Breast cancer
Section editor transclusions Are you looking for a regimen, but can't find it here? It is possible that we've moved it to the historical regimens page. For placebo or observational studies in this condition, please visit this page. If you still can't find it, please let us know so we can add it!
- Note: this page contains regimens which were not tested in biomarker-specific populations. The following links will take you to biomarker-specific subpages:
- Regimens for ER/PR positive breast cancer are here.
- Regimens for HER2 positive breast cancer are here.
- Regimens for ER/HER2 co-expressing ("double positive") breast cancer are here.
- Regimens for Triple negative breast cancer (TNBC) are here.
- Regimens for BRCA-mutated breast cancer are here.
- Regimens for PIK3CA-mutated breast cancer are here.
- Regimens for CNS metastases are here.
- Because docetaxel and paclitaxel are both often abbreviated as "T," we try to always make clear in the regimen name which agent is being used. For sequential protocols, we use "T" for paclitaxel and "D" for docetaxel; e.g., AC-T and AC-D.
143 regimens on this page
330 variants on this page
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Guidelines
ASCO
- 2021: Korde et al. Neoadjuvant Chemotherapy, Endocrine Therapy, and Targeted Therapy for Breast Cancer: ASCO Guideline
- 2020: Denduluri et al. Selection of Optimal Adjuvant Chemotherapy and Targeted Therapy for Early Breast Cancer: ASCO Guideline Update
- 2020: Hassett et al. Management of Male Breast Cancer: ASCO Guideline PubMed
- 2016: Burstein et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: American Society of Clinical Oncology clinical practice guideline update on ovarian suppression PubMed
Older
- 2018: Denduluri et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO clinical practice guideline focused update PubMed
- 2016: Harris et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology clinical practice guideline
- 2015: van Poznak et al. Use of biomarkers to guide decisions on systemic therapy for women with metastatic breast cancer: American Society of Clinical Oncology Clinical practice guideline
- 2014: Partridge et al. Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Clinical Practice Guideline
ASCO/CCO
- 2017: Role of bone-modifying agents in metastatic breast cancer: an American Society of Clinical Oncology–Cancer Care Ontario focused guideline update PubMed
ESMO
- 2021: Gennari et al. ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer
- 2019: Cardoso et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Older
- 2015: Senkus et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
ESO/ESMO
- 2020: Paluch-Shimon et al. ESO–ESMO 4th International Consensus Guidelines for Breast Cancer in Young Women (BCY4)
- 2018: Cardoso et al. 4th ESO–ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4)
Older
- 2017: Cardoso et al. 3rd ESO-ESMO International consensus guidelines for advanced breast cancer (ABC3) PubMed
- 2014: Cardoso et al. ESO-ESMO 2nd International consensus guidelines for advanced breast cancer (ABC2)
- 2012: Cardoso et al. 1st International consensus guidelines for advanced breast cancer (ABC 1)
EUSOMA/SIOG
Older
- 2012: Biganzoli et al. Management of elderly patients with breast cancer: updated recommendations of the International Society of Geriatric Oncology (SIOG) and European Society of Breast Cancer Specialists (EUSOMA)
- 2007: Wildiers et al. Management of breast cancer in elderly individuals: recommendations of the International Society of Geriatric Oncology
KSMO/ESMO
NCCN
St Gallen Breast Guidelines
- 2021: Burstein et al. Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021
Older
- 2019: Burstein et al. Estimating the benefits of therapy for early-stage breast cancer: the St. Gallen International Consensus Guidelines for the primary therapy of early breast cancer 2019
- 2017: Curigliano et al. St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2017
- 2015: Coates et al. Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015
Neoadjuvant chemotherapy
AC-D
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AC-D: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Docetaxel
Protocol #1, 60/600/75
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kim et al. 2020 (NEST) | 2012-2014 | Phase 3 (C) | Goserelin & Tamoxifen | Inconclusive whether non-inferior clinical response |
Chemotherapy, AC portion
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles, followed by:
Chemotherapy, T portion
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
Protocol #2, 60/600/100
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2005 (GeparDuo) | 1999-2001 | Phase 3 (E-esc) | Dose-dense Docetaxel & Doxorubicin (ddAT) | Superior pCR rate |
Chemotherapy, AC portion
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles, followed by:
Chemotherapy, T portion
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
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 contains verified protocol PubMed NCT00793377
- NEST: Kim HJ, Noh WC, Lee ES, Jung YS, Kim LS, Han W, Nam SJ, Gong G-, Kim HJ, Ahn SH. Efficacy of neoadjuvant endocrine therapy compared with neoadjuvant chemotherapy in pre-menopausal patients with oestrogen receptor-positive and HER2-negative, lymph node-positive breast cancer. Breast Cancer Res. 2020 May 27;22(1):54. link to original article link to PMC article contains verified protocol PubMed NCT01622361
AC-T
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AC-T: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel)
Protocol
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ellis et al. 2011 (SWOG 0012) | 2001-2005 | Phase 3 (C) | AC-T; daily cyclophosphamide | Did not meet primary endpoint of pCR rate |
Chemotherapy, AC portion
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 5 cycles, followed by:
Chemotherapy, T portion
- Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1, 8, 15
21-day cycle for 4 cycles
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 contains verified protocol link to PMC article PubMed NCT00016406
Capecitabine & Docetaxel (TX)
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TX: Taxotere (Docetaxel) & Xeloda (Capecitabine)
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lee et al. 2007 | 2002-2005 | Phase 3 (E-switch-ic) | AC | Seems to have superior pCR rate |
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 4 cycles
Subsequent treatment
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 contains verified protocol PubMed
Cyclophosphamide & Doxorubicin (AC)
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AC: Adriamycin (Doxorubicin) & Cyclophosphamide
Regimen variant #1, 4 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fisher et al. 1997 (NSABP B-18) | 1988-1993 | Phase 3 (E-switch-ic) | Adjuvant AC | Superior resectability |
Bear et al. 2003 (NSABP B-27) | 1995-2000 | Phase 3 (C) | See link | See link |
Lee et al. 2007 | 2002-2005 | Phase 3 (C) | TX | Seems to have inferior pCR rate |
Bear et al. 2012 (NSABP B-40) | 2007-2010 | Phase 3 (C) | See link | See link |
Preceding treatment
- NSABP B-40: T (Taxotere) x 4 versus TX x 4 versus TG x 4
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- NSABP B-18 & B-40: Surgery
- Lee et al. 2007: Surgery, then TX x 4
- NSABP B-27: T (Taxotere) x 4, then surgery versus surgery versus surgery, then T (Taxotere) x 4
Regimen variant #2, 6 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Smith et al. 2004 (TOPIC) | 1995-1999 | Phase 3 (C) | ECisF | Did not meet primary endpoints of RFS/OS |
Chua et al. 2005 (TOPIC 2) | 1998-2002 | Phase 3 (C) | VE | Did not meet primary endpoint of RFS |
Evans et al. 2005 | 1999-2001 | Phase 3 (C) | AD | Did not meet primary endpoint of ORR |
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Subsequent treatment
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 contains verified protocol 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 contains verified protocol 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 contains protocol 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 contains verified protocol 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 contains verified protocol 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 contains protocol PubMed
- NSABP B-40: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. link to original article link to PMC article contains verified protocol 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
- 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 PubMed NCT01822314
Cyclophosphamide & Doxorubicin (AC) & Bevacizumab
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AC+Bev: Adriamycin (Doxorubicin), Cyclophosphamide, Bevacizumab
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bear et al. 2012 (NSABP B-40) | 2007-2010 | Phase 3 (E-esc) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) as follows:
- Cycles 1 & 2: 15 mg/kg IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- Surgery, then adjuvant bevacizumab
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 contains verified protocol 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
Dose-dense Cyclophosphamide & Doxorubicin (ddAC)
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ddAC: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide
Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Burstein et al. 2005 | 2003-2004 | Non-randomized |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Supportive medications
- 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 dose-dense paclitaxel, then surgery or surgery, then 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 contains verified protocol PubMed
Cyclophosphamide & Epirubicin (EC)
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EC: Epirubicin & Cyclophosphamide
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Untch et al. 2011 (PREPARE) | 2002-2005 | Phase 3 (C) | See link | See link |
von Minckwitz et al. 2010 (GeparQuattro) | 2005-NR | Non-randomized portion of RCT | ||
Earl et al. 2013 (Neo-tAnGo) | 2005-2007 | Phase 3 (C) | See link | See link |
von Minckwitz et al. 2012 (GeparQuinto) | 2007-2010 | Phase 3 (C) | See link | See link |
Untch et al. 2016 (GeparSepto) | 2012-2013 | Non-randomized portion of 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. 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.
Preceding treatment
- GeparSepto: nab-Paclitaxel x 4 versus weekly Paclitaxel x 12
- Neo-tAnGo (taxanes-EC arm): ddT x 4 versus ddTG x 4
Chemotherapy
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- GeparQuattro: T (Taxotere) x 4 versus T-X versus TX, then surgery
- GeparQuinto: Docetaxel, then surgery
- Neo-tAnGo (EC-taxane arms): ddT x 4 versus ddTG x 4, then surgery
- GeparSepto: Surgery
References
- PREPARE: Untch M, von Minckwitz G, Konecny GE, Conrad U, Fett W, Kurzeder C, Lück HJ, Stickeler E, Urbaczyk H, Liedtke B, Beckmann MW, Salat C, Harbeck N, Müller V, Schmidt M, Hasmüller S, Lenhard M, Nekljudova V, Lebeau A, Loibl S, Fasching PA; Arbeitsgemeinschaft Gynäkologische Onkologie PREPARE investigators. PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel, and CMF versus a standard-dosed epirubicin-cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer--outcome on prognosis. Ann Oncol. 2011 Sep;22(9):1999-2006. Epub 2011 Mar 7. link to original article contains protocol PubMed NCT00544232
- GeparQuattro: von Minckwitz G, Rezai M, Loibl S, Fasching PA, Huober J, Tesch H, Bauerfeind I, Hilfrich J, Eidtmann H, Gerber B, Hanusch C, Kühn T, du Bois A, Blohmer JU, Thomssen C, Dan Costa S, Jackisch C, Kaufmann M, Mehta K, Untch M. Capecitabine in addition to anthracycline- and taxane-based neoadjuvant treatment in patients with primary breast cancer: phase III GeparQuattro study. J Clin Oncol. 2010 Apr 20;28(12):2015-23. Epub 2010 Mar 22. link to original article contains protocol 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 contains verified protocol PubMed NCT00567554
- Neo-tAnGo: Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, Iddawela M, Abraham J, Hughes-Davies L, Gounaris I, McAdam K, Houston S, Hickish T, Skene A, Chan S, Dean S, Ritchie D, Laing R, Harries M, Gallagher C, Wishart G, Dunn J, Provenzano E, Caldas C; Neo-tAnGo Investigators. Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2×2 factorial randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):201-12. Epub 2013 Dec 19. link to original article contains verified protocol PubMed NCT00070278
- GeparSepto: Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Wiebringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Darb-Esfahani S, Schmitt WD, Dan Costa S, Gerber B, Engels K, Nekljudova V, Loibl S, von Minckwitz G; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie—Breast (AGO-B) Investigators. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. Epub 2016 Feb 8. 2016 Mar;17(3):345-56. link to original article contains verified protocol 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 contains verified protocol PubMed NCT01822314
DI EC
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DI EC: Dose-Intense Epirubicin & Cyclophosphamide
Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Gonçalves et al. 2015 (UNICANCER PEGASE 07) | 2001-2005 | Non-randomized portion of phase III RCT |
This regimen required hematopoeitic stem cell support; see paper for details.
Chemotherapy
- Epirubicin (Ellence) 150 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 4000 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- Surgery, then Docetaxel & 5-FU versus no further treatment
References
- UNICANCER PEGASE 07: Gonçalves A, Pierga JY, Ferrero JM, Mouret-Reynier MA, Bachelot T, Delva R, Fabbro M, Lerebours F, Lotz JP, Linassier C, Dohollou N, Eymard JC, Leduc B, Lemonnier J, Martin AL, Boher JM, Viens P, Roché H. UNICANCER-PEGASE 07 study: a randomized phase III trial evaluating postoperative docetaxel-5FU regimen after neoadjuvant dose-intense chemotherapy for treatment of inflammatory breast cancer. Ann Oncol. 2015 Aug;26(8):1692-7. Epub 2015 May 5. link to original article contains protocol PubMed NCT02324088
Docetaxel & Epirubicin (DE)
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DE: Docetaxel & Epirubicin
ED: Epirubicin & Docetaxel
ET: Epirubicin & Taxotere (Docetaxel)
Regimen variant #1, 3 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Chen et al. 2017 (CBCRT01) | 2011-2015 | Phase 3 (C) | DEE | Inferior ORR |
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
21-day cycle for 3 cycles
Subsequent treatment
Regimen variant #2, 6 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Steger et al. 2007 (ABCSG-14) | 1999-2002 | Phase 3 (E-esc) | ED x 3 | Superior pCR rate |
Han et al. 2009 | 2003-2005 | Phase 3 (E-esc) | ED x 4 | Seems to have superior pCR rate |
Steger et al. 2013 (ABCSG-24) | 2004-2008 | Phase 3 (C) | EDC | Seems to have inferior pCR rate |
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Subsequent treatment
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 contains protocol 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 contains protocol 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 contains protocol 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 contains verified protocol PubMed NCT01479036
Docetaxel monotherapy
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D: Docetaxel
T: Taxotere (Docetaxel)
Regimen variant #1, 75 mg/m2 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bear et al. 2012 (NSABP B-40) | 2007-2010 | Phase 3 (C) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
Regimen variant #2, 100 mg/m2 x 3
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Earl et al. 2015 (ARTemis) | 2009-2013 | Phase 3 (C) | Docetaxel & Bevacizumab | 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
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
21-day cycle for 3 cycles
Subsequent treatment
Regimen variant #3, 100 mg/m2 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bear et al. 2003 (NSABP B-27) | 1995-2000 | Phase 3 (E-esc) | See link | See link |
von Minckwitz et al. 2012 (GeparQuinto) | 2007-2010 | Phase 3 (C) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
21-day cycle for 4 cycles
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 contains verified protocol 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
- GeparQuinto: von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Kreienberg R, Solbach C, Gerber B, Jackisch C, Kunz G, Blohmer JU, Huober J, Hauschild M, Fehm T, Müller BM, Denkert C, Loibl S, Nekljudova V, Untch M; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie–Breast Study Groups. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012 Jan 26;366(4):299-309. link to original article contains verified protocol PubMed NCT00567554
- NSABP B-40: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. link to original article link to PMC article contains verified protocol 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
- ARTemis: Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Abraham J, Thomas J, Provenzano E, Hughes-Davies L, Gounaris I, McAdam K, Chan S, Ahmad R, Hickish T, Houston S, Rea D, Bartlett J, Caldas C, Cameron DA, Hayward L; ARTemis Investigators. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):656-66. Epub 2015 May 11. link to original article contains verified protocol PubMed NCT01093235
Docetaxel & Bevacizumab
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Bev+D: Bevacizumab & Docetaxel
T+Bev: Taxotere (Docetaxel) & Bevacizumab
Regimen variant #1, docetaxel 75 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bear et al. 2012 (NSABP B-40) | 2007-2010 | Phase 3 (E-esc) | See link | See link |
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) 75 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
Regimen variant #2, docetaxel 100 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Earl et al. 2015 (ARTemis) | 2009-2013 | Phase 3 (E-esc) | Docetaxel | Seems to have superior 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. A total of four bevacizumab doses are given, with the fourth given with the first cycle of FEC.
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 3 cycles
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 contains verified protocol 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
- ARTemis: Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Abraham J, Thomas J, Provenzano E, Hughes-Davies L, Gounaris I, McAdam K, Chan S, Ahmad R, Hickish T, Houston S, Rea D, Bartlett J, Caldas C, Cameron DA, Hayward L; ARTemis Investigators. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):656-66. Epub 2015 May 11. link to original article contains verified protocol PubMed NCT01093235
EDC
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EDC: Epirubicin, Docetaxel, Capecitabine
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Steger et al. 2013 (ABCSG-24) | 2004-2008 | Phase 3 (E-esc) | ED | Seems to have superior pCR rate |
Chemotherapy
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 6 cycles
Subsequent treatment
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 contains protocol PubMed NCT00309556
Epirubicin & Paclitaxel (EP)
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EP: Epirubicin & Paclitaxel
ET: Epirubicin & Taxol (Paclitaxel)
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Untch et al. 2009 (TECHNO) | 1998-2002 | Phase 3 (C) | ddE, then ddP | Seems to have inferior OS |
Frasci et al. 2006 | 1999-2004 | Phase 3 (C) | PET | Seems to have inferior pCR rate |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Chemotherapy
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- Frasci et al. 2006: Surgery, then CMF x 4 or FEC x 4, depending on number of involved lymph nodes
- TECHNO: Surgery, then CMF x 3
References
- Frasci G, D'Aiuto G, Comella P, Thomas R, Botti G, Di Bonito M, De Rosa V, Iodice G, Rubulotta MR, Comella G; Southern Italy Cooperative Oncology Group. Weekly cisplatin, epirubicin, and paclitaxel with granulocyte colony-stimulating factor support vs triweekly epirubicin and paclitaxel in locally advanced breast cancer: final analysis of a SICOG phase III study. Br J Cancer. 2006 Oct 23;95(8):1005-12. link to original article contains protocol 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 contains verified protocol PubMed
FAC
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FAC: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide
Regimen variant #1, 500/50/500
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Arun et al. 2011 (MDACC 91-0156) | 1992-1997 | Phase 3 (C) | DI FAC | Did not meet primary endpoint of pCR rate |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2/day IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
Regimen variant #2, 600/50/600
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Baldini et al. 1997 | NR in abstract | Phase 3 (C) | DES-CAF | Did not meet primary endpoint of pCR rate |
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2/day IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 3 cycles
Subsequent treatment
Regimen variant #3, 1000/50/500
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Buzdar et al. 1999 | 1994-1998 | Phase 3 (C) | Paclitaxel; q3wk x 4 | Did not meet primary endpoint of DFS |
Green et al. 2005 | 1998-2001 | Non-randomized portion of 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
- Green et al. 2005: Weekly paclitaxel x 12 versus q3wk paclitaxel x 4
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 4
- Doxorubicin (Adriamycin) 16.7 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m2)
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
Regimen variant #4, 2000/50/100
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Scholl et al. 1994 (S6) | 1986-1990 | Phase 3 (E-switch-ic) | Adjuvant FAC | Seems to have superior OS |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1, 3, 5, 8
- Doxorubicin (Adriamycin) 25 mg/m2/day 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 contains verified protocol 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 contains protocol 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 contains verified protocol PubMed
- Green MC, Buzdar AU, Smith T, Ibrahim NK, Valero V, Rosales MF, Cristofanilli M, Booser DJ, Pusztai L, Rivera E, Theriault RL, Carter C, Frye D, Hunt KK, Symmans WF, Strom EA, Sahin AA, Sikov W, Hortobagyi GN. Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks. J Clin Oncol. 2005 Sep 1;23(25):5983-92. Epub 2005 Aug 8. link to original article contains verified protocol 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 contains protocol link to PMC article PubMed
FEC
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FEC: Fluorouracil, Epirubicin, Cyclophosphamide
Regimen variant #1, 500/100/500 x 3
Study | Years of enrollment | Evidence |
---|---|---|
Earl et al. 2015 (ARTemis) | 2009-2013 | Non-randomized portion of RCT |
Note that for the patients randomized to the bevacizumab arm, a fourth dose was given with the first cycle of FEC. This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
- Docetaxel & Bevacizumab x 3 versus Docetaxel x 3
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 3 cycles
Subsequent treatment
Regimen variant #2, 500/100/500 x 4 ("FEC 100")
Study | Years of enrollment | Evidence |
---|---|---|
Kelly et al. 2012 (MDACC ID01-580) | 2002-2008 | Non-randomized portion of 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
- Weekly paclitaxel x 12 versus XT
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
Subsequent treatment
Regimen variant #3, 600/60/600 x 3
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Baldini et al. 2003 | 1992-1997 | Phase 3 (C) | Dose-dense FEC | Did not meet primary endpoint of pCR rate |
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 3 cycles
Subsequent treatment
- Surgery, then CEF/CMF x 3
Regimen variant #4, 600/60/600 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
van der Hage et al. 2001 (EORTC 10902) | 1991-1999 | Phase 3 (E-switch-ic) | FEC; adjuvant | Did not meet primary endpoint of OS |
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
Regimen variant #5, 1000/120/1050 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Therasse et al. 2003 (EORTC 10921) | 1993-1996 | Phase III (C) | Dose-dense Cyclophosphamide & Epirubicin (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 contains verified protocol 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 contains verified protocol 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 contains protocol PubMed
- MDACC ID01-580: Kelly CM, Green MC, Broglio K, Thomas ES, Brewster AM, Valero V, Ibrahim NK, Gonzalez-Angulo AM, Booser DJ, Walters RS, Hunt KK, Hortobagyi GN, Buzdar AU. Phase III trial evaluating weekly paclitaxel versus docetaxel in combination with capecitabine in operable breast cancer. J Clin Oncol. 2012 Mar 20;30(9):930-5. Epub 2012 Feb 13. link to original article contains verified protocol PubMed NCT00050167
- ARTemis: Earl HM, Hiller L, Dunn JA, Blenkinsop C, Grybowicz L, Vallier AL, Abraham J, Thomas J, Provenzano E, Hughes-Davies L, Gounaris I, McAdam K, Chan S, Ahmad R, Hickish T, Houston S, Rea D, Bartlett J, Caldas C, Cameron DA, Hayward L; ARTemis Investigators. Efficacy of neoadjuvant bevacizumab added to docetaxel followed by fluorouracil, epirubicin, and cyclophosphamide, for women with HER2-negative early breast cancer (ARTemis): an open-label, randomised, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):656-66. Epub 2015 May 11. link to original article contains verified protocol PubMed NCT01093235
- 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 PubMed NCT01822314
Paclitaxel monotherapy, weekly
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T: Taxol (Paclitaxel)
Regimen variant #1, 80 mg/m2 weekly
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Green et al. 2005 | 1998-2001 | Phase 3 (E-switch-ic) | Paclitaxel; q3wk | Seems to have superior pCR rate |
Kelly et al. 2012 (MDACC ID01-580) | 2002-2008 | Phase 3 (C) | XT | Did not meet primary endpoint of RFS |
Untch et al. 2016 (GeparSepto) | 2012-2013 | Phase 3 (C) | nab-Paclitaxel | 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.
Preceding treatment
- SWOG 0012: AC x 5 versus weekly doxorubicin & daily cyclophosphamide
Chemotherapy
- Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1, 8, 15
21-day cycle for 4 cycles
Subsequent treatment
- Green et al. 2005: FAC x 4, then surgery
- Kelly et al 2012: FEC x 4, then surgery
- GeparSepto: EC x 4, then surgery
Regimen variant #2, 90 mg/m2, 3 out of 4 weeks
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gianni et al. 2018 (ETNA) | 2013-2015 | Phase 3 (C) | nab-Paclitaxel | Did not meet primary endpoint of pCR rate |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Chemotherapy
- Paclitaxel (Taxol) 90 mg/m2 IV once per day on days 1, 8, 15
4-week cycle for 4 cycles
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 contains verified protocol PubMed
- MDACC ID01-580: Kelly CM, Green MC, Broglio K, Thomas ES, Brewster AM, Valero V, Ibrahim NK, Gonzalez-Angulo AM, Booser DJ, Walters RS, Hunt KK, Hortobagyi GN, Buzdar AU. Phase III trial evaluating weekly paclitaxel versus docetaxel in combination with capecitabine in operable breast cancer. J Clin Oncol. 2012 Mar 20;30(9):930-5. Epub 2012 Feb 13. link to original article contains verified protocol PubMed NCT00050167
- GeparSepto: Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Wiebringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Darb-Esfahani S, Schmitt WD, Dan Costa S, Gerber B, Engels K, Nekljudova V, Loibl S, von Minckwitz G; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie—Breast (AGO-B) Investigators. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. Epub 2016 Feb 8. 2016 Mar;17(3):345-56. link to original article contains verified protocol 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 contains verified protocol PubMed NCT01822314
Paclitaxel monotherapy, dose-dense (q2wk)
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ddT: dose-dense Taxol (Paclitaxel)
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Burstein et al. 2005 | 2003-2004 | Non-randomized | ||
Earl et al. 2013 (Neo-tAnGo) | 2005-2007 | Phase 3 (C) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
Supportive medications
- Burstein et al. 2005: Pegfilgrastim (Neulasta) 6 mg SC once on day 2
- Neo-tAnGo: primary propyhylaxis not provided
14-day cycle for 4 cycles
Subsequent treatment
- Burstein et al. 2005 and Neo-tAnGo (EC-ddT arm): Surgery
- Neo-tAnGo (ddT-EC arm): EC x 4, then surgery
References
- Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. link to original article contains verified protocol PubMed
- Neo-tAnGo: Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, Iddawela M, Abraham J, Hughes-Davies L, Gounaris I, McAdam K, Houston S, Hickish T, Skene A, Chan S, Dean S, Ritchie D, Laing R, Harries M, Gallagher C, Wishart G, Dunn J, Provenzano E, Caldas C; Neo-tAnGo Investigators. Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2×2 factorial randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):201-12. Epub 2013 Dec 19. link to original article contains verified protocol PubMed NCT00070278
nab-Paclitaxel monotherapy
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Untch et al. 2016 (GeparSepto) | 2012-2013 | Phase 3 (E-switch-ic) | Paclitaxel; weekly | Superior pCR rate |
Note: this is the dose after study amendment due to increased treatment discontinuation and sensory neuropathy. This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m2 IV once per day on days 1, 8, 15
21-day cycle for 4 cycles
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. Epub 2016 Feb 8. 2016 Mar;17(3):345-56. link to original article contains verified protocol 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 PubMed NCT01822314
PET
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PET: Platinol (Cisplatin), Epirubicin, Taxol (Paclitaxel)
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Frasci et al. 2006 | 1999-2004 | Phase 3 (E-esc) | EP | Seems to have superior pCR rate |
Chemotherapy
- Cisplatin (Platinol) 30 mg/m2 IV once per day on days 1, 8, 15
- Epirubicin (Ellence) 50 mg/m2 IV once per day on days 1, 8, 15
- Paclitaxel (Taxol) 120 mg/m2 IV once per day on days 1, 8, 15
21-day cycle for 4 cycles
Subsequent treatment
- Frasci et al. 2006: Surgery
References
- Frasci G, D'Aiuto G, Comella P, Thomas R, Botti G, Di Bonito M, De Rosa V, Iodice G, Rubulotta MR, Comella G; Southern Italy Cooperative Oncology Group. Weekly cisplatin, epirubicin, and paclitaxel with granulocyte colony-stimulating factor support vs triweekly epirubicin and paclitaxel in locally advanced breast cancer: final analysis of a SICOG phase III study. Br J Cancer. 2006 Oct 23;95(8):1005-12. link to original article contains protocol link to PMC article PubMed
TAC (Taxotere)
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TAC: Taxotere (Docetaxel), Adriamycin (Doxorubicin), Cyclophosphamide
ATC: Adriamycin (Doxorubicin), Taxotere (Docetaxel), Cyclophosphamide
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2008 (GeparTrio) | 2002-2005 | Phase 3 (E-switch-ic) | TAC x 2, then NX x 4 | Non-inferior sonographic response |
Vriens et al. 2013 (INTENS) | 2006-2009 | Phase 3 (E-switch-ic) | AC, then T | 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 contains verified protocol PubMed NCT00544765
- INTENS: Vriens BE, Aarts MJ, de Vries B, van Gastel SM, Wals J, Smilde TJ, van Warmerdam LJ, de Boer M, van Spronsen DJ, Borm GF, Tjan-Heijnen VC; BOOG. Doxorubicin/cyclophosphamide with concurrent versus sequential docetaxel as neoadjuvant treatment in patients with breast cancer. Eur J Cancer. 2013 Oct;49(15):3102-10. Epub 2013 Jul 10. link to original article contains protocol 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)
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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
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- 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)
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- 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)
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- 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
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- 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
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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
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This system is proprietary to the AJCC. Please visit their site or consult the AJCC Manual for further details.
Adjuvant chemotherapy
AC-CMF
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AC-CMF: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Cyclophosphamide, Methotrexate, Fluorouracil
Protocol
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Basser et al. 2006 (IBCSG 15-95) | 1995-2000 | Phase 3 (C) | DI-EC | Seems to have inferior DFS1 |
1Reported efficacy is based on the 2009 update.
Preceding treatment
Chemotherapy, AC portion
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles, followed by:
Chemotherapy, CMF portion
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 3 cycles
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 contains verified protocol 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
AC-D
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AC-D: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Docetaxel
Protocol
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Swain et al. 2010 (NSABP B-30) | 1999-2004 | Phase 3 (E-switch-ic) | 1. AT | Seems to have superior OS |
2. TAC | Might have superior OS | |||
Eiermann et al. 2011 (BCIRG-005) | 2000-2003 | Phase 3 (E-switch-ic) | TAC | Did not meet primary endpoint of DFS60 |
Preceding treatment
Chemotherapy, AC portion
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles, followed by:
Chemotherapy, D portion
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 4 cycles
References
- NSABP B-30: Swain SM, Jeong JH, Geyer CE Jr, Costantino JP, Pajon ER, Fehrenbacher L, Atkins JN, Polikoff J, Vogel VG, Erban JK, Rastogi P, Livingston RB, Perez EA, Mamounas EP, Land SR, Ganz PA, Wolmark N. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med. 2010 Jun 3;362(22):2053-65. link to original article link to PMC article contains verified protocol 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 contains verified protocol 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
AC-T
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AC-T: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel)
Protocol #1, q3wk paclitaxel
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Citron et al. 2003 (CALGB 9741) | 1997-1999 | Phase 3 (C) | See link | See link |
Loesch et al. 2010 | 2000-2002 | Phase 3 (C) | See link | See link |
Burnell et al. 2009 (NCIC-CTG MA.21) | 2000-2005 | Phase 3 (C) | See link | See link |
Note: this regimen has been studied in many trials; these may be referenced under the individual components AC or T. Over time we will migrate these studies here.
Preceding treatment
Chemotherapy, AC portion
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles, followed by:
Chemotherapy, T portion
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
21-day cycle for 4 cycles
Protocol #2, weekly paclitaxel
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fehrenbacher et al. 2019 (NSABP B-47) | 2011-2015 | Phase 3 (C) | 1. AC-T & Trastuzumab 2. Dose-dense AC-T & Trastuzumab 3. TC & Trastuzumab |
Did not meet primary endpoint of IDFS |
Note: this regimen has been studied in many trials; these may be referenced under the individual components AC or T. Over time we will migrate these studies here.
Biomarker eligiblity 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
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles, followed by:
Chemotherapy, T portion
- Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
7-day cycle for 12 cycles
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 contains verified protocol PubMed NCT00003088
- NCIC-CTG MA.21: Burnell M, Levine MN, Chapman JA, Bramwell V, Gelmon K, Walley B, Vandenberg T, Chalchal H, Albain KS, Perez EA, Rugo H, Pritchard K, O'Brien P, Shepherd LE. Cyclophosphamide, epirubicin, and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol. 2010 Jan 1;28(1):77-82. Epub 2009 Nov 9. link to original article link to PMC article contains verified protocol 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 contains verified protocol 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 contains verified protocol PubMed NCT01275677
Dose-dense AC-T
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ddAC-T: dose-dense Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel)
Protocol #1, q2wk paclitaxel
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Citron et al. 2003 (CALGB 9741) | 1997-1999 | Phase 3 (E-esc) | See link | See link |
Preceding treatment
Chemotherapy, ddAC portion
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Supportive medications
- Filgrastim (Neupogen) 5 mcg/kg (rounded to either 300 or 480 mcg) SC once per day on days 3 to 10
- Note: Citron et al. 2003 says the schedule was "filgrastim days 3 to 10 of each cycle (a total of seven doses)," so it is unclear whether 7 or 8 doses was actually used).
