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| ===References=== | | ===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. [https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(09)70307-9/fulltext link to original article] [https://pubmed.ncbi.nlm.nih.gov/19906561 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://doi.org/10.1016/s1470-2045(09)70307-9 link to original article] [https://pubmed.ncbi.nlm.nih.gov/19906561 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://doi.org/10.1200/JCO.2011.35.4639 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22105826 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://doi.org/10.1200/JCO.2011.35.4639 link to original article] [https://pubmed.ncbi.nlm.nih.gov/22105826 PubMed] |
| | | |
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".
COG AAML0531
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
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
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
C9710
Note: this trial included a second randomization during the maintenance phase, which is not complex and is therefore not reported here.
Arm 1
Arm 2, with ATO3
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
ABCSG-8
ABCSG-8: Austrian Breast and Colorectal Cancer Study Group 8
Arm 1, monotherapy (Control)
Arm 2, sequential (Experimental)
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; 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
- 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
Arm 1 (Control)
Arm 2 (Experimental)
Comparative efficacy
Approach
|
Efficacy
|
Sequential trastuzumab (C)
|
Did not meet primary endpoint of pCR
|
Concurrent trastuzumab (E)
|
Did not meet primary endpoint of pCR
|
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
- Update: Buzdar AU, Suman VJ, Meric-Bernstam F, Leitch AM, Ellis MJ, Boughey JC, Unzeitig GW, Royce ME, Hunt KK. Disease-Free and Overall Survival Among Patients With Operable HER2-Positive Breast Cancer Treated With Sequential vs Concurrent Chemotherapy: The ACOSOG Z1041 (Alliance) Randomized Clinical Trial. JAMA Oncol. 2019 Jan 1;5(1):45-50. link to original article link to PMC article PubMed
ARNO 95
Arm 1, monotherapy (Control)
Arm 2, sequential (Experimental)
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
- 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
Arm 1
Arm 2
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 006
Arm 1, sequential without trastuzumab
Arm 2, sequential with trastuzumab
Arm 3, concurrent with trastuzumab
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
Arm 1, monotherapy
Arm 2, sequential
Arm 3, monotherapy
Arm 4, sequential
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; BIG. 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
- 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
- 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. 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
- 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
- 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; International Breast Cancer Study Group. 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
- 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
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. 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
- Update: Oakman C, Francis PA, Crown J, Quinaux E, Buyse M, De Azambuja E, Margeli Vila M, Andersson M, Nordenskjöld B, Jakesz R, Thürlimann B, Gutiérrez J, Harvey V, Punzalan L, Dell'orto P, Larsimont D, Steinberg I, Gelber RD, Piccart-Gebhart M, Viale G, Di Leo A. Overall survival benefit for sequential doxorubicin-docetaxel compared with concurrent doxorubicin and docetaxel in node-positive breast cancer--8-year results of the Breast International Group 02-98 phase III trial. Ann Oncol. 2013 May;24(5):1203-11. Epub 2013 Jan 4. link to original article PubMed
- Update: Sonnenblick A, Francis PA, Azim HA Jr, de Azambuja E, Nordenskjöld B, Gutiérez J, Quinaux E, Mastropasqua MG, Ameye L, Anderson M, Lluch A, Gnant M, Goldhirsch A, Di Leo A, Barnadas A, Cortes-Funes H, Piccart M, Crown J. Final 10-year results of the Breast International Group 2-98 phase III trial and the role of Ki67 in predicting benefit of adjuvant docetaxel in patients with oestrogen receptor positive breast cancer. Eur J Cancer. 2015 Aug;51(12):1481-9. Epub 2015 Jun 11. link to original article PubMed
BR9601
Arm 1 (Control)
Arm 2 (Experimental)
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
Arm 1 (Control)
Arm 2 (Experimental)
