L; Gruppo Italiano Mammella Investigators. Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial. Lancet Oncol. 2022 Dec;23(12):1571-1582. Epub 2022 Nov 10. link to original article 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)
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, D portion (cycles 4 to 6)
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 6 cycles (EC x 3; D x 3)
Regimen variant #2, 4+4 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Martín et al. 2015 (GEICAM 2003-10) | 2004-2007 | Phase 3 (C) | ET-X x 4+4 | Seems to have superior IDFS (primary endpoint) IDFS60: 86% vs 82% (HR 0.77, 95% CI 0.61-0.97) |
Nitz et al. 2014 (WSG-AGO EC-Doc) | 2000-2005 | Phase 3 (E-switch-ic) | 1a. CMF 1b. FEC |
Seems to have superior EFS (primary endpoint) EFS60: 89.8% vs 87.3% (HR 0.74, 95% CI 0.57-0.97) Seems to have superior OS (secondary endpoint) OS60: 94.5% vs 92.8% (HR 0.70, 95% CI 0.49-0.99) |
Preceding treatment
Chemotherapy, EC portion (cycles 1 to 4)
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, D portion (cycles 5 to 8)
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 8 cycles (EC x 4; D x 4)
References
- WSG-AGO EC-Doc: Nitz U, Gluz O, Huober J, Kreipe HH, Kates RE, Hartmann A, Erber R, Moustafa Z, Scholz M, Lisboa B, Mohrmann S, Möbus V, Augustin D, Hoffmann G, Weiss E, Böhmer S, Kreienberg R, Du Bois A, Sattler D, Thomssen C, Kiechle M, Jänicke F, Wallwiener D, Harbeck N, Kuhn W. Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression. Ann Oncol. 2014 Aug;25(8):1551-7. Epub 2014 May 14. Erratum in: Ann Oncol. 2017 Nov 1;28(11):2899. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02115204
- GEICAM 2003-10: Martín M, Ruiz Simón A, Ruiz Borrego M, Ribelles N, Rodríguez-Lescure A, Muñoz-Mateu M, González S, Margelí Vila M, Barnadas A, Ramos M, Del Barco Berron S, Jara C, Calvo L, Martínez-Jáñez N, Mendiola Fernández C, Rodríguez CA, Martínez de Dueñas E, Andrés R, Plazaola A, de la Haba-Rodríguez J, López-Vega JM, Adrover E, Ballesteros AI, Santaballa A, Sánchez-Rovira P, Baena-Cañada JM, Casas M, del Carmen Cámara M, Carrasco EM, Lluch A. Epirubicin plus cyclophosphamide followed by docetaxel versus epirubicin plus docetaxel followed by capecitabine as adjuvant therapy for node-positive early breast cancer: results from the GEICAM/2003-10 study. J Clin Oncol. 2015 Nov 10;33(32):3788-95. Epub 2015 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00129935
- DBCG 07-READ: Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen MB, Knoop AS, Højris I, Ewertz M, Balslev E, Danø H, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. Adjuvant cyclophosphamide and docetaxel with or without epirubicin for early TOP2A-normal breast cancer: DBCG 07-READ, an open-label, phase III, randomized trial. J Clin Oncol. 2017 Aug 10;35(23):2639-2646. Epub 2017 Jun 29. link to original article dosing details in manuscript have been reviewed by our editors 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)
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, T portion (cycles 5 to 16)
- Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
21-day cycle for 4 cycles, then 7-day cycle for 12 cycles (EC x 4; T x 12)
Regimen variant #2, 90/600
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Earl et al. 2017 (tAnGo) | 2001-2004 | Phase 3 (C) | EC-TG | Did not meet primary endpoint of 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)
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, T portion (cycles 5 to 8)
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
21-day cycle for 8 cycles (EC x 4; T x 4)
References
- GIM2: Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; GIM. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 x 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00433420
- Update: Del Mastro L, Poggio F, Blondeaux E, De Placido S, Giuliano M, Forestieri V, De Laurentiis M, Gravina A, Bisagni G, Rimanti A, Turletti A, Nisticò C, Vaccaro A, Cognetti F, Fabi A, Gasparro S, Garrone O, Alicicco MG, Urracci Y, Mansutti M, Poletti P, Correale P, Bighin C, Puglisi F, Montemurro F, Colantuoni G, Lambertini M, Boni L; Gruppo Italiano Mammella Investigators. Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial. Lancet Oncol. 2022 Dec;23(12):1571-1582. Epub 2022 Nov 10. link to original article PubMed
- tAnGo: Earl HM, Hiller L, Howard HC, Dunn JA, Young J, Bowden SJ, McDermaid M, Waterhouse AK, Wilson G, Agrawal R, O'Reilly S, Bowman A, Ritchie DM, Goodman A, Hickish T, McAdam K, Cameron D, Dodwell D, Rea DW, Caldas C, Provenzano E, Abraham JE, Canney P, Crown JP, Kennedy MJ, Coleman R, Leonard RC, Carmichael JA, Wardley AM, Poole CJ; tAnGo trial collaborators. Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Jun;18(6):755-769. Epub 2017 May 4. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00039546
- SPECTRUMbrca: Yu KD, Ge JY, Liu XY, Mo M, He M, Shao ZM; SPECTRUM Investigators. Cyclophosphamide-Free Adjuvant Chemotherapy for Ovarian Protection in Young Women With Breast Cancer: A Randomized Phase 3 Trial. J Natl Cancer Inst. 2021 Oct 1;113(10):1352-1359. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT01026116
- CH-BC-006: Yuan P, Kang Y, Ma F, Fan Y, Wang J, Wang X, Yue J, Luo Y, Zhang P, Li Q, Xu B. Effect of Epirubicin Plus Paclitaxel vs Epirubicin and Cyclophosphamide Followed by Paclitaxel on Disease-Free Survival Among Patients With Operable ERBB2-Negative and Lymph Node-Positive Breast Cancer: A Randomized Clinical Trial. JAMA Netw Open. 2023 Feb 1;6(2):e230122. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT01134523
- CH-BC-012: NCT01378533
- Fudan BC MASTER: NCT01314833
ddEC-T
ddEC-T: dose-dense Epirubicin and Cyclophosphamide, followed by Taxol (Paclitaxel)
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Burnell et al. 2009 (NCIC-CTG MA.21) | 2000-2005 | Phase 3 (E-esc) | 1. AC-T | 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)
- Epirubicin (Ellence) 120 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 830 mg/m2 IV once on day 1
Supportive therapy, ddEC portion (cycles 1 to 6)
- Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 2 to 13
- Epoetin alfa (Procrit) 40,000 units SC once per day on days 1 & 8
Chemotherapy, T portion (cycles 7 to 10)
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
14-day cycle for 6 cycles, then 21-day cycle for 4 cycles (ddEC x 6; T x 4)
References
- NCIC-CTG MA.21: Burnell M, Levine MN, Chapman JA, Bramwell V, Gelmon K, Walley B, Vandenberg T, Chalchal H, Albain KS, Perez EA, Rugo H, Pritchard K, O'Brien P, Shepherd LE. Cyclophosphamide, epirubicin, and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol. 2010 Jan 1;28(1):77-82. Epub 2009 Nov 9. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors 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)
- Epirubicin (Ellence) 150 mg/m2 IV once on day 1
Chemotherapy, iddnP portion (cycles 4 to 6)
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 330 mg/m2 IV once on day 1
Chemotherapy, iddC portion (cycles 7 to 9)
- Cyclophosphamide (Cytoxan) 2000 mg/m2 IV once on day 1
Supportive therapy, all portions (cycles 1 to 9)
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4
14-day cycle for 9 cycles (iddE x 3; iddnP x 3; iddC x 3)
References
- GAIN-2: Möbus V, Lück HJ, Ladda E, Klare P, Schmidt M, Schneeweiss A, Grischke EM, Wachsmann G, Forstbauer H, Untch M, Marmé F, Blohmer JU, Jackisch C, Huober J, Stickeler E, Reinisch M, Link T, Sinn BV, Janni W, Denkert C, Furlanetto J, Engels K, Solbach C, Schmatloch S, Rey J, Burchardi N, Loibl S; GBG and AGO-B. Phase III randomised trial comparing intense dose-dense chemotherapy to tailored dose-dense chemotherapy in high-risk early breast cancer (GAIN-2). Eur J Cancer. 2021 Oct;156:138-148. Epub 2021 Aug 24. link to original article dosing details in manuscript have been reviewed by our editors 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)
- Epirubicin (Ellence) 150 mg/m2 IV once on day 1
Chemotherapy, iddP portion (cycles 4 to 6)
- Paclitaxel (Taxol) 225 mg/m2 IV once on day 1
Chemotherapy, iddC portion (cycles 7 to 9)
- Cyclophosphamide (Cytoxan) 2000 mg/m2 IV once on day 1
Supportive therapy, all portions (cycles 1 to 9)
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4
14-day cycle for 9 cycles (iddE x 3; iddP x 3; iddC x 3)
References
- AGO-iddEPC: Moebus V, Jackisch C, Lueck HJ, du Bois A, Thomssen C, Kurbacher C, Kuhn W, Nitz U, Schneeweiss A, Huober J, Harbeck N, von Minckwitz G, Runnebaum IB, Hinke A, Kreienberg R, Konecny GE, Untch M. Intense dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide compared with conventionally scheduled chemotherapy in high-risk primary breast cancer: mature results of an AGO phase III study. J Clin Oncol. 2010 Jun 10;28(17):2874-80. Epub 2010 May 10. link to original article PubMed
- Update: Möbus V, Jackisch C, Lück HJ, du Bois A, Thomssen C, Kuhn W, Nitz U, Schneeweiss A, Huober J, Harbeck N, von Minckwitz G, Runnebaum IB, Hinke A, Konecny GE, Untch M, Kurbacher C; AGO Breast Study Group (AGO-B). Ten-year results of intense dose-dense chemotherapy show superior survival compared with a conventional schedule in high-risk primary breast cancer: final results of AGO phase III iddEPC trial. Ann Oncol. 2018 Jan 1;29(1):178-185. link to original article PubMed
- GAIN: Möbus V, von Minckwitz G, Jackisch C, Lück HJ, Schneeweiss A, Tesch H, Elling D, Harbeck N, Conrad B, Fehm T, Huober J, Müller V, Bauerfeind I, du Bois A, Loibl S, Nekljudova V, Untch M, Thomssen C; German Breast Group; AGO Breast Study Group (AGO-B); NOGGO. German Adjuvant Intergroup Node-positive Study (GAIN): a phase III trial comparing two dose-dense regimens (iddEPC versus ddEC-PwX) in high-risk early breast cancer patients. Ann Oncol. 2017 Aug 1;28(8):1803-1810. link to original article dosing details in manuscript have been reviewed by our editors 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)
- Epirubicin (Ellence) 83 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 187 mg/m2 IV once on day 1
Chemotherapy, ddCMF portion (cycles 5 to 7)
- Cyclophosphamide (Cytoxan) 840 mg/m2 IV once on day 1
- Methotrexate (MTX) 57 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 840 mg/m2 IV once on day 1
Supportive therapy, ddCMF portion (cycles 5 to 7)
- G-CSF (dose not specified) SC once per day on days 2 to 10
21-day cycle for 4 cycles, then 14-day cycle for 3 cycles (EP x 4; ddCMF x 3)
References
- HE 10/00: Fountzilas G, Dafni U, Gogas H, Linardou H, Kalofonos HP, Briasoulis E, Pectasides D, Samantas E, Bafaloukos D, Stathopoulos GP, Karina M, Papadimitriou C, Skarlos D, Pisanidis N, Papakostas P, Markopoulos C, Tzorakoeleftherakis E, Dimitrakakis K, Makrantonakis P, Xiros N, Polichronis A, Varthalitis I, Karanikiotis C, Dimopoulos AM; Hellenic Cooperative Oncology Group. Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: safety analysis of the Hellenic Cooperative Oncology Group randomized phase III trial HE 10/00. Ann Oncol. 2008 May;19(5):853-60. Epub 2007 Nov 27. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Gogas H, Dafni U, Karina M, Papadimitriou C, Batistatou A, Bobos M, Kalofonos HP, Eleftheraki AG, Timotheadou E, Bafaloukos D, Christodoulou C, Markopoulos C, Briasoulis E, Papakostas P, Samantas E, Kosmidis P, Stathopoulos GP, Karanikiotis C, Pectasides D, Dimopoulos MA, Fountzilas G. Postoperative dose-dense sequential versus concomitant administration of epirubicin and paclitaxel in patients with node-positive breast cancer: 5-year results of the Hellenic Cooperative Oncology Group HE 10/00 phase III Trial. Breast Cancer Res Treat. 2012 Apr;132(2):609-19. Epub 2011 Dec 21. 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)
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
Chemotherapy, T portion (cycles 5 to 12)
- Paclitaxel (Taxol) 100 mg/m2 IV once on day 1
21-day cycle for 4 cycles, then 7-day cycle for 8 cycles (FAC x 4; T x 8)
References
- GEICAM 2003-02: Martín M, Ruiz A, Ruiz Borrego M, Barnadas A, González S, Calvo L, Margelí Vila M, Antón A, Rodríguez-Lescure A, Seguí-Palmer MA, Muñoz-Mateu M, Dorca Ribugent J, López-Vega JM, Jara C, Espinosa E, Mendiola Fernández C, Andrés R, Ribelles N, Plazaola A, Sánchez-Rovira P, Salvador Bofill J, Crespo C, Carabantes FJ, Servitja S, Chacón JI, Rodríguez CA, Hernando B, Álvarez I, Carrasco E, Lluch A. Fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus FAC followed by weekly paclitaxel as adjuvant therapy for high-risk, node-negative breast cancer: results from the GEICAM/2003-02 study. J Clin Oncol. 2013 Jul 10;31(20):2593-9. Epub 2013 Jun 3. link to original article dosing details in manuscript have been reviewed by our editors 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 |
de Gregorio et al. 2022 (LMU Success C) | 2008-2011 | Phase 3 (C) | TC | Inconclusive whether non-inferior DFS2 (primary endpoint) |
1Reported efficacy for FNCLCC PACS 01 is based on the 2012 update.
2LMU Success C was designed as a non-inferiority trial but was reported using a superiority design post-hoc analysis.
Preceding treatment
Chemotherapy, FEC portion (cycles 1 to 3)
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
Chemotherapy, D portion (cycles 4 to 6)
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 6 cycles (FEC x 3; D x 3)
Regimen variant #2, 4 x 4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ellis et al. 2009 (TACT) | 2001-2003 | Phase 3 (E-switch-ic) | 1a. E-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)
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 40 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, D portion (cycles 5 to 8)
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 8 cycles (FEC x 4; D x 4)
References
- FNCLCC PACS 01: Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulié P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Genève J, Asselain B. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006 Dec 20;24(36):5664-71. Epub 2006 Nov 20. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Coudert B, Asselain B, Campone M, Spielmann M, Machiels JP, Pénault-Llorca F, Serin D, Lévy C, Romieu G, Canon JL, Orfeuvre H, Piot G, Petit T, Jerusalem G, Audhuy B, Veyret C, Beauduin M, Eymard JC, Martin AL, Roché H; UNICANCER Breast Group. Extended benefit from sequential administration of docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide regimen for node-positive breast cancer: the 8-year follow-up results of the UNICANCER-PACS01 trial. Oncologist. 2012;17(7):900-9. Epub 2012 May 18. link to original article link to PMC article PubMed
- TACT: Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed ISRCTN79718493
- Sakr H, Hamed RH, Anter AH, Yossef T. Sequential docetaxel as adjuvant chemotherapy for node-positive or/and T3 or T4 breast cancer: clinical outcome (Mansoura University). Med Oncol. 2013 Mar;30(1):457. Epub 2013 Jan 16. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- PANTHER: Foukakis T, von Minckwitz G, Bengtsson NO, Brandberg Y, Wallberg B, Fornander T, Mlineritsch B, Schmatloch S, Singer CF, Steger G, Egle D, Karlsson E, Carlsson L, Loibl S, Untch M, Hellström M, Johansson H, Anderson H, Malmström P, Gnant M, Greil R, Möbus V, Bergh J; Swedish Breast Cancer Group; German Breast Group; Austrian Breast & Colorectal Cancer Study Group. Effect of tailored dose-dense chemotherapy vs standard 3-weekly adjuvant chemotherapy on recurrence-free survival among women with high-risk early breast cancer: a randomized clinical trial. JAMA. 2016 Nov 8;316(18):1888-1896. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00798070
- UCBG 2-08: Campone M, Lacroix-Triki M, Roca L, Spielmann M, Wildiers H, Cottu P, Kerbrat P, Levy C, Desmoulins I, Bachelot T, Winston T, Eymard JC, Uwer L, Duhoux FP, Verhoeven D, Jaubert D, Coeffic D, Orfeuvre H, Canon JL, Asselain B, Martin AL, Lemonnier J, Roché H. UCBG 2-08: 5-year efficacy results from the UNICANCER-PACS08 randomised phase III trial of adjuvant treatment with FEC100 and then either docetaxel or ixabepilone in patients with early-stage, poor prognosis breast cancer. Eur J Cancer. 2018 Nov;103:184-194. Epub 2018 Sep 26. link to original article PubMed NCT00630032
- MINDACT: Delaloge S, Piccart M, Rutgers E, Litière S, van 't Veer LJ, van den Berkmortel F, Brain E, Dudek-Peric A, Gil-Gil M, Gomez P, Hilbers FS, Khalil Z, Knox S, Kuemmel S, Kunz G, Lesur A, Pierga JY, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Thompson AM, Viale G, Zoppoli G, Vuylsteke P, Tryfonidis K, Poncet C, Bogaerts J, Cardoso F; MINDACT investigators and the TRANSBIG Consortium. Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial. J Clin Oncol. 2020 Apr 10;38(11):1186-1197. Epub 2020 Feb 21. link to original article contains dosing details in supplement link to PMC article PubMed NCT00433589
- SUCCESS-A: de Gregorio A, Häberle L, Fasching PA, Müller V, Schrader I, Lorenz R, Forstbauer H, Friedl TWP, Bauer E, de Gregorio N, Deniz M, Fink V, Bekes I, Andergassen U, Schneeweiss A, Tesch H, Mahner S, Brucker SY, Blohmer JU, Fehm TN, Heinrich G, Lato K, Beckmann MW, Rack B, Janni W. Gemcitabine as adjuvant chemotherapy in patients with high-risk early breast cancer-results from the randomized phase III SUCCESS-A trial. Breast Cancer Res. 2020 Oct 23;22(1):111. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT02181101
- LMU Success C: de Gregorio A, Janni W, Friedl TWP, Nitz U, Rack B, Schneeweiss A, Kates R, Fehm T, Kreipe H, Christgen M, Kuemmel S, Trapp E, Wuerstlein R, Hartkopf A, Clemens M, Reimer T, Haberle L, Fasching PA, Gluz O, Harbeck N. The impact of anthracyclines in intermediate and high-risk HER2-negative early breast cancer-a pooled analysis of the randomised clinical trials PlanB and SUCCESS C. Br J Cancer. 2022 Jun;126(12):1715-1724. Epub 2022 Feb 22. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00847444
ddFEC-ddD
ddFEC-D: dose-dense Fluorouracil, Epirubicin, Cyclophosphamide followed by dose-dense Docetaxel
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Saloustros et al. 2014 (HORG CT/04.22) | 2004-2007 | Phase 3 (E-switch-ic) | ddFEC-T | Did not meet primary endpoint of DFS36 |
Mavroudis et al. 2016 (HORG CT/07.17) | 2007-2013 | Phase 3 (C) | TC | Inconclusive whether non-inferior DFS36 |
Preceding treatment
Chemotherapy, ddFEC portion (cycles 1 to 4)
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
Chemotherapy, ddD portion (cycles 5 to 8)
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
Supportive therapy, both portions (cycles 1 to 8)
- G-CSF support (drug/dose/schedule not specified)
14-day cycle for 8 cycles (ddFEC x 4; ddD x 4)
References
- HORG CT/04.22: Saloustros E, Malamos N, Boukovinas I, Kakolyris S, Kouroussis C, Athanasiadis A, Ziras N, Kentepozidis N, Makrantonakis P, Polyzos A, Christophyllakis C, Georgoulias V, Mavroudis D. Dose-dense paclitaxel versus docetaxel following FEC as adjuvant chemotherapy in axillary node-positive early breast cancer: a multicenter randomized study of the Hellenic Oncology Research Group (HORG). Breast Cancer Res Treat. 2014 Dec;148(3):591-7. Epub 2014 Nov 16. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00431080
- HORG CT/07.17: Mavroudis D, Matikas A, Malamos N, Papakotoulas P, Kakolyris S, Boukovinas I, Athanasiadis A, Kentepozidis N, Ziras N, Katsaounis P, Saloustros E, Georgoulias V; HORG. Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2016 Oct;27(10):1873-8. Epub 2016 Aug 8. link to original article dosing details in manuscript have been reviewed by our editors 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)
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Chemotherapy, P portion (cycles 5 to 12)
- Paclitaxel (Taxol) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 4 cycles, then 7-day cycle for 8 cycles (FEC x 4; P x 8)
References
- GEICAM 9906: Martín M, Rodríguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Munárriz B, Rodríguez CA, Crespo C, de Alava E, López García-Asenjo JA, Guitián MD, Almenar S, González-Palacios JF, Vera F, Palacios J, Ramos M, Gracia Marco JM, Lluch A, Alvarez I, Seguí MA, Mayordomo JI, Antón A, Baena JM, Plazaola A, Modolell A, Pelegrí A, Mel JR, Aranda E, Adrover E, Alvarez JV, García Puche JL, Sánchez-Rovira P, Gonzalez S, López-Vega JM; GEICAM. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst. 2008 Jun 4;100(11):805-14. Epub 2008 May 27. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00129922
- GIM2: Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; GIM. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 x 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00433420
- Update: Del Mastro L, Poggio F, Blondeaux E, De Placido S, Giuliano M, Forestieri V, De Laurentiis M, Gravina A, Bisagni G, Rimanti A, Turletti A, Nisticò C, Vaccaro A, Cognetti F, Fabi A, Gasparro S, Garrone O, Alicicco MG, Urracci Y, Mansutti M, Poletti P, Correale P, Bighin C, Puglisi F, Montemurro F, Colantuoni G, Lambertini M, Boni L; Gruppo Italiano Mammella Investigators. Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial. Lancet Oncol. 2022 Dec;23(12):1571-1582. Epub 2022 Nov 10. link to original article 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)
- Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
Chemotherapy, FEC portion (cycles 13 to 16)
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
7-day cycle for 12 cycles, then 21-day cycle for 4 cycles (T x 12; FEC x 4)
References
- MDACC ID01-580: Kelly CM, Green MC, Broglio K, Thomas ES, Brewster AM, Valero V, Ibrahim NK, Gonzalez-Angulo AM, Booser DJ, Walters RS, Hunt KK, Hortobagyi GN, Buzdar AU. Phase III trial evaluating weekly paclitaxel versus docetaxel in combination with capecitabine in operable breast cancer. J Clin Oncol. 2012 Mar 20;30(9):930-5. Epub 2012 Feb 13. link to original article dosing details in manuscript have been reviewed by our editors 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)
- Docetaxel (Taxotere) 60 mg/m2 IV over 60 minutes once on day 1
- Capecitabine (Xeloda) 900 mg/m2 PO twice per day on days 1 to 15
Chemotherapy, CEX portion (cycles 4 to 6)
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Capecitabine (Xeloda) 900 mg/m2 PO twice per day on days 1 to 15
21-day cycle for 6 cycles (TX x 3; CEX x 3)
References
- FinXX: Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Asola R, Kokko R, Ahlgren J, Auvinen P, Hemminki A, Paija O, Helle L, Nuortio L, Villman K, Nilsson G, Lahtela SL, Lehtiö K, Pajunen M, Poikonen P, Nyandoto P, Kataja V, Bono P, Leinonen M, Lindman H; FinXX Study Investigators. Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer: an open-label, randomised controlled trial. Lancet Oncol. 2009 Dec;10(12):1145-51. Epub 2009 Nov 10. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00114816
- Update: Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Kokko R, Ahlgren J, Auvinen P, Paija O, Helle L, Villman K, Nyandoto P, Nilsson G, Pajunen M, Asola R, Poikonen P, Leinonen M, Kataja V, Bono P, Lindman H. Adjuvant capecitabine, docetaxel, cyclophosphamide, and epirubicin for early breast cancer: final analysis of the randomized FinXX trial. J Clin Oncol. 2012 Jan 1;30(1):11-8. Epub 2011 Nov 21. link to original article PubMed
- Update: Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola A, Tanner M, Ahlgren J, Auvinen P, Lahdenperä O, Villman K, Nyandoto P, Nilsson G, Poikonen-Saksela P, Kataja V, Bono P, Junnila J, Lindman H. Adjuvant Capecitabine for Early Breast Cancer: 15-Year Overall Survival Results From a Randomized Trial. J Clin Oncol. 2022 Apr 1;40(10):1051-1058. Epub 2022 Jan 12. 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)
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 6 cycles (V x 3; FEC x 3)
References
- FinHer: Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article dosing details in manuscript have been reviewed by our editors PubMed ISRCTN76560285
- Update: Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. Epub 2009 Nov 2. 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 |
References
- NSABP B-40: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00408408
- Update: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Paik S, Swain SM, Mamounas EP, Wolmark N. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1037-1048. Epub 2015 Aug 10. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. link to original article link to PMC article 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
- CALGB 49907: Surgery
- CREATE-X: Neoadjuvant chemotherapy containing anthracycline, taxane, or both, then surgery
Chemotherapy
- Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 6 to 8 cycles
References
- CALGB 49907: Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Becker HP, Kartcheske PA, Wheeler JD, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Magrinat G, Parker BA, Hart RD, Grenier D, Norton L, Hudis CA, Winer EP; CALGB. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009 May 14;360(20):2055-65. Erratum in: N Engl J Med. 2009 Oct 22;361(17):1714. Magrinat, Gutav [corrected to Magrinat, Gustav]. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00024102
- Update: Muss HB, Polley MC, Berry DA, Liu H, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Kartcheske PA, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Sutton LM, Magrinat G, Parker BA, Hart RD, Grenier D, Hurria A, Jatoi A, Norton L, Hudis CA, Winer EP, Carey L. Randomized Trial of Standard Adjuvant Chemotherapy Regimens Versus Capecitabine in Older Women With Early Breast Cancer: 10-Year Update of the CALGB 49907 Trial. J Clin Oncol. 2019 Sep 10;37(26):2338-2348. Epub 2019 Jul 24. link to original article link to PMC article PubMed
- CREATE-X: Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, Kuroi K, Im SA, Park BW, Kim SB, Yanagita Y, Ohno S, Takao S, Aogi K, Iwata H, Jeong J, Kim A, Park KH, Sasano H, Ohashi Y, Toi M; Japan Breast Cancer Research Group; Korean Breast Cancer Study Group; Korean Cancer Study Group. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017 Jun 1;376(22):2147-2159. link to original article dosing details in manuscript have been reviewed by our editors 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
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
- Methotrexate (MTX) 40 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Regimen variant #2, 600/40/600 x 6 to 8
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sparano et al. 2018 (TAILORx) | 2006-2010 | Phase 3 (C) | No chemotherapy | Non-inferior IDFS (primary endpoint) |
Eligibility criteria
- TAILORx: Oncotype DX score of 11 to 25
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
- Methotrexate (MTX) 40 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
21-day cycle for 6 to 8 cycles
Regimen variant #3, 600/40/600 x 8, q4wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Overgaard et al. 1997 (DBCG 82b) | 1982-1989 | Phase 3 (E-switch-ooc) | See link | See link |
Note: in DBCG 82b, radiotherapy was given between cycles 1 & 2.
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
- Methotrexate (MTX) 40 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
28-day cycle for 8 cycles
Regimen variant #4, 600/40/600 x 9
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ejlertsen et al. 2007 (DBCG 89D) | 1990-1998 | Phase 3 (C) | FEC x 9 | 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
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
- Methotrexate (MTX) 40 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
21-day cycle for 9 cycles
Regimen variant #5, 600/60/600 x 6
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Martin et al. 2003 (GEICAM 8701) | 1987-1991 | Phase 3 (C) | FAC; 500/50/500 x 6 | Might have 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
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
- Methotrexate (MTX) 60 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Regimen variant #6, 700/30/700 x 24
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Clahsen et al. 1995 (EORTC 09771) | 1976-1980 | Phase 3 (E-esc) | Observation | Seems to have superior OS |
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 50 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 15 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 350 mg/m2 IV once per day on days 1 & 8
1-month cycle for 24 cycles
Regimen variant #7, 750/50/600 x 6-8 ("Scottish Breast Group schedule")
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Stewart et al. 1993 | 1980-1990 | Phase 3 (C) | 1. CMFP 2. Bilateral oophorectomy 3. Oophorectomy & Prednisolone |
Did not meet primary endpoint of EFS |
Poole et al. 2006 (BR9601) | 1996-2001 | Phase 3 (C) | E-CMF x 4+4 | Inferior OS |
Fernando et al. 2019 (SECRAB) | 1998-2004 | Phase 3 (C) | 1a. CMF & RT 1b. E-CMF & RT 1c. A-CMF & RT 1d. MMM & RT |
Inferior LRFS |
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
- Methotrexate (MTX) 50 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
21-day cycle for varying durations: 6 to 8 cycles; 8 cycles (BR9601)
Regimen variant #8, 840/50/800
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hubay et al. 1980 | Not reported | Randomized (C) | 1. CMFT | Seems to have inferior RFS |
2. CMFT & BCG | Did not meet endpoints of RFS/OS |
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 30 mg/m2 PO twice per day on days 1 to 14
- Methotrexate (MTX) 25 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 & 8
28-day cycle for 12 cycles
Regimen variant #9, 1000/80/1000 x 6
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kimura et al. 2009 | 1996-2000 | Phase 3 (C) | FEC | Did not meet primary endpoint of DFS |
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 8
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 cycles
Regimen variant #10, 1000/80/1200 x 6
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Jonat et al. 2002 (ZEBRA) | 1990-1996 | Phase 3 (C) | Goserelin x 2 y | Did not meet primary endpoint of DFS |
Schmid et al. 2007 (TABLE) | 1995-1998 | Phase 3 (C) | Leuprolide | Inferior OS |
Preceding treatment
- Surgery, within 6 weeks
Chemotherapy
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 8
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 cycles
Regimen variant #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
- Cyclophosphamide (Cytoxan) 80 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
1-month cycle for 12 cycles
Regimen variant #12, 1120/64/960 x 12
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Howell et al. 1984 | 1976-1983 | Phase 3 (E-esc) | Observation | Superior RFS |
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 80 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 32 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 4800 mg/m2 IV once per day on days 1 & 8
28-day cycle for 12 cycles
Regimen variant #13, 1200/80/1200 x 1
Historic variant |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Goldhirsch et al. 1989 (LCBS V) | 1981-1985 | Phase 3 (E-esc) | No further treatment | Seems to have superior DFS |
Note: leucovorin was not used for antineoplastic effect in this regimen.
