Complex multipart regimens

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

Breast cancer

BCIRG-005

Arm 1, sequential

• AC, then T

Arm 2, concurrent

• TAC

Comparative efficacy

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

References

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

BCIRG 006

Arm 1, sequential without trastuzumab

• AC, then T

Arm 2, sequential with trastuzumab

• AC, then TH

Arm 3, concurrent with trastuzumab

• TCH

Comparative efficacy

• Analyzed using a step-down design

Comparison 1

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

Comparison 2

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

References

1. 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

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.

Arm 1, sequential

• A, then T, then C

Arm 2, dose-dense sequential

• ddA, then ddT, then ddC

Arm 3, "concurrent"

• AC, then T

Arm 4, dose-dense "concurrent"

• ddAC, then ddT

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

1. 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

GEICAM 9906

Arm 1

• FEC x 6

Arm 2

• FEC x 4, then T

Comparative efficacy

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

References

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

NSABP B-38

Arm 1, sequential without gemcitabine

• ddAC, then ddP

Arm 1, sequential with gemcitabine

• ddAC, then ddPG

Arm 3, concurrent

• TAC

Comparative efficacy

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

References

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