Breast cancer

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Note: this is one of the most complicated pages on HemOnc.org, owing to the large number of breast cancer regimens. Please read these notes to ease your navigation:

  • The page is laid out in the logical order that patients might receive systemic treatment for breast cancer:
  1. Neoadjuvant chemotherapy and chemoradiation (currently missing many regimens)
  2. Adjuvant chemotherapy
  3. Adjuvant endocrine therapy
  4. Endocrine therapy for metastatic disease
  5. Chemotherapy for metastatic disease
  • Adjuvant chemotherapy is separated by HER-2 status, since there are nearly as many regimens for HER-2 positive breast cancer as there are for HER-2 negative breast cancer
  • Chemotherapy for metastatic disease is also separated by HER-2 status, and single-agent regimens are additionally separated for ease of navigation
  • Because docetaxel and paclitaxel are both often abbreviated as "T," we try to always make clear in the regimen name which agent is being used
143 regimens on this page
330 variants on this page


Neoadjuvant chemotherapy, HER-2 positive

Docetaxel, Pertuzumab, Trastuzumab

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Regimen

Study Evidence Comparator Efficacy
Gianni et al. 2011 (NeoSphere) Randomized Phase II Docetaxel & Pertuzumab Seems not superior
Pertuzumab & Trastuzumab Seems not superior
TH Seems to have superior pCR rate

Chemotherapy

21-day cycle for 4 cycles, then surgery

After surgery, patients were treated with adjuvant FEC & H.

References

  1. Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Jan;13(1):25-32. Epub 2011 Dec 6. link to original article contains verified protocol PubMed
    1. Update: Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, Starosławska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi GV, Magazzù D, McNally V, Douthwaite H, Ross G, Valagussa P. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016 Jun;17(6):791-800. Epub 2016 May 11. link to original article PubMed

TCHP (Docetaxel)

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TCHP: Taxotere (Docetaxel), Carboplatin, Herceptin (Trastuzumab), Pertuzumab

Regimen

Study Evidence Comparator Efficacy
Schneeweiss et al. 2013 (TRYPHAENA) Randomized Phase II FEC & HP -> THP Not reported
FEC -> THP Not reported

Neoadjuvant chemotherapy

21-day cycle for 6 cycles, then surgery

Post-operative chemotherapy

  • Trastuzumab (Herceptin) 6 mg/kg IV once on day 1
  • "Further adjuvant treatment (radiotherapy, chemotherapy, hormonal treatment) according to local guidelines."

21-day cycles, to complete 1 year of total therapy with Trastuzumab (Herceptin)

References

  1. 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. link to original article contains verified protocol PubMed

T (Taxol) -> AC

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T -> AC: Taxol (Paclitaxel) followed by Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Rugo et al. 2016 (I-SPY 2) Adaptively Randomized Phase II Paclitaxel, Carboplatin, Veliparib -> AC Seems to have inferior pCR rate

T portion

12-week course, followed by:

AC portion

14- to 21-day cycle for 4 cycles, followed by surgery

References

  1. Rugo HS, Olopade OI, DeMichele A, Yau C, van 't Veer LJ, Buxton MB, Hogarth M, Hylton NM, Paoloni M, Perlmutter J, Symmans WF, Yee D, Chien AJ, Wallace AM, Kaplan HG, Boughey JC, Haddad TC, Albain KS, Liu MC, Isaacs C, Khan QJ, Lang JE, Viscusi RK, Pusztai L, Moulder SL, Chui SY, Kemmer KA, Elias AD, Edmiston KK, Euhus DM, Haley BB, Nanda R, Northfelt DW, Tripathy D, Wood WC, Ewing C, Schwab R, Lyandres J, Davis SE, Hirst GL, Sanil A, Berry DA, Esserman LJ; I-SPY 2 Investigators. Adaptive Randomization of Veliparib-Carboplatin Treatment in Breast Cancer. N Engl J Med. 2016 Jul 7;375(1):23-34. link to original article contains verified protocol PubMed

TH (Taxol) -> AC

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TH -> AC: Taxol (Paclitaxel) & Herceptin (Trastuzumab) followed by Adriamycin (Doxorubicin) & Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Park et al. 2016 (I-SPY 2) Adaptively Randomized Phase II Paclitaxel & Neratinib -> AC Seems to have inferior pCR rate

TH portion

12-week course, followed by:

AC portion

14- to 21-day cycle for 4 cycles, followed by surgery

References

  1. Park JW, Liu MC, Yee D, Yau C, van 't Veer LJ, Symmans WF, Paoloni M, Perlmutter J, Hylton NM, Hogarth M, DeMichele A, Buxton MB, Chien AJ, Wallace AM, Boughey JC, Haddad TC, Chui SY, Kemmer KA, Kaplan HG, Isaacs C, Nanda R, Tripathy D, Albain KS, Edmiston KK, Elias AD, Northfelt DW, Pusztai L, Moulder SL, Lang JE, Viscusi RK, Euhus DM, Haley BB, Khan QJ, Wood WC, Melisko M, Schwab R, Helsten T, Lyandres J, Davis SE, Hirst GL, Sanil A, Esserman LJ, Berry DA; I-SPY 2 Investigators. Adaptive Randomization of Neratinib in Early Breast Cancer. N Engl J Med. 2016 Jul 7;375(1):11-22. link to original article contains verified protocol PubMed

TH (Taxol) -> FEC & H

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TH -> FEC & H: Taxol (Paclitaxel) & Herceptin (Trastuzumab) followed by Fluorouracil, Epirubicin, Cyclophosphamide, Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Buzdar et al. 2005 Randomized T -> FEC Seems to have superior pCR rate

TH portion

  • Paclitaxel (Taxol) 225 mg/m2 IV continuous infusion over 24 hours on day 1
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 4 mg/kg IV once on day 1 prior to first dose of paclitaxel, then 2 mg/kg IV once per day on days 8 & 15
    • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 4 cycles, followed by:

FEC & H portion

21-day cycle for 4 cycles, followed by surgery

References

  1. 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

Adjuvant chemotherapy, HER-2 negative

AC

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AC: Adriamycin (Doxorubicin), Cyclophosphamide

Example orders

Regimen

Study Evidence Comparator Efficacy
Fisher et al. 2001 (NSABP B-23) Phase III CMF Seems not superior
Henderson et al. 2003 (INT C9344) Phase III AC -> T
High-dose AC -> T
Very-high-dose AC -> T 		Inferior OS
High-dose AC
Very-high-dose AC 		Seems not superior
Mamounas et al. 2005 (NSABP B-28) Phase III AC -> T Inferior DFS
Jones et al. 2006 (US Oncology Trial 9735) Phase III TC Seems to have inferior OS

Chemotherapy

21-day cycle for 4 cycles

Patients in NSABP B-23 were subsequently randomized to tamoxifen versus no further treatment.

References

  1. Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, Dimitrov NV, Atkins JN, Abramson N, Merajver S, Romond EH, Kardinal CG, Shibata HR, Margolese RG, Farrar WB. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001 Feb 15;19(4):931-42. link to original article PubMed
  2. Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L. Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003 Mar 15;21(6):976-83. link to original article PubMed
  3. Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol. 2005 Jun 1;23(16):3686-96. Epub 2005 May 16. link to original article PubMed
  4. Jones SE, Savin MA, Holmes FA, O'Shaughnessy JA, Blum JL, Vukelja S, McIntyre KJ, Pippen JE, Bordelon JH, Kirby R, Sandbach J, Hyman WJ, Khandelwal P, Negron AG, Richards DA, Anthony SP, Mennel RG, Boehm KA, Meyer WG, Asmar L. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol. 2006 Dec 1;24(34):5381-7. Erratum in: J Clin Oncol. 2007 May 1;25(13):1819. link to original article PubMed
    1. Update: Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL, Sandbach J, Hyman WJ, Richards DA, Mennel RG, Boehm KA, Meyer WG, Asmar L, Mackey D, Riedel S, Muss H, Savin MA. Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. J Clin Oncol. 2009 Mar 10;27(8):1177-83. Epub 2009 Feb 9. link to original article PubMed

AC -> T (Taxol)

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AC -> T: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel)

Example orders

Regimen #1, q3wk paclitaxel (175 mg/m2)

Study Evidence Comparator Efficacy
Henderson et al. 2003 (INT C9344) Phase III AC
High-dose AC
Very-high-dose AC 		Superior OS
High-dose AC -> T
Very-high-dose AC -> T 		Seems not superior
Citron et al. 2003 (CALGB 9741) Phase III A -> T -> C Seems not superior
ddA -> ddT -> ddC
ddAC -> T 		Seems to have inferior OS
Romond et al. 2005 (NSABP B-31) Phase III AC -> TH Inferior OS
Sparano et al. 2008 (ECOG E1199) Phase III AC -> T (Taxol), weekly dosing Inferior OS
AC -> T (Taxotere), q3wk dosing Seems to have inferior DFS
AC -> T (Taxotere), weekly dosing Seems not superior

After 2003, patients enrolled in NSABP B-31 could also receive weekly paclitaxel at the investigator's discretion.

AC portion

21-day cycle for 4 cycles, followed by:

T portion

3-week cycle for 4 cycles

Regimen #2, weekly paclitaxel

Study Evidence Comparator Efficacy
Romond et al. 2005 (NSABP B-31/NCCTG N9831) Phase III AC -> T -> H
AC -> TH 		Inferior OS
Sparano et al. 2008 (ECOG E1199) Phase III AC -> T (Taxol), q3wk dosing Superior OS
AC -> T (Taxotere), q3wk dosing
AC -> T (Taxotere), weekly dosing 		Not reported

This paclitaxel dosing schedule was an option after 2003 in NSABP B-31, and was used for all patients in NCCTG N9831.

AC portion

21-day cycle for 4 cycles, followed by:

T portion

12-week course

Regimen #3, q3wk paclitaxel (225 mg/m2)

Study Evidence Comparator Efficacy
Mamounas et al. 2005 (NSABP B-28) Phase III AC Superior DFS

AC portion

21-day cycle for 4 cycles, followed by:

T portion

3-week cycle for 4 cycles

References

  1. Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L. Improved outcomes from adding sequential Paclitaxel but not from escalating Doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003 Mar 15;21(6):976-83. link to original article PubMed
  2. 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
  3. Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol. 2005 Jun 1;23(16):3686-96. Epub 2005 May 16. link to original article PubMed
  4. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. link to original article PubMed
    1. Update: Perez EA, 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
  5. Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. link to original article PubMed
    1. Update: Sparano JA, Zhao F, Martino S, Ligibel JA, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Long-Term Follow-Up of the E1199 Phase III Trial Evaluating the Role of Taxane and Schedule in Operable Breast Cancer. J Clin Oncol. 2015 Jul 20;33(21):2353-60. Epub 2015 Jun 15. link to original article PubMed

AC -> T (Taxotere)

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AC -> T: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxotere (Docetaxel)

Example orders

Regimen #1, q3wk docetaxel

Study Evidence Comparator Efficacy
Sparano et al. 2008 (ECOG E1199) Phase III AC -> T (Taxol), q3wk dosing Seems to have superior DFS
AC -> T (Taxol), weekly dosing
AC -> T (Taxotere), weekly dosing 		Not reported
Eiermann et al. 2011 (BCIRG-005) Phase III TAC Seems not superior
Slamon et al. 2011 (BCIRG 006) Phase III AC -> TH Inferior OS
TCH Seems to have inferior OS

AC portion

21-day cycle for 4 cycles, followed by:

T portion

21-day cycle for 4 cycles

Regimen #2, weekly docetaxel

Study Evidence Comparator Efficacy
Sparano et al. 2008 (ECOG E1199) Phase III AC -> T (Taxol), q3wk dosing Seems not superior
AC -> T (Taxol), weekly dosing
AC -> T (Taxotere), q3wk dosing 		Not reported

AC portion

21-day cycle for 4 cycles, followed by:

T portion

12-week course

References

  1. Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008 Apr 17;358(16):1663-71. link to original article PubMed
    1. Update: Sparano JA, Zhao F, Martino S, Ligibel JA, Perez EA, Saphner T, Wolff AC, Sledge GW Jr, Wood WC, Davidson NE. Long-Term Follow-Up of the E1199 Phase III Trial Evaluating the Role of Taxane and Schedule in Operable Breast Cancer. J Clin Oncol. 2015 Jul 20;33(21):2353-60. Epub 2015 Jun 15. link to original article PubMed
  2. 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
  3. 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 PubMed

CEF; FEC

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CEF: Cyclophosphamide, Epirubicin, Fluorouracil
FEC: Fluorouracil, Epirubicin, Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Levine et al. 1998 (NCIC CTG MA5) Phase III CMF Superior RFS
Coombes et al. 2005 (ICCG HDT trial) Phase III FEC x 3 -> HDT Seems not superior
Roché et al. 2006 (FNCLCC PACS 01) Phase III FEC-D Seems to have inferior OS
Martín et al. 2008 (GEICAM 9906) Phase III FEC-P Inferior DFS

Chemotherapy

28-day cycle for 6 cycles

References

  1. Coombes RC, Bliss JM, Wils J, Morvan F, Espié M, Amadori D, Gambrosier P, Richards M, Aapro M, Villar-Grimalt A, McArdle C, Pérez-López FR, Vassilopoulos P, Ferreira EP, Chilvers CE, Coombes G, Woods EM, Marty M. Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. The International Collaborative Cancer Group. J Clin Oncol. 1996 Jan;14(1):35-45. link to original article PubMed
  2. Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, Findlay B, Warr D, Bowman D, Myles J, Arnold A, Vandenberg T, MacKenzie R, Robert J, Ottaway J, Burnell M, Williams CK, Tu D. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1998 Aug;16(8):2651-8. link to original article PubMed
    1. Update: Levine MN, Pritchard KI, Bramwell VH, Shepherd LE, Tu D, Paul N; National Cancer Institute of Canada Clinical Trials Group.. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol. 2005 Aug 1;23(22):5166-70. link to original article PubMed
  3. Coombes RC, Howell A, Emson M, Peckitt C, Gallagher C, Bengala C, Tres A, Welch R, Lawton P, Rubens R, Woods E, Haviland J, Vigushin D, Kanfer E, Bliss JM. High dose chemotherapy and autologous stem cell transplantation as adjuvant therapy for primary breast cancer patients with four or more lymph nodes involved: long-term results of an international randomised trial. Ann Oncol. 2005 May;16(5):726-34. Epub 2005 Apr 7. link to original article PubMed
  4. Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulié P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Genève J, Asselain B. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006 Dec 20;24(36):5664-71. Epub 2006 Nov 20. link to original article PubMed
  5. 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 protocol PubMed

CMF

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CMF: Cyclophosphamide, Methotrexate, Fluorouracil

Regimen #1, IV cyclophosphamide

Study Evidence Comparator Efficacy
Schmid et al. 2007 (TABLE) Phase III Leuprolide Inferior OS

Chemotherapy

28-day cycle for 6 cycles

Regimen #2, Classic CMF x 6 cycles

Study Evidence Comparator Efficacy
Levine et al. 1998 (NCIC CTG MA5) Phase III CEF Inferior RFS
Fisher et al. 2001 (NSABP B-23) Phase III AC Seems not superior
Piccart et al. 2001 Phase III Full-dose EC Seems not superior
Moderate-dose EC Not reported
Hutchins et al. 2005 (INT-0102) Phase III CAF Seems to have inferior OS
Poole et al. 2006 (NEAT) Phase III Epirubicin -> CMF Inferior OS

Chemotherapy

28-day cycle for 6 cycles

Patients in NSABP B-23 and INT-0102 were randomized to receive tamoxifen x 5 years versus no further treatment.

Regimen #3, Modified CMF

Study Evidence Comparator Efficacy
Poole et al. 2006 (BR9601) Phase III Epirubicin -> CMF Inferior OS

Chemotherapy

21-day cycle for 8 cycles

Regimen #4, Classic CMF

Study Evidence Comparator Efficacy
Bonadonna et al. 1976 Phase III Observation Superior RFS

Chemotherapy

28-day cycle for 12 cycles

References

  1. Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, De Lena M, Tancini G, Bajetta E, Musumeci R, Veronesi U. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976 Feb 19;294(8):405-10. link to original article contains verified protocol PubMed
    1. Update: Bonadonna G, Rossi A, Valagussa P, Banfi A, Veronesi U. The CMF program for operable breast cancer with positive axillary nodes. Updated analysis on the disease-free interval, site of relapse and drug tolerance. Cancer. 1977 Jun;39(6 Suppl):2904-15. link to original article PubMed
    2. Update: Bonadonna G, Valagussa P, Rossi A, Tancini G, Brambilla C, Zambetti M, Veronesi U. Ten-year experience with CMF-based adjuvant chemotherapy in resectable breast cancer. Breast Cancer Res Treat. 1985;5(2):95-115. PubMed
  2. Tormey DC, Gray R, Gilchrist K, Grage T, Carbone PP, Wolter J, Woll JE, Cummings FJ. Adjuvant chemohormonal therapy with cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen compared with CMF for premenopausal breast cancer patients. An Eastern Cooperative Oncology Group trial. Cancer. 1990 Jan 15;65(2):200-6. link to original article PubMed
  3. Coombes RC, Bliss JM, Wils J, Morvan F, Espié M, Amadori D, Gambrosier P, Richards M, Aapro M, Villar-Grimalt A, McArdle C, Pérez-López FR, Vassilopoulos P, Ferreira EP, Chilvers CE, Coombes G, Woods EM, Marty M. Adjuvant cyclophosphamide, methotrexate, and fluorouracil versus fluorouracil, epirubicin, and cyclophosphamide chemotherapy in premenopausal women with axillary node-positive operable breast cancer: results of a randomized trial. The International Collaborative Cancer Group. J Clin Oncol. 1996 Jan;14(1):35-45. link to original article PubMed
  4. Review: Goldhirsch A, Colleoni M, Coates AS, Castiglione-Gertsch M, Gelber RD. Adding adjuvant CMF chemotherapy to either radiotherapy or tamoxifen: are all CMFs alike? The International Breast Cancer Study Group (IBCSG). Ann Oncol. 1998 May;9(5):489-93. link to original article contains protocol PubMed
  5. Levine MN, Bramwell VH, Pritchard KI, Norris BD, Shepherd LE, Abu-Zahra H, Findlay B, Warr D, Bowman D, Myles J, Arnold A, Vandenberg T, MacKenzie R, Robert J, Ottaway J, Burnell M, Williams CK, Tu D. Randomized trial of intensive cyclophosphamide, epirubicin, and fluorouracil chemotherapy compared with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer. National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1998 Aug;16(8):2651-8. link to original article PubMed
    1. Update: Levine MN, Pritchard KI, Bramwell VH, Shepherd LE, Tu D, Paul N; National Cancer Institute of Canada Clinical Trials Group.. Randomized trial comparing cyclophosphamide, epirubicin, and fluorouracil with cyclophosphamide, methotrexate, and fluorouracil in premenopausal women with node-positive breast cancer: update of National Cancer Institute of Canada Clinical Trials Group Trial MA5. J Clin Oncol. 2005 Aug 1;23(22):5166-70. link to original article PubMed
  6. Fisher B, Anderson S, Tan-Chiu E, Wolmark N, Wickerham DL, Fisher ER, Dimitrov NV, Atkins JN, Abramson N, Merajver S, Romond EH, Kardinal CG, Shibata HR, Margolese RG, Farrar WB. Tamoxifen and chemotherapy for axillary node-negative, estrogen receptor-negative breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-23. J Clin Oncol. 2001 Feb 15;19(4):931-42. link to original article PubMed
  7. Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M, Nogaret JM. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol. 2001 Jun 15;19(12):3103-10. link to original article PubMed
  8. Hutchins LF, Green SJ, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol. 2005 Nov 20;23(33):8313-21. link to original article PubMed
  9. 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
  10. Schmid P, Untch M, Kossé V, Bondar G, Vassiljev L, Tarutinov V, Lehmann U, Maubach L, Meurer J, Wallwiener D, Possinger K. Leuprorelin acetate every-3-months depot versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in premenopausal patients with node-positive breast cancer: the TABLE study. J Clin Oncol. 2007 Jun 20;25(18):2509-15. link to original article contains verified protocol PubMed

ddAC

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ddAC: dose-dense Adriamycin (Doxorubicin), Cyclophosphamide

Example orders

Regimen

Study Evidence Comparator Efficacy
Shulman et al. 2012 (CALGB 40101) Phase III ddAC x 6 Seems not superior
Paclitaxel x 4 Seems not superior
Paclitaxel x 6 Seems not superior

Note: CALGB 40101 originally specified 21-day cycles but was amended to 14-day cycles after results of CALGB 9741 - Citron et al. 2003 were available.

