Difference between revisions of "Breast cancer - null regimens"

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The purpose of this page is to provide references to "null therapy" such as placebo and observation. While not clinically relevant, these references provide further insight into the historical development of the treatment landscape. See the [[Breast cancer|main breast cancer page]] for current regimens.
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The purpose of this page is to provide references to "null therapy" such as placebo and observation. These references provide further insight into the historical development of the treatment landscape. See the [[Breast cancer|main breast cancer page]] for regimens that include active anticancer treatment.
  
 
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−
=Neoadjuvant therapy=
 
−
 
−
==No neoadjuvant therapy==
 
−
{| class="wikitable" style="float:right; margin-left: 5px;"
 
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
−
===Regimen===
 
−
{| class="wikitable sortable" style="width: 100%; text-align:center;"
 
−
!style="width: 20%"|Study
 
−
!style="width: 20%"|Years of enrollment
 
−
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
−
!style="width: 20%"|Comparator
 
−
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
−
|-
 
−
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7606901/ Smith et al. 2020 (POETIC)]
 
−
|2008-2014
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|1. Anastrozole<br> 2. Letrozole
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of TTR
 
−
|-
 
−
|}
 
−
''No treatment prior to surgical resection.''
 
−
====Subsequent treatment====
 
−
*[[Surgery#Breast_cancer_surgery|Surgery]]
 
−
===References===
 
−
#'''POETIC:''' Smith I, Robertson J, Kilburn L, Wilcox M, Evans A, Holcombe C, Horgan K, Kirwan C, Mallon E, Sibbering M, Skene A, Vidya R, Cheang M, Banerji J, Morden J, Sidhu K, Dodson A, Bliss JM, Dowsett M. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020 Nov;21(11):1443-1454. [https://doi.org/10.1016/s1470-2045(20)30458-7 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc7606901/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/33152284 PubMed] NCT02338310
 
  
 
=Adjuvant therapy=
 
=Adjuvant therapy=
 
==Observation==
 
==Observation==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
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<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Regimen===
 
===Regimen===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
−
!style="width: 20%"|Years of enrollment
+
!style="width: 20%"|Dates of enrollment
 
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 20%"|Comparator
 
!style="width: 20%"|Comparator
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(80)90057-4/fulltext Lacour et al. 1980]
+
|[https://doi.org/10.1016/S0140-6736(80)90057-4 Lacour et al. 1980]
 
|1972-1979
 
|1972-1979
−
|style="background-color:#1a9851"|Phase III (C)
+
|style="background-color:#1a9851"|Phase 3 (C)
−
|Polya.Polyu
+
|[[#Polya.Polyu_333|Polya.Polyu]]
 
| style="background-color:#fee08b" |Might have inferior OS
 
| style="background-color:#fee08b" |Might have inferior OS
 
|-
 
|-
−
|[https://www.nejm.org/doi/full/10.1056/NEJM197602192940801 Bonadonna et al. 1976]
+
|[https://doi.org/10.1056/NEJM197602192940801 Bonadonna et al. 1976]
 
|1973-1975
 
|1973-1975
−
|style="background-color:#1a9851"|Phase III (C)
+
|style="background-color:#1a9851"|Phase 3 (C)
 
|[[Breast_cancer#CMF|CMF]]
 
|[[Breast_cancer#CMF|CMF]]
 
|style="background-color:#d73027"|Inferior RFS
 
|style="background-color:#d73027"|Inferior RFS
 
|-
 
|-
−
|[http://www.tandfonline.com/doi/full/10.1080/0284186X.2017.1400179 Jensen et al. 2017 (CBC 02)]
+
|[https://doi.org/10.1016/S0140-6736(83)91385-5 Rubens et al. 1983]
−
|1975-1978
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 2 y
 
−
| style="background-color:#fc8d59" |Seems to have inferior OS
 
−
|-
 
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(83)91385-5/fulltext Rubens et al. 1983]
 
 
|1975-1979
 
|1975-1979
−
|style="background-color:#1a9851"|Phase III (C)
+
|style="background-color:#1a9851"|Phase 3 (C)
 
|[[Breast_cancer_-_historical#Melphalan_monotherapy|Melphalan]]
 
|[[Breast_cancer_-_historical#Melphalan_monotherapy|Melphalan]]
 
| style="background-color:#fee08b" |Might have inferior RFS
 
| style="background-color:#fee08b" |Might have inferior RFS
 
|-
 
|-
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(83)91683-5/abstract Baum et al. 1983 (NATO)]
+
|-
−
|1977-1981
+
|[https://doi.org/10.1200/JCO.1995.13.1.33 Clahsen et al. 1995 (EORTC 09771)]
 +
|1976-1980
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 2 y
+
|[[Breast_cancer#CMF|CMF]]; 700/30/700 x 24
−
| style="background-color:#d73027" |Inferior OS
+
| style="background-color:#fc8d59" |Seems to have inferior OS
 
|-
 
|-
−
|rowspan=3|[https://link.springer.com/article/10.1007/BF01806239 Brinker et al. 1983 (DBCG 77B)]
+
|[https://doi.org/10.1016/S0140-6736(84)92684-9 Howell et al. 1984]
 +
|1976-1983
 +
|style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer#CMF|CMF]]; 1120/64/960 x 12
 +
| style="background-color:#d73027" |Inferior RFS
 +
|-
 +
|rowspan=3|[https://doi.org/10.1007/BF01806239 Brinker et al. 1983 (DBCG 77B)]
 
|rowspan=3|1977-1983
 
|rowspan=3|1977-1983
 
|rowspan=3 style="background-color:#1a9851" |Phase 3 (C)
 
|rowspan=3 style="background-color:#1a9851" |Phase 3 (C)
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|-
 
|-
 
|3. [[Breast_cancer_-_historical#Levamisole_monotherapy|Levamisole]]
 
|3. [[Breast_cancer_-_historical#Levamisole_monotherapy|Levamisole]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoints of IDFS/OS
+
| style="background-color:#ffffbf" |Did not meet co-primary endpoints of IDFS/OS
 
|-
 
|-
−
|rowspan = 2|[https://www.thelancet.com/journals/lancet/article/PIIS0140673684924450/fulltext Goldhirsch et al. 1984 (LBCS III)]
+
|rowspan = 2|[https://doi.org/10.1016/S0140-6736(84)92445-0 Goldhirsch et al. 1984 (LBCS III)]
 
|rowspan=2|1978-1981
 
|rowspan=2|1978-1981
 
|rowspan = 2 style="background-color:#1a9851" |Phase 3 (C)
 
|rowspan = 2 style="background-color:#1a9851" |Phase 3 (C)
Line 96: Line 70:
 
| style="background-color:#d73027" |Inferior DFS
 
| style="background-color:#d73027" |Inferior DFS
 
|-
 
|-
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140673684924450/fulltext Goldhirsch et al. 1984 (LBCS IV)]
+
|[https://doi.org/10.1016/S0140-6736(84)92445-0 Goldhirsch et al. 1984 (LBCS IV)]
 
|1978-1981
 
|1978-1981
 
|style="background-color:#1a9851" |Phase 3 (C)
 
|style="background-color:#1a9851" |Phase 3 (C)
Line 102: Line 76:
 
| style="background-color:#fc8d59" |Seems to have inferior DFS
 
| style="background-color:#fc8d59" |Seems to have inferior DFS
 
|-
 
|-
−
|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(87)90762-8/fulltext Stewart et al. 1987 (Scottish Tamoxifen Trial)]
+
|[https://doi.org/10.1056/NEJM198902233200801 Fisher et al. 1989 (NSABP B-13)]
−
|1978-1984
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 5 y
 
−
| style="background-color:#d73027" |Inferior OS<sup>2</sup>
 
−
|-
 
−
|[https://www.nejm.org/doi/full/10.1056/NEJM198902233200801 Fisher et al. 1989 (NSABP B-13)]
 
 
|1981-1988
 
|1981-1988
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
 
|[[Breast_cancer_-_historical#MF|MF]]; sequential
 
|[[Breast_cancer_-_historical#MF|MF]]; sequential
−
| style="background-color:#d73027" |Inferior DFS<sup>3</sup>
+
| style="background-color:#d73027" |Inferior DFS<sup>2</sup>
 
|-
 
|-
−
|[https://www.nejm.org/doi/full/10.1056/NEJM198902233200803 Mansour et al. 1989 (INT-0011)]
+
|[https://doi.org/10.1056/NEJM198902233200803 Mansour et al. 1989 (ECOG E1180)]
 
|1981-1988
 
|1981-1988
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
Line 120: Line 88:
 
|style="background-color:#d73027"|Inferior DFS
 
|style="background-color:#d73027"|Inferior DFS
 
|-
 
|-
−
|[https://www.ejcancer.com/article/S0959-8049(97)10010-7/fulltext Jakesz et al. 1998]
+
|[https://doi.org/10.1016/s0959-8049(97)10010-7 Jakesz et al. 1998]
 
|1984-1990
 
|1984-1990
 
|style="background-color:#1a9851" |Phase 3 (C)
 
|style="background-color:#1a9851" |Phase 3 (C)
−
|AV-CMF
+
|[[#AV-CMF_999|AV-CMF]]
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS60
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS60
 
|-
 
|-
−
|[https://www.ejcancer.com/article/S0959-8049(04)00565-9/fulltext Rydén et al. 2005 (SBII:2pre)]
+
|[https://www.jle.com/fr/revues/bdc/e-docs/epirubicin_based_chemotherapy_as_adjuvant_treatment_for_poor_prognosis_node_negative_breast_cancer_10_year_follow_up_results__272048/article.phtml Héry et al. 2006 (FASG 03)]
−
|1986-1991
+
|1988-1994
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 2 y
+
|[[Breast_cancer#FEC_2|FEC50]] x 6
−
| style="background-color:#d73027" |Inferior RFS
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS120
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2005.08.071 Hutchins et al. 2005 (INT-0102)]
+
|[https://doi.org/10.1200/JCO.2000.18.17.3125 Amadori et al. 2000]
 
|1989-1993
 
|1989-1993
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 5 y
+
|[[Breast_cancer#CMF|CMF]] x 6
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
+
| style="background-color:#fc8d59" |Seems to have inferior DFS
 
|-
 
|-
 
|[https://doi.org/10.1200/JCO.2001.19.19.3929 Paradiso et al. 2001]
 
|[https://doi.org/10.1200/JCO.2001.19.19.3929 Paradiso et al. 2001]
 
|1989-1994
 
|1989-1994
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[Breast_cancer#FEC_2|FEC]]
+
|[[Breast_cancer#FEC_2|FEC]] x 6
 
| style="background-color:#fc8d59" |Seems to have inferior DFS
 
| style="background-color:#fc8d59" |Seems to have inferior DFS
 
|-
 
|-
−
|[https://doi.org/10.1200/JCO.2005.03.0783 Colleoni et al. 2006 (IBCSG 13-93)]
+
|[https://doi.org/10.1080/02841860510029987 Arriagada et al. 2005]
−
|1993-1999
+
|1989-1996
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 5 y
+
|[[Breast_cancer#FEC_2|FEC50]] x 6
−
| style="background-color:#1a9850" |Superior DFS
+
| style="background-color:#d73027" |Inferior DFS
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2003.02.063 Henderson et al. 2003 (INT 0148/CALGB 9344)]
+
|[https://doi.org/10.1093/jnci/92.3.225 Hortobagyi et al. 2000]
−
|1994-1999
+
|1990-1997
−
|style="background-color:#1a9851"|Phase III (C)
+
| style="background-color:#1a9851" |Randomized (C)
−
|[[Breast_cancer_-_historical#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel]]; q3wk
+
|[[#CEP.2C_then_auto_HSCT_999|CEP with auto HSCT]]
−
|style="background-color:#d73027"|Inferior OS
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 +
|-
 +
|[https://doi.org/10.1093/jnci/djk108 Adjuvant Breast Cancer Trials Collaborative Group 2007 (NCRI ABC-CT)]
 +
|1992-2000
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[Breast_cancer#CMF|CMF]]; 1400/80/1200 x 6
 +
| style="background-color:#fc8d59" |Seems to have inferior OS
 
|-
 
|-
 
|[https://doi.org/10.1200/jco.2005.10.517 Mamounas et al. 2005 (NSABP B-28)]
 
|[https://doi.org/10.1200/jco.2005.10.517 Mamounas et al. 2005 (NSABP B-28)]
 
|1995-1998
 
|1995-1998
−
|style="background-color:#1a9851"|Phase III (C)
+
|style="background-color:#1a9851"|Phase 3 (C)
 
|[[Breast_cancer_-_historical#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel]]; q3wk
 
|[[Breast_cancer_-_historical#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel]]; q3wk
 
|style="background-color:#d73027"|Inferior DFS
 
|style="background-color:#d73027"|Inferior DFS
Line 165: Line 139:
 
|2000-2012
 
|2000-2012
 
|style="background-color:#1a9851" |Phase 3 (C)
 
|style="background-color:#1a9851" |Phase 3 (C)
−
|CM
+
|[[#Cyclophosphamide_.26_Methotrexate_.28CM.29_999|CM]]
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 
|-
 
|-
−
|[https://doi.org/10.1200/jco.2009.23.0946 Spielmann et al. 2009 (FNCLCC PACS 04)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3982874/ Aebi et al. 2014 (CALOR)]
−
|2001-2004
+
|2003-2010
 
|style="background-color:#1a9851" |Phase 3 (C)
 
|style="background-color:#1a9851" |Phase 3 (C)
−
|[[Breast_cancer,_HER2-positive#Trastuzumab_monotherapy_2|Trastuzumab]] x 12 mo
+
|[[Regimen_classes#Chemotherapy-based_regimen|Chemotherapy]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
+
| style="background-color:#fc8d59" |Seems to have inferior DFS
−
|-
 
