Breast cancer - historical

The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. Is there a regimen missing from this list? See the main breast cancer page for current regimens.

44 regimens on this page 63 variants on this page

Neoadjuvant therapy

CVAP

CVAP: Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Prednisone
VACP: Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide, Prednisone

Regimen

Study	Dates of enrollment	Evidence
Thomas et al. 2004b	1985-1989	Non-randomized part of RCT

Chemotherapy

• Cyclophosphamide (Cytoxan) as follows:
  • Cycle 1: 600 mg/m² IV over 15 minutes once on day 1
  • Cycle 2: 700 mg/m² IV over 15 minutes once on day 1
  • Cycle 3: 750 mg/m² IV over 15 minutes once on day 1
• Vincristine (Oncovin) by the following age-based criteria:
  • Younger than 50 years old: 1.5 mg/m² (maximum dose of 2 mg) IV once on day 1
  • Older than 50 years old: 1.5 mg/m² (maximum dose of 1.5 mg) IV once on day 1
• Doxorubicin (Adriamycin) as follows:
  • Cycle 1: 60 mg/m² IV continuous infusion over 72 hours, started on day 1
  • Cycle 2: 70 mg/m² IV continuous infusion over 72 hours, started on day 1
  • Cycle 3: 75 mg/m² IV continuous infusion over 72 hours, started on day 1

Endocrine therapy

• Prednisone (Sterapred) 40 mg PO once per day on days 1 to 5

21-day cycle for 3 cycles

Subsequent treatment

• Surgery

References

1. Thomas E, Holmes FA, Smith TL, Buzdar AU, Frye DK, Fraschini G, Singletary SE, Theriault RL, McNeese MD, Ames F, Walters R, Hortobagyi GN. The use of alternate, non-cross-resistant adjuvant chemotherapy on the basis of pathologic response to a neoadjuvant doxorubicin-based regimen in women with operable breast cancer: long-term results from a prospective randomized trial. J Clin Oncol. 2004 Jun 15;22(12):2294-302. link to original article contains dosing details in manuscript PubMed

CVAP (Prednisolone)

CVAP: Cyclophosphamide, Vincristine, Adriamycin (Doxorubicin), Prednisolone
VACP: Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide, Prednisolone

Regimen

Study	Dates of enrollment	Evidence
Smith et al. 2002	1996-07 to 1999-03	Non-randomized part of RCT

Chemotherapy

• Cyclophosphamide (Cytoxan) 1000 mg/m² IV once on day 1
• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1

Endocrine therapy

• Prednisolone (Millipred) 40 mg PO once per day on days 1 to 5

21-day cycle for 4 cycles

Subsequent treatment

• Smith et al. 2002, responders: Neoadjuvant CVAP x 4 versus D x 4, then Surgery
• Smith et al. 2002, nonresponders: Neoadjuvant D x 4, then Surgery

References

1. Smith IC, Heys SD, Hutcheon AW, Miller ID, Payne S, Gilbert FJ, Ah-See AK, Eremin O, Walker LG, Sarkar TK, Eggleton SP, Ogston KN. Neoadjuvant chemotherapy in breast cancer: significantly enhanced response with docetaxel. J Clin Oncol. 2002 Mar 15;20(6):1456-66. link to original article contains dosing details in manuscript PubMed

Adjuvant therapy, sequential regimens

FAC-MV

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Assikis et al. 2003	1986-1994	Phase 3 (E-switch-ooc)	Tamoxifen	Did not meet primary endpoint of OS

Preceding treatment

• Surgery

Chemotherapy, FAC portion (cycles 1 to 6)

• Fluorouracil (5-FU) 500 mg/m² IV once per day on days 1 & 8
• Doxorubicin (Adriamycin) 16.7 mg/m²/day continuous infusion over 72 hours, started on day 1 (total dose per cycle: 50 mg/m²)
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

Chemotherapy, MV portion (cycles 7 to 10)

• Methotrexate (MTX) 75 mg/m² IV once on day 1
• Vinblastine (Velban) 1.7 mg/m²/day continuous infusion over 120 hours, started on day 1 (total dose per cycle: 8.5 mg/m²)

Supportive therapy, MV portion (cycles 7 to 10)

• Leucovorin (Folinic acid) rescue

21- to 28-day cycle for 10 cycles (FAC x 6; MV x 4)

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 dosing details in manuscript PubMed

Adjuvant therapy

AVCF

AVCF: Adriamycin (Doxorubicin), Vincristine, Cyclophosphamide, Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Misset et al. 1996 (OncoFrance)	1978-1981	Phase 3 (E-esc)	CMF	Superior OS

Note: OncoFrance was one of the studies analyzed in the 1998 EBCTCG meta-analysis that supported FDA approval of doxorubicin for this indication.

Preceding treatment

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin) 30 mg/m² (maximum dose of 50 mg) IV once on day 1
• Vincristine (Oncovin) 1 mg/m² IV once on day 2
• Cyclophosphamide (Cytoxan) 300 mg/m² Iv once per day on days 3 to 6
• Fluorouracil (5-FU) 400 mg/m² IV once per day on days 3 to 6

Monthly cycle for 12 cycles

References

1. OncoFrance: Misset JL, di Palma M, Delgado M, Plagne R, Chollet P, Fumoleau P, Le Mevel B, Belpomme D, Guerrin J, Fargeot P, Metz R, Ithzaki M, Hill C, Mathé G. Adjuvant treatment of node-positive breast cancer with cyclophosphamide, doxorubicin, fluorouracil, and vincristine versus cyclophosphamide, methotrexate, and fluorouracil: final report after a 16-year median follow-up duration. J Clin Oncol. 1996 Apr;14(4):1136-45. link to original article contains dosing details in manuscript PubMed
2. Meta-analysis: Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998 Sep 19;352(9132):930-42. link to original article PubMed

AVCMF

AVCMF: Adriamycin (Doxorubicin), Vinblastine, Cyclophosphamide, Methotrexate, Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ploner et al. 2003 (ABCSG 3)	1984-NR	Randomized (E-esc)	CMF	Did not meet endpoints of DFS/OS

Note: ABCSG 3 was one of the studies analyzed in the 1998 EBCTCG meta-analysis that supported FDA approval of doxorubicin for this indication.

Preceding treatment

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin)
• Vinblastine (Velban)
• Cyclophosphamide (Cytoxan)
• Methotrexate (MTX)
• Fluorouracil (5-FU)

References

1. Meta-analysis: Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Polychemotherapy for early breast cancer: an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group. Lancet. 1998 Sep 19;352(9132):930-42. link to original article PubMed
2. ABCSG 3: Ploner F, Jakesz R, Hausmaninger H, Kolb R, Stierer M, Fridrik M, Steindorfer P, Gnant M, Haider K, Mlineritsch B, Tschurtschenthaler G, Steger G, Seifert M, Kubista E, Samonigg H; ABCSG. Randomised trial: One cycle of anthracycline-containing adjuvant chemotherapy compared with six cycles of CMF treatment in node-positive, hormone receptor-negative breast cancer patients. Onkologie. 2003 Apr;26(2):115-9. link to original article PubMed

CAMFP

CAMFP: Cyclophosphamide, Adriamycin (Doxorubicin), Methotrexate, Fluorouracil, Prednisone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Recht et al. 1996	1984-1992	Phase 3 (E-switch-ic)	See link	See link

Note: this was a trial examining sequencing of chemotherapy and radiotherapy; see text for efficacy details.