Chemotherapy

Supportive medications

  • Recommended growth factor support with one of the following:
    • Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Sargramostim (Leukine) 250 to 500 mcg/m2 SC on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Pegfilgrastim (Neulasta) 6 mg SC, administered once 24 to 36 hours after chemotherapy

14-day cycle for 4 cycles

References

  1. Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article contains verified protocol link to study protocol PDF PubMed
    1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. link to PMC article PubMed

ddAC -> T (Taxol)

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ddAC -> T: dose-dense Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel)

Example orders

Regimen

Study Evidence Comparator Efficacy
Citron et al. 2003 (CALGB 9741) Phase III A -> T -> C
AC -> T 		Seems to have superior OS
ddA -> ddT -> ddC
 Seems not superior

ddAC portion

Supportive medications

  • (varies depending on reference):
  • Citron et al. 2003: Filgrastim (Neupogen) 5 mcg/kg (rounded to either 300 or 480 mcg) SC once per day on days 3 to 10 (note: Citron et al. 2003 says the schedule was "filgrastim days 3 to 10 of each cycle (a total of seven doses)," so it is unclear whether 7 or 8 doses was actually used).
  • Burstein et al. 2005:

14-day cycle for 4 cycles, followed by:

T portion

14-day cycle for 4 cycles

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
  2. Burstein HJ, Parker LM, Keshaviah A, Doherty J, Partridge AH, Schapira L, Ryan PD, Younger J, Harris LN, Moy B, Come SE, Schumer ST, Bunnell CA, Haldoupis M, Gelman R, Winer EP. Efficacy of pegfilgrastim and darbepoetin alfa as hematopoietic support for dose-dense every-2-week adjuvant breast cancer chemotherapy. J Clin Oncol. 2005 Nov 20;23(33):8340-7. link to original article contains verified protocol PubMed

ddA -> ddT (Paclitaxel) -> ddC

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ddA -> ddT -> ddC: Sequential dose-dense Adriamycin (Doxorubicin), Taxol (Paclitaxel), Cyclophosphamide

Regimen #1

Study Evidence
Kahan et al. 2005 Phase II

ddA portion

Supportive medications

14-day cycle for 4 cycles, followed by:

ddT portion

Supportive medications

14-day cycle for 4 cycles, followed by:

ddC portion

Supportive medications

14-day cycle for 4 cycles

Regimen #2, alternate dosing

Alternate dosing per NCCN (primary reference not found).

ddA portion

Supportive medications

14-day cycle for 4 cycles, followed by:

ddT portion

Supportive medications

14-day cycle for 4 cycles, followed by:

ddC portion

Supportive medications

14-day cycle for 4 cycles

References

  1. Kahan Z, Uhercsak G, Hajnal-Papp R, Boda K, Thurzo L. Dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy is well tolerated and safe in high-risk early breast cancer. Oncology. 2005;68(4-6):446-53. Epub 2005 Jul 13. link to original article PubMed
    1. Update: Kelemen G, Uhercsák G, Ormándi K, Eller J, Thurzó L, Kahán Z. Long-term efficiency and toxicity of adjuvant dose-dense sequential adriamycin-Paclitaxel-cyclophosphamide chemotherapy in high-risk breast cancer. Oncology. 2010;78(3-4):271-3. Epub 2010 Jun 7. link to original article PubMed

EC

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EC: Epirubicin, Cyclophosphamide

Regimen #1, high-dose EC

Study Evidence Comparator Efficacy
Piccart et al. 2001 Phase III CMF Seems not superior
Moderate-dose EC Seems to have superior OS

Chemotherapy

21-day cycle for 8 cycles

Regimen #2, moderate-dose EC

Study Evidence Comparator Efficacy
Piccart et al. 2001 Phase III CMF Not reported
High-dose EC Seems to have inferior OS

Chemotherapy

21-day cycle for 8 cycles

References

  1. Piccart MJ, Di Leo A, Beauduin M, Vindevoghel A, Michel J, Focan C, Tagnon A, Ries F, Gobert P, Finet C, Closon-Dejardin MT, Dufrane JP, Kerger J, Liebens F, Beauvois S, Bartholomeus S, Dolci S, Lobelle JP, Paesmans M, Nogaret JM. Phase III trial comparing two dose levels of epirubicin combined with cyclophosphamide with cyclophosphamide, methotrexate, and fluorouracil in node-positive breast cancer. J Clin Oncol. 2001 Jun 15;19(12):3103-10. link to original article PubMed

Epirubicin -> CMF

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CMF: Cyclophosphamide, Methotrexate, Fluorouracil

Regimen #1

Study Evidence Comparator Efficacy
Poole et al. 2006 (NEAT) Phase III Classic CMF Superior OS

Epirubicin portion

3-week cycle for 4 cycles, followed by:

CMF portion

28-day cycle for 4 cycles

Regimen #2

Study Evidence Comparator Efficacy
Poole et al. 2006 (BR9601) Phase III Modified CMF Superior OS

Epirubicin portion

3-week cycle for 4 cycles, followed by:

CMF portion

21-day cycle for 4 cycles

References

  1. 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

FAC; CAF

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FAC: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide
CAF: Cyclophosphamide, Adriamycin (Doxorubicin), Fluorouracil

Regimen #1

Study Evidence Comparator Efficacy
Martin et al. 2005 (BCIRG 001) Phase III TAC Inferior OS
Martín et al. 2010 (GEICAM 9805) Phase III TAC Inferior DFS
Martín et al. 2013 (GEICAM/2003-02) Phase III FAC-wP Seems to have inferior DFS

Chemotherapy

Supportive medications

  • If patients had febrile neutropenia or infection: Ciprofloxacin (Cipro) 500 mg PO BID on days 5 to 14 of every cycle
  • G-CSF not originally routinely administered unless patients had febrile neutropenia:

21-day cycle for 6 cycles

Regimen #2

Study Evidence Comparator Efficacy
Hutchins et al. 2005 (INT-0102) Phase III CMF Seems to have superior OS

Chemotherapy

28-day cycle for 6 cycles

Regimen #3

Study Evidence Comparator Efficacy
Buzdar et al. 1984 Phase III FAC + BCG Seems not superior

Chemotherapy

21-day cycles until cumulative doxorubicin dose of 300 mg/m2 reached.

After reaching cumulative maximum doxorubicin, patients would go on to receive maintenance CMF. This is now obsolete.

References

  1. Buzdar AU, Blumenschein GR, Smith TL, Powell KC, Hortobagyi GN, Yap HY, Schell FC, Barnes BC, Ames FC, Martin RG, et al. Adjuvant chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide, with or without Bacillus Calmette-Guerin and with or without irradiation in operable breast cancer. A prospective randomized trial. Cancer. 1984 Feb 1;53(3):384-9. link to original article contains verified protocol PubMed
    1. Update: Buzdar AU, Kau SW, Smith TL, Hortobagyi GN. Ten-year results of FAC adjuvant chemotherapy trial in breast cancer. Am J Clin Oncol. 1989 Apr;12(2):123-8. PubMed
  2. Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C; Breast Cancer International Research Group 001 Investigators. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med. 2005 Jun 2;352(22):2302-13. link to original article contains protocol PubMed
    1. Update: Mackey JR, Martin M, Pienkowski T, Rolski J, Guastalla JP, Sami A, Glaspy J, Juhos E, Wardley A, Fornander T, Hainsworth J, Coleman R, Modiano MR, Vinholes J, Pinter T, Rodríguez-Lescure A, Colwell B, Whitlock P, Provencher L, Laing K, Walde D, Price C, Hugh JC, Childs BH, Bassi K, Lindsay MA, Wilson V, Rupin M, Houé V, Vogel C; TRIO/BCIRG 001 investigators. Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial. Lancet Oncol. 2013 Jan;14(1):72-80. Epub 2012 Dec 12. link to original article PubMed
  3. Hutchins LF, Green SJ, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol. 2005 Nov 20;23(33):8313-21. link to original article PubMed
  4. Martín M, Seguí MA, Antón A, Ruiz A, Ramos M, Adrover E, Aranda I, Rodríguez-Lescure A, Grosse R, Calvo L, Barnadas A, Isla D, Martinez del Prado P, Ruiz Borrego M, Zaluski J, Arcusa A, Muñoz M, López Vega JM, Mel JR, Munarriz B, Llorca C, Jara C, Alba E, Florián J, Li J, López García-Asenjo JA, Sáez A, Rios MJ, Almenar S, Peiró G, Lluch A; GEICAM 9805 Investigators. Adjuvant docetaxel for high-risk, node-negative breast cancer. N Engl J Med. 2010 Dec 2;363(23):2200-10. link to original article PubMed
  5. 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

FAC -> MV

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FAC -> MV: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide followed by Methotrexate & Vinblastine

Not commonly used but was a comparator arm; for reference purposes only.

Regimen

Study Evidence Comparator Efficacy
Assikis et al. 2003 Phase III Tamoxifen Seems not superior

FAC portion

21-day cycle for 6 cycles, followed by:

MV portion

21- to 28-day cycle for 4 cycles

References

  1. 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

FEC-D

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FEC-D: Fluorouracil, Epirubicin, Cyclophosphamide, Docetaxel

Regimen

Study Evidence Comparator Efficacy
Roché et al. 2006 (FNCLCC PACS 01) Phase III FEC Seems to have superior OS

FEC portion

21-day cycle for 3 cycles, followed by:

D portion

21-day cycle for 3 cycles

References

  1. Roché H, Fumoleau P, Spielmann M, Canon JL, Delozier T, Serin D, Symann M, Kerbrat P, Soulié P, Eichler F, Viens P, Monnier A, Vindevoghel A, Campone M, Goudier MJ, Bonneterre J, Ferrero JM, Martin AL, Genève J, Asselain B. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. J Clin Oncol. 2006 Dec 20;24(36):5664-71. Epub 2006 Nov 20. link to original article PubMed

FEC-P

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FEC-P: Fluorouracil, Epirubicin, Cyclophosphamide, Paclitaxel

Regimen

Study Evidence Comparator Efficacy
Martín et al. 2008 (GEICAM 9906) Phase III FEC Superior DFS

FEC portion

21-day cycle for 4 cycles, followed by 3 weeks of no treatment, followed by:

P portion

8 week course

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 protocol PubMed

No additional therapy

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Regimen

Study Evidence Comparator Efficacy
Bonadonna et al. 1976 Phase III CMF Inferior RFS

Used as a comparator arm, historically; here for reference purposes only.

References

  1. Bonadonna G, Brusamolino E, Valagussa P, Rossi A, Brugnatelli L, Brambilla C, De Lena M, Tancini G, Bajetta E, Musumeci R, Veronesi U. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med. 1976 Feb 19;294(8):405-10. link to original article PubMed
    1. Update: Bonadonna G, Rossi A, Valagussa P, Banfi A, Veronesi U. The CMF program for operable breast cancer with positive axillary nodes. Updated analysis on the disease-free interval, site of relapse and drug tolerance. Cancer. 1977 Jun;39(6 Suppl):2904-15. link to original article PubMed
    2. Update: Bonadonna G, Valagussa P, Rossi A, Tancini G, Brambilla C, Zambetti M, Veronesi U. Ten-year experience with CMF-based adjuvant chemotherapy in resectable breast cancer. Breast Cancer Res Treat. 1985;5(2):95-115. PubMed

Paclitaxel (Taxol)

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Regimen #1, q2wk dosing

Study Evidence Comparator Efficacy
Shulman et al. 2012 (CALGB 40101) Phase III ddAC x 4 Seems not superior
ddAC x 6 Seems not superior
Paclitaxel x 6 Seems not superior

Note: this is the dosing interval after a mid-protocol amendment in 2003. Weekly dosing was also an option, this was not described as a randomization so was presumably left to investigator choice.

Chemotherapy

Supportive medications

  • Diphenhydramine (Benadryl) 12.5-50 mg IV 30 to 60 minutes prior to paclitaxel
  • One of the following H2 blockers:
  • One of the following dexamethasone choices:
  • Recommended growth factor support with one of the following:
    • Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Sargramostim (Leukine) 250 to 500 mcg/m2 SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Pegfilgrastim (Neulasta) 6 mg SC, administered once 24 to 36 hours after chemotherapy

14-day cycle for 4 cycles

Regimen #2, weekly dosing

Study Evidence Comparator Efficacy
Shulman et al. 2012 (CALGB 40101) Phase III ddAC x 4 Seems not superior
ddAC x 6 Seems not superior
Paclitaxel x 6 Seems not superior

Chemotherapy

Supportive medications

  • Diphenhydramine (Benadryl) 12.5-50 mg IV 30 to 60 minutes prior to paclitaxel
  • One of the following H2 blockers:
  • One of the following dexamethasone choices:
  • Recommended growth factor support with one of the following:
    • Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Sargramostim (Leukine) 250 to 500 mcg/m2 SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Pegfilgrastim (Neulasta) 6 mg SC, administered once 24 to 36 hours after chemotherapy

8-week course

References

  1. Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article contains verified protocol link to study protocol PDF PubMed
    1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. link to PMC article PubMed

T (Taxotere) -> FEC

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T -> FEC: Taxotere (Docetaxel) followed by Fluorouracil, Epirubicin, Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Joensuu et al. 2006 (FinHer) Phase III TH -> FEC
VH -> FEC 		Seems not superior
V -> FEC Superior DDFS

Patients without HER2/neu amplification were only randomized to this regimen vs. V -> FEC.

T portion

21-day cycle for 3 cycles, followed by FEC:

FEC portion

21-day cycle for 3 cycles

Monitoring

  • Cardiac function: echocardiogram at baseline, after last cycle of FEC, 12 months after completion of chemotherapy, and 36 months after completion of chemotherapy

References

  1. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article PubMed
    1. Update: Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. link to original article PubMed

TAC (Docetaxel)

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TAC: Taxotere (Docetaxel), Adriamycin (Doxorubicin), Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Martin et al. 2005 (BCIRG 001) Phase III FAC Superior OS
Martín et al. 2010 (GEICAM 9805) Phase III FAC Superior DFS
Eiermann et al. 2011 (BCIRG-005) Phase III AC -> T Seems not superior

Chemotherapy

Supportive medications

  • Dexamethasone 8 mg PO every 12 hours x 6 total doses, starting the day before treatment
  • Ciprofloxacin (Cipro) 500 mg PO BID on days 5 to 14 of every cycle (prophylaxis)
  • G-CSF not originally routinely administered unless patients had febrile neutropenia, but NCCN currently recommends routine filgrastim support:

21-day cycle for 6 cycles

References

  1. Martin M, Pienkowski T, Mackey J, Pawlicki M, Guastalla JP, Weaver C, Tomiak E, Al-Tweigeri T, Chap L, Juhos E, Guevin R, Howell A, Fornander T, Hainsworth J, Coleman R, Vinholes J, Modiano M, Pinter T, Tang SC, Colwell B, Prady C, Provencher L, Walde D, Rodriguez-Lescure A, Hugh J, Loret C, Rupin M, Blitz S, Jacobs P, Murawsky M, Riva A, Vogel C; Breast Cancer International Research Group 001 Investigators. Adjuvant docetaxel for node-positive breast cancer. N Engl J Med. 2005 Jun 2;352(22):2302-13. link to original article contains protocol PubMed
    1. Update: Mackey JR, Martin M, Pienkowski T, Rolski J, Guastalla JP, Sami A, Glaspy J, Juhos E, Wardley A, Fornander T, Hainsworth J, Coleman R, Modiano MR, Vinholes J, Pinter T, Rodríguez-Lescure A, Colwell B, Whitlock P, Provencher L, Laing K, Walde D, Price C, Hugh JC, Childs BH, Bassi K, Lindsay MA, Wilson V, Rupin M, Houé V, Vogel C; TRIO/BCIRG 001 investigators. Adjuvant docetaxel, doxorubicin, and cyclophosphamide in node-positive breast cancer: 10-year follow-up of the phase 3 randomised BCIRG 001 trial. Lancet Oncol. 2013 Jan;14(1):72-80. Epub 2012 Dec 12. link to original article PubMed
  2. Martín M, Seguí MA, Antón A, Ruiz A, Ramos M, Adrover E, Aranda I, Rodríguez-Lescure A, Grosse R, Calvo L, Barnadas A, Isla D, Martinez del Prado P, Ruiz Borrego M, Zaluski J, Arcusa A, Muñoz M, López Vega JM, Mel JR, Munarriz B, Llorca C, Jara C, Alba E, Florián J, Li J, López García-Asenjo JA, Sáez A, Rios MJ, Almenar S, Peiró G, Lluch A; GEICAM 9805 Investigators. Adjuvant docetaxel for high-risk, node-negative breast cancer. N Engl J Med. 2010 Dec 2;363(23):2200-10. link to original article PubMed
  3. 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

TC (Docetaxel)

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TC: Taxotere (Docetaxel), Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Jones et al. 2006 (US Oncology Trial 9735) Phase III AC Seems to have superior OS

Chemotherapy

Supportive medications

21-day cycle for 4 cycles

References

  1. Jones SE, Savin MA, Holmes FA, O'Shaughnessy JA, Blum JL, Vukelja S, McIntyre KJ, Pippen JE, Bordelon JH, Kirby R, Sandbach J, Hyman WJ, Khandelwal P, Negron AG, Richards DA, Anthony SP, Mennel RG, Boehm KA, Meyer WG, Asmar L. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol. 2006 Dec 1;24(34):5381-7. Erratum in: J Clin Oncol. 2007 May 1;25(13):1819. link to original article PubMed
    1. Update: Jones S, Holmes FA, O'Shaughnessy J, Blum JL, Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL, Sandbach J, Hyman WJ, Richards DA, Mennel RG, Boehm KA, Meyer WG, Asmar L, Mackey D, Riedel S, Muss H, Savin MA. Docetaxel With Cyclophosphamide Is Associated With an Overall Survival Benefit Compared With Doxorubicin and Cyclophosphamide: 7-Year Follow-Up of US Oncology Research Trial 9735. J Clin Oncol. 2009 Mar 10;27(8):1177-83. Epub 2009 Feb 9. link to original article PubMed

V -> FEC

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V -> FEC: Vinorelbine followed by Fluorouracil, Epirubicin, Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Joensuu et al. 2006 (FinHer) Phase III T -> FEC Inferior DDFS
TH -> FEC
VH -> FEC 		Seems not superior

Patients without HER2/neu amplification were only randomized to this regimen vs. T -> FEC.