−
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6968797/ Lluch et al. 2019 (GEICAM/2003-11; CIBOMA/2004-01)]
 
−
|2006-2011
 
−
|style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[Breast_cancer,_triple_negative#Capecitabine_monotherapy|Capecitabine]]
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 
−
|-
 
−
|[https://doi.org/10.1093/annonc/mdw055 Zdenkowski et al. 2016 (ANZ0501 LATER)]
 
−
|2007-2012
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[Breast_cancer,_ER-positive#Letrozole_monotherapy_2|Letrozole]] x 5 y
 
−
| style="background-color:#fee08b" |Might have inferior DFS
 
−
|-
 
−
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671866/ Nasr et al. 2015]
 
−
|2008-2014
 
−
|style="background-color:#1a9851" |Phase 3 (C)
 
−
|CM
 
−
| style="background-color:#fc8d59" |Seems to have inferior OS
 
−
|-
 
−
|[https://jamanetwork.com/journals/jamaoncology/fullarticle/2682589 Joensuu et al. 2018 (SOLD)]
 
−
|2008-2014
 
−
|style="background-color:#1a9851"|Phase III (E-de-esc)
 
−
|[[Breast_cancer,_HER2-positive#Trastuzumab_monotherapy_2|Trastuzumab]] x 12 mo
 
−
|style="background-color:#ffffbf"|Inconclusive whether non-inferior DFS
 
 
|-
 
|-
 
|}
 
|}
 
''<sup>1</sup>Reported efficacy for DBCG 77B is based on the 2010 update.''<br>
 
''<sup>1</sup>Reported efficacy for DBCG 77B is based on the 2010 update.''<br>
−
''<sup>2</sup>Reported efficacy for the Scottish Tamoxifen Trial is based on the 2001 update.''<br>
+
''<sup>2</sup>Reported efficacy for NSABP B-13 is based on the 1996 update.''<br>
−
''<sup>3</sup>Reported efficacy for NSABP B-13 is based on the 1996 update.''<br>
+
''Note: No further systemic treatment; many of these trials incorporated RT, however (see individual papers for details). Jakesz et al. 1998 was conducted prior to routine testing of HER2, so it technically included "double-negative" patients. ECOG E1180 is also known as INT-0011.''
−
''Note: No further systemic treatment; many of these trials incorporated RT, however (see individual papers for details). Jakesz et al. 1998 was conducted prior to routine testing of HER2, so it technically included "double-negative" patients.''
+
<div class="toccolours" style="background-color:#cbd5e8">
−
====Biomarker eligibility criteria====
 
−
*FNCLCC PACS 04 & SOLD: HER2 overexpression
 
 
====Preceding treatment====
 
====Preceding treatment====
 
*Bonadonna et al. 1976: [[Surgery#Mastectomy|Mastectomy]]
 
*Bonadonna et al. 1976: [[Surgery#Mastectomy|Mastectomy]]
 
*ECOG E1180: [[Surgery#Modified_radical_mastectomy|Modified radical mastectomy]] or [[Surgery#Mastectomy|total mastectomy]] with [[Surgery#Axillary_lymph_node_dissection|low axillary-node dissection]]
 
*ECOG E1180: [[Surgery#Modified_radical_mastectomy|Modified radical mastectomy]] or [[Surgery#Mastectomy|total mastectomy]] with [[Surgery#Axillary_lymph_node_dissection|low axillary-node dissection]]
−
*INT 0148/CALGB 9344: [[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4 versus high-dose AC x 4 versus very-high-dose AC x 4
+
*NSABP B-28: [[Surgery#Breast_cancer_surgery|Surgery]], then adjuvant [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4
−
*NSABP B-28: [[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4
 
−
*INT-0102: [[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#FAC_2|CAF]] x 6 versus [[Breast_cancer#CMF|CMF]] x 6
 
−
*IBCSG 13-93: [[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4 or [[Breast_cancer#Cyclophosphamide_.26_Epirubicin_.28EC.29_2|EC]] x 4, then [[Breast_cancer#CMF|CMF]] x 3
 
−
*FNCLCC PACS 04: [[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#FEC_2|FEC]] x 6 versus [[Breast_cancer#Docetaxel_.26_Epirubicin_.28DE.29|ED]] x 6
 
−
*ANZ0501 LATER: At least 4 years of any endocrine therapy
 
 
*Jakesz et al. 1998: [[Surgery#Breast_cancer_surgery|Surgery]]
 
*Jakesz et al. 1998: [[Surgery#Breast_cancer_surgery|Surgery]]
−
*IBCSG 22-00: [[Surgery#Breast_cancer_surgery|Surgery]], then adjuvant chemotherapy
+
*IBCSG 22-00: [[Surgery#Breast_cancer_surgery|Surgery]], then adjuvant [[Regimen_classes#Chemotherapy-based_regimen|chemotherapy]]
−
*SOLD: [[Surgery#Breast_cancer_surgery|Surgery]], then [[#TH_.28Taxotere.29_2|TH (Taxotere)]] x 3, then [[Breast_cancer#FEC_2|FEC]] x 3
+
</div></div>
−
 
 
 