14-day cycle for 4 cycles, followed by:
Chemotherapy, T portion
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
Supportive medications
- Diphenhydramine (Benadryl) 12.5 to 50 mg IV once on day 1; 30 to 60 minutes prior to Paclitaxel (Taxol)
- One of the following H2 blockers:
- Ranitidine (Zantac) 50 mg IV once on day 1; 30 to 60 minutes prior to Paclitaxel (Taxol)
- Cimetidine (Tagamet) 300 mg IV once on day 1; 30 to 60 minutes prior to Paclitaxel (Taxol)
- Famotidine (Pepcid) 20 mg IV once on day 1; 30 to 60 minutes prior to Paclitaxel (Taxol)
- One of the following dexamethasone choices:
- Dexamethasone (Decadron) 10 mg IV once on day 1, within 60 minutes prior to Paclitaxel (Taxol)
- Dexamethasone (Decadron) 10 mg PO once on day 1, at least 60 minutes prior to Paclitaxel (Taxol)
- Dexamethasone (Decadron) 20 mg PO twice on day 1; 6 hours and 12 hours prior to Paclitaxel (Taxol)
- Recommended growth factor support with one of the following:
- Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
- Sargramostim (Leukine) 250 to 500 mcg/m2 SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
- Pegfilgrastim (Neulasta) 6 mg SC once, given 24 to 36 hours after chemotherapy
- GIM2: a mid-protocol amendment suggested giving the pegilgrastim at least 72 h after chemotherapy
14-day cycle for 4 cycles
Protocol #2, weekly paclitaxel
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fehrenbacher et al. 2019 (NSABP B-47) | 2011-2015 | Phase 3 (C) | 1. AC-T & Trastuzumab 2. Dose-dense AC-T & Trastuzumab 3. TC & Trastuzumab |
Did not meet primary endpoint of IDFS |
Note: Fehrenbacher et al. 2019 does not explicitly describe the use of filgrastim, but it is typically used for this regimen.
Biomarker eligiblity 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
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Supportive medications
- Filgrastim (Neupogen) 5 mcg/kg (rounded to either 300 or 480 mcg) SC once per day on days 3 to 10
14-day cycle for 4 cycles
Chemotherapy, T portion
- Paclitaxel (Taxol) 80 mg/m2 IV once on day 1
7-day cycle for 12 cycles
References
- CALGB 9741: Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. link to original article contains verified protocol PubMed NCT00003088
- NSABP B-47: Fehrenbacher L, Cecchini RS, Geyer CE Jr, Rastogi P, Costantino JP, Atkins JN, Crown JP, Polikoff J, Boileau JF, Provencher L, Stokoe C, Moore TD, Robidoux A, Flynn PJ, Borges VF, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020 Feb 10;38(5):444-453. Epub 2019 Dec 10. link to original article link to PMC article contains verified protocol PubMed NCT01275677
Bevacizumab monotherapy
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bear et al. 2012 (NSABP B-40) | 2007-2010 | Phase 3 (E-esc) | See link | See link |
Preceding treatment
- Neoadjuvant AC+Bev x 4, then surgery
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for 10 cycles
References
- NSABP B-40: Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. link to original article link to PMC article contains verified protocol 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
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Regimen variant #1, 4 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Martín et al. 2015 (GEICAM 2003-10) | 2004-2007 | Phase 3 (E-switch-ic) | See link | See link |
Cameron et al. 2017 (TACT2) | 2005-2008 | Phase 3 (E-de-esc) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
- GEICAM 2003-10: ET x 4
- TACT2: ddE x 4 versus Epirubicin x 4
Chemotherapy
- Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 4 cycles
Regimen variant #2, 6 to 8 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Muss et al. 2009 (CALGB 49907) | 2001-2006 | Phase 3 (E-de-esc) | Physician's choice of: 1. AC x 4 2. CMF x 6 |
Seems to have inferior OS |
Masuda et al. 2017 (CREATE-X) | 2007-2012 | Phase 3 (E-esc) | Standard therapy | Superior OS (HR 0.59, 95% CI 0.39-0.90) |
Note: patients in CALGB 49907 received a maximum of 6 cycles. All patients in CREATE-X had residual disease at time of surgical resection. Concomitant endocrine therapy was allowed.
Preceding treatment
- CALGB 49907: Surgery
- CREATE-X: Neoadjuvant chemotherapy containing anthracycline, taxane, or both, then surgery
Chemotherapy
- Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 6 to 8 cycles
References
- CALGB 49907: Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Becker HP, Kartcheske PA, Wheeler JD, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Magrinat G, Parker BA, Hart RD, Grenier D, Norton L, Hudis CA, Winer EP; CALGB. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009 May 14;360(20):2055-65. Erratum in: N Engl J Med. 2009 Oct 22;361(17):1714. Magrinat, Gutav [corrected to Magrinat, Gustav]. link to original article link to PMC article contains verified protocol PubMed NCT00024102
- GEICAM 2003-10: Martín M, Ruiz Simón A, Ruiz Borrego M, Ribelles N, Rodríguez-Lescure A, Muñoz-Mateu M, González S, Margelí Vila M, Barnadas A, Ramos M, Del Barco Berron S, Jara C, Calvo L, Martínez-Jáñez N, Mendiola Fernández C, Rodríguez CA, Martínez de Dueñas E, Andrés R, Plazaola A, de la Haba-Rodríguez J, López-Vega JM, Adrover E, Ballesteros AI, Santaballa A, Sánchez-Rovira P, Baena-Cañada JM, Casas M, del Carmen Cámara M, Carrasco EM, Lluch A. Epirubicin plus cyclophosphamide followed by docetaxel versus epirubicin plus docetaxel followed by capecitabine as adjuvant therapy for node-positive early breast cancer: results from the GEICAM/2003-10 study. J Clin Oncol. 2015 Nov 10;33(32):3788-95. Epub 2015 Sep 28. link to original article contains verified protocol PubMed NCT00129935
- CREATE-X: Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, Kuroi K, Im SA, Park BW, Kim SB, Yanagita Y, Ohno S, Takao S, Aogi K, Iwata H, Jeong J, Kim A, Park KH, Sasano H, Ohashi Y, Toi M. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017 Jun 1;376(22):2147-2159. link to original article contains verified protocol PubMed UMIN000000843
- TACT2: Cameron D, Morden JP, Canney P, Velikova G, Coleman R, Bartlett J, Agrawal R, Banerji J, Bertelli G, Bloomfield D, Brunt AM, Earl H, Ellis P, Gaunt C, Gillman A, Hearfield N, Laing R, Murray N, Couper N, Stein RC, Verrill M, Wardley A, Barrett-Lee P, Bliss JM; TACT2 Investigators. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2017 Jul;18(7):929-945. Epub 2017 Jun 7. link to original article link to PMC article contains verified protocol PubMed NCT00301925
CMF
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CMF: Cyclophosphamide, Methotrexate, Fluorouracil
Regimen variant #1, 600/40/600 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ron et al. 2001 | 1988-1992 | Phase 3 (C) | CNF | Seems to have inferior DFS |
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
- Methotrexate (MTX) 40 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Regimen variant #2, 600/40/600 x 8
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Buzzoni et al. 1991 (Milan trial) | 1982-1987 | Phase 3 (E-switch-ic) | See link | See link |
Overgaard et al. 1997 (DBCG 82b) | 1982-1989 | Phase 3 (E-switch-ooc) | See link | See link |
Note: in DBCG 82b, radiotherapy was given between cycles 1 & 2
Preceding treatment
- Milan trial: Surgery, then A x 4
- DBCG 82b: Mastectomy
Chemotherapy
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
- Methotrexate (MTX) 40 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
28-day cycle for 8 cycles
Regimen variant #3, 600/50/600 x 8
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Leonard et al. 2004 | 1995-1999 | Phase 3 (C) | Cyclophosphamide & Thiotepa with auto HSCT | Did not meet primary endpoint of RFS |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
- Methotrexate (MTX) 50 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
28-day cycle for 8 cycles
Regimen variant #4, 700/30/700 x 24
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Clahsen et al. 1995 (EORTC 09771) | 1976-1980 | Phase 3 (E-esc) | Observation | Seems to have superior OS |
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 50 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 15 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 350 mg/m2 IV once per day on days 1 & 8
1-month cycle for 24 cycles
Regimen variant #5, 750/50/600 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Poole et al. 2006 (BR9601) | 1996-2001 | Phase 3 (E-switch-ic) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
- E x 4
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 4 cycles
Regimen variant #6, 750/50/600 x 8
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Stewart et al. 1993 | 1980-1990 | Phase 3 (C) | 1. CMFP 2. Oophorectomy 3. Oophorectomy & Prednisolone |
Did not meet primary endpoint of EFS |
Poole et al. 2006 (BR9601) | 1996-2001 | Phase 3 (C) | Epirubicin, then CMF x 4 | Inferior OS |
Note: after 1984, patients in Stewart et al. 1993 only received 6 cycles.
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 8 cycles (see note)
Regimen variant #7, 840/50/800
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hubay et al. 1980 | NR | Randomized (C) | 1. CMFT | Seems to have inferior RFS |
2. CMFT & BCG | Did not meet endpoints of RFS/OS |
Preceding treatment
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 #8, 1000/80/1000 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kimura et al. 2009 | 1996-2000 | Phase 3 (C) | FEC | Did not meet primary endpoint of DFS |
Preceding treatment
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 #9, 1000/80/1200 x 3
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Zander et al. 2004 | 1993-2000 | Phase 3 (C) | Cyclophosphamide, Mitoxantrone, Thiotepa with auto HSCT | Might have inferior EFS |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 8
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 3 cycles
Regimen variant #10, 1000/80/1200 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Jonat et al. 2002 (ZEBRA) | 1990-1996 | Phase 3 (C) | Goserelin x 2 y | Did not meet primary endpoint of DFS |
Schmid et al. 2007 (TABLE) | 1995-1998 | Phase 3 (C) | Leuprolide | Inferior OS |
Preceding treatment
- Surgery, within 6 weeks
Chemotherapy
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once per day on days 1 & 8
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 cycles
Regimen variant #11, 1120/60/1000 x 12
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brincker et al. 1983 (DBCG 77B) | 1977-1983 | Phase 3 (E-esc) | 1. Cyclophosphamide | Did not meet primary endpoint of RFS |
2. Levamisole | Not reported | |||
3. No chemotherapy | Seems to have superior OS1 |
1Reported efficacy versus no chemotherapy is based on the 2010 update.
Preceding treatment
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 | Years 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 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Poole et al. 2006 (NEAT) | 1996-2001 | Phase 3 (E-esc) | See link | See link |
Gianni et al. 2009 (ECTO) | 1996-2002 | Phase 3 (C) | See link | See link |
Ellis et al. 2009 (TACT) | 2001-2003 | Randomized Phase II (C) | See link | See link |
Perrone et al. 2014 (ELDA) | 2003-2011 | Phase 3 (C) | Docetaxel | Did not meet primary endpoint of DFS |
Cameron et al. 2017 (TACT2) | 2005-2008 | Phase 3 (C) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. In ELDA, this protocol was for ER/PR+ patients.
Preceding treatment
- NEAT, TACT, TACT2: Surgery, then E x 4
- ECTO: Surgery, then A x 4 versus AT (Taxol) x 4
Chemotherapy
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once per day on days 1 & 8
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 4 cycles
Regimen variant #14, 1200/80/1200 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ragaz et al. 1997 | 1978-1986 | Phase 3 (C) | CMF & RT | Seems to have inferior OS |
Coombes et al. 1996 | 1984-1992 | Phase 3 (C) | FEC | Did not meet primary endpoints of RFS/OS |
Taucher et al. 2007 (ABCSG-07) | 1991-1999 | Phase 3 (C) | CMF; neoadjuvant | Seems to have superior RFS |
Poole et al. 2006 (NEAT) | 1996-2001 | Phase 3 (C) | Epirubicin, then CMF x 4 | Inferior OS |
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 #15, 1400/80/1000 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Watanabe et al. 2009 (NSAS BC-01) | 1996-2001 | Phase 3 (C) | UFT | Inconclusive whether non-inferior RFS |
Preceding treatment
Chemotherapy
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 cycles
Regimen variant #16, 1400/80/1200 x 3
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Castiglione-Gertsch et al. 1996 (IBCSG VI) | 1986-1993 | Phase 3 (E-de-esc) | 1. CMF x 6 | Seems to have inferior DFS |
2. CMF x 3, with re-introduction 3. CMF x 6, with re-introduction |
Might have inferior DFS | |||
Colleoni et al. 2006 (IBCSG 13-93) | 1993-1999 | Non-randomized portion of RCT |
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
- IBCSG VI: Tamoxifen x 5 y versus no further treatment
Regimen variant #17, 1400/80/1200 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Poole et al. 2006 (NEAT) | 1996-2001 | Phase 3 (E-esc) | See link | See link |
Cameron et al. 2017 (TACT2) | 2005-2008 | Phase 3 (C) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
- E x 4
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 4 cycles
Regimen variant #18, 1400/80/1200 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Tancini et al. 1979 | 1975-NR | Phase 3 (E-de-esc) | CMF x 12 | Did not meet primary endpoint of RFS |
Coombes et al. 1996 | 1984-1992 | Phase 3 (C) | FEC | Did not meet primary endpoints of RFS/OS |
Castiglione-Gertsch et al. 1996 (IBCSG VI) | 1986-1993 | Phase 3 (C) | 1. CMF x 3 | Seems to have superior DFS |
2. CMF x 3, with re-introduction 3. CMF x 6, with re-introduction |
Might have inferior DFS | |||
Piccart et al. 2001 (Belgian trial) | 1988-1996 | Phase 3 (C) | 1. EC; full-dose | Did not meet primary endpoint of EFS |
2. EC; moderate-dose | Did not meet primary endpoint of EFS | |||
Levine et al. 1998 (NCIC-CTG MA.5) | 1989-1993 | Phase 3 (C) | CEF | Inferior RFS |
Amadori et al. 2000 | 1989-1993 | Phase 3 (E-esc) | Observation | Seems to have superior DFS |
Hutchins et al. 2005 (INT-0102) | 1989-1993 | Phase 3 (C) | CAF | Seems to have inferior OS |
Jonat et al. 2002 (ZEBRA) | 1990-1996 | Phase 3 (C) | Goserelin x 2 y | Did not meet primary endpoint of DFS |
Fisher et al. 2001 (NSABP B-23) | 1991-1998 | Phase 3 (C) | AC | Did not meet primary endpoint of OS |
Adjuvant Breast Cancer Trials Collaborative Group 2007 (NCRI ABC-CT) | 1992-2000 | Phase 3 (E-esc) | Observation | Seems to have superior OS (HR 0.83, 95% CI 0.70-0.99) |
Poole et al. 2006 (NEAT) | 1996-2001 | Phase 3 (C) | Epirubicin, then CMF x 4 | Inferior OS |
Muss et al. 2009 (CALGB 49907) | 2001-2006 | Phase 3 (C) | Capecitabine | Seems to have superior 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 6 cycles
Subsequent treatment
Regimen variant #19, 1400/80/1200 x 12
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bonadonna et al. 1976 | 1973-1975 | Phase 3 (E-esc) | Observation | Superior RFS |
Tancini et al. 1979 | 1975-NR | Phase 3 (C) | CMF x 6 | Did not meet primary endpoint of RFS |
Misset et al. 1996 (OncoFrance) | 1978-1981 | Phase 3 (C) | AVCF | Inferior OS |
Tormey et al. 1990 (ECOG E5177) | 1978-1982 | Phase 3 (C) | 1. CMFP 2. CMFPT |
Did not meet primary endpoints of TTR/OS |
Preceding treatment
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 contains verified protocol 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
- 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 contains verified protocol 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
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- ECOG E5177: Tormey DC, Gray R, Gilchrist K, Grage T, Carbone PP, Wolter J, Woll JE, Cummings FJ. Adjuvant chemohormonal therapy with cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen compared with CMF for premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial. Cancer. 1990 Jan 15;65(2):200-6. link to original article contains verified protocol PubMed
- Milan trial: Buzzoni R, Bonadonna G, Valagussa P, Zambetti M. Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes. J Clin Oncol. 1991 Dec;9(12):2134-40. link to original article PubMed
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- Coombes RC, Bliss JM, Wils J, Morvan F, Espié M, Amadori D, Gambrosier P, Richards M, Aapro M, Villar-Grimalt A, McArdle C, Pérez-López FR, Vassilopoulos P, Ferreira EP, Chilvers CE, Coombes G, Woods EM, Marty M; International Collaborative Cancer Group. Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. J Clin Oncol. 1996 Jan;14(1):35-45. link to original article contains verified protocol 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 contains verified protocol 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 contains verified protocol 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
- DBCG 82b: Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, Kjaer M, Gadeberg CC, Mouridsen HT, Jensen MB, Zedeler K. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy: Danish Breast Cancer Cooperative Group 82b trial. N Engl J Med. 1997 Oct 2;337(14):949-55. link to original article contains verified protocol 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 contains protocol 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 contains protocol 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 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 contains verified protocol 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
- Belgian trial: Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M, Nogaret JM. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol. 2001 Jun 15;19(12):3103-10. link to original article PubMed
- 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 contains verified protocol PubMed
- Zander AR, Kröger N, Schmoor C, Krüger W, Möbus V, Frickhofen N, Metzner B, Schultze W, Berdel WE, Koenigsmann M, Thiel E, Wandt H, Possinger K, Trümper L, Kreienberg R, Carstensen M, Schmidt EH, Jänicke F, Schumacher M, Jonat W. High-dose chemotherapy with autologous hematopoietic stem-cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: first results of a randomized trial. J Clin Oncol. 2004 Jun 15;22(12):2273-83. Epub 2004 Apr 26. link to original article contains protocol 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 contains protocol 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
- IBCSG 13-93: Colleoni M, Gelber S, Goldhirsch A, Aebi S, Castiglione-Gertsch M, Price KN, Coates AS, Gelber RD; International Breast Cancer Study Group. Tamoxifen after adjuvant chemotherapy for premenopausal women with lymph node-positive breast cancer: International Breast Cancer Study Group Trial 13-93. J Clin Oncol. 2006 Mar 20;24(9):1332-41. Epub 2006 Feb 27. link to original article contains verified protocol PubMed
- NEAT/BR9601: Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. link to original article PubMed NCT00003577; 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 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 contains verified protocol 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 contains verified protocol 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 contains protocol 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 contains verified protocol PubMed NCT00152191
- ECTO: Gianni L, Baselga J, Eiermann W, Porta VG, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Cussac AL, Bozhok A, Martinez-Agulló A, Greco M, Byakhov M, Lopez JJ, Mansutti M, Valagussa P, Bonadonna G. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. J Clin Oncol. 2009 May 20;27(15):2474-81. Epub 2009 Mar 30. link to original article contains verified protocol PubMed NCT00003013
- TACT: Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. link to original article link to PMC article contains protocol 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 contains verified protocol PubMed NCT00024102
- Kimura M, Tominaga T, Takatsuka Y, Toi M, Abe R, Koyama H, Takashima S, Nomura Y, Miura S, Kimijima I, Tashiro H, Ohashi Y; Adjuvant CEF Research Group for Breast Cancer. Randomized trial of cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil with node-positive breast cancer in Japan. Breast Cancer. 2010 Jul;17(3):190-8. Epub 2009 Jul 3. link to original article contains protocol 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 contains protocol PubMed NCT00331097
- TACT2: Cameron D, Morden JP, Canney P, Velikova G, Coleman R, Bartlett J, Agrawal R, Banerji J, Bertelli G, Bloomfield D, Brunt AM, Earl H, Ellis P, Gaunt C, Gillman A, Hearfield N, Laing R, Murray N, Couper N, Stein RC, Verrill M, Wardley A, Barrett-Lee P, Bliss JM; TACT2 Investigators. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2017 Jul;18(7):929-945. Epub 2017 Jun 7. link to original article link to PMC article contains verified protocol PubMed NCT00301925
CMFT
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CMFT: Cyclophosphamide, Methotrexate, Fluorouracil, Tamoxifen
Regimen variant #1, 600/40/600/30
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Overgaard et al. 1999 (DBCG 82C) | 1982-1990 | Phase 3 (E-esc) | 1. Tamoxifen | Superior DFS1 |
2. Tamoxifen & RT | Not reported |
1Reported efficacy for this arm versus tamoxifen monotherapy is based on the 2013 update.
Preceding treatment
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
Endocrine therapy
- Tamoxifen (Nolvadex) 30 mg PO once per day
28-day cycle for 9 cycles (tamoxifen continued for one year total)
Regimen variant #2, 840/50/800/40
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hubay et al. 1980 | NR | Randomized (E-RT-esc) | 1. CMF | Seems to have superior RFS |
2. CMFT & BCG | Did not meet endpoints of RFS/OS |
Preceding treatment
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
- NCIC-CTG MA.4: Pritchard KI, Paterson AH, Paul NA, Zee B, Fine S, Pater J; National Cancer Institute of Canada Clinical Trials Group. Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. J Clin Oncol. 1996 Oct;14(10):2731-7. link to original article PubMed
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- NSABP B-20: Fisher B, Dignam J, Wolmark N, DeCillis A, Emir B, Wickerham DL, Bryant J, Dimitrov NV, Abramson N, Atkins JN, Shibata H, Deschenes L, Margolese RG. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst. 1997 Nov 19;89(22):1673-82. link to original article contains verified protocol PubMed
- 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 contains protocol 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 contains verified protocol PubMed
Dose-dense Cyclophosphamide monotherapy
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ddC: dose-dense Cyclophosphamide
Regimen variant #1, 600 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Citron et al. 2003 (CALGB 9741) | 1997-1999 | Phase 3 (E-esc) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
- ddT x 4
Chemotherapy
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Supportive medications
- Filgrastim (Neupogen) 5 mcg/kg (rounded to either 300 or 480 mcg) SC once per day on days 3 to 10
- Note: Citron et al. 2003 says the schedule was "filgrastim days 3 to 10 of each cycle (a total of seven doses)," so it is unclear whether 7 or 8 doses was actually used).
14-day cycle for 4 cycles
Regimen variant #2, 800 mg/m2
Study | Years of enrollment | Evidence |
---|---|---|
Kahan et al. 2005 | 2000-2003 | Phase II |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
- ddT x 4
Chemotherapy
- Cyclophosphamide (Cytoxan) 800 mg/m2 IV once on day 1
Supportive medications
14-day cycle for 4 cycles
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 contains verified protocol 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 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
Cyclophosphamide & Docetaxel (TC)
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TC: Taxotere (Docetaxel) & Cyclophosphamide
DC: Docetaxel & Cyclophosphamide
Regimen variant #1, 4 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Jones et al. 2006 (USOR 9735) | 1997-1999 | Phase 3 (E-switch-ic) | AC | Seems to have superior OS |
Blum et al. 2017 (USOR 06-090) | 2007-2009 | Phase 3 (C) | TAC | Seems to have inferior IDFS |
Blum et al. 2017 (NSABP-46-I/USOR 07132) | 2009-2012 | Phase 3 (C) | TAC | Seems to have inferior IDFS |
Blum et al. 2017 (NSABP B-49) | 2012-2013 | Phase 3 (C) | TAC | Seems to have inferior IDFS |
Note: Blum et al. 2017 is a pooled analysis of three RCTs, some of which had arms other than TAC and TC. Refer to the paper for further details.
Preceding treatment
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Supportive medications
- All cycles given with Filgrastim (Neupogen) support
21-day cycle for 4 cycles
Regimen variant #2, 6 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Nitz et al. 2019 (WSG PlanB) | 2000-2005 | Phase 3 (E-de-esc) | EC, then D | Non-inferior DFS |
Mavroudis et al. 2016 (HORG CT/07.17) | 2007-2013 | Phase 3 (E-de-esc) | ddFEC, then D | Inconclusive whether non-inferior DFS36 |
Ejlertsen et al. 2017 (DBCG 07-READ) | 2008-2012 | Phase 3 (E-de-esc) | EC, then D | Did not meet primary endpoint of DFS |
Fehrenbacher et al. 2019 (NSABP B-47) | 2011-2015 | Phase 3 (C) | 1. AC-T & Trastuzumab 2. Dose-dense AC-T & Trastuzumab 3. TC & Trastuzumab |
Did not meet primary endpoint of IDFS |
Biomarker eligiblity 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 contains verified protocol PubMed NCT01985724
- USOR 06-090; NSABP-46-I/USOR 07132; NSABP B-49: Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article contains verified protocol PubMed NCT00493870; NCT00887536; NCT01547741
- DBCG 07-READ: Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen MB, Knoop AS, Højris I, Ewertz M, Balslev E, Danø H, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. Adjuvant cyclophosphamide and docetaxel with or without epirubicin for early TOP2A-normal breast cancer: DBCG 07-READ, an open-label, phase III, randomized trial. J Clin Oncol. 2017 Aug 10;35(23):2639-2646. Epub 2017 Jun 29. link to original article contains verified protocol PubMed NCT00689156
- WSG PlanB: Nitz U, Gluz O, Clemens M, Malter W, Reimer T, Nuding B, Aktas B, Stefek A, Pollmanns A, Lorenz-Salehi F, Uleer C, Krabisch P, Kuemmel S, Liedtke C, Shak S, Wuerstlein R, Christgen M, Kates RE, Kreipe HH, Harbeck N; West German Study Group. West German Study PlanB trial: adjuvant four cycles of epirubicin and cyclophosphamide plus docetaxel versus six cycles of docetaxel and cyclophosphamide in HER2-negative early breast cancer. J Clin Oncol. 2019 Apr 1;37(10):799-808. Epub 2019 Feb 20. link to original article contains protocol PubMed NCT01049425
- NSABP B-47: Fehrenbacher L, Cecchini RS, Geyer CE Jr, Rastogi P, Costantino JP, Atkins JN, Crown JP, Polikoff J, Boileau JF, Provencher L, Stokoe C, Moore TD, Robidoux A, Flynn PJ, Borges VF, Albain KS, Swain SM, Paik S, Mamounas EP, Wolmark N. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020 Feb 10;38(5):444-453. Epub 2019 Dec 10. link to original article link to PMC article contains verified protocol PubMed NCT01275677
Cyclophosphamide & Doxorubicin (AC)
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AC: Adriamycin (Doxorubicin) and Cyclophosphamide
CA: Cyclophosphamide and Adriamycin (Doxorubicin)
Regimen variant #1, 54/1200 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Linden et al. 2007 (INT-0137) | 1994-1997 | Phase 3 (C) | A, then C | Did not meet primary endpoint of DFS |
Preceding treatment
Chemotherapy
- Doxorubicin (Adriamycin) 54 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 1200 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Regimen variant #2, 60/600 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fisher et al. 1997 (NSABP B-18) | 1988-1993 | Phase 3 (C) | AC; neoadjuvant | Inferior resectability |
Fisher et al. 1997 (NSABP B-22) | 1989-1991 | Phase 3 (C) | 1. AC; intensified 2. AC; intensified & increased |
Did not meet primary endpoints of DFS/OS |
Fisher et al. 2001 (NSABP B-23) | 1991-1998 | Phase 3 (E-switch-ic) | CMF | Did not meet primary endpoint of OS |
Içli et al. 2001 | 1992-1996 | Non-randomized portion of RCT | ||
Colleoni et al. 2006 (IBCSG 13-93) | 1993-1999 | Non-randomized portion of RCT | ||
Henderson et al. 2003 (INT 0148/CALGB 9344) | 1994-1999 | Phase 3 (C) | 1. AC; high-dose 2. AC; very high dose |
Did not meet primary endpoint of DFS |
Mamounas et al. 2005 (NSABP B-28) | 1995-1998 | Non-randomized portion of RCT | ||
Jones et al. 2006 (USOR 9735) | 1997-1999 | Phase 3 (C) | TC | Seems to have inferior OS |
Francis et al. 2008 (BIG 02-98) | 1998-2001 | Phase 3 (C) | See link | See link |
Goldstein et al. 2008 (ECOG E2197) | 1998-2000 | Phase 3 (C) | AT (Taxotere) | Did not meet primary endpoint of DFS |
Sparano et al. 2008 (ECOG E1199) | 1999-2002 | Non-randomized portion of RCT | ||
Brain et al. 2005 (RAPP-01) | 1999-2003 | Phase 3 (C) | AT (Taxotere) | Not reported |
Muss et al. 2009 (CALGB 49907) | 2001-2006 | Phase 3 (C) | Capecitabine | Seems to have superior OS |
Watanabe et al. 2017 (NSAS BC-02) | 2001-2006 | Phase 3 (C) | See link | See link |
Miller et al. 2018 (ECOG E5103) | 2007-2011 | Phase 3 (C) | See link | See link |
Preceding treatment
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- NSABP B-23: Tamoxifen x 5 y versus placebo
- Içli et al. 2001: EP x 2 versus no further treatment
- INT 0148/CALGB 9344 and NSABP B-28: q3wk T (Taxol) x 4 versus no further therapy
- IBCSG 13-93: CMF x 3, then Tamoxifen x 5 y versus no further treatment
- BIG 02-98: CMF x 3
- ECOG E1199: q3wk T (Taxotere) x 4 versus weekly T (Taxotere) x 12 versus q3wk T (Taxol) x 4 versus weekly T (Taxol) x 12
- NSAS BC-02: q3wk T (Taxotere) x 4 versus T (Taxol) q3wk x 4
- ECOG E5103: weekly T (Taxol) x 12
Regimen variant #3, 80/600 x 4
Study | Years of enrollment | Evidence |
---|---|---|
Moore et al. 2007 (SWOG S9623) | 1996-2001 | Non-randomized portion of phase III RCT |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Doxorubicin (Adriamycin) 80 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- STAMP-I or STAMP-V, with auto HSCT
References
- NSABP B-22: Fisher B, Anderson S, Wickerham DL, DeCillis A, Dimitrov N, Mamounas E, Wolmark N, Pugh R, Atkins JN, Meyers FJ, Abramson N, Wolter J, Bornstein RS, Levy L, Romond EH, Caggiano V, Grimaldi M, Jochimsen P, Deckers P. Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol. 1997 May;15(5):1858-69. link to original article contains verified protocol 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
- NSABP B-18: Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB Jr, Fisher ER, Wickerham DL, Wolmark N, DeCillis A, Hoehn JL, Lees AW, Dimitrov NV. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997 Jul;15(7):2483-93. link to original article contains verified protocol 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-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
- Içli F, Akbulut H, Dinçol D, Onur H, Demirkazik A, Cam R, Cay F, Demirci S, Uner A, Erekul S. A randomized trial of four cycles of adjuvant AC (adriamycin + cyclophosphamide) +/- two cycles of EP (etoposide + cisplatin) in node positive patients with breast cancer. Ann Oncol. 2001 Jul;12(7):1011-3. link to original article contains protocol PubMed
- INT 0148/CALGB 9344: Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003 Mar 15;21(6):976-83. link to original article contains verified protocol PubMed
- NSABP B-28: Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol. 2005 Jun 1;23(16):3686-96. Epub 2005 May 16. link to original article PubMed
- RAPP-01: Brain EG, Bachelot T, Serin D, Kirscher S, Graic Y, Eymard JC, Extra JM, Combe M, Fourme E, Noguès C, Rouëssé J; RAPP-01 Trial Investigators. Life-threatening sepsis associated with adjuvant doxorubicin plus docetaxel for intermediate-risk breast cancer. JAMA. 2005 May 18;293(19):2367-71. link to original article contains protocol 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 contains verified protocol PubMed
- USOR 9735: Jones SE, Savin MA, Holmes FA, O'Shaughnessy JA, Blum JL, Vukelja S, McIntyre KJ, Pippen JE, Bordelon JH, Kirby R, Sandbach J, Hyman WJ, Khandelwal P, Negron AG, Richards DA, Anthony SP, Mennel RG, Boehm KA, Meyer WG, Asmar L. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol. 2006 Dec 1;24(34):5381-7. Erratum in: J Clin Oncol. 2007 May 1;25(13):1819. link to original article contains protocol 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
- INT-0137: Linden HM, Haskell CM, Green SJ, Osborne CK, Sledge GW Jr, Shapiro CL, Ingle JN, Lew D, Hutchins LF, Livingston RB, Martino S. Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer: final analysis from INT-0137 (S9313). J Clin Oncol. 2007 Feb 20;25(6):656-61. link to original article contains protocol PubMed
- SWOG S9623: Moore HC, Green SJ, Gralow JR, Bearman SI, Lew D, Barlow WE, Hudis C, Wolff AC, Ingle JN, Chew HK, Elias AD, Livingston RB, Martino S; SWOG. Intensive dose-dense compared with high-dose adjuvant chemotherapy for high-risk operable breast cancer: Southwest Oncology Group/Intergroup study 9623. J Clin Oncol. 2007 May 1;25(13):1677-82. Epub 2007 Apr 2. link to original article contains verified protocol PubMed NCT00002772
- BIG 02-98: Francis P, Crown J, Di Leo A, Buyse M, Balil A, Andersson M, Nordenskjöld B, Lang I, Jakesz R, Vorobiof D, Gutiérrez J, van Hazel G, Dolci S, Jamin S, Bendahmane B, Gelber RD, Goldhirsch A, Castiglione-Gertsch M, Piccart-Gebhart M; BIG. Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial. J Natl Cancer Inst. 2008 Jan 16;100(2):121-33. Epub 2008 Jan 8. Erratum in: J Natl Cancer Inst. 2008 Nov 19;100(22):1655. link to original article contains protocol 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
- ECOG E1199: Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. link to original article link to PMC article PubMed NCT00004125
- 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
- ECOG E2197: Goldstein LJ, O'Neill A, Sparano JA, Perez EA, Shulman LN, Martino S, Davidson NE. Concurrent doxorubicin plus docetaxel is not more effective than concurrent doxorubicin plus cyclophosphamide in operable breast cancer with 0 to 3 positive axillary nodes: North American Breast Cancer Intergroup Trial E 2197. J Clin Oncol. 2008 Sep 1;26(25):4092-9. Epub 2008 Aug 4. link to original article link to PMC article contains protocol PubMed NCT00003519
- CALGB 49907: Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Becker HP, Kartcheske PA, Wheeler JD, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Magrinat G, Parker BA, Hart RD, Grenier D, Norton L, Hudis CA, Winer EP; CALGB. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009 May 14;360(20):2055-65. Erratum in: N Engl J Med. 2009 Oct 22;361(17):1714. Magrinat, Gutav [corrected to Magrinat, Gustav]. link to original article link to PMC article contains verified protocol PubMed NCT00024102
- NSAS BC-02: Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. link to original article contains protocol PubMed
- ECOG E5103: Miller KD, O'Neill A, Gradishar W, Hobday TJ, Goldstein LJ, Mayer IA, Bloom S, Brufsky AM, Tevaarwerk AJ, Sparano JA, Le-Lindqwister NA, Hendricks CB, Northfelt DW, Dang CT, Sledge GW Jr. Double-blind phase III trial of adjuvant chemotherapy with and without bevacizumab in patients with lymph node-positive and high-risk lymph node-negative breast cancer (E5103). J Clin Oncol. 2018 Sep 1;36(25):2621-2629. Epub 2018 Jul 24. link to original article refers to ECOG E1199 protocol PubMed NCT00433511
Dose-dense Cyclophosphamide & Doxorubicin (ddAC)
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ddAC: dose-dense Adriamycin (Doxorubicin) and Cyclophosphamide
Regimen variant #1, 60/600 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Shulman et al. 2012 (CALGB 40101) | 2002-2008 | Phase 3 (E-de-esc) | 1. ddAC x 6 | Did not meet primary endpoint of RFS |
2. ddT x 4 | Did not meet primary endpoint of RFS | |||
3. ddT x 6 | Did not meet primary endpoint of RFS | |||
Burstein et al. 2005 | 2003-2004 | Non-randomized | ||
Swain et al. 2013 (NSABP B-38) | 2004-2007 | Phase 3 (C) | See link | See link |
Note: CALGB 40101 originally specified 21-day cycles but was amended to 14-day cycles after results of CALGB 9741 were available.