Preceding treatment

• Lumpectomy

Chemotherapy

• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 45 mg/m² IV once on day 3
• Methotrexate (MTX) 200 mg/m² IV once per day on days 1 & 15
• Fluorouracil (5-FU) 500 mg/m² IV once on day 1

Endocrine therapy

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 5

Supportive therapy

• Leucovorin (Folinic acid) 10 mg/m² PO four times per day on days 2 to 4, 16 to 18

21-day cycle for 4 cycles

References

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

CEF/CMF

CEF/CMF: Cyclophosphamide, Epirubicin, Fluorouracil alternating with Cyclophosphamide, Methotrexate, Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bedognetti et al. 2011	1985-1992	Phase 3 (C)	CEFT/CMFT	Did not meet primary endpoint of OS

Preceding treatment

• Surgery

Chemotherapy, CEF portion (cycles 1, 3, 5, 7, 9, 11)

• 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

Chemotherapy, CMF portion (cycles 2, 4, 6, 8, 10, 12)

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

21-day cycle for 12 cycles

References

1. Bedognetti D, Sertoli MR, Pronzato P, Del Mastro L, Venturini M, Taveggia P, Zanardi E, Siffredi G, Pastorino S, Queirolo P, Gardin G, Wang E, Monzeglio C, Boccardo F, Bruzzi P. Concurrent vs sequential adjuvant chemotherapy and hormone therapy in breast cancer: a multicenter randomized phase III trial. J Natl Cancer Inst. 2011 Oct 19;103(20):1529-39. Epub 2011 Sep 15. link to original article link to PMC article contains dosing details in manuscript PubMed

CFP

CFP: Cyclophosphamide, Fluorouracil, Prednisone

Regimen variant #1, weight-based

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Caprini et al. 1980	1975-1979	Phase 3 (E-esc)	1. Melphalan	Seems to have superior DFS
			2. CFP & BCG	Did not meet primary endpoint of DFS

Preceding treatment

• Surgery

Chemotherapy

• Cyclophosphamide (Cytoxan) 4 mg/kg IV once per day on days 1 to 5
• Fluorouracil (5-FU) 8 mg/kg IV once per day on days 1 to 5

Endocrine therapy

• Prednisone (Sterapred) 30 mg PO once per day on days 1 to 7

42-day cycle for 9 cycles

Regimen variant #2, BSA-based

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ahmann et al. 1978	NR	Phase 3 (E-esc)	Melphalan	Seems to have superior OS

Note: Ahmann et al. 1978 had several other arms that closed early in the study and were not included in the analysis.

Preceding treatment

• Surgery

Chemotherapy

• Cyclophosphamide (Cytoxan) 150 mg/m² IV push once per day on days 1 to 5
• Fluorouracil (5-FU) 300 mg/m² IV push once per day on days 1 to 5

Endocrine therapy

• Prednisone (Sterapred) 30 mg PO once per day on days 1 to 7

42-day cycle for 10 cycles

References

1. Ahmann DL, Scanlon PW, Bisel HF, Edmonson JH, Frytak S, Payne WS, O'Fallon JR, Hahn RG, Ingle JN, O'Connell MJ, Rubin J. Repeated adjuvant chemotherapy with phenylalanine mustard or 5-fluorouracil, cyclophosphamide, and prednisone with or without radiation, after mastectomy for breast cancer. Lancet. 1978 Apr 29;1(8070):893-6. link to original article contains dosing details in manuscript PubMed
2. Caprini JA, Oviedo MA, Cunningham MP, Cohen E, Trueheart RS, Khandekar JD, Scanlon EF. Adjuvant chemotherapy for stage II and III breast carcinoma. JAMA. 1980 Jul 18;244(3):243-6. link to original article contains dosing details in manuscript PubMed

CMFP

CMFP: Cyclophosphamide, Methotrexate, Fluorouracil, Prednisone

Regimen variant #1, 6 cycles with low-dose prednisone

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Goldhirsch et al. 1988 (IBCSG V)	1981-1985	Phase 3 (C)	CMFL x 1	Seems to have superior OS

Preceding treatment

• Modified radical mastectomy or total mastectomy with low axillary-node dissection

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

Endocrine therapy

• Prednisone (Sterapred) 7.5 mg PO once per day on days 1 to 28

28-day cycle for 6 cycles

Regimen variant #2, 6 cycles with high-dose prednisone

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Mansour et al. 1989 (ECOG E1180)	1981-1988	Phase 3 (E-esc)	No further treatment	Superior DFS

Note: ECOG E1180 is also known as INT-0011.

Preceding treatment

• Modified radical mastectomy or total mastectomy with low axillary-node dissection

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

Endocrine therapy

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 14

28-day cycle for 6 cycles

Regimen variant #3, 12 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tormey et al. 1990 (ECOG E5177)	1978-1982	Phase 3 (E-esc)	1. CMF 2. CMFPT	Did not meet co-primary endpoints of TTR/OS

Preceding treatment

• Modified radical mastectomy or total mastectomy with low axillary-node dissection

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

Endocrine therapy

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 14

28-day cycle for 12 cycles

References

1. IBCSG V: Goldhirsch A; Ludwig Breast Cancer Study Group. Combination adjuvant chemotherapy for node-positive breast cancer: inadequacy of a single perioperative cycle. N Engl J Med. 1988 Sep 15;319(11):677-83. link to original article contains dosing details in manuscript PubMed
2. ECOG E1180: Mansour EG, Gray R, Shatila AH, Osborne CK, Tormey DC, Gilchrist KW, Cooper MR, Falkson G. Efficacy of adjuvant chemotherapy in high-risk node-negative breast cancer: an intergroup study. N Engl J Med. 1989 Feb 23;320(8):485-90. link to original article contains dosing details in manuscript PubMed
   1. Update: Mansour EG, Eudey L, Tormey DC, Shatila AH, Osborne CK, Gilchrist KW, Cooper MR, Falkson G. Chemotherapy versus observation in high-risk node-negative breast cancer patients. J Natl Cancer Inst Monogr. 1992;(11):97-104. PubMed
3. ECOG E5177: Tormey DC, Gray R, Gilchrist K, Grage T, Carbone PP, Wolter J, Woll JE, Cummings FJ. Adjuvant chemohormonal therapy with cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen compared with CMF for premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial. Cancer. 1990 Jan 15;65(2):200-6. link to original article contains dosing details in manuscript PubMed

CMFPT

CMFPT: Cyclophosphamide, Methotrexate, Fluorouracil, Prednisone, Tamoxifen

Regimen variant #1, 6 cycles

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Goldhirsch et al. 1988 (IBCSG V)	1981-1985	Phase 3 (C)	CMFL x 1	Seems to have superior OS

Preceding treatment

• Modified radical mastectomy or total mastectomy with low axillary-node dissection

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

Endocrine therapy

• Prednisone (Sterapred) 7.5 mg PO once per day on days 1 to 28
• Tamoxifen (Nolvadex) 20 mg PO once per day on days 1 to 28

28-day cycle for 6 cycles

Regimen variant #2, 12 cycles with low-dose prednisone

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Goldhirsch et al. 1984 (LBCS III)	1978-1981	Phase 3 (E-esc)	1. Observation	Superior DFS
			2. PT	Seems to have superior DFS

Preceding treatment

• Modified radical mastectomy or total mastectomy with low axillary-node dissection

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

Endocrine therapy

• Prednisone (Sterapred) 7.5 mg PO once per day on days 1 to 28
• Tamoxifen (Nolvadex) 20 mg PO once per day on days 1 to 28

28-day cycle for 12 cycles

Regimen variant #3, 12 cycles with high-dose prednisone

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tormey et al. 1990 (ECOG E5177)	1978-1982	Phase 3 (E-esc)	1. CMF 2. CMFP	Did not meet co-primary endpoints of TTR/OS
Falkson et al. 1990	1982-NR	Phase 3 (C)	CMFPT x 4	Did not meet primary endpoint of DFS
Tormey et al. 1992 (ECOG E5181)	1982-02 to 1987-06	Phase 3 (C)	CMFPTH/ALTER	Seems to have inferior TTR

Preceding treatment

• Modified radical mastectomy or total mastectomy with low axillary-node dissection

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

Endocrine therapy

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 14
• Tamoxifen (Nolvadex) 10 mg PO twice per day on days 1 to 28