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 400 mg/m2 IV once per day on days 1 & 8
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
Supportive therapy
- Leucovorin (Folinic acid) 15 mg IV once on day 2, then 15 mg PO once on day 9
8-day course
Regimen variant #14, 1200/80/1200 x 4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Perrone et al. 2014 (ELDA) | 2003-2011 | Phase 3 (C) | Docetaxel | Did not meet primary endpoint of DFS |
Note: In ELDA, this protocol was for ER/PR+ patients.
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once per day on days 1 & 8
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 4 cycles
Regimen variant #15, 1200/80/1200 x 6 ("Classical" IV)
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ragaz et al. 1997 | 1978-1986 | Phase 3 (C) | CMF & RT | Seems to have 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
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once per day on days 1 & 8
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 cycles
Regimen variant #16, 1400/60/1200 x 12
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Rubens et al. 1989 (EORTC 10792) | 1979-1985 | Phase 3 (E-esc) | 1. Observation | Did not meet endpoint of OS |
2. Tamoxifen 3. CMFT |
Not reported |
Note: this trial had a complex efficacy analysis; see paper for details.
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 12 cycles
Regimen variant #17, 1400/80/1000 x 6
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Watanabe et al. 2009 (NSAS BC-01) | 1996-2001 | Phase 3 (C) | UFT | Inconclusive whether non-inferior RFS |
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 cycles
Regimen variant #18, 1400/80/1200 x 3
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Castiglione-Gertsch et al. 1996 (IBCSG VI) | 1986-1993 | Phase 3 (E-de-esc) | 1. CMF x 6 | Seems to have inferior DFS |
2. CMF x 3, with re-introduction 3. CMF x 6, with re-introduction |
Might have inferior DFS |
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 3 cycles
Subsequent treatment
- Adjuvant Tamoxifen x 5 y versus no further treatment
Regimen variant #19, 1400/80/1200 x 6
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Tancini et al. 1979 (CALGB 7581) | 1975 to not reported | Phase 3 (E-de-esc) | CMF x 12 | Did not meet primary endpoint of RFS |
Coombes et al. 1996 | 1984-1992 | Phase 3 (C) | FEC | Did not meet co-primary endpoints of RFS/OS |
Castiglione-Gertsch et al. 1996 (IBCSG VI) | 1986-1993 | Phase 3 (C) | 1. CMF x 3 | Seems to have 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
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 cycles
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 to not reported | Phase 3 (C) | CMF x 6 | Did not meet primary endpoint of RFS |
Misset et al. 1996 (OncoFrance) | 1978-1981 | Phase 3 (C) | AVCF | 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
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 12 cycles
References
- Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, De Lena M, Tancini G, Bajetta E, Musumeci R, Veronesi U. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976 Feb 19;294(8):405-10. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Bonadonna G, Rossi A, Valagussa P, Banfi A, Veronesi U. The CMF program for operable breast cancer with positive axillary nodes: updated analysis on the disease-free interval, site of relapse and drug tolerance. Cancer. 1977 Jun;39(6 Suppl):2904-15. link to original article PubMed
- Update: Bonadonna G, Valagussa P, Rossi A, Tancini G, Brambilla C, Zambetti M, Veronesi U. Ten-year experience with CMF-based adjuvant chemotherapy in resectable breast cancer. Breast Cancer Res Treat. 1985;5(2):95-115. link to original article PubMed
- Update: Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995 Apr 6;332(14):901-6. link to original article PubMed
- CALGB 7581: Tancini G, Bajetta E, Marchini S, Valagussa P, Bonadonna G, Veronesi U. Preliminary 3-year results of 12 versus 6 cycles of surgical adjuvant CMF in premenopausal breast cancer. Cancer Clin Trials. 1979 Winter;2(4):285-92. PubMed
- Update: Tancini G, Bonadonna G, Valagussa P, Marchini S, Veronesi U. Adjuvant CMF in breast cancer: comparative 5-year results of 12 versus 6 cycles. J Clin Oncol. 1983 Jan;1(1):2-10. link to original article PubMed
- Hubay CA, Pearson OH, Marshall JS, Rhodes RS, Debanne SM, Mansour EG, Hermann RE, Jones JC, Flynn WJ, Eckert C, McGuire WL. Antiestrogen, cytotoxic chemotherapy, and bacillus Calmette-Guerin vaccination in stage II breast cancer: a preliminary report. Surgery. 1980 May;87(5):494-501. link to original article PubMed
- Update: Hubay CA, Pearson OH, Marshall JS, Rhodes RS, DeBanne SM, Rosenblatt J, Mansour EG, Hermann RE, Jones JC, Flynn WJ, Eckert C, McGuire WL. Adjuvant chemotherapy, antiestrogen therapy and immunotherapy for stage II breast cancer: 45-month follow-up of a prospective, randomized clinical trial. Cancer. 1980 Dec 15;46(12 Suppl):2805-8. link to original article PubMed
- DBCG 77B: Brincker H, Mouridsen HT, Andersen KW. Adjuvant chemotherapy with cyclophosphamide or CMF in premenopausal women with stage II breast cancer. Breast Cancer Res Treat. 1983;3(1):91-5. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Andersson M, Kamby C, Knoop AS; Danish Breast Cancer Cooperative Group. Cyclophosphamide, methotrexate, and fluorouracil; oral cyclophosphamide; levamisole; or no adjuvant therapy for patients with high-risk, premenopausal breast cancer. Cancer. 2010 May 1;116(9):2081-9. link to original article PubMed
- Howell A, Bush H, George WD, Howat JM, Crowther D, Sellwood RA, Rubens RD, Hayward JL, Bulbrook RD, Fentiman IS, Chaudary M. Controlled trial of adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil for breast cancer. Lancet. 1984 Aug 11;2(8398):307-11. link to original article PubMed
- LCBS V: Goldhirsch A, Gelber RD; Ludwig Breast Cancer Study Group. Prolonged disease-free survival after one course of perioperative adjuvant chemotherapy for node-negative breast cancer. N Engl J Med. 1989 Feb 23;320(8):491-6. link to original article PubMed
- ECOG E5177: Tormey DC, Gray R, Gilchrist K, Grage T, Carbone PP, Wolter J, Woll JE, Cummings FJ. Adjuvant chemohormonal therapy with cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen compared with CMF for premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial. Cancer. 1990 Jan 15;65(2):200-6. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Stewart HJ, Forrest APM, Hawkins RA, Prescott RJ, Smith DC, Everington D, Richards MA, George WD; Scottish Cancer Trials Breast Group and ICRF Breast Unit Guy's Hospital London. Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast carcinoma: the Scottish trial. Lancet. 1993 May 22;341(8856):1293-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- EORTC 09771: Clahsen PC, van de Velde CJ, Welvaart K, Repelaer van Driel OJ, Sylvester RJ; Cooperating Investigators. Ten-year results of a randomized trial evaluating prolonged low-dose adjuvant chemotherapy in node-positive breast cancer: a joint European Organisation for Research and Treatment of Cancer-Dutch Breast Cancer Working Party Study. J Clin Oncol. 1995 Jan;13(1):33-41. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Coombes RC, Bliss JM, Wils J, Morvan F, Espié M, Amadori D, Gambrosier P, Richards M, Aapro M, Villar-Grimalt A, McArdle C, Pérez-López FR, Vassilopoulos P, Ferreira EP, Chilvers CE, Coombes G, Woods EM, Marty M; International Collaborative Cancer Group. Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. J Clin Oncol. 1996 Jan;14(1):35-45. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- OncoFrance: Misset JL, di Palma M, Delgado M, Plagne R, Chollet P, Fumoleau P, Le Mevel B, Belpomme D, Guerrin J, Fargeot P, Metz R, Ithzaki M, Hill C, Mathé G. Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: final report after a 16-year median follow-up duration. J Clin Oncol. 1996 Apr;14(4):1136-45. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- IBCSG VI: Castiglione-Gertsch M, Goldhirsch A; International Breast Cancer Study Group. Duration and reintroduction of adjuvant chemotherapy for node-positive premenopausal breast cancer patients. J Clin Oncol. 1996 Jun;14(6):1885-94. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Pooled QoL analysis: Hürny C, Bernhard J, Coates AS, Castiglione-Gertsch M, Peterson HF, Gelber RD, Forbes JF, Rudenstam CM, Simoncini E, Crivellari D, Goldhirsch A, Senn HJ; International Breast Cancer Study Group. Impact of adjuvant therapy on quality of life in women with node-positive operable breast cancer. Lancet. 1996 May 11;347(9011):1279-84. Erratum in: Lancet 1997 Jul 26;350(9073):298. link to original article PubMed
- EORTC 10792: Rubens RD, Bartelink H, Engelsman E, Hayward JL, Rotmensz N, Sylvester R, van der Schueren E, Papadiamantis J, Vassilaros SD, Wildiers J, Winter PJ. Locally advanced breast cancer: the contribution of cytotoxic and endocrine treatment to radiotherapy - an EORTC Breast Cancer Co-operative Group Trial (10792). Eur J Cancer Clin Oncol. 1989 Apr;25(4):667-78. link to original article PubMed
- Update: Bartelink H, Rubens RD, van der Schueren E, Sylvester R. Hormonal therapy prolongs survival in irradiated locally advanced breast cancer: a European Organization for Research and Treatment of Cancer Randomized Phase III Trial. J Clin Oncol. 1997 Jan;15(1):207-15. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- DBCG 82b: Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, Kjaer M, Gadeberg CC, Mouridsen HT, Jensen MB, Zedeler K. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy: Danish Breast Cancer Cooperative Group 82b trial. N Engl J Med. 1997 Oct 2;337(14):949-55. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Ragaz J, Jackson SM, Le N, Plenderleith IH, Spinelli JJ, Basco VE, Wilson KS, Knowling MA, Coppin CM, Paradis M, Coldman AJ, Olivotto IA. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med. 1997 Oct 2;337(14):956-62. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Review: Goldhirsch A, Colleoni M, Coates AS, Castiglione-Gertsch M, Gelber RD; International Breast Cancer Study Group. Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: are all CMFs alike?. Ann Oncol. 1998 May;9(5):489-93. link to original article dosing details in abstract have been reviewed by our editors PubMed
- NCIC-CTG MA.5: Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, Findlay B, Warr D, Bowman D, Myles J, Arnold A, Vandenberg T, MacKenzie R, Robert J, Ottaway J, Burnell M, Williams CK, Tu D; National Cancer Institute of Canada Clinical Trials Group. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. J Clin Oncol. 1998 Aug;16(8):2651-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Levine MN, Pritchard KI, Bramwell VH, Shepherd LE, Tu D, Paul N; National Cancer Institute of Canada Clinical Trials Group. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol. 2005 Aug 1;23(22):5166-70. link to original article PubMed
- Subgroup analysis: Pritchard KI, Shepherd LE, O'Malley FP, Andrulis IL, Tu D, Bramwell VH, Levine MN; National Cancer Institute of Canada Clinical Trials Group. HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med. 2006 May 18;354(20):2103-11. link to original article PubMed
- Amadori D, Nanni O, Marangolo M, Pacini P, Ravaioli A, Rossi A, Gambi A, Catalano G, Perroni D, Scarpi E, Giunchi DC, Tienghi A, Becciolini A, Volpi A. Disease-free survival advantage of adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with node-negative, rapidly proliferating breast cancer: a randomized multicenter study. J Clin Oncol. 2000 Sep;18(17):3125-34. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Amadori D, Nanni O, Volpi A, Casadei Giunchi D, Marangolo M, Livi L, Ravaioli A, Rossi AP, Gambi A, Luzi Fedeli S, Perroni D, Scarpi E, Becciolini A, Silvestrini R. Phase III randomized multicenter study on the effects of adjuvant CMF in patients with node-negative, rapidly proliferating breast cancer: twelve-year results and retrospective subgroup analysis. Breast Cancer Res Treat. 2008 Mar;108(2):259-64. Epub 2007 May 26. link to original article PubMed
- NSABP B-23: Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, Dimitrov NV, Atkins JN, Abramson N, Merajver S, Romond EH, Kardinal CG, Shibata HR, Margolese RG, Farrar WB. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001 Feb 15;19(4):931-42. link to original article PubMed
- Update: Fisher B, Jeong JH, Anderson S, Wolmark N. Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst. 2004 Dec 15;96(24):1823-31. link to original article PubMed
- Belgian trial: Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M, Nogaret JM. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol. 2001 Jun 15;19(12):3103-10. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: de Azambuja E, Paesmans M, Beauduin M, Vindevoghel A, Cornez N, Finet C, Ries F, Closon-Dejardin MT, Kerger J, Gobert P, Focan C, Tagnon A, Dolci S, Nogaret JM, di Leo A, Piccart-Gebhart MJ. Long-term benefit of high-dose epirubicin in adjuvant chemotherapy for node-positive breast cancer: 15-year efficacy results of the Belgian multicentre study. J Clin Oncol. 2009 Feb 10;27(5):720-5. Epub 2008 Dec 22. link to original article PubMed
- Ron IG, Wigler N, Borovik R, Brufman G, Rizel S, Shani A, Brenner J, Farbstein H, Dale A, Inbar MJ, Brenner HJ, Chaitchik S, Catane R. CMF (cyclophosphamide, methotrexate, 5-fluorouracil) versus CNF (cyclophosphamide, mitoxantrone, 5-fluorouracil) as adjuvant chemotherapy for stage II lymph-node positive breast cancer: a phase III randomized multicenter study. Am J Clin Oncol. 2001 Aug;24(4):323-7. link to original article PubMed
- ZEBRA: Jonat W, Kaufmann M, Sauerbrei W, Blamey R, Cuzick J, Namer M, Fogelman I, de Haes JC, de Matteis A, Stewart A, Eiermann W, Szakolczai I, Palmer M, Schumacher M, Geberth M, Lisboa B; Zoladex Early Breast Cancer Research Association Study. Goserelin versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy in premenopausal patients with node-positive breast cancer: the Zoladex Early Breast Cancer Research Association study. J Clin Oncol. 2002 Dec 15;20(24):4628-35. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- GEICAM 8701: Martin M, Villar A, Sole-Calvo A, Gonzalez R, Massuti B, Lizon J, Camps C, Carrato A, Casado A, Candel MT, Albanell J, Aranda J, Munarriz B, Campbell J, Diaz-Rubio E; GEICAM. Doxorubicin in combination with fluorouracil and cyclophosphamide (iv FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (iv CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Ann Oncol. 2003 Jun;14(6):833-42. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- INT-0102: Hutchins LF, Green SJ, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of intergroup protocol INT-0102. J Clin Oncol. 2005 Nov 20;23(33):8313-21. link to original article PubMed
- NEAT: Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00003577
- Update: Earl HM, Hiller L, Dunn JA, Vallier AL, Bowden SJ, Jordan SD, Blows F, Munro A, Bathers S, Grieve R, Spooner DA, Agrawal R, Fernando I, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, McAdam K, Foster L, Leonard RC, Twelves CJ, Cameron D, Bartlett JM, Pharoah P, Provenzano E, Caldas C, Poole CJ; NEAT Investigators and the SCTBG. Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials. Br J Cancer. 2012 Oct 9;107(8):1257-67. Epub 2012 Sep 11. link to original article link to PMC article PubMed
- BR9601: Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00003012
- Update: Earl HM, Hiller L, Dunn JA, Vallier AL, Bowden SJ, Jordan SD, Blows F, Munro A, Bathers S, Grieve R, Spooner DA, Agrawal R, Fernando I, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, McAdam K, Foster L, Leonard RC, Twelves CJ, Cameron D, Bartlett JM, Pharoah P, Provenzano E, Caldas C, Poole CJ; NEAT Investigators and the SCTBG. Adjuvant epirubicin followed by cyclophosphamide, methotrexate and fluorouracil (CMF) vs CMF in early breast cancer: results with over 7 years median follow-up from the randomised phase III NEAT/BR9601 trials. Br J Cancer. 2012 Oct 9;107(8):1257-67. Epub 2012 Sep 11. link to original article link to PMC article PubMed
- DBCG 89D: Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Cold S, Edlund P, Ewertz M, Jensen BB, Kamby C, Nordenskjold B, Bergh J. Improved outcome from substituting methotrexate with epirubicin: results from a randomised comparison of CMF versus CEF in patients with primary breast cancer. Eur J Cancer. 2007 Mar;43(5):877-84. Epub 2007 Feb 16. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- NCRI ABC-CT: Adjuvant Breast Cancer Trials Collaborative Group. Polychemotherapy for early breast cancer: results from the international adjuvant breast cancer chemotherapy randomized trial. J Natl Cancer Inst. 2007 Apr 4;99(7):506-15. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00002582
- TABLE: Schmid P, Untch M, Kossé V, Bondar G, Vassiljev L, Tarutinov V, Lehmann U, Maubach L, Meurer J, Wallwiener D, Possinger K. Leuprorelin acetate every-3-months depot versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in premenopausal patients with node-positive breast cancer: the TABLE study. J Clin Oncol. 2007 Jun 20;25(18):2509-15. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- ABCSG-07: Taucher S, Steger GG, Jakesz R, Tausch C, Wette V, Schippinger W, Kwasny W, Reiner G, Greil R, Dubsky P, Poestlberger S, Tschmelitsch J, Samonigg H, Gnant M; ABCSG. The potential risk of neoadjuvant chemotherapy in breast cancer patients--results from a prospective randomized trial of the Austrian Breast and Colorectal Cancer Study Group (ABCSG-07). Breast Cancer Res Treat. 2008 Nov;112(2):309-16. Epub 2007 Dec 14. link to original article dosing details in abstract have been reviewed by our editors PubMed
- NSAS BC-01: Watanabe T, Sano M, Takashima S, Kitaya T, Tokuda Y, Yoshimoto M, Kohno N, Nakagami K, Iwata H, Shimozuma K, Sonoo H, Tsuda H, Sakamoto G, Ohashi Y. Oral uracil and tegafur compared with classic cyclophosphamide, methotrexate, fluorouracil as postoperative chemotherapy in patients with node-negative, high-risk breast cancer: National Surgical Adjuvant Study for Breast Cancer 01 trial. J Clin Oncol. 2009 Mar 20;27(9):1368-74. Epub 2009 Feb 9. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00152191
- TACT: Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. link to original article link to PMC article dosing details in abstract have been reviewed by our editors PubMed ISRCTN79718493
- CALGB 49907: Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Becker HP, Kartcheske PA, Wheeler JD, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Magrinat G, Parker BA, Hart RD, Grenier D, Norton L, Hudis CA, Winer EP; CALGB. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009 May 14;360(20):2055-65. Erratum in: N Engl J Med. 2009 Oct 22;361(17):1714. Magrinat, Gutav [corrected to Magrinat, Gustav]. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00024102
- Update: Muss HB, Polley MC, Berry DA, Liu H, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Kartcheske PA, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Sutton LM, Magrinat G, Parker BA, Hart RD, Grenier D, Hurria A, Jatoi A, Norton L, Hudis CA, Winer EP, Carey L. Randomized Trial of Standard Adjuvant Chemotherapy Regimens Versus Capecitabine in Older Women With Early Breast Cancer: 10-Year Update of the CALGB 49907 Trial. J Clin Oncol. 2019 Sep 10;37(26):2338-2348. Epub 2019 Jul 24. link to original article link to PMC article PubMed
- Kimura M, Tominaga T, Takatsuka Y, Toi M, Abe R, Koyama H, Takashima S, Nomura Y, Miura S, Kimijima I, Tashiro H, Ohashi Y; Adjuvant CEF Research Group for Breast Cancer. Randomized trial of cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil with node-positive breast cancer in Japan. Breast Cancer. 2010 Jul;17(3):190-8. Epub 2009 Jul 3. link to original article dosing details in abstract have been reviewed by our editors PubMed
- ELDA: Perrone F, Nuzzo F, Di Rella F, Gravina A, Iodice G, Labonia V, Landi G, Pacilio C, Rossi E, De Laurentiis M, D'Aiuto M, Botti G, Forestieri V, Lauria R, De Placido S, Tinessa V, Daniele B, Gori S, Colantuoni G, Barni S, Riccardi F, De Maio E, Montanino A, Morabito A, Daniele G, Di Maio M, Piccirillo MC, Signoriello S, Gallo C, de Matteis A. Weekly docetaxel versus CMF as adjuvant chemotherapy for older women with early breast cancer: final results of the randomized phase III ELDA trial. Ann Oncol. 2015 Apr;26(4):675-82. Epub 2014 Dec 8. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00331097
- TAILORx: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. link to original article link to PMC article contains dosing details in supplement PubMed NCT00310180
- SECRAB: Fernando IN, Bowden SJ, Herring K, Brookes CL, Ahmed I, Marshall A, Grieve R, Churn M, Spooner D, Latief TN, Agrawal RK, Brunt AM, Stevens A, Goodman A, Canney P, Bishop J, Ritchie D, Dunn J, Poole CJ, Rea DW; SECRAB Investigators. Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial. Radiother Oncol. 2020 Jan;142:52-61. Epub 2019 Nov 27. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors 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
- Cyclophosphamide (Cytoxan) as follows:
- Cycles 1 to 9: 600 mg/m2 IV once on day 1
- Methotrexate (MTX) as follows:
- Cycles 1 to 9: 40 mg/m2 IV once on day 1
- Fluorouracil (5-FU) as follows:
- Cycles 1 to 9: 600 mg/m2 IV once on day 1
Endocrine therapy
- Tamoxifen (Nolvadex) 30 mg PO once per day on days 1 to 28
28-day cycle for 13 cycles
Regimen variant #2, 780/80/1000 x 6, 20 x 2 yr
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Park et al. 2009 (Taiho 91023033) | 1996-2000 | Phase 3 (C) | UFT & Tamoxifen | Non-inferior RFS60 |
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) as follows:
- Cycles 1 to 6: 65 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) as follows:
- Cycles 1 to 6: 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) as follows:
- Cycles 1 to 6: 500 mg/m2 IV once per day on days 1 & 8
Endocrine therapy
- Tamoxifen (Nolvadex) 20 mg PO once per day on days 1 to 28
28-day cycle for 26 cycles
Regimen variant #3, 840/50/800/40 x 12
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hubay et al. 1980 | Not reported | Randomized (E-RT-esc) | 1. CMF | Seems to have superior RFS |
2. CMFT & BCG | Did not meet endpoints of RFS/OS |
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 30 mg/m2 PO twice per day on days 1 to 14
- Methotrexate (MTX) 25 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 & 8
Endocrine therapy
- Tamoxifen (Nolvadex) 20 mg PO twice per day
28-day cycle for 12 cycles
References
- Hubay CA, Pearson OH, Marshall JS, Rhodes RS, Debanne SM, Mansour EG, Hermann RE, Jones JC, Flynn WJ, Eckert C, McGuire WL. Antiestrogen, cytotoxic chemotherapy, and bacillus Calmette-Guerin vaccination in stage II breast cancer: a preliminary report. Surgery. 1980 May;87(5):494-501. link to original article PubMed
- Update: Hubay CA, Pearson OH, Marshall JS, Rhodes RS, DeBanne SM, Rosenblatt J, Mansour EG, Hermann RE, Jones JC, Flynn WJ, Eckert C, McGuire WL. Adjuvant chemotherapy, antiestrogen therapy and immunotherapy for stage II breast cancer: 45-month follow-up of a prospective, randomized clinical trial. Cancer. 1980 Dec 15;46(12 Suppl):2805-8. link to original article PubMed
- NSABP B-20: Fisher B, Dignam J, Wolmark N, DeCillis A, Emir B, Wickerham DL, Bryant J, Dimitrov NV, Abramson N, Atkins JN, Shibata H, Deschenes L, Margolese RG. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst. 1997 Nov 19;89(22):1673-82. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Pooled update: Fisher B, Jeong JH, Bryant J, Anderson S, Dignam J, Fisher ER, Wolmark N; National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet. 2004 Sep 4-10;364(9437):858-68. link to original article PubMed
- Pooled update: Taghian AG, Jeong JH, Mamounas EP, Parda DS, Deutsch M, Costantino JP, Wolmark N. Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol. 2006 Aug 20;24(24):3927-32. link to original article PubMed
- DBCG 82C: Overgaard M, Jensen MB, Overgaard J, Hansen PS, Rose C, Andersson M, Kamby C, Kjaer M, Gadeberg CC, Rasmussen BB, Blichert-Toft M, Mouridsen HT. Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial. Lancet. 1999 May 15;353(9165):1641-8. link to original article does not contain dosing details in manuscript PubMed
- Update: Ejlertsen B, Jensen MB, Elversang J, Rasmussen BB, Andersson M, Andersen J, Nielsen DL, Cold S, Mouridsen HT. One year of adjuvant tamoxifen compared with chemotherapy and tamoxifen in postmenopausal patients with stage II breast cancer. Eur J Cancer. 2013 Sep;49(14):2986-94. Epub 2013 Jun 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Taiho 91023033: Park Y, Okamura K, Mitsuyama S, Saito T, Koh J, Kyono S, Higaki K, Ogita M, Asaga T, Inaji H, Komichi H, Kohno N, Yamazaki K, Tanaka F, Ito T, Nishikawa H, Osaki A, Koyama H, Suzuki T. Uracil-tegafur and tamoxifen vs cyclophosphamide, methotrexate, fluorouracil, and tamoxifen in post-operative adjuvant therapy for stage I, II, or IIIA lymph node-positive breast cancer: a comparative study. Br J Cancer. 2009 Aug 18;101(4):598-604. Epub 2009 Jul 28. Erratum in: Br J Cancer. 2009 Sep 15;101(6):1031. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors 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
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Supportive therapy
- Most protocols: all cycles given with Filgrastim (Neupogen) support
21-day cycle for 4 cycles
Regimen variant #2, 6 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Mavroudis et al. 2016 (HORG CT/07.17) | 2007-2013 | Phase 3 (E-de-esc) | ddFEC-D | Inconclusive whether non-inferior DFS36 (primary endpoint) |
de Gregorio et al. 2022 (LMU Success C) | 2008-2011 | Phase 3 (E-de-esc) | FEC-D | Inconclusive whether non-inferior DFS1 (primary endpoint) |
Ejlertsen et al. 2017 (DBCG 07-READ) | 2008-2012 | Phase 3 (E-de-esc) | EC-D | Did not meet primary endpoint of 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
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 6 cycles
References
- USOR 9735: Jones SE, Savin MA, Holmes FA, O'Shaughnessy JA, Blum JL, Vukelja S, McIntyre KJ, Pippen JE, Bordelon JH, Kirby R, Sandbach J, Hyman WJ, Khandelwal P, Negron AG, Richards DA, Anthony SP, Mennel RG, Boehm KA, Meyer WG, Asmar L. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol. 2006 Dec 1;24(34):5381-7. Erratum in: J Clin Oncol. 2007 May 1;25(13):1819. link to original article PubMed
- Update: Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL, Sandbach J, Hyman WJ, Richards DA, Mennel RG, Boehm KA, Meyer WG, Asmar L, Mackey D, Riedel S, Muss H, Savin MA. Docetaxel with cyclophosphamide is associated with an overall survival benefit compared with doxorubicin and cyclophosphamide: 7-year follow-up of US Oncology research trial 9735. J Clin Oncol. 2009 Mar 10;27(8):1177-83. Epub 2009 Feb 9. link to original article PubMed
- HORG CT/07.17: Mavroudis D, Matikas A, Malamos N, Papakotoulas P, Kakolyris S, Boukovinas I, Athanasiadis A, Kentepozidis N, Ziras N, Katsaounis P, Saloustros E, Georgoulias V; HORG. Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2016 Oct;27(10):1873-8. Epub 2016 Aug 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01985724
- USOR 06-090: Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00493870
- Pooled update: Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. link to original article link to PMC article PubMed
- NSABP-46-I/USOR 07132: Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00887536
- Pooled update: Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. link to original article link to PMC article PubMed
- NSABP B-49: Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT01547741
- Pooled update: Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. link to original article link to PMC article PubMed
- DBCG 07-READ: Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen MB, Knoop AS, Højris I, Ewertz M, Balslev E, Danø H, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. Adjuvant cyclophosphamide and docetaxel with or without epirubicin for early TOP2A-normal breast cancer: DBCG 07-READ, an open-label, phase III, randomized trial. J Clin Oncol. 2017 Aug 10;35(23):2639-2646. Epub 2017 Jun 29. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00689156
- TAILORx: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. link to original article link to PMC article contains dosing details in supplement PubMed NCT00310180
- WSG PlanB: Nitz U, Gluz O, Clemens M, Malter W, Reimer T, Nuding B, Aktas B, Stefek A, Pollmanns A, Lorenz-Salehi F, Uleer C, Krabisch P, Kuemmel S, Liedtke C, Shak S, Wuerstlein R, Christgen M, Kates RE, Kreipe HH, Harbeck N; West German Study Group. West German Study PlanB trial: adjuvant four cycles of epirubicin and cyclophosphamide plus docetaxel versus six cycles of docetaxel and cyclophosphamide in HER2-negative early breast cancer. J Clin Oncol. 2019 Apr 1;37(10):799-808. Epub 2019 Feb 20. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT01049425
- Pooled update: de Gregorio A, Janni W, Friedl TWP, Nitz U, Rack B, Schneeweiss A, Kates R, Fehm T, Kreipe H, Christgen M, Kuemmel S, Trapp E, Wuerstlein R, Hartkopf A, Clemens M, Reimer T, Haberle L, Fasching PA, Gluz O, Harbeck N. The impact of anthracyclines in intermediate and high-risk HER2-negative early breast cancer-a pooled analysis of the randomised clinical trials PlanB and SUCCESS C. Br J Cancer. 2022 Jun;126(12):1715-1724. Epub 2022 Feb 22. link to original article link to PMC article PubMed
- NSABP B-47: Fehrenbacher L, Cecchini RS, Geyer CE Jr, Rastogi P, Costantino JP, Atkins JN, Crown JP, Polikoff J, Boileau JF, Provencher L, Stokoe C, Moore TD, Robidoux A, Flynn PJ, Borges VF, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020 Feb 10;38(5):444-453. Epub 2019 Dec 10. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT01275677
- LMU Success C: de Gregorio A, Janni W, Friedl TWP, Nitz U, Rack B, Schneeweiss A, Kates R, Fehm T, Kreipe H, Christgen M, Kuemmel S, Trapp E, Wuerstlein R, Hartkopf A, Clemens M, Reimer T, Haberle L, Fasching PA, Gluz O, Harbeck N. The impact of anthracyclines in intermediate and high-risk HER2-negative early breast cancer-a pooled analysis of the randomised clinical trials PlanB and SUCCESS C. Br J Cancer. 2022 Jun;126(12):1715-1724. Epub 2022 Feb 22. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00847444
- ASTER 70s: NCT01564056
Dose-dense Cyclophosphamide & Doxorubicin (ddAC)
ddAC: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide
Regimen variant #1, 60/600 x 4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Shulman et al. 2012 (CALGB 40101) | 2002-2008 | Phase 3 (E-de-esc) | 1. ddAC x 6 | Did not meet primary endpoint of RFS |
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
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Supportive therapy
- (varies depending on reference):
- CALGB 40101: one of the following:
- Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
- Sargramostim (Leukine) 250 to 500 mcg/m2 SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
- Pegfilgrastim (Neulasta) 6 mg SC once, given 24 to 36 hours after chemotherapy
14-day cycle for 4 cycles
Regimen variant #2, 60/600 x 6
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
van Rossum et al. 2018 (MATADOR) | 2004-2012 | Phase 3 (E-switch-ic) | TAC | Did not meet secondary endpoints of RFS/OS |
Preceding treatment
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Supportive therapy
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2
14-day cycle for 6 cycles
References
- CALGB 40101: Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article dosing details in manuscript have been reviewed by our editors link to study protocol PDF link to PMC article PubMed NCT00041119
- Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. Epub 2014 Jun 16. link to original article link to PMC article PubMed
- TAILORx: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. link to original article link to PMC article contains dosing details in supplement PubMed NCT00310180
- MATADOR: van Rossum AGJ, Kok M, van Werkhoven E, Opdam M, Mandjes IAM, van Leeuwen-Stok AE, van Tinteren H, Imholz ALT, Portielje JEA, Bos MMEM, van Bochove A, Wesseling J, Rutgers EJ, Linn SC, Oosterkamp HM; MATADOR Trialists' Group. Adjuvant dose-dense doxorubicin-cyclophosphamide versus docetaxel-doxorubicin-cyclophosphamide for high-risk breast cancer: first results of the randomised MATADOR trial (BOOG 2004-04). Eur J Cancer. 2018 Oct;102:40-48. link to original article dosing details in manuscript have been reviewed by our editors 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
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 8 cycles
Regimen variant #2, 75/600 x 4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Pico et al. 2004 (GEICAM 9401) | 1995-2000 | Phase 3 (E-de-esc) | ECT (Tamoxifen) | Did not meet primary endpoint of DFS60 |
Preceding treatment
Chemotherapy
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- Adjuvant tamoxifen
Regimen variant #3, 100/830 x 8
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Piccart et al. 2001 (Belgian trial) | 1988-1996 | Phase 3 (E-esc) | 1. CMF | Did not meet primary endpoint of EFS |
2. EC; moderate-dose | Seems to have superior EFS |
Preceding treatment
Chemotherapy
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 830 mg/m2 IV once on day 1
21-day cycle for 8 cycles
Regimen variant #4, 120/600 x 4 (high-dose)
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Papaldo et al. 2003 | 1991-1994 | Phase 3 (C) | 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 |
Chemotherapy
- Epirubicin (Ellence) 120 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles
References
- Belgian trial: Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M, Nogaret JM. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol. 2001 Jun 15;19(12):3103-10. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: de Azambuja E, Paesmans M, Beauduin M, Vindevoghel A, Cornez N, Finet C, Ries F, Closon-Dejardin MT, Kerger J, Gobert P, Focan C, Tagnon A, Dolci S, Nogaret JM, di Leo A, Piccart-Gebhart MJ. Long-term benefit of high-dose epirubicin in adjuvant chemotherapy for node-positive breast cancer: 15-year efficacy results of the Belgian multicentre study. J Clin Oncol. 2009 Feb 10;27(5):720-5. Epub 2008 Dec 22. link to original article PubMed
- Papaldo P, Lopez M, Cortesi E, Cammilluzzi E, Antimi M, Terzoli E, Lepidini G, Vici P, Barone C, Ferretti G, Di Cosimo S, Nistico C, Carlini P, Conti F, Di Lauro L, Botti C, Vitucci C, Fabi A, Giannarelli D, Marolla P. Addition of either lonidamine or granulocyte colony-stimulating factor does not improve survival in early breast cancer patients treated with high-dose epirubicin and cyclophosphamide. J Clin Oncol. 2003 Sep 15;21(18):3462-8. link to original article dosing details in abstract have been reviewed by our editors PubMed
- GEICAM 9401: Pico C, Martin M, Jara C, Barnadas A, Pelegri A, Balil A, Camps C, Frau A, Rodriguez-Lescure A, Lopez-Vega JM, De La Haba J, Tres A, Alvarez I, Alba E, Arcusa A, Oltra A, Batista N, Checa T, Perez-Carrion R, Curto J; GEICAM. Epirubicin-cyclophosphamide adjuvant chemotherapy plus tamoxifen administered concurrently versus sequentially: randomized phase III trial in postmenopausal node-positive breast cancer patients: a GEICAM 9401 study. Ann Oncol. 2004 Jan;15(1):79-87. link to original article dosing details in abstract have been reviewed by our editors PubMed
- GOIM 9902: Vici P, Brandi M, Giotta F, Foggi P, Schittulli F, Di Lauro L, Gebbia N, Massidda B, Filippelli G, Giannarelli D, Di Benedetto A, Mottolese M, Colucci G, Lopez M. A multicenter phase III prospective randomized trial of high-dose epirubicin in combination with cyclophosphamide (EC) versus docetaxel followed by EC in node-positive breast cancer: GOIM (Gruppo Oncologico Italia Meridionale) 9902 study. Ann Oncol. 2012 May;23(5):1121-9. Epub 2011 Sep 28. link to original article link to PMC article dosing details in abstract have been reviewed by our editors PubMed
- GIM2: Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 x 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00433420
- Update: Del Mastro L, Poggio F, Blondeaux E, De Placido S, Giuliano M, Forestieri V, De Laurentiis M, Gravina A, Bisagni G, Rimanti A, Turletti A, Nisticò C, Vaccaro A, Cognetti F, Fabi A, Gasparro S, Garrone O, Alicicco MG, Urracci Y, Mansutti M, Poletti P, Correale P, Bighin C, Puglisi F, Montemurro F, Colantuoni G, Lambertini M, Boni L; Gruppo Italiano Mammella Investigators. Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial. Lancet Oncol. 2022 Dec;23(12):1571-1582. Epub 2022 Nov 10. link to original article 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.