Preceding treatment
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Supportive medications
- (varies depending on reference):
- Burstein et al. 2005:
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2, given 24 hours after chemotherapy
- Burstein et al. 2005, for patients with Hb 10 to 12 g/dL:
- Darbepoetin alfa (Aranesp) 200 mcg SC once on day 1
- See Burstein et al. 2005 for additional dose adjustments
- Darbepoetin alfa (Aranesp) 200 mcg SC once on day 1
- CALGB 40101: one of the following:
- Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
- Sargramostim (Leukine) 250 to 500 mcg/m2 SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
- Pegfilgrastim (Neulasta) 6 mg SC once, given 24 to 36 hours after chemotherapy
14-day cycle for 4 cycles
Subsequent treatment
- Burstein et al. 2005: ddT (Taxol) x 4
- NSABP B-38: ddT (Taxol) x 4 versus ddPG x 4
Regimen variant #2, 60/600 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Budd et al. 2014 (SWOG S0221) | 2003-2010 | Phase 3 (C) | AC; continuous | Did not meet primary endpoint of DFS |
van Rossum et al. 2018 (MATADOR) | 2004-2012 | Phase 3 (E-switch-ic) | TAC | Did not meet secondary endpoints of RFS/OS |
Preceding treatment
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Supportive medications
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2
14-day cycle for 6 cycles
Subsequent treatment
- SWOG S0221: Bi-weekly paclitaxel versus weekly paclitaxel
References
- Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. link to original article contains verified protocol 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 contains verified protocol 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. link to original article link to PMC 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 contains verified protocol 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 contains verified protocol link to PMC article PubMed NCT00070564
- ECOG E5103: Miller KD, O'Neill A, Gradishar W, Hobday TJ, Goldstein LJ, Mayer IA, Bloom S, Brufsky AM, Tevaarwerk AJ, Sparano JA, Le-Lindqwister NA, Hendricks CB, Northfelt DW, Dang CT, Sledge GW Jr. Double-blind phase III trial of adjuvant chemotherapy with and without bevacizumab in patients with lymph node-positive and high-risk lymph node-negative breast cancer (E5103). J Clin Oncol. 2018 Sep 1;36(25):2621-2629. Epub 2018 Jul 24. link to original article refers to ECOG E1199 protocol PubMed NCT00433511
- MATADOR: van Rossum AGJ, Kok M, van Werkhoven E, Opdam M, Mandjes IAM, van Leeuwen-Stok AE, van Tinteren H, Imholz ALT, Portielje JEA, Bos MMEM, van Bochove A, Wesseling J, Rutgers EJ, Linn SC, Oosterkamp HM; MATADOR Trialists' Group. Adjuvant dose-dense doxorubicin-cyclophosphamide versus docetaxel-doxorubicin-cyclophosphamide for high-risk breast cancer: first results of the randomised MATADOR trial (BOOG 2004-04). Eur J Cancer. 2018 Oct;102:40-48. link to original article contains protocol PubMed ISRCTN61893718
Cyclophosphamide & Epirubicin (EC)
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EC: Epirubicin and Cyclophosphamide
Regimen variant #1, 60/500 x 8
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Piccart et al. 2001 (Belgian trial) | 1988-1996 | Phase 3 (E-de-esc) | 1. CMF | Did not meet primary endpoint of EFS |
2. EC; high-dose | Seems to have inferior EFS |
Preceding treatment
Chemotherapy
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 8 cycles
Regimen variant #2, 75/600 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Pico et al. 2004 (GEICAM 9401) | 1995-2000 | Phase 3 (E-de-esc) | ECT (Tamoxifen) | Did not meet primary endpoint of DFS60 |
Preceding treatment
Chemotherapy
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- Tamoxifen
Regimen variant #3, 75/700 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Polyzos et al. 2009 | 1995-2004 | Phase 3 (E-switch-ic) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
- Surgery, then T (Taxotere) x 4
Chemotherapy
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 700 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Regimen variant #4, 90/600 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Zander et al. 2004 | 1993-2000 | Non-randomized portion of RCT | ||
Colleoni et al. 2006 (IBCSG 13-93) | 1993-1999 | Non-randomized portion of RCT | ||
Kümmel et al. 2006 | 1996-2000 | Phase 3 (C) | See link | See link |
Earl et al. 2017 (tAnGo) | 2001-2004 | Non-randomized portion of RCT | ||
Del Mastro et al. 2015 (GIM2) | 2003-2006 | Phase 3 (C) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- Zander et al. 2004: CMF x 3 versus cyclophosphamide, mitoxantrone, thiotepa with auto HSCT
- IBCSG 13-93: CMF x 3, then Tamoxifen x 5 y versus no further treatment
- GIM2: Paclitaxel, q3wk dosing x 4
- tAnGo: Paclitaxel, q3wk dosing x 4 versus TG x 4
Regimen variant #5, 100/830 x 8
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Piccart et al. 2001 (Belgian trial) | 1988-1996 | Phase 3 (E-esc) | 1. CMF | Did not meet primary endpoint of EFS |
2. EC; moderate-dose | Seems to have superior EFS |
Preceding treatment
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 #6, 120/600 x 4 (high-dose)
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Papaldo et al. 2003 | 1991-1994 | Phase 3 (C) | EC & Lonidamine | Did not meet primary endpoint of DFS60 |
Vici et al. 2011 (GOIM 9902) | 1999-2005 | Phase 3 (C) | D-EC | Did not meet primary endpoint of DFS60 |
Preceding treatment
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 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 contains protocol 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 contains protocol PubMed
- Zander AR, Kröger N, Schmoor C, Krüger W, Möbus V, Frickhofen N, Metzner B, Schultze W, Berdel WE, Koenigsmann M, Thiel E, Wandt H, Possinger K, Trümper L, Kreienberg R, Carstensen M, Schmidt EH, Jänicke F, Schumacher M, Jonat W. High-dose chemotherapy with autologous hematopoietic stem-cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: first results of a randomized trial. J Clin Oncol. 2004 Jun 15;22(12):2273-83. Epub 2004 Apr 26. link to original article contains protocol 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 contains verified protocol 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 contains protocol 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
- Polyzos A, Malamos N, Boukovinas I, Adamou A, Ziras N, Kalbakis K, Kakolyris S, Syrigos K, Papakotoulas P, Kouroussis C, Karvounis N, Vamvakas L, Christophyllakis C, Athanasiadis A, Varthalitis I, Georgoulias V, Mavroudis D; Hellenic Oncology Research Group. FEC versus sequential docetaxel followed by epirubicin/cyclophosphamide as adjuvant chemotherapy in women with axillary node-positive early breast cancer: a randomized study of the Hellenic Oncology Research Group (HORG). Breast Cancer Res Treat. 2010 Jan;119(1):95-104. Epub 2009 Jul 28. link to original article contains protocol 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 contains protocol 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 × 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article contains verified protocol PubMed NCT00433420
- tAnGo: Earl HM, Hiller L, Howard HC, Dunn JA, Young J, Bowden SJ, McDermaid M, Waterhouse AK, Wilson G, Agrawal R, O'Reilly S, Bowman A, Ritchie DM, Goodman A, Hickish T, McAdam K, Cameron D, Dodwell D, Rea DW, Caldas C, Provenzano E, Abraham JE, Canney P, Crown JP, Kennedy MJ, Coleman R, Leonard RC, Carmichael JA, Wardley AM, Poole CJ; tAnGo trial collaborators. Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Jun;18(6):755-769. Epub 2017 May 4. link to original article contains protocol PubMed NCT00039546
Dose-dense Cyclophosphamide & Epirubicin (ddEC)
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ddEC: dose-dense Epirubicin and Cyclophosphamide
Regimen variant #1, 90/600
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Nitz et al. 2005 (WSG AM-01) | 1995-2002 | Phase 3 (C) | EC, then ECT with auto HSCT x 2 | Seems to have inferior OS |
Del Mastro et al. 2015 (GIM2) | 2003-2006 | Phase 3 (E-esc) | See link | See link |
Note: a mid-protocol amendment of GIM2 suggested giving the pegilgrastim at least 72 h after chemotherapy.
Preceding treatment
Chemotherapy
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
Supportive medications
- WSG AM-01: Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 5 to 12
- GIM2: Pegfilgrastim (Neulasta) 6 mg SC once on day 2
14-day cycle for 4 cycles
Subsequent treatment
- WSG AM-01: ddCMF x 3
- GIM2: Dose-dense Paclitaxel
Regimen variant #2, 120/830
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Burnell et al. 2009 (NCIC-CTG MA.21) | 2000-2005 | Phase 3 (E-esc) | See link | See link |
Preceding treatment
Chemotherapy
- Epirubicin (Ellence) 120 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 830 mg/m2 IV once on day 1
Supportive medications
- Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 2 to 13
- Epoetin alfa (Procrit) 40,000 units SC once per day on days 1 & 8
14-day cycle for 6 cycles
Subsequent treatment
- T (Taxol) x 4
References
- WSG AM-01: Nitz UA, Mohrmann S, Fischer J, Lindemann W, Berdel WE, Jackisch C, Werner C, Ziske C, Kirchner H, Metzner B, Souchon R, Ruffert U, Schütt G, Pollmanns A, Schmoll HJ, Middecke C, Baltzer J, Schrader I, Wiebringhaus H, Ko Y, Rösel S, Schwenzer T, Wernet P, Hinke A, Bender HG, Frick M; West German Study Group. Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial. Lancet. 2005 Dec 3;366(9501):1935-44. Erratum in: Lancet. 2006 Mar 4;367(9512):730. link to original article contains verified protocol 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 contains verified protocol PubMed NCT00014222
- GIM2: Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article contains verified protocol PubMed NCT00433420
Docetaxel monotherapy
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D: Docetaxel
T: Taxotere (Docetaxel)
dT: doceTaxel
Regimen variant #1, 35 mg/m2 weekly x 12
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sparano et al. 2008 (ECOG E1199) | 1999-2002 | Phase 3 (E-switch-ic) | 1. Paclitaxel, q3wk dosing | Did not meet primary endpoint of DFS |
2. Paclitaxel, weekly dosing 3. Docetaxel, q3wk dosing |
Not reported |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
- AC x 4
Chemotherapy
- Docetaxel (Taxotere) 35 mg/m2 IV over 60 minutes once per day on days 1, 8, 15
21-day cycle for 4 cycles
Regimen variant #2, 75 mg/m2 q3wk x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Watanabe et al. 2017 (NSAS BC-02) | 2001-2006 | Phase 3 (C) | See link | See link |
Mavroudis et al. 2017 (HORG CT/01.04) | 2001-2013 | Phase 3 (E-switch-ic) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 4 cycles
Regimen variant #3, 80 mg/m2 q3wk x 3
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Joensuu et al. 2009 (FinXX) | 2004-2007 | Phase 3 (C) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Docetaxel (Taxotere) 80 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 3 cycles
Subsequent treatment
- CEF x 3
Regimen variant #4, 100 mg/m2 q3wk x 3
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Coombes et al. 2011 (DEVA) | 1997-2005 | Phase 3 (E-switch-ic) | See link | See link |
Joensuu et al. 2006 (FinHer) | 2000-2003 | Phase 3 (C) | Vinorelbine | Superior RFS (HR 0.58, 95% CI 0.40-0.85) |
Campone et al. 2018 (UCBG 2-08) | 2007-2010 | Phase 3 (C) | Ixabepilone | Did not meet primary endpoint of DFS60 |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Patients in FinHer without HER2/neu amplification were only randomized to this or the vinorelbine arm.
Preceding treatment
- UCBG 2-08: Surgery, then FEC x 3
- DEVA: Surgery, then Epirubicin x 3
Chemotherapy
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 3 cycles
Regimen variant #5, 100 mg/m2 q3wk x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bear et al. 2003 (NSABP B-27) | 1995-2000 | Phase 3 (E-esc) | See link | See link |
Polyzos et al. 2009 | 1995-2004 | Phase 3 (E-switch-ic) | See link | See link |
Sparano et al. 2008 (ECOG E1199) | 1999-2002 | Phase 3 (E-switch-ic) | 1. Paclitaxel, q3wk dosing | Seems to have superior DFS |
2. Paclitaxel, weekly dosing 3. Docetaxel, weekly dosing |
Not reported | |||
Ellis et al. 2009 (TACT) | 2001-2003 | Randomized Phase II (E-switch-ic) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
- NSABP B-27: Neoadjuvant AC x 4, then surgery
- ECOG E1199: Surgery, then AC x 4
- Polyzos et al. 2009: Surgery
- TACT: Surgery, then FEC x 4
Chemotherapy
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- Polyzos et al. 2009: EC x 4
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 contains verified protocol 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
- FinHer: Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article contains verified protocol 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. link to original article 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 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
- TACT: Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. link to original article link to PMC article contains verified protocol PubMed ISRCTN79718493
- Polyzos A, Malamos N, Boukovinas I, Adamou A, Ziras N, Kalbakis K, Kakolyris S, Syrigos K, Papakotoulas P, Kouroussis C, Karvounis N, Vamvakas L, Christophyllakis C, Athanasiadis A, Varthalitis I, Georgoulias V, Mavroudis D; Hellenic Oncology Research Group. FEC versus sequential docetaxel followed by epirubicin/cyclophosphamide as adjuvant chemotherapy in women with axillary node-positive early breast cancer: a randomized study of the Hellenic Oncology Research Group (HORG). Breast Cancer Res Treat. 2010 Jan;119(1):95-104. Epub 2009 Jul 28. link to original article contains protocol 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 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
- DEVA: Coombes RC, Bliss JM, Espie M, Erdkamp F, Wals J, Tres A, Marty M, Coleman RE, Tubiana-Mathieu N, den Boer MO, Wardley A, Kilburn LS, Cooper D, Thomas MW, Reise JA, Wilkinson K, Hupperets P. Randomized, phase III trial of sequential epirubicin and docetaxel versus epirubicin alone in postmenopausal patients with node-positive breast cancer. J Clin Oncol. 2011 Aug 20;29(24):3247-54. Epub 2011 Jul 18. link to original article contains protocol PubMed ISRCTN89772270
- NSAS BC-02: Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. link to original article contains protocol PubMed
- HORG CT/01.04: Mavroudis D, Saloustros E, Boukovinas I, Papakotoulas P, Kakolyris S, Ziras N, Christophylakis C, Kentepozidis N, Fountzilas G, Rigas G, Varthalitis I, Kalbakis K, Agelaki S, Hatzidaki D, Georgoulias V; Hellenic Oncology Research Group. Sequential vs concurrent epirubicin and docetaxel as adjuvant chemotherapy for high-risk, node-negative, early breast cancer: an interim analysis of a randomised phase III study from the Hellenic Oncology Research Group. Br J Cancer. 2017 Jul 11;117(2):164-170. Epub 2017 Jun 22. link to original article contains verified protocol link to PMC article PubMed NCT00424606
- 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
Dose-dense Docetaxel monotherapy
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ddT: dose-dense Taxotere (Docetaxel)
ddD: dose-dense Docetaxel
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Saloustros et al. 2014 (HORG CT/04.22) | 2004-2007 | Phase 3 (E-switch-ic) | ddT (Taxol) | Did not meet primary endpoint of DFS36 |
Mavroudis et al. 2016 (HORG CT/07.17) | 2007-2013 | Phase 3 (C) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
- ddFEC x 4
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
Supportive medications
- Filgrastim or Pegfilgrastim support (drug/dose/schedule not specified)
14-day cycle for 4 cycles
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 contains protocol 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; Hellenic Oncology Research Group. Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2016 Oct;27(10):1873-8. Epub 2016 Aug 8. link to original article contains verified protocol PubMed NCT01985724
Doxorubicin monotherapy
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A: Adriamycin (Doxorubicin)
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Buzzoni et al. 1991 (Milan trial) | 1982-1987 | Phase 3 (E-switch-ic) | See link | See link |
Leonard et al. 2004 | 1995-1999 | Non-randomized portion of RCT | ||
Gianni et al. 2009 (ECTO) | 1996-2002 | Phase 3 (C) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
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 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 contains protocol 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 contains verified protocol PubMed NCT00003013
Dose-dense Doxorubicin monotherapy
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ddA: dose-dense Adriamycin (Doxorubicin)
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Citron et al. 2003 (CALGB 9741) | 1997-1999 | Phase 3 (E-esc) | See link | See link |
Kahan et al. 2005 | 2000-2003 | Phase II |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
Supportive medications
14-day cycle for 4 cycles
Subsequent treatment
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 contains verified protocol 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 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
Doxorubicin & Paclitaxel (AT)
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AT: Adriamycin (Doxorubicin) & Taxol (Paclitaxel)
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gianni et al. 2009 (ECTO) | 1996-2002 | Phase 3 (E-esc) | See link | See link |
Preceding treatment
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- CMF x 4
References
- ECTO: Gianni L, Baselga J, Eiermann W, Porta VG, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Cussac AL, Bozhok A, Martinez-Agulló A, Greco M, Byakhov M, Lopez JJ, Mansutti M, Valagussa P, Bonadonna G. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. J Clin Oncol. 2009 May 20;27(15):2474-81. Epub 2009 Mar 30. link to original article contains verified protocol PubMed NCT00003013
EC-CMF
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EC-CMF: Epirubicin & Cyclophosphamide followed by Cyclophosphamide, Methotrexate, Fluorouracil
Protocol
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Basser et al. 2006 (IBCSG 15-95) | 1995-2000 | Phase 3 (C) | DI-EC | Seems to have inferior DFS1 |
1Reported efficacy is based on the 2009 update.
Preceding treatment
Chemotherapy, EC portion
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles, followed by:
Chemotherapy, CMF portion
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 3 cycles
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 contains verified protocol 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
EC-D
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EC-D: Epirubicin and Cyclophosphamide followed by Docetaxel
EC-T: Epirubicin and Cyclophosphamide followed by Taxotere (Docetaxel)
Protocol variant #1, 3+3 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ejlertsen et al. 2017 (DBCG 07-READ) | 2008-2012 | Phase 3 (E-esc) | DC x 6 | Did not meet primary endpoint of DFS |
Biomarker eligibility criteria
- TOP2A normal as determined by FISH
Preceding treatment
Chemotherapy, part 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 3 cycles
Chemotherapy, part 2
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 3 cycles
Protocol variant #2, 4+4 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Martín et al. 2015 (GEICAM 2003-10) | 2004-2007 | Phase 3 (C) | ET x 4, then X x 4 | Seems to have superior IDFS |
Preceding treatment
Chemotherapy, part 1
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Chemotherapy, part 2
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 4 cycles
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 contains protocol 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 contains verified protocol 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 contains verified protocol PubMed NCT00689156
Epirubicin & Paclitaxel (EP)
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EP: Epirubicin & Paclitaxel
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fountzilas et al. 2007 (HE 10/00) | 2000-2005 | Phase 3 (C) | ddE, then ddP | Did not meet primary endpoint of DFS36 |
Preceding treatment
Chemotherapy
- Epirubicin (Ellence) 83 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 187 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- ddCMF x 3
References
- HE 10/00: Fountzilas G, Dafni U, Gogas H, Linardou H, Kalofonos HP, Briasoulis E, Pectasides D, Samantas E, Bafaloukos D, Stathopoulos GP, Karina M, Papadimitriou C, Skarlos D, Pisanidis N, Papakostas P, Markopoulos C, Tzorakoeleftherakis E, Dimitrakakis K, Makrantonakis P, Xiros N, Polichronis A, Varthalitis I, Karanikiotis C, Dimopoulos AM; Hellenic Cooperative Oncology Group. Postoperative dose-dense sequential chemotherapy with epirubicin, paclitaxel and CMF in patients with high-risk breast cancer: safety analysis of the Hellenic Cooperative Oncology Group randomized phase III trial HE 10/00. Ann Oncol. 2008 May;19(5):853-60. Epub 2007 Nov 27. link to original article contains verified protocol 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
iddEnPC
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iddEnPC: intense dose-dense Epirubicin, nab-Paclitaxel, Cyclophosphamide
Protocol
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Möbus et al. 2021 (GAIN-2) | 2012-2017 | Phase 3 (C) | dtEC-dtD | Did not meet primary endpoint of iDFS |
Note: growth factor support is not specifically mentioned in the manuscript. The details below for pegfilgrastim are based on the GAIN trial of iddEPC.
Preceding treatment
Chemotherapy, part 1
- Epirubicin (Ellence) 150 mg/m2 IV once on day 1
Supportive medications
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4
14-day cycle for 3 cycles, then:
Chemotherapy, part 2
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 330 mg/m2 IV once on day 1
Supportive medications
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4
14-day cycle for 3 cycles, then:
Chemotherapy, part 3
- Cyclophosphamide (Cytoxan) 2000 mg/m2 IV once on day 1
Supportive medications
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4
14-day cycle for 3 cycles
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 contains verified protocol PubMed NCT01690702
iddEPC
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iddEPC: intense dose-dense Epirubicin, Paclitaxel, Cyclophosphamide
IDD-ETC: Intense Dose-Dense Epirubicin, Taxol (Paclitaxel), Cyclophosphamide
Protocol
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Möbus et al. 2010 (AGO-iddEPC) | 1998-2003 | Phase 3 (E-esc) | EC, then Paclitaxel | Superior OS1 OS120: 69% vs 59% (HR 0.72, 95% CI 0.60-0.87) |
Möbus et al. 2017 (GAIN) | 2004-2008 | Phase 3 (C) | ddEC, then PwX | 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, part 1
- Epirubicin (Ellence) 150 mg/m2 IV once on day 1
Supportive medications
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4
14-day cycle for 3 cycles, then:
Chemotherapy, part 2
- Paclitaxel (Taxol) 225 mg/m2 IV once on day 1
Supportive medications
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4
14-day cycle for 3 cycles, then:
Chemotherapy, part 3
- Cyclophosphamide (Cytoxan) 2000 mg/m2 IV once on day 1
Supportive medications
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2 or 4
14-day cycle for 3 cycles
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 contains verified protocol PubMed NCT00196872
Epirubicin monotherapy
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E: Epirubicin
Regimen variant #1, 50 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Coombes et al. 2011 (DEVA) | 1997-2005 | Phase 3 (E-switch-ic) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Epirubicin (Ellence) 50 mg/m2 IV once per day on days 1 & 8
28-day cycle for 3 cycles
Subsequent treatment
- Docetaxel x 3
Regimen variant #2, 75 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Boccardo et al. 1990 (GROCTA-1) | 1983-1987 | Phase 3 (E-esc) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- Tamoxifen x 5 y versus no further treatment
Regimen variant #3, 90 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Mavroudis et al. 2017 (HORG CT/01.04) | 2001-2013 | Phase 3 (E-switch-ic) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Epirubicin (Ellence) 90 mg/m2 IV over 5 to 15 minutes once on day 1
21-day cycle for 4 cycles
Subsequent treatment
Regimen variant #4, 100 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Poole et al. 2006 (NEAT) | 1996-2001 | Phase 3 (E-esc) | See link | See link |
Poole et al. 2006 (BR9601) | 1996-2001 | Phase 3 (E-switch-ic) | See link | See link |
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) | See link | See link |
Ellis et al. 2009 (TACT) | 2001-2003 | Randomized Phase II (C) | See link | See link |
Cameron et al. 2017 (TACT2) | 2005-2008 | Phase 3 (C) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- NEAT, TACT, BR9601, Boccardo et al. 2010: CMF
- TACT2: Capecitabine versus CMF
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 contains verified protocol 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
- NEAT/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 contains verified protocol PubMed NCT00003577; 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 contains verified protocol 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 contains protocol 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 contains verified protocol PubMed NCT01031030
- DEVA: Coombes RC, Bliss JM, Espie M, Erdkamp F, Wals J, Tres A, Marty M, Coleman RE, Tubiana-Mathieu N, den Boer MO, Wardley A, Kilburn LS, Cooper D, Thomas MW, Reise JA, Wilkinson K, Hupperets P. Randomized, phase III trial of sequential epirubicin and docetaxel versus epirubicin alone in postmenopausal patients with node-positive breast cancer. J Clin Oncol. 2011 Aug 20;29(24):3247-54. Epub 2011 Jul 18. link to original article contains protocol PubMed ISRCTN89772270
- TACT2: Cameron D, Morden JP, Canney P, Velikova G, Coleman R, Bartlett J, Agrawal R, Banerji J, Bertelli G, Bloomfield D, Brunt AM, Earl H, Ellis P, Gaunt C, Gillman A, Hearfield N, Laing R, Murray N, Couper N, Stein RC, Verrill M, Wardley A, Barrett-Lee P, Bliss JM; TACT2 Investigators. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2017 Jul;18(7):929-945. Epub 2017 Jun 7. link to original article link to PMC article contains verified protocol PubMed NCT00301925
- HORG CT/01.04: Mavroudis D, Saloustros E, Boukovinas I, Papakotoulas P, Kakolyris S, Ziras N, Christophylakis C, Kentepozidis N, Fountzilas G, Rigas G, Varthalitis I, Kalbakis K, Agelaki S, Hatzidaki D, Georgoulias V; Hellenic Oncology Research Group. Sequential vs concurrent epirubicin and docetaxel as adjuvant chemotherapy for high-risk, node-negative, early breast cancer: an interim analysis of a randomised phase III study from the Hellenic Oncology Research Group. Br J Cancer. 2017 Jul 11;117(2):164-170. Epub 2017 Jun 22. link to original article contains verified protocol link to PMC article PubMed NCT00424606
Dose-dense Epirubicin monotherapy
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ddE: dose-dense Epirubicin
Regimen variant #1, 3 cycles
Study | Years of enrollment | Evidence |
---|---|---|
Fountzilas et al. 2014 (HE10/05) | 2005-2008 | Non-randomized portion of phase III RCT |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Epirubicin (Ellence) 110 mg/m2 IV once on day 1
14-day cycle for 3 cycles
Subsequent treatment
- Intensified CMF
Regimen variant #2, 4 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fountzilas et al. 2005 (HE 10/97) | 1997-2000 | Phase 3 (C) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Epirubicin (Ellence) 110 mg/m2 IV once on day 1
Supportive medications
- Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 3 to 10
14-day cycle for 4 cycles
Subsequent treatment
- Intensified CMF
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 contains verified protocol PubMed
- HE10/05: Fountzilas G, Dafni U, Papadimitriou C, Timotheadou E, Gogas H, Eleftheraki AG, Xanthakis I, Christodoulou C, Koutras A, Papandreou CN, Papakostas P, Miliaras S, Markopoulos C, Dimitrakakis C, Korantzopoulos P, Karanikiotis C, Bafaloukos D, Kosmidis P, Samantas E, Varthalitis I, Pavlidis N, Pectasides D, Dimopoulos MA. Dose-dense sequential adjuvant chemotherapy followed, as indicated, by trastuzumab for one year in patients with early breast cancer: first report at 5-year median follow-up of a Hellenic Cooperative Oncology Group randomized phase III trial. BMC Cancer. 2014 Jul 15;14:515. link to original article link to PMC article contains verified protocol PubMed
E-CMF
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E-CMF: Epirubicin followed by Cyclophosphamide, Methotrexate, Fluorouracil
Protocol variant #1, classic CMF
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Delaloge et al. 2020 (MINDACT) | 2007-2011 | Phase 3 (C) | TX (Taxotere) | Did not meet primary endpoint of DFS |
Preceding treatment
Chemotherapy, E portion
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Chemotherapy, CMF portion
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 4 cycles
Protocol variant #2, IV dose modified CMF
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Delaloge et al. 2020 (MINDACT) | 2007-2011 | Phase 3 (C) | TX (Taxotere) | Did not meet primary endpoint of DFS |
Preceding treatment
Chemotherapy, E portion
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Chemotherapy, CMF portion
- 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 4 cycles
References
- 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 verified protocol in supplement PubMed NCT00433589
FAC
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FAC: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide
CAF: Cyclophosphamide, Adriamycin (Doxorubicin), Fluorouracil
Regimen variant #1, 500/40/500 x 6
Study | Years of enrollment | Evidence |
---|---|---|
Martín et al. 2013 (GEICAM 2003-02) | 1993-1999 | Non-randomized portion of 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, then tamoxifen versus tamoxifen
Regimen variant #2, 500/50/500 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Martín et al. 2013 (GEICAM 2003-02) | 2003-2008 | Phase 3 (E-switch-ic) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- wP x 8
Regimen variant #3, 500/50/500 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Martin et al. 2003 (GEICAM 8701) | 1987-1991 | Phase 3 (E-switch-ic) | CMF | Might have superior DFS |
Martin et al. 2005 (BCIRG 001) | 1997-1999 | Phase 3 (C) | TAC | Inferior OS |
Martín et al. 2010 (GEICAM 9805) | 1999-2003 | Phase 3 (C) | TAC | Inferior DFS |
Martín et al. 2013 (GEICAM 2003-02) | 2003-2008 | Phase 3 (C) | FAC, then wP | Seems to have inferior DFS |
Delaloge et al. 2020 (MINDACT) | 2007-2011 | Phase 3 (C) | TX (Taxotere) | 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 medications
- If patients had febrile neutropenia or infection: Ciprofloxacin (Cipro) 500 mg PO twice per day on days 5 to 14
- If patients had febrile neutropenia, one of the following:
- Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 4 to 11
- Lenograstim (Granocyte) 150 mcg/m2 SC once per day on days 4 to 11
21-day cycle for 6 cycles
Regimen variant #4, 800/40/400 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Wood et al. 1994 (CALGB 8541) | 1985-NR | Phase 3 (C) | 1. FAC; 600/30/300 x 4 | Superior OS |
2. FAC; 1200/60/600 x 4 | Did not meet primary endpoint of DFS |
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
28-day cycle for 6 cycles
Regimen variant #5, 800/40/400 until max doxorubicin
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Buzdar et al. 1984 | 1977-1980 | Phase 3 (C) | FAC + BCG | Did not meet primary endpoint of DFS |
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
21-day cycles until cumulative doxorubicin dose of 300 mg/m2 reached.