28-day cycle for 12 cycles

Subsequent treatment

• ECOG E5181: Adjuvant Tamoxifen x 4 y versus no further treatment

References

1. LBCS III: Goldhirsch A; Ludwig Breast Cancer Study Group. Randomised trial of chemo-endocrine therapy, endocrine therapy, and mastectomy alone in postmenopausal patients with operable breast cancer and axillary node metastasis. Lancet. 1984 Jun 9;1(8389):1256-60. link to original article contains dosing details in manuscript PubMed
2. LBCS IV: Goldhirsch A; Ludwig Breast Cancer Study Group. Randomised trial of chemo-endocrine therapy, endocrine therapy, and mastectomy alone in postmenopausal patients with operable breast cancer and axillary node metastasis. Lancet. 1984 Jun 9;1(8389):1256-60. link to original article PubMed
3. IBCSG V: Goldhirsch A; Ludwig Breast Cancer Study Group. Combination adjuvant chemotherapy for node-positive breast cancer: inadequacy of a single perioperative cycle. N Engl J Med. 1988 Sep 15;319(11):677-83. link to original article contains dosing details in manuscript PubMed
4. ECOG E5177: Tormey DC, Gray R, Gilchrist K, Grage T, Carbone PP, Wolter J, Woll JE, Cummings FJ. Adjuvant chemohormonal therapy with cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP) or CMFP plus tamoxifen compared with CMF for premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial. Cancer. 1990 Jan 15;65(2):200-6. link to original article contains dosing details in manuscript PubMed
5. Falkson HC, Gray R, Wolberg WH, Gillchrist KW, Harris JE, Tormey DC, Falkson G; ECOG. Adjuvant trial of 12 cycles of CMFPT followed by observation or continuous tamoxifen versus four cycles of CMFPT in postmenopausal women with breast cancer: an Eastern Cooperative Oncology Group phase III study. J Clin Oncol. 1990 Apr;8(4):599-607. Erratum in: J Clin Oncol 1990 Sep;8(9):1603. link to original article contains dosing details in manuscript PubMed
6. ECOG E5181: Tormey DC, Gray R, Abeloff MD, Roseman DL, Gilchrist KW, Barylak EJ, Stott P, Falkson G. Adjuvant therapy with a doxorubicin regimen and long-term tamoxifen in premenopausal breast cancer patients: an Eastern Cooperative Oncology Group trial. J Clin Oncol. 1992 Dec;10(12):1848-56. link to original article contains dosing details in manuscript PubMed

CMFVP

CMFVP: Cyclophosphamide, Methotrexate, Fluorouracil, Vincristine, Prednisone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Glucksberg et al. 1982 (SWOG S7436)	1975-1978	Randomized (E-esc)	Melphalan	Superior OS
Tormey et al. 1983a	1975-1980	Phase 3 (E-esc)	1. CMF	Superior DFS
			2. CMF-MER	Not reported
Rivkin et al. 1993 (SWOG S7827ER-)	1979-1984	Phase 3 (C)	CMFVP x 2 y	Did not meet co-primary endpoints of DFS/OS
Rivkin et al. 1996 (SWOG S7821)	1979-1989	Randomized (C)	CMFVP & Oophorectomy	Did not meet co-primary endpoints of DFS/OS
Perloff et al. 1996 (CALGB 8082)	1980-1984	Non-randomized part of RCT
Budd et al. 1995 (SWOG S8313)	1984-1990	Phase 3 (C)	FAC-M	Might have superior DFS

Note: it is not clear from Rivkin et al. 1993 whether prednisone was stopped after the 6th week, and what the tapering schedule was.

Preceding treatment

• Surgery

Chemotherapy

• Cyclophosphamide (Cytoxan) 60 mg/m² PO once per day on days 1 to 7
• Methotrexate (MTX) 15 mg/m² IV once on day 1
• Fluorouracil (5-FU) 400 mg/m² IV once on day 1
• Vincristine (Oncovin) as follows:
  • Cycles 1 to 10: 0.625 mg/m² IV once on day 1

Endocrine therapy

• Prednisone (Sterapred) as follows:
  • Cycles 1 to 6: 30 mg/m²/day PO tapering to 10 mg/m²/day PO

7-day cycle for 52 cycles (1 year)

References

1. SWOG S7436: Glucksberg H, Rivkin SE, Rasmussen S, Tranum B, Gad-el-Mawla N, Costanzi J, Hoogstraten B, Athens J, Maloney T, McCracken J, Vaughn C. Combination chemotherapy (CMFVP) versus L-phenylalanine mustard (L-PAM) for operable breast cancer with positive axillary nodes: a Southwest Oncology Group Study. Cancer. 1982 Aug 1;50(3):423-34. link to original article PubMed
   1. Update: Rivkin SE, Green S, Metch B, Glucksberg H, Gad-el-Mawla N, Constanzi JJ, Hoogstraten B, Athens J, Maloney T, Osborne CK, Vaughn CB. Adjuvant CMFVP versus melphalan for operable breast cancer with positive axillary nodes: 10-year results of a Southwest Oncology Group Study. J Clin Oncol. 1989 Sep;7(9):1229-38. link to original article PubMed
   2. Update: Rivkin SE, Green SJ, Lew D, Costanzi JJ, Athens JW, Osborne CK, Vaughn CB, Martino S. Adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil, vincristine, and prednisone compared with single-agent L-phenylalanine mustard for patients with operable breast carcinoma and positive axillary lymph nodes: 20-year results of a Southwest Oncology Group study. Cancer. 2003 Jan 1;97(1):21-9. link to original article PubMed
2. Tormey DC, Weinberg VE, Holland JF, Weiss RB, Glidewell OJ, Perloff M, Falkson G, Falkson HC, Henry PH, Leone LA, Rafla S, Ginsberg SJ, Silver RT, Blom J, Carey RW, Schein PS, Lesnick GJ. A randomized trial of five and three drug chemotherapy and chemoimmunotherapy in women with operable node positive breast cancer. J Clin Oncol. 1983 Feb;1(2):138-45. link to original article PubMed
3. SWOG S7827_ER-: Rivkin SE, Green S, Metch B, Jewell WR, Costanzi JJ, Altman SJ, Minton JP, O'Bryan RM, Osborne CK. One versus 2 years of CMFVP adjuvant chemotherapy in axillary node-positive and estrogen receptor-negative patients: a Southwest Oncology Group study. J Clin Oncol. 1993 Sep;11(9):1710-6. link to original article contains dosing details in manuscript PubMed
4. SWOG S8313: Budd GT, Green S, O'Bryan RM, Martino S, Abeloff MD, Rinehart JJ, Hahn R, Harris J, Tormey D, O'Sullivan J, Osborne CK. Short-course FAC-M versus 1 year of CMFVP in node-positive, hormone receptor-negative breast cancer: an intergroup study. J Clin Oncol. 1995 Apr;13(4):831-9. link to original article PubMed
5. SWOG S7821: Rivkin SE, Green S, O'Sullivan J, Cruz AB, Abeloff MD, Jewell WR, Costanzi JJ, Farrar WB, Osborne CK. Adjuvant CMFVP versus adjuvant CMFVP plus ovariectomy for premenopausal, node-positive, and estrogen receptor-positive breast cancer patients: a Southwest Oncology Group study. J Clin Oncol. 1996 Jan;14(1):46-51. link to original article PubMed
6. CALGB 8082: Perloff M, Norton L, Korzun AH, Wood WC, Carey RW, Gottlieb A, Aust JC, Bank A, Silver RT, Saleh F, Canellos GP, Perry MC, Weiss RB, Holland JF. Postsurgical adjuvant chemotherapy of stage II breast carcinoma with or without crossover to a non-cross-resistant regimen: a Cancer and Leukemia Group B study. J Clin Oncol. 1996 May;14(5):1589-98. link to original article PubMed

CPB

CPB: Cyclophosphamide, Platinol (Cisplatin), BCNU (Carmustine)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Peters et al. 2005 (CALGB 9082)	1991-1998	Phase 3 (E-de-esc)	HD-CPB with auto HSCT	Did not meet primary endpoint of EFS

Note: this trial is of important historic significance. Although neither arm was standard of care, the results established the non-value of high-dose therapy with autologous HSCT in the adjuvant treatment of breast cancer.