===References===
 
===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. [https://www.nejm.org/doi/full/10.1056/NEJM197602192940801 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1246307 PubMed]
+
# 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. [https://doi.org/10.1056/NEJM197602192940801 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1246307/ PubMed]
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## '''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. [https://onlinelibrary.wiley.com/doi/10.1002/1097-0142(197706)39:6%3C2904::AID-CNCR2820390677%3E3.0.CO;2-8/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/326384 PubMed]
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## '''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. [https://doi.org/10.1002/1097-0142(197706)39:6%3C2904::AID-CNCR2820390677%3E3.0.CO;2-8 link to original article] [https://pubmed.ncbi.nlm.nih.gov/326384/ PubMed]
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## '''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. [https://pubmed.ncbi.nlm.nih.gov/3839424 PubMed]
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## '''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. [https://doi.org/10.1007/bf01805984 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3839424/ PubMed]
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## '''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. [https://www.nejm.org/doi/ref/10.1056/NEJM199504063321401 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7877646 PubMed]
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## '''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. [https://doi.org/10.1056/NEJM199504063321401 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7877646/ PubMed]
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# Lacour J, Lacour F, Spira A, Michelson M, Petit JY, Delage G, Sarrazin D, Contesso G, Viguier J. Adjuvant treatment with polyadenylic-polyuridylic acid (Polya-Polyu) in operable breast cancer. Lancet. 1980 Jul 26;2(8187):161-4. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(80)90057-4/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/6105336 PubMed]
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# Lacour J, Lacour F, Spira A, Michelson M, Petit JY, Delage G, Sarrazin D, Contesso G, Viguier J. Adjuvant treatment with polyadenylic-polyuridylic acid (Polya-Polyu) in operable breast cancer. Lancet. 1980 Jul 26;2(8187):161-4. [https://doi.org/10.1016/S0140-6736(80)90057-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6105336/ PubMed]
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# '''NATO:''' Baum M, Brinkley DM, Dosset JA, McPherson K, Patterson JS, Rubens RD, Smiddy FG, Stoll BA, Wilson A, Lea JC, Richards D, Ellis SH. Controlled trial of tamoxifen as adjuvant agent in management of early breast cancer: interim analysis at four years by Nolvadex Adjuvant Trial Organisation. Lancet. 1983 Feb 5;1(8319):257-61. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(83)91683-5/abstract link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/6130291 PubMed]
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# Rubens RD, Hayward JL, Knight RK, Bulbrook RD, Fentiman IS, Chaudary M, Howell A, Bush H, Crowther D, Sellwood RA, George WD, Howat JM. Controlled trial of adjuvant chemotherapy with melphalan for breast cancer. Lancet. 1983 Apr 16;1(8329):839-43. [https://doi.org/10.1016/S0140-6736(83)91385-5 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6132179/ PubMed]
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## '''Update:''' Baum M, Brinkley DM, Dosset JA, McPherson K, Patterson JS, Rubens RD, Smiddy FG, Stoll BA, Wilson A, Richards D, Ellis SH. Controlled trial of tamoxifen as single adjuvant agent in management of early breast cancer: analysis at six years by Nolvadex Adjuvant Trial Organisation. Lancet. 1985 Apr 13;1(8433):836-40. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(85)92206-8/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/2858709 PubMed]
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# '''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. [https://doi.org/10.1007/BF01806239 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6347278/ PubMed]
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# Rubens RD, Hayward JL, Knight RK, Bulbrook RD, Fentiman IS, Chaudary M, Howell A, Bush H, Crowther D, Sellwood RA, George WD, Howat JM. Controlled trial of adjuvant chemotherapy with melphalan for breast cancer. Lancet. 1983 Apr 16;1(8329):839-43. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(83)91385-5/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/6132179 PubMed]
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## '''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. [https://doi.org/10.1002/cncr.24969 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20186830/ PubMed]
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# '''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. [https://link.springer.com/article/10.1007/BF01806239 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/6347278 PubMed]
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# '''LBCS III/IV:''' Goldhirsch A; Ludwig Breast Cancer Study Group. Randomised trial of chemo-endocrine therapy, endocrine therapy, and mastectomy alone in postmenopausal patients with operable breast cancer and axillary node metastasis. Lancet. 1984 Jun 9;1(8389):1256-60. [https://doi.org/10.1016/S0140-6736(84)92445-0 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6144974/ PubMed]
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## '''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. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.24969/full link to original article] [https://pubmed.ncbi.nlm.nih.gov/20186830 PubMed]
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# Howell A, Bush H, George WD, Howat JM, Crowther D, Sellwood RA, Rubens RD, Hayward JL, Bulbrook RD, Fentiman IS, Chaudary M. Controlled trial of adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil for breast cancer. Lancet. 1984 Aug 11;2(8398):307-11. [https://doi.org/10.1016/S0140-6736(84)92684-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/6146861/ PubMed]
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# '''LBCS III/IV:''' Goldhirsch A; Ludwig Breast Cancer Study Group. Randomised trial of chemo-endocrine therapy, endocrine therapy, and mastectomy alone in postmenopausal patients with operable breast cancer and axillary node metastasis. Lancet. 1984 Jun 9;1(8389):1256-60. [https://www.thelancet.com/journals/lancet/article/PIIS0140673684924450/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/6144974 PubMed]
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# '''NSABP B-13:''' Fisher B, Redmond C, Dimitrov NV, Bowman D, Legault-Poisson S, Wickerham DL, Wolmark N, Fisher ER, Margolese R, Sutherland C, Glass A, Foster R, Caplan R. A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors. N Engl J Med. 1989 Feb 23;320(8):473-8. [https://doi.org/10.1056/NEJM198902233200801 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2644531/ PubMed]
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# Howell A, Bush H, George WD, Howat JM, Crowther D, Sellwood RA, Rubens RD, Hayward JL, Bulbrook RD, Fentiman IS, Chaudary M. Controlled trial of adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil for breast cancer. Lancet. 1984 Aug 11;2(8398):307-11. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(84)92684-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/6146861 PubMed]
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## '''Update:''' Fisher B, Dignam J, Mamounas EP, Costantino JP, Wickerham DL, Redmond C, Wolmark N, Dimitrov NV, Bowman DM, Glass AG, Atkins JN, Abramson N, Sutherland CM, Aron BS, Margolese RG. Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol. 1996 Jul;14(7):1982-92. [https://doi.org/10.1200/JCO.1996.14.7.1982 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8683228/ PubMed]
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# '''Scottish Tamoxifen Trial:''' Stewart HJ, Taylor W, Forrest P. Adjuvant tamoxifen in the management of operable breast cancer: the Scottish Trial: report from the Breast Cancer Trials Committee, Scottish Cancer Trials Office (MRC), Edinburgh. Lancet. 1987 Jul 25;2(8552):171-5. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(87)90762-8/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/2885637 PubMed]
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## '''Update:''' Fisher B, Jeong JH, Anderson S, Wolmark N. Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst. 2004 Dec 15;96(24):1823-31. [https://doi.org/10.1093/jnci/djh338 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15601638/ PubMed]
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## '''Update:''' Stewart HJ, Forrest AP, Everington D, McDonald CC, Dewar JA, Hawkins RA, Prescott RJ, George WD; Scottish Cancer Trials Breast Group. Randomised comparison of 5 years of adjuvant tamoxifen with continuous therapy for operable breast cancer. Br J Cancer. 1996 Jul;74(2):297-9. [https://www.nature.com/articles/bjc1996356 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2074573/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/8688340 PubMed]
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## '''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. [https://doi.org/10.1200/JCO.2006.06.9054 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16921044/ PubMed]
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## '''Update:''' Stewart HJ, Prescott RJ, Forrest AP. Scottish adjuvant tamoxifen trial: a randomized study updated to 15 years. J Natl Cancer Inst. 2001 Mar 21;93(6):456-62. [https://academic.oup.com/jnci/article/93/6/456/2906503 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11259471 PubMed]
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# '''ECOG E1180:''' Mansour EG, Gray R, Shatila AH, Osborne CK, Tormey DC, Gilchrist KW, Cooper MR, Falkson G. Efficacy of adjuvant chemotherapy in high-risk node-negative breast cancer: an intergroup study. N Engl J Med. 1989 Feb 23;320(8):485-90. [https://doi.org/10.1056/NEJM198902233200803 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2915651/ PubMed]
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# '''NSABP B-13:''' Fisher B, Redmond C, Dimitrov NV, Bowman D, Legault-Poisson S, Wickerham DL, Wolmark N, Fisher ER, Margolese R, Sutherland C, Glass A, Foster R, Caplan R. A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors. N Engl J Med. 1989 Feb 23;320(8):473-8. [https://www.nejm.org/doi/full/10.1056/NEJM198902233200801 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2644531 PubMed]
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# '''LCBS V:''' Goldhirsch A, Gelber RD; Ludwig Breast Cancer Study Group. Prolonged disease-free survival after one course of perioperative adjuvant chemotherapy for node-negative breast cancer. N Engl J Med. 1989 Feb 23;320(8):491-6. [https://doi.org/10.1056/NEJM198902233200804 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2644533/ PubMed]
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## '''Update:''' Fisher B, Dignam J, Mamounas EP, Costantino JP, Wickerham DL, Redmond C, Wolmark N, Dimitrov NV, Bowman DM, Glass AG, Atkins JN, Abramson N, Sutherland CM, Aron BS, Margolese RG. Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol. 1996 Jul;14(7):1982-92. [https://doi.org/10.1200/JCO.1996.14.7.1982 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8683228 PubMed]
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# '''EORTC 09771:''' Clahsen PC, van de Velde CJ, Welvaart K, Repelaer van Driel OJ, Sylvester RJ; Cooperating Investigators. Ten-year results of a randomized trial evaluating prolonged low-dose adjuvant chemotherapy in node-positive breast cancer: a joint European Organisation for Research and Treatment of Cancer-Dutch Breast Cancer Working Party Study. J Clin Oncol. 1995 Jan;13(1):33-41. [https://doi.org/10.1200/JCO.1995.13.1.33 link to original article] [https://pubmed.ncbi.nlm.nih.gov/7799039/ PubMed]
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## '''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. [https://doi.org/10.1200/JCO.2006.06.9054 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16921044 PubMed]
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# Jakesz R, Samonigg H, Gnant M, Kubista E, Steindorfer P, Hausmaninger H, Sevelda P, Tschurtschenthaler B, Fridrik M, Stierer M, Kolb R, Steger G; Austrian Breast Cancer Study Group. Very low-dose adjuvant chemotherapy in steroid receptor negative stage I breast cancer patients. Eur J Cancer. 1998 Jan; 34 (1): 66-70. [https://doi.org/10.1016/s0959-8049(97)10010-7 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9624239/ PubMed]
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# '''INT-0011:''' Mansour EG, Gray R, Shatila AH, Osborne CK, Tormey DC, Gilchrist KW, Cooper MR, Falkson G. Efficacy of adjuvant chemotherapy in high-risk node-negative breast cancer: an intergroup study. N Engl J Med. 1989 Feb 23;320(8):485-90. [https://www.nejm.org/doi/full/10.1056/NEJM198902233200803 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2915651 PubMed]
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# 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. [https://doi.org/10.1093/jnci/92.3.225 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10655439/ PubMed]
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# '''LCBS V:''' Goldhirsch A, Gelber RD; Ludwig Breast Cancer Study Group. Prolonged disease-free survival after one course of perioperative adjuvant chemotherapy for node-negative breast cancer. N Engl J Med. 1989 Feb 23;320(8):491-6. [https://www.nejm.org/doi/full/10.1056/NEJM198902233200804 link to original article] [https://pubmed.ncbi.nlm.nih.gov/2644533 PubMed]
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# 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. [https://doi.org/10.1200/JCO.2000.18.17.3125 link to original article] [https://pubmed.ncbi.nlm.nih.gov/10963641/ PubMed]
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# '''EORTC 09771:''' Clahsen PC, van de Velde CJ, Welvaart K, Repelaer van Driel OJ, Sylvester RJ; Cooperating Investigators. Ten-year results of a randomized trial evaluating prolonged low-dose adjuvant chemotherapy in node-positive breast cancer: a joint European Organisation for Research and Treatment of Cancer-Dutch Breast Cancer Working Party Study. J Clin Oncol. 1995 Jan;13(1):33-41. [https://doi.org/10.1200/JCO.1995.13.1.33 link to original article] '''contains protocol''' [https://pubmed.ncbi.nlm.nih.gov/7799039 PubMed]
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## '''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. [https://doi.org/10.1007/s10549-007-9593-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17530429/ PubMed]
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# Jakesz R, Samonigg H, Gnant M, Kubista E, Steindorfer P, Hausmaninger H, Sevelda P, Tschurtschenthaler B, Fridrik M, Stierer M, Kolb R, Steger G; Austrian Breast Cancer Study Group. Very low-dose adjuvant chemotherapy in steroid receptor negative stage I breast cancer patients. Eur J Cancer. 1998 Jan; 34 (1): 66-70. [https://www.ejcancer.com/article/S0959-8049(97)10010-7/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/9624239 PubMed]
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# 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. [https://doi.org/10.1200/JCO.2001.19.19.3929 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11579113/ PubMed]
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# 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. [https://doi.org/10.1200/JCO.2001.19.19.3929 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/11579113 PubMed]
 
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# '''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. [https://doi.org/10.1200/jco.2003.02.063 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/12637460 PubMed]
 
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# '''SBII:2pre:''' Rydén L, Jönsson PE, Chebil G, Dufmats M, Fernö M, Jirström K, Källström AC, Landberg G, Stål O, Thorstenson S, Nordenskjöld B; South Swedish Breast Cancer Group; South-East Swedish Breast Cancer Group. Two years of adjuvant tamoxifen in premenopausal patients with breast cancer: a randomised, controlled trial with long-term follow-up. Eur J Cancer. 2005 Jan;41(2):256-64. [https://www.ejcancer.com/article/S0959-8049(04)00565-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/15661551 PubMed]
 
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## '''Update:''' Ekholm M, Bendahl PO, Fernö M, Nordenskjöld B, Stål O, Rydén L. Two years of adjuvant tamoxifen provides a survival benefit compared with no systemic treatment in premenopausal patients with primary breast cancer: Long-term follow-up (> 25 years) of the phase III SBII:2pre trial. J Clin Oncol. 2016 Jul 1;34(19):2232-8. Epub 2016 May 9. [https://doi.org/10.1200/jco.2015.65.6272 link to original article] [https://pubmed.ncbi.nlm.nih.gov/27161974 PubMed]
 
 
<!-- Presented in abstract form at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003; interim results were presented at the 2000 NIH Consensus Development Conference, Bethesda, MD, November 1-3, 2000. -->
 
<!-- Presented in abstract form at the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003; interim results were presented at the 2000 NIH Consensus Development Conference, Bethesda, MD, November 1-3, 2000. -->
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# '''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. [https://doi.org/10.1200/jco.2005.10.517 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15897552 PubMed]
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# '''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. [https://doi.org/10.1200/jco.2005.10.517 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15897552/ PubMed]
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# '''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. [https://doi.org/10.1200/jco.2005.08.071 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16293862 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. [https://doi.org/10.1080/02841860510029987 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16118079/ PubMed]
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# '''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. [https://doi.org/10.1200/JCO.2005.03.0783 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/16505417 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. [https://www.jle.com/fr/revues/bdc/e-docs/epirubicin_based_chemotherapy_as_adjuvant_treatment_for_poor_prognosis_node_negative_breast_cancer_10_year_follow_up_results__272048/article.phtml link to original article] [https://pubmed.ncbi.nlm.nih.gov/17074656/ 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. [https://doi.org/10.1200/jco.2009.23.0946 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19917839 PubMed] NCT00054587
+
# '''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. [https://doi.org/10.1093/jnci/djk108 link to original article] [https://pubmed.ncbi.nlm.nih.gov/17405995/ PubMed] [https://clinicaltrials.gov/study/NCT00002582 NCT00002582]
−
# Nasr KE, Osman MA, Elkady MS, Ellithy MA. Metronomic methotrexate and cyclophosphamide after carboplatin included adjuvant chemotherapy in triple negative breast cancer: a phase III study. Ann Transl Med. 2015 Nov;3(19):284. [http://atm.amegroups.com/article/view/8241/8988 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4671866/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/26697444 PubMed]
+
#'''CALOR:''' Aebi S, Gelber S, Anderson SJ, Láng I, Robidoux A, Martín M, Nortier JW, Paterson AH, Rimawi MF, Cañada JM, Thürlimann B, Murray E, Mamounas EP, Geyer CE Jr, Price KN, Coates AS, Gelber RD, Rastogi P, Wolmark N, Wapnir IL; CALOR investigators. Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial. Lancet Oncol. 2014 Feb;15(2):156-63. Epub 2014 Jan 16. [https://doi.org/10.1016/s1470-2045(13)70589-8 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc3982874/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/24439313/ PubMed] [https://clinicaltrials.gov/study/NCT00074152 NCT00074152]
−
# '''ANZ0501 LATER:''' Zdenkowski N, Forbes JF, Boyle FM, Kannourakis G, Gill PG, Bayliss E, Saunders C, Della-Fiorentina S, Kling N, Campbell I, Mann GB, Coates AS, Gebski V, Davies L, Thornton R, Reaby L, Cuzick J, Green M; Australia and New Zealand Breast Cancer Trials Group. Observation versus late reintroduction of letrozole as adjuvant endocrine therapy for hormone receptor-positive breast cancer (ANZ0501 LATER): an open-label randomised, controlled trial. Ann Oncol. 2016 May;27(5):806-12. Epub 2016 Feb 9. [https://doi.org/10.1093/annonc/mdw055 link to original article] [https://pubmed.ncbi.nlm.nih.gov/26861603 PubMed]
+
##'''Update:''' Wapnir IL, Price KN, Anderson SJ, Robidoux A, Martín M, Nortier JWR, Paterson AHG, Rimawi MF, Láng I, Baena-Cañada JM, Thürlimann B, Mamounas EP, Geyer CE Jr, Gelber S, Coates AS, Gelber RD, Rastogi P, Regan MM, Wolmark N, Aebi S; International Breast Cancer Study Group; NRG Oncology; GEICAM Spanish Breast Cancer Group; BOOG Dutch Breast Cancer Trialists' Group; Breast International Group. Efficacy of Chemotherapy for ER-Negative and ER-Positive Isolated Locoregional Recurrence of Breast Cancer: Final Analysis of the CALOR Trial. J Clin Oncol. 2018 Apr 10;36(11):1073-1079. Epub 2018 Feb 14. [https://doi.org/10.1200/jco.2017.76.5719 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5891132/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/29443653/ PubMed]
−
# '''IBCSG 22-00:''' Colleoni M, Gray KP, Gelber S, Láng I, Thürlimann B, Gianni L, Abdi EA, Gomez HL, Linderholm BK, Puglisi F, Tondini C, Kralidis E, Eniu A, Cagossi K, Rauch D, Chirgwin J, Gelber RD, Regan MM, Coates AS, Price KN, Viale G, Goldhirsch A. Low-dose oral cyclophosphamide and methotrexate maintenance for hormone receptor-negative early breast cancer: International Breast Cancer Study Group trial 22-00. J Clin Oncol. 2016 Oct 1;34(28):3400-8. Epub 2016 Jun 20. [https://doi.org/10.1200/JCO.2015.65.6595 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035120/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27325862 PubMed] NCT00022516
+
# '''IBCSG 22-00:''' Colleoni M, Gray KP, Gelber S, Láng I, Thürlimann B, Gianni L, Abdi EA, Gomez HL, Linderholm BK, Puglisi F, Tondini C, Kralidis E, Eniu A, Cagossi K, Rauch D, Chirgwin J, Gelber RD, Regan MM, Coates AS, Price KN, Viale G, Goldhirsch A. Low-dose oral cyclophosphamide and methotrexate maintenance for hormone receptor-negative early breast cancer: International Breast Cancer Study Group trial 22-00. J Clin Oncol. 2016 Oct 1;34(28):3400-8. Epub 2016 Jun 20. [https://doi.org/10.1200/JCO.2015.65.6595 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035120/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/27325862/ PubMed] [https://clinicaltrials.gov/study/NCT00022516 NCT00022516]
−
# '''CBC 02:''' Jensen MB, Krarup JF, Palshof T, Mouridsen HT, Ejlertsen B. Two years of tamoxifen or no adjuvant systemic therapy for patients with high-risk breast cancer: long-term follow-up of the Copenhagen Breast Cancer Trial. Acta Oncol. 2018 Jan;57(1):26-30. Epub 2017 Nov 22. [http://www.tandfonline.com/doi/full/10.1080/0284186X.2017.1400179 link to original article] [https://pubmed.ncbi.nlm.nih.gov/29165021 PubMed]
+
#'''SWOG S1418:''' [https://clinicaltrials.gov/study/NCT02954874 NCT02954874]
−
# '''GEICAM/2003-11; CIBOMA/2004-01:''' Lluch A, Barrios CH, Torrecillas L, Ruiz-Borrego M, Bines J, Segalla J, Guerrero-Zotano Á, García-Sáenz JA, Torres R, de la Haba J, García-Martínez E, Gómez HL, Llombart A, Bofill JS, Baena-Cañada JM, Barnadas A, Calvo L, Pérez-Michel L, Ramos M, Fernández I, Rodríguez-Lescure Á, Cárdenas J, Vinholes J, Martínez de Dueñas E, Godes MJ, Seguí MA, Antón A, López-Álvarez P, Moncayo J, Amorim G, Villar E, Reyes S, Sampaio C, Cardemil B, Escudero MJ, Bezares S, Carrasco E, Martín M; GEICAM Spanish Breast Cancer Group; CIBOMA (Iberoamerican Coalition for Research in Breast Oncology); LACOG (Latin American Cooperative Oncology Group). Phase III Trial of Adjuvant Capecitabine After Standard Neo-/Adjuvant Chemotherapy in Patients With Early Triple-Negative Breast Cancer (GEICAM/2003-11_CIBOMA/2004-01). J Clin Oncol. 2020 Jan 20;38(3):203-213. Epub 2019 Dec 5. Erratum in: J Clin Oncol. 2020 Mar 10;38(8):847. [https://doi.org/10.1200/jco.19.00904 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc6968797/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/31804894/ PubMed]
 