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
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
Arm 3, "concurrent"
Arm 4, dose-dense "concurrent"
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
Arm 1 (Experimental)
Arm 2 (Control)
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
DEVA
Arm 1 (Control)
Arm 2 (Experimental)
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
Arm A (Control)
Arm B (Experimental)
- Surgery, then AC-Bev x 4 or ddAC-Bev x 4, then wP-Bev
Arm C (Experimental)
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
Arm A (Control)
Arm B (Experimental)
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
Arm 1
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
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
Arm 1 (Control)
Arm 2 (Experimental)
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
- 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
GEICAM 9906
Arm 1 (Control)
Arm 2 (Experimental)
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. 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
Arm 1, FAC (Control)
Arm 2, FAC-wP (Experimental)
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
Arm 1, EC-D (Control)
Arm 2, ET-X (Experimental)
Comparative efficacy
Regimen
|
Efficacy
|
EC-D
|
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
Arm 1, ddAT (Experimental)
Arm 2, AC-T (Experimental)
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
Arm 1A - Control (HER2-negative)
Arm 1B - Control (HER2-positive)
Arm 2A - Experimental (HER2-negative)
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; 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
- 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
Arm 1, "q3EC-P" (Control)
Arm 2, "q3FEC-P" (Experimental)
Arm 3, "q2EC-P" (Experimental)
Arm 4, "q2FEC-P" (Experimental)
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; GIM. 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
Arm 1, CT (Experimental)
Arm 2, T (Experimental)
Arm 3, CTT (Experimental)
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
- 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
Arm 1, IV trastuzumab
Arm 2, SC trastuzumab
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
- 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
HE 10/97
Arm 1 (Experimental)
- Surgery, then ddE x 3, then T x 3, then intensified CMF x 3
Arm 2 (Control)
Comparative efficacy
Regimen
|
Efficacy
|
Experimental arm (with taxane)
|
Did not meet primary endpoint of DFS
|
Control arm
|
Did not meet primary endpoint of DFS
|
References
- Fountzilas G, Skarlos D, Dafni U, Gogas H, Briasoulis E, Pectasides D, Papadimitriou C, Markopoulos C, Polychronis A, Kalofonos HP, Siafaka V, Kosmidis P, Timotheadou E, Tsavdaridis D, Bafaloukos D, Papakostas P, Razis E, Makrantonakis P, Aravantinos G, Christodoulou C, Dimopoulos AM. Postoperative dose-dense sequential chemotherapy with epirubicin, followed by CMF with or without paclitaxel, in patients with high-risk operable breast cancer: a randomized phase III study conducted by the Hellenic Cooperative Oncology Group. Ann Oncol. 2005 Nov;16(11):1762-71. Epub 2005 Sep 7. link to original article PubMed
HORG Polyzos et al. 2010
Arm 1 (Experimental)
Arm 2 (Control)
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
Arm 1
Arm 2
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; HORG. Dose-dense FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive early breast cancer: a multicenter randomized study by the Hellenic Oncology Research Group (HORG). Ann Oncol. 2016 Oct;27(10):1873-8. Epub 2016 Aug 8. link to original article PubMed
IES
IES: Intergroup Exemestane Study
Arm 1, monotherapy (Control)
Arm 2, sequential (Experimental)
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
- 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
- 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
IMpassion031
Arm 1 (Control)
Arm 2 (Experimental)
Comparative efficacy
Regimen
|
Comparative Efficacy
|
Control (no ICI)
|
Inferior pCR rate
|
Experimental (+ ICI)
|
Superior pCR rate
|
References
- IMpassion031: Mittendorf EA, Zhang H, Barrios CH, Saji S, Jung KH, Hegg R, Koehler A, Sohn J, Iwata H, Telli ML, Ferrario C, Punie K, Penault-Llorca F, Patel S, Duc AN, Liste-Hermoso M, Maiya V, Molinero L, Chui SY, Harbeck N. Neoadjuvant atezolizumab in combination with sequential nab-paclitaxel and anthracycline-based chemotherapy versus placebo and chemotherapy in patients with early-stage triple-negative breast cancer (IMpassion031): a randomised, double-blind, phase 3 trial. Lancet. 2020 Sep 18:S0140-6736(20)31953-X. Epub ahead of print. link to original article PubMed