Preceding treatment

• Surgery, then adjuvant FAC x 3

Chemotherapy

• Cyclophosphamide (Cytoxan) 900 mg/m² IV over 60 minutes once per day on days 1 to 3
• Cisplatin (Platinol) 30 mg/mg²/day IV continuous infusion over 72 hours, started on day 1 (total dose: 90 mg/m²)
• Carmustine (BCNU) 90 mg/m² IV over 18 hours once on day 3

One course

Subsequent treatment

• Adjuvant FAC x 1

References

1. CALGB 9082: Peters WP, Rosner GL, Vredenburgh JJ, Shpall EJ, Crump M, Richardson PG, Schuster MW, Marks LB, Cirrincione C, Norton L, Henderson IC, Schilsky RL, Hurd DD. Prospective, randomized comparison of high-dose chemotherapy with stem-cell support versus intermediate-dose chemotherapy after surgery and adjuvant chemotherapy in women with high-risk primary breast cancer: a report of CALGB 9082, SWOG 9114, and NCIC MA-13. J Clin Oncol. 2005 Apr 1;23(10):2191-200. Epub 2005 Mar 14. link to original article contains dosing details in manuscript PubMed

CTCb, then auto HSCT

CTCb: Cyclophosphamide, Thiotepa, Carboplatin
STAMP-V

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Eder et al. 1990	1987-1988	Phase 1/2
Rodenhuis et al. 1998	1991-1995	Randomized Phase 2 (E-esc)	Standard adjuvant therapy	Did not meet primary endpoint of PFS
Rodenhuis et al. 2003 (Dutch National Study)	1993-1999	Phase 3 (E-esc)	FEC x 5	Did not meet primary endpoint of OS1
Bergh et al. 2000 (SBG 9401)	1994-1998	Phase 3 (C)	See link	See link

¹Reported efficacy for the Dutch National Study is based on the 2020 update.

Preceding treatment

• Rodenhuis et al. 1998: Neoadjuvant FEC x 3, then surgery, then adjuvant FEC x 1
• Dutch National Study: Adjuvant FEC x 4

Chemotherapy

• Cyclophosphamide (Cytoxan) 1500 mg/m²/day IV on days -7 to -4
• Thiotepa (Thioplex) 125 mg/m²/day IV on days -7 to -4
• Carboplatin (Paraplatin) 200 mg/m²/day IV on days -7 to -4

Supportive therapy

• Autologous stem cells re-infused on day 0

One course

References

1. Eder JP, Elias A, Shea TC, Schryber SM, Teicher BA, Hunt M, Burke J, Siegel R, Schnipper LE, Frei E 3rd, Antman K. A phase I-II study of cyclophosphamide, thiotepa, and carboplatin with autologous bone marrow transplantation in solid tumor patients. J Clin Oncol. 1990 Jul;8(7):1239-45. link to original article PubMed
2. Rodenhuis S, Richel DJ, van der Wall E, Schornagel JH, Baars JW, Koning CC, Peterse JL, Borger JH, Nooijen WJ, Bakx R, Dalesio O, Rutgers E. Randomised trial of high-dose chemotherapy and haemopoietic progenitor-cell support in operable breast cancer with extensive axillary lymph-node involvement. Lancet. 1998 Aug 15;352(9127):515-21. link to original article PubMed
3. SBG 9401: Bergh J, Wiklund T, Erikstein B, Lidbrink E, Lindman H, Malmström P, Kellokumpu-Lehtinen P, Bengtsson NO, Söderlund G, Anker G, Wist E, Ottosson S, Salminen E, Ljungman P, Holte H, Nilsson J, Blomqvist C, Wilking N; Scandinavian Breast Group. Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrow-supported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Lancet. 2000 Oct 21;356(9239):1384-91. Erratum in: Lancet 2000 Dec 23-30;356(9248):2196. link to original article PubMed
4. Dutch National Study: Rodenhuis S, Bontenbal M, Beex LV, Wagstaff J, Richel DJ, Nooij MA, Voest EE, Hupperets P, van Tinteren H, Peterse HL, TenVergert EM, de Vries EG; Netherlands Working Party on Autologous Transplantation in Solid Tumors. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med. 2003 Jul 3;349(1):7-16. link to original article PubMed NCT03087409
   1. Update: Rodenhuis S, Bontenbal M, van Hoesel QG, Smit WM, Nooij MA, Voest EE, van der Wall E, Hupperets P, van Tinteren H, Peterse JL, van de Vijver MJ, de Vries EG; Netherlands Working Party on Autologous Transplantation in Solid Tumours. Efficacy of high-dose alkylating chemotherapy in HER2/neu-negative breast cancer. Ann Oncol. 2006 Apr;17(4):588-96. Epub 2006 Jan 30. link to original article PubMed
   2. Update: Steenbruggen TG, Steggink LC, Seynaeve CM, van der Hoeven JJM, Hooning MJ, Jager A, Konings IR, Kroep JR, Smit WM, Tjan-Heijnen VCG, van der Wall E, Bins AD, Linn SC, Schaapveld M, Jacobse JN, van Leeuwen FE, Schröder CP, van Tinteren H, de Vries EGE, Sonke GS, Gietema JA. High-Dose Chemotherapy With Hematopoietic Stem Cell Transplant in Patients With High-Risk Breast Cancer and 4 or More Involved Axillary Lymph Nodes: 20-Year Follow-up of a Phase 3 Randomized Clinical Trial. JAMA Oncol. 2020 Apr 1;6(4):528-534. link to original article link to PMC article PubMed

Cyclophosphamide monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Brinker et al. 1983 (DBCG 77B)	1977-1983	Phase 3 (E-esc)	1. CMF	Did not meet primary endpoint of RFS
			2. Observation	Seems to have superior OS1
			3. Levamisole	Not reported
Killander et al. 2009	1978-1983	Phase 3 (E-switch-ooc)	1. RT 2. Cyclophosphamide & RT	Not reported

¹Reported efficacy for DBCG 77B is based on the 2010 update.

Preceding treatment

• Surgery

Chemotherapy

• Cyclophosphamide (Cytoxan) 130 mg/m² PO once per day on days 1 to 14

1-month cycle for 12 cycles

References

1. DBCG 77B: Brincker H, Mouridsen HT, Andersen KW. Adjuvant chemotherapy with cyclophosphamide or CMF in premenopausal women with stage II breast cancer. Breast Cancer Res Treat. 1983;3(1):91-5. link to original article contains dosing details in manuscript PubMed
   1. Update: Ejlertsen B, Mouridsen HT, Jensen MB, Andersen J, Andersson M, Kamby C, Knoop AS; Danish Breast Cancer Cooperative Group. Cyclophosphamide, methotrexate, and fluorouracil; oral cyclophosphamide; levamisole; or no adjuvant therapy for patients with high-risk, premenopausal breast cancer. Cancer. 2010 May 1;116(9):2081-9. link to original article PubMed
2. Killander F, Anderson H, Rydén S, Möller T, Hafström LO, Malmström P. Efficient reduction of loco-regional recurrences but no effect on mortality twenty years after postmastectomy radiation in premenopausal women with stage II breast cancer - a randomized trial from the South Sweden Breast Cancer Group. Breast. 2009 Oct;18(5):309-15. Epub 2009 Oct 6. link to original article PubMed

Cyclophosphamide & Doxorubicin (AC)

AC: Adriamycin (Doxorubicin) and Cyclophosphamide
CA: Cyclophosphamide and Adriamycin (Doxorubicin)

Regimen variant #1, 54/1200 x 6

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Linden et al. 2007 (INT-0137)	1994-1997	Phase 3 (C)	A-C	Did not meet primary endpoint of DFS

Preceding treatment

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin) 54 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 1200 mg/m² IV once on day 1