V portion

21-day cycle for 3 cycles, followed by FEC:

FEC portion

21-day cycle for 3 cycles

Monitoring

  • Cardiac function: echocardiogram at baseline, after last cycle of FEC, 12 months after completion of chemotherapy, and 36 months after completion of chemotherapy

References

  1. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article PubMed
    1. Update: Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. link to original article PubMed

Adjuvant chemotherapy, HER-2 positive

AC -> T -> H

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AC -> T -> H: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel) followed by Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Romond et al. 2005 (NCCTG N9831) Phase III AC -> T Superior OS
AC -> TH Not reported

This dosing schema was evaluated in NCCTG N9831 but is not commonly used and is here for reference purposes only.

AC portion

21-day cycle for 4 cycles, followed by:

T portion

12-week course, followed by:

H portion

52-week course

Monitoring

  • Cardiac function: echocardiogram at baseline, then every 3 months while on Trastuzumab (Herceptin)

References

  1. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. link to original article PubMed
    1. Update: Perez EA, 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

AC -> TH (Taxol)

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AC -> TH: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxol (Paclitaxel) & Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Romond et al. 2005 (NSABP B-31/NCCTG N9831) Phase III AC -> T Superior OS

AC portion

21-day cycle for 4 cycles, followed by:

TH portion

  • Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
    • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 4 cycles, followed by:

40 additional weeks to complete a total of 52 weeks of therapy

References

  1. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1673-84. link to original article PubMed
    1. Update: Perez EA, 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

AC -> TH (Taxotere)

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AC -> TH: Adriamycin (Doxorubicin) & Cyclophosphamide followed by Taxotere (Docetaxel) & Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Slamon et al. 2011 (BCIRG 006) Phase III AC -> T Superior OS
TCH Seems not superior

AC portion

21-day cycle for 4 cycles, followed by:

TH portion

  • Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
    • Cycles 2 to 4: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 4 cycles, followed by:

3-week cycle for 14 additional cycles to complete a total of 52 weeks of therapy

Monitoring

  • Cardiac function: echocardiogram at baseline, then every 3 months while on Trastuzumab (Herceptin)

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 PubMed

ddAC -> H

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ddAC -> H: dose-dense Adriamycin (Doxorubicin) & Cyclophosphamide followed by Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Shulman et al. 2012 (CALGB 40101) Phase III TH Seems not superior
T -> H Seems not superior

ddAC portion

Supportive medications

  • Recommended growth factor support with one of the following:
    • Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Sargramostim (Leukine) 250 to 500 mcg/m2 SC on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Pegfilgrastim (Neulasta) 6 mg SC, administered once 24 to 36 hours after chemotherapy

14-day cycle for 4 cycles; the study protocol originally specified 21-day cycles but was amended to 14-day cycles after results of CALGB 9741 - Citron et al. 2003 were available

Trastuzumab (Herceptin) to begin 3 to 8 weeks after the completion of AC:

H portion

  • One of the following doses & schedules of trastuzumab:

52-week course

References

  1. Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article contains verified protocol link to study protocol PDF PubMed
    1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. link to PMC article PubMed

ddAC -> PT

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ddAC -> PT: dose-dense Adriamycin (Doxorubicin) & Cyclophosphamide followed by Paclitaxel & Trastuzumab

Regimen

Study Evidence
Dang et al. 2008 Phase II

ddAC portion

14-day cycle for 4 cycles, followed by:

PT portion

  • Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 4 mg/kg IV once with first dose of paclitaxel, then 2 mg/kg IV once on day 8
    • Cycles 2 to 4: 2 mg/kg IV once per day on days 1 & 8

14-day cycle for 4 cycles, followed by:

  • EITHER Trastuzumab (Herceptin) 2 mg/kg IV, 1-week cycle for 44 additional cycles/weeks to complete a total of 52 weeks of therapy
  • OR Trastuzumab (Herceptin) 6 mg/kg IV, 3-week cycle for 15 additional cycles/weeks to complete a total of 52 weeks of therapy

Supportive medications

All chemotherapy cycles given with Filgrastim (Neupogen) support

Monitoring

  • Cardiac function: echocardiogram at baseline, then every 3 months while on Trastuzumab (Herceptin)

References

  1. Dang C, Fornier M, Sugarman S, Troso-Sandoval T, Lake D, D'Andrea G, Seidman A, Sklarin N, Dickler M, Currie V, Gilewski T, Moynahan ME, Drullinsky P, Robson M, Wasserheit-Leiblich C, Mills N, Steingart R, Panageas K, Norton L, Hudis C. The safety of dose-dense doxorubicin and cyclophosphamide followed by paclitaxel with trastuzumab in HER-2/neu overexpressed/amplified breast cancer. J Clin Oncol. 2008 Mar 10;26(8):1216-22. link to original article PubMed

FEC & H

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Regimen

Study Evidence
Gianni et al. 2011 (NeoSphere) Non-randomized portion of RCT

Treatment preceded by neoadjuvant docetaxel & pertuzumab versus neoadjuvant docetaxel, pertuzumab, trastuzumab versus neoadjuvant pertuzumab & trastuzumab versus neoadjvuant TH.

Chemotherapy

21-day cycle for 3 cycles, followed by:

  • Trastuzumab (Herceptin) 6 mg/kg IV once on day 1
  • Radiation therapy and/or hormone therapy for ER positive patients is given "per local guidelines"

21-day cycles, to complete 1 year of total therapy with trastuzumab

References

  1. Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (NeoSphere): a randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Jan;13(1):25-32. Epub 2011 Dec 6. link to original article contains verified protocol PubMed
    1. Update: Gianni L, Pienkowski T, Im YH, Tseng LM, Liu MC, Lluch A, Starosławska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi GV, Magazzù D, McNally V, Douthwaite H, Ross G, Valagussa P. 5-year analysis of neoadjuvant pertuzumab and trastuzumab in patients with locally advanced, inflammatory, or early-stage HER2-positive breast cancer (NeoSphere): a multicentre, open-label, phase 2 randomised trial. Lancet Oncol. 2016 Jun;17(6):791-800. Epub 2016 May 11. link to original article PubMed

TCH (Carboplatin)

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TCH: Taxotere (Docetaxel), Carboplatin, Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Slamon et al. 2011 (BCIRG 006) Phase III AC -> T Seems to have superior OS
AC -> TH Seems not superior

Chemotherapy

21-day cycle for 6 cycles, followed by:

3-week cycle for 12 additional cycles to complete a total of 52 weeks of therapy

Monitoring

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 PubMed

TCH (Cyclophosphamide)

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TCH: Taxotere, Cyclophosphamide, Herceptin

Regimen

Study Evidence
Jones et al. 2013 Phase II

Induction therapy

Chemotherapy started within 84 days of surgery.

Supportive medications

21-day cycle for 4 cycles, then proceed to trastuzumab monotherapy

Trastuzumab monotherapy

21-day cycles, given until patient receives 1 year total of trastuzumab therapy

References

  1. Jones SE, Collea R, Paul D, Sedlacek S, Favret AM, Gore I Jr, Lindquist DL, Holmes FA, Allison MA, Brooks BD, Portillo RM, Vukelja SJ, Steinberg MS, Stokoe C, Crockett MW, Wang Y, Asmar L, Robert NJ, O'Shaughnessy J. Adjuvant docetaxel and cyclophosphamide plus trastuzumab in patients with HER2-amplified early stage breast cancer: a single-group, open-label, phase 2 study. Lancet Oncol. 2013 Oct;14(11):1121-8. Epub 2013 Sep 2. link to original article contains verified protocol PubMed

TH

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TH: Taxol (Paclitaxel), Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Shulman et al. 2012 (CALGB 40101) Phase III ddAC -> H Seems not superior
T -> H Seems not superior

TH portion

  • Paclitaxel (Taxol) 175 mg/m2 IV over 3 hours once on day 1
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once on day 8
    • Cycles 2 to 4: 2 mg/kg IV once per day on days 1 & 8

Supportive medications

  • Diphenhydramine (Benadryl) 12.5-50 mg IV once 30 to 60 minutes prior to paclitaxel
  • One of the following H2 blockers:
  • One of the following dexamethasone choices:
  • Recommended growth factor support with one of the following:
    • Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Sargramostim (Leukine) 250 to 500 mcg/m2 SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Pegfilgrastim (Neulasta) 6 mg SC once, given 24 to 36 hours after chemotherapy

14-day cycle for 4 cycles, followed by:

Trastuzumab monotherapy

44-week course, which, counting doses given as part of TH, will result in a total of 52 weeks of trastuzumab therapy

Regimen #2

Study Evidence
Tolaney et al. 2015 (APT) Phase II

TH portion

12-week course, then proceed to trastuzumab only phase

Trastuzumab monotherapy

3-week cycle for 13 additional cycles (for 39 weeks of trastuzumab only therapy)

References

  1. Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article contains verified protocol link to study protocol PDF PubMed
    1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. link to PMC article PubMed
  2. Tolaney SM, Barry WT, Dang CT, Yardley DA, Moy B, Marcom PK, Albain KS, Rugo HS, Ellis M, Shapira I, Wolff AC, Carey LA, Overmoyer BA, Partridge AH, Guo H, Hudis CA, Krop IE, Burstein HJ, Winer EP. Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer. N Engl J Med. 2015 Jan 8;372(2):134-41. Erratum in: N Engl J Med. 2015 Nov 12;373(20):1989. link to original article PubMed

T -> H

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T -> H: Sequential Taxol (Paclitaxel), Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Shulman et al. 2012 (CALGB 40101) Phase III ddAC -> H Seems not superior
TH Seems not superior

T portion

Supportive medications

  • Diphenhydramine (Benadryl) 12.5 to 50 mg IV once 30 to 60 minutes prior to paclitaxel
  • One of the following H2 blockers:
  • One of the following dexamethasone choices:
  • Recommended growth factor support with one of the following:
    • Filgrastim (Neupogen) 5 mcg/kg (rounded to 300 mcg or 480 mcg, whichever is closer) SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Sargramostim (Leukine) 250-500 mcg/m2 SC once per day on days 3 to 10; may be discontinued before day 10 if ANC has recovered to an "acceptable range, as determined by the treating physician"
    • Pegfilgrastim (Neulasta) 6 mg SC once, given 24 to 36 hours after chemotherapy

14-day cycle for 4 cycles, followed by:

Trastuzumab monotherapy

One of the following doses & schedules of trastuzumab:

52-week course of therapy

References

  1. Shulman LN, Cirrincione CT, Berry DA, Becker HP, Perez EA, O'Regan R, Martino S, Atkins JN, Mayer E, Schneider CJ, Kimmick G, Norton L, Muss H, Winer EP, Hudis C. Six Cycles of Doxorubicin and Cyclophosphamide or Paclitaxel Are Not Superior to Four Cycles As Adjuvant Chemotherapy for Breast Cancer in Women With Zero to Three Positive Axillary Nodes: Cancer and Leukemia Group B 40101. J Clin Oncol. 2012 Nov 20;30(33):4071-6. Epub 2012 Jul 23. link to original article contains verified protocol link to study protocol PDF PubMed
    1. Update: Shulman LN, Berry DA, Cirrincione CT, Becker HP, Perez EA, O'Regan R, Martino S, Shapiro CL, Schneider CJ, Kimmick G, Burstein HJ, Norton L, Muss H, Hudis CA, Winer EP. Comparison of doxorubicin and cyclophosphamide versus single-agent paclitaxel as adjuvant therapy for breast cancer in women with 0 to 3 positive axillary nodes: CALGB 40101 (Alliance). J Clin Oncol. 2014 Aug 1;32(22):2311-7. link to PMC article PubMed

TH (Taxotere) -> FEC

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TH -> FEC: Taxotere (Docetaxel) & Herceptin (Trastuzumab) followed by Fluorouracil, Epirubicin, Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Joensuu et al. 2006 (FinHer) Phase III T -> FEC
V -> FEC 		Seems not superior
VH -> FEC Not reported

TH portion

  • Docetaxel (Taxotere) 100 mg/m2 IV over 1 hour once on day 1
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
    • Cycles 2 & 3: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 3 cycles, followed by:

FEC portion

21-day cycle for 3 cycles

Monitoring

  • Cardiac function: echocardiogram at baseline, after last cycle of FEC, 12 months after completion of chemotherapy, and 36 months after completion of chemotherapy

References

  1. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article PubMed
    1. Update: Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. link to original article PubMed

VH -> FEC

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VH -> FEC: Vinorelbine & Herceptin (Trastuzumab) followed by Fluorouracil, Epirubicin, Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Joensuu et al. 2006 (FinHer) Phase III T -> FEC
V -> FEC 		Seems not superior
TH -> FEC Not reported

VH portion

  • Vinorelbine (Navelbine) 24 mg/m2 IV over 5 to 10 minutes once per day on days 1, 8, 15
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
    • Cycles 2 & 3: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for 3 cycles, followed by:

FEC portion

21-day cycle for 3 cycles

Monitoring

  • Cardiac function: echocardiogram at baseline, after last cycle of FEC, 12 months after completion of chemotherapy, and 36 months after completion of chemotherapy

References

  1. Joensuu H, Kellokumpu-Lehtinen PL, Bono P, Alanko T, Kataja V, Asola R, Utriainen T, Kokko R, Hemminki A, Tarkkanen M, Turpeenniemi-Hujanen T, Jyrkkiö S, Flander M, Helle L, Ingalsuo S, Johansson K, Jääskeläinen AS, Pajunen M, Rauhala M, Kaleva-Kerola J, Salminen T, Leinonen M, Elomaa I, Isola J; FinHer Study Investigators. Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med. 2006 Feb 23;354(8):809-20. link to original article PubMed
    1. Update: Joensuu H, Bono P, Kataja V, Alanko T, Kokko R, Asola R, Utriainen T, Turpeenniemi-Hujanen T, Jyrkkiö S, Möykkynen K, Helle L, Ingalsuo S, Pajunen M, Huusko M, Salminen T, Auvinen P, Leinonen H, Leinonen M, Isola J, Kellokumpu-Lehtinen PL. Fluorouracil, epirubicin, and cyclophosphamide with either docetaxel or vinorelbine, with or without trastuzumab, as adjuvant treatments of breast cancer: final results of the FinHer Trial. J Clin Oncol. 2009 Dec 1;27(34):5685-92. link to original article PubMed

Trastuzumab (Herceptin)

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Regimen

Study Evidence Comparator Efficacy
Piccart-Gebhart et al. 2005 (HERA/BIG 01-01) Phase III No trastuzumab after (neo-)adjuvant chemotherapy Superior DFS

Participants in HERA had already received at least four courses of an approved (neo-)adjuvant chemotherapy regimen. See supplement for a list of these regimens.

Chemotherapy

  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 8 mg/kg IV over 90 minutes once on day 1
    • Cycle 2 onwards: 6 mg/kg IV over 90 minutes once on day 1

3-week cycle for 1 to 2 years

References

  1. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Láng I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Rüschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gelber RD; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005 Oct 20;353(16):1659-72. link to original article contains verified protocol [link to data supplement] PubMed
    1. Update: Smith I, Procter M, Gelber RD, Guillaume S, Feyereislova A, Dowsett M, Goldhirsch A, Untch M, Mariani G, Baselga J, Kaufmann M, Cameron D, Bell R, Bergh J, Coleman R, Wardley A, Harbeck N, Lopez RI, Mallmann P, Gelmon K, Wilcken N, Wist E, Sánchez Rovira P, Piccart-Gebhart MJ; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007 Jan 6;369(9555):29-36. link to original article contains verified protocol PubMed
    2. Update: Gianni L, Dafni U, Gelber RD, Azambuja E, Muehlbauer S, Goldhirsch A, Untch M, Smith I, Baselga J, Jackisch C, Cameron D, Mano M, Pedrini JL, Veronesi A, Mendiola C, Pluzanska A, Semiglazov V, Vrdoljak E, Eckart MJ, Shen Z, Skiadopoulos G, Procter M, Pritchard KI, Piccart-Gebhart MJ, Bell R; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol. 2011 Mar;12(3):236-44. Epub 2011 Feb 25. link to original article contains verified protocol PubMed

Adjuvant endocrine therapy

Anastrozole (Arimidex)

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Regimen

Study Evidence Comparator Efficacy
Howell et al. 2005 (ATAC) Phase III Anastrozole & Tamoxifen Not reported
Tamoxifen Seems to have superior DFS
Goss et al. 2013 (NCIC CTG MA.27) Phase III Exemestane Seems not superior

Endocrine therapy

5-year course of therapy

References

  1. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS; ATAC Trialists' Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet. 2005 Jan 1-7;365(9453):60-2. link to original article PubMed
    1. Update: Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists' Group, Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 2008 Jan;9(1):45-53. link to original article PubMed
    2. Update: Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, Forbes JF; ATAC/LATTE investigators.. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010 Dec;11(12):1135-41. link to original article PubMed
  2. Goss PE, Ingle JN, Pritchard KI, Ellis MJ, Sledge GW, Budd GT, Rabaglio M, Ansari RH, Johnson DB, Tozer R, D'Souza DP, Chalchal H, Spadafora S, Stearns V, Perez EA, Liedke PE, Lang I, Elliott C, Gelmon KA, Chapman JA, Shepherd LE. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial. J Clin Oncol. 2013 Apr 10;31(11):1398-404. Epub 2013 Jan 28. link to original article contains verified protocol PubMed

Exemestane (Aromasin)

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OFS: Ovarian Function Suppression

Regimen #1, with OFS

Study Evidence Comparator Efficacy
Pagani et al. 2014 (TEXT/SOFT) Phase III Tamoxifen Superior DFS
Tamoxifen & OFS Superior DFS

These regimens are intended for premenopausal patients. Pagani et al. 2014 report on two trials, but only SOFT had the tamoxifen only arm.

Endocrine therapy

  • Exemestane (Aromasin) 25 mg PO once per day
  • Ovarian Suppression as follows:
    • TEXT: Triptorelin (Trelstar LA) 3.75 mg IM every 28 days
      • "Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin."
    • SOFT: Choice of mechanism left to investigators

5 years of therapy

Regimen #2, no OFS

Study Evidence Comparator Efficacy
Goss et al. 2013 (NCIC CTG MA.27) Phase III Anastrozole Seems not superior

Endocrine therapy

5-year course of therapy

References

  1. Goss PE, Ingle JN, Pritchard KI, Ellis MJ, Sledge GW, Budd GT, Rabaglio M, Ansari RH, Johnson DB, Tozer R, D'Souza DP, Chalchal H, Spadafora S, Stearns V, Perez EA, Liedke PE, Lang I, Elliott C, Gelmon KA, Chapman JA, Shepherd LE. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27--a randomized controlled phase III trial. J Clin Oncol. 2013 Apr 10;31(11):1398-404. Epub 2013 Jan 28. link to original article contains verified protocol PubMed
  2. Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Perez EA, Ciruelos E, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Pinotti G, Puglisi F, Crivellari D, Ruhstaller T, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Bernhard J, Luo W, Ribi K, Viale G, Coates AS, Gelber RD, Goldhirsch A, Francis PA; TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014 Jul 10;371(2):107-18. Epub 2014 Jun 1. link to PMC article link to original article contains verified protocol PubMed

Letrozole (Femara)

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Regimen

Study Evidence Comparator Efficacy
Goss et al. 2003 (NCIC CTG MA.17) Phase III Placebo Superior DFS
Breast International Group (BIG) 1-98 Collaborative Group 2006 Phase III Letrozole -> Tamoxifen Seems not superior
Tamoxifen Superior OS
Tamoxifen -> Letrozole Seems not superior

Patients in NCIC CTG MA.17 received 5 years of tamoxifen therapy prior to starting letrozole.

