Revision as of 03:30, 14 December 2019

The purpose of this page is to capture information about complex comparisons that is not easily conveyed on the treatment regimen pages. Many complex multipart RCTs are of the "Y-shaped" format "A followed by B1 versus B2" or "A1 versus A2 followed by B" and this can be captured on the treatment regimen pages. This page will convey information on more complicated designs, such as "A followed by B versus B followed by A" or "A followed by B versus C followed by D".

Acute myeloid leukemia

COG AAML0531

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To be completed

References

Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014 Sep 20;32(27):3021-32. link to original article link to PMC article PubMed

UK MRC AML12

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To be completed

References

Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the randomized MRC trial. Blood. 1999 Jun 15;93(12):4131-43. link to original article PubMed

UK MRC AML15

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To be completed

References

Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. link to original article PubMed

Acute promyelocytic leukemia

C9710

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Note: this trial included a second randomization during the maintenance phase, which is not complex and is therefore not reported here.

Arm 1

ATRA, Cytarabine, Daunorubicin, then ATRA & Daunorubicin

Arm 2, with ATO3

ATRA, Cytarabine, Daunorubicin, then arsenic trioxide, then ATRA & Daunorubicin

Comparative efficacy

Regimen	Efficacy
Without ATO3	Inferior EFS
With ATO3	Superior EFS

References

Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. link to original article contains verified protocol link to PMC article PubMed

Breast cancer

ABCSG-8

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ABCSG-8: Austrian Breast and Colorectal Cancer Study Group 8

Arm 1, monotherapy (Control)

Tamoxifen x 5y

Arm 2, sequential (Experimental)

Tamoxifen x 2y, then Anastrozole x 3y

Comparative efficacy

Efficacy is based on the 2012 update.

Regimen	Efficacy
Tamoxifen	Might have inferior RFS
Tamoxifen, then Anastrozole	Might have superior RFS

References

Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, Hilfrich J, Kwasny W, Menzel C, Samonigg H, Seifert M, Gademann G, Kaufmann M, Wolfgang J; ABCSG and the GABG. Switching of postmenopausal women with endocrine-responsiveearly breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005 Aug 6-12;366(9484):455-62. link to original article PubMed
1. Update: Dubsky PC, Jakesz R, Mlineritsch B, Pöstlberger S, Samonigg H, Kwasny W, Tausch C, Stöger H, Haider K, Fitzal F, Singer CF, Stierer M, Sevelda P, Luschin-Ebengreuth G, Taucher S, Rudas M, Bartsch R, Steger GG, Greil R, Filipcic L, Gnant M. Tamoxifen and anastrozole as a sequencing strategy: a randomized controlled trial in postmenopausal patients with endocrine-responsive early breast cancer from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. 2012 Mar 1;30(7):722-8. Epub 2012 Jan 23. link to original article PubMed

ACOSOG Z1041

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Arm 1 (Control)

FEC-75 x 4, then TH (Taxol) x 12 wk, then surgery

Arm 2 (Experimental)

TH (Taxol) x 12 wk, then FEC & H x 4, then surgery

Comparative efficacy

Approach	Efficacy
Sequential trastuzumab (C)	Seems not superior
Concurrent trastuzumab (E)	Seems not superior

References

Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig G, Royce M, McCall LM, Ewer MS, Hunt KK; American College of Surgeons Oncology Group investigators. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1317-25. Epub 2013 Nov 13. link to original article link to PMC article PubMed

ARNO 95

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Arm 1, monotherapy (Control)

Tamoxifen x 5y

Arm 2, sequential (Experimental)

Tamoxifen x 2y, then Anastrozole x 3y

Comparative efficacy

Efficacy is based on the 2007 update.

Regimen	Comparative Efficacy
Tamoxifen, then Anastrozole	Seems to have superior OS
Tamoxifen	Seems to have inferior OS

References

Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, Hilfrich J, Kwasny W, Menzel C, Samonigg H, Seifert M, Gademann G, Kaufmann M, Wolfgang J; ABCSG and the GABG. Switching of postmenopausal women with endocrine-responsiveearly breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005 Aug 6-12;366(9484):455-62. link to original article PubMed
1. Update: Kaufmann M, Jonat W, Hilfrich J, Eidtmann H, Gademann G, Zuna I, von Minckwitz G. Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 Study. J Clin Oncol. 2007 Jul 1;25(19):2664-70. Epub 2007 Jun 11. link to original article PubMed

Assikis et al. 2003

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Arm 1

FAC, then MV

Arm 2

Tamoxifen

Comparative efficacy

Regimen	Efficacy
FAC, then MV	Seems not superior
Tamoxifen	Seems not superior

References

Assikis V, Buzdar A, Yang Y, Smith T, Theriault R, Booser D, Valero V, Walters R, Singletary E, Ames F, Hortobagyi G. A phase III trial of sequential adjuvant chemotherapy for operable breast carcinoma: final analysis with 10-year follow-up. Cancer. 2003 Jun 1;97(11):2716-23. link to original article contains protocol PubMed

BCIRG-005

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Arm 1, sequential (Experimental)

AC, then T

Arm 2, concurrent (Control)

TAC

Comparative efficacy

Schedule	Efficacy
Sequential (AC, then T)	Seems not superior
Concurrent (TAC)	Seems not superior

References

Eiermann W, Pienkowski T, Crown J, Sadeghi S, Martin M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press M, Sauter G, Lindsay MA, Riva A, Buyse M, Drevot P, Taupin H, Mackey JR. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol. 2011 Oct 10;29(29):3877-84. Epub 2011 Sep 12. link to original article PubMed

BCIRG 006

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Arm 1, sequential without trastuzumab

AC, then T

Arm 2, sequential with trastuzumab

AC, then TH

Arm 3, concurrent with trastuzumab

TCH

Comparative efficacy

Analyzed using a step-down design

Comparison 1

Trastuzumab-containing regimens vs. AC, then T	Efficacy
AC, then TH	Superior OS
TCH	Seems to have superior OS

Comparison 2

Trastuzumab-containing regimens	Efficacy
AC, then TH	Seems not superior
TCH	Seems not superior

References

Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83. link to original article link to PMC article PubMed

BIG 1-98

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Comparative efficacy

Analyzed by several methods; efficacy here is based on the 2011 update.

Comparison 1

Reported efficacy is based on the 2018 update.

Monotherapy	Efficacy
Letrozole	Might have superior OS
Tamoxifen	Might have inferior OS

Comparison 2

Sequential therapies	Efficacy
Letrozole, then Tamoxifen	Seems not superior
Tamoxifen, then Letrozole	Seems not superior

Comparison 3

Letrozole-containing therapies	Efficacy
Letrozole	Seems not superior
Letrozole, then Tamoxifen	Seems not superior
Tamoxifen, then Letrozole	Seems not superior

References

Thürlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardley A, Price KN, Goldhirsch A; Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005 Dec 29;353(26):2747-57. Erratum in: N Engl J Med. 2006 May 18;354(20):2200. Wardly, Andrew [corrected to Wardley, Andrew ]. link to original article PubMed
1. Update: Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol. 2007 Feb 10;25(5):486-92. Epub 2007 Jan 2. link to original article PubMed
2. Subgroup analysis: Rasmussen BB, Regan MM, Lykkesfeldt AE, Dell'Orto P, Del Curto B, Henriksen KL, Mastropasqua MG, Price KN, Méry E, Lacroix-Triki M, Braye S, Altermatt HJ, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Gusterson BA, Thürlimann B, Coates AS, Viale G; BIG 1-98 Collaborative and International Breast Cancer Study Groups. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol. 2008 Jan;9(1):23-8. Epub 2007 Dec 20. link to original article PubMed
3. Subgroup analysis: Crivellari D, Sun Z, Coates AS, Price KN, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens RJ, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Gladieff L, Rabaglio M, Smith IE, Chirgwin JH, Goldhirsch A. Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial. J Clin Oncol. 2008 Apr 20;26(12):1972-9. Epub 2008 Mar 10. link to original article PubMed
4. Update: Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, Forbes JF, Smith I, Láng I, Wardley A, Rabaglio M, Price KN, Gelber RD, Coates AS, Thürlimann B; BIG 1-98 Collaborative Group.; International Breast Cancer Study Group (IBCSG). Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol. 2011 Nov;12(12):1101-8. link to original article link to PMC article PubMed
5. Update: Ruhstaller T, Giobbie-Hurder A, Colleoni M, Jensen MB, Ejlertsen B, de Azambuja E, Neven P, Láng I, Jakobsen EH, Gladieff L, Bonnefoi H, Harvey VJ, Spazzapan S, Tondini C, Del Mastro L, Veyret C, Simoncini E, Gianni L, Rochlitz C, Kralidis E, Zaman K, Jassem J, Piccart-Gebhart M, Di Leo A, Gelber RD, Coates AS, Goldhirsch A, Thürlimann B, Regan MM; members of the BIG 1-98 Collaborative Group and the International Breast Cancer Study Group. Adjuvant Letrozole and Tamoxifen Alone or Sequentially for Postmenopausal Women With Hormone Receptor-Positive Breast Cancer: Long-Term Follow-Up of the BIG 1-98 Trial. J Clin Oncol. 2018 Nov 26:JCO1800440. [Epub ahead of print] link to original article PubMed

BIG 02-98

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Arm 1, sequential control

Surgery, then A x 4, then CMF x 3

Arm 2, concurrent control

Surgery, then AC x 4, then CMF x 3

Arm 3, sequential experimental

Surgery, then A x 4, D x 3, then CMF x 3

Arm 4, concurrent experimental

Surgery, then AT x 4, then CMF x 3

Comparative efficacy

This trial was analyzed with a 2 x 2 factorial design. Reported efficacy is based on the 2015 update.

Comparison 1 - addition of docetaxel

Regimen	Efficacy
Non-docetaxel-containing (C)	Seems not superior (*)
Docetaxel containing (E)	Seems not superior (*)

Comparison 2 - sequencing

Regimen	Efficacy
Sequential	Seems not superior (*)
Concurrent	Seems not superior (*)

References

Francis P, Crown J, Di Leo A, Buyse M, Balil A, Andersson M, Nordenskjöld B, Lang I, Jakesz R, Vorobiof D, Gutiérrez J, van Hazel G, Dolci S, Jamin S, Bendahmane B, Gelber RD, Goldhirsch A, Castiglione-Gertsch M, Piccart-Gebhart M; BIG 02-98 Collaborative Group. Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial. J Natl Cancer Inst. 2008 Jan 16;100(2):121-33. Epub 2008 Jan 8. Erratum in: J Natl Cancer Inst. 2008 Nov 19;100(22):1655. link to original article PubMed
1. Update: Oakman C, Francis PA, Crown J, Quinaux E, Buyse M, De Azambuja E, Margeli Vila M, Andersson M, Nordenskjöld B, Jakesz R, Thürlimann B, Gutiérrez J, Harvey V, Punzalan L, Dell'orto P, Larsimont D, Steinberg I, Gelber RD, Piccart-Gebhart M, Viale G, Di Leo A. Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trial. Ann Oncol. 2013 May;24(5):1203-11. Epub 2013 Jan 4. link to original article PubMed
2. Update: Sonnenblick A, Francis PA, Azim HA Jr, de Azambuja E, Nordenskjöld B, Gutiérez J, Quinaux E, Mastropasqua MG, Ameye L, Anderson M, Lluch A, Gnant M, Goldhirsch A, Di Leo A, Barnadas A, Cortes-Funes H, Piccart M, Crown J. Final 10-year results of the Breast International Group 2-98 phase III trial and the role of Ki67 in predicting benefit of adjuvant docetaxel in patients with oestrogen receptor positive breast cancer. Eur J Cancer. 2015 Aug;51(12):1481-9. Epub 2015 Jun 11. link to original article PubMed

BR9601

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Arm 1 (Control)

CMF x 8

Arm 2 (Experimental)

EC x 4, then CMF x 4

Comparative efficacy

Regimen	Efficacy
CMF x 8	Inferior OS
EC x 4, then CMF x 4	Superior OS

References

Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. link to original article PubMed

Buzdar et al. 2005

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Arm 1 (Control)

T x 4, then FEC x 4, then surgery

Arm 2 (Experimental)

TH x 4, then FEC & H x 4, then surgery

Comparative efficacy

Regimen	Efficacy
T, then FEC	Seems to have inferior pCR rate
TH, then FEC & H	Seems to have superior pCR rate

References

Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005 Jun 1;23(16):3676-85. Epub 2005 Feb 28. link to original article PubMed

CALGB 9741

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Note: what is referred to in this study as concurrent is in fact the same regimen that is referred to as sequential in other studies. The taxane studied in this trial was paclitaxel.

Arm 1, sequential

A x 4, then T q3wk x 4, then C x 4

Arm 2, dose-dense sequential

ddA x 4, then ddT x 4, then ddC x 4

Arm 3, "concurrent"

AC x 4, then T q3wk x 4

Arm 4, dose-dense "concurrent"

ddAC x 4, then ddT x 4

Comparative efficacy

Analyzed using a 2 x 2 factorial design

Comparison 1

Dose density	Efficacy
Dose-dense (q2wk)	Seems to have superior OS
Standard (q3wk)	Seems to have inferior OS

Comparison 2

Schedule	Efficacy
Concurrent	Seems not superior
Sequential	Seems not superior

References

Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. link to original article contains verified protocol PubMed

DBCG 82b

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Arm 1 (Experimental)

Mastectomy, then CMF x 1, then radiotherapy, then CMF x 7

Arm 2 (Control)

Mastectomy, then CMF x 9

Comparative efficacy

Regimen	Efficacy
With RT	Superior OS
Without RT	Inferior OS

References

Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, Kjaer M, Gadeberg CC, Mouridsen HT, Jensen MB, Zedeler K. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy: Danish Breast Cancer Cooperative Group 82b trial. N Engl J Med. 1997 Oct 2;337(14):949-55. link to original article PubMed

DBCG 07-READ

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Arm 1

Surgery, then DC x 6

Arm 2, "EC-D"

Surgery, then EC x 3, then D x 3

Comparative efficacy

Regimen	Efficacy
DC x 6	Seems not superior
EC x 3, then D x 3	Seems not superior

References

Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen MB, Knoop AS, Højris I, Ewertz M, Balslev E, Danø H, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. Adjuvant cyclophosphamide and docetaxel with or without epirubicin for early TOP2A-normal breast cancer: DBCG 07-READ, an open-label, phase III, randomized trial. J Clin Oncol. 2017 Aug 10;35(23):2639-2646. Epub 2017 Jun 29. link to original article contains verified protocol PubMed

DEVA

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Arm 1 (Control)

Surgery, then Epirubicin x 6

Arm 2 (Experimental)

Surgery, then Epirubicin x 3, then Docetaxel x 3

Comparative efficacy

Regimen	Efficacy
Epirubicin	Inferior DFS
Epirubicin, then Docetaxel	Superior DFS

References

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

ECOG E5103

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Arm A (Control)

Surgery, then AC x 4 or ddAC x 4, then wP x 12

Arm B (Experimental)

Surgery, then AC-Bev x 4 or ddAC-Bev x 4, then wP-Bev

Arm C (Experimental)

Surgery, then AC-Bev x 4 or ddAC-Bev x 4, then wP-Bev, then bevacizumab x 10

Comparative efficacy

Backbone	Efficacy
No bevacizumab	Seems not superior
With bevacizumab	Seems not superior

References

Miller KD, O'Neill A, Gradishar W, Hobday TJ, Goldstein LJ, Mayer IA, Bloom S, Brufsky AM, Tevaarwerk AJ, Sparano JA, Le-Lindqwister NA, Hendricks CB, Northfelt DW, Dang CT, Sledge GW Jr. Double-blind phase III trial of adjuvant chemotherapy with and without bevacizumab in patients with lymph node-positive and high-risk lymph node-negative breast cancer (E5103). J Clin Oncol. 2018 Sep 1;36(25):2621-2629. Epub 2018 Jul 24. link to original article PubMed

ECTO

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Arm A (Control)

Surgery, then A x 4, then CMF x 4

Arm B (Experimental)

Surgery, then AT (Taxol) x 4, then CMF x 4

Arm C (Experimental)

AT (Taxol) x 4, then CMF x 4, then surgery

Comparative efficacy

Comparison 1

Paclitaxel	Efficacy
Included	Seems to have superior RFS
Not included	Seems to have inferior RFS

Comparison 2

Timing	Efficacy
Adjuvant AT-CMF	Seems not superior
Neoadjuvant AT-CMF	Seems not superior

References

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

FATA-GIM3

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Arm 1

Anastrazole x 5 y

Arm 2

Exemestane x 5 y

Arm 3

Letrozole x 5 y

Arm 4

Tamoxifen x 2 y, then Anastrazole x 3 y

Arm 5

Tamoxifen x 2 y, then Exemestane x 3 y

Arm 6

Tamoxifen x 2 y, then Letrozole x 3 y

Comparative efficacy

Approach	Efficacy
AI x 5 y	Seems not superior
Tamoxifen x 2 y, then AI x 3 y	Seems not superior

References

De Placido S, Gallo C, De Laurentiis M, Bisagni G, Arpino G, Sarobba MG, Riccardi F, Russo A, Del Mastro L, Cogoni AA, Cognetti F, Gori S, Foglietta J, Frassoldati A, Amoroso D, Laudadio L, Moscetti L, Montemurro F, Verusio C, Bernardo A, Lorusso V, Gravina A, Moretti G, Lauria R, Lai A, Mocerino C, Rizzo S, Nuzzo F, Carlini P, Perrone F; GIM Investigators. Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial. Lancet Oncol. 2018 Apr;19(4):474-485. Epub 2018 Feb 23. Erratum in: Lancet Oncol. 2018 Apr;19(4):e184. link to original article PubMed

FinXX

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Arm 1 (Control)

T (Docetaxel) x 3, then CEF x 3

Arm 2 (Experimental)

TX x 3, then CEX x 3

Comparative efficacy

Regimen	Efficacy
T x 3, then CEF x 3	Might have inferior RFS
TX x 3, then CEX x 3	Might have superior RFS

References

Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Asola R, Kokko R, Ahlgren J, Auvinen P, Hemminki A, Paija O, Helle L, Nuortio L, Villman K, Nilsson G, Lahtela SL, Lehtiö K, Pajunen M, Poikonen P, Nyandoto P, Kataja V, Bono P, Leinonen M, Lindman H; FinXX Study Investigators. Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer: an open-label, randomised controlled trial. Lancet Oncol. 2009 Dec;10(12):1145-51. Epub 2009 Nov 10. link to original article PubMed
1. Update: Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Kokko R, Ahlgren J, Auvinen P, Paija O, Helle L, Villman K, Nyandoto P, Nilsson G, Pajunen M, Asola R, Poikonen P, Leinonen M, Kataja V, Bono P, Lindman H. Adjuvant capecitabine, docetaxel, cyclophosphamide, and epirubicin for early breast cancer: final analysis of the randomized FinXX trial. J Clin Oncol. 2012 Jan 1;30(1):11-8. Epub 2011 Nov 21. link to original article PubMed

FNCLCC PACS 01

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Arm 1 (Control)

FEC x 6

Arm 2 (Experimental)

FEC x 3, then D x 3

Comparative efficacy

Note: efficacy is based on the 2012 update.

Regimen	Efficacy
FEC	Inferior OS (*)
FEC-D	Superior OS (*)

References

Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulié P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Genève J, Asselain B. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006 Dec 20;24(36):5664-71. Epub 2006 Nov 20. link to original article PubMed
1. Update: Coudert B, Asselain B, Campone M, Spielmann M, Machiels JP, Pénault-Llorca F, Serin D, Lévy C, Romieu G, Canon JL, Orfeuvre H, Piot G, Petit T, Jerusalem G, Audhuy B, Veyret C, Beauduin M, Eymard JC, Martin AL, Roché H; UNICANCER Breast Group. Extended benefit from sequential administration of docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide regimen for node-positive breast cancer: the 8-year follow-up results of the UNICANCER-PACS01 trial. Oncologist. 2012;17(7):900-9. Epub 2012 May 18. link to original article link to PMC article PubMed

GEICAM 9906

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Arm 1 (Control)

FEC x 6

Arm 2 (Experimental)

FEC x 4, then weekly T (Taxol) x 12

Comparative efficacy

Regimen	Efficacy
FEC x 6	Inferior DFS
FEC x 4, then T	Superior DFS

References

Martín M, Rodríguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Munárriz B, Rodríguez CA, Crespo C, de Alava E, López García-Asenjo JA, Guitián MD, Almenar S, González-Palacios JF, Vera F, Palacios J, Ramos M, Gracia Marco JM, Lluch A, Alvarez I, Seguí MA, Mayordomo JI, Antón A, Baena JM, Plazaola A, Modolell A, Pelegrí A, Mel JR, Aranda E, Adrover E, Alvarez JV, García Puche JL, Sánchez-Rovira P, Gonzalez S, López-Vega JM; GEICAM 9906 Study Investigators. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst. 2008 Jun 4;100(11):805-14. Epub 2008 May 27. link to original article PubMed

GEICAM/2003-02

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Arm 1, FAC (Control)

Surgery, then FAC x 6

Arm 2, FAC-wP (Experimental)

Surgery, then FAC x 4, then wP x 8

Comparative efficacy

Regimen	Efficacy
FAC	Seems to have inferior DFS
FAC-wP	Seems to have superior DFS

References

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

GEICAM/2003-10

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Arm 1, EC-T (Control)

Surgery, then EC x 4, then T (Taxotere) x 4

Arm 2, ET-X (Experimental)

Surgery, then ET x 4, then X x 4

Comparative efficacy

Regimen	Efficacy
EC-T	Seems to have superior IDFS
ET-X	Seems to have inferior IDFS

References

Martín M, Ruiz Simón A, Ruiz Borrego M, Ribelles N, Rodríguez-Lescure Á, Muñoz-Mateu M, González S, Margelí Vila M, Barnadas A, Ramos M, Del Barco Berron S, Jara C, Calvo L, Martínez-Jáñez N, Mendiola Fernández C, Rodríguez CA, Martínez de Dueñas E, Andrés R, Plazaola A, de la Haba-Rodríguez J, López-Vega JM, Adrover E, Ballesteros AI, Santaballa A, Sánchez-Rovira P, Baena-Cañada JM, Casas M, del Carmen Cámara M, Carrasco EM, Lluch A. Epirubicin plus cyclophosphamide followed by docetaxel versus epirubicin plus docetaxel followed by capecitabine as adjuvant therapy for node-positive early breast cancer: results from the GEICAM/2003-10 study. J Clin Oncol. 2015 Nov 10;33(32):3788-95. Epub 2015 Sep 28. link to original article PubMed

GeparDuo

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Arm 1, ddAT (Experimental)

ddAT x 4, then surgery

Arm 2, AC-T (Experimental)

AC x 4, then T (Taxotere) x 4, then surgery

Comparative efficacy

Regimen	Efficacy
ddAT	Inferior pCR rate
AC-T	Superior pCR rate

References

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

GeparQuinto

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Arm 1A - Control (HER2-negative)

EC x 4, then Docetaxel x 4, then surgery

Arm 1B - Control (HER2-positive)

ECH x 4, then TH (Taxotere) x 4, then surgery

Arm 2A - Experimental (HER2-negative)

EC & Bevacizumab x 4, then Docetaxel & Bevacizumab x 4, then surgery

Arm 2B - Experimental (HER2-positive)

ECL x 4, then TL (Taxotere) x 4, then surgery

Comparative efficacy

Comparison 1 (HER2-negative)

Note that while this study met the primary efficacy endpoint, the advantage for bevacizumab was only seen in the triple-negative breast cancer patients, with p=0.003 in this subgroup.

Regimen	Efficacy
No bevacizumab	Seems to have inferior pCR rate
With bevacizumab	Seems to have superior pCR rate

Comparison 2 (HER2-positive)

Regimen	Efficacy
With lapatinib	Seems to have inferior pCR rate
With trastuzumab	Seems to have superior pCR rate

References

von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Kreienberg R, Solbach C, Gerber B, Jackisch C, Kunz G, Blohmer JU, Huober J, Hauschild M, Fehm T, Müller BM, Denkert C, Loibl S, Nekljudova V, Untch M; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie–Breast Study Groups. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012 Jan 26;366(4):299-309. link to original article PubMed
Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, Hilfrich J, Strumberg D, Fasching PA, Kreienberg R, Tesch H, Hanusch C, Gerber B, Rezai M, Jackisch C, Huober J, Kühn T, Nekljudova V, von Minckwitz G; German Breast Group (GBG); Arbeitsgemeinschaft Gynäkologische Onkologie-Breast (AGO-B) Study Group. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 2012 Feb;13(2):135-44. Epub 2012 Jan 17. link to original article PubMed
1. Update: Untch M, von Minckwitz G, Gerber B, Schem C, Rezai M, Fasching PA, Tesch H, Eggemann H, Hanusch C, Huober J, Solbach C, Jackisch C, Kunz G, Blohmer JU, Hauschild M, Fehm T, Nekljudova V, Loibl S; GBG and the AGO-B Study Group. Survival analysis after neoadjuvant chemotherapy with trastuzumab or lapatinib in patients with human epidermal growth factor receptor 2-positive breast cancer in the GeparQuinto (G5) study (GBG 44). J Clin Oncol. 2018 May 1;36(13):1308-1316. Epub 2018 Mar 15. link to original article PubMed

GIM2

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Arm 1, "q3EC-P" (Control)

Surgery, then EC x 4, then P x 4

Arm 2, "q3FEC-P" (Experimental)

Surgery, then FEC x 4, then P x 4

Arm 3, "q2EC-P" (Experimental)

Surgery, then ddEC x 4, then ddP x 4

Arm 4, "q2FEC-P" (Experimental)

Surgery, then ddEC x 4, then ddP x 4

Comparative efficacy

Analyzed using a 2 x 2 factorial design

Comparison 1

Dose density	Efficacy
Dose-dense (q2wk)	Superior OS
Standard (q3wk)	Inferior OS

Comparison 2

Inclusion of 5-FU	Efficacy
Yes (FEC-based)	Seems not superior
No (EC-based)	Seems not superior

References

Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella (GIM) investigators. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. link to original article PubMed

GROCTA-1

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Arm 1, CT (Experimental)

Surgery, then CMF x 6, then E x 4

Arm 2, T (Experimental)

Surgery, then Tamoxifen x 5 y

Arm 3, CTT (Experimental)

Surgery, then CMF x 6, then E x 4, then Tamoxifen x 5 y

Comparative efficacy

Note: reported efficacy is based on the 2011 update.

Comparison 1

Regimen	Efficacy
T	Seems to have superior OS
CT	Seems to have inferior OS

Comparison 2

Regimen	Efficacy
CTT	Superior OS
CT	Inferior OS

References

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

HannaH

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Arm 1, IV trastuzumab

TH x 4, then FEC & H x 4, then surgery, then adjuvant trastuzumab

Arm 2, SC trastuzumab

TH x 4, then FEC & H x 4, then surgery, then adjuvant trastuzumab and hyaluronidase

Comparative efficacy

Route of administration	Efficacy
IV trastuzumab	Non-inferior pCR rate
SC trastuzumab	Non-inferior pCR rate

References

Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012 Sep;13(9):869-78. Epub 2012 Aug 9. link to original article contains verified protocol PubMed
1. Update: Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B, Chen SC, Meyenberg C, Al-Sakaff N, Heinzmann D, Hegg R. Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: final analysis of the HannaH phase 3 randomized clinical trial. JAMA Oncol. 2019 May 1;5(5):e190339. Epub 2019 May 9. link to original article link to PMC article PubMed

HORG Polyzos et al. 2010

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Arm 1 (Experimental)

Surgery, then D x 4, then EC x 4

Arm 2 (Control)

Surgery, then FEC x 6

Comparative efficacy

Regimen	Efficacy
D/EC	Seems to have superior DFS
FEC	Seems to have inferior DFS

References

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

HORG CT/07.17

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Arm 1

Surgery, then ddFEC x 4, then D x 4

Arm 2

Surgery, then TC x 6

Comparative efficacy

Regimen	Efficacy
ddFEC → D	Inconclusive whether non-inferior
TC	Inconclusive whether non-inferior

References

Mavroudis D, Matikas A, Malamos N, Papakotoulas P, Kakolyris S, Boukovinas I, Athanasiadis A, Kentepozidis N, Ziras N, Katsaounis P, Saloustros E, Georgoulias V; Breast Cancer Investigators of the Hellenic Oncology Research Group (HORG), Athens, Greece. Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2016 Oct;27(10):1873-8. Epub 2016 Aug 8. link to original article PubMed

IES

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IES: Intergroup Exemestane Study

Arm 1, monotherapy (Control)

Tamoxifen x 5y

Arm 2, sequential (Experimental)

Tamoxifen x 2-3y, then Exemestane x 2-3y

Comparative efficacy

Note: reported efficacy is based on the 2011 update.

Regimen	Efficacy
Tamoxifen x 5y	Seems to have inferior OS
Tamoxifen x 2-3y, then Exemestane x 2-3y (5y total)	Seems to have superior OS

References

Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM, van de Velde C; Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004 Mar 11;350(11):1081-92. link to original article PubMed
1. Update: Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, Van de Velde CJ, Delozier T, Alvarez I, Del Mastro L, Ortmann O, Diedrich K, Coates AS, Bajetta E, Holmberg SB, Dodwell D, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Forbes J, Castiglione M, Stuart N, Stewart A, Fallowfield LJ, Bertelli G, Hall E, Bogle RG, Carpentieri M, Colajori E, Subar M, Ireland E, Bliss JM; Intergroup Exemestane Study. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 2007 Feb 17;369(9561):559-70. link to original article PubMed
2. Update: Bliss JM, Kilburn LS, Coleman RE, Forbes JF, Coates AS, Jones SE, Jassem J, Delozier T, Andersen J, Paridaens R, van de Velde CJ, Lønning PE, Morden J, Reise J, Cisar L, Menschik T, Coombes RC. Disease-related outcomes with long-term follow-up: an updated analysis of the Intergroup Exemestane Study. J Clin Oncol. 2012 Mar 1;30(7):709-17. Epub 2011 Oct 31. link to original article PubMed

IRST-IBIS-03

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Arm 1

Surgery, then E, then CMF

Arm 2

Surgery, then CMF, then E

Comparative efficacy

Regimen	Comparative Efficacy
E -> CMF	Seems not superior
CMF -> E	Seems not superior

References

Amadori D, Silvestrini R, De Lena M, Boccardo F, Rocca A, Scarpi E, Schittulli F, Brandi M, Maltoni R, Serra P, Ponzone R, Biglia N, Gianni L, Tienghi A, Valerio MR, Bonginelli P, Amaducci L, Faedi M, Baldini E, Paradiso A. Randomized phase III trial of adjuvant epirubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) versus CMF followed by epirubicin in patients with node-negative or 1-3 node-positive rapidly proliferating breast cancer. Breast Cancer Res Treat. 2011 Feb;125(3):775-84. Epub 2010 Dec 4. link to original article PubMed

Kümmel et al. 2006

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Arm 1, control

Surgery, then EC x 4, then CMF x 3

Arm 2, experimental

Surgery, then ddEP x 4, then ddCMF x 3

Comparative efficacy

Regimen	Efficacy
EC-CMF	Might have inferior OS
ddEP-ddCMF	Might have superior OS

References

Kümmel S, Krocker J, Kohls A, Breitbach GP, Morack G, Budner M, Blohmer JU, Elling D. Randomised trial: survival benefit and safety of adjuvant dose-dense chemotherapy for node-positive breast cancer. Br J Cancer. 2006 May 8;94(9):1237-44. link to original article link to PMC article PubMed

Loesch et al. 2010

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Arm 1, control

Surgery, then AC x 4, then T (Taxol) x 4

Arm 2, experimental

Surgery, then AT (Taxol) x 4, then wP x 12

Comparative efficacy

Regimen	Efficacy
AC-P	Seems not superior
AP-WP	Seems not superior

References

Loesch D, Greco FA, Senzer NN, Burris HA, Hainsworth JD, Jones S, Vukelja SJ, Sandbach J, Holmes F, Sedlacek S, Pippen J, Lindquist D, McIntyre K, Blum JL, Modiano MR, Boehm KA, Zhan F, Asmar L, Robert N. Phase III multicenter trial of doxorubicin plus cyclophosphamide followed by paclitaxel compared with doxorubicin plus paclitaxel followed by weekly paclitaxel as adjuvant therapy for women with high-risk breast cancer. J Clin Oncol. 2010 Jun 20;28(18):2958-65. Epub 2010 May 17. link to original article PubMed

Mavroudis et al. 2017

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Arm 1, sequential

Surgery, then Epirubicin, then Docetaxel

Arm 2, concurrent

Surgery, then Docetaxel & Epirubicin

Comparative efficacy

Schedule	Efficacy
Sequential	Might have superior DFS
Concurrent	Might have inferior DFS

References

Mavroudis D, Saloustros E, Boukovinas I, Papakotoulas P, Kakolyris S, Ziras N, Christophylakis C, Kentepozidis N, Fountzilas G, Rigas G, Varthalitis I, Kalbakis K, Agelaki S, Hatzidaki D, Georgoulias V. Sequential vs concurrent epirubicin and docetaxel as adjuvant chemotherapy for high-risk, node-negative, early breast cancer: an interim analysis of a randomised phase III study from the Hellenic Oncology Research Group. Br J Cancer. 2017 Jul 11;117(2):164-170. Epub 2017 Jun 22. link to original article contains verified protocol link to PMC article PubMed

Milan trial

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Arm 1 (Experimental)

Surgery, then A x 4, then CMF x 8

Arm 2 (Experimental)

Surgery, then A alternating with CMF every 2 cycles (12 cycles total)

Comparative efficacy

Approach	Efficacy
Sequential	Superior OS
Alternating	Inferior OS

References

Buzzoni R, Bonadonna G, Valagussa P, Zambetti M. Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes. J Clin Oncol. 1991 Dec;9(12):2134-40. link to original article PubMed
1. Update: Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes: ten-year results. JAMA. 1995 Feb 15;273(7):542-7. link to original article PubMed

NCCTG N9831

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The taxane used in this trial was paclitaxel.

Arm 1, no trastuzumab (Control)

AC, then T

Arm 2, sequential trastuzumab (Experimental)

AC, then T, then H

Arm 3, concurrent trastuzumab (Experimental)

AC, then TH

Comparative efficacy

Comparison 1

Note: Arm 2 was not included in this joint analysis. Efficacy is based on the 2014 update.

Regimen	Efficacy
AC, then T	Inferior OS
AC, then TH	Superior OS

Comparison 2

Note: efficacy is as reported in the 2011 update.

Trastuzumab-containing regimens	Efficacy
AC, then T, then H	Might have inferior DFS
AC, then TH	Might have superior DFS

References

Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. link to original article PubMed
1. Update: Perez EA, Suman VJ, Davidson NE, Gralow JR, Kaufman PA, Visscher DW, Chen B, Ingle JN, Dakhil SR, Zujewski J, Moreno-Aspitia A, Pisansky TM, Jenkins RB. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4491-7. Epub 2011 Oct 31. link to original article link to PMC article PubMed
2. Update: Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014 Nov 20;32(33):3744-52. link to original article link to PMC article PubMed

NCIC CTG MA.21

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Arm 1, CEF (Control)

Surgery, then FEC x 6

Arm 2, AC/T (Control)

Surgery, then AC x 4, then T (Taxol) x 4

Arm 3, ddEC/T (Experimental)

Surgery, then ddEC x 6, then T (Taxol) x 4

Comparative efficacy

Comparison 1

Regimen	Efficacy
AC/T	Inferior RFS
CEF	Superior RFS

Comparison 2

Regimen	Efficacy
AC/T	Inferior RFS
ddEC/T	Superior RFS

Comparison 3

Regimen	Efficacy
CEF	Seems not superior
ddEC/T	Seems not superior

References

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

NEAT

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Arm 1 (Control)

CMF x 6

Arm 2 (Experimental)

Epirubicin x 4, then CMF x 4

Comparative efficacy

Regimen	Efficacy
CMF x 6	Inferior OS
E x 4, then CMF x 4	Superior OS

References

Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. link to original article contains verified protocol PubMed

NeoALTTO

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Arm 1, trastuzumab (C)

Trastuzumab x 6 wk, then TH (Taxol) x 12 wk, then surgery, then FEC x 3, then Trastuzumab x 34 wk

Arm 1, lapatinib (E)

Lapatinib x 6 wk, then TL (Taxol) x 12 wk, then surgery, then FEC x 3, then Lapatinib x 34 wk

Arm 3, lapatinib & trastuzumab (E)

Lapatinib & Trastuzumab x 6 wk, then THL (Taxol) x 12 wk, then surgery, then FEC x 3, then Lapatinib & Trastuzumab x 34 wk

Comparative efficacy

The primary endpoint was pathologic complete response (pCR) rate. Comparison was only between experimental and control arms (i.e., 2 comparisons).

Backbone	Efficacy
Trastuzumab vs. Lapatinib	Seems not superior
Trastuzumab vs. Lapatinib & Trastuzumab	Inferior pCR rate
Lapatinib vs. Trastuzumab	Seems not superior
Lapatinib & Trastuzumab vs. Trastuzumab	Superior pCR rate

References

Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. link to original article link to PMC article contains verified protocol PubMed
1. Update: de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. link to original article PubMed

Neo-tAnGo

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Arm 1, EC-ddT

EC x 4, then ddT x 4, then surgery

Arm 2, ddT-EC

ddT x 4, then EC x 4, then surgery

Arm 3, EC-ddTG

EC x 4, then ddTG x 4, then surgery

Arm 4, ddTG-EC

ddTG x 4, then EC x 4, then surgery

Comparative efficacy

Analyzed using a 2 x 2 factorial design

Comparison 1

Sequencing	Efficacy
Taxane first	Seems to have superior pCR rate
EC first	Seems to have inferior pCR rate

Comparison 2

Addition of gemcitabine	Efficacy
Without gemcitabine	Seems not superior
With gemcitabine	Seems not superior

References

Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, Iddawela M, Abraham J, Hughes-Davies L, Gounaris I, McAdam K, Houston S, Hickish T, Skene A, Chan S, Dean S, Ritchie D, Laing R, Harries M, Gallagher C, Wishart G, Dunn J, Provenzano E, Caldas C; Neo-tAnGo Investigators. Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2×2 factorial randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):201-12. Epub 2013 Dec 19. link to original article PubMed

NOAH

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Arm 1, no trastuzumab (Control)

AT (Taxol) x 3, then T (Taxol) x 3, then CMF x 3, then surgery

Arm 2, with trastuzumab (Experimental)

ATH (Taxol) x 3, then TH x 3, then CMF & H x 3, then surgery, then trastuzumab for a total of 1 year

Comparative efficacy

Sequencing	Efficacy
With trastuzumab	Seems to have superior EFS
No trastuzumab	Seems to have inferior EFS

References

Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, Zambetti M, Vazquez F, Byakhow M, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Baronio R, Feyereislova A, Barton C, Valagussa P, Baselga J. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010 Jan 30;375(9712):377-84. link to original article PubMed
1. Update: Gianni L, Eiermann W, Semiglazov V, Lluch A, Tjulandin S, Zambetti M, Moliterni A, Vazquez F, Byakhov MJ, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Magazzù D, Heinzmann D, Steinseifer J, Valagussa P, Baselga J. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol. 2014 May;15(6):640-7. Epub 2014 Mar 20. Erratum in: Lancet Oncol. 2018 Dec;19(12):e667. link to original article PubMed

NSABP B-27

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Arm 1, no taxane (Control)

AC x 4, then surgery

Arm 2, preoperative taxane (Experimental)

AC x 4, T (Taxotere) x 4, then surgery

Arm 3, postoperative taxane (Experimental)

AC x 4, then surgery, then T (Taxotere) x 4

Comparative efficacy

Regimen	Efficacy
AC, then surgery	Inferior pCR rate
AC, then T, then surgery	Superior pCR rate
AC, then surgery, then T	Inferior pCR rate

References

Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, Wolmark N; National Surgical Adjuvant Breast and Bowel Project Protocol B-27. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003 Nov 15;21(22):4165-74. Epub 2003 Oct 14. link to original article PubMed

NSABP B-30

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Arm 1, AC -> T

AC x 4, then T (Taxotere) x 4

Arm 2, AT

AT x 4

Arm 3, ACT

ACT x 4

Comparative efficacy

Comparison 1

Schedule	Efficacy
Sequential AC -> T	Might have superior OS
Concurrent ACT	Might have inferior OS

Comparison 2

Schedule	Efficacy
Sequential AC -> T	Seems to have superior OS
Concurrent AT	Seems to have inferior OS

References

Swain SM, Jeong JH, Geyer CE Jr, Costantino JP, Pajon ER, Fehrenbacher L, Atkins JN, Polikoff J, Vogel VG, Erban JK, Rastogi P, Livingston RB, Perez EA, Mamounas EP, Land SR, Ganz PA, Wolmark N. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med. 2010 Jun 3;362(22):2053-65. link to original article link to PMC article PubMed

NSABP B-38

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Arm 1, sequential without gemcitabine (Control)

Surgery, then ddAC x 4, then ddP x 4

Arm 2, sequential with gemcitabine (Experimental)

Surgery, then ddAC x 4, then ddPG x 4

Arm 3, concurrent

Surgery, then TAC x 6

Comparative efficacy

Schedule	Efficacy
Sequential (ddAC, then ddP)	Seems not superior
Sequential (ddAC, then ddPG)	Seems not superior
Concurrent (TAC)	Seems not superior

References

Swain SM, Tang G, Geyer CE Jr, Rastogi P, Atkins JN, Donnellan PP, Fehrenbacher L, Azar CA, Robidoux A, Polikoff JA, Brufsky AM, Biggs DD, Levine EA, Zapas JL, Provencher L, Northfelt DW, Paik S, Costantino JP, Mamounas EP, Wolmark N. Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial. J Clin Oncol. 2013 Sep 10;31(26):3197-204. Epub 2013 Aug 12. link to original article link to PMC article PubMed

NSABP B-40

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Arm 1 - Control

T (Taxotere) x 4, then AC x 4, then surgery

Arm 2

T+Bev, then AC+Bev, then surgery, then Bevacizumab x 10

Arm 3

TX x 4, then AC x 4, then surgery

Arm 4

TX+Bev x 4, then AC+Bev, then surgery, then Bevacizumab x 10

Arm 5

TG x 4, then AC x 4, then surgery

Arm 6

TG+Bev x 4, then AC+Bev, then surgery, then Bevacizumab x 10

Comparative efficacy

This trial was analyzed using a 3 x 2 factorial design; primary endpoint was pathologic complete response (pCR) rate.

Addition of bevacizumab

Regimen	Efficacy
No bevacizumab (C)	Seems to have inferior pCR rate
Bevacizumab-based therapy (E)	Seems to have superior pCR rate

Addition of capecitabine or gemcitabine

Regimen	Efficacy
Docetaxel alone (C)	Seems not superior
TX or TG (E)	Seems not superior

References

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

NSAS BC-02

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Arm 1 - Control

Surgery, AC x 4, then T (Taxotere) x 4

Arm 2 - Control

Surgery, AC x 4, then T (Taxol) x 4

Arm 3

Surgery, then docetaxel x 8

Arm 4

Surgery, then paclitaxel x 8

Comparative efficacy

This trial was analyzed using a 2 x 2 factorial design.

Use of AC

Regimen	Efficacy
AC-containing	Inconclusive whether non-inferior
AC-free	Inconclusive whether non-inferior

Taxane

Regimen	Efficacy
Docetaxel	Seems to have superior OS
Paclitaxel (q3wk)	Seems to have inferior OS

References

Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. link to original article PubMed

PREPARE

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Arm 1, control

EC x 4, then T (Taxol) x 4, then surgery

Arm 2, experimental

ddE x 3, then ddT (Taxol) x 3, then CMF x 3, then surgery

Comparative efficacy

Regimen	Efficacy
Control	Seems not superior
Experimental	Seems not superior

References

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

Recht et al. 1996

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Arm 1, chemo first

Lumpectomy, then CAMFP, then RT

Arm 2, RT first

Lumpectomy, then RT, then CAMFP

Comparative efficacy

anti-HER2 medication	Comparative Efficacy
Chemo first	Seems to have superior MFS
RT first	Seems to have inferior MFS

References

Recht A, Come SE, Henderson IC, Gelman RS, Silver B, Hayes DF, Shulman LN, Harris JR. The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med. 1996 May 23;334(21):1356-61. link to original article PubMed

SB3-G31-BC

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Arm 1, trastuzumab (control)

TH x 4, then FEC & H x 4, then surgery, then adjuvant trastuzumab

Arm 2, SB3 (experimental trastuzumab biosimilar)

Same schedule with SB3 instead of trastuzumab

Comparative efficacy

anti-HER2 medication	Comparative Efficacy
Trastuzumab	Equivalent pCR rate
SB3 (trastuzumab biosimilar)	Equivalent pCR rate

References

Pivot X, Bondarenko I, Nowecki Z, Dvorkin M, Trishkina E, Ahn JH, Vinnyk Y, Im SA, Sarosiek T, Chatterjee S, Wojtukiewicz MZ, Moiseyenko V, Shparyk Y, Bello M 3rd, Semiglazov V, Song S, Lim J. Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients treated with neoadjuvant therapy for human epidermal growth factor receptor 2-positive early breast cancer. J Clin Oncol. 2018 Apr 1;36(10):968-974. Epub 2018 Jan 26. link to original article PubMed

SBG 9401

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Arm 1 (control)

Surgery, then FEC x 2, then HD-FEC x 1, then CTCb with auto HSCT

Arm 2 (experimental)

Tailored FEC x 6

Comparative efficacy

Regimen	Efficacy
Control	Seems to have inferior RFS
Experimental	Seems to have superior RFS

References

Bergh J, Wiklund T, Erikstein B, Lidbrink E, Lindman H, Malmström P, Kellokumpu-Lehtinen P, Bengtsson NO, Söderlund G, Anker G, Wist E, Ottosson S, Salminen E, Ljungman P, Holte H, Nilsson J, Blomqvist C, Wilking N; Scandinavian Breast Group 9401 study. Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Lancet. 2000 Oct 21;356(9239):1384-91. Erratum in: Lancet 2000 Dec 23-30;356(9248):2196. link to SD article PubMed

SWOG-8814

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Arm 1 (Control)

Surgery, then tamoxifen x 5 y

Arm 2, CAF-T (Experimental)

Surgery, then CAF x 6, then tamoxifen x 5 y

Arm 3, CAFT (Experimental)

Surgery, then CAFT

Comparative efficacy

Comparison 1

Design	Efficacy
No chemotherapy	Might have inferior OS
With chemotherapy	Might have superior OS

Comparison 2

Timing	Efficacy
Concurrent (CAFT)	Might have inferior DFS
Sequential (CAF-T)	Might have superior DFS

References

Albain KS, Barlow WE, Ravdin PM, Farrar WB, Burton GV, Ketchel SJ, Cobau CD, Levine EG, Ingle JN, Pritchard KI, Lichter AS, Schneider DJ, Abeloff MD, Henderson IC, Muss HB, Green SJ, Lew D, Livingston RB, Martino S, Osborne CK; Breast Cancer Intergroup of North America. Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009 Dec 19;374(9707):2055-2063. Epub 2009 Dec 10. link to original article link to PMC article PubMed

TACT

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Arm 1 (Experimental)

Surgery, then FEC x 4, then D x 4

Arm 2 (Control)

Surgery, then FEC x 8

Arm 3 (Control)

Surgery, then E x 4, then CMF x 4

Comparative efficacy

Regimen	Efficacy
Experimental (with docetaxel)	Seems not superior
Standard (no docetaxel)	Seems not superior

References

Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. link to original article link to PMC article PubMed

TACT2

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Arm 1 (Experimental)

ddE, then capecitabine

Arm 2 (Experimental)

ddE, then CMF

Arm 3 (Experimental)

E, then capecitabine

Arm 4 (Control)

E, then CMF

Comparative efficacy

Analyzed using a 2 x 2 factorial design

Comparison 1

Dose density of epirubicin	Efficacy
Dose-dense (q2wk)	Seems not superior
Standard (q3wk)	Seems not superior

Comparison 2

Capecitabine vs. CMF	Efficacy
Capecitabine	Non-inferior TTR
CMF	Non-inferior TTR

References

Cameron D, Morden JP, Canney P, Velikova G, Coleman R, Bartlett J, Agrawal R, Banerji J, Bertelli G, Bloomfield D, Brunt AM, Earl H, Ellis P, Gaunt C, Gillman A, Hearfield N, Laing R, Murray N, Couper N, Stein RC, Verrill M, Wardley A, Barrett-Lee P, Bliss JM; TACT2 Investigators. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2017 Jul;18(7):929-945. Epub 2017 Jun 7. link to original article link to PMC article PubMed

TEAM

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Arm 1, monotherapy (Control)

Tamoxifen x 5y

Arm 2, sequential (Experimental)

Tamoxifen x 2.5-3y, then Exemestane x 2-2.5y

Comparative efficacy

Regimen	Efficacy
Tamoxifen x 5y	Seems not superior
Tamoxifen x 2.5-3y, then Exemestane x 2-2.5y	Seems not superior

References

van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel JM, Paridaens R, Markopoulos C, Hozumi Y, Hille ET, Kieback DG, Asmar L, Smeets J, Nortier JW, Hadji P, Bartlett JM, Jones SE. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet. 2011 Jan 22;377(9762):321-31. link to original article contains verified protocol PubMed
1. Update: Derks MGM, Blok EJ, Seynaeve C, Nortier JWR, Kranenbarg EM, Liefers GJ, Putter H, Kroep JR, Rea D, Hasenburg A, Markopoulos C, Paridaens R, Smeets JBE, Dirix LY, van de Velde CJH. Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Sep;18(9):1211-1220. Epub 2017 Jul 18. link to original article PubMed

TRYPHAENA

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Arm A

FEC & HP x 3, then THP x 3, then surgery

Arm B

FEC x 3, then THP x 3, then surgery

Arm C

TCHP x 6, then surgery

Comparative efficacy

Note: this was a cardiac safety study; efficacy findings are not reported.