21-day cycle for 6 cycles

Regimen variant #2, 60/600 x 4

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fisher et al. 1997 (NSABP B-18)	1988-1993	Phase 3 (C)	AC; neoadjuvant	Inferior resectability
Fisher et al. 1997 (NSABP B-22)	1989-1991	Phase 3 (C)	1. AC; intensified 2. AC; intensified & increased	Did not meet co-primary endpoints of DFS/OS
Fisher et al. 2001 (NSABP B-23)	1991-1998	Phase 3 (E-switch-ic)	CMF	Did not meet primary endpoint of OS
Içli et al. 2001	1992-1996	Phase 3 (C)	AC-EP	Did not meet primary endpoint of OS
Henderson et al. 2003 (INT 0148/CALGB 9344)	1994-1999	Phase 3 (C)	1. AC; high-dose 2. AC; very high-dose	Did not meet primary endpoint of DFS
			3. AC-T 4. AC-T; high-dose AC 5. AC-T; very high-dose AC	Inferior OS
Mamounas et al. 2005 (NSABP B-28)	1995-1998	Phase 3 (C)	AC-T	Inferior DFS
Jones et al. 2006 (USOR 9735)	1997-1999	Phase 3 (C)	TC	Seems to have inferior OS
Goldstein et al. 2008 (ECOG E2197)	1998-2000	Phase 3 (C)	AT	Did not meet primary endpoint of DFS
Brain et al. 2005 (RAPP-01)	1999-2003	Phase 3 (C)	AT	Not reported
Muss et al. 2009 (CALGB 49907)	2001-2006	Phase 3 (C)	Capecitabine	Seems to have superior OS1 (secondary endpoint) RFS120: 56% vs 50% (HR 0.80, 95% CI 0.62-0.98) Seems to have superior RFS (primary endpoint)
Geyer et al. 2022 (NSABP B-36)	2004-05-20 to 2008-07-25	Phase 3 (C)	FEC-100 x 6	Did not meet primary endpoint of DFS
Sparano et al. 2018 (TAILORx)	2006-2010	Phase 3 (C)	No chemotherapy	Non-inferior IDFS (primary endpoint)

¹Reported efficacy for CALGB 49907 is based on the 2019 update.

Eligibility criteria

• TAILORx: Oncotype DX score of 11 to 25

Preceding treatment

• Surgery
• INT 0148/CALGB 9344: Surgery, within 84 days

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

Subsequent treatment

• NSABP B-23: Adjuvant tamoxifen x 5 y versus placebo

Regimen variant #3, 80/600 x 4

Study	Dates of enrollment	Evidence
Moore et al. 2007 (SWOG S9623)	1996-2001	Non-randomized part of phase 3 RCT

Note: this is a component of a sequential treatment protocol; to our knowledge there are no references to support using it as a stand-alone treatment.

Preceding treatment

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin) 80 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for 4 cycles

Subsequent treatment

• STAMP-I or STAMP-V, with auto HSCT consolidation

References

1. NSABP B-22: Fisher B, Anderson S, Wickerham DL, DeCillis A, Dimitrov N, Mamounas E, Wolmark N, Pugh R, Atkins JN, Meyers FJ, Abramson N, Wolter J, Bornstein RS, Levy L, Romond EH, Caggiano V, Grimaldi M, Jochimsen P, Deckers P. Increased intensification and total dose of cyclophosphamide in a doxorubicin-cyclophosphamide regimen for the treatment of primary breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-22. J Clin Oncol. 1997 May;15(5):1858-69. link to original article contains dosing details in manuscript PubMed
   1. Pooled update: Taghian A, Jeong JH, Mamounas E, Anderson S, Bryant J, Deutsch M, Wolmark N. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol. 2004 Nov 1;22(21):4247-54. Epub 2004 Sep 27. link to original article PubMed
2. NSABP B-18: Fisher B, Brown A, Mamounas E, Wieand S, Robidoux A, Margolese RG, Cruz AB Jr, Fisher ER, Wickerham DL, Wolmark N, DeCillis A, Hoehn JL, Lees AW, Dimitrov NV. Effect of preoperative chemotherapy on local-regional disease in women with operable breast cancer: findings from National Surgical Adjuvant Breast and Bowel Project B-18. J Clin Oncol. 1997 Jul;15(7):2483-93. link to original article contains dosing details in manuscript PubMed
   1. Update: Fisher B, Bryant J, Wolmark N, Mamounas E, Brown A, Fisher ER, Wickerham DL, Begovic M, DeCillis A, Robidoux A, Margolese RG, Cruz AB Jr, Hoehn JL, Lees AW, Dimitrov NV, Bear HD. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998 Aug;16(8):2672-85. link to original article PubMed
   2. Update: Wolmark N, Wang J, Mamounas E, Bryant J, Fisher B. Preoperative chemotherapy in patients with operable breast cancer: nine-year results from National Surgical Adjuvant Breast and Bowel Project B-18. J Natl Cancer Inst. 2001;(30):96-102. link to original article PubMed
   3. Pooled update: Taghian A, Jeong JH, Mamounas E, Anderson S, Bryant J, Deutsch M, Wolmark N. Patterns of locoregional failure in patients with operable breast cancer treated by mastectomy and adjuvant chemotherapy with or without tamoxifen and without radiotherapy: results from five National Surgical Adjuvant Breast and Bowel Project randomized clinical trials. J Clin Oncol. 2004 Nov 1;22(21):4247-54. Epub 2004 Sep 27. link to original article PubMed
   4. Pooled update: Rastogi P, Anderson SJ, Bear HD, Geyer CE, Kahlenberg MS, Robidoux A, Margolese RG, Hoehn JL, Vogel VG, Dakhil SR, Tamkus D, King KM, Pajon ER, Wright MJ, Robert J, Paik S, Mamounas EP, Wolmark N. Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27. J Clin Oncol. 2008 Feb 10;26(5):778-85. Erratum in: J Clin Oncol. 2008 Jun 1;26(16):2793. link to original article PubMed
3. NSABP B-23: 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
   1. Update: Fisher B, Jeong JH, Anderson S, Wolmark N. Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst. 2004 Dec 15;96(24):1823-31. link to original article PubMed
4. Içli F, Akbulut H, Dinçol D, Onur H, Demirkazik A, Cam R, Cay F, Demirci S, Uner A, Erekul S. A randomized trial of four cycles of adjuvant AC (adriamycin + cyclophosphamide) +/- two cycles of EP (etoposide + cisplatin) in node positive patients with breast cancer. Ann Oncol. 2001 Jul;12(7):1011-3. link to original article contains dosing details in abstract PubMed
5. INT 0148/CALGB 9344: Henderson IC, Berry DA, Demetri GD, Cirrincione CT, Goldstein LJ, Martino S, Ingle JN, Cooper MR, Hayes DF, Tkaczuk KH, Fleming G, Holland JF, Duggan DB, Carpenter JT, Frei E 3rd, Schilsky RL, Wood WC, Muss HB, Norton L. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol. 2003 Mar 15;21(6):976-83. link to original article contains dosing details in manuscript PubMed
6. NSABP B-28: Mamounas EP, Bryant J, Lembersky B, Fehrenbacher L, Sedlacek SM, Fisher B, Wickerham DL, Yothers G, Soran A, Wolmark N. Paclitaxel after doxorubicin plus cyclophosphamide as adjuvant chemotherapy for node-positive breast cancer: results from NSABP B-28. J Clin Oncol. 2005 Jun 1;23(16):3686-96. Epub 2005 May 16. link to original article PubMed
7. RAPP-01: Brain EG, Bachelot T, Serin D, Kirscher S, Graic Y, Eymard JC, Extra JM, Combe M, Fourme E, Noguès C, Rouëssé J; RAPP-01 Trial Investigators. Life-threatening sepsis associated with adjuvant doxorubicin plus docetaxel for intermediate-risk breast cancer. JAMA. 2005 May 18;293(19):2367-71. link to original article contains dosing details in abstract PubMed
8. USOR 9735: 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 contains dosing details in abstract 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
9. INT-0137: Linden HM, Haskell CM, Green SJ, Osborne CK, Sledge GW Jr, Shapiro CL, Ingle JN, Lew D, Hutchins LF, Livingston RB, Martino S. Sequenced compared with simultaneous anthracycline and cyclophosphamide in high-risk stage I and II breast cancer: final analysis from INT-0137 (S9313). J Clin Oncol. 2007 Feb 20;25(6):656-61. link to original article contains dosing details in abstract PubMed
10. SWOG S9623: Moore HC, Green SJ, Gralow JR, Bearman SI, Lew D, Barlow WE, Hudis C, Wolff AC, Ingle JN, Chew HK, Elias AD, Livingston RB, Martino S; SWOG. Intensive dose-dense compared with high-dose adjuvant chemotherapy for high-risk operable breast cancer: Southwest Oncology Group/Intergroup study 9623. J Clin Oncol. 2007 May 1;25(13):1677-82. Epub 2007 Apr 2. link to original article contains dosing details in manuscript PubMed NCT00002772
11. ECOG E2197: Goldstein LJ, O'Neill A, Sparano JA, Perez EA, Shulman LN, Martino S, Davidson NE. Concurrent doxorubicin plus docetaxel is not more effective than concurrent doxorubicin plus cyclophosphamide in operable breast cancer with 0 to 3 positive axillary nodes: North American Breast Cancer Intergroup Trial E 2197. J Clin Oncol. 2008 Sep 1;26(25):4092-9. Epub 2008 Aug 4. link to original article link to PMC article contains dosing details in abstract PubMed NCT00003519
12. CALGB 49907: Muss HB, Berry DA, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Becker HP, Kartcheske PA, Wheeler JD, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Magrinat G, Parker BA, Hart RD, Grenier D, Norton L, Hudis CA, Winer EP; CALGB. Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med. 2009 May 14;360(20):2055-65. Erratum in: N Engl J Med. 2009 Oct 22;361(17):1714. Magrinat, Gutav [corrected to Magrinat, Gustav]. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00024102
    1. Update: Muss HB, Polley MC, Berry DA, Liu H, Cirrincione CT, Theodoulou M, Mauer AM, Kornblith AB, Partridge AH, Dressler LG, Cohen HJ, Kartcheske PA, Perez EA, Wolff AC, Gralow JR, Burstein HJ, Mahmood AA, Sutton LM, Magrinat G, Parker BA, Hart RD, Grenier D, Hurria A, Jatoi A, Norton L, Hudis CA, Winer EP, Carey L. Randomized Trial of Standard Adjuvant Chemotherapy Regimens Versus Capecitabine in Older Women With Early Breast Cancer: 10-Year Update of the CALGB 49907 Trial. J Clin Oncol. 2019 Sep 10;37(26):2338-2348. Epub 2019 Jul 24. link to original article link to PMC article PubMed
13. TAILORx: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer CE Jr, Dees EC, Goetz MP, Olson JA Jr, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez Moreno HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge GW Jr. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018 Jul 12;379(2):111-121. Epub 2018 Jun 3. link to original article link to PMC article contains dosing details in supplement PubMed NCT00310180
14. NSABP B-36: Geyer CE Jr, Bandos H, Rastogi P, Jacobs SA, Robidoux A, Fehrenbacher L, Ward PJ, Polikoff J, Brufsky AM, Provencher L, Paterson AHG, Hamm JT, Carolla RL, Baez-Diaz L, Julian TB, Swain SM, Mamounas EP, Wolmark N. Definitive results of a phase III adjuvant trial comparing six cycles of FEC-100 to four cycles of AC in women with operable node-negative breast cancer: the NSABP B-36 trial (NRG Oncology). Breast Cancer Res Treat. 2022 Jun;193(3):555-564. Epub 2022 Mar 1. Erratum in: Breast Cancer Res Treat. 2022 May 4. link to original article link to PMC article contains dosing details in manuscript PubMed NCT00087178
15. ASTER 70s: NCT01564056