Endocrine therapy

5-year course of therapy

References

  1. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003 Nov 6;349(19):1793-802. Epub 2003 Oct 9. link to original article PubMed
    1. Update: Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Pater JL. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2005 Sep 7;97(17):1262-71. link to original article PubMed
    2. Update: Muss HB, Tu D, Ingle JN, Martino S, Robert NJ, Pater JL, Whelan TJ, Palmer MJ, Piccart MJ, Shepherd LE, Pritchard KI, He Z, Goss PE. Efficacy, toxicity, and quality of life in older women with early-stage breast cancer treated with letrozole or placebo after 5 years of tamoxifen: NCIC CTG intergroup trial MA.17. J Clin Oncol. 2008 Apr 20;26(12):1956-64. Epub 2008 Mar 10. link to original article PubMed
    3. Subgroup analysis: Goss PE, Ingle JN, Pater JL, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Tu D. Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen. J Clin Oncol. 2008 Apr 20;26(12):1948-55. Epub 2008 Mar 10. link to original article PubMed
    4. Update: Jin H, Tu D, Zhao N, Shepherd LE, Goss PE. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. J Clin Oncol. 2012 Mar 1;30(7):718-21. Epub 2011 Oct 31. link to original article PubMed
  2. Breast International Group (BIG) 1-98 Collaborative Group, 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. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005 Dec 29;353(26):2747-57. Erratum in: N Engl J Med. 2006 May 18;354(20):2200. Wardly, Andrew [corrected to Wardley, Andrew ]. link to original article PubMed
    1. Update: Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol. 2007 Feb 10;25(5):486-92. Epub 2007 Jan 2. link to original article PubMed
    2. Subgroup analysis: Rasmussen BB, Regan MM, Lykkesfeldt AE, Dell'Orto P, Del Curto B, Henriksen KL, Mastropasqua MG, Price KN, Méry E, Lacroix-Triki M, Braye S, Altermatt HJ, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Gusterson BA, Thürlimann B, Coates AS, Viale G; BIG 1-98 Collaborative and International Breast Cancer Study Groups. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol. 2008 Jan;9(1):23-8. Epub 2007 Dec 20. link to original article PubMed
    3. Subgroup analysis: Crivellari D, Sun Z, Coates AS, Price KN, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens RJ, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Gladieff L, Rabaglio M, Smith IE, Chirgwin JH, Goldhirsch A. Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial. J Clin Oncol. 2008 Apr 20;26(12):1972-9. Epub 2008 Mar 10. link to original article PubMed
    4. Update: Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, Forbes JF, Smith I, Láng I, Wardley A, Rabaglio M, Price KN, Gelber RD, Coates AS, Thürlimann B; BIG 1-98 Collaborative Group.; International Breast Cancer Study Group (IBCSG).. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol. 2011 Nov;12(12):1101-8. link to original article link to PMC article PubMed

Letrozole -> Tamoxifen

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Regimen

Study Evidence Comparator Efficacy
Breast International Group (BIG) 1-98 Collaborative Group 2006 Phase III Letrozole Seems not superior
Tamoxifen Not reported
Tamoxifen -> Letrozole Seems not superior

Endocrine therapy

2-year course, followed by:

3-year course

References

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

Leuprolide (Lupron)

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Regimen

Study Evidence Comparator Efficacy
Schmid et al. 2007 (TABLE) Phase III CMF Superior OS

Endocrine therapy

Every 3 months x 2 years

References

  1. Schmid P, Untch M, Kossé V, Bondar G, Vassiljev L, Tarutinov V, Lehmann U, Maubach L, Meurer J, Wallwiener D, Possinger K. Leuprorelin acetate every-3-months depot versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in premenopausal patients with node-positive breast cancer: the TABLE study. J Clin Oncol. 2007 Jun 20;25(18):2509-15. link to original article contains verified protocol PubMed

Observation or Placebo

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Regimen

Study Evidence Comparator Efficacy
Goss et al. 2003 (NCIC CTG MA.17) Phase III Letrozole Inferior DFS
Rydén et al. 2005 (SBII:2pre) Phase III Tamoxifen Inferior RFS
Hutchins et al. 2005 (INT-0102) Phase III Tamoxifen Seems not superior

Patients in NCIC CTG MA.17 received 5 years of tamoxifen therapy prior to the observation period. Patients in INT-0102 were treated with CAF x6 versus CMF x 6 prior to the observation period.

No active hormonal treatment. Used as a comparator arm.

References

  1. Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003 Nov 6;349(19):1793-802. Epub 2003 Oct 9. link to original article PubMed
    1. Update: Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Pater JL. Randomized trial of letrozole following tamoxifen as extended adjuvant therapy in receptor-positive breast cancer: updated findings from NCIC CTG MA.17. J Natl Cancer Inst. 2005 Sep 7;97(17):1262-71. link to original article PubMed
    2. Update: Muss HB, Tu D, Ingle JN, Martino S, Robert NJ, Pater JL, Whelan TJ, Palmer MJ, Piccart MJ, Shepherd LE, Pritchard KI, He Z, Goss PE. Efficacy, toxicity, and quality of life in older women with early-stage breast cancer treated with letrozole or placebo after 5 years of tamoxifen: NCIC CTG intergroup trial MA.17. J Clin Oncol. 2008 Apr 20;26(12):1956-64. Epub 2008 Mar 10. link to original article PubMed
    3. Subgroup analysis: Goss PE, Ingle JN, Pater JL, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Cameron DA, Palmer MJ, Tu D. Late extended adjuvant treatment with letrozole improves outcome in women with early-stage breast cancer who complete 5 years of tamoxifen. J Clin Oncol. 2008 Apr 20;26(12):1948-55. Epub 2008 Mar 10. link to original article PubMed
    4. Update: Jin H, Tu D, Zhao N, Shepherd LE, Goss PE. Longer-term outcomes of letrozole versus placebo after 5 years of tamoxifen in the NCIC CTG MA.17 trial: analyses adjusting for treatment crossover. J Clin Oncol. 2012 Mar 1;30(7):718-21. Epub 2011 Oct 31. link to original article PubMed
  2. Rydén L, Jönsson PE, Chebil G, Dufmats M, Fernö M, Jirström K, Källström AC, Landberg G, Stål O, Thorstenson S, Nordenskjöld B; South Swedish Breast Cancer Group; South-East Swedish Breast Cancer Group. Two years of adjuvant tamoxifen in premenopausal patients with breast cancer: a randomised, controlled trial with long-term follow-up. Eur J Cancer. 2005 Jan;41(2):256-64. link to original article PubMed
    1. Update: Ekholm M, Bendahl PO, Fernö M, Nordenskjöld B, Stål O, Rydén L. Two Years of Adjuvant Tamoxifen Provides a Survival Benefit Compared With No Systemic Treatment in Premenopausal Patients With Primary Breast Cancer: Long-Term Follow-Up (> 25 years) of the Phase III SBII:2pre Trial. J Clin Oncol. 2016 Jul 1;34(19):2232-8. Epub 2016 May 9. link to original article PubMed
  3. Hutchins LF, Green SJ, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol. 2005 Nov 20;23(33):8313-21. link to original article PubMed

Tamoxifen (Nolvadex)

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OFS: Ovarian Function Suppression

Regimen #1, no OFS

Study Evidence Comparator Efficacy
Assikis et al. 2003 Phase III FAC -> MV Seems not superior
Coombes et al. 2004 (Intergroup Exemestane Study) Phase III Tamoxifen -> Exemestane Inferior DFS
Hutchins et al. 2005 (INT-0102) Phase III Observation Seems not superior
Breast International Group (BIG) 1-98 Collaborative Group 2006 Phase III Letrozole Inferior OS
Letrozole -> Tamoxifen Not reported
Tamoxifen -> Letrozole Not reported
Kaufmann et al. 2007 (ARNO 95) Phase III Tamoxifen -> Anastrozole Seems to have inferior OS
Mamounas et al. 2008 (NSABP B-33) Phase III Tamoxifen -> Exemestane Inferior RFS
Davies et al. 2013 (ATLAS) Phase III Tamoxifen x 10 years Inferior OS
Pagani et al. 2014 (SOFT) Phase III Exemestane & OFS Inferior DFS
Tamoxifen & OFS Not reported
Chapman et al. 2015 (NCIC CTG MA.14 & NSABP B-29) Phase III Tamoxifen & Octreotide LAR Seems not superior

Treatment in INT-0102 preceded by CAF x6 versus CMF x6. Pagani et al. 2014 report on two trials, but only SOFT had the tamoxifen only arm.

Endocrine therapy

5 years of therapy

Regimen #2, with OFS

Study Evidence Comparator Efficacy
Pagani et al. 2014 (TEXT/SOFT) Phase III Exemestane & OFS Inferior DFS
Tamoxifen Not reported

These regimens are intended for premenopausal patients. Pagani et al. 2014 report on two trials, but only SOFT had the tamoxifen only arm.

Endocrine therapy

  • Tamoxifen (Nolvadex) 20 mg PO once per day
  • Ovarian Suppression as follows:
    • TEXT: Triptorelin (Trelstar LA) 3.75 mg IM every 28 days
      • "Bilateral oophorectomy or ovarian irradiation was allowed after at least 6 months of triptorelin."
    • SOFT: Choice of mechanism left to investigators

5 years of therapy

Regimen #3, 10-years

Study Evidence Comparator Efficacy
Davies et al. 2013 (ATLAS) Phase III Tamoxifen x 5 years Superior OS

Endocrine therapy

10 years of therapy

References

  1. Review: Jaiyesimi IA, Buzdar AU, Decker DA, Hortobagyi GN. Use of tamoxifen for breast cancer: twenty-eight years later. J Clin Oncol. 1995 Feb;13(2):513-29. link to original article PubMed
  2. 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
  3. Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM, van de Velde C; Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004 Mar 11;350(11):1081-92. link to original article PubMed
    1. Update: Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, Van de Velde CJ, Delozier T, Alvarez I, Del Mastro L, Ortmann O, Diedrich K, Coates AS, Bajetta E, Holmberg SB, Dodwell D, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Forbes J, Castiglione M, Stuart N, Stewart A, Fallowfield LJ, Bertelli G, Hall E, Bogle RG, Carpentieri M, Colajori E, Subar M, Ireland E, Bliss JM; Intergroup Exemestane Study. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 2007 Feb 17;369(9561):559-70. link to original article PubMed
  4. Howell A, Cuzick J, Baum M, Buzdar A, Dowsett M, Forbes JF, Hoctin-Boes G, Houghton J, Locker GY, Tobias JS; ATAC Trialists' Group. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet. 2005 Jan 1-7;365(9453):60-2. link to original article PubMed
    1. Update: Arimidex, Tamoxifen, Alone or in Combination (ATAC) Trialists' Group, Forbes JF, Cuzick J, Buzdar A, Howell A, Tobias JS, Baum M. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 100-month analysis of the ATAC trial. Lancet Oncol. 2008 Jan;9(1):45-53. link to original article PubMed
    2. Update: Cuzick J, Sestak I, Baum M, Buzdar A, Howell A, Dowsett M, Forbes JF; ATAC/LATTE investigators.. Effect of anastrozole and tamoxifen as adjuvant treatment for early-stage breast cancer: 10-year analysis of the ATAC trial. Lancet Oncol. 2010 Dec;11(12):1135-41. link to original article PubMed
  5. Rydén L, Jönsson PE, Chebil G, Dufmats M, Fernö M, Jirström K, Källström AC, Landberg G, Stål O, Thorstenson S, Nordenskjöld B; South Swedish Breast Cancer Group; South-East Swedish Breast Cancer Group. Two years of adjuvant tamoxifen in premenopausal patients with breast cancer: a randomised, controlled trial with long-term follow-up. Eur J Cancer. 2005 Jan;41(2):256-64. link to original article PubMed
    1. Update: Ekholm M, Bendahl PO, Fernö M, Nordenskjöld B, Stål O, Rydén L. Two Years of Adjuvant Tamoxifen Provides a Survival Benefit Compared With No Systemic Treatment in Premenopausal Patients With Primary Breast Cancer: Long-Term Follow-Up (> 25 years) of the Phase III SBII:2pre Trial. J Clin Oncol. 2016 Jul 1;34(19):2232-8. Epub 2016 May 9. link to original article PubMed
  6. Review: Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005 May 14-20;365(9472):1687-717. link to original article PubMed
  7. Hutchins LF, Green SJ, Ravdin PM, Lew D, Martino S, Abeloff M, Lyss AP, Allred C, Rivkin SE, Osborne CK. Randomized, controlled trial of cyclophosphamide, methotrexate, and fluorouracil versus cyclophosphamide, doxorubicin, and fluorouracil with and without tamoxifen for high-risk, node-negative breast cancer: treatment results of Intergroup Protocol INT-0102. J Clin Oncol. 2005 Nov 20;23(33):8313-21. link to original article PubMed
  8. Breast International Group (BIG) 1-98 Collaborative Group, 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. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005 Dec 29;353(26):2747-57. Erratum in: N Engl J Med. 2006 May 18;354(20):2200. Wardly, Andrew [corrected to Wardley, Andrew ]. link to original article PubMed
    1. Update: Coates AS, Keshaviah A, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens R, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Smith I, Chirgwin J, Nogaret JM, Pienkowski T, Wardley A, Jakobsen EH, Price KN, Goldhirsch A. Five years of letrozole compared with tamoxifen as initial adjuvant therapy for postmenopausal women with endocrine-responsive early breast cancer: update of study BIG 1-98. J Clin Oncol. 2007 Feb 10;25(5):486-92. Epub 2007 Jan 2. link to original article PubMed
    2. Subgroup analysis: Rasmussen BB, Regan MM, Lykkesfeldt AE, Dell'Orto P, Del Curto B, Henriksen KL, Mastropasqua MG, Price KN, Méry E, Lacroix-Triki M, Braye S, Altermatt HJ, Gelber RD, Castiglione-Gertsch M, Goldhirsch A, Gusterson BA, Thürlimann B, Coates AS, Viale G; BIG 1-98 Collaborative and International Breast Cancer Study Groups. Adjuvant letrozole versus tamoxifen according to centrally-assessed ERBB2 status for postmenopausal women with endocrine-responsive early breast cancer: supplementary results from the BIG 1-98 randomised trial. Lancet Oncol. 2008 Jan;9(1):23-8. Epub 2007 Dec 20. link to original article PubMed
    3. Subgroup analysis: Crivellari D, Sun Z, Coates AS, Price KN, Thürlimann B, Mouridsen H, Mauriac L, Forbes JF, Paridaens RJ, Castiglione-Gertsch M, Gelber RD, Colleoni M, Láng I, Del Mastro L, Gladieff L, Rabaglio M, Smith IE, Chirgwin JH, Goldhirsch A. Letrozole compared with tamoxifen for elderly patients with endocrine-responsive early breast cancer: the BIG 1-98 trial. J Clin Oncol. 2008 Apr 20;26(12):1972-9. Epub 2008 Mar 10. link to original article PubMed
    4. Update: Regan MM, Neven P, Giobbie-Hurder A, Goldhirsch A, Ejlertsen B, Mauriac L, Forbes JF, Smith I, Láng I, Wardley A, Rabaglio M, Price KN, Gelber RD, Coates AS, Thürlimann B; BIG 1-98 Collaborative Group.; International Breast Cancer Study Group (IBCSG).. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8·1 years median follow-up. Lancet Oncol. 2011 Nov;12(12):1101-8. link to original article link to PMC article PubMed
  9. 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
  10. Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, Eisen A, Fehrenbacher L, Farrar WB, Atkins JN, Pajon ER, Vogel VG, Kroener JF, Hutchins LF, Robidoux A, Hoehn JL, Ingle JN, Geyer CE Jr, Costantino JP, Wolmark N. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin Oncol. 2008 Apr 20;26(12):1965-71. Epub 2008 Mar 10. link to original article PubMed
  11. Davies C, Pan H, Godwin J, Gray R, Arriagada R, Raina V, Abraham M, Medeiros Alencar VH, Badran A, Bonfill X, Bradbury J, Clarke M, Collins R, Davis SR, Delmestri A, Forbes JF, Haddad P, Hou MF, Inbar M, Khaled H, Kielanowska J, Kwan WH, Mathew BS, Mittra I, Müller B, Nicolucci A, Peralta O, Pernas F, Petruzelka L, Pienkowski T, Radhika R, Rajan B, Rubach MT, Tort S, Urrútia G, Valentini M, Wang Y, Peto R; Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) Collaborative Group. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial. Lancet. 2013 Mar 9;381(9869):805-16. Erratum in: Lancet. 2013 Mar 9;381(9869):804. link to original article contains verified protocol PubMed
  12. Pagani O, Regan MM, Walley BA, Fleming GF, Colleoni M, Láng I, Gomez HL, Tondini C, Burstein HJ, Perez EA, Ciruelos E, Stearns V, Bonnefoi HR, Martino S, Geyer CE Jr, Pinotti G, Puglisi F, Crivellari D, Ruhstaller T, Winer EP, Rabaglio-Poretti M, Maibach R, Ruepp B, Giobbie-Hurder A, Price KN, Bernhard J, Luo W, Ribi K, Viale G, Coates AS, Gelber RD, Goldhirsch A, Francis PA; TEXT and SOFT Investigators; International Breast Cancer Study Group. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014 Jul 10;371(2):107-18. Epub 2014 Jun 1. link to PMC article link to original article contains verified protocol PubMed
  13. Chapman JA, Costantino JP, Dong B, Margolese RG, Pritchard KI, Shepherd LE, Gelmon KA, Wolmark N, Pollak MN. Octreotide LAR and tamoxifen versus tamoxifen in phase III randomize early breast cancer trials: NCIC CTG MA.14 and NSABP B-29. Breast Cancer Res Treat. 2015 Sep;153(2):353-60. Epub 2015 Aug 15. link to original article PubMed

Tamoxifen -> Anastrozole

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Regimen

Study Evidence Comparator Efficacy
Kaufmann et al. 2007 (ARNO 95) Phase III Tamoxifen Seems to have superior OS

Endocrine therapy, part 1

2-year course, followed by:

Endocrine therapy, part 2

3-year course

References

  1. 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

Tamoxifen -> Exemestane

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Regimen #1

Study Evidence Comparator Efficacy
Mamounas et al. 2008 (NSABP B-33) Phase III Tamoxifen Superior RFS

Endocrine therapy, part 1

5 years of therapy, followed by:

Endocrine therapy, part 2

5 years of therapy to complete a 10-year course

Regimen #2

Study Evidence Comparator Efficacy
Coombes et al. 2004 (Intergroup Exemestane Study) Phase III Tamoxifen Superior DFS

Endocrine therapy, part 1

2 to 3 years of therapy, followed by:

Endocrine therapy, part 2

2 to 3 years to complete a 5-year course

References

  1. Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM, van de Velde C; Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004 Mar 11;350(11):1081-92. link to original article PubMed
    1. Update: Coombes RC, Kilburn LS, Snowdon CF, Paridaens R, Coleman RE, Jones SE, Jassem J, Van de Velde CJ, Delozier T, Alvarez I, Del Mastro L, Ortmann O, Diedrich K, Coates AS, Bajetta E, Holmberg SB, Dodwell D, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Forbes J, Castiglione M, Stuart N, Stewart A, Fallowfield LJ, Bertelli G, Hall E, Bogle RG, Carpentieri M, Colajori E, Subar M, Ireland E, Bliss JM; Intergroup Exemestane Study. Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. Lancet. 2007 Feb 17;369(9561):559-70. link to original article PubMed
  2. Mamounas EP, Jeong JH, Wickerham DL, Smith RE, Ganz PA, Land SR, Eisen A, Fehrenbacher L, Farrar WB, Atkins JN, Pajon ER, Vogel VG, Kroener JF, Hutchins LF, Robidoux A, Hoehn JL, Ingle JN, Geyer CE Jr, Costantino JP, Wolmark N. Benefit from exemestane as extended adjuvant therapy after 5 years of adjuvant tamoxifen: intention-to-treat analysis of the National Surgical Adjuvant Breast And Bowel Project B-33 trial. J Clin Oncol. 2008 Apr 20;26(12):1965-71. Epub 2008 Mar 10. link to original article PubMed