−
#'''SWOG S1418:''' NCT02954874
 
  
 
==Placebo==
 
==Placebo==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Regimen===
 
===Regimen===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
−
!style="width: 20%"|Years of enrollment
+
!style="width: 20%"|Dates of enrollment
 
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 20%"|Comparator
 
!style="width: 20%"|Comparator
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
!style="width: 20%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 
|-
 
|-
−
|[https://www.nejm.org/doi/full/10.1056/NEJM197501162920301 Fisher et al. 1975 (NSABP B-05)]
+
|[https://doi.org/10.1056/NEJM197501162920301 Fisher et al. 1975 (NSABP B-05)]
−
|1972-1975
+
|1972-1974
−
|style="background-color:#1a9851"|Phase III (C)
+
|style="background-color:#1a9851"|Phase 3 (C)
 
|[[Breast_cancer_-_historical#Melphalan_monotherapy|Melphalan]]
 
|[[Breast_cancer_-_historical#Melphalan_monotherapy|Melphalan]]
 
|style="background-color:#fee08b" |Might have inferior DFS<sup>1</sup>
 
|style="background-color:#fee08b" |Might have inferior DFS<sup>1</sup>
 
|-
 
|-
−
|[https://www.nejm.org/doi/full/10.1056/NEJM198902233200802 Fisher et al. 1989 (NSABP B-14)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4970583/ Paterson et al. 2012 (NSABP B-34)]
−
|1982-1987
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]]
 
−
| style="background-color:#d73027" |Inferior OS<sup>2</sup>
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2001.19.4.931 Fisher et al. 2001 (NSABP B-23)]
 
−
|1991-1998
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]]
 
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 
−
|-
 
−
|[https://www.nejm.org/doi/full/10.1056/NEJMoa032312 Goss et al. 2003 (NCIC-CTG MA.17)]
 
−
|1998-2002
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[Breast_cancer,_ER-positive#Letrozole_monotherapy_2|Letrozole]]
 
−
| style="background-color:#d73027" |Inferior DFS
 
−
|-
 
−
|[https://doi.org/10.1200/jco.2007.14.0228 Mamounas et al. 2008 (NSABP B-33)]
 
−
|2001-2003
 
−
| style="background-color:#1a9851" |Phase 3 (C)
 
−
|[[Breast_cancer,_ER-positive#Exemestane_monotherapy|Exemestane]]
 
−
| style="background-color:#d73027" |Inferior RFS
 
−
|-
 
−
|[http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4970583/ Paterson et al. 2012 (NSABP B-34)]
 
 
|2001-2004
 
|2001-2004
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|Clodronate
+
|[[#Clodronate_monotherapy_999|Clodronate]]
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
 
|-
 
|-
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70508-9/fulltext Goss et al. 2012 (TEACH)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283666/ Coombes et al. 2021 (REACT)]
−
|2006-2008
+
|2007-2012
−
|style="background-color:#1a9851"|Phase III (C)
+
|style="background-color:#1a9851"|Phase 3 (C)
−
|Lapatinib
+
|[[#Celecoxib_monotherapy_999|Celecoxib]]
−
| style="background-color:#fee08b" |Might have inferior DFS
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
−
|-
 
−
|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00551-3/fulltext Chan et al. 2016 (ExteNET)]
 
−
|2009-2011
 
−
|style="background-color:#1a9851"|Phase III (C)
 
−
|[[Breast_cancer,_HER2-positive#Neratinib_monotherapy|Neratinib]]
 
−
|style="background-color:#d73027"|Inferior invasive DFS
 
 
|-
 
|-
 
|[https://doi.org/10.1016/s1470-2045(19)30687-4 Coleman et al. 2019 (D-CARE)]
 
|[https://doi.org/10.1016/s1470-2045(19)30687-4 Coleman et al. 2019 (D-CARE)]
 
|2010-2012
 
|2010-2012
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|Denosumab
+
|[[#Denosumab_monotherapy_999|Denosumab]]
−
| style="background-color:#ffffbf" |Did not meet primary composite endpoint of bone MFS
+
| style="background-color:#ffffbf" |Did not meet composite primary endpoint of bone MFS
 
|-
 
|-
−
|[https://doi.org/10.1158/1078-0432.ccr-18-2867 Mittendorf et al. 2019 (PRESENT)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9131745/ Goodwin et al. 2022 (NCIC CTG MA.32)]
−
|2011-2015
+
|2010-2013
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|Nelipepimut-S
+
|[[#Metformin_monotherapy_999|Metformin]]
−
| style="background-color:#ffffbf" |Did not meet primary endpoint of DFS
+
| style="background-color:#ffffbf" |Did not meet primary endpoint of IDFS
 
|-
 
|-
−
|[https://doi.org/10.1056/nejmoa2105215 Tutt et al. 2021 (OlympiA)]
+
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9126186/ Tutt et al. 2021 (OlympiA)]
 
|2014-2019
 
|2014-2019
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
 
|[[Breast_cancer,_BRCA-mutated#Olaparib_monotherapy|Olaparib]]
 
|[[Breast_cancer,_BRCA-mutated#Olaparib_monotherapy|Olaparib]]
−
|style="background-color:#d73027"|Inferior invasive DFS
+
|style="background-color:#d73027"|Inferior OS<sup>2</sup>
 +
|-
 +
|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11059055/ Chen et al. 2024 (Alliance A011502)]
 +
|2017-01-06 to 2020-12-04
 +
| style="background-color:#1a9851" |Phase 3 (C)
 +
|[[#Aspirin_monotherapy_999|Aspirin]]
 +
| style="background-color:#d9ef8b" |Might have superior iDFS (primary endpoint)<br>(HR 0.79, 95% CI 0.61-1.01)
 
|-
 
|-
 
|}
 
|}
 
''<sup>1</sup>Reported efficacy for NSABP B-05 is based on the 1986 update.''<br>
 
''<sup>1</sup>Reported efficacy for NSABP B-05 is based on the 1986 update.''<br>
−
''<sup>2</sup>Reported efficacy for NSABP B-14 based on the 2004 update.''<br>
+
''<sup>2</sup>Reported efficacy for OlympiA is based on the 2022 update.''<br>
−
''No active antineoplastic treatment. Used as a comparator arm, historically.''
+
''No active antineoplastic treatment within the study design. Used as a comparator arm. Note that some trials do have other ongoing antineoplastic treatments outside of the study design, such as adjuvant radiation therapy.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
 
*NSABP B-05: [[Surgery#Mastectomy|Mastectomy]]
 
*NSABP B-05: [[Surgery#Mastectomy|Mastectomy]]
−
*NSABP B-14: [[Surgery#Breast_cancer_surgery|Surgery]]
+
</div></div>
−
*NSABP B-23: [[Breast_cancer#CMF|CMF]] x 6 versus [[Breast_cancer#Cyclophosphamide_.26_Doxorubicin_.28AC.29_2|AC]] x 4
 
−
*NCIC-CTG MA.17: [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 5y
 
−
*NSABP B-33: [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 5y
 
−
*TEACH: [[Surgery#Breast_cancer_surgery|Surgery]] and adjuvant chemotherapy but not trastuzumab
 
−
*ExteNET: [[Surgery#Breast_cancer_surgery|Surgery]] and trastuzumab-containing chemotherapy (neoadjuvant or adjuvant)
 
  
 