Chemotherapy
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 4 cycles
References
- NSABP B-27: Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, Wolmark N; National Surgical Adjuvant Breast and Bowel Project. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003 Nov 15;21(22):4165-74. Epub 2003 Oct 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00002707
- Update: Bear HD, Anderson S, Smith RE, Geyer CE Jr, Mamounas EP, Fisher B, Brown AM, Robidoux A, Margolese R, Kahlenberg MS, Paik S, Soran A, Wickerham DL, Wolmark N. Sequential preoperative or postoperative docetaxel added to preoperative doxorubicin plus cyclophosphamide for operable breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2006 May 1;24(13):2019-27. Epub 2006 Apr 10. link to original article PubMed
- Pooled update: Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008 Feb 10;26(5):778-85. Erratum in: J Clin Oncol. 2008 Jun 1;26(16):2793. link to original article PubMed
- NSAS BC-02: Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. link to original article 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
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycle for 6 cycles
References
- CH-BC-006: Yuan P, Kang Y, Ma F, Fan Y, Wang J, Wang X, Yue J, Luo Y, Zhang P, Li Q, Xu B. Effect of Epirubicin Plus Paclitaxel vs Epirubicin and Cyclophosphamide Followed by Paclitaxel on Disease-Free Survival Among Patients With Operable ERBB2-Negative and Lymph Node-Positive Breast Cancer: A Randomized Clinical Trial. JAMA Netw Open. 2023 Feb 1;6(2):e230122. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors 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
References
- DEVA: Coombes RC, Bliss JM, Espie M, Erdkamp F, Wals J, Tres A, Marty M, Coleman RE, Tubiana-Mathieu N, den Boer MO, Wardley A, Kilburn LS, Cooper D, Thomas MW, Reise JA, Wilkinson K, Hupperets P. Randomized, phase III trial of sequential epirubicin and docetaxel versus epirubicin alone in postmenopausal patients with node-positive breast cancer. J Clin Oncol. 2011 Aug 20;29(24):3247-54. Epub 2011 Jul 18. link to original article dosing details in manuscript have been reviewed by our editors 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
Subsequent treatment
- CMF; intensified
References
- HE10/05: Fountzilas G, Dafni U, Papadimitriou C, Timotheadou E, Gogas H, Eleftheraki AG, Xanthakis I, Christodoulou C, Koutras A, Papandreou CN, Papakostas P, Miliaras S, Markopoulos C, Dimitrakakis C, Korantzopoulos P, Karanikiotis C, Bafaloukos D, Kosmidis P, Samantas E, Varthalitis I, Pavlidis N, Pectasides D, Dimopoulos MA. Dose-dense sequential adjuvant chemotherapy followed, as indicated, by trastuzumab for one year in patients with early breast cancer: first report at 5-year median follow-up of a Hellenic Cooperative Oncology Group randomized phase III trial. BMC Cancer. 2014 Jul 15;14:515. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors 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
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Subsequent treatment
- Cyclophosphamide & Thiotepa, then auto HSCT consolidation followed by adjuvant tamoxifen versus adjuvant tamoxifen
Regimen variant #2, 500/50/500 x 6
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Martin et al. 2003 (GEICAM 8701) | 1987-1991 | Phase 3 (E-switch-ic) | CMF | Might have 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
- If patients had febrile neutropenia or infection: Ciprofloxacin (Cipro) 500 mg PO twice per day on days 5 to 14
- If patients had febrile neutropenia, one of the following:
- Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 4 to 11
- Lenograstim (Granocyte) 150 mcg/m2 SC once per day on days 4 to 11
21-day cycle for 6 cycles
Regimen variant #3, 500/50/500 until max anthracycline
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hurteloup 1988 (FESG) | 1982-1984 | Phase 3 (C) | FEC | Did not meet endpoint of OS50% |
Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for up to 11 cycles (maximum cumulative doxorubicin dose of 550 mg/m2)
Regimen variant #4, 800/40/400 x 6
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Wood et al. 1994 (CALGB 8541) | 1985 to not reported | Phase 3 (E-de-esc) | 1. FAC; 600/30/300 x 4 | Superior OS |
2. FAC; 1200/60/600 x 4 | Did not meet primary endpoint of DFS |
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
28-day cycle for 6 cycles
Regimen variant #5, 800/40/400 until max doxorubicin
Historic variant |
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Buzdar et al. 1984 | 1977-1980 | Phase 3 (C) | FAC + BCG | Did not meet primary endpoint of DFS |
Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
21-day cycles until cumulative doxorubicin dose of 300 mg/m2 reached.
Subsequent treatment
- After reaching cumulative maximum doxorubicin, patients would go on to receive: maintenance CMF. This is now obsolete.
Regimen variant #6, 1000/50/500 x 8
Study | Dates of enrollment | Evidence |
---|---|---|
Hortobagyi et al. 2000 | 1990-1997 | Non-randomized part of RCT |
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 4
- Doxorubicin (Adriamycin) 16.7 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m2)
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 8 cycles
Subsequent treatment
- CEP with auto HSCT consolidation versus no further treatment
Regimen variant #7, 1000/60/1400 x 6
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Davidson et al. 2005 (ECOG E5188) | 1989-1994 | Non-randomized part of phase 3 RCT | ||
Hutchins et al. 2005 (INT-0102) | 1989-1993 | Phase 3 (E-switch-ic) | CMF | 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
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
28-day cycle for 6 cycles
Subsequent treatment
- INT-0121: Cyclophosphamide & thiotepa, then auto HSCT consolidation versus no further chemotherapy
- ECOG E5188: Adjuvant Goserelin x 5 y versus Goserelin & Tamoxifen x 5 y versus no further treatment
- SWOG-8814: Adjuvant Tamoxifen x 5 y
Regimen variant #8, 1200/60/600 x 4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Wood et al. 1994 (CALGB 8541) | 1985 to not reported | Phase 3 (C) | 1. FAC; 600/30/300 x 4 | 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
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
28-day cycle for 4 cycles
Regimen variant #9, 1200/60/600 x 6
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Delaloge et al. 2020 (MINDACT) | 2007-2011 | Phase 3 (C) | TX | Did not meet primary endpoint of 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
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
28-day cycle for 6 cycles
Regimen variant #10, 2000/50/100 x 4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Scholl et al. 1994 (S6) | 1986-1990 | Phase 3 (C) | Neoadjuvant FAC | Seems to have 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
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1, 3, 5, 8
- Doxorubicin (Adriamycin) 25 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 5
28-day cycle for 4 cycles
References
- Buzdar AU, Blumenschein GR, Smith TL, Powell KC, Hortobagyi GN, Yap HY, Schell FC, Barnes BC, Ames FC, Martin RG, Hersh EM. Adjuvant chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide, with or without Bacillus Calmette-Guérin and with or without irradiation in operable breast cancer: a prospective randomized trial. Cancer. 1984 Feb 1;53(3):384-9. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Buzdar AU, Kau SW, Smith TL, Hortobagyi GN. Ten-year results of FAC adjuvant chemotherapy trial in breast cancer. Am J Clin Oncol. 1989 Apr;12(2):123-8. link to original article PubMed
- FESG: Hurteloup P; French Epirubicin Study Group. A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol. 1988 Apr;6(4):679-88. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- CALGB 8541: Wood WC, Budman DR, Korzun AH, Cooper MR, Younger J, Hart RD, Moore A, Ellerton JA, Norton L, Ferree CR, Colangelo Ballow A, Frei E, Henderson IC. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994 May 5;330(18):1253-9. Erratum in: N Engl J Med 1994 Jul 14;331(2):139. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Subgroup analysis: Muss HB, Thor AD, Berry DA, Kute T, Liu ET, Koerner F, Cirrincione CT, Budman DR, Wood WC, Barcos M, Henderson IC. c-erbB-2 expression and response to adjuvant therapy in women with node-positive early breast cancer. N Engl J Med. 1994 May 5;330(18):1260-6. Erratum in: N Engl J Med 1994 Jul 21;331(3):211. link to original article PubMed
- S6: Scholl SM, Fourquet A, Asselain B, Pierga JY, Vilcoq JR, Durand JC, Dorval T, Palangié T, Jouve M, Beuzeboc P, Garcio-Giralt E, Salmon RJ, de la Rochefordiere A, Campana F, Pouillart P. Neoadjuvant versus adjuvant chemotherapy in premenopausal patients with tumours considered too large for breast conserving surgery: preliminary results of a randomised trial: S6. Eur J Cancer. 1994;30A(5):645-52. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Hortobagyi GN, Buzdar AU, Theriault RL, Valero V, Frye D, Booser DJ, Holmes FA, Giralt S, Khouri I, Andersson B, Gajewski JL, Rondon G, Smith TL, Singletary SE, Ames FC, Sneige N, Strom EA, McNeese MD, Deisseroth AB, Champlin RE. Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst. 2000 Feb 2;92(3):225-33. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- GEICAM 8701: Martin M, Villar A, Sole-Calvo A, Gonzalez R, Massuti B, Lizon J, Camps C, Carrato A, Casado A, Candel MT, Albanell J, Aranda J, Munarriz B, Campbell J, Diaz-Rubio E; GEICAM. Doxorubicin in combination with fluorouracil and cyclophosphamide (iv FAC regimen, day 1, 21) versus methotrexate in combination with fluorouracil and cyclophosphamide (iv CMF regimen, day 1, 21) as adjuvant chemotherapy for operable breast cancer: a study by the GEICAM group. Ann Oncol. 2003 Jun;14(6):833-42. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- INT-0121: Tallman MS, Gray R, Robert NJ, LeMaistre CF, Osborne CK, Vaughan WP, Gradishar WJ, Pisansky TM, Fetting J, Paietta E, Lazarus HM. Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med. 2003 Jul 3;349(1):17-26. link to original article PubMed
- BCIRG 001: Martín M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C; Breast Cancer International Research Group. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med. 2005 Jun 2;352(22):2302-13. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00688740
- Update: Mackey JR, Martín M, Pienkowski T, Rolski J, Guastalla JP, Sami A, Glaspy J, Juhos E, Wardley A, Fornander T, Hainsworth J, Coleman R, Modiano MR, Vinholes J, Pinter T, Rodríguez-Lescure A, Colwell B, Whitlock P, Provencher L, Laing K, Walde D, Price C, Hugh JC, Childs BH, Bassi K, Lindsay MA, Wilson V, Rupin M, Houé V, Vogel C; TRIO/BCIRG 001 investigators. Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial. Lancet Oncol. 2013 Jan;14(1):72-80. Epub 2012 Dec 12. link to original article PubMed
- ECOG E5188: Davidson NE, O'Neill AM, Vukov AM, Osborne CK, Martino S, White DR, Abeloff MD. Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: results from INT 0101 (E5188). J Clin Oncol. 2005 Sep 1;23(25):5973-82. Epub 2005 Aug 8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- INT-0102: Hutchins LF, Green SJ, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of intergroup protocol INT-0102. J Clin Oncol. 2005 Nov 20;23(33):8313-21. link to original article PubMed
- JCOG 9208: Tokuda Y, Tajima T, Narabayashi M, Takeyama K, Watanabe T, Fukutomi T, Chou T, Sano M, Igarashi T, Sasaki Y, Ogura M, Miura S, Okamoto S, Ogita M, Kasai M, Kobayashi T, Fukuda H, Takashima S, Tobinai K; Autologous Bone Marrow Transplantation Study Group; Breast Cancer Study Group of the Japan Clinical Oncology Group (JCOG). Phase III study to evaluate the use of high-dose chemotherapy as consolidation of treatment for high-risk postoperative breast cancer: Japan Clinical Oncology Group study, JCOG 9208. Cancer Sci. 2008 Jan;99(1):145-51. Epub 2007 Oct 25. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed
- SWOG-8814: Albain KS, Barlow WE, Ravdin PM, Farrar WB, Burton GV, Ketchel SJ, Cobau CD, Levine EG, Ingle JN, Pritchard KI, Lichter AS, Schneider DJ, Abeloff MD, Henderson IC, Muss HB, Green SJ, Lew D, Livingston RB, Martino S, Osborne CK; Breast Cancer Intergroup of North America. Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009 Dec 19;374(9707):2055-2063. Epub 2009 Dec 10. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00929591
- GEICAM 9805: Martín M, Seguí MA, Antón A, Ruiz A, Ramos M, Adrover E, Aranda I, Rodríguez-Lescure A, Grosse R, Calvo L, Barnadas A, Isla D, Martinez del Prado P, Ruiz Borrego M, Zaluski J, Arcusa A, Muñoz M, López Vega JM, Mel JR, Munarriz B, Llorca C, Jara C, Alba E, Florián J, Li J, López García-Asenjo JA, Sáez A, Rios MJ, Almenar S, Peiró G, Lluch A; GEICAM. Adjuvant docetaxel for high-risk, node-negative breast cancer. N Engl J Med. 2010 Dec 2;363(23):2200-10. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00121992
- GEICAM 2003-02: Martín M, Ruiz A, Ruiz Borrego M, Barnadas A, González S, Calvo L, Margelí Vila M, Antón A, Rodríguez-Lescure A, Seguí-Palmer MA, Muñoz-Mateu M, Dorca Ribugent J, López-Vega JM, Jara C, Espinosa E, Mendiola Fernández C, Andrés R, Ribelles N, Plazaola A, Sánchez-Rovira P, Salvador Bofill J, Crespo C, Carabantes FJ, Servitja S, Chacón JI, Rodríguez CA, Hernando B, Álvarez I, Carrasco E, Lluch A. Fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus FAC followed by weekly paclitaxel as adjuvant therapy for high-risk, node-negative breast cancer: results from the GEICAM/2003-02 study. J Clin Oncol. 2013 Jul 10;31(20):2593-9. Epub 2013 Jun 3. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00129389
- MINDACT: Delaloge S, Piccart M, Rutgers E, Litière S, van 't Veer LJ, van den Berkmortel F, Brain E, Dudek-Peric A, Gil-Gil M, Gomez P, Hilbers FS, Khalil Z, Knox S, Kuemmel S, Kunz G, Lesur A, Pierga JY, Ravdin P, Rubio IT, Saghatchian M, Smilde TJ, Thompson AM, Viale G, Zoppoli G, Vuylsteke P, Tryfonidis K, Poncet C, Bogaerts J, Cardoso F; MINDACT investigators and the TRANSBIG Consortium. Standard Anthracycline Based Versus Docetaxel-Capecitabine in Early High Clinical and/or Genomic Risk Breast Cancer in the EORTC 10041/BIG 3-04 MINDACT Phase III Trial. J Clin Oncol. 2020 Apr 10;38(11):1186-1197. Epub 2020 Feb 21. link to original article 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
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Regimen variant #2, 500/50/500 until max anthracycline
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hurteloup 1988 (FESG) | 1982-1984 | Phase 3 (E-switch-ic) | FAC | Did not meet endpoint of OS50% |
Note: While this was a negative study, this arm was better tolerated in the treated population and this study likely established the popularity of epirubicin-based regimens in Europe.
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for up to 15 cycles (maximum cumulative epirubicin dose of 720 mg/m2)
Regimen variant #3, 500/60/500 x 4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Rouëssé et al. 2006 | 1994-1999 | Phase 3 (C) | FNC & RT | Did not meet primary endpoint of DFS |
Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Regimen variant #4, 500/90/500 x 5
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Rodenhuis et al. 2003 (Dutch National Study) | 1993-1999 | Phase 3 (C) | FEC x 4, then CTCb with auto HSCT | Did not meet primary endpoint of OS1 |
1Reported efficacy for the Dutch National Study is based on the 2020 update.
Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 5 cycles
Regimen variant #5, 500/100/500 x 4 ("FEC 100")
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kerbrat et al. 2017 (UCBG-0106) | 2002-2006 | Phase 3 (E-de-esc) | FEC; FEC 100 x 6 | Did not meet primary endpoint of DFS60 |
Note: This was an experimental arm that did not meet its primary endpoint; included here because it represents a de-escalation strategy.
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Regimen variant #6, 500/100/500 x 6 ("FEC 100")
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bonneterre 2001 (FASG 05) | 1990-1993 | Phase 3 (E-RT-esc) | FEC; FEC 50 x 6 | Superior OS |
Kerbrat et al. 2007 (FASG 09) | 1993-1998 | Phase 3 (C) | VE | Did not meet primary endpoint of DFS |
Roché et al. 2006 (FNCLCC PACS 01) | 1997-2000 | Phase 3 (C) | FEC-D | Inferior OS1 |
Delbaldo et al. 2013 (Trial B2000) | 2000-2002 | Phase 3 (C) | FEC-P | Did not meet primary endpoint of DFS |
Nitz et al. 2014 (WSG-AGO EC-Doc) | 2000-2005 | Phase 3 (C) | EC-D | Seems to have inferior OS |
Spielmann et al. 2009 (FNCLCC PACS 04) | 2001-2004 | Phase 3 (C) | ED | Did not meet primary endpoint of DFS2 |
Kerbrat et al. 2017 (UCBG-0106) | 2002-2006 | Phase 3 (C) | FEC; FEC 100 x 4 | Did not meet primary endpoint of DFS60 |
Geyer et al. 2022 (NSABP B-36) | 2004-05-20 to 2008-07-25 | Phase 3 (E-esc) | AC x 4 | Did not meet primary endpoint of DFS DFS9y: 79.4% vs 80.1% (HR 1.09, 95% CI 0.92-1.29) |
Sakr et al. 2013 | 2006-2010 | Phase 3 (C) | FEC-D | Seems to have inferior OS |
Sparano et al. 2018 (TAILORx) | 2006-2010 | Phase 3 (C) | No chemotherapy | Non-inferior IDFS (primary endpoint) |
Delaloge et al. 2020 (MINDACT) | 2007-2011 | Phase 3 (C) | TX | Did not meet primary endpoint of DFS |
1Reported efficacy for FNCLCC PACS 01 is based on the 2012 update.
2Reported efficacy for FNCLCC PACS 04 is based on the 2019 update.
Note: This was the upper bound of epirubicin dosing in TAILORx.
Eligibility criteria
- TAILORx: Oncotype DX score of 11 to 25
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Regimen variant #7, 600/50/600 x 8
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Coombes et al. 1996 | 1984-1992 | Phase 3 (E-switch-ic) | CMF | Did not meet co-primary endpoints of RFS/OS |
Coombes et al. 2016 (HMFEC) | 1992-2000 | Phase 3 (C) | FEC; FEC 75 | Did not meet primary endpoint of DFS |
Note: This was an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 8 cycles
Regimen variant #8, 600/60/600 x 4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
van der Hage et al. 2001 (EORTC 10902) | 1991-1999 | Phase 3 (C) | FEC; neoadjuvant | Did not meet primary endpoint of OS |
Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Regimen variant #9, 600/60/600 x 6
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Venturini et al. 2005 (MIG-1) | 1992-1997 | Phase 3 (C) | ddFEC | Did not meet primary endpoint of 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
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Regimen variant #10, 600/60/600 x 8
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ellis et al. 2009 (TACT) | 2001-2003 | Phase 3 (C) | FEC-D | Did not meet primary endpoint of DFS |
Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 8 cycles
Regimen variant #11, 600/60/600 x 9
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ejlertsen et al. 2007 (DBCG 89D) | 1990-1998 | Phase 3 (E-switch-ic) | CMF | Superior OS |
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 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
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Regimen variant #13, 700/75/700 x 6
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Polyzos et al. 2009 | 1995-2004 | Phase 3 (C) | D-EC | Seems to have 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
- Fluorouracil (5-FU) 700 mg/m2 IV once on day 1
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 700 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Regimen variant #14, 1000/50/500 x 6
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Paradiso et al. 2001 | 1989-1994 | Phase 3 (E-esc) | Observation | Seems to have superior DFS |
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Epirubicin (Ellence) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
Regimen variant #15, 1000/120/740 x 6 ("Canadian CEF (IV)")
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Delaloge et al. 2020 (MINDACT) | 2007-2011 | Phase 3 (C) | TX | Did not meet primary endpoint of 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
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Epirubicin (Ellence) 60 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 370 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 cycles
Regimen variant #16, 1000/120/1050 x 6 ("FEC 120"; "Canadian CEF")
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Levine et al. 1998 (NCIC-CTG MA.5) | 1989-1993 | Phase 3 (E-RT-switch-ic) | CMF | 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
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Epirubicin (Ellence) 60 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 75 mg/m2 PO once per day on days 1 to 14
28-day cycle for 6 cycles
Regimen variant #17, 1200/50/1200 x 6
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Coombes et al. 1996 | 1984-1992 | Phase 3 (E-switch-ic) | CMF | Did not meet co-primary endpoints of RFS/OS |
Note: This was an experimental arm that did not meet its primary endpoint; however, based on a subgroup analysis, it became a preferred regimen.
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
- Epirubicin (Ellence) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 cycles
References
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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
- Mitomycin (Mutamycin) 8 mg/m2 IV once on day 1
- Mitoxantrone (Novantrone) 8 mg/m2 IV once on day 1
- Methotrexate (MTX) 35 mg/m2 IV once on day 1
21-day cycle for 6 cycles
References
- SECRAB: Fernando IN, Bowden SJ, Herring K, Brookes CL, Ahmed I, Marshall A, Grieve R, Churn M, Spooner D, Latief TN, Agrawal RK, Brunt AM, Stevens A, Goodman A, Canney P, Bishop J, Ritchie D, Dunn J, Poole CJ, Rea DW; SECRAB Investigators. Synchronous versus sequential chemo-radiotherapy in patients with early stage breast cancer (SECRAB): A randomised, phase III, trial. Radiother Oncol. 2020 Jan;142:52-61. Epub 2019 Nov 27. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors 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.
