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

• Regimens for HER-2 receptor positive breast cancer as on a separate page, here.
• Chemotherapy for metastatic disease is separated into single-agent and combination regimens 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

Guidelines

ESMO

• Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PubMed
• 3rd ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 3). PubMed
• BRCA in breast cancer: ESMO Clinical Practice Guidelines PubMed

NCCN

• NCCN Guidelines - Breast Cancer

Neoadjuvant chemotherapy

nab-Paclitaxel -> EC

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EC: Epirubicin & Cyclophosphamide

Regimen

Study	Evidence	Comparator	Efficacy
Untch et al. 2016 (GBG 69)	Phase III	T -> EC	Superior pCR rate

Note: this is the dose after study amendment due to increased treatment discontinuation and sensory neuropathy.

nab-Paclitaxel portion

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m² IV once per day on days 1, 8, 15

3-week cycle for 4 cycles, followed by:

EC portion

• Epirubicin (Ellence) 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

3-week cycle for 4 cycles, followed by surgery

References

1. Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Wiebringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Darb-Esfahani S, Schmitt WD, Dan Costa S, Gerber B, Engels K, Nekljudova V, Loibl S, von Minckwitz G; German Breast Group (GBG).; Arbeitsgemeinschaft Gynäkologische Onkologie—Breast (AGO-B) Investigators. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. Epub 2016 Feb 8. 2016 Mar;17(3):345-56. link to SD 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

• Paclitaxel (Taxol) 80 mg/m² IV once per week

12-week course, followed by:

AC portion

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

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

T (Taxol) -> EC

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T -> EC: Taxol (Paclitaxel) followed by Epirubicin & Cyclophosphamide

Regimen

Study	Evidence	Comparator	Efficacy
Untch et al. 2016 (GBG 69)	Phase III	nab-Paclitaxel -> EC	Inferior pCR rate

T portion

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1, 8, 15

3-week cycle for 4 cycles, followed by:

EC portion

• Epirubicin (Ellence) 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

3-week cycle for 4 cycles, followed by surgery

References

1. Untch M, Jackisch C, Schneeweiss A, Conrad B, Aktas B, Denkert C, Eidtmann H, Wiebringhaus H, Kümmel S, Hilfrich J, Warm M, Paepke S, Just M, Hanusch C, Hackmann J, Blohmer JU, Clemens M, Darb-Esfahani S, Schmitt WD, Dan Costa S, Gerber B, Engels K, Nekljudova V, Loibl S, von Minckwitz G; German Breast Group (GBG).; Arbeitsgemeinschaft Gynäkologische Onkologie—Breast (AGO-B) Investigators. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. Epub 2016 Feb 8. 2016 Mar;17(3):345-56. link to SD article contains verified protocol PubMed

Adjuvant chemotherapy

AC

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AC: Adriamycin (Doxorubicin), Cyclophosphamide

Example orders

• Example orders for AC in breast cancer

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

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

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

• Example orders for AC to T (Taxol) in breast cancer

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

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 4 cycles, followed by:

T portion

• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

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

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 4 cycles, followed by:

T portion

• Paclitaxel (Taxol) 80 mg/m² IV over 1 hour once per week

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

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 4 cycles, followed by:

T portion

• Paclitaxel (Taxol) 225 mg/m² IV over 3 hours once on day 1

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

• Example orders for AC to T (Taxotere) in breast cancer

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

• Doxorubicin (Adriamycin) 60 mg/m² IV over 15 minutes once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV over 5 to 60 minutes once on day 1

21-day cycle for 4 cycles, followed by:

T portion

• Docetaxel (Taxotere) 100 mg/m² IV over 1 hour once on day 1

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

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 4 cycles, followed by:

T portion

• Docetaxel (Taxotere) 35 mg/m² IV over 1 hour once per week

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 #1

Study	Evidence	Comparator	Efficacy
del Mastro et al. 2016 (GONO-MIG5)	Phase III	EP x 4	Seems not superior

Chemotherapy

• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 60 mg/m² IV once on day 1
• Fluorouracil (5-FU) 600 mg/m² IV once on day 1

21-day cycle for 6 cycles

Regimen #2

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

• Cyclophosphamide (Cytoxan) 75 mg/m² PO once per day on days 1 to 14
• Epirubicin (Ellence) 60 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 & 8