ECT, then auto HSCT

ECT: Epirubicin, Cyclophosphamide, Thiotepa

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Nitz et al. 2005 (WSG AM-01)	1995-2002	Phase 3 (E-esc)	ddEC-ddCMF	Superior EFS (primary endpoint) EFS48: 60% vs 44% Seems to have superior OS (secondary endpoint) OS48: 75% vs 70%

No longer used, but of historical interest.

Preceding treatment

• Surgery

Chemotherapy

• Epirubicin (Ellence) 90 mg/m² IV over 60 minutes once on day -5, given first
• Cyclophosphamide (Cytoxan) 1000 mg/m² IV over 2 to 3 hours once per day on days -5 to -3, given second (total dose: 3000 mg/m²)
• Thiotepa (Thioplex) 133 mg/m² IV over 2 to 3 hours once per day on days -5 to -3, given third (total dose: 400 mg/m²)

Supportive therapy

• Mesna (Mesnex)
• Autologous stem cells reinfused on day 0

2 courses

References

1. WSG AM-01: Nitz UA, Mohrmann S, Fischer J, Lindemann W, Berdel WE, Jackisch C, Werner C, Ziske C, Kirchner H, Metzner B, Souchon R, Ruffert U, Schütt G, Pollmanns A, Schmoll HJ, Middecke C, Baltzer J, Schrader I, Wiebringhaus H, Ko Y, Rösel S, Schwenzer T, Wernet P, Hinke A, Bender HG, Frick M; West German Study Group. Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheral-blood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial. Lancet. 2005 Dec 3;366(9501):1935-44. Erratum in: Lancet. 2006 Mar 4;367(9512):730. link to original article contains dosing details in manuscript PubMed

FAC & BCG

FAC & BCG: Fluorouracil, Adriamycin (Doxorubicin), Cyclophosphamide, BCG

Regimen

Study	Dates of enrollment	Evidence
Buzdar et al. 1979	1974-1977	Non-randomized

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU) 400 mg/m² IV once per day on days 1 & 8
• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 7: 40 mg/m² IV once on day 1
  • Cycle 8: 20 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 400 mg/m² IV once on day 1

Immunotherapy

• BCG vaccine by scarification on days 9, 16, 23

28-day cycle for 8 cycles

Subsequent treatment

• CMF & BCG maintenance for a total of 2 years of treatment

References

1. Buzdar AU, Blumenschein GR, Gutterman JU, Tashima CK, Hortobagyi GN, Smith TL, Campos LT, Wheeler WL, Hersh EM, Freireich EJ, Gehan EA. Postoperative adjuvant chemotherapy with fluorouracil, doxorubicin, cyclophosphamide, and BCG vaccine: a follow-up report. JAMA. 1979 Oct 5;242(14):1509-13. link to original article contains dosing details in manuscript PubMed

Fluorouracil & Methotrexate (MF)

MF: Methotrexate & 5-Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shapiro et al. 1993	1976-1985	Phase 3 (C)	CMF	Did not meet endpoints of TTF/OS
Fisher et al. 1989 (NSABP B-13)	1981-1988	Phase 3 (E-esc)	Observation	Superior DFS1
Fisher et al. 1996 (NSABP B-19)	1988-1990	Phase 3 (C)	CMF	Might have inferior OS

¹Reported efficacy for NSABP B-13 is based on the 1996 update.

Preceding treatment

• Surgery

Chemotherapy

• Methotrexate (MTX) 60 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 8 cycles

References

1. NSABP B-13: Fisher B, Redmond C, Dimitrov NV, Bowman D, Legault-Poisson S, Wickerham DL, Wolmark N, Fisher ER, Margolese R, Sutherland C, Glass A, Foster R, Caplan R. A randomized clinical trial evaluating sequential methotrexate and fluorouracil in the treatment of patients with node-negative breast cancer who have estrogen-receptor-negative tumors. N Engl J Med. 1989 Feb 23;320(8):473-8. link to original article PubMed
   1. Update: Fisher B, Dignam J, Mamounas EP, Costantino JP, Wickerham DL, Redmond C, Wolmark N, Dimitrov NV, Bowman DM, Glass AG, Atkins JN, Abramson N, Sutherland CM, Aron BS, Margolese RG. Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol. 1996 Jul;14(7):1982-92. link to original article PubMed
   2. Update: Fisher B, Jeong JH, Anderson S, Wolmark N. Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst. 2004 Dec 15;96(24):1823-31. link to original article PubMed
   3. Pooled update: Taghian AG, Jeong JH, Mamounas EP, Parda DS, Deutsch M, Costantino JP, Wolmark N. Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol. 2006 Aug 20;24(24):3927-32. link to original article PubMed
2. Shapiro CL, Gelman RS, Hayes DF, Osteen R, Obando A, Canellos GP, Frei E 3rd, Henderson IC. Comparison of adjuvant chemotherapy with methotrexate and fluorouracil with and without cyclophosphamide in breast cancer patients with one to three positive axillary lymph nodes. J Natl Cancer Inst. 1993 May 19;85(10):812-7. link to original article contains dosing details in manuscript PubMed
3. NSABP B-19: Fisher B, Dignam J, Mamounas EP, Costantino JP, Wickerham DL, Redmond C, Wolmark N, Dimitrov NV, Bowman DM, Glass AG, Atkins JN, Abramson N, Sutherland CM, Aron BS, Margolese RG. Sequential methotrexate and fluorouracil for the treatment of node-negative breast cancer patients with estrogen receptor-negative tumors: eight-year results from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-13 and first report of findings from NSABP B-19 comparing methotrexate and fluorouracil with conventional cyclophosphamide, methotrexate, and fluorouracil. J Clin Oncol. 1996 Jul;14(7):1982-92. link to original article PubMed
   1. Update: Fisher B, Jeong JH, Anderson S, Wolmark N. Treatment of axillary lymph node-negative, estrogen receptor-negative breast cancer: updated findings from National Surgical Adjuvant Breast and Bowel Project clinical trials. J Natl Cancer Inst. 2004 Dec 15;96(24):1823-31. link to original article PubMed
   2. Pooled update: Taghian AG, Jeong JH, Mamounas EP, Parda DS, Deutsch M, Costantino JP, Wolmark N. Low locoregional recurrence rate among node-negative breast cancer patients with tumors 5 cm or larger treated by mastectomy, with or without adjuvant systemic therapy and without radiotherapy: results from five national surgical adjuvant breast and bowel project randomized clinical trials. J Clin Oncol. 2006 Aug 20;24(24):3927-32. link to original article PubMed