References
- CALGB 40101: Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article dosing details in manuscript have been reviewed by our editors link to study protocol PDF link to PMC article PubMed NCT00041119
- Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. Epub 2014 Jun 16. link to original article link to PMC article 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
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
Supportive therapy
- Diphenhydramine (Benadryl) 12.5 to 50 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
- One of the following H2 blockers:
- Ranitidine (Zantac) 50 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
- Cimetidine (Tagamet) 300 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
- Famotidine (Pepcid) 20 mg IV once on day 1; 30 to 60 minutes prior to paclitaxel
- One of the following dexamethasone choices:
- Dexamethasone (Decadron) 10 mg IV once on day 1, within 60 minutes prior to paclitaxel
- Dexamethasone (Decadron) 10 mg PO once on day 1, at least 60 minutes prior to paclitaxel
- Dexamethasone (Decadron) 20 mg PO twice on day 1; 6 hours and 12 hours prior to paclitaxel
- Recommended growth factor support with one of the following:
- Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
- Sargramostim (Leukine) 250 to 500 mcg/m2 SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
- Pegfilgrastim (Neulasta) 6 mg SC once, given 24 to 36 hours after chemotherapy
14-day cycle for 4 cycles
References
- Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- CALGB 40101: Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article dosing details in manuscript have been reviewed by our editors link to study protocol PDF link to PMC article PubMed NCT00041119
- Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. Epub 2014 Jun 16. link to original article link to PMC article 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
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV over 15 minutes once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV over 1 to 5 minutes once on day 1
21-day cycle for 4 cycles
Regimen variant #2, 6 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Martin et al. 2005 (BCIRG 001) | 1997-1999 | Phase 3 (E-RT-switch-ic) | FAC | 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
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given third, one hour after cyclophosphamide
- Doxorubicin (Adriamycin) 50 mg/m2 IV over 15 minutes once on day 1, given first
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV over 1 to 5 minutes once on day 1, given second
Supportive therapy
- Dexamethasone (Decadron) 8 mg PO every 12 hours for 6 total doses, starting the day before treatment
- Ciprofloxacin (Cipro) 500 mg PO twice per day on days 5 to 14
- G-CSF not originally routinely administered unless patients had febrile neutropenia, but some guidelines recommend one of the following:
- Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 4 to 11
- Lenograstim (Granocyte) 150 mcg/m2 SC once per day on days 4 to 11
21-day cycle for 6 cycles
References
- BCIRG 001: Martín M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C; Breast Cancer International Research Group. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med. 2005 Jun 2;352(22):2302-13. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00688740
- Update: Mackey JR, Martín M, Pienkowski T, Rolski J, Guastalla JP, Sami A, Glaspy J, Juhos E, Wardley A, Fornander T, Hainsworth J, Coleman R, Modiano MR, Vinholes J, Pinter T, Rodríguez-Lescure A, Colwell B, Whitlock P, Provencher L, Laing K, Walde D, Price C, Hugh JC, Childs BH, Bassi K, Lindsay MA, Wilson V, Rupin M, Houé V, Vogel C; TRIO/BCIRG 001 investigators. Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial. Lancet Oncol. 2013 Jan;14(1):72-80. Epub 2012 Dec 12. link to original article PubMed
- NSABP B-30: Swain SM, Jeong JH, Geyer CE Jr, Costantino JP, Pajon ER, Fehrenbacher L, Atkins JN, Polikoff J, Vogel VG, Erban JK, Rastogi P, Livingston RB, Perez EA, Mamounas EP, Land SR, Ganz PA, Wolmark N. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med. 2010 Jun 3;362(22):2053-65. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00003782
- GEICAM 9805: Martín M, Seguí MA, Antón A, Ruiz A, Ramos M, Adrover E, Aranda I, Rodríguez-Lescure A, Grosse R, Calvo L, Barnadas A, Isla D, Martinez del Prado P, Ruiz Borrego M, Zaluski J, Arcusa A, Muñoz M, López Vega JM, Mel JR, Munarriz B, Llorca C, Jara C, Alba E, Florián J, Li J, López García-Asenjo JA, Sáez A, Rios MJ, Almenar S, Peiró G, Lluch A; GEICAM. Adjuvant docetaxel for high-risk, node-negative breast cancer. N Engl J Med. 2010 Dec 2;363(23):2200-10. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00121992
- BCIRG-005: Eiermann W, Pienkowski T, Crown J, Sadeghi S, Martín M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press M, Sauter G, Lindsay MA, Riva A, Buyse M, Drevot P, Taupin H, Mackey JR. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol. 2011 Oct 10;29(29):3877-84. Epub 2011 Sep 12. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00312208
- Update: Mackey JR, Pieńkowski T, Crown J, Sadeghi S, Martín M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press MF, Sauter G, Lindsay M, Houé V, Buyse M, Drevot P, Hitier S, Bensfia S, Eiermann W; Translational Research In Oncology (TRIO)/ Breast Cancer International Research Group (BCIRG)-005 investigators. Long-term outcomes after adjuvant treatment of sequential versus combination docetaxel with doxorubicin and cyclophosphamide in node-positive breast cancer: BCIRG-005 randomized trial. Ann Oncol. 2016 Jun;27(6):1041-7. Epub 2016 Mar 2. link to original article PubMed
- NSABP B-38: Swain SM, Tang G, Geyer CE Jr, Rastogi P, Atkins JN, Donnellan PP, Fehrenbacher L, Azar CA, Robidoux A, Polikoff JA, Brufsky AM, Biggs DD, Levine EA, Zapas JL, Provencher L, Northfelt DW, Paik S, Costantino JP, Mamounas EP, Wolmark N. Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial. J Clin Oncol. 2013 Sep 10;31(26):3197-204. Epub 2013 Aug 12. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00093795
- USOR 06-090: Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00493870
- Pooled update: Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. link to original article link to PMC article PubMed
- NSABP-46-I/USOR 07132: Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00887536
- Pooled update: Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. link to original article link to PMC article PubMed
- NSABP B-49: Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT01547741
- Pooled update: Geyer CE Jr, Blum JL, Yothers G, Asmar L, Flynn PJ, Robert NJ, Hopkins JO, O'Shaughnessy JA, Rastogi P, Puhalla SL, Hilton CJ, Dang CT, Gómez HL, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Colangelo LH, Swain SM, Mamounas EP, Wolmark N. Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]). J Clin Oncol. 2024 Apr 20;42(12):1344-1349. Epub 2024 Feb 9. link to original article link to PMC article PubMed
- TAILORx: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. link to original article link to PMC article contains dosing details in supplement PubMed NCT00310180
- MATADOR: van Rossum AGJ, Kok M, van Werkhoven E, Opdam M, Mandjes IAM, van Leeuwen-Stok AE, van Tinteren H, Imholz ALT, Portielje JEA, Bos MMEM, van Bochove A, Wesseling J, Rutgers EJ, Linn SC, Oosterkamp HM; MATADOR Trialists' Group. Adjuvant dose-dense doxorubicin-cyclophosphamide versus docetaxel-doxorubicin-cyclophosphamide for high-risk breast cancer: first results of the randomised MATADOR trial (BOOG 2004-04). Eur J Cancer. 2018 Oct;102:40-48. link to original article dosing details in manuscript have been reviewed by our editors PubMed ISRCTN61893718
- PUMCH-Breast-TCX: NCT01354522
Metastatic disease, first-line chemotherapy
Note: in many of these regimens, patients were allowed to have received (neo)adjuvant chemotherapy and hormonal therapy (when applicable). These are first-line regimens in the metastatic setting, with a few being specifically for the locally advanced but unresectable setting.
Cyclophosphamide & Doxorubicin (AC)
AC: Adriamycin (Doxorubicin) & Cyclophosphamide
Regimen variant #1, 40/400
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Rosner et al. 1987 | 1981-1985 | Randomized (E-de-esc) | 1. CFP 2. CMFVP |
Did not meet primary endpoint of OS |
Chemotherapy
- Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
28-day cycles
Regimen variant #2, 40/500
Study | 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
- Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Regimen variant #3, 40/800 (PO)
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Jones et al. 1975 | 1973-1974 | Non-randomized | ||
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
- Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 200 mg/m2/day PO in divided doses on days 3 to 6
21- to 28-day cycles
Regimen variant #4, 50/750
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Forbes 1986 | 1978-1981 | Randomized (C) | 1. ACT 2. Tamoxifen |
Did not meet primary endpoint of OS |
Chemotherapy
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
21-day cycle for up to 9 cycles
Regimen variant #5, 60/600
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Biganzoli et al. 2002 (EORTC 10961) | 1996-1999 | Phase 3 (C) | AT (Taxol) | Did not meet primary endpoint of PFS |
Nabholtz et al. 2003 (TAX 306) | Not reported | Phase 3 (C) | AT (Taxotere) | Seems to have inferior TTP |
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV over 15 minutes once on day 1, given first
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 15 minutes once on day 1, given second
21-day cycle of varying durations: 6 cycles (EORTC 10961); 8 cycles (TAX 306)
Regimen variant #6, with range
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robert et al. 2011 (RIBBON-1) | 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
- Doxorubicin (Adriamycin) 50 to 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 to 600 mg/m2 IV once on day 1
21-day cycle for up to 8 cycles
References
- Jones SE, Durie BG, Salmon SE. Combination chemotherapy with adriamycin and cyclophosphamide for advanced breast cancer. Cancer. 1975 Jul;36(1):90-7. link to original article dosing details in abstract have been reviewed by our editors PubMed
- SWOG-7405B: Tranum BL, McDonald B, Thigpen T, Vaughn C, Wilson H, Maloney T, Costanzi J, Bickers J, el Mawli NG, Palmer R, Hoogstraten B, Heilburn L, Rasmusen S; SWOG. Adriamycin combinations in advanced breast cancer: a Southwest Oncology Group Study. Cancer. 1982 Mar 1;49(5):835-9. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Forbes JF; Australian and New Zealand Breast Cancer Trials Group, Clinical Oncological Society of Australia. A randomized trial in postmenopausal patients with advanced breast cancer comparing endocrine and cytotoxic therapy given sequentially or in combination. J Clin Oncol. 1986 Feb;4(2):186-93. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Rosner D, Nemoto T, Lane WW. A randomized study of intensive versus moderate chemotherapy programs in metastatic breast cancer. Cancer. 1987 Mar 1;59(5):874-83. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- EORTC 10961: Biganzoli L, Cufer T, Bruning P, Coleman R, Duchateau L, Calvert AH, Gamucci T, Twelves C, Fargeot P, Epelbaum R, Lohrisch C, Piccart MJ. Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organisation for Research and Treatment of Cancer 10961 multicenter phase III trial. J Clin Oncol. 2002 Jul 15;20(14):3114-21. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- TAX 306: Nabholtz JM, Falkson C, Campos D, Szanto J, Martín M, Chan S, Pienkowski T, Zaluski J, Pinter T, Krzakowski M, Vorobiof D, Leonard R, Kennedy I, Azli N, Murawsky M, Riva A, Pouillart P; TAX 306 Study Group. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol. 2003 Mar 15;21(6):968-75. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- JCOG9802: Katsumata N, Watanabe T, Minami H, Aogi K, Tabei T, Sano M, Masuda N, Andoh J, Ikeda T, Shibata T, Takashima S. Phase III trial of doxorubicin plus cyclophosphamide (AC), docetaxel, and alternating AC and docetaxel as front-line chemotherapy for metastatic breast cancer: Japan Clinical Oncology Group trial (JCOG9802). Ann Oncol. 2009 Jul;20(7):1210-5. Epub 2009 Mar 2. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article dosing details in manuscript have been reviewed by our editors 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
- Doxorubicin (Adriamycin) 50 to 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 to 600 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for up to 8 cycles
Subsequent treatment
- RIBBON-1, SD or better: Bevacizumab maintenance
References
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article dosing details in manuscript have been reviewed by our editors 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 |
Regimen variant #2, 1000 mg/m2 PO twice per day, limited duration
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Smorenburg et al. 2014 (OMEGA) | 2007-2011 | Phase 3 (E-switch-ic) | PLD | Did not meet primary endpoint of PFS |
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 8 cycles
Regimen variant #3, 1000 mg/m2 PO twice per day, indefinite
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bajetta et al. 2005 | 1999-2003 | Phase 2 | ||
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 |
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) |
References
- Bajetta E, Procopio G, Celio L, Gattinoni L, Della Torre S, Mariani L, Catena L, Ricotta R, Longarini R, Zilembo N, Buzzoni R. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol. 2005 Apr 1;23(10):2155-61. Epub 2005 Feb 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00262067
- ANZ 0001: Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B, Van Hazel G, Wilcken NR, Grimison PS, Nowak AK, Gainford MC, Fong A, Paksec L, Sourjina T, Zannino D, Gebski V, Simes RJ, Forbes JF, Coates AS. Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4498-504. Epub 2011 Oct 24. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- OMEGA: Smorenburg CH, de Groot SM, van Leeuwen-Stok AE, Hamaker ME, Wymenga AN, de Graaf H, de Jongh FE, Braun JJ, Los M, Maartense E, van Tinteren H, Nortier JW, Seynaeve C; Dutch Breast Cancer Research Group. A randomized phase III study comparing pegylated liposomal doxorubicin with capecitabine as first-line chemotherapy in elderly patients with metastatic breast cancer: results of the OMEGA study of the Dutch Breast Cancer Research Group BOOG. Ann Oncol. 2014 Mar;25(3):599-605. Epub 2014 Feb 6. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed ISRCTN11114726
- PELICAN: Harbeck N, Saupe S, Jäger E, Schmidt M, Kreienberg R, Müller L, Otremba BJ, Waldenmaier D, Dorn J, Warm M, Scholz M, Untch M, de Wit M, Barinoff J, Lück HJ, Harter P, Augustin D, Harnett P, Beckmann MW, Al-Batran SE; PELICAN Investigators. A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study. Breast Cancer Res Treat. 2017 Jan;161(1):63-72. Epub 2016 Oct 31. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00266799
- 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
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00262067
- TURANDOT: Lang I, Brodowicz T, Ryvo L, Kahan Z, Greil R, Beslija S, Stemmer SM, Kaufman B, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Messinger D, Zielinski C; Central European Cooperative Oncology Group. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial. Lancet Oncol. 2013 Feb;14(2):125-33. Epub 2013 Jan 10. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00600340
- Update: Zielinski C, Láng I, Inbar M, Kahán Z, Greil R, Beslija S, Stemmer SM, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Petruzelka L, Eniu A, Nisenbaum B, Dank M, Anghel R, Messinger D, Brodowicz T; TURANDOT investigators. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1230-9. Epub 2016 Aug 5. link to original article dosing details in abstract have been reviewed by our editors PubMed
- CARIN: Welt A, Marschner N, Lerchenmueller C, Decker T, Steffens CC, Koehler A, Depenbusch R, Busies S, Hegewisch-Becker S. Capecitabine and bevacizumab with or without vinorelbine in first-line treatment of HER2/neu-negative metastatic or locally advanced breast cancer: final efficacy and safety data of the randomised, open-label superiority phase 3 CARIN trial. Breast Cancer Res Treat. 2016 Feb;156(1):97-107. Epub 2016 Feb 29. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00868634
Capecitabine & Paclitaxel
TX: Taxol (Paclitaxel), Xeloda (Capecitabine)
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Blum et al. 2006 | 2003 | Phase 2 |
Chemotherapy
- Capecitabine (Xeloda) 825 mg/m2 (rounded to nearest 500 mg) PO twice per day on days 1 to 14
- Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1 & 8
21-day cycles
References
- Blum JL, Dees EC, Chacko A, Doane L, Ethirajan S, Hopkins J, McMahon R, Merten S, Negron A, Neubauer M, Ilegbodu D, Boehm KA, Asmar L, O'Shaughnessy JA. Phase II trial of capecitabine and weekly paclitaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2006 Sep 20;24(27):4384-90. Epub 2006 Aug 22. link to original article dosing details in manuscript have been reviewed by our editors PubMed
Capecitabine & Paclitaxel, nanoparticle albumin-bound
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Schwartzberg et al. 2011 | Not reported | Phase 2 |
Chemotherapy
- Capecitabine (Xeloda) 825 mg/m2 (rounded to nearest 500 mg) PO twice per day on days 1 to 15
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m2 IV once per day on days 1 & 8
21-day cycles
References
- Schwartzberg LS, Arena FP, Mintzer DM, Epperson AL, Walker MS. Phase II multicenter trial of albumin-bound paclitaxel and capecitabine in first-line treatment of patients with metastatic breast cancer. Clin Breast Cancer. 2012 Apr;12(2):87-93. Epub 2011 Dec 6. link to original article dosing details in abstract have been reviewed by our editors 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
- Cyclophosphamide (Cytoxan) 350 mg/m2 IV once on day 1
- Methotrexate (MTX) 20 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 350 mg/m2 IV once on day 1
21-day cycles
Regimen variant #2, 600/40/600
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Tannock et al. 1988 | 1981-1986 | Phase 3 (C) | CMF; lower-dose | Might have superior OS |
Ingle et al. 1994 (NCCTG 87-32-52) | 1987-1991 | Randomized (C) | DES-CEF | Might have inferior ORR |
Chemotherapy
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
- Methotrexate (MTX) 40 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
21-day cycles
Regimen variant #3, 1000/80/1200
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ackland et al. 2001 (HEPI 013) | 1990-1992 | Phase 3 (C) | CEF | Inferior TTP |
Chemotherapy
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 8
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
21- to 28-day cycle for 6 to 9 cycles
Regimen variant #4, 1400/80/1000
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Aisner et al. 1987 (CALGB 7682) | 1976-1980 | Phase 3 (C) | 1. CAF | Seems to have inferior OS |
2. CAFVP | Inferior ORR |
Chemotherapy
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
28-day cycles
Regimen variant #5, 1400/60/800
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Canellos et al. 1976 | Not reported | Phase 3 (E-esc) | Melphalan | Seems to have superior OS |
Note: this was the dose used for patients older than 60 in the revised protocol of Canellos et al. 1976.
Chemotherapy
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 & 8
28-day cycles
Regimen variant #6, 1400/80/1200
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brambilla et al. 1976 | 1973-1974 | Randomized (C) | AV | Did not meet primary endpoint of ORR |
Canellos et al. 1976 | Not reported | Phase 3 (E-esc) | Melphalan | Seems to have superior OS |
Bull et al. 1978 | Not reported | 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 | Not reported | 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 |
Stadtmauer et al. 2000 | 1990-1997 | Phase 3 (C) | CMF x 4-6, then HDT | Did not meet primary endpoint of OS |
von Minckwitz et al. 2005 | 1996-2001 | Phase 3 (C) | BMF | Inferior TTP |
Stockler et al. 2011 (ANZ 0001) | 2001-2005 | Phase 3 (C) | 1. Capecitabine; continuous 2. Capecitabine; intermittent |
Seems to have inferior OS |
Note: this was the dose used for patients younger than 60 in the revised protocol of Canellos et al. 1976.
Chemotherapy
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycles
Regimen variant #7, 1400/120/1200
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Canellos et al. 1976 | Not reported | Phase 3 (E-esc) | Melphalan | Seems to have superior OS |
Note: this was the dose used for patients in the original protocol of Canellos et al. 1976 and was deemed too myelotoxic.
Chemotherapy
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 60 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycles
References
- 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
- 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
- Bull JM, Tormey DC, Li SH, Carbone PP, Falkson G, Blom J, Perlin E, Simon R. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978 May;41(5):1649-57. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- ECOG E2173: Tormey DC, Gelman R, Band PR, Sears M, Rosenthal SN, DeWys W, Perlia C, Rice MA. Comparison of induction chemotherapies for metastatic breast cancer: an Eastern Cooperative Oncology Group Trial. Cancer. 1982 Oct 1;50(7):1235-44. link to original article PubMed
- Muss HB, Richards F 2nd, Jackson DV, Cooper MR, White DR, Stuart JJ, Ramseur W, Christian RM, Wells HB, Pope E, Spurr CL; Piedmont Oncology Association. Vincristine, doxorubicin, and cyclophosphamide versus low-dose intravenous cyclophosphamide, methotrexate, and 5-fluorouracil in advanced breast cancer: a randomized trial of the Piedmont Oncology Association. Cancer. 1982 Dec 1;50(11):2269-74. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Cocconi G, De Lisi V, Boni C, Mori P, Malacarne P, Amadori D, Giovanelli E. Chemotherapy versus combination of chemotherapy and endocrine therapy in advanced breast cancer: a prospective randomized study. Cancer. 1983 Feb 15;51(4):581-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Viladiu P, Alonso MC, Avella A, Beltrán M, Borrás J, Ojeda B, Bosch FX. Chemotherapy versus chemotherapy plus hormonotherapy in postmenopausal advanced breast cancer patients: a randomized trial. Cancer. 1985 Dec 15;56(12):2745-50. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- CALGB 7682: Aisner J, Weinberg V, Perloff M, Weiss R, Perry M, Korzun A, Ginsberg S, Holland JF; CALGB. Chemotherapy versus chemoimmunotherapy (CAF v CAFVP v CMF each +/- MER) for metastatic carcinoma of the breast: a CALGB study. J Clin Oncol. 1987 Oct;5(10):1523-33. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Tannock IF, Boyd NF, DeBoer G, Erlichman C, Fine S, Larocque G, Mayers C, Perrault D, Sutherland H. A randomized trial of two dose levels of cyclophosphamide, methotrexate, and fluorouracil chemotherapy for patients with metastatic breast cancer. J Clin Oncol. 1988 Sep;6(9):1377-87. link to original article PubMed
- Cocconi G, Bisagni G, Bacchi M, Buzzi F, Canaletti R, Carpi A, Ceci G, Colozza A, De Lisi V, Lottici R, Passalacqua R, Peracchia G; GOIRC. A comparison of continuation versus late intensification followed by discontinuation of chemotherapy in advanced breast cancer: a prospective randomized trial of the Italian Oncology Group for Clinical Research (GOIRC). Ann Oncol. 1990;1(1):36-44. link to original article PubMed
- EORTC 10808: Engelsman E, Klijn JC, Rubens RD, Wildiers J, Beex LV, Nooij MA, Rotmensz N, Sylvester R. "Classical" CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer: an EORTC Breast Cancer Co-operative Group Phase III Trial (10808). Eur J Cancer. 1991;27(8):966-70. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Cocconi G, Bisagni G, Bacchi M, Boni C, Bartolucci R, Ceci G, Colozza MA, De Lisi V, Lottici R, Mosconi AM, Passalacqua R, Tonato M; Italian Oncology Group for Clinical Research. Cisplatin and etoposide as first-line chemotherapy for metastatic breast carcinoma: a prospective randomized trial of the Italian Oncology Group for Clinical Research. J Clin Oncol. 1991 Apr;9(4):664-9. link to original article PubMed
- Yosef H, Slater A, Keen CW, Bunting JS, Hope-Stone H, Parmar H, Roberts JT, Termander B, Nilsson B. Prednimustine (Sterecyt) versus cyclophosphamide both in combination with methotrexate and 5-fluorouracil in the treatment of advanced breast cancer. Eur J Cancer. 1993;29A(8):1100-5. link to original article dosing details in abstract have been reviewed by our editors PubMed
- NCCTG 87-32-52: Ingle JN, Foley JF, Mailliard JA, Krook JE, Hartmann LC, Jung SH, Veeder MH, Gesme DH Jr, Hatfield AK, Goldberg RM. Randomized trial of cyclophosphamide, methotrexate, and 5-fluorouracil with or without estrogenic recruitment in women with metastatic breast cancer. Cancer. 1994 May 1;73(9):2337-43. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Stadtmauer EA, O'Neill A, Goldstein LJ, Crilley PA, Mangan KF, Ingle JN, Brodsky I, Martino S, Lazarus HM, Erban JK, Sickles C, Glick JH; Philadelphia Bone Marrow Transplant Group. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J Med. 2000 Apr 13;342(15):1069-76. link to original article PubMed
- HEPI 013: Ackland SP, Anton A, Breitbach GP, Colajori E, Tursi JM, Delfino C, Efremidis A, Ezzat A, Fittipaldo A, Kolaric K, Lopez M, Viaro D; HEPI 013 study group. Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study. J Clin Oncol. 2001 Feb 15;19(4):943-53. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- von Minckwitz G, Chernozemsky I, Sirakova L, Chilingirov P, Souchon R, Marschner N, Kleeberg U, Tsekov C, Fritze D, Thomssen C, Stuart N, Vermorken JB, Loibl S, Merkle Kh, Kaufmann M. Bendamustine prolongs progression-free survival in metastatic breast cancer (MBC): a phase III prospective, randomized, multicenter trial of bendamustine hydrochloride, methotrexate and 5-fluorouracil (BMF) versus cyclophosphamide, methotrexate and 5-fluorouracil (CMF) as first-line treatment of MBC. Anticancer Drugs. 2005 Sep;16(8):871-7. link to original article PubMed
- ANZ 0001: Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B, Van Hazel G, Wilcken NR, Grimison PS, Nowak AK, Gainford MC, Fong A, Paksec L, Sourjina T, Zannino D, Gebski V, Simes RJ, Forbes JF, Coates AS. Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4498-504. Epub 2011 Oct 24. link to original article dosing details in manuscript have been reviewed by our editors 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 | Not reported | Randomized (E-esc) | CMF | Might have superior TTF |
Chemotherapy
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
Endocrine therapy
- Tamoxifen (Nolvadex) 10 mg PO twice per day on days 1 to 28
28-day cycles
Regimen variant #2, higher-dose tamoxifen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Viladiu et al. 1985 | 1978-1981 | Randomized (E-esc) | 1. CMF 2. CMF & MPA |
Seems to have superior ORR |
Chemotherapy
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
Endocrine therapy
- Tamoxifen (Nolvadex) 20 mg PO twice per day on days 1 to 28
28-day cycles
References
- Cocconi G, De Lisi V, Boni C, Mori P, Malacarne P, Amadori D, Giovanelli E. Chemotherapy versus combination of chemotherapy and endocrine therapy in advanced breast cancer: a prospective randomized study. Cancer. 1983 Feb 15;51(4):581-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Viladiu P, Alonso MC, Avella A, Beltrán M, Borrás J, Ojeda B, Bosch FX. Chemotherapy versus chemotherapy plus hormonotherapy in postmenopausal advanced breast cancer patients: a randomized trial. Cancer. 1985 Dec 15;56(12):2745-50. link to original article dosing details in manuscript have been reviewed by our editors 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) |
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
- Docetaxel (Taxotere) 40 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
8-week cycles
Regimen variant #4, 60 mg/m2 q3wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Katsumata et al. 2009 (JCOG9802) | 1999-2003 | Phase 3 (E-de-esc) | 1. AC 2. AC/D |
Did not meet primary endpoint of TTF | |
Takashima et al. 2015 (SELECT BC) | 2006-2010 | Phase 3 (C) | S-1 | Seems to have non-inferior OS | Inferior EQ-5D score |
Chemotherapy
- Docetaxel (Taxotere) 60 mg/m2 IV over 60 minutes once on day 1
21-day cycle for varying durations: 6 cycles (JCOG9802); indefinitely (SELECT BC)
Regimen variant #5, 60 mg/m2 q4wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Takashima et al. 2015 (SELECT BC) | 2006-2010 | Phase 3 (C) | S-1 | Seems to have non-inferior OS | Inferior EQ-5D score |
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 |
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 |
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 |
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 |
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 |
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 |
References
- Trudeau ME, Eisenhauer EA, Higgins BP, Letendre F, Lofters WS, Norris BD, Vandenberg TA, Delorme F, Muldal AM; National Cancer Institute of Canada-Clinical Trials Group. Docetaxel in patients with metastatic breast cancer: a phase II study of the National Cancer Institute of Canada-Clinical Trials Group. J Clin Oncol. 1996 Feb;14(2):422-8. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Review: Burris HA 3rd. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin Oncol. 1999 Jun;26(3 Suppl 9):1-6. PubMed
- Burstein HJ, Manola J, Younger J, Parker LM, Bunnell CA, Scheib R, Matulonis UA, Garber JE, Clarke KD, Shulman LN, Winer EP. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol. 2000 Mar;18(6):1212-9. link to original article PubMed content property of HemOnc.org
- Pacilio C, Morabito A, Nuzzo F, Gravina A, Labonia V, Landi G, Rossi E, De Maio E, Di Maio M, D'Aiuto G, Botti G, Normanno N, Chiodini P, Gallo C, Perrone F, de Matteis A; NCI-Naples Breast Cancer Group. Is epirubicin effective in first-line chemotherapy of metastatic breast cancer (MBC) after an epirubicin-containing adjuvant treatment? A single centre phase III trial. Br J Cancer. 2006 May 8;94(9):1233-6. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed
- NCIC-CTG MA.16: Crump M, Gluck S, Tu D, Stewart D, Levine M, Kirkbride P, Dancey J, O'Reilly S, Shore T, Couban S, Girouard C, Marlin S, Shepherd L, Pritchard KI. Randomized trial of high-dose chemotherapy with autologous peripheral-blood stem-cell support compared with standard-dose chemotherapy in women with metastatic breast cancer: NCIC MA.16. J Clin Oncol. 2008 Jan 1;26(1):37-43. Epub 2007 Nov 19. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00003032
- Rivera E, Mejia JA, Arun BK, Adinin RB, Walters RS, Brewster A, Broglio KR, Yin G, Esmaeli B, Hortobagyi GN, Valero V. Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic breast cancer. Cancer. 2008 Apr 1;112(7):1455-61. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- JCOG9802: Katsumata N, Watanabe T, Minami H, Aogi K, Tabei T, Sano M, Masuda N, Andoh J, Ikeda T, Shibata T, Takashima S. Phase III trial of doxorubicin plus cyclophosphamide (AC), docetaxel, and alternating AC and docetaxel as front-line chemotherapy for metastatic breast cancer: Japan Clinical Oncology Group trial (JCOG9802). Ann Oncol. 2009 Jul;20(7):1210-5. Epub 2009 Mar 2. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009 Aug 1;27(22):3611-9. Epub 2009 May 26. Erratum in: J Clin Oncol. 2011 Jul 1;29(19):2739. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- DOXIL-BCA-3001: Sparano JA, Makhson AN, Semiglazov VF, Tjulandin SA, Balashova OI, Bondarenko IN, Bogdanova NV, Manikhas GM, Oliynychenko GP, Chatikhine VA, Zhuang SH, Xiu L, Yuan Z, Rackoff WR. Pegylated liposomal doxorubicin plus docetaxel significantly improves time to progression without additive cardiotoxicity compared with docetaxel monotherapy in patients with advanced breast cancer previously treated with neoadjuvant-adjuvant anthracycline therapy: results from a randomized phase III study. J Clin Oncol. 2009 Sep 20;27(27):4522-9. Epub 2009 Aug 17. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00091442
- B9E-MC-S241: Joensuu H, Sailas L, Alanko T, Sunela K, Huuhtanen R, Utriainen M, Kokko R, Bono P, Wigren T, Pyrhönen S, Turpeenniemi-Hujanen T, Asola R, Leinonen M, Hahka-Kemppinen M, Kellokumpu-Lehtinen P. Docetaxel versus docetaxel alternating with gemcitabine as treatments of advanced breast cancer: final analysis of a randomised trial. Ann Oncol. 2010 May;21(5):968-73. Epub 2009 Oct 9. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00191243