IRST-IBIS-03
Arm 1
Arm 2
Comparative efficacy
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
KEYNOTE-522
Arm 1, control
Arm 2, experimental
Comparative efficacy
Regimen
|
Efficacy
|
Control arm
|
Inferior pCR rate
|
Pembrolizumab arm
|
Superior pCR rate
|
References
- Schmid P, Cortes J, Pusztai L, McArthur H, Kümmel S, Bergh J, Denkert C, Park YH, Hui R, Harbeck N, Takahashi M, Foukakis T, Fasching PA, Cardoso F, Untch M, Jia L, Karantza V, Zhao J, Aktan G, Dent R, O'Shaughnessy J; KEYNOTE-522 Investigators. Pembrolizumab for Early Triple-Negative Breast Cancer. N Engl J Med. 2020 Feb 27;382(9):810-821. link to original article PubMed
Kümmel et al. 2006
Arm 1, control
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
Arm 1, control
Arm 2, experimental
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
Arm 1, sequential
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
Arm 1 (Experimental)
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
- 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
The taxane used in this trial was paclitaxel.
Arm 1, no trastuzumab (Control)
Arm 2, sequential trastuzumab (Experimental)
Arm 3, concurrent trastuzumab (Experimental)
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
- 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
- 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
Arm 1, CEF (Control)
Arm 2, AC/T (Control)
Arm 3, ddEC/T (Experimental)
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
Arm 1 (Control)
Arm 2 (Experimental)
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
Arm 1, trastuzumab (C)
Arm 1, lapatinib (E)
Arm 3, lapatinib & trastuzumab (E)
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
- 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
Arm 1, EC-ddT
Arm 2, ddT-EC
Arm 3, EC-ddTG
Arm 4, ddTG-EC
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
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)
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
- 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
Arm 1, no taxane (Control)
Arm 2, preoperative taxane (Experimental)
Arm 3, postoperative taxane (Experimental)
Comparative efficacy
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. 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-38
Arm 1, sequential without gemcitabine (Control)
Arm 2, sequential with gemcitabine (Experimental)
Arm 3, concurrent
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
Arm 1 - Control
Arm 2
Arm 3
Arm 4
Arm 5
Arm 6
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
- 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
Arm 1 - Control
Arm 2 - Control
Arm 3
Arm 4
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
Arm 1, control
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
Arm 1, chemo first
Arm 2, RT first
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
Arm 1, trastuzumab (control)
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
Arm 1 (control)
Arm 2 (experimental)
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 original article PubMed
SWOG-8814
Arm 1 (Control)
Arm 2, CAF-T (Experimental)
Arm 3, CAFT (Experimental)
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
Arm 1 (Experimental)
Arm 2 (Control)
Arm 3 (Control)
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
Arm 1 (Experimental)
Arm 2 (Experimental)
Arm 3 (Experimental)
Arm 4 (Control)
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
Arm 1, monotherapy (Control)
Arm 2, sequential (Experimental)
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
- 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
Arm A
Arm B
Arm C
Comparative efficacy
Note: this was a cardiac safety study; efficacy findings are not reported.
References
- 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
Arm 1 (Control)
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
CAIRO
Arm 1, sequential single agent (Control)
Arm 2, sequential combinations (Experimental)
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
Arm 1, sequential (Control)
Arm 2, combination (Experimental)
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
SWOG S8736
Arm 1 - Control
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
PORTEC-3
Arm 1 - Control
Arm 2 - Experimental
Comparative efficacy
Modality
|
Efficacy
|
Radiotherapy
|
Seems to have inferior OS (*)
|
Chemoradiotherapy
|
Seems to have superior OS (*)
|
Note: reported efficacy is based on the 2019 update.