References

TRYPHAENA: Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortés J. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013 Sep;24(9):2278-84. Epub 2013 May 22. link to original article PubMed

Cervical cancer

NOGGO-AGO

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Arm 1 (Control)

Surgery, then adjuvant Carboplatin & Ifosfamide x 4, then EBRT

Arm 2 (Experimental)

Surgery, then adjuvant Carboplatin, Ifosfamide, Erythropoietin alfa, then EBRT & Erythropoietin alfa

Comparative efficacy

Regimen	Efficacy
No EPO	Might have inferior RFS
With EPO	Might have superior RFS

References

Blohmer JU, Paepke S, Sehouli J, Boehmer D, Kolben M, Würschmidt F, Petry KU, Kimmig R, Elling D, Thomssen C, von Minckwitz G, Möbus V, Hinke A, Kümmel S, Budach V, Lichtenegger W, Schmid P. Randomized phase III trial of sequential adjuvant chemoradiotherapy with or without erythropoietin Alfa in patients with high-risk cervical cancer: results of the NOGGO-AGO intergroup study. J Clin Oncol. 2011 Oct 1;29(28):3791-7. Epub 2011 Aug 22. link to original article PubMed

Colorectal cancer

CAIRO

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Arm 1, sequential single agent (Control)

First-line capecitabine, then second-line irinotecan, then third-line CapeOx

Arm 2, sequential combinations (Experimental)

First-line CAPIRI, then second-line CapeOx

Comparative efficacy

Approach	Efficacy
Sequential single agent	Seems not superior
Sequential combinations	Seems not superior

References

Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. link to original article PubMed

FFCD 2000-05

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Arm 1, sequential (Control)

First-line sLV5FU2, then second-line mFOLFOX6, then third-line FOLFIRI

Arm 2, combination (Experimental)

First-line mFOLFOX6, then second-line FOLFIRI

Comparative efficacy

Approach	Efficacy	Toxicity
Sequential	Seems not superior	Less toxic
Combination	Seems not superior	More toxic

References

Ducreux M, Malka D, Mendiboure J, Etienne PL, Texereau P, Auby D, Rougier P, Gasmi M, Castaing M, Abbas M, Michel P, Gargot D, Azzedine A, Lombard-Bohas C, Geoffroy P, Denis B, Pignon JP, Bedenne L, Bouché O; Fédération Francophone de Cancérologie Digestive (FFCD) 2000–05 Collaborative Group. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol. 2011 Oct;12(11):1032-44. Epub 2011 Sep 6. link to original article PubMed

Diffuse large B-cell lymphoma

SWOG S8736

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Arm 1 - Control

CHOP x 8

Arm 2 - Experimental

CHOP x 3, then RT x 40 to 55 Gy

Comparative efficacy

Regimen	Efficacy
CHOP x 8	Seems to have inferior OS
CHOP x 3, then RT	Seems to have superior OS

References

Miller TP, Dahlberg S, Cassady JR, Adelstein DJ, Spier CM, Grogan TM, LeBlanc M, Carlin S, Chase E, Fisher RI. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med. 1998 Jul 2;339(1):21-6. link to original article PubMed

Follicular lymphoma

GALLIUM

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Arm 1 - Control

BR x 6 or R-CHOP x 8 or R-CVP x 8, then Rituximab maintenance x 2 y

Arm 2 - Experimental

Bendamustine & Obinutuzumab x 6 or G-CHOP x 8 or G-CVP x 8, then Obinutuzumab maintenance x 2y

Comparative efficacy

mAb	Efficacy	Toxicity
Rituximab-chemotherapy	Inferior PFS	Superior toxicity
Obinutuzumab-chemotherapy	Superior PFS	Inferior toxicity

References

Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. link to original article link to appendix PubMed

Gastroesophageal cancer

ACCORD 07

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Arm 1 - Control

Surgery alone

Arm 2 - Experimental

Neoadjuvant CF, then surgery, then adjuvant CF

Comparative efficacy

Regimen	Efficacy
Surgery alone	Seems to have inferior OS
Perioperative CF	Seems to have superior OS

References

Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. Epub 2011 Mar 28. link to original article PubMed

FLOT4-AIO

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Arm 1 - Control

ECF or ECX x 3, then surgery, then ECF or ECX x 3

Arm 2 - Experimental

FLOT x 4, then surgery, then FLOT x 4

Comparative efficacy

Regimen	Efficacy
ECF/ECX	Seems to have inferior OS
FLOT	Seems to have superior OS

References

Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, Meiler J, Homann N, Lorenzen S, Schmalenberg H, Probst S, Koenigsmann M, Egger M, Prasnikar N, Caca K, Trojan J, Martens UM, Block A, Fischbach W, Mahlberg R, Clemens M, Illerhaus G, Zirlik K, Behringer DM, Schmiegel W, Pohl M, Heike M, Ronellenfitsch U, Schuler M, Bechstein WO, Königsrainer A, Gaiser T, Schirmacher P, Hozaeel W, Reichart A, Goetze TO, Sievert M, Jäger E, Mönig S, Tannapfel A. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 2016 Dec;17(12):1697-1708. Epub 2016 Oct 22. link to original article PubMed
1. Update: Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, Kopp HG, Mayer F, Haag GM, Luley K, Lindig U, Schmiegel W, Pohl M, Stoehlmacher J, Folprecht G, Probst S, Prasnikar N, Fischbach W, Mahlberg R, Trojan J, Koenigsmann M, Martens UM, Thuss-Patience P, Egger M, Block A, Heinemann V, Illerhaus G, Moehler M, Schenk M, Kullmann F, Behringer DM, Heike M, Pink D, Teschendorf C, Löhr C, Bernhard H, Schuch G, Rethwisch V, from Weikersthal LF, Hartmann JT, Kneba M, Daum S, Schulmann K, Less J, Belle S, Gaiser T, Oduncu FS, Güntner M, Hozaeel W, Reichart A, Hunter E, Kraus T, Mönig S, Bechstein WO, Schuler M, Schmalenberg H, Hofheinz RD; FLOT4-AIO Investigators. perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomized, phase 2/3 trial. Lancet. 2019 Apr 10. [Epub ahead of print] link to original article PubMed

MAGIC

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Arm 1 - Control

Surgery

Arm 2 - Experimental

ECF x 3, then surgery, then ECF x 3

Comparative efficacy

Regimen	Efficacy
Surgery alone	Inferior OS
Perioperative ECF	Superior OS

References

Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ, MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. link to original article PubMed

POET

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Arm 1

PLF x 15 wk, then surgery

Arm 2

PLF x 12 wk, then Cisplatin, Etoposide, RT, then surgery

Comparative efficacy

Regimen	Efficacy
Neoadjuvant chemotherapy only	Might have inferior OS
Neoadjuvant chemotherapy and chemoradiotherapy	Might have superior OS

References

Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, Riera-Knorrenschild J, Langer P, Engenhart-Cabillic R, Bitzer M, Königsrainer A, Budach W, Wilke H. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol. 2009 Feb 20;27(6):851-6. Epub 2009 Jan 12. link to original article PubMed

PRODIGE5/ACCORD17

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Arm 1 - Control

Definitive CF & RT, then CF x 2

Arm 2 - Experimental

Definitive FOLFOX4 & RT, then FOLFOX4 x 3

Comparative efficacy

Regimen	Efficacy
CF-based	Seems not superior
FOLFOX4-based	Seems not superior

References

Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, François E, Créhange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A; Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014 Mar;15(3):305-14. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. link to original article PubMed

Glioblastoma

AVAglio

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Arm 1, control

Surgery, then adjuvant temozolomide & RT, then temozolomide maintenance

Arm 2, experimental

Surgery, then adjuvant temozolomide, bevacizumab, RT, then temozolomide & bevacizumab maintenance, then bevacizumab maintenance

Comparative efficacy

Regimen	Efficacy
Temozolomide alone	Inferior PFS
Bevacizumab-containing arm	Superior PFS

References

Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):709-22. link to original article PubMed

EORTC 22981/26981; NCIC CTG CE.3

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Arm 1, control

Surgery, then adjuvant radiotherapy

Arm 2, experimental

Surgery, then adjuvant Temozolomide & RT, then Temozolomide maintenance

Comparative efficacy

Regimen	Efficacy
Radiotherapy alone	Inferior OS
Temozolomide-containing arm	Superior OS

References

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. link to original article PubMed

HERBY

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Arm 1, control

Surgery, then adjuvant temozolomide & RT, then temozolomide maintenance

Arm 2, experimental

Surgery, then adjuvant temozolomide, bevacizumab, RT, then temozolomide & bevacizumab maintenance

Comparative efficacy

Regimen	Efficacy
Temozolomide alone	Seems not superior
Bevacizumab-containing arm	Seems not superior

References

Grill J, Massimino M, Bouffet E, Azizi AA, McCowage G, Cañete A, Saran F, Le Deley MC, Varlet P, Morgan PS, Jaspan T, Jones C, Giangaspero F, Smith H, Garcia J, Elze MC, Rousseau RF, Abrey L, Hargrave D, Vassal G. Phase II, open-label, randomized, multicenter trial (HERBY) of bevacizumab in pediatric patients with newly diagnosed high-grade glioma. J Clin Oncol. 2018 Apr 1;36(10):951-958. Epub 2018 Feb 7. link to original article PubMed

RTOG 0825

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Arm 1, control

Surgery, then adjuvant Temozolomide & RT, then Temozolomide maintenance

Arm 2, experimental

Surgery, then adjuvant Temozolomide, Bevacizumab, RT, then Temozolomide & Bevacizumab maintenance

Comparative efficacy

Note: although the control regimen had inferior PFS, the effect size did not reach the prespecified improvement target.

Regimen	Efficacy
Temozolomide alone	Inferior PFS
Bevacizumab-containing arm	Superior PFS

References

Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. link to original article link to PMC article PubMed

Head and neck cancer

EORTC 24954

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Arm 1, control

CF x 4, then RT

Arm 2, experimental

CF/RT

Comparative efficacy

Regimen	Efficacy
Sequential RT	Seems not superior
Alternating RT	Seems not superior

References

Lefebvre JL, Rolland F, Tesselaar M, Bardet E, Leemans CR, Geoffrois L, Hupperets P, Barzan L, de Raucourt D, Chevalier D, Licitra L, Lunghi F, Stupp R, Lacombe D, Bogaerts J, Horiot JC, Bernier J, Vermorken JB; EORTC Head and Neck Cancer Cooperative Group; EORTC Radiation Oncology Group. Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy. J Natl Cancer Inst. 2009 Feb 4;101(3):142-52. Epub 2009 Jan 27. link to original article link to PMC article PubMed

RTOG 91-11

Arm 1, induction chemotherapy, then radiotherapy (Control)

PF x 3, then RT

Arm 2, concurrent chemoradiotherapy (Experimental)

Cisplatin & RT

Arm 3, radiotherapy (Experimental)

RT

Comparative efficacy

Efficacy is based on the 2012 update.

Regimen vs.	Arm 1	Arm 2	Arm 3
Arm 1 vs.		Inferior LFS	Seems to have superior LFS
Arm 2 vs.	Superior LFS		Seems to have superior LFS
Arm 3 vs.	Seems to have inferior LFS	Seems to have inferior LFS

References

Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, Glisson B, Trotti A, Ridge JA, Chao C, Peters G, Lee DJ, Leaf A, Ensley J, Cooper J. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003 Nov 27;349(22):2091-8. link to original article PubMed
1. Update: Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, Pajak TF, Morrison W, Glisson B, Trotti A, Ridge JA, Thorstad W, Wagner H, Ensley JF, Cooper JS. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013 Mar 1;31(7):845-52. Epub 2012 Nov 26. link to original article contains partial protocol link to PMC article PubMed

Hodgkin lymphoma

EORTC 20012

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Arm 1

eBEACOPP x 4, then BEACOPP x 4

Arm 2

ABVD x 8

Comparative efficacy

Regimen	Efficacy
BEACOPP₄₊₄	Did not meet primary endpoint of EFS
ABVD x 8	Did not meet primary endpoint of EFS

References

Carde P, Karrasch M, Fortpied C, Brice P, Khaled H, Casasnovas O, Caillot D, Gaillard I, Bologna S, Ferme C, Lugtenburg PJ, Morschhauser F, Aurer I, Coiffier B, Meyer R, Seftel M, Wolf M, Glimelius B, Sureda A, Mounier N. Eight cycles of ABVD versus four cycles of BEACOPP_escalated plus four cycles of BEACOPP_baseline in stage III to IV, International Prognostic Score ≥ 3, high-risk Hodgkin lymphoma: First results of the phase III EORTC 20012 Intergroup trial. J Clin Oncol. 2016 Jun 10;34(17):2028-36. Epub 2016 Apr 25. link to original article contains verified protocol PubMed

EORTC-GELA H8-F

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Arm 1

MOPP-ABV x 3, then IFRT

Arm 2

STNI

Comparative efficacy

Regimen	Efficacy
MOPP-ABV x 3, then IFRT	Superior OS
STNI	Inferior OS

References

Fermé C, Eghbali H, Meerwaldt JH, Rieux C, Bosq J, Berger F, Girinsky T, Brice P, van't Veer MB, Walewski JA, Lederlin P, Tirelli U, Carde P, Van den Neste E, Gyan E, Monconduit M, Diviné M, Raemaekers JM, Salles G, Noordijk EM, Creemers GJ, Gabarre J, Hagenbeek A, Reman O, Blanc M, Thomas J, Vié B, Kluin-Nelemans JC, Viseu F, Baars JW, Poortmans P, Lugtenburg PJ, Carrie C, Jaubert J, Henry-Amar M; EORTC-GELA H8 Trial. Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med. 2007 Nov 8;357(19):1916-27. link to original article contains verified protocol in supplement PubMed

EORTC-GELA H8-U

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Arm 1

MOPP-ABV x 4, then IFRT

Arm 2

MOPP-ABV x 4, then STNI

Arm 3

MOPP-ABV x 6, then IFRT

Comparative efficacy

Note: the paper describes this as an equivalence study, although the primary endpoint of EFS had p=0.80.

Regimen	Efficacy
MOPP-ABV x 4, then IFRT	Inconclusive whether equivalent
MOPP-ABV x 4, then STNI	Inconclusive whether equivalent
MOPP-ABV x 6, then IFRT	Inconclusive whether equivalent

References

Fermé C, Eghbali H, Meerwaldt JH, Rieux C, Bosq J, Berger F, Girinsky T, Brice P, van't Veer MB, Walewski JA, Lederlin P, Tirelli U, Carde P, Van den Neste E, Gyan E, Monconduit M, Diviné M, Raemaekers JM, Salles G, Noordijk EM, Creemers GJ, Gabarre J, Hagenbeek A, Reman O, Blanc M, Thomas J, Vié B, Kluin-Nelemans JC, Viseu F, Baars JW, Poortmans P, Lugtenburg PJ, Carrie C, Jaubert J, Henry-Amar M; EORTC-GELA H8 Trial. Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med. 2007 Nov 8;357(19):1916-27. link to original article contains verified protocol in supplement PubMed

EORTC/LYSA/FIL H10

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Note: randomization in this trial occurred before treatment, but took effect after 2 cycles of ABVD, and only if interim PET-CT was negative.

Arm 1

Favorable: ABVD x 4
Unfavorable: ABVD x 6

Arm 2

Favorable: ABVD x 3, then INRT
Unfavorable: ABVD x 4, then INRT

Comparative efficacy

Regimen	Efficacy
ABVD x 4	Inconclusive whether non-inferior
ABVD x 3, then INRT	Inconclusive whether non-inferior

References

Raemaekers JM, André MP, Federico M, Girinsky T, Oumedaly R, Brusamolino E, Brice P, Fermé C, van der Maazen R, Gotti M, Bouabdallah R, Sebban CJ, Lievens Y, Re A, Stamatoullas A, Morschhauser F, Lugtenburg PJ, Abruzzese E, Olivier P, Casasnovas RO, van Imhoff G, Raveloarivahy T, Bellei M, van der Borght T, Bardet S, Versari A, Hutchings M, Meignan M, Fortpied C. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014 Apr 20;32(12):1188-94. Epub 2014 Mar 17. link to original article PubMed
1. Update: André MPE, Girinsky T, Federico M, Reman O, Fortpied C, Gotti M, Casasnovas O, Brice P, van der Maazen R, Re A, Edeline V, Fermé C, van Imhoff G, Merli F, Bouabdallah R, Sebban C, Specht L, Stamatoullas A, Delarue R, Fiaccadori V, Bellei M, Raveloarivahy T, Versari A, Hutchings M, Meignan M, Raemaekers J. Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2017 Jun 1;35(16):1786-1794. Epub 2017 Mar 14. link to original article PubMed

GHSG HD11

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Note: the primary endpoints of this trial, which were to determine the superiority of BEACOPP vs. ABVD and noninferiority of 20 Gy vs. 30 Gy of IFRT, were not reported in the manuscript.

Arm 1

ABVD x 4, then IFRT x 30 Gy

Arm 2

ABVD x 4, then IFRT x 20 Gy

Arm 3

BEACOPP x 4, then IFRT x 30 Gy

Arm 4

BEACOPP x 4, then IFRT x 20 Gy

Comparative efficacy

Designed using a 2 x 2 factorial design

Comparison 1

Chemotherapy	Efficacy
ABVD	Not reported
BEACOPP	Not reported

Comparison 2

Radiotherapy	Efficacy
IFRT x 20 Gy	Not reported
IFRT x 30 Gy	Not reported

References

Eich HT, Diehl V, Görgen H, Pabst T, Markova J, Debus J, Ho A, Dörken B, Rank A, Grosu AL, Wiegel T, Karstens JH, Greil R, Willich N, Schmidberger H, Döhner H, Borchmann P, Müller-Hermelink HK, Müller RP, Engert A. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol. 2010 Sep 20;28(27):4199-206. Epub 2010 Aug 16. link to original article PubMed

GHSG HD12

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Arm 1

eBEACOPP x 8, then ISRT x 30 Gy for patients with initial bulky disease or residual disease

Arm 2

eBEACOPP x 8, then no further treatment for patients with initial bulky disease or residual disease

Arm 3

eBEACOPP x 4, then BEACOPP x 4, then ISRT x 30 Gy for patients with initial bulky disease or residual disease

Arm 4

eBEACOPP x 4, then BEACOPP x 4, then no further treatment for patients with initial bulky disease or residual disease

Comparative efficacy

Designed using a 2 x 2 factorial design

Comparison 1

Reported efficacy is based on the 2018 update.

Chemotherapy	Efficacy
eBEACOPP x 8	Non-inferior OS (*)
eBEACOPP x 4, then BEACOPP x 4	Non-inferior OS (*)

Comparison 2

Radiotherapy	Efficacy
ISRT x 30 Gy	Might have superior 5-year FFTF
No radiotherapy	Might have inferior 5-year FFTF

References

Borchmann P, Haverkamp H, Diehl V, Cerny T, Markova J, Ho AD, Eich HT, Mueller-Hermelink HK, Kanz L, Greil R, Rank A, Paulus U, Smardova L, Huber C, Dörken B, Nerl C, Krause SW, Mueller RP, Fuchs M, Engert A. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkin's lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011 Nov 10;29(32):4234-42. Epub 2011 Oct 11. link to original article PubMed
1. Update: von Tresckow B, Kreissl S, Dipl-Math HG, Bröckelmann PJ, Pabst T, Fridrik M, Rummel M, Jung W, Thiemer J, Sasse S, Bürkle C, Baues C, Diehl V, Engert A, Borchmann P; German Hodgkin Study Group. Intensive treatment strategies in advanced-stage Hodgkin's lymphoma (HD9 and HD12): analysis of long-term survival in two randomised trials. Lancet Haematol. 2018 Oct 01;5(10):e462-73. link to original article PubMed

GHSG HD14

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Arm 1

ABVD x 4, then IFRT x 30 Gy

Arm 2

eBEACOPP x 2, then ABVD x 2, then IFRT x 30 Gy

Comparative efficacy

Chemotherapy	Efficacy
ABVD x 4	Inferior FFTF
eBEACOPP x 2, then ABVD x 2	Superior FFTF

References

von Tresckow B, Plütschow A, Fuchs M, Klimm B, Markova J, Lohri A, Kral Z, Greil R, Topp MS, Meissner J, Zijlstra JM, Soekler M, Stein H, Eich HT, Mueller RP, Diehl V, Borchmann P, Engert A. Dose-intensification in early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol. 2012 Mar 20;30(9):907-13. Epub 2012 Jan 23. link to original article PubMed

GSM-HD

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Arm 1

eBEACOPP x 4, then BEACOPP x 4

Arm 2

ABVD x 8

Comparative efficacy

Regimen	Efficacy
BEACOPP₄₊₄	Seems to have superior FFFP
ABVD x 8	Seems to have inferior FFFP

References

Viviani S, Zinzani PL, Rambaldi A, Brusamolino E, Levis A, Bonfante V, Vitolo U, Pulsoni A, Liberati AM, Specchia G, Valagussa P, Rossi A, Zaja F, Pogliani EM, Pregno P, Gotti M, Gallamini A, Rota Scalabrini D, Bonadonna G, Gianni AM; Michelangelo Foundation; Gruppo Italiano di Terapie Innovative nei Linfomi; Intergruppo Italiano Linfomi. ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned. N Engl J Med. 2011 Jul 21;365(3):203-12. link to original article PubMed

LYSA H34

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Arm 1

eBEACOPP x 4, then BEACOPP x 4

Arm 2

ABVD x 8

Comparative efficacy

Regimen	Efficacy
BEACOPP₄₊₄	Might have superior EFS
ABVD x 8	Might have inferior EFS

References

Mounier N, Brice P, Bologna S, Briere J, Gaillard I, Heczko M, Gabarre J, Casasnovas O, Jaubert J, Colin P, Delmer A, Devidas A, Bachy E, Nicolas-Virelizier E, Aoudjhane A, Humbrecht C, Andre M, Carde P; Lymphoma Study Association (LYSA). ABVD (8 cycles) versus BEACOPP (4 escalated cycles ≥4 baseline): final results in stage III-IV low-risk Hodgkin lymphoma (IPS 0-2) of the LYSA H34 randomized trial. Ann Oncol. 2014 Aug;25(8):1622-8. Epub 2014 May 14. link to original article contains verified protocol PubMed

NCIC CTG/ECOG HD.6

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Note: this randomization was for patients with unfavorable risk.

Arm 1

ABVD x 4

Arm 2

ABVD x 2, then STNI

Comparative efficacy

Efficacy is based on the 2011 update.

Regimen	Efficacy
ABVD x 4	Seems to have superior OS
ABVD x 2, then STNI	Seems to have inferior OS

References

Meyer RM, Gospodarowicz MK, Connors JM, Pearcey RG, Bezjak A, Wells WA, Burns BF, Winter JN, Horning SJ, Dar AR, Djurfeldt MS, Ding K, Shepherd LE; National Cancer Institute of Canada Clinical Trials Group; Eastern Cooperative Oncology Group. Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol. 2005 Jul 20;23(21):4634-42. Epub 2005 Apr 18. link to original article PubMed
1. Update: Meyer RM, Gospodarowicz MK, Connors JM, Pearcey RG, Wells WA, Winter JN, Horning SJ, Dar AR, Shustik C, Stewart DA, Crump M, Djurfeldt MS, Chen BE, Shepherd LE; NCIC Clinical Trials Group; Eastern Cooperative Oncology Group. ABVD alone versus radiation-based therapy in limited-stage Hodgkin's lymphoma. N Engl J Med. 2012 Feb 2;366(5):399-408. Epub 2011 Dec 11. link to original article link to PMC article PubMed

Mantle cell lymphoma

MCL Younger

Arm 1 (Control)

R-CHOP x 6, then Dexa-BEAM, then Cy/TBI auto HSCT

Arm 2 (Experimental)

R-CHOP/R-DHAP x 6, then cytarabine, melphalan, TBI auto HSCT

Comparative efficacy

Regimen	Efficacy
SOC	Seems to have inferior TTTF
Cytarabine-based	Seems to have superior TTTF

References

Hermine O, Hoster E, Walewski J, Bosly A, Stilgenbauer S, Thieblemont C, Szymczyk M, Bouabdallah R, Kneba M, Hallek M, Salles G, Feugier P, Ribrag V, Birkmann J, Forstpointner R, Haioun C, Hänel M, Casasnovas RO, Finke J, Peter N, Bouabdallah K, Sebban C, Fischer T, Dührsen U, Metzner B, Maschmeyer G, Kanz L, Schmidt C, Delarue R, Brousse N, Klapper W, Macintyre E, Delfau-Larue MH, Pott C, Hiddemann W, Unterhalt M, Dreyling M; European Mantle Cell Lymphoma Network. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016 Aug 6;388(10044):565-75. Epub 2016 Jun 14. link to original article PubMed

Multiple myeloma

HOVON-50

Arm 1 (Control)

VAD, then CAD & G-CSF stem cell mobilization, then single or tandem melphalan auto HSCT, then interferon alfa maintenance

Arm 2 (Experimental)

TAD x 3, then CAD & G-CSF stem cell mobilization, then single or tandem melphalan auto HSCT, then thalidomide maintenance

Comparative efficacy

Regimen	Efficacy
SOC	Inferior PFS
Thalidomide-based	Superior PFS

References

Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. link to original article PubMed
1. Update: van de Donk NW, van der Holt B, Minnema MC, Vellenga E, Croockewit S, Kersten MJ, von dem Borne PA, Ypma P, Schaafsma R, de Weerdt O, Klein SK, Delforge M, Levin MD, Bos GM, Jie KG, Sinnige H, Coenen JL, de Waal EG, Zweegman S, Sonneveld P, Lokhorst HM. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial. Lancet Haematol. 2018 Oct;5(10):e479-e492. link to original article PubMed

Non-small cell lung cancer

CONVINCE

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Arm 1 (Control)

Cis-Pem x 4, then Pemetrexed maintenance

Arm 2 (Experimental)

Icotinib

Comparative efficacy

Regimen	Efficacy
Cis-Pem, then Pem	Inferior PFS
Icotinib	Superior PFS

References

Shi YK, Wang L, Han BH, Li W, Yu P, Liu YP, Ding CM, Song X, Ma ZY, Ren XL, Feng JF, Zhang HL, Chen GY, Han XH, Wu N, Yao C, Song Y, Zhang SC, Song W, Liu XQ, Zhao SJ, Lin YC, Ye XQ, Li K, Shu YQ, Ding LM, Tan FL, Sun Y. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol. 2017 Oct 1;28(10):2443-2450. link to original article PubMed

ECOG 3598

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Arm 1 (Control)

PC induction, then Carboplatin, Paclitaxel, RT

Arm 2, with thalidomide (Experimental)

TPC, then Carboplatin, Paclitaxel, Thalidomide, RT

Comparative efficacy

Regimen	Efficacy
Without thalidomide	Seems not superior
With thalidomide	Seems not superior

References

Hoang T, Dahlberg SE, Schiller JH, Mehta MP, Fitzgerald TJ, Belinsky SA, Johnson DH. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol. 2012 Feb 20;30(6):616-22. Epub 2012 Jan 23. link to original article link to PMC article PubMed

ECOG E4599

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Arm 1 (Control)

Carboplatin & Paclitaxel x 6

Arm 2, with bevacizumab (Experimental)

PacCBev x 6, then bevacizumab maintenance

Comparative efficacy

Regimen	Efficacy
Platinum doublet	Inferior OS
With bevacizumab	Superior OS

References

Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. link to original article PubMed
1. Subgroup analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; Eastern Cooperative Oncology Group. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. link to original article PubMed

IUNO

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Arm 1, "early" erlotinib

Maintenance erlotinib

Arm 2, "late" erlotinib

Placebo until progression or intolerance, then erlotinib

Comparative efficacy

Timing	Efficacy
Maintenance erlotinib	Seems not superior
Second-line erlotinib	Seems not superior

References

Cicènas S, Geater SL, Petrov P, Hotko Y, Hooper G, Xia F, Mudie N, Wu YL. Maintenance erlotinib versus erlotinib at disease progression in patients with advanced non-small-cell lung cancer who have not progressed following platinum-based chemotherapy (IUNO study). Lung Cancer. 2016 Dec;102:30-37. Epub 2016 Oct 20. link to original article contains verified protocol PubMed

KEYNOTE-021

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Arm 1 (Control)

Carbo-Pem x 4, then pemetrexed maintenance

Arm 2, with pembrolizumab (Experimental)

Carboplatin, Pemetrexed, Pembrolizumab x 4, then Pemetrexed & Pembrolizumab maintenance

Comparative efficacy

Regimen	Efficacy
Control	Inferior ORR
Experimental (with pembrolizumab)	Superior ORR

References

Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. link to original article supplementary appendix PubMed

KEYNOTE-189

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Arm 1 (Control)

Investigator's choice of:
- Carbo-Pem x 4, then pemetrexed maintenance
- Cis-Pem x 4, then pemetrexed maintenance

Arm 2, with pembrolizumab (Experimental)

Investigator's choice of:
- Carboplatin, Pemetrexed, Pembrolizumab x 4, then Pemetrexed & Pembrolizumab maintenance
- Cisplatin, Pemetrexed, Pembrolizumab x 4, then Pemetrexed & Pembrolizumab maintenance

Comparative efficacy

Regimen	Efficacy
Control	Inferior OS
Experimental (with pembrolizumab)	Superior OS

References

Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. link to original article link to protocol PubMed

KEYNOTE-407

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Arm 1 (Control)

Investigator's choice of:
- Carboplatin & nab-Paclitaxel x 4
- CP x 4

Arm 2, with pembrolizumab (Experimental)

Investigator's choice of:
- Carboplatin, nab-Paclitaxel, Pembrolizumab x 4, then Pembrolizumab maintenance
- Carboplatin, Paclitaxel, Pembrolizumab x 4, then Pembrolizumab maintenance

Comparative efficacy

Regimen	Efficacy
Control	Inferior OS
Experimental (with pembrolizumab)	Superior OS

References

Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. Epub 2018 Sep 25. link to original article PubMed

PRONOUNCE

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Arm 1

Carbo-Pem x 4, then pemetrexed maintenance

Arm 2

PacCBev x 4, then bevacizumab maintenance

Comparative efficacy

Regimen	Efficacy
Arm 1	Seems not superior
Arm 2	Seems not superior

References

Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. link to original article link to PMC article PubMed

RTOG 9410

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Arm 1, sequential

Cisplatin & Vinblastine, then RT

Arm 2, concurrent

Cisplatin, Etoposide, RT

Arm 3, concurrent

Cisplatin, Vinblastine, RT

Comparative efficacy

Schedule	Efficacy
Concurrent	Seems to have superior OS
Sequential	Seems to have inferior OS

References

Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. link to original article link to PMC article PubMed

Ovarian cancer

GOG 114

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Arm 1 - Control

Cisplatin & Paclitaxel x 6

Arm 2 - Experimental

Carboplatin AUC 9 x 2, then IP Cisplatin & IV Paclitaxel x 6

Comparative efficacy

Regimen	Efficacy
Control	Seems to have inferior OS
Experimental	Seems to have superior OS

References

Markman M, Bundy BN, Alberts DS, Fowler JM, Clark-Pearson DL, Carson LF, Wadler S, Sickel J. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol. 2001 Feb 15;19(4):1001-7. link to original article PubMed

OCEANS

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Arm 1 - Control

Carboplatin & Gemcitabine x 6 to 10

Arm 2 - Experimental

Carboplatin, Gemcitabine, Bevacizumab x 6 to 10, then Bevacizumab maintenance

Comparative efficacy

Regimen	Efficacy
Carbo-Gem	Inferior PFS
With Bevacizumab	Superior PFS

References

Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, Sovak MA, Yi J, Nycum LR. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012 Jun 10;30(17):2039-45. Epub 2012 Apr 23. link to original article link to PMC article PubMed

Pancreatic cancer

GERCOR LAP07

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This study had two randomizations; the second only occurred if patients were progression-free after 4 cycles.

Arm 1 - Control

Gemcitabine x 6

Arm 2 - Experimental

Gemcitabine x 4, then Capecitabine & RT

Arm 3 - Experimental

Erlotinib & Gemcitabine x 6

Arm 4 - Experimental

Erlotinib & Gemcitabine x 4, then Capecitabine, Erlotinib, RT

Comparative efficacy

First randomization

Regimen	Efficacy
Gemcitabine	Might have superior OS
With Erlotinib	Might have inferior OS

Second randomization

Modality	Efficacy
Chemotherapy	Seems not superior
Chemoradiotherapy	Seems not superior

References

Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. link to original article PubMed

Small cell lung cancer

IMpower133

Arm 1 (Control)

CE x 4

Arm 2 (Experimental)

CE & Atezolizumab x 4, then Atezolizumab maintenance

Comparative efficacy

Regimen	Efficacy
With atezolizumab	Superior OS
Without atezolizumab	Inferior OS

References

Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ, Huemer F, Losonczy G, Johnson ML, Nishio M, Reck M, Mok T, Lam S, Shames DS, Liu J, Ding B, Lopez-Chavez A, Kabbinavar F, Lin W, Sandler A, Liu SV; IMpower133 Study Group. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018 Sep 25. [Epub ahead of print] link to original article PubMed