- AVADO: Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010 Jul 10;28(20):3239-47. Epub 2010 May 24. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00333775
- D2: Stemmler HJ, Harbeck N, Gröll de Rivera I, Vehling Kaiser U, Rauthe G, Abenhardt W, Artmann A, Sommer H, Meerpohl HG, Kiechle M, Heinemann V. Prospective multicenter randomized phase III study of weekly versus standard docetaxel (D2) for first-line treatment of metastatic breast cancer. Oncology. 2010;79(3-4):197-203. Epub 2011 Mar 1. link to original article dosing details in abstract have been reviewed by our editors PubMed
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00262067
- Nielsen DL, Bjerre KD, Jakobsen EH, Cold S, Stenbygaard L, Sørensen PG, Kamby C, Møller S, Jørgensen CL, Andersson M; Danish Breast Cancer Cooperative Group. Gemcitabine plus docetaxel versus docetaxel in patients with predominantly human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: a randomized, phase III study by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 2011 Dec 20;29(36):4748-54. Epub 2011 Nov 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- SUN 1064: Bergh J, Bondarenko IM, Lichinitser MR, Liljegren A, Greil R, Voytko NL, Makhson AN, Cortes J, Lortholary A, Bischoff J, Chan A, Delaloge S, Huang X, Kern KA, Giorgetti C. First-line treatment of advanced breast cancer with sunitinib in combination with docetaxel versus docetaxel alone: results of a prospective, randomized phase III study. J Clin Oncol. 2012 Mar 20;30(9):921-9. Epub 2012 Feb 13. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00393939
- ROSE/TRIO-12: Mackey JR, Ramos-Vazquez M, Lipatov O, McCarthy N, Krasnozhon D, Semiglazov V, Manikhas A, Gelmon KA, Konecny GE, Webster M, Hegg R, Verma S, Gorbunova V, Abi Gerges D, Thireau F, Fung H, Simms L, Buyse M, Ibrahim A, Martín M. Primary results of ROSE/TRIO-12, a randomized placebo-controlled phase III trial evaluating the addition of ramucirumab to first-line docetaxel chemotherapy in metastatic breast cancer. J Clin Oncol. 2015 Jan 10;33(2):141-8. Epub 2014 Sep 2. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00703326
- SELECT BC: Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T, Hozumi Y, Tsurutani J, Imoto S, Watanabe T, Sagara Y, Nishimura R, Shimozuma K, Ohashi Y; SELECT BC Study Group. Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2016 Jan;17(1):90-8. Epub 2015 Nov 27. link to original article dosing details in manuscript have been reviewed by our editors PubMed UMIN C000000416
- HRQoL analysis: Shiroiwa T, Fukuda T, Shimozuma K, Mouri M, Hagiwara Y, Doihara H, Akabane H, Kashiwaba M, Watanabe T, Ohashi Y, Mukai H. Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial. Qual Life Res. 2017 Feb;26(2):445-453. Epub 2016 Aug 12. 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
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
Regimen variant #2, 100/15, 9 cycles
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Miles et al. 2010 (AVADO) | 2006-03 to 2007-04 | Phase 3 (E-esc) | 1. Docetaxel | 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
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for up to 9 cycles
Subsequent treatment
- Bevacizumab maintenance
Regimen variant #3, 100/15, indefinite
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robert et al. 2011 (RIBBON-1) | 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
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- AVADO: Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010 Jul 10;28(20):3239-47. Epub 2010 May 24. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00333775
- 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00262067
- TABEA: Lück HJ, Lübbe K, Reinisch M, Maass N, Feisel-Schwickardi G, Tomé O, Janni W, Aydogdu M, Neunhöffer T, Ober A, Aktas B, Park-Simon TW, Schumacher C, Höffkes HG, Illmer T, Wagner H, Mehta K, von Minckwitz G, Nekljudova V, Loibl S. Phase III study on efficacy of taxanes plus bevacizumab with or without capecitabine as first-line chemotherapy in metastatic breast cancer. Breast Cancer Res Treat. 2015 Jan;149(1):141-9. Epub 2014 Dec 18. link to original article dosing details in abstract have been reviewed by our editors PubMed
- GINECO-BR107: Trédan O, Follana P, Moullet I, Cropet C, Trager-Maury S, Dauba J, Lavau-Denes S, Diéras V, Béal-Ardisson D, Gouttebel M, Orfeuvre H, Stefani L, Jouannaud C, Bürki F, Petit T, Guardiola E, Becuwe C, Blot E, Pujade-Lauraine E, Bachelot T. A phase III trial of exemestane plus bevacizumab maintenance therapy in patients with metastatic breast cancer after first-line taxane and bevacizumab: a GINECO group study. Ann Oncol. 2016 Jun;27(6):1020-9. Epub 2016 Feb 24. link to original article dosing details in manuscript have been reviewed by our editors 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
- Doxorubicin (Adriamycin) as follows:
- Cycles 1 to 4: 50 mg/m2 IV over 15 minutes once on day 1, given first
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given second
21-day cycle for 8 cycles
Regimen variant #2, 50/75 x 6
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Bontenbal et al. 2005 | 1997-2002 | Phase 2/3 (E-de-esc) | FAC | Seems to have superior OS (secondary endpoint) Superior TTP (primary endpoint) |
|
Alba et al. 2004 (GEICAM-9903) | 1999-2001 | Phase 3 (C) | A-D | More toxic |
Chemotherapy
- Doxorubicin (Adriamycin) 50 mg/m2 IV bolus once on day 1, given first
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given second, 1 hour after doxorubicin
21-day cycle for 6 cycles
Regimen variant #3, 50/75 x 8
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Nabholtz et al. 2003 (TAX 306) | Not reported | Phase 3 (E-switch-ic) | AC | Seems to have superior TTP | |
Stemmler et al. 2010 (D4) | 2001-2008 | Phase 3 (C) | AT (Taxotere); weekly docetaxel | Did not meet secondary endpoint of TTP | Did not meet primary endpoint of hematotoxicity |
Chemotherapy
- Doxorubicin (Adriamycin) 50 mg/m2 IV over 15 minutes once on day 1, given first
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given second, 60 minutes after doxorubicin
21-day cycle for 8 cycles
References
- TAX 306: Nabholtz JM, Falkson C, Campos D, Szanto J, Martín M, Chan S, Pienkowski T, Zaluski J, Pinter T, Krzakowski M, Vorobiof D, Leonard R, Kennedy I, Azli N, Murawsky M, Riva A, Pouillart P; TAX 306 Study Group. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol. 2003 Mar 15;21(6):968-75. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- GEICAM-9903: Alba E, Martín M, Ramos M, Adrover E, Balil A, Jara C, Barnadas A, Fernández-Aramburo A, Sánchez-Rovira P, Amenedo M, Casado A; GEICAM. Multicenter randomized trial comparing sequential with concomitant administration of doxorubicin and docetaxel as first-line treatment of metastatic breast cancer: a Spanish Breast Cancer Research Group (GEICAM-9903) phase III study. J Clin Oncol. 2004 Jul 1;22(13):2587-93. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Bontenbal M, Creemers GJ, Braun HJ, de Boer AC, Janssen JT, Leys RB, Ruit JB, Goey SH, van der Velden PC, Kerkhofs LG, Schothorst KL, Schmitz PI, Bokma HJ, Verweij J, Seynaeve C; Dutch Community Setting Trial for the Clinical Trial Group. Phase II to III study comparing doxorubicin and docetaxel with fluorouracil, doxorubicin, and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer: results of a Dutch Community Setting Trial for the Clinical Trial Group of the Comprehensive Cancer Centre. J Clin Oncol. 2005 Oct 1;23(28):7081-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- ERASME 3: Cassier PA, Chabaud S, Trillet-Lenoir V, Peaud PY, Tigaud JD, Cure H, Orfeuvre H, Salles B, Martin C, Jacquin JP, Agostini C, Guastalla JP, Pérol D, Bachelot T. A phase-III trial of doxorubicin and docetaxel versus doxorubicin and paclitaxel in metastatic breast cancer: results of the ERASME 3 study. Breast Cancer Res Treat. 2008 May;109(2):343-50. Epub 2007 Jul 5. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- D4: Stemmler HJ, Harbeck N, Gröll de Rivera I, Vehling Kaiser U, Rauthe G, Abenhardt W, Artmann A, Sommer H, Meerpohl HG, Kiechle M, Heinemann V. Prospective multicenter randomized phase III study of weekly versus standard docetaxel plus doxorubicin (D4) for first-line treatment of metastatic breast cancer. Oncology. 2010;79(3-4):204-10. Epub 2011 Mar 1. link to original article dosing details in abstract have been reviewed by our editors 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
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
- Epirubicin (Ellence) 75 mg/m2 IV over 10 minutes once on day 1
21-day cycle for up to 8 cycles
Regimen variant #2, indefinite
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Mavroudis et al. 2009 (HORG CT/02.09) | 2002-2007 | Phase 3 (C) | TX | Did not meet primary endpoint of TTP |
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
21-day cycles
References
- Bonneterre J, Dieras V, Tubiana-Hulin M, Bougnoux P, Bonneterre ME, Delozier T, Mayer F, Culine S, Dohoulou N, Bendahmane B. Phase II multicentre randomised study of docetaxel plus epirubicin vs 5-fluorouracil plus epirubicin and cyclophosphamide in metastatic breast cancer. Br J Cancer. 2004 Oct 18;91(8):1466-71. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed
- HORG CT/02.09: Mavroudis D, Papakotoulas P, Ardavanis A, Syrigos K, Kakolyris S, Ziras N, Kouroussis C, Malamos N, Polyzos A, Christophyllakis C, Kentepozidis N, Georgoulias V; Hellenic Oncology Research Group. Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer. Ann Oncol. 2010 Jan;21(1):48-54. Epub 2009 Nov 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00429871
- Blohmer JU, Schmid P, Hilfrich J, Friese K, Kleine-Tebbe A, Koelbl H, Sommer H, Morack G, Wischnewsky MB, Lichtenegger W, Kuemmel S. Epirubicin and cyclophosphamide versus epirubicin and docetaxel as first-line therapy for women with metastatic breast cancer: final results of a randomised phase III trial. Ann Oncol. 2010 Jul;21(7):1430-5. Epub 2010 Jan 20. link to original article dosing details in manuscript have been reviewed by our editors 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
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given first
- Nielsen et al. 2011 gave docetaxel on day 8
- Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 minutes once per day on days 1 & 8
21-day cycle of varying durations: 6 to 10 cycles (B9E-IT-S376); indefinitely (Nielsen et al. 2011)
Subsequent treatment
- B9E-MC-S273, upon progression: Second-line Capecitabine
References
- Fountzilas G, Dafni U, Dimopoulos MA, Koutras A, Skarlos D, Papakostas P, Gogas H, Bafaloukos D, Kalogera-Fountzila A, Samantas E, Briasoulis E, Pectasides D, Maniadakis N, Matsiakou F, Aravantinos G, Papadimitriou C, Karina M, Christodoulou C, Kosmidis P, Kalofonos HP; Hellenic Cooperative Oncology Group. A randomized phase III study comparing three anthracycline-free taxane-based regimens, as first line chemotherapy, in metastatic breast cancer: a Hellenic Cooperative Oncology Group study. Breast Cancer Res Treat. 2009 May;115(1):87-99. Epub 2008 May 16. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- B9E-MC-S273: Seidman AD, Brufsky A, Ansari RH, Hart LL, Stein RS, Schwartzberg LS, Stewart JF, Russell CA, Chen SC, Fein LE, De La Cruz Vargas JA, Kim SB, Cavalheiro J, Zhao L, Gill JF, Obasaju CK, Orlando M, Tai DF. Phase III trial of gemcitabine plus docetaxel versus capecitabine plus docetaxel with planned crossover to the alternate single agent in metastatic breast cancer. Ann Oncol. 2011 May;22(5):1094-101. Epub 2010 Nov 17. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00191438
- Pooled update: Seidman AD, Chan S, Wang J, Zhu C, Xu C, Xu B. A pooled analysis of gemcitabine plus docetaxel versus capecitabine plus docetaxel in metastatic breast cancer. Oncologist. 2014 May;19(5):443-52. Epub 2014 Apr 4. link to original article link to PMC article PubMed
- Nielsen DL, Bjerre KD, Jakobsen EH, Cold S, Stenbygaard L, Sørensen PG, Kamby C, Møller S, Jørgensen CL, Andersson M; Danish Breast Cancer Cooperative Group. Gemcitabine plus docetaxel versus docetaxel in patients with predominantly human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: a randomized, phase III study by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 2011 Dec 20;29(36):4748-54. Epub 2011 Nov 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- B9E-IT-S376: Del Mastro L, Fabi A, Mansutti M, De Laurentiis M, Durando A, Merlo DF, Bruzzi P, La Torre I, Ceccarelli M, Kazeem G, Marchi P, Boy D, Venturini M, De Placido S, Cognetti F. Randomised phase 3 open-label trial of first-line treatment with gemcitabine in association with docetaxel or paclitaxel in women with metastatic breast cancer: a comparison of different schedules and treatments. BMC Cancer. 2013 Mar 28;13:164. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors 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 |
Note: Maximum cumulative dose in these trials was 750 mg/m2.
Chemotherapy
- Doxorubicin (Adriamycin) 20 mg/m2 IV over 5 to 10 minutes once on day 1
7-day cycle for 37 cycles
Regimen variant #2, 60 mg/m2 q3wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gottlieb et al. 1974 (SWG02) | 1972-01 to 1972-10 | Phase 3 (E-switch-ic) | 1. 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 (7 cycles). Treatment in Ingle et al. 1989 was given until a cumulative dose of 500 mg/m2. Treatment in Perez et al. 1991 was given until a cumulative dose of 550 mg/m2
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
21-day cycle of variation durations: 7 cycles (NCIC-CTG MA.8); 8 cycles (ECOG E1193, Ingle et al. 1989); 9 cycles (Perez et al. 1991); indefinitely (O'Brien et al. 2004)
Regimen variant #3, 75 mg/m2 q3wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Paridaens et al. 2000 (EORTC 10923) | 1993-1996 | Phase 3 (C) | Paclitaxel | Superior PFS |
Chemotherapy
- Doxorubicin (Adriamycin) 75 mg/m2 IV over 5 to 15 minutes once on day 1
21-day cycle for up to 7 cycles
References
- SWG02: Gottlieb JA, Rivkin SE, Spigel SC, Hoogstraten B, O'Bryan RM, Delaney FC, Singhakowinta A; SWOG. Proceedings: Superiority of adriamycin over oral nitrosoureas in patients with advanced breast carcinoma: a Southwest Cancer Chemotherapy study Group study. Cancer. 1974 Feb;33(2):519-26. link to original article PubMed
- Hoogstraten B, George SL, Samal B, Rivkin SE, Costanzi JJ, Bonnet JD, Thigpen T, Braine H; SWOG. Combination chemotherapy and adriamycin in patients with advanced breast cancer: a Southwest Oncology Group study. Cancer. 1976 Jul;38(1):13-20. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Gundersen S, Kvinnsland S, Klepp O, Kvaløy S, Lund E, Høst H. Weekly adriamycin versus VAC in advanced breast cancer: a randomized trial. Eur J Cancer Clin Oncol. 1986 Dec;22(12):1431-4. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- SWOG S8020: Vaughn CB, Green SJ, O'Bryan R, Reed M, Grozea PN, Fletcher WS, Green JB, Metch B, Oishi N. VP-16 + adriamycin vs adriamycin alone in advanced adenocarcinoma of the breast, phase II, a randomized trial: a Southwest Oncology Group Study. Med Pediatr Oncol. 1988;16(5):312-9. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Ingle JN, Mailliard JA, Schaid DJ, Krook JE, Gerstner JB, Pfeifle DM, Marschke RF Jr, Long HJ, McCormack GW, Foley JF; NCCTG. Randomized trial of doxorubicin alone or combined with vincristine and mitomycin C in women with metastatic breast cancer. Am J Clin Oncol. 1989 Dec;12(6):474-80. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Gundersen S, Kvinnsland S, Klepp O, Lund E, Høst H; Norwegian Breast Cancer Group. Weekly Adriamycin vs 4-epidoxorubicin every second week in advanced breast cancer: a randomized trial. Eur J Cancer. 1990 Jan;26(1):45-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Perez DJ, Harvey VJ, Robinson BA, Atkinson CH, Dady PJ, Kirk AR, Evans BD, Chapman PJ. A randomized comparison of single-agent doxorubicin and epirubicin as first-line cytotoxic therapy in advanced breast cancer. J Clin Oncol. 1991 Dec;9(12):2148-52. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Gundersen S, Hannisdal E, Lundgren S, Wist E; Norwegian Breast Cancer Group. Weekly doxorubicin with or without high-dose medroxyprogesterone acetate in hormone-resistant advanced breast cancer: a randomised study. Eur J Cancer. 1994;30A(12):1775-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- EORTC 10923: Paridaens R, Biganzoli L, Bruning P, Klijn JG, Gamucci T, Houston S, Coleman R, Schachter J, Van Vreckem A, Sylvester R, Awada A, Wildiers J, Piccart M. Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European Organisation for Research and Treatment of Cancer Randomized Study with cross-over. J Clin Oncol. 2000 Feb;18(4):724-33. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- HRQoL analysis: Kramer JA, Curran D, Piccart M, de Haes JC, Bruning PF, Klijn JG, Bontenbal M, van Pottelsberghe C, Groenvold M, Paridaens R. Randomised trial of paclitaxel versus doxorubicin as first-line chemotherapy for advanced breast cancer: quality of life evaluation using the EORTC QLQ-C30 and the Rotterdam symptom checklist. Eur J Cancer. 2000 Aug;36(12):1488-97. link to original article PubMed
- NCIC-CTG MA.8: Norris B, Pritchard KI, James K, Myles J, Bennett K, Marlin S, Skillings J, Findlay B, Vandenberg T, Goss P, Latreille J, Rudinskas L, Lofters W, Trudeau M, Osoba D, Rodgers A. Phase III comparative study of vinorelbine combined with doxorubicin versus doxorubicin alone in disseminated metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group study MA8. J Clin Oncol. 2000 Jun;18(12):2385-94. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- ECOG E1193: Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, Wood WC. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol. 2003 Feb 15;21(4):588-92. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C; CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004 Mar;15(3):440-9. link to original article dosing details in manuscript have been reviewed by our editors 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
- Doxorubicin (Adriamycin) as follows:
- Cycles 1 to 4: 50 mg/m2 IV over 15 minutes once on day 1, given first
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1, given second
21-day cycle for 8 cycles
Regimen variant #3, 50/220
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Jassem et al. 2001 | 1996-1998 | Phase 3 (E-de-esc) | FAC | Superior OS1 Median OS: 23 vs 18.3 mo |
1Reported efficacy is based on the 2009 update.
Chemotherapy
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 220 mg/m2 IV over 3 hours once on day 2
21-day cycle for up to 8 cycles
Regimen variant #4, 60/175->200
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Biganzoli et al. 2002 (EORTC 10961) | 1996-1999 | Phase 3 (E-switch-ic) | AC | Did not meet primary endpoint of PFS |
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV over 15 minutes once on day 1, given first
- Paclitaxel (Taxol) as follows:
- Cycle 1: 175 mg/m2 IV over 3 hours once on day 1, given second, 30 minutes after end of doxorubicin
- Cycles 2 to 5: 200 mg/m2 IV over 3 hours once on day 1, given second, 30 minutes after end of doxorubicin
21-day cycle for up to 6 cycles
Regimen variant #5, 60/200
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Schmid et al. 2005 | 1998-2002 | Phase 3 (C) | Tandem auto HSCT | Did not meet primary endpoint of CR rate |
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV over 15 minutes once on day 1
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
21-day cycle for up to 6 cycles
Regimen variant #6, with range
Study | Dates of enrollment | Evidence |
---|---|---|
Gianni et al. 1995 | 1993-1994 | Non-randomized |
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 125 to 200 mg/m2 IV once on day 1
21-day cycles
References
- 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
- Jassem J, Pieńkowski T, Płuzańska A, Jelic S, Gorbunova V, Mrsic-Krmpotic Z, Berzins J, Nagykalnai T, Wigler N, Renard J, Munier S, Weil C; Central & Eastern Europe and Israel Pacitaxel Breast Cancer Study Group. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J Clin Oncol. 2001 Mar 15;19(6):1707-15. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Jassem J, Pienkowski T, Pluzanska A, Jelic S, Gorbunova V, Berzins J, Nagykalnai T, Biganzoli L, Aloe A, Astier L, Munier S. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin and cyclophosphamide as first-line therapy for women with advanced breast cancer: long-term analysis of the previously published trial. Onkologie. 2009 Sep;32(8-9):468-72. Epub 2009 Jul 20. link to original article PubMed
- EORTC 10961: Biganzoli L, Cufer T, Bruning P, Coleman R, Duchateau L, Calvert AH, Gamucci T, Twelves C, Fargeot P, Epelbaum R, Lohrisch C, Piccart MJ. Doxorubicin and paclitaxel versus doxorubicin and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: The European Organisation for Research and Treatment of Cancer 10961 multicenter phase III trial. J Clin Oncol. 2002 Jul 15;20(14):3114-21. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- ECOG E1193: Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, Wood WC. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol. 2003 Feb 15;21(4):588-92. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Schmid P, Schippinger W, Nitsch T, Huebner G, Heilmann V, Schultze W, Hausmaninger H, Wischnewsky M, Possinger K. Up-front tandem high-dose chemotherapy compared with standard chemotherapy with doxorubicin and paclitaxel in metastatic breast cancer: results of a randomized trial. J Clin Oncol. 2005 Jan 20;23(3):432-40. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- ERASME 3: Cassier PA, Chabaud S, Trillet-Lenoir V, Peaud PY, Tigaud JD, Cure H, Orfeuvre H, Salles B, Martin C, Jacquin JP, Agostini C, Guastalla JP, Pérol D, Bachelot T. A phase-III trial of doxorubicin and docetaxel versus doxorubicin and paclitaxel in metastatic breast cancer: results of the ERASME 3 study. Breast Cancer Res Treat. 2008 May;109(2):343-50. Epub 2007 Jul 5. link to original article dosing details in manuscript have been reviewed by our editors 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
- Pegylated liposomal doxorubicin (Doxil) 45 mg/m2 IV once on day 1
28-day cycle for 6 cycles
Regimen variant #2, 50 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
O'Brien et al. 2004 | 1998-06 to 2000-08 | Phase 3 (E-switch-ic) | Doxorubicin | Seems to have non-inferior PFS (co-primary endpoint) Median PFS: 6.9 vs 7.8 mo (HR 1.00, 95% CI 0.82-1.22) |
Harbeck et al. 2016 (PELICAN) | 2006-2010 | Phase 3 (E-switch-ic) | Capecitabine | Inconclusive whether non-inferior TTP (primary endpoint) |
Chemotherapy
- Pegylated liposomal doxorubicin (Doxil) 50 mg/m2 IV over up to 60 minutes once on day 1
28-day cycles
Dose and schedule modifications
- If infusion reactions occurred, infusion could be given over up to 90 minutes
References
- O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C; CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004 Mar;15(3):440-9. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- OMEGA: Smorenburg CH, de Groot SM, van Leeuwen-Stok AE, Hamaker ME, Wymenga AN, de Graaf H, de Jongh FE, Braun JJ, Los M, Maartense E, van Tinteren H, Nortier JW, Seynaeve C; Dutch Breast Cancer Research Group. A randomized phase III study comparing pegylated liposomal doxorubicin with capecitabine as first-line chemotherapy in elderly patients with metastatic breast cancer: results of the OMEGA study of the Dutch Breast Cancer Research Group BOOG. Ann Oncol. 2014 Mar;25(3):599-605. Epub 2014 Feb 6. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed ISRCTN11114726
- PELICAN: Harbeck N, Saupe S, Jäger E, Schmidt M, Kreienberg R, Müller L, Otremba BJ, Waldenmaier D, Dorn J, Warm M, Scholz M, Untch M, de Wit M, Barinoff J, Lück HJ, Harter P, Augustin D, Harnett P, Beckmann MW, Al-Batran SE; PELICAN Investigators. A randomized phase III study evaluating pegylated liposomal doxorubicin versus capecitabine as first-line therapy for metastatic breast cancer: results of the PELICAN study. Breast Cancer Res Treat. 2017 Jan;161(1):63-72. Epub 2016 Oct 31. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors 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. Infusion and sequencing instructions are as per Chan et al. 2004.
Chemotherapy
- Epirubicin (Ellence) 75 mg/m2 IV over 60 minutes once on day 1, given second
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 15 minutes once on day 1, given first
21-day cycle for varying durations: 6 cycles (UKNCRI AB01); 8 cycles (Chan et al. 2004)
Regimen variant #2, 90/600
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Blohmer et al. 2010 | 2000-2003 | Phase 3 (C) | ED | Did not meet primary endpoint of ORR |
Note: to our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
Chemotherapy
- Epirubicin (Ellence) 90 mg/m2 IV bolus once on day 1, given first
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 30 minutes once on day 1, given second
21-day cycle for 6 to 8 cycles
Regimen variant #3, with range
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robert et al. 2011 (RIBBON-1) | 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
- Epirubicin (Ellence) 90 to 100 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 to 600 mg/m2 IV once on day 1
21-day cycle for up to 8 cycles
References
- Chan S, Davidson N, Juozaityte E, Erdkamp F, Pluzanska A, Azarnia N, Lee LW. Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer. Ann Oncol. 2004 Oct;15(10):1527-34. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- UKNCRI AB01: Langley RE, Carmichael J, Jones AL, Cameron DA, Qian W, Uscinska B, Howell A, Parmar M. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute trial AB01. J Clin Oncol. 2005 Nov 20;23(33):8322-30. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Blohmer JU, Schmid P, Hilfrich J, Friese K, Kleine-Tebbe A, Koelbl H, Sommer H, Morack G, Wischnewsky MB, Lichtenegger W, Kuemmel S. Epirubicin and cyclophosphamide versus epirubicin and docetaxel as first-line therapy for women with metastatic breast cancer: final results of a randomised phase III trial. Ann Oncol. 2010 Jul;21(7):1430-5. Epub 2010 Jan 20. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article dosing details in manuscript have been reviewed by our editors 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
- Epirubicin (Ellence) 90 to 100 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 to 600 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for up to 8 cycles
Subsequent treatment
- RIBBON-1, SD or better: Bevacizumab maintenance
References
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article dosing details in manuscript have been reviewed by our editors 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
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycle for up to 6 cycles
Regimen variant #2, 75/175
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hatschek et al. 2011 (TEX trial) | 2002-2007 | Phase 3 (C) | TEX | Did not meet primary endpoint of PFS |
Note: the doses of this regimen were individually adjusted after cycle 1; see paper for details.
Chemotherapy
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycles
Regimen variant #3, 75/200
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Langley et al. 2005 (UKNCRI AB01) | 1996-1999 | Phase 3 (E-switch-ic) | EC | Did not meet primary endpoint of PFS |
Chemotherapy
- Epirubicin (Ellence) 75 mg/m2 IV bolus once on day 1, given first
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1, given second
21-day cycle for up to 6 cycles
Regimen variant #4, 80/175
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fountzilas et al. 2004 | 1999-2002 | Phase 3 (C) | CP | Did not meet primary endpoint of OS |
Chemotherapy
- Epirubicin (Ellence) 80 mg/m2 IV once on day 1, given second
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1, given first
21-day cycle for up to 6 cycles
Regimen variant #5, 90/200
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Conte et al. 2004 | 1996-2001 | Phase 3 (C) | E-T | Seems to have non-inferior ORR |
Chemotherapy
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 200 mg/m2 IV once on day 1
21-day cycle for 8 cycles
References
- Conte PF, Guarneri V, Bruzzi P, Prochilo T, Salvadori B, Bolognesi A, Aldrighetti D, Venturini M, Rosso R, Mammoliti S, Carnino F, Giannessi P, Costantini M, Moyano A, Baldini E; GONO. Concomitant versus sequential administration of epirubicin and paclitaxel as first-line therapy in metastatic breast carcinoma: results for the Gruppo Oncologico Nord Ovest randomized trial. Cancer. 2004 Aug 15;101(4):704-12. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Fountzilas G, Kalofonos HP, Dafni U, Papadimitriou C, Bafaloukos D, Papakostas P, Kalogera-Fountzila A, Gogas H, Aravantinos G, Moulopoulos LA, Economopoulos T, Pectasides D, Maniadakis N, Siafaka V, Briasoulis E, Christodoulou C, Tsavdaridis D, Makrantonakis P, Razis E, Kosmidis P, Skarlos D, Dimopoulos MA; Hellenic Cooperative Oncology Group. Paclitaxel and epirubicin versus paclitaxel and carboplatin as first-line chemotherapy in patients with advanced breast cancer: a phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol. 2004 Oct;15(10):1517-26. link to original article dosing details in abstract have been reviewed by our editors PubMed
- UKNCRI AB01: Langley RE, Carmichael J, Jones AL, Cameron DA, Qian W, Uscinska B, Howell A, Parmar M. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute trial AB01. J Clin Oncol. 2005 Nov 20;23(33):8322-30. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- TEX trial: Hatschek T, Carlsson L, Einbeigi Z, Lidbrink E, Linderholm B, Lindh B, Loman N, Malmberg M, Rotstein S, Söderberg M, Sundquist M, Walz TM, Hellström M, Svensson H, Aström G, Brandberg Y, Carstensen J, Fernö M, Bergh J. Individually tailored treatment with epirubicin and paclitaxel with or without capecitabine as first-line chemotherapy in metastatic breast cancer: a randomized multicenter trial. Breast Cancer Res Treat. 2012 Feb;131(3):939-47. Epub 2011 Nov 18. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT01433614
- Lück HJ, Du Bois A, Loibl S, Schrader I, Huober J, Heilmann V, Beckmann M, Stähler A, Jackisch C, Hubalek M, Richter B, Stickeler E, Eidtmann H, Thomssen C, Untch M, Wollschläger K, Schuster T, von Minckwitz G; AGO Breast Cancer Study Group. Capecitabine plus paclitaxel versus epirubicin plus paclitaxel as first-line treatment for metastatic breast cancer: efficacy and safety results of a randomized, phase III trial by the AGO Breast Cancer Study Group. Breast Cancer Res Treat. 2013 Jun;139(3):779-87. Epub 2013 Jun 15. link to original article dosing details in abstract have been reviewed by our editors 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 |
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 |
Note: In Bastholt et al. 1996, the maximum cumulative dose was 1000 mg/m2.
Regimen variant #3, 50 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gundersen et al. 1990 | 1984-1986 | Phase 3 (E-switch-ic) | Doxorubicin | Did not meet endpoints of ORR/OS |
Note: Maximum cumulative dose in Gundersen et al. 1990 was 750 mg/m2.
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 |
Note: In Bastholt et al. 1996, the maximum cumulative dose was 1000 mg/m2; this was also the case for Nielsen et al. 1990 after a mid-protocol amendment.
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
- Epirubicin (Ellence) 70 mg/m2 IV once per day on days 1 & 8
28-day cycles until maximum dose of epirubicin reached (1000 mg/m2)
Regimen variant #6, 75 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bonneterre & Hurteloup 1991 | Not reported | Phase 3 (E-de-esc) | 1. FEC; FEC 50 | Seems to have inferior ORR |
2. FEC; FEC 75 | Inferior ORR |
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 |
Note: In SBG 9403, epirubicin was discontinued once the cumulative dose exceeded 900 mg/m2 but before it exceeded 950 mg/m2, after a mid-protocol amendment. In Bastholt et al. 1996, the maximum cumulative dose was 1000 mg/m2.
Chemotherapy
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
21-day cycle of varying durations: 6 or more cycles (Perez et al. 1991); 10 cycles (SBG 9403); 11 cycles (Bastholt et al. 1996)
Regimen variant #8, 120 mg/m2, split doses
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Dogliotti et al. 1996 | 1991-1993 | Phase 3 (C) | Epirubicin & Lonidamine | 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 |
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 |
Note: In Bastholt et al. 1996, the maximum cumulative dose was 1000 mg/m2.