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
6. Del Mastro L, Levaggi A, Michelotti A, Cavazzini G, Adami F, Scotto T, Piras M, Danese S, Garrone O, Durando A, Accortanzo V, Bighin C, Miglietta L, Pastorino S, Pronzato P, Castiglione F, Landucci E, Conte P, Bruzzi P. 5-Fluorouracil, epirubicin and cyclophosphamide versus epirubicin and paclitaxel in node-positive early breast cancer: a phase-III randomized GONO-MIG5 trial. Breast Cancer Res Treat. 2016 Jan;155(1):117-26. link to original article contains verified 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

• Cyclophosphamide (Cytoxan) 500 mg/m² IV once per day on days 1 & 8
• Methotrexate (MTX) 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 600 mg/m² IV once per day on days 1 & 8

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

• Cyclophosphamide (Cytoxan) 100 mg/m² PO once per day on days 1 to 14
• Methotrexate (MTX) 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 600 mg/m² IV once per day on days 1 & 8

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

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Methotrexate (MTX) 50 mg/m² IV once on day 1
• Fluorouracil (5-FU) 600 mg/m² IV once on day 1

21-day cycle for 8 cycles

Regimen #4, Classic CMF

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

Chemotherapy

• Cyclophosphamide (Cytoxan) 100 mg/m² PO once per day on days 1 to 14
• Methotrexate (MTX) 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 600 mg/m² IV once per day on days 1 & 8

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

• Example orders for ddAC in breast cancer

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

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

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

• Example orders for ddAC followed by T in breast cancer

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

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV bolus once on day 1

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:
  • Pegfilgrastim (Neulasta) 6 mg SC once on day 2, given 24 hours after chemotherapy
  • Darbepoetin alfa (Aranesp) 200 mcg SC once on day 1 for patients with Hb 10 to 12 g/dL; see Burstein et al. 2005 for additional dose adjustments

14-day cycle for 4 cycles, followed by:

T portion

• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

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

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1

Supportive medications

• Filgrastim (Neupogen)

14-day cycle for 4 cycles, followed by:

ddT portion

• Paclitaxel (Taxol) 200 mg/m² IV over 3 hours day 1

Supportive medications

• Filgrastim (Neupogen)

14-day cycle for 4 cycles, followed by:

ddC portion

• Cyclophosphamide (Cytoxan) 800 mg/m² IV once on day 1

Supportive medications

• Filgrastim (Neupogen)

14-day cycle for 4 cycles

Regimen #2, alternate dosing

Alternate dosing per NCCN (primary reference not found).

ddA portion

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1

Supportive medications

• Filgrastim (Neupogen)

14-day cycle for 4 cycles, followed by:

ddT portion

• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

Supportive medications

• Filgrastim (Neupogen)

14-day cycle for 4 cycles, followed by:

ddC portion

• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Supportive medications

• Filgrastim (Neupogen)

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

• Epirubicin (Ellence) 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 830 mg/m² IV once on day 1

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

• Epirubicin (Ellence) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

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

• Epirubicin (Ellence) 100 mg/m² IV once on day 1

3-week cycle for 4 cycles, followed by:

CMF portion

• Cyclophosphamide (Cytoxan) 100 mg/m² PO once per day on days 1 to 14 or 600 mg/m² IV once per day on days 1 & 8
• Methotrexate (MTX) 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 600 mg/m² IV once per day on days 1 & 8

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

• Epirubicin (Ellence) 100 mg/m² IV once on day 1

3-week cycle for 4 cycles, followed by:

CMF portion

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Methotrexate (MTX) 50 mg/m² IV once on day 1
• Fluorouracil (5-FU) 600 mg/m² IV once on day 1

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

• Fluorouracil (5-FU) 500 mg/m² IV over 15 minutes once on day 1, given second
• Doxorubicin (Adriamycin) 50 mg/m² IV over 15 minutes once on day 1, given first
• Cyclophosphamide (Cytoxan) 500 mg/m² IV over 1 to 5 minutes once on day 1, given third

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:
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 4 to 11
  • OR Lenograstim (Granocyte) 150 mcg/m² SC once per day on days 4 to 11

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

• Cyclophosphamide (Cytoxan) 100 mg/m² IV once per day on days 1 to 14
• Doxorubicin (Adriamycin) 30 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 & 8