References
- de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, Ottevanger PB, Ledermann JA, Khaw P, Colombo A, Fyles A, Baron MH, Jürgenliemk-Schulz IM, Kitchener HC, Nijman HW, Wilson G, Brooks S, Carinelli S, Provencher D, Hanzen C, Lutgens LCHW, Smit VTHBM, Singh N, Do V, D'Amico R, Nout RA, Feeney A, Verhoeven-Adema KW, Putter H, Creutzberg CL; PORTEC study group. Adjuvant chemoradiotherapy versus radiotherapy alone for women with high-risk endometrial cancer (PORTEC-3): final results of an international, open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2018 Mar;19(3):295-309. Epub 2018 Feb 12. link to original article link to PMC article PubMed
- Update: de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, Haie-Meder C, Ottevanger PB, Ledermann JA, Khaw P, D'Amico R, Fyles A, Baron MH, Jürgenliemk-Schulz IM, Kitchener HC, Nijman HW, Wilson G, Brooks S, Gribaudo S, Provencher D, Hanzen C, Kruitwagen RF, Smit VTHBM, Singh N, Do V, Lissoni A, Nout RA, Feeney A, Verhoeven-Adema KW, Putter H, Creutzberg CL; PORTEC Study Group. Adjuvant chemoradiotherapy versus radiotherapy alone in women with high-risk endometrial cancer (PORTEC-3): patterns of recurrence and post-hoc survival analysis of a randomised phase 3 trial. Lancet Oncol. 2019 Sep;20(9):1273-1285. Epub 2019 Jul 22. Erratum in: Lancet Oncol. 2019 Sep;20(9):e468. link to original article PubMed
GALLIUM
Arm 1 - Control
Arm 2 - Experimental
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
Arm 1 - Control
Arm 2 - Experimental
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
Arm 1 - Control
Arm 2 - Experimental
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
- 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
Arm 1 - Control
Arm 2 - Experimental
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
Arm 1
Arm 2
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
Arm 1 - Control
Arm 2 - Experimental
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
AVAglio
Arm 1, control
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
Arm 1, control
Arm 2, experimental
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; EORTC 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
Arm 1, control
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
Arm 1, control
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
EORTC 24954
Arm 1, control
Arm 2, experimental
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)
Arm 2, concurrent chemoradiotherapy (Experimental)
Arm 3, radiotherapy (Experimental)
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
- 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
EORTC 20012
Arm 1
Arm 2
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 BEACOPPescalated plus four cycles of BEACOPPbaseline 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
Arm 1
Arm 2
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. 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
Arm 1
Arm 2
Arm 3
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
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
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
- 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
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
Arm 2
Arm 3
Arm 4
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
Arm 1
- eBEACOPP x 8, then ISRT x 30 Gy for patients with initial bulky disease or residual disease
Arm 2
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
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
- 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
Arm 1
Arm 2
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
GHSG HD17
Arm 1 (Control)
Arm 2 (Experimental)
Comparative efficacy
Chemotherapy
|
Efficacy
|
2+2 -> IFRT
|
Non-inferior PFS
|
PET-guided therapy
|
Non-inferior PFS
|
References
- Borchmann P, Plütschow A, Kobe C, Greil R, Meissner J, Topp MS, Ostermann H, Dierlamm J, Mohm J, Thiemer J, Sökler M, Kerkhoff A, Ahlborn M, Halbsguth TV, Martin S, Keller U, Balabanov S, Pabst T, Vogelhuber M, Hüttmann A, Wilhelm M, Zijlstra JM, Moccia A, Kuhnert G, Bröckelmann PJ, von Tresckow B, Fuchs M, Klimm B, Rosenwald A, Eich H, Baues C, Marnitz S, Hallek M, Diehl V, Dietlein M, Engert A. PET-guided omission of radiotherapy in early-stage unfavourable Hodgkin lymphoma (GHSG HD17): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2021 Feb;22(2):223-234. link to original article PubMed NCT01356680
GSM-HD
Arm 1
Arm 2
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
Arm 1
Arm 2
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. 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
Note: this randomization was for patients with unfavorable risk.