References
- Gundersen S, Kvinnsland S, Klepp O, Lund E, Høst H; Norwegian Breast Cancer Group. Weekly Adriamycin vs 4-epidoxorubicin every second week in advanced breast cancer: a randomized trial. Eur J Cancer. 1990 Jan;26(1):45-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Nielsen D, Dombernowsky P, Skovsgaard T, Jensen J, Andersen E, Engelholm SA, Hansen M. Epirubicin or epirubicin and vindesine in advanced breast cancer: a phase III study. Ann Oncol. 1990 Jul;1(4):275-80. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Bonneterre J, Hurteloup P; French Epirubicin Study Group. A prospective randomized trial comparing epirubicin monochemotherapy to two fluorouracil, cyclophosphamide, and epirubicin regimens differing in epirubicin dose in advanced breast cancer patients. J Clin Oncol. 1991 Feb;9(2):305-12. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Perez DJ, Harvey VJ, Robinson BA, Atkinson CH, Dady PJ, Kirk AR, Evans BD, Chapman PJ. A randomized comparison of single-agent doxorubicin and epirubicin as first-line cytotoxic therapy in advanced breast cancer. J Clin Oncol. 1991 Dec;9(12):2148-52. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Bastholt L, Dalmark M, Gjedde SB, Pfeiffer P, Pedersen D, Sandberg E, Kjaer M, Mouridsen HT, Rose C, Nielsen OS, Jakobsen P, Bentzen SM; Danish Breast Cancer Cooperative Group. Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 1996 Apr;14(4):1146-55. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Dogliotti L, Berruti A, Buniva T, Zola P, Baù MG, Farris A, Sarobba MG, Bottini A, Alquati P, Deltetto F, Gosso P, Monzeglio C, Moro G, Sussio M, Perroni D. Lonidamine significantly increases the activity of epirubicin in patients with advanced breast cancer: results from a multicenter prospective randomized trial. J Clin Oncol. 1996 Apr;14(4):1165-72. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Nielsen D, Dombernowsky P, Larsen SK, Hansen OP, Skovsgaard T. Epirubicin or epirubicin and cisplatin as first-line therapy in advanced breast cancer: a phase III study. Cancer Chemother Pharmacol. 2000;46(6):459-66. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Berruti A, Bitossi R, Gorzegno G, Bottini A, Alquati P, De Matteis A, Nuzzo F, Giardina G, Danese S, De Lena M, Lorusso V, Farris A, Sarobba MG, DeFabiani E, Bonazzi G, Castiglione F, Bumma C, Moro G, Bruzzi P, Dogliotti L; Epirubicin-Lonidamine Group. Time to progression in metastatic breast cancer patients treated with epirubicin is not improved by the addition of either cisplatin or lonidamine: final results of a phase III study with a factorial design. J Clin Oncol. 2002 Oct 15;20(20):4150-9. link to original article dosing details in abstract have been reviewed by our editors PubMed
- SBG 9403: Ejlertsen B, Mouridsen HT, Langkjer ST, Andersen J, Sjöström J, Kjaer M; Scandinavian Breast Group. Phase III study of intravenous vinorelbine in combination with epirubicin versus epirubicin alone in patients with advanced breast cancer: a Scandinavian Breast Group Trial (SBG9403). J Clin Oncol. 2004 Jun 15;22(12):2313-20. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Feher O, Vodvarka P, Jassem J, Morack G, Advani SH, Khoo KS, Doval DC, Ermisch S, Roychowdhury D, Miller MA, von Minckwitz G. First-line gemcitabine versus epirubicin in postmenopausal women aged 60 or older with metastatic breast cancer: a multicenter, randomized, phase III study. Ann Oncol. 2005 Jun;16(6):899-908. Epub 2005 Apr 8. link to original article dosing details in abstract have been reviewed by our editors 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
- Fluorouracil (5-FU) 500 mg/m2 IV bolus once on day 1, given second
- Doxorubicin (Adriamycin) 50 mg/m2 IV bolus once on day 1, given first
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV over 15 minutes once on day 1, given third
21-day cycle for varying durations: 6 cycles (Muss et al. 1991; Bontenbal et al. 2005); 6 or more cycles (Namer et al. 2001); 8 cycles (Jassem et al. 2001; RIBBON-1); 9 cycles (Bennett et al. 1988); 10 cycles (Smalley et al. 1977); 11 cycles (Blajman et al. 1999)
Subsequent treatment
- Muss et al. 1991: CMFP continuation versus observation followed by second-line CMFP at progression
Regimen variant #2, 600/50/600
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Alonso et al. 1995 | 1988-1991 | Phase 3 (C) | CNF | Did not meet endpoints of ORR/OS |
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for up to 10 cycles
Regimen variant #3, 800/40/400
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Tranum et al. 1978 | Not reported | Randomized (E-esc) | 1. AF 2. AFCM |
Did not meet primary endpoint of ORR |
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
21-day cycles
Regimen variant #4, 1000/40/500
Study | 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
- Fluorouracil (5-FU) 200 mg/m2 IV once per day on days 1 to 5
- Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycles
Regimen variant #5, 1000/50/500, indefinite
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hortobagyi et al. 1979 | 1974 to not reported | Phase 3 (C) | FAC-BCG | Inferior OS in responders |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8 or days 1 & 4
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycles
Regimen variant #6, 1000/50/500 until max anthracycline
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Ambrosini et al. 1988 | 1983-1985 | Phase 3 (C) | FEC | Did not meet primary endpoint | More toxic |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for up to 11 cycles (maximum of 550 mg/m2 doxorubicin)
Regimen variant #7, 1000/50/1400
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Aisner et al. 1987 (CALGB 7682) | 1976-1980 | Phase 3 (E-switch-ic) | 1. CAFVP | Not reported |
2. CMF | Superior ORR | |||
Kardinal et al. 1983 (CALGB 8081) | 1980-1982 | Randomized (C) | CAFT | Did not meet primary endpoint of ORR |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 25 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
28-day cycle for up to 9 cycles
Regimen variant #8, 1000/60/1400
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bull et al. 1978 | Not reported | Phase 3 (E-switch-ic) | CMF | Might have superior ORR |
Cummings et al. 1985 | 1978-1979 | Randomized (E-de-esc) | CMFP | Did not meet primary endpoint of ORR |
Falkson et al. 1987 (ECOG E2177) | Not reported-1983 | Randomized (C) | O+CAF | Did not meet co-primary endpoints of ORR/TTF/OS |
Tominaga et al. 1994 | Not reported | Phase 3 (C) | CAF & MPA | Seems to have inferior ORR |
Sledge et al. 2000 (ECOG E3186) | 1988-1992 | Phase 3 (C) | CAFTH | Might have inferior TTF |
Note: Doxorubicin was stopped once a cumulative dose of 450 mg/m2 was reached (Bull et al. 1978) or 500 mg/m2 was reached (Cummings et al. 1985, ECOG E2177).
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
28-day cycle for varying durations: 3 cycles (Tominaga et al. 1994); 6 cycles (ECOG E3186); 7 cycles (Bull et al. 1978); 8 cycles (Cummings et al. 1985, ECOG E2177)
Subsequent treatment
- Tominaga et al. 1994: 5-FU maintenance
References
- Smalley RV, Carpenter J, Bartolucci A, Vogel C, Krauss S; Southeastern Cancer Study Group. A comparison of cyclophosphamide, adriamycin, 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisone (CMFVP) in patients with metastatic breast cancer: a Southeastern Cancer Study Group project. Cancer. 1977 Aug;40(2):625-32. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Smalley RV, Lefante J, Bartolucci A, Carpenter J, Vogel C, Krauss S. A comparison of cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone (CMFVP) in patients with advanced breast cancer. Breast Cancer Res Treat. 1983;3(2):209-20. link to original article PubMed
- Bull JM, Tormey DC, Li SH, Carbone PP, Falkson G, Blom J, Perlin E, Simon R. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978 May;41(5):1649-57. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Tranum B, Hoogstraten B, Kennedy A, Vaughn CB, Samal B, Thigpen T, Rivkin S, Smith F, Palmer RL, Costanzi J, Tucker WG, Wilson H, Maloney TR; 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
- 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
- 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
- Update: Perry MC, Kardinal CG, Korzun AH, Ginsberg SJ, Raich PC, Holland JF, Ellison RR, Kopel S, Schilling A, Aisner J, Schulman P, Weinberg V, Rice MA, Wood W. Chemohormonal therapy in advanced carcinoma of the breast: Cancer and Leukemia Group B protocol 8081. J Clin Oncol. 1987 Oct;5(10):1534-45. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Cummings FJ, Gelman R, Horton J. Comparison of CAF versus CMFP in metastatic breast cancer: analysis of prognostic factors. J Clin Oncol. 1985 Jul;3(7):932-40. link to original article PubMed
- ECOG E2177: Falkson G, Gelman RS, Tormey DC, Falkson CI, Wolter JM, Cummings FJ. Treatment of metastatic breast cancer in premenopausal women using CAF with or without oophorectomy: an Eastern Cooperative Oncology Group Study. J Clin Oncol. 1987 Jun;5(6):881-9. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Falkson G, Holcroft C, Gelman RS, Tormey DC, Wolter JM, Cummings FJ. Ten-year follow-up study of premenopausal women with metastatic breast cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol. 1995 Jun;13(6):1453-8. link to original article PubMed
- CALGB 7682: Aisner J, Weinberg V, Perloff M, Weiss R, Perry M, Korzun A, Ginsberg S, Holland JF; CALGB. Chemotherapy versus chemoimmunotherapy (CAF v CAFVP v CMF each +/- MER) for metastatic carcinoma of the breast: a CALGB study. J Clin Oncol. 1987 Oct;5(10):1523-33. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Ambrosini G, Balli M, Garusi G, Demicheli R, Jirillo A, Bonciarelli G, Bruscagnin G, Fila G, Bumma C, Lacroix F, Buzzi F, Di Costanzo F, Padalino D, Brugia M, Calabresi F, Natali M, Cartei G, Chiesa G, Blasina B, Ciambellotti E, Moro G, D'Aquino S, Altavilla G, Adamo V, De Maria D, Falchi AM, Bertoncelli P, Farris A, Fiorentino M, Fornasiero A, Fosser V, Daniele O, Foggi CM, Speranza GB, Sartori S, Camilluzzi E, Gallo L, Poggio R, Secondo V, Gambi A, Grignani F, Capodicasa E, Lopez M, Papaldo P, Di Lauro L, Vici P, Marenco G, Folco U, Bonanni F, Marsilio P, Palazzotto G, Di Carlo A, Cusimano MP, Pastorino G, Puccetti C, Giusto M, Rausa L, Gebbia N, Palmeri S, D'Alessandro N, Saccani F, Becchi G, Schieppati G, Spinelli I, Tagliagambe A, Tonato M, Minotti V, Ardia A, Viaro D, De Micheli P, Zingali G, Sacchetti G, Intini C; Italian Multicentre Breast Study with Epirubicin. Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: an Italian multicentre trial. J Clin Oncol. 1988 Jun;6(6):976-82. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Bennett JM, Muss HB, Doroshow JH, Wolff S, Krementz ET, Cartwright K, Dukart G, Reisman A, Schoch I. A randomized multicenter trial comparing mitoxantrone, cyclophosphamide, and fluorouracil with doxorubicin, cyclophosphamide, and fluorouracil in the therapy of metastatic breast carcinoma. J Clin Oncol. 1988 Oct;6(10):1611-20. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Muss HB, Case LD, Richards F 2nd, White DR, Cooper MR, Cruz JM, Powell BL, Spurr CL, Capizzi RL; Piedmont Oncology Association. Interrupted versus continuous chemotherapy in patients with metastatic breast cancer. N Engl J Med. 1991 Nov 7;325(19):1342-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Tominaga T, Abe O, Ohshima A, Hayasaka H, Uchino J, Abe R, Enomoto K, Izuo M, Watanabe H, Takatani O, Yoshida M, Sakai K, Koyama H, Hattori T, Senoo T, Monden Y, Nomura Y. Comparison of chemotherapy with or without medroxyprogesterone acetate for advanced or recurrent breast cancer. Eur J Cancer. 1994;30A(7):959-64. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Alonso MC, Tabernero JM, Ojeda B, Llanos M, Solà C, Climent MA, Seguí MA, López JJ. A phase III randomized trial of cyclophosphamide, mitoxantrone, and 5-fluorouracil (CNF) versus cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) in patients with metastatic breast cancer. Breast Cancer Res Treat. 1995 Apr;34(1):15-24. link to original article dosing details in abstract have been reviewed by our editors PubMed
- CALGB 8281: Aisner J, Cirrincione C, Perloff M, Perry M, Budman D, Abrams J, Panasci L, Muss H, Citron M, Holland J, Wood W, Henderson IC. Combination chemotherapy for metastatic or recurrent carcinoma of the breast--a randomized phase III trial comparing CAF versus VATH versus VATH alternating with CMFVP: Cancer and Leukemia Group B Study 8281. J Clin Oncol. 1995 Jun;13(6):1443-52. link to original article does not contain dosing details PubMed
- Blajman C, Balbiani L, Block J, Coppola F, Chacon R, Fein L, Bonicatto S, Alvarez A, Schmilovich A, Delgado FM. A prospective, randomized Phase III trial comparing combination chemotherapy with cyclophosphamide, doxorubicin, and 5-fluorouracil with vinorelbine plus doxorubicin in the treatment of advanced breast carcinoma. Cancer. 1999 Mar 1;85(5):1091-7. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- ECOG E3186: Sledge GW Jr, Hu P, Falkson G, Tormey D, Abeloff M. Comparison of chemotherapy with chemohormonal therapy as first-line therapy for metastatic, hormone-sensitive breast cancer: an Eastern Cooperative Oncology Group study. J Clin Oncol. 2000 Jan;18(2):262-6. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Jassem J, Pieńkowski T, Płuzańska A, Jelic S, Gorbunova V, Mrsic-Krmpotic Z, Berzins J, Nagykalnai T, Wigler N, Renard J, Munier S, Weil C; Central & Eastern Europe and Israel Pacitaxel Breast Cancer Study Group. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin, and cyclophosphamide as first-line therapy for women with metastatic breast cancer: final results of a randomized phase III multicenter trial. J Clin Oncol. 2001 Mar 15;19(6):1707-15. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Jassem J, Pienkowski T, Pluzanska A, Jelic S, Gorbunova V, Berzins J, Nagykalnai T, Biganzoli L, Aloe A, Astier L, Munier S. Doxorubicin and paclitaxel versus fluorouracil, doxorubicin and cyclophosphamide as first-line therapy for women with advanced breast cancer: long-term analysis of the previously published trial. Onkologie. 2009 Sep;32(8-9):468-72. Epub 2009 Jul 20. link to original article PubMed
- Namer M, Soler-Michel P, Turpin F, Chinet-Charrot P, de Gislain C, Pouillart P, Delozier T, Luporsi E, Etienne PL, Schraub S, Eymard JC, Serin D, Ganem G, Calais G, Maillart P, Colin P, Trillet-Lenoir V, Prevost G, Tigaud D, Clavère P, Marti P, Romieu G, Wendling JL. Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer. Eur J Cancer. 2001 Jun;37(9):1132-40. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- CALGB 9140: Parnes HL, Cirrincione C, Aisner J, Berry DA, Allen SL, Abrams J, Chuang E, Cooper MR, Perry MC, Duggan DB, Szatrowski TP, Henderson IC, Norton L; CALGB. Phase III study of cyclophosphamide, doxorubicin, and fluorouracil (CAF) plus leucovorin versus CAF for metastatic breast cancer: Cancer and Leukemia Group B 9140. J Clin Oncol. 2003 May 1;21(9):1819-24. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Bontenbal M, Creemers GJ, Braun HJ, de Boer AC, Janssen JT, Leys RB, Ruit JB, Goey SH, van der Velden PC, Kerkhofs LG, Schothorst KL, Schmitz PI, Bokma HJ, Verweij J, Seynaeve C; Dutch Community Setting Trial for the Clinical Trial Group. Phase II to III study comparing doxorubicin and docetaxel with fluorouracil, doxorubicin, and cyclophosphamide as first-line chemotherapy in patients with metastatic breast cancer: results of a Dutch Community Setting Trial for the Clinical Trial Group of the Comprehensive Cancer Centre. J Clin Oncol. 2005 Oct 1;23(28):7081-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article dosing details in manuscript have been reviewed by our editors 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
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for up to 8 cycles
Subsequent treatment
- RIBBON-1, SD or better: Bevacizumab maintenance
References
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article dosing details in manuscript have been reviewed by our editors 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 | Not reported | 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 |
Note: Bonneterre & Hurteloup 1991 allowed a total cumulative epirubicin dose of 825 mg/m2. Focan et al. 1993 allowed a total cumulative epirubicin dose of 1000 mg/m2.
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for varying durations: 6 or more cycles (Namer et al. 2001); 8 cycles (HEPI 010); 12 cycles (GER-AIO-01/92); 16 cycles (Bonneterre & Hurteloup 1991); 20 cycles (Focan et al. 1993)
Regimen variant #2, 500/60/500
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Blomqvist et al. 1993 | 1987-1991 | Phase 3 (C) | FEC; weekly | Superior OS |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
28-day cycles
Regimen variant #3, 500/75/500 ("FEC 75")
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bonneterre & Hurteloup 1991 | Not reported | 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
- Fluorouracil (5-FU) 500 mg/m2 IV over 60 minutes once on day 1
- Epirubicin (Ellence) 75 mg/m2 IV over 10 minutes once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV over 30 minutes once on day 1
21-day cycle for varying durations: 6 or more cycles (Capotorto et al. 2003); 8 cycles (Bonneterre et al. 2004, Pacini et al. 2000); 11 cycles (Bonneterre & Hurteloup 1991)
Regimen variant #4, 500/90/500
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Zielinksi et al. 2005 (CECOG BM1) | 1999-2002 | Phase 3 (C) | GET | Did not meet primary endpoint of TTP |
Robert et al. 2011 (RIBBON-1) | 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
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for up to 8 cycles
Regimen variant #5, 500/100/500 ("FEC 100")
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufman et al. 1997 (HEPI 010) | 1989-1992 | Phase 3 (E-esc) | FEC; FEC 50 | 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
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 8 cycles
Regimen variant #6, 500/100/500, split epirubicin ("FEC 100")
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Focan et al. 1993 | 1985-1990 | Phase 3 (E-esc) | FEC; FEC 50 | Seems to have superior TTP |
Note: Focan et al. 1993 allowed a total cumulative epirubicin dose of 1000 mg/m2.
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 50 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 10 cycles
Regimen variant #7, 600/60/600 ("CEF21")
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Conte et al. 1987 | 1983-1985 | Randomized (C) | DES-CEF | Did not meet primary endpoint of ORR |
Conte et al. 1996 | 1985-1990 | Phase 3 (C) | DES-CEF | Did not meet primary endpoint of ORR |
Del Mastro et al. 2001 | 1994-1997 | Phase 3 (C) | HD-CEF14 | Did not meet primary endpoint of ORR |
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle of varying durations: 8 to 12 cycles (Del Mastro et al. 2001); 10 cycles (Conte et al. 1996); 11 cycles (Conte et al. 1987)
Regimen variant #8, 1000/50/500 until max anthracycline
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Ambrosini et al. 1988 | 1983-1985 | Phase 3 (E-switch-ic) | FAC | Did not meet primary endpoint | Less toxic |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Epirubicin (Ellence) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for up to 14 cycles (maximum of 700 mg/m2 epirubicin)
Regimen variant #9, 1000/60/1400
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Esteban et al. 1999 | 1987-1993 | Phase 3 (C) | CNF | Seems to have superior OS |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Epirubicin (Ellence) 30 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
28-day cycles
Regimen variant #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
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Epirubicin (Ellence) 50 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 400 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 to 9 cycles
References
- Conte PF, Pronzato P, Rubagotti A, Alama A, Amadori D, Demicheli R, Gardin G, Gentilini P, Jacomuzzi A, Lionetto R, Monzeglio C, Nicolin A, Rosso R, Sismondi P, Sussio M, Santi L. Conventional versus cytokinetic polychemotherapy with estrogenic recruitment in metastatic breast cancer: results of a randomized cooperative trial. J Clin Oncol. 1987 Mar;5(3):339-47. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Ambrosini G, Balli M, Garusi G, Demicheli R, Jirillo A, Bonciarelli G, Bruscagnin G, Fila G, Bumma C, Lacroix F, Buzzi F, Di Costanzo F, Padalino D, Brugia M, Calabresi F, Natali M, Cartei G, Chiesa G, Blasina B, Ciambellotti E, Moro G, D'Aquino S, Altavilla G, Adamo V, De Maria D, Falchi AM, Bertoncelli P, Farris A, Fiorentino M, Fornasiero A, Fosser V, Daniele O, Foggi CM, Speranza GB, Sartori S, Camilluzzi E, Gallo L, Poggio R, Secondo V, Gambi A, Grignani F, Capodicasa E, Lopez M, Papaldo P, Di Lauro L, Vici P, Marenco G, Folco U, Bonanni F, Marsilio P, Palazzotto G, Di Carlo A, Cusimano MP, Pastorino G, Puccetti C, Giusto M, Rausa L, Gebbia N, Palmeri S, D'Alessandro N, Saccani F, Becchi G, Schieppati G, Spinelli I, Tagliagambe A, Tonato M, Minotti V, Ardia A, Viaro D, De Micheli P, Zingali G, Sacchetti G, Intini C; Italian Multicentre Breast Study with Epirubicin. Phase III randomized study of fluorouracil, epirubicin, and cyclophosphamide v fluorouracil, doxorubicin, and cyclophosphamide in advanced breast cancer: an Italian multicentre trial. J Clin Oncol. 1988 Jun;6(6):976-82. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Bonneterre J, Hurteloup P; French Epirubicin Study Group. A prospective randomized trial comparing epirubicin monochemotherapy to two fluorouracil, cyclophosphamide, and epirubicin regimens differing in epirubicin dose in advanced breast cancer patients. J Clin Oncol. 1991 Feb;9(2):305-12. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Blomqvist C, Elomaa I, Rissanen P, Hietanen P, Nevasaari K, Helle L. Influence of treatment schedule on toxicity and efficacy of cyclophosphamide, epirubicin, and fluorouracil in metastatic breast cancer: a randomized trial comparing weekly and every-4-week administration. J Clin Oncol. 1993 Mar;11(3):467-73. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Focan C, Andrien JM, Closon MT, Dicato M, Driesschaert P, Focan-Henrard D, Lemaire M, Lobelle JP, Longree L, Ries F. Dose-response relationship of epirubicin-based first-line chemotherapy for advanced breast cancer: a prospective randomized trial. J Clin Oncol. 1993 Jul;11(7):1253-63. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Conte PF, Baldini E, Gardin G, Pronzato P, Amadori D, Carnino F, Monzeglio C, Gentilini P, Gallotti P, DeMicheli R, Venturini M, Rubagotti A, Rosso R; GONO. Chemotherapy with or without estrogenic recruitment in metastatic breast cancer: a randomized trial of the Gruppo Oncologico Nord Ovest (GONO). Ann Oncol. 1996 Jul;7(5):487-90. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- HEPI 010: Brufman G, Colajori E, Ghilezan N, Lassus M, Martoni A, Perevodchikova N, Tosello C, Viaro D, Zielinski C; Epirubicin High Dose (HEPI 010) Study Group. Doubling epirubicin dose intensity (100 mg/m2 versus 50 mg/m2) in the FEC regimen significantly increases response rates: an international randomised phase III study in metastatic breast cancer. Ann Oncol. 1997 Feb;8(2):155-62. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Esteban E, Lacave AJ, Fernández JL, Corral N, Buesa JM, Estrada E, Palacio I, Vieitez JM, Muñiz I, Alvarez E. Phase III trial of cyclophosphamide, epirubicin, fluorouracil (CEF) versus cyclophosphamide, mitoxantrone, fluorouracil (CNF) in women with metastatic breast cancer. Breast Cancer Res Treat. 1999 Nov;58(2):141-50. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Pacini P, Rinaldini M, Algeri R, Guarneri A, Tucci E, Barsanti G, Neri B, Bastiani P, Marzano S, Fallai C. FEC (5-fluorouracil, epidoxorubicin and cyclophosphamide) versus EM (epidoxorubicin and mitomycin-C) with or without lonidamine as first-line treatment for advanced breast cancer, a multicentric randomised study: final results. Eur J Cancer. 2000 May;36(8):966-75. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- HEPI 013: Ackland SP, Anton A, Breitbach GP, Colajori E, Tursi JM, Delfino C, Efremidis A, Ezzat A, Fittipaldo A, Kolaric K, Lopez M, Viaro D; HEPI 013 study group. Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study. J Clin Oncol. 2001 Feb 15;19(4):943-53. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Del Mastro L, Venturini M, Lionetto R, Carnino F, Guarneri D, Gallo L, Contu A, Pronzato P, Vesentini L, Bergaglio M, Comis S, Rosso R; GONO; MIG. Accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) compared with standard CEF in metastatic breast cancer patients: results of a multicenter, randomized phase III study of the Italian Gruppo Oncologico Nord-Ouest-Mammella Inter Gruppo Group. J Clin Oncol. 2001 Apr 15;19(8):2213-21. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Namer M, Soler-Michel P, Turpin F, Chinet-Charrot P, de Gislain C, Pouillart P, Delozier T, Luporsi E, Etienne PL, Schraub S, Eymard JC, Serin D, Ganem G, Calais G, Maillart P, Colin P, Trillet-Lenoir V, Prevost G, Tigaud D, Clavère P, Marti P, Romieu G, Wendling JL. Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer. Eur J Cancer. 2001 Jun;37(9):1132-40. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- GER-AIO-01/92: Heidemann E, Stoeger H, Souchon R, Hirschmann WD, Bodenstein H, Oberhoff C, Fischer JT, Schulze M, Clemens M, Andreesen R, Mahlke M, König M, Scharl A, Fehnle K, Kaufmann M. Is first-line single-agent mitoxantrone in the treatment of high-risk metastatic breast cancer patients as effective as combination chemotherapy? No difference in survival but higher quality of life were found in a multicenter randomized trial. Ann Oncol. 2002 Nov;13(11):1717-29. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00002544
- Capotorto AM, Pavesi L, Pedrazzoli P, Da Prada GA, Zamagni C, Massidda B, Farris A, Martoni A, Lelli G, Robustelli della Cuna G. Randomized, controlled, multicenter phase III trial of standard-dose fluorouracil-epirubicin-cyclophosphamide (FEC), compared with time-intensive FEC (FEC-G) and mitoxantrone-methotrexate-mitomycin C (MMM-G) in metastatic breast carcinoma. J Chemother. 2003 Apr;15(2):184-91. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Bonneterre J, Dieras V, Tubiana-Hulin M, Bougnoux P, Bonneterre ME, Delozier T, Mayer F, Culine S, Dohoulou N, Bendahmane B. Phase II multicentre randomised study of docetaxel plus epirubicin vs 5-fluorouracil plus epirubicin and cyclophosphamide in metastatic breast cancer. Br J Cancer. 2004 Oct 18;91(8):1466-71. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed
- CECOG BM1: Zielinski C, Beslija S, Mrsic-Krmpotic Z, Welnicka-Jaskiewicz M, Wiltschke C, Kahan Z, Grgic M, Tzekova V, Inbar M, Cervek J, Chernozemsky I, Szanto J, Spanik S, Wagnerova M, Ghilezan N, Pawlega J, Vrbanec D, Khamtsov D, Soldatenkova V, Brodowicz T. Gemcitabine, epirubicin, and paclitaxel versus fluorouracil, epirubicin, and cyclophosphamide as first-line chemotherapy in metastatic breast cancer: a Central European Cooperative Oncology Group International, multicenter, prospective, randomized phase III trial. J Clin Oncol. 2005 Mar 1;23(7):1401-8. link to original article dosing details in abstract have been reviewed by our editors PubMed
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article dosing details in manuscript have been reviewed by our editors 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
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 90 to 100 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for up to 8 cycles
Subsequent treatment
- RIBBON-1, SD or better: Bevacizumab maintenance
References
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00262067
Gemcitabine monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Carmichael et al. 1995 | Not reported | Phase 2, less than 20 pts in this subgroup |
Chemotherapy
- Gemcitabine (Gemzar) 800 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
28-day cycles
References
- Carmichael J, Possinger K, Philip P, Beykirch M, Kerr H, Walling J, Harris AL. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol. 1995 Nov;13(11):2731-6. link to original article dosing details in manuscript have been reviewed by our editors PubMed
Gemcitabine & Paclitaxel
GT: Gemcitabine & Taxol (Paclitaxel)
PG: Paclitaxel & Gemcitabine
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Albain et al. 2008 | 1999-2002 | Phase 3 (E-RT-esc) | Paclitaxel | Seems to have 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 |
Park et al. 2013 (KCSG-BR07-02) | 2007-2010 | Non-randomized part of phase 3 RCT |
Chemotherapy
- Gemcitabine (Gemzar) 1250 mg/m2 IV over 30 to 60 minutes once per day on days 1 & 8, given second on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1, given first
21-day cycle for varying durations: 6 cycles (KCSG-BR07-02); 6 to 10 cycles (B9E-IT-S376); indefintely (Albain et al. 2008)
Subsequent treatment
- KCSG-BR07-02: PG maintenance versus Observation
References
- Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, Rolski J, Melemed AS, Reyes-Vidal JM, Sekhon JS, Simms L, O'Shaughnessy J. Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008 Aug 20;26(24):3950-7. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- B9E-IT-S376: Del Mastro L, Fabi A, Mansutti M, De Laurentiis M, Durando A, Merlo DF, Bruzzi P, La Torre I, Ceccarelli M, Kazeem G, Marchi P, Boy D, Venturini M, De Placido S, Cognetti F. Randomised phase 3 open-label trial of first-line treatment with gemcitabine in association with docetaxel or paclitaxel in women with metastatic breast cancer: a comparison of different schedules and treatments. BMC Cancer. 2013 Mar 28;13:164. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00236899
- KCSG-BR07-02: Park YH, Jung KH, Im SA, Sohn JH, Ro J, Ahn JH, Kim SB, Nam BH, Oh DY, Han SW, Lee S, Park IH, Lee KS, Kim JH, Kang SY, Lee MH, Park HS, Ahn JS, Im YH. Phase III, multicenter, randomized trial of maintenance chemotherapy versus observation in patients with metastatic breast cancer after achieving disease control with six cycles of gemcitabine plus paclitaxel as first-line chemotherapy: KCSG-BR07-02. J Clin Oncol. 2013 May 10;31(14):1732-9. Epub 2013 Apr 8. link to original article dosing details in manuscript have been reviewed by our editors 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
- Non-pegylated liposomal doxorubicin (Myocet) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycles
Regimen variant #2, 75/600
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Chan et al. 2004 | 1996-05 to 1997-08 | Phase 3 (E-switch-ic) | EC | Superior TTP Median TTP: 7.7 vs 5.6 mo (HR 0.66, 95% CI 0.45-0.94) |
Chemotherapy
- Non-pegylated liposomal doxorubicin (Myocet) 75 mg/m2 IV over 60 minutes once on day 1, given second
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV over 15 minutes once on day 1, given first
21-day cycle for up to 8 cycles
References
- Chan S, Davidson N, Juozaityte E, Erdkamp F, Pluzanska A, Azarnia N, Lee LW. Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer. Ann Oncol. 2004 Oct;15(10):1527-34. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Lorusso V, Giotta F, Bordonaro R, Maiello E, Del Prete S, Gebbia V, Filippelli G, Pisconti S, Cinieri S, Romito S, Riccardi F, Forcignanò R, Ciccarese M, Petrucelli L, Saracino V, Lupo LI, Gambino A, Leo S, Colucci G; Gruppo Oncologico Dell'Italia Meridionale. Non-pegylated liposome-encapsulated doxorubicin citrate plus cyclophosphamide or vinorelbine in metastatic breast cancer not previously treated with chemotherapy:a multicenter phase III study. Int J Oncol. 2014 Nov;45(5):2137-42. Epub 2014 Aug 18. link to original article dosing details in abstract have been reviewed by our editors PubMed
Paclitaxel monotherapy, weekly
Regimen variant #1, 80 mg/m2 weekly
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Perez et al. 2001 | Not reported | Phase 2 | ||
Seidman et al. 2008 (CALGB 9840) | 1998 to not reported | 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
- Paclitaxel (Taxol) 80 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22
28-day cycles
Regimen variant #2, 80 mg/m2 3 weeks out of 4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Takashima et al. 2015 (SELECT BC) | 2006-2010 | Phase 3 (C) | S-1 | Seems to have non-inferior OS | 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.
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 |
Regimen variant #4, 100 mg/m2 weekly
Study | Dates of enrollment | Evidence |
---|---|---|
Seidman et al. 1998 | Not reported | Phase 2, less than 20 pts in this subgroup |
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.