Subsequent treatment
- After reaching cumulative maximum doxorubicin, patients would go on to receive maintenance CMF. This is now obsolete.
Regimen variant #6, 1000/50/500 x 8
Study | Years of enrollment | Evidence |
---|---|---|
Hortobagyi et al. 2000 | 1990-1997 | Non-randomized portion of RCT |
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 4
- Doxorubicin (Adriamycin) 16.7 mg/m2/day IV continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m2)
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 8 cycles
Subsequent treatment
- CEP with auto HSCT versus no further treatment
Regimen variant #7, 1000/60/1400 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Davidson et al. 2005 (ECOG E5188) | 1989-1994 | Non-randomized portion of RCT | ||
Hutchins et al. 2005 (INT-0102) | 1989-1993 | Phase 3 (E-switch-ic) | CMF | Seems to have superior OS |
Albain et al. 2009 (SWOG-8814) | 1989-1995 | Phase 3 (E-esc) | See link | See link |
Tallman et al. 2003 (INT-0121) | 1991-1998 | Non-randomized portion of RCT |
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
28-day cycle for 6 cycles
Subsequent treatment
- INT-0121: Cyclophosphamide & thiotepa, then auto HSCT versus no further chemotherapy
- ECOG E5188: Goserelin x 5 y versus Goserelin & Tamoxifen x 5 y versus no further treatment
- SWOG-8814: Tamoxifen x 5 y
Regimen variant #8, 1200/60/600 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Wood et al. 1994 (CALGB 8541) | 1985-NR | Phase 3 (C) | 1. FAC; 600/30/300 x 4 | Superior OS |
2. FAC; 800/40/400 x 6 | Did not meet primary endpoint of DFS |
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
28-day cycle for 4 cycles
Regimen variant #9, 1200/60/600 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Delaloge et al. 2020 (MINDACT) | 2007-2011 | Phase 3 (C) | TX (Taxotere) | Did not meet primary endpoint of DFS |
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
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 contains verified protocol 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
- CALGB 8541: Wood WC, Budman DR, Korzun AH, Cooper MR, Younger J, Hart RD, Moore A, Ellerton JA, Norton L, Ferree CR, Colangelo Ballow A, Frei E, Henderson IC. Dose and dose intensity of adjuvant chemotherapy for stage II, node-positive breast carcinoma. N Engl J Med. 1994 May 5;330(18):1253-9. Erratum in: N Engl J Med 1994 Jul 14;331(2):139. link to original article contains verified protocol 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
- Hortobagyi GN, Buzdar AU, Theriault RL, Valero V, Frye D, Booser DJ, Holmes FA, Giralt S, Khouri I, Andersson B, Gajewski JL, Rondon G, Smith TL, Singletary SE, Ames FC, Sneige N, Strom EA, McNeese MD, Deisseroth AB, Champlin RE. Randomized trial of high-dose chemotherapy and blood cell autografts for high-risk primary breast carcinoma. J Natl Cancer Inst. 2000 Feb 2;92(3):225-33. link to original article contains verified protocol 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 contains protocol PubMed
- Assikis V, Buzdar A, Yang Y, Smith T, Theriault R, Booser D, Valero V, Walters R, Singletary E, Ames F, Hortobagyi G. A phase III trial of sequential adjuvant chemotherapy for operable breast carcinoma: final analysis with 10-year follow-up. Cancer. 2003 Jun 1;97(11):2716-23. link to original article contains protocol 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 contains protocol 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 contains verified protocol 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 contains verified protocol [ncbi.nlm.nih.gov/pubmed/17970786 PubMed]
- SWOG-8814: Albain KS, Barlow WE, Ravdin PM, Farrar WB, Burton GV, Ketchel SJ, Cobau CD, Levine EG, Ingle JN, Pritchard KI, Lichter AS, Schneider DJ, Abeloff MD, Henderson IC, Muss HB, Green SJ, Lew D, Livingston RB, Martino S, Osborne CK; Breast Cancer Intergroup of North America. Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009 Dec 19;374(9707):2055-2063. Epub 2009 Dec 10. link to original article link to PMC article contains verified protocol 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 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 contains verified protocol 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 verified protocol in supplement PubMed NCT00433589
FEC
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FEC: Fluorouracil, Epirubicin, Cyclophosphamide
CEF: Cyclophosphamide, Epirubicin, Fluorouracil
Regimen variant #1, 500/50/500 x 6 ("FEC 50")
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hurteloup 1988 (FESG) | 1982-1984 | Phase 3 (E-switch-ic) | FAC | Did not meet endpoint of OS50% |
Fumoleau et al. 2003 (FASG 01) | 1986-1990 | Phase 3 (E-esc) | 1. FEC; FEC 50 x 3 | Might have superior OS |
2. FEC; FEC 75 x 3 | Did not meet primary endpoint of OS120 | |||
Héry et al. 2006 (FASG 03) | 1988-1994 | Phase 3 (E-esc) | Observation | Did not meet primary endpoint of DFS120 |
Arriagada et al. 2005 | 1989-1996 | Phase 3 (E-esc) | Observation | Superior DFS |
Bonneterre 2001 (FASG 05) | 1990-1993 | Phase 3 (C) | FEC; FEC 100 x 6 | Inferior OS |
Roché et al. 2006 (FASG 06) | 1990-1998 | Phase 3 (C) | Goserelin & Tamoxifen x 3y | Did not meet primary endpoint of DFS60 |
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Regimen variant #2, 500/60/500 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Rouëssé et al. 2006 | 1994-1999 | Phase 3 (C) | FNC & RT | Did not meet primary endpoint of DFS |
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Regimen variant #3, 500/100/500 x 3 ("FEC 100")
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Campone et al. 2018 (UCBG 2-08) | 2007-2010 | Non-randomized portion of RCT |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- 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 3 cycles
Subsequent treatment
- UCBG 2-08: Docetaxel x 3 versus Ixabepilone x 3
Regimen variant #4, 500/100/500 x 4 ("FEC 100")
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Kerbrat et al. 2017 (UCBG-0106) | 2002-2006 | Phase 3 (E-de-esc) | FEC; FEC 100 x 6 | Did not meet primary endpoint of DFS60 |
Kelly et al. 2012 (MDACC ID01-580) | 2002-2008 | Non-randomized portion of RCT |
Note: this is an experimental arm that did not meet its primary endpoint; included here because it represents a de-escalation strategy.
Preceding treatment
- MDACC ID01-580: Surgery, then weekly paclitaxel x 12 versus XT
- UCBG-0106: Surgery
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Regimen variant #5, 500/100/500 x 6 ("FEC 100")
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bonneterre 2001 (FASG 05) | 1990-1993 | Phase 3 (E-RT-esc) | FEC; FEC 50 x 6 | Superior OS |
Kerbrat et al. 2007 (FASG 09) | 1993-1998 | Phase 3 (C) | VE | Did not meet primary endpoint of DFS |
Roché et al. 2006 (FNCLCC PACS 01) | 1997-2000 | Phase 3 (C) | FEC-D | Inferior OS1 |
Delbaldo et al. 2013 (Trial B2000) | 2000-2002 | Phase 3 (C) | FEC 100 x 4, then Taxol; q3wk x 4 | Did not meet primary endpoint of DFS |
Nitz et al. 2014 (WSG-AGO EC-Doc) | 2000-2005 | Phase 3 (C) | EC-D | Seems to have inferior OS |
Spielmann et al. 2009 (FNCLCC PACS 04) | 2001-2004 | Phase 3 (C) | ED | Did not meet primary endpoint of DFS2 |
Kerbrat et al. 2017 (UCBG-0106) | 2002-2006 | Phase 3 (C) | FEC; FEC 100 x 4 | Did not meet primary endpoint of DFS60 |
Sakr et al. 2013 | 2006-2010 | Phase 3 (C) | FEC-D | Seems to have inferior OS |
Delaloge et al. 2020 (MINDACT) | 2007-2011 | Phase 3 (C) | TX (Taxotere) | Did not meet primary endpoint of DFS |
1Reported efficacy for FNCLCC PACS 01 is based on the 2012 update.
2Reported efficacy for FNCLCC PACS 04 is based on the 2019 update.
Preceding treatment
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 #6, 600/50/600 x 8
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Coombes et al. 1996 | 1984-1992 | Phase 3 (E-switch-ic) | CMF | Did not meet primary endpoints of RFS/OS |
Coombes et al. 2016 (HMFEC) | 1992-2000 | Phase 3 (C) | FEC; FEC 75 | Did not meet primary endpoint of DFS |
Note: this is an experimental arm that did not meet its primary endpoint; included here because other variants of this regimen have demonstrated comparative superiority.
Preceding treatment
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 #7, 600/60/600 x 3
Study | Years of enrollment | Evidence |
---|---|---|
Joensuu et al. 2006 (FinHer) | 2000-2003 | Non-randomized portion of RCT |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
- Docetaxel x 3 versus Vinorelbine x 3
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 3 cycles
Regimen variant #8, 600/60/600 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
van der Hage et al. 2001 (EORTC 10902) | 1991-1999 | Phase 3 (C) | FEC; neoadjuvant | Did not meet primary endpoint of OS |
Ellis et al. 2009 (TACT) | 2001-2003 | Randomized Phase II (E-switch-ic) | See link | See link |
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
Subsequent treatment
- TACT: D x 4
Regimen variant #9, 600/60/600 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Venturini et al. 2005 (MIG-1) | 1992-1997 | Phase 3 (C) | Dose-dense FEC | Did not meet primary endpoint of OS |
Sirohi et al. 2010 (TRAFIC) | 1995-2002 | Phase 3 (C) | ECisF | Did not meet primary endpoint of RFS |
del Mastro et al. 2016 (GONO-MIG5) | 1996-2001 | Phase 3 (C) | EP x 4 | Did not meet primary endpoint of OS |
Preceding treatment
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 | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ellis et al. 2009 (TACT) | 2001-2003 | Randomized Phase II (C) | See link | See link |
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 | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ejlertsen et al. 2007 (DBCG 89D) | 1990-1998 | Phase III (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, 600/75/600 x 3
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Joensuu et al. 2009 (FinXX) | 2004-2007 | Phase 3 (C) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
- Surgery, then T (Taxotere) x 3
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 3 cycles
Regimen variant #13, 600/90/600 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Martín et al. 2008 (GEICAM 9906) | 1999-2002 | Phase 3 (E-switch-ic) | See link | See link |
Del Mastro et al. 2015 (GIM2) | 2003-2006 | Phase 3 (E-esc) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 4 cycles
Subsequent treatment
- GEICAM 9906: Weekly Paclitaxel
- GIM2: Paclitaxel, q3wk dosing
Regimen variant #14, 600/90/600 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Martín et al. 2008 (GEICAM 9906) | 1999-2002 | Phase 3 (C) | FEC x 4, then wP | Inferior DFS |
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 #15, 700/75/700 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Polyzos et al. 2009 | 1995-2004 | Phase 3 (C) | D, then EC | Seems to have inferior DFS |
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 #16, 1000/50/500 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Paradiso et al. 2001 | 1989-1994 | Phase 3 (E-esc) | Observation | Seems to have superior DFS |
Preceding treatment
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 #17, 1000/120/740 x 6 ("Canadian CEF (IV)")
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Delaloge et al. 2020 (MINDACT) | 2007-2011 | Phase 3 (C) | TX (Taxotere) | 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) 370 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 cycles
Regimen variant #18, 1000/120/1050 x 6 ("FEC 120"; "Canadian CEF")
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Levine et al. 1998 (NCIC-CTG MA.5) | 1989-1993 | Phase 3 (E-RT-switch-ic) | CMF | Superior RFS |
Coombes et al. 2005 (ICCG HDT trial) | 1993-2001 | Phase 3 (C) | FEC x 3, then HDT | Did not meet primary endpoints of RFS/EFS/OS |
Burnell et al. 2009 (NCIC-CTG MA.21) | 2000-2005 | Phase 3 (C) | 1. AC x 4, then T (Taxol); q3wk x 4 | Superior RFS |
2. ddEC x 6, then T (Taxol); q3wk x 4 | Did not meet primary endpoint of RFS | |||
Janni et al. 2016 (ADEBAR) | 2001-2005 | Phase 3 (C) | EC x 3, then Docetaxel | Did not meet primary endpoint of TTP |
Delaloge et al. 2020 (MINDACT) | 2007-2011 | Phase 3 (C) | TX (Taxotere) | 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 #19, 1200/50/1200 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Coombes et al. 1996 | 1984-1992 | Phase 3 (E-switch-ic) | CMF | Did not meet primary endpoints of RFS/OS |
Note: this is an experimental arm that did not meet its primary endpoint; however, based on a subgroup analysis, it became a preferred regimen.
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
- Epirubicin (Ellence) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 cycles
References
- FESG: Hurteloup P; French Epirubicin Study Group. A prospective randomized phase III trial comparing combination chemotherapy with cyclophosphamide, fluorouracil, and either doxorubicin or epirubicin. J Clin Oncol. 1988 Apr;6(4):679-88. link to original article contains protocol 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 contains verified protocol 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 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
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- Update: Bonneterre J, Roché H, Kerbrat P, Brémond A, Fumoleau P, Namer M, Goudier MJ, Schraub S, Fargeot P, Chapelle-Marcillac I. Epirubicin increases long-term survival in adjuvant chemotherapy of patients with poor-prognosis, node-positive, early breast cancer: 10-year follow-up results of the French Adjuvant Study Group 05 randomized trial. J Clin Oncol. 2005 Apr 20;23(12):2686-93. link to original article PubMed
- Paradiso A, Schittulli F, Cellamare G, Mangia A, Marzullo F, Lorusso V, De Lena M. Randomized clinical trial of adjuvant fluorouracil, epirubicin, and cyclophosphamide chemotherapy for patients with fast-proliferating, node-negative breast cancer. J Clin Oncol. 2001 Oct 1;19(19):3929-37. link to original article contains verified protocol PubMed
- EORTC 10902: van der Hage JA, van de Velde CJ, Julien JP, Tubiana-Hulin M, Vandervelden C, Duchateau L. Preoperative chemotherapy in primary operable breast cancer: results from the European Organisation for Research and Treatment of Cancer trial 10902. J Clin Oncol. 2001 Nov 15;19(22):4224-37. link to original article contains verified protocol 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
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- Arriagada R, Spielmann M, Koscielny S, Le Chevalier T, Delozier T, Rémé-Saumon M, Ducourtieux M, Tursz T, Hill C. Results of two randomized trials evaluating adjuvant anthracycline-based chemotherapy in 1146 patients with early breast cancer. Acta Oncol. 2005;44(5):458-66. link to original article contains verified protocol PubMed
- ICCG HDT trial: Coombes RC, Howell A, Emson M, Peckitt C, Gallagher C, Bengala C, Tres A, Welch R, Lawton P, Rubens R, Woods E, Haviland J, Vigushin D, Kanfer E, Bliss JM. High dose chemotherapy and autologous stem cell transplantation as adjuvant therapy for primary breast cancer patients with four or more lymph nodes involved: long-term results of an international randomised trial. Ann Oncol. 2005 May;16(5):726-34. Epub 2005 Apr 7. link to original article PubMed
- MIG-1: Venturini M, Del Mastro L, Aitini E, Baldini E, Caroti C, Contu A, Testore F, Brema F, Pronzato P, Cavazzini G, Sertoli MR, Canavese G, Rosso R, Bruzzi P; Mammella InterGruppo. Dose-dense adjuvant chemotherapy in early breast cancer patients: results from a randomized trial. J Natl Cancer Inst. 2005 Dec 7;97(23):1724-33. link to original article contains verified protocol PubMed
- Update: Blondeaux E, Lambertini M, Michelotti A, Conte B, Benasso M, Dellepiane C, Bighin C, Pastorino S, Levaggi A, Alonzo A, Poggio F, Buzzatti G, Molinelli C, Fregatti P, Bertoglio S, Boccardo F, Del Mastro L. Dose-dense adjuvant chemotherapy in early breast cancer patients: 15-year results of the Phase 3 Mammella InterGruppo (MIG)-1 study. Br J Cancer. 2020 Mar 31. Epub ahead of print. link to original article PubMed
- FinHer: Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article contains verified protocol 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. link to original article PubMed
- FASG 06: Roché H, Kerbrat P, Bonneterre J, Fargeot P, Fumoleau P, Monnier A, Clavère P, Goudier MJ, Chollet P, Guastalla JP, Serin D. Complete hormonal blockade versus epirubicin-based chemotherapy in premenopausal, one to three node-positive, and hormone-receptor positive, early breast cancer patients: 7-year follow-up results of French Adjuvant Study Group 06 randomised trial. Ann Oncol. 2006 Aug;17(8):1221-7. Epub 2006 May 26. link to original article contains protocol PubMed
- FASG 03: Héry M, Bonneterre J, Roché H, Luporsi E, Kerbrat P, Namer M, Fumoleau P, Monnier A, Fargeot P. Epirubicin-based chemotherapy as adjuvant treatment for poor prognosis, node-negative breast cancer: 10-year follow-up results of the French Adjuvant Study Group 03 trial. Bull Cancer. 2006 Oct;93(10):E109-14. link to original article contains protocol PubMed
- Rouëssé J, de la Lande B, Bertheault-Cvitkovic F, Serin D, Graïc Y, Combe M, Leduc B, Lucas V, Demange L, Nguyen TD, Castèra D, Krzisch C, Villet R, Mouret-Fourme E, Garbay JR, Noguès C; Centre René Huguenin Breast Cancer Group. A phase III randomized trial comparing adjuvant concomitant chemoradiotherapy versus standard adjuvant chemotherapy followed by radiotherapy in operable node-positive breast cancer: final results. Int J Radiat Oncol Biol Phys. 2006 Mar 15;64(4):1072-80. link to original article contains protocol PubMed
- FNCLCC PACS 01: Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulié P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Genève J, Asselain B. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006 Dec 20;24(36):5664-71. Epub 2006 Nov 20. link to original article PubMed
- 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
- DBCG 89D: Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Cold S, Edlund P, Ewertz M, Jensen BB, Kamby C, Nordenskjold B, Bergh J. Improved outcome from substituting methotrexate with epirubicin: results from a randomised comparison of CMF versus CEF in patients with primary breast cancer. Eur J Cancer. 2007 Mar;43(5):877-84. Epub 2007 Feb 16. link to original article contains verified protocol PubMed
- FASG 09: Kerbrat P, Roché H, Bonneterre J, Veyret C, Lortholary A, Monnier A, Fumoleau P, Fargeot P, Namer M, Chollet P, Goudier MJ, Audhuy B, Simon H, Montcuquet P, Eymard JC, Walter S, Clavère P, Guastalla JP; French Adjuvant Study Group. Epirubicin-vinorelbine vs FEC100 for node-positive, early breast cancer: French Adjuvant Study Group 09 trial. Br J Cancer. 2007 Jun 4;96(11):1633-8. Epub 2007 May 15. link to original article link to PMC article PubMed
- GEICAM 9906: Martín M, Rodríguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Munárriz B, Rodríguez CA, Crespo C, de Alava E, López García-Asenjo JA, Guitián MD, Almenar S, González-Palacios JF, Vera F, Palacios J, Ramos M, Gracia Marco JM, Lluch A, Alvarez I, Seguí MA, Mayordomo JI, Antón A, Baena JM, Plazaola A, Modolell A, Pelegrí A, Mel JR, Aranda E, Adrover E, Alvarez JV, García Puche JL, Sánchez-Rovira P, Gonzalez S, López-Vega JM; GEICAM. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst. 2008 Jun 4;100(11):805-14. Epub 2008 May 27. link to original article contains verified protocol PubMed NCT00129922
- TACT: Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. link to original article link to PMC article contains verified protocol PubMed ISRCTN79718493
- Polyzos A, Malamos N, Boukovinas I, Adamou A, Ziras N, Kalbakis K, Kakolyris S, Syrigos K, Papakotoulas P, Kouroussis C, Karvounis N, Vamvakas L, Christophyllakis C, Athanasiadis A, Varthalitis I, Georgoulias V, Mavroudis D; Hellenic Oncology Research Group. FEC versus sequential docetaxel followed by epirubicin/cyclophosphamide as adjuvant chemotherapy in women with axillary node-positive early breast cancer: a randomized study of the Hellenic Oncology Research Group (HORG). Breast Cancer Res Treat. 2010 Jan;119(1):95-104. Epub 2009 Jul 28. link to original article contains protocol 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 contains verified protocol PubMed NCT00014222
- FinXX: Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Asola R, Kokko R, Ahlgren J, Auvinen P, Hemminki A, Paija O, Helle L, Nuortio L, Villman K, Nilsson G, Lahtela SL, Lehtiö K, Pajunen M, Poikonen P, Nyandoto P, Kataja V, Bono P, Leinonen M, Lindman H; FinXX Study Investigators. Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer: an open-label, randomised controlled trial. Lancet Oncol. 2009 Dec;10(12):1145-51. Epub 2009 Nov 10. link to original article contains verified protocol 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
- FNCLCC PACS 04: Spielmann M, Roché H, Delozier T, Canon JL, Romieu G, Bourgeois H, Extra JM, Serin D, Kerbrat P, Machiels JP, Lortholary A, Orfeuvre H, Campone M, Hardy-Bessard AC, Coudert B, Maerevoet M, Piot G, Kramar A, Martin AL, Penault-Llorca F. Trastuzumab for patients with axillary-node-positive breast cancer: results of the FNCLCC-PACS 04 trial. J Clin Oncol. 2009 Dec 20;27(36):6129-34. Epub 2009 Nov 16. link to original article PubMed NCT00054587
- Update: D'Hondt V, Canon JL, Roca L, Levy C, Pierga JY, Le Du F, Campone M, Desmoulins I, Goncalves A, Debled M, Rios M, Ferrero JM, Serin D, Hardy-Bessard AC, Piot G, Brain E, Dohollou N, Orfeuvre H, Lemonnier J, Roché H, Delaloge S, Dalenc F. UCBG 2-04: Long-term results of the PACS 04 trial evaluating adjuvant epirubicin plus docetaxel in node-positive breast cancer and trastuzumab in the human epidermal growth factor receptor 2-positive subgroup. Eur J Cancer. 2019 Nov;122:91-100. Epub 2019 Oct 18. link to original article contains verified protocol PubMed
- TRAFIC: Sirohi B, A'Hern R, Coombes G, Bliss JM, Hickish T, Perren T, Crawford M, O'Brien M, Iveson T, Ebbs S, Skene A, Laing R, Smith IE. A randomised comparative trial of infusional ECisF versus conventional FEC as adjuvant chemotherapy in early breast cancer: the TRAFIC trial. Ann Oncol. 2010 Aug;21(8):1623-9. Epub 2010 Jan 21. link to original article contains protocol PubMed ISRCTN83324925
- MDACC ID01-580: Kelly CM, Green MC, Broglio K, Thomas ES, Brewster AM, Valero V, Ibrahim NK, Gonzalez-Angulo AM, Booser DJ, Walters RS, Hunt KK, Hortobagyi GN, Buzdar AU. Phase III trial evaluating weekly paclitaxel versus docetaxel in combination with capecitabine in operable breast cancer. J Clin Oncol. 2012 Mar 20;30(9):930-5. Epub 2012 Feb 13. link to original article contains verified protocol PubMed NCT00050167
- Sakr H, Hamed RH, Anter AH, Yossef T. Sequential docetaxel as adjuvant chemotherapy for node-positive or/and T3 or T4 breast cancer: clinical outcome (Mansoura University). Med Oncol. 2013 Mar;30(1):457. Epub 2013 Jan 16. link to original article contains verified protocol PubMed
- AERO-B2000: Delbaldo C, Serin D, Mousseau M, Greget S, Audhuy B, Priou F, Berdah JF, Teissier E, Laplaige P, Zelek L, Quinaux E, Buyse M, Piedbois P; Association Européenne de Recherche en Oncologie (AERO). A phase III adjuvant randomised trial of 6 cycles of 5-fluorouracil-epirubicine-cyclophosphamide (FEC100) versus 4 FEC 100 followed by 4 Taxol (FEC-T) in node positive breast cancer patients (Trial B2000). Eur J Cancer. 2014 Jan;50(1):23-30. Epub 2013 Oct 29. link to original article PubMed
- WSG-AGO EC-Doc: Nitz U, Gluz O, Huober J, Kreipe HH, Kates RE, Hartmann A, Erber R, Moustafa Z, Scholz M, Lisboa B, Mohrmann S, Möbus V, Augustin D, Hoffmann G, Weiss E, Böhmer S, Kreienberg R, Du Bois A, Sattler D, Thomssen C, Kiechle M, Jänicke F, Wallwiener D, Harbeck N, Kuhn W. Final analysis of the prospective WSG-AGO EC-Doc versus FEC phase III trial in intermediate-risk (pN1) early breast cancer: efficacy and predictive value of Ki67 expression. Ann Oncol. 2014 Aug;25(8):1551-7. Epub 2014 May 14. Erratum in: Ann Oncol. 2017 Nov 1;28(11):2899. link to original article contains protocol PubMed NCT02115204
- GIM2: Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article contains verified protocol PubMed NCT00433420
- GONO-MIG5: Del Mastro L, Levaggi A, Michelotti A, Cavazzini G, Adami F, Scotto T, Piras M, Danese S, Garrone O, Durando A, Accortanzo V, Bighin C, Miglietta L, Pastorino S, Pronzato P, Castiglione F, Landucci E, Conte P, Bruzzi P. 5-Fluorouracil, epirubicin and cyclophosphamide versus epirubicin and paclitaxel in node-positive early breast cancer: a phase-III randomized GONO-MIG5 trial. Breast Cancer Res Treat. 2016 Jan;155(1):117-26. link to original article contains verified protocol PubMed NCT02450058
- ADEBAR: Janni W, Harbeck N, Rack B, Augustin D, Jueckstock J, Wischnik A, Annecke K, Scholz C, Huober J, Zwingers T, Friedl TW, Kiechle M. Randomised phase III trial of FEC120 vs EC-docetaxel in patients with high-risk node-positive primary breast cancer: final survival analysis of the ADEBAR study. Br J Cancer. 2016 Apr 12;114(8):863-71. Epub 2016 Mar 31. link to original article link to PMC article contains verified protocol PubMed NCT00047099
- HMFEC: Coombes RC, Kilburn LS, Tubiana-Mathieu N, Olmos T, Van Bochove A, Perez-Lopez FR, Palmieri C, Stebbing J, Bliss JM. Epirubicin dose and sequential hormonal therapy-Mature results of the HMFEC randomised phase III trial in premenopausal patients with node positive early breast cancer. Eur J Cancer. 2016 Jun;60:146-53. Epub 2016 Apr 26. link to original article PubMed ISRCTN98335268
- UCBG-0106: Kerbrat P, Desmoulins I, Roca L, Levy C, Lortholary A, Marre A, Delva R, Rios M, Viens P, Brain É, Serin D, Edel M, Debled M, Campone M, Mourret-Reynier MA, Bachelot T, Foucher-Goudier MJ, Asselain B, Lemonnier J, Martin AL, Roché H. Optimal duration of adjuvant chemotherapy for high-risk node-negative (N-) breast cancer patients: 6-year results of the prospective randomised multicentre phase III UNICANCER-PACS 05 trial (UCBG-0106). Eur J Cancer. 2017 Jul;79:166-175. Epub 2017 May 11. link to original article contains verified protocol PubMed
- 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 verified protocol in supplement PubMed NCT00433589
Dose-dense FEC
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ddFEC: dose-dense Fluorouracil, Epirubicin, Cyclophosphamide
Regimen variant #1, 500/75/500
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Mavroudis et al. 2016 (HORG CT/07.17) | 2007-2013 | Phase 3 (C) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
Supportive medications
- Filgrastim or Pegfilgrastim (Neulasta) support (drug/dose/schedule not specified)
14-day cycle for 4 cycles
Subsequent treatment
Regimen variant #2, 600/90/600
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Del Mastro et al. 2015 (GIM2) | 2003-2006 | Phase 3 (E-esc) | See link | See link |
Note: a mid-protocol amendment suggested giving the pegilgrastim at least 72 h after chemotherapy. This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- 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
Supportive medications
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2
14-day cycle for 4 cycles
Subsequent treatment
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 × 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article contains verified protocol PubMed NCT00433420
- HORG CT/07.17: Mavroudis D, Matikas A, Malamos N, Papakotoulas P, Kakolyris S, Boukovinas I, Athanasiadis A, Kentepozidis N, Ziras N, Katsaounis P, Saloustros E, Georgoulias V; HORG. Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2016 Oct;27(10):1873-8. Epub 2016 Aug 8. link to original article contains verified protocol PubMed NCT01985724
FEC-D
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FEC-D: Fluorouracil, Epirubicin, Cyclophosphamide followed by Docetaxel
Protocol
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Roché et al. 2006 (FNCLCC PACS 01) | 1997-2000 | Phase 3 (E-switch-ic) | See link | Superior OS1 (HR 0.75, 95% CI 0.62-0.92) |
de Gregorio et al. 2020 (SUCCESS-A) | 2005-2007 | Phase 3 (C) | FEC-DG | Did not meet primary endpoint of DFS |
Sakr et al. 2013 | 2006-2010 | Phase 3 (E-switch-ic) | FEC; FEC 100 x 6 | Seems to have superior OS |
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 (Taxotere) | Did not meet primary endpoint of DFS |
1Reported efficacy for FNCLCC PACS 01 is based on the 2012 update.