===References===
 
===References===
−
# '''NSABP B-05:''' Fisher B, Carbone P, Economou SG, Frelick R, Glass A, Lerner H, Redmond C, Zelen M, Band P, Katrych DL, Wolmark N, Fisher ER. 1-Phenylalanine mustard (L-PAM) in the management of primary breast cancer: a report of early findings. N Engl J Med. 1975 Jan 16;292(3):117-22. [https://www.nejm.org/doi/full/10.1056/NEJM197501162920301 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1105174 PubMed]
+
# '''NSABP B-05:''' Fisher B, Carbone P, Economou SG, Frelick R, Glass A, Lerner H, Redmond C, Zelen M, Band P, Katrych DL, Wolmark N, Fisher ER. 1-Phenylalanine mustard (L-PAM) in the management of primary breast cancer: a report of early findings. N Engl J Med. 1975 Jan 16;292(3):117-22. [https://doi.org/10.1056/NEJM197501162920301 link to original article] [https://pubmed.ncbi.nlm.nih.gov/1105174/ PubMed]
−
## '''Update:''' Fisher B, Glass A, Redmond C, Fisher ER, Barton B, Such E, Carbone P, Economou S, Foster R, Frelick R, Lerner H, Levitt M, Margolese R, MacFarlane J, Plotkin D, Shibata H, Volk H. L-phenylalanine mustard (L-PAM) in the management of primary breast cancer: an update of earlier findings and a comparison with those utilizing L-PAM plus 5-fluorouracil (5-FU). Cancer. 1977 Jun;39(6 Suppl):2883-903. [https://onlinelibrary.wiley.com/doi/10.1002/1097-0142(197706)39:6%3C2883::AID-CNCR2820390676%3E3.0.CO;2-9/abstract link to original article] [https://pubmed.ncbi.nlm.nih.gov/194679 PubMed]
+
## '''Update:''' Fisher B, Glass A, Redmond C, Fisher ER, Barton B, Such E, Carbone P, Economou S, Foster R, Frelick R, Lerner H, Levitt M, Margolese R, MacFarlane J, Plotkin D, Shibata H, Volk H. L-phenylalanine mustard (L-PAM) in the management of primary breast cancer: an update of earlier findings and a comparison with those utilizing L-PAM plus 5-fluorouracil (5-FU). Cancer. 1977 Jun;39(6 Suppl):2883-903. [https://doi.org/10.1002/1097-0142(197706)39:6%3C2883::AID-CNCR2820390676%3E3.0.CO;2-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/194679/ PubMed]
−
## '''Update:''' Fisher B, Fisher ER, Redmond C. Ten-year results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial evaluating the use of L-phenylalanine mustard (L-PAM) in the management of primary breast cancer. J Clin Oncol. 1986 Jun;4(6):929-41. [https://doi.org/10.1200/JCO.1986.4.6.929 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3519883 PubMed]
+
## '''Update:''' Fisher B, Fisher ER, Redmond C. Ten-year results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial evaluating the use of L-phenylalanine mustard (L-PAM) in the management of primary breast cancer. J Clin Oncol. 1986 Jun;4(6):929-41. [https://doi.org/10.1200/JCO.1986.4.6.929 link to original article] [https://pubmed.ncbi.nlm.nih.gov/3519883/ PubMed]
−
# '''NSABP B-14:''' Fisher B, Costantino J, Redmond C, Poisson R, Bowman D, Couture J, Dimitrov NV, Wolmark N, Wickerham DL, Fisher ER, Margolese R, Robidoux A, Shibata H, Terz J, Peterson AHG, Feldman MI, Farrar W, Evans J, Lickley HL, Ketner M. A randomized clinical trial evaluating tamoxifen in the treatment of patients with node-negative breast cancer who have estrogen-receptor-positive tumors. N Engl J Med. 1989 Feb 23;320(8):479-84. [https://www.nejm.org/doi/full/10.1056/NEJM198902233200802 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/2644532 PubMed]
+
# '''NSABP B-34:''' Paterson AH, Anderson SJ, Lembersky BC, Fehrenbacher L, Falkson CI, King KM, Weir LM, Brufsky AM, Dakhil S, Lad T, Baez-Diaz L, Gralow JR, Robidoux A, Perez EA, Zheng P, Geyer CE Jr, Swain SM, Costantino JP, Mamounas EP, Wolmark N. Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial. Lancet Oncol. 2012 Jul;13(7):734-42. Epub 2012 Jun 14. [https://doi.org/10.1016/s1470-2045(12)70226-7 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/pmc4970583/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22704583/ PubMed] [https://clinicaltrials.gov/study/NCT00009945 NCT00009945]
−
## '''Update:''' Fisher B, Dignam J, Bryant J, DeCillis A, Wickerham DL, Wolmark N, Costantino J, Redmond C, Fisher ER, Bowman DM, Deschênes L, Dimitrov NV, Margolese RG, Robidoux A, Shibata H, Terz J, Paterson AH, Feldman MI, Farrar W, Evans J, Lickley HL. Five versus more than five years of tamoxifen therapy for breast cancer patients with negative lymph nodes and estrogen receptor-positive tumors. J Natl Cancer Inst. 1996 Nov 6;88(21):1529-42. [https://academic.oup.com/jnci/article/88/21/1529/922662 link to original article] [https://pubmed.ncbi.nlm.nih.gov/8901851 PubMed]
+
# '''D-CARE:''' Coleman R, Finkelstein DM, Barrios C, Martin M, Iwata H, Hegg R, Glaspy J, Periañez AM, Tonkin K, Deleu I, Sohn J, Crown J, Delaloge S, Dai T, Zhou Y, Jandial D, Chan A. Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):60-72. Epub 2019 Dec 2. [https://doi.org/10.1016/s1470-2045(19)30687-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31806543/ PubMed] [https://clinicaltrials.gov/study/NCT01077154 NCT01077154]
−
## '''Update:''' Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001 May 2;93(9):684-90. [https://academic.oup.com/jnci/article/93/9/684/2906559 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11333290 PubMed]
+
# '''OlympiA:''' Tutt ANJ, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P, Gelber RD, de Azambuja E, Fielding A, Balmaña J, Domchek SM, Gelmon KA, Hollingsworth SJ, Korde LA, Linderholm B, Bandos H, Senkus E, Suga JM, Shao Z, Pippas AW, Nowecki Z, Huzarski T, Ganz PA, Lucas PC, Baker N, Loibl S, McConnell R, Piccart M, Schmutzler R, Steger GG, Costantino JP, Arahmani A, Wolmark N, McFadden E, Karantza V, Lakhani SR, Yothers G, Campbell C, Geyer CE Jr; OlympiA Clinical Trial Steering Committee and Investigators. Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer. N Engl J Med. 2021 Jun 24;384(25):2394-2405. Epub 2021 Jun 3. [https://doi.org/10.1056/nejmoa2105215 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9126186/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34081848/ PubMed] [https://clinicaltrials.gov/study/NCT02032823 NCT02032823]
−
## '''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. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(04)16981-X/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/15351193 PubMed]
+
##'''Update:''' Geyer CE Jr, Garber JE, Gelber RD, Yothers G, Taboada M, Ross L, Rastogi P, Cui K, Arahmani A, Aktan G, Armstrong AC, Arnedos M, Balmaña J, Bergh J, Bliss J, Delaloge S, Domchek SM, Eisen A, Elsafy F, Fein LE, Fielding A, Ford JM, Friedman S, Gelmon KA, Gianni L, Gnant M, Hollingsworth SJ, Im SA, Jager A, Jóhannsson ÓÞ, Lakhani SR, Janni W, Linderholm B, Liu TW, Loman N, Korde L, Loibl S, Lucas PC, Marmé F, Martinez de Dueñas E, McConnell R, Phillips KA, Piccart M, Rossi G, Schmutzler R, Senkus E, Shao Z, Sharma P, Singer CF, Španić T, Stickeler E, Toi M, Traina TA, Viale G, Zoppoli G, Park YH, Yerushalmi R, Yang H, Pang D, Jung KH, Mailliez A, Fan Z, Tennevet I, Zhang J, Nagy T, Sonke GS, Sun Q, Parton M, Colleoni MA, Schmidt M, Brufsky AM, Razaq W, Kaufman B, Cameron D, Campbell C, Tutt ANJ; OlympiA Clinical Trial Steering Committee and Investigators. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer. Ann Oncol. 2022 Dec 1;33(12):1250-1268. Epub 2022 Oct 10. [https://doi.org/10.1016/j.annonc.2022.09.159 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10207856/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/36228963/ 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. [https://doi.org/10.1200/JCO.2006.06.9054 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16921044 PubMed]
+
##'''PRO analysis:''' Ganz PA, Bandos H, Španić T, Friedman S, Müller V, Kuemmel S, Delaloge S, Brain E, Toi M, Yamauchi H, de Dueñas EM, Armstrong A, Im SA, Song CG, Zheng H, Sarosiek T, Sharma P, Geng C, Fu P, Rhiem K, Frauchiger-Heuer H, Wimberger P, t'Kint de Roodenbeke D, Liao N, Goodwin A, Chakiba-Brugère C, Friedlander M, Lee KS, Giacchetti S, Takano T, Henao-Carrasco F, Virani S, Valdes-Albini F, Domchek SM, Bane C, McCarron EC, Mita M, Rossi G, Rastogi P, Fielding A, Gelber RD, Scheepers ED, Cameron D, Garber J, Geyer CE, Tutt ANJ. Patient-Reported Outcomes in OlympiA: A Phase III, Randomized, Placebo-Controlled Trial of Adjuvant Olaparib in gBRCA1/2 Mutations and High-Risk Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer. J Clin Oncol. 2024 Apr 10;42(11):1288-1300. Epub 2024 Feb 1. [https://doi.org/10.1200/jco.23.01214 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11095886/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/38301187/ 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. [https://doi.org/10.1200/jco.2001.19.4.931 link to original article] [https://pubmed.ncbi.nlm.nih.gov/11181655 PubMed]
+
#'''REACT:''' Coombes RC, Tovey H, Kilburn L, Mansi J, Palmieri C, Bartlett J, Hicks J, Makris A, Evans A, Loibl S, Denkert C, Murray E, Grieve R, Coleman R, Borley A, Schmidt M, Rautenberg B, Kunze CA, Rhein U, Mehta K, Mousa K, Dibble T, Lu XL, von Minckwitz G, Bliss JM; Randomized European Celecoxib Trial (REACT) Trial Management Group and Investigators. Effect of Celecoxib vs Placebo as Adjuvant Therapy on Disease-Free Survival Among Patients With Breast Cancer: The REACT Randomized Clinical Trial. JAMA Oncol. 2021 Sep 1;7(9):1291-1301. [https://doi.org/10.1001/jamaoncol.2021.2193 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283666/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/34264305/ PubMed] [https://clinicaltrials.gov/study/NCT02429427 NCT02429427]
−
## '''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. [https://doi.org/10.1200/JCO.2006.06.9054 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16921044 PubMed]
+
#'''NCIC CTG MA.32:''' Goodwin PJ, Chen BE, Gelmon KA, Whelan TJ, Ennis M, Lemieux J, Ligibel JA, Hershman DL, Mayer IA, Hobday TJ, Bliss JM, Rastogi P, Rabaglio-Poretti M, Mukherjee SD, Mackey JR, Abramson VG, Oja C, Wesolowski R, Thompson AM, Rea DW, Stos PM, Shepherd LE, Stambolic V, Parulekar WR. Effect of Metformin vs Placebo on Invasive Disease-Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial. JAMA. 2022 May 24;327(20):1963-1973. [https://doi.org/10.1001/jama.2022.6147 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9131745/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/35608580/ PubMed] [https://clinicaltrials.gov/study/NCT01101438 NCT01101438]
−
# '''NCIC-CTG MA.17:''' Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003 Nov 6;349(19):1793-802. Epub 2003 Oct 9. [https://www.nejm.org/doi/full/10.1056/NEJMoa032312 link to original article] [https://pubmed.ncbi.nlm.nih.gov/14551341 PubMed]
+
#'''Alliance A011502:''' Chen WY, Ballman KV, Partridge AH, Hahn OM, Briccetti FM, Irvin WJ, Symington B, Visvanathan K, Pohlmann PR, Openshaw TH, Weiss A, Winer EP, Carey LA, Holmes MD. Aspirin vs Placebo as Adjuvant Therapy for Breast Cancer: The Alliance A011502 Randomized Trial. JAMA. 2024 May 28;331(20):1714-1721. Epub 2024 Apr 29. [https://doi.org/10.1001/jama.2024.4840 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11059055/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/38683596/ PubMed] [https://clinicaltrials.gov/study/NCT02927249 NCT02927249]
−
## '''Update:''' Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Pater JL. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC-CTG MA.17. J Natl Cancer Inst. 2005 Sep 7;97(17):1262-71. [http://jnci.oxfordjournals.org/content/97/17/1262.long link to original article] [https://pubmed.ncbi.nlm.nih.gov/16145047 PubMed]
 
−
## '''QoL analysis:''' Whelan TJ, Goss PE, Ingle JN, Pater JL, Tu D, Pritchard K, Liu S, Shepherd LE, Palmer M, Robert NJ, Martino S, Muss HB. Assessment of quality of life in MA.17: a randomized, placebo-controlled trial of letrozole after 5 years of tamoxifen in postmenopausal women. J Clin Oncol. 2005 Oct 1;23(28):6931-40. Epub 2005 Sep 12. [https://doi.org/10.1200/JCO.2005.11.181 link to original article] [https://pubmed.ncbi.nlm.nih.gov/16157934 PubMed]
 
−
## '''Update:''' Muss HB, Tu D, Ingle JN, Martino S, Robert NJ, Pater JL, Whelan TJ, Palmer MJ, Piccart MJ, Shepherd LE, Pritchard KI, He Z, Goss PE. Efficacy, toxicity, and quality of life in older women with early-stage breast cancer treated with letrozole or placebo after 5 years of tamoxifen: NCIC-CTG intergroup trial MA.17. J Clin Oncol. 2008 Apr 20;26(12):1956-64. Epub 2008 Mar 10. [https://doi.org/10.1200/jco.2007.12.6334 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18332474 PubMed]
 
−
## '''Subgroup analysis:''' Goss PE, Ingle JN, Pater JL, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Tu D. Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen. J Clin Oncol. 2008 Apr 20;26(12):1948-55. Epub 2008 Mar 10. [https://doi.org/10.1200/jco.2007.11.6798 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18332475 PubMed]
 
−
## '''Update:''' Jin H, Tu D, Zhao N, Shepherd LE, Goss PE. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC-CTG MA.17 trial: analyses adjusting for treatment crossover. J Clin Oncol. 2012 Mar 1;30(7):718-21. Epub 2011 Oct 31. [https://doi.org/10.1200/jco.2010.34.4010 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295549/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22042967 PubMed]
 