FNC

FNC: Fluorouracil, Novantrone (Mitoxantrone), Cyclophosphamide
CNF: Cyclophosphamide, Novantrone (Mitoxantrone), Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ron et al. 2001	1988-1992	Phase 3 (E-switch-ic)	CMF	Seems to have superior DFS
Fountzilas et al. 2004 (HE 10/92)	1992-1998	Phase 3 (C)	Tamoxifen	Did not meet primary endpoint of RFS
Toledano et al. 2007 (ARCOSEIN)	1996-2000	Phase 3 (C)	FNC & RT	Did not meet primary endpoint of DFS

Preceding treatment

• Breast-conserving surgery

Chemotherapy

• Fluorouracil (5-FU) 500 mg/m² IV once on day 1
• Mitoxantrone (Novantrone) 12 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

21-day cycle for 6 cycles

Subsequent treatment

• ARCOSEIN: RT

References

1. Ron IG, Wigler N, Borovik R, Brufman G, Rizel S, Shani A, Brenner J, Farbstein H, Dale A, Inbar MJ, Brenner HJ, Chaitchik S, Catane R. CMF (cyclophosphamide, methotrexate, 5-fluorouracil) versus CNF (cyclophosphamide, mitoxantrone, 5-fluorouracil) as adjuvant chemotherapy for stage II lymph-node positive breast cancer: a phase III randomized multicenter study. Am J Clin Oncol. 2001 Aug;24(4):323-7. link to original article PubMed
2. HE 10/92: Fountzilas G, Stathopoulos G, Kouvatseas G, Polychronis A, Klouvas G, Samantas E, Zamboglou N, Kyriakou K, Adamou A, Pectasidis D, Ekonomopoulos T, Kalofonos HP, Bafaloukos D, Georgoulias V, Razis E, Koukouras D, Zombolas V, Kosmidis P, Skarlos D, Pavlidis N; Hellenic Cooperative Oncology Group. Adjuvant cytotoxic and endocrine therapy in pre- and postmenopausal patients with breast cancer and one to nine infiltrated nodes: five-year results of the Hellenic Cooperative Oncology Group randomized HE 10/92 study. Am J Clin Oncol. 2004 Feb;27(1):57-67. link to original article PubMed
3. ARCOSEIN: Toledano A, Azria D, Garaud P, Fourquet A, Serin D, Bosset JF, Miny-Buffet J, Favre A, Le Floch O, Calais G. Phase III trial of concurrent or sequential adjuvant chemoradiotherapy after conservative surgery for early-stage breast cancer: final results of the ARCOSEIN trial. J Clin Oncol. 2007 Feb 1;25(4):405-10. Erratum in: J Clin Oncol. 2007 Jun 1;25(16):2334. link to original article contains dosing details in manuscript PubMed

Levamisole monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rojas et al. 1976	NR	Randomized (E-esc)	Observation	Seems to have superior OS
Brincker et al. 1980	NR	Randomized (E-switch-ooc)	RT	Seems to have inferior RFS

Note: Rojas et al. 1976 included patients with inoperable breast cancer; definitive therapy was RT.

Preceding treatment

• Rojas et al. 1976: Radiotherapy
• Brincker et al. 1980: Surgery

Immunotherapy

• Levamisole (Ergamisol) 150 mg PO once per day on days 1 to 3

14-day cycles

References

1. Rojas AF, Feierstein JN, Mickiewicz E, Glait H, Olivari AJ. Levamisole in advanced human breast cancer. Lancet. 1976 Jan 31;1(7953):211-5. link to original article contains dosing details in manuscript PubMed
2. Brincker H, Mouridsen HT, Andersen KW, Andersen J, Castberg T, Fischermann K, Henriksen E, Hou-Jensen C, Johansen H, Rossing N, Rorth M; Danish Breast Cancer Cooperative Group. Increased breast-cancer recurrence rate after adjuvant therapy with levamisole: a preliminary report. Lancet. 1980 Oct 18;2(8199):824-7. link to original article PubMed

Melphalan monotherapy

P: Phenylalanine mustard (Melphalan)

Regimen variant #1, 0.15 mg/kg x 9

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Caprini et al. 1980	1975-1979	Phase 3 (C)	1. CFP 2. CFP & BCG	Seems to have inferior DFS

Preceding treatment

• Surgery

Chemotherapy

• Melphalan (Alkeran) 0.15 mg/kg PO once per day on days 1 to 5

42-day cycle for 9 cycles

Regimen variant #2, 0.15 mg/kg x 18

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fisher et al. 1975 (NSABP B-05)	1972-1974	Phase 3 (E-esc)	Placebo	Might have superior DFS1

¹Reported efficacy for NSABP B-05 is based on the 1986 update.

Preceding treatment

• Surgery

Chemotherapy

• Melphalan (Alkeran) 0.15 mg/kg PO once per day on days 1 to 5

42-day cycle for up to 18 cycles (2 years)

Regimen variant #3, 5 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Glucksberg et al. 1982 (SWOG S7436)	1975-1978	Randomized (C)	CMFVP	Inferior OS

Preceding treatment

• Surgery

Chemotherapy

• Melphalan (Alkeran) 5 mg/m² PO once per day on days 1 to 5

42-day cycle for up to 18 cycles (2 years)

Regimen variant #4, 6 mg/m² x 10

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ahmann et al. 1978	NR	Phase 3 (C)	CFP	Seems to have inferior OS

Preceding treatment

• Surgery

Chemotherapy

• Melphalan (Alkeran) 6 mg/m² PO once per day on days 1 to 5

42-day cycle for 10 cycles

Regimen variant #5, 6 mg/m² x 18

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fisher et al. 1977 (NSABP B-07)	1975-02-03 to 1976-05-25	Phase 3 (C)	PF	Seems to have inferior RFS

Note: Fisher et al. 1977 is an update for NSABP B-05 and also the primary results for NSABP B-07.