Preceding treatment
Chemotherapy, FEC portion
- 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 3 cycles
Chemotherapy, D portion
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
21-day cycle for 3 cycles
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 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
- Sakr H, Hamed RH, Anter AH, Yossef T. Sequential docetaxel as adjuvant chemotherapy for node-positive or/and T3 or T4 breast cancer: clinical outcome (Mansoura University). Med Oncol. 2013 Mar;30(1):457. Epub 2013 Jan 16. link to original article contains verified protocol 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 contains verified protocol PubMed NCT00798070
- 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 verified protocol in supplement 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 contains verified protocol PubMed NCT02181101
Paclitaxel monotherapy, weekly
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T: Taxol (Paclitaxel)
P: Paclitaxel
pT: pacliTaxel
wP: weekly Paclitaxel
wT: weekly Taxol (Paclitaxel)
Regimen variant #1, 80 mg/m2 x 12
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sparano et al. 2008 (ECOG E1199) | 1999-2002 | Phase 3 (E-switch-ic) | 1. Paclitaxel; q3wk | Superior OS |
2. Docetaxel; q3wk 3. Docetaxel; weekly |
Not reported | |||
Kelly et al. 2012 (MDACC ID01-580) | 2002-2008 | Phase 3 (C) | XT | Did not meet primary endpoint of RFS |
Shulman et al. 2012 (CALGB 40101) | 2002-2008 | Phase 3 (E-de-esc) | 1. AC x 4 | Did not meet primary endpoint of RFS |
2. AC x 6 | Did not meet primary endpoint of RFS | |||
3. Paclitaxel; weekly x 18 | Did not meet primary endpoint of RFS | |||
Budd et al. 2014 (SWOG S0221) | 2003-2010 | Phase 3 (C) | ddT x 6 | Did not meet primary endpoint of DFS |
Miller et al. 2018 (ECOG E5103) | 2007-2011 | Phase 3 (C) | See link | See link |
Note: In CALGB 40101, this is the dosing before a mid-protocol amendment in 2003. This is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
- ECOG E1199: Surgery, then AC x 4
- MDACC ID01-580: Surgery
- SWOG S0221: Surgery, then ddAC x 6 versus continuous AC
- ECOG E5103: Surgery, then AC x 4 or ddAC x 4
Chemotherapy
- Paclitaxel (Taxol) 80 mg/m2 IV over 60 minutes once per day on days 1, 8, 15
21-day cycle for 4 cycles
Subsequent treatment
- MDACC ID01-580: FEC x 4
Regimen variant #2, 100 mg/m2 x 8
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Martín et al. 2008 (GEICAM 9906) | 1999-2002 | Phase 3 (E-switch-ic) | See link | See link |
Martín et al. 2013 (GEICAM 2003-02) | 2003-2008 | Phase 3 (E-switch-ic) | See link | See link |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
Chemotherapy
- Paclitaxel (Taxol) 100 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycle for 2 cycles
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 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
- GEICAM 9906: Martín M, Rodríguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Munárriz B, Rodríguez CA, Crespo C, de Alava E, López García-Asenjo JA, Guitián MD, Almenar S, González-Palacios JF, Vera F, Palacios J, Ramos M, Gracia Marco JM, Lluch A, Alvarez I, Seguí MA, Mayordomo JI, Antón A, Baena JM, Plazaola A, Modolell A, Pelegrí A, Mel JR, Aranda E, Adrover E, Alvarez JV, García Puche JL, Sánchez-Rovira P, Gonzalez S, López-Vega JM; GEICAM. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst. 2008 Jun 4;100(11):805-14. Epub 2008 May 27. link to original article contains verified protocol PubMed NCT00129922
- MDACC ID01-580: Kelly CM, Green MC, Broglio K, Thomas ES, Brewster AM, Valero V, Ibrahim NK, Gonzalez-Angulo AM, Booser DJ, Walters RS, Hunt KK, Hortobagyi GN, Buzdar AU. Phase III trial evaluating weekly paclitaxel versus docetaxel in combination with capecitabine in operable breast cancer. J Clin Oncol. 2012 Mar 20;30(9):930-5. Epub 2012 Feb 13. link to original article contains verified protocol PubMed NCT00050167
- CALGB 40101: Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six cycles of doxorubicin and cyclophosphamide or paclitaxel are not superior to four cycles as adjuvant chemotherapy for breast cancer in women with zero to three positive axillary nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article contains verified protocol 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. link to original article link to PMC article PubMed
- GEICAM 2003-02: Martín M, Ruiz A, Ruiz Borrego M, Barnadas A, González S, Calvo L, Margelí Vila M, Antón A, Rodríguez-Lescure A, Seguí-Palmer MA, Muñoz-Mateu M, Dorca Ribugent J, López-Vega JM, Jara C, Espinosa E, Mendiola Fernández C, Andrés R, Ribelles N, Plazaola A, Sánchez-Rovira P, Salvador Bofill J, Crespo C, Carabantes FJ, Servitja S, Chacón JI, Rodríguez CA, Hernando B, Álvarez I, Carrasco E, Lluch A. Fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus FAC followed by weekly paclitaxel as adjuvant therapy for high-risk, node-negative breast cancer: results from the GEICAM/2003-02 study. J Clin Oncol. 2013 Jul 10;31(20):2593-9. Epub 2013 Jun 3. link to original article contains verified protocol PubMed NCT00129389
- SWOG S0221: Budd GT, Barlow WE, Moore HC, Hobday TJ, Stewart JA, Isaacs C, Salim M, Cho JK, Rinn KJ, Albain KS, Chew HK, Burton GV, Moore TD, Srkalovic G, McGregor BA, Flaherty LE, Livingston RB, Lew DL, Gralow JR, Hortobagyi GN. SWOG S0221: a phase III trial comparing chemotherapy schedules in high-risk early-stage breast cancer. J Clin Oncol. 2015 Jan 1;33(1):58-64. Epub 2014 Nov 24. link to original article contains verified protocol link to PMC article PubMed NCT00070564
- ECOG E5103: Miller KD, O'Neill A, Gradishar W, Hobday TJ, Goldstein LJ, Mayer IA, Bloom S, Brufsky AM, Tevaarwerk AJ, Sparano JA, Le-Lindqwister NA, Hendricks CB, Northfelt DW, Dang CT, Sledge GW Jr. Double-blind phase III trial of adjuvant chemotherapy with and without bevacizumab in patients with lymph node-positive and high-risk lymph node-negative breast cancer (E5103). J Clin Oncol. 2018 Sep 1;36(25):2621-2629. Epub 2018 Jul 24. link to original article refers to ECOG E1199 protocol PubMed NCT00433511
Paclitaxel monotherapy, dose-dense (q2wk)
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ddT: dose-dense Taxol (Paclitaxel)
ddP: dose-dense Paclitaxel
Regimen variant #1, 175 mg/m2 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Citron et al. 2003 (CALGB 9741) | 1997-1999 | Phase 3 (E-esc) | See link | See link |
Shulman et al. 2012 (CALGB 40101) | 2002-2008 | Phase 3 (E-de-esc) | 1. ddAC x 4 | Did not meet primary endpoint of RFS |
2. ddAC x 6 | Did not meet primary endpoint of RFS | |||
3. ddT x 6 | Did not meet primary endpoint of RFS | |||
Burstein et al. 2005 | 2003-2004 | Non-randomized | ||
Del Mastro et al. 2015 (GIM2) | 2003-2006 | Phase 3 (E-esc) | See link | See link |
Swain et al. 2013 (NSABP B-38) | 2004-2007 | Phase 3 (C) | See link | See link |
Note: in CALGB 40101, this is the dosing after a mid-protocol amendment in 2003.
Preceding treatment
- CALGB 9741: ddA x 4
- Burstein et al. 2005: Neoadjuvant ddAC, then surgery or surgery, then adjuvant ddAC
- CALGB 40101: Surgery, within 90 days
- NSABP B-38: ddAC x 4
- GIM2: ddEC x 4 versus ddFEC x 4
Chemotherapy
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
Supportive medications
- Diphenhydramine (Benadryl) 12.5 to 50 mg IV once on day 1; 30 to 60 minutes prior to Paclitaxel (Taxol)
- One of the following H2 blockers:
- Ranitidine (Zantac) 50 mg IV once on day 1; 30 to 60 minutes prior to Paclitaxel (Taxol)
- Cimetidine (Tagamet) 300 mg IV once on day 1; 30 to 60 minutes prior to Paclitaxel (Taxol)
- Famotidine (Pepcid) 20 mg IV once on day 1; 30 to 60 minutes prior to Paclitaxel (Taxol)
- One of the following dexamethasone choices:
- Dexamethasone (Decadron) 10 mg IV once on day 1, within 60 minutes prior to Paclitaxel (Taxol)
- Dexamethasone (Decadron) 10 mg PO once on day 1, at least 60 minutes prior to Paclitaxel (Taxol)
- Dexamethasone (Decadron) 20 mg PO twice on day 1; 6 hours and 12 hours prior to Paclitaxel (Taxol)
- Recommended growth factor support with one of the following:
- Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
- Sargramostim (Leukine) 250 to 500 mcg/m2 SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
- Pegfilgrastim (Neulasta) 6 mg SC once, given 24 to 36 hours after chemotherapy
- GIM2: a mid-protocol amendment suggested giving the pegilgrastim at least 72 h after chemotherapy
14-day cycle for 4 cycles
Subsequent treatment
- CALGB 9741: ddC x 4
Regimen variant #2, 175 mg/m2 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Budd et al. 2014 (SWOG S0221) | 2003-2010 | Phase 3 (E-switch-ic) | Paclitaxel; weekly | Did not meet primary endpoint of DFS |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
- ddAC x 6 versus continuous AC
Chemotherapy
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
Supportive medications
- Pegfilgrastim (Neulasta) 6 mg SC once on day 2
14-day cycle for 6 cycles
Regimen variant #3, 200 mg/m2 x 4
Study | Years of enrollment | Evidence |
---|---|---|
Kahan et al. 2005 | 2000-2003 | Phase II |
Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.
Preceding treatment
- ddA x 4
Chemotherapy
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours day 1
Supportive medications
14-day cycle for 4 cycles
Subsequent treatment
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 contains verified protocol 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 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
- Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. link to original article contains verified protocol 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 contains verified protocol 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. link to original article link to PMC 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 contains verified protocol 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 contains verified protocol link to PMC article PubMed NCT00070564
- GIM2: Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article contains verified protocol PubMed NCT00433420
TAC (Taxotere)
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TAC: Taxotere (Docetaxel), Adriamycin (Doxorubicin), Cyclophosphamide
ACT: Adriamycin (Doxorubicin), Cyclophosphamide, Taxotere (Docetaxel)
Regimen variant #1, 4 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Swain et al. 2010 (NSABP B-30) | 1999-2004 | Phase 3 (C) | 1. AC-D | Might have inferior OS |
2. AT | Not reported |
Note: this was a mid-protocol dosing amendment.
Preceding treatment
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV over 15 minutes once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV over 1 to 5 minutes once on day 1
21-day cycle for 4 cycles
Regimen variant #2, 6 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Martin et al. 2005 (BCIRG 001) | 1997-1999 | Phase 3 (E-RT-switch-ic) | FAC | Superior OS |
Martín et al. 2010 (GEICAM 9805) | 1999-2003 | Phase 3 (E-switch-ic) | FAC | Superior DFS (HR 0.68, 95% CI 0.49-0.93) |
Eiermann et al. 2011 (BCIRG-005) | 2000-2003 | Phase 3 (C) | AC-D | Did not meet primary endpoint of DFS60 |
Swain et al. 2013 (NSABP B-38) | 2004-2007 | Phase 3 (C) | 1. ddAC, then ddP | Did not meet primary endpoint of DFS |
2. ddAC, then ddPG | Did not meet primary endpoint of DFS | |||
van Rossum et al. 2018 (MATADOR) | 2004-2012 | Phase 3 (E-switch-ic) | ddAC | Did not meet secondary endpoints of RFS/OS |
Blum et al. 2017 (USOR 06-090) | 2007-2009 | Phase 3 (C) | TC | Seems to have superior IDFS |
Blum et al. 2017 (NSABP-46-I/USOR 07132) | 2009-2012 | Phase 3 (C) | TC | Seems to have superior IDFS |
Blum et al. 2017 (NSABP B-49) | 2012-2013 | Phase 3 (C) | TC | Seems to have superior IDFS |
Note: Blum et al. 2017 is a pooled analysis of three RCTs, some of which had arms other than TAC and TC. Refer to the paper for further details.
Preceding treatment
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 medications
- 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 contains protocol 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 contains verified protocol 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 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 contains verified protocol 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 contains verified protocol PubMed NCT00093795
- USOR 06-090; NSABP-46-I/USOR 07132; NSABP B-49: Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, Robert NJ, Hopkins JO, O'Shaughnessy JA, Dang CT, Gómez HL, Fehrenbacher L, Vukelja SJ, Lyss AP, Paul D, Brufsky AM, Jeong JH, Colangelo LH, Swain SM, Mamounas EP, Jones SE, Wolmark N. Anthracyclines in early breast cancer: The ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017 Aug 10;35(23):2647-2655. Epub 2017 Apr 11. link to original article link to PMC article contains verified protocol PubMed NCT00493870; NCT00887536; NCT01547741
- MATADOR: van Rossum AGJ, Kok M, van Werkhoven E, Opdam M, Mandjes IAM, van Leeuwen-Stok AE, van Tinteren H, Imholz ALT, Portielje JEA, Bos MMEM, van Bochove A, Wesseling J, Rutgers EJ, Linn SC, Oosterkamp HM; MATADOR Trialists' Group. Adjuvant dose-dense doxorubicin-cyclophosphamide versus docetaxel-doxorubicin-cyclophosphamide for high-risk breast cancer: first results of the randomised MATADOR trial (BOOG 2004-04). Eur J Cancer. 2018 Oct;102:40-48. link to original article contains protocol PubMed ISRCTN61893718
Vinorelbine monotherapy
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V: Vinorelbine
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Joensuu et al. 2006 (FinHer) | 2000-2003 | Phase 3 (E-switch-ic) | Docetaxel | Inferior DDFS |
Note: Patients without HER2/neu amplification were only randomized to this arm verus the docetaxel arm.
Preceding treatment
Chemotherapy
- Vinorelbine (Navelbine) as follows:
- Cycles 1 & 2: 25 mg/m2 IV over 5 to 10 minutes once per day on days 1, 8, 15
- Cycle 3: 25 mg/m2 IV over 5 to 10 minutes once per day on days 1 & 8
21-day cycle for 3 cycles
Subsequent treatment
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 contains verified protocol 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. link to original article PubMed
Metastatic disease, first-line chemotherapy
Note: in many of these regimens, patients were allowed to have received (neo)adjuvant chemotherapy and hormonal therapy (when applicable). These are first-line regimens in the metastatic setting, with a few being specifically for the locally advanced but unresectable setting.
Cyclophosphamide & Doxorubicin (AC)
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AC: Adriamycin (Doxorubicin) & Cyclophosphamide
Regimen variant #1, 40/400
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Rosner et al. 1987 | 1981-1985 | Randomized (E-de-esc) | 1. CFP 2. CMFVP |
Did not meet primary endpoint of OS |
Chemotherapy
- Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
28-day cycles
Regimen variant #2, 40/500
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Katsumata et al. 2009 (JCOG9802) | 1999-2003 | Phase 3 (C) | 1. AC/D 2. Docetaxel |
Did not meet primary endpoint of TTF |
Chemotherapy
- Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Regimen variant #3, 40/800 (PO)
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Jones et al. 1975 | 1973-1974 | Non-randomized | ||
Tranum et al. 1982 (SWOG-7405B) | 1974-1977 | Phase 3 (E-de-esc) | 1. FAC 2. A, then CMFVP |
Did not meet primary endpoint of ORR |
Chemotherapy
- Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 200 mg/m2/day PO in divided doses on days 3 to 6
21- to 28-day cycles
Regimen variant #4, 50/750
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Forbes 1986 | 1978-1981 | Randomized (C) | 1. ACT 2. Tamoxifen |
Did not meet primary endpoint of OS |
Chemotherapy
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 750 mg/m2 IV once on day 1
21-day cycle for up to 9 cycles
Regimen variant #5, 60/600
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Biganzoli et al. 2002 (EORTC 10961) | 1996-1999 | Phase 3 (C) | AT (Taxol) | Did not meet primary endpoint of PFS |
Nabholtz et al. 2003 (TAX 306) | NR | Phase 3 (C) | AT (Taxotere) | Seems to have inferior TTP |
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycles (see note)
Regimen variant #6, with range
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Phase 3 (C) | AC & Bevacizumab | Inferior PFS |
Chemotherapy
- Doxorubicin (Adriamycin) 50 to 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 to 600 mg/m2 IV once on day 1
21-day cycle for up to 8 cycles
References
- Jones SE, Durie BG, Salmon SE. Combination chemotherapy with adriamycin and cyclophosphamide for advanced breast cancer. Cancer. 1975 Jul;36(1):90-7. link to original article contains protocol 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 contains verified protocol 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 contains verified protocol 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 contains verified protocol 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 contains protocol 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 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 contains protocol 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 contains verified protocol PubMed NCT00262067
Cyclophosphamide & Doxorubicin (AC) & Bevacizumab
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AC & Bevacizumab: Adriamycin (Doxorubicin), Cyclophosphamide, Bevacizumab
Regimen variant #1, with range
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Phase 3 (E-esc) | AC | Superior PFS (HR 0.64, 95% CI 0.52-0.80) |
Chemotherapy
- Doxorubicin (Adriamycin) 50 to 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 to 600 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for up to 8 cycles
Subsequent treatment
- Bevacizumab maintenance, if no PD
References
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed NCT00262067
Doxorubicin & Paclitaxel (AT)
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AT: Adriamycin (Doxorubicin) & Taxol (Paclitaxel)
Regimen variant #1, 50/150
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sledge et al. 2003 (ECOG E1193) | 1993-1995 | Phase 3 (E-esc) | 1. Doxorubicin 2. Paclitaxel; q3wk |
Superior TTF |
Chemotherapy
- Doxorubicin (Adriamycin) as follows, given first:
- Cycles 1 to 8: 50 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 150 mg/m2 IV continuous infusion over 24 hours, started on day 1, given second, 3 hours after doxorubicin
21-day cycles
Regimen variant #2, 50/175
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Cassier et al. 2007 (ERASME 3) | 2000-2004 | Phase 3 (C) | AT (Taxotere) | Might have superior OS |
Chemotherapy
- Doxorubicin (Adriamycin) 50 mg/m2 IV over 15 minutes once on day 1, given first
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1, given second
21-day cycle for 4 cycles
Subsequent treatment
- Paclitaxel x 4
Regimen variant #3, 50/220
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Jassem et al. 2001 | 1996-1998 | Phase 3 (E-de-esc) | FAC | Seems to have superior OS |
Chemotherapy
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 220 mg/m2 IV over 3 hours once on day 2
21-day cycle for up to 8 cycles
Regimen variant #4, 60/200
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Biganzoli et al. 2002 (EORTC 10961) | 1996-1999 | Phase 3 (E-switch-ic) | AC | Did not meet primary endpoint of PFS |
Schmid et al. 2005 | 1998-2002 | Phase 3 (C) | Tandem auto HSCT | Did not meet primary endpoint of CR rate |
Note: in EORTC 10961, first cycle of paclitaxel was 175 mg/m2.
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV over 15 minutes once on day 1
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
21-day cycle for up to 6 cycles
Regimen variant #5, with range
Study | Years of enrollment | Evidence |
---|---|---|
Gianni et al. 1995 | 1993-1994 | Non-randomized |
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 125 to 200 mg/m2 IV once on day 1
21-day cycles
References
- 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 contains protocol 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 contains protocol 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 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 contains verified protocol 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 contains verified protocol PubMed
Docetaxel & Doxorubicin (AT)
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AT: Adriamycin (Doxorubicin) & Taxotere (Docetaxel)
AD: Adriamycin (Doxorubicin) & Docetaxel
Regimen variant #1, 50/75 x 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Cassier et al. 2007 (ERASME 3) | 2000-2004 | Phase 3 (C) | AT (Taxol) | Might have inferior OS |
Chemotherapy
- Doxorubicin (Adriamycin) 50 mg/m2 IV over 15 minutes once on day 1, given first
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1, given second
21-day cycle for 4 cycles
Subsequent treatment
- Docetaxel x 4
Regimen variant #2, 50/75 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Bontenbal et al. 2005 | 1997-2002 | Phase 3 (E-de-esc) | FAC | Seems to have superior OS | |
Alba et al. 2004 (GEICAM-9903) | 1999-2001 | Phase 3 (C) | A, then T (Taxotere) | More toxic |
Chemotherapy
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Regimen variant #3, 50/75 x 8
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Nabholtz et al. 2003 (TAX 306) | NR | Phase 3 (E-switch-ic) | AC | Seems to have superior TTP | |
Stemmler et al. 2010 (D4) | 2001-2008 | Phase 3 (C) | AT (Taxotere); weekly docetaxel | Did not meet secondary endpoint of TTP | Did not meet primary endpoint of hematotoxicity |
Chemotherapy
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycle for 8 cycles
References
- TAX 306: Nabholtz JM, Falkson C, Campos D, Szanto J, Martín M, Chan S, Pienkowski T, Zaluski J, Pinter T, Krzakowski M, Vorobiof D, Leonard R, Kennedy I, Azli N, Murawsky M, Riva A, Pouillart P; TAX 306 Study Group. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol. 2003 Mar 15;21(6):968-75. link to original article PubMed
- GEICAM-9903: Alba E, Martín M, Ramos M, Adrover E, Balil A, Jara C, Barnadas A, Fernández-Aramburo A, Sánchez-Rovira P, Amenedo M, Casado A; GEICAM. Multicenter randomized trial comparing sequential with concomitant administration of doxorubicin and docetaxel as first-line treatment of metastatic breast cancer: a Spanish Breast Cancer Research Group (GEICAM-9903) phase III study. J Clin Oncol. 2004 Jul 1;22(13):2587-93. link to original article contains protocol 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 contains protocol 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 contains verified protocol 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 contains protocol PubMed
Capecitabine monotherapy
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Regimen variant #1, 650 mg/m2 PO twice per day, continuous
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Stockler et al. 2011 (ANZ 0001) | 2001-2005 | Phase 3 (E-de-esc) | 1. CMF | Seems to have superior OS |
2. Capecitabine; intermittent | Did not meet primary endpoint of quality-adjusted PFS |
Chemotherapy
- Capecitabine (Xeloda) 650 mg/m2 PO twice per day
21-day cycles
Regimen variant #2, 1000 mg/m2 PO twice per day, limited duration
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Smorenburg et al. 2014 (OMEGA) | 2007-2011 | Phase 3 (E-switch-ic) | PLD | Did not meet primary endpoint of PFS |
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycle for 8 cycles
Regimen variant #3, 1000 mg/m2 PO twice per day, indefinite
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bajetta et al. 2005 | 1999-2003 | Phase II | ||
Stockler et al. 2011 (ANZ 0001) | 2001-2005 | Phase 3 (E-de-esc) | 1. CMF | Seems to have superior OS |
2. Capecitabine; continuous | Did not meet primary endpoint of quality-adjusted PFS | |||
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Phase 3 (C) | Capecitabine & Bevacizumab | Inferior PFS |
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycles
Regimen variant #4, 1250 mg/m2 PO twice per day
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bajetta et al. 2005 | 1999-2003 | Phase II | ||
Harbeck et al. 2016 (PELICAN) | 2006-2010 | Phase 3 (E-switch-ic) | Pegylated liposomal doxorubicin | Inconclusive whether non-inferior TTP |
Preceding treatment
- JO21095: Docetaxel, with PD
Chemotherapy
- Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
21-day cycles
References
- Bajetta E, Procopio G, Celio L, Gattinoni L, Della Torre S, Mariani L, Catena L, Ricotta R, Longarini R, Zilembo N, Buzzoni R. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol. 2005 Apr 1;23(10):2155-61. Epub 2005 Feb 14. link to original article contains verified protocol 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 contains verified protocol 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 contains verified protocol 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 contains protocol 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 contains verified protocol PubMed NCT00266799
- CONTESSA: NCT03326674
Capecitabine & Bevacizumab
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Phase 3 (E-esc) | Capecitabine | Superior PFS (HR 0.69, 95% CI 0.56-0.84) |
Lang et al. 2013 (TURANDOT) | 2008-2010 | Phase 3 (E-switch-ic) | Paclitaxel & Bevacizumab | Non-inferior OS1 |
Welt et al. 2016 (CARIN) | 2009-2012 | Phase 3 (C) | Capecitabine, Vinorelbine, Bevacizumab | Might have inferior PFS |
1Reported efficacy for TURANDOT is based on the 2016 update.
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol 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 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 contains protocol 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. link to original article link to PMC article PubMed NCT00868634
Capecitabine & Paclitaxel
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TX: Taxol (Paclitaxel), Xeloda (Capecitabine)
Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Blum et al. 2006 | 2003 | Phase II |
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 contains verified protocol PubMed
Capecitabine & Paclitaxel, nanoparticle albumin-bound
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Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Schwartzberg et al. 2011 | NR | Phase II |
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 contains protocol PubMed
CMF
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CMF: Cyclophosphamide, Methotrexate, Fluorouracil
Regimen variant #1, 600/40/600
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Tannock et al. 1988 | 1981-1986 | Phase 3 (C) | CMF; lower-dose | Might have superior OS |
Ingle et al. 1994 (NCCTG 87-32-52) | 1987-1991 | Randomized (C) | DES-CEF | Might have inferior ORR |
Chemotherapy
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
- Methotrexate (MTX) 40 mg/m2 IV once on day 1
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
21-day cycles
Regimen variant #2, 1400/80/1000
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Aisner et al. 1987 | 1976-1980 | Phase 3 (C) | 1. CAF | Seems to have inferior OS |
2. CAFVP | Inferior ORR |
Chemotherapy
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
28-day cycles
Regimen variant #3, 1400/60/800
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Canellos et al. 1976 | NR | Phase 3 (E-esc) | Melphalan | Seems to have superior OS |
Note: this was the dose used for patients older than 60 in the revised protocol of Canellos et al. 1976.
Chemotherapy
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 30 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 & 8
28-day cycles
Regimen variant #4, 1400/80/1200
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brambilla et al. 1976 | 1973-1974 | Randomized (C) | AV | Did not meet primary endpoint of ORR |
Canellos et al. 1976 | NR | Phase 3 (E-esc) | Melphalan | Seems to have superior OS |
Bull et al. 1978 | NR | Phase 3 (C) | CAF | Might have inferior ORR |
Tormey et al. 1982 (ECOG E2173) | 1973-1974 | Randomized (C) | 1. AV 2. CMFP |
Seems to have inferior OS |
Viladiu et al. 1985 | 1978-1981 | Randomized (C) | 1. CMFT 2. CMF & MPA |
Seems to have inferior ORR |
Engelsman et al. 1991 (EORTC 10808) | 1981-1984 | Phase 3 (C) | CMF; 600/40/600 (IV) | Seems to have superior OS |
Cocconi et al. 1990 | 1981-1985 | Randomized (C) | CMF x 6, then intensification | Did not meet endpoints of TTP/OS |
Yosef et al. 1993 | 1983-1987 | Randomized (C) | SMF | Did not meet endpoints of TTF/OS |
Cocconi et al. 1991 | 1985-1988 | Randomized (C) | PE | Might have inferior ORR |
Ackland et al. 2001 (HEPI 013) | 1990-1992 | Phase 3 (C) | CEF | Inferior TTP |
Stadtmauer et al. 2000 | 1990-1997 | Phase 3 (C) | CMF x 4-6, then HDT | Did not meet primary endpoint of OS |
von Minckwitz et al. 2005 | 1996-2001 | Phase 3 (C) | BMF | Inferior TTP |
Stockler et al. 2011 (ANZ 0001) | 2001-2005 | Phase 3 (C) | 1. Capecitabine; continuous 2. Capecitabine; intermittent |
Seems to have inferior OS |
Note: this was the dose used for patients younger than 60 in the revised protocol of Canellos et al. 1976.
Chemotherapy
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 40 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycles
Regimen variant #5, 1400/120/1200
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Canellos et al. 1976 | NR | Phase 3 (E-esc) | Melphalan | Seems to have superior OS |
Note: this was the dose used for patients in the original protocol of Canellos et al. 1976 and was deemed too myelotoxic.
Chemotherapy
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
- Methotrexate (MTX) 60 mg/m2 IV once per day on days 1 & 8
- Fluorouracil (5-FU) 600 mg/m2 IV once per day on days 1 & 8
28-day cycles
References
- 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 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
- Viladiu P, Alonso MC, Avella A, Beltrán M, Borrás J, Ojeda B, Bosch FX. Chemotherapy versus chemotherapy plus hormonotherapy in postmenopausal advanced breast cancer patients: a randomized trial. Cancer. 1985 Dec 15;56(12):2745-50. link to original article contains verified protocol PubMed
- Aisner J, Weinberg V, Perloff M, Weiss R, Perry M, Korzun A, Ginsberg S, Holland JF; CALGB. Chemotherapy versus chemoimmunotherapy (CAF v CAFVP v CMF each +/- MER) for metastatic carcinoma of the breast: a CALGB study. J Clin Oncol. 1987 Oct;5(10):1523-33. link to original article contains protocol 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 contains verified protocol 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 contains protocol 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 contains protocol 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 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 PubMed
CMFT
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CMFT: Cyclophosphamide, Methotrexate, Fluorouracil, Tamoxifen
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Cocconi et al. 1983 | NR | Randomized (E-esc) | CMF | Might have superior TTF |
Viladiu et al. 1985 | 1978-1981 | Randomized (E-esc) | 1. CMF 2. CMF & MPA |
Seems to have superior ORR |
Chemotherapy
Endocrine therapy
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 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 PubMed
Docetaxel & Epirubicin (DE)
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DE: Docetaxel & Epirubicin
ED: Epirubicin & Docetaxel
ET: Epirubicin & Taxotere (Docetaxel)
Regimen variant #1, 8 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bonneterre et al. 2004 | 1998-2000 | Randomized Phase II (E-de-esc) | FEC | Superior ORR |
Blohmer et al. 2010 | 2000-2003 | Phase 3 (E-switch-ic) | EC | Did not meet primary endpoint of ORR |
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
21-day cycle for up to 8 cycles
Regimen variant #2, indefinite
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Mavroudis et al. 2009 (HORG CT/02.09) | 2002-2007 | Phase 3 (C) | TX | Did not meet primary endpoint of TTP |
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
21-day cycles
References
- Bonneterre J, Dieras V, Tubiana-Hulin M, Bougnoux P, Bonneterre ME, Delozier T, Mayer F, Culine S, Dohoulou N, Bendahmane B. Phase II multicentre randomised study of docetaxel plus epirubicin vs 5-fluorouracil plus epirubicin and cyclophosphamide in metastatic breast cancer. Br J Cancer. 2004 Oct 18;91(8):1466-71. link to original article link to PMC article contains protocol 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 contains verified protocol 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 contains verified protocol PubMed
Docetaxel monotherapy
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D: Docetaxel
T: Taxotere (Docetaxel)
Regimen variant #1, 30 mg/m2 3 weeks out of 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Stemmler et al. 2011 (D2) | 2001-2008 | Phase 3 (E-switch-ic) | Docetaxel; q3wk | Seems to have inferior ORR | Superior hematotoxicity |
Chemotherapy
- Docetaxel (Taxotere) 30 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Regimen variant #2, 40 mg/m2 3 weeks out of 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Rivera et al. 2008 | 2001-2004 | Phase 3 (E-switch-ic) | Docetaxel; q3wk | Did not meet primary endpoint of ORR | Superior toxicity |
Chemotherapy
- Docetaxel (Taxotere) as follows:
- Cycle 1: 35 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
- Cycle 2 onwards: 40 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
28-day cycles
Regimen variant #3, 40 mg/m2 6 weeks out of 8
Study | Years of enrollment | Evidence |
---|---|---|
Burstein et al. 2000 | 1998 | Phase II |
Chemotherapy
- Docetaxel (Taxotere) 40 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
8-week cycles
Regimen variant #4, 60 mg/m2 q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Katsumata et al. 2009 (JCOG9802) | 1999-2003 | Phase 3 (E-de-esc) | 1. AC 2. AC/D |
Did not meet primary endpoint of TTF | |
Takashima et al. 2015 (SELECT BC) | 2006-2010 | Phase 3 (C) | S-1 | Seems to have non-inferior OS | Inferior EQ-5D score |
Chemotherapy
- Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
21-day cycle for up to 6 cycles
Regimen variant #5, 60 mg/m2 q4wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Takashima et al. 2015 (SELECT BC) | 2006-2010 | Phase 3 (C) | S-1 | Seems to have non-inferior OS | Inferior EQ-5D score |
Chemotherapy
- Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
28-day cycles
Regimen variant #6, 75 mg/m2 q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Stemmler et al. 2011 (D2) | 2001-2008 | Phase 3 (C) | Docetaxel; weekly | Seems to have superior ORR | Inferior hematotoxicity |
Sparano et al. 2009 (DOXIL-BCA-3001) | 2004-2006 | Phase 3 (C) | Docetaxel & PLD | Inferior TTP | Less toxic |
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Phase 3 (C) | Docetaxel & Bevacizumab | Inferior PFS | |
Takashima et al. 2015 (SELECT BC) | 2006-2010 | Phase 3 (C) | S-1 | Seems to have non-inferior OS | Inferior EQ-5D score |
Mackey et al. 2014 (ROSE/TRIO-12) | 2008-2011 | Phase 3 (C) | Docetaxel & Ramucirumab | Might have inferior PFS |
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycles
Regimen variant #7, 75 mg/m2 q4wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Takashima et al. 2015 (SELECT BC) | 2006-2010 | Phase 3 (C) | S-1 | Seems to have non-inferior OS | Inferior EQ-5D score |
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
28-day cycles
Regimen variant #8, 100 mg/m2 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Pacilio et al. 2006 | 2000-2003 | Phase 3 (C) | Docetaxel & Epirubicin | Did not meet primary endpoint of ORR |
Chemotherapy
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
21-day cycle for 6 cycles
Regimen variant #9, 100 mg/m2 x 8
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Crump et al. 2007 (NCIC-CTG MA.16) | 1997-2000 | Phase 3 (C) | 1. FAC x 4, then HDCT with auto HSCT 2. FEC x 4, then HDCT with auto HSCT 3. Paclitaxel x 4, , then HDCT with auto HSCT 4. Docetaxel x 4, then HDCT with auto HSCT |
Did not meet primary endpoint of OS |
Chemotherapy
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
21-day cycle for 8 cycles
Regimen variant #10, 100 mg/m2 x 9
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Miles et al. 2010 (AVADO) | 2006-2007 | Phase 3 (C) | 1. Docetaxel & Bevacizumab; 100/7.5 | Did not meet primary endpoint of PFS |
2. Docetaxel & Bevacizumab; 100/15 | Inferior PFS |
Chemotherapy
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
21-day cycle for up to 9 cycles
Regimen variant #11, 100 mg/m2, indefinite
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Trudeau et al. 1996 | 1992-1993 | Phase II | |||
Rivera et al. 2008 | 2001-2004 | Phase 3 (C) | Docetaxel; weekly | Did not meet primary endpoint of ORR | Inferior toxicity |
Nielsen et al. 2011 | 2001-2005 | Phase 3 (C) | Docetaxel & Gemcitabine | Might have inferior TTP | |
Joensuu et al. 2009 (B9E-MC-S241) | 2002-2006 | Phase 3 (C) | D/G | Did not meet primary endpoint of TTF | More toxic |
Gradishar et al. 2009 | 2005-2006 | Randomized Phase II (C) | 1. nab-Paclitaxel; higher-dose weekly 2. nab-Paclitaxel; lower-dose weekly 3. nab-Paclitaxel; q3wk |
Did not meet primary endpoint of ORR | |
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Phase 3 (C) | Docetaxel & Bevacizumab | Inferior PFS | |
Bergh et al. 2012 (SUN 1064) | 2007-2009 | Phase 3 (C) | Docetaxel & Sunitinib | Did not meet primary endpoint of PFS |
Chemotherapy
- Docetaxel (Taxotere) 100 mg/m2 IV over 60 minutes once on day 1
- Note: Rivera et al. 2008 gave 75 mg/m2 in cycle 1, with escalation to 100 mg/m2 depending on toxicity
21-day cycles
References
- Trudeau ME, Eisenhauer EA, Higgins BP, Letendre F, Lofters WS, Norris BD, Vandenberg TA, Delorme F, Muldal AM; National Cancer Institute of Canada-Clinical Trials Group. Docetaxel in patients with metastatic breast cancer: a phase II study of the National Cancer Institute of Canada-Clinical Trials Group. J Clin Oncol. 1996 Feb;14(2):422-8. link to original article contains protocol 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 contains verified protocol 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 contains verified protocol 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 contains verified protocol 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 contains protocol 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 contains verified protocol 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 contains verified protocol 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 contains verified protocol 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 contains verified protocol 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 contains protocol 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 contains verified protocol 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 contains protocol 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 contains verified protocol 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 contains protocol 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 contains verified protocol 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
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Regimen variant #1, 75/15, indefinite
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Phase 3 (E-esc) | Docetaxel | Superior PFS (HR 0.64, 95% CI 0.52-0.80) |
Lück et al. 2014 (TABEA) | 2009-2012 | Phase 3 (C) | TBX | Did not meet primary endpoint of PFS |
Trédan et al. 2016 (GINECO-BR107) | 2010-2013 | Phase 3 (C) | Docetaxel & Bevacizumab, then Exemestane & Bevacizumab | Did not meet primary endpoint of PFS |
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
Regimen variant #2, 100/15, 9 cycles
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Miles et al. 2010 (AVADO) | 2006-2007 | Phase 3 (C) | 1. Docetaxel | Superior PFS |
2. Docetaxel & Bevacizumab; 100/7.5 | Not reported |
Chemotherapy
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for up to 9 cycles
Subsequent treatment
Regimen variant #3, 100/15, indefinite
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Phase 3 (E-esc) | Docetaxel | Superior PFS (HR 0.64, 95% CI 0.52-0.80) |
Chemotherapy
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- AVADO: Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010 Jul 10;28(20):3239-47. Epub 2010 May 24. link to original article contains verified protocol 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 contains verified protocol 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 contains protocol 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 contains verified protocol PubMed NCT01303679
Docetaxel & Gemcitabine
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GD: Gemcitabine & Docetaxel
GDoc: Gemcitabine & Docetaxel
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Nielsen et al. 2011 | 2001-2005 | Phase 3 (E-esc) | Docetaxel | Might have superior TTP |
Fountzilas et al. 2008 | 2002-2006 | Phase 3 (E-esc) | 1. Carboplatin & Paclitaxel | Did not meet primary endpoint of OS |
2. Paclitaxel; weekly | Seems to have inferior OS | |||
Seidman et al. 2010 (B9E-MC-S273) | 2002-2008 | Phase 3 (C) | TX | Did not meet primary endpoint of TTP |
Del Mastro et al. 2013 (B9E-IT-S376) | 2005-2010 | Phase 3 (E-switch-ic) | 1. GD; weekly 2. GT; q3wk 3. GT; weekly |
Did not meet primary endpoint of TTP |
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
- Nielsen et al. 2011 gave docetaxel on day 8
- Gemcitabine (Gemzar) 1000 mg/m2 IV over 30 minutes once per day on days 1 & 8
21-day cycles
Subsequent treatment
- B9E-MC-S273, upon progression: Capecitabine
References
- Fountzilas G, Dafni U, Dimopoulos MA, Koutras A, Skarlos D, Papakostas P, Gogas H, Bafaloukos D, Kalogera-Fountzila A, Samantas E, Briasoulis E, Pectasides D, Maniadakis N, Matsiakou F, Aravantinos G, Papadimitriou C, Karina M, Christodoulou C, Kosmidis P, Kalofonos HP; Hellenic Cooperative Oncology Group. A randomized phase III study comparing three anthracycline-free taxane-based regimens, as first line chemotherapy, in metastatic breast cancer: a Hellenic Cooperative Oncology Group study. Breast Cancer Res Treat. 2009 May;115(1):87-99. Epub 2008 May 16. link to original article contains verified protocol 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 contains protocol PubMed NCT00191438
- Nielsen DL, Bjerre KD, Jakobsen EH, Cold S, Stenbygaard L, Sørensen PG, Kamby C, Møller S, Jørgensen CL, Andersson M; Danish Breast Cancer Cooperative Group. Gemcitabine plus docetaxel versus docetaxel in patients with predominantly human epidermal growth factor receptor 2-negative locally advanced or metastatic breast cancer: a randomized, phase III study by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 2011 Dec 20;29(36):4748-54. Epub 2011 Nov 14. link to original article contains verified protocol 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 contains protocol PubMed NCT00236899
Doxorubicin monotherapy
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Regimen variant #1, 20 mg/m2 weekly
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gundersen et al. 1986 | 1982-1983 | Phase 3 (E-de-esc) | VAC | Did not meet endpoint of OS |
Gundersen et al. 1990 | 1984-1986 | Phase 3 (C) | Epirubicin | Did not meet endpoints of ORR/OS |
Gundersen et al. 1994 | 1987-1990 | Randomized (C) | Doxorubicin & MPA | Might have inferior ORR |
Chemotherapy
- Doxorubicin (Adriamycin) 20 mg/m2 IV once on day 1
7-day cycles
Regimen variant #2, 60 mg/m2 q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gottlieb et al. 1974 (SWG02) | 1972 | Phase 3 (E-switch-ic) | 1. Lomustine 2. Semustine |
Superior OS |
Hoogstraten et al. 1976 | 1972-1974 | Phase 3 (C) | CMFVP | Seems to have inferior ORR |
Vaughn et al. 1988 (SWOG S8020) | 1980-1982 | Phase 3 (C) | Doxorubicin & Etoposide | Seems to have inferior TTP |
Perez et al. 1991 | 1985-1988 | Phase 3 (C) | Epirubicin | Did not meet endpoints of ORR/OS |
Norris et al. 2000 (NCIC-CTG MA.8) | 1992-1995 | Phase 3 (C) | Doxorubicin & Vinorelbine | Did not meet primary endpoint of OS |
Sledge et al. 2003 (ECOG E1193) | 1993-1995 | Phase 3 (C) | 1. AT (Taxol) | Inferior TTF |
2. Paclitaxel | Did not meet primary endpoint of ORR | |||
O'Brien et al. 2004 | 1998-2000 | Phase 3 (C) | Pegylated liposomal doxorubicin | Seems to have non-inferior PFS |
Note: in NCIC-CTG MA.8, this dose was after a mid-protocol amendment. Treatment in NCIC-CTG MA.8 was given until a cumulative dose of 450 mg/m2.
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
21-day cycles (see note)
Regimen variant #3, 75 mg/m2 q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Paridaens et al. 2000 (EORTC 10923) | 1993-1996 | Phase 3 (C) | Paclitaxel | Superior PFS |
Chemotherapy
- Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
21-day cycle for 7 cycles
References
- 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 contains verified protocol 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 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 contains protocol 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 contains protocol 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 contains protocol 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 contains protocol 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 contains protocol 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 contains protocol 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 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 PubMed
Doxorubicin pegylated liposomal monotherapy
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Regimen variant #1, 45 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Smorenburg et al. 2014 (OMEGA) | 2007-2011 | Phase 3 (E-switch-ic) | Capecitabine | Did not meet primary endpoint of PFS |
Chemotherapy
- Pegylated liposomal doxorubicin (Doxil) 45 mg/m2 IV once on day 1
28-day cycle for 6 cycles
Regimen variant #2, 50 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
O'Brien et al. 2004 | 1998-2000 | Phase 3 (E-switch-ic) | Doxorubicin | Seems to have non-inferior PFS |
Harbeck et al. 2016 (PELICAN) | 2006-2010 | Phase 3 (E-switch-ic) | Capecitabine | Inconclusive whether non-inferior TTP |
Chemotherapy
- Pegylated liposomal doxorubicin (Doxil) 50 mg/m2 IV over up to 60 minutes once on day 1
- If infusion reactions occurred, infusion could be given over up to 90 minutes
28-day cycles
References
- O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C; CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004 Mar;15(3):440-9. link to original article contains verified protocol 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 contains protocol 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 contains verified protocol PubMed NCT00266799
Cyclophosphamide & Epirubicin (EC)
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EC: Epirubicin & Cyclophosphamide
Regimen variant #1, 75/600
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Chan et al. 2004 | 1996-1997 | Phase 3 (C) | MC | Seems to have inferior TTP |
Langley et al. 2005 (UKNCRI AB01) | 1996-1999 | Phase 3 (C) | EP | Did not meet primary endpoint of PFS |
Chemotherapy
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for up to 6 to 8 cycles
Regimen variant #2, 90/600
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Blohmer et al. 2010 | 2000-2003 | Phase 3 (C) | ED | Did not meet primary endpoint of ORR |
Chemotherapy
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for up to 8 cycles
Regimen variant #3, with range
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Phase 3 (C) | EC & Bevacizumab | Inferior PFS |
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 contains protocol 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 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 contains protocol 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 contains verified protocol PubMed NCT00262067
Cyclophosphamide & Epirubicin (EC) & Bevacizumab
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EC & Bevacizumab: Epirubicin, Cyclophosphamide, Bevacizumab
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Phase 3 (E-esc) | EC | Superior PFS (HR 0.64, 95% CI 0.52-0.80) |
Chemotherapy
- Epirubicin (Ellence) 90 to 100 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 to 600 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for up to 8 cycles
Subsequent treatment
- Bevacizumab maintenance, if no PD
References
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed NCT00262067
Epirubicin & Paclitaxel (EP)
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EP: Epirubicin & Paclitaxel
ET: Epirubicin & Taxol (Paclitaxel)
Regimen variant #1, 60/175
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lück et al. 2013 | 2002-2005 | Phase 3 (C) | XP | Inconclusive whether non-inferior PFS |
Chemotherapy
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycle for up to 6 cycles
Regimen variant #2, 75/175
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hatschek et al. 2011 (TEX trial) | 2002-2007 | Phase 3 (C) | TEX | Did not meet primary endpoint of PFS |
Note: the doses of this regimen were individually adjusted after cycle 1; see paper for details.
Chemotherapy
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
21-day cycles
Regimen variant #3, 75/200
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Langley et al. 2005 (UKNCRI AB01) | 1996-1999 | Phase 3 (E-switch-ic) | EC | Did not meet primary endpoint of PFS |
Chemotherapy
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 200 mg/m2 IV once on day 1
21-day cycle for up to 6 cycles
Regimen variant #4, 80/175
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Fountzilas et al. 2004 | 1999-2002 | Phase 3 (C) | Carboplatin & Paclitaxel (CP) | Did not meet primary endpoint of OS |
Chemotherapy
- Epirubicin (Ellence) 80 mg/m2 IV once on day 1, given second
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1, given first
21-day cycle for up to 6 cycles
Regimen variant #5, 90/200
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Conte et al. 2004 | 1996-2001 | Phase 3 (C) | E, then P | Seems to have non-inferior ORR |
Chemotherapy
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Paclitaxel (Taxol) 200 mg/m2 IV once on day 1
21-day cycle for 8 cycles
References
- Conte PF, Guarneri V, Bruzzi P, Prochilo T, Salvadori B, Bolognesi A, Aldrighetti D, Venturini M, Rosso R, Mammoliti S, Carnino F, Giannessi P, Costantini M, Moyano A, Baldini E; GONO. Concomitant versus sequential administration of epirubicin and paclitaxel as first-line therapy in metastatic breast carcinoma: results for the Gruppo Oncologico Nord Ovest randomized trial. Cancer. 2004 Aug 15;101(4):704-12. link to original article contains protocol 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 contains protocol 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 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 contains protocol 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 contains protocol PubMed
Epirubicin monotherapy
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Regimen variant #1, 35 mg/m2, 3 out of 4 weeks
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Feher et al. 2005 | 1996-1999 | Phase 3 (C) | Gemcitabine | Superior OS |
Chemotherapy
- Epirubicin (Ellence) 35 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Regimen variant #2, 40 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bastholt et al. 1996 | 1987-1991 | Phase 3 (E-de-esc) | 1. Epirubicin; 60 mg/m2 | Did not meet primary endpoint of TTP |
2. Epirubicin; 90 mg/m2 | Inferior TTP | |||
3. Epirubicin; 135 mg/m2 | Did not meet primary endpoint of TTP |
Chemotherapy
- Epirubicin (Ellence) 40 mg/m2 IV once on day 1
21-day cycles
Regimen variant #3, 50 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gundersen et al. 1990 | 1984-1986 | Phase 3 (E-switch-ic) | Doxorubicin | Did not meet endpoints of ORR/OS |
Chemotherapy
- Epirubicin (Ellence) 50 mg/m2 IV once on day 1
14-day cycles
Regimen variant #4, 60 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Nielsen et al. 1990 | 1983-1986 | Phase 3 (C) | Epirubicin & Vindesine | Did not meet primary endpoint of ORR |
Bastholt et al. 1996 | 1987-1991 | Phase 3 (E-de-esc) | 1. Epirubicin; 40 mg/m2 2. Epirubicin; 90 mg/m2 3. Epirubicin; 135 mg/m2 |
Did not meet primary endpoint of TTP |
Chemotherapy
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
21-day cycles
Regimen variant #5, 70 mg/m2, 2 out of 4 weeks
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Nielsen et al. 2000 | 1987-1990 | Phase 3 (C) | Cisplatin & Epirubicin | Seems to have inferior TTP | Superior toxicity |
Chemotherapy
- Epirubicin (Ellence) 70 mg/m2 IV once per day on days 1 & 8
28-day cycles until maximum dose of epirubicin reached (1000 mg/m2)
Regimen variant #6, 75 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bonneterre & Hurteloup 1991 | NR | Phase 3 (E-de-esc) | FEC; FEC 50 | Seems to have inferior ORR |
FEC; FEC 75 | Inferior ORR |
Chemotherapy
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
21-day cycles
Regimen variant #7, 90 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Perez et al. 1991 | 1985-1988 | Phase 3 (E-switch-ic) | Doxorubicin | Did not meet endpoints of ORR/OS |
Bastholt et al. 1996 | 1987-1991 | Phase 3 (C) | 1. Epirubicin; 40 mg/m2 | Superior TTP |
2. Epirubicin; 60 mg/m2 3. Epirubicin; 135 mg/m2 |
Did not meet primary endpoint of TTP | |||
Ejlertsen et al. 2004 (SBG 9403) | 1995-1999 | Phase 3 (C) | VE | Seems to have inferior PFS |
Chemotherapy
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
21-day cycles
Regimen variant #8, 120 mg/m2, split doses
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Dogliotti et al. 1996 | 1991-1993 | Phase 3 (C) | Epirubicin & Lonidamine | Inferior ORR |
Berruti et al. 2002 | 1995-1999 | Phase 3 (C) | 1. Cisplatin & Epirubicin 2. Cisplatin, Epirubicin, Lonidamine 3. Epirubicin & Lonidamine |
Did not meet primary endpoint of TTP |
Chemotherapy
- Epirubicin (Ellence) 60 mg/m2 IV once per day on days 1 & 2
21-day cycles
Regimen variant #9, 135 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bastholt et al. 1996 | 1987-1991 | Phase 3 (E-esc) | 1. Epirubicin; 40 mg/m2 2. Epirubicin; 60 mg/m2 3. Epirubicin; 90 mg/m2 |
Did not meet primary endpoint of TTP |
Chemotherapy
- Epirubicin (Ellence) 135 mg/m2 IV once on day 1
21-day cycles
References
- Gundersen S, Kvinnsland S, Klepp O, Lund E, Høst H; Norwegian Breast Cancer Group. Weekly Adriamycin vs 4-epidoxorubicin every second week in advanced breast cancer: a randomized trial. Eur J Cancer. 1990 Jan;26(1):45-8. link to original article contains protocol 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 contains protocol 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 contains verified protocol 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 contains protocol 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 contains verified protocol 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 contains protocol 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 contains protocol 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 contains protocol 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 contains protocol 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 contains protocol PubMed
FAC
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FAC: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide
CAF: Cyclophosphamide, Adriamycin (Doxorubicin), Fluorouracil
AFC: Adriamycin (Doxorubicin), Fluorouracil, Cyclophosphamide
Regimen variant #1, 500/50/500
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Smalley et al. 1977 | 1974-1975 | Phase 3 (E-de-esc) | CMFVP | Might have superior OS1 |
Bennett et al. 1988 | 1983-1985 | Phase 3 (C) | CNF | Did not meet endpoints of TTF/OS |
Muss et al. 1991 | 1984-1989 | Non-randomized portion of RCT | ||
Blajman et al. 1999 | 1991-1994 | Phase 3 (C) | NA | Did not meet primary endpoint of ORR |
Jassem et al. 2001 | 1996-1998 | Phase 3 (C) | AT (Taxol) | Seems to have inferior OS |
Bontenbal et al. 2005 | 1997-2002 | Phase 3 (C) | AT (Taxotere) | Seems to have inferior OS |
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Phase 3 (C) | FAC & Bevacizumab | Inferior PFS |
1Reported efficacy for Smalley et al. 1977 is based on the 1983 update.
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for up to 6 to 8 cycles
Subsequent treatment
- Muss et al. 1991: CMFP versus observation, then CMFP at progression
Regimen variant #2, 600/50/600
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Alonso et al. 1995 | 1988-1991 | Phase 3 (C) | CNF | Did not meet endpoints of ORR/OS |
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2/day IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for up to 10 cycles
Regimen variant #3, 800/40/400
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Tranum et al. 1978 | NR | Randomized (E-esc) | 1. AF 2. AFCM |
Did not meet primary endpoint of ORR |
Chemotherapy
- Fluorouracil (5-FU) 400 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 400 mg/m2 IV once on day 1
21-day cycles
Regimen variant #4, 1000/40/500
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Aisner et al. 1995 (CALGB 8281) | 1982-1987 | Phase 3 (C) | 1. VATH 2. VATH/CMFVP |
Did not meet primary endpoint of ORR |
Parnes et al. 2003 (CALGB 9140) | 1991-1995 | Phase 3 (C) | FAC & Leucovorin | Did not meet primary endpoint of ORR |
Note: Aisner et al. 1995 does not describe dosing; included here because it is a CALGB study.
Chemotherapy
- Fluorouracil (5-FU) 200 mg/m2 IV once per day on days 1 to 5
- Doxorubicin (Adriamycin) 40 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycles
Regimen variant #5, 1000/50/500
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Hortobagyi et al. 1979 | 1974-NR | Phase 3 (C) | FAC-BCG | Inferior OS in responders |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8 or days 1 & 4
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycles
Regimen variant #6, 1000/50/1400
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Aisner et al. 1987 | 1976-1980 | Phase 3 (E-switch-ic) | 1. CAFVP | Not reported |
2. CMF | Superior ORR | |||
Kardinal et al. 1983 (CALGB 8081) | 1980-1982 | Randomized (C) | CAFT | Did not meet primary endpoint of ORR |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 25 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
28-day cycle for up to 9 cycles
Regimen variant #7, 1000/60/1400 x 6
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sledge et al. 2000 (ECOG E3186) | 1988-1992 | Phase 3 (C) | CAFTH | Might have inferior TTF |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
28-day cycle for up to 6 cycles
Regimen variant #8, 1000/60/1400, maximum doxorubicin of 500 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Cummings et al. 1985 | 1978-1979 | Randomized (E-de-esc) | CMFP | Did not meet primary endpoint of ORR |
Falkson et al. 1987 (ECOG E2177) | NR-1983 | Randomized (C) | O+CAF | Did not meet primary endpoints of ORR/TTF/OS |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
28-day cycles until maximum cumulative dose of doxorubicin of 500 mg/m2
Regimen variant #9, 1000/60/1400, indefinite
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bull et al. 1978 | NR | Phase 3 (E-switch-ic) | CMF | Might have superior ORR |
Tominaga et al. 1994 | NR | Phase 3 (C) | CAF & MPA | Seems to have inferior ORR |
Note: the dosing details of Tominaga et al. 1994 are not described in the abstract.
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Doxorubicin (Adriamycin) 30 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
28-day cycles
References
- Smalley RV, Carpenter J, Bartolucci A, Vogel C, Krauss S; Southeastern Cancer Study Group. A comparison of cyclophosphamide, adriamycin, 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisone (CMFVP) in patients with metastatic breast cancer: a Southeastern Cancer Study Group project. Cancer. 1977 Aug;40(2):625-32. link to original article contains verified protocol 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 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
- 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 contains verified protocol 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
- Aisner J, Weinberg V, Perloff M, Weiss R, Perry M, Korzun A, Ginsberg S, Holland JF; CALGB. Chemotherapy versus chemoimmunotherapy (CAF v CAFVP v CMF each +/- MER) for metastatic carcinoma of the breast: a CALGB study. J Clin Oncol. 1987 Oct;5(10):1523-33. link to original article contains protocol 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 contains verified protocol 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 contains protocol 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 contains verified protocol 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 contains protocol 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 contains protocol 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 protocol 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 contains verified protocol 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 contains verified protocol 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 contains protocol 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 contains protocol 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 contains protocol 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 contains verified protocol PubMed NCT00262067
FAC & Bevacizumab
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FAC & Bevacizumab: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide, Bevacizumab
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Phase 3 (E-esc) | FAC | Superior PFS (HR 0.64, 95% CI 0.52-0.80) |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Doxorubicin (Adriamycin) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for up to 8 cycles
Subsequent treatment
- Bevacizumab maintenance, if no PD
References
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed NCT00262067
FEC
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FEC: Fluorouracil, Epirubicin, Cyclophosphamide
CEF: Cyclophosphamide, Epirubicin, Fluorouracil
Regimen variant #1, 500/50/500 ("FEC 50")
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bonneterre & Hurteloup 1991 | NR | Phase 3 (C) | Epirubicin | Seems to have superior ORR |
FEC; FEC 75 | Did not meet primary endpoint of ORR | |||
Focan et al. 1993 | 1985-1990 | Phase 3 (C) | FEC; FEC 100 | Seems to have inferior TTP |
Brufman et al. 1997 (HEPI 010) | 1989-1992 | Phase 3 (C) | FEC; FEC 100 | Inferior ORR |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 6 to 8 cycles
Regimen variant #2, 500/60/500
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Blomqvist et al. 1993 | 1987-1991 | Phase 3 (C) | FEC; weekly | Superior OS |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
28-day cycles
Regimen variant #3, 500/75/500 ("FEC 75")
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bonneterre & Hurteloup 1991 | NR | Phase 3 (E-esc) | Epirubicin | Superior ORR |
FEC; FEC 50 | Did not meet primary endpoint of ORR | |||
Pacini et al. 2000 | 1991-1996 | Phase 3 (C) | EM +/- Lonidamine | Inferior OS |
Capotorto et al. 2003 | 1995-1998 | Phase 3 (C) | 1. Dose-dense FEC | Inferior ORR |
2. Dose-dense MMM | Did not meet endpoint of ORR | |||
Bonneterre et al. 2004 | 1998-2000 | Randomized Phase II (C) | DE | Inferior ORR |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 75 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycles
Regimen variant #4, 500/90/500
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Zielinksi et al. 2005 (CECOG BM1) | 1999-2002 | Phase 3 (C) | GET | Did not meet primary endpoint of TTP |
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Phase 3 (C) | FEC & Bevacizumab | Inferior PFS |
Note: this is the lower bound of the dosing range allowed in RIBBON-1.
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for up to 8 cycles
Regimen variant #5, 500/100/500 ("FEC 100")
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Focan et al. 1993 | 1985-1990 | Phase 3 (E-esc) | FEC; FEC 50 | Seems to have superior TTP |
Brufman et al. 1997 (HEPI 010) | 1989-1992 | Phase 3 (E-esc) | FEC; FEC 50 | Superior ORR |
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Phase 3 (C) | FEC & Bevacizumab | Inferior PFS |
Note: this is the upper bound of the dosing range allowed in RIBBON-1.
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 100 mg/m2 IV once on day 1
- Note: in Focan et al. 1993, dose was split: 50 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for 6 to 8 cycles
Regimen variant #6, 600/60/600 ("CEF21")
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Conte et al. 1987 | 1983-1985 | Randomized (C) | DES-CEF | Did not meet primary endpoint of ORR |
Conte et al. 1996 | 1985-1990 | Phase 3 (C) | DES-CEF | Did not meet primary endpoint of ORR |
Ejlertsen et al. 1993 | 1986-1989 | Phase 3 (C) | FEC x 18 mo | Inferior OS |
Del Mastro et al. 2001 | 1994-1997 | Phase 3 (C) | HD-CEF14 | Did not meet primary endpoint of ORR |
Note: dosing information was not available in the abstract of Ejlertsen et al. 1993; this dosing has been used in other studies by this group.
Chemotherapy
- Fluorouracil (5-FU) 600 mg/m2 IV once on day 1
- Epirubicin (Ellence) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for 8 to 12 cycles
Regimen variant #7, 1000/50/500 until max anthracycline
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Ambrosini et al. 1988 | 1983-1985 | Phase 3 (E-switch-ic) | FAC | Did not meet primary endpoint | Less toxic |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Epirubicin (Ellence) 50 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
21-day cycle for up to 14 cycles (maximum of 700 mg/m2 epirubicin)
Regimen variant #8, 1000/60/1400
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Esteban et al. 1999 | 1987-1993 | Phase 3 (C) | CNF | Seems to have superior OS |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Epirubicin (Ellence) 30 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 100 mg/m2 PO once per day on days 1 to 14
28-day cycles
Regimen variant #9, 1000/100/800
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ackland et al. 2001 (HEPI 013) | 1990-1992 | Phase 3 (E-switch-ic) | CMF | Superior TTP |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once per day on days 1 & 8
- Epirubicin (Ellence) 50 mg/m2 IV once per day on days 1 & 8
- Cyclophosphamide (Cytoxan) 400 mg/m2 IV once per day on days 1 & 8
28-day cycle for 6 to 8 cycles
References
- Conte PF, Pronzato P, Rubagotti A, Alama A, Amadori D, Demicheli R, Gardin G, Gentilini P, Jacomuzzi A, Lionetto R, Monzeglio C, Nicolin A, Rosso R, Sismondi P, Sussio M, Santi L. Conventional versus cytokinetic polychemotherapy with estrogenic recruitment in metastatic breast cancer: results of a randomized cooperative trial. J Clin Oncol. 1987 Mar;5(3):339-47. link to original article contains protocol 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 contains protocol 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 contains verified protocol PubMed
- Ejlertsen B, Pfeiffer P, Pedersen D, Mouridsen HT, Rose C, Overgaard M, Sandberg E, Kristensen B. Decreased efficacy of cyclophosphamide, epirubicin and 5-fluorouracil in metastatic breast cancer when reducing treatment duration from 18 to 6 months. Eur J Cancer. 1993;29A(4):527-31. link to original article 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 contains protocol 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 contains protocol 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 contains protocol 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 contains verified protocol 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 contains protocol 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 contains protocol 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 contains protocol 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 contains verified protocol PubMed
- Capotorto AM, Pavesi L, Pedrazzoli P, Da Prada GA, Zamagni C, Massidda B, Farris A, Martoni A, Lelli G, Robustelli della Cuna G. Randomized, controlled, multicenter phase III trial of standard-dose fluorouracil-epirubicin-cyclophosphamide (FEC), compared with time-intensive FEC (FEC-G) and mitoxantrone-methotrexate-mitomycin C (MMM-G) in metastatic breast carcinoma. J Chemother. 2003 Apr;15(2):184-91. link to original article contains protocol 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 contains protocol 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 contains protocol 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 contains verified protocol PubMed NCT00262067
FEC & Bevacizumab
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FEC & Bevacizumab: Fluorouracil, Epirubicin, Cyclophosphamide, Bevacizumab
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Phase 3 (E-esc) | FEC | Superior PFS (HR 0.64, 95% CI 0.52-0.80) |
Chemotherapy
- Fluorouracil (5-FU) 500 mg/m2 IV once on day 1
- Epirubicin (Ellence) 90 to 100 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 500 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycle for up to 8 cycles
Subsequent treatment
- Bevacizumab maintenance, if no PD
References
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol PubMed NCT00262067
Gemcitabine monotherapy
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Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Carmichael et al. 1995 | NR | Phase II, <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, Phillip P, Beykirch M, Kerr H, Walling J, Harris AL. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol. 1995 Nov;13(11):2731-6. link to original article contains protocol PubMed
Gemcitabine & Paclitaxel
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GT: Gemcitabine & Taxol (Paclitaxel)
PG: Paclitaxel & Gemcitabine
Regimen variant #1, 6 cycles
Study | Years of enrollment | Evidence |
---|---|---|
Park et al. 2013 (KCSG-BR07-02) | 2007-2010 | Non-randomized portion of RCT |
Chemotherapy
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8, given second on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1, given first
21-day cycle for 6 cycles
Subsequent treatment
- Maintenance PG versus Observation
Regimen variant #2, indefinite
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Albain et al. 2008 | 1999-2002 | Phase 3 (E-RT-esc) | Paclitaxel | Seems to have superior OS |
Del Mastro et al. 2013 (B9E-IT-S376) | 2005-2010 | Phase 3 (E-switch-ic) | 1. GD; weekly 2. GD; q3wk 3. GT; weekly |
Did not meet primary endpoint of TTP |
Chemotherapy
- Gemcitabine (Gemzar) 1250 mg/m2 IV over 30 to 60 minutes once per day on days 1 & 8, given second on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1, given first
21-day cycles
References
- Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, Rolski J, Melemed AS, Reyes-Vidal JM, Sekhon JS, Simms L, O'Shaughnessy J. Gemcitabine plus paclitaxel versus paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008 Aug 20;26(24):3950-7. link to original article contains verified protocol 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 contains protocol 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 contains verified protocol PubMed NCT00561119
Cyclophosphamide & NPLD (MC)
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MC: Myocet (non-pegylated liposomal doxorubicin) & Cyclophosphamide
Regimen variant #1, 60/600
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Lorusso et al. 2014 | 2006-2011 | Phase 3 (C) | NPLD & Vinorelbine | Did not meet primary endpoint of TTP |
Chemotherapy
- Non-pegylated liposomal doxorubicin (Myocet) 60 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycles
Regimen variant #2, 75/600
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Chan et al. 2004 | 1996-1997 | Phase 3 (E-switch-ic) | EC | Seems to have superior TTP |
Chemotherapy
- Non-pegylated liposomal doxorubicin (Myocet) 75 mg/m2 IV once on day 1
- Cyclophosphamide (Cytoxan) 600 mg/m2 IV once on day 1
21-day cycle for up to 8 cycles
References
- Chan S, Davidson N, Juozaityte E, Erdkamp F, Pluzanska A, Azarnia N, Lee LW. Phase III trial of liposomal doxorubicin and cyclophosphamide compared with epirubicin and cyclophosphamide as first-line therapy for metastatic breast cancer. Ann Oncol. 2004 Oct;15(10):1527-34. link to original article contains protocol 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 contains protocol PubMed
Paclitaxel monotherapy, weekly
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Regimen variant #1, 80 mg/m2 weekly
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Perez et al. 2001 | NR | Phase II | ||
Seidman et al. 2008 (CALGB 9840) | 1998-NR | Phase 3 (E-switch-ic) | Paclitaxel; q3wk | Superior OS |
Fountzilas et al. 2008 | 2002-2006 | Phase 3 (E-de-esc) | 1. Carboplatin & Paclitaxel 2. Docetaxel & Gemcitabine |
Seems to have superior OS |
Martin et al. 2017 (BELLE-4) | 2012-2014 | Phase 3 (C) | Buparlisib & Paclitaxel | Did not meet primary endpoint of PFS |
Chemotherapy
- Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycles
Regimen variant #2, 80 mg/m2 3 weeks out of 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Takashima et al. 2015 (SELECT BC) | 2006-2010 | Phase 3 (C) | S-1 | Seems to have non-inferior OS | Inferior EQ-5D score |
Fujiwara et al. 2019 (A3105301) | 2012-2014 | Phase 3 (C) | NK105 | Inconclusive whether non-inferior PFS | Higher rate of CIPN |
Note: this is the lower limit of dosing allowed in SELECT BC.
Chemotherapy
- Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Regimen variant #3, 90 mg/m2 3 weeks out of 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Miller et al. 2007 (ECOG E2100) | 2001-2004 | Phase 3 (C) | Paclitaxel & Bevacizumab | Inferior PFS |
Miles et al. 2016 (MERiDiAN) | 2012-2013 | Phase 3 (C) | Paclitaxel & Bevacizumab | Inferior PFS |
Chemotherapy
- Paclitaxel (Taxol) 90 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Regimen variant #4, 100 mg/m2 weekly
Study | Years of enrollment | Evidence |
---|---|---|
Seidman et al. 1998 | NR | Phase II, <20 pts in this subgroup |
Chemotherapy
- Paclitaxel (Taxol) 100 mg/m2 IV over 60 minutes once per day on days 1, 8, 15
21-day cycles
Regimen variant #5, 100 mg/m2 3 weeks out of 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Takashima et al. 2015 (SELECT BC) | 2006-2010 | Phase 3 (C) | S-1 | Seems to have non-inferior OS | Inferior EQ-5D score |
Note: this is the upper limit of dosing allowed in SELECT BC.
Chemotherapy
- Paclitaxel (Taxol) 100 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
References
- Seidman AD, Hudis CA, Albanell J, Tong W, Tepler I, Currie V, Moynahan ME, Theodoulou M, Gollub M, Baselga J, Norton L. Dose-dense therapy with weekly 1-hour paclitaxel infusions in the treatment of metastatic breast cancer. J Clin Oncol. 1998 Oct;16(10):3353-61. Erratum in: J Clin Oncol. 2006 May 10;24(14):2220. Albanel, J [corrected to Albanell, J ]. link to original article contains protocol 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 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 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 contains verified protocol 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 contains verified protocol 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 contains protocol 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 contains verified protocol 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 contains protocol PubMed NCT01644890
Paclitaxel monotherapy, q3wk
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Regimen variant #1, 175 mg/m2 q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Seidman et al. 1995 | NR | Phase II | |||
Winer et al. 2004 (CALGB 9342) | 1994-1997 | Phase 3 (C) | 1. Paclitaxel; 210 mg/m2 q3wk 2. Paclitaxel; 250 mg/m2 q3wk |
Did not meet primary endpoint of ORR | |
Seidman et al. 2008 (CALGB 9840) | 1998-NR | Phase 3 (C) | Paclitaxel; weekly | Inferior OS | |
Albain et al. 2008 | 1999-2002 | Phase 3 (C) | GT | Seems to have inferior OS | |
Gradishar et al. 2005 (CA012-0) | 2001-2002 | Phase 3 (C) | nab-Paclitaxel | Inferior TTP | |
Di Leo et al. 2008 (EGF30001) | 2004-2005 | Phase 3 (C) | Lapatinib & Paclitaxel | Did not meet primary endpoint of TTP | Less toxic |
Takashima et al. 2015 (SELECT BC) | 2006-2010 | Phase 3 (C) | S-1 | Seems to have non-inferior OS | Inferior EQ-5D score |
Park et al. 2016 (GPMBC301) | 2008-2013 | Phase 3 (C) | Genexol-PM | Seems to have non-inferior ORR |
Note: patients in EGF30001 were NOT required to be HER2-positive.
Chemotherapy
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
21-day cycles
Regimen variant #2, 175 mg/m2, CI
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Sledge et al. 2003 (ECOG E1193) | 1993-1995 | Phase 3 (C) | 1. AT (Taxol) | Inferior TTF |
2. Doxorubicin | Did not meet primary endpoint of ORR |
Chemotherapy
- Paclitaxel (Taxol) 175 mg/m2 IV continuous infusion over 24 hours, started on day 1
21-day cycles
Regimen variant #3, 175 mg/m2 q4wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Takashima et al. 2015 (SELECT BC) | 2006-2010 | Phase 3 (C) | S-1 | Seems to have non-inferior OS | Inferior EQ-5D score |
Chemotherapy
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
28-day cycles
Regimen variant #4, 200 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bishop et al. 1999 | 1993-NR | Phase 3 (E-de-esc) | CMFP | Seems to have superior OS |
Paridaens et al. 2000 (EORTC 10923) | 1993-1996 | Phase 3 (E-switch-ic) | Doxorubicin | Inferior PFS |
Chemotherapy
- Paclitaxel (Taxol) 200 mg/m2 IV over 3 hours once on day 1
21-day cycle for 7 or 8 cycles
Regimen variant #5, 250 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Holmes et al. 1991 | 1990 | Phase II | ||
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 contains protocol 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 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 contains protocol 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 contains protocol 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 contains protocol 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 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 contains protocol 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 contains verified protocol 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 contains protocol 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 contains verified protocol 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 contains protocol PubMed NCT00876486
Paclitaxel & Bevacizumab
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Miller et al. 2007 (ECOG E2100) | 2001-2004 | Phase 3 (E-RT-esc) | Paclitaxel | Superior PFS Median PFS: 11.8 vs 5.9 mo (HR 0.60) |
Robert et al. 2011 (SUN 1094) | 2006-2009 | Phase 3 (C) | Paclitaxel & Sunitinib | Did not meet primary endpoint of PFS |
Lang et al. 2013 (TURANDOT) | 2008-2010 | Phase 3 (E-switch-ic) | Capecitabine & Bevacizumab | Non-inferior OS1 |
Rugo et al. 2015 (CALGB 40502/NCCTG N063H) | 2008-2011 | Phase 3 (C) | 1. Ixabepilone & Bevacizumab | Superior PFS |
2. nab-Paclitaxel & Bevacizumab | Might have superior PFS | |||
Rochlitz et al. 2016 (SAKK 24/09) | 2010-2012 | Phase 3 (C) | Capecitabine, Cyclophosphamide, Bevacizumab | Did not meet secondary endpoint of PFS |
Miles et al. 2016 (MERiDiAN) | 2012-2013 | Phase 3 (E-esc) | Paclitaxel | Superior PFS Median PFS: 11 vs 8.8 mo (HR 0.68, 99% CI 0.51-0.91) |
1Reported efficacy for TURANDOT is based on the 2016 update.
Note: ECOG E2100 was the basis for accelerated approval of bevacizumab in breast cancer.
Chemotherapy
- Paclitaxel (Taxol) 90 mg/m2 IV over 60 minutes once per day on days 1, 8, 15
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
References
- ECOG E2100: Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76. link to original article PubMed NCT00028990
- SUN 1094: Robert NJ, Saleh MN, Paul D, Generali D, Gressot L, Copur MS, Brufsky AM, Minton SE, Giguere JK, Smith JW 2nd, Richards PD, Gernhardt D, Huang X, Liau KF, Kern KA, Davis J. Sunitinib plus paclitaxel versus bevacizumab plus paclitaxel for first-line treatment of patients with advanced breast cancer: a phase III, randomized, open-label trial. Clin Breast Cancer. 2011 Apr;11(2):82-92. Epub 2011 Apr 11. Erratum in: Clin Breast Cancer. 2011 Aug;11(4):273. link to original article link to PMC article contains verified protocol 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 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 contains protocol 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 contains verified protocol 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 contains verified protocol 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 contains protocol 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
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Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Romero Acuña et al. 1999 | 1995-1997 | Phase II |
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 contains protocol PubMed
nab-Paclitaxel monotherapy
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Example orders
Regimen variant #1, 100 mg/m2, 3 weeks out of 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gradishar et al. 2009 | 2005-2006 | Randomized Phase II (E-switch-ic) | 1. Docetaxel 2. nab-Paclitaxel; weekly, 150 mg/m2 3. nab-Paclitaxel; q3wk |
Did not meet primary endpoint of ORR |
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Regimen variant #2, 150 mg/m2 weekly, 3 weeks out of 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gradishar et al. 2009 | 2005-2006 | Randomized Phase II (E-switch-ic) | 1. Docetaxel 2. nab-Paclitaxel; weekly, 100 mg/m2 3. nab-Paclitaxel; q3wk |
Did not meet primary endpoint of ORR |
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 150 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Regimen variant #3, 260 mg/m2 q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gradishar et al. 2005 (CA012-0) | 2001-2002 | Phase 3 (E-switch-ic) | Paclitaxel; q3wk | Superior TTP |
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Phase 3 (C) | nab-Paclitaxel & Bevacizumab | Inferior PFS |
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m2 IV over 30 minutes once on day 1
Supportive medications
- CA012-0: No corticosteroid or antihistamine premedication
21-day cycles
Regimen variant #4, 300 mg/m2 q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gradishar et al. 2009 | 2005-2006 | Randomized Phase II (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 contains verified protocol 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 contains verified protocol 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 contains verified protocol PubMed NCT00262067
Paclitaxel, nanoparticle albumin-bound & Bevacizumab
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Example orders
Regimen variant #1, 150 mg/m2, 3 weeks out of 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Rugo et al. 2015 (CALGB 40502/NCCTG N063H) | 2008-2011 | Phase 3 (E-switch-ic) | 1. Ixabepilone & Bevacizumab | Not reported |
2. Paclitaxel & Bevacizumab | Might have inferior PFS |
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 150 mg/m2 IV once per day on days 1, 8, 15
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
Regimen variant #2, 260 mg/m2 q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Phase 3 (E-esc) | nab-Paclitaxel | Superior PFS (HR 0.64, 95% CI 0.52-0.80) |
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- RIBBON-1: Robert NJ, Diéras V, Glaspy J, Brufsky AM, Bondarenko I, Lipatov ON, Perez EA, Yardley DA, Chan SY, Zhou X, Phan SC, O'Shaughnessy J. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol. 2011 Apr 1;29(10):1252-60. Epub 2011 Mar 7. link to original article contains verified protocol 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 PubMed NCT00785291
Pemetrexed monotherapy
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Regimen variant #1, 500 mg/m2
Study | Years of enrollment | Evidence |
---|---|---|
Gomez et al. 2006 | 2001-2002 | Phase II |
Patients in the study were "chemotherapy-naïve, with advanced (T4 and N0-N2, M0, M1) breast cancer."
Chemotherapy
- Pemetrexed (Alimta) 500 mg/m2 IV over 10 minutes once on day 1
Supportive medications
- Dexamethasone (Decadron) 4 mg PO twice per day on days -1 to 2 (3 days)
- Folic acid (Folate) 350 to 1000 mcg PO once per day, to start 5 to 7 days prior to start of Pemetrexed (Alimta), to continue throughout therapy
- Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, the first dose given before the study's pretreatment biopsy, to continue throughout therapy
21-day cycle for up to 3 cycles
Regimen variant #2, 600 mg/m2
Study | Years of enrollment | Evidence |
---|---|---|
Robert et al. 2011 | 2005-2006 | Phase II |
Chemotherapy
- Pemetrexed (Alimta) 600 mg/m2 IV once on day 1
Supportive medications
- Dexamethasone (Decadron) 4 mg PO twice per day on days -1 to 2 (3 days)
- Folic acid (Folate) 350 to 1000 mcg PO once per day, to start at least 5 days prior to start of Pemetrexed (Alimta), to continue throughout therapy, and until 3 weeks after the last dose of pemetrexed
- Cyanocobalamin (Vitamin B12) 1000 mcg IM every 8 to 10 weeks, the first dose given at least 1 week prior to start of Pemetrexed (Alimta), to continue throughout therapy, and until 3 weeks after the last dose of pemetrexed
14-day cycles
References
- Gomez HL, Santillana SL, Vallejos CS, Velarde R, Sanchez J, Wang X, Bauer NL, Hockett RD, Chen VJ, Niyikiza C, Hanauske AR. A phase II trial of pemetrexed in advanced breast cancer: clinical response and association with molecular target expression. Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):832-8. link to original article contains verified protocol 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 contains verified protocol PubMed
S-1 monotherapy
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Takashima et al. 2015 (SELECT BC) | 2006-2010 | Phase 3 (E-switch-ic) | 1. Docetaxel 2. Paclitaxel |
Seems to have non-inferior OS | Superior EQ-5D score |
Chemotherapy
- Tegafur, gimeracil, oteracil (S-1) as follows:
- BSA less than 1.25 m2: 40 mg PO twice per day on days 1 to 28
- BSA at least 1.25 m2 and less than 1.5 m2: 50 mg PO twice per day on days 1 to 28
- BSA 1.5 m2 or more: 60 mg PO twice per day on days 1 to 28
42-day cycles
References
- SELECT BC: Takashima T, Mukai H, Hara F, Matsubara N, Saito T, Takano T, Park Y, Toyama T, Hozumi Y, Tsurutani J, Imoto S, Watanabe T, Sagara Y, Nishimura R, Shimozuma K, Ohashi Y; SELECT BC Study Group. Taxanes versus S-1 as the first-line chemotherapy for metastatic breast cancer (SELECT BC): an open-label, non-inferiority, randomised phase 3 trial. Lancet Oncol. 2016 Jan;17(1):90-8. Epub 2015 Nov 27. link to original article contains verified protocol 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
Capecitabine & Docetaxel (TX)
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TX: Taxotere (Docetaxel) & Xeloda (Capecitabine)
CD: Capecitabine & Docetaxel
Regimen variant #1, 1900/75
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Mavroudis et al. 2009 (HORG CT/02.09) | 2002-2007 | Phase 3 (E-switch-ic) | DE | Did not meet primary endpoint of TTP |
Chemotherapy
- Capecitabine (Xeloda) 950 mg/m2 PO twice per day on days 1 to 14
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycles
Regimen variant #2, 2000/75, limited duration of docetaxel
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Wang et al. 2015 (ML25241) | 2010-2013 | Phase 3 (C) | NX | Inconclusive whether non-inferior PFS |
Note: only patients without progression proceeded to the capecitabine maintenance phase.
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
- Docetaxel (Taxotere) as follows:
- Cycles 1 to 6 up to 8: 75 mg/m2 IV once on day 1
21-day cycles
Regimen variant #3, 2000/75, indefinite
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Seidman et al. 2010 (B9E-MC-S273) | 2002-2008 | Phase 3 (C) | GD | Did not meet primary endpoint of TTP |
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycles
Subsequent treatment
- Upon progression: Gemcitabine
References
- HORG CT/02.09: Mavroudis D, Papakotoulas P, Ardavanis A, Syrigos K, Kakolyris S, Ziras N, Kouroussis C, Malamos N, Polyzos A, Christophyllakis C, Kentepozidis N, Georgoulias V; Hellenic Oncology Research Group. Randomized phase III trial comparing docetaxel plus epirubicin versus docetaxel plus capecitabine as first-line treatment in women with advanced breast cancer. Ann Oncol. 2010 Jan;21(1):48-54. Epub 2009 Nov 11. link to original article contains protocol 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 contains protocol PubMed NCT00191438
- ML25241: Wang J, Xu B, Yuan P, Ma F, Li Q, Zhang P, Cai R, Fan Y, Luo Y, Li Q. Capecitabine combined with docetaxel versus vinorelbine followed by capecitabine maintenance medication for first-line treatment of patients with advanced breast cancer: phase 3 randomized trial. Cancer. 2015 Oct 1;121(19):3412-21. Epub 2015 Jun 19. link to original article contains verified protocol PubMed NCT01126138
Epirubicin & Vinorelbine (VE)
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VE: Vinorelbine & Epirubicin
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Ejlertsen et al. 2004 (SBG 9403) | 1995-1999 | Phase 3 (E-esc) | Epirubicin | Seems to have superior PFS |
Chemotherapy
- Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 8
- Epirubicin (Ellence) 90 mg/m2 IV once on day 1
21-day cycle for up to 18 cycles (1 year)
References
- SBG 9403: Ejlertsen B, Mouridsen HT, Langkjer ST, Andersen J, Sjöström J, Kjaer M; Scandinavian Breast Group. Phase III study of intravenous vinorelbine in combination with epirubicin versus epirubicin alone in patients with advanced breast cancer: a Scandinavian Breast Group Trial (SBG9403). J Clin Oncol. 2004 Jun 15;22(12):2313-20. link to original article contains protocol PubMed
Metastatic disease, maintenance after first-line therapy
Bevacizumab monotherapy
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Robert et al. 2011 (RIBBON-1) | 2005-2007 | Non-randomized portion of RCT | ||
Miles et al. 2010 (AVADO) | 2006-2007 | Non-randomized portion of RCT | ||
Gligorov et al. 2014 (IMELDA) | 2009-2011 | Phase 3 (C) | Capecitabine & Bevacizumab | Inferior OS |
Preceding treatment
- AVADO: Docetaxel & Bev x 9
- RIBBON-1: AC & Bev x 8 or EC & Bev x 8 or FAC & Bev x 8 or FEC & Bev x 8
- IMELDA: Docetaxel & Bev x 3 to 6
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- AVADO: Miles DW, Chan A, Dirix LY, Cortés J, Pivot X, Tomczak P, Delozier T, Sohn JH, Provencher L, Puglisi F, Harbeck N, Steger GG, Schneeweiss A, Wardley AM, Chlistalla A, Romieu G. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010 Jul 10;28(20):3239-47. Epub 2010 May 24. link to original article contains verified protocol 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 contains verified protocol 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 contains protocol PubMed NCT00929240
Capecitabine & Bevacizumab
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Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gligorov et al. 2014 (IMELDA) | 2009-2011 | Phase 3 (E-esc) | Bevacizumab | Superior OS (HR 0.43, 95% CI 0.26-0.69) |
Preceding treatment
- Docetaxel & Bev x 3 to 6
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- IMELDA: Gligorov J, Doval D, Bines J, Alba E, Cortes P, Pierga JY, Gupta V, Costa R, Srock S, de Ducla S, Freudensprung U, Mustacchi G. Maintenance capecitabine and bevacizumab versus bevacizumab alone after initial first-line bevacizumab and docetaxel for patients with HER2-negative metastatic breast cancer (IMELDA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014 Nov;15(12):1351-60. Epub 2014 Sep 28. link to original article contains protocol PubMed NCT00929240
Gemcitabine & Paclitaxel
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GT: Gemcitabine & Taxol (Paclitaxel)
PG: Paclitaxel & Gemcitabine
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Park et al. 2013 (KCSG-BR07-02) | 2007-2010 | Phase 3 (E-esc) | Observation | Seems to have superior OS |
Preceding treatment
- PG x 6
Chemotherapy
- Gemcitabine (Gemzar) 1250 mg/m2 IV once per day on days 1 & 8, given second on day 1
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1, given first
21-day cycles
References
- KCSG-BR07-02: Park YH, Jung KH, Im SA, Sohn JH, Ro J, Ahn JH, Kim SB, Nam BH, Oh DY, Han SW, Lee S, Park IH, Lee KS, Kim JH, Kang SY, Lee MH, Park HS, Ahn JS, Im YH. Phase III, multicenter, randomized trial of maintenance chemotherapy versus observation in patients with metastatic breast cancer after achieving disease control with six cycles of gemcitabine plus paclitaxel as first-line chemotherapy: KCSG-BR07-02. J Clin Oncol. 2013 May 10;31(14):1732-9. Epub 2013 Apr 8. link to original article contains verified protocol PubMed NCT00561119
Metastatic disease, subsequent lines of chemotherapy
Abemaciclib monotherapy
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Regimen
FDA-recommended dose |
Study | Years of enrollment | Evidence | Efficacy |
---|---|---|---|
Dickler et al. 2017 (MONARCH 1) | 2014-2015 | Phase II | 20% (95% CI 13-27.5) |
Targeted therapy
- Abemaciclib (Verzenio) 200 mg PO twice per day
Continued indefinitely
References
- MONARCH 1: Dickler MN, Tolaney SM, Rugo HS, Cortés J, Diéras V, Patt D, Wildiers H, Hudis CA, O'Shaughnessy J, Zamora E, Yardley DA, Frenzel M, Koustenis A, Baselga J. MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 Inhibitor, as a single agent, in patients with refractory HR(+)/HER2(-) metastatic breast cancer. Clin Cancer Res. 2017 Sep 1;23(17):5218-5224. Epub 2017 May 22. link to original article link to PMC article contains protocol PubMed NCT02102490
Capecitabine monotherapy
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Regimen variant #1, 1000 mg/m2 PO twice per day
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Gemcitabine & Bevacizumab 4. Paclitaxel & Bevacizumab 5. nab-Paclitaxel & Bevacizumab 6. Vinorelbine & Bevacizumab |
Inferior PFS |
Barrios et al. 2010 (SUN 1107) | 2006-2009 | Phase 3 (C) | Sunitinib | Superior PFS Median PFS: 4.2 vs 2.8 mo (HR 0.68, 95% CI 0.53-0.86) |
Baselga et al. 2017 (RESILIENCE) | 2010-NR | Phase 3 (C) | Capecitabine & Sorafenib | Did not meet primary endpoint of PFS |
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Note: in SUN 1107, this dosage was used for patients older than 65 years.
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
21-day cycles
Regimen variant #2, 1250 mg/m2 PO twice per day
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Blum et al. 1999 | 1996 | Phase II (RT) | ||
Reichardt et al. 2003 | 1999-2000 | Phase II | ||
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 |
Thomas et al. 2007 (CA163-046) | 2003-2006 | Phase 3 (C) | Capecitabine & Ixabepilone | Inferior PFS |
Sparano et al. 2010 (CA163-048) | 2003-2006 | Phase 3 (C) | Capecitabine & Ixabepilone | Might have inferior OS |
Barrios et al. 2010 (SUN 1107) | 2006-2009 | Phase 3 (C) | Sunitinib | Superior PFS Median PFS: 4.2 vs 2.8 mo (HR 0.68, 95% CI 0.53-0.86) |
Kaufman et al. 2015 (E7389-G000-301) | 2006-2009 | Phase 3 (C) | Eribulin | Might have inferior OS |
Crown et al. 2013 (A6181099) | 2007-2009 | Phase 3 (C) | Capecitabine & Sunitinib | Did not meet primary endpoint of PFS |
Yamamoto et al. 2016 (JO21095) | 2008-2010 | Non-randomized portion of 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) | CAPIRI | Did not meet primary endpoint of PFS |
Zhang et al. 2017 (BG01-1323L) | 2014-2015 | Phase 3 (C) | Capecitabine & Utidelone | Seems to have inferior OS1 |
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.
Preceding treatment
- JO21095: Docetaxel, with PD
Chemotherapy
- Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
21-day cycles
References
- Blum JL, Jones SE, Buzdar AU, Mucci LoRusso P, Kuter I, Vogel C, Osterwalder B, Burger HU, Stoner Brown C, Griffin T. Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer. J Clin Oncol. 1999 Feb;17(2):485-93. link to original article contains protocol 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 contains protocol 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 contains protocol 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. link to original article contains verified protocol PubMed
- 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 contains protocol 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. link to original article contains verified protocol 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 contains protocol 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 contains verified protocol 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 contains verified protocol 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 contains verified protocol 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 contains verified protocol 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 contains verified protocol 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 contains protocol 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 contains protocol 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 contains protocol 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 contains protocol PubMed NCT01095003
- EVER-132-002: NCT04639986
- TROPICS-02: NCT03901339
Capecitabine & Bevacizumab
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Regimen variant #1, 2000/15
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Gemcitabine 4. Paclitaxel 5. nab-Paclitaxel 6. Vinorelbine |
Superior PFS Median PFS: 7.2 vs 5.1 mo (HR 0.78, 95% CI 0.64-0.93) |
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel |
Superior PFS Median PFS: 6.3 vs 4.2 mo (HR 0.75, 95% CI 0.61-0.93) |
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
Regimen variant #2, 2500/15
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Miller et al. 2005 (AVF2119g) | 2000-2002 | Phase 3 (E-esc) | Capecitabine | Did not meet primary endpoint of PFS |
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 contains protocol 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 contains verified protocol 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 contains verified protocol 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)
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TX: Taxotere (Docetaxel) & Xeloda (Capecitabine)
XT: Xeloda (Capecitabine) & Taxotere (Docetaxel)
DC: Docetaxel & Capecitabine
Regimen variant #1, 825/60
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Yamamoto et al. 2016 (JO21095) | 2008-2010 | Phase 3 (E-esc) | Docetaxel | Seems to have superior PFS |
Chemotherapy
- Capecitabine (Xeloda) 825 mg/m2 PO twice per day on days 1 to 14
- Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
21-day cycles
Regimen variant #2, 1250/75
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
O'Shaughnessy et al. 2002 | NR | Phase 3 (E-RT-esc) | Docetaxel | Superior OS1 |
Chan et al. 2009 | 2002-2004 | Phase 3 (C) | GD | Did not meet primary endpoint of PFS |
1Reported efficacy for O'Shaughnessy et al. 2002 is based on the 2004 update.
Chemotherapy
- Capecitabine (Xeloda) 1250 mg/m2 PO twice per day on days 1 to 14
- Docetaxel (Taxotere) 75 mg/m2 IV over 60 minutes once on day 1
21-day cycles
References
- O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. link to original article contains verified protocol PubMed
- Update: Miles D, Vukelja S, Moiseyenko V, Cervantes G, Mauriac L, Van Hazel G, Liu WY, Ayoub JP, O'Shaughnessy JA. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Clin Breast Cancer. 2004 Oct;5(4):273-8. link to original article PubMed
- Chan S, Romieu G, Huober J, Delozier T, Tubiana-Hulin M, Schneeweiss A, Lluch A, Llombart A, du Bois A, Kreienberg R, Mayordomo JI, Antón A, Harrison M, Jones A, Carrasco E, Vaury AT, Frimodt-Moller B, Fumoleau P. Phase III study of gemcitabine plus docetaxel compared with capecitabine plus docetaxel for anthracycline-pretreated patients with metastatic breast cancer. J Clin Oncol. 2009 Apr 10;27(11):1753-60. Epub 2009 Mar 9. link to original article contains protocol 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 contains verified protocol PubMed
Capecitabine & Ixabepilone
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XI: Xeloda (Capecitabine) & Ixabepilone
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Thomas et al. 2007 (CA163-046) | 2003-2006 | Phase 3 (E-RT-esc) | Capecitabine | Superior PFS Median PFS: 5.8 vs 4.2 mo (HR 0.75, 95% CI 0.64-0.88) |
Sparano et al. 2010 (CA163-048) | 2003-2006 | Phase 3 (E-RT-esc) | Capecitabine | Might have superior OS Median OS: 16.4 vs 15.6 mo (HR 0.90, 95% CI 0.78-1.03) |
Chemotherapy
- Capecitabine (Xeloda) 1000 mg/m2 PO twice per day on days 1 to 14
- Ixabepilone (Ixempra) 40 mg/m2 IV once on day 1
21-day cycles
References
- CA163-046: Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. link to original article contains verified protocol PubMed
- 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. link to original article contains verified protocol link to PMC article PubMed NCT00082433
Carboplatin & Gemcitabine (GCb)
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Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Nagourney et al. 2008 | 2002-2005 | Pilot, <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 contains protocol PubMed
Cisplatin & Vinorelbine
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Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Ray-Coquard et al. 1998 | 1992-1994 | Phase II |
Vassilomanolakis et al. 2000 | NR | Phase II |
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 medications
- Normal saline 200 mL bolus after Vinorelbine (Navelbine) to prevent phlebitis
- Normal saline 2000 mL with KCl (unspecified amount of KCl) IV over 4 hours once on day 1, prior to Cisplatin (Platinol)
- Furosemide (Lasix) 40 mg IV once on day 1; 20 minutes prior to Cisplatin (Platinol)
- Normal saline 1000 mL and D5W 1000 mL IV over 4 hours once on day 1, after Cisplatin (Platinol)
- Paper did not say whether fluids were given sequentially or concurrently
- 5-HT3 antagonists used
21-day cycle for up to 6 cycles
References
- 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 contains verified protocol Pubmed
Cyclophosphamide & Methotrexate (CM)
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CM: Cyclophosphamide & Methotrexate
Regimen variant #1
Study | Years of enrollment | Evidence |
---|---|---|
Colleoni et al. 2002 | 1997-2000 | Non-randomized |
Chemotherapy
- Cyclophosphamide (Cytoxan) 50 mg PO once per day
- Methotrexate (MTX) 2.5 mg PO twice per day on days 1 & 2
7-day cycles
Regimen variant #2, metronomic
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Colleoni et al. 2005 | 2000-2003 | Randomized (C) | CM & Thalidomide | Did not meet primary endpoint of % reduction in VEGF after 2 months of treatment |
Note: to our knowledge, this regimen was not tested as an experimental arm in an RCT prior to becoming a standard comparator arm.