28-day cycle for 6 cycles

Regimen #3

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

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV once per day on days 1 & 8
• Doxorubicin (Adriamycin) 40 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 400 mg/m² IV once on day 1

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

• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 & 8 or days 1 & 4
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1 or via 72-hour continuous infusion
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

21-day cycle for 6 cycles, followed by:

MV portion

• Methotrexate (MTX) 75 mg/m² IV once on day 1 with Folinic acid (Leucovorin) rescue
• Vinblastine (Velban) 1.7 mg/m²/day continuous infusion on days 1 to 5

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

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

21-day cycle for 3 cycles, followed by:

D portion

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

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

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 90 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

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

P portion

• Paclitaxel (Taxol) 100 mg/m² IV once per week

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

• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

Supportive medications

• Diphenhydramine (Benadryl) 12.5-50 mg IV 30 to 60 minutes prior to paclitaxel
• One of the following H2 blockers:
  • Ranitidine (Zantac) 50 mg IV 30 to 60 minutes prior to paclitaxel
  • Cimetidine (Tagamet) 300 mg IV 30 to 60 minutes prior to paclitaxel
  • Famotidine (Pepcid) 20 mg IV 30 to 60 minutes prior to paclitaxel
• One of the following dexamethasone choices:
  • Dexamethasone (Decadron) 10 mg IV <60 minutes prior to paclitaxel
  • Dexamethasone (Decadron) 10 mg PO >60 minutes prior to paclitaxel
  • Dexamethasone (Decadron) 20 mg PO 6 hours and 12 hour prior to paclitaxel
• 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

• Paclitaxel (Taxol) 80 mg/m² IV once per week

Supportive medications

• Diphenhydramine (Benadryl) 12.5-50 mg IV 30 to 60 minutes prior to paclitaxel
• One of the following H2 blockers:
  • Ranitidine (Zantac) 50 mg IV 30 to 60 minutes prior to paclitaxel
  • Cimetidine (Tagamet) 300 mg IV 30 to 60 minutes prior to paclitaxel
  • Famotidine (Pepcid) 20 mg IV 30 to 60 minutes prior to paclitaxel
• One of the following dexamethasone choices:
  • Dexamethasone (Decadron) 10 mg IV <60 minutes prior to paclitaxel
  • Dexamethasone (Decadron) 10 mg PO >60 minutes prior to paclitaxel
  • Dexamethasone (Decadron) 20 mg PO 6 hours and 12 hour prior to paclitaxel
• 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

• Docetaxel (Taxotere) 100 mg/m² IV over 1 hour once on day 1

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

FEC portion

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

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

• Docetaxel (Taxotere) 75 mg/m² IV over 1 hour once on day 1, administered third, one hour after cyclophosphamide
• Doxorubicin (Adriamycin) 50 mg/m² IV over 15 minutes once on day 1, administered first
• Cyclophosphamide (Cytoxan) 500 mg/m² IV over 1 to 5 minutes once on day 1, administered second

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:
  • Filgrastim (Neupogen) 5 mcg/kg SC once per day on days 4 to 11
  • OR Lenograstim (Granocyte) 150 mcg/m² SC once per day on days 4 to 11

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

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

Supportive medications

• All cycles given with Filgrastim (Neupogen) support

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

• Vinorelbine (Navelbine) 24 mg/m² IV over 5 to 10 minutes once per day on days 1, 8, 15

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

FEC portion

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

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 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

• Anastrozole (Arimidex) 1 mg PO once per day

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

• Exemestane (Aromasin) 25 mg PO once per day

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

• Letrozole (Femara) 2.5 mg PO once per day

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

• Letrozole (Femara) 2.5 mg PO once per day

2-year course, followed by:

• Tamoxifen (Nolvadex) 20 mg PO once per day

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

• Leuprolide (Lupron) 3-month depot 11.25 mg SC

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

• Tamoxifen (Nolvadex) 20 mg PO once per day

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

• Tamoxifen (Nolvadex) 20 mg PO once per day

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

• Tamoxifen (Nolvadex) 20 mg PO once per day

2-year course, followed by:

Endocrine therapy, part 2

• Anastrozole (Arimidex) 1 mg PO once per day

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

• Tamoxifen (Nolvadex) 20 mg PO once per day

5 years of therapy, followed by:

Endocrine therapy, part 2

• Exemestane (Aromasin) 25 mg PO once per day

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

• Tamoxifen (Nolvadex) 20 mg PO once per day

2 to 3 years of therapy, followed by:

Endocrine therapy, part 2

• Exemestane (Aromasin) 25 mg PO once per day

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

• Tamoxifen (Nolvadex) 20 mg PO once per day

2-year course, followed by:

• Letrozole (Femara) 2.5 mg PO once per day

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

• Anastrozole (Arimidex) 1 mg PO once per day

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

• Anastrozole (Arimidex) 1 mg PO once per day on days 1 to 56
• Fulvestrant (Faslodex) 500 mg IM once on day 1, then 250 mg IM once per day on days 14 & 28

56-day course, then proceed to subsequent therapy:

Subsequent therapy

• Anastrozole (Arimidex) 1 mg PO once per day
• Fulvestrant (Faslodex) 250 mg IM once on day 1
  • Patients who progressed on this therapy were allowed to receive a higher dose, 500 mg IM once on day 1

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

• Exemestane (Aromasin) 25 mg PO once per day

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

• Everolimus (Afinitor) 10 mg PO once per day
• Exemestane (Aromasin) 25 mg PO once per day

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

• Fulvestrant (Faslodex) 500 mg IM every 2 weeks x 3 doses, and then every 4 weeks thereafter

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

• Letrozole (Femara) 2.5 mg PO once per day

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

• Letrozole (Femara) 2.5 mg PO once per day
• Palbociclib (Ibrance) 125 mg PO once per day on days 1 to 21

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

• Tamoxifen (Nolvadex) 20 mg PO once per day

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

• Tamoxifen (Nolvadex) 40 mg PO once per day

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

• Tamoxifen (Nolvadex) 20 mg PO once per day
• Everolimus (Afinitor) 10 mg PO once per day

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

• Toremifene (Fareston) 60 mg PO once per day

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

• Capecitabine (Xeloda) 1250 mg/m² PO BID on days 1 to 14

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

• Capecitabine (Xeloda) 1000 mg/m² PO BID on days 1 to 14

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

• Capecitabine (Xeloda) 650 mg/m² PO BID

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

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

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

• Docetaxel (Taxotere) 60 mg/m² IV once on day 1

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

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

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

• Docetaxel (Taxotere) 100 mg/m² IV once on day 1

21-day cycle for up to 7 cycles

Regimen #5, weekly dosing

Study	Evidence
Burstein et al. 2000	Phase II

Chemotherapy

• Docetaxel (Taxotere) 40 mg/m² IV once per week for weeks 1 to 6, then off for weeks 7 & 8

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

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1

21-day cycles

Regimen #2

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

Chemotherapy

• Doxorubicin (Adriamycin) 75 mg/m² IV once on day 1

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

• Doxorubicin (Adriamycin) 20 mg/m² IV once per week

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

• Epirubicin (Ellence) 40 mg/m² IV once on day 1

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

• Epirubicin (Ellence) 60 mg/m² IV once on day 1

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

• Epirubicin (Ellence) 90 mg/m² IV once on day 1

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

• Epirubicin (Ellence) 135 mg/m² IV once on day 1

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

• Eribulin (Halaven) 1.4 mg/m² IV over 2 to 5 minutes once per day on days 1 & 8

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

• Gemcitabine (Gemzar) 800 to 1200 mg/m² IV once per day on days 1, 8, 15

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

• Olaparib (Lynparza) 400 mg PO BID

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

• Paclitaxel (Taxol) 175 mg/m² IV over 3 hours once on day 1

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

• Paclitaxel (Taxol) 80 mg/m² IV once per week

4-week cycles

Regimen #3

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

Chemotherapy

• Paclitaxel (Taxol) 90 mg/m² IV once per day on days 1, 8, 15

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

• Paclitaxel (Taxol) 250 mg/m² IV over 3 hours once on day 1

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

• Example orders for Paclitaxel, nanoparticle albumin-bound (Abraxane) in breast cancer

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

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 100 mg/m² IV once per day on days 1, 8, 15

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

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 150 mg/m² IV once per day on days 1, 8, 15

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

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 300 mg/m² IV over 30 minutes once on day 1