Preceding treatment

• Surgery

Chemotherapy

• Melphalan (Alkeran) 6 mg/m² PO once per day on days 1 to 5

42-day cycle for up to 18 cycles (2 years)

Regimen variant #6, 6 mg/m² with dose cap

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rubens et al. 1983	1975-1979	Phase 3 (E-esc)	Observation	Might have superior RFS

Preceding treatment

• Surgery

Chemotherapy

• Melphalan (Alkeran) 6 mg/m² (maximum dose of 10 mg) PO once per day on days 1 to 5

42-day cycle for up to 16 cycles

References

1. NSABP B-05: Fisher B, Carbone P, Economou SG, Frelick R, Glass A, Lerner H, Redmond C, Zelen M, Band P, Katrych DL, Wolmark N, Fisher ER. 1-Phenylalanine mustard (L-PAM) in the management of primary breast cancer: a report of early findings. N Engl J Med. 1975 Jan 16;292(3):117-22. link to original article contains dosing details in manuscript PubMed
   1. Update: Fisher B, Glass A, Redmond C, Fisher ER, Barton B, Such E, Carbone P, Economou S, Foster R, Frelick R, Lerner H, Levitt M, Margolese R, MacFarlane J, Plotkin D, Shibata H, Volk H. L-phenylalanine mustard (L-PAM) in the management of primary breast cancer: an update of earlier findings and a comparison with those utilizing L-PAM plus 5-fluorouracil (5-FU). Cancer. 1977 Jun;39(6 Suppl):2883-903. link to original article PubMed
   2. Update: Fisher B, Fisher ER, Redmond C. Ten-year results from the National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trial evaluating the use of L-phenylalanine mustard (L-PAM) in the management of primary breast cancer. J Clin Oncol. 1986 Jun;4(6):929-41. link to original article PubMed
2. NSABP B-07: Fisher B, Glass A, Redmond C, Fisher ER, Barton B, Such E, Carbone P, Economou S, Foster R, Frelick R, Lerner H, Levitt M, Margolese R, MacFarlane J, Plotkin D, Shibata H, Volk H. L-phenylalanine mustard (L-PAM) in the management of primary breast cancer: an update of earlier findings and a comparison with those utilizing L-PAM plus 5-fluorouracil (5-FU). Cancer. 1977 Jun;39(6 Suppl):2883-903. link to original article contains dosing details in manuscript PubMed
3. Ahmann DL, Scanlon PW, Bisel HF, Edmonson JH, Frytak S, Payne WS, O'Fallon JR, Hahn RG, Ingle JN, O'Connell MJ, Rubin J. Repeated adjuvant chemotherapy with phenylalanine mustard or 5-fluorouracil, cyclophosphamide, and prednisone with or without radiation, after mastectomy for breast cancer. Lancet. 1978 Apr 29;1(8070):893-6. link to original article contains dosing details in manuscript PubMed
4. Caprini JA, Oviedo MA, Cunningham MP, Cohen E, Trueheart RS, Khandekar JD, Scanlon EF. Adjuvant chemotherapy for stage II and III breast carcinoma. JAMA. 1980 Jul 18;244(3):243-6. link to original article contains dosing details in manuscript PubMed
5. SWOG S7436: Glucksberg H, Rivkin SE, Rasmussen S, Tranum B, Gad-el-Mawla N, Costanzi J, Hoogstraten B, Athens J, Maloney T, McCracken J, Vaughn C. Combination chemotherapy (CMFVP) versus L-phenylalanine mustard (L-PAM) for operable breast cancer with positive axillary nodes: a Southwest Oncology Group Study. Cancer. 1982 Aug 1;50(3):423-34. link to original article contains dosing details in manuscript PubMed
   1. Update: Rivkin SE, Green S, Metch B, Glucksberg H, Gad-el-Mawla N, Constanzi JJ, Hoogstraten B, Athens J, Maloney T, Osborne CK, Vaughn CB. Adjuvant CMFVP versus melphalan for operable breast cancer with positive axillary nodes: 10-year results of a Southwest Oncology Group Study. J Clin Oncol. 1989 Sep;7(9):1229-38. link to original article PubMed
   2. Update: Rivkin SE, Green SJ, Lew D, Costanzi JJ, Athens JW, Osborne CK, Vaughn CB, Martino S. Adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil, vincristine, and prednisone compared with single-agent L-phenylalanine mustard for patients with operable breast carcinoma and positive axillary lymph nodes: 20-year results of a Southwest Oncology Group study. Cancer. 2003 Jan 1;97(1):21-9. link to original article PubMed
6. Rubens RD, Hayward JL, Knight RK, Bulbrook RD, Fentiman IS, Chaudary M, Howell A, Bush H, Crowther D, Sellwood RA, George WD, Howat JM. Controlled trial of adjuvant chemotherapy with melphalan for breast cancer. Lancet. 1983 Apr 16;1(8329):839-43. link to original article contains dosing details in manuscript PubMed

PAF

PAF: Phenylalanine mustard (Melphalan), Adriamycin (Doxorubicin), Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fisher et al. 1989 (NSABP B-11)	1981-1984	Phase 3 (E-esc)	PF	Seems to have superior OS

Preceding treatment

• Surgery

Chemotherapy

• Melphalan (Alkeran) 4 mg/m² PO once per day on days 1 to 5
• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 5: 30 mg/m² IV once per day on days 1 & 22
• Fluorouracil (5-FU) 300 mg/m² IV once per day on days 1 to 5

42-day cycle for 17 cycles

References

1. NSABP B-11: Fisher B, Redmond C, Wickerham DL, Bowman D, Schipper H, Wolmark N, Sass R, Fisher ER, Jochimsen P, Legault-Poisson S, Dimitrov N, Wolter J, Bornstein R, Elias EG, LiCalzi N, Paterson AHG, Sutherland CM. Doxorubicin-containing regimens for the treatment of stage II breast cancer: the National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol. 1989 May;7(5):572-82. link to original article contains dosing details in manuscript PubMed

PF

PF: Phenylalanine mustard (Melphalan) & Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fisher et al. 1977 (NSABP B-07)	1975-02-03 to 1976-05-25	Phase 3 (E-esc)	P	Seems to have superior RFS
Fisher et al. 1980 (NSABP B-08)	1976-04 to 1977-04	Phase 3 (C)	PFM	Did not meet endpoint of OS
Fisher et al. 1981 (NSABP B-09)	1977-1980	Phase 3 (C)	PFT	Inferior RFS
Fisher et al. 1990 (NSABP B-10)	1977-1981	Phase 3 (C)	PFCp	Did not meet endpoints of DFS/OS
Fisher et al. 1989 (NSABP B-11)	1981-1984	Phase 3 (C)	PAF	Seems to have inferior OS

Note: Fisher et al. 1980 is more of a meta-analysis than a primary publication, but is to our knowledge the first manuscript to report the findings from NSABP B-08, which was a negative trial.

Preceding treatment

• Surgery

Chemotherapy

• Melphalan (Alkeran) 4 mg/m² PO once per day on days 1 to 5
• Fluorouracil (5-FU) 300 mg/m² IV once per day on days 1 to 5

42-day cycles

References

1. NSABP B-07: Fisher B, Glass A, Redmond C, Fisher ER, Barton B, Such E, Carbone P, Economou S, Foster R, Frelick R, Lerner H, Levitt M, Margolese R, MacFarlane J, Plotkin D, Shibata H, Volk H. L-phenylalanine mustard (L-PAM) in the management of primary breast cancer: an update of earlier findings and a comparison with those utilizing L-PAM plus 5-fluorouracil (5-FU). Cancer. 1977 Jun;39(6 Suppl):2883-903. link to original article contains dosing details in manuscript PubMed
2. NSABP B-08: Fisher B, Redmond C, Fisher ER. The contribution of recent NSABP clinical trials of primary breast cancer therapy to an understanding of tumor biology--an overview of findings. Cancer. 1980 Aug 15;46(4 Suppl):1009-25. link to original article PubMed
3. NSABP B-09: Fisher B, Redmond C, Brown A, Wolmark N, Wittliff J, Fisher ER, Plotkin D, Bowman D, Sachs S, Wolter J, Frelick R, Desser R, LiCalzi N, Geggie P, Campbell T, Elias EG, Prager D, Koontz P, Volk H, Dimitrov N, Gardner B, Lerner H, Shibata H. Treatment of primary breast cancer with chemotherapy and tamoxifen. N Engl J Med. 1981 Jul 2;305(1):1-6. link to original article PubMed
   1. Update: Fisher B, Redmond C, Brown A, Fisher ER, Wolmark N, Bowman D, Plotkin D, Wolter J, Bornstein R, Legault-Poisson S, Saffer EA. Adjuvant chemotherapy with and without tamoxifen in the treatment of primary breast cancer: 5-year results from the National Surgical Adjuvant Breast and Bowel Project Trial. