title: Adjuvant chemotherapy for early female breast cancer: a systematic review of the evidence for the 2014 Cancer Care Ontario systemic therapy guideline.
abstract: BACKGROUND
  The Program in Evidence-Based Care (pebc) of Cancer Care Ontario recently created an evidence-based consensus guideline on the systemic treatment of early breast cancer. The evidence for the guideline was compiled using a systematic review to answer the question "What is the optimal systemic therapy for patients with early-stage, operable breast cancer, when patient and disease factors are considered?" The question was addressed in three parts: cytotoxic chemotherapy, endocrine treatment, and human epidermal growth factor receptor 2 (her2)-directed therapy.
  
  
  METHODS
  For the systematic review, the medline and embase databases were searched for the period January 2008 to May 2014. The Standards and Guidelines Evidence directory of cancer guidelines and the Web sites of major oncology guideline organizations were also searched. The basic search terms were "breast cancer" and "systemic therapy" (chemotherapy, endocrine therapy, targeted agents, ovarian suppression), and results were limited to randomized controlled trials (rcts), guidelines, systematic reviews, and meta-analyses.
  
  
  RESULTS
  Several hundred documents that met the inclusion criteria were retrieved. The Early Breast Cancer Trialists' Collaborative Group meta-analyses encompassed many of the rcts found. Several additional studies that met the inclusion criteria were retained, as were other guidelines and systematic reviews. Chemotherapy was reviewed mainly in three classes: anti-metabolite-based regimens (for example, cyclophosphamide-methotrexate-5-fluorouracil), anthracyclines, and taxane-based regimens. In general, single-agent chemotherapy is not recommended for the adjuvant treatment of breast cancer in any patient population. Anthracycline-taxane-based polychemotherapy regimens are, overall, considered superior to earlier-generation regimens and have the most significant impact on patient survival outcomes. Regimens with varying anthracycline and taxane doses and schedules are options; in general, paclitaxel given every 3 weeks is inferior. Evidence does not support the use of bevacizumab in the adjuvant setting; other systemic therapy agents such as metformin and vaccines remain investigatory. Adjuvant bisphosphonates for menopausal women will be discussed in later work.
  
  
  CONCLUSIONS
  The results of this systematic review constitute a comprehensive compilation of the high-level evidence that is the basis for the 2014 pebc guideline on systemic therapy for early breast cancer. Use of cytotoxic chemotherapy is presented here; the results addressing endocrine therapy and her2-targeted treatment, and the final clinical practice recommendations, are published separately in this supplement.
authors.affiliation: Sunnybrook Health Science Centre, Toronto, ON.
authors.forename: S
authors.initials: S
authors.lastname: Gandhi
authors.affiliation: Program in Evidence-Based Care, Cancer Care Ontario; and Department of Oncology, McMaster University, Hamilton, ON.
authors.forename: G G
authors.initials: GG
authors.lastname: Fletcher
authors.affiliation: Sunnybrook Health Science Centre, Toronto, ON.
authors.forename: A
authors.initials: A
authors.lastname: Eisen
authors.affiliation: Cancer Centre of Southeastern Ontario, Kinston General Hospital; and Queen's University, Kingston, ON.
authors.forename: M
authors.initials: M
authors.lastname: Mates
authors.affiliation: Durham Regional Cancer Centre, Oshawa, ON.
authors.forename: O C
authors.initials: OC
authors.lastname: Freedman
authors.affiliation: The Ottawa Hospital Cancer Centre and University of Ottawa, Ottawa, ON.
authors.forename: S F
authors.initials: SF
authors.lastname: Dent
authors.affiliation: Sunnybrook Health Science Centre, Toronto, ON.