References
- Seidman AD, Hudis CA, Albanell J, Tong W, Tepler I, Currie V, Moynahan ME, Theodoulou M, Gollub M, Baselga J, Norton L. Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol. 1998 Oct;16(10):3353-61. Erratum in: J Clin Oncol. 2006 May 10;24(14):2220. Albanel, J [corrected to Albanell, J ]. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Perez EA, Vogel CL, Irwin DH, Kirshner JJ, Patel R. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2001 Nov 15;19(22):4216-23. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- ECOG E2100: Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00028990
- 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
- Fountzilas G, Dafni U, Dimopoulos MA, Koutras A, Skarlos D, Papakostas P, Gogas H, Bafaloukos D, Kalogera-Fountzila A, Samantas E, Briasoulis E, Pectasides D, Maniadakis N, Matsiakou F, Aravantinos G, Papadimitriou C, Karina M, Christodoulou C, Kosmidis P, Kalofonos HP; Hellenic Cooperative Oncology Group. A randomized phase III study comparing three anthracycline-free taxane-based regimens, as first line chemotherapy, in metastatic breast cancer: a Hellenic Cooperative Oncology Group study. Breast Cancer Res Treat. 2009 May;115(1):87-99. Epub 2008 May 16. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- SELECT BC: Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T, Hozumi Y, Tsurutani J, Imoto S, Watanabe T, Sagara Y, Nishimura R, Shimozuma K, Ohashi Y; SELECT BC Study Group. Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2016 Jan;17(1):90-8. Epub 2015 Nov 27. link to original article dosing details in manuscript have been reviewed by our editors PubMed UMIN C000000416
- HRQoL analysis: Shiroiwa T, Fukuda T, Shimozuma K, Mouri M, Hagiwara Y, Doihara H, Akabane H, Kashiwaba M, Watanabe T, Ohashi Y, Mukai H. Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial. Qual Life Res. 2017 Feb;26(2):445-453. Epub 2016 Aug 12. link to original article link to PMC article PubMed
- MERiDiAN: Miles D, Cameron D, Bondarenko I, Manzyuk L, Alcedo JC, Lopez RI, Im SA, Canon JL, Shparyk Y, Yardley DA, Masuda N, Ro J, Denduluri N, Hubeaux S, Quah C, Bais C, O'Shaughnessy J. Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation. Eur J Cancer. 2017 Jan;70:146-155. Epub 2016 Nov 4. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01663727
- Update: Miles D, Cameron D, Hilton M, Garcia J, O'Shaughnessy J. Overall survival in MERiDiAN, a double-blind placebo-controlled randomised phase III trial evaluating first-line bevacizumab plus paclitaxel for HER2-negative metastatic breast cancer. Eur J Cancer. 2018 Feb;90:153-155. Epub 2017 Nov 23. link to original article PubMed
- BELLE-4: Martín M, Chan A, Dirix L, O'Shaughnessy J, Hegg R, Manikhas A, Shtivelband M, Krivorotko P, Batista López N, Campone M, Ruiz Borrego M, Khan QJ, Beck JT, Ramos Vázquez M, Urban P, Goteti S, Di Tomaso E, Massacesi C, Delaloge S. A randomized adaptive phase II/III study of buparlisib, a pan-class I PI3K inhibitor, combined with paclitaxel for the treatment of HER2- advanced breast cancer (BELLE-4). Ann Oncol. 2017 Feb 1;28(2):313-320. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01572727
- A3105301: Fujiwara Y, Mukai H, Saeki T, Ro J, Lin YC, Nagai SE, Lee KS, Watanabe J, Ohtani S, Kim SB, Kuroi K, Tsugawa K, Tokuda Y, Iwata H, Park YH, Yang Y, Nambu Y. A multi-national, randomised, open-label, parallel, phase III non-inferiority study comparing NK105 and paclitaxel in metastatic or recurrent breast cancer patients. Br J Cancer. 2019 Mar;120(5):475-480. Epub 2019 Feb 12. link to original article dosing details in abstract have been reviewed by our editors link to PMC article 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 | Not reported | 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 to not reported | 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.
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
- Paclitaxel (Taxol) 175 mg/m2 IV continuous infusion over 24 hours, started on day 1
21-day cycles
Regimen variant #3, 175 mg/m2 q4wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Takashima et al. 2015 (SELECT BC) | 2006-2010 | Phase 3 (C) | S-1 | Seems to have non-inferior OS | Inferior EQ-5D score |
Regimen variant #4, 200 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bishop et al. 1999 | 1993 to not reported | Phase 3 (E-de-esc) | CMFP | Seems to have superior OS |
Paridaens et al. 2000 (EORTC 10923) | 1993-1996 | Phase 3 (E-switch-ic) | Doxorubicin | Inferior PFS |
Chemotherapy
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
21-day cycle for 7 (EORTC 10923) or 8 (Bishop et al. 1999) cycles
Regimen variant #5, 250 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Holmes et al. 1991 | 1990 | Phase 2 | ||
Smith et al. 1996 (NSABP B-26) | 1994-1996 | Phase 3 (C) | Paclitaxel; 250 mg/m2 over 3 hours | Did not meet primary endpoint of ORR |
Note: Holmes et al. 1991 is of historic interest, being the first phase II trial of a taxane in breast cancer.
Chemotherapy
- Paclitaxel (Taxol) 250 mg/m2 IV continuous infusion over 24 hours, started on day 1
21-day cycles
References
- Holmes FA, Walters RS, Theriault RL, Forman AD, Newton LK, Raber MN, Buzdar AU, Frye DK, Hortobagyi GN. Phase II trial of taxol, an active drug in the treatment of metastatic breast cancer. J Natl Cancer Inst. 1991 Dec 18;83(24):1797-805. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Seidman AD, Tiersten A, Hudis C, Gollub M, Barrett S, Yao TJ, Lepore J, Gilewski T, Currie V, Crown J, Hakes T, Baselga J, Sklarin N, Moynihan ME, Tong W, Egorin M, Kearns C, Spriggs D, Norton L. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2575-81. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Bishop JF, Dewar J, Toner GC, Smith J, Tattersall MH, Olver IN, Ackland S, Kennedy I, Goldstein D, Gurney H, Walpole E, Levi J, Stephenson J, Canetta R. Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2355-64. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- NSABP B-26: Smith RE, Brown AM, Mamounas EP, Anderson SJ, Lembersky BC, Atkins JH, Shibata HR, Baez L, DeFusco PA, Davila E, Tipping SJ, Bearden JD, Thirlwell MP. Randomized trial of 3-hour versus 24-hour infusion of high-dose paclitaxel in patients with metastatic or locally advanced breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-26. J Clin Oncol. 1999 Nov;17(11):3403-11. link to original article dosing details in abstract have been reviewed by our editors PubMed
- EORTC 10923: Paridaens R, Biganzoli L, Bruning P, Klijn JG, Gamucci T, Houston S, Coleman R, Schachter J, Van Vreckem A, Sylvester R, Awada A, Wildiers J, Piccart M. Paclitaxel versus doxorubicin as first-line single-agent chemotherapy for metastatic breast cancer: a European Organisation for Research and Treatment of Cancer Randomized Study with cross-over. J Clin Oncol. 2000 Feb;18(4):724-33. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- HRQoL analysis: Kramer JA, Curran D, Piccart M, de Haes JC, Bruning PF, Klijn JG, Bontenbal M, van Pottelsberghe C, Groenvold M, Paridaens R. Randomised trial of paclitaxel versus doxorubicin as first-line chemotherapy for advanced breast cancer: quality of life evaluation using the EORTC QLQ-C30 and the Rotterdam symptom checklist. Eur J Cancer. 2000 Aug;36(12):1488-97. link to original article PubMed
- ECOG E1193: Sledge GW, Neuberg D, Bernardo P, Ingle JN, Martino S, Rowinsky EK, Wood WC. Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193). J Clin Oncol. 2003 Feb 15;21(4):588-92. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- CALGB 9342: Winer EP, Berry DA, Woolf S, Duggan D, Kornblith A, Harris LN, Michaelson RA, Kirshner JA, Fleming GF, Perry MC, Graham ML, Sharp SA, Keresztes R, Henderson IC, Hudis C, Muss H, Norton L. Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: Cancer and Leukemia Group B trial 9342. J Clin Oncol. 2004 Jun 1;22(11):2061-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- CA012-0: Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00046527
- CALGB 9840: Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. link to original article PubMed NCT00003440
- Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, Rolski J, Melemed AS, Reyes-Vidal JM, Sekhon JS, Simms L, O'Shaughnessy J. Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008 Aug 20;26(24):3950-7. link to original article PubMed
- EGF30001: Di Leo A, Gomez HL, Aziz Z, Zvirbule Z, Bines J, Arbushites MC, Guerrera SF, Koehler M, Oliva C, Stein SH, Williams LS, Dering J, Finn RS, Press MF. Phase III, double-blind, randomized study comparing lapatinib plus paclitaxel with placebo plus paclitaxel as first-line treatment for metastatic breast cancer. J Clin Oncol. 2008 Dec 1;26(34):5544-52. Epub 2008 Oct 27. Erratum in: J Clin Oncol. 2009 Apr 10;27(11):1923. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00075270
- SELECT BC: Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T, Hozumi Y, Tsurutani J, Imoto S, Watanabe T, Sagara Y, Nishimura R, Shimozuma K, Ohashi Y; SELECT BC Study Group. Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2016 Jan;17(1):90-8. Epub 2015 Nov 27. link to original article dosing details in manuscript have been reviewed by our editors PubMed UMIN C000000416
- HRQoL analysis: Shiroiwa T, Fukuda T, Shimozuma K, Mouri M, Hagiwara Y, Doihara H, Akabane H, Kashiwaba M, Watanabe T, Ohashi Y, Mukai H. Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial. Qual Life Res. 2017 Feb;26(2):445-453. Epub 2016 Aug 12. link to original article link to PMC article PubMed
- GPMBC301: Park IH, Sohn JH, Kim SB, Lee KS, Chung JS, Lee SH, Kim TY, Jung KH, Cho EK, Kim YS, Song HS, Seo JH, Ryoo HM, Lee SA, Yoon SY, Kim CS, Kim YT, Kim SY, Jin MR, Ro J. An Open-Label, Randomized, Parallel, Phase III Trial Evaluating the Efficacy and Safety of Polymeric Micelle-Formulated Paclitaxel Compared to Conventional Cremophor EL-Based Paclitaxel for Recurrent or Metastatic HER2-Negative Breast Cancer. Cancer Res Treat. 2017 Jul;49(3):569-577. Epub 2016 Sep 12. link to original article link to PMC article dosing details in abstract have been reviewed by our editors 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
- Paclitaxel (Taxol) 90 mg/m2 IV over 60 minutes once per day on days 1, 8, 15
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
References
- ECOG E2100: Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00028990
- SUN 1094: Robert NJ, Saleh MN, Paul D, Generali D, Gressot L, Copur MS, Brufsky AM, Minton SE, Giguere JK, Smith JW 2nd, Richards PD, Gernhardt D, Huang X, Liau KF, Kern KA, Davis J. Sunitinib plus paclitaxel versus bevacizumab plus paclitaxel for first-line treatment of patients with advanced breast cancer: a phase III, randomized, open-label trial. Clin Breast Cancer. 2011 Apr;11(2):82-92. Epub 2011 Apr 11. Erratum in: Clin Breast Cancer. 2011 Aug;11(4):273. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00373256
- TURANDOT: Lang I, Brodowicz T, Ryvo L, Kahan Z, Greil R, Beslija S, Stemmer SM, Kaufman B, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Messinger D, Zielinski C; Central European Cooperative Oncology Group. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer: interim efficacy results of the randomised, open-label, non-inferiority, phase 3 TURANDOT trial. Lancet Oncol. 2013 Feb;14(2):125-33. Epub 2013 Jan 10. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00600340
- Update: Zielinski C, Láng I, Inbar M, Kahán Z, Greil R, Beslija S, Stemmer SM, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Petruzelka L, Eniu A, Nisenbaum B, Dank M, Anghel R, Messinger D, Brodowicz T; TURANDOT investigators. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1230-9. Epub 2016 Aug 5. link to original article dosing details in abstract have been reviewed by our editors PubMed
- CALGB 40502/NCCTG N063H: Rugo HS, Barry WT, Moreno-Aspitia A, Lyss AP, Cirrincione C, Leung E, Mayer EL, Naughton M, Toppmeyer D, Carey LA, Perez EA, Hudis C, Winer EP. Randomized phase III trial of paclitaxel once per week compared with nanoparticle albumin-bound nab-paclitaxel once per week or ixabepilone with bevacizumab as first-line chemotherapy for locally recurrent or metastatic breast cancer: CALGB 40502/NCCTG N063H (Alliance). J Clin Oncol. 2015 Jul 20;33(21):2361-9. Epub 2015 Jun 8. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00785291
- SAKK 24/09: Rochlitz C, Bigler M, von Moos R, Bernhard J, Matter-Walstra K, Wicki A, Zaman K, Anchisi S, Küng M, Na KJ, Bärtschi D, Borner M, Rordorf T, Rauch D, Müller A, Ruhstaller T, Vetter M, Trojan A, Hasler-Strub U, Cathomas R, Winterhalder R; Swiss Group for Clinical Cancer Research (SAKK). SAKK 24/09: safety and tolerability of bevacizumab plus paclitaxel vs bevacizumab plus metronomic cyclophosphamide and capecitabine as first-line therapy in patients with HER2-negative advanced stage breast cancer - a multicenter, randomized phase III trial. BMC Cancer. 2016 Oct 10;16(1):780. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT01131195
- MERiDiAN: Miles D, Cameron D, Bondarenko I, Manzyuk L, Alcedo JC, Lopez RI, Im SA, Canon JL, Shparyk Y, Yardley DA, Masuda N, Ro J, Denduluri N, Hubeaux S, Quah C, Bais C, O'Shaughnessy J. Bevacizumab plus paclitaxel versus placebo plus paclitaxel as first-line therapy for HER2-negative metastatic breast cancer (MERiDiAN): A double-blind placebo-controlled randomised phase III trial with prospective biomarker evaluation. Eur J Cancer. 2017 Jan;70:146-155. Epub 2016 Nov 4. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01663727
- Update: Miles D, Cameron D, Hilton M, Garcia J, O'Shaughnessy J. Overall survival in MERiDiAN, a double-blind placebo-controlled randomised phase III trial evaluating first-line bevacizumab plus paclitaxel for HER2-negative metastatic breast cancer. Eur J Cancer. 2018 Feb;90:153-155. Epub 2017 Nov 23. link to original article PubMed
Paclitaxel & Vinorelbine
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Romero Acuña et al. 1999 | 1995-1997 | Phase 2 |
Chemotherapy
- Paclitaxel (Taxol) 135 mg/m2 IV over 3 hours once on day 1, given second
- Vinorelbine (Navelbine) 30 mg/m2 IV over 20 minutes once per day on days 1 & 8
28-day cycles
References
- Romero Acuña L, Langhi M, Pérez J, Romero Acuña J, Machiavelli M, Lacava J, Vallejo C, Romero A, Fasce H, Ortiz E, Grasso S, Amato S, Rodríguez R, Barbieri M, Leone B. Vinorelbine and paclitaxel as first-line chemotherapy in metastatic breast cancer. J Clin Oncol. 1999 Jan;17(1):74-81. link to original article dosing details in abstract have been reviewed by our editors 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
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Regimen variant #2, 150 mg/m2 weekly, 3 weeks out of 4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gradishar et al. 2009 | 2005-2006 | Randomized Phase 2 (E-switch-ic) | 1. Docetaxel 2. nab-Paclitaxel; weekly, 100 mg/m2 3. nab-Paclitaxel; q3wk |
Did not meet primary endpoint of ORR |
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 150 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Regimen variant #3, 260 mg/m2 q3wk
Study | 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
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m2 IV over 30 minutes once on day 1
Supportive therapy
- CA012-0: No corticosteroid or antihistamine premedication
21-day cycles
Regimen variant #4, 300 mg/m2 q3wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gradishar et al. 2009 | 2005-2006 | Randomized Phase 2 (E-switch-ic) | 1. Docetaxel 2. nab-Paclitaxel; weekly, 100 mg/m2 3. nab-Paclitaxel; weekly, 150 mg/m2 |
Did not meet primary endpoint of ORR |
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 300 mg/m2 IV over 30 minutes once on day 1
21-day cycles
References
- CA012-0: Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00046527
- Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009 Aug 1;27(22):3611-9. Epub 2009 May 26. Erratum in: J Clin Oncol. 2011 Jul 1;29(19):2739. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article dosing details in manuscript have been reviewed by our editors 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
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 150 mg/m2 IV once per day on days 1, 8, 15
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
Regimen variant #2, 260 mg/m2 q3wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robert et al. 2011 (RIBBON-1) | 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
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00262067
- CALGB 40502/NCCTG N063H: Rugo HS, Barry WT, Moreno-Aspitia A, Lyss AP, Cirrincione C, Leung E, Mayer EL, Naughton M, Toppmeyer D, Carey LA, Perez EA, Hudis C, Winer EP. Randomized phase III trial of paclitaxel once per week compared with nanoparticle albumin-bound nab-paclitaxel once per week or ixabepilone with bevacizumab as first-line chemotherapy for locally recurrent or metastatic breast cancer: CALGB 40502/NCCTG N063H (Alliance). J Clin Oncol. 2015 Jul 20;33(21):2361-9. Epub 2015 Jun 8. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors 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
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
Supportive therapy
- Dexamethasone (Decadron) 4 mg PO twice per day on days -1 to 2 (3 days)
- Folic acid (Folate) 350 to 1000 mcg PO once per day, to start 5 to 7 days prior to pemetrexed, to continue throughout therapy
- Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, the first dose given before the study's pretreatment biopsy, to continue throughout therapy
21-day cycle for up to 3 cycles
Regimen variant #2, 600 mg/m2
Study | Dates of enrollment | Evidence |
---|---|---|
Robert et al. 2011 | 2005-2006 | Phase 2 |
Chemotherapy
- Pemetrexed (Alimta) 600 mg/m2 IV once on day 1
Supportive therapy
- Dexamethasone (Decadron) 4 mg PO twice per day on days -1 to 2 (3 days)
- Folic acid (Folate) 350 to 1000 mcg PO once per day, to start at least 5 days prior to pemetrexed, to continue throughout therapy, and until 3 weeks after the last dose of pemetrexed
- Cyanocobalamin (Vitamin B12) 1000 mcg IM every 8 to 10 weeks, the first dose given at least 1 week prior to pemetrexed, to continue throughout therapy, and until 3 weeks after the last dose of pemetrexed
14-day cycles
References
- Gomez HL, Santillana SL, Vallejos CS, Velarde R, Sanchez J, Wang X, Bauer NL, Hockett RD, Chen VJ, Niyikiza C, Hanauske AR. A phase II trial of pemetrexed in advanced breast cancer: clinical response and association with molecular target expression. Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):832-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Robert NJ, Conkling PR, O'Rourke MA, Kuefler PR, McIntyre KJ, Zhan F, Asmar L, Wang Y, Shonukan OO, O'Shaughnessy JA. Results of a phase II study of pemetrexed as first-line chemotherapy in patients with advanced or metastatic breast cancer. Breast Cancer Res Treat. 2011 Feb;126(1):101-8. Epub 2010 Dec 25. link to original article dosing details in manuscript have been reviewed by our editors 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
- SELECT BC: Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T, Hozumi Y, Tsurutani J, Imoto S, Watanabe T, Sagara Y, Nishimura R, Shimozuma K, Ohashi Y; SELECT BC Study Group. Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2016 Jan;17(1):90-8. Epub 2015 Nov 27. link to original article dosing details in manuscript have been reviewed by our editors PubMed UMIN C000000416
- HRQoL analysis: Shiroiwa T, Fukuda T, Shimozuma K, Mouri M, Hagiwara Y, Doihara H, Akabane H, Kashiwaba M, Watanabe T, Ohashi Y, Mukai H. Long-term health status as measured by EQ-5D among patients with metastatic breast cancer: comparison of first-line oral S-1 and taxane therapies in the randomized phase III SELECT BC trial. Qual Life Res. 2017 Feb;26(2):445-453. Epub 2016 Aug 12. link to original article link to PMC article PubMed
- SELECT BC-CONFIRM: Mukai H, Uemura Y, Akabane H, Watanabe T, Park Y, Takahashi M, Sagara Y, Nishimura R, Takashima T, Fujisawa T, Hozumi Y, Kawahara T. Anthracycline-containing regimens or taxane versus S-1 as first-line chemotherapy for metastatic breast cancer. Br J Cancer. 2021 Oct;125(9):1217-1225. Epub 2021 Sep 3. link to original article dosing details in manuscript have been reviewed by our editors 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
- Capecitabine (Xeloda) 950 mg/m2 PO twice per day on days 1 to 14
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycles
Regimen variant #2, 2000/75, limited duration of docetaxel
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Wang et al. 2015 (ML25241) | 2010-2013 | Phase 3 (C) | NX | Inconclusive whether non-inferior PFS |
Note: only patients without progression proceeded to the capecitabine maintenance phase.
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
- Docetaxel (Taxotere) as follows:
- Cycles 1 to 6 up to 8: 75 mg/m2 IV once on day 1
21-day cycles
Regimen variant #3, 2000/75, indefinite
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Seidman et al. 2010 (B9E-MC-S273) | 2002-2008 | Phase 3 (E-switch-ic) | GD | Did not meet primary endpoint of TTP |
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycles
Subsequent treatment
- B9E-MC-S273, upon progression: second-line Gemcitabine
References
- HORG CT/02.09: Mavroudis D, Papakotoulas P, Ardavanis A, Syrigos K, Kakolyris S, Ziras N, Kouroussis C, Malamos N, Polyzos A, Christophyllakis C, Kentepozidis N, Georgoulias V; Hellenic Oncology Research Group. Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer. Ann Oncol. 2010 Jan;21(1):48-54. Epub 2009 Nov 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00429871
- B9E-MC-S273: Seidman AD, Brufsky A, Ansari RH, Hart LL, Stein RS, Schwartzberg LS, Stewart JF, Russell CA, Chen SC, Fein LE, De La Cruz Vargas JA, Kim SB, Cavalheiro J, Zhao L, Gill JF, Obasaju CK, Orlando M, Tai DF. Phase III trial of gemcitabine plus docetaxel versus capecitabine plus docetaxel with planned crossover to the alternate single agent in metastatic breast cancer. Ann Oncol. 2011 May;22(5):1094-101. Epub 2010 Nov 17. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00191438
- Pooled update: Seidman AD, Chan S, Wang J, Zhu C, Xu C, Xu B. A pooled analysis of gemcitabine plus docetaxel versus capecitabine plus docetaxel in metastatic breast cancer. Oncologist. 2014 May;19(5):443-52. Epub 2014 Apr 4. link to original article link to PMC article PubMed
- ML25241: Wang J, Xu B, Yuan P, Ma F, Li Q, Zhang P, Cai R, Fan Y, Luo Y, Li Q. Capecitabine combined with docetaxel versus vinorelbine followed by capecitabine maintenance medication for first-line treatment of patients with advanced breast cancer: phase 3 randomized trial. Cancer. 2015 Oct 1;121(19):3412-21. Epub 2015 Jun 19. link to original article dosing details in manuscript have been reviewed by our editors 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 |
Note: Epirubicin was discontinued once the cumulative dose exceeded 900 mg/m2 but before it exceeded 950 mg/m2, after a mid-protocol amendment.
Chemotherapy
- Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 8
- Epirubicin (Ellence) as follows (see note):
- Cycles 1 to 10: 90 mg/m2 IV once on day 1
21-day cycle for up to 18 cycles (1 year)
References
- SBG 9403: Ejlertsen B, Mouridsen HT, Langkjer ST, Andersen J, Sjöström J, Kjaer M; Scandinavian Breast Group. Phase III study of intravenous vinorelbine in combination with epirubicin versus epirubicin alone in patients with advanced breast cancer: a Scandinavian Breast Group Trial (SBG9403). J Clin Oncol. 2004 Jun 15;22(12):2313-20. link to original article dosing details in manuscript have been reviewed by our editors 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
- AVADO: First-line Docetaxel & Bev x 9
- RIBBON-1: First-line AC & Bev x 8 or EC & Bev x 8 or FAC & Bev x 8 or FEC & Bev x 8
- IMELDA: First-line Docetaxel & Bev x 3 to 6
References
- AVADO: Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010 Jul 10;28(20):3239-47. Epub 2010 May 24. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00333775
- 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 dosing details in manuscript have been reviewed by our editors PubMed NCT00262067
- IMELDA: Gligorov J, Doval D, Bines J, Alba E, Cortes P, Pierga JY, Gupta V, Costa R, Srock S, de Ducla S, Freudensprung U, Mustacchi G. Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1351-60. Epub 2014 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors 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
- First-line Docetaxel & Bev x 3 to 6
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- IMELDA: Gligorov J, Doval D, Bines J, Alba E, Cortes P, Pierga JY, Gupta V, Costa R, Srock S, de Ducla S, Freudensprung U, Mustacchi G. Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1351-60. Epub 2014 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors 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
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8, given second on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1, given first
21-day cycles
References
- KCSG-BR07-02: Park YH, Jung KH, Im SA, Sohn JH, Ro J, Ahn JH, Kim SB, Nam BH, Oh DY, Han SW, Lee S, Park IH, Lee KS, Kim JH, Kang SY, Lee MH, Park HS, Ahn JS, Im YH. Phase III, multicenter, randomized trial of maintenance chemotherapy versus observation in patients with metastatic breast cancer after achieving disease control with six cycles of gemcitabine plus paclitaxel as first-line chemotherapy: KCSG-BR07-02. J Clin Oncol. 2013 May 10;31(14):1732-9. Epub 2013 Apr 8. link to original article dosing details in manuscript have been reviewed by our editors 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 to not reported | 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
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
References
- SO14697: Blum JL, Jones SE, Buzdar AU, Mucci LoRusso P, Kuter I, Vogel C, Osterwalder B, Burger HU, Stoner Brown C, Griffin T. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol. 1999 Feb;17(2):485-93. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Reichardt P, Von Minckwitz G, Thuss-Patience PC, Jonat W, Kölbl H, Jänicke F, Kieback DG, Kuhn W, Schindler AE, Mohrmann S, Kaufmann M, Lück HJ. Multicenter phase II study of oral capecitabine (Xeloda) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy. Ann Oncol. 2003 Aug;14(8):1227-33. link to original article dosing details in abstract have been reviewed by our editors PubMed
- AVF2119g: Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005 Feb 1;23(4):792-9. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00109239
- CA163-046: Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. Epub 2007 Oct 29. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00080301
- Update: Hortobagyi GN, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Lerzo GL, Pivot XB, Hurtado de Mendoza F, Xu B, Vahdat LT, Peck RA, Mukhopadhyay P, Roché HH. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes. Breast Cancer Res Treat. 2010 Jul;122(2):409-18. Epub 2010 May 8. link to original article PubMed
- SUN 1107: Barrios CH, Liu MC, Lee SC, Vanlemmens L, Ferrero JM, Tabei T, Pivot X, Iwata H, Aogi K, Lugo-Quintana R, Harbeck N, Brickman MJ, Zhang K, Kern KA, Martin M. Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer. Breast Cancer Res Treat. 2010 May;121(1):121-31. Epub 2010 Mar 26. link to original article link to PMC article dosing details in abstract have been reviewed by our editors PubMed
- CA163-048: Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010 Jul 10;28(20):3256-63. Epub 2010 Jun 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT00082433
- HORG CT/02.11: Pallis AG, Boukovinas I, Ardavanis A, Varthalitis I, Malamos N, Georgoulias V, Mavroudis D; Hellenic Oncology Research Group. A multicenter randomized phase III trial of vinorelbine/gemcitabine doublet versus capecitabine monotherapy in anthracycline- and taxane-pretreated women with metastatic breast cancer. Ann Oncol. 2012 May;23(5):1164-9. Epub 2011 Sep 21. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00431106
- RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00281697
- A6181099: Crown JP, Diéras V, Staroslawska E, Yardley DA, Bachelot T, Davidson N, Wildiers H, Fasching PA, Capitain O, Ramos M, Greil R, Cognetti F, Fountzilas G, Blasinska-Morawiec M, Liedtke C, Kreienberg R, Miller WH Jr, Tassell V, Huang X, Paolini J, Kern KA, Romieu G. Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer. J Clin Oncol. 2013 Aug 10;31(23):2870-8. Epub 2013 Jul 15. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00435409
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01250379
- Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed
- E7389-G000-301: Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, Olivo MS, He Y, Dutcus CE, Cortes J. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015 Feb 20;33(6):594-601. Epub 2015 Jan 20. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00337103
- JO21095: Yamamoto D, Sato N, Rai Y, Yamamoto Y, Saito M, Iwata H, Masuda N, Oura S, Watanabe J, Hattori S, Matsuura Y, Kuroi K. Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. Breast Cancer Res Treat. 2017 Feb;161(3):473-482. Epub 2016 Dec 22. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- BG01-1323L: Zhang P, Sun T, Zhang Q, Yuan Z, Jiang Z, Wang XJ, Cui S, Teng Y, Hu XC, Yang J, Pan H, Tong Z, Li H, Yao Q, Wang Y, Yin Y, Sun P, Zheng H, Cheng J, Lu J, Zhang B, Geng C, Liu J, Peng R, Yan M, Zhang S, Huang J, Tang L, Qiu R, Xu B; BG01-1323L study group. Utidelone plus capecitabine versus capecitabine alone for heavily pretreated metastatic breast cancer refractory to anthracyclines and taxanes: a multicentre, open-label, superiority, phase 3, randomised controlled trial. Lancet Oncol. 2017 Mar;18(3):371-383. Epub 2017 Feb 11. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT02253459
- Update: Xu B, Sun T, Zhang Q, Zhang P, Yuan Z, Jiang Z, Wang X, Cui S, Teng Y, Hu XC, Yang J, Pan H, Tong Z, Li H, Yao Q, Wang Y, Yin Y, Sun P, Zheng H, Cheng J, Lu J, Zhang B, Geng C, Liu J, Shen K, Yu S, Li H, Tang L, Qiu R; study group of BG01-1323L. Efficacy of utidelone plus capecitabine versus capecitabine for heavily pretreated, anthracycline- and taxane-refractory metastatic breast cancer: final analysis of overall survival in a phase III randomised controlled trial. Ann Oncol. 2021 Feb;32(2):218-228. Epub 2020 Nov 11. link to original article PubMed
- RESILIENCE: Baselga J, Zamagni C, Gómez P, Bermejo B, Nagai SE, Melichar B, Chan A, Mángel L, Bergh J, Costa F, Gómez HL, Gradishar WJ, Hudis CA, Rapoport BL, Roché H, Maeda P, Huang L, Meinhardt G, Zhang J, Schwartzberg LS. RESILIENCE: phase III randomized, double-blind trial comparing sorafenib with capecitabine versus placebo with capecitabine in locally advanced or metastatic HER2-negative breast cancer. Clin Breast Cancer. 2017 Dec;17(8):585-594.e4. Epub 2017 May 22. link to original article dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT01234337
- PROCEED: Park IH, Im SA, Jung KH, Sohn JH, Park YH, Lee KS, Sim SH, Park KH, Kim JH, Nam BH, Kim HJ, Kim TY, Lee KH, Kim SB, Ahn JH, Lee S, Ro J. Randomized open label phase III trial of irinotecan plus capecitabine versus capecitabine monotherapy in patients with metastatic breast cancer previously treated with anthracycline and taxane: PROCEED trial (KCSG BR 11-01). Cancer Res Treat. 2019 Jan;51(1):43-52. Epub 2018 Feb 14. link to original article dosing details in abstract have been reviewed by our editors link to PMC article PubMed NCT01501669
- L00070 IN 305 B0: Martin M, Campone M, Bondarenko I, Sakaeva D, Krishnamurthy S, Roman L, Lebedeva L, Vedovato JC, Aapro M. Randomised phase III trial of vinflunine plus capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with an anthracycline and resistant to taxane. Ann Oncol. 2018 May 1;29(5):1195-1202. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01095003
- DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT03734029
- 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
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
Regimen variant #2, 2500/15
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Miller et al. 2005 (AVF2119g) | 2000-2002 | Phase 3 (E-esc) | Capecitabine | Did not meet primary endpoint of 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
- Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- AVF2119g: Miller KD, Chap LI, Holmes FA, Cobleigh MA, Marcom PK, Fehrenbacher L, Dickler M, Overmoyer BA, Reimann JD, Sing AP, Langmuir V, Rugo HS. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol. 2005 Feb 1;23(4):792-9. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00109239
- RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00281697
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01250379
- Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article 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
- Capecitabine (Xeloda) 825 mg/m2 PO twice per day on days 1 to 14
- Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
21-day cycles
Regimen variant #2, 1250/75
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
O'Shaughnessy et al. 2002 (SO14999) | Not reported | Phase 3 (E-RT-esc) | Docetaxel | 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
- Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycles
References
- SO14999: O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Miles D, Vukelja S, Moiseyenko V, Cervantes G, Mauriac L, Van Hazel G, Lui WY, Ayoub JP, O'Shaughnessy JA. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Clin Breast Cancer. 2004 Oct;5(4):273-8. link to original article PubMed
- B9E-US-S188: Chan S, Romieu G, Huober J, Delozier T, Tubiana-Hulin M, Schneeweiss A, Lluch A, Llombart A, du Bois A, Kreienberg R, Mayordomo JI, Antón A, Harrison M, Jones A, Carrasco E, Vaury AT, Frimodt-Moller B, Fumoleau P. Phase III study of gemcitabine plus docetaxel compared with capecitabine plus docetaxel for anthracycline-pretreated patients with metastatic breast cancer. J Clin Oncol. 2009 Apr 10;27(11):1753-60. Epub 2009 Mar 9. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00191152
- Pooled update: Seidman AD, Chan S, Wang J, Zhu C, Xu C, Xu B. A pooled analysis of gemcitabine plus docetaxel versus capecitabine plus docetaxel in metastatic breast cancer. Oncologist. 2014 May;19(5):443-52. Epub 2014 Apr 4. link to original article link to PMC article PubMed
- JO21095: Yamamoto D, Sato N, Rai Y, Yamamoto Y, Saito M, Iwata H, Masuda N, Oura S, Watanabe J, Hattori S, Matsuura Y, Kuroi K. Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. Breast Cancer Res Treat. 2017 Feb;161(3):473-482. Epub 2016 Dec 22. link to original article dosing details in manuscript have been reviewed by our editors 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
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
- Ixabepilone (Ixempra) 40 mg/m2 IV once on day 1
21-day cycles
References
- CA163-046: Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. Epub 2007 Oct 29. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00080301
- Update: Hortobagyi GN, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Lerzo GL, Pivot XB, Hurtado de Mendoza F, Xu B, Vahdat LT, Peck RA, Mukhopadhyay P, Roché HH. Analysis of overall survival from a phase III study of ixabepilone plus capecitabine versus capecitabine in patients with MBC resistant to anthracyclines and taxanes. Breast Cancer Res Treat. 2010 Jul;122(2):409-18. Epub 2010 May 8. link to original article PubMed
- CA163-048: Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010 Jul 10;28(20):3256-63. Epub 2010 Jun 7. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article 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
- Capecitabine (Xeloda) 825 mg/m2 PO twice per day on days 1 to 14
- Vinflunine (Javlor) 280 mg/m2 IV once on day 1
21-day cycles
References
- L00070 IN 305 B0: Martin M, Campone M, Bondarenko I, Sakaeva D, Krishnamurthy S, Roman L, Lebedeva L, Vedovato JC, Aapro M. Randomised phase III trial of vinflunine plus capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with an anthracycline and resistant to taxane. Ann Oncol. 2018 May 1;29(5):1195-1202. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01095003
Carboplatin & Gemcitabine (GCb)
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Nagourney et al. 2008 | 2002-2005 | Pilot, less than 20 pts |
Chemotherapy
- Carboplatin (Paraplatin) AUC 2 IV over 60 minutes once per day on days 1 & 8
- Gemcitabine (Gemzar) 800 mg/m2 IV over 60 minutes once per day on days 1 & 8
21-day cycles until CR or indefinitely
References
- Nagourney RA, Flam M, Link J, Hager S, Blitzer J, Lyons W, Sommers BL, Evans S. Carboplatin plus gemcitabine repeating doublet therapy in recurrent breast cancer. Clin Breast Cancer. 2008 Oct;8(5):432-5. link to original article dosing details in abstract have been reviewed by our editors 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 | Not reported | Phase 2 |
Chemotherapy
- Cisplatin (Platinol) 75 mg/m2 IV over 60 minutes once on day 1
- Vinorelbine (Navelbine) 25 mg/m2 IV over 5 to 10 minutes once per day on days 1 & 8
Supportive therapy
- Normal saline 200 mL bolus after vinorelbine 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
- 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
- Vassilomanolakis M, Koumakis G, Barbounis V, Demiri M, Pateras H, Efremidis AP. Vinorelbine and cisplatin in metastatic breast cancer patients previously treated with anthracyclines. Ann Oncol. 2000 Sep;11(9):1155-60. link to original article dosing details in manuscript have been reviewed by our editors PubMed
Cyclophosphamide & Methotrexate (CM)
CM: Cyclophosphamide & Methotrexate
Regimen variant #1
Study | Dates of enrollment | Evidence |
---|---|---|
Colleoni et al. 2002 | 1997-2000 | Non-randomized |
Chemotherapy
- Cyclophosphamide (Cytoxan) 50 mg PO once per day on days 1 to 7
- Methotrexate (MTX) 2.5 mg PO twice per day on days 1 & 2
7-day cycles
Regimen variant #2, metronomic
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Colleoni et al. 2005 | 2000-2003 | Randomized (C) | CM & Thalidomide | Did not meet primary endpoint of percent reduction in VEGF after 2 months of treatment |
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.
Chemotherapy
- Cyclophosphamide (Cytoxan) 50 mg PO once per day on days 1 to 7
- Methotrexate (MTX) 2.5 mg PO twice per day on days 1 & 4
7-day cycles
References
- Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nolè F, Peruzzotti G, Robertson C, Orlando L, Cinieri S, de Braud F, Viale G, Goldhirsch A. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol. 2002 Jan;13(1):73-80. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Colleoni M, Orlando L, Sanna G, Rocca A, Maisonneuve P, Peruzzotti G, Ghisini R, Sandri MT, Zorzino L, Nolè F, Viale G, Goldhirsch A. Metronomic low-dose oral cyclophosphamide and methotrexate plus or minus thalidomide in metastatic breast cancer: antitumor activity and biological effects. Ann Oncol. 2006 Feb;17(2):232-8. Epub 2005 Dec 1. link to original article dosing details in abstract have been reviewed by our editors PubMed
Cyclophosphamide monotherapy
Regimen
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Cortes et al. 2018 (L00070 IN 308 B0) | 2009-2011 | Phase 3 (C) | Vinflunine | Did not meet primary endpoint of OS Median OS: 9.3 vs 9.1 mo (HR 0.96) |
Note: this was the most commonly used comparator arm; doses were not provided in the manuscript or CT.gov.
Chemotherapy
References
- 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
- Docetaxel (Taxotere) 40 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
8-week cycles
Regimen variant #3, 60 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Adachi et al. 1996 | 1993 | Phase 2 | ||
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
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 |
Subsequent treatment
- JO21095, upon progression: Subsequent-line Capecitabine
Regimen variant #5, 75 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Harvey et al. 2006 (TAX 313) | 1995-2001 | Phase 3 (E-RT-esc) | 1. Docetaxel; 60 mg/m2 q3wk | Might have 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.
Dose and schedule modifications
- Rivera et al. 2008 gave 75 mg/m2 in cycle 1, with escalation to 100 mg/m2 depending on toxicity
Regimen variant #6, 100 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
ten Bokkel Huinink et al. 1994 | Not reported | Phase 2 | |||
Nabholtz et al. 1999 (TAX 304) | Not reported | 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) | Not reported | 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.
Chemotherapy
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle of varying durations: 7 cycles (TAX 303); 10 cycles (TAX 304); indefinitely (Nielsen et al. 2011, TAX 311, others)
References
- ten Bokkel Huinink WW, Prove AM, Piccart M, Steward W, Tursz T, Wanders J, Franklin H, Clavel M, Verweij J, Alakl M, Bayssas M, Kaye SB; EORTC Early Clinical Trials Group. A phase II trial with docetaxel (Taxotere) in second line treatment with chemotherapy for advanced breast cancer: a study of the EORTC Early Clinical Trials Group. Ann Oncol. 1994 Jul;5(6):527-32. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Adachi I, Watanabe T, Takashima S, Narabayashi M, Horikoshi N, Aoyama H, Taguchi T. A late phase II study of RP56976 (docetaxel) in patients with advanced or recurrent breast cancer. Br J Cancer. 1996 Jan;73(2):210-6. link to original article link to PMC article dosing details in abstract have been reviewed by our editors PubMed
- TAX 304: Nabholtz JM, Senn HJ, Bezwoda WR, Melnychuk D, Deschênes L, Douma J, Vandenberg TA, Rapoport B, Rosso R, Trillet-Lenoir V, Drbal J, Molino A, Nortier JW, Richel DJ, Nagykalnai T, Siedlecki P, Wilking N, Genot JY, Hupperets PS, Pannuti F, Skarlos D, Tomiak EM, Murawsky M, Alakl M, Aapro M; 304 Study Group. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. J Clin Oncol. 1999 May;17(5):1413-24. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Review: Burris HA 3rd. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin Oncol. 1999 Jun;26(3 Suppl 9):1-6. PubMed
- TAX 303: Chan S, Friedrichs K, Noel D, Pintér T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, González Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J; 303 Study Group. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2341-54. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Sjöström J, Blomqvist C, Mouridsen H, Pluzanska A, Ottosson-Lönn S, Bengtsson NO, Ostenstad B, Mjaaland I, Palm-Sjövall M, Wist E, Valvere V, Anderson H, Bergh J; Scandinavian Breast Group. Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: a randomised phase III study with crossover on progression by the Scandinavian Breast Group. Eur J Cancer. 1999 Aug;35(8):1194-201. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- SO14999: O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Update: Miles D, Vukelja S, Moiseyenko V, Cervantes G, Mauriac L, Van Hazel G, Lui WY, Ayoub JP, O'Shaughnessy JA. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Clin Breast Cancer. 2004 Oct;5(4):273-8. link to original article PubMed
- Bonneterre J, Roché H, Monnier A, Guastalla JP, Namer M, Fargeot P, Assadourian S. Docetaxel vs 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure. Br J Cancer. 2002 Nov 18;87(11):1210-5. link to original article dosing details in abstract have been reviewed by our editors link to PMC article PubMed
- TAX 311: Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, Laufman L, Sundaram S, Urba WJ, Pritchard KI, Mennel R, Richards D, Olsen S, Meyers ML, Ravdin PM. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005 Aug 20;23(24):5542-51. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00002662
- TAX 313: Harvey V, Mouridsen H, Semiglazov V, Jakobsen E, Voznyi E, Robinson BA, Groult V, Murawsky M, Cold S. Phase III trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol. 2006 Nov 1;24(31):4963-70. Epub 2006 Oct 10. link to original article PubMed
- Rivera E, Mejia JA, Arun BK, Adinin RB, Walters RS, Brewster A, Broglio KR, Yin G, Esmaeli B, Hortobagyi GN, Valero V. Phase 3 study comparing the use of docetaxel on an every-3-week versus weekly schedule in the treatment of metastatic breast cancer. Cancer. 2008 Apr 1;112(7):1455-61. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Schröder CP, de Munck L, Westermann AM, Smit WM, Creemers GJ, de Graaf H, Stouthard JM, van Deijk G, Erjavec Z, van Bochove A, Vader W, Willemse PH. Weekly docetaxel in metastatic breast cancer patients: no superior benefits compared to three-weekly docetaxel. Eur J Cancer. 2011 Jun;47(9):1355-62. Epub 2011 Jan 19. link to original article PubMed
- RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00281697
- Nielsen DL, Bjerre KD, Jakobsen EH, Cold S, Stenbygaard L, Sørensen PG, Kamby C, Møller S, Jørgensen CL, Andersson M; Danish Breast Cancer Cooperative Group. Gemcitabine plus docetaxel versus docetaxel in patients with predominantly human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: a randomized, phase III study by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 2011 Dec 20;29(36):4748-54. Epub 2011 Nov 14. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01250379
- Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed
- JO21095: Yamamoto D, Sato N, Rai Y, Yamamoto Y, Saito M, Iwata H, Masuda N, Oura S, Watanabe J, Hattori S, Matsuura Y, Kuroi K. Efficacy and safety of low-dose capecitabine plus docetaxel versus single-agent docetaxel in patients with anthracycline-pretreated HER2-negative metastatic breast cancer: results from the randomized phase III JO21095 trial. Breast Cancer Res Treat. 2017 Feb;161(3):473-482. Epub 2016 Dec 22. link to original article dosing details in manuscript have been reviewed by our editors 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
- Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
Regimen variant #2, docetaxel 75 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (E-esc) | 1a. 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
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
Regimen variant #3, docetaxel 100 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (E-esc) | 1a. 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
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00281697
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01250379
- Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article 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
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 8
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1 & 8
21-day cycle for 8 cycles
References
- Tomova A, Bartsch R, Brodowicz T, Tzekova V, Timcheva C, Wiltschke C, Gerges DA, Pawlega J, Spanik S, Inbar M, Zielinski CC. Concomitant docetaxel plus gemcitabine versus sequential docetaxel followed by gemcitabine in anthracycline-pretreated metastatic or locally recurrent inoperable breast cancer patients: a prospective multicentre trial of the Central European Cooperative Oncology Group (CECOG). Breast Cancer Res Treat. 2010 Jan;119(1):169-76. link to original article dosing details in abstract have been reviewed by our editors 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.
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.
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.
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
- Doxorubicin (Adriamycin) 75 mg/m2 IV over 15 to 20 minutes once on day 1
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.
References
- SWOG S8203: Cowan JD, Neidhart J, McClure S, Coltman CA Jr, Gumbart C, Martino S, Hutchins LF, Stephens RL, Vaughan CB, Osborne CK. Randomized trial of doxorubicin, bisantrene, and mitoxantrone in advanced breast cancer: a Southwest Oncology Group study. J Natl Cancer Inst. 1991 Aug 7;83(15):1077-84. link to original article dosing details in abstract have been reviewed by our editors PubMed
- EORTC 10811: Bontenbal M, Andersson M, Wildiers J, Cocconi G, Jassem J, Paridaens R, Rotmensz N, Sylvester R, Mouridsen HT, Klijn JG, van Oosterom AT; EORTC Breast Cancer Cooperative Group. Doxorubicin vs epirubicin, report of a second-line randomized phase II/III study in advanced breast cancer. Br J Cancer. 1998 Jun;77(12):2257-63. link to original article link to PMC article dosing details in abstract have been reviewed by our editors PubMed
- TAX 303: Chan S, Friedrichs K, Noel D, Pintér T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, González Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J; 303 Study Group. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2341-54. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- NCIC-CTG MA.8: Norris B, Pritchard KI, James K, Myles J, Bennett K, Marlin S, Skillings J, Findlay B, Vandenberg T, Goss P, Latreille J, Rudinskas L, Lofters W, Trudeau M, Osoba D, Rodgers A. Phase III comparative study of vinorelbine combined with doxorubicin versus doxorubicin alone in disseminated metastatic/recurrent breast cancer: National Cancer Institute of Canada Clinical Trials Group study MA8. J Clin Oncol. 2000 Jun;18(12):2385-94. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- 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
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01250379
- Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article 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
- Doxorubicin (Adriamycin) 20 mg/m2 IV once per day on days 1, 8, 15, 22
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
Regimen variant #2, doxorubicin 25 mg/m2 weekly
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1a. 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
- Doxorubicin (Adriamycin) 25 mg/m2 IV once per day on days 1, 8, 15, 22
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
Regimen variant #3, doxorubicin 60 mg/m2 q3wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1a. 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
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
Regimen variant #4, doxorubicin 75 mg/m2 q3wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1a. 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
- Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01250379
- Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article 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
- Eribulin (Halaven) 1.4 mg/m2 IV over 2 to 5 minutes once per day on days 1 & 8
21-day cycles
References
- EMBRACE: Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Diéras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389) investigators. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011 Mar 12;377(9769):914-23. Epub 2011 Mar 2. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00388726
- E7389-G000-301: Kaufman PA, Awada A, Twelves C, Yelle L, Perez EA, Velikova G, Olivo MS, He Y, Dutcus CE, Cortes J. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015 Feb 20;33(6):594-601. Epub 2015 Jan 20. link to original article link to PMC article dosing details in manuscript have been reviewed by our editors PubMed NCT00337103
- 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
- E7389-C086-304: Yuan P, Hu X, Sun T, Li W, Zhang Q, Cui S, Cheng Y, Ouyang Q, Wang X, Chen Z, Hiraiwa M, Saito K, Funasaka S, Xu B. Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial. Eur J Cancer. 2019 May;112:57-65. Epub 2019 Mar 29. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02225470
- 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 dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT03734029
- 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 | Not reported | 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
- Gemcitabine (Gemzar) 800 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
28-day cycles
Regimen variant #2, 1000 mg/m2 3 weeks out of 4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1a. Capecitabine & Bevacizumab 1b. Docetaxel & Bevacizumab 1c. Doxorubicin & Bevacizumab 1d. NPLD & Bevacizumab 1e. PLD & Bevacizumab 1f. Gemcitabine & Bevacizumab 1g. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Regimen variant #3, 1200 mg/m2 3 weeks out of 4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Spielmann et al. 2001 | Not reported | 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
- Gemcitabine (Gemzar) 1200 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
28-day cycles
Regimen variant #4, 1250 mg/m2 2 weeks out of 3
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (C) | 1a. Capecitabine & 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
- Gemcitabine (Gemzar) 1250 mg/m2 IV over 30 minutes once per day on days 1 & 8
21-day cycles
References
- Carmichael J, Possinger K, Philip P, Beykirch M, Kerr H, Walling J, Harris AL. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol. 1995 Nov;13(11):2731-6. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Spielmann M, Llombart-Cussac A, Kalla S, Espié M, Namer M, Ferrero JM, Diéras V, Fumoleau P, Cuvier C, Perrocheau G, Ponzio A, Kayitalire L, Pouillart P. Single-agent gemcitabine is active in previously treated metastatic breast cancer. Oncology. 2001;60(4):303-7. link to original article PubMed
- RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00281697
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01250379
- Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed
- DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT03734029
- 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
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
Regimen variant #2, 1250 mg/m2, 2 weeks out of 3
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (E-esc) | 1a. 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
- Gemcitabine (Gemzar) 1250 mg/m2 IV over 30 minutes once per day on days 1 & 8
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00281697
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01250379
- Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed
Ixabepilone monotherapy
Regimen
Study | Dates of enrollment | Evidence |
---|---|---|
Perez et al. 2007 (CA163-081) | 2004-2005 | Phase 2 (RT) |
Chemotherapy
- Ixabepilone (Ixempra) 40 mg/m2 IV over 3 hours once on day 1
21-day cycle for up to 18 cycles
References
- CA163-081: Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, Viens P, Cai C, Mullaney B, Peck R, Hortobagyi GN. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007 Aug 10;25(23):3407-14. Epub 2007 Jul 2. link to original article dosing details in manuscript have been reviewed by our editors 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 |
References
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01250379
- Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article 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
- Non-pegylated liposomal doxorubicin (Myocet) 60 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01250379
- Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed
Paclitaxel monotherapy, weekly
Regimen variant #1, 80 mg/m2 weekly
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Perez et al. 2001 | Not reported | Phase 2 | ||
Seidman et al. 2008 (CALGB 9840) | 1998 to not reported | 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
- Paclitaxel (Taxol) 80 mg/m2 IV over 60 minutes once per day on days 1, 8, 15, 22
28-day cycles
Regimen variant #2, 90 mg/m2 3 weeks out of 4
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (C) | 1a. Capecitabine & Bevacizumab 1b. Docetaxel & Bevacizumab 1c. Gemcitabine & Bevacizumab 1d. Paclitaxel & Bevacizumab 1e. nab-Paclitaxel & Bevacizumab 1f. Vinorelbine & Bevacizumab |
Inferior PFS |
References
- Perez EA, Vogel CL, Irwin DH, Kirshner JJ, Patel R. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2001 Nov 15;19(22):4216-23. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- CALGB 9840: Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. link to original article PubMed NCT00003440
- RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00281697
- DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article 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.
Regimen variant #2, 175 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Seidman et al. 1995 | Not reported | 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 to not reported | 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
References
- Seidman AD, Tiersten A, Hudis C, Gollub M, Barrett S, Yao TJ, Lepore J, Gilewski T, Currie V, Crown J, Hakes T, Baselga J, Sklarin N, Moynihan ME, Tong W, Egorin M, Kearns C, Spriggs D, Norton L. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2575-81. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Nabholtz JM, Gelmon K, Bontenbal M, Spielmann M, Catimel G, Conte P, Klaassen U, Namer M, Bonneterre J, Fumoleau P, Winograd B. Multicenter, randomized comparative study of two doses of paclitaxel in patients with metastatic breast cancer. J Clin Oncol. 1996 Jun;14(6):1858-67. link to original article dosing details in abstract have been reviewed by our editors PubMed
- CALGB 9342: Winer EP, Berry DA, Woolf S, Duggan D, Kornblith A, Harris LN, Michaelson RA, Kirshner JA, Fleming GF, Perry MC, Graham ML, Sharp SA, Keresztes R, Henderson IC, Hudis C, Muss H, Norton L. Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: Cancer and Leukemia Group B trial 9342. J Clin Oncol. 2004 Jun 1;22(11):2061-8. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- Icli F, Akbulut H, Uner A, Yalcin B, Baltali E, Altinbas M, Coşkun S, Komurcu S, Erkisi M, Demirkazik A, Senler FC, Sencan O, Büyükcelik A, Boruban C, Onur H, Zengin N, Sak SD; Turkish Oncology Group. Cisplatin plus oral etoposide (EoP) combination is more effective than paclitaxel in patients with advanced breast cancer pretreated with anthracyclines: a randomised phase III trial of Turkish Oncology Group. Br J Cancer. 2005 Feb 28;92(4):639-44. link to original article link to PMC article dosing details in abstract have been reviewed by our editors PubMed
- TAX 311: Jones SE, Erban J, Overmoyer B, Budd GT, Hutchins L, Lower E, Laufman L, Sundaram S, Urba WJ, Pritchard KI, Mennel R, Richards D, Olsen S, Meyers ML, Ravdin PM. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005 Aug 20;23(24):5542-51. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00002662
- CA012-0: Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00046527
- CALGB 9840: Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. link to original article PubMed NCT00003440
- RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00281697
- DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article PubMed NCT03734029
- KX-ORAX-001: Rugo HS, Umanzor GA, Barrios FJ, Vasallo RH, Chivalan MA, Bejarano S, Ramirez JR, Fein L, Kowalyszyn RD, Kramer ED, Wang H, Kwan MR, Cutler DL. Open-Label, Randomized, Multicenter, Phase III Study Comparing Oral Paclitaxel Plus Encequidar Versus Intravenous Paclitaxel in Patients With Metastatic Breast Cancer. J Clin Oncol. 2023 Jan 1;41(1):65-74. Epub 2022 Jul 20. 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
- Paclitaxel (Taxol) 90 mg/m2 IV over 60 minutes once per day on days 1, 8, 15
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
Regimen variant #2, 175 mg/m2 q3wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (E-esc) | 1a. 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
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article dosing details in manuscript have been reviewed by our editors 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
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Regimen variant #2, 125 mg/m2, 3 weeks out of 4
Study | 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
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Regimen variant #3, 260 mg/m2 q3wk
Study | 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
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m2 IV over 30 minutes once on day 1
Supportive therapy
- CA012-0: No corticosteroid or antihistamine premedication
21-day cycles
Regimen variant #4, 300 mg/m2 q3wk
Study | Dates of enrollment | Evidence |
---|---|---|
Ibrahim et al. 2005 | 1999-2001 | Phase 2 (RT) |
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 300 mg/m2 IV over 30 minutes once on day 1
21-day cycles
References
- Ibrahim NK, Samuels B, Page R, Doval D, Patel KM, Rao SC, Nair MK, Bhar P, Desai N, Hortobagyi GN. Multicenter phase II trial of ABI-007, an albumin-bound paclitaxel, in women with metastatic breast cancer. J Clin Oncol. 2005 Sep 1;23(25):6019-26. link to original article dosing details in abstract have been reviewed by our editors PubMed
- CA012-0: Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00046527
- RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00281697
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01250379
- Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article PubMed
- DESTINY-Breast04: Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9-20. Epub 2022 Jun 5. link to original article dosing details in manuscript have been reviewed by our editors link to PMC article 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
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV once per day on days 1, 8, 15, 22
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
Regimen variant #2, 260 mg/m2 q3wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (E-esc) | 1a. 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
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00281697
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01250379
- Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article 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.
Regimen variant #2, 50 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Keller et al. 2004 | Not reported | Phase 3 (E-switch-ic) | 1a. MV 1b. Vinorelbine |
Did not meet primary endpoint of PFS |
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1a. Capecitabine & Bevacizumab 1b. Docetaxel & Bevacizumab 1c. Doxorubicin & Bevacizumab 1d. NPLD & Bevacizumab 1e. PLD & Bevacizumab 1f. Gemcitabine & Bevacizumab 1g. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Note: this was the higher end of the range of pegylated liposomal doxorubicin dosing described in TANIA.
Prior treatment criteria
- Keller et al. 2004: Taxane exposure
Chemotherapy
- Pegylated liposomal doxorubicin (Doxil) 50 mg/m2 IV over 60 minutes once on day 1
28-day cycles
References
- Keller AM, Mennel RG, Georgoulias VA, Nabholtz JM, Erazo A, Lluch A, Vogel CL, Kaufmann M, von Minckwitz G, Henderson IC, Mellars L, Alland L, Tendler C. Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol. 2004 Oct 1;22(19):3893-901. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01250379
- Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article 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
- Pegylated liposomal doxorubicin (Doxil) 40 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
Regimen variant #2, 50 mg/m2
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1a. 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
- Pegylated liposomal doxorubicin (Doxil) 50 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
References
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01250379
- Update: Vrdoljak E, Marschner N, Zielinski C, Gligorov J, Cortes J, Puglisi F, Aapro M, Fallowfield L, Fontana A, Inbar M, Kahan Z, Welt A, Lévy C, Brain E, Pivot X, Putzu C, González Martín A, de Ducla S, Easton V, von Minckwitz G. Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer. Ann Oncol. 2016 Nov;27(11):2046-2052. Epub 2016 Aug 8. link to original article 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
- Trastuzumab deruxtecan (Enhertu) 5.4 mg/kg IV once on day 1
21-day cycles
References
- 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 dosing details in manuscript have been reviewed by our editors link to PMC article 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 |
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 | Not reported | Phase 3 (C) | PLD | Did not meet primary endpoint of PFS |
Prior treatment criteria
- Jones et al. 1995a: Anthracycline exposure
- Keller et al. 2004: Taxane exposure
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 |
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 |
References
- Gasparini G, Caffo O, Barni S, Frontini L, Testolin A, Guglielmi RB, Ambrosini G. Vinorelbine is an active antiproliferative agent in pretreated advanced breast cancer patients: a phase II study. J Clin Oncol. 1994 Oct;12(10):2094-101. link to original article PubMed
- Jones S, Winer E, Vogel C, Laufman L, Hutchins L, O'Rourke M, Lembersky B, Budman D, Bigley J, Hohneker J. Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. J Clin Oncol. 1995 Oct;13(10):2567-74. link to original article dosing details in abstract have been reviewed by our editors PubMed
- Zelek L, Barthier S, Riofrio M, Fizazi K, Rixe O, Delord JP, Le Cesne A, Spielmann M. Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer. 2001 Nov 1;92(9):2267-72. link to original article PubMed
- Keller AM, Mennel RG, Georgoulias VA, Nabholtz JM, Erazo A, Lluch A, Vogel CL, Kaufmann M, von Minckwitz G, Henderson IC, Mellars L, Alland L, Tendler C. Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol. 2004 Oct 1;22(19):3893-901. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- GEICAM 2000-04: Martín M, Ruiz A, Muñoz M, Balil A, García-Mata J, Calvo L, Carrasco E, Mahillo E, Casado A, García-Saenz JA, Escudero MJ, Guillem V, Jara C, Ribelles N, Salas F, Soto C, Morales-Vasquez F, Rodríguez CA, Adrover E, Mel JR; GEICAM. Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial. Lancet Oncol. 2007 Mar;8(3):219-25. link to original article dosing details in abstract have been reviewed by our editors PubMed NCT00128310
- RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00281697
- E7389-C086-304: Yuan P, Hu X, Sun T, Li W, Zhang Q, Cui S, Cheng Y, Ouyang Q, Wang X, Chen Z, Hiraiwa M, Saito K, Funasaka S, Xu B. Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial. Eur J Cancer. 2019 May;112:57-65. Epub 2019 Mar 29. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT02225470
- VicTORia: Decker T, Marschner N, Muendlein A, Welt A, Hagen V, Rauh J, Schröder H, Jaehnig P, Potthoff K, Lerchenmüller C. VicTORia: a randomised phase II study to compare vinorelbine in combination with the mTOR inhibitor everolimus versus vinorelbine monotherapy for second-line chemotherapy in advanced HER2-negative breast cancer. Breast Cancer Res Treat. 2019 Aug;176(3):637-647. Epub 2019 May 21. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT01520103
- 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
- Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 8
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once on day 1
14-day cycles
Regimen variant #2, vinorelbine 30 mg/m2 q3wk
Study | Dates of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (E-esc) | 1a. 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
- Vinorelbine (Navelbine) 30 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- Burstein HJ, Chen YH, Parker LM, Savoie J, Younger J, Kuter I, Ryan PD, Garber JE, Chen H, Campos SM, Shulman LN, Harris LN, Gelman R, Winer EP. VEGF as a marker for outcome among advanced breast cancer patients receiving anti-VEGF therapy with bevacizumab and vinorelbine chemotherapy. Clin Cancer Res. 2008 Dec 1;14(23):7871-7. link to original article dosing details in manuscript have been reviewed by our editors PubMed
- RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article dosing details in manuscript have been reviewed by our editors PubMed NCT00281697