Chemotherapy
- Cyclophosphamide (Cytoxan) 50 mg PO once per day
- Methotrexate (MTX) 2.5 mg PO twice per day on days 1 & 4
7-day cycles
References
- Colleoni M, Rocca A, Sandri MT, Zorzino L, Masci G, Nolè F, Peruzzotti G, Robertson C, Orlando L, Cinieri S, de Braud F, Viale G, Goldhirsch A. Low-dose oral methotrexate and cyclophosphamide in metastatic breast cancer: antitumor activity and correlation with vascular endothelial growth factor levels. Ann Oncol. 2002 Jan;13(1):73-80. link to original article contains verified protocol 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 contains protocol PubMed
Cyclophosphamide monotherapy
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Regimen
Study | Years 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 |
Note: this was the most commonly used comparator arm; doses were not provided in the manuscript.
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 PubMed NCT01091168
Docetaxel monotherapy
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D: Docetaxel
T: Taxotere (Docetaxel)
Regimen variant #1, 40 mg/m2 3 weeks out of 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
Rivera et al. 2008 | 2001-2004 | Phase III (C), <20 pts in this subgroup | Docetaxel; q3wk | Did not meet primary endpoint of ORR | Superior toxicity |
Chemotherapy
- Docetaxel (Taxotere) as follows:
- Cycle 1: 35 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
- Cycle 2 onwards: 40 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
28-day cycles
Regimen variant #2, 40 mg/m2 6 weeks out of 8
Study | Years of enrollment | Evidence |
---|---|---|
Burstein et al. 2000 | 1998 | Phase II |
Chemotherapy
- Docetaxel (Taxotere) 40 mg/m2 IV once per day on days 1, 8, 15, 22, 29, 36
8-week cycles
Regimen variant #3, 60 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Adachi et al. 1996 | 1993 | Phase II | ||
Harvey et al. 2006 (TAX 313) | 1995-2001 | Phase 3 (E-RT-de-esc) | 1. Docetaxel; 75 mg/m2 q3wk | Might have inferior TTP |
2. Docetaxel; 100 mg/m2 q3wk | Might have inferior TTP | |||
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Note: this is the dosage used for Japanese patients; Adachi et al. 1996 reported 21- to 28-day cycles
Chemotherapy
- Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
21-day cycles
Regimen variant #4, 70 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Yamamoto et al. 2016 (JO21095) | 2008-2010 | Phase 3 (C) | TX | Seems to have inferior OS |
Chemotherapy
- Docetaxel (Taxotere) 70 mg/m2 IV once on day 1
21-day cycles
Subsequent treatment
- Upon progression: Capecitabine
Regimen variant #5, 75 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Harvey et al. 2006 (TAX 313) | 1995-2001 | Phase 3 (E-RT-esc) | 1. Docetaxel; 60 mg/m2 q3wk | Might have superior TTP |
2. Docetaxel; 100 mg/m2 q3wk | Might have inferior TTP | |||
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Gemcitabine & Bevacizumab 4. Paclitaxel & Bevacizumab 5. nab-Paclitaxel & Bevacizumab 6. Vinorelbine & Bevacizumab |
Inferior PFS |
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Note: This is the lower end of the range of docetaxel dosing described in TANIA.
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
21-day cycles
Regimen variant #6, 100 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy | Comparative Toxicity |
---|---|---|---|---|---|
ten Bokkel Huinink et al. 1994 | NR | Phase II | |||
Nabholtz et al. 1999 (TAX 304) | NR | Phase 3 (E-RT-de-esc) | MV | Superior OS | |
Chan et al. 1999 (TAX 303) | 1994-1997 | Phase 3 (E-RT-switch-ic) | Doxorubicin | Superior ORR | |
Sjöström et al. 1999 | 1994-1997 | Phase 3 (E-de-esc) | MF | Superior TTP | |
O'Shaughnessy et al. 2002 | NR | Phase 3 (C) | TX | Inferior OS1 | |
Jones et al. 2005 (TAX 311) | 1994-2001 | Phase 3 (E-switch-ic) | Paclitaxel | Seems to have superior OS | |
Bonneterre et al. 2002 | 1995-1997 | Phase 3 (E-de-esc) | 5-FU & Vinorelbine | Did not meet primary endpoint of TTP | Less toxic |
Harvey et al. 2006 (TAX 313) | 1995-2001 | Phase 3 (E-RT-esc) | 1. Docetaxel; 60 mg/m2 q3wk | Might have superior TTP | |
2. Docetaxel; 75 mg/m2 q3wk | Might have superior TTP | ||||
Rivera et al. 2008 | 2001-2004 | Phase III (C), <20 pts in this subgroup | Docetaxel; weekly | Did not meet primary endpoint of ORR | Inferior toxicity |
Nielsen et al. 2011 | 2001-2005 | Phase 3 (C) | Docetaxel & Gemcitabine | Might have inferior TTP | |
Schröder et al. 2011 | 2001-2006 | Phase 3 (C) | Docetaxel; weekly | Seems to have superior OS | |
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Gemcitabine & Bevacizumab 4. Paclitaxel & Bevacizumab 5. nab-Paclitaxel & Bevacizumab 6. Vinorelbine & Bevacizumab |
Inferior PFS | |
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
1Reported efficacy for O'Shaughnessy et al. 2002 is based on the 2004 update.
Note: this is the upper end of the range of docetaxel dosing described in TANIA. TAX 304 stopped treatment after 10 cycles. TAX 303 stopped treatment after 7 cycles.
Chemotherapy
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
- Note: Rivera et al. 2008 gave 75 mg/m2 in cycle 1, with escalation to 100 mg/m2 depending on toxicity
21-day cycles (see note)
References
- ten Bokkel Huinink WW, Prove AM, Piccart M, Steward W, Tursz T, Wanders J, Franklin H, Clavel M, Verweij J, Alakl M, Bayssas M, Kaye SB; EORTC Early Clinical Trials Group. A phase II trial with docetaxel (Taxotere) in second line treatment with chemotherapy for advanced breast cancer: a study of the EORTC Early Clinical Trials Group. Ann Oncol. 1994 Jul;5(6):527-32. link to original article contains protocol 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 contains protocol 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 contains protocol 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 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 contains protocol PubMed
- O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. link to original article contains verified protocol PubMed
- Update: Miles D, Vukelja S, Moiseyenko V, Cervantes G, Mauriac L, Van Hazel G, Liu WY, Ayoub JP, O'Shaughnessy JA. Survival benefit with capecitabine/docetaxel versus docetaxel alone: analysis of therapy in a randomized phase III trial. Clin Breast Cancer. 2004 Oct;5(4):273-8. link to original article PubMed
- Bonneterre J, Roché H, Monnier A, Guastalla JP, Namer M, Fargeot P, Assadourian S. Docetaxel vs 5-fluorouracil plus vinorelbine in metastatic breast cancer after anthracycline therapy failure. Br J Cancer. 2002 Nov 18;87(11):1210-5. link to original article contains protocol 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 contains protocol 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 contains verified protocol 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 contains verified protocol 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 contains protocol 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 contains verified protocol 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 contains verified protocol PubMed
Docetaxel & Bevacizumab
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Regimen variant #1, docetaxel 60 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel |
Superior PFS Median PFS: 6.3 vs 4.2 mo (HR 0.75, 95% CI 0.61-0.93) |
Note: this is the dosage used for Japanese patients.
Chemotherapy
- Docetaxel (Taxotere) 60 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
Regimen variant #2, docetaxel 75 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Gemcitabine 4. Paclitaxel 5. nab-Paclitaxel 6. Vinorelbine |
Superior PFS Median PFS: 7.2 vs 5.1 mo (HR 0.78, 95% CI 0.64-0.93) |
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel |
Superior PFS Median PFS: 6.3 vs 4.2 mo (HR 0.75, 95% CI 0.61-0.93) |
Note: this is the lower end of the range of docetaxel dosing described in TANIA.
Chemotherapy
- Docetaxel (Taxotere) 75 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
Regimen variant #3, docetaxel 100 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Gemcitabine 4. Paclitaxel 5. nab-Paclitaxel 6. Vinorelbine |
Superior PFS Median PFS: 7.2 vs 5.1 mo (HR 0.78, 95% CI 0.64-0.93) |
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel |
Superior PFS Median PFS: 6.3 vs 4.2 mo (HR 0.75, 95% CI 0.61-0.93) |
Note: this is the upper end of the range of docetaxel dosing described in TANIA.
Chemotherapy
- Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains verified protocol 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 contains verified protocol 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 monotherapy
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Regimen variant #1, 20 mg/m2 weekly
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Note: this is the lower end of the range of weekly doxorubicin dosing described in TANIA.
Chemotherapy
- Doxorubicin (Adriamycin) 20 mg/m2 IV once on day 1
7-day cycles
Regimen variant #2, 25 mg/m2 weekly
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Note: this is the higher end of the range of weekly doxorubicin dosing described in TANIA.
Chemotherapy
- Doxorubicin (Adriamycin) 25 mg/m2 IV once on day 1
7-day cycles
Regimen variant #3, 60 mg/m2 q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Cowan et al. 1991 (SWOG S8203) | 1983-1986 | Phase 3 (E-switch-ic) | 1. Bisantrene 2. Mitoxantrone |
Seems to have superior OS |
Norris et al. 2000 (NCIC-CTG MA.8) | 1992-1995 | Phase 3 (C) | Doxorubicin & Vinorelbine | Did not meet primary endpoint of OS |
Reyno et al. 2004 (NCIC CT MA.19) | 1998-1999 | Phase 3 (C) | Doxorubicin & Tesmilifene | Did not meet primary endpoint of PFS |
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Note: in NCIC-CTG MA.8, this dose was after a mid-protocol amendment. Treatment in NCIC-CTG MA.8 & MA.19 was given until a cumulative dose of 450 mg/m2. This is the lower end of the range of q3wk doxorubicin dosing described in TANIA.
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
21-day cycles (see note)
Regimen variant #4, 75 mg/m2 q3wk, limited duration
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Chan et al. 1999 (TAX 303) | 1994-1997 | Phase 3 (C) | Docetaxel | Inferior ORR |
Chemotherapy
- Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
21-day cycle for up to 7 cycles
Regimen variant #5, 75 mg/m2 q3wk, indefinite
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Bontenbal et al. 1998 (EORTC 10811) | 1982-1986 | Phase 3 (C) | Epirubicin | Did not meet primary endpoint of ORR |
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Note: this is the higher end of the range of q3wk doxorubicin dosing described in TANIA.
Chemotherapy
- Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
21-day cycles
References
- SWOG S8203: Cowan JD, Neidhart J, McClure S, Coltman CA Jr, Gumbart C, Martino S, Hutchins LF, Stephens RL, Vaughan CB, Osborne CK. Randomized trial of doxorubicin, bisantrene, and mitoxantrone in advanced breast cancer: a Southwest Oncology Group study. J Natl Cancer Inst. 1991 Aug 7;83(15):1077-84. link to original article contains protocol 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 contains protocol 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 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 contains protocol 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 contains verified protocol 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
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Regimen variant #1, doxorubicin 20 mg/m2 weekly
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel |
Superior PFS Median PFS: 6.3 vs 4.2 mo (HR 0.75, 95% CI 0.61-0.93) |
Note: this is the lower end of the range of weekly doxorubicin dosing described in TANIA.
Chemotherapy
- Doxorubicin (Adriamycin) 20 mg/m2 IV once per day on days 1, 8, 15, 22
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
Regimen variant #2, doxorubicin 25 mg/m2 weekly
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel |
Superior PFS Median PFS: 6.3 vs 4.2 mo (HR 0.75, 95% CI 0.61-0.93) |
Note: this is the higher end of the range of weekly doxorubicin dosing described in TANIA.
Chemotherapy
- Doxorubicin (Adriamycin) 25 mg/m2 IV once per day on days 1, 8, 15, 22
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
Regimen variant #3, doxorubicin 60 mg/m2 q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel |
Superior PFS Median PFS: 6.3 vs 4.2 mo (HR 0.75, 95% CI 0.61-0.93) |
Note: this is the lower end of the range of q3wk doxorubicin dosing described in TANIA.
Chemotherapy
- Doxorubicin (Adriamycin) 60 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
Regimen variant #4, doxorubicin 75 mg/m2 q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel |
Superior PFS Median PFS: 6.3 vs 4.2 mo (HR 0.75, 95% CI 0.61-0.93) |
Note: this is the higher end of the range of q3wk doxorubicin dosing described in TANIA.
Chemotherapy
- Doxorubicin (Adriamycin) 75 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains verified protocol 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 non-pegylated liposomal monotherapy
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NPLD: Non-Pegylated Liposomal Doxorubicin
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Chemotherapy
- Non-pegylated liposomal doxorubicin (Myocet) 60 mg/m2 IV once on day 1
21-day cycles
References
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains verified protocol 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 non-pegylated liposomal & Bevacizumab
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NPLD/Bev: Non-Pegylated Liposomal Doxorubicin & Bevacizumab
Regimen
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel |
Superior PFS Median PFS: 6.3 vs 4.2 mo (HR 0.75, 95% CI 0.61-0.93) |
Chemotherapy
- Non-pegylated liposomal doxorubicin (Myocet) 60 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains verified protocol 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 pegylated liposomal monotherapy
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PLD: Pegylated Liposomal Doxorubicin
Regimen variant #1, 40 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Note: this is the lower end of the range of pegylated liposomal doxorubicin dosing described in TANIA.
Chemotherapy
- Pegylated liposomal doxorubicin (Doxil) 40 mg/m2 IV once on day 1
28-day cycles
Regimen variant #2, 50 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Keller et al. 2004 | NR | Phase 3 (E-switch-ic) | 1. Mitomycin & Vinblastine 2. Vinorelbine |
Did not meet primary endpoint of PFS |
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Note: this is the higher end of the range of pegylated liposomal doxorubicin dosing described in TANIA.
Chemotherapy
- Pegylated liposomal doxorubicin (Doxil) 50 mg/m2 IV once on day 1
28-day cycles
References
- Keller AM, Mennel RG, Georgoulias VA, Nabholtz JM, Erazo A, Lluch A, Vogel CL, Kaufmann M, von Minckwitz G, Henderson IC, Mellars L, Alland L, Tendler C. Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol. 2004 Oct 1;22(19):3893-901. link to original article contains protocol 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 contains verified protocol 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 pegylated liposomal monotherapy
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PLD: Pegylated Liposomal Doxorubicin
Regimen variant #1, 40 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Note: this is the lower end of the range of pegylated liposomal doxorubicin dosing described in TANIA.
Chemotherapy
- Pegylated liposomal doxorubicin (Doxil) 40 mg/m2 IV once on day 1
28-day cycles
Regimen variant #2, 50 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Keller et al. 2004 | NR | Phase 3 (E-switch-ic) | 1. Mitomycin & Vinblastine 2. Vinorelbine |
Did not meet primary endpoint of PFS |
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Note: this is the higher end of the range of pegylated liposomal doxorubicin dosing described in TANIA.
Chemotherapy
- Pegylated liposomal doxorubicin (Doxil) 50 mg/m2 IV once on day 1
28-day cycles
References
- Keller AM, Mennel RG, Georgoulias VA, Nabholtz JM, Erazo A, Lluch A, Vogel CL, Kaufmann M, von Minckwitz G, Henderson IC, Mellars L, Alland L, Tendler C. Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer. J Clin Oncol. 2004 Oct 1;22(19):3893-901. link to original article contains protocol 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 contains verified protocol 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 pegylated liposomal & Bevacizumab
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PLD/Bev: Pegylated Liposomal Doxorubicin & Bevacizumab
Regimen variant #1, 40 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel |
Superior PFS Median PFS: 6.3 vs 4.2 mo (HR 0.75, 95% CI 0.61-0.93) |
Note: this is the lower end of the range of pegylated liposomal doxorubicin dosing described in TANIA.
Chemotherapy
- Pegylated liposomal doxorubicin (Doxil) 40 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
Regimen variant #2, 50 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel |
Superior PFS Median PFS: 6.3 vs 4.2 mo (HR 0.75, 95% CI 0.61-0.93) |
Note: this is the higher end of the range of pegylated liposomal doxorubicin dosing described in TANIA.
Chemotherapy
- Pegylated liposomal doxorubicin (Doxil) 50 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
References
- TANIA: von Minckwitz G, Puglisi F, Cortes J, Vrdoljak E, Marschner N, Zielinski C, Villanueva C, Romieu G, Lang I, Ciruelos E, De Laurentiis M, Veyret C, de Ducla S, Freudensprung U, Srock S, Gligorov J. Bevacizumab plus chemotherapy versus chemotherapy alone as second-line treatment for patients with HER2-negative locally recurrent or metastatic breast cancer after first-line treatment with bevacizumab plus chemotherapy (TANIA): an open-label, randomised phase 3 trial. Lancet Oncol. 2014 Oct;15(11):1269-78. Epub 2014 Sep 28. link to original article contains verified protocol 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
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Regimen
Study | Years 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 Median OS: 13.1 vs 10.6 mo (HR 0.81, 95% CI 0.66-0.99) |
Kaufman et al. 2015 (E7389-G000-301) | 2006-2009 | Phase 3 (E-switch-ic) | Capecitabine | Seems to have superior OS Median OS: 15.9 vs. 14.5 mo (HR 0.88, 95% CI 0.77-1.00) |
Yuan et al. 2019 (E7389-C086-304) | 2013-2015 | Phase 3 (E-switch-ic) | Vinorelbine | Seems to have superior PFS Median PFS: 2.8 vs 2.8 mo (HR 0.80, 95% CI 0.65-0.98) |
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 contains protocol 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 contains verified protocol PubMed NCT00337103
- E7389-C086-304: Yuan P, Hu X, Sun T, Li W, Zhang Q, Cui S, Cheng Y, Ouyang Q, Wang X, Chen Z, Hiraiwa M, Saito K, Funasaka S, Xu B. Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial. Eur J Cancer. 2019 May;112:57-65. Epub 2019 Mar 29. link to original article contains protocol PubMed NCT02225470
- EVER-132-002: NCT04639986
- TROPICS-02: NCT03901339
Gemcitabine monotherapy
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Regimen variant #1, 800 mg/m2 3 weeks out of 4
Study | Years of enrollment | Evidence |
---|---|---|
Carmichael et al. 1995 | NR | Phase II |
Chemotherapy
- Gemcitabine (Gemzar) 800 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
28-day cycles
Regimen variant #2, 1000 mg/m2 3 weeks out of 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Chemotherapy
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
Regimen variant #3, 1200 mg/m2 3 weeks out of 4
Study | Years of enrollment | Evidence |
---|---|---|
Spielmann et al. 2001 | NR | Phase II |
Chemotherapy
- Gemcitabine (Gemzar) 1200 mg/m2 IV over 30 minutes once per day on days 1, 8, 15
28-day cycles
Regimen variant #4, 1250 mg/m2 2 weeks out of 3
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Gemcitabine & Bevacizumab 4. Paclitaxel & Bevacizumab 5. nab-Paclitaxel & Bevacizumab 6. Vinorelbine & Bevacizumab |
Inferior PFS |
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Chemotherapy
- Gemcitabine (Gemzar) 1250 mg/m2 IV over 30 minutes once per day on days 1 & 8
21-day cycles
References
- Carmichael J, Possinger K, Phillip P, Beykirch M, Kerr H, Walling J, Harris AL. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol. 1995 Nov;13(11):2731-6. link to original article contains protocol 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 contains verified protocol 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 contains verified protocol 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
- EVER-132-002: NCT04639986
- TROPICS-02: NCT03901339
Gemcitabine & Bevacizumab
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Regimen variant #1, 1000 mg/m2, 3 weeks out of 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel |
Superior PFS Median PFS: 6.3 vs 4.2 mo (HR 0.75, 95% CI 0.61-0.93) |
Chemotherapy
- Gemcitabine (Gemzar) 1000 mg/m2 IV once per day on days 1, 8, 15
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
Regimen variant #2, 1250 mg/m2, 2 weeks out of 3
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Gemcitabine 4. Paclitaxel 5. nab-Paclitaxel 6. Vinorelbine |
Superior PFS Median PFS: 7.2 vs 5.1 mo (HR 0.78, 95% CI 0.64-0.93) |
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel |
Superior PFS Median PFS: 6.3 vs 4.2 mo (HR 0.75, 95% CI 0.61-0.93) |
Chemotherapy
- Gemcitabine (Gemzar) 1250 mg/m2 IV over 30 minutes once per day on days 1 & 8
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains verified protocol 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 contains verified protocol 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
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Regimen
Study | Years of enrollment | Evidence |
---|---|---|
Perez et al. 2007 | 2004-2005 | Phase II (RT) |
Chemotherapy
- Ixabepilone (Ixempra) 40 mg/m2 IV over 3 hours once on day 1
21-day cycles
References
- Perez EA, Lerzo G, Pivot X, Thomas E, Vahdat L, Bosserman L, Viens P, Cai C, Mullaney B, Peck R, Hortobagyi GN. Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2007 Aug 10;25(23):3407-14. Epub 2007 Jul 2. link to original article PubMed
Paclitaxel monotherapy, weekly
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Regimen variant #1, 80 mg/m2 weekly
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Perez et al. 2001 | NR | Phase II | ||
Seidman et al. 2008 (CALGB 9840) | 1998-NR | Phase 3 (E-switch-ic) | Paclitaxel q3wk | Superior OS Median OS: 24 vs 12 mo (HR 0.78, 95% CI 0.65-0.94) |
Chemotherapy
- Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycles
Regimen variant #2, 90 mg/m2 3 weeks out of 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Gemcitabine & Bevacizumab 4. Paclitaxel & Bevacizumab 5. nab-Paclitaxel & Bevacizumab 6. Vinorelbine & Bevacizumab |
Inferior PFS |
Chemotherapy
- Paclitaxel (Taxol) 90 mg/m2 IV once per day on days 1, 8, 15
28-day cycles
References
- Perez EA, Vogel CL, Irwin DH, Kirshner JJ, Patel R. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2001 Nov 15;19(22):4216-23. link to original article PubMed
- 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 contains verified protocol PubMed NCT00281697
Paclitaxel monotherapy, q3wk
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Regimen variant #1, 135 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Nabholtz et al. 1996 | 1992 | Phase 3 (E-RT-de-esc) | Paclitaxel; 175 mg/m2 q3wk | Did not meet primary endpoint of ORR1 |
1Although Nabholtz et al. 1996 did not meet its primary endpoint, there seemed to be a TTP disadvantage in the lower-dose arm.
Chemotherapy
- Paclitaxel (Taxol) 135 mg/m2 IV over 3 hours once on day 1
21-day cycles
Regimen variant #2, 175 mg/m2
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Seidman et al. 1995 | NR | Phase II | ||
Nabholtz et al. 1996 | 1992 | Phase 3 (E-RT-esc) | Paclitaxel; 135 mg/m2 q3wk | Did not meet primary endpoint of ORR1 |
Winer et al. 2004 (CALGB 9342) | 1994-1997 | Phase 3 (C) | 1. Paclitaxel; 210 mg/m2 q3wk 2. Paclitaxel; 250 mg/m2 q3wk |
Did not meet primary endpoint of ORR |
Jones et al. 2005 (TAX 311) | 1994-2001 | Phase 3 (E-switch-ic) | Docetaxel | Seems to have inferior OS |
Icli et al. 2005 | 1997-2002 | Phase 3 (C) | EoP | Seems to have inferior OS |
Seidman et al. 2008 (CALGB 9840) | 1998-NR | Phase 3 (C) | Weekly paclitaxel | Inferior OS |
Gradishar et al. 2005 (CA012-0) | 2001-2002 | Phase 3 (C) | nab-Paclitaxel | Inferior TTP |
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Gemcitabine & Bevacizumab 4. Paclitaxel & Bevacizumab 5. nab-Paclitaxel & Bevacizumab 6. Vinorelbine & Bevacizumab |
Inferior PFS |
1Although Nabholtz et al. 1996 did not meet its primary endpoint, there seemed to be a TTP advantage in the higher-dose arm, which subsequently led to its adoption as the standard-of-care.
Chemotherapy
- Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
21-day cycles
References
- Seidman AD, Tiersten A, Hudis C, Gollub M, Barrett S, Yao TJ, Lepore J, Gilewski T, Currie V, Crown J, Hakes T, Baselga J, Sklarin N, Moynihan ME, Tong W, Egorin M, Kearns C, Spriggs D, Norton L. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2575-81. link to original article 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 contains protocol 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 contains protocol 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 contains protocol 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 contains protocol 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 contains verified protocol 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 contains verified protocol PubMed NCT00281697
Paclitaxel & Bevacizumab
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Regimen variant #1, 90 mg/m2 3 weeks out of 4
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Gemcitabine 4. Paclitaxel 5. nab-Paclitaxel 6. Vinorelbine |
Superior PFS Median PFS: 7.2 vs 5.1 mo (HR 0.78, 95% CI 0.64-0.93) |
Chemotherapy
- Paclitaxel (Taxol) 90 mg/m2 IV over 60 minutes once per day on days 1, 8, 15
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
Regimen variant #2, 175 mg/m2 q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Gemcitabine 4. Paclitaxel 5. nab-Paclitaxel 6. Vinorelbine |
Superior PFS Median PFS: 7.2 vs 5.1 mo (HR 0.78, 95% CI 0.64-0.93) |
Chemotherapy
- Paclitaxel (Taxol) 175 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains verified protocol PubMed NCT00281697
nab-Paclitaxel monotherapy
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Example orders
Regimen variant #1, 100 mg/m2 weekly
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Note: the details of this regimen are minimal in the manuscript; it is unclear if this is truly given once per week or given in a 3 weeks on, 1 week off schedule.
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV once per day on days 1, 8, 15, 22
28-day cycles
Regimen variant #2, 260 mg/m2 q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gradishar et al. 2005 (CA012-0) | 2001-2002 | Phase 3 (E-RT-switch-ic) | Paclitaxel | Superior TTP Median TTP: 23 vs 16.9 weeks (HR 0.75) |
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Gemcitabine & Bevacizumab 4. Paclitaxel & Bevacizumab 5. nab-Paclitaxel & Bevacizumab 6. Vinorelbine & Bevacizumab |
Inferior PFS |
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Doxorubicin & Bevacizumab 4. NPLD & Bevacizumab 5. PLD & Bevacizumab 6. Gemcitabine & Bevacizumab 7. nab-Paclitaxel & Bevacizumab |
Inferior PFS |
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m2 IV over 30 minutes once on day 1
Supportive medications
- CA012-0: No corticosteroid or antihistamine premedication
21-day cycles
Regimen variant #3, 300 mg/m2 q3wk
Study | Years of enrollment | Evidence |
---|---|---|
Ibrahim et al. 2005 | 1999-2001 | Phase II (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 contains protocol 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 contains verified protocol 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 contains verified protocol 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 contains verified protocol 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, nanoparticle albumin-bound & Bevacizumab
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Example orders
Regimen variant #1, 100 mg/m2 weekly
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel |
Superior PFS Median PFS: 6.3 vs 4.2 mo (HR 0.75, 95% CI 0.61-0.93) |
Note: the schedule of bevacizumab is inferred, as there was insufficient detail in the description in the manuscript.
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m2 IV once per day on days 1, 8, 15, 22
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15
28-day cycles
Regimen variant #2, 260 mg/m2 q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Gemcitabine 4. Paclitaxel 5. nab-Paclitaxel 6. Vinorelbine |
Superior PFS Median PFS: 7.2 vs 5.1 mo (HR 0.78, 95% CI 0.64-0.93) |
von Minckwitz et al. 2014 (TANIA) | 2011-2013 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Doxorubicin 4. NPLD 5. PLD 6. Gemcitabine 7. nab-Paclitaxel |
Superior PFS Median PFS: 6.3 vs 4.2 mo (HR 0.75, 95% CI 0.61-0.93) |
Chemotherapy
- Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- RIBBON-2: Brufsky AM, Hurvitz S, Perez E, Swamy R, Valero V, O'Neill V, Rugo HS. RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2011 Nov 10;29(32):4286-93. Epub 2011 Oct 11. link to original article contains verified protocol 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 contains verified protocol 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
Vinorelbine monotherapy
back to top |
Regimen variant #1, 25 mg/m2 weekly
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Gasparini et al. 1994 | 1991-1993 | Phase II | ||
Zelek et al. 2001 | 1997-1999 | Phase II | ||
Decker et al. 2019 (VicTORia) | 2011-2016 | Randomized Phase II (C) | Everolimus & Vinorelbine | Did not meet primary endpoint of PFS |
Yuan et al. 2019 (E7389-C086-304) | 2013-2015 | Phase 3 (C) | Eribulin | Seems to have inferior PFS |
Chemotherapy
- Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1, 8, 15
21-day cycles
Regimen variant #2, 30 mg/m2 weekly
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Jones et al. 1995a | 1990-1992 | Phase 3 (E-switch-ic) | Melphalan | Seems to have superior OS |
Keller et al. 2004 | NR | Phase 3 (C) | 1. Mitomycin & Vinblastine 2. PLD |
Did not meet primary endpoint of PFS |
Chemotherapy
- Vinorelbine (Navelbine) 30 mg/m2 IV once per day on days 1, 8, 15
21-day cycles
Regimen variant #3, 30 mg/m2 q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (C) | 1. Capecitabine & Bevacizumab 2. Docetaxel & Bevacizumab 3. Gemcitabine & Bevacizumab 4. Paclitaxel & Bevacizumab 5. nab-Paclitaxel & Bevacizumab 6. Vinorelbine & Bevacizumab |
Inferior PFS |
Chemotherapy
- Vinorelbine (Navelbine) 30 mg/m2 IV once on day 1
21-day cycles
Regimen variant #4, 30 mg/m2 2 out of 3 weeks
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Martín et al. 2007 (GEICAM 2000-04) | 2001-2005 | Phase 3 (C) | Gemcitabine & Vinorelbine | Inferior PFS |
Chemotherapy
- Vinorelbine (Navelbine) 30 mg/m2 IV once per day on days 1 & 8
21-day cycles
References
- 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 contains protocol 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 contains protocol 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 contains protocol 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 contains verified protocol 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 contains protocol 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 contains verified protocol PubMed NCT01520103
- EVER-132-002: NCT04639986
- TROPICS-02: NCT03901339
Vinorelbine & Bevacizumab
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Example orders
Regimen variant #1, vinorelbine 25 mg/m2 weekly
Study | Years of enrollment | Evidence |
---|---|---|
Burstein et al. 2008 | 2001-2002 | Phase II |
Chemotherapy
- Vinorelbine (Navelbine) 25 mg/m2 IV once per day on days 1 & 8
Targeted therapy
- Bevacizumab (Avastin) 10 mg/kg IV once on day 1
14-day cycles
Regimen variant #2, vinorelbine 30 mg/m2 q3wk
Study | Years of enrollment | Evidence | Comparator | Comparative Efficacy |
---|---|---|---|---|
Brufsky et al. 2011 (RIBBON-2) | 2006-2008 | Phase 3 (E-esc) | 1. Capecitabine 2. Docetaxel 3. Gemcitabine 4. Paclitaxel 5. nab-Paclitaxel 6. Vinorelbine |
Superior PFS Median PFS: 7.2 vs 5.1 mo (HR 0.78, 95% CI 0.64-0.93) |
Chemotherapy
- Vinorelbine (Navelbine) 30 mg/m2 IV once on day 1
Targeted therapy
- Bevacizumab (Avastin) 15 mg/kg IV once on day 1
21-day cycles
References
- Burstein HJ, Chen YH, Parker LM, Savoie J, Younger J, Kuter I, Ryan PD, Garber JE, Chen H, Campos SM, Shulman LN, Harris LN, Gelman R, Winer EP. VEGF as a marker for outcome among advanced breast cancer patients receiving anti-VEGF therapy with bevacizumab and vinorelbine chemotherapy. Clin Cancer Res. 2008 Dec 1;14(23):7871-7. link to original article contains verified protocol 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 contains verified protocol PubMed NCT00281697
Additional resources
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- Gail model Breast Cancer Risk Assessment Tool
- Breast cancer BRCA1 & BRCA2 genetic testing
- Adjuvant! Online (requires login)
- My Cancer Genome
- PREDICT