authors.forename: M E
authors.initials: ME
authors.lastname: Trudeau
keywords: Early breast cancer; adjuvant; chemotherapy; cytotoxic; drug therapy; systemic treatment
references.citation: J Clin Oncol. 2009 Jun 10;27(17):2809-15
references.pmid: 19380452
references.citation: Clin Cancer Res. 2013 Aug 15;19(16):4521-31
references.pmid: 23812670
references.citation: J Clin Oncol. 2013 Sep 10;31(26):3197-204
references.pmid: 23940225
references.citation: Br J Cancer. 2008 Oct 21;99(8):1226-31
references.pmid: 18797468
references.citation: Breast Cancer Res. 2009;11(5):R69
references.pmid: 19758440
references.citation: Cancer. 2010 May 1;116(9):2081-9
references.pmid: 20186830
references.citation: Med Oncol. 2013 Mar;30(1):457
references.pmid: 23322524
references.citation: Eur J Cancer. 2007 Mar;43(5):877-84
references.pmid: 17306974
references.citation: Lancet. 2012 Feb 4;379(9814):432-44
references.pmid: 22152853
references.citation: Ann Oncol. 2013 May;24(5):1203-11
references.pmid: 23293111
references.citation: Acta Oncol. 2008;47(4):662-71
references.pmid: 18465334
references.citation: Trials. 2013 Aug 19;14:261
references.pmid: 23958221
references.citation: Breast Cancer Res Treat. 2009 May;115(1):101-13
references.pmid: 18484198
references.citation: J Clin Oncol. 2003 Mar 15;21(6):976-83
references.pmid: 12637460
references.citation: Breast Cancer Res Treat. 2011 Jul;128(2):421-7
references.pmid: 21553292
references.citation: J Clin Oncol. 2012 Jan 1;30(1):11-8
references.pmid: 22105826
references.citation: J Clin Oncol. 2000 Sep;18(17):3125-34
references.pmid: 10963641
references.citation: J Clin Oncol. 2011 Mar 10;29(8):1022-8
references.pmid: 21300923
references.citation: Lancet. 2011 Aug 27;378(9793):771-84
references.pmid: 21802721
references.citation: Lancet. 2009 May 16;373(9676):1681-92
references.pmid: 19447249
references.citation: N Engl J Med. 2010 Dec 2;363(23):2200-10
references.pmid: 21121833
references.citation: N Engl J Med. 2005 Jun 2;352(22):2302-13
references.pmid: 15930421
references.citation: N Engl J Med. 2010 Dec 2;363(23):2268-70
references.pmid: 21121855
references.citation: Breast Cancer Res Treat. 2011 Feb;125(3):775-84
references.pmid: 21132360
references.citation: BMC Med Res Methodol. 2007 Feb 15;7:10
references.pmid: 17302989
references.citation: Eur J Cancer. 2014 Jan;50(1):23-30
references.pmid: 24183460
references.citation: Clin Cancer Res. 2012 Apr 15;18(8):2402-12
references.pmid: 22351696
references.citation: J Clin Oncol. 2008 Sep 1;26(25):4092-9
references.pmid: 18678836
references.citation: J Clin Oncol. 2009 Feb 10;27(5):720-5
references.pmid: 19103732
references.citation: Ann Oncol. 2014 Sep;25(9):1735-42
references.pmid: 24907636
references.citation: Clin Cancer Res. 2011 Aug 1;17(15):5170-8
references.pmid: 21693655
references.citation: Br J Cancer. 2008 Aug 19;99(4):597-603
references.pmid: 18665163
references.citation: Breast Cancer Res. 2011;13(6):R109
references.pmid: 22044691
references.citation: Breast Cancer. 2010 Jul;17(3):190-8
references.pmid: 19575284
references.citation: J Clin Oncol. 2015 Jan 1;33(1):58-64
references.pmid: 25422488
references.citation: J Clin Oncol. 2006 Dec 20;24(36):5664-71
references.pmid: 17116941
references.citation: J Clin Oncol. 2011 Aug 20;29(24):3247-54
references.pmid: 21768453
references.citation: Ann Oncol. 2012 May;23(5):1121-9
references.pmid: 21965475
references.citation: J Clin Oncol. 2012 Mar 20;30(9):930-5
references.pmid: 22331946
references.citation: Breast Cancer Res Treat. 2010 Aug;122(3):787-94
references.pmid: 20559708
references.citation: Br J Cancer. 2012 Oct 9;107(8):1257-67
references.pmid: 23047592
references.citation: Breast Cancer Res Treat. 2010 Jan;119(1):95-104
references.pmid: 19636702
references.citation: J Clin Oncol. 2005 Jun 1;23(16):3686-96
references.pmid: 15897552
references.citation: J Clin Oncol. 2012 Nov 20;30(33):4071-6
references.pmid: 22826271
references.citation: J Clin Oncol. 2009 Mar 10;27(8):1177-83
references.pmid: 19204201
references.citation: J Clin Oncol. 2005 Jan 1;23(1):30-40
references.pmid: 15545661
references.citation: Breast Cancer Res Treat. 2008 Jun;109(3):481-9
references.pmid: 17653851
references.citation: Value Health. 2011 Jul-Aug;14(5):746-51
references.pmid: 21839414
references.citation: J Clin Oncol. 2009 Mar 10;27(8):1168-76
references.pmid: 19204205
references.citation: N Engl J Med. 2005 Oct 27;353(17 ):1784-92
references.pmid: 16251534