@@ Line 1: / Line 1: @@
-The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the [http://www.nccn.org/professionals/physician_gls/f_guidelines.asp NCCN Guidelines]. Is there a regimen missing from this list? See the [[Breast_cancer|main breast cancer page]] for current regimens.
+The purpose of this page is to capture information about complex comparisons that is not easily conveyed on the treatment regimen pages. Many complex multipart RCTs are of the "Y-shaped" format "A followed by B1 versus B2" or "A1 versus A2 followed by B" and this can be captured on the treatment regimen pages. This page will convey information on more complicated designs, such as "A followed by B versus B followed by A" or "A followed by B versus C followed by D".
-{| class="wikitable" style="float:right; margin-right: 5px;"
+{{TOC limit|limit=3}}
+=[[Acute myeloid leukemia]]=
+==COG AAML0531==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+To be completed
+===References===
+# Gamis AS, Alonzo TA, Meshinchi S, Sung L, Gerbing RB, Raimondi SC, Hirsch BA, Kahwash SB, Heerema-McKenney A, Winter L, Glick K, Davies SM, Byron P, Smith FO, Aplenc R. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s Oncology Group trial AAML0531. J Clin Oncol. 2014 Sep 20;32(27):3021-32. [https://ascopubs.org/doi/full/10.1200/JCO.2014.55.3628 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162498/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25092781 PubMed]
+==UK MRC AML12==
+{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|<div style="background-color: #fee0d1; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}" align="right"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]]  |?Regimen |limit=10000|format=sum}} [[Tutorial#Regimens|regimens]] on this page</b></font></div>
+|[[#top|back to top]]
-<div style="background-color: #deebf6; border: 1px solid #808000; padding: 5px; {{border-radius|16px}}"><font size="4"><b>{{#ask: [[-Has subobject::{{FULLPAGENAME}}]]  |?Variant |limit=10000|format=sum}} [[Tutorial#Variants|variants]] on this page</b></font></div>
+|}
-|}
+To be completed
+===References===
+# Burnett AK, Grimwade D, Solomon E, Wheatley K, Goldstone AH. Presenting white blood cell count and kinetics of molecular remission predict prognosis in acute promyelocytic leukemia treated with all-trans retinoic acid: result of the randomized MRC trial. Blood. 1999 Jun 15;93(12):4131-43. [http://www.bloodjournal.org/content/93/12/4131.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10361110 PubMed]
-{{TOC limit|limit=3}}
+==UK MRC AML15==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+To be completed
+===References===
+# Burnett AK, Hills RK, Milligan D, Kjeldsen L, Kell J, Russell NH, Yin JA, Hunter A, Goldstone AH, Wheatley K. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: results of the MRC AML15 trial. J Clin Oncol. 2011 Feb 1;29(4):369-77. Epub 2010 Dec 20. [https://ascopubs.org/doi/10.1200/JCO.2010.31.4310 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21172891 PubMed]
-=Neoadjuvant therapy=
+=[[Acute promyelocytic leukemia]]=
-==CVAP {{#subobject:4a01b8|Regimen=1}}==
+==C9710==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CVAP: '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin),  '''<u>P</u>'''rednisolone
+''Note: this trial included a second randomization during the maintenance phase, which is not complex and is therefore not reported here.''
-<br>VACP: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, '''<u>P</u>'''rednisolone
+===Arm 1===
-===Regimen {{#subobject:7b4b85|Variant=1}}===
+*[[Acute_promyelocytic_leukemia#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, Cytarabine, Daunorubicin]], then [[Acute_promyelocytic_leukemia#ATRA_.26_Daunorubicin_2|ATRA & Daunorubicin]]
-{| class="wikitable" style="width: 50%; text-align:center;"
+===Arm 2, with ATO3===
-!style="width: 25%"|Study
+*[[Acute_promyelocytic_leukemia#ATRA.2C_Cytarabine.2C_Daunorubicin|ATRA, Cytarabine, Daunorubicin]], then [[Acute_promyelocytic_leukemia#Arsenic_trioxide_monotherapy_2|arsenic trioxide]], then [[Acute_promyelocytic_leukemia#ATRA_.26_Daunorubicin_2|ATRA & Daunorubicin]]
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2002.20.6.1456 Smith et al. 2002]
+|Without ATO3
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+|style="background-color:#d73027"|Inferior EFS
 |-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2004.05.207 Thomas E et al. 2004]
+|With ATO3
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+|style="background-color:#1a9850"|Superior EFS
 |-
 |}
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Vincristine (Oncovin)]]
-*[[Doxorubicin (Adriamycin)]]
-====Hormonotherapy====
-*[[Prednisolone (Millipred)]]
-====Subsequent treatment====
-*[[Surgery#Breast_cancer_surgery|Surgery]]
 ===References===
-# Smith IC, Heys SD, Hutcheon AW, Miller ID, Payne S, Gilbert FJ, Ah-See AK, Eremin O, Walker LG, Sarkar TK, Eggleton SP, Ogston KN. Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol. 2002 Mar 15;20(6):1456-66. [https://ascopubs.org/doi/full/10.1200/JCO.2002.20.6.1456 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11896092 PubMed]
+# Powell BL, Moser B, Stock W, Gallagher RE, Willman CL, Stone RM, Rowe JM, Coutre S, Feusner JH, Gregory J, Couban S, Appelbaum FR, Tallman MS, Larson RA. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood. 2010 Nov 11;116(19):3751-7. Epub 2010 Aug 12. [http://www.bloodjournal.org/content/116/19/3751.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2981533/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20705755 PubMed]
-# Thomas E, Holmes FA, Smith TL, Buzdar AU, Frye DK, Fraschini G, Singletary SE, Theriault RL, McNeese MD, Ames F, Walters R, Hortobagyi GN. The use of alternate, non-cross-resistant adjuvant chemotherapy on the basis of pathologic response to a neoadjuvant doxorubicin-based regimen in women with operable breast cancer: long-term results from a prospective randomized trial. J Clin Oncol. 2004 Jun 15;22(12):2294-302. [https://ascopubs.org/doi/full/10.1200/JCO.2004.05.207 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15197190 PubMed]
-==Epirubicin monotherapy {{#subobject:c54ed1|Regimen=1}}==
+=[[Breast cancer]]=
+==ABCSG-8==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Regimen {{#subobject:21c010|Variant=1}}===
+ABCSG-8: '''<u>A</u>'''ustrian '''<u>B</u>'''reast and '''<u>C</u>'''olorectal Cancer '''<u>S</u>'''tudy '''<u>G</u>'''roup '''<u>8</u>'''
+===Arm 1, monotherapy (Control)===
+*[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 5y
+===Arm 2, sequential (Experimental)===
+*[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 2y, then [[Breast_cancer,_ER-positive#Anastrozole_monotherapy_2|Anastrozole]] x 3y
+===Comparative efficacy===
+''Efficacy is based on the 2012 update.''
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://erc.bioscientifica.com/view/journals/erc/12/2/0120383.xml Bottini et al. 2005]
+|Tamoxifen
-| style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#fee08b"|Might have inferior RFS
-|Epirubicin & Tamoxifen
+|-
-| style="background-color:#ffffbf" |Seems not superior
+|Tamoxifen, then Anastrozole
+|style="background-color:#d9ef8b"|Might have superior RFS
 |-
 |}
-====Chemotherapy====
-*[[Epirubicin (Ellence)]]
-====Subsequent treatment====
-*[[Surgery#Breast_cancer_surgery|Surgery]]
 ===References===
-# Bottini A, Berruti A, Brizzi MP, Bersiga A, Generali D, Allevi G, Aguggini S, Bolsi G, Bonardi S, Tondelli B, Vana F, Tampellini M, Alquati P, Dogliotti L. Cytotoxic and antiproliferative activity of the single agent epirubicin versus epirubicin plus tamoxifen as primary chemotherapy in human breast cancer: a single-institution phase III trial. Endocr Relat Cancer. 2005 Jun;12(2):383-92. [https://erc.bioscientifica.com/view/journals/erc/12/2/0120383.xml link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15947110 PubMed]
+# Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, Hilfrich J, Kwasny W, Menzel C, Samonigg H, Seifert M, Gademann G, Kaufmann M, Wolfgang J; ABCSG and the GABG. Switching of postmenopausal women with endocrine-responsiveearly breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005 Aug 6-12;366(9484):455-62. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)67059-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16084253 PubMed]
+<!-- Presented in poster format at the 46th Annual Meeting of the American Society of Clinical Oncology, June 4-8, 2010, Chicago, IL. -->
+## '''Update:''' Dubsky PC, Jakesz R, Mlineritsch B, Pöstlberger S, Samonigg H, Kwasny W, Tausch C, Stöger H, Haider K, Fitzal F, Singer CF, Stierer M, Sevelda P, Luschin-Ebengreuth G, Taucher S, Rudas M, Bartsch R, Steger GG, Greil R, Filipcic L, Gnant M. Tamoxifen and anastrozole as a sequencing strategy: a randomized controlled trial in postmenopausal patients with endocrine-responsive early breast cancer from the Austrian Breast and Colorectal Cancer Study Group. J Clin Oncol. 2012 Mar 1;30(7):722-8. Epub 2012 Jan 23. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.8993 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22271481 PubMed]
-=Adjuvant therapy=
+==ACOSOG Z1041==
-==ACT {{#subobject:4a01b8|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-ACT: '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''amoxifen
+===Arm 1 (Control)===
-===Regimen {{#subobject:7b4b85|Variant=1}}===
+*[[Breast_cancer#FEC|FEC-75]] x 4, then [[Breast_cancer,_HER2-positive#TH_.28Taxol.29|TH (Taxol)]] x 12 wk, then [[surgery]]
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Arm 2 (Experimental)===
-!style="width: 25%"|Study
+*[[Breast_cancer,_HER2-positive#TH_.28Taxol.29|TH (Taxol)]] x 12 wk, then [[Breast_cancer,_HER2-positive#FEC_.26_H|FEC & H]] x 4, then [[surgery]]
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+===Comparative efficacy===
-!style="width: 25%"|Comparator
+{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!'''Approach'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|rowspan=2|[https://ascopubs.org/doi/abs/10.1200/JCO.1990.8.6.1005 Fisher et al. 1990 (NSABP B-16)]
+|Sequential trastuzumab (C)
-|rowspan=2 style="background-color:#1a9851" |Phase III (E-esc)
+|style="background-color:#ffffbf"|Seems not superior
-|1. [[#PFT|PFT]]
-| style="background-color:#d3d3d3" |Not reported
 |-
-|2. [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]]
+|Concurrent trastuzumab (E)
-| style="background-color:#91cf60" |Seems to have superior OS
+|style="background-color:#ffffbf"|Seems not superior
+|-
+|}
+===References===
+# Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig G, Royce M, McCall LM, Ewer MS, Hunt KK; American College of Surgeons Oncology Group investigators. Fluorouracil, epirubicin, and cyclophosphamide (FEC-75) followed by paclitaxel plus trastuzumab versus paclitaxel plus trastuzumab followed by FEC-75 plus trastuzumab as neoadjuvant treatment for patients with HER2-positive breast cancer (Z1041): a randomised, controlled, phase 3 trial. Lancet Oncol. 2013 Dec;14(13):1317-25. Epub 2013 Nov 13. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70502-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176878/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24239210 PubMed]
+==ARNO 95==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1, monotherapy (Control)===
+*[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 5y
+===Arm 2, sequential (Experimental)===
+*[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 2y, then [[Breast_cancer,_ER-positive#Anastrozole_monotherapy_2|Anastrozole]] x 3y
+===Comparative efficacy===
+''Efficacy is based on the 2007 update.''
+{| class="wikitable" style="width: 100%; text-align:center;"
+!style="width: 50%"|'''Regimen'''
+!style="width: 50%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://link.springer.com/article/10.1007%2Fs10147-013-0657-z Shien et al. 2014 (JCOG9401)]
+|Tamoxifen, then Anastrozole
-|style="background-color:#1a9851" |Phase III (E-esc)
+|style="background-color:#91cf60"|Seems to have superior OS
-|[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]]
-| style="background-color:#91cf60" |Seems to have superior RFS
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143604/ Shien et al. 2014 (JCOG9404)]
+|Tamoxifen
-|style="background-color:#1a9851" |Phase III (E-de-esc)
+|style="background-color:#fc8d59"|Seems to have inferior OS
-|TUFT
-| style="background-color:#ffffbf" |Seems not superior
 |-
 |}
-====Preceding treatment====
-*[[Surgery#Breast_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Doxorubicin (Adriamycin)]]
-*[[Cyclophosphamide (Cytoxan)]]
-====Hormonotherapy====
-*[[Tamoxifen (Nolvadex)]]
 ===References===
-# '''NSABP B-16:''' Fisher B, Redmond C, Legault-Poisson S, Dimitrov NV, Brown AM, Wickerham DL, Wolmark N, Margolese RG, Bowman D, Glass AG, Kardinal CG, Robidoux A, Jochimsen P, Cronin W, Deutsch M, Fisher ER, Myers DB, Hoehn JL. Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol. 1990 Jun;8(6):1005-18. [https://ascopubs.org/doi/abs/10.1200/JCO.1990.8.6.1005 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2189950 PubMed]
+# Jakesz R, Jonat W, Gnant M, Mittlboeck M, Greil R, Tausch C, Hilfrich J, Kwasny W, Menzel C, Samonigg H, Seifert M, Gademann G, Kaufmann M, Wolfgang J; ABCSG and the GABG. Switching of postmenopausal women with endocrine-responsiveearly breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet. 2005 Aug 6-12;366(9484):455-62. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)67059-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16084253 PubMed]
-## '''Pooled update:''' Taghian A, Jeong JH, Mamounas E, Anderson S, Bryant J, Deutsch M, Wolmark N. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol. 2004 Nov 1;22(21):4247-54. Epub 2004 Sep 27. [https://ascopubs.org/doi/full/10.1200/JCO.2004.01.042 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15452182 PubMed]
+<!-- Presented in part in abstract format at the 42nd Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, June 2-6, 2006. -->
-# '''JCOG9401:''' Shien T, Iwata H, Aogi K, Fukutomi T, Inoue K, Kinoshita T, Takahashi M, Matsui A, Shibata T, Fukuda H. Tamoxifen versus tamoxifen plus doxorubicin and cyclophosphamide as adjuvant therapy for node-positive postmenopausal breast cancer: results of a Japan Clinical Oncology Group Study (JCOG9401). Int J Clin Oncol. 2014 Dec;19(6):982-8. Epub 2014 Jan 7. [https://link.springer.com/article/10.1007%2Fs10147-013-0657-z link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24395447 PubMed]
+## '''Update:''' Kaufmann M, Jonat W, Hilfrich J, Eidtmann H, Gademann G, Zuna I, von Minckwitz G. Improved overall survival in postmenopausal women with early breast cancer after anastrozole initiated after treatment with tamoxifen compared with continued tamoxifen: the ARNO 95 Study. J Clin Oncol. 2007 Jul 1;25(19):2664-70. Epub 2007 Jun 11. [http://jco.ascopubs.org/content/25/19/2664.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17563395 PubMed]
-# '''JCOG9404:''' Shien T, Iwata H, Fukutomi T, Inoue K, Aogi K, Kinoshita T, Ando J, Takashima S, Nakamura K, Shibata T, Fukuda H. Tamoxifen plus tegafur-uracil (TUFT) versus tamoxifen plus Adriamycin (doxorubicin) and cyclophosphamide (ACT) as adjuvant therapy to treat node-positive premenopausal breast cancer (PreMBC): results of Japan Clinical Oncology Group Study 9404. Cancer Chemother Pharmacol. 2014 Sep;74(3):603-9. Epub 2014 Jul 24. [https://link.springer.com/article/10.1007%2Fs00280-014-2545-2 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4143604/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25055938 PubMed]
-==AVCF {{#subobject:4a0878|Regimen=1}}==
+==Assikis et al. 2003==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-AVCF: '''<u>A</u>'''driamycin (Doxorubicin), '''<u>V</u>'''incristine, '''<u>C</u>'''yclophosphamide, '''<u>F</u>'''luorouracil
+===Arm 1===
-===Regimen {{#subobject:7b4c73|Variant=1}}===
+*[[Breast_cancer#FAC|FAC]], then [[Breast_cancer_-_historical#MV|MV]]
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Arm 2===
-!style="width: 25%"|Study
+*[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]]
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+===Comparative efficacy===
-!style="width: 25%"|Comparator
+{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|FAC, then MV
+|style="background-color:#ffffbf"|Seems not superior
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.4.1136 Misset et al. 1996 (OncoFrance)]
+|Tamoxifen
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
+|style="background-color:#ffffbf"|Seems not superior
-|[[Breast_cancer#CMF|CMF]]
-| style="background-color:#1a9850" |Superior OS
 |-
 |}
-====Preceding treatment====
-*[[Surgery#Breast_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Doxorubicin (Adriamycin)]]
-*[[Vincristine (Oncovin)]]
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Fluorouracil (5-FU)]]
 ===References===
-# '''OncoFrance:''' Misset JL, di Palma M, Delgado M, Plagne R, Chollet P, Fumoleau P, Le Mevel B, Belpomme D, Guerrin J, Fargeot P, Metz R, Ithzaki M, Hill C, Mathé G. Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: final report after a 16-year median follow-up duration. J Clin Oncol. 1996 Apr;14(4):1136-45. [https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.4.1136 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8648368 PubMed]
+# Assikis V, Buzdar A, Yang Y, Smith T, Theriault R, Booser D, Valero V, Walters R, Singletary E, Ames F, Hortobagyi G. A phase III trial of sequential adjuvant chemotherapy for operable breast carcinoma: final analysis with 10-year follow-up. Cancer. 2003 Jun 1;97(11):2716-23. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.11396/full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12767083 PubMed]
-==AV-CMF {{#subobject:4a3928|Regimen=1}}==
+==BCIRG-005==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-AV-CMF: '''<u>A</u>'''driamycin (Doxorubicin), '''<u>V</u>'''inblastine, '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil
+===Arm 1, sequential (Experimental)===
-===Regimen {{#subobject:7bcju3|Variant=1}}===
+*[[Breast_cancer#AC|AC]], then [[Breast_cancer#Docetaxel_monotherapy_2|T]]
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Arm 2, concurrent (Control)===
-!style="width: 25%"|Study
+*[[Breast_cancer#TAC_.28Taxotere.29|TAC]]
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+===Comparative efficacy===
-!style="width: 25%"|Comparator
+{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!'''Schedule'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Sequential (AC, then T)
+|style="background-color:#ffffbf"|Seems not superior
 |-
-|[https://www.karger.com/Article/PDF/69831 Ploner et al. 2003 (ABCSG 3)]
+|Concurrent (TAC)
-| style="background-color:#1a9851" |Randomized (E-RT-esc)
+|style="background-color:#ffffbf"|Seems not superior
-|[[Breast_cancer#CMF|CMF]]
-| style="background-color:#ffffbf" |Seems not superior
 |-
 |}
-====Preceding treatment====
-*[[Surgery#Breast_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Doxorubicin (Adriamycin)]]
-*[[Vinblastine (Velban)]]
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Methotrexate (MTX)]]
-*[[Fluorouracil (5-FU)]]
 ===References===
-# '''ABCSG 3:''' Ploner F, Jakesz R, Hausmaninger H, Kolb R, Stierer M, Fridrik M, Steindorfer P, Gnant M, Haider K, Mlineritsch B, Tschurtschenthaler G, Steger G, Seifert M, Kubista E, Samonigg H; Austrian Breast And Colorectal Cancer Study Group. Randomised trial: One cycle of anthracycline-containing adjuvant chemotherapy compared with six cycles of CMF treatment in node-positive, hormone receptor-negative breast cancer patients. Onkologie. 2003 Apr;26(2):115-9. [https://www.karger.com/Article/PDF/69831 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12771518 PubMed]
+# Eiermann W, Pienkowski T, Crown J, Sadeghi S, Martin M, Chan A, Saleh M, Sehdev S, Provencher L, Semiglazov V, Press M, Sauter G, Lindsay MA, Riva A, Buyse M, Drevot P, Taupin H, Mackey JR. Phase III study of doxorubicin/cyclophosphamide with concomitant versus sequential docetaxel as adjuvant treatment in patients with human epidermal growth factor receptor 2-normal, node-positive breast cancer: BCIRG-005 trial. J Clin Oncol. 2011 Oct 10;29(29):3877-84. Epub 2011 Sep 12. [http://jco.ascopubs.org/content/29/29/3877.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21911726 PubMed]
-==CAMFP {{#subobject:4a01b8|Regimen=1}}==
+==BCIRG 006==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CAMFP: '''<u>C</u>'''yclophosphamide,  '''<u>A</u>'''driamycin (Doxorubicin), '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil, '''<u>P</u>'''rednisone
+===Arm 1, sequential without trastuzumab===
-===Regimen {{#subobject:7b4b85|Variant=1}}===
+*[[Breast_cancer#AC|AC]], then [[Breast_cancer#Docetaxel_monotherapy_2|T]]
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Arm 2, sequential with trastuzumab===
-!style="width: 25%"|Study
+*[[Breast_cancer#AC|AC]], then [[Breast_cancer,_HER2-positive#TH_.28Taxotere.29_2|TH]]
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+===Arm 3, concurrent with trastuzumab===
-!style="width: 25%"|Comparator
+*[[Breast_cancer,_HER2-positive#TCH_.28Taxotere.2C_Carboplatin.29|TCH]]
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+===Comparative efficacy===
+*Analyzed using a step-down design
+====Comparison 1====
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Trastuzumab-containing regimens vs. AC, then T'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|AC, then TH
+|style="background-color:#1a9850"|Superior OS
+|-
+|TCH
+|style="background-color:#91cf60"|Seems to have superior OS
+|-
+|}
+====Comparison 2====
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Trastuzumab-containing regimens'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|AC, then TH
+|style="background-color:#ffffbf"|Seems not superior
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM199605233342102 Recht et al. 1996]
+|TCH
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+|style="background-color:#ffffbf"|Seems not superior
-|[[Complex_multipart_regimens#Recht_et_al._1996|See link]]
-|[[Complex_multipart_regimens#Recht_et_al._1996|See link]]
 |-
 |}
-''Note: this was a trial examining sequencing of chemotherapy and radiotherapy; see text for efficacy details.''
-====Preceding treatment====
-*[[Surgery#Lumpectomy|Lumpectomy]]
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Doxorubicin (Adriamycin)]]
-*[[Methotrexate (MTX)]]
-*[[Fluorouracil (5-FU)]]
-====Hormonotherapy====
-*[[Prednisone (Sterapred)]]
-'''21-day cycle for 4 cycles'''
 ===References===
-# Recht A, Come SE, Henderson IC, Gelman RS, Silver B, Hayes DF, Shulman LN, Harris JR. The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med. 1996 May 23;334(21):1356-61. [https://www.nejm.org/doi/full/10.1056/NEJM199605233342102 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8614420 PubMed]
+# Slamon D, Eiermann W, Robert N, Pienkowski T, Martin M, Press M, Mackey J, Glaspy J, Chan A, Pawlicki M, Pinter T, Valero V, Liu MC, Sauter G, von Minckwitz G, Visco F, Bee V, Buyse M, Bendahmane B, Tabah-Fisch I, Lindsay MA, Riva A, Crown J; Breast Cancer International Research Group. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011 Oct 6;365(14):1273-83. [https://www.nejm.org/doi/full/10.1056/NEJMoa0910383 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268553/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21991949 PubMed]
-==CEF/CMF {{#subobject:682333|Regimen=1}}==
+==BIG 1-98==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CEF/CMF: '''<u>C</u>'''yclophosphamide, '''<u>E</u>'''pirubicin, '''<u>F</u>'''luorouracil alternating with '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil
+===Arm 1, monotherapy===
-===Regimen {{#subobject:3d1971|Variant=1}}===
+*[[Breast_cancer,_ER-positive#Letrozole_monotherapy|Letrozole]] x 5y
+===Arm 2, sequential===
+*[[Breast_cancer,_ER-positive#Letrozole_monotherapy|Letrozole]] x 2y, then [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 3y
+===Arm 3, monotherapy===
+*[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 5y
+===Arm 4, sequential===
+*[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 2y, then [[Breast_cancer,_ER-positive#Letrozole_monotherapy|Letrozole]] x 3y
+===Comparative efficacy===
+*Analyzed by several methods; efficacy here is based on the 2011 update.
+====Comparison 1====
+''Reported efficacy is based on the 2018 update.''
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Monotherapy'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
+|-
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|Letrozole
+| style="background-color:#d9ef8b" |Might have superior OS
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202939/ Bedognetti et al. 2011]
+|Tamoxifen
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#fee08b" |Might have inferior OS
-|CEFT/CMFT
+|-
-| style="background-color:#ffffbf" |Seems not superior
+|}
+====Comparison 2====
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Sequential therapies'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Letrozole, then Tamoxifen
+|style="background-color:#ffffbf"|Seems not superior
+|-
+|Tamoxifen, then Letrozole
+|style="background-color:#ffffbf"|Seems not superior
+|-
+|}
+====Comparison 3====
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Letrozole-containing therapies'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Letrozole
+|style="background-color:#ffffbf"|Seems not superior
+|-
+|Letrozole, then Tamoxifen
+|style="background-color:#ffffbf"|Seems not superior
+|-
+|Tamoxifen, then Letrozole
+|style="background-color:#ffffbf"|Seems not superior
 |-
 |}
-====Preceding treatment====
-*[[Surgery#Breast_cancer_surgery|Surgery]]
-====Chemotherapy, CEF portion====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Epirubicin (Ellence)]]
-*[[Fluorouracil (5-FU)]]
-====Chemotherapy, CMF portion====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Methotrexate (MTX)]]
-*[[Fluorouracil (5-FU)]]
 ===References===
-# Bedognetti D, Sertoli MR, Pronzato P, Del Mastro L, Venturini M, Taveggia P, Zanardi E, Siffredi G, Pastorino S, Queirolo P, Gardin G, Wang E, Monzeglio C, Boccardo F, Bruzzi P. Concurrent vs sequential adjuvant chemotherapy and hormone therapy in breast cancer: a multicenter randomized phase III trial. J Natl Cancer Inst. 2011 Oct 19;103(20):1529-39. Epub 2011 Sep 15. [https://academic.oup.com/jnci/article/103/20/1529/905862 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3202939/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21921285 PubMed]
+# Thürlimann B, Keshaviah A, Coates AS, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Rabaglio M, Smith I, Wardley A, Price KN, Goldhirsch A; Breast International Group (BIG) 1-98 Collaborative Group. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005 Dec 29;353(26):2747-57. Erratum in: N Engl J Med. 2006 May 18;354(20):2200. Wardly, Andrew [corrected to Wardley, Andrew ]. [https://www.nejm.org/doi/full/10.1056/NEJMoa052258 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16382061 PubMed]
+## '''Update:''' Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol. 2007 Feb 10;25(5):486-92. Epub 2007 Jan 2. [http://jco.ascopubs.org/content/25/5/486.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17200148 PubMed]
+## '''Subgroup analysis:''' Rasmussen BB, Regan MM, Lykkesfeldt AE, Dell'Orto P, Del Curto B, Henriksen KL, Mastropasqua MG, Price KN, Méry E, Lacroix-Triki M, Braye S, Altermatt HJ, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Gusterson BA, Thürlimann B, Coates AS, Viale G; BIG 1-98 Collaborative and International Breast Cancer Study Groups. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol. 2008 Jan;9(1):23-8. Epub 2007 Dec 20. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045%2807%2970386-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18083065 PubMed]
+## '''Subgroup analysis:''' Crivellari D, Sun Z, Coates AS, Price KN, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens RJ, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Gladieff L, Rabaglio M, Smith IE, Chirgwin JH, Goldhirsch A. Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial. J Clin Oncol. 2008 Apr 20;26(12):1972-9. Epub 2008 Mar 10. [http://jco.ascopubs.org/content/26/12/1972.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18332471 PubMed]
+## '''Update:''' Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, Forbes JF, Smith I, Láng I, Wardley A, Rabaglio M, Price KN, Gelber RD, Coates AS, Thürlimann B; BIG 1-98 Collaborative Group.; International Breast Cancer Study Group (IBCSG). Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol. 2011 Nov;12(12):1101-8. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70270-4/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235950/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22018631 PubMed]
+## '''Update:''' Ruhstaller T, Giobbie-Hurder A, Colleoni M, Jensen MB, Ejlertsen B, de Azambuja E, Neven P, Láng I, Jakobsen EH, Gladieff L, Bonnefoi H, Harvey VJ, Spazzapan S, Tondini C, Del Mastro L, Veyret C, Simoncini E, Gianni L, Rochlitz C, Kralidis E, Zaman K, Jassem J, Piccart-Gebhart M, Di Leo A, Gelber RD, Coates AS, Goldhirsch A, Thürlimann B, Regan MM; members of the BIG 1-98 Collaborative Group and the International Breast Cancer Study Group. Adjuvant Letrozole and Tamoxifen Alone or Sequentially for Postmenopausal Women With Hormone Receptor-Positive Breast Cancer: Long-Term Follow-Up of the BIG 1-98 Trial. J Clin Oncol. 2018 Nov 26:JCO1800440. [Epub ahead of print] [https://ascopubs.org/doi/full/10.1200/JCO.18.00440 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30475668 PubMed]
-==CFP {{#subobject:b514cd|Regimen=1}}==
+==BIG 02-98==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CFP: '''<u>C</u>'''yclophosphamide, '''<u>F</u>'''luorouracil, '''<u>P</u>'''rednisone
+===Arm 1, sequential control===
-===Regimen {{#subobject:3b8f7d|Variant=1}}===
+*Surgery, then [[Breast_cancer#Doxorubicin_monotherapy|A]] x 4, then [[Breast_cancer#CMF|CMF]] x 3
+===Arm 2, concurrent control===
+*Surgery, then [[Breast_cancer#AC_2|AC]] x 4, then [[Breast_cancer#CMF|CMF]] x 3
+===Arm 3, sequential experimental===
+*Surgery, then [[Breast_cancer#Doxorubicin_monotherapy|A]] x 4, [[Breast_cancer#Docetaxel_monotherapy_2|D]] x 3, then [[Breast_cancer#CMF|CMF]] x 3
+===Arm 4, concurrent experimental===
+*Surgery, then AT x 4, then [[Breast_cancer#CMF|CMF]] x 3
+===Comparative efficacy===
+''This trial was analyzed with a 2 x 2 factorial design. Reported efficacy is based on the 2015 update.''
+====Comparison 1 - addition of docetaxel====
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+|'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
+|-
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|Non-docetaxel-containing (C)
+|style="background-color:#ffffbf"|Seems not superior (*)
+|-
+|Docetaxel containing (E)
+|style="background-color:#ffffbf"|Seems not superior (*)
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(78)90678-5/fulltext Ahmann et al. 1978]
+|}
-|style="background-color:#1a9851" |Phase III (E-esc)
+====Comparison 2 - sequencing====
-|[[#Melphalan_monotherapy|Melphalan]]
+{| class="wikitable" style="width: 100%; text-align:center;"
-| style="background-color:#91cf60" |Seems to have superior OS
+|'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|rowspan=2|[https://jamanetwork.com/journals/jama/article-abstract/370748 Caprini et al. 1980]
+|Sequential
-|rowspan=2 style="background-color:#1a9851" |Phase III (E-esc)
+|style="background-color:#ffffbf"|Seems not superior (*)
-|1. [[#Melphalan_monotherapy|Melphalan]]
-| style="background-color:#91cf60" |Seems to have superior DFS
 |-
-|2. CFP & BCG
+|Concurrent
-| style="background-color:#ffffbf" |Seems not superior
+|style="background-color:#ffffbf"|Seems not superior (*)
 |-
 |}
-====Preceding treatment====
-*[[Surgery#Breast_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Fluorouracil (5-FU)]]
-====Hormonotherapy====
-*[[Prednisone (Sterapred)]]
 ===References===
-# Ahmann DL, Scanlon PW, Bisel HF, Edmonson JH, Frytak S, Payne WS, O'Fallon JR, Hahn RG, Ingle JN, O'Connell MJ, Rubin J. Repeated adjuvant chemotherapy with phenylalanine mustard or 5-fluorouracil, cyclophosphamide, and prednisone with or without radiation, after mastectomy for breast cancer. Lancet. 1978 Apr 29;1(8070):893-6. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(78)90678-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/76842 PubMed]
+# Francis P, Crown J, Di Leo A, Buyse M, Balil A, Andersson M, Nordenskjöld B, Lang I, Jakesz R, Vorobiof D, Gutiérrez J, van Hazel G, Dolci S, Jamin S, Bendahmane B, Gelber RD, Goldhirsch A, Castiglione-Gertsch M, Piccart-Gebhart M; BIG 02-98 Collaborative Group. Adjuvant chemotherapy with sequential or concurrent anthracycline and docetaxel: Breast International Group 02-98 randomized trial. J Natl Cancer Inst. 2008 Jan 16;100(2):121-33. Epub 2008 Jan 8. Erratum in: J Natl Cancer Inst. 2008 Nov 19;100(22):1655. [https://academic.oup.com/jnci/article/100/2/121/1130035 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18182617 PubMed]
-# Caprini JA, Oviedo MA, Cunningham MP, Cohen E, Trueheart RS, Khandekar JD, Scanlon EF. Adjuvant chemotherapy for stage II and III breast carcinoma. JAMA. 1980 Jul 18;244(3):243-6. [https://jamanetwork.com/journals/jama/article-abstract/370748 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6991733 PubMed]
+## '''Update:''' Oakman C, Francis PA, Crown J, Quinaux E, Buyse M, De Azambuja E, Margeli Vila M, Andersson M, Nordenskjöld B, Jakesz R, Thürlimann B, Gutiérrez J, Harvey V, Punzalan L, Dell'orto P, Larsimont D, Steinberg I, Gelber RD, Piccart-Gebhart M, Viale G, Di Leo A. Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trial. Ann Oncol. 2013 May;24(5):1203-11. Epub 2013 Jan 4. [https://academic.oup.com/annonc/article/24/5/1203/215838 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23293111 PubMed]
+## '''Update:''' Sonnenblick A, Francis PA, Azim HA Jr, de Azambuja E, Nordenskjöld B, Gutiérez J, Quinaux E, Mastropasqua MG, Ameye L, Anderson M, Lluch A, Gnant M, Goldhirsch A, Di Leo A, Barnadas A, Cortes-Funes H, Piccart M, Crown J. Final 10-year results of the Breast International Group 2-98 phase III trial and the role of Ki67 in predicting benefit of adjuvant docetaxel in patients with oestrogen receptor positive breast cancer. Eur J Cancer. 2015 Aug;51(12):1481-9. Epub 2015 Jun 11. [https://www.ejcancer.com/article/S0959-8049(15)00285-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26074397 PubMed]
-==CFP & Oophorectomy {{#subobject:ba429d|Regimen=1}}==
+==BR9601==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CFP & Oophorectomy: '''<u>C</u>'''yclophosphamide, '''<u>F</u>'''luorouracil, '''<u>P</u>'''rednisone & Bilateral Oophorectomy
+===Arm 1 (Control)===
-===Regimen {{#subobject:26519a|Variant=1}}===
+*[[Breast_cancer#CMF|CMF]] x 8
+===Arm 2 (Experimental)===
+*[[Breast_cancer#EC_2|EC]] x 4, then [[Breast_cancer#CMF|CMF]] x 4
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM197708182970704 Ahmann et al. 1977]
+|CMF x 8
-| style="background-color:#1a9851" |Phase III (E-esc)
+|style="background-color:#d73027"|Inferior OS
-|[[#Oophorectomy|Oophorectomy]]
+|-
-| style="background-color:#91cf60" |Seems to have superior PFS
+|EC x 4, then CMF x 4
+|style="background-color:#1a9850"|Superior OS
 |-
 |}
-====Preceding treatment====
+===References===
-*[[Surgery#Breast_cancer_surgery|Surgery]]
+<!-- no pre-pub disclosed -->
-====Chemotherapy====
+# Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. [https://www.nejm.org/doi/full/10.1056/NEJMoa052084 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17079759 PubMed]
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Fluorouracil (5-FU)]]
-====Hormonotherapy====
-*[[Prednisone (Sterapred)]]
-*[[Endocrine_ablation_surgery#Bilateral_oophorectomy|Bilateral oophorectomy]]
+==Buzdar et al. 2005==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1 (Control)===
+*[[Breast_cancer#Paclitaxel_monotherapy|T]] x 4, then [[Breast_cancer#FEC|FEC]] x 4, then [[surgery]]
+===Arm 2 (Experimental)===
+*[[Breast_cancer,_HER2-positive#TH_.28Taxol.29|TH]] x 4, then [[Breast_cancer,_HER2-positive#FEC_.26_H|FEC & H]] x 4, then [[surgery]]
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|T, then FEC
+|style="background-color:#fc8d59"|Seems to have inferior pCR rate
+|-
+|TH, then FEC & H
+|style="background-color:#91cf60"|Seems to have superior pCR rate
+|-
+|}
 ===References===
-# Ahmann DL, O'Connell MJ, Hahn RG, Bisel HF, Lee RA, Edmonson JH. An evaluation of early or delayed adjuvant chemotherapy in premenopausal patients with advanced breast cancer undergoing oophorectomy. N Engl J Med. 1977 Aug 18;297(7):356-60. [https://www.nejm.org/doi/full/10.1056/NEJM197708182970704 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/876327 PubMed]
+# Buzdar AU, Ibrahim NK, Francis D, Booser DJ, Thomas ES, Theriault RL, Pusztai L, Green MC, Arun BK, Giordano SH, Cristofanilli M, Frye DK, Smith TL, Hunt KK, Singletary SE, Sahin AA, Ewer MS, Buchholz TA, Berry D, Hortobagyi GN. Significantly higher pathologic complete remission rate after neoadjuvant therapy with trastuzumab, paclitaxel, and epirubicin chemotherapy: results of a randomized trial in human epidermal growth factor receptor 2-positive operable breast cancer. J Clin Oncol. 2005 Jun 1;23(16):3676-85. Epub 2005 Feb 28. [http://jco.ascopubs.org/content/23/16/3676.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15738535 PubMed]
-==CMFL {{#subobject:1abd14|Regimen=1}}==
+==CALGB 9741==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CMFL: '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil, '''<u>L</u>'''eucovorin (Folinic acid)
+''Note: what is referred to in this study as concurrent is in fact the same regimen that is referred to as sequential in other studies. The taxane studied in this trial was paclitaxel.''
-===Regimen {{#subobject:3dbcd1|Variant=1}}===
+===Arm 1, sequential===
-{| class="wikitable" style="width: 100%; text-align:center;"
+*A x 4, then [[Breast_cancer_-_historical#Paclitaxel_monotherapy.2C_q3wk|T q3wk]] x 4, then C x 4
-!style="width: 25%"|Study
+===Arm 2, dose-dense sequential===
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+*[[Breast_cancer#ddA|ddA]] x 4, then [[Breast_cancer#Paclitaxel_monotherapy.2C_dose-dense_.28q2wk.29_2|ddT]] x 4, then [[Breast_cancer#ddC|ddC]] x 4
-!style="width: 25%"|Comparator
+===Arm 3, "concurrent"===
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+*[[Breast_cancer#AC_2|AC]] x 4, then [[Breast_cancer_-_historical#Paclitaxel_monotherapy.2C_q3wk|T q3wk]] x 4
+===Arm 4, dose-dense "concurrent"===
+*[[Breast_cancer#ddAC_2|ddAC]] x 4, then [[Breast_cancer#Paclitaxel_monotherapy.2C_dose-dense_.28q2wk.29_2|ddT]] x 4
+===Comparative efficacy===
+*Analyzed using a 2 x 2 factorial design
+====Comparison 1====
+{| class="wikitable" style="width: 100%; text-align:center;"
+|'''Dose density'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM198902233200804 Goldhirsch et al. 1989 (LCBS V)]
+|Dose-dense (q2wk)
-| style="background-color:#1a9851" |Phase III (E-esc)
+|style="background-color:#91cf60"|Seems to have superior OS
-|[[#Observation|No further treatment]]
+|-
-| style="background-color:#91cf60" |Seems to have superior DFS
+|Standard (q3wk)
+|style="background-color:#fc8d59"|Seems to have inferior OS
+|-
+|}
+====Comparison 2====
+{| class="wikitable" style="width: 100%; text-align:center;"
+|'''Schedule'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Concurrent
+|style="background-color:#ffffbf"|Seems not superior
+|-
+|Sequential
+|style="background-color:#ffffbf"|Seems not superior
 |-
 |}
-====Preceding treatment====
+===References===
-*[[Surgery#Mastectomy|Mastectomy]]
+# Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, Davidson NE, Martino S, Livingston R, Ingle JN, Perez EA, Carpenter J, Hurd D, Holland JF, Smith BL, Sartor CI, Leung EH, Abrams J, Schilsky RL, Muss HB, Norton L. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: first report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003 Apr 15;21(8):1431-9. Epub 2003 Feb 13. [http://jco.ascopubs.org/content/21/8/1431.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12668651 PubMed]
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Methotrexate (MTX)]]
-*[[Fluorouracil (5-FU)]]
-*[[Folinic acid (Leucovorin)]]
-'''8-day course'''
+==DBCG 82b==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1 (Experimental)===
+*[[Mastectomy]], then [[Breast_cancer#CMF|CMF]] x 1, then radiotherapy, then [[Breast_cancer#CMF|CMF]] x 7
+===Arm 2 (Control)===
+*[[Mastectomy]], then [[Breast_cancer#CMF|CMF]] x 9
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|With RT
+| style="background-color:#1a9850" |Superior OS
+|-
+|Without RT
+| style="background-color:#d73027" |Inferior OS
+|-
+|}
+===References===
+# Overgaard M, Hansen PS, Overgaard J, Rose C, Andersson M, Bach F, Kjaer M, Gadeberg CC, Mouridsen HT, Jensen MB, Zedeler K. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy: Danish Breast Cancer Cooperative Group 82b trial. N Engl J Med. 1997 Oct 2;337(14):949-55. [https://www.nejm.org/doi/full/10.1056/NEJM199710023371401 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9395428 PubMed]
+==DBCG 07-READ==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1===
+*[[Surgery]], then [[Breast_cancer#TC|DC]] x 6
+===Arm 2, "EC-D"===
+*[[Surgery]], then [[Breast_cancer#EC_2|EC]] x 3, then [[Breast_cancer#Docetaxel_monotherapy_2|D]] x 3
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|DC x 6
+|style="background-color:#ffffbf"|Seems not superior
+|-
+|EC x 3, then D x 3
+|style="background-color:#ffffbf"|Seems not superior
+|-
+|}
 ===References===
-# '''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://www.ncbi.nlm.nih.gov/pubmed/2644533 PubMed]
+# Ejlertsen B, Tuxen MK, Jakobsen EH, Jensen MB, Knoop AS, Højris I, Ewertz M, Balslev E, Danø H, Vestlev PM, Kenholm J, Nielsen DL, Bechmann T, Andersson M, Cold S, Nielsen HM, Maae E, Carlsen D, Mouridsen HT. Adjuvant cyclophosphamide and docetaxel with or without epirubicin for early TOP2A-normal breast cancer: DBCG 07-READ, an open-label, phase III, randomized trial. J Clin Oncol. 2017 Aug 10;35(23):2639-2646. Epub 2017 Jun 29. [https://ascopubs.org/doi/full/10.1200/JCO.2017.72.3494 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28661759 PubMed]
-==CMFP {{#subobject:527931|Regimen=1}}==
+==DEVA==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CMFP: '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil, '''<u>P</u>'''rednisone
+===Arm 1 (Control)===
-===Regimen {{#subobject:3feec0|Variant=1}}===
+*[[Surgery]], then [[Breast_cancer#Epirubicin_monotherapy|Epirubicin]] x 6
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Arm 2 (Experimental)===
-!style="width: 25%"|Study
+*[[Surgery]], then [[Breast_cancer#Epirubicin_monotherapy|Epirubicin]] x 3, then [[Breast_cancer#Docetaxel_monotherapy_2|Docetaxel]] x 3
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+===Comparative efficacy===
-!style="width: 25%"|Comparator
+{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Epirubicin
+|style="background-color:#d73027"|Inferior DFS
+|-
+|Epirubicin, then Docetaxel
+|style="background-color:#1a9850"|Superior DFS
+|-
+|}
+===References===
+<!-- Presented at the 46th Annual Meeting of the American Society of Clinical Oncology, June 4-8, 2010, Chicago, IL. -->
+# Coombes RC, Bliss JM, Espie M, Erdkamp F, Wals J, Tres A, Marty M, Coleman RE, Tubiana-Mathieu N, den Boer MO, Wardley A, Kilburn LS, Cooper D, Thomas MW, Reise JA, Wilkinson K, Hupperets P. Randomized, phase III trial of sequential epirubicin and docetaxel versus epirubicin alone in postmenopausal patients with  node-positive breast cancer. J Clin Oncol. 2011 Aug 20;29(24):3247-54. Epub 2011 Jul 18. [https://ascopubs.org/doi/full/10.1200/JCO.2010.32.7254 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21768453 PubMed]
+==ECOG E5103==
+{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM198809153191104 Goldhirsch et al. 1988 (IBCSG V)]
+|[[#top|back to top]]
-| style="background-color:#1a9851" |Phase III (C)
+|}
-|[[#CMFL|CMFL]] x 1
+===Arm A (Control)===
-| style="background-color:#91cf60" |Seems to have superior OS
+*[[Surgery]], then [[Breast_cancer#AC_2|AC]] x 4 or [[Breast_cancer#ddAC_2|ddAC]] x 4, then [[Breast_cancer#Paclitaxel_monotherapy.2C_weekly_2|wP]] x 12
+===Arm B (Experimental)===
+*[[Surgery]], then AC-Bev x 4 or ddAC-Bev x 4, then wP-Bev
+===Arm C (Experimental)===
+*[[Surgery]], then AC-Bev x 4 or ddAC-Bev x 4, then wP-Bev, then [[Breast_cancer#Bevacizumab_monotherapy|bevacizumab]] x 10
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Backbone'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM198902233200803 Mansour et al. 1989 (INT-0011)]
+|No bevacizumab
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#ffffbf" |Seems not superior
-|[[#Observation|No further treatment]]
-| style="background-color:#1a9850" |Superior DFS
 |-
-|[https://onlinelibrary.wiley.com/doi/10.1002/1097-0142(19900115)65:2%3C200::AID-CNCR2820650203%3E3.0.CO;2-Q/abstract Tormey et al. 1990 (ECOG E5177)]
+|With bevacizumab
-| style="background-color:#1a9851" |Phase III (E-esc)
-|1. [[Breast_cancer#CMF|CMF]]<br> 2. [[#CMFPT|CMFPT]]
 | style="background-color:#ffffbf" |Seems not superior
 |-
 |}
-====Preceding treatment====
-*[[Surgery#Modified_radical_mastectomy|Modified radical mastectomy]] or [[Surgery#Mastectomy|total mastectomy]] with [[Surgery#Axillary_lymph_node_dissection|low axillary-node dissection]]
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Methotrexate (MTX)]]
-*[[Fluorouracil (5-FU)]]
-====Hormonotherapy====
-*[[Prednisone (Sterapred)]]
-'''28-day cycle for 6 to 12 cycles'''
 ===References===
-# '''IBCSG V:''' Goldhirsch A; Ludwig Breast Cancer Study Group. Combination adjuvant chemotherapy for node-positive breast cancer: inadequacy of a single perioperative cycle. N Engl J Med. 1988 Sep 15;319(11):677-83. [https://www.nejm.org/doi/full/10.1056/NEJM198809153191104 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2901037 PubMed]
+# Miller KD, O'Neill A, Gradishar W, Hobday TJ, Goldstein LJ, Mayer IA, Bloom S, Brufsky AM, Tevaarwerk AJ, Sparano JA, Le-Lindqwister NA, Hendricks CB, Northfelt DW, Dang CT, Sledge GW Jr. Double-blind phase III trial of adjuvant chemotherapy with and without bevacizumab in patients with lymph node-positive and high-risk lymph node-negative breast cancer (E5103). J Clin Oncol. 2018 Sep 1;36(25):2621-2629. Epub 2018 Jul 24. [https://ascopubs.org/doi/full/10.1200/JCO.2018.79.2028 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30040523 PubMed]
-# '''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://www.nejm.org/doi/full/10.1056/NEJM198902233200803 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2915651 PubMed]
-## '''Update:''' Mansour EG, Eudey L, Tormey DC, Shatila AH, Osborne CK, Gilchrist KW, Cooper MR, Falkson G. Chemotherapy versus observation in high-risk node-negative breast cancer patients. J Natl Cancer Inst Monogr. 1992;(11):97-104. [https://www.ncbi.nlm.nih.gov/pubmed/1627437 PubMed]
-# '''ECOG E5177:''' Tormey DC, Gray R, Gilchrist K, Grage T, Carbone PP, Wolter J, Woll JE, Cummings FJ. Adjuvant chemohormonal therapy with cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen compared with CMF for premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial. Cancer. 1990 Jan 15;65(2):200-6. [https://onlinelibrary.wiley.com/doi/10.1002/1097-0142(19900115)65:2%3C200::AID-CNCR2820650203%3E3.0.CO;2-Q/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2403834 PubMed]
-==CMFPT {{#subobject:204d9d|Regimen=1}}==
+==ECTO==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CMFPT: '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil, '''<u>P</u>'''rednisone, '''<u>T</u>'''amoxifen
+===Arm A (Control)===
-===Regimen {{#subobject:3a762a|Variant=1}}===
+*[[Surgery]], then [[Breast_cancer#Doxorubicin_monotherapy|A]] x 4, then [[Breast_cancer#CMF|CMF]] x 4
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Arm B (Experimental)===
-!style="width: 25%"|Study
+*[[Surgery]], then [[Breast_cancer#AT_.28Taxol.29|AT (Taxol)]] x 4, then [[Breast_cancer#CMF|CMF]] x 4
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+===Arm C (Experimental)===
-!style="width: 25%"|Comparator
+*AT (Taxol) x 4, then CMF x 4, then [[surgery]]
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+===Comparative efficacy===
+====Comparison 1====
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Paclitaxel'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|rowspan = 2|[https://www.thelancet.com/journals/lancet/article/PIIS0140673684924450/fulltext Goldhirsch et al. 1984 (LBCS III)]
+|Included
-|rowspan = 2 style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#91cf60" |Seems to have superior RFS
-|1. [[#Observation|Observation]]
-| style="background-color:#1a9850" |Superior DFS
 |-
-|2. [[#PT|PT]]
+|Not included
-| style="background-color:#91cf60" |Seems to have superior DFS
+| style="background-color:#fc8d59" |Seems to have inferior RFS
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM198809153191104 Goldhirsch et al. 1988 (IBCSG V)]
+|}
-| style="background-color:#1a9851" |Phase III (C)
+====Comparison 2====
-|[[#CMFL|CMFL]] x 1
+{| class="wikitable" style="width: 100%; text-align:center;"
-| style="background-color:#91cf60" |Seems to have superior OS
+!'''Timing'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://onlinelibrary.wiley.com/doi/10.1002/1097-0142(19900115)65:2%3C200::AID-CNCR2820650203%3E3.0.CO;2-Q/abstract Tormey et al. 1990 (ECOG E5177)]
+|Adjuvant AT-CMF
-| style="background-color:#1a9851" |Phase III (E-esc)
-|1. [[Breast_cancer#CMF|CMF]]<br> 2. CMFP
 | style="background-color:#ffffbf" |Seems not superior
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1990.8.4.599 Falkson et al. 1990]
+|Neoadjuvant AT-CMF
-| style="background-color:#1a9851" |Phase III (C)
-|CMFPT x 4
 | style="background-color:#ffffbf" |Seems not superior
 |-
 |}
-====Preceding treatment====
+===References===
-*[[Surgery#Modified_radical_mastectomy|Modified radical mastectomy]] or [[Surgery#Mastectomy|total mastectomy]] with [[Surgery#Axillary_lymph_node_dissection|low axillary-node dissection]]
+# Gianni L, Baselga J, Eiermann W, Porta VG, Semiglazov V, Lluch A, Zambetti M, Sabadell D, Raab G, Cussac AL, Bozhok A, Martinez-Agulló A, Greco M, Byakhov M, Lopez JJ, Mansutti M, Valagussa P, Bonadonna G. Phase III trial evaluating the addition of paclitaxel to doxorubicin followed by cyclophosphamide, methotrexate, and fluorouracil, as adjuvant or primary systemic therapy: European Cooperative Trial in Operable Breast Cancer. J Clin Oncol. 2009 May 20;27(15):2474-81. Epub 2009 Mar 30. [https://ascopubs.org/doi/full/10.1200/JCO.2008.19.2567 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19332727 PubMed]
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Methotrexate (MTX)]]
-*[[Fluorouracil (5-FU)]]
-====Hormonotherapy====
-*[[Prednisone (Sterapred)]]
-*[[Tamoxifen (Nolvadex)]]
-'''28-day cycle for 6 to 12 cycles'''
+==FATA-GIM3==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1===
+*[[Breast_cancer,_ER-positive#Anastrozole_monotherapy_2|Anastrazole]] x 5 y
+===Arm 2===
+*[[Breast_cancer,_ER-positive#Exemestane_monotherapy|Exemestane]] x 5 y
+===Arm 3===
+*[[Breast_cancer,_ER-positive#Letrozole_monotherapy_2|Letrozole]] x 5 y
+===Arm 4===
+*[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 2 y, then [[Breast_cancer,_ER-positive#Anastrozole_monotherapy_2|Anastrazole]] x 3 y
+===Arm 5===
+*[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 2 y, then [[Breast_cancer,_ER-positive#Exemestane_monotherapy|Exemestane]] x 3 y
+===Arm 6===
+*[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 2 y, then [[Breast_cancer,_ER-positive#Letrozole_monotherapy_2|Letrozole]] x 3 y
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Approach'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|AI x 5 y
+| style="background-color:#ffffbf" |Seems not superior
+|-
+|Tamoxifen x 2 y, then AI x 3 y
+| style="background-color:#ffffbf" |Seems not superior
+|-
+|}
+===References===
+# De Placido S, Gallo C, De Laurentiis M, Bisagni G, Arpino G, Sarobba MG, Riccardi F, Russo A, Del Mastro L, Cogoni AA, Cognetti F, Gori S, Foglietta J, Frassoldati A, Amoroso D, Laudadio L, Moscetti L, Montemurro F, Verusio C, Bernardo A, Lorusso V, Gravina A, Moretti G, Lauria R, Lai A, Mocerino C, Rizzo S, Nuzzo F, Carlini P, Perrone F; GIM Investigators. Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial. Lancet Oncol. 2018 Apr;19(4):474-485. Epub 2018 Feb 23. Erratum in: Lancet Oncol. 2018 Apr;19(4):e184. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(18)30116-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29482983 PubMed]
+==FinXX==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1 (Control)===
+*[[Breast_cancer#Docetaxel_monotherapy_2|T (Docetaxel)]] x 3, then [[Breast_cancer#FEC_2|CEF]] x 3
+===Arm 2 (Experimental)===
+*TX x 3, then CEX x 3
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|T x 3, then CEF x 3
+|style="background-color:#fee08b"|Might have inferior RFS
+|-
+|TX x 3, then CEX x 3
+|style="background-color:#d9ef8b"|Might have superior RFS
+|-
+|}
 ===References===
-# '''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://www.ncbi.nlm.nih.gov/pubmed/6144974 PubMed]
+# Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Asola R, Kokko R, Ahlgren J, Auvinen P, Hemminki A, Paija O, Helle L, Nuortio L, Villman K, Nilsson G, Lahtela SL, Lehtiö K, Pajunen M, Poikonen P, Nyandoto P, Kataja V, Bono P, Leinonen M, Lindman H; FinXX Study Investigators. Adjuvant capecitabine in combination with docetaxel and cyclophosphamide plus epirubicin for breast cancer: an open-label, randomised controlled trial. Lancet Oncol. 2009 Dec;10(12):1145-51. Epub 2009 Nov 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70307-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19906561 PubMed]
-# '''IBCSG V:''' Goldhirsch A; Ludwig Breast Cancer Study Group. Combination adjuvant chemotherapy for node-positive breast cancer: inadequacy of a single perioperative cycle. N Engl J Med. 1988 Sep 15;319(11):677-83. [https://www.nejm.org/doi/full/10.1056/NEJM198809153191104 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2901037 PubMed]
+## '''Update:''' Joensuu H, Kellokumpu-Lehtinen PL, Huovinen R, Jukkola-Vuorinen A, Tanner M, Kokko R, Ahlgren J, Auvinen P, Paija O, Helle L, Villman K, Nyandoto P, Nilsson G, Pajunen M, Asola R, Poikonen P, Leinonen M, Kataja V, Bono P, Lindman H. Adjuvant capecitabine, docetaxel, cyclophosphamide, and epirubicin for early breast cancer: final analysis of the randomized FinXX trial. J Clin Oncol. 2012 Jan 1;30(1):11-8. Epub 2011 Nov 21. [https://ascopubs.org/doi/full/10.1200/JCO.2011.35.4639 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22105826 PubMed]
-# '''ECOG E5177:''' Tormey DC, Gray R, Gilchrist K, Grage T, Carbone PP, Wolter J, Woll JE, Cummings FJ. Adjuvant chemohormonal therapy with cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen compared with CMF for premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial. Cancer. 1990 Jan 15;65(2):200-6. [https://onlinelibrary.wiley.com/doi/10.1002/1097-0142(19900115)65:2%3C200::AID-CNCR2820650203%3E3.0.CO;2-Q/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2403834 PubMed]
-# Falkson HC, Gray R, Wolberg WH, Gillchrist KW, Harris JE, Tormey DC, Falkson G. Adjuvant trial of 12 cycles of CMFPT followed by observation or continuous tamoxifen versus four cycles of CMFPT in postmenopausal women with breast cancer: an Eastern Cooperative Oncology Group phase III study. J Clin Oncol. 1990 Apr;8(4):599-607. Erratum in: J Clin Oncol 1990 Sep;8(9):1603. [https://ascopubs.org/doi/abs/10.1200/JCO.1990.8.4.599 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2179477 PubMed]
-==CMFT {{#subobject:204b9d|Regimen=1}}==
+==FNCLCC PACS 01==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CMFT: '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil, '''<u>T</u>'''amoxifen
+===Arm 1 (Control)===
-===Regimen {{#subobject:3agt2a|Variant=1}}===
+*[[Breast_cancer#FEC_2|FEC]] x 6
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Arm 2 (Experimental)===
-!style="width: 25%"|Study
+*[[Breast_cancer#FEC_2|FEC]] x 3, then [[Breast_cancer#Docetaxel_monotherapy_2|D]] x 3
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+===Comparative efficacy===
-!style="width: 25%"|Comparator
+''Note: efficacy is based on the 2012 update.''
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|FEC
+| style="background-color:#d73027" |Inferior OS (*)
 |-
-|[https://www.surgjournal.com/article/0039-6060(80)90244-5/fulltext Hubay et al. 1980]
+|FEC-D
-| style="background-color:#1a9851" |Randomized (E-RT-esc)
+| style="background-color:#1a9850" |Superior OS (*)
-|CMF
-| style="background-color:#91cf60" |Seems to have superior RFS
 |-
 |}
-====Preceding treatment====