−
<!-- Presented in part in abstract format in the Breast Cancer Research Treatment 100:S22, 2006 (suppl; abstr A40). -->
 
−
# '''NSABP B-33:''' Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, Eisen A, Fehrenbacher L, Farrar WB, Atkins JN, Pajon ER, Vogel VG, Kroener JF, Hutchins LF, Robidoux A, Hoehn JL, Ingle JN, Geyer CE Jr, Costantino JP, Wolmark N. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin Oncol. 2008 Apr 20;26(12):1965-71. Epub 2008 Mar 10. [https://doi.org/10.1200/jco.2007.14.0228 link to original article] [https://pubmed.ncbi.nlm.nih.gov/18332472 PubMed]
 
−
# '''NSABP B-34:''' Paterson AH, Anderson SJ, Lembersky BC, Fehrenbacher L, Falkson CI, King KM, Weir LM, Brufsky AM, Dakhil S, Lad T, Baez-Diaz L, Gralow JR, Robidoux A, Perez EA, Zheng P, Geyer CE Jr, Swain SM, Costantino JP, Mamounas EP, Wolmark N. Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial. Lancet Oncol. 2012 Jul;13(7):734-42. Epub 2012 Jun 14. [https://doi.org/10.1016/s1470-2045(12)70226-7 link to original article] [http://www.ncbi.nlm.nih.gov/pmc/articles/pmc4970583/ link to PMC article] [https://pubmed.ncbi.nlm.nih.gov/22704583/ PubMed] NCT00009945
 
−
# '''TEACH:''' Goss PE, Smith IE, O'Shaughnessy J, Ejlertsen B, Kaufmann M, Boyle F, Buzdar AU, Fumoleau P, Gradishar W, Martin M, Moy B, Piccart-Gebhart M, Pritchard KI, Lindquist D, Chavarri-Guerra Y, Aktan G, Rappold E, Williams LS, Finkelstein DM; TEACH investigators. Adjuvant lapatinib for women with early-stage HER2-positive breast cancer: a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Jan;14(1):88-96. Epub 2012 Dec 10. Erratum in: Lancet Oncol. 2013 Feb;14(2):e47. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70508-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/23234763 PubMed] NCT00374322
 
−
# '''ExteNET:''' Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harvey VJ, Robert NJ, Silovski T, Gokmen E, von Minckwitz G, Ejlertsen B, Chia SK, Mansi J, Barrios CH, Gnant M, Buyse M, Gore I, Smith J 2nd, Harker G, Masuda N, Petrakova K, Zotano AG, Iannotti N, Rodriguez G, Tassone P, Wong A, Bryce R, Ye Y, Yao B, Martin M; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016 Mar;17(3):367-77. Epub 2016 Feb 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00551-3/fulltext link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/26874901 PubMed] NCT00878709
 
−
## '''Update:''' Martin M, Holmes FA, Ejlertsen B, Delaloge S, Moy B, Iwata H, von Minckwitz G, Chia SKL, Mansi J, Barrios CH, Gnant M, Tomašević Z, Denduluri N, Šeparović R, Gokmen E, Bashford A, Ruiz Borrego M, Kim SB, Jakobsen EH, Ciceniene A, Inoue K, Overkamp F, Heijns JB, Armstrong AC, Link JS, Joy AA, Bryce R, Wong A, Moran S, Yao B, Xu F, Auerbach A, Buyse M, Chan A; ExteNET Study Group. Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017 Dec;18(12):1688-1700. Epub 2017 Nov 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30717-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/29146401 PubMed]
 
−
## '''HRQoL analysis:''' Delaloge S, Cella D, Ye Y, Buyse M, Chan A, Barrios CH, Holmes FA, Mansi J, Iwata H, Ejlertsen B, Moy B, Chia SKL, Gnant M, Smichkoska S, Ciceniene A, Martinez N, Filipović S, Ben-Baruch NE, Joy AA, Langkjer ST, Senecal F, de Boer RH, Moran S, Yao B, Bryce R, Auerbach A, Fallowfield L, Martin M. Effects of neratinib on health-related quality of life in women with HER2-positive early-stage breast cancer: longitudinal analyses from the randomized phase III ExteNET trial. Ann Oncol. 2019 Apr 1;30(4):567-574. [https://doi.org/10.1093/annonc/mdz016 link to original article] [https://pubmed.ncbi.nlm.nih.gov/30689703 PubMed]
 
−
## '''Subgroup analysis:''' Iwata H, Masuda N, Kim SB, Inoue K, Rai Y, Fujita T, Chiu J, Ohtani S, Takahashi M, Miyaki T, Lu YS, Xu B, Yap YS, Bustam A, Yao B, Zhang B, Bryce R, Chan A. Neratinib after trastuzumab-based adjuvant therapy in patients from Asia with early stage HER2-positive breast cancer. Future Oncol. 2019 Jul;15(21):2489-2501. Epub 2019 May 29. [https://www.futuremedicine.com/doi/abs/10.2217/fon-2019-0143 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31140297 PubMed]
 
−
## '''Update:''' Chan A, Moy B, Mansi J, Ejlertsen B, Holmes FA, Chia S, Iwata H, Gnant M, Loibl S, Barrios CH, Somali I, Smichkoska S, Martinez N, Alonso MG, Link JS, Mayer IA, Cold S, Murillo SM, Senecal F, Inoue K, Ruiz-Borrego M, Hui R, Denduluri N, Patt D, Rugo HS, Johnston SRD, Bryce R, Zhang B, Xu F, Wong A, Martin M; ExteNET Study Group. Final Efficacy Results of Neratinib in HER2-positive Hormone Receptor-positive Early-stage Breast Cancer From the Phase III ExteNET Trial. Clin Breast Cancer. 2021 Feb;21(1):80-91.e7. Epub 2020 Oct 6. [https://doi.org/10.1016/j.clbc.2020.09.014 link to original article] [https://pubmed.ncbi.nlm.nih.gov/33183970/ PubMed]
 
−
#'''PRESENT:''' Mittendorf EA, Lu B, Melisko M, Price Hiller J, Bondarenko I, Brunt AM, Sergii G, Petrakova K, Peoples GE. Efficacy and Safety Analysis of Nelipepimut-S Vaccine to Prevent Breast Cancer Recurrence: A Randomized, Multicenter, Phase III Clinical Trial. Clin Cancer Res. 2019 Jul 15;25(14):4248-4254. Epub 2019 Apr 29. [https://doi.org/10.1158/1078-0432.ccr-18-2867 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31036542/ PubMed] NCT01479244
 
−
# '''D-CARE:''' Coleman R, Finkelstein DM, Barrios C, Martin M, Iwata H, Hegg R, Glaspy J, Periañez AM, Tonkin K, Deleu I, Sohn J, Crown J, Delaloge S, Dai T, Zhou Y, Jandial D, Chan A. Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):60-72. Epub 2019 Dec 2. [https://doi.org/10.1016/s1470-2045(19)30687-4 link to original article] [https://pubmed.ncbi.nlm.nih.gov/31806543 PubMed] NCT01077154
 
−
# '''OlympiA:''' Tutt ANJ, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P, Gelber RD, de Azambuja E, Fielding A, Balmaña J, Domchek SM, Gelmon KA, Hollingsworth SJ, Korde LA, Linderholm B, Bandos H, Senkus E, Suga JM, Shao Z, Pippas AW, Nowecki Z, Huzarski T, Ganz PA, Lucas PC, Baker N, Loibl S, McConnell R, Piccart M, Schmutzler R, Steger GG, Costantino JP, Arahmani A, Wolmark N, McFadden E, Karantza V, Lakhani SR, Yothers G, Campbell C, Geyer CE Jr; OlympiA Clinical Trial Steering Committee and Investigators. Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer. N Engl J Med. 2021 Jun 24;384(25):2394-2405. Epub 2021 Jun 3. [https://doi.org/10.1056/nejmoa2105215 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/34081848/ PubMed] NCT02032823
 
  
 
=Metastatic disease, maintenance after first-line therapy=
 
=Metastatic disease, maintenance after first-line therapy=
 
==Observation==
 
==Observation==
−
{| class="wikitable" style="float:right; margin-left: 5px;"
+
<div class="toccolours" style="background-color:#eeeeee">
−
|-
 
−
|[[#top|back to top]]
 
−
|}
 
 
===Regimen===
 
===Regimen===
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
{| class="wikitable sortable" style="width: 100%; text-align:center;"  
 
!style="width: 20%"|Study
 
!style="width: 20%"|Study
−
!style="width: 20%"|Years of enrollment
+
!style="width: 20%"|Dates of enrollment
 
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 20%"|[[Levels_of_Evidence#Evidence|Evidence]]
 
!style="width: 20%"|Comparator
 
!style="width: 20%"|Comparator
Line 396: Line 281:
 
|1982-1992
 
|1982-1992
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|CMF(P)TH
+
|[[#CMFPTH_888|CMF(P)TH]]
 
| style="background-color:#d73027" |Inferior RFS
 
| style="background-color:#d73027" |Inferior RFS
 
|-
 
|-
Line 402: Line 287:
 
|1997-2001
 
|1997-2001
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|Marimastat
+
|[[#Marimastat_monotherapy_999|Marimastat]]
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 
| style="background-color:#ffffbf" |Did not meet primary endpoint of PFS
 
|-
 
|-
−
|[https://link.springer.com/article/10.1007%2Fs10549-010-0860-9 Alba et al. 2010 (GEICAM 2001-01)]
+
|[https://doi.org/10.1007/s10549-010-0860-9 Alba et al. 2010 (GEICAM 2001-01)]
 
|2002-2007
 
|2002-2007
 
| style="background-color:#1a9851" |Phase 3 (C)
 
| style="background-color:#1a9851" |Phase 3 (C)
−
|PLD x 6
+
|[[#Breast_cancer#Pegylated_liposomal_doxorubicin_monotherapy_888|PLD]] x 6
 
| style="background-color:#d73027" |Inferior TTP
 
| style="background-color:#d73027" |Inferior TTP
 
|-
 
|-
Line 419: Line 304:
 
|}
 
|}
 
''No further treatment.''
 
''No further treatment.''
 +
<div class="toccolours" style="background-color:#cbd5e8">
 
====Preceding treatment====
 
====Preceding treatment====
−
*ECOG E2196: Doxorubicin- and/or taxane-containing chemotherapy x 6-8
+
*ECOG E2196: First-line doxorubicin- and/or taxane-containing [[Regimen_classes#Chemotherapy-based_regimen|chemotherapy]] x 6-8
−
*GEICAM 2001-01: A x 3, then D x 3
+
*GEICAM 2001-01: First-line [[#A-D_888|A-D]]
−
*KCSG-BR07-02: [[Breast_cancer#Gemcitabine_.26_Paclitaxel|PG]] x 6
+
*KCSG-BR07-02: First-line [[Breast_cancer#Gemcitabine_.26_Paclitaxel|PG]] x 6
−
 