21-day cycles

Regimen #4

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

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 260 mg/m² IV over 30 minutes once on day 1

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

• Pemetrexed (Alimta) 600 mg/m² IV once on day 1

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

• Pemetrexed (Alimta) 500 mg/m² IV over 10 minutes once on day 1

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

• Vinorelbine (Navelbine) 25 mg/m² IV once per week

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

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

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

• Doxorubicin (Adriamycin) 60 mg/m² IV once on day 1
• Paclitaxel (Taxol) 125-200 mg/m² IV once on day 1

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

• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Docetaxel (Taxotere) 75 mg/m² IV once on day 1

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

• Cyclophosphamide (Cytoxan) 100 mg/m² PO once per day on days 1 to 14
• Doxorubicin (Adriamycin) 30 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 & 8

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

• Capecitabine (Xeloda) 1000 mg/m² PO BID on days 1 to 14
• Bevacizumab (Avastin) 10 to 15 mg/kg IV once on day 1

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

• Capecitabine (Xeloda) 2000 mg/m² PO once per day on days 1 to 14
• Ixabepilone (Ixempra) 40 mg/m² IV once on day 1

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

• Fluorouracil (5-FU) 600 mg/m² IV once on day 1
• Epirubicin (Ellence) 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once once on day 1

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

• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 & 8
• Epirubicin (Ellence) 50 mg/m² IV once per day on days 1 & 8
• Cyclophosphamide (Cytoxan) 400 mg/m² IV once per day on days 1 & 8

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

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 100 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once once on day 1

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

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Epirubicin (Ellence) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once once on day 1

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

• Cisplatin (Platinol) 75 mg/m² IV over 1 hour once on day 1
• Vinorelbine (Navelbine) 25 mg/m² IV over 5 to 10 minutes once per day on days 1 & 8

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

• Cyclophosphamide (Cytoxan) 100 mg/m² PO once per day on days 1 to 14
• Methotrexate (MTX) 40 mg/m² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 600 mg/m² IV oncer per day on days 1 & 8

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

• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

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

• Epirubicin (Ellence) 75 mg/m² IV once on day 1
• Paclitaxel (Taxol) 200 mg/m² IV once on day 1

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

• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 & 8 or days 1 & 4
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

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

• Gemcitabine (Gemzar) 800 mg/m² IV over 1 hour once per day on days 1 & 8
• Carboplatin (Paraplatin) AUC 2 IV over 1 hour once per day on days 1 & 8

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

• Gemcitabine (Gemzar) 1250 mg/m² IV once per day on days 1 & 8; on day 1, administer after paclitaxel
• Paclitaxel (Taxol) 175 mg/m² IV once on day 1

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

• Paclitaxel (Taxol) 90 mg/m² IV over 1 hour once per day on days 1, 8, 15
• Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15

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

• Example orders for Paclitaxel, nanoparticle albumin-bound & Bevacizumab in breast cancer

Regimen

Study	Evidence
Danso et al. 2008	Phase II

Chemotherapy

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 90 mg/m² IV over 1 hour once per day on days 1, 8, 15
• Bevacizumab (Avastin) 10 mg/kg IV once per day on days 1 & 15

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

• Paclitaxel, nanoparticle albumin-bound (Abraxane) 125 mg/m² IV once per day on days 1 & 8
• Capecitabine (Xeloda) 825 mg/m² (rounded to nearest 500 mg) PO BID on days 1 to 15

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

• Docetaxel (Taxotere) 75 mg/m² IV once on day 1
• Capecitabine (Xeloda) 950 to 1250 mg/m² PO BID days 1 to 14

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

• Paclitaxel (Taxol) 80 mg/m² IV once per day on days 1 & 8
• Capecitabine (Xeloda) 825 mg/m² (rounded to nearest 500 mg) PO BID on days 1 to 14

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

• Vincristine (Oncovin)
• Doxorubicin (Adriamycin)
• Cyclophosphamide (Cytoxan)

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

• Example orders for Vinorelbine and Bevacizumab in breast cancer

Regimen

Study	Evidence
Burstein et al. 2008	Phase II

Chemotherapy

• Vinorelbine (Navelbine) 25 mg/m² IV once per week
• Bevacizumab (Avastin) 10 mg/kg IV once every other week

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

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Patient information

• Alcohol and risk of breast cancer infographic