-*[[Surgery#Modified_radical_mastectomy|Modified radical mastectomy]] or [[Surgery#Mastectomy|total mastectomy]] with [[Surgery#Axillary_lymph_node_dissection|low axillary-node dissection]]
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Methotrexate (MTX)]]
-*[[Fluorouracil (5-FU)]]
-====Hormonotherapy====
-*[[Tamoxifen (Nolvadex)]]
 ===References===
-# Hubay CA, Pearson OH, Marshall JS, Rhodes RS, Debanne SM, Mansour EG, Hermann RE, Jones JC, Flynn WJ, Eckert C, McGuire WL. Antiestrogen, cytotoxic chemotherapy, and bacillus Calmette-Guerin vaccination in stage II breast cancer: a preliminary report. Surgery. 1980 May;87(5):494-501. [https://www.surgjournal.com/article/0039-6060(80)90244-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7368100 PubMed]
+<!-- Presented in oral format at the 27th Annual San Antonio Breast Cancer Symposium, San Antonio, TX, December 8-11, 2004. -->
-## '''Update:''' Hubay CA, Pearson OH, Marshall JS, Rhodes RS, DeBanne SM, Rosenblatt J, Mansour EG, Hermann RE, Jones JC, Flynn WJ, Eckert C, McGuire WL. Adjuvant chemotherapy, antiestrogen therapy and immunotherapy for stage II breast cancer: 45-month follow-up of a prospective, randomized clinical trial. Cancer. 1980 Dec 15;46(12 Suppl):2805-8. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19801215)46:12%2B%3C2805::AID-CNCR2820461413%3E3.0.CO;2-H link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7004624 PubMed]
+# Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulié P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Genève J, Asselain B. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006 Dec 20;24(36):5664-71. Epub 2006 Nov 20. [http://jco.ascopubs.org/content/24/36/5664.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17116941 PubMed]
+## '''Update:''' Coudert B, Asselain B, Campone M, Spielmann M, Machiels JP, Pénault-Llorca F, Serin D, Lévy C, Romieu G, Canon JL, Orfeuvre H, Piot G, Petit T, Jerusalem G, Audhuy B, Veyret C, Beauduin M, Eymard JC, Martin AL, Roché H; UNICANCER Breast Group. Extended benefit from sequential administration of docetaxel after standard fluorouracil, epirubicin, and cyclophosphamide regimen for node-positive breast cancer: the 8-year follow-up results of the UNICANCER-PACS01 trial. Oncologist. 2012;17(7):900-9. Epub 2012 May 18. [http://theoncologist.alphamedpress.org/content/17/7/900.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3399644/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22610153 PubMed]
-==CMFVP {{#subobject:ae7a82|Regimen=1}}==
+==GEICAM 9906==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CMFVP: '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil, '''<u>V</u>'''incristine, '''<u>P</u>'''rednisone
+===Arm 1 (Control)===
-===Regimen {{#subobject:538cb7|Variant=1}}===
+*[[Breast_cancer#FEC_2|FEC]] x 6
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Arm 2 (Experimental)===
-!style="width: 25%"|Study
+*[[Breast_cancer#FEC_2|FEC]] x 4, then [[Breast_cancer#Paclitaxel_monotherapy.2C_weekly_2|weekly T (Taxol)]] x 12
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
-!style="width: 25%"|Comparator
+===Comparative efficacy===
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|FEC x 6
+|style="background-color:#d73027"|Inferior DFS
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(197607)38:1%3C13::AID-CNCR2820380104%3E3.0.CO;2-5 Hoogstraten et al. 1976]
+|FEC x 4, then T
-|style="background-color:#1a9851" |Phase III (E-esc)
+|style="background-color:#1a9850"|Superior DFS
-|[[Breast_cancer#Doxorubicin_monotherapy_3|Doxorubicin]]
-| style="background-color:#91cf60" |Seems to have superior ORR
 |-
-|[https://www.sciencedirect.com/science/article/pii/0014296480900377 Carmo-Pereira et al. 1980]
+|}
-|style="background-color:#1a9851" |Phase III (E-esc)
+===References===
-|5-FU
+# Martín M, Rodríguez-Lescure A, Ruiz A, Alba E, Calvo L, Ruiz-Borrego M, Munárriz B, Rodríguez CA, Crespo C, de Alava E, López García-Asenjo JA, Guitián MD, Almenar S, González-Palacios JF, Vera F, Palacios J, Ramos M, Gracia Marco JM, Lluch A, Alvarez I, Seguí MA, Mayordomo JI, Antón A, Baena JM, Plazaola A, Modolell A, Pelegrí A, Mel JR, Aranda E, Adrover E, Alvarez JV, García Puche JL, Sánchez-Rovira P, Gonzalez S, López-Vega JM; GEICAM 9906 Study Investigators. Randomized phase 3 trial of fluorouracil, epirubicin, and cyclophosphamide alone or followed by paclitaxel for early breast cancer. J Natl Cancer Inst. 2008 Jun 4;100(11):805-14. Epub 2008 May 27. [http://jnci.oxfordjournals.org/content/100/11/805.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18505968 PubMed]
-| style="background-color:#1a9850" |Superior OS
+==GEICAM/2003-02==
+{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19820801)50:3%3C423::AID-CNCR2820500307%3E3.0.CO;2-O Glucksberg et al. 1982 (SWOG S7436)]
+|[[#top|back to top]]
-|style="background-color:#1a9851" |Phase III (E-esc)
+|}
-|[[#Melphalan_monotherapy|Melphalan]]
+===Arm 1, FAC (Control)===
-| style="background-color:#1a9850" |Superior OS
+*[[Surgery]], then [[Breast_cancer#FAC_2|FAC]] x 6
+===Arm 2, FAC-wP (Experimental)===
+*[[Surgery]], then [[Breast_cancer#FAC_2|FAC]] x 4, then [[Breast_cancer#Paclitaxel_monotherapy.2C_weekly_2|wP]] x 8
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|rowspan=2|[https://ascopubs.org/doi/abs/10.1200/JCO.1983.1.2.138 Tormey et al. 1983a]
+|FAC
-|rowspan=2 style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#fc8d59" |Seems to have inferior DFS
-|[[Breast_cancer#CMF|CMF]]
-| style="background-color:#1a9850" |Superior DFS
 |-
-|CMF-MER
+|FAC-wP
-| style="background-color:#d3d3d3" |Not reported
+| style="background-color:#91cf60" |Seems to have superior DFS
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1993.11.9.1710 Rivkin et al. 1993 (SWOG S7827<sub>ER-</sub>)]
+|}
-|style="background-color:#1a9851" |Phase III (C)
+===References===
-|CMFVP x 2 y
+# Martín M, Ruiz A, Ruiz Borrego M, Barnadas A, González S, Calvo L, Margelí Vila M, Antón A, Rodríguez-Lescure A, Seguí-Palmer MA, Muñoz-Mateu M, Dorca Ribugent J, López-Vega JM, Jara C, Espinosa E, Mendiola Fernández C, Andrés R, Ribelles N, Plazaola A, Sánchez-Rovira P, Salvador Bofill J, Crespo C, Carabantes FJ, Servitja S, Chacón JI, Rodríguez CA, Hernando B, Álvarez I, Carrasco E, Lluch A. Fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus FAC followed by weekly paclitaxel as adjuvant therapy for high-risk, node-negative breast cancer: results from the GEICAM/2003-02 study. J Clin Oncol. 2013 Jul 10;31(20):2593-9. Epub 2013 Jun 3. [http://jco.ascopubs.org/content/31/20/2593.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23733779 PubMed]
-| style="background-color:#ffffbf" |Seems not superior
+==GEICAM/2003-10==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1, EC-T (Control)===
+*[[Surgery]], then [[Breast_cancer#EC_2|EC]] x 4, then [[Breast_cancer#Docetaxel_monotherapy_2|T (Taxotere)]] x 4
+===Arm 2, ET-X (Experimental)===
+*[[Surgery]], then ET x 4, then [[Breast_cancer#Capecitabine_monotherapy|X]] x 4
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1995.13.4.831 Budd et al. 1995 (SWOG S8313)]
+|EC-T
-|style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#91cf60" |Seems to have superior IDFS
-|FAC-M
-| style="background-color:#ffffbf" |Seems not superior
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.1.46 Rivkin et al. 1996 (SWOG S7821)]
+|ET-X
-|style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#fc8d59" |Seems to have inferior IDFS
-|CMFVP & Oophorectomy
-| style="background-color:#ffffbf" |Seems not superior
 |-
 |}
-====Preceding treatment====
-*[[Surgery#Breast_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Methotrexate (MTX)]]
-*[[Fluorouracil (5-FU)]]
-*[[Vincristine (Oncovin)]]
-====Hormonotherapy====
-*[[Prednisone (Sterapred)]]
 ===References===
-# Hoogstraten B, George SL, Samal B, Rivkin SE, Costanzi JJ, Bonnet JD, Thigpen T, Braine H. Combination chemotherapy and adriamycin in patients with advanced breast cancer: a Southwest Oncology Group study. Cancer. 1976 Jul;38(1):13-20. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(197607)38:1%3C13::AID-CNCR2820380104%3E3.0.CO;2-5 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/947510 PubMed]
+# Martín M, Ruiz Simón A, Ruiz Borrego M, Ribelles N, Rodríguez-Lescure Á, Muñoz-Mateu M, González S, Margelí Vila M, Barnadas A, Ramos M, Del Barco Berron S, Jara C, Calvo L, Martínez-Jáñez N, Mendiola Fernández C, Rodríguez CA, Martínez de Dueñas E, Andrés R, Plazaola A, de la Haba-Rodríguez J, López-Vega JM, Adrover E, Ballesteros AI, Santaballa A, Sánchez-Rovira P, Baena-Cañada JM, Casas M, del Carmen Cámara M, Carrasco EM, Lluch A. Epirubicin plus cyclophosphamide followed by docetaxel versus epirubicin plus docetaxel followed by capecitabine as adjuvant therapy for node-positive early breast cancer: results from the GEICAM/2003-10 study. J Clin Oncol. 2015 Nov 10;33(32):3788-95. Epub 2015 Sep 28. [https://ascopubs.org/doi/full/10.1200/JCO.2015.61.9510 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/26416999 PubMed]
-# Carmo-Pereira J, Costa FO, Henriques E. Single-drug vs combination cytotoxic chemotherapy in advanced breast cancer: a randomized study. Eur J Cancer. 1980 Dec;16(12):1621-5. [https://www.sciencedirect.com/science/article/pii/0014296480900377 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/7014228 PubMed]
-# '''SWOG S7436:''' Glucksberg H, Rivkin SE, Rasmussen S, Tranum B, Gad-el-Mawla N, Costanzi J, Hoogstraten B, Athens J, Maloney T, McCracken J, Vaughn C. Combination chemotherapy (CMFVP) versus L-phenylalanine mustard (L-PAM) for operable breast cancer with positive axillary nodes: a Southwest Oncology Group Study. Cancer. 1982 Aug 1;50(3):423-34. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19820801)50:3%3C423::AID-CNCR2820500307%3E3.0.CO;2-O link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7046900 PubMed]
-## '''Update:''' Rivkin SE, Green SJ, Lew D, Costanzi JJ, Athens JW, Osborne CK, Vaughn CB, Martino S. Adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil, vincristine, and prednisone compared with single-agent L-phenylalanine mustard for patients with operable breast carcinoma and positive axillary lymph nodes: 20-year results of a Southwest Oncology Group study. Cancer. 2003 Jan 1;97(1):21-9. [https://onlinelibrary.wiley.com/doi/full/10.1002/cncr.10982 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12491501 PubMed]
-# Tormey DC, Weinberg VE, Holland JF, Weiss RB, Glidewell OJ, Perloff M, Falkson G, Falkson HC, Henry PH, Leone LA, Rafla S, Ginsberg SJ, Silver RT, Blom J, Carey RW, Schein PS, Lesnick GJ. A randomized trial of five and three drug chemotherapy and chemoimmunotherapy in women with operable node positive breast cancer. J Clin Oncol. 1983 Feb;1(2):138-45. [https://ascopubs.org/doi/abs/10.1200/JCO.1983.1.2.138 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6366133 PubMed]
-# '''SWOG S7827:''' Rivkin SE, Green S, Metch B, Jewell WR, Costanzi JJ, Altman SJ, Minton JP, O'Bryan RM, Osborne CK. One versus 2 years of CMFVP adjuvant chemotherapy in axillary node-positive and estrogen receptor-negative patients: a Southwest Oncology Group study. J Clin Oncol. 1993 Sep;11(9):1710-6. [https://ascopubs.org/doi/abs/10.1200/JCO.1993.11.9.1710 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8355037 PubMed]
-# '''SWOG S8313:''' Budd GT, Green S, O'Bryan RM, Martino S, Abeloff MD, Rinehart JJ, Hahn R, Harris J, Tormey D, O'Sullivan J, Osborne CK. Short-course FAC-M versus 1 year of CMFVP in node-positive, hormone receptor-negative breast cancer: an intergroup study. J Clin Oncol. 1995 Apr;13(4):831-9. [https://ascopubs.org/doi/abs/10.1200/JCO.1995.13.4.831 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7707108 PubMed]
-# '''SWOG S7821:''' Rivkin SE, Green S, O'Sullivan J, Cruz AB, Abeloff MD, Jewell WR, Costanzi JJ, Farrar WB, Osborne CK. Adjuvant CMFVP versus adjuvant CMFVP plus ovariectomy for premenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study. J Clin Oncol. 1996 Jan;14(1):46-51. [https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.1.46 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8558219 PubMed]
-==CPB {{#subobject:0d159a|Regimen=1}}==
+==GeparDuo==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CPB: '''<u>C</u>'''yclophosphamide, '''<u>P</u>'''latinol (Cisplatin), '''<u>B</u>'''CNU (Carmustine)
+===Arm 1, ddAT (Experimental)===
-===Regimen {{#subobject:683965|Variant=1}}===
+*ddAT x 4, then [[surgery]]
+===Arm 2, AC-T (Experimental)===
+*[[Breast_cancer#AC|AC]] x 4, then [[Breast_cancer#Docetaxel_monotherapy|T (Taxotere)]] x 4, then [[surgery]]
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2005.10.202 Peters et al. 2005 (CALGB 9082)]
+|ddAT
-| style="background-color:#1a9851" |Phase III (E-de-esc)
+| style="background-color:#d73027" |Inferior pCR rate
-|HD-CPB with auto HSCT
+|-
-| style="background-color:#ffffbf" |Seems not superior
+|AC-T
+| style="background-color:#1a9850" |Superior pCR rate
 |-
 |}
-''Note: this trial is of important historic significance. Although neither arm was standard of care, the results established the non-value of high-dose therapy with autologous HSCT in the adjuvant treatment of breast cancer.''
-====Preceding treatment====
-*[[Surgery#Breast_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Cisplatin (Platinol)]]
-*[[Carmustine (BCNU)]]
 ===References===
-# '''CALGB 9082:''' Peters WP, Rosner GL, Vredenburgh JJ, Shpall EJ, Crump M, Richardson PG, Schuster MW, Marks LB, Cirrincione C, Norton L, Henderson IC, Schilsky RL, Hurd DD. Prospective, randomized comparison of high-dose chemotherapy with stem-cell support versus intermediate-dose chemotherapy after surgery and adjuvant chemotherapy in women with high-risk primary breast cancer: a report of CALGB 9082, SWOG 9114, and NCIC MA-13. J Clin Oncol. 2005 Apr 1;23(10):2191-200. Epub 2005 Mar 14. [https://ascopubs.org/doi/full/10.1200/JCO.2005.10.202 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15767638 PubMed]
+# von Minckwitz G, Raab G, Caputo A, Schütte M, Hilfrich J, Blohmer JU, Gerber B, Costa SD, Merkle E, Eidtmann H, Lampe D, Jackisch C, du Bois A, Kaufmann M. Doxorubicin with cyclophosphamide followed by docetaxel every 21 days compared with doxorubicin and docetaxel every 14 days as preoperative treatment in operable breast cancer: the GEPARDUO study of the German Breast Group. J Clin Oncol. 2005 Apr 20;23(12):2676-85. [https://ascopubs.org/doi/full/10.1200/JCO.2005.05.078 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15837982 PubMed]
-==CTCb, then auto HSCT {{#subobject:7a4fec|Regimen=1}}==
+==GeparQuinto==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CTCb: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''hiotepa, '''<u>C</u>'''ar'''<u>b</u>'''oplatin
+===Arm 1A - Control (HER2-negative)===
-<br>STAMP-V
+*[[Breast_cancer#EC|EC]] x 4, then [[Breast_cancer#Docetaxel_monotherapy|Docetaxel]] x 4, then [[surgery]]
-===Regimen {{#subobject:9d0c8a|Variant=1}}===
+===Arm 1B - Control (HER2-positive)===
+*[[Breast_cancer,_HER2-positive#ECH|ECH]] x 4, then [[Breast_cancer,_HER2-positive#TH_.28Taxotere.29|TH (Taxotere)]] x 4, then [[surgery]]
+===Arm 2A - Experimental (HER2-negative)===
+*[[Breast_cancer,_triple_negative#EC_.26_Bevacizumab|EC & Bevacizumab]] x 4, then [[Breast_cancer,_triple_negative#Docetaxel_.26_Bevacizumab|Docetaxel & Bevacizumab]] x 4, then [[surgery]]
+===Arm 2B - Experimental (HER2-positive)===
+*ECL x 4, then TL (Taxotere) x 4, then [[surgery]]
+===Comparative efficacy===
+====Comparison 1 (HER2-negative)====
+''Note that while this study met the primary efficacy endpoint, the advantage for bevacizumab was only seen in the triple-negative breast cancer patients, with p=0.003 in this subgroup.''
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
+|-
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|No bevacizumab
+|style="background-color:#fc8d59"|Seems to have inferior pCR rate
 |-
-|[http://jco.ascopubs.org/content/8/7/1239.long Eder et al. 1990]
+|With bevacizumab
-| style="background-color:#91cf61" |Phase I/II
+|style="background-color:#91cf60"|Seems to have superior pCR rate
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)01350-6/fulltext Rodenhuis et al. 1998]
+|}
-| style="background-color:#1a9851" |Randomized Phase II (E-esc)
+====Comparison 2 (HER2-positive)====
-|Standard adjuvant therapy
+{| class="wikitable" style="width: 100%; text-align:center;"
-| style="background-color:#ffffbf" |Seems not superior
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.sciencedirect.com/science/article/pii/S0140673600028415 Bergh et al. 2000 (SBG 9401)]
+|With lapatinib
-| style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#fc8d59"|Seems to have inferior pCR rate
-|[[Complex_multipart_regimens#SBG_9401|See link]]
-| style="background-color:#fc8d59" |[[Complex_multipart_regimens#SBG_9401|See link]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa022794 Rodenhuis et al. 2003]
+|With trastuzumab
-| style="background-color:#1a9851" |Phase III (E-esc)
+|style="background-color:#91cf60"|Seems to have superior pCR rate
-|[[Breast_cancer#FEC_2|FEC]] x 5
-| style="background-color:#d9ef8b" |Might have superior RFS
 |-
 |}
-''No longer used, but of historical interest.''
-====Preceding treatment====
-*Rodenhuis et al. 1998: [[Breast_cancer#FEC|Neoadjuvant FEC]] x 3, then [[Surgery#Breast_cancer_surgery|surgery]], then [[Breast_cancer#FEC_2|FEC]] x 1
-*Rodenhuis et al. 2003: [[Breast_cancer#FEC_2|FEC]] x 4
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]] 1500 mg/m<sup>2</sup>/day on days -7 to -4
-*[[Thiotepa (Thioplex)]] 125 mg/m<sup>2</sup>/day on days -7 to -4
-*[[Carboplatin (Paraplatin)]] 200 mg/m<sup>2</sup>/day on days -7 to -4
-'''Stem cells re-infused on day 0'''
 ===References===
-# Eder JP, Elias A, Shea TC, Schryber SM, Teicher BA, Hunt M, Burke J, Siegel R, Schnipper LE, Frei E 3rd, Antman K. A phase I-II study of cyclophosphamide, thiotepa, and carboplatin with autologous bone marrow transplantation in solid tumor patients. J Clin Oncol. 1990 Jul;8(7):1239-45. [http://jco.ascopubs.org/content/8/7/1239.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2162912 PubMed]
+# von Minckwitz G, Eidtmann H, Rezai M, Fasching PA, Tesch H, Eggemann H, Schrader I, Kittel K, Hanusch C, Kreienberg R, Solbach C, Gerber B, Jackisch C, Kunz G, Blohmer JU, Huober J, Hauschild M, Fehm T, Müller BM, Denkert C, Loibl S, Nekljudova V, Untch M; German Breast Group; Arbeitsgemeinschaft Gynäkologische Onkologie–Breast Study Groups. Neoadjuvant chemotherapy and bevacizumab for HER2-negative breast cancer. N Engl J Med. 2012 Jan 26;366(4):299-309. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111065 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22276820 PubMed]
-# Rodenhuis S, Richel DJ, van der Wall E, Schornagel JH, Baars JW, Koning CC, Peterse JL, Borger JH, Nooijen WJ, Bakx R, Dalesio O, Rutgers E. Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement. Lancet. 1998 Aug 15;352(9127):515-21. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(98)01350-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9716055 PubMed]
+# Untch M, Loibl S, Bischoff J, Eidtmann H, Kaufmann M, Blohmer JU, Hilfrich J, Strumberg D, Fasching PA, Kreienberg R, Tesch H, Hanusch C, Gerber B, Rezai M, Jackisch C, Huober J, Kühn T, Nekljudova V, von Minckwitz G; German Breast Group (GBG); Arbeitsgemeinschaft Gynäkologische Onkologie-Breast (AGO-B) Study Group. Lapatinib versus trastuzumab in combination with neoadjuvant anthracycline-taxane-based chemotherapy (GeparQuinto, GBG 44): a randomised phase 3 trial. Lancet Oncol. 2012 Feb;13(2):135-44. Epub 2012 Jan 17. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(11)70397-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22257523 PubMed]
-# '''SBG 9401:''' Bergh J, Wiklund T, Erikstein B, Lidbrink E, Lindman H, Malmström P, Kellokumpu-Lehtinen P, Bengtsson NO, Söderlund G, Anker G, Wist E, Ottosson S, Salminen E, Ljungman P, Holte H, Nilsson J, Blomqvist C, Wilking N; Scandinavian Breast Group 9401 study. Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Lancet. 2000 Oct 21;356(9239):1384-91. Erratum in: Lancet 2000 Dec 23-30;356(9248):2196. [https://www.sciencedirect.com/science/article/pii/S0140673600028415 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/11052580 PubMed]
+## '''Update:''' Untch M, von Minckwitz G, Gerber B, Schem C, Rezai M, Fasching PA, Tesch H, Eggemann H, Hanusch C, Huober J, Solbach C, Jackisch C, Kunz G, Blohmer JU, Hauschild M, Fehm T, Nekljudova V, Loibl S; GBG and the AGO-B Study Group. Survival analysis after neoadjuvant chemotherapy with trastuzumab or lapatinib in patients with human epidermal growth factor receptor 2-positive breast cancer in the GeparQuinto (G5) study (GBG 44). J Clin Oncol. 2018 May 1;36(13):1308-1316. Epub 2018 Mar 15. [https://ascopubs.org/doi/full/10.1200/JCO.2017.75.9175 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29543566 PubMed]
-# Rodenhuis S, Bontenbal M, Beex LV, Wagstaff J, Richel DJ, Nooij MA, Voest EE, Hupperets P, van Tinteren H, Peterse HL, TenVergert EM, de Vries EG; Netherlands Working Party on Autologous Transplantation in Solid Tumors. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med. 2003 Jul 3;349(1):7-16. [https://www.nejm.org/doi/full/10.1056/NEJMoa022794 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/12840087 PubMed]
-==Cyclophosphamide monotherapy {{#subobject:7b2fec|Regimen=1}}==
+==GIM2==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Regimen {{#subobject:9d3c8a|Variant=1}}===
+===Arm 1, "q3EC-P" (Control)===
+*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#EC_2|EC]] x 4, then [[Breast_cancer_-_historical#Paclitaxel_monotherapy.2C_q3wk|P]] x 4
+===Arm 2, "q3FEC-P" (Experimental)===
+*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#FEC_2|FEC]] x 4, then [[Breast_cancer_-_historical#Paclitaxel_monotherapy.2C_q3wk|P]] x 4
+===Arm 3, "q2EC-P" (Experimental)===
+*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#ddEC|ddEC]] x 4, then [[Breast_cancer#Paclitaxel_monotherapy.2C_dose-dense_.28q2wk.29_2|ddP]] x 4
+===Arm 4, "q2FEC-P" (Experimental)===
+*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#ddFEC|ddEC]] x 4, then [[Breast_cancer#Paclitaxel_monotherapy.2C_dose-dense_.28q2wk.29_2|ddP]] x 4
+===Comparative efficacy===
+*Analyzed using a 2 x 2 factorial design
+====Comparison 1====
+{| class="wikitable" style="width: 100%; text-align:center;"
+|'''Dose density'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Dose-dense (q2wk)
+|style="background-color:#1a9850"|Superior OS
+|-
+|Standard (q3wk)
+|style="background-color:#d73027"|Inferior OS
+|-
+|}
+====Comparison 2====
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+|'''Inclusion of 5-FU'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
+|-
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|Yes (FEC-based)
+|style="background-color:#ffffbf"|Seems not superior
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2025018/ Rubens et al. 1975]
+|No (EC-based)
-| style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#ffffbf"|Seems not superior
-|CMFV
-| style="background-color:#ffffbf" |Seems not superior
 |-
 |}
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
 ===References===
-# Rubens RD, Knight RK, Hayward JL. Chemotherapy of advanced breast cancer: a controlled randomized trial of cyclophosphamide versus a four-drug combination. Br J Cancer. 1975 Dec;32(6):730-6. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2025018/ link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/766800 PubMed]
+# Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella (GIM) investigators. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62048-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25740286 PubMed]
-# '''DBCG 77B:''' Brincker H, Mouridsen HT, Andersen KW. Adjuvant chemotherapy with cyclophosphamide or CMF in premenopausal women with stage II breast cancer. Breast Cancer Res Treat. 1983;3(1):91-5. [https://link.springer.com/article/10.1007/BF01806239 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/6347278 PubMed]
-## '''Update:''' Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Andersson M, Kamby C, Knoop AS; Danish Breast Cancer Cooperative Group. Cyclophosphamide, methotrexate, and fluorouracil; oral cyclophosphamide; levamisole; or no adjuvant therapy for patients with high-risk, premenopausal breast cancer. Cancer. 2010 May 1;116(9):2081-9. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.24969/full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20186830 PubMed]
-==ECT, then auto HSCT {{#subobject:7a4gab|Regimen=1}}==
+==GROCTA-1==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-ECT: '''<u>E</u>'''pirubicin, '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''hiotepa
+===Arm 1, CT (Experimental)===
-===Regimen {{#subobject:9d0a2n|Variant=1}}===
+*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#CMF|CMF]] x 6, then [[Breast_cancer#Epirubicin_monotherapy|E]] x 4
+===Arm 2, T (Experimental)===
+*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 5 y
+===Arm 3, CTT (Experimental)===
+*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#CMF|CMF]] x 6, then [[Breast_cancer#Epirubicin_monotherapy|E]] x 4, then [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 5 y
+===Comparative efficacy===
+''Note: reported efficacy is based on the 2011 update.''
+====Comparison 1====
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+|'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)67784-7/fulltext Nitz et al. 2005 (WSG AM-01)]
+|T
-|style="background-color:#1a9851" |Phase III (E-esc)
-|[[Breast_cancer#ddEC|ddEC]] x 4, then ddCMF x 3
 | style="background-color:#91cf60" |Seems to have superior OS
+|-
+|CT
+| style="background-color:#fc8d59" |Seems to have inferior OS
+|-
+|}
+====Comparison 2====
+{| class="wikitable" style="width: 100%; text-align:center;"
+|'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|CTT
+|style="background-color:#1a9850"|Superior OS
+|-
+|CT
+|style="background-color:#d73027"|Inferior OS
 |-
 |}
-''No longer used, but of historical interest.''
-====Preceding treatment====
-*[[Surgery#Breast_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Epirubicin (Ellence)]]
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Thiotepa (Thioplex)]]
 ===References===
-# '''WSG AM-01:''' Nitz UA, Mohrmann S, Fischer J, Lindemann W, Berdel WE, Jackisch C, Werner C, Ziske C, Kirchner H, Metzner B, Souchon R, Ruffert U, Schütt G, Pollmanns A, Schmoll HJ, Middecke C, Baltzer J, Schrader I, Wiebringhaus H, Ko Y, Rösel S, Schwenzer T, Wernet P, Hinke A, Bender HG, Frick M; West German Study Group. Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial. Lancet. 2005 Dec 3;366(9501):1935-44. Erratum in: Lancet. 2006 Mar 4;367(9512):730. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(05)67784-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16325695 PubMed]
+# Boccardo F, Rubagotti A, Bruzzi P, Cappellini M, Isola G, Nenci I, Piffanelli A, Scanni A, Sismondi P, Santi L, Genta F, Saccani F, Sassi M, Malacarne P, Donati D, Farris A, Castagnetta L, Di Carlo A, Traina A, Galletto L, Smerieri F, Buzzi F; Breast Cancer Adjuvant Chemo-Hormone Therapy Cooperative Group. Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, estrogen receptor-positive breast cancer patients: results of a multicentric Italian study. J Clin Oncol. 1990 Aug;8(8):1310-20. [https://ascopubs.org/doi/abs/10.1200/JCO.1990.8.8.1310 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2199618 PubMed]
+## '''Update:''' Boccardo F, Guglielmini P, Parodi A, Rubagotti A. Chemotherapy versus tamoxifen versus chemotherapy plus tamoxifen in node-positive, oestrogen receptor-positive breast cancer patients: very late results of the 'gruppo di ricerca per la chemio-ormonoterapia adiuvante (GROCTA)' 01-Trial in early breast cancer. Breast Cancer Res Treat. 2011 Apr;126(3):653-61. Epub 2011 Feb 24. [https://link.springer.com/article/10.1007%2Fs10549-011-1405-6 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21347647 PubMed]
-==FAC & BCG {{#subobject:19f556|Regimen=1}}==
+==HannaH==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-FAC & BCG: '''<u>F</u>'''luorouracil, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide, BCG
+===Arm 1, IV trastuzumab===
-===Regimen {{#subobject:08e709|Variant=1}}===
+*[[Breast_cancer,_HER2-positive#TH_.28Taxotere.29|TH]] x 4, then [[Breast_cancer,_HER2-positive#FEC_.26_H|FEC & H]] x 4, then [[Surgery#Breast_cancer_surgery|surgery]], then adjuvant [[Breast_cancer,_HER2-positive#Trastuzumab_monotherapy_2|trastuzumab]]
-{| class="wikitable" style="width: 50%; text-align:center;"
+===Arm 2, SC trastuzumab===
-!style="width: 25%"|Study
+*[[Breast_cancer,_HER2-positive#TH_.28Taxotere.2FSC.29|TH]] x 4, then [[Breast_cancer,_HER2-positive#FEC_.26_H_.28SC.29|FEC & H]] x 4, then [[Surgery#Breast_cancer_surgery|surgery]], then adjuvant [[Breast_cancer,_HER2-positive#Trastuzumab_and_hyaluronidase_monotherapy|trastuzumab and hyaluronidase]]
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Route of administration'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://jamanetwork.com/journals/jama/article-abstract/366766 Buzdar et al. 1979]
+|IV trastuzumab
-| style="background-color:#91cf61" |Non-randomized
+|style="background-color:#eeee01"|Non-inferior pCR rate
+|-
+|SC trastuzumab
+|style="background-color:#eeee01"|Non-inferior pCR rate
 |-
 |}
-====Preceding treatment====
-*[[Surgery#Breast_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]]
-*[[Doxorubicin (Adriamycin)]]
-*[[Cyclophosphamide (Cytoxan)]]
-====Immunotherapy====
-*[[Bacillus Calmette-Guérin (BCG)]]
 ===References===
-# Buzdar AU, Blumenschein GR, Gutterman JU, Tashima CK, Hortobagyi GN, Smith TL, Campos LT, Wheeler WL, Hersh EM, Freireich EJ, Gehan EA. Postoperative adjuvant chemotherapy with fluorouracil, doxorubicin, cyclophosphamide, and BCG vaccine: a follow-up report. JAMA. 1979 Oct 5;242(14):1509-13. [https://jamanetwork.com/journals/jama/article-abstract/366766 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/470088 PubMed]
+# Ismael G, Hegg R, Muehlbauer S, Heinzmann D, Lum B, Kim SB, Pienkowski T, Lichinitser M, Semiglazov V, Melichar B, Jackisch C. Subcutaneous versus intravenous administration of (neo)adjuvant trastuzumab in patients with HER2-positive, clinical stage I-III breast cancer (HannaH study): a phase 3, open-label, multicentre, randomised trial. Lancet Oncol. 2012 Sep;13(9):869-78. Epub 2012 Aug 9. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(12)70329-7/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22884505 PubMed]
+## '''Update:''' Jackisch C, Stroyakovskiy D, Pivot X, Ahn JS, Melichar B, Chen SC, Meyenberg C, Al-Sakaff N, Heinzmann D, Hegg R. Subcutaneous vs intravenous trastuzumab for patients with ERBB2-positive early breast cancer: final analysis of the HannaH phase 3 randomized clinical trial. JAMA Oncol. 2019 May 1;5(5):e190339. Epub 2019 May 9. [https://jamanetwork.com/journals/jamaoncology/fullarticle/2730632 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512301/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/30998824 PubMed]
-==FNC {{#subobject:152c11|Regimen=1}}==
+==HORG Polyzos et al. 2010==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-FNC: '''<u>F</u>'''luorouracil, '''<u>N</u>'''ovantrone (Mitoxantrone), '''<u>C</u>'''yclophosphamide
+===Arm 1 (Experimental)===
-<br>CNF: '''<u>C</u>'''yclophosphamide, '''<u>N</u>'''ovantrone (Mitoxantrone), '''<u>F</u>'''luorouracil
+*[[Surgery]], then [[Breast_cancer#ddT_.28Taxotere.29|D]] x 4, then [[Breast_cancer#EC_2|EC]] x 4
-===Regimen {{#subobject:950f9d|Variant=1}}===
+===Arm 2 (Control)===
-{| class="wikitable" style="width: 100%; text-align:center;"
+*[[Surgery]], then [[Breast_cancer#FEC_2|FEC]] x 6
-!style="width: 25%"|Study
+===Comparative efficacy===
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Comparator
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://insights.ovid.com/pubmed?pmid=11474254 Ron et al. 2001]
+|D/EC
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[Breast_cancer#CMF|CMF]]
 | style="background-color:#91cf60" |Seems to have superior DFS
 |-
-|[https://insights.ovid.com/pubmed?pmid=14758135 Fountzilas et al. 2004 (HE 10/92)]
+|FEC
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#fc8d59" |Seems to have inferior DFS
-|[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]]
-| style="background-color:#ffffbf" |Seems not superior
-|-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2006.07.8576 Toledano et al. 2007 (ARCOSEIN)]
-| style="background-color:#1a9851" |Phase III (C)
-|FNC & RT
-| style="background-color:#ffffbf" |Seems not superior
 |-
 |}
-====Preceding treatment====
-*[[Surgery#Lumpectomy|Breast-conserving surgery]]
-====Chemotherapy====
-*[[Fluorouracil (5-FU)]]
-*[[Mitoxantrone (Novantrone)]]
-*[[Cyclophosphamide (Cytoxan)]]
-'''21-day cycle for 6 cycles'''
-====Subsequent treatment====
-*ARCOSEIN: RT
 ===References===
-# Ron IG, Wigler N, Borovik R, Brufman G, Rizel S, Shani A, Brenner J, Farbstein H, Dale A, Inbar MJ, Brenner HJ, Chaitchik S, Catane R. CMF (cyclophosphamide, methotrexate, 5-fluorouracil) versus CNF (cyclophosphamide, mitoxantrone, 5-fluorouracil) as adjuvant chemotherapy for stage II lymph-node positive breast  cancer: a phase III randomized multicenter study. Am J Clin Oncol. 2001 Aug;24(4):323-7. [https://insights.ovid.com/pubmed?pmid=11474254 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11474254 PubMed]
+# Polyzos A, Malamos N, Boukovinas I, Adamou A, Ziras N, Kalbakis K, Kakolyris S, Syrigos K, Papakotoulas P, Kouroussis C, Karvounis N, Vamvakas L, Christophyllakis C, Athanasiadis A, Varthalitis I, Georgoulias V, Mavroudis D. FEC versus sequential docetaxel followed by epirubicin/cyclophosphamide as adjuvant chemotherapy in women with axillary node-positive early breast cancer: a randomized study of the Hellenic Oncology Research Group (HORG). Breast Cancer Res Treat. 2010 Jan;119(1):95-104. Epub 2009 Jul 28. [https://link.springer.com/article/10.1007%2Fs10549-009-0468-0 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19636702 PubMed]
-# '''HE 10/92:''' Fountzilas G, Stathopoulos G, Kouvatseas G, Polychronis A, Klouvas G, Samantas E, Zamboglou N, Kyriakou K, Adamou A, Pectasidis D, Ekonomopoulos T, Kalofonos HP, Bafaloukos D, Georgoulias V, Razis E, Koukouras D, Zombolas V, Kosmidis P, Skarlos D, Pavlidis N; Hellenic Cooperative Oncology Group. Adjuvant cytotoxic and endocrine therapy in pre- and postmenopausal patients with breast cancer and one to nine infiltrated nodes: five-year results of the Hellenic Cooperative Oncology Group randomized HE 10/92 study. Am J Clin Oncol. 2004 Feb;27(1):57-67. [https://insights.ovid.com/pubmed?pmid=14758135 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14758135 PubMed]
-# '''ARCOSEIN:''' Toledano A, Azria D, Garaud P, Fourquet A, Serin D, Bosset JF, Miny-Buffet J, Favre A, Le Floch O, Calais G. Phase III trial of concurrent or sequential adjuvant chemoradiotherapy after conservative surgery for early-stage breast cancer: final results of the ARCOSEIN trial. J Clin Oncol. 2007 Feb 1;25(4):405-10. Erratum in: J Clin Oncol. 2007 Jun 1;25(16):2334. [https://ascopubs.org/doi/full/10.1200/JCO.2006.07.8576 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17264336 PubMed]
-==Levamisole monotherapy {{#subobject:b051c5|Regimen=1}}==
+==HORG CT/07.17==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Regimen {{#subobject:ec3553|Variant=1}}===
+===Arm 1===
+*[[Surgery]], then [[Breast_cancer#ddFEC|ddFEC]] x 4, then [[Breast_cancer#ddT_.28Taxotere.29|D]] x 4
+===Arm 2===
+*[[Surgery]], then [[Breast_cancer#TC_.28Taxotere.29|TC]] x 6
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(76)91337-4/fulltext Rojas et al. 1976]
+|ddFEC → D
-|style="background-color:#1a9851"|Randomized (E-esc)
+|style="background-color:#ffffbf"|Inconclusive whether non-inferior
-|[[#Observation|Observation]]
-| style="background-color:#91cf60" |Seems to have superior OS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(80)90173-7/fulltext Brincker et al. 1980]
+|TC
-|style="background-color:#1a9851"|Randomized (E-switch-ooc)
+|style="background-color:#ffffbf"|Inconclusive whether non-inferior
-|RT
-| style="background-color:#fc8d59" |Seems to have inferior RFS
 |-
 |}
-''Note: Rojas et al. 1976 included patients with inoperable breast cancer; definitive therapy was RT.''
-====Preceding treatment====
-*Rojas et al. 1976: Radiotherapy
-*Brincker et al. 1980: [[Surgery#Breast_cancer_surgery|Surgery]]
-====Immunotherapy====
-*[[Levamisole (Ergamisol)]]
 ===References===
-# Rojas AF, Feierstein JN, Mickiewicz E, Glait H, Olivari AJ. Levamisole in advanced human breast cancer. Lancet. 1976 Jan 31;1(7953):211-5. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(76)91337-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/55529 PubMed]
+# Mavroudis D, Matikas A, Malamos N, Papakotoulas P, Kakolyris S, Boukovinas I, Athanasiadis A, Kentepozidis N, Ziras N, Katsaounis P, Saloustros E, Georgoulias V; Breast Cancer Investigators of the Hellenic Oncology Research Group (HORG), Athens, Greece. Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2016 Oct;27(10):1873-8. Epub 2016 Aug 8. [https://academic.oup.com/annonc/article/27/10/1873/2389052 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27502729 PubMed]
-# Brincker H, Mouridsen HT, Andersen KW, Andersen J, Castberg T, Fischermann K, Henriksen E, Hou-Jensen C, Johansen H, Rossing N, Rorth M; Executive Committee of the Danish Breast Cancer Cooperative Group. Increased breast-cancer recurrence rate after adjuvant therapy with levamisole: a preliminary report. Lancet. 1980 Oct 18;2(8199):824-7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(80)90173-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6107500 PubMed]
-==Melphalan monotherapy {{#subobject:b062c5|Regimen=1}}==
+==IES==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-P: '''<u>P</u>'''henylalanine mustard (Melphalan)
+IES: '''<u>I</u>'''ntergroup '''<u>E</u>'''xemestane '''<u>S</u>'''tudy
-===Regimen {{#subobject:ec3663|Variant=1}}===
+===Arm 1, monotherapy (Control)===
+*[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 5y
+===Arm 2, sequential (Experimental)===
+*[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 2-3y, then [[Breast_cancer,_ER-positive#Exemestane_monotherapy_2|Exemestane]] x 2-3y
+===Comparative efficacy===
+''Note: reported efficacy is based on the 2011 update.''
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[https://www.nejm.org/doi/full/10.1056/NEJM197501162920301 Fisher et al. 1975 (NSABP B-05)]
-|style="background-color:#1a9851"|Phase III (E-esc)
-|[[#Placebo|Placebo]]
-| style="background-color:#d9ef8b" |Might have superior DFS (*)
 |-
-|[https://onlinelibrary.wiley.com/doi/10.1002/1097-0142%28197706%2939%3A6%3C2883%3A%3AAID-CNCR2820390676%3E3.0.CO%3B2-9 Fisher et al. 1977 (NSABP B-07)]
+|Tamoxifen x 5y
-| style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#fc8d59"|Seems to have inferior OS
-|[[#PF|PF]]
-| style="background-color:#fc8d59" |Seems to have inferior RFS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(83)91385-5/fulltext Rubens et al. 1983]
+|Tamoxifen x 2-3y, then Exemestane x 2-3y (5y total)
-|style="background-color:#1a9851"|Phase III (E-esc)
+|style="background-color:#91cf60"|Seems to have superior OS
-|[[#Observation|Observation]]
-| style="background-color:#d9ef8b" |Might have superior RFS
 |-
 |}
-''Note: Fisher et al. 1977 is an update for NSABP B-05 and also the primary results for NSABP B-07. Efficacy for NSABP B-05 is based on the 1986 update.''
-====Preceding treatment====
-*[[Surgery#Breast_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Melphalan (Alkeran)]]
 ===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://www.ncbi.nlm.nih.gov/pubmed/1105174 PubMed]
+# Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM, van de Velde C; Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004 Mar 11;350(11):1081-92. [https://www.nejm.org/doi/full/10.1056/NEJMoa040331 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15014181 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://www.ncbi.nlm.nih.gov/pubmed/194679 PubMed]
+## '''Update:''' Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, Van de Velde CJ, Delozier T, Alvarez I, Del Mastro L, Ortmann O, Diedrich K, Coates AS, Bajetta E, Holmberg SB, Dodwell D, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Forbes J, Castiglione M, Stuart N, Stewart A, Fallowfield LJ, Bertelli G, Hall E, Bogle RG, Carpentieri M, Colajori E, Subar M, Ireland E, Bliss JM; Intergroup Exemestane Study. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 2007 Feb 17;369(9561):559-70. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2807%2960200-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17307102 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://ascopubs.org/doi/full/10.1200/JCO.1986.4.6.929 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3519883 PubMed]
+## '''Update:''' Bliss JM, Kilburn LS, Coleman RE, Forbes JF, Coates AS, Jones SE, Jassem J, Delozier T, Andersen J, Paridaens R, van de Velde CJ, Lønning PE, Morden J, Reise J, Cisar L, Menschik T, Coombes RC. Disease-related outcomes with long-term follow-up: an updated analysis of the Intergroup Exemestane Study. J Clin Oncol. 2012 Mar 1;30(7):709-17. Epub 2011 Oct 31. [https://ascopubs.org/doi/full/10.1200/JCO.2010.33.7899 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22042946 PubMed]
-# '''NSABP B-07:''' 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%28197706%2939%3A6%3C2883%3A%3AAID-CNCR2820390676%3E3.0.CO%3B2-9 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/194679 PubMed]
-# 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://www.ncbi.nlm.nih.gov/pubmed/6132179 PubMed]
-==MF {{#subobject:e1def3|Regimen=1}}==
+==IRST-IBIS-03==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-MF: '''<u>M</u>'''ethotrexate & 5-'''<u>F</u>'''luorouracil
+===Arm 1===
-===Regimen {{#subobject:c6e0a3|Variant=1}}===
+*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#Epirubicin_monotherapy|E]], then [[Breast_cancer#CMF|CMF]]
+===Arm 2===
+*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#CMF|CMF]], then [[Breast_cancer#Epirubicin_monotherapy|E]]
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 50%"|'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 50%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM198902233200801 Fisher et al. 1989 (NSABP B-13)]
+|E -> CMF
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#ffffbf" |Seems not superior
-|[[#Observation|Observation]]
-| style="background-color:#1a9850" |Superior DFS (*)
 |-
-|[https://academic.oup.com/jnci/article-abstract/85/10/812/1024452 Shapiro et al. 1993]
+|CMF -> E
-| style="background-color:#1a9851" |Phase III (C)
-|[[Breast_cancer#CMF|CMF]]
 | style="background-color:#ffffbf" |Seems not superior
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.7.1982 Fisher et al. 1996 (NSABP B-19)]
+|}
-| style="background-color:#1a9851" |Phase III (C)
+===References===
-|[[Breast_cancer#CMF|CMF]]
+# Amadori D, Silvestrini R, De Lena M, Boccardo F, Rocca A, Scarpi E, Schittulli F, Brandi M, Maltoni R, Serra P, Ponzone R, Biglia N, Gianni L, Tienghi A, Valerio MR, Bonginelli P, Amaducci L, Faedi M, Baldini E, Paradiso A. Randomized phase III trial of adjuvant epirubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) versus CMF followed by epirubicin in patients with node-negative or 1-3 node-positive rapidly proliferating breast cancer. Breast Cancer Res Treat. 2011 Feb;125(3):775-84. Epub 2010 Dec 4. [https://link.springer.com/article/10.1007%2Fs10549-010-1257-5 link to original article]  [https://www.ncbi.nlm.nih.gov/pubmed/21132360 PubMed]
+==Kümmel et al. 2006==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1, control===
+*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#EC_2|EC]] x 4, then [[Breast_cancer#CMF|CMF]] x 3
+===Arm 2, experimental===
+*[[Surgery#Breast_cancer_surgery|Surgery]], then ddEP x 4, then ddCMF x 3
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!style="width: 50%"|'''Regimen'''
+!style="width: 50%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|EC-CMF
 | style="background-color:#fee08b" |Might have inferior OS
+|-
+|ddEP-ddCMF
+| style="background-color:#d9ef8b" |Might have superior OS
 |-
 |}
-''Note: Reported efficacy for NSABP B-13 is based on the 1996 update.''
-====Preceding treatment====
-*[[Surgery#Breast_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Methotrexate (MTX)]]
-*[[Fluorouracil (5-FU)]]
 ===References===
-# '''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://www.ncbi.nlm.nih.gov/pubmed/2644531 PubMed]
+# Kümmel S, Krocker J, Kohls A, Breitbach GP, Morack G, Budner M, Blohmer JU, Elling D. Randomised trial: survival benefit and safety of adjuvant dose-dense chemotherapy for node-positive breast cancer. Br J Cancer. 2006 May 8;94(9):1237-44. [https://www.nature.com/articles/6603085 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2361407/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/16622463 PubMed]
-## '''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://ascopubs.org/doi/abs/10.1200/JCO.1996.14.7.1982 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8683228 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://ascopubs.org/doi/full/10.1200/JCO.2006.06.9054 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16921044 PubMed]
-# Shapiro CL, Gelman RS, Hayes DF, Osteen R, Obando A, Canellos GP, Frei E 3rd, Henderson IC. Comparison of adjuvant chemotherapy with methotrexate and fluorouracil with and without cyclophosphamide in breast cancer patients with one to three positive axillary lymph nodes. J Natl Cancer Inst. 1993 May 19;85(10):812-7. [https://academic.oup.com/jnci/article-abstract/85/10/812/1024452 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8487326 PubMed]
-# '''NSABP B-19:''' 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://ascopubs.org/doi/abs/10.1200/JCO.1996.14.7.1982 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8683228 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://ascopubs.org/doi/full/10.1200/JCO.2006.06.9054 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16921044 PubMed]
-==MV {{#subobject:eb48eb|Regimen=1}}==
+==Loesch et al. 2010==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-MV: '''<u>M</u>'''ethotrexate & '''<u>V</u>'''inblastine
+===Arm 1, control===
-===Regimen {{#subobject:883648|Variant=1}}===
+*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#AC_2|AC]] x 4, then [[Breast_cancer_-_historical#Paclitaxel_monotherapy.2C_q3wk|T (Taxol)]] x 4
+===Arm 2, experimental===
+*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#AT_.28Taxol.29|AT (Taxol)]] x 4, then [[#Paclitaxel_monotherapy.2C_weekly_2|wP]] x 12
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://onlinelibrary.wiley.com/doi/10.1002/cncr.11396/full Assikis et al. 2003]
+|AC-P
-|style="background-color:#1a9851"|Phase III (E-switch-ooc)
+| style="background-color:#ffffbf" |Seems not superior
-|[[Complex_multipart_regimens#Assikis_et_al._2003|See link]]
+|-
-| style="background-color:#ffffbf" |[[Complex_multipart_regimens#Assikis_et_al._2003|See link]]
+|AP-WP
+| style="background-color:#ffffbf" |Seems not superior
 |-
 |}
-''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
+===References===
-====Preceding treatment====
+# Loesch D, Greco FA, Senzer NN, Burris HA, Hainsworth JD, Jones S, Vukelja SJ, Sandbach J, Holmes F, Sedlacek S, Pippen J, Lindquist D, McIntyre K, Blum JL, Modiano MR, Boehm KA, Zhan F, Asmar L, Robert N. Phase III multicenter trial of doxorubicin plus cyclophosphamide followed by paclitaxel compared with doxorubicin plus paclitaxel followed by weekly paclitaxel as adjuvant therapy for women with high-risk breast cancer. J Clin Oncol. 2010 Jun 20;28(18):2958-65. Epub 2010 May 17. [https://ascopubs.org/doi/full/10.1200/JCO.2009.24.1000 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20479419 PubMed]
-*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#FAC|FAC]] x 6
-====Chemotherapy====
-*[[Methotrexate (MTX)]] 75 mg/m<sup>2</sup> IV once on day 1
-*[[Vinblastine (Velban)]] 1.7 mg/m<sup>2</sup>/day continuous infusion over 120 hours, started on day 1 (total dose per cycle: 8.5 mg/m<sup>2</sup>)
-====Supportive medications====
+==Mavroudis et al. 2017==
-*[[Folinic acid (Leucovorin)]] rescue
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1, sequential===
+*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#Epirubicin_monotherapy|Epirubicin]], then [[Breast_cancer#Docetaxel_monotherapy_2|Docetaxel]]
+===Arm 2, concurrent===
+*[[Surgery#Breast_cancer_surgery|Surgery]], then Docetaxel & Epirubicin
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Schedule'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Sequential
+|style="background-color:#d9ef8b"|Might have superior DFS
+|-
+|Concurrent
+|style="background-color:#fee08b"|Might have inferior DFS
+|-
+|}
+===References===
+# Mavroudis D, Saloustros E, Boukovinas I, Papakotoulas P, Kakolyris S, Ziras N, Christophylakis C, Kentepozidis N, Fountzilas G, Rigas G, Varthalitis I, Kalbakis K, Agelaki S, Hatzidaki D, Georgoulias V. Sequential vs concurrent epirubicin and docetaxel as adjuvant chemotherapy for high-risk, node-negative, early breast cancer: an interim analysis of a randomised phase III study from the Hellenic Oncology Research Group. Br J Cancer. 2017 Jul 11;117(2):164-170. Epub 2017 Jun 22. [https://www.nature.com/bjc/journal/v117/n2/full/bjc2017158a.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584474/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28641315 PubMed]
-'''21- to 28-day cycle for 4 cycles'''
+==Milan trial==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1 (Experimental)===
+*[[Surgery]], then [[Breast_cancer#Doxorubicin_monotherapy|A]] x 4, then [[Breast_cancer#CMF|CMF]] x 8
+===Arm 2 (Experimental)===
+*[[Surgery]], then A alternating with CMF every 2 cycles (12 cycles total)
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!style="width: 50%"|Approach
+!style="width: 50%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Sequential
+| style="background-color:#1a9850" |Superior OS
+|-
+|Alternating
+| style="background-color:#d73027" |Inferior OS
+|-
+|}
+===References===
+# Buzzoni R, Bonadonna G, Valagussa P, Zambetti M. Adjuvant chemotherapy with doxorubicin plus cyclophosphamide, methotrexate, and fluorouracil in the treatment of resectable breast cancer with more than three positive axillary nodes. J Clin Oncol. 1991 Dec;9(12):2134-40. [https://ascopubs.org/doi/abs/10.1200/JCO.1991.9.12.2134 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1960555 PubMed]
+## '''Update:''' Bonadonna G, Zambetti M, Valagussa P. Sequential or alternating doxorubicin and CMF regimens in breast cancer with more than three positive nodes: ten-year results. JAMA. 1995 Feb 15;273(7):542-7. [https://jamanetwork.com/journals/jama/fullarticle/387001 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7837388 PubMed]
+==NCCTG N9831==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+''The taxane used in this trial was paclitaxel.''
+===Arm 1, no trastuzumab (Control)===
+*[[Breast_cancer#AC|AC]], then [[Breast_cancer#Paclitaxel_monotherapy.2C_weekly_2|T]]
+===Arm 2, sequential trastuzumab (Experimental)===
+*[[Breast_cancer#AC|AC]], then [[Breast_cancer#Paclitaxel_monotherapy.2C_weekly_2|T]], then [[Breast_cancer#Trastuzumab_monotherapy_2|H]]
+===Arm 3, concurrent trastuzumab (Experimental)===
+*[[Breast_cancer#AC|AC]], then [[Breast_cancer,_HER2-positive#TH_.28Taxol.29_2|TH]]
+===Comparative efficacy===
+====Comparison 1====
+''Note: Arm 2 was not included in this joint analysis. Efficacy is based on the 2014 update.''
+{| class="wikitable" style="width: 100%; text-align:center;"
+!style="width: 50%"|Regimen
+!style="width: 50%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|AC, then T
+|style="background-color:#d73027"|Inferior OS
+|-
+|AC, then TH
+|style="background-color:#1a9850"|Superior OS
+|-
+|}
+====Comparison 2====
+''Note: efficacy is as reported in the 2011 update.''
+{| class="wikitable" style="width: 100%; text-align:center;"
+!style="width: 50%"|Trastuzumab-containing regimens
+!style="width: 50%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|AC, then T, then H
+|style="background-color:#fee08b"|Might have inferior DFS
+|-
+|AC, then TH
+|style="background-color:#d9ef8b"|Might have superior DFS
+|-
+|}
 ===References===
-# Assikis V, Buzdar A, Yang Y, Smith T, Theriault R, Booser D, Valero V, Walters R, Singletary E, Ames F, Hortobagyi G. A phase III trial of sequential adjuvant chemotherapy for operable breast carcinoma: final analysis with 10-year follow-up. Cancer. 2003 Jun 1;97(11):2716-23. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.11396/full link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12767083 PubMed]
+# Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. [https://www.nejm.org/doi/full/10.1056/NEJMoa052122 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16236738 PubMed]
+## '''Update:''' Perez EA, Suman VJ, Davidson NE, Gralow JR, Kaufman PA, Visscher DW, Chen B, Ingle JN, Dakhil SR, Zujewski J, Moreno-Aspitia A, Pisansky TM, Jenkins RB. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4491-7. Epub 2011 Oct 31. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.7045 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236650/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22042958 PubMed]
+## '''Update:''' Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014 Nov 20;32(33):3744-52. [https://ascopubs.org/doi/full/10.1200/JCO.2014.55.5730 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226805/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25332249 PubMed]
-==Observation==
+==NCIC CTG MA.21==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Regimen===
+===Arm 1, CEF (Control)===
+*[[Surgery]], then [[Breast_cancer#FEC_2|FEC]] x 6
+===Arm 2, AC/T (Control)===
+*[[Surgery]], then [[Breast_cancer#AC_2|AC]] x 4, then [[Breast_cancer_-_historical#Paclitaxel_monotherapy.2C_q3wk|T (Taxol)]] x 4
+===Arm 3, ddEC/T (Experimental)===
+*[[Surgery]], then [[Breast_cancer#ddEC|ddEC]] x 6, then [[Breast_cancer_-_historical#Paclitaxel_monotherapy.2C_q3wk|T (Taxol)]] x 4
+===Comparative efficacy===
+====Comparison 1====
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM197602192940801 Bonadonna et al. 1976]
+|AC/T
-|style="background-color:#1a9851"|Phase III (C)
-|[[Breast_cancer#CMF|CMF]]
 |style="background-color:#d73027"|Inferior RFS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(80)90057-4/fulltext Lacour et al. 1980]
+|CEF
-|style="background-color:#1a9851"|Phase III (C)
+|style="background-color:#1a9850"|Superior RFS
-|Polya.Polyu
+|-
-| style="background-color:#fee08b" |Might have inferior OS
+|}
+====Comparison 2====
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|AC/T
+|style="background-color:#d73027"|Inferior RFS
+|-
+|ddEC/T
+|style="background-color:#1a9850"|Superior RFS
 |-
-|rowspan=3|[https://link.springer.com/article/10.1007/BF01806239 Brinker et al. 1983 (DBCG 77B)]
+|}
-|rowspan=3 style="background-color:#1a9851" |Phase III (C)
+====Comparison 3====
-|1. [[Breast_cancer#CMF|CMF]]
+{| class="wikitable" style="width: 100%; text-align:center;"
-| style="background-color:#fc8d59" |Seems to have inferior OS (*)
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|2. [[#Cyclophosphamide_monotherapy|Cyclophosphamide]]
+|CEF
-| style="background-color:#fc8d59" |Seems to have inferior OS (*)
+| style="background-color:#ffffbf" |Seems not superior
 |-
-|3. [[#Levamisole_monotherapy|Levamisole]]
+|ddEC/T
 | style="background-color:#ffffbf" |Seems not superior
 |-
-|rowspan = 2|[https://www.thelancet.com/journals/lancet/article/PIIS0140673684924450/fulltext Goldhirsch et al. 1984 (LBCS III)]
+|}
-|rowspan = 2 style="background-color:#1a9851" |Phase III (C)
+===References===
-|1. [[#CMFPT|CMFPT]]
+# Burnell M, Levine MN, Chapman JA, Bramwell V, Gelmon K, Walley B, Vandenberg T, Chalchal H, Albain KS, Perez EA, Rugo H, Pritchard K, O'Brien P, Shepherd LE. Cyclophosphamide, epirubicin, and fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by paclitaxel versus doxorubicin and cyclophosphamide followed by paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol. 2010 Jan 1;28(1):77-82. Epub 2009 Nov 9. [https://ascopubs.org/doi/full/10.1200/JCO.2009.22.1077 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2799234/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19901117 PubMed]
-| style="background-color:#d73027" |Inferior DFS
+==NEAT==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1 (Control)===
+*[[Breast_cancer#CMF|CMF]] x 6
+===Arm 2 (Experimental)===
+*[[Breast_cancer#Epirubicin_monotherapy|Epirubicin]] x 4, then [[Breast_cancer#CMF|CMF]] x 4
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!style="width: 50%"|Regimen
+!style="width: 50%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|2. [[#PT|PT]]