Arm 1
Arm 2
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; ECOG. 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
- 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; ECOG. 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
MCL Younger
Arm 1 (Control)
Arm 2 (Experimental)
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
HOVON-50
Arm 1 (Control)
Arm 2 (Experimental)
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
- 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
CONVINCE
Arm 1 (Control)
Arm 2 (Experimental)
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
Arm 1 (Control)
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
Arm 1 (Control)
Arm 2, with bevacizumab (Experimental)
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
- Subgroup analysis: Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; ECOG. 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
Arm 1, "early" erlotinib
Arm 2, "late" 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
Arm 1 (Control)
Arm 2, with pembrolizumab (Experimental)
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
Arm 1 (Control)
- Investigator's choice of:
Arm 2, with pembrolizumab (Experimental)
- Investigator's choice of:
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
Arm 1 (Control)
- Investigator's choice of:
Arm 2, with pembrolizumab (Experimental)
- Investigator's choice of:
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
Arm 1
Arm 2
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
Arm 1, sequential
Arm 2, concurrent
Arm 3, concurrent
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
GOG 114
Arm 1 - Control
Arm 2 - Experimental
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
Arm 1 - Control
Arm 2 - Experimental
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
GERCOR LAP07
This study had two randomizations; the second only occurred if patients were progression-free after 4 cycles.
Arm 1 - Control
Arm 2 - Experimental
Arm 3 - Experimental
Arm 4 - Experimental
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
CinClare
Arm 1 (Control)
Capecitabine & RT, then CapeOx x 1, then TME, then CapeOx x 5
Arm 2 (Experimental)
Genotype-dosed CAPIRI & RT, then genotype-dosed CAPIRI x 1, then TME, then CapeOx x 5
Comparative efficacy
Regimen
|
Efficacy
|
Control
|
Inferior pCR rate
|
Experimental
|
Superior pCR rate
|
References
- Zhu J, Liu A, Sun X, Liu L, Zhu Y, Zhang T, Jia J, Tan S, Wu J, Wang X, Zhou J, Yang J, Zhang C, Zhang H, Zhao Y, Cai G, Zhang W, Xia F, Wan J, Zhang H, Shen L, Cai S, Zhang Z. Multicenter, Randomized, Phase III Trial of Neoadjuvant Chemoradiation With Capecitabine and Irinotecan Guided by UGT1A1 Status in Patients With Locally Advanced Rectal Cancer. J Clin Oncol. 2020 Dec 20;38(36):4231-4239. Epub 2020 Oct 29. link to original article link to PMC article PubMed NCT02605265
RAPIDO
Arm 1 (Control)
Capecitabine & RT, then TME, then (per hospital policy) CapeOx x 8 or FOLFOX4 x 12
Arm 2 (Experimental)
RT, then CapeOx x 6 or FOLFOX4 x 9, then TME
Comparative efficacy
Regimen
|
Efficacy
|
RT, then chemo, then TME
|
Seems to have superior DRTF
|
Chemo-RT, then TME, +/- adjuvant chemo
|
Seems to have inferior DRTF
|
References
- Bahadoer RR, Dijkstra EA, van Etten B, Marijnen CAM, Putter H, Kranenbarg EM, Roodvoets AGH, Nagtegaal ID, Beets-Tan RGH, Blomqvist LK, Fokstuen T, Ten Tije AJ, Capdevila J, Hendriks MP, Edhemovic I, Cervantes A, Nilsson PJ, Glimelius B, van de Velde CJH, Hospers GAP; RAPIDO collaborative investigators. Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial. Lancet Oncol. 2021 Jan;22(1):29-42. Epub 2020 Dec 7. link to original article PubMed
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