+
</div></div>
 
===References===
 
===References===
−
# '''INT-0077:''' Falkson G, Gelman RS, Pandya KJ, Osborne CK, Tormey D, Cummings FJ, Sledge GW, Abeloff MD. Eastern Cooperative Oncology Group randomized trials of observation versus maintenance therapy for patients with metastatic breast cancer in complete remission following induction treatment. J Clin Oncol. 1998 May;16(5):1669-76. [https://doi.org/10.1200/JCO.1998.16.5.1669 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9586877 PubMed]
+
# '''INT-0077:''' Falkson G, Gelman RS, Pandya KJ, Osborne CK, Tormey D, Cummings FJ, Sledge GW, Abeloff MD. Eastern Cooperative Oncology Group randomized trials of observation versus maintenance therapy for patients with metastatic breast cancer in complete remission following induction treatment. J Clin Oncol. 1998 May;16(5):1669-76. [https://doi.org/10.1200/JCO.1998.16.5.1669 link to original article] [https://pubmed.ncbi.nlm.nih.gov/9586877/ PubMed]
−
# '''ECOG E2196:''' Sparano JA, Bernardo P, Stephenson P, Gradishar WJ, Ingle JN, Zucker S, Davidson NE. Randomized phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: Eastern Cooperative Oncology Group trial E2196. J Clin Oncol. 2004 Dec 1;22(23):4683-90. Erratum in: J Clin Oncol. 2005 Jan 1;23(1):248. [https://doi.org/10.1200/JCO.2004.08.054 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15570070 PubMed] NCT00003010
+
# '''ECOG E2196:''' Sparano JA, Bernardo P, Stephenson P, Gradishar WJ, Ingle JN, Zucker S, Davidson NE. Randomized phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: Eastern Cooperative Oncology Group trial E2196. J Clin Oncol. 2004 Dec 1;22(23):4683-90. Erratum in: J Clin Oncol. 2005 Jan 1;23(1):248. [https://doi.org/10.1200/JCO.2004.08.054 link to original article] [https://pubmed.ncbi.nlm.nih.gov/15570070/ PubMed] [https://clinicaltrials.gov/study/NCT00003010 NCT00003010]
−
# '''GEICAM 2001-01:''' Alba E, Ruiz-Borrego M, Margelí M, Rodríguez-Lescure A, Sánchez-Rovira P, Ruiz A, Mel-Lorenzo JR, Ramos-Vázquez M, Ribelles N, Calvo E, Casado A, Márquez A, Vicente D, García-Sáenz JA, Martín M. Maintenance treatment with pegylated liposomal doxorubicin versus observation following induction chemotherapy for metastatic breast cancer: GEICAM 2001-01 study. Breast Cancer Res Treat. 2010 Jul;122(1):169-76. Epub 2010 Apr 2. [https://link.springer.com/article/10.1007%2Fs10549-010-0860-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20361253 PubMed] NCT00128778
+
# '''GEICAM 2001-01:''' Alba E, Ruiz-Borrego M, Margelí M, Rodríguez-Lescure A, Sánchez-Rovira P, Ruiz A, Mel-Lorenzo JR, Ramos-Vázquez M, Ribelles N, Calvo E, Casado A, Márquez A, Vicente D, García-Sáenz JA, Martín M. Maintenance treatment with pegylated liposomal doxorubicin versus observation following induction chemotherapy for metastatic breast cancer: GEICAM 2001-01 study. Breast Cancer Res Treat. 2010 Jul;122(1):169-76. Epub 2010 Apr 2. [https://doi.org/10.1007/s10549-010-0860-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/20361253/ PubMed] [https://clinicaltrials.gov/study/NCT00128778 NCT00128778]
−
# '''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. [https://doi.org/10.1200/JCO.2012.45.2490 link to original article] '''contains verified protocol''' [https://pubmed.ncbi.nlm.nih.gov/23569309 PubMed] NCT00532857
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# '''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. [https://doi.org/10.1200/JCO.2012.45.2490 link to original article] [https://pubmed.ncbi.nlm.nih.gov/23569309/ PubMed] [https://clinicaltrials.gov/study/NCT00561119 NCT00561119]
  
 
[[Category:Breast cancer regimens]]
 
[[Category:Breast cancer regimens]]

Latest revision as of 11:19, 6 July 2024

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The purpose of this page is to provide references to "null therapy" such as placebo and observation. These references provide further insight into the historical development of the treatment landscape. See the main breast cancer page for regimens that include active anticancer treatment.


Adjuvant therapy

Observation

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Lacour et al. 1980 1972-1979 Phase 3 (C) Polya.Polyu Might have inferior OS
Bonadonna et al. 1976 1973-1975 Phase 3 (C) CMF Inferior RFS
Rubens et al. 1983 1975-1979 Phase 3 (C) Melphalan Might have inferior RFS
Clahsen et al. 1995 (EORTC 09771) 1976-1980 Phase 3 (C) CMF; 700/30/700 x 24 Seems to have inferior OS
Howell et al. 1984 1976-1983 Phase 3 (C) CMF; 1120/64/960 x 12 Inferior RFS
Brinker et al. 1983 (DBCG 77B) 1977-1983 Phase 3 (C) 1. CMF Seems to have inferior OS1
2. Cyclophosphamide Seems to have inferior OS1
3. Levamisole Did not meet co-primary endpoints of IDFS/OS
Goldhirsch et al. 1984 (LBCS III) 1978-1981 Phase 3 (C) 1. CMFPT Inferior DFS
2. PT Inferior DFS
Goldhirsch et al. 1984 (LBCS IV) 1978-1981 Phase 3 (C) PT Seems to have inferior DFS
Fisher et al. 1989 (NSABP B-13) 1981-1988 Phase 3 (C) MF; sequential Inferior DFS2
Mansour et al. 1989 (ECOG E1180) 1981-1988 Phase 3 (C) CMFP Inferior DFS
Jakesz et al. 1998 1984-1990 Phase 3 (C) AV-CMF Did not meet primary endpoint of DFS60
Héry et al. 2006 (FASG 03) 1988-1994 Phase 3 (C) FEC50 x 6 Did not meet primary endpoint of DFS120
Amadori et al. 2000 1989-1993 Phase 3 (C) CMF x 6 Seems to have inferior DFS
Paradiso et al. 2001 1989-1994 Phase 3 (C) FEC x 6 Seems to have inferior DFS
Arriagada et al. 2005 1989-1996 Phase 3 (C) FEC50 x 6 Inferior DFS
Hortobagyi et al. 2000 1990-1997 Randomized (C) CEP with auto HSCT Did not meet primary endpoint of DFS
Adjuvant Breast Cancer Trials Collaborative Group 2007 (NCRI ABC-CT) 1992-2000 Phase 3 (C) CMF; 1400/80/1200 x 6 Seems to have inferior OS
Mamounas et al. 2005 (NSABP B-28) 1995-1998 Phase 3 (C) Paclitaxel; q3wk Inferior DFS
Colleoni et al. 2016 (IBCSG 22-00) 2000-2012 Phase 3 (C) CM Did not meet primary endpoint of DFS
Aebi et al. 2014 (CALOR) 2003-2010 Phase 3 (C) Chemotherapy Seems to have inferior DFS

1Reported efficacy for DBCG 77B is based on the 2010 update.
2Reported efficacy for NSABP B-13 is based on the 1996 update.
Note: No further systemic treatment; many of these trials incorporated RT, however (see individual papers for details). Jakesz et al. 1998 was conducted prior to routine testing of HER2, so it technically included "double-negative" patients. ECOG E1180 is also known as INT-0011.

Preceding treatment

References

  1. Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, De Lena M, Tancini G, Bajetta E, Musumeci R, Veronesi U. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976 Feb 19;294(8):405-10. link to original article PubMed
    1. Update: Bonadonna G, Rossi A, Valagussa P, Banfi A, Veronesi U. The CMF program for operable breast cancer with positive axillary nodes: updated analysis on the disease-free interval, site of relapse and drug tolerance. Cancer. 1977 Jun;39(6 Suppl):2904-15. link to original article PubMed
    2. Update: Bonadonna G, Valagussa P, Rossi A, Tancini G, Brambilla C, Zambetti M, Veronesi U. Ten-year experience with CMF-based adjuvant chemotherapy in resectable breast cancer. Breast Cancer Res Treat. 1985;5(2):95-115. link to original article PubMed
    3. Update: Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995 Apr 6;332(14):901-6. link to original article PubMed
  2. Lacour J, Lacour F, Spira A, Michelson M, Petit JY, Delage G, Sarrazin D, Contesso G, Viguier J. Adjuvant treatment with polyadenylic-polyuridylic acid (Polya-Polyu) in operable breast cancer. Lancet. 1980 Jul 26;2(8187):161-4. link to original article PubMed
  3. Rubens RD, Hayward JL, Knight RK, Bulbrook RD, Fentiman IS, Chaudary M, Howell A, Bush H, Crowther D, Sellwood RA, George WD, Howat JM. Controlled trial of adjuvant chemotherapy with melphalan for breast cancer. Lancet. 1983 Apr 16;1(8329):839-43. link to original article PubMed
  4. DBCG 77B: Brincker H, Mouridsen HT, Andersen KW. Adjuvant chemotherapy with cyclophosphamide or CMF in premenopausal women with stage II breast cancer. Breast Cancer Res Treat. 1983;3(1):91-5. link to original article PubMed
    1. Update: Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Andersson M, Kamby C, Knoop AS; Danish Breast Cancer Cooperative Group. Cyclophosphamide, methotrexate, and fluorouracil; oral cyclophosphamide; levamisole; or no adjuvant therapy for patients with high-risk, premenopausal breast cancer. Cancer. 2010 May 1;116(9):2081-9. link to original article PubMed
  5. LBCS III/IV: Goldhirsch A; Ludwig Breast Cancer Study Group. Randomised trial of chemo-endocrine therapy, endocrine therapy, and mastectomy alone in postmenopausal patients with operable breast cancer and axillary node metastasis. Lancet. 1984 Jun 9;1(8389):1256-60. link to original article PubMed
  6. Howell A, Bush H, George WD, Howat JM, Crowther D, Sellwood RA, Rubens RD, Hayward JL, Bulbrook RD, Fentiman IS, Chaudary M. Controlled trial of adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil for breast cancer. Lancet. 1984 Aug 11;2(8398):307-11. link to original article PubMed
  7. NSABP B-13: Fisher B, Redmond C, Dimitrov NV, Bowman D, Legault-Poisson S, Wickerham DL, Wolmark N, Fisher ER, Margolese R, Sutherland C, Glass A, Foster R, Caplan R. A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors. N Engl J Med. 1989 Feb 23;320(8):473-8. link to original article PubMed
    1. Update: Fisher B, Dignam J, Mamounas EP, Costantino JP, Wickerham DL, Redmond C, Wolmark N, Dimitrov NV, Bowman DM, Glass AG, Atkins JN, Abramson N, Sutherland CM, Aron BS, Margolese RG. Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol. 1996 Jul;14(7):1982-92. link to original article PubMed
    2. Update: Fisher B, Jeong JH, Anderson S, Wolmark N. Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst. 2004 Dec 15;96(24):1823-31. link to original article PubMed
    3. 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
  8. ECOG E1180: Mansour EG, Gray R, Shatila AH, Osborne CK, Tormey DC, Gilchrist KW, Cooper MR, Falkson G. Efficacy of adjuvant chemotherapy in high-risk node-negative breast cancer: an intergroup study. N Engl J Med. 1989 Feb 23;320(8):485-90. link to original article PubMed
  9. LCBS V: Goldhirsch A, Gelber RD; Ludwig Breast Cancer Study Group. Prolonged disease-free survival after one course of perioperative adjuvant chemotherapy for node-negative breast cancer. N Engl J Med. 1989 Feb 23;320(8):491-6. link to original article PubMed
  10. EORTC 09771: Clahsen PC, van de Velde CJ, Welvaart K, Repelaer van Driel OJ, Sylvester RJ; Cooperating Investigators. Ten-year results of a randomized trial evaluating prolonged low-dose adjuvant chemotherapy in node-positive breast cancer: a joint European Organisation for Research and Treatment of Cancer-Dutch Breast Cancer Working Party Study. J Clin Oncol. 1995 Jan;13(1):33-41. link to original article PubMed
  11. Jakesz R, Samonigg H, Gnant M, Kubista E, Steindorfer P, Hausmaninger H, Sevelda P, Tschurtschenthaler B, Fridrik M, Stierer M, Kolb R, Steger G; Austrian Breast Cancer Study Group. Very low-dose adjuvant chemotherapy in steroid receptor negative stage I breast cancer patients. Eur J Cancer. 1998 Jan; 34 (1): 66-70. link to original article PubMed
  12. 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 PubMed
  13. 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 PubMed
    1. Update: Amadori D, Nanni O, Volpi A, Casadei Giunchi D, Marangolo M, Livi L, Ravaioli A, Rossi AP, Gambi A, Luzi Fedeli S, Perroni D, Scarpi E, Becciolini A, Silvestrini R. Phase III randomized multicenter study on the effects of adjuvant CMF in patients with node-negative, rapidly proliferating breast cancer: twelve-year results and retrospective subgroup analysis. Breast Cancer Res Treat. 2008 Mar;108(2):259-64. Epub 2007 May 26. link to original article PubMed
  14. 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 PubMed
  15. 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
  16. 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 PubMed
  17. 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 PubMed
  18. 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 PubMed NCT00002582
  19. CALOR: Aebi S, Gelber S, Anderson SJ, Láng I, Robidoux A, Martín M, Nortier JW, Paterson AH, Rimawi MF, Cañada JM, Thürlimann B, Murray E, Mamounas EP, Geyer CE Jr, Price KN, Coates AS, Gelber RD, Rastogi P, Wolmark N, Wapnir IL; CALOR investigators. Chemotherapy for isolated locoregional recurrence of breast cancer (CALOR): a randomised trial. Lancet Oncol. 2014 Feb;15(2):156-63. Epub 2014 Jan 16. link to original article link to PMC article PubMed NCT00074152
    1. Update: Wapnir IL, Price KN, Anderson SJ, Robidoux A, Martín M, Nortier JWR, Paterson AHG, Rimawi MF, Láng I, Baena-Cañada JM, Thürlimann B, Mamounas EP, Geyer CE Jr, Gelber S, Coates AS, Gelber RD, Rastogi P, Regan MM, Wolmark N, Aebi S; International Breast Cancer Study Group; NRG Oncology; GEICAM Spanish Breast Cancer Group; BOOG Dutch Breast Cancer Trialists' Group; Breast International Group. Efficacy of Chemotherapy for ER-Negative and ER-Positive Isolated Locoregional Recurrence of Breast Cancer: Final Analysis of the CALOR Trial. J Clin Oncol. 2018 Apr 10;36(11):1073-1079. Epub 2018 Feb 14. link to original article link to PMC article PubMed
  20. IBCSG 22-00: Colleoni M, Gray KP, Gelber S, Láng I, Thürlimann B, Gianni L, Abdi EA, Gomez HL, Linderholm BK, Puglisi F, Tondini C, Kralidis E, Eniu A, Cagossi K, Rauch D, Chirgwin J, Gelber RD, Regan MM, Coates AS, Price KN, Viale G, Goldhirsch A. Low-dose oral cyclophosphamide and methotrexate maintenance for hormone receptor-negative early breast cancer: International Breast Cancer Study Group trial 22-00. J Clin Oncol. 2016 Oct 1;34(28):3400-8. Epub 2016 Jun 20. link to original article link to PMC article PubMed NCT00022516
  21. SWOG S1418: NCT02954874