+|CMF x 6
-| style="background-color:#d73027" |Inferior DFS
+|style="background-color:#d73027"|Inferior OS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673684924450/fulltext Goldhirsch et al. 1984 (LBCS IV)]
+|E x 4, then CMF x 4
-|style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#1a9850"|Superior OS
-|[[#PT|PT]]
+|-
-| style="background-color:#fc8d59" |Seems to have inferior DFS
+|}
+===References===
+<!-- no pre-pub disclosed -->
+# Poole CJ, Earl HM, Hiller L, Dunn JA, Bathers S, Grieve RJ, Spooner DA, Agrawal RK, Fernando IN, Brunt AM, O'Reilly SM, Crawford SM, Rea DW, Simmonds P, Mansi JL, Stanley A, Harvey P, McAdam K, Foster L, Leonard RC, Twelves CJ; NEAT Investigators and the SCTBG. Epirubicin and cyclophosphamide, methotrexate, and fluorouracil as adjuvant therapy for early breast cancer. N Engl J Med. 2006 Nov 2;355(18):1851-62. [https://www.nejm.org/doi/full/10.1056/NEJMoa052084 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/17079759 PubMed]
+==NeoALTTO==
+{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM198902233200801 Fisher et al. 1989 (NSABP B-13)]
+|[[#top|back to top]]
-| style="background-color:#1a9851" |Phase III (C)
+|}
-|Sequential MF
+===Arm 1, trastuzumab (C)===
-| style="background-color:#d73027" |Inferior DFS (*)
+*[[Breast_cancer,_HER2-positive#Trastuzumab_monotherapy|Trastuzumab]] x 6 wk, then [[Breast_cancer,_HER2-positive#TH_.28Taxol.29|TH (Taxol)]] x 12 wk, then [[surgery]], then [[Breast_cancer#FEC_2|FEC]] x 3, then [[Breast_cancer,_HER2-positive#Trastuzumab_monotherapy_2|Trastuzumab]] x 34 wk
+===Arm 1, lapatinib (E)===
+*Lapatinib x 6 wk, then [[Breast_cancer,_HER2-positive#TL_.28Taxol.29|TL (Taxol)]] x 12 wk, then [[surgery]], then [[Breast_cancer#FEC_2|FEC]] x 3, then Lapatinib x 34 wk
+===Arm 3, lapatinib & trastuzumab (E)===
+*[[Breast_cancer,_HER2-positive#Lapatinib_.26_Trastuzumab|Lapatinib & Trastuzumab]] x 6 wk, then [[Breast_cancer,_HER2-positive#THL_.28Taxol.29|THL (Taxol)]] x 12 wk, then [[surgery]], then [[Breast_cancer#FEC_2|FEC]] x 3, then [[Breast_cancer,_HER2-positive#Lapatinib_.26_Trastuzumab_2|Lapatinib & Trastuzumab]] x 34 wk
+===Comparative efficacy===
+''The primary endpoint was pathologic complete response (pCR) rate. Comparison was only between experimental and control arms (i.e., 2 comparisons).''
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Backbone'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM198902233200803 Mansour et al. 1989 (INT-0011)]
+|Trastuzumab vs. Lapatinib
-| style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#ffffbf"|Seems not superior
-|[[#CMFP|CMFP]]
-|style="background-color:#d73027"|Inferior DFS
 |-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2001.19.19.3929 Paradiso et al. 2001]
+|Trastuzumab vs. Lapatinib & Trastuzumab
-| style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#d73027"|Inferior pCR rate
-|[[Breast_cancer#FEC_2|FEC]]
-| style="background-color:#fc8d59" |Seems to have inferior DFS
 |-
-|[http://jco.ascopubs.org/content/21/6/976.long Henderson et al. 2003 (INT 0148/CALGB 9344)]
+|Lapatinib vs. Trastuzumab
-|style="background-color:#1a9851"|Phase III (C)
+|style="background-color:#ffffbf"|Seems not superior
-|[[#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel q3wk]]
-|style="background-color:#d73027"|Inferior OS
 |-
-|[http://jco.ascopubs.org/content/23/16/3686.long Mamounas et al. 2005 (NSABP B-28)]
+|Lapatinib & Trastuzumab vs. Trastuzumab
-|style="background-color:#1a9851"|Phase III (C)
+|style="background-color:#1a9850"|Superior pCR rate
-|[[#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel q3wk]]
-|style="background-color:#d73027"|Inferior DFS
 |-
 |}
-''No further systemic treatment; many of these trials incorporated RT, however (see individual papers for details). Reported efficacy for DBCG 77B is based on the 2010 update. Reported efficacy for NSABP B-13 is based on the 1996 update.''
-====Preceding treatment====
-*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]]
-*INT 0148/CALGB 9344: [[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#AC_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 [[Breast_cancer#AC_2|AC]] x 4
 ===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://www.ncbi.nlm.nih.gov/pubmed/1246307 PubMed]
+# Baselga J, Bradbury I, Eidtmann H, Di Cosimo S, de Azambuja E, Aura C, Gómez H, Dinh P, Fauria K, Van Dooren V, Aktan G, Goldhirsch A, Chang TW, Horváth Z, Coccia-Portugal M, Domont J, Tseng LM, Kunz G, Sohn JH, Semiglazov V, Lerzo G, Palacova M, Probachai V, Pusztai L, Untch M, Gelber RD, Piccart-Gebhart M; NeoALTTO Study Team. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2012 Feb 18;379(9816):633-40. Epub 2012 Jan 17. Erratum in: Lancet. 2012 Feb 18;379(9816):616. Dosage error in published abstract; MEDLINE/PubMed abstract corrected. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)61847-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705192/ link to PMC article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/22257673 PubMed]
-## '''Update:''' Bonadonna G, Rossi A, Valagussa P, Banfi A, Veronesi U. The CMF program for operable breast cancer with positive axillary nodes: updated analysis on the disease-free interval, site of relapse and drug tolerance. Cancer. 1977 Jun;39(6 Suppl):2904-15. [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://www.ncbi.nlm.nih.gov/pubmed/326384 PubMed]
+## '''Update:''' de Azambuja E, Holmes AP, Piccart-Gebhart M, Holmes E, Di Cosimo S, Swaby RF, Untch M, Jackisch C, Lang I, Smith I, Boyle F, Xu B, Barrios CH, Perez EA, Azim HA Jr, Kim SB, Kuemmel S, Huang CS, Vuylsteke P, Hsieh RK, Gorbunova V, Eniu A, Dreosti L, Tavartkiladze N, Gelber RD, Eidtmann H, Baselga J. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response. Lancet Oncol. 2014 Sep;15(10):1137-46. Epub 2014 Aug 14. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70320-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/25130998 PubMed]
-## '''Update:''' Bonadonna G, Valagussa P, Rossi A, Tancini G, Brambilla C, Zambetti M, Veronesi U. Ten-year experience with CMF-based adjuvant chemotherapy in resectable breast cancer. Breast Cancer Res Treat. 1985;5(2):95-115. [https://www.ncbi.nlm.nih.gov/pubmed/3839424 PubMed]
-## '''Update:''' Bonadonna G, Valagussa P, Moliterni A, Zambetti M, Brambilla C. Adjuvant cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer: the results of 20 years of follow-up. N Engl J Med. 1995 Apr 6;332(14):901-6. [https://www.nejm.org/doi/ref/10.1056/NEJM199504063321401 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7877646 PubMed]
-# 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://www.ncbi.nlm.nih.gov/pubmed/6105336 PubMed]
-# '''DBCG 77B:''' Brincker H, Mouridsen HT, Andersen KW. Adjuvant chemotherapy with cyclophosphamide or CMF in premenopausal women with stage II breast cancer. Breast Cancer Res Treat. 1983;3(1):91-5. [https://link.springer.com/article/10.1007/BF01806239 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/6347278 PubMed]
-## '''Update:''' Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Andersson M, Kamby C, Knoop AS; Danish Breast Cancer Cooperative Group. Cyclophosphamide, methotrexate, and fluorouracil; oral cyclophosphamide; levamisole; or no adjuvant therapy for patients with high-risk, premenopausal breast cancer. Cancer. 2010 May 1;116(9):2081-9. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.24969/full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20186830 PubMed]
-# '''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://www.ncbi.nlm.nih.gov/pubmed/6144974 PubMed]
-# '''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://www.ncbi.nlm.nih.gov/pubmed/2644531 PubMed]
-## '''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://ascopubs.org/doi/abs/10.1200/JCO.1996.14.7.1982 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8683228 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://ascopubs.org/doi/full/10.1200/JCO.2006.06.9054 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16921044 PubMed]
-# '''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://www.ncbi.nlm.nih.gov/pubmed/2915651 PubMed]
-# '''LCBS V:''' Goldhirsch A, Gelber RD; Ludwig Breast Cancer Study Group. Prolonged disease-free survival after one course of perioperative adjuvant chemotherapy for node-negative breast cancer. N Engl J Med. 1989 Feb 23;320(8):491-6. [https://www.nejm.org/doi/full/10.1056/NEJM198902233200804 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2644533 PubMed]
-# Paradiso A, Schittulli F, Cellamare G, Mangia A, Marzullo F, Lorusso V, De Lena M. Randomized clinical trial of adjuvant fluorouracil, epirubicin, and cyclophosphamide chemotherapy for patients with fast-proliferating, node-negative breast cancer. J Clin Oncol. 2001 Oct 1;19(19):3929-37. [https://ascopubs.org/doi/full/10.1200/JCO.2001.19.19.3929 link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11579113 PubMed]
-# '''INT 0148/CALGB 9344:''' Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003 Mar 15;21(6):976-83. [http://jco.ascopubs.org/content/21/6/976.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12637460 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. -->
-# '''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. [http://jco.ascopubs.org/content/23/16/3686.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15897552 PubMed]
-==Oophorectomy==
+==Neo-tAnGo==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Regimen===
+===Arm 1, EC-ddT===
+*[[Breast_cancer#EC|EC]] x 4, then [[Breast_cancer#Paclitaxel_monotherapy.2C_dose-dense_.28q2wk.29|ddT]] x 4, then [[surgery]]
+===Arm 2, ddT-EC===
+*[[Breast_cancer#Paclitaxel_monotherapy.2C_dose-dense_.28q2wk.29|ddT]] x 4, then [[Breast_cancer#EC|EC]] x 4, then [[surgery]]
+===Arm 3, EC-ddTG===
+*[[Breast_cancer#EC|EC]] x 4, then ddTG x 4, then [[surgery]]
+===Arm 4, ddTG-EC===
+*ddTG x 4, then [[Breast_cancer#EC|EC]] x 4, then [[surgery]]
+===Comparative efficacy===
+*Analyzed using a 2 x 2 factorial design
+====Comparison 1====
+{| class="wikitable" style="width: 100%; text-align:center;"
+|'''Sequencing'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Taxane first
+|style="background-color:#91cf60"|Seems to have superior pCR rate
+|-
+|EC first
+|style="background-color:#fc8d59"|Seems to have inferior pCR rate
+|-
+|}
+====Comparison 2====
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+|'''Addition of gemcitabine'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
+|-
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|Without gemcitabine
+|style="background-color:#ffffbf"|Seems not superior
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM197708182970704 Ahmann et al. 1977]
+|With gemcitabine
-| style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#ffffbf"|Seems not superior
-|[[#CFP_.26_Oophorectomy|CFP & Oophorectomy]]
-| style="background-color:#fc8d59" |Seems to have inferior PFS
 |-
 |}
-====Preceding treatment====
-*[[Surgery#Breast_cancer_surgery|Surgery]]
-====Hormonotherapy====
-*[[Endocrine_ablation_surgery#Bilateral_oophorectomy|Bilateral oophorectomy]]
 ===References===
-# Ahmann DL, O'Connell MJ, Hahn RG, Bisel HF, Lee RA, Edmonson JH. An evaluation of early or delayed adjuvant chemotherapy in premenopausal patients with advanced breast cancer undergoing oophorectomy. N Engl J Med. 1977 Aug 18;297(7):356-60. [https://www.nejm.org/doi/full/10.1056/NEJM197708182970704 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/876327 PubMed]
+# Earl HM, Vallier AL, Hiller L, Fenwick N, Young J, Iddawela M, Abraham J, Hughes-Davies L, Gounaris I, McAdam K, Houston S, Hickish T, Skene A, Chan S, Dean S, Ritchie D, Laing R, Harries M, Gallagher C, Wishart G, Dunn J, Provenzano E, Caldas C; Neo-tAnGo Investigators. Effects of the addition of gemcitabine, and paclitaxel-first sequencing, in neoadjuvant sequential epirubicin, cyclophosphamide, and paclitaxel for women with high-risk early breast cancer (Neo-tAnGo): an open-label, 2×2 factorial randomised phase 3 trial. Lancet Oncol. 2014 Feb;15(2):201-12. Epub 2013 Dec 19. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(13)70554-0/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24360787 PubMed]
-==Paclitaxel monotherapy, q3wk {{#subobject:1cb87f|Regimen=1}}==
+==NOAH==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-T: '''<u>T</u>'''axol (Paclitaxel)
+===Arm 1, no trastuzumab (Control)===
-<br>P: '''<u>P</u>'''aclitaxel
+*AT (Taxol) x 3, then T (Taxol) x 3, then CMF x 3, then [[surgery]]
-<br>pT: '''<u>p</u>'''acli'''<u>T</u>'''axel
+===Arm 2, with trastuzumab (Experimental)===
-===Variant #1, 175 mg/m<sup>2</sup> q3wk {{#subobject:c084f5|Variant=1}}===
+*ATH (Taxol) x 3, then [[Breast_cancer,_HER2-positive#TH_.28Taxol.29|TH]] x 3, then CMF & H x 3, then [[surgery]], then [[Breast_cancer,_HER2-positive#Trastuzumab_monotherapy_2|trastuzumab for a total of 1 year]]
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+|'''Sequencing'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/21/6/976.long Henderson et al. 2003 (INT 0148/CALGB 9344)]
+|With trastuzumab
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
+|style="background-color:#91cf60"|Seems to have superior EFS
-|[[#Observation|Observation]]
-| style="background-color:#1a9850" |Superior OS
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJMoa052122 Romond et al. 2005 (NSABP B-31)]
+|No trastuzumab
-| style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#fc8d59"|Seems to have inferior EFS
-|[[Breast_cancer,_HER2-positive#TH_.28Taxol.29_2|TH]]
-| style="background-color:#d73027" |Inferior OS
 |-
-| rowspan="3" |[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743943/ Sparano et al. 2008 (ECOG E1199)]
+|}
-| rowspan="3" style="background-color:#1a9851" |Phase III (C)
+===References===
-|1. [[Breast_cancer#Paclitaxel_monotherapy.2C_weekly_2|Weekly Paclitaxel]]
+# Gianni L, Eiermann W, Semiglazov V, Manikhas A, Lluch A, Tjulandin S, Zambetti M, Vazquez F, Byakhow M, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Baronio R, Feyereislova A, Barton C, Valagussa P, Baselga J. Neoadjuvant chemotherapy with trastuzumab followed by adjuvant trastuzumab versus neoadjuvant chemotherapy alone, in patients with HER2-positive locally advanced breast cancer (the NOAH trial): a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet. 2010 Jan 30;375(9712):377-84. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61964-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20113825 PubMed]
-| style="background-color:#d73027" |Inferior OS
+## '''Update:''' Gianni L, Eiermann W, Semiglazov V, Lluch A, Tjulandin S, Zambetti M, Moliterni A, Vazquez F, Byakhov MJ, Lichinitser M, Climent MA, Ciruelos E, Ojeda B, Mansutti M, Bozhok A, Magazzù D, Heinzmann D, Steinseifer J, Valagussa P, Baselga J. Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort. Lancet Oncol. 2014 May;15(6):640-7. Epub 2014 Mar 20. Erratum in: Lancet Oncol. 2018 Dec;19(12):e667. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70080-4/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24657003 PubMed]
+==NSABP B-27==
+{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|2. [[Breast_cancer#Docetaxel_monotherapy_2|Docetaxel q3wk]]
+|[[#top|back to top]]
-| style="background-color:#fc8d59" |Seems to have inferior DFS
+|}
+===Arm 1, no taxane (Control)===
+*[[Breast_cancer#AC|AC]] x 4, then [[surgery]]
+===Arm 2, preoperative taxane (Experimental)===
+*[[Breast_cancer#AC|AC]] x 4, [[Breast_cancer#Docetaxel_monotherapy|T (Taxotere)]] x 4, then [[surgery]]
+===Arm 3, postoperative taxane (Experimental)===
+*[[Breast_cancer#AC|AC]] x 4, then [[surgery]], then [[Breast_cancer#Docetaxel_monotherapy_2|T (Taxotere)]] x 4
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|3. [[Breast_cancer#Docetaxel_monotherapy_2|Docetaxel weekly]]
+|AC, then [[surgery]]
-| style="background-color:#ffffbf" |Seems not superior
+| style="background-color:#d73027" |Inferior pCR rate
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62048-1/fulltext Del Mastro et al. 2015 (GIM2)]
+|AC, then T, then [[surgery]]
-|style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9850" |Superior pCR rate
-|[[Complex_multipart_regimens#GIM2|See link]]
-|[[Complex_multipart_regimens#GIM2|See link]]
 |-
-|[https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30319-4/fulltext Earl et al. 2017 (tAnGo)]
+|AC, then [[surgery]], then T
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#d73027" |Inferior pCR rate
-|TG
-| style="background-color:#ffffbf" |Seems not superior
 |-
 |}
-''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment. Patients in '''NSABP B-31''' were HER2-positive.''
+===References===
-====Preceding treatment====
+# Bear HD, Anderson S, Brown A, Smith R, Mamounas EP, Fisher B, Margolese R, Theoret H, Soran A, Wickerham DL, Wolmark N; National Surgical Adjuvant Breast and Bowel Project Protocol B-27. The effect on tumor response of adding sequential preoperative docetaxel to preoperative doxorubicin and cyclophosphamide: preliminary results from National Surgical Adjuvant Breast and Bowel Project Protocol B-27. J Clin Oncol. 2003 Nov 15;21(22):4165-74. Epub 2003 Oct 14. [https://ascopubs.org/doi/full/10.1200/JCO.2003.12.005 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14559892 PubMed]
-*INT 0148/CALGB 9344: [[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#AC_2|AC]] x 4 versus high-dose AC x 4 versus very-high-dose AC x 4
-*NSABP B-31, and ECOG E1199: [[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#AC_2|AC]] x 4
-*GIM2: [[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#EC_2|EC]] x 4 versus [[Breast_cancer#FEC_2|FEC]] x 4
-*tAnGo: [[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#EC_2|EC]] x 4
-====Chemotherapy====
-*[[Paclitaxel (Taxol)]] 175 mg/m<sup>2</sup> IV over 3 hours once on day 1
-'''21-day cycle for 4 cycles'''
+==NSABP B-30==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1, AC -> T===
+*[[Breast_cancer#AC_2|AC]] x 4, then [[Breast_cancer#Docetaxel_monotherapy_2|T (Taxotere)]] x 4
+===Arm 2, AT===
+*AT x 4
+===Arm 3, ACT===
+*[[Breast_cancer#TAC_.28Taxotere.29|ACT]] x 4
-===Variant #2, 225 mg/m<sup>2</sup> q3wk {{#subobject:b7a984|Variant=1}}===
+===Comparative efficacy===
+====Comparison 1====
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Schedule'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[http://jco.ascopubs.org/content/23/16/3686.long Mamounas et al. 2005 (NSABP B-28)]
+|Sequential AC -> T
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#d9ef8b" |Might have superior OS
-|[[#Observation|Observation]]
+|-
-| style="background-color:#1a9850" |Superior PFS
+|Concurrent ACT
+| style="background-color:#fee08b" |Might have inferior OS
+|-
+|}
+====Comparison 2====
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Schedule'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Sequential AC -> T
+| style="background-color:#91cf60" |Seems to have superior OS
+|-
+|Concurrent AT
+| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
 |}
-''Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.''
+===References===
-====Preceding treatment====
+# Swain SM, Jeong JH, Geyer CE Jr, Costantino JP, Pajon ER, Fehrenbacher L, Atkins JN, Polikoff J, Vogel VG, Erban JK, Rastogi P, Livingston RB, Perez EA, Mamounas EP, Land SR, Ganz PA, Wolmark N. Longer therapy, iatrogenic amenorrhea, and survival in early breast cancer. N Engl J Med. 2010 Jun 3;362(22):2053-65. [https://www.nejm.org/doi/10.1056/NEJMoa0909638 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2935316/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20519679 PubMed]
-*[[Surgery#Breast_cancer_surgery|Surgery]], then [[Breast_cancer#AC_2|AC]] x 4
-====Chemotherapy====
-*[[Paclitaxel (Taxol)]] 225 mg/m<sup>2</sup> IV over 3 hours once on day 1
-'''21-day cycle for 4 cycles'''
+==NSABP B-38==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1, sequential without gemcitabine (Control)===
+*[[Surgery]], then [[Breast_cancer#ddAC_2|ddAC]] x 4, then [[Breast_cancer#Paclitaxel_monotherapy.2C_dose-dense_.28q2wk.29_2|ddP]] x 4
+===Arm 2, sequential with gemcitabine (Experimental)===
+*[[Surgery]], then [[Breast_cancer#ddAC_2|ddAC]] x 4, then ddPG x 4
+===Arm 3, concurrent===
+*[[Surgery]], then [[Breast_cancer#TAC_.28Taxotere.29|TAC]] x 6
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Schedule'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Sequential (ddAC, then ddP)
+|style="background-color:#ffffbf"|Seems not superior
+|-
+|Sequential (ddAC, then ddPG)
+|style="background-color:#ffffbf"|Seems not superior
+|-
+|Concurrent (TAC)
+|style="background-color:#ffffbf"|Seems not superior
+|-
+|}
+===References===
+# Swain SM, Tang G, Geyer CE Jr, Rastogi P, Atkins JN, Donnellan PP, Fehrenbacher L, Azar CA, Robidoux A, Polikoff JA, Brufsky AM, Biggs DD, Levine EA, Zapas JL, Provencher L, Northfelt DW, Paik S, Costantino JP, Mamounas EP, Wolmark N. Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial. J Clin Oncol. 2013 Sep 10;31(26):3197-204. Epub 2013 Aug 12. [https://ascopubs.org/doi/full/10.1200/JCO.2012.48.1275 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3757290/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23940225 PubMed]
+==NSABP B-40==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1 - Control===
+*[[Breast_cancer#Docetaxel_monotherapy|T (Taxotere)]] x 4, then [[Breast_cancer#AC|AC]] x 4, then [[surgery]]
+===Arm 2===
+*[[Breast_cancer#Docetaxel_.26_Bevacizumab|T+Bev]], then [[Breast_cancer#AC_.26_Bevacizumab|AC+Bev]], then [[surgery]], then [[Breast_cancer#Bevacizumab_monotherapy|Bevacizumab]] x 10
+===Arm 3===
+*TX x 4, then [[Breast_cancer#AC|AC]] x 4, then [[surgery]]
+===Arm 4===
+*TX+Bev x 4, then [[Breast_cancer#AC_.26_Bevacizumab|AC+Bev]], then [[surgery]], then [[Breast_cancer#Bevacizumab_monotherapy|Bevacizumab]] x 10
+===Arm 5===
+*TG x 4, then [[Breast_cancer#AC|AC]] x 4, then [[surgery]]
+===Arm 6===
+*TG+Bev x 4, then [[Breast_cancer#AC_.26_Bevacizumab|AC+Bev]], then [[surgery]], then [[Breast_cancer#Bevacizumab_monotherapy|Bevacizumab]] x 10
+===Comparative efficacy===
+''This trial was analyzed using a 3 x 2 factorial design; primary endpoint was pathologic complete response (pCR) rate.''
+====Addition of bevacizumab====
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|No bevacizumab (C)
+|style="background-color:#fc8d59"|Seems to have inferior pCR rate
+|-
+|Bevacizumab-based therapy (E)
+|style="background-color:#91cf60"|Seems to have superior pCR rate
+|-
+|}
+====Addition of capecitabine or gemcitabine====
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Docetaxel alone (C)
+|style="background-color:#ffffbf"|Seems not superior
+|-
+|TX or TG (E)
+|style="background-color:#ffffbf"|Seems not superior
+|-
+|}
 ===References===
-# '''INT 0148/CALGB 9344:''' Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003 Mar 15;21(6):976-83. [http://jco.ascopubs.org/content/21/6/976.long link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/12637460 PubMed]
+# Bear HD, Tang G, Rastogi P, Geyer CE Jr, Robidoux A, Atkins JN, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Swain SM, Mamounas EP, Wolmark N. Bevacizumab added to neoadjuvant chemotherapy for breast cancer. N Engl J Med. 2012 Jan 26;366(4):310-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111097 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401076/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22276821 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. -->
+## '''Update:''' Bear HD, Tang G, Rastogi P, Geyer CE Jr, Liu Q, Robidoux A, Baez-Diaz L, Brufsky AM, Mehta RS, Fehrenbacher L, Young JA, Senecal FM, Gaur R, Margolese RG, Adams PT, Gross HM, Costantino JP, Paik S, Swain SM, Mamounas EP, Wolmark N. Neoadjuvant plus adjuvant bevacizumab in early breast cancer (NSABP B-40 [NRG Oncology]): secondary outcomes of a phase 3, randomised controlled trial. Lancet Oncol. 2015 Sep;16(9):1037-1048. Epub 2015 Aug 10. Erratum in: Lancet Oncol. 2015 Dec;16(16):e589. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(15)00041-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624323/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26272770 PubMed]
-# '''NSABP B-28:''' Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol. 2005 Jun 1;23(16):3686-96. Epub 2005 May 16. [http://jco.ascopubs.org/content/23/16/3686.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15897552 PubMed]
-<!-- no pre-pub disclosed -->
-<!-- no pre-pub disclosed -->
-# '''NSABP B-31/NCCTG N9831:''' Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. [https://www.nejm.org/doi/full/10.1056/NEJMoa052122 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16236738 PubMed]
-## '''Update:''' Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE Jr, Martino S, Mamounas EP, Kaufman PA, Wolmark N. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011 Sep 1;29(25):3366-73. Epub 2011 Jul 18. [https://ascopubs.org/doi/full/10.1200/JCO.2011.35.0868 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3164242/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21768458 PubMed]
-## '''Update:''' Perez EA, Suman VJ, Davidson NE, Gralow JR, Kaufman PA, Visscher DW, Chen B, Ingle JN, Dakhil SR, Zujewski J, Moreno-Aspitia A, Pisansky TM, Jenkins RB. Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4491-7. Epub 2011 Oct 31. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.7045 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3236650/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22042958 PubMed]
-## '''Update:''' Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014 Nov 20;32(33):3744-52. [https://ascopubs.org/doi/full/10.1200/JCO.2014.55.5730 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226805/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25332249 PubMed]
-## '''Update and HRQoL analysis:''' Ganz PA, Romond EH, Cecchini RS, Rastogi P, Geyer CE Jr, Swain SM, Jeong JH, Fehrenbacher L, Gross HM, Brufsky AM, Flynn PJ, Wahl TA, Seay TE, Wade JL 3rd, Biggs DD, Atkins JN, Polikoff J, Zapas JL, Mamounas EP, Wolmark N. Long-term follow-up of cardiac function and quality of life for patients in NSABP protocol B-31/NRG Oncology: a randomized trial comparing the safety and efficacy of doxorubicin and cyclophosphamide (AC) followed by paclitaxel with AC followed by paclitaxel and trastuzumab in patients with node-positive breast cancer with tumors overexpressing human epidermal growth factor receptor 2. J Clin Oncol. 2017 Dec 10;35(35):3942-3948. Epub 2017 Oct 26. [https://ascopubs.org/doi/full/10.1200/JCO.2017.74.1165 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5721228/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/29072977 PubMed]
-<!-- Presented in part at the San Antonio Breast Cancer Symposium, San Antonio, Texas, December 8–11, 2007, and the American Society of Clinical Oncology meeting, Chicago, June 1–4, 2005. -->
-# '''ECOG E1199:''' Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. [https://www.nejm.org/doi/full/10.1056/NEJMoa0707056 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2743943/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/18420499 PubMed]
-## '''Update:''' Sparano JA, Zhao F, Martino S, Ligibel JA, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Long-term follow-up of the E1199 phase III trial evaluating the role of taxane and schedule in operable breast cancer. J Clin Oncol. 2015 Jul 20;33(21):2353-60. Epub 2015 Jun 15. [http://jco.ascopubs.org/content/33/21/2353.full link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500829/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/26077235 PubMed]
-# '''GIM2:''' Del Mastro L, De Placido S, Bruzzi P, De Laurentiis M, Boni C, Cavazzini G, Durando A, Turletti A, Nisticò C, Valle E, Garrone O, Puglisi F, Montemurro F, Barni S, Ardizzoni A, Gamucci T, Colantuoni G, Giuliano M, Gravina A, Papaldo P, Bighin C, Bisagni G, Forestieri V, Cognetti F; Gruppo Italiano Mammella (GIM) investigators. Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: an open-label, 2 × 2 factorial, randomised phase 3 trial. Lancet. 2015 May 9;385(9980):1863-72. Epub 2015 Mar 2. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(14)62048-1/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/25740286 PubMed]
-# '''tAnGo:''' Earl HM, Hiller L, Howard HC, Dunn JA, Young J, Bowden SJ, McDermaid M, Waterhouse AK, Wilson G, Agrawal R, O'Reilly S, Bowman A, Ritchie DM, Goodman A, Hickish T, McAdam K, Cameron D, Dodwell D, Rea DW, Caldas C, Provenzano E, Abraham JE, Canney P, Crown JP, Kennedy MJ, Coleman R, Leonard RC, Carmichael JA, Wardley AM, Poole CJ; tAnGo trial collaborators. Addition of gemcitabine to paclitaxel, epirubicin, and cyclophosphamide adjuvant chemotherapy for women with early-stage breast cancer (tAnGo): final 10-year follow-up of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Jun;18(6):755-769. Epub 2017 May 4. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30319-4/fulltext link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/28479233 PubMed]
-==PAF {{#subobject:5750af|Regimen=1}}==
+==NSAS BC-02==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-PAF: '''<u>P</u>'''henylalanine mustard (Melphalan), '''<u>A</u>'''driamycin (Doxorubicin), '''<u>F</u>'''luorouracil
+===Arm 1 - Control===
-===Regimen {{#subobject:763980|Variant=1}}===
+*[[Surgery]], [[Breast_cancer#AC_2|AC]] x 4, then [[Breast_cancer#Docetaxel_monotherapy_2|T (Taxotere)]] x 4
+===Arm 2 - Control===
+*[[Surgery]], [[Breast_cancer#AC_2|AC]] x 4, then [[Breast_cancer_-_historical#Paclitaxel_monotherapy.2C_q3wk|T (Taxol)]] x 4
+===Arm 3===
+*[[Surgery]], then docetaxel x 8
+===Arm 4===
+*[[Surgery]], then paclitaxel x 8
+===Comparative efficacy===
+''This trial was analyzed using a 2 x 2 factorial design.''
+====Use of AC====
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.5.572 Fisher et al. 1989 (NSABP B-11)]
+|AC-containing
-| style="background-color:#1a9851" |Phase III (E-esc)
+|style="background-color:#ffffbf"|Inconclusive whether non-inferior
-|[[#PF|PF]]
+|-
+|AC-free
+|style="background-color:#ffffbf"|Inconclusive whether non-inferior
+|-
+|}
+====Taxane====
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Docetaxel
 | style="background-color:#91cf60" |Seems to have superior OS
+|-
+|Paclitaxel (q3wk)
+| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
 |}
-====Preceding treatment====
-*[[Surgery#Breast_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Melphalan (Alkeran)]]
-*[[Doxorubicin (Adriamycin)]]
-*[[Fluorouracil (5-FU)]]
 ===References===
-# '''NSABP B-11:''' Fisher B, Redmond C, Wickerham DL, Bowman D, Schipper H, Wolmark N, Sass R, Fisher ER, Jochimsen P, Legault-Poisson S, Dimitrov N, Wolter J, Bornstein R, Elias EG, LiCalzi N, Paterson AHG, Sutherland CM. Doxorubicin-containing regimens for the treatment of stage II breast cancer: the National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol. 1989 May;7(5):572-82. [https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.5.572 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2651576 PubMed]
+# Watanabe T, Kuranami M, Inoue K, Masuda N, Aogi K, Ohno S, Iwata H, Mukai H, Uemura Y, Ohashi Y. Comparison of an AC-taxane versus AC-free regimen and paclitaxel versus docetaxel in patients with lymph node-positive breast cancer: final results of the National Surgical Adjuvant Study of Breast Cancer 02 trial, a randomized comparative phase 3 study. Cancer. 2017 Mar 1;123(5):759-768. Epub 2017 Jan 12. [https://onlinelibrary.wiley.com/doi/10.1002/cncr.30421/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28081304 PubMed]
-==PF {{#subobject:3a5d5f|Regimen=1}}==
+==PREPARE==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-PF: '''<u>P</u>'''henylalanine mustard (Melphalan) & '''<u>F</u>'''luorouracil
+===Arm 1, control===
-===Regimen {{#subobject:06f47d|Variant=1}}===
+*[[Breast_cancer#EC|EC]] x 4, then [[Breast_cancer_-_historical#Paclitaxel_monotherapy.2C_q3wk|T (Taxol)]] x 4, then [[Surgery#Breast_cancer_surgery|surgery]]
+===Arm 2, experimental===
+*ddE x 3, then ddT (Taxol) x 3, then CMF x 3, then [[Surgery#Breast_cancer_surgery|surgery]]
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://onlinelibrary.wiley.com/doi/10.1002/1097-0142%28197706%2939%3A6%3C2883%3A%3AAID-CNCR2820390676%3E3.0.CO%3B2-9 Fisher et al. 1977 (NSABP B-07)]
+|Control
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#ffffbf" |Seems not superior
-|[[#Melphalan_monotherapy|P]]
-| style="background-color:#91cf60" |Seems to have superior RFS
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19800815)46:4%2B%3C1009::AID-CNCR2820461326%3E3.0.CO;2-H Fisher et al. 1980 (NSABP B-08)]
+|Experimental
-| style="background-color:#1a9851" |Phase III (C)
-|PFM
 | style="background-color:#ffffbf" |Seems not superior
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM198107023050101 Fisher et al. 1981 (NSABP B-09)]
+|}
-| style="background-color:#1a9851" |Phase III (C)
+===References===
-|[[#PFT|PFT]]
+# Untch M, von Minckwitz G, Konecny GE, Conrad U, Fett W, Kurzeder C, Lück HJ, Stickeler E, Urbaczyk H, Liedtke B, Beckmann MW, Salat C, Harbeck N, Müller V, Schmidt M, Hasmüller S, Lenhard M, Nekljudova V, Lebeau A, Loibl S, Fasching PA; Arbeitsgemeinschaft Gynäkologische Onkologie PREPARE investigators. PREPARE trial: a randomized phase III trial comparing preoperative, dose-dense, dose-intensified chemotherapy with epirubicin, paclitaxel, and CMF versus a standard-dosed epirubicin-cyclophosphamide followed by paclitaxel with or without darbepoetin alfa in primary breast cancer--outcome on prognosis. Ann Oncol. 2011 Sep;22(9):1999-2006. Epub 2011 Mar 7. [https://academic.oup.com/annonc/article/22/9/1999/211410 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21382868 PubMed]
-| style="background-color:#d73027" |Inferior RFS
+==Recht et al. 1996==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1, chemo first===
+*[[Surgery#Lumpectomy|Lumpectomy]], then [[Breast_cancer_-_historical#CAMFP|CAMFP]], then RT
+===Arm 2, RT first===
+*[[Surgery#Lumpectomy|Lumpectomy]], then RT, then [[Breast_cancer_-_historical#CAMFP|CAMFP]]
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!style="width: 50%"|'''anti-HER2 medication'''
+!style="width: 50%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.5.572 Fisher et al. 1989 (NSABP B-11)]
+|Chemo first
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#91cf60" |Seems to have superior MFS
-|[[#PAF|PAF]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
-|[https://onlinelibrary.wiley.com/doi/10.1002/1097-0142%2819900715%2966%3A2%3C220%3A%3AAID-CNCR2820660205%3E3.0.CO%3B2-6 Fisher et al. 1990 (NSABP B-10)]
+|RT first
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#fc8d59" |Seems to have inferior MFS
-|PFCp
-| style="background-color:#ffffbf" |Seems not superior
 |-
 |}
-''Note: Fisher et al. 1980 is more of a meta-analysis than a primary publication, but is to our knowledge the first manuscript to report the findings from NSABP B-08, which was a negative trial.''
-====Preceding treatment====
-*[[Surgery#Breast_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Melphalan (Alkeran)]]
-*[[Fluorouracil (5-FU)]]
 ===References===
-# '''NSABP B-07:''' 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%28197706%2939%3A6%3C2883%3A%3AAID-CNCR2820390676%3E3.0.CO%3B2-9 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/194679 PubMed]
+# Recht A, Come SE, Henderson IC, Gelman RS, Silver B, Hayes DF, Shulman LN, Harris JR. The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med. 1996 May 23;334(21):1356-61. [https://www.nejm.org/doi/full/10.1056/NEJM199605233342102 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8614420 PubMed]
-# '''NSABP B-08:''' Fisher B, Redmond C, Fisher ER. The contribution of recent NSABP clinical trials of primary breast cancer therapy to an understanding of tumor biology--an overview of findings. Cancer. 1980 Aug 15;46(4 Suppl):1009-25. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19800815)46:4%2B%3C1009::AID-CNCR2820461326%3E3.0.CO;2-H link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6994873 PubMed]
-# '''NSABP B-09:''' Fisher B, Redmond C, Brown A, Wolmark N, Wittliff J, Fisher ER, Plotkin D, Bowman D, Sachs S, Wolter J, Frelick R, Desser R, LiCalzi N, Geggie P, Campbell T, Elias EG, Prager D, Koontz P, Volk H, Dimitrov N, Gardner B, Lerner H, Shibata H. Treatment of primary breast cancer with chemotherapy and tamoxifen. N Engl J Med. 1981 Jul 2;305(1):1-6. [https://www.nejm.org/doi/full/10.1056/NEJM198107023050101 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7015139 PubMed]
-## '''Update:''' Fisher B, Redmond C, Brown A, Fisher ER, Wolmark N, Bowman D, Plotkin D, Wolter J, Bornstein R, Legault-Poisson S, Saffer EA. Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project Trial. J Clin Oncol. 1986 Apr;4(4):459-71. [https://ascopubs.org/doi/abs/10.1200/JCO.1986.4.4.459 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2856857 PubMed]
-## '''Update:''' Fisher B, Brown A, Wolmark N, Redmond C, Wickerham DL, Wittliff J, Dimitrov N, Legault-Poisson S, Schipper H, Prager D. Prolonging tamoxifen therapy for primary breast cancer: findings from the National Surgical Adjuvant Breast and Bowel Project clinical trial. Ann Intern Med. 1987 May;106(5):649-54. [http://annals.org/aim/article-abstract/701830/prolonging-tamoxifen-therapy-primary-breast-cancer-findings-from-national-surgical link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3551710 PubMed]
-# '''NSABP B-11:''' Fisher B, Redmond C, Wickerham DL, Bowman D, Schipper H, Wolmark N, Sass R, Fisher ER, Jochimsen P, Legault-Poisson S, Dimitrov N, Wolter J, Bornstein R, Elias EG, LiCalzi N, Paterson AHG, Sutherland CM. Doxorubicin-containing regimens for the treatment of stage II breast cancer: the National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol. 1989 May;7(5):572-82. [https://ascopubs.org/doi/abs/10.1200/JCO.1989.7.5.572 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2651576 PubMed]
-# '''NSABP B-10:''' Fisher B, Brown A, Wolmark N, Fisher ER, Redmond C, Wickerham DL, Margolese R, Dimitrov N, Pilch Y, Glass A, Sutherland C, Foster R. Evaluation of the worth of corynebacterium parvum in conjunction with chemotherapy as adjuvant treatment for primary breast cancer: eight-year results from the National Surgical Adjuvant Breast and Bowel Project B-10. Cancer. 1990 Jul 15;66(2):220-7. [https://onlinelibrary.wiley.com/doi/10.1002/1097-0142%2819900715%2966%3A2%3C220%3A%3AAID-CNCR2820660205%3E3.0.CO%3B2-6 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2196108 PubMed]
-==PFT {{#subobject:1cb87f|Regimen=1}}==
+==SB3-G31-BC==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-PFT: '''<u>P</u>'''henylalanine mustard (Melphalan), 5-'''<u>F</u>'''luorouracil, '''<u>T</u>'''amoxifen
+===Arm 1, trastuzumab (control)===
-===Regimen {{#subobject:c084f5|Variant=1}}===
+*[[Breast_cancer,_HER2-positive#TH_.28Taxotere.29|TH]] x 4, then [[Breast_cancer,_HER2-positive#FEC_.26_H|FEC & H]] x 4, then [[surgery]], then [[Breast_cancer,_HER2-positive#Trastuzumab_monotherapy_2|adjuvant trastuzumab]]
+===Arm 2, SB3 (experimental trastuzumab biosimilar)===
+*Same schedule with SB3 instead of trastuzumab
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 50%"|'''anti-HER2 medication'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 50%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM198107023050101 Fisher et al. 1981 (NSABP B-09)]
+|Trastuzumab
-| style="background-color:#1a9851" |Phase III (E-RT-esc)
+|style="background-color:#eeee01"|Equivalent pCR rate
-|[[#PF|PF]]
-| style="background-color:#1a9850" |Superior RFS
 |-
-|rowspan=2|[https://ascopubs.org/doi/abs/10.1200/JCO.1990.8.6.1005 Fisher et al. 1990 (NSABP B-16)]
+|SB3 (trastuzumab biosimilar)
-|rowspan=2 style="background-color:#1a9851" |Phase III (E-esc)
+|style="background-color:#eeee01"|Equivalent pCR rate
-|1. [[#ACT|ACT]]
-| style="background-color:#d3d3d3" |Not reported
-|-
-|2. [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]]
-| style="background-color:#91cf60" |Seems to have superior DDFS
 |-
 |}
-====Preceding treatment====
-*[[Surgery#Breast_cancer_surgery|Surgery]]
-====Chemotherapy====
-*[[Melphalan (Alkeran)]]
-*[[Fluorouracil (5-FU)]]
-====Hormonotherapy====
-*[[Tamoxifen (Nolvadex)]]
 ===References===
-# '''NSABP B-09:''' Fisher B, Redmond C, Brown A, Wolmark N, Wittliff J, Fisher ER, Plotkin D, Bowman D, Sachs S, Wolter J, Frelick R, Desser R, LiCalzi N, Geggie P, Campbell T, Elias EG, Prager D, Koontz P, Volk H, Dimitrov N, Gardner B, Lerner H, Shibata H. Treatment of primary breast cancer with chemotherapy and tamoxifen. N Engl J Med. 1981 Jul 2;305(1):1-6. [https://www.nejm.org/doi/full/10.1056/NEJM198107023050101 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7015139 PubMed]
+# Pivot X, Bondarenko I, Nowecki Z, Dvorkin M, Trishkina E, Ahn JH, Vinnyk Y, Im SA, Sarosiek T, Chatterjee S, Wojtukiewicz MZ, Moiseyenko V, Shparyk Y, Bello M 3rd, Semiglazov V, Song S, Lim J. Phase III, randomized, double-blind study comparing the efficacy, safety, and immunogenicity of SB3 (trastuzumab biosimilar) and reference trastuzumab in patients treated with neoadjuvant therapy for human epidermal growth factor receptor 2-positive early breast cancer. J Clin Oncol. 2018 Apr 1;36(10):968-974. Epub 2018 Jan 26. [https://ascopubs.org/doi/full/10.1200/JCO.2017.74.0126 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29373094 PubMed]
-## '''Update:''' Fisher B, Redmond C, Brown A, Fisher ER, Wolmark N, Bowman D, Plotkin D, Wolter J, Bornstein R, Legault-Poisson S, Saffer EA. Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project Trial. J Clin Oncol. 1986 Apr;4(4):459-71. [https://ascopubs.org/doi/abs/10.1200/JCO.1986.4.4.459 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2856857 PubMed]
-## '''Update:''' Fisher B, Brown A, Wolmark N, Redmond C, Wickerham DL, Wittliff J, Dimitrov N, Legault-Poisson S, Schipper H, Prager D. Prolonging tamoxifen therapy for primary breast cancer: findings from the National Surgical Adjuvant Breast and Bowel Project clinical trial. Ann Intern Med. 1987 May;106(5):649-54. [http://annals.org/aim/article-abstract/701830/prolonging-tamoxifen-therapy-primary-breast-cancer-findings-from-national-surgical link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3551710 PubMed]
-# '''NSABP B-16:''' Fisher B, Redmond C, Legault-Poisson S, Dimitrov NV, Brown AM, Wickerham DL, Wolmark N, Margolese RG, Bowman D, Glass AG, Kardinal CG, Robidoux A, Jochimsen P, Cronin W, Deutsch M, Fisher ER, Myers DB, Hoehn JL. Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol. 1990 Jun;8(6):1005-18. [https://ascopubs.org/doi/abs/10.1200/JCO.1990.8.6.1005 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2189950 PubMed]
-## '''Pooled update:''' Taghian A, Jeong JH, Mamounas E, Anderson S, Bryant J, Deutsch M, Wolmark N. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol. 2004 Nov 1;22(21):4247-54. Epub 2004 Sep 27. [https://ascopubs.org/doi/full/10.1200/JCO.2004.01.042 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15452182 PubMed]
-==Placebo==
+==SBG 9401==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Regimen===
+===Arm 1 (control)===
+*[[Surgery]], then [[Breast_cancer#FEC_2|FEC]] x 2, then HD-FEC x 1, then [[Breast_cancer_-_historical#CTCb.2C_then_auto_HSCT|CTCb with auto HSCT]]
+===Arm 2 (experimental)===
+*Tailored FEC x 6
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
+|-
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|Control
+| style="background-color:#fc8d59" |Seems to have inferior RFS
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM197501162920301 Fisher et al. 1975 (NSABP B-05)]
+|Experimental
-|style="background-color:#1a9851"|Phase III (C)
+| style="background-color:#91cf60" |Seems to have superior RFS
-|[[#Melphalan_monotherapy|Melphalan]]
-|style="background-color:#fee08b" |Might have inferior DFS (*)
 |-
 |}
-''No active antineoplastic treatment after mastectomy. Used as a comparator arm, historically. Reported efficacy for NSABP B-05 is based on the 1986 update.''
-====Preceding treatment====
-*[[Surgery#Mastectomy|Mastectomy]]
 ===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://www.ncbi.nlm.nih.gov/pubmed/1105174 PubMed]
+# Bergh J, Wiklund T, Erikstein B, Lidbrink E, Lindman H, Malmström P, Kellokumpu-Lehtinen P, Bengtsson NO, Söderlund G, Anker G, Wist E, Ottosson S, Salminen E, Ljungman P, Holte H, Nilsson J, Blomqvist C, Wilking N; Scandinavian Breast Group 9401 study. Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Lancet. 2000 Oct 21;356(9239):1384-91. Erratum in: Lancet 2000 Dec 23-30;356(9248):2196. [https://www.sciencedirect.com/science/article/pii/S0140673600028415 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/11052580 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://www.ncbi.nlm.nih.gov/pubmed/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://ascopubs.org/doi/full/10.1200/JCO.1986.4.6.929 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3519883 PubMed]
-==PT {{#subobject:c08464|Regimen=1}}==
+==SWOG-8814==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-PT: '''<u>P</u>'''rednisone & '''<u>T</u>'''amoxifen
+===Arm 1 (Control)===
-===Regimen {{#subobject:2fc709|Variant=1}}===
+*[[Surgery]], then [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|tamoxifen]] x 5 y
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Arm 2, CAF-T (Experimental)===
-!style="width: 25%"|Study
+*[[Surgery]], then [[Breast_cancer#FAC_2|CAF]] x 6, then [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|tamoxifen]] x 5 y
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+===Arm 3, CAFT (Experimental)===
-!style="width: 25%"|Comparator
+*[[Surgery]], then CAFT
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+===Comparative efficacy===
+====Comparison 1====
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Design'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|No chemotherapy
+| style="background-color:#fee08b" |Might have inferior OS
 |-
-|rowspan = 2|[https://www.thelancet.com/journals/lancet/article/PIIS0140673684924450/fulltext Goldhirsch et al. 1984 (LBCS III)]
+|With chemotherapy
-|rowspan = 2 style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#d9ef8b" |Might have superior OS
-|1. [[#CMFPT|CMFPT]]
+|-
-| style="background-color:#fc8d59" |Seems to have inferior DFS
+|}
+====Comparison 2====
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Timing'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|2. [[#Observation|Observation]]
+|Concurrent (CAFT)
-| style="background-color:#1a9850" |Superior DFS
+| style="background-color:#fee08b" |Might have inferior DFS
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140673684924450/fulltext Goldhirsch et al. 1984 (LBCS IV)]
+|Sequential (CAF-T)
-|style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#d9ef8b" |Might have superior DFS
-|[[#Observation|Observation]]
-| style="background-color:#91cf60" |Seems to have superior DFS
 |-
 |}
-====Preceding treatment====
-*[[Surgery#Mastectomy|Mastectomy]]
-====Hormonotherapy====
-*[[Prednisone (Sterapred)]]
-*[[Tamoxifen (Nolvadex)]]
 ===References===
-# '''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://www.ncbi.nlm.nih.gov/pubmed/6144974 PubMed]
+# Albain KS, Barlow WE, Ravdin PM, Farrar WB, Burton GV, Ketchel SJ, Cobau CD, Levine EG, Ingle JN, Pritchard KI, Lichter AS, Schneider DJ, Abeloff MD, Henderson IC, Muss HB, Green SJ, Lew D, Livingston RB, Martino S, Osborne CK; Breast Cancer Intergroup of North America. Adjuvant chemotherapy and timing of tamoxifen in postmenopausal patients with endocrine-responsive, node-positive breast cancer: a phase 3, open-label, randomised controlled trial. Lancet. 2009 Dec 19;374(9707):2055-2063. Epub 2009 Dec 10. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)61523-3/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3140679/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/20004966 PubMed]
-==TMF {{#subobject:c08464|Regimen=1}}==
+==TACT==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-TMF: '''<u>T</u>'''hiotepa, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil
+===Arm 1 (Experimental)===
-===Regimen {{#subobject:2fc709|Variant=1}}===
+*[[Surgery]], then [[Breast_cancer#FEC_2|FEC]] x 4, then [[#Docetaxel_monotherapy_2|D]] x 4
-{| class="wikitable" style="width: 50%; text-align:center;"
+===Arm 2 (Control)===
-!style="width: 25%"|Study
+*[[Surgery]], then [[Breast_cancer#FEC_2|FEC]] x 8
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+===Arm 3 (Control)===
+*[[Surgery]], then [[Breast_cancer#Epirubicin_monotherapy|E]] x 4, then [[Breast_cancer#CMF|CMF]] x 4
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Experimental (with docetaxel)
+|style="background-color:#ffffbf"|Seems not superior
 |-
-|[https://academic.oup.com/annonc/article-abstract/5/7/591/206435 Semiglazov et al. 1994]
+|Standard (no docetaxel)
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+|style="background-color:#ffffbf"|Seems not superior
 |-
 |}
-====Preceding treatment====
-*[[Surgery#Mastectomy|Mastectomy]]
-====Chemotherapy====
-*[[Thiotepa (Thioplex)]]
-*[[Methotrexate (MTX)]]
-*[[Fluorouracil (5-FU)]]
 ===References===
-# Semiglazov VF, Topuzov EE, Bavli JL, Moiseyenko VM, Ivanova OA, Seleznev IK, Orlov AA, Barash NY, Golubeva OM, Chepic OF. Primary (neoadjuvant) chemotherapy and radiotherapy compared with primary radiotherapy alone in stage IIb-IIIa breast cancer. Ann Oncol. 1994 Sep;5(7):591-5. [https://academic.oup.com/annonc/article-abstract/5/7/591/206435 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7993833 PubMed]
+# Ellis P, Barrett-Lee P, Johnson L, Cameron D, Wardley A, O'Reilly S, Verrill M, Smith I, Yarnold J, Coleman R, Earl H, Canney P, Twelves C, Poole C, Bloomfield D, Hopwood P, Johnston S, Dowsett M, Bartlett JM, Ellis I, Peckitt C, Hall E, Bliss JM; TACT Trial Management Group; TACT Trialists. Sequential docetaxel as adjuvant chemotherapy for early breast cancer (TACT): an open-label, phase III, randomised controlled trial. Lancet. 2009 May 16;373(9676):1681-92. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(09)60740-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2687939/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19447249 PubMed]
-=Metastatic disease, all lines of therapy=
+==TACT2==
-==Aminoglutethimide monotherapy {{#subobject:821a2c|Regimen=1}}==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Regimen {{#subobject:f62b32|Variant=1}}===
+===Arm 1 (Experimental)===
+*ddE, then [[Breast_cancer#Capecitabine_monotherapy|capecitabine]]
+===Arm 2 (Experimental)===
+*ddE, then [[Breast_cancer#CMF|CMF]]
+===Arm 3 (Experimental)===
+*[[Breast_cancer#Epirubicin_monotherapy|E]], then [[Breast_cancer#Capecitabine_monotherapy|capecitabine]]
+===Arm 4 (Control)===
+*[[Breast_cancer#Epirubicin_monotherapy|E]], then [[Breast_cancer#CMF|CMF]]
+===Comparative efficacy===
+*Analyzed using a 2 x 2 factorial design
+====Comparison 1====
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Dose density of epirubicin'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(78)92759-9/fulltext Smith et al. 1978]
+|Dose-dense (q2wk)
-| style="background-color:#91cf61" |Non-randomized
+|style="background-color:#ffffbf"|Seems not superior
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM198109033051003 Santen et al. 1981]
+|Standard (q3wk)
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+|style="background-color:#ffffbf"|Seems not superior
-|Bilateral adrenalectomy
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(84)90596-8/fulltext Stuart-Harris et al. 1984]
+|}
-| style="background-color:#91cf61" |Phase II
+====Comparison 2====
-| style="background-color:#d3d3d3" |
+{| class="wikitable" style="width: 100%; text-align:center;"
-| style="background-color:#d3d3d3" |
+!'''Capecitabine vs. CMF'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://academic.oup.com/jnci/article-abstract/80/14/1147/908657 Canney et al. 1988]
+|Capecitabine
-|style="background-color:#1a9851"|Phase III (E-switch-ic)
+|style="background-color:#eeee01"|Non-inferior TTR
-|[[#Medroxyprogesterone_monotherapy|MPA]]
-|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR
 |-
-|[https://link.springer.com/article/10.1007/BF01810736 Lundgren et al. 1989]
+|CMF
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+|style="background-color:#eeee01"|Non-inferior TTR
-|[[#Megestrol_monotherapy|Megestrol]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
-|[https://link.springer.com/article/10.1007/BF01961246 Garcia-Giralt et al. 1992]
+|}
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+===References===
-|[[#Medroxyprogesterone_monotherapy|MPA]]
+# Cameron D, Morden JP, Canney P, Velikova G, Coleman R, Bartlett J, Agrawal R, Banerji J, Bertelli G, Bloomfield D, Brunt AM, Earl H, Ellis P, Gaunt C, Gillman A, Hearfield N, Laing R, Murray N, Couper N, Stein RC, Verrill M, Wardley A, Barrett-Lee P, Bliss JM; TACT2 Investigators. Accelerated versus standard epirubicin followed by cyclophosphamide, methotrexate, and fluorouracil or capecitabine as adjuvant therapy for breast cancer in the randomised UK TACT2 trial (CRUK/05/19): a multicentre, phase 3, open-label, randomised, controlled trial. Lancet Oncol. 2017 Jul;18(7):929-945. Epub 2017 Jun 7. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30404-7/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489700/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/28600210 PubMed]
-| style="background-color:#91cf60" |Seems to have superior TTP
+==TEAM==
+{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[https://www.ncbi.nlm.nih.gov/pubmed/8135469 Robustelli della Cuna et al. 1993]
+|[[#top|back to top]]
-| style="background-color:#1a9851" |Phase III (C)
+|}
-|[[#Aminoglutethimide_monotherapy|Aminoglutethimide]]; higher-dose
+===Arm 1, monotherapy (Control)===
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
+*[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 5y
+===Arm 2, sequential (Experimental)===
+*[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy|Tamoxifen]] x 2.5-3y, then [[Breast_cancer,_ER-positive#Exemestane_monotherapy|Exemestane]] x 2-2.5y
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19940115)73:2%3C354::AID-CNCR2820730220%3E3.0.CO;2-J Gale et al. 1994]
+|Tamoxifen x 5y
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+|style="background-color:#ffffbf"|Seems not superior
-|1. [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_2|Tamoxifen]]<br> 2. Bilateral adrenalectomy
+|-
-| style="background-color:#ffffbf" |Did not meet primary endpoints of DOR/TTF/OS
+|Tamoxifen x 2.5-3y, then Exemestane x 2-2.5y
+|style="background-color:#ffffbf"|Seems not superior
 |-
 |}
-====Hormonotherapy====
+===References===
-*[[Aminoglutethimide (Cytadren)]]
+# van de Velde CJ, Rea D, Seynaeve C, Putter H, Hasenburg A, Vannetzel JM, Paridaens R, Markopoulos C, Hozumi Y, Hille ET, Kieback DG, Asmar L, Smeets J, Nortier JW, Hadji P, Bartlett JM, Jones SE. Adjuvant tamoxifen and exemestane in early breast cancer (TEAM): a randomised phase 3 trial. Lancet. 2011 Jan 22;377(9762):321-31. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62312-4/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/21247627 PubMed]
+## '''Update:''' Derks MGM, Blok EJ, Seynaeve C, Nortier JWR, Kranenbarg EM, Liefers GJ, Putter H, Kroep JR, Rea D, Hasenburg A, Markopoulos C, Paridaens R, Smeets JBE, Dirix LY, van de Velde CJH. Adjuvant tamoxifen and exemestane in women with postmenopausal early breast cancer (TEAM): 10-year follow-up of a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017 Sep;18(9):1211-1220. Epub 2017 Jul 18. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(17)30419-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28732650 PubMed]
-====Supportive medications====
+==TRYPHAENA==
-*[[Hydrocortisone (Cortef)]]
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm A===
+*FEC & HP x 3, then [[Breast_cancer,_HER2-positive#THP_.28Taxotere.29|THP]] x 3, then [[surgery]]
+===Arm B===
+*[[Breast_cancer#FEC|FEC]] x 3, then [[Breast_cancer,_HER2-positive#THP_.28Taxotere.29|THP]] x 3, then [[surgery]]
+===Arm C===
+*[[Breast_cancer,_HER2-positive#TCHP_.28Taxotere.29|TCHP]] x 6, then [[surgery]]
+===Comparative efficacy===
+''Note: this was a cardiac safety study; efficacy findings are not reported.''
 ===References===
-# Smith IE, Fitzharris BM, McKinna JA, Fahmy DR, Nash AG, Neville AM, Gazet JC, Ford HT, Powles TJ. Aminoglutethimide in treatment of metastatic breast carcinoma. Lancet. 1978 Sep 23;2(8091):646-9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(78)92759-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/80576 PubMed]
+# '''TRYPHAENA:''' Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortés J. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013 Sep;24(9):2278-84. Epub 2013 May 22. [http://annonc.oxfordjournals.org/content/24/9/2278.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/23704196 PubMed]