references.citation: N Engl J Med. 2009 May 14;360(20):2055-65
references.pmid: 19439741
references.citation: J Natl Cancer Inst. 2008 Apr 16;100(8):552-62
references.pmid: 18398094
references.citation: N Engl J Med. 2006 Nov 2;355(18):1851-62
references.pmid: 17079759
references.citation: Lancet Oncol. 2014 Feb;15(2):201-12
references.pmid: 24360787
references.citation: J Natl Cancer Inst. 2008 Apr 16;100(8):542-51
references.pmid: 18398097
references.citation: Breast Cancer Res Treat. 2010 Aug;123(1):149-57
references.pmid: 20037779
references.citation: J Natl Cancer Inst. 2008 Jun 4;100(11):805-14
references.pmid: 18505968
references.citation: Breast Cancer Res Treat. 2014 Apr;144(2):307-18
references.pmid: 24381054
references.citation: Ann Oncol. 2011 Sep;22(9):1999-2006
references.pmid: 21382868
references.citation: N Engl J Med. 2008 Apr 17;358(16):1663-71
references.pmid: 18420499
references.citation: N Engl J Med. 2010 Jun 3;362(22):2053-65
references.pmid: 20519679
references.citation: N Engl J Med. 2007 Oct 11;357(15):1496-506
references.pmid: 17928597
references.citation: Eur J Cancer. 2013 Sep;49(14):2986-94
references.pmid: 23756360
references.citation: J Clin Oncol. 2012 Sep 1;30(25):3051-7
references.pmid: 22851566
references.citation: Breast Cancer Res Treat. 2013 Nov;142(1):69-80
references.pmid: 24122389
references.citation: J Clin Oncol. 2014 Aug 1;32(22):2311-7
references.pmid: 24934787
references.citation: Lancet. 1996 Nov 2;348(9036):1189-96
references.pmid: 8898035
references.citation: J Clin Oncol. 2003 Apr 15;21(8):1431-9
references.pmid: 12668651
references.citation: J Clin Oncol. 2011 Mar 20;29(9):1110-6
references.pmid: 21300930
references.citation: Ann Oncol. 2011 Mar;22(3):609-17
references.pmid: 20732932
references.citation: Breast Cancer Res. 2012 May 02;14(3):R70
references.pmid: 22551440
references.citation: Lancet. 2008 Jan 5;371(9606):29-40
references.pmid: 18177773
references.citation: Breast Cancer Res Treat. 2012 Apr;132(2):609-19
references.pmid: 22187126
references.citation: J Clin Oncol. 2013 Oct 10;31(29):3623-30
references.pmid: 24002511
references.citation: J Clin Oncol. 2010 Jun 10;28(17):2874-80
references.pmid: 20458045
references.citation: J Clin Oncol. 2010 Jun 20;28(18):2958-65
references.pmid: 20479419
references.citation: Breast Cancer Res Treat. 2008 Mar;108(2):259-64
references.pmid: 17530429
references.citation: J Clin Oncol. 2010 Jan 1;28(1):77-82
references.pmid: 19901117
references.citation: J Clin Oncol. 2009 Sep 10;27(26):4287-92
references.pmid: 19667268
references.citation: J Clin Oncol. 2008 Feb 10;26(5):778-85
references.pmid: 18258986
references.citation: Ann Oncol. 2011 Sep;22(9):1988-98
references.pmid: 21385882
references.citation: J Clin Oncol. 2005 May 1;23(13):2988-95
references.pmid: 15860854
references.citation: Lancet Oncol. 2013 Jan;14(1):72-80
references.pmid: 23246022
references.citation: J Clin Oncol. 2009 Jun 20;27(18):2938-45
references.pmid: 19364964
references.citation: Lancet. 2005 May 14-20;365(9472):1687-717
references.pmid: 15894097
references.citation: J Natl Cancer Inst. 2008 Jan 16;100(2):121-33
references.pmid: 18182617
references.citation: J Clin Oncol. 2011 Oct 10;29(29):3877-84
references.pmid: 21911726
references.citation: J Clin Oncol. 2009 Dec 1;27(34):5685-92
references.pmid: 19884557
references.citation: Lancet Oncol. 2013 Sep;14(10):933-42
references.pmid: 23932548
references.citation: Ann Oncol. 2012 Oct;23(10):2552-61
references.pmid: 22431701
references.citation: Breast Cancer Res Treat. 2008 Nov;112(2):309-16
references.pmid: 18080748
references.citation: Oncologist. 2012;17(7):900-9
references.pmid: 22610153
references.citation: J Clin Oncol. 2013 Jul 10;31(20):2593-9
references.pmid: 23733779
references.citation: Lancet Oncol. 2010 Mar;11(3):266-74
references.pmid: 20079691
references.citation: Clin Trials. 2005;2(3):209-17
references.pmid: 16279144
references.citation: J Clin Oncol. 2009 May 20;27(15):2474-81
references.pmid: 19332727
references.citation: Support Care Cancer. 2012 Dec;20(12):3355-64
references.pmid: 22584733
references.citation: J Clin Oncol. 2002 Sep 1;20(17):3628-36
references.pmid: 12202663
references.citation: Ann Oncol. 2008 May;19(5):853-60
references.pmid: 18042835
references.citation: Clin Cancer Res. 2010 Aug 1;16(15):3988-97
references.pmid: 20576719
references.citation: J Clin Oncol. 2009 Mar 20;27(9):1368-74
references.pmid: 19204202