Tamoxifen -> Letrozole

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Regimen

Study Evidence Comparator Efficacy
Breast International Group (BIG) 1-98 Collaborative Group 2006 Phase III Letrozole Seems not superior
Letrozole -> Tamoxifen Seems not superior
Tamoxifen Not reported

Endocrine therapy

2-year course, followed by:

3-year course

References

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

Metastatic disease, endocrine therapy

Anastrozole (Arimidex)

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Regimen

Study Evidence Comparator Efficacy
Howell et al. 2002 Phase III Fulvestrant Seems to have non-inferior TTP
Mehta et al. 2012 (SWOG S0226) Phase III Anastrozole & Fulvestrant Seems to have inferior OS
Robertson et al. 2016 (FALCON) Phase III Fulvestrant Seems to have inferior PFS

Endocrine therapy

References

  1. Howell A, Robertson JF, Quaresma Albano J, Aschermannova A, Mauriac L, Kleeberg UR, Vergote I, Erikstein B, Webster A, Morris C. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002 Aug 15;20(16):3396-403. link to original article PubMed
  2. Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Livingston RB, Hortobagyi GN. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012 Aug 2;367(5):435-44. link to original article contains verified protocol PubMed
  3. Robertson JF, Bondarenko IM, Trishkina E, Dvorkin M, Panasci L, Manikhas A, Shparyk Y, Cardona-Huerta S, Cheung KL, Philco-Salas MJ, Ruiz-Borrego M, Shao Z, Noguchi S, Rowbottom J, Stuart M, Grinsted LM, Fazal M, Ellis MJ. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Nov 28. [Epub ahead of print] link to original article contains protocol PubMed

Anastrozole & Fulvestrant

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Regimen

Study Evidence Comparator Efficacy
Mehta et al. 2012 (SWOG S0226) Phase III Anastrozole Seems to have superior OS

Initial therapy

56-day course, then proceed to subsequent therapy:

Subsequent therapy

28-day cycles, given until progression of disease or unacceptable toxicity

References

  1. Mehta RS, Barlow WE, Albain KS, Vandenberg TA, Dakhil SR, Tirumali NR, Lew DL, Hayes DF, Gralow JR, Livingston RB, Hortobagyi GN. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012 Aug 2;367(5):435-44. link to original article contains verified protocol PubMed

Exemestane (Aromasin)

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Regimen

Study Evidence Comparator Efficacy
Chia et al. 2008 (EFECT) Phase III Fulvestrant Seems not superior
Baselga et al. 2012 (BOLERO-2) Phase III Everolimus & Exemestane Inferior PFS

Endocrine therapy

References

  1. Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, Fein L, Romieu G, Buzdar A, Robertson JF, Brufsky A, Possinger K, Rennie P, Sapunar F, Lowe E, Piccart M. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008 Apr 1;26(10):1664-70. Epub 2008 Mar 3. link to original article PubMed
  2. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012 Feb 9;366(6):520-9. Epub 2011 Dec 7. link to original article contains verified protocol PubMed
    1. Update: Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, Hortobagyi GN, Campone M, Pistilli B, Piccart M, Melichar B, Petrakova K, Arena FP, Erdkamp F, Harb WA, Feng W, Cahana A, Taran T, Lebwohl D, Rugo HS. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013 Oct;30(10):870-84. Erratum in: Adv Ther. 2014 Sep;31(9):1008-9. link to PMC article PubMed

See references for Exemestane (Aromasin)

Exemestane & Everolimus

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Regimen

Study Evidence Comparator Efficacy
Baselga et al. 2012 (BOLERO-2) Phase III Exemestane Superior PFS

Therapy

Given until progression of disease or unacceptable toxicity

References

  1. Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T, Noguchi S, Gnant M, Pritchard KI, Lebrun F, Beck JT, Ito Y, Yardley D, Deleu I, Perez A, Bachelot T, Vittori L, Xu Z, Mukhopadhyay P, Lebwohl D, Hortobagyi GN. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012 Feb 9;366(6):520-9. Epub 2011 Dec 7. link to original article contains verified protocol PubMed
    1. Update: Yardley DA, Noguchi S, Pritchard KI, Burris HA 3rd, Baselga J, Gnant M, Hortobagyi GN, Campone M, Pistilli B, Piccart M, Melichar B, Petrakova K, Arena FP, Erdkamp F, Harb WA, Feng W, Cahana A, Taran T, Lebwohl D, Rugo HS. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013 Oct;30(10):870-84. Erratum in: Adv Ther. 2014 Sep;31(9):1008-9. link to PMC article PubMed

Fulvestrant (Faslodex)

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Regimen

Study Evidence Comparator Efficacy
Howell et al. 2002 Phase III Anastrozole Seems to have non-inferior TTP
Howell et al. 2004 Phase III Tamoxifen Might have inferior TTP
Chia et al. 2008 (EFECT) Phase III Exemestane Seems not superior
Robertson et al. 2016 (FALCON) Phase III Anastrozole Seems to have superior PFS

Endocrine therapy

References

  1. Howell A, Robertson JF, Quaresma Albano J, Aschermannova A, Mauriac L, Kleeberg UR, Vergote I, Erikstein B, Webster A, Morris C. Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol. 2002 Aug 15;20(16):3396-403. link to original article PubMed
  2. Howell A, Robertson JF, Abram P, Lichinitser MR, Elledge R, Bajetta E, Watanabe T, Morris C, Webster A, Dimery I, Osborne CK. Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol. 2004 May 1;22(9):1605-13. link to original article PubMed
  3. Perey L, Paridaens R, Hawle H, Zaman K, Nolé F, Wildiers H, Fiche M, Dietrich D, Clément P, Köberle D, Goldhirsch A, Thürlimann B. Clinical benefit of fulvestrant in postmenopausal women with advanced breast cancer and primary or acquired resistance to aromatase inhibitors: final results of phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00). Ann Oncol. 2007 Jan;18(1):64-9. Epub 2006 Oct 9. link to original article PubMed
  4. Chia S, Gradishar W, Mauriac L, Bines J, Amant F, Federico M, Fein L, Romieu G, Buzdar A, Robertson JF, Brufsky A, Possinger K, Rennie P, Sapunar F, Lowe E, Piccart M. Double-blind, randomized placebo controlled trial of fulvestrant compared with exemestane after prior nonsteroidal aromatase inhibitor therapy in postmenopausal women with hormone receptor-positive, advanced breast cancer: results from EFECT. J Clin Oncol. 2008 Apr 1;26(10):1664-70. Epub 2008 Mar 3. link to original article PubMed
  5. Robertson JF, Bondarenko IM, Trishkina E, Dvorkin M, Panasci L, Manikhas A, Shparyk Y, Cardona-Huerta S, Cheung KL, Philco-Salas MJ, Ruiz-Borrego M, Shao Z, Noguchi S, Rowbottom J, Stuart M, Grinsted LM, Fazal M, Ellis MJ. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Nov 28. [Epub ahead of print] link to original article contains protocol PubMed

Letrozole (Femara)

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Regimen

Study Evidence Comparator Efficacy
Finn et al. 2015 (PALOMA-1/TRIO-18) Randomized Phase II Letrozole & Palbociclib Inferior PFS
Dickler et al. 2016 (CALGB 40503) Phase III Letrozole & Bevacizumab Seems to have inferior PFS
Finn et al. 2016 (PALOMA-2) Randomized Phase II Letrozole & Palbociclib Inferior PFS

Endocrine therapy

References

See references for Letrozole (Femara)

  1. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35. link to original article contains verified protocol PubMed
  2. Dickler MN, Barry WT, Cirrincione CT, Ellis MJ, Moynahan ME, Innocenti F, Hurria A, Rugo HS, Lake DE, Hahn O, Schneider BP, Tripathy D, Carey LA, Winer EP, Hudis CA. Phase III Trial Evaluating Letrozole As First-Line Endocrine Therapy With or Without Bevacizumab for the Treatment of Postmenopausal Women With Hormone Receptor-Positive Advanced-Stage Breast Cancer: CALGB 40503 (Alliance). J Clin Oncol. 2016 Aug 1;34(22):2602-9. Epub 2016 May 2. link to original article contains protocol PubMed
  3. Richard S. Finn, M.D., Miguel Martin, M.D., Hope S. Rugo, M.D., Stephen Jones, M.D., Seock-Ah Im, M.D., Ph.D., Karen Gelmon, M.D., Nadia Harbeck, M.D., Ph.D., Oleg N. Lipatov, M.D., Janice M. Walshe, M.D., Stacy Moulder, M.D., Eric Gauthier, Pharm.D., Ph.D., Dongrui R. Lu, M.Sc., Sophia Randolph, M.D., Ph.D., Véronique Diéras, M.D., and Dennis J. Slamon, M.D., Ph.D. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med 2016; 375:1925-1936. link to original article

Letrozole & Palbociclib

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Regimen

Study Evidence Comparator Efficacy
Finn et al. 2015 (PALOMA-1/TRIO-18) Randomized Phase II Letrozole Superior PFS
Finn et al. 2016 (PALOMA-2) Phase III Letrozole Superior PFS

Therapy

28-day cycles, given until progression of disease or unacceptable toxicity

References

  1. Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015 Jan;16(1):25-35. link to original article contains verified protocol PubMed
  2. Richard S. Finn, M.D., Miguel Martin, M.D., Hope S. Rugo, M.D., Stephen Jones, M.D., Seock-Ah Im, M.D., Ph.D., Karen Gelmon, M.D., Nadia Harbeck, M.D., Ph.D., Oleg N. Lipatov, M.D., Janice M. Walshe, M.D., Stacy Moulder, M.D., Eric Gauthier, Pharm.D., Ph.D., Dongrui R. Lu, M.Sc., Sophia Randolph, M.D., Ph.D., Véronique Diéras, M.D., and Dennis J. Slamon, M.D., Ph.D. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med 2016; 375:1925-1936. link to original article

Tamoxifen (Nolvadex)

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Regimen #1, standard dosing (20 mg per day)

Study Evidence Comparator Efficacy
Hayes et al. 1995 Phase III Toremifene 60 mg per day Seems not superior
Toremifene 200 mg per day Seems not superior
Howell et al. 2004 Phase III Fulvestrant Might have superior TTP
Bachelot et al. 2012 Randomized Phase II Tamoxifen & Everolimus Inferior OS

Endocrine therapy

Regimen #2, high-dose (40 mg per day)

Study Evidence Comparator Efficacy
Gershanovich et al. 1997 Phase III Toremifene 60 mg per day Seems not superior
Toremifene 240 mg per day Seems not superior
Pyrhönen et al. 1997 Phase III Toremifene 60 mg per day Seems to have superior TTP

Endocrine therapy

References

  1. Hayes DF, Van Zyl JA, Hacking A, Goedhals L, Bezwoda WR, Mailliard JA, Jones SE, Vogel CL, Berris RF, Shemano I et al. Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2556-66. link to original article PubMed
  2. Gershanovich M, Garin A, Baltina D, Kurvet A, Kangas L, Ellmén J. A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer. Eastern European Study Group. Breast Cancer Res Treat. 1997 Sep;45(3):251-62. link to original article PubMed
  3. Pyrhönen S, Valavaara R, Modig H, Pawlicki M, Pienkowski T, Gundersen S, Bauer J, Westman G, Lundgren S, Blanco G, Mella O, Nilsson I, Hietanen T, Hindy I, Vuorinen J, Hajba A. Comparison of toremifene and tamoxifen in post-menopausal patients with advanced breast cancer: a randomized double-blind, the 'nordic' phase III study. Br J Cancer. 1997;76(2):270-7. link to PMC article PubMed
  4. Howell A, Robertson JF, Abram P, Lichinitser MR, Elledge R, Bajetta E, Watanabe T, Morris C, Webster A, Dimery I, Osborne CK. Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: a multinational, double-blind, randomized trial. J Clin Oncol. 2004 May 1;22(9):1605-13. link to original article PubMed
  5. Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaëth D, Legouffe E, Allouache D, El Kouri C, Pujade-Lauraine E. Randomized Phase II Trial of Everolimus in Combination With Tamoxifen in Patients With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer With Prior Exposure to Aromatase Inhibitors: A GINECO Study. J Clin Oncol. 2012 Aug 1;30(22):2718-24. Epub 2012 May 7. link to original article contains verified protocol PubMed

See references for Tamoxifen (Nolvadex)

Tamoxifen & Everolimus

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Regimen

Study Evidence Comparator Efficacy
Bachelot et al. 2012 Randomized Phase II Tamoxifen Superior OS

Therapy

Given until progression of disease or unacceptable toxicity

References

  1. Bachelot T, Bourgier C, Cropet C, Ray-Coquard I, Ferrero JM, Freyer G, Abadie-Lacourtoisie S, Eymard JC, Debled M, Spaëth D, Legouffe E, Allouache D, El Kouri C, Pujade-Lauraine E. Randomized Phase II Trial of Everolimus in Combination With Tamoxifen in Patients With Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer With Prior Exposure to Aromatase Inhibitors: A GINECO Study. J Clin Oncol. 2012 Aug 1;30(22):2718-24. Epub 2012 May 7. link to original article contains verified protocol PubMed

Toremifene (Fareston)

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Regimen

Study Evidence Comparator Efficacy
Hayes et al. 1995 Phase III Tamoxifen Seems not superior
Toremifene 200 mg per day Seems not superior
Gershanovich et al. 1997 Phase III Tamoxifen 40 mg per day Seems not superior
Toremifene 240 mg per day Seems not superior
Pyrhönen et al. 1997 Phase III Tamoxifen 40 mg per day Seems to have inferior TTP

Endocrine therapy

Given until progression

References

  1. Hayes DF, Van Zyl JA, Hacking A, Goedhals L, Bezwoda WR, Mailliard JA, Jones SE, Vogel CL, Berris RF, Shemano I et al. Randomized comparison of tamoxifen and two separate doses of toremifene in postmenopausal patients with metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2556-66. link to original article PubMed
  2. Gershanovich M, Garin A, Baltina D, Kurvet A, Kangas L, Ellmén J. A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer. Eastern European Study Group. Breast Cancer Res Treat. 1997 Sep;45(3):251-62. link to original article PubMed
  3. Pyrhönen S, Valavaara R, Modig H, Pawlicki M, Pienkowski T, Gundersen S, Bauer J, Westman G, Lundgren S, Blanco G, Mella O, Nilsson I, Hietanen T, Hindy I, Vuorinen J, Hajba A. Comparison of toremifene and tamoxifen in post-menopausal patients with advanced breast cancer: a randomized double-blind, the 'nordic' phase III study. Br J Cancer. 1997;76(2):270-7. link to PMC article PubMed
  4. Toremifene (Fareston) package insert

Metastatic disease, single agent therapy

Capecitabine (Xeloda)

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Regimen #1, Intermittent 2500 mg/m2 daily dose

Study Evidence Comparator Efficacy
Bajetta et al. 2005 Phase II
Geyer et al. 2006 Phase III Capecitabine & Lapatinib Inferior TTP
Thomas et al. 2007 Phase III Capecitabine & Ixabepilone Inferior PFS
von Minckwitz et al. 2009 (GBG 26/BIG 3-05) Phase III Capecitabine & Trastuzumab Seems to have inferior TTP
Sparano et al. 2010 Phase III Capecitabine & Ixabepilone Inferior PFS
Crown et al. 2013 Phase III Capecitabine & Sunitinib Seems not superior

Chemotherapy

21-day cycles

Regimen #2, intermittent 2000 mg/m2 daily dose

Study Evidence Comparator Efficacy
Bajetta et al. 2005 Phase II
Stockler et al. 2011 Phase III CMF Seems to have superior OS
Continuous Capecitabine Seems not superior

Chemotherapy

21-day cycles

Regimen #3, continuous

Study Evidence Comparator Efficacy
Stockler et al. 2011 Phase III CMF Seems to have superior OS
Intermittent Capecitabine Seems not superior

Chemotherapy

21-day cycles

References

  1. Bajetta E, Procopio G, Celio L, Gattinoni L, Della Torre S, Mariani L, Catena L, Ricotta R, Longarini R, Zilembo N, Buzzoni R. Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women. J Clin Oncol. 2005 Apr 1;23(10):2155-61. Epub 2005 Feb 14. link to original article contains verified protocol PubMed
  2. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006 Dec 28;355(26):2733-43. link to original article contains verified protocol PubMed
    1. Update: Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, Chan S, Jagiello-Gruszfeld A, Kaufman B, Crown J, Chan A, Campone M, Viens P, Davidson N, Gorbounova V, Raats JI, Skarlos D, Newstat B, Roychowdhury D, Paoletti P, Oliva C, Rubin S, Stein S, Geyer CE. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat. 2008 Dec;112(3):533-43. link to original article PubMed
    2. Update: Cameron D, Casey M, Oliva C, Newstat B, Imwalle B, Geyer CE. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist. 2010;15(9):924-34. link to original article PubMed
  3. Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. link to original article contains verified protocol PubMed
  4. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer W, Baumann KH, Clemens MR, Duerr R, Uleer C, Andersson M, Stein RC, Nekljudova V, Loibl S. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study. J Clin Oncol. 2009 Apr 20;27(12):1999-2006. Epub 2009 Mar 16. link to original article contains verified protocol PubMed
    1. Update: von Minckwitz G, Schwedler K, Schmidt M, Barinoff J, Mundhenke C, Cufer T, Maartense E, de Jongh FE, Baumann KH, Bischoff J, Harbeck N, Lück HJ, Maass N, Zielinski C, Andersson M, Stein RC, Nekljudova V, Loibl S; GBG 26/BIG 03-05 study group and participating investigators. Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. Eur J Cancer. 2011 Oct;47(15):2273-81. Epub 2011 Jul 7. link to original article contains verified protocol PubMed
  5. Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010 Jul 10;28(20):3256-63.link to original article contains verified protocol PubMed
  6. Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B, Van Hazel G, Wilcken NR, Grimison PS, Nowak AK, Gainford MC, Fong A, Paksec L, Sourjina T, Zannino D, Gebski V, Simes RJ, Forbes JF, Coates AS. Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4498-504. Epub 2011 Oct 24. link to original article contains verified protocol PubMed
  7. Crown JP, Diéras V, Staroslawska E, Yardley DA, Bachelot T, Davidson N, Wildiers H, Fasching PA, Capitain O, Ramos M, Greil R, Cognetti F, Fountzilas G, Blasinska-Morawiec M, Liedtke C, Kreienberg R, Miller WH Jr, Tassell V, Huang X, Paolini J, Kern KA, Romieu G. Phase III Trial of Sunitinib in Combination With Capecitabine Versus Capecitabine Monotherapy for the Treatment of Patients With Pretreated Metastatic Breast Cancer. J Clin Oncol. 2013 Aug 10;31(23):2870-8. Epub 2013 Jul 15. link to original article contains verified protocol PubMed

Docetaxel (Taxotere)

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Regimen #1, q3wk dosing

Study Evidence Comparator Efficacy
O'Shaughnessy et al. 2002 Phase III Capecitabine & Docetaxel Seems to have inferior OS
Marty et al. 2005 (M77001) Phase III Docetaxel & Trastuzumab Seems to have inferior OS
Harvey et al. 2006 Phase III Low-dose q3wk docetaxel Might have superior TTP
Lower-dose q3wk docetaxel Might have superior TTP
Gradishar et al. 2009 Phase III Higher-dose weekly nanoparticle albumin-bound paclitaxel Inferior PFS
Lower-dose weekly nanoparticle albumin-bound paclitaxel Seems not superior
q3wk nanoparticle albumin-bound paclitaxel Seems not superior