-# Santen RJ, Worgul TJ, Samojlik E, Interrante A, Boucher AE, Lipton A, Harvey HA, White DS, Smart E, Cox C, Wells SA. A randomized trial comparing surgical adrenalectomy with aminoglutethimide plus hydrocortisone in women with advanced breast cancer. N Engl J Med. 1981 Sep 3;305(10):545-51. [https://www.nejm.org/doi/full/10.1056/NEJM198109033051003 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7019703 PubMed]
-# Stuart-Harris R, Dowsett M, Bozek T, McKinna JA, Gazet JC, Jeffcoate SL, Kurkure A, Carr L, Smith IE. Low-dose aminoglutethimide in treatment of advanced breast cancer. Lancet. 1984 Sep 15;2(8403):604-7. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(84)90596-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6147642 PubMed]
-# Canney PA, Priestman TJ, Griffiths T, Latief TN, Mould JJ, Spooner D. Randomized trial comparing aminoglutethimide with high-dose medroxyprogesterone acetate in therapy for advanced breast carcinoma. J Natl Cancer Inst. 1988 Sep 21;80(14):1147-51. [https://academic.oup.com/jnci/article-abstract/80/14/1147/908657 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2970555 PubMed]
-# Lundgren S, Gundersen S, Klepp R, Lønning PE, Lund E, Kvinnsland S. Megestrol acetate versus aminoglutethimide for metastatic breast cancer. Breast Cancer Res Treat. 1989 Nov;14(2):201-6. [https://link.springer.com/article/10.1007/BF01810736 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2690972 PubMed]
-# Garcia-Giralt E, Ayme Y, Carton M, Daban A, Delozier T, Fargeot P, Fumoleau P, Gorins A, Guerin D, Guerin R, Maillart P, Mauriac L, May-Levin F, Metz R, Namer M, Olivier JP, Pommatau E, Pouillart P, Pujade-Lauraine E, Rouesse J, Serrou B, Vitse M, Zylberait D. Second and third line hormonotherapy in advanced post-menopausal breast cancer: a multicenter randomized trial comparing medroxyprogesterone acetate with aminoglutethimide in patients who have become resistant to tamoxifen. Breast Cancer Res Treat. 1992;24(2):139-45. [https://link.springer.com/article/10.1007/BF01961246 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8443401 PubMed]
-# Robustelli della Cuna G, Pannuti F, Martoni A, Camaggi CM, Strocchi E, Da Prada GA, Tanneberger S; Italian Cooperative Group. Aminoglutethimide in advanced breast cancer: prospective, randomized comparison of two dose levels. Anticancer Res. 1993 Nov-Dec;13(6B):2367-71. [https://www.ncbi.nlm.nih.gov/pubmed/8135469 PubMed]
-# Gale KE, Andersen JW, Tormey DC, Mansour EG, Davis TE, Horton J, Wolter JM, Smith TJ, Cummings FJ. Hormonal treatment for metastatic breast cancer: an Eastern Cooperative Oncology Group Phase III trial comparing aminoglutethimide to tamoxifen. Cancer. 1994 Jan 15;73(2):354-61. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19940115)73:2%3C354::AID-CNCR2820730220%3E3.0.CO;2-J link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8293400 PubMed]
-==CAMF {{#subobject:4b99b8|Regimen=1}}==
+=Cervical cancer=
+==NOGGO-AGO==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CAMF: '''<u>C</u>'''yclophosphamide,  '''<u>A</u>'''driamycin (Doxorubicin), '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil
+===Arm 1 (Control)===
-<br>AFCM: '''<u>A</u>'''driamycin (Doxorubicin), '''<u>F</u>'''luorouracil, '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate
+*[[Surgery]], then [[Cervical_cancer#Carboplatin_.26_Ifosfamide|adjuvant Carboplatin & Ifosfamide]] x 4, then [[Cervical_cancer#Radiation_therapy_2|EBRT]]
-===Regimen {{#subobject:7c9b85|Variant=1}}===
+===Arm 2 (Experimental)===
-{| class="wikitable" style="width: 100%; text-align:center;"
+*[[Surgery]], then adjuvant Carboplatin, Ifosfamide, Erythropoietin alfa, then EBRT & Erythropoietin alfa
-!style="width: 25%"|Study
+===Comparative efficacy===
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Comparator
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|No EPO
+|style="background-color:#fee08b"|Might have inferior RFS
+|-
+|With EPO
+|style="background-color:#d9ef8b"|Might have superior RFS
+|-
+|}
+===References===
+# Blohmer JU, Paepke S, Sehouli J, Boehmer D, Kolben M, Würschmidt F, Petry KU, Kimmig R, Elling D, Thomssen C, von Minckwitz G, Möbus V, Hinke A, Kümmel S, Budach V, Lichtenegger W, Schmid P. Randomized phase III trial of sequential adjuvant chemoradiotherapy with or without erythropoietin Alfa in patients with high-risk cervical cancer: results of the NOGGO-AGO intergroup study. J Clin Oncol. 2011 Oct 1;29(28):3791-7. Epub 2011 Aug 22. [https://ascopubs.org/doi/full/10.1200/JCO.2010.30.4899 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21860000 PubMed]
+=[[Colon cancer|Colorectal cancer]]=
+==CAIRO==
+{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(197806)41:6%3C2078::AID-CNCR2820410602%3E3.0.CO;2-Q Tranum et al. 1978]
+|[[#top|back to top]]
-| style="background-color:#1a9851" |Randomized (E-esc)
+|}
-|1. AF<br> 2. [[Breast_cancer#FAC_3|FAC]]
+===Arm 1, sequential single agent (Control)===
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
+*[[Colon_cancer#Capecitabine_monotherapy_2|First-line capecitabine]], then [[Colon_cancer#Irinotecan_monotherapy_2|second-line irinotecan]], then [[Colon_cancer#CapeOx_4|third-line CapeOx]]
+===Arm 2, sequential combinations (Experimental)===
+*[[Colon_cancer#CAPIRI|First-line CAPIRI]], then [[Colon_cancer#CapeOx_3|second-line CapeOx]]
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Approach'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(197908)44:2%3C392::AID-CNCR2820440204%3E3.0.CO;2-D Bezwoda et al. 1979]
+|Sequential single agent
-|style="background-color:#1a9851" |Randomized (E-switch-ic)
+| style="background-color:#ffffbf" |Seems not superior
-|[[#CMFV|CMFV]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1984.2.1.28 Lippman et al. 1984]
+|Sequential combinations
-| style="background-color:#1a9851" |Randomized (C)
-|CAMFTP
 | style="background-color:#ffffbf" |Seems not superior
 |-
 |}
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Doxorubicin (Adriamycin)]]
-*[[Methotrexate (MTX)]]
-*[[Fluorouracil (5-FU)]]
 ===References===
-# Tranum B, Hoogstraten B, Kennedy A, Vaughn CB, Samal B, Thigpen T, Rivkin S, Smith F, Palmer RL, Costanzi J, Tucker WG, Wilson H, Maloney TR. Adriamycin in combination for the treatment of breast cancer: a Southwest Oncology Group study. Cancer. 1978 Jun;41(6):2078-83. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(197806)41:6%3C2078::AID-CNCR2820410602%3E3.0.CO;2-Q link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/657081 PubMed]
+# Koopman M, Antonini NF, Douma J, Wals J, Honkoop AH, Erdkamp FL, de Jong RS, Rodenburg CJ, Vreugdenhil G, Loosveld OJ, van Bochove A, Sinnige HA, Creemers GM, Tesselaar ME, Slee PHTJ, Werter MJ, Mol L, Dalesio O, Punt CJ. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet. 2007 Jul 14;370(9582):135-142. [https://www.thelancet.com/journals/lancet/article/PIIS0140673607610861/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17630036 PubMed]
-# Bezwoda WR, de Moor NG, Derman D, Lange M, Saner R, Dando R. Combination chemotherapy of metastatic breast cancer: a randomized trial comparing the use of adriamycin to that of Vinblastine. Cancer. 1979 Aug;44(2):392-7. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(197908)44:2%3C392::AID-CNCR2820440204%3E3.0.CO;2-D link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/383254 PubMed]
-# Lippman ME, Cassidy J, Wesley M, Young RC. A randomized attempt to increase the efficacy of cytotoxic chemotherapy in metastatic breast cancer by hormonal synchronization. J Clin Oncol. 1984 Jan;2(1):28-36. [https://ascopubs.org/doi/abs/10.1200/JCO.1984.2.1.28 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6321686 PubMed]
-==CAF & MPA {{#subobject:6c7ff9|Regimen=1}}==
+==FFCD 2000-05==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CAF & MPA: '''<u>C</u>'''yclophosphamide,  '''<u>A</u>'''driamycin (Doxorubicin), '''<u>F</u>'''luorouracil, '''<u>M</u>'''edroxy'''<u>P</u>'''rogesterone '''<u>A</u>'''cetate
+===Arm 1, sequential (Control)===
-===Regimen {{#subobject:b2ce67|Variant=1}}===
+*[[Colon_cancer#Fluorouracil_.26_Folinic_acid_2|First-line sLV5FU2]], then [[Colon_cancer#mFOLFOX6_4|second-line mFOLFOX6]], then [[Colon_cancer#FOLFIRI_4|third-line FOLFIRI]]
+===Arm 2, combination (Experimental)===
+*[[Colon_cancer#mFOLFOX6_3|First-line mFOLFOX6]], then [[Colon_cancer#FOLFIRI_3|second-line FOLFIRI]]
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Approach'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
+![[Levels_of_Evidence#Toxicity|Toxicity]]
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|-
+|Sequential
+| style="background-color:#ffffbf" |Seems not superior
+| style="background-color:#1a9850" |Less toxic
 |-
-|[https://www.ejcancer.com/article/0959-8049(94)90123-6/pdf Tominaga et al. 1994]
+|Combination
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#ffffbf" |Seems not superior
-|[[Breast_cancer#FAC_3|CAF]]
+| style="background-color:#d73027" |More toxic
-| style="background-color:#91cf60" |Seems to have superior ORR
 |-
 |}
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Doxorubicin (Adriamycin)]]
-*[[Fluorouracil (5-FU)]]
-====Hormonotherapy====
-*[[Medroxyprogesterone (MPA)]]
 ===References===
-# Tominaga T, Abe O, Ohshima A, Hayasaka H, Uchino J, Abe R, Enomoto K, Izuo M, Watanabe H, Takatani O, Yoshida M, Sakai K, Koyama H, Hattori T, Senoo T, Monden Y, Nomura Y. Comparison of chemotherapy with or without medroxyprogesterone acetate for advanced or recurrent breast cancer. Eur J Cancer. 1994;30A(7):959-64. [https://www.ejcancer.com/article/0959-8049(94)90123-6/pdf link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/7946592 PubMed]
+# Ducreux M, Malka D, Mendiboure J, Etienne PL, Texereau P, Auby D, Rougier P, Gasmi M, Castaing M, Abbas M, Michel P, Gargot D, Azzedine A, Lombard-Bohas C, Geoffroy P, Denis B, Pignon JP, Bedenne L, Bouché O; Fédération Francophone de Cancérologie Digestive (FFCD) 2000–05 Collaborative Group. Sequential versus combination chemotherapy for the treatment of advanced colorectal cancer (FFCD 2000-05): an open-label, randomised, phase 3 trial. Lancet Oncol. 2011 Oct;12(11):1032-44. Epub 2011 Sep 6. [https://www.thelancet.com/journals/lancetonc/article/PIIS1470204511701991/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21903473 PubMed]
-==CAFVP {{#subobject:918bda|Regimen=1}}==
+=[[Diffuse large B-cell lymphoma]]=
+==SWOG S8736==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CAFVP: '''<u>C</u>'''yclophosphamide, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>F</u>'''luorouracil, '''<u>V</u>'''incristine, '''<u>P</u>'''rednisone
+===Arm 1 - Control===
-===Regimen {{#subobject:e01caf|Variant=1}}===
+*[[Diffuse_large_B-cell_lymphoma_-_historical#CHOP|CHOP]] x 8
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Arm 2 - Experimental===
-!style="width: 25%"|Study
+*[[Diffuse_large_B-cell_lymphoma_-_historical#CHOP|CHOP]] x 3, then [[Diffuse_large_B-cell_lymphoma#Radiation_therapy|RT]] x 40 to 55 Gy
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+===Comparative efficacy===
-!style="width: 25%"|Comparator
+{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!'''Regimen'''
-|-
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(197811)42:5%3C2141::AID-CNCR2820420509%3E3.0.CO;2-3 Muss et al. 1978]
-|style="background-color:#1a9851" |Phase III (E-switch-ic)
-|[[#CMFVP_2|CMFVP]]
-| style="background-color:#d9ef8b" |Might have superior OS
 |-
-|rowspan=2|[https://ascopubs.org/doi/abs/10.1200/JCO.1987.5.10.1523 Aisner et al. 1987]
+|CHOP x 8
-|rowspan=2 style="background-color:#1a9851" |Phase III (E-esc)
+|style="background-color:#fc8d59"|Seems to have inferior OS
-|1. [[Breast_cancer#FAC_3|CAF]]
-| style="background-color:#d3d3d3" |Not reported
 |-
-|2. [[Breast_cancer#CMF_2|CMF]]
+|CHOP x 3, then RT
-| style="background-color:#1a9850" |Superior ORR
+|style="background-color:#91cf60"|Seems to have superior OS
 |-
 |}
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Doxorubicin (Adriamycin)]]
-*[[Fluorouracil (5-FU)]]
-*[[Vincristine (Oncovin)]]
-====Hormonotherapy====
-*[[Prednisone (Sterapred)]]
 ===References===
-# Muss HB, White DR, Richards F 2nd, Cooper MR, Stuart JJ, Jackson DV, Rhyne L, Spurr CL. Adriamycin versus methotrexate in five-drug combination chemotherapy for advanced breast cancer: a randomized trial. Cancer. 1978 Nov;42(5):2141-8. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(197811)42:5%3C2141::AID-CNCR2820420509%3E3.0.CO;2-3 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/363253 PubMed]
+# Miller TP, Dahlberg S, Cassady JR, Adelstein DJ, Spier CM, Grogan TM, LeBlanc M, Carlin S, Chase E, Fisher RI. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med. 1998 Jul 2;339(1):21-6. [https://www.nejm.org/doi/full/10.1056/NEJM199807023390104 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9647875 PubMed]
-# Aisner J, Weinberg V, Perloff M, Weiss R, Perry M, Korzun A, Ginsberg S, Holland JF; Cancer and Leukemia Group B. Chemotherapy versus chemoimmunotherapy (CAF v CAFVP v CMF each +/- MER) for metastatic carcinoma of the breast: a CALGB study. J Clin Oncol. 1987 Oct;5(10):1523-33. [https://ascopubs.org/doi/abs/10.1200/JCO.1987.5.10.1523 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/3655855 PubMed]
-==CFP {{#subobject:ba429d|Regimen=1}}==
+=[[Follicular lymphoma]]=
+==GALLIUM==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CFP: '''<u>C</u>'''yclophosphamide, '''<u>F</u>'''luorouracil, '''<u>P</u>'''rednisone
+===Arm 1 - Control===
-===Regimen {{#subobject:26519a|Variant=1}}===
+*[[Follicular_lymphoma#BR|BR]] x 6 or [[Follicular_lymphoma#R-CHOP|R-CHOP]] x 8 or [[Follicular_lymphoma#R-CVP|R-CVP]] x 8, then [[Follicular_lymphoma#Rituximab_monotherapy.2C_extended_course|Rituximab maintenance]] x 2 y
+===Arm 2 - Experimental===
+*[[Follicular_lymphoma#Bendamustine_.26_Obinutuzumab|Bendamustine & Obinutuzumab]] x 6 or [[Follicular_lymphoma#G-CHOP|G-CHOP]] x 8 or [[Follicular_lymphoma#G-CVP|G-CVP]] x 8, then [[Follicular_lymphoma#Obinutuzumab_monotherapy|Obinutuzumab maintenance]] x 2y
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''mAb'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
+![[Levels_of_Evidence#Toxicity|Toxicity]]
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://ascopubs.org/doi/10.1200/JCO.1984.2.11.1260 Creagan et al. 1984]
+|Rituximab-chemotherapy
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#d73027" |Inferior PFS
-|CAP, then CFP
+| style="background-color:#1a9850" |Superior toxicity
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19870301)59:5%3C874::AID-CNCR2820590503%3E3.0.CO;2-O Rosner et al. 1987]
+|Obinutuzumab-chemotherapy
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#1a9850" |Superior PFS
-|1. [[Breast_cancer#AC_3|CA]]<br> 2. [[#CMFVP_2|CMFVP]]
+| style="background-color:#d73027" |Inferior toxicity
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
-|-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19890515)63:10%3C1931::AID-CNCR2820631011%3E3.0.CO;2-F Marschke et al. 1989]
-| style="background-color:#1a9851" |Phase III (C)
-|[[#CMFP_2|CMFP]]
-| style="background-color:#fee08b" |Might have inferior ORR
 |-
 |}
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Fluorouracil (5-FU)]]
-====Hormonotherapy====
-*[[Prednisone (Sterapred)]]
 ===References===
-# Creagan ET, Green SJ, Ahmann DL, Ingle JN, Edmonson JH, Marschke RF Jr. A phase III clinical trial comparing the combination cyclophosphamide, adriamycin, cisplatin with cyclophosphamide, 5-fluorouracil, prednisone in patients with advanced breast cancer. J Clin Oncol. 1984 Nov;2(11):1260-5. [https://ascopubs.org/doi/10.1200/JCO.1984.2.11.1260 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6387059 PubMed]
+# Marcus R, Davies A, Ando K, Klapper W, Opat S, Owen C, Phillips E, Sangha R, Schlag R, Seymour JF, Townsend W, Trněný M, Wenger M, Fingerle-Rowson G, Rufibach K, Moore T, Herold M, Hiddemann W. Obinutuzumab for the first-line treatment of follicular lymphoma. N Engl J Med. 2017 Oct 5;377(14):1331-1344. [https://www.nejm.org/doi/10.1056/NEJMoa1614598 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1614598/suppl_file/nejmoa1614598_appendix.pdf link to appendix] [https://www.ncbi.nlm.nih.gov/pubmed/28976863 PubMed]
-# Rosner D, Nemoto T, Lane WW. A randomized study of intensive versus moderate chemotherapy programs in metastatic breast cancer. Cancer. 1987 Mar 1;59(5):874-83. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19870301)59:5%3C874::AID-CNCR2820590503%3E3.0.CO;2-O link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3815266 PubMed]
-# Marschke RF Jr, Ingle JN, Schaid DJ, Krook JE, Mailliard JA, Cullinan SA, Pfeifle DM, Votava HJ, Ebbert LP, Windschitl HE. Randomized clinical trial of CFP versus CMFP in women with metastatic breast cancer. Cancer. 1989 May 15;63(10):1931-7. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19890515)63:10%3C1931::AID-CNCR2820631011%3E3.0.CO;2-F link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2649221 PubMed]
-==Chlorambucil & Prednisolone {{#subobject:2cde9a|Regimen=1}}==
+=Gastroesophageal cancer=
+==ACCORD 07==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Regimen {{#subobject:0044a9|Variant=1}}===
+===Arm 1 - Control===
-{| class="wikitable" style="width: 50%; text-align:center;"
+*[[Surgery]] alone
-!style="width: 25%"|Study
+===Arm 2 - Experimental===
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+*[[Esophageal_cancer#Cisplatin_.26_Fluorouracil|Neoadjuvant CF]], then [[surgery]], then [[Esophageal_cancer#Cisplatin_.26_Fluorouracil_3|adjuvant CF]]
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Surgery alone
+| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
-|[https://jamanetwork.com/journals/jama/article-abstract/1163685 Freckman et al. 1964]
+|Perioperative CF
-| style="background-color:#91cf61" |Non-randomized
+| style="background-color:#91cf60" |Seems to have superior OS
 |-
 |}
-====Chemotherapy====
-*[[Chlorambucil (Leukeran)]]
-====Hormonotherapy====
-*[[Prednisolone (Millipred)]]
 ===References===
-# Freckman HA, Fry HL, Mendez FL, Maurer ER. Chlorambucil-prednisolone therapy for disseminated breast carcinoma. JAMA. 1964 Jul 6;189:23-6. [https://jamanetwork.com/journals/jama/article-abstract/1163685 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14149018 PubMed]
+# Ychou M, Boige V, Pignon JP, Conroy T, Bouché O, Lebreton G, Ducourtieux M, Bedenne L, Fabre JM, Saint-Aubert B, Genève J, Lasser P, Rougier P. Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial. J Clin Oncol. 2011 May 1;29(13):1715-21. Epub 2011 Mar 28. [https://ascopubs.org/doi/full/10.1200/JCO.2010.33.0597 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21444866 PubMed]
-==CHUT, then auto HSCT {{#subobject:e9e363|Regimen=1}}==
+==FLOT4-AIO==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Regimen {{#subobject:392c1c|Variant=1}}===
+===Arm 1 - Control===
+*[[Esophageal_cancer#ECF|ECF]] or [[Esophageal_cancer#ECX|ECX]] x 3, then [[surgery]], then [[Esophageal_cancer#ECF_2|ECF]] or [[Esophageal_cancer#ECX_2|ECX]] x 3
+===Arm 2 - Experimental===
+*[[Esophageal_cancer#FLOT|FLOT]] x 4, then [[surgery]], then [[Esophageal_cancer#FLOT_2|FLOT]] x 4
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.nature.com/articles/1705935 Biron et al. 2007 (Pegase 03)]
+|ECF/ECX
-| style="background-color:#1a9851" |Phase III (E-esc)
+|style="background-color:#fc8d59"|Seems to have inferior OS
-|No further treatment
+|-
-| style="background-color:#1a9850" |Superior DFS
+|FLOT
+|style="background-color:#91cf60"|Seems to have superior OS
 |-
 |}
-====Preceding treatment====
-*[[Breast_cancer#FEC_3|FEC]] x 4
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]] 6000 mg/m<sup>2</sup>
-*[[Thiotepa (Thioplex)]] 800 mg/m<sup>2</sup>
 ===References===
-# '''Pegase 03:''' Biron P, Durand M, Roché H, Delozier T, Battista C, Fargeot P, Spaeth D, Bachelot T, Poiget E, Monnot F, Tanguy ML, Curé H. Pegase 03: a prospective randomized phase III trial of FEC with or without high-dose thiotepa, cyclophosphamide and autologous stem cell transplantation in first-line treatment of metastatic breast cancer. Bone Marrow Transplant. 2008 Mar;41(6):555-62. Epub 2007 Nov 26. [https://www.nature.com/articles/1705935 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18037940 PubMed]
+# Al-Batran SE, Hofheinz RD, Pauligk C, Kopp HG, Haag GM, Luley KB, Meiler J, Homann N, Lorenzen S, Schmalenberg H, Probst S, Koenigsmann M, Egger M, Prasnikar N, Caca K, Trojan J, Martens UM, Block A, Fischbach W, Mahlberg R, Clemens M, Illerhaus G, Zirlik K, Behringer DM, Schmiegel W, Pohl M, Heike M, Ronellenfitsch U, Schuler M, Bechstein WO, Königsrainer A, Gaiser T, Schirmacher P, Hozaeel W, Reichart A, Goetze TO, Sievert M, Jäger E, Mönig S, Tannapfel A. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 2016 Dec;17(12):1697-1708. Epub 2016 Oct 22. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30531-9/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27776843 PubMed]
+## '''Update:''' Al-Batran SE, Homann N, Pauligk C, Goetze TO, Meiler J, Kasper S, Kopp HG, Mayer F, Haag GM, Luley K, Lindig U, Schmiegel W, Pohl M, Stoehlmacher J, Folprecht G, Probst S, Prasnikar N, Fischbach W, Mahlberg R, Trojan J, Koenigsmann M, Martens UM, Thuss-Patience P, Egger M, Block A, Heinemann V, Illerhaus G, Moehler M, Schenk M, Kullmann F, Behringer DM, Heike M, Pink D, Teschendorf C, Löhr C, Bernhard H, Schuch G, Rethwisch V, from Weikersthal LF, Hartmann JT, Kneba M, Daum S, Schulmann K, Less J, Belle S, Gaiser T, Oduncu FS, Güntner M, Hozaeel W, Reichart A, Hunter E, Kraus T, Mönig S, Bechstein WO, Schuler M, Schmalenberg H, Hofheinz RD; FLOT4-AIO Investigators. perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomized, phase 2/3 trial. Lancet. 2019 Apr 10. [Epub ahead of print] [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(18)32557-1/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30982686 PubMed]
-==CMFP {{#subobject:d1eccf|Regimen=1}}==
+==MAGIC==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CMFP: '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil, '''<u>P</u>'''rednisone
+===Arm 1 - Control===
-===Regimen {{#subobject:6c96a9|Variant=1}}===
+*[[Esophageal_cancer#Surgery_alone|Surgery]]
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Arm 2 - Experimental===
-!style="width: 25%"|Study
+*[[Esophageal_cancer#ECF|ECF]] x 3, then [[surgery]], then [[Esophageal_cancer#ECF_2|ECF]] x 3
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+===Comparative efficacy===
-!style="width: 25%"|Comparator
+{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1633086/ Canellos et al. 1974]
+|Surgery alone
-| style="background-color:#91cf61" |Non-randomized
+|style="background-color:#d73027"|Inferior OS
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19821001)50:7%3C1235::AID-CNCR2820500703%3E3.0.CO;2-L Tormey et al. 1982 (ECOG E2173)]
+|Perioperative ECF
-| style="background-color:#1a9851" |Phase III (E-esc)
+|style="background-color:#1a9850"|Superior OS
-|1. AV<br> 2. [[Breast_cancer#CMF_2|CMF]]
-| style="background-color:#91cf60" |Seems to have superior OS
 |-
-|[https://link.springer.com/article/10.1007/BF01806026 Segaloff et al. 1985]
+|}
-| style="background-color:#1a9851" |Phase III (C)
+===References===
-|[[#CMFVP_2|CMFVP]]
+# Cunningham D, Allum WH, Stenning SP, Thompson JN, Van de Velde CJ, Nicolson M, Scarffe JH, Lofts FJ, Falk SJ, Iveson TJ, Smith DB, Langley RE, Verma M, Weeden S, Chua YJ, MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer. N Engl J Med. 2006 Jul 6;355(1):11-20. [https://www.nejm.org/doi/full/10.1056/NEJMoa055531 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16822992 PubMed]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+==POET==
+{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1985.3.7.932 Cummings et al. 1985]
+|[[#top|back to top]]
-| style="background-color:#1a9851" |Phase III (E-esc)
+|}
-|[[#FAC_3|CAF]]
+===Arm 1===
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
+*[[Esophageal_cancer#CLF|PLF]] x 15 wk, then [[surgery]]
+===Arm 2===
+*[[Esophageal_cancer#CLF|PLF]] x 12 wk, then [[Esophageal_cancer#Cisplatin.2C_Etoposide.2C_RT|Cisplatin, Etoposide, RT]], then [[surgery]]
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19890515)63:10%3C1931::AID-CNCR2820631011%3E3.0.CO;2-F Marschke et al. 1989]
+|Neoadjuvant chemotherapy only
-| style="background-color:#1a9851" |Phase III (E-esc)
+|style="background-color:#fee08b"|Might have inferior OS
-|[[#CFP_2|CFP]]
-| style="background-color:#d9ef8b" |Might have superior ORR
 |-
-|[https://ascopubs.org/doi/10.1200/JCO.1999.17.8.2355 Bishop et al. 1999]
+|Neoadjuvant chemotherapy and chemoradiotherapy
-| style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#d9ef8b"|Might have superior OS
-|[[Breast_cancer#Paclitaxel_monotherapy.2C_q3wk|Paclitaxel]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
 |}
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Methotrexate (MTX)]]
-*[[Fluorouracil (5-FU)]]
-====Hormonotherapy====
-*[[Prednisone (Sterapred)]]
 ===References===
-# Canellos GP, Devita VT, Gold GL, Chabner BA, Schein PS, Young RC. Cyclical combination chemotherapy for advanced breast carcinoma. Br Med J. 1974 Feb 9;1(5901):218-20. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1633086/ link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/4818162 PubMed]
+# Stahl M, Walz MK, Stuschke M, Lehmann N, Meyer HJ, Riera-Knorrenschild J, Langer P, Engenhart-Cabillic R, Bitzer M, Königsrainer A, Budach W, Wilke H. Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esophagogastric junction. J Clin Oncol. 2009 Feb 20;27(6):851-6. Epub 2009 Jan 12. [https://ascopubs.org/doi/full/10.1200/JCO.2008.17.0506 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19139439 PubMed]
-# '''ECOG E2173:''' Tormey DC, Gelman R, Band PR, Sears M, Rosenthal SN, DeWys W, Perlia C, Rice MA. Comparison of induction chemotherapies for metastatic breast cancer: an Eastern Cooperative Oncology Group Trial. Cancer. 1982 Oct 1;50(7):1235-44. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19821001)50:7%3C1235::AID-CNCR2820500703%3E3.0.CO;2-L link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7049347 PubMed]
-# Segaloff A, Hankey BF, Carter AC, Escher GC, Ansfield FJ, Talley RW. An evaluation of the effect of vincristine added to cyclophosphamide, 5-fluorouracil, methotrexate, and prednisone in advanced breast cancer. Breast Cancer Res Treat. 1985;5(3):311-9. [https://link.springer.com/article/10.1007/BF01806026 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3896353 PubMed]
-# Cummings FJ, Gelman R, Horton J. Comparison of CAF versus CMFP in metastatic breast cancer: analysis of prognostic factors. J Clin Oncol. 1985 Jul;3(7):932-40. [https://ascopubs.org/doi/abs/10.1200/JCO.1985.3.7.932 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3894587 PubMed]
-# Marschke RF Jr, Ingle JN, Schaid DJ, Krook JE, Mailliard JA, Cullinan SA, Pfeifle DM, Votava HJ, Ebbert LP, Windschitl HE. Randomized clinical trial of CFP versus CMFP in women with metastatic breast cancer. Cancer. 1989 May 15;63(10):1931-7. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19890515)63:10%3C1931::AID-CNCR2820631011%3E3.0.CO;2-F link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2649221 PubMed]
-# Bishop JF, Dewar J, Toner GC, Smith J, Tattersall MH, Olver IN, Ackland S, Kennedy I, Goldstein D, Gurney H, Walpole E, Levi J, Stephenson J, Canetta R. Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2355-64. [https://ascopubs.org/doi/10.1200/JCO.1999.17.8.2355 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10561297 PubMed]
-==CMFV {{#subobject:e18ffa|Regimen=1}}==
+==PRODIGE5/ACCORD17==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CMFV: '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil, '''<u>V</u>'''inblastine
+===Arm 1 - Control===
-<br>CVMF: '''<u>C</u>'''yclophosphamide, '''<u>V</u>'''inblastine, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil
+*[[Esophageal_cancer#Cisplatin.2C_Fluorouracil.2C_RT_2|Definitive CF & RT]], then [[Esophageal_cancer#Cisplatin_.26_Fluorouracil_2|CF]] x 2
-===Regimen {{#subobject:405835|Variant=1}}===
+===Arm 2 - Experimental===
-{| class="wikitable" style="width: 100%; text-align:center;"
+*[[Esophageal_cancer#FOLFOX4_.26_RT|Definitive FOLFOX4 & RT]], then [[Esophageal_cancer#FOLFOX4|FOLFOX4]] x 3
-!style="width: 25%"|Study
+===Comparative efficacy===
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Comparator
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.sciencedirect.com/science/article/pii/S0140673675906765 Edelstyn et al. 1975]
+|CF-based
-|style="background-color:#1a9851" |Randomized (E-esc)
+| style="background-color:#ffffbf" |Seems not superior
-|[[#CMFV|CMFV]]; 1-day
-| style="background-color:#1a9850" |Superior ORR
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(197908)44:2%3C392::AID-CNCR2820440204%3E3.0.CO;2-D Bezwoda et al. 1979]
+|FOLFOX4-based
-|style="background-color:#1a9851" |Randomized (C)
+| style="background-color:#ffffbf" |Seems not superior
-|[[#CAMF|CAMF]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
 |}
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Methotrexate (MTX)]]
-*[[Fluorouracil (5-FU)]]
-*[[Vincristine (Oncovin)]]
 ===References===
-# Edelstyn GA, Bates TD, Brinkley D, MacRae KD, Spittle MF, Wheeler T. Comparison of 5-day, 1-day, and 2-day cyclical combination chemotherapy in advanced breast cancer. Lancet. 1975 Aug 2;2(7927):209-11. [https://www.sciencedirect.com/science/article/pii/S0140673675906765 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/51964 PubMed]
+# Conroy T, Galais MP, Raoul JL, Bouché O, Gourgou-Bourgade S, Douillard JY, Etienne PL, Boige V, Martel-Lafay I, Michel P, Llacer-Moscardo C, François E, Créhange G, Abdelghani MB, Juzyna B, Bedenne L, Adenis A; Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial. Lancet Oncol. 2014 Mar;15(3):305-14. Erratum in: Lancet Oncol. 2014 Dec;15(13):e587. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(14)70028-2/abstract link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24556041 PubMed]
-# Bezwoda WR, de Moor NG, Derman D, Lange M, Saner R, Dando R. Combination chemotherapy of metastatic breast cancer: a randomized trial comparing the use of adriamycin to that of Vinblastine. Cancer. 1979 Aug;44(2):392-7. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(197908)44:2%3C392::AID-CNCR2820440204%3E3.0.CO;2-D link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/383254 PubMed]
-==CMFVP {{#subobject:9920da|Regimen=1}}==
+=[[Glioblastoma]]=
+==AVAglio==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CMFVP: '''<u>C</u>'''yclophosphamide, '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil, '''<u>V</u>'''incristine, '''<u>P</u>'''rednisone
+===Arm 1, control===
-<br>COMFP: '''<u>C</u>'''yclophosphamide, '''<u>O</u>'''ncovin (Vincristine), '''<u>M</u>'''ethotrexate, '''<u>F</u>'''luorouracil, '''<u>P</u>'''rednisone
+*[[Surgery]], then [[Glioblastoma#Temozolomide_.26_RT|adjuvant temozolomide & RT]], then [[Glioblastoma#Temozolomide_monotherapy_2|temozolomide maintenance]]
-<br>CFPMV: '''<u>C</u>'''yclophosphamide, '''<u>F</u>'''luorouracil, '''<u>P</u>'''rednisone, '''<u>M</u>'''ethotrexate, '''<u>V</u>'''incristine
+===Arm 2, experimental===
-===Regimen {{#subobject:e01cbf|Variant=1}}===
+*[[Surgery]], then adjuvant temozolomide, bevacizumab, RT, then temozolomide & bevacizumab maintenance, then bevacizumab maintenance
-{| class="wikitable" style="width: 100%; text-align:center;"
+===Comparative efficacy===
-!style="width: 25%"|Study
+{| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!'''Regimen'''
-!style="width: 25%"|Comparator
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(197708)40:2%3C625::AID-CNCR2820400206%3E3.0.CO;2-M Smalley et al. 1977]
+|Temozolomide alone
-|style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#d73027"|Inferior PFS
-|[[Breast_cancer#FAC_3|CAF]]
+|-
-| style="background-color:#fee08b" |Might have inferior OS (*)
+|Bevacizumab-containing arm
+|style="background-color:#1a9850"|Superior PFS
+|-
+|}
+===References===
+# Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):709-22. [https://www.nejm.org/doi/full/10.1056/NEJMoa1308345 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24552318 PubMed]
+==EORTC 22981/26981; NCIC CTG CE.3==
+{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(197811)42:5%3C2141::AID-CNCR2820420509%3E3.0.CO;2-3 Muss et al. 1978]
+|[[#top|back to top]]
-|style="background-color:#1a9851" |Phase III (C)
+|}
-|[[#CAFVP|CAFVP]]
+===Arm 1, control===
-| style="background-color:#fee08b" |Might have inferior OS
+*[[Surgery]], then [[Glioblastoma#Radiation_therapy|adjuvant radiotherapy]]
+===Arm 2, experimental===
+*[[Surgery]], then [[Glioblastoma#Temozolomide_.26_RT|adjuvant Temozolomide & RT]], then [[Glioblastoma#Temozolomide_monotherapy_2|Temozolomide]] maintenance
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://link.springer.com/article/10.1007/BF01806026 Segaloff et al. 1985]
+|Radiotherapy alone
-| style="background-color:#1a9851" |Phase III (E-esc)
+|style="background-color:#d73027"|Inferior OS
-|[[#CMFP_2|CMFP]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19870301)59:5%3C874::AID-CNCR2820590503%3E3.0.CO;2-O Rosner et al. 1987]
+|Temozolomide-containing arm
-| style="background-color:#1a9851" |Phase III (E-esc)
+|style="background-color:#1a9850"|Superior OS
-|1. [[Breast_cancer#AC_3|CA]]<br> 2. [[#CFP_2|CFP]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
 |-
 |}
-''Note: reported efficacy for Smalley et al. 1977 is based on the 1983 update.''
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Methotrexate (MTX)]]
-*[[Fluorouracil (5-FU)]]
-*[[Vincristine (Oncovin)]]
-====Hormonotherapy====
-*[[Prednisone (Sterapred)]]
 ===References===
-# Smalley RV, Carpenter J, Bartolucci A, Vogel C, Krauss S. A comparison of cyclophosphamide, adriamycin, 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisone (CMFVP) in patients with metastatic breast cancer: a Southeastern Cancer Study Group project. Cancer. 1977 Aug;40(2):625-32. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(197708)40:2%3C625::AID-CNCR2820400206%3E3.0.CO;2-M link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/329975 PubMed]
+# Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. [https://www.nejm.org/doi/full/10.1056/NEJMoa043330 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15758009 PubMed]
-## '''Update:''' Smalley RV, Lefante J, Bartolucci A, Carpenter J, Vogel C, Krauss S. A comparison of cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone (CMFVP) in patients with advanced breast cancer. Breast Cancer Res Treat. 1983;3(2):209-20. [https://link.springer.com/article/10.1007/BF01803563 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6688538 PubMed]
-# Muss HB, White DR, Richards F 2nd, Cooper MR, Stuart JJ, Jackson DV, Rhyne L, Spurr CL. Adriamycin versus methotrexate in five-drug combination chemotherapy for advanced breast cancer: a randomized trial. Cancer. 1978 Nov;42(5):2141-8. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(197811)42:5%3C2141::AID-CNCR2820420509%3E3.0.CO;2-3 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/363253 PubMed]
-# Segaloff A, Hankey BF, Carter AC, Escher GC, Ansfield FJ, Talley RW. An evaluation of the effect of vincristine added to cyclophosphamide, 5-fluorouracil, methotrexate, and prednisone in advanced breast cancer. Breast Cancer Res Treat. 1985;5(3):311-9. [https://link.springer.com/article/10.1007/BF01806026 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3896353 PubMed]
-# Rosner D, Nemoto T, Lane WW. A randomized study of intensive versus moderate chemotherapy programs in metastatic breast cancer. Cancer. 1987 Mar 1;59(5):874-83. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19870301)59:5%3C874::AID-CNCR2820590503%3E3.0.CO;2-O link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3815266 PubMed]
-==DES monotherapy {{#subobject:0a1860|Regimen=1}}==
+==HERBY==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Regimen {{#subobject:128a40|Variant=1}}===
+===Arm 1, control===
+*[[Surgery]], then [[Glioblastoma#Temozolomide_.26_RT|adjuvant temozolomide & RT]], then [[Glioblastoma#Temozolomide_monotherapy_2|temozolomide maintenance]]
+===Arm 2, experimental===
+*[[Surgery]], then adjuvant temozolomide, bevacizumab, RT, then temozolomide & bevacizumab maintenance
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
+|-
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|Temozolomide alone
+| style="background-color:#ffffbf" |Seems not superior
+|-
+|Bevacizumab-containing arm
+| style="background-color:#ffffbf" |Seems not superior
 |-
-|[https://www.ncbi.nlm.nih.gov/pubmed/14285946 Kennedy 1965]
+|}
-| style="background-color:#1a9851" |Randomized (E-switch-ic)
+===References===
-|Testosterone
+# Grill J, Massimino M, Bouffet E, Azizi AA, McCowage G, Cañete A, Saran F, Le Deley MC, Varlet P, Morgan PS, Jaspan T, Jones C, Giangaspero F, Smith H, Garcia J, Elze MC, Rousseau RF, Abrey L, Hargrave D, Vassal G. Phase II, open-label, randomized, multicenter trial (HERBY) of bevacizumab in pediatric patients with newly diagnosed high-grade glioma. J Clin Oncol. 2018 Apr 1;36(10):951-958. Epub 2018 Feb 7. [https://ascopubs.org/doi/full/10.1200/JCO.2017.76.0611 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/29412784 PubMed]
-| style="background-color:#d3d3d3" |Not available
+==RTOG 0825==
+{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[https://jamanetwork.com/journals/jama/article-abstract/353009 Carter et al. 1977]
+|[[#top|back to top]]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+|}
-|[[#DES_monotherapy|DES]]; other dosings
+===Arm 1, control===
-| style="background-color:#d3d3d3" |See paper
+*[[Surgery]], then [[Glioblastoma#Temozolomide_.26_RT|adjuvant Temozolomide & RT]], then [[Glioblastoma#Temozolomide_monotherapy_2|Temozolomide]] maintenance
+===Arm 2, experimental===
+*[[Surgery]], then adjuvant Temozolomide, Bevacizumab, RT, then Temozolomide & Bevacizumab maintenance
+===Comparative efficacy===
+''Note: although the control regimen had inferior PFS, the effect size did not reach the prespecified improvement target.''
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM198101013040104 Ingle et al. 1981]
+|Temozolomide alone
-| style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#d73027"|Inferior PFS
-|[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_2|Tamoxifen]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19810201)47:3%3C452::AID-CNCR2820470305%3E3.0.CO;2-Y Kiang et al. 1981]
+|Bevacizumab-containing arm
-| style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#1a9850"|Superior PFS
-|Cyclophosphamide, 5-FU, DES
-| style="background-color:#fc8d59" |Seems to have inferior OS (*)
 |-
 |}
-''No longer used, but of historical interest. Reported efficacy for Kiang et al. 1981 is based on the 1985 update.''
-====Hormonotherapy====
-*[[Diethylstilbestrol (DES)]]
 ===References===
-# Kennedy BJ. Diethylstilbestrol versus testosterone propionate therapy in advanced breast cancer. Surg Gynecol Obstet. 1965 Jun;120:1246-50. [https://www.ncbi.nlm.nih.gov/pubmed/14285946 PubMed]
+# Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. [https://www.nejm.org/doi/full/10.1056/NEJMoa1308573 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4201043/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/24552317 PubMed]
-# Carter AC, Sedransk N, Kelley RM, Ansfield FJ, Ravdin RG, Talley RW, Potter NR. Diethylstilbestrol: recommended dosages for different categories of breast cancer patients: report of the Cooperative Breast Cancer Group. JAMA. 1977 May 9;237(19):2079-8. [https://jamanetwork.com/journals/jama/article-abstract/353009 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/576887 PubMed]
-# Ingle JN, Ahmann DL, Green SJ, Edmonson JH, Bisel HF, Kvols LK, Nichols WC, Creagan ET, Hahn RG, Rubin J, Frytak S. Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer. N Engl J Med. 1981 Jan 1;304(1):16-21. [https://www.nejm.org/doi/full/10.1056/NEJM198101013040104 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7001242 PubMed]
-# Kiang DT, Frenning DH, Gay J, Goldman AI, Kennedy BJ. Combination therapy of hormone and cytotoxic agents in advanced breast cancer. Cancer. 1981 Feb 1;47(3):452-6. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19810201)47:3%3C452::AID-CNCR2820470305%3E3.0.CO;2-Y link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/7013960 PubMed]
-## '''Update:''' Kiang DT, Gay J, Goldman A, Kennedy BJ. A randomized trial of chemotherapy and hormonal therapy in advanced breast cancer. N Engl J Med. 1985 Nov 14;313(20):1241-6. [https://www.nejm.org/doi/full/10.1056/NEJM198511143132001 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3903501 PubMed]
-==CTCb, then auto HSCT {{#subobject:02f569|Regimen=1}}==
+=[[Head and neck cancer]]=
+==EORTC 24954==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-CTCb: '''<u>C</u>'''yclophosphamide, '''<u>T</u>'''hiotepa, '''<u>C</u>'''ar'''<u>b</u>'''oplatin
+===Arm 1, control===
+*[[Head_and_neck_cancer#Cisplatin_.26_Fluorouracil|CF]] x 4, then [[Head_and_neck_cancer#Radiation_therapy|RT]]
+===Arm 2, experimental===
+*[[Head_and_neck_cancer#Cisplatin.2C_Fluorouracil.2C_RT|CF/RT]]
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Sequential RT
+| style="background-color:#ffffbf" |Seems not superior
+|-
+|Alternating RT
+| style="background-color:#ffffbf" |Seems not superior
+|-
+|}
+===References===
+# Lefebvre JL, Rolland F, Tesselaar M, Bardet E, Leemans CR, Geoffrois L, Hupperets P, Barzan L, de Raucourt D, Chevalier D, Licitra L, Lunghi F, Stupp R, Lacombe D, Bogaerts J, Horiot JC, Bernier J, Vermorken JB; EORTC Head and Neck Cancer Cooperative Group; EORTC Radiation Oncology Group. Phase 3 randomized trial on larynx preservation comparing sequential vs alternating chemotherapy and radiotherapy. J Natl Cancer Inst. 2009 Feb 4;101(3):142-52. Epub 2009 Jan 27. [https://academic.oup.com/jnci/article/101/3/142/947754 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2724854/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/19176454 PubMed]
-===Regimen {{#subobject:3dea9c|Variant=1}}===
+==RTOG 91-11==
+===Arm 1, induction chemotherapy, then radiotherapy (Control)===
+*[[Head_and_neck_cancer#Cisplatin_.26_Fluorouracil|PF]] x 3, then [[Head_and_neck_cancer#Radiation_therapy|RT]]
+===Arm 2, concurrent chemoradiotherapy (Experimental)===
+*[[Head_and_neck_cancer#Cisplatin_.26_RT|Cisplatin & RT]]
+===Arm 3, radiotherapy (Experimental)===
+*[[Head_and_neck_cancer#Radiation_therapy|RT]]
+===Comparative efficacy===
+''Efficacy is based on the 2012 update.''
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen vs.'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!'''Arm 1'''
-!style="width: 25%"|Comparator
+!'''Arm 2'''
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+!'''Arm 3'''
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM200004133421501 Stadtmauer et al. 2000]
+|Arm 1 vs.
-| style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#d3d3d3" |
-|[[Breast_cancer#CMF_2|CMF]]
+| style="background-color:#d73027" |Inferior LFS
-| style="background-color:#ffffbf" |Did not meet primary endpoint of OS
+| style="background-color:#91cf60" |Seems to have superior LFS
+|-
+|Arm 2 vs.
+| style="background-color:#1a9850" |Superior LFS
+| style="background-color:#d3d3d3" |
+| style="background-color:#91cf60" |Seems to have superior LFS
+|-
+|Arm 3 vs.
+| style="background-color:#fc8d59" |Seems to have inferior LFS
+| style="background-color:#fc8d59" |Seems to have inferior LFS
+| style="background-color:#d3d3d3" |
 |-
 |}
-''No longer used, but of historical interest.''
-====Chemotherapy====
-*[[Cyclophosphamide (Cytoxan)]]
-*[[Thiotepa (Thioplex)]]
-*[[Carboplatin (Paraplatin)]]
 ===References===
-# Stadtmauer EA, O'Neill A, Goldstein LJ, Crilley PA, Mangan KF, Ingle JN, Brodsky I, Martino S, Lazarus HM, Erban JK, Sickles C, Glick JH; Philadelphia Bone Marrow Transplant Group. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J Med. 2000 Apr 13;342(15):1069-76. [https://www.nejm.org/doi/full/10.1056/NEJM200004133421501 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10760307 PubMed]
+# Forastiere AA, Goepfert H, Maor M, Pajak TF, Weber R, Morrison W, Glisson B, Trotti A, Ridge JA, Chao C, Peters G, Lee DJ, Leaf A, Ensley J, Cooper J. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer. N Engl J Med. 2003 Nov 27;349(22):2091-8. [https://www.nejm.org/doi/full/10.1056/NEJMoa031317 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14645636 PubMed]
+## '''Update:''' Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, Pajak TF, Morrison W, Glisson B, Trotti A, Ridge JA, Thorstad W, Wagner H, Ensley JF, Cooper JS. Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol. 2013 Mar 1;31(7):845-52. Epub 2012 Nov 26. [http://jco.ascopubs.org/content/31/7/845.long link to original article] '''contains partial protocol''' [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3577950/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/23182993 PubMed]
-==Estradiol monotherapy {{#subobject:edd4bd|Regimen=1}}==
+=[[Hodgkin lymphoma]]=
+==EORTC 20012==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Variant #1, 6 mg/day {{#subobject:8e8202|Variant=1}}===
+===Arm 1===
+*[[Hodgkin_lymphoma#eBEACOPP_2|eBEACOPP]] x 4, then [[Hodgkin_lymphoma#BEACOPP_2|BEACOPP]] x 4
+===Arm 2===
+*[[Hodgkin_lymphoma#ABVD_3|ABVD]] x 8
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460383/ Ellis et al. 2009]
+|BEACOPP<sub>4+4</sub>
-| style="background-color:#1a9851" |Randomized Phase II (E-de-esc)
+|style="background-color:#ffffbf"|Did not meet primary endpoint of EFS
-|[[#Estradiol_monotherapy|Estradiol]]; 30 mg/day
+|-
-| style="background-color:#ffffbf" |Did not meet primary endpoint of CBR
+|ABVD x 8
+|style="background-color:#ffffbf"|Did not meet primary endpoint of EFS
 |-
 |}
-====Hormonotherapy====
-*[[Estradiol]] 6 mg PO once per day
-'''Continued indefinitely'''
+===References===
+# Carde P, Karrasch M, Fortpied C, Brice P, Khaled H, Casasnovas O, Caillot D, Gaillard I, Bologna S, Ferme C, Lugtenburg PJ, Morschhauser F, Aurer I, Coiffier B, Meyer R, Seftel M, Wolf M, Glimelius B, Sureda A, Mounier N. Eight cycles of ABVD versus four cycles of BEACOPP<sub>escalated</sub> plus four cycles of BEACOPP<sub>baseline</sub> in stage III to IV, International Prognostic Score ≥ 3, high-risk Hodgkin lymphoma: First results of the phase III EORTC 20012 Intergroup trial. J Clin Oncol. 2016 Jun 10;34(17):2028-36. Epub 2016 Apr 25. [http://jco.ascopubs.org/content/34/17/2028.full link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27114593 PubMed]
-===Variant #2, 30 mg/day {{#subobject:8fahc02|Variant=1}}===
+==EORTC-GELA H8-F==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1===
+*[[Hodgkin_lymphoma#MOPP-ABV|MOPP-ABV]] x 3, then [[Hodgkin_lymphoma#Radiotherapy_2|IFRT]]
+===Arm 2===
+*[[Hodgkin_lymphoma#Radiotherapy|STNI]]
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460383/ Ellis et al. 2009]
+|MOPP-ABV x 3, then IFRT
-| style="background-color:#1a9851" |Randomized Phase II (C)
+|style="background-color:#1a9850"|Superior OS
-|[[#Estradiol_monotherapy|Estradiol]]; 6 mg/day
+|-
-| style="background-color:#ffffbf" |Did not meet primary endpoint of CBR
+|STNI
+|style="background-color:#d73027"|Inferior OS
 |-
 |}
-====Hormonotherapy====
-*[[Estradiol]] 30 mg PO once per day
-'''Continued indefinitely'''
 ===References===
-# Ellis MJ, Gao F, Dehdashti F, Jeffe DB, Marcom PK, Carey LA, Dickler MN, Silverman P, Fleming GF, Kommareddy A, Jamalabadi-Majidi S, Crowder R, Siegel BA. Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. JAMA. 2009 Aug 19;302(7):774-80. [https://jamanetwork.com/journals/jama/fullarticle/184425 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460383/ link to PMC article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/19690310 PubMed]
+# Fermé C, Eghbali H, Meerwaldt JH, Rieux C, Bosq J, Berger F, Girinsky T, Brice P, van't Veer MB, Walewski JA, Lederlin P, Tirelli U, Carde P, Van den Neste E, Gyan E, Monconduit M, Diviné M, Raemaekers JM, Salles G, Noordijk EM, Creemers GJ, Gabarre J, Hagenbeek A, Reman O, Blanc M, Thomas J, Vié B, Kluin-Nelemans JC, Viseu F, Baars JW, Poortmans P, Lugtenburg PJ, Carrie C, Jaubert J, Henry-Amar M; EORTC-GELA H8 Trial. Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med. 2007 Nov 8;357(19):1916-27. [https://www.nejm.org/doi/full/10.1056/NEJMoa064601 link to original article] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/17989384 PubMed]
-==Fluoxymesterone monotherapy {{#subobject:835187|Regimen=1}}==
+==EORTC-GELA H8-U==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Regimen {{#subobject:1914f4|Variant=1}}===
+===Arm 1===
-{| class="wikitable" style="width: 50%; text-align:center;"
+*[[Hodgkin_lymphoma#MOPP-ABV_2|MOPP-ABV]] x 4, then [[Hodgkin_lymphoma#Radiotherapy_2|IFRT]]
-!style="width: 25%"|Study
+===Arm 2===
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+*[[Hodgkin_lymphoma#MOPP-ABV_2|MOPP-ABV]] x 4, then [[Hodgkin_lymphoma#Radiotherapy_2|STNI]]
+===Arm 3===
+*[[Hodgkin_lymphoma#MOPP-ABV_2|MOPP-ABV]] x 6, then [[Hodgkin_lymphoma#Radiotherapy_2|IFRT]]
+===Comparative efficacy===
+''Note: the paper describes this as an equivalence study, although the primary endpoint of EFS had p=0.80.''
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|MOPP-ABV x 4, then IFRT
+|style="background-color:#ffffbf"|Inconclusive whether equivalent
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM195810022591404 Kennedy 1958]
+|MOPP-ABV x 4, then STNI
-| style="background-color:#91cf61" |Non-randomized
+|style="background-color:#ffffbf"|Inconclusive whether equivalent
+|-
+|MOPP-ABV x 6, then IFRT
+|style="background-color:#ffffbf"|Inconclusive whether equivalent
 |-
 |}
-====Hormonotherapy====
-*[[Fluoxymesterone (Halotestin)]]
 ===References===
-# Kennedy BJ. Fluoxymesterone therapy in advanced breast cancer. N Engl J Med. 1958 Oct 2;259(14):673-5. [https://www.nejm.org/doi/full/10.1056/NEJM195810022591404 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/13590423 PubMed]
+# Fermé C, Eghbali H, Meerwaldt JH, Rieux C, Bosq J, Berger F, Girinsky T, Brice P, van't Veer MB, Walewski JA, Lederlin P, Tirelli U, Carde P, Van den Neste E, Gyan E, Monconduit M, Diviné M, Raemaekers JM, Salles G, Noordijk EM, Creemers GJ, Gabarre J, Hagenbeek A, Reman O, Blanc M, Thomas J, Vié B, Kluin-Nelemans JC, Viseu F, Baars JW, Poortmans P, Lugtenburg PJ, Carrie C, Jaubert J, Henry-Amar M; EORTC-GELA H8 Trial. Chemotherapy plus involved-field radiation in early-stage Hodgkin's disease. N Engl J Med. 2007 Nov 8;357(19):1916-27. [https://www.nejm.org/doi/full/10.1056/NEJMoa064601 link to original article] '''contains verified protocol in supplement''' [https://www.ncbi.nlm.nih.gov/pubmed/17989384 PubMed]
-==Formestane monotherapy {{#subobject:6c7bb9|Regimen=1}}==
+==EORTC/LYSA/FIL H10==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Regimen {{#subobject:8b5e67|Variant=1}}===
+''Note: randomization in this trial occurred before treatment, but took effect after 2 cycles of ABVD, and only if interim PET-CT was negative.''
+===Arm 1===
+*Favorable: [[Hodgkin_lymphoma#ABVD|ABVD]] x 4
+*Unfavorable: [[Hodgkin_lymphoma#ABVD|ABVD]] x 6
+===Arm 2===
+*Favorable: [[Hodgkin_lymphoma#ABVD|ABVD]] x 3, then [[Hodgkin_lymphoma#Radiotherapy_2|INRT]]
+*Unfavorable: [[Hodgkin_lymphoma#ABVD|ABVD]] x 4, then [[Hodgkin_lymphoma#Radiotherapy_2|INRT]]
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(84)92795-8/fulltext Coombes et al. 1984]
+|ABVD x 4
-| style="background-color:#ffffbe" |Pilot
+|style="background-color:#ffffbf"|Inconclusive whether non-inferior
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
 |-
-|[https://www.ejcancer.com/article/S0959-8049(97)00105-6/pdf Thürlimann et al. 1997 (SAKK 20/90)]
+|ABVD x 3, then INRT
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+|style="background-color:#ffffbf"|Inconclusive whether non-inferior
-|[[#Megestrol_monotherapy|Megestrol]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of TTF
 |-
 |}
-====Hormonotherapy====
-*[[Formestane (Lentaron)]]
 ===References===
-# Coombes RC, Goss P, Dowsett M, Gazet JC, Brodie A. 4-Hydroxyandrostenedione in treatment of postmenopausal patients with advanced breast cancer. Lancet. 1984 Dec 1;2(8414):1237-9. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(84)92795-8/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6150277 PubMed]
+# Raemaekers JM, André MP, Federico M, Girinsky T, Oumedaly R, Brusamolino E, Brice P, Fermé C, van der Maazen R, Gotti M, Bouabdallah R, Sebban CJ, Lievens Y, Re A, Stamatoullas A, Morschhauser F, Lugtenburg PJ, Abruzzese E, Olivier P, Casasnovas RO, van Imhoff G, Raveloarivahy T, Bellei M, van der Borght T, Bardet S, Versari A, Hutchings M, Meignan M, Fortpied C. Omitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: Clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2014 Apr 20;32(12):1188-94. Epub 2014 Mar 17. [http://jco.ascopubs.org/content/32/12/1188.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/24637998 PubMed]
-# '''SAKK 20/90:''' Thürlimann B, Castiglione M, Hsu-Schmitz SF, Cavalli F, Bonnefoi H, Fey MF, Morant R, Löhnert T, Goldhirsch A; Swiss Group for Clinical Cancer Research (SAKK). Formestane versus megestrol acetate in postmenopausal breast cancer patients after failure of tamoxifen: a phase III prospective randomised cross over trial of second-line hormonal treatment (SAKK 20/90). Eur J Cancer. 1997 Jun;33(7):1017-24. [https://www.ejcancer.com/article/S0959-8049(97)00105-6/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9376181 PubMed]
+## '''Update:''' André MPE, Girinsky T, Federico M, Reman O, Fortpied C, Gotti M, Casasnovas O, Brice P, van der Maazen R, Re A, Edeline V, Fermé C, van Imhoff G, Merli F, Bouabdallah R, Sebban C, Specht L, Stamatoullas A, Delarue R, Fiaccadori V, Bellei M, Raveloarivahy T, Versari A, Hutchings M, Meignan M, Raemaekers J. Early positron emission tomography response-adapted treatment in stage I and II Hodgkin lymphoma: final results of the randomized EORTC/LYSA/FIL H10 trial. J Clin Oncol. 2017 Jun 1;35(16):1786-1794. Epub 2017 Mar 14. [https://ascopubs.org/doi/full/10.1200/JCO.2016.68.6394 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28291393 PubMed]
-==Medroxyprogesterone monotherapy {{#subobject:6c7bb9|Regimen=1}}==
+==GHSG HD11==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Variant #1, 500 mg/day {{#subobject:8b5e67|Variant=1}}===
+''Note: the primary endpoints of this trial, which were to determine the superiority of BEACOPP vs. ABVD and noninferiority of 20 Gy vs. 30 Gy of IFRT, were not reported in the manuscript.''
+===Arm 1===
+*[[Hodgkin_lymphoma#ABVD_2|ABVD]] x 4, then [[Hodgkin_lymphoma#Radiotherapy_2|IFRT]] x 30 Gy
+===Arm 2===
+*[[Hodgkin_lymphoma#ABVD_2|ABVD]] x 4, then [[Hodgkin_lymphoma#Radiotherapy_2|IFRT]] x 20 Gy
+===Arm 3===
+*[[Hodgkin_lymphoma#BEACOPP|BEACOPP]] x 4, then [[Hodgkin_lymphoma#Radiotherapy_2|IFRT]] x 30 Gy
+===Arm 4===
+*[[Hodgkin_lymphoma#BEACOPP|BEACOPP]] x 4, then [[Hodgkin_lymphoma#Radiotherapy_2|IFRT]] x 20 Gy
+===Comparative efficacy===
+*Designed using a 2 x 2 factorial design
+====Comparison 1====
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+|'''Chemotherapy'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://journals.sagepub.com/doi/abs/10.1177/030089167806400204 Cuna et al. 1978]
+|ABVD
-|style="background-color:#1a9851"|Phase III (E-de-esc)
+|style="background-color:#d3d3d3"|Not reported
-|[[#Medroxyprogesterone_monotherapy|MPA]]; 1000 mg/day
-|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR
 |-
-|[https://www.ejcancer.com/article/0014-2964(79)90097-5/abstract Pannuti et al. 1979]
+|BEACOPP
-|style="background-color:#1a9851"|Phase III (C)
+|style="background-color:#d3d3d3"|Not reported
-|[[#Medroxyprogesterone_monotherapy|MPA]]; 1500 mg/day
-|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR
 |-
-|[https://academic.oup.com/jnci/article-abstract/80/14/1147/908657 Canney et al. 1988]
+|}
-|style="background-color:#1a9851"|Phase III (C)
+====Comparison 2====
-|[[#Aminoglutethimide_monotherapy|Aminoglutethimide]]
+{| class="wikitable" style="width: 100%; text-align:center;"
-|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR
+|'''Radiotherapy'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.9.3141 Byrne et al. 1997 (ANZ8613)]
+|IFRT x 20 Gy
-|style="background-color:#1a9851"|Phase III (C)
+|style="background-color:#d3d3d3"|Not reported
-|MPA & Tamoxifen
+|-
-|style="background-color:#ffffbf"|Did not meet primary endpoint of TTP
+|IFRT x 30 Gy
+|style="background-color:#d3d3d3"|Not reported
 |-
 |}
-''Note: Canney et al. 1988 does not have dosing information in the abstract.''
+===References===
-====Hormonotherapy====
+# Eich HT, Diehl V, Görgen H, Pabst T, Markova J, Debus J, Ho A, Dörken B, Rank A, Grosu AL, Wiegel T, Karstens JH, Greil R, Willich N, Schmidberger H, Döhner H, Borchmann P, Müller-Hermelink HK, Müller RP, Engert A. Intensified chemotherapy and dose-reduced involved-field radiotherapy in patients with early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD11 trial. J Clin Oncol. 2010 Sep 20;28(27):4199-206. Epub 2010 Aug 16. [http://jco.ascopubs.org/content/28/27/4199.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/20713848 PubMed]