Placebo

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Fisher et al. 1975 (NSABP B-05) 1972-1974 Phase 3 (C) Melphalan Might have inferior DFS1
Paterson et al. 2012 (NSABP B-34) 2001-2004 Phase 3 (C) Clodronate Did not meet primary endpoint of DFS
Coombes et al. 2021 (REACT) 2007-2012 Phase 3 (C) Celecoxib Did not meet primary endpoint of DFS
Coleman et al. 2019 (D-CARE) 2010-2012 Phase 3 (C) Denosumab Did not meet composite primary endpoint of bone MFS
Goodwin et al. 2022 (NCIC CTG MA.32) 2010-2013 Phase 3 (C) Metformin Did not meet primary endpoint of IDFS
Tutt et al. 2021 (OlympiA) 2014-2019 Phase 3 (C) Olaparib Inferior OS2
Chen et al. 2024 (Alliance A011502) 2017-01-06 to 2020-12-04 Phase 3 (C) Aspirin Might have superior iDFS (primary endpoint)
(HR 0.79, 95% CI 0.61-1.01)

1Reported efficacy for NSABP B-05 is based on the 1986 update.
2Reported efficacy for OlympiA is based on the 2022 update.
No active antineoplastic treatment within the study design. Used as a comparator arm. Note that some trials do have other ongoing antineoplastic treatments outside of the study design, such as adjuvant radiation therapy.

Preceding treatment

References

  1. NSABP B-05: Fisher B, Carbone P, Economou SG, Frelick R, Glass A, Lerner H, Redmond C, Zelen M, Band P, Katrych DL, Wolmark N, Fisher ER. 1-Phenylalanine mustard (L-PAM) in the management of primary breast cancer: a report of early findings. N Engl J Med. 1975 Jan 16;292(3):117-22. link to original article PubMed
    1. Update: Fisher B, Glass A, Redmond C, Fisher ER, Barton B, Such E, Carbone P, Economou S, Foster R, Frelick R, Lerner H, Levitt M, Margolese R, MacFarlane J, Plotkin D, Shibata H, Volk H. L-phenylalanine mustard (L-PAM) in the management of primary breast cancer: an update of earlier findings and a comparison with those utilizing L-PAM plus 5-fluorouracil (5-FU). Cancer. 1977 Jun;39(6 Suppl):2883-903. link to original article PubMed
    2. Update: Fisher B, Fisher ER, Redmond C. Ten-year results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial evaluating the use of L-phenylalanine mustard (L-PAM) in the management of primary breast cancer. J Clin Oncol. 1986 Jun;4(6):929-41. link to original article PubMed
  2. NSABP B-34: Paterson AH, Anderson SJ, Lembersky BC, Fehrenbacher L, Falkson CI, King KM, Weir LM, Brufsky AM, Dakhil S, Lad T, Baez-Diaz L, Gralow JR, Robidoux A, Perez EA, Zheng P, Geyer CE Jr, Swain SM, Costantino JP, Mamounas EP, Wolmark N. Oral clodronate for adjuvant treatment of operable breast cancer (National Surgical Adjuvant Breast and Bowel Project protocol B-34): a multicentre, placebo-controlled, randomised trial. Lancet Oncol. 2012 Jul;13(7):734-42. Epub 2012 Jun 14. link to original article link to PMC article PubMed NCT00009945
  3. D-CARE: Coleman R, Finkelstein DM, Barrios C, Martin M, Iwata H, Hegg R, Glaspy J, Periañez AM, Tonkin K, Deleu I, Sohn J, Crown J, Delaloge S, Dai T, Zhou Y, Jandial D, Chan A. Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial. Lancet Oncol. 2020 Jan;21(1):60-72. Epub 2019 Dec 2. link to original article PubMed NCT01077154
  4. OlympiA: Tutt ANJ, Garber JE, Kaufman B, Viale G, Fumagalli D, Rastogi P, Gelber RD, de Azambuja E, Fielding A, Balmaña J, Domchek SM, Gelmon KA, Hollingsworth SJ, Korde LA, Linderholm B, Bandos H, Senkus E, Suga JM, Shao Z, Pippas AW, Nowecki Z, Huzarski T, Ganz PA, Lucas PC, Baker N, Loibl S, McConnell R, Piccart M, Schmutzler R, Steger GG, Costantino JP, Arahmani A, Wolmark N, McFadden E, Karantza V, Lakhani SR, Yothers G, Campbell C, Geyer CE Jr; OlympiA Clinical Trial Steering Committee and Investigators. Adjuvant Olaparib for Patients with BRCA1- or BRCA2-Mutated Breast Cancer. N Engl J Med. 2021 Jun 24;384(25):2394-2405. Epub 2021 Jun 3. link to original article link to PMC article PubMed NCT02032823
    1. Update: Geyer CE Jr, Garber JE, Gelber RD, Yothers G, Taboada M, Ross L, Rastogi P, Cui K, Arahmani A, Aktan G, Armstrong AC, Arnedos M, Balmaña J, Bergh J, Bliss J, Delaloge S, Domchek SM, Eisen A, Elsafy F, Fein LE, Fielding A, Ford JM, Friedman S, Gelmon KA, Gianni L, Gnant M, Hollingsworth SJ, Im SA, Jager A, Jóhannsson ÓÞ, Lakhani SR, Janni W, Linderholm B, Liu TW, Loman N, Korde L, Loibl S, Lucas PC, Marmé F, Martinez de Dueñas E, McConnell R, Phillips KA, Piccart M, Rossi G, Schmutzler R, Senkus E, Shao Z, Sharma P, Singer CF, Španić T, Stickeler E, Toi M, Traina TA, Viale G, Zoppoli G, Park YH, Yerushalmi R, Yang H, Pang D, Jung KH, Mailliez A, Fan Z, Tennevet I, Zhang J, Nagy T, Sonke GS, Sun Q, Parton M, Colleoni MA, Schmidt M, Brufsky AM, Razaq W, Kaufman B, Cameron D, Campbell C, Tutt ANJ; OlympiA Clinical Trial Steering Committee and Investigators. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer. Ann Oncol. 2022 Dec 1;33(12):1250-1268. Epub 2022 Oct 10. link to original article link to PMC article PubMed
    2. PRO analysis: Ganz PA, Bandos H, Španić T, Friedman S, Müller V, Kuemmel S, Delaloge S, Brain E, Toi M, Yamauchi H, de Dueñas EM, Armstrong A, Im SA, Song CG, Zheng H, Sarosiek T, Sharma P, Geng C, Fu P, Rhiem K, Frauchiger-Heuer H, Wimberger P, t'Kint de Roodenbeke D, Liao N, Goodwin A, Chakiba-Brugère C, Friedlander M, Lee KS, Giacchetti S, Takano T, Henao-Carrasco F, Virani S, Valdes-Albini F, Domchek SM, Bane C, McCarron EC, Mita M, Rossi G, Rastogi P, Fielding A, Gelber RD, Scheepers ED, Cameron D, Garber J, Geyer CE, Tutt ANJ. Patient-Reported Outcomes in OlympiA: A Phase III, Randomized, Placebo-Controlled Trial of Adjuvant Olaparib in gBRCA1/2 Mutations and High-Risk Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer. J Clin Oncol. 2024 Apr 10;42(11):1288-1300. Epub 2024 Feb 1. link to original article link to PMC article PubMed
  5. REACT: Coombes RC, Tovey H, Kilburn L, Mansi J, Palmieri C, Bartlett J, Hicks J, Makris A, Evans A, Loibl S, Denkert C, Murray E, Grieve R, Coleman R, Borley A, Schmidt M, Rautenberg B, Kunze CA, Rhein U, Mehta K, Mousa K, Dibble T, Lu XL, von Minckwitz G, Bliss JM; Randomized European Celecoxib Trial (REACT) Trial Management Group and Investigators. Effect of Celecoxib vs Placebo as Adjuvant Therapy on Disease-Free Survival Among Patients With Breast Cancer: The REACT Randomized Clinical Trial. JAMA Oncol. 2021 Sep 1;7(9):1291-1301. link to original article link to PMC article PubMed NCT02429427
  6. NCIC CTG MA.32: Goodwin PJ, Chen BE, Gelmon KA, Whelan TJ, Ennis M, Lemieux J, Ligibel JA, Hershman DL, Mayer IA, Hobday TJ, Bliss JM, Rastogi P, Rabaglio-Poretti M, Mukherjee SD, Mackey JR, Abramson VG, Oja C, Wesolowski R, Thompson AM, Rea DW, Stos PM, Shepherd LE, Stambolic V, Parulekar WR. Effect of Metformin vs Placebo on Invasive Disease-Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial. JAMA. 2022 May 24;327(20):1963-1973. link to original article link to PMC article PubMed NCT01101438
  7. Alliance A011502: Chen WY, Ballman KV, Partridge AH, Hahn OM, Briccetti FM, Irvin WJ, Symington B, Visvanathan K, Pohlmann PR, Openshaw TH, Weiss A, Winer EP, Carey LA, Holmes MD. Aspirin vs Placebo as Adjuvant Therapy for Breast Cancer: The Alliance A011502 Randomized Trial. JAMA. 2024 May 28;331(20):1714-1721. Epub 2024 Apr 29. link to original article link to PMC article PubMed NCT02927249

Metastatic disease, maintenance after first-line therapy

Observation

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Falkson et al. 1998 (INT-0077) 1982-1992 Phase 3 (C) CMF(P)TH Inferior RFS
Sparano et al. 2004 (ECOG E2196) 1997-2001 Phase 3 (C) Marimastat Did not meet primary endpoint of PFS
Alba et al. 2010 (GEICAM 2001-01) 2002-2007 Phase 3 (C) PLD x 6 Inferior TTP
Park et al. 2013 (KCSG-BR07-02) 2007-2010 Phase 3 (C) PG Seems to have inferior OS

No further treatment.

Preceding treatment

  • ECOG E2196: First-line doxorubicin- and/or taxane-containing chemotherapy x 6-8
  • GEICAM 2001-01: First-line A-D
  • KCSG-BR07-02: First-line PG x 6

References

  1. INT-0077: Falkson G, Gelman RS, Pandya KJ, Osborne CK, Tormey D, Cummings FJ, Sledge GW, Abeloff MD. Eastern Cooperative Oncology Group randomized trials of observation versus maintenance therapy for patients with metastatic breast cancer in complete remission following induction treatment. J Clin Oncol. 1998 May;16(5):1669-76. link to original article PubMed
  2. ECOG E2196: Sparano JA, Bernardo P, Stephenson P, Gradishar WJ, Ingle JN, Zucker S, Davidson NE. Randomized phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: Eastern Cooperative Oncology Group trial E2196. J Clin Oncol. 2004 Dec 1;22(23):4683-90. Erratum in: J Clin Oncol. 2005 Jan 1;23(1):248. link to original article PubMed NCT00003010
  3. GEICAM 2001-01: Alba E, Ruiz-Borrego M, Margelí M, Rodríguez-Lescure A, Sánchez-Rovira P, Ruiz A, Mel-Lorenzo JR, Ramos-Vázquez M, Ribelles N, Calvo E, Casado A, Márquez A, Vicente D, García-Sáenz JA, Martín M. Maintenance treatment with pegylated liposomal doxorubicin versus observation following induction chemotherapy for metastatic breast cancer: GEICAM 2001-01 study. Breast Cancer Res Treat. 2010 Jul;122(1):169-76. Epub 2010 Apr 2. link to original article PubMed NCT00128778
  4. 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 PubMed NCT00561119
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