Chemotherapy

21-day cycles

Regimen #2, low-dose q3wk dosing

Study Evidence Comparator Efficacy
Harvey et al. 2006 Phase III Lower-dose q3wk docetaxel Might have inferior TTP
Standard-dose q3wk docetaxel Might have inferior TTP

Chemotherapy

21-day cycles

Regimen #3, lower-dose q3wk dosing

Study Evidence Comparator Efficacy
Harvey et al. 2006 Phase III Low-dose q3wk docetaxel Might have superior TTP
Standard-dose q3wk docetaxel Might have inferior TTP

Chemotherapy

21-day cycles

Regimen #4, q3wk dosing of limited duration

Study Evidence Comparator Efficacy
Chan et al. 1999 (303 Study Group) Phase III Doxorubicin Superior ORR

Chemotherapy

21-day cycle for up to 7 cycles

Regimen #5, weekly dosing

Study Evidence
Burstein et al. 2000 Phase II

Chemotherapy

8-week cycles

References

  1. Review: Burris HA 3rd. Single-agent docetaxel (Taxotere) in randomized phase III trials. Semin Oncol. 1999 Jun;26(3 Suppl 9):1-6. PubMed
  2. Chan S, Friedrichs K, Noel D, Pintér T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, González Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J; 303 Study Group. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2341-54. link to original article PubMed
  3. Alexandre J, Bleuzen P, Bonneterre J, Sutherland W, Misset JL, Guastalla J, Viens P, Faivre S, Chahine A, Spielman M, Bensmaïne A, Marty M, Mahjoubi M, Cvitkovic E. Factors predicting for efficacy and safety of docetaxel in a compassionate-use cohort of 825 heavily pretreated advanced breast cancer patients. J Clin Oncol. 2000 Feb;18(3):562-73. link to original article PubMed
  4. Burstein HJ, Manola J, Younger J, Parker LM, Bunnell CA, Scheib R, Matulonis UA, Garber JE, Clarke KD, Shulman LN, Winer EP. Docetaxel administered on a weekly basis for metastatic breast cancer. J Clin Oncol. 2000 Mar;18(6):1212-9. link to original article PubMed content property of HemOnc.org
  5. O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. link to original article PubMed
  6. Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Antón A, Lluch A, Kennedy J, O'Byrne K, Conte P, Green M, Ward C, Mayne K, Extra JM. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005 Jul 1;23(19):4265-74. Epub 2005 May 23. link to original article contains verified protocol PubMed
  7. Harvey V, Mouridsen H, Semiglazov V, Jakobsen E, Voznyi E, Robinson BA, Groult V, Murawsky M, Cold S. Phase III trial comparing three doses of docetaxel for second-line treatment of advanced breast cancer. J Clin Oncol. 2006 Nov 1;24(31):4963-70. Epub 2006 Oct 10. link to original article PubMed
  8. Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009 Aug 1;27(22):3611-9. Epub 2009 May 26. Erratum in: J Clin Oncol. 2011 Jul 1;29(19):2739. link to original article contains verified protocol PubMed

Doxorubicin (Adriamycin)

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Regimen #1

Study Evidence Comparator Efficacy
O'Brien et al. 2004 (CAELYX Breast Cancer Study Group) Phase III Pegylated liposomal doxorubicin Seems to have non-inferior PFS

Chemotherapy

21-day cycles

Regimen #2

Study Evidence Comparator Efficacy
Chan et al. 1999 (303 Study Group) Phase III Docetaxel Inferior ORR

Chemotherapy

21-day cycle for up to 7 cycles

Regimen #3

Study Evidence Comparator Efficacy
Gundersen et al. 1986 Phase III VAC Seems not superior

Chemotherapy

Duration not specified

References

  1. Gundersen S, Kvinnsland S, Klepp O, Kvaløy S, Lund E, Høst H. Weekly adriamycin versus VAC in advanced breast cancer. A randomized trial. Eur J Cancer Clin Oncol. 1986 Dec;22(12):1431-4. link to SD article PubMed
  2. Chan S, Friedrichs K, Noel D, Pintér T, Van Belle S, Vorobiof D, Duarte R, Gil Gil M, Bodrogi I, Murray E, Yelle L, von Minckwitz G, Korec S, Simmonds P, Buzzi F, González Mancha R, Richardson G, Walpole E, Ronzoni M, Murawsky M, Alakl M, Riva A, Crown J; 303 Study Group. Prospective randomized trial of docetaxel versus doxorubicin in patients with metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2341-54. link to original article PubMed
  3. O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C; CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004 Mar;15(3):440-9. link to original article PubMed

Doxorubicin liposomal (Doxil)

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Regimen

Study Evidence Comparator Efficacy
O'Brien et al. 2004 (CAELYX Breast Cancer Study Group) Phase III Doxorubicin Seems to have non-inferior PFS

Chemotherapy

  • Doxorubicin liposomal (Doxil) 50 mg/m2 IV over up to 60 minutes once on day 1
    • If infusion reactions occurred, infusion could be given over up to 90 minutes

28-day cycles

References

  1. O'Brien ME, Wigler N, Inbar M, Rosso R, Grischke E, Santoro A, Catane R, Kieback DG, Tomczak P, Ackland SP, Orlandi F, Mellars L, Alland L, Tendler C; CAELYX Breast Cancer Study Group. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004 Mar;15(3):440-9. link to original article contains verified protocol PubMed

Epirubicin (Ellence)

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Regimen #1, 40 mg/m2

Study Evidence Comparator Efficacy
Bastholt et al. 1996 Phase III Epirubicin 60 mg/m2 Seems not superior
Epirubicin 90 mg/m2 Inferior TTP
Epirubicin 135 mg/m2 Seems not superior

Chemotherapy

21-day cycles

Regimen #2, 60 mg/m2

Study Evidence Comparator Efficacy
Bastholt et al. 1996 Phase III Epirubicin 40 mg/m2 Seems not superior
Epirubicin 90 mg/m2 Seems not superior
Epirubicin 135 mg/m2 Seems not superior

Chemotherapy

21-day cycles

Regimen #3, 90 mg/m2

Study Evidence Comparator Efficacy
Bastholt et al. 1996 Phase III Epirubicin 40 mg/m2 Superior TTP
Epirubicin 60 mg/m2 Seems not superior
Epirubicin 135 mg/m2 Seems not superior

Chemotherapy

21-day cycles

Regimen #4, 135 mg/m2

Study Evidence Comparator Efficacy
Bastholt et al. 1996 Phase III Epirubicin 40 mg/m2 Seems not superior
Epirubicin 60 mg/m2 Seems not superior
Epirubicin 90 mg/m2 Seems not superior

Chemotherapy

21-day cycles

References

  1. Bastholt L, Dalmark M, Gjedde SB, Pfeiffer P, Pedersen D, Sandberg E, Kjaer M, Mouridsen HT, Rose C, Nielsen OS, Jakobsen P, Bentzen SM. Dose-response relationship of epirubicin in the treatment of postmenopausal patients with metastatic breast cancer: a randomized study of epirubicin at four different dose levels performed by the Danish Breast Cancer Cooperative Group. J Clin Oncol. 1996 Apr;14(4):1146-55. link to original article contains verified protocol PubMed

Eribulin (Halaven)

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Regimen

Study Evidence Comparator Efficacy
Cortes et al. 2011 (EMBRACE) Phase III Investigator's choice Seems to have superior OS

Chemotherapy

21-day cycles

References

  1. Cortes J, O'Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, Chollet P, Manikas A, Diéras V, Delozier T, Vladimirov V, Cardoso F, Koh H, Bougnoux P, Dutcus CE, Seegobin S, Mir D, Meneses N, Wanders J, Twelves C; EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician's Choice Versus E7389) investigators. Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011 Mar 12;377(9769):914-23. Epub 2011 Mar 2. link to original article contains protocol PubMed
  2. Eribulin (Halaven) package insert

Gemcitabine (Gemzar)

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Regimen

Study Evidence
Carmichael et al. 1995 Phase II
Spielmann et al. 2001 Phase II

Chemotherapy

28-day cycles

References

  1. Carmichael J, Possinger K, Phillip P, Beykirch M, Kerr H, Walling J, Harris AL. Advanced breast cancer: a phase II trial with gemcitabine. J Clin Oncol. 1995 Nov;13(11):2731-6. link to original article PubMed
  2. Spielmann M, Llombart-Cussac A, Kalla S, Espié M, Namer M, Ferrero JM, Diéras V, Fumoleau P, Cuvier C, Perrocheau G, Ponzio A, Kayitalire L, Pouillart P. Single-agent gemcitabine is active in previously treated metastatic breast cancer. Oncology. 2001;60(4):303-7. link to original article PubMed

Olaparib (Lynparza)

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Regimen

Study Evidence
Kaufman et al. 2014 Phase II

Patients had germline BRCA1/2 mutations and had progressed after at least three lines of treatment for metastatic disease.

Chemotherapy

Continued until progression

References

  1. Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmaña J, Mitchell G, Fried G, Stemmer SM, Hubert A, Rosengarten O, Steiner M, Loman N, Bowen K, Fielding A, Domchek SM. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015 Jan 20;33(3):244-50. Epub 2014 Nov 3. link to original article contains verified protocol PubMed

Paclitaxel (Taxol)

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Regimen #1, q3wk dosing

Study Evidence Comparator Efficacy
Seidman et al. 1995 Phase II
Slamon et al. 2001 Phase III TH Seems to have inferior OS
Gradishar et al. 2005 Phase III Nanoparticle albumin-bound paclitaxel Inferior TTP
Seidman et al. 2008 (CALGB 9840) Phase III Weekly paclitaxel Inferior OS
Albain et al. 2008 Phase III Gemcitabine & Paclitaxel Seems to have inferior OS

Chemotherapy

21-day cycles

Regimen #2, weekly dosing

Study Evidence Comparator Efficacy
Perez et al. 2001 Phase II
Seidman et al. 2008 (CALGB 9840) Phase III Every three-week paclitaxel Superior OS

Chemotherapy

4-week cycles

Regimen #3

Study Evidence Comparator Efficacy
Miller et al. 2007 Phase III Paclitaxel & Bevacizumab Inferior PFS

Chemotherapy

28-day cycles

Regimen #4

Study Evidence
Seidman et al. 1995 Phase II

Note: this is the dose used in untreated patients in Seidman et al. 1995. It is not a common dosing.

Chemotherapy

21-day cycles

References

  1. Seidman AD, Tiersten A, Hudis C, Gollub M, Barrett S, Yao TJ, Lepore J, Gilewski T, Currie V, Crown J et al. Phase II trial of paclitaxel by 3-hour infusion as initial and salvage chemotherapy for metastatic breast cancer. J Clin Oncol. 1995 Oct;13(10):2575-81. link to original article PubMed
  2. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. link to original article PubMed
  3. Perez EA, Vogel CL, Irwin DH, Kirshner JJ, Patel R. Multicenter phase II trial of weekly paclitaxel in women with metastatic breast cancer. J Clin Oncol. 2001 Nov 15;19(22):4216-23. link to original article PubMed
  4. Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. link to original article contains verified protocol PubMed
  5. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76. link to original article PubMed
  6. Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. link to original article PubMed
  7. Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, Rolski J, Melemed AS, Reyes-Vidal JM, Sekhon JS, Simms L, O'Shaughnessy J. Gemcitabine plus Paclitaxel versus Paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008 Aug 20;26(24):3950-7. link to original article PubMed

Paclitaxel, nanoparticle albumin-bound (Abraxane)

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Example orders

Regimen #1, weekly dosing (100 mg/m2)

Study Evidence Comparator Efficacy
Gradishar et al. 2009 Randomized Phase II Docetaxel Seems not superior
Weekly nab-paclitaxel (150 mg/m2) Not reported
q3wk nab-paclitaxel Not reported

Chemotherapy

28-day cycles

Regimen #2, weekly dosing (150 mg/m2)

Study Evidence Comparator Efficacy
Gradishar et al. 2009 Randomized Phase II Docetaxel Superior PFS
Weekly nab-paclitaxel (100 mg/m2) Not reported
q3wk nab-paclitaxel Not reported

Chemotherapy

28-day cycles

Regimen #3, q3wk nab-paclitaxel

Study Evidence Comparator Efficacy
Gradishar et al. 2009 Randomized Phase II Docetaxel Seems not superior
Weekly nab-paclitaxel (100 mg/m2) Not reported
Weekly nab-paclitaxel (150 mg/m2) Not reported

Chemotherapy

21-day cycles

Regimen #4

Study Evidence Comparator Efficacy
Gradishar et al. 2005 Phase III Paclitaxel Superior TTP

Chemotherapy

Supportive medications

  • No corticosteroid or antihistamine premedication

21-day cycles

References

  1. Gradishar WJ, Tjulandin S, Davidson N, Shaw H, Desai N, Bhar P, Hawkins M, O'Shaughnessy J. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005 Nov 1;23(31):7794-803. Epub 2005 Sep 19. link to original article contains verified protocol PubMed
  2. Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009 Aug 1;27(22):3611-9. Epub 2009 May 26. Erratum in: J Clin Oncol. 2011 Jul 1;29(19):2739. link to original article contains verified protocol PubMed

Pemetrexed (Alimta)

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Regimen #1

Study Evidence
Robert et al. 2011 Phase II

Chemotherapy

Supportive medications

  • Dexamethasone (Decadron) 4 mg PO BID the day before, day of, and day after chemotherapy
  • Folic acid 350 to 1000 mcg PO once per day, to start at least 5 days prior to start of pemetrexed therapy, to continue throughout therapy with pemetrexed, and until 3 weeks after the last dose of pemetrexed
  • Cyanocobalamin (Vitamin B12) 1000 mcg IM every 8 to 10 weeks, the first dose given at least 1 week prior to start of pemetrexed therapy, to continue throughout therapy with pemetrexed, and until 3 weeks after the last dose of pemetrexed

14-day cycles, given until progression of disease or unacceptable toxicity

Regimen #2

Study Evidence
Gomez et al. 2006 Phase II

Patients in the study were "chemotherapy-naïve, with advanced (T4 and N0-N2, M0, M1) breast cancer."

Chemotherapy

Supportive medications

  • Dexamethasone (Decadron) 4 mg PO BID the day before, day of, and day after chemotherapy
  • Folic acid 350 to 1000 mcg PO once per day, to start 5 to 7 days prior to start of pemetrexed therapy, to continue throughout therapy with pemetrexed
  • Cyanocobalamin (Vitamin B12) 1000 mcg IM every 9 weeks, the first dose given before the study's pretreatment biopsy, to continue throughout therapy with pemetrexed

21-day cycle for up to 3 cycles

References

  1. Gomez HL, Santillana SL, Vallejos CS, Velarde R, Sanchez J, Wang X, Bauer NL, Hockett RD, Chen VJ, Niyikiza C, Hanauske AR. A phase II trial of pemetrexed in advanced breast cancer: clinical response and association with molecular target expression. Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):832-8. link to original article contains verified protocol PubMed
  2. Robert NJ, Conkling PR, O'Rourke MA, Kuefler PR, McIntyre KJ, Zhan F, Asmar L, Wang Y, Shonukan OO, O'Shaughnessy JA. Results of a phase II study of pemetrexed as first-line chemotherapy in patients with advanced or metastatic breast cancer. Breast Cancer Res Treat. 2011 Feb;126(1):101-8. Epub 2010 Dec 25. link to original article contains verified protocol PubMed

Vinorelbine (Navelbine)

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Regimen

Study Evidence
Gasparini et al. 1994 Phase II
Zelek et al. 2001 Phase II

Chemotherapy

References

  1. Gasparini G, Caffo O, Barni S, Frontini L, Testolin A, Guglielmi RB, Ambrosini G. Vinorelbine is an active antiproliferative agent in pretreated advanced breast cancer patients: a phase II study. J Clin Oncol. 1994 Oct;12(10):2094-101. link to original article PubMed
  2. Zelek L, Barthier S, Riofrio M, Fizazi K, Rixe O, Delord JP, Le Cesne A, Spielmann M. Weekly vinorelbine is an effective palliative regimen after failure with anthracyclines and taxanes in metastatic breast carcinoma. Cancer. 2001 Nov 1;92(9):2267-72. PubMed

Metastatic disease, combination chemotherapy

AC

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AC: Adriamycin (Doxorubicin), Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Fisher et al. 1990 (NSABP B-15) Phase III AC -> CMF Seems not superior
CMF Seems not superior
Slamon et al. 2001 Phase III ACH Seems to have inferior OS
Nabholtz et al. 2003 Phase III AT (Taxotere) Seems to have inferior TTP

Note: patients in Slamon et al. 2001 had not previously received adjuvant (postoperative) therapy with an anthracycline.