-*[[Medroxyprogesterone (MPA)]] 500 mg PO once per day
-'''Continued indefinitely'''
+==GHSG HD12==
+{| class="wikitable" style="float:right; margin-left: 5px;"
-===Variant #2, 900 mg/day {{#subobject:88ge67|Variant=1}}===
+|-
+|[[#top|back to top]]
+|}
+===Arm 1===
+*[[Hodgkin_lymphoma#eBEACOPP_2|eBEACOPP]] x 8, then [[Hodgkin_lymphoma#Radiotherapy_2|ISRT]] x 30 Gy for patients with initial bulky disease or residual disease
+===Arm 2===
+*[[Hodgkin_lymphoma#eBEACOPP_2|eBEACOPP]] x 8, then [[Hodgkin_lymphoma#Observation|no further treatment]] for patients with initial bulky disease or residual disease
+===Arm 3===
+*[[Hodgkin_lymphoma#eBEACOPP_2|eBEACOPP]] x 4, then [[Hodgkin_lymphoma#BEACOPP_2|BEACOPP]] x 4, then [[Hodgkin_lymphoma#Radiotherapy_2|ISRT]] x 30 Gy for patients with initial bulky disease or residual disease
+===Arm 4===
+*[[Hodgkin_lymphoma#eBEACOPP_2|eBEACOPP]] x 4, then [[Hodgkin_lymphoma#BEACOPP_2|BEACOPP]] x 4, then [[Hodgkin_lymphoma#Observation|no further treatment]] for patients with initial bulky disease or residual disease
+===Comparative efficacy===
+*Designed using a 2 x 2 factorial design
+====Comparison 1====
+''Reported efficacy is based on the 2018 update.''
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+|'''Chemotherapy'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
+|-
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|eBEACOPP x 8
+|style="background-color:#eeee01"|Non-inferior OS (*)
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19860701)58:1%3C7::AID-CNCR2820580103%3E3.0.CO;2-%23 van Veelen et al. 1986]
+|eBEACOPP x 4, then BEACOPP x 4
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+|style="background-color:#eeee01"|Non-inferior OS (*)
-|[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_2|Tamoxifen]]
-|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR
 |-
 |}
-====Hormonotherapy====
+====Comparison 2====
-*[[Medroxyprogesterone (MPA)]] 300 mg PO three times per day
-'''Continued indefinitely'''
-===Variant #3, 1000 mg/day (high-dose) {{#subobject:62af61|Variant=1}}===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+|'''Radiotherapy'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1984.2.5.414 Cavalli et al. 1984]
+|ISRT x 30 Gy
-|style="background-color:#1a9851"|Phase III (E-esc)
+|style="background-color:#d9ef8b"|Might have superior 5-year FFTF
-|[[#Medroxyprogesterone_monotherapy|MPA]]; low-dose
-| style="background-color:#1a9850" |Superior ORR
 |-
-|[https://link.springer.com/article/10.1007/BF01961246 Garcia-Giralt et al. 1992]
+|No radiotherapy
-| style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#fee08b"|Might have inferior 5-year FFTF
-|[[#Aminoglutethimide_monotherapy|Aminoglutethimide]]
-| style="background-color:#fc8d59" |Seems to have inferior TTP
 |-
-|[https://academic.oup.com/annonc/article-abstract/4/9/735/170824 Castiglione-Gertsch et al. 1993]
+|}
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+===References===
-|[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_2|Tamoxifen]]
+# Borchmann P, Haverkamp H, Diehl V, Cerny T, Markova J, Ho AD, Eich HT, Mueller-Hermelink HK, Kanz L, Greil R, Rank A, Paulus U, Smardova L, Huber C, Dörken B, Nerl C, Krause SW, Mueller RP, Fuchs M, Engert A. Eight cycles of escalated-dose BEACOPP compared with four cycles of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or without radiotherapy in patients with advanced-stage hodgkin's lymphoma: final analysis of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011 Nov 10;29(32):4234-42. Epub 2011 Oct 11. [http://jco.ascopubs.org/content/29/32/4234.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21990399 PubMed]
-| style="background-color:#d9ef8b" |Might have superior TTP
+## '''Update:''' von Tresckow B, Kreissl S, Dipl-Math HG, Bröckelmann PJ, Pabst T, Fridrik M, Rummel M, Jung W, Thiemer J, Sasse S, Bürkle C, Baues C, Diehl V, Engert A, Borchmann P; German Hodgkin Study Group. Intensive treatment strategies in advanced-stage Hodgkin's lymphoma (HD9 and HD12): analysis of long-term survival in two randomised trials. Lancet Haematol. 2018 Oct 01;5(10):e462-73. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(18)30140-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30290903 PubMed]
+==GHSG HD14==
+{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1994.12.8.1630 Muss et al. 1994]
+|[[#top|back to top]]
-|style="background-color:#1a9851"|Phase III (E-switch-ic)
+|}
-|[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_2|Tamoxifen]]
+===Arm 1===
-| style="background-color:#d9ef8b" |Might have superior OS
+*[[Hodgkin_lymphoma#ABVD_2|ABVD]] x 4, then [[Hodgkin_lymphoma#Radiotherapy_2|IFRT]] x 30 Gy
+===Arm 2===
+*[[Hodgkin_lymphoma#eBEACOPP|eBEACOPP]] x 2, then [[Hodgkin_lymphoma#ABVD_2|ABVD]] x 2, then [[Hodgkin_lymphoma#Radiotherapy_2|IFRT]] x 30 Gy
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+|'''Chemotherapy'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|ABVD x 4
+|style="background-color:#d73027"|Inferior FFTF
+|-
+|eBEACOPP x 2, then ABVD x 2
+|style="background-color:#1a9850"|Superior FFTF
 |-
 |}
-====Hormonotherapy====
-*[[Medroxyprogesterone (MPA)]] 1000 mg PO or IM once per day
-**Garcia-Giralt et al. 1992 gave as 500 mg PO twice per day
-'''Continued indefinitely'''
 ===References===
-# Cuna GR, Calciati A, Strada MR, Bumma C, Campio L. High dose medroxyprogesterone acetate (MPA) treatment in metastatic carcinoma of the breast: a dose-response evaluation. Tumori. 1978 Apr 30;64(2):143-9. [https://journals.sagepub.com/doi/abs/10.1177/030089167806400204 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/354147 PubMed]
+<!-- Presented in part at the 52nd Annual Meeting of the American Society of Hematology, December 4-7, 2010, Orlando, FL. -->
-# Pannuti F, Martoni A, Di Marco AR, Piana E, Saccani F, Becchi G, Mattioli G, Barbanti F, Marra GA, Persiani W, Cacciari L, Spagnolo F, Palenzona D, Rocchetta G. Prospective, randomized clinical trial of two different high dosages of medroxyprogesterone acetate (MAP) in the treatment of metastatic breast cancer. Eur J Cancer. 1979 Apr;15(4):593-601. [https://www.ejcancer.com/article/0014-2964(79)90097-5/abstract link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/86447 PubMed]
+# von Tresckow B, Plütschow A, Fuchs M, Klimm B, Markova J, Lohri A, Kral Z, Greil R, Topp MS, Meissner J, Zijlstra JM, Soekler M, Stein H, Eich HT, Mueller RP, Diehl V, Borchmann P, Engert A. Dose-intensification in early unfavorable Hodgkin's lymphoma: final analysis of the German Hodgkin Study Group HD14 trial. J Clin Oncol. 2012 Mar 20;30(9):907-13. Epub 2012 Jan 23. [http://jco.ascopubs.org/content/30/9/907.long link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/22271480 PubMed]
-# Cavalli F, Goldhirsch A, Jungi F, Martz G, Mermillod B, Alberto P. Randomized trial of low- versus high-dose medroxyprogesterone acetate in the induction treatment of postmenopausal patients with advanced breast cancer. J Clin Oncol. 1984 May;2(5):414-9. [https://ascopubs.org/doi/abs/10.1200/JCO.1984.2.5.414 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6233398 PubMed]
-# van Veelen H, Willemse PH, Tjabbes T, Schweitzer MJ, Sleijfer DT. Oral high-dose medroxyprogesterone acetate versus tamoxifen: a randomized crossover trial in postmenopausal patients with advanced breast cancer. Cancer. 1986 Jul 1;58(1):7-13. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(19860701)58:1%3C7::AID-CNCR2820580103%3E3.0.CO;2-%23 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/2939943 PubMed]
-# Canney PA, Priestman TJ, Griffiths T, Latief TN, Mould JJ, Spooner D. Randomized trial comparing aminoglutethimide with high-dose medroxyprogesterone acetate in therapy for advanced breast carcinoma. J Natl Cancer Inst. 1988 Sep 21;80(14):1147-51. [https://academic.oup.com/jnci/article-abstract/80/14/1147/908657 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2970555 PubMed]
-# Garcia-Giralt E, Ayme Y, Carton M, Daban A, Delozier T, Fargeot P, Fumoleau P, Gorins A, Guerin D, Guerin R, Maillart P, Mauriac L, May-Levin F, Metz R, Namer M, Olivier JP, Pommatau E, Pouillart P, Pujade-Lauraine E, Rouesse J, Serrou B, Vitse M, Zylberait D. Second and third line hormonotherapy in advanced post-menopausal breast cancer: a multicenter randomized trial comparing medroxyprogesterone acetate with aminoglutethimide in patients who have become resistant to tamoxifen. Breast Cancer Res Treat. 1992;24(2):139-45. [https://link.springer.com/article/10.1007/BF01961246 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8443401 PubMed]
-# Castiglione-Gertsch M, Pampallona S, Varini M, Cavalli F, Brunner K, Senn HJ, Goldhirsch A, Metzger U. Primary endocrine therapy for advanced breast cancer: to start with tamoxifen or with medroxyprogesterone acetate?. Ann Oncol. 1993 Nov;4(9):735-40. [https://academic.oup.com/annonc/article-abstract/4/9/735/170824 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8280653 PubMed]
-# Muss HB, Case LD, Atkins JN, Bearden JD 3rd, Cooper MR, Cruz JM, Jackson DV Jr, O'Rourke MA, Pavy MD, Powell BL, Richards F, SPurr CL, Eagle K, White DR. Tamoxifen versus high-dose oral medroxyprogesterone acetate as initial endocrine therapy for patients with metastatic breast cancer: a Piedmont Oncology Association study. J Clin Oncol. 1994 Aug;12(8):1630-8. [https://ascopubs.org/doi/abs/10.1200/JCO.1994.12.8.1630 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8040675 PubMed]
-# '''ANZ8613:''' Byrne MJ, Gebski V, Forbes J, Tattersall MH, Simes RJ, Coates AS, Dewar J, Lunn M, Flower C, Gill PG, Stewart J; Australian-New Zealand Breast Cancer Trials Group. Medroxyprogesterone acetate addition or substitution for tamoxifen in advanced tamoxifen-resistant breast cancer: a phase III randomized trial. J Clin Oncol. 1997 Sep;15(9):3141-8. [https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.9.3141 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9294477 PubMed]
-==Megestrol monotherapy {{#subobject:a806f8|Regimen=1}}==
+==GSM-HD==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Regimen {{#subobject:27fd99|Variant=1}}===
+===Arm 1===
+*[[Hodgkin_lymphoma#eBEACOPP_2|eBEACOPP]] x 4, then [[Hodgkin_lymphoma#BEACOPP_2|BEACOPP]] x 4
+===Arm 2===
+*[[Hodgkin_lymphoma#ABVD_3|ABVD]] x 8
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1988.6.7.1098 Muss et al. 1988]
+|BEACOPP<sub>4+4</sub>
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+|style="background-color:#91cf60"|Seems to have superior FFFP
-|[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_2|Tamoxifen]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
-|[https://link.springer.com/article/10.1007/BF01810736 Lundgren et al. 1989]
+|ABVD x 8
-| style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#fc8d59"|Seems to have inferior FFFP
-|[[#Aminoglutethimide_monotherapy|Aminoglutethimide]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
-|[https://ascopubs.org/doi/10.1200/jco.1990.8.11.1797 Muss et al. 1990]
+|}
-| style="background-color:#1a9851" |Phase III (C)
+===References===
-|[[#Megestrol_monotherapy|Megestrol]]; higher-dose
+# Viviani S, Zinzani PL, Rambaldi A, Brusamolino E, Levis A, Bonfante V, Vitolo U, Pulsoni A, Liberati AM, Specchia G, Valagussa P, Rossi A, Zaja F, Pogliani EM, Pregno P, Gotti M, Gallamini A, Rota Scalabrini D, Bonadonna G, Gianni AM; Michelangelo Foundation; Gruppo Italiano di Terapie Innovative nei Linfomi; Intergruppo Italiano Linfomi. ABVD versus BEACOPP for Hodgkin's lymphoma when high-dose salvage is planned. N Engl J Med. 2011 Jul 21;365(3):203-12. [https://www.nejm.org/doi/full/10.1056/NEJMoa1100340 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/21774708 PubMed]
-| style="background-color:#fc8d59" |Seems to have inferior OS
+==LYSA H34==
+{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[https://academic.oup.com/annonc/article-abstract/4/9/741/170864 Gill et al. 1993]
+|[[#top|back to top]]
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+|}
-|1. [[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_2|Tamoxifen]]<br> 2. Megestrol & Tamoxifen
+===Arm 1===
-| style="background-color:#ffffbf" |Seems not superior
+*[[Hodgkin_lymphoma#eBEACOPP_2|eBEACOPP]] x 4, then [[Hodgkin_lymphoma#BEACOPP_2|BEACOPP]] x 4
+===Arm 2===
+*[[Hodgkin_lymphoma#ABVD_3|ABVD]] x 8
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.ejcancer.com/article/0959-8049(95)00014-3/pdf Jonat et al. 1996]
+|BEACOPP<sub>4+4</sub>
-| style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#d9ef8b"|Might have superior EFS
-|[[Breast_cancer,_ER-positive#Anastrozole_monotherapy_4|Anastrozole]]
-| style="background-color:#fc8d59" |Seems to have inferior OS (*)
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/(SICI)1097-0142(19960615)77:12%3C2503::AID-CNCR13%3E3.0.CO;2-W Buzdar et al. 1996 (Protocol 03)]
+|ABVD x 8
-| style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#fee08b"|Might have inferior EFS
-|Fadrozole
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/(SICI)1097-0142(19960615)77:12%3C2503::AID-CNCR13%3E3.0.CO;2-W Buzdar et al. 1996 (Protocol 06)]
+|}
-| style="background-color:#1a9851" |Phase III (C)
+===References===
-|Fadrozole
+# Mounier N, Brice P, Bologna S, Briere J, Gaillard I, Heczko M, Gabarre J, Casasnovas O, Jaubert J, Colin P, Delmer A, Devidas A, Bachy E, Nicolas-Virelizier E, Aoudjhane A, Humbrecht C, Andre M, Carde P; Lymphoma Study Association (LYSA). ABVD (8 cycles) versus BEACOPP (4 escalated cycles ≥4 baseline): final results in stage III-IV low-risk Hodgkin lymphoma (IPS 0-2) of the LYSA H34 randomized trial. Ann Oncol. 2014 Aug;25(8):1622-8. Epub 2014 May 14. [http://annonc.oxfordjournals.org/content/25/8/1622.full.html link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/24827123 PubMed]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
+==NCIC CTG/ECOG HD.6==
+{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.7.2000 Buzdar et al. 1996a]
+|[[#top|back to top]]
-| style="background-color:#1a9851" |Phase III (C)
+|}
-|[[Breast_cancer,_ER-positive#Anastrozole_monotherapy_4|Anastrozole]]
+''Note: this randomization was for patients with unfavorable risk.''
-| style="background-color:#fc8d59" |Seems to have inferior OS (*)
+===Arm 1===
+*[[Hodgkin_lymphoma#ABVD_2|ABVD]] x 4
+===Arm 2===
+*[[Hodgkin_lymphoma#ABVD_2|ABVD]] x 2, then [[Hodgkin_lymphoma#Radiotherapy_2|STNI]]
+===Comparative efficacy===
+''Efficacy is based on the 2011 update.''
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.ejcancer.com/article/0959-8049(96)00191-8/pdf Stuart et al. 1996]
+|ABVD x 4
-| style="background-color:#1a9851" |Phase III (E-switch-ic)
+|style="background-color:#91cf60"|Seems to have superior OS
-|[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_2|Tamoxifen]]
-| style="background-color:#ffffbf" |Seems not superior
 |-
-|[https://www.ejcancer.com/article/S0959-8049(97)00105-6/pdf Thürlimann et al. 1997 (SAKK 20/90)]
+|ABVD x 2, then STNI
-| style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#fc8d59"|Seems to have inferior OS
-|[[#Formestane_monotherapy|Formestane]]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of TTF
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.7.2494 Russell et al. 1997 (SWOG S8312)]
+|}
-| style="background-color:#1a9851" |Phase III (C)
+===References===
-|Aminoglutethimide, Hydrocortisone, Megestrol
+# Meyer RM, Gospodarowicz MK, Connors JM, Pearcey RG, Bezjak A, Wells WA, Burns BF, Winter JN, Horning SJ, Dar AR, Djurfeldt MS, Ding K, Shepherd LE; National Cancer Institute of Canada Clinical Trials Group; Eastern Cooperative Oncology Group. Randomized comparison of ABVD chemotherapy with a strategy that includes radiation therapy in patients with limited-stage Hodgkin's lymphoma: National Cancer Institute of Canada Clinical Trials Group and the Eastern Cooperative Oncology Group. J Clin Oncol. 2005 Jul 20;23(21):4634-42. Epub 2005 Apr 18. [https://ascopubs.org/doi/10.1200/JCO.2005.09.085 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/15837968 PubMed]
-| style="background-color:#ffffbf" |Seems not superior
+## '''Update:''' Meyer RM, Gospodarowicz MK, Connors JM, Pearcey RG, Wells WA, Winter JN, Horning SJ, Dar AR, Shustik C, Stewart DA, Crump M, Djurfeldt MS, Chen BE, Shepherd LE; NCIC Clinical Trials Group; Eastern Cooperative Oncology Group. ABVD alone versus radiation-based therapy in limited-stage Hodgkin's lymphoma. N Engl J Med. 2012 Feb 2;366(5):399-408. Epub 2011 Dec 11. [https://www.nejm.org/doi/full/10.1056/NEJMoa1111961 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932020/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22149921 PubMed]
+=[[Mantle cell lymphoma]]=
+==MCL Younger==
+===Arm 1 (Control)===
+*[[Mantle_cell_lymphoma#R-CHOP|R-CHOP]] x 6, then [[Stem_cell_mobilization#DexaBEAM_.26_G-CSF|Dexa-BEAM]], then [[Mantle_cell_lymphoma#Cyclophosphamide_.26_TBI.2C_then_auto_HSCT|Cy/TBI auto HSCT]]
+===Arm 2 (Experimental)===
+*[[Mantle_cell_lymphoma#R-CHOP.2FR-DHAP|R-CHOP/R-DHAP]] x 6, then cytarabine, melphalan, TBI auto HSCT
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!style="width: 50%"|Regimen
+!style="width: 50%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|rowspan=2|[https://ascopubs.org/doi/10.1200/JCO.1998.16.2.453 Dombernowsky et al. 1998]
+|SOC
-|rowspan=2 style="background-color:#1a9851"|Randomized (C)
+| style="background-color:#fc8d59" |Seems to have inferior TTTF
-|[[Breast_cancer,_ER-positive#Letrozole_monotherapy_4|Letrozole]]; 0.5 mg/day
-| style="background-color:#d3d3d3" |Not reported
 |-
-|[[Breast_cancer,_ER-positive#Letrozole_monotherapy_4|Letrozole]]; 2.5 mg/day
+|Cytarabine-based
-| style="background-color:#fc8d59" |Seems to have inferior OS
+|style="background-color:#91cf60"|Seems to have superior TTTF
 |-
-|[https://ascopubs.org/doi/full/10.1200/JCO.1999.17.1.52 Goss et al. 1999]
+|}
-| style="background-color:#1a9851" |Phase III (C)
+===References===
-|Vorozole
+# Hermine O, Hoster E, Walewski J, Bosly A, Stilgenbauer S, Thieblemont C, Szymczyk M, Bouabdallah R, Kneba M, Hallek M, Salles G, Feugier P, Ribrag V, Birkmann J, Forstpointner R, Haioun C, Hänel M, Casasnovas RO, Finke J, Peter N, Bouabdallah K, Sebban C, Fischer T, Dührsen U, Metzner B, Maschmeyer G, Kanz L, Schmidt C, Delarue R, Brousse N, Klapper W, Macintyre E, Delfau-Larue MH, Pott C, Hiddemann W, Unterhalt M, Dreyling M; European Mantle Cell Lymphoma Network. Addition of high-dose cytarabine to immunochemotherapy before autologous stem-cell transplantation in patients aged 65 years or younger with mantle cell lymphoma (MCL Younger): a randomised, open-label, phase 3 trial of the European Mantle Cell Lymphoma Network. Lancet. 2016 Aug 6;388(10044):565-75. Epub 2016 Jun 14. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)00739-X/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27313086 PubMed]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
+=[[Multiple myeloma]]=
+==HOVON-50==
+===Arm 1 (Control)===
+*[[Multiple_myeloma_-_historical#VAD|VAD]], then [[Stem_cell_mobilization#CAD_.26_G-CSF|CAD & G-CSF stem cell mobilization]], then [[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|single]] or [[Multiple_myeloma,_consolidation_and_maintenance#Tandem_melphalan.2C_then_auto_HSCT|tandem]] melphalan auto HSCT, then [[Multiple_myeloma_-_historical#Interferon_alfa_monotherapy|interferon alfa maintenance]]
+===Arm 2 (Experimental)===
+*[[Multiple_myeloma,_induction#TAD_.28Thalidomide.29|TAD]] x 3, then [[Stem_cell_mobilization#CAD_.26_G-CSF|CAD & G-CSF stem cell mobilization]], then [[Multiple_myeloma,_consolidation_and_maintenance#Melphalan.2C_then_auto_HSCT|single]] or [[Multiple_myeloma,_consolidation_and_maintenance#Tandem_melphalan.2C_then_auto_HSCT|tandem]] melphalan auto HSCT, then [[Multiple_myeloma,_consolidation_and_maintenance#Thalidomide_monotherapy|thalidomide maintenance]]
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!style="width: 50%"|Regimen
+!style="width: 50%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://ascopubs.org/doi/10.1200/jco.1999.17.1.64 Abrams et al. 1999 (CALGB 8741)]
+|SOC
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#d73027" |Inferior PFS
-|[[#Megestrol_monotherapy|Megestrol]]; higher-dose
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
 |-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2000.18.7.1399 Kaufmann et al. 2000]
+|Thalidomide-based
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9850" |Superior PFS
-|[[Breast_cancer,_ER-positive#Exemestane_monotherapy_3|Exemestane]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
-|[https://ascopubs.org/doi/full/10.1200/JCO.2001.19.14.3357 Buzdar et al. 2001]
+|}
-| style="background-color:#1a9851"|Phase III (C)
+===References===
-|1. [[#Letrozole_monotherapy_4|Letrozole]]; 0.5 mg/day<br> 2. [[#Letrozole_monotherapy_4|Letrozole]]; 2.5 mg/day
+# Lokhorst HM, van der Holt B, Zweegman S, Vellenga E, Croockewit S, van Oers MH, von dem Borne P, Wijermans P, Schaafsma R, de Weerdt O, Wittebol S, Delforge M, Berenschot H, Bos GM, Jie KS, Sinnige H, van Marwijk-Kooy M, Joosten P, Minnema MC, van Ammerlaan R, Sonneveld P; Dutch-Belgian Hemato-Oncology Group (HOVON). A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide maintenance in patients with multiple myeloma. Blood. 2010 Feb 11;115(6):1113-20. Epub 2009 Oct 30. [http://www.bloodjournal.org/content/115/6/1113 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/19880501 PubMed]
-| style="background-color:#ffffbf" |Did not meet primary endpoint of ORR
+## '''Update:''' van de Donk NW, van der Holt B, Minnema MC, Vellenga E, Croockewit S, Kersten MJ, von dem Borne PA, Ypma P, Schaafsma R, de Weerdt O, Klein SK, Delforge M, Levin MD, Bos GM, Jie KG, Sinnige H, Coenen JL, de Waal EG, Zweegman S, Sonneveld P, Lokhorst HM. Thalidomide before and after autologous stem cell transplantation in recently diagnosed multiple myeloma (HOVON-50): long-term results from the phase 3, randomised controlled trial. Lancet Haematol. 2018 Oct;5(10):e479-e492. [https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(18)30149-2/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30290905 PubMed]
+=[[Non-small cell lung cancer]]=
+==CONVINCE==
+{| class="wikitable" style="float:right; margin-left: 5px;"
 |-
+|[[#top|back to top]]
 |}
-''Note: Reported efficacy for Jonat et al. 1996 & Buzdar et al. 1996a is based on the 1998 pooled update.''
+===Arm 1 (Control)===
-====Hormonotherapy====
+*[[Non-small_cell_lung_cancer#Cisplatin_.26_Pemetrexed_3|Cis-Pem]] x 4, then [[Non-small_cell_lung_cancer#Pemetrexed_monotherapy_2|Pemetrexed maintenance]]
-*[[Megestrol (Megace)]] 160 mg PO once per day
+===Arm 2 (Experimental)===
-**Kaufmann et al. 2000 gave as 40 mg PO four times per day
+*[[Non-small_cell_lung_cancer,_EGFR-mutated#Icotinib_monotherapy|Icotinib]]
-'''Continued indefinitely'''
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Cis-Pem, then Pem
+| style="background-color:#d73027" |Inferior PFS
+|-
+|Icotinib
+| style="background-color:#1a9850" |Superior PFS
+|-
+|}
+===References===
+# Shi YK, Wang L, Han BH, Li W, Yu P, Liu YP, Ding CM, Song X, Ma ZY, Ren XL, Feng JF, Zhang HL, Chen GY, Han XH, Wu N, Yao C, Song Y, Zhang SC, Song W, Liu XQ, Zhao SJ, Lin YC, Ye XQ, Li K, Shu YQ, Ding LM, Tan FL, Sun Y. First-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance therapy for patients with advanced EGFR mutation-positive lung adenocarcinoma (CONVINCE): a phase 3, open-label, randomized study. Ann Oncol. 2017 Oct 1;28(10):2443-2450. [https://academic.oup.com/annonc/article/28/10/2443/4091563 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/28945850 PubMed]
+==ECOG 3598==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1 (Control)===
+*[[Non-small_cell_lung_cancer#Carboplatin_.26_Paclitaxel_2|PC]] induction, then [[Non-small_cell_lung_cancer#Carboplatin.2C_Paclitaxel.2C_RT|Carboplatin, Paclitaxel, RT]]
+===Arm 2, with thalidomide (Experimental)===
+*TPC, then Carboplatin, Paclitaxel, Thalidomide, RT
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Without thalidomide
+|style="background-color:#ffffbf"|Seems not superior
+|-
+|With thalidomide
+|style="background-color:#ffffbf"|Seems not superior
+|-
+|}
 ===References===
-# Muss HB, Wells HB, Paschold EH, Black WR, Cooper MR, Capizzi RL, Christian R, Cruz JM, Jackson DV, Powell BL, Richards F, White DR, Zekan PJ, Spurr CL, Pope E, Case D, Morgan TM. Megestrol acetate versus tamoxifen in advanced breast cancer: 5-year analysis--a phase III trial of the Piedmont Oncology Association. J Clin Oncol. 1988 Jul;6(7):1098-106. [https://ascopubs.org/doi/abs/10.1200/JCO.1988.6.7.1098 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3292710 PubMed]
+# Hoang T, Dahlberg SE, Schiller JH, Mehta MP, Fitzgerald TJ, Belinsky SA, Johnson DH. Randomized phase III study of thoracic radiation in combination with paclitaxel and carboplatin with or without thalidomide in patients with stage III non-small-cell lung cancer: the ECOG 3598 study. J Clin Oncol. 2012 Feb 20;30(6):616-22. Epub 2012 Jan 23. [https://ascopubs.org/doi/full/10.1200/JCO.2011.36.9116 link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3295560/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22271472 PubMed]
-# Lundgren S, Gundersen S, Klepp R, Lønning PE, Lund E, Kvinnsland S. Megestrol acetate versus aminoglutethimide for metastatic breast cancer. Breast Cancer Res Treat. 1989 Nov;14(2):201-6. [https://link.springer.com/article/10.1007/BF01810736 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2690972 PubMed]
-# Muss HB, Case LD, Capizzi RL, Cooper MR, Cruz J, Jackson D, Richards F 2nd, Powell BL, Spurr CL, White D, Zekan P, Read S, Cates-Wilkie S, Bearden J, McCullough J, Callahan R, Karb K, Atkins J, Paschal B, Ramseur B, Lusk J, Stanley V. High- versus standard-dose megestrol acetate in women with advanced breast cancer: a phase III trial of the Piedmont Oncology Association. J Clin Oncol. 1990 Nov;8(11):1797-805. [https://ascopubs.org/doi/10.1200/jco.1990.8.11.1797 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/2230868 PubMed]
-# Gill PG, Gebski V, Snyder R, Burns I, Levi J, Byrne M, Coates A. Randomized comparison of the effects of tamoxifen, megestrol acetate, or tamoxifen plus megestrol acetate on treatment response and survival in patients with metastatic breast cancer. Ann Oncol. 1993 Nov;4(9):741-4. [https://academic.oup.com/annonc/article-abstract/4/9/741/170864 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8280654 PubMed]
-# Jonat W, Howell A, Blomqvist C, Eiermann W, Winblad G, Tyrrell C, Mauriac L, Roche H, Lundgren S, Hellmund R, Azab M. A randomised trial comparing two doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer. Eur J Cancer. 1996 Mar;32A(3):404-12. [https://www.ejcancer.com/article/0959-8049(95)00014-3/pdf link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8814682 PubMed]
-## '''Pooled update:''' Buzdar A, Jonat W, Howell A, Jones SE, Blomqvist C, Vogel CL, Eiermann W, Wolter JM, Azab M, Webster A, Plourde PV; Arimidex Study Group. Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. J Clin Oncol. 1996 Jul;14(7):2000-11. [https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.7.2000 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8683230 PubMed]
-## '''Pooled update:''' Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP, Vogel CL, Eiermann W, Wolter JM, Steinberg M, Webster A, Lee D; Arimidex Study Group. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Cancer. 1998 Sep 15;83(6):1142-52. Erratum in: Cancer 1999 Feb 15;85(4):1010. [https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819980915%2983%3A6%3C1142%3A%3AAID-CNCR13%3E3.0.CO%3B2-5 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9740079 PubMed]
-# Buzdar AU, Smith R, Vogel C, Bonomi P, Keller AM, Favis G, Mulagha M, Cooper J. Fadrozole HCL (CGS-16949A) versus megestrol acetate treatment of postmenopausal patients with metastatic breast carcinoma: results of two randomized double blind controlled multiinstitutional trials. Cancer. 1996 Jun 15;77(12):2503-13. [https://onlinelibrary.wiley.com/doi/abs/10.1002/(SICI)1097-0142(19960615)77:12%3C2503::AID-CNCR13%3E3.0.CO;2-W link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8640699 PubMed]
-# Buzdar A, Jonat W, Howell A, Jones SE, Blomqvist C, Vogel CL, Eiermann W, Wolter JM, Azab M, Webster A, Plourde PV; Arimidex Study Group. Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. J Clin Oncol. 1996 Jul;14(7):2000-11. [https://ascopubs.org/doi/abs/10.1200/JCO.1996.14.7.2000 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8683230 PubMed]
-## '''Update:''' Buzdar AU, Jones SE, Vogel CL, Wolter J, Plourde P, Webster A; Arimidex Study Group. A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma. Cancer. 1997 Feb 15;79(4):730-9. [https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819970215%2979%3A4%3C730%3A%3AAID-CNCR10%3E3.0.CO%3B2-0 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9024711 PubMed]
-## '''Pooled update:''' Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP, Vogel CL, Eiermann W, Wolter JM, Steinberg M, Webster A, Lee D; Arimidex Study Group. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Cancer. 1998 Sep 15;83(6):1142-52. Erratum in: Cancer 1999 Feb 15;85(4):1010. [https://onlinelibrary.wiley.com/doi/full/10.1002/%28SICI%291097-0142%2819980915%2983%3A6%3C1142%3A%3AAID-CNCR13%3E3.0.CO%3B2-5 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9740079 PubMed]
-# Stuart NS, Warwick J, Blackledge GR, Spooner D, Keen C, Taylor AR, Tyrell C, Webster DJ, Earl H. A randomised phase III cross-over study of tamoxifen versus megestrol acetate in advanced and recurrent breast cancer. Eur J Cancer. 1996 Oct;32A(11):1888-92. [https://www.ejcancer.com/article/0959-8049(96)00191-8/pdf link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/8943670 PubMed]
-# '''SAKK 20/90:''' Thürlimann B, Castiglione M, Hsu-Schmitz SF, Cavalli F, Bonnefoi H, Fey MF, Morant R, Löhnert T, Goldhirsch A; Swiss Group for Clinical Cancer Research (SAKK). Formestane versus megestrol acetate in postmenopausal breast cancer patients after failure of tamoxifen: a phase III prospective randomised cross over trial of second-line hormonal treatment (SAKK 20/90). Eur J Cancer. 1997 Jun;33(7):1017-24. [https://www.ejcancer.com/article/S0959-8049(97)00105-6/pdf link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9376181 PubMed]
-# '''SWOG S8312:''' Russell CA, Green SJ, O'Sullivan J, Hynes HE, Budd GT, Congdon JE, Martino S, Osborne CK. Megestrol acetate and aminoglutethimide/hydrocortisone in sequence or in combination as second-line endocrine therapy of estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group phase III trial. J Clin Oncol. 1997 Jul;15(7):2494-501. [https://ascopubs.org/doi/abs/10.1200/JCO.1997.15.7.2494 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/9215817 PubMed]
-# Dombernowsky P, Smith I, Falkson G, Leonard R, Panasci L, Bellmunt J, Bezwoda W, Gardin G, Gudgeon A, Morgan M, Fornasiero A, Hoffmann W, Michel J, Hatschek T, Tjabbes T, Chaudri HA, Hornberger U, Trunet PF. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol. 1998 Feb;16(2):453-61. [https://ascopubs.org/doi/10.1200/JCO.1998.16.2.453 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/9469328 PubMed]
-# Goss PE, Winer EP, Tannock IF, Schwartz LH; North American Vorozole Study Group. Randomized phase III trial comparing the new potent and selective third-generation aromatase inhibitor vorozole with megestrol acetate in postmenopausal advanced breast cancer patients. J Clin Oncol. 1999 Jan;17(1):52-63. [https://ascopubs.org/doi/full/10.1200/JCO.1999.17.1.52 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/10458218 PubMed]
-# '''CALGB 8741:''' Abrams J, Aisner J, Cirrincione C, Berry DA, Muss HB, Cooper MR, Henderson IC, Panasci L, Kirshner J, Ellerton J, Norton L. Dose-response trial of megestrol acetate in advanced breast cancer: Cancer and Leukemia Group B phase III study 8741. J Clin Oncol. 1999 Jan;17(1):64-73. [https://ascopubs.org/doi/10.1200/jco.1999.17.1.64 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10458219 PubMed]
-# Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N, Dugardyn JL, Nasurdi C, Mennel RG, Cervek J, Fowst C, Polli A, di Salle E, Arkhipov A, Piscitelli G, Miller LL, Massimini G; The Exemestane Study Group. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. J Clin Oncol. 2000 Apr;18(7):1399-411. [https://ascopubs.org/doi/full/10.1200/JCO.2000.18.7.1399 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/10735887 PubMed]
-# Buzdar A, Douma J, Davidson N, Elledge R, Morgan M, Smith R, Porter L, Nabholtz J, Xiang X, Brady C. Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol. 2001 Jul 15;19(14):3357-66. [https://ascopubs.org/doi/full/10.1200/JCO.2001.19.14.3357 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/11454883 PubMed]
-==Melphalan monotherapy {{#subobject:b913c5|Regimen=1}}==
+==ECOG E4599==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-P: '''<u>P</u>'''henylalanine mustard (Melphalan)
+===Arm 1 (Control)===
-===Regimen {{#subobject:ab3663|Variant=1}}===
+*[[Non-small_cell_lung_cancer#Carboplatin_.26_Paclitaxel_4|Carboplatin & Paclitaxel]] x 6
+===Arm 2, with bevacizumab (Experimental)===
+*[[Non-small_cell_lung_cancer#Carboplatin.2C_Paclitaxel.2C_Bevacizumab|PacCBev]] x 6, then [[Non-small_cell_lung_cancer#Bevacizumab_monotherapy|bevacizumab maintenance]]
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
+|-
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|Platinum doublet
+| style="background-color:#d73027" |Inferior OS
 |-
-|[https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(197611)38:5%3C1882::AID-CNCR2820380503%3E3.0.CO;2-H Canellos et al. 1976]
+|With bevacizumab
-| style="background-color:#1a9851" |Phase III (C)
+| style="background-color:#1a9850" |Superior OS
-|[[Breast_cancer#CMF_2|CMF]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
 |}
-====Chemotherapy====
+===References===
-*[[Melphalan (Alkeran)]] 6 mg/m<sup>2</sup> PO once per day on days 1 to 5
+# Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. [https://www.nejm.org/doi/full/10.1056/NEJMoa061884 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/17167137 PubMed]
+## '''Subgroup analysis:''' Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; Eastern Cooperative Oncology Group. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. [http://jco.ascopubs.org/content/26/1/60.full link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/18165641 PubMed]
-'''42-day cycles'''
+==IUNO==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1, "early" erlotinib===
+*[[Non-small_cell_lung_cancer#Erlotinib_monotherapy|Maintenance erlotinib]]
+===Arm 2, "late" erlotinib===
+*[[Non-small_cell_lung_cancer#Placebo_3|Placebo]] until progression or intolerance, then [[Non-small_cell_lung_cancer#Erlotinib_monotherapy_2|erlotinib]]
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Timing'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Maintenance erlotinib
+|style="background-color:#ffffbf"|Seems not superior
+|-
+|Second-line erlotinib
+|style="background-color:#ffffbf"|Seems not superior
+|-
+|}
 ===References===
-# Canellos GP, Pocock SJ, Taylor SG 3rd, Sears ME, Klaasen DJ, Band PR. Combination chemotherapy for metastatic breast carcinoma: prospective comparison of multiple drug therapy with L-phenylalanine mustard. Cancer. 1976 Nov;38(5):1882-6. [https://onlinelibrary.wiley.com/doi/abs/10.1002/1097-0142(197611)38:5%3C1882::AID-CNCR2820380503%3E3.0.CO;2-H link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/991103 PubMed]
+# Cicènas S, Geater SL, Petrov P, Hotko Y, Hooper G, Xia F, Mudie N, Wu YL. Maintenance erlotinib versus erlotinib at disease progression in patients with advanced non-small-cell lung cancer who have not progressed following platinum-based chemotherapy (IUNO study). Lung Cancer. 2016 Dec;102:30-37. Epub 2016 Oct 20. [http://www.lungcancerjournal.info/article/S0169-5002(16)30504-9/fulltext link to original article] '''contains verified protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/27987585 PubMed]
-==Methotrexate & Thiotepa {{#subobject:c67a88|Regimen=1}}==
+==KEYNOTE-021==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Regimen {{#subobject:4c1582|Variant=1}}===
+===Arm 1 (Control)===
-{| class="wikitable" style="width: 50%; text-align:center;"
+*[[Non-small_cell_lung_cancer#Carboplatin_.26_Pemetrexed_2|Carbo-Pem]] x 4, then [[Non-small_cell_lung_cancer#Pemetrexed_monotherapy_2|pemetrexed maintenance]]
-!style="width: 25%"|Study
+===Arm 2, with pembrolizumab (Experimental)===
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+*[[Non-small_cell_lung_cancer#Carboplatin.2C_Pemetrexed.2C_Pembrolizumab|Carboplatin, Pemetrexed, Pembrolizumab]] x 4, then [[Non-small_cell_lung_cancer#Pemetrexed_.26_Pembrolizumab|Pemetrexed & Pembrolizumab maintenance]]
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.ncbi.nlm.nih.gov/pubmed/13950199 Greenspan et al. 1963]
+|Control
-| style="background-color:#91cf61" |Non-randomized
+| style="background-color:#d73027" |Inferior ORR
+|-
+|Experimental (with pembrolizumab)
+|style="background-color:#1a9850"|Superior ORR
 |-
 |}
-''Note: this is possibly the first published trial of combination chemotherapy in breast cancer.''
+===References===
-====Chemotherapy====
+# Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. Epub 2016 Oct 10. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(16)30498-3/fulltext link to original article] [http://thelancet.com/cms/attachment/2074509559/2069027402/mmc1.pdf supplementary appendix] [https://www.ncbi.nlm.nih.gov/pubmed/27745820 PubMed]
-*[[Methotrexate (MTX)]]
-*[[Thiotepa (Tepadina)]]
+==KEYNOTE-189==
+{| class="wikitable" style="float:right; margin-left: 5px;"
+|-
+|[[#top|back to top]]
+|}
+===Arm 1 (Control)===
+*Investigator's choice of:
+**[[Non-small_cell_lung_cancer#Carboplatin_.26_Pemetrexed_2|Carbo-Pem]] x 4, then [[Non-small_cell_lung_cancer#Pemetrexed_monotherapy_2|pemetrexed maintenance]]
+**[[Non-small_cell_lung_cancer#Cisplatin_.26_Pemetrexed_3|Cis-Pem]] x 4, then [[Non-small_cell_lung_cancer#Pemetrexed_monotherapy_2|pemetrexed maintenance]]
+===Arm 2, with pembrolizumab (Experimental)===
+*Investigator's choice of:
+**[[Non-small_cell_lung_cancer#Carboplatin.2C_Pemetrexed.2C_Pembrolizumab|Carboplatin, Pemetrexed, Pembrolizumab]] x 4, then [[Non-small_cell_lung_cancer#Pemetrexed_.26_Pembrolizumab|Pemetrexed & Pembrolizumab maintenance]]
+**[[Non-small_cell_lung_cancer#Cisplatin.2C_Pemetrexed.2C_Pembrolizumab|Cisplatin, Pemetrexed, Pembrolizumab]] x 4, then [[Non-small_cell_lung_cancer#Pemetrexed_.26_Pembrolizumab|Pemetrexed & Pembrolizumab maintenance]]
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Control
+| style="background-color:#d73027" |Inferior OS
+|-
+|Experimental (with pembrolizumab)
+|style="background-color:#1a9850"|Superior OS
+|-
+|}
 ===References===
-# Greenspan EM, Fieber M, Lesnick G, Edelman S. Response of advanced breast carcinoma to the combination of the antimetabolite, Methotrexate, and the alkylating agent, thio-TEPA. J Mt Sinai Hosp N Y. 1963 May-Jun;30:246-67. [https://www.ncbi.nlm.nih.gov/pubmed/13950199 PubMed]
+# Gandhi L, Rodríguez-Abreu D, Gadgeel S, Esteban E, Felip E, De Angelis F, Domine M, Clingan P, Hochmair MJ, Powell SF, Cheng SY, Bischoff HG, Peled N, Grossi F, Jennens RR, Reck M, Hui R, Garon EB, Boyer M, Rubio-Viqueira B, Novello S, Kurata T, Gray JE, Vida J, Wei Z, Yang J, Raftopoulos H, Pietanza MC, Garassino MC; KEYNOTE-189 Investigators. Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med. 2018 May 31;378(22):2078-2092. Epub 2018 Apr 16. [https://www.nejm.org/doi/full/10.1056/NEJMoa1801005 link to original article] [https://www.nejm.org/doi/suppl/10.1056/NEJMoa1801005/suppl_file/nejmoa1801005_protocol.pdf link to protocol] [https://www.ncbi.nlm.nih.gov/pubmed/29658856 PubMed]
-==Mitoxantrone monotherapy {{#subobject:c67f55|Regimen=1}}==
+==KEYNOTE-407==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Regimen {{#subobject:4c8527|Variant=1}}===
+===Arm 1 (Control)===
+*Investigator's choice of:
+**[[Non-small_cell_lung_cancer#Carboplatin_.26_nab-Paclitaxel|Carboplatin & nab-Paclitaxel]] x 4
+**[[Non-small_cell_lung_cancer#Carboplatin_.26_Paclitaxel_6|CP]] x 4
+===Arm 2, with pembrolizumab (Experimental)===
+*Investigator's choice of:
+**[[Non-small_cell_lung_cancer#Carboplatin.2C_nab-Paclitaxel.2C_Pembrolizumab|Carboplatin, nab-Paclitaxel, Pembrolizumab]] x 4, then [[Non-small_cell_lung_cancer#Pembrolizumab_monotherapy_2|Pembrolizumab maintenance]]
+**[[Non-small_cell_lung_cancer#Carboplatin.2C_Paclitaxel.2C_Pembrolizumab|Carboplatin, Paclitaxel, Pembrolizumab]] x 4, then [[Non-small_cell_lung_cancer#Pembrolizumab_monotherapy_2|Pembrolizumab maintenance]]
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PII0140-6736(90)90277-C/fulltext Harris et al. 1990]
+|Control
-| style="background-color:#91cf61" |Non-randomized portion of RCT
+| style="background-color:#d73027" |Inferior OS
-| style="background-color:#d3d3d3" |
-| style="background-color:#d3d3d3" |
 |-
-|[https://academic.oup.com/jnci/article-abstract/83/15/1077/882648 Cowan et al. 1991 (SWOG S8203)]
+|Experimental (with pembrolizumab)
-| style="background-color:#1a9851" |Phase III (C)
+|style="background-color:#1a9850"|Superior OS
-|1. Bisantrene<br> 2. [[Breast_cancer#Doxorubicin_monotherapy_3|Doxorubicin]]
-| style="background-color:#fc8d59" |Seems to have inferior OS
 |-
 |}
-====Chemotherapy====
-*[[Mitoxantrone (Novantrone)]] 14 mg/m<sup>2</sup> IV once on day 1
-'''21-day cycles'''
 ===References===
-# Harris AL, Cantwell BM, Carmichael J, Wilson R, Farndon J, Dawes P, Ghani S, Evans RG. Comparison of short-term and continuous chemotherapy (mitozantrone) for advanced breast cancer. Lancet. 1990 Jan 27;335(8683):186-90. [https://www.thelancet.com/journals/lancet/article/PII0140-6736(90)90277-C/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1967666 PubMed]
+# Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gümüş M, Mazières J, Hermes B, Çay Şenler F, Csőszi T, Fülöp A, Rodríguez-Cid J, Wilson J, Sugawara S, Kato T, Lee KH, Cheng Y, Novello S, Halmos B, Li X, Lubiniecki GM, Piperdi B, Kowalski DM; KEYNOTE-407 Investigators. Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med. 2018 Nov 22;379(21):2040-2051. Epub 2018 Sep 25. [https://www.nejm.org/doi/10.1056/NEJMoa1810865 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30280635 PubMed]
-# '''SWOG S8203:''' Cowan JD, Neidhart J, McClure S, Coltman CA Jr, Gumbart C, Martino S, Hutchins LF, Stephens RL, Vaughan CB, Osborne CK. Randomized trial of doxorubicin, bisantrene, and mitoxantrone in advanced breast cancer: a Southwest Oncology Group study. J Natl Cancer Inst. 1991 Aug 7;83(15):1077-84. [https://academic.oup.com/jnci/article-abstract/83/15/1077/882648 link to original article] '''contains protocol''' [https://www.ncbi.nlm.nih.gov/pubmed/1875415 PubMed]
-==STAMP-I {{#subobject:c08ab4|Regimen=1}}==
+==PRONOUNCE==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Regimen {{#subobject:7gy709|Variant=1}}===
+===Arm 1===
-{| class="wikitable" style="width: 100%; text-align:center;"
+*[[Non-small_cell_lung_cancer#Carboplatin_.26_Pemetrexed_2|Carbo-Pem]] x 4, then [[Non-small_cell_lung_cancer#Pemetrexed_monotherapy_2|pemetrexed maintenance]]
-!style="width: 25%"|Study
+===Arm 2===
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+*[[Non-small_cell_lung_cancer#Carboplatin.2C_Paclitaxel.2C_Bevacizumab_2|PacCBev]] x 4, then [[Non-small_cell_lung_cancer#Bevacizumab_monotherapy|bevacizumab maintenance]]
-!style="width: 25%"|Comparator
+===Comparative efficacy===
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.nature.com/articles/1705367 Vredenburgh et al. 2006]
+|Arm 1
-|style="background-color:#1a9851" |Phase III (E-esc)
+| style="background-color:#ffffbf" |Seems not superior
-|Observation
+|-
-| style="background-color:#1a9850" |Superior EFS
+|Arm 2
+| style="background-color:#ffffbf" |Seems not superior
 |-
 |}
-====Preceding treatment====
-*Duke AFM x 2 to 4
-====Chemotherapy====
-*[[Carmustine (BCNU)]]
-*[[Cisplatin (Platinol)]]
-*[[Cyclophosphamide (Cytoxan)]]
 ===References===
-# Vredenburgh JJ, Madan B, Coniglio D, Ross M, Broadwater G, Niedzwiecki D, Edwards J, Marks L, Vandemark R, McDonald C, Affronti ML, Peters WP. A randomized phase III comparative trial of immediate consolidation with high-dose chemotherapy and autologous peripheral blood progenitor cell support compared to observation with delayed consolidation in women with metastatic breast cancer and only bone metastases following intensive induction chemotherapy. Bone Marrow Transplant. 2006 Jun;37(11):1009-15. [https://www.nature.com/articles/1705367 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/16633363 PubMed]
+# Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. [http://www.jto.org/article/S1556-0864(15)30782-6/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4276572/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/25371077 PubMed]
-==TAD (Tamoxifen) {{#subobject:1ac555|Regimen=1}}==
+==RTOG 9410==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-TAD: '''<u>T</u>'''amoxifen, '''<u>A</u>'''minoglutethimide, '''<u>D</u>'''anazol
+===Arm 1, sequential===
-===Regimen {{#subobject:0b2c27|Variant=1}}===
+*[[Non-small_cell_lung_cancer#Cisplatin_.26_Vinblastine_2|Cisplatin & Vinblastine]], then [[Non-small_cell_lung_cancer#Radiation_therapy|RT]]
+===Arm 2, concurrent===
+*[[Non-small_cell_lung_cancer#Cisplatin.2C_Etoposide.2C_RT|Cisplatin, Etoposide, RT]]
+===Arm 3, concurrent===
+*[[Non-small_cell_lung_cancer#Cisplatin.2C_Vinblastine.2C_RT|Cisplatin, Vinblastine, RT]]
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Schedule'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
 |-
-|[https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(84)91872-5/fulltext Powles et al. 1984]
+|Concurrent
-| style="background-color:#1a9851" |Phase III (E-esc)
+|style="background-color:#91cf60"|Seems to have superior OS
-|[[Breast_cancer,_ER-positive#Tamoxifen_monotherapy_2|Tamoxifen]]
+|-
-| style="background-color:#91cf60" |Seems to have superior ORR
+|Sequential
+|style="background-color:#fc8d59"|Seems to have inferior OS
 |-
 |}
-''Note: this patient population was not selected by hormone receptor status.''
-====Hormonotherapy====
-*[[Tamoxifen (Nolvadex)]]
-*[[Aminoglutethimide (Cytadren)]]
-*[[Danazol (Danocrine)]]
 ===References===
-# Powles TJ, Ashley S, Ford HT, Gazet JC, Nash AG, Neville AM, Coombes RC. Treatment of disseminated breast cancer with tamoxifen, aminoglutethimide, hydrocortisone, and danazol, used in combination or sequentially. Lancet. 1984 Jun 23;1(8391):1369-73. [https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(84)91872-5/fulltext link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/6145832 PubMed]
+# Curran WJ Jr, Paulus R, Langer CJ, Komaki R, Lee JS, Hauser S, Movsas B, Wasserman T, Rosenthal SA, Gore E, Machtay M, Sause W, Cox JD. Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410. J Natl Cancer Inst. 2011 Oct 5;103(19):1452-60. Epub 2011 Sep 8. Erratum in: J Natl Cancer Inst. 2012;104(1):79. [http://jnci.oxfordjournals.org/content/103/19/1452.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186782/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/21903745 PubMed]
-==Thiotepa monotherapy {{#subobject:123f55|Regimen=1}}==
+=[[Ovarian cancer]]=
+==GOG 114==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-===Regimen {{#subobject:4a8d27|Variant=1}}===
+===Arm 1 - Control===
-{| class="wikitable" style="width: 50%; text-align:center;"
+*[[Ovarian_cancer#Cisplatin_.26_Paclitaxel|Cisplatin & Paclitaxel]] x 6
-!style="width: 25%"|Study
+===Arm 2 - Experimental===
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+*[[Ovarian_cancer#Carboplatin_monotherapy|Carboplatin]] AUC 9 x 2, then [[Ovarian_cancer#Cisplatin_.26_Paclitaxel_2|IP Cisplatin & IV Paclitaxel]] x 6
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!style="width: 50%"|'''Regimen'''
+!style="width: 50%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
 |-
-|[https://www.nejm.org/doi/full/10.1056/NEJM195505262522101 Bateman 1955]
+|Control
-| style="background-color:#91cf61" |Non-randomized
+| style="background-color:#fc8d59" |Seems to have inferior OS
+|-
+|Experimental
+| style="background-color:#91cf60" |Seems to have superior OS
 |-
 |}
-====Chemotherapy====
-*[[Thiotepa (Thioplex)]]
 ===References===
-# Bateman JC. Chemotherapy of solid tumors with triethylene thiophosphoramide. N Engl J Med. 1955 May 26;252(21):879-87. [https://www.nejm.org/doi/full/10.1056/NEJM195505262522101 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/14370446 PubMed]
+# Markman M, Bundy BN, Alberts DS, Fowler JM, Clark-Pearson DL, Carson LF, Wadler S, Sickel J. Phase III trial of standard-dose intravenous cisplatin plus paclitaxel versus moderately high-dose carboplatin followed by intravenous paclitaxel and intraperitoneal cisplatin in small-volume stage III ovarian carcinoma: an intergroup study of the Gynecologic Oncology Group, Southwestern Oncology Group, and Eastern Cooperative Oncology Group. J Clin Oncol. 2001 Feb 15;19(4):1001-7. [https://ascopubs.org/doi/full/10.1200/JCO.2001.19.4.1001 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/11181662 PubMed]
-==VAC (Adriamycin) {{#subobject:90f8d0|Regimen=1}}==
+==OCEANS==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-VAC: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin), '''<u>C</u>'''yclophosphamide
+===Arm 1 - Control===
-===Regimen {{#subobject:4da860|Variant=1}}===
+*[[Ovarian_cancer#Carboplatin_.26_Gemcitabine_2|Carboplatin & Gemcitabine]] x 6 to 10
+===Arm 2 - Experimental===
+*[[Ovarian_cancer#Carboplatin.2C_Gemcitabine.2C_Bevacizumab|Carboplatin, Gemcitabine, Bevacizumab]] x 6 to 10, then [[Ovarian_cancer#Bevacizumab_monotherapy|Bevacizumab maintenance]]
+===Comparative efficacy===
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!style="width: 50%"|'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+!style="width: 50%"|[[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
-|-
-|[http://www.sciencedirect.com/science/article/pii/0277537986900751 Gundersen et al. 1986]
-|style="background-color:#1a9851"|Phase III (C)
-|[[Breast_cancer#Doxorubicin_monotherapy_2|Doxorubicin]]
-|style="background-color:#ffffbf"|Seems not superior
 |-
-|[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1977504/ Powles et al. 1991]
+|Carbo-Gem
-|style="background-color:#1a9851"|Phase III (C)
+|style="background-color:#d73027"|Inferior PFS
-|3M
-|style="background-color:#ffffbf"|Did not meet primary endpoint of ORR
 |-
-|[https://link.springer.com/article/10.1007/BF01806182 Green et al. 1996]
+|With Bevacizumab
-|style="background-color:#1a9851"|Phase III (C)
+|style="background-color:#1a9850"|Superior PFS
-|VNC
-| style="background-color:#d9ef8b" |Might have superior ORR
 |-
 |}
-''Used as a comparator arm in older trials and found to be more toxic; here for reference purposes only.''
-====Chemotherapy====
-*[[Vincristine (Oncovin)]]
-*[[Doxorubicin (Adriamycin)]]
-*[[Cyclophosphamide (Cytoxan)]]
 ===References===
-# Gundersen S, Kvinnsland S, Klepp O, Kvaløy S, Lund E, Høst H. Weekly adriamycin versus VAC in advanced breast cancer: a randomized trial. Eur J Cancer Clin Oncol. 1986 Dec;22(12):1431-4. [http://www.sciencedirect.com/science/article/pii/0277537986900751 link to SD article] [https://www.ncbi.nlm.nih.gov/pubmed/3595668 PubMed]
+# Aghajanian C, Blank SV, Goff BA, Judson PL, Teneriello MG, Husain A, Sovak MA, Yi J, Nycum LR. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012 Jun 10;30(17):2039-45. Epub 2012 Apr 23. [http://jco.ascopubs.org/content/30/17/2039.long link to original article] [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646321/ link to PMC article] [https://www.ncbi.nlm.nih.gov/pubmed/22529265 PubMed]
-# Powles TJ, Jones AL, Judson IR, Hardy JR, Ashley SE. A randomised trial comparing combination chemotherapy using mitomycin C, mitozantrone and methotrexate (3M) with vincristine, anthracycline and cyclophosphamide (VAC) in advanced breast cancer. Br J Cancer. 1991 Aug;64(2):406-10. [https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1977504/ link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/1892775 PubMed]
-# Green JA, Slater AJ, Campbell IR, Kelly V. Advanced breast cancer: a randomized study of doxorubicin or mitoxantrone in combination with cyclophosphamide and vincristine. Breast Cancer Res Treat. 1996;39(2):155-63. [https://link.springer.com/article/10.1007/BF01806182 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/8872324 PubMed]
-==VAP {{#subobject:4b99b8|Regimen=1}}==
+=[[Pancreatic cancer]]=
+==GERCOR LAP07==
 {| class="wikitable" style="float:right; margin-left: 5px;"
 |-
 |[[#top|back to top]]
 |}
-VAP: '''<u>V</u>'''incristine, '''<u>A</u>'''driamycin (Doxorubicin),  '''<u>P</u>'''rednisolone
+''This study had two randomizations; the second only occurred if patients were progression-free after 4 cycles.''
-===Regimen {{#subobject:7d4b85|Variant=1}}===
+===Arm 1 - Control===
+*[[Pancreatic_cancer#Gemcitabine_monotherapy_2|Gemcitabine]] x 6
+===Arm 2 - Experimental===
+*[[Pancreatic_cancer#Gemcitabine_monotherapy_2|Gemcitabine]] x 4, then Capecitabine & RT
+===Arm 3 - Experimental===
+*[[Pancreatic_cancer#Erlotinib_.26_Gemcitabine|Erlotinib & Gemcitabine]] x 6
+===Arm 4 - Experimental===
+*[[Pancreatic_cancer#Erlotinib_.26_Gemcitabine|Erlotinib & Gemcitabine]] x 4, then Capecitabine, Erlotinib, RT
+===Comparative efficacy===
+====First randomization====
 {| class="wikitable" style="width: 100%; text-align:center;"
-!style="width: 25%"|Study
+!'''Regimen'''
-!style="width: 25%"|[[Levels_of_Evidence#Evidence|Evidence]]
+![[Levels_of_Evidence#Efficacy|Efficacy]]
-!style="width: 25%"|Comparator
+|-
-!style="width: 25%"|[[Levels_of_Evidence#Comparative_efficacy|Comparative Efficacy]]
+|Gemcitabine
+|style="background-color:#d9ef8b"|Might have superior OS
+|-
+|With Erlotinib
+|style="background-color:#fee08b"|Might have inferior OS
+|-
+|}
+====Second randomization====
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Modality'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|Chemotherapy
+|style="background-color:#ffffbf"|Seems not superior
 |-
-|[https://ascopubs.org/doi/abs/10.1200/JCO.1987.5.7.1056 Leonard et al. 1987]
+|Chemoradiotherapy
-|style="background-color:#1a9851"|Phase III (C)
-|VMP
 |style="background-color:#ffffbf"|Seems not superior
 |-
 |}
-====Chemotherapy====
-*[[Vincristine (Oncovin)]]
-*[[Doxorubicin (Adriamycin)]]
-====Hormonotherapy====
-*[[Prednisolone (Millipred)]]
 ===References===
-# Leonard RC, Cornbleet MA, Kaye SB, Soukop M, White G, Hutcheon AW, Robinson S, Kerr ME, Smyth JF. Mitoxantrone versus doxorubicin in combination chemotherapy for advanced carcinoma of the breast. J Clin Oncol. 1987 Jul;5(7):1056-63. [https://ascopubs.org/doi/abs/10.1200/JCO.1987.5.7.1056 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/3298559 PubMed]
+# Hammel P, Huguet F, van Laethem JL, Goldstein D, Glimelius B, Artru P, Borbath I, Bouché O, Shannon J, André T, Mineur L, Chibaudel B, Bonnetain F, Louvet C; LAP07 Trial Group. Effect of chemoradiotherapy vs chemotherapy on survival in patients with locally advanced pancreatic cancer controlled after 4 months of gemcitabine with or without erlotinib: The LAP07 randomized clinical trial. JAMA. 2016 May 3;315(17):1844-53. [https://jamanetwork.com/journals/jama/fullarticle/10.1001/jama.2016.4324 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/27139057 PubMed]
+=[[Small cell lung cancer]]=
+==IMpower133==
+===Arm 1 (Control)===
+[[Small_cell_lung_cancer#Carboplatin_.26_Etoposide_2|CE]] x 4
+===Arm 2 (Experimental)===
+[[Small_cell_lung_cancer#Carboplatin.2C_Etoposide.2C_Atezolizumab|CE & Atezolizumab]] x 4, then [[Small_cell_lung_cancer#Atezolizumab_maintenance|Atezolizumab maintenance]]
+===Comparative efficacy===
+{| class="wikitable" style="width: 100%; text-align:center;"
+!'''Regimen'''
+![[Levels_of_Evidence#Efficacy|Efficacy]]
+|-
+|With atezolizumab
+| style="background-color:#1a9850" |Superior OS
+|-
+|Without atezolizumab
+| style="background-color:#d73027" |Inferior OS
+|-
+|}
+===References===
+# Horn L, Mansfield AS, Szczęsna A, Havel L, Krzakowski M, Hochmair MJ, Huemer F, Losonczy G, Johnson ML, Nishio M, Reck M, Mok T, Lam S, Shames DS, Liu J, Ding B, Lopez-Chavez A, Kabbinavar F, Lin W, Sandler A, Liu SV; IMpower133 Study Group. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018 Sep 25. [Epub ahead of print] [https://www.nejm.org/doi/full/10.1056/NEJMoa1809064 link to original article] [https://www.ncbi.nlm.nih.gov/pubmed/30280641 PubMed]
-[[Category:Breast cancer regimens]]
+[[Category:General reference pages]]
-[[Category:Historical regimens]]
-[[Category:Disease-specific pages]]
-[[Category:Solid tumors]]

Difference between revisions of "Complex multipart regimens"

Revision as of 03:30, 14 December 2019

Acute myeloid leukemia

COG AAML0531

References

UK MRC AML12

References

UK MRC AML15

References

Acute promyelocytic leukemia

C9710

Arm 1

Arm 2, with ATO3

Comparative efficacy

References

Breast cancer

ABCSG-8

Arm 1, monotherapy (Control)

Arm 2, sequential (Experimental)

Comparative efficacy

References

ACOSOG Z1041

Arm 1 (Control)

Arm 2 (Experimental)

Comparative efficacy

References

ARNO 95

Arm 1, monotherapy (Control)

Arm 2, sequential (Experimental)

Comparative efficacy

References

Assikis et al. 2003

Arm 1

Arm 2

Comparative efficacy

References

BCIRG-005

Arm 1, sequential (Experimental)

Arm 2, concurrent (Control)

Comparative efficacy

References

BCIRG 006

Arm 1, sequential without trastuzumab

Arm 2, sequential with trastuzumab

Arm 3, concurrent with trastuzumab

Comparative efficacy

Comparison 1

Comparison 2

References

BIG 1-98

Arm 1, monotherapy

Arm 2, sequential

Arm 3, monotherapy

Arm 4, sequential

Comparative efficacy

Comparison 1

Comparison 2

Comparison 3

References

BIG 02-98

Arm 1, sequential control

Arm 2, concurrent control

Arm 3, sequential experimental

Arm 4, concurrent experimental

Comparative efficacy

Comparison 1 - addition of docetaxel

Comparison 2 - sequencing

References

BR9601

Arm 1 (Control)

Arm 2 (Experimental)

Comparative efficacy

References

Buzdar et al. 2005

Arm 1 (Control)

Arm 2 (Experimental)

Comparative efficacy

References

CALGB 9741

Arm 1, sequential