Chemotherapy

21-day cycles

References

  1. Jones SE, Durie BG, Salmon SE. Combination chemotherapy with adriamycin and cyclophosphamide for advanced breast cancer. Cancer. 1975 Jul;36(1):90-7. link to original article PubMed
  2. Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, Bowman D, Wolmark N, Wickerham DL, Kardinal CG et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol. 1990 Sep;8(9):1483-96. link to original article PubMed
  3. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. link to original article PubMed
  4. Nabholtz JM, Falkson C, Campos D, Szanto J, Martin M, Chan S, Pienkowski T, Zaluski J, Pinter T, Krzakowski M, Vorobiof D, Leonard R, Kennedy I, Azli N, Murawsky M, Riva A, Pouillart P; TAX 306 Study Group. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol. 2003 Mar 15;21(6):968-75. link to original article PubMed

AT (Taxol)

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AT: Adriamycin, Taxol

Regimen

Study Evidence
Gianni et al. 1995 Non-randomized

Chemotherapy

21-day cycles

References

  1. Gianni L, Munzone E, Capri G, Fulfaro F, Tarenzi E, Villani F, Spreafico C, Laffranchi A, Caraceni A, Martini C et al. Paclitaxel by 3-hour infusion in combination with bolus doxorubicin in women with untreated metastatic breast cancer: high antitumor efficacy and cardiac effects in a dose-finding and sequence-finding study. J Clin Oncol. 1995 Nov;13(11):2688-99. link to original article PubMed

AT (Taxotere)

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AT: Adriamycin (Doxorubicin), Taxotere (Docetaxel)

Regimen

Study Evidence Comparator Efficacy
Nabholtz et al. 2003 Phase III AC Seems to have superior TTP

Chemotherapy

21-day cycles

References

  1. Nabholtz JM, Falkson C, Campos D, Szanto J, Martin M, Chan S, Pienkowski T, Zaluski J, Pinter T, Krzakowski M, Vorobiof D, Leonard R, Kennedy I, Azli N, Murawsky M, Riva A, Pouillart P; TAX 306 Study Group. Docetaxel and doxorubicin compared with doxorubicin and cyclophosphamide as first-line chemotherapy for metastatic breast cancer: results of a randomized, multicenter, phase III trial. J Clin Oncol. 2003 Mar 15;21(6):968-75. link to original article PubMed

CAF

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CAF: Cyclophosphamide, Adriamycin (Doxorubicin), Fluorouracil

Regimen

Study Evidence Comparator Efficacy
Bull et al. 1978 Phase III CMF Might have superior ORR

Chemotherapy

28-day cycles

References

  1. Bull JM, Tormey DC, Li SH, Carbone PP, Falkson G, Blom J, Perlin E, Simon R. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978 May;41(5):1649-57. link to original article PubMed

Capecitabine & Bevacizumab

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Regimen

Study Evidence Comparator Efficacy
Welt et al. 2016 (CARIN) Phase III Capecitabine, Vinorelbine, Bevacizumab Might have inferior PFS
Zielinski et al. 2016 (TURANDOT) Phase III Paclitaxel & Bevacizumab Non-inferior OS

Chemotherapy

21-day cycles

References

  1. Welt A, Marschner N, Lerchenmueller C, Decker T, Steffens CC, Koehler A, Depenbusch R, Busies S, Hegewisch-Becker S. Capecitabine and bevacizumab with or without vinorelbine in first-line treatment of HER2/neu-negative metastatic or locally advanced breast cancer: final efficacy and safety data of the randomised, open-label superiority phase 3 CARIN trial. Breast Cancer Res Treat. 2016 Feb;156(1):97-107. link to PMC article PubMed
  2. Zielinski C, Láng I, Inbar M, Kahán Z, Greil R, Beslija S, Stemmer SM, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Petruzelka L, Eniu A, Nisenbaum B, Dank M, Anghel R, Messinger D, Brodowicz T; TURANDOT investigators. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1230-9. Epub 2016 Aug 5. link to original article contains protocol PubMed

Capecitabine & Ixabepilone

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Regimen

Study Evidence Comparator Efficacy
Thomas et al. 2007 Phase III Capecitabine Superior PFS
Sparano et al. 2010 Phase III Capecitabine Superior PFS

Chemotherapy

21-day cycles

References

  1. Thomas ES, Gomez HL, Li RK, Chung HC, Fein LE, Chan VF, Jassem J, Pivot XB, Klimovsky JV, de Mendoza FH, Xu B, Campone M, Lerzo GL, Peck RA, Mukhopadhyay P, Vahdat LT, Roché HH. Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment. J Clin Oncol. 2007 Nov 20;25(33):5210-7. link to original article contains verified protocol PubMed
  2. Sparano JA, Vrdoljak E, Rixe O, Xu B, Manikhas A, Medina C, Da Costa SC, Ro J, Rubio G, Rondinon M, Perez Manga G, Peck R, Poulart V, Conte P. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010 Jul 10;28(20):3256-63. link to original article contains protocol PubMed

CEF; FEC

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CEF: Cyclophosphamide, Epirubicin, Fluorouracil
FEC: Fluorouracil, Epirubicin, Cyclophosphamide

Regimen #1, "CEF21"

Study Evidence Comparator Efficacy
Del Mastro et al. 2001 Phase III HD-CEF14 Seems not superior

Chemotherapy

21-day cycle for 8 to 12 cycles

Regimen #2

Study Evidence Comparator Efficacy
Ackland et al. 2001 (HEPI 013) Phase III CMF Superior TTP

Chemotherapy

28-day cycle for 6 to 8 cycles

Regimen #3, "FEC 100"

Study Evidence Comparator Efficacy
Brufman et al. 1997 (HEPI 010) Phase III FEC 50 Superior ORR

Chemotherapy

21-day cycle for 6 to 8 cycles

Regimen #4, "FEC 50"

Study Evidence Comparator Efficacy
Brufman et al. 1997 (HEPI 010) Phase III FEC 100 Inferior ORR

Chemotherapy

21-day cycle for 6 to 8 cycles

References

  1. Brufman G, Colajori E, Ghilezan N, Lassus M, Martoni A, Perevodchikova N, Tosello C, Viaro D, Zielinski C. Doubling epirubicin dose intensity (100 mg/m2 versus 50 mg/m2) in the FEC regimen significantly increases response rates. An international randomised phase III study in metastatic breast cancer. The Epirubicin High Dose (HEPI 010) Study Group. Ann Oncol. 1997 Feb;8(2):155-62. link to original article contains verified protocol PubMed
  2. Ackland SP, Anton A, Breitbach GP, Colajori E, Tursi JM, Delfino C, Efremidis A, Ezzat A, Fittipaldo A, Kolaric K, Lopez M, Viaro D; HEPI 013 study group. Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study. J Clin Oncol. 2001 Feb 15;19(4):943-53. link to original article PubMed
  3. Del Mastro L, Venturini M, Lionetto R, Carnino F, Guarneri D, Gallo L, Contu A, Pronzato P, Vesentini L, Bergaglio M, Comis S, Rosso R. Accelerated-intensified cyclophosphamide, epirubicin, and fluorouracil (CEF) compared with standard CEF in metastatic breast cancer patients: results of a multicenter, randomized phase III study of the Italian Gruppo Oncologico Nord-Ouest-Mammella Inter Gruppo Group. J Clin Oncol. 2001 Apr 15;19(8):2213-21. link to original article contains verified protocol PubMed

Cisplatin & Vinorelbine

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Regimen

Study Evidence
Ray-Coquard et al. 1998 Phase II
Vassilomanolakis et al. 2000 Phase II

Chemotherapy

Supportive medications

  • Normal saline 200 mL bolus after vinorelbine to prevent phlebitis
  • Normal saline 2000 mL with KCl (unspecified amount of KCl) IV over 4 hours (infusion rate: 500 mL/H) once prior to cisplatin
  • Furosemide (Lasix) 40 mg IV once 20 minutes prior to cisplatin
  • Normal saline 1000 mL and D5W 1000 mL IV over 4 hours (overall infusion rate: 500 mL/H; paper did not say whether fluids were given sequentially or concurrently) once after cisplatin
  • 5-HT3 antagonists used

21-day cycle for up to 6 cycles or progression of disease

References

  1. Ray-Coquard I, Biron P, Bachelot T, Guastalla JP, Catimel G, Merrouche Y, Droz JP, Chauvin F, Blay JY. Vinorelbine and cisplatin (CIVIC regimen) for the treatment of metastatic breast carcinoma after failure of anthracycline- and/or paclitaxel-containing regimens. Cancer. 1998 Jan 1;82(1):134-40. PubMed
  2. Vassilomanolakis M, Koumakis G, Barbounis V, Demiri M, Pateras H, Efremidis AP. Vinorelbine and cisplatin in metastatic breast cancer patients previously treated with anthracyclines. Ann Oncol. 2000 Sep;11(9):1155-60. link to original article contains verified protocol Pubmed

CMF

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CMF: Cyclophosphamide, Methotrexate, Fluorouracil

Regimen

Study Evidence Comparator Efficacy
Bull et al. 1978 Phase III CAF Might have inferior ORR
Fisher et al. 1990 (NSABP B-15) Phase III AC Seems not superior
AC -> CMF Seems not superior
Stadtmauer et al. 2000 (Philadelphia Bone Marrow Transplant Group) Phase III CMF x 4-6 -> HDT Seems not superior
Ackland et al. 2001 (HEPI 013) Phase III CEF Inferior TTP
Stockler et al. 2011 Phase III Continuous Capecitabine
Intermittent Capecitabine 		Seems to have inferior OS

Chemotherapy

28-day cycles

References

  1. Bull JM, Tormey DC, Li SH, Carbone PP, Falkson G, Blom J, Perlin E, Simon R. A randomized comparative trial of adriamycin versus methotrexate in combination drug therapy. Cancer. 1978 May;41(5):1649-57. link to original article PubMed
  2. Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, Bowman D, Wolmark N, Wickerham DL, Kardinal CG et al. Two months of doxorubicin-cyclophosphamide with and without interval reinduction therapy compared with 6 months of cyclophosphamide, methotrexate, and fluorouracil in positive-node breast cancer patients with tamoxifen-nonresponsive tumors: results from the National Surgical Adjuvant Breast and Bowel Project B-15. J Clin Oncol. 1990 Sep;8(9):1483-96. link to original article PubMed
  3. Stadtmauer EA, O'Neill A, Goldstein LJ, Crilley PA, Mangan KF, Ingle JN, Brodsky I, Martino S, Lazarus HM, Erban JK, Sickles C, Glick JH. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. Philadelphia Bone Marrow Transplant Group. N Engl J Med. 2000 Apr 13;342(15):1069-76. link to original article PubMed
  4. Ackland SP, Anton A, Breitbach GP, Colajori E, Tursi JM, Delfino C, Efremidis A, Ezzat A, Fittipaldo A, Kolaric K, Lopez M, Viaro D; HEPI 013 study group. Dose-intensive epirubicin-based chemotherapy is superior to an intensive intravenous cyclophosphamide, methotrexate, and fluorouracil regimen in metastatic breast cancer: a randomized multinational study. J Clin Oncol. 2001 Feb 15;19(4):943-53. link to original article PubMed
  5. Stockler MR, Harvey VJ, Francis PA, Byrne MJ, Ackland SP, Fitzharris B, Van Hazel G, Wilcken NR, Grimison PS, Nowak AK, Gainford MC, Fong A, Paksec L, Sourjina T, Zannino D, Gebski V, Simes RJ, Forbes JF, Coates AS. Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer. J Clin Oncol. 2011 Dec 1;29(34):4498-504. Epub 2011 Oct 24. link to original article PubMed

EC

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EC: Epirubicin, Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Slamon et al. 2001 Phase III ECH Seems to have inferior OS
Langley et al. 2005 (UKNCRI AB01) Phase III EP Seems not superior

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. link to original article PubMed
  2. Langley RE, Carmichael J, Jones AL, Cameron DA, Qian W, Uscinska B, Howell A, Parmar M. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute trial AB01. J Clin Oncol. 2005 Nov 20;23(33):8322-30. link to original article PubMed

EP

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EP: Epirubicin, Paclitaxel

Regimen

Study Evidence Comparator Efficacy
Langley et al. 2005 (UKNCRI AB01) Phase III EC Seems not superior

Chemotherapy

21-day cycle for up to 6 cycles

References

  1. Langley RE, Carmichael J, Jones AL, Cameron DA, Qian W, Uscinska B, Howell A, Parmar M. Phase III trial of epirubicin plus paclitaxel compared with epirubicin plus cyclophosphamide as first-line chemotherapy for metastatic breast cancer: United Kingdom National Cancer Research Institute trial AB01. J Clin Oncol. 2005 Nov 20;23(33):8322-30. link to original article PubMed

FAC

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FAC: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Hortobagyi et al. 1979 Phase III FAC-BCG Inferior OS in responders

Chemotherapy

21-day cycles

References

  1. Hortobagyi GN, Gutterman JU, Blumenschein GR, Tashima CK, Burgess MA, Einhorn L, Buzdar AU, Richman SP, Hersh EM. Combination chemoimmunotherapy of metastatic breast cancer with 5-fluorouracil, adriamycin, cyclophosphamide, and BCG. Cancer. 1979 Nov;44(5):1955-62. link to original article PubMed

Gemcitabine & Carboplatin

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Regimen

Study Evidence
Nagourney et al. 2008 Pilot, <20 pts

Chemotherapy

21-day cycles, given until complete remission, progression of disease, or unacceptable toxicity

References

  1. Nagourney RA, Flam M, Link J, Hager S, Blitzer J, Lyons W, Sommers BL, Evans S. Carboplatin plus gemcitabine repeating doublet therapy in recurrent breast cancer. Clin Breast Cancer. 2008 Oct;8(5):432-5. link to original article contains protocol PubMed

GT (Paclitaxel)

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GT: Gemcitabine, Taxol (Paclitaxel)

Regimen

Study Evidence Comparator Efficacy
Albain et al. 2008 Phase III Paclitaxel Seems to have superior OS

Chemotherapy

21-day cycles

References

  1. Albain KS, Nag SM, Calderillo-Ruiz G, Jordaan JP, Llombart AC, Pluzanska A, Rolski J, Melemed AS, Reyes-Vidal JM, Sekhon JS, Simms L, O'Shaughnessy J. Gemcitabine plus Paclitaxel versus Paclitaxel monotherapy in patients with metastatic breast cancer and prior anthracycline treatment. J Clin Oncol. 2008 Aug 20;26(24):3950-7. link to original article PubMed

Paclitaxel & Bevacizumab

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Regimen

Study Evidence Comparator Efficacy
Miller et al. 2007 Phase III Paclitaxel Superior PFS
Zielinski et al. 2016 (TURANDOT) Phase III Capecitabine & Bevacizumab Non-inferior OS

Chemotherapy

28-day cycles

References

  1. Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007 Dec 27;357(26):2666-76. link to original article PubMed
  2. Zielinski C, Láng I, Inbar M, Kahán Z, Greil R, Beslija S, Stemmer SM, Zvirbule Z, Steger GG, Melichar B, Pienkowski T, Sirbu D, Petruzelka L, Eniu A, Nisenbaum B, Dank M, Anghel R, Messinger D, Brodowicz T; TURANDOT investigators. Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial. Lancet Oncol. 2016 Sep;17(9):1230-9. Epub 2016 Aug 5. link to original article contains protocol PubMed

Paclitaxel, nanoparticle albumin-bound & Bevacizumab

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Example orders

Regimen

Study Evidence
Danso et al. 2008 Phase II

Chemotherapy

28-day cycles

References

  1. Abstract: M. A. Danso, J. L. Blum, N. J. Robert, L. Krekow, R. Rotche, D. A. Smith, P. Richards, T. Anderson, D. A. Richards and J. O'Shaughnessy. Phase II trial of weekly nab-paclitaxel in combination with bevacizumab as first-line treatment in metastatic breast cancer. 2008 ASCO Annual Meeting abstract 1075. link to abstract

Paclitaxel, nanoparticle albumin-bound & Capecitabine

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Regimen

Study Evidence
Schwartzberg et al. 2011 Phase II

Chemotherapy

21-day cycles, given until progression of disease or unacceptable toxicity

References

  1. Schwartzberg LS, Arena FP, Mintzer DM, Epperson AL, Walker MS. Phase II multicenter trial of albumin-bound paclitaxel and capecitabine in first-line treatment of patients with metastatic breast cancer. Clin Breast Cancer. 2012 Apr;12(2):87-93. Epub 2011 Dec 6. link to original article contains protocol PubMed

TX - Capecitabine & Docetaxel

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TX: Taxotere (Docetaxel), Xeloda (Capecitabine)

Regimen

Study Evidence Comparator Efficacy
O'Shaughnessy et al. 2002 Phase III Docetaxel Seems to have superior OS

Chemotherapy

21-day cycles

References

  1. O'Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui WY, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard R. Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results. J Clin Oncol. 2002 Jun 15;20(12):2812-23. link to original article PubMed

TX - Capecitabine & Paclitaxel

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TX: Taxol (Paclitaxel), Xeloda (Capecitabine)

Regimen

Study Evidence
Blum et al. 2006 Phase II

Chemotherapy

21-day cycles, given until progression of disease or unacceptable toxicity

References

  1. Blum JL, Dees EC, Chacko A, Doane L, Ethirajan S, Hopkins J, McMahon R, Merten S, Negron A, Neubauer M, Ilegbodu D, Boehm KA, Asmar L, O'Shaughnessy JA. Phase II trial of capecitabine and weekly paclitaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2006 Sep 20;24(27):4384-90. Epub 2006 Aug 22. link to original article contains verified protocol PubMed

VAC

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VAC: Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide

Regimen

Study Evidence Comparator Efficacy
Gundersen et al. 1986 Phase III Doxorubicin Seems not superior

Used as a comparator arm in older trials and found to be more toxic; here for reference purposes only.

Chemotherapy

References

  1. Gundersen S, Kvinnsland S, Klepp O, Kvaløy S, Lund E, Høst H. Weekly adriamycin versus VAC in advanced breast cancer. A randomized trial. Eur J Cancer Clin Oncol. 1986 Dec;22(12):1431-4. link to SD article PubMed

Vinorelbine & Bevacizumab

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Example orders

Regimen

Study Evidence
Burstein et al. 2008 Phase II

Chemotherapy

Given until progression of disease or unacceptable toxicity

References

  1. Burstein HJ, Chen YH, Parker LM, Savoie J, Younger J, Kuter I, Ryan PD, Garber JE, Chen H, Campos SM, Shulman LN, Harris LN, Gelman R, Winer EP. VEGF as a marker for outcome among advanced breast cancer patients receiving anti-VEGF therapy with bevacizumab and vinorelbine chemotherapy. Clin Cancer Res. 2008 Dec 1;14(23):7871-7. link to original article contains verified protocol PubMed

Metastatic disease, HER-2 positive

ACH

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ACH: Adriamycin (Doxorubicin), Cyclophosphamide, Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Slamon et al. 2001 Phase III AC Seems to have superior OS

Note: patients had not previously received adjuvant (postoperative) therapy with an anthracycline. Not commonly used; here for reference purposes only.

Chemotherapy

References

  1. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. link to original article PubMed

Ado-trastuzumab emtansine (Kadcyla)

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Example orders

Regimen

Study Evidence Comparator Efficacy
Verma et al. 2012 (EMILIA) Phase III Capecitabine & Lapatinib Superior OS
Hurvitz et al. 2013 Randomized Phase II TH Seems to have superior PFS

Chemotherapy

21-day cycles, given until progression of disease or unacceptable toxicity

References

  1. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012 Nov 8;367(19):1783-91. Epub 2012 Oct 1. link to original article contains verified protocol PubMed
  2. Hurvitz SA, Dirix L, Kocsis J, Bianchi GV, Lu J, Vinholes J, Guardino E, Song C, Tong B, Ng V, Chu YW, Perez EA. Phase II Randomized Study of Trastuzumab Emtansine Versus Trastuzumab Plus Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer. J Clin Oncol. 2013 Mar 20;31(9):1157-63. Epub 2013 Feb 4. Erratum in: J Clin Oncol. 2013 Aug 10;31(23):2977. link to original article contains verified protocol PubMed

Bevacizumab, Capecitabine, Trastuzumab

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Regimen

Study Evidence
Martín et al. 2012 Phase II

Chemotherapy

21-day cycles, given until progression of disease or unacceptable toxicity

References

  1. Martín M, Makhson A, Gligorov J, Lichinitser M, Lluch A, Semiglazov V, Scotto N, Mitchell L, Tjulandin S. Phase II study of bevacizumab in combination with trastuzumab and capecitabine as first-line treatment for HER-2-positive locally recurrent or metastatic breast cancer. Oncologist. 2012;17(4):469-75. Epub 2012 Mar 30. link to original article contains verified protocol [1]
  2. A Study of Avastin (Bevacizumab) in Combination With Herceptin (Trastuzumab) and Xeloda (Capecitabine) in Patients With HER2-Positive Breast Cancer at ClinicalTrials.gov, NCT00811135

Capecitabine & Lapatinib

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Regimen

Study Evidence Comparator Efficacy
Geyer et al. 2006 Phase III Capecitabine Superior TTP
Verma et al. 2012 (EMILIA) Phase III T-DM1 Inferior OS

Chemotherapy

21-day cycles

References

  1. Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006 Dec 28;355(26):2733-43. link to original article PubMed
    1. Update: Cameron D, Casey M, Press M, Lindquist D, Pienkowski T, Romieu CG, Chan S, Jagiello-Gruszfeld A, Kaufman B, Crown J, Chan A, Campone M, Viens P, Davidson N, Gorbounova V, Raats JI, Skarlos D, Newstat B, Roychowdhury D, Paoletti P, Oliva C, Rubin S, Stein S, Geyer CE. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat. 2008 Dec;112(3):533-43. link to original article PubMed
    2. Update: Cameron D, Casey M, Oliva C, Newstat B, Imwalle B, Geyer CE. Lapatinib plus capecitabine in women with HER-2-positive advanced breast cancer: final survival analysis of a phase III randomized trial. Oncologist. 2010;15(9):924-34. link to original article PubMed
  2. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012 Nov 8;367(19):1783-91. Epub 2012 Oct 1. link to original article contains verified protocol PubMed

ECH

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ECH: Epirubicin, Cyclophosphamide, Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Slamon et al. 2001 Phase III EC Seems to have superior OS

Not commonly used; here for reference purposes only.

Chemotherapy

References

  1. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. link to original article PubMed

Lapatinib (Tykerb)

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Regimen

Study Evidence Comparator Efficacy
Blackwell et al. 2010 (EGF104900) Phase III Lapatinib & Trastuzumab Seems to have inferior OS

Chemotherapy

(presumably) given until progression of disease or unacceptable toxicity

References

  1. Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010 Mar 1;28(7):1124-30. Epub 2010 Feb 1. link to original article PubMed
    1. Update: Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, Ellis C, Florance A, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012 Jul 20;30(21):2585-92. Epub 2012 Jun 11. link to original article PubMed

Lapatinib & Trastuzumab

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Regimen

Study Evidence Comparator Efficacy
Blackwell et al. 2010 (EGF104900) Phase III Lapatinib Seems to have superior OS

Chemotherapy

(presumably) given until progression of disease or unacceptable toxicity

References

  1. Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010 Mar 1;28(7):1124-30. Epub 2010 Feb 1. link to original article PubMed
    1. Update: Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, Ellis C, Florance A, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: final results from the EGF104900 Study. J Clin Oncol. 2012 Jul 20;30(21):2585-92. Epub 2012 Jun 11. link to original article PubMed

Pertuzumab & Trastuzumab

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Regimen #1, q3wk trastuzumab

Study Evidence
Baselga et al. 2010 Phase II

Chemotherapy

Loading dose:

Cycles 1 to 8:

21-day cycle for 8 cycles; treatment can be continued if there is no progressive disease

Regimen #2, weekly trastuzumab

Study Evidence
Baselga et al. 2010 Phase II

Chemotherapy

Loading dose:

Cycles 1 to 8:

21-day cycle for 8 cycles; treatment can be continued if there is no progressive disease

References

  1. Baselga J, Gelmon KA, Verma S, Wardley A, Conte P, Miles D, Bianchi G, Cortes J, McNally VA, Ross GA, Fumoleau P, Gianni L. Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 2010 Mar 1;28(7):1138-44. Epub 2010 Feb 1. link to original article contains verified protocol PubMed

TCH (Docetaxel)

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TCH: Taxotere (Docetaxel), Carboplatin, Herceptin (Trastuzumab)

Regimen

Study Evidence Comparator Efficacy
Valero et al. 2011 (BCIRG 007) Phase III TH Seems not superior

Chemotherapy

21-day cycle for 8 cycles, followed by:

References

  1. Valero V, Forbes J, Pegram MD, Pienkowski T, Eiermann W, von Minckwitz G, Roche H, Martin M, Crown J, Mackey JR, Fumoleau P, Rolski J, Mrsic-Krmpotic Z, Jagiello-Gruszfeld A, Riva A, Buyse M, Taupin H, Sauter G, Press MF, Slamon DJ. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol. 2011 Jan 10;29(2):149-56. Epub 2010 Nov 29. link to original article contains verified protocol PubMed

TCH (Paclitaxel)

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TCH: Taxol (Paclitaxel), Carboplatin, Herceptin (Trastuzumab)
TPC: Trastuzumab, Paclitaxel, Carboplatin

Regimen

Study Evidence Comparator Efficacy
Robert et al. 2006 Phase III TP Seems to have superior PFS

Chemotherapy

21-day cycle for at least 6 cycles, followed by:

21-day cycles until progression or intolerance

Monitoring

  • Cardiac function: echocardiogram at baseline, then every 3 months while on Trastuzumab (Herceptin)

References

  1. Perez EA, Suman VJ, Rowland KM, Ingle JN, Salim M, Loprinzi CL, Flynn PJ, Mailliard JA, Kardinal CG, Krook JE, Thrower AR, Visscher DW, Jenkins RB. Two concurrent phase II trials of paclitaxel/carboplatin/trastuzumab (weekly or every-3-week schedule) as first-line therapy in women with HER2-overexpressing metastatic breast cancer: NCCTG study 983252. Clin Breast Cancer. 2005 Dec;6(5):425-32. link to original article PubMed
  2. Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre R, Cobleigh M, Albain K, McCullough C, Fuchs L, Slamon D. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006 Jun 20;24(18):2786-92. link to original article PubMed

TH (Paclitaxel)

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TH: Taxol (Paclitaxel), Herceptin (Trastuzumab)
TP: Trastuzumab, Paclitaxel

Regimen #1, weekly paclitaxel (3 weeks on, 1 week off)

Study Evidence Comparator Efficacy
Hurvitz et al. 2015 (BOLERO-1) Phase III Everolimus, Paclitaxel, Trastuzumab Seems not superior

Chemotherapy

  • Paclitaxel (Taxol) 80 mg/m2 IV once per day on days 1, 8, 15
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8, 15, 22
    • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15, 22

4-week cycles

Regimen #2, q3wk paclitaxel

Study Evidence Comparator Efficacy
Slamon et al. 2001 Phase III Paclitaxel Seems to have superior OS
Robert et al. 2006 Phase III TPC Seems to have inferior PFS
Seidman et al. 2008 (CALGB 9840) Phase III TH, weekly paclitaxel (80 mg/m2) Inferior OS

Chemotherapy

  • Paclitaxel (Taxol) 175 mg/m2 IV once on day 2
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
    • Cycle 2 onwards: 2 mg/kg IV once per day on days 1, 8, 15

21-day cycle for at least 6 cycles, followed by:

21-day cycles until progression or intolerance

Monitoring

  • Cardiac function: echocardiogram at baseline, then every 3 months while on Trastuzumab (Herceptin)

Regimen #3, weekly paclitaxel (80 mg/m2)

Study Evidence Comparator Efficacy
Burstein et al. 2007 (TRAVIOTA) Phase III Trastuzumab & Vinorelbine Might have inferior TTP
Seidman et al. 2008 (CALGB 9840) Phase III TH, q3wk paclitaxel Superior OS

Chemotherapy

8-week cycles

Regimen #4, weekly paclitaxel (90 mg/m2)

Study Evidence
Seidman et al. 2001 Phase II

Chemotherapy

Given until progression

References

  1. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001 Mar 15;344(11):783-92. link to original article PubMed
  2. Seidman AD, Fornier MN, Esteva FJ, Tan L, Kaptain S, Bach A, Panageas KS, Arroyo C, Valero V, Currie V, Gilewski T, Theodoulou M, Moynahan ME, Moasser M, Sklarin N, Dickler M, D'Andrea G, Cristofanilli M, Rivera E, Hortobagyi GN, Norton L, Hudis CA. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol. 2001 May 15;19(10):2587-95. link to original article PubMed
  3. Robert N, Leyland-Jones B, Asmar L, Belt R, Ilegbodu D, Loesch D, Raju R, Valentine E, Sayre R, Cobleigh M, Albain K, McCullough C, Fuchs L, Slamon D. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006 Jun 20;24(18):2786-92. link to original article PubMed
  4. Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. link to original article PubMed
  5. Seidman AD, Berry D, Cirrincione C, Harris L, Muss H, Marcom PK, Gipson G, Burstein H, Lake D, Shapiro CL, Ungaro P, Norton L, Winer E, Hudis C. Randomized phase III trial of weekly compared with every-3-weeks paclitaxel for metastatic breast cancer, with trastuzumab for all HER-2 overexpressors and random assignment to trastuzumab or not in HER-2 nonoverexpressors: final results of Cancer and Leukemia Group B protocol 9840. J Clin Oncol. 2008 Apr 1;26(10):1642-9. link to original article PubMed
  6. Hurvitz SA, Andre F, Jiang Z, Shao Z, Mano MS, Neciosup SP, Tseng LM, Zhang Q, Shen K, Liu D, Dreosti LM, Burris HA, Toi M, Buyse ME, Cabaribere D, Lindsay MA, Rao S, Pacaud LB, Taran T, Slamon D. Combination of everolimus with trastuzumab plus paclitaxel as first-line treatment for patients with HER2-positive advanced breast cancer (BOLERO-1): a phase 3, randomised, double-blind, multicentre trial. Lancet Oncol. 2015 Jul;16(7):816-29. Epub 2015 Jun 16. link to original article PubMed

TH (Docetaxel)

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TH: Taxotere (Docetaxel), Herceptin (Trastuzumab)

Regimen #1

Study Evidence Comparator Efficacy
Hurvitz et al. 2013 Randomized Phase II T-DM1 Seems to have inferior PFS
Gianni et al. 2013 (AVAREL) Randomized Phase II BTH Might have inferior PFS

Chemotherapy

  • Docetaxel (Taxotere) 75 or 100 mg/m2 IV once on day 1
    • Dose in Hurvitz et al. 2013 was per investigator's discretion; all patients in AVAREL received 100 mg/m2
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 8 mg/kg IV once on day 2
    • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycles, given until progression of disease or unacceptable toxicity

Regimen #2

Study Evidence Comparator Efficacy
Baselga et al. 2011 (CLEOPATRA) Phase III THP Inferior OS

This unusual schedule with both medications being given on day 2 of cycle 1 is due to this regimen being the control arm of CLEOPATRA, in which patients in one arm received a placebo instead of pertuzumab on day 1. It is reasonable to assume that in practice, drugs in this regimen will be given on day 1 from the beginning.

Chemotherapy

  • Docetaxel (Taxotere) as follows:
    • Cycle 1: 75 mg/m2 IV once on day 2
    • Cycle 2 onwards: 75 mg/m2 IV once on day 1
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 8 mg/kg IV once on day 2
    • Cycle 2 onwards: 6 mg/kg IV once on day 1

21-day cycle for at least 6 cycles, given until progression of disease or unacceptable toxicity

If it is decided to no longer administer Docetaxel (Taxotere) with this regimen, then patients could continue to receive:

21-day cycles, given until progression of disease or unacceptable toxicity

Regimen #3

Study Evidence Comparator Efficacy
Valero et al. 2010 (BCIRG 007) Phase III TCH Seems not superior

Induction therapy

  • Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 4 mg/kg IV over 90 minutes once on day 1, then 2 mg/kg IV over 30 minutes once per day on days 8 & 15
    • Cycles 2 to 8: 2 mg/kg IV over 30 minutes once per day on days 1, 8, 15

Supportive medications

  • Dexamethasone (Decadron) 8 mg (or equivalent) PO BID x 6 doses, starting the night before docetaxel
  • "Antiemetic premedication was mandatory" (no additional details given).

21-day cycle for 8 cycles

Patients then proceeded to maintenance trastuzumab therapy:

Maintenance trastuzumab

Given until progression of disease or unacceptable toxicity

Regimen #4

Study Evidence Comparator Efficacy
Esteva et al. 2002 Phase II
Burstein et al. 2007 (TRAVIOTA) Phase III Trastuzumab & Vinorelbine Might have inferior TTP

Esteva et al. 2002 described the day before the start of a cycle as "day 0," which is not the typical convention, so day -1 is being used instead.

Chemotherapy

  • Docetaxel (Taxotere) 35 mg/m2 IV over 30 minutes once per day on days 1, 8, 15, given first
  • Trastuzumab (Herceptin) given second as follows:
    • Cycle 1: 4 mg/kg IV over 90 minutes once on day -1, then 2 mg/kg IV over 30 minutes once per day on days 8 & 15
    • Cycle 2 onwards: 2 mg/kg IV over 30 minutes once per day on days 1, 8, 15

Supportive medications

  • Dexamethasone (Decadron) 4 mg PO every 12 hours x 3 doses on cycles 1 & 2, starting the night before Docetaxel (Taxotere). Patients who did not have "hypersensitivity reactions and no significant fluid retention during the first 8 weeks" received 4 mg PO BID on day 1 for at least the next two cycles. Patients who "remained free of fluid retention after 8 additional weeks" then received 4 mg PO once on day 1 prior to Docetaxel (Taxotere) in subsequent cycles.

28-day cycles, given until progression of disease or unacceptable toxicity

Regimen #5

Study Evidence Comparator Efficacy
Marty et al. 2005 (M77001) Randomized Phase II Docetaxel Seems to have superior OS

Marty et al. 2005 did not exactly specify days of therapy; this is the best guess for what was used based on the description.

Induction therapy

  • Docetaxel (Taxotere) 100 mg/m2 IV once on day 1
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 4 mg/kg IV once on day 1, then 2 mg/kg IV once per day on days 8 & 15
    • Cycles 2 to 6: 2 mg/kg IV once per day on days 1, 8, 15

Supportive medications

21-day cycle for 6 cycles, given until progression of disease or unacceptable toxicity

Patients could receive docetaxel beyond six cycles at the discretion of the investigator. Otherwise, patients proceeded to maintenance trastuzumab therapy:

Maintenance trastuzumab

Given until progression of disease or unacceptable toxicity

References

  1. Esteva FJ, Valero V, Booser D, Guerra LT, Murray JL, Pusztai L, Cristofanilli M, Arun B, Esmaeli B, Fritsche HA, Sneige N, Smith TL, Hortobagyi GN. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2002 Apr 1;20(7):1800-8. link to original article contains verified protocol PubMed
  2. Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M, Chan S, Grimes D, Antón A, Lluch A, Kennedy J, O'Byrne K, Conte P, Green M, Ward C, Mayne K, Extra JM. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005 Jul 1;23(19):4265-74. Epub 2005 May 23. link to original article contains verified protocol PubMed
  3. Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. link to original article PubMed
  4. Valero V, Forbes J, Pegram MD, Pienkowski T, Eiermann W, von Minckwitz G, Roche H, Martin M, Crown J, Mackey JR, Fumoleau P, Rolski J, Mrsic-Krmpotic Z, Jagiello-Gruszfeld A, Riva A, Buyse M, Taupin H, Sauter G, Press MF, Slamon DJ. Multicenter phase III randomized trial comparing docetaxel and trastuzumab with docetaxel, carboplatin, and trastuzumab as first-line chemotherapy for patients with HER2-gene-amplified metastatic breast cancer (BCIRG 007 study): two highly active therapeutic regimens. J Clin Oncol. 2011 Jan 10;29(2):149-56. Epub 2010 Nov 29. link to original article contains verified protocol PubMed
  5. Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. Epub 2011 Dec 7. link to original article contains verified protocol PubMed
    1. Update: Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. Epub 2013 Apr 18. link to original article link to PMC article contains verified protocol PubMed
  6. Hurvitz SA, Dirix L, Kocsis J, Bianchi GV, Lu J, Vinholes J, Guardino E, Song C, Tong B, Ng V, Chu YW, Perez EA. Phase II Randomized Study of Trastuzumab Emtansine Versus Trastuzumab Plus Docetaxel in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer. J Clin Oncol. 2013 Mar 20;31(9):1157-63. Epub 2013 Feb 4. Erratum in: J Clin Oncol. 2013 Aug 10;31(23):2977. link to original article contains verified protocol PubMed
  7. Gianni L, Romieu GH, Lichinitser M, Serrano SV, Mansutti M, Pivot X, Mariani P, Andre F, Chan A, Lipatov O, Chan S, Wardley A, Greil R, Moore N, Prot S, Pallaud C, Semiglazov V. AVEREL: a randomized phase III Trial evaluating bevacizumab in combination with docetaxel and trastuzumab as first-line therapy for HER2-positive locally recurrent/metastatic breast cancer. J Clin Oncol. 2013 May 10;31(14):1719-25. Epub 2013 Apr 8. link to original article contains verified protocol PubMed

THP (Docetaxel)

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THP: Taxotere (Docetaxel), Herceptin (Trastuzumab), Pertuzumab

Regimen

Study Evidence Comparator Efficacy
Baselga et al. 2011 (CLEOPATRA) Phase III Docetaxel & Trastuzumab Superior OS

Chemotherapy

  • Docetaxel (Taxotere) as follows:
    • Cycle 1: 75 mg/m2 IV once on day 2
    • Cycle 2 onwards: 75 mg/m2 IV once on day 1
  • Trastuzumab (Herceptin) as follows:
    • Cycle 1: 8 mg/kg IV once on day 2
    • Cycle 2 onwards: 6 mg/kg IV once on day 1
  • Pertuzumab (Perjeta) as follows:
    • Cycle 1: 840 mg IV once on day 1
    • Cycle 2 onwards: 420 mg IV once on day 1

21-day cycle for at least 6 cycles, given until progression of disease or unacceptable toxicity

If it is decided to no longer administer Docetaxel (Taxotere) with this regimen, then patients could continue to receive:

21-day cycles, given until progression of disease or unacceptable toxicity

References

  1. Baselga J, Cortés J, Kim SB, Im SA, Hegg R, Im YH, Roman L, Pedrini JL, Pienkowski T, Knott A, Clark E, Benyunes MC, Ross G, Swain SM; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012 Jan 12;366(2):109-19. Epub 2011 Dec 7. link to original article contains verified protocol PubMed
    1. Update: Swain SM, Kim SB, Cortés J, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Knott A, Clark E, Ross G, Benyunes MC, Baselga J. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA study): overall survival results from a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Oncol. 2013 May;14(6):461-71. Epub 2013 Apr 18. link to original article link to PMC article contains verified protocol PubMed

XH

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XH: Xeloda, Herceptin

Regimen #1

Study Evidence Comparator Efficacy
von Minckwitz et al. 2009 (GBG 26/BIG 3-05) Phase III Capecitabine Seems to have superior TTP

Chemotherapy

21-day cycles

Regimen #2

Study Evidence
Bartsch et al. 2007 Phase II

Chemotherapy

21-day cycles

References

  1. Bartsch R, Wenzel C, Altorjai G, Pluschnig U, Rudas M, Mader RM, Gnant M, Zielinski CC, Steger GG. Capecitabine and trastuzumab in heavily pretreated metastatic breast cancer. J Clin Oncol. 2007 Sep 1;25(25):3853-8. Epub 2007 Aug 6. link to original article PubMed
  2. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer W, Baumann KH, Clemens MR, Duerr R, Uleer C, Andersson M, Stein RC, Nekljudova V, Loibl S. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a german breast group 26/breast international group 03-05 study. J Clin Oncol. 2009 Apr 20;27(12):1999-2006. Epub 2009 Mar 16. link to original article PubMed
    1. Update: von Minckwitz G, Schwedler K, Schmidt M, Barinoff J, Mundhenke C, Cufer T, Maartense E, de Jongh FE, Baumann KH, Bischoff J, Harbeck N, Lück HJ, Maass N, Zielinski C, Andersson M, Stein RC, Nekljudova V, Loibl S; GBG 26/BIG 03-05 study group and participating investigators. Trastuzumab beyond progression: overall survival analysis of the GBG 26/BIG 3-05 phase III study in HER2-positive breast cancer. Eur J Cancer. 2011 Oct;47(15):2273-81. Epub 2011 Jul 7. link to original article PubMed

Trastuzumab (Herceptin) & other single agent chemotherapy

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Regimen

21-day cycles

References

See single agent chemotherapy regimens

Trastuzumab & Vinorelbine

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Regimen

Study Evidence Comparator Efficacy
Burstein et al. 2007 (TRAVIOTA) Phase III TH (Docetaxel)
TH (Paclitaxel) 		Might have superior TTP
André et al. 2014 (BOLERO-3) Phase III Everolimus, Trastuzumab, Vinorelbine Inferior PFS

Chemotherapy

8-week cycles, given until progression

References

  1. Burstein HJ, Keshaviah A, Baron AD, Hart RD, Lambert-Falls R, Marcom PK, Gelman R, Winer EP. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007 Sep 1;110(5):965-72. link to original article PubMed
  2. André F, O'Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, Masuda N, Wilks S, Arena F, Isaacs C, Yap YS, Papai Z, Lang I, Armstrong A, Lerzo G, White M, Shen K, Litton J, Chen D, Zhang Y, Ali S, Taran T, Gianni L. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014 May;15(6):580-91. Epub 2014 Apr 14. link to original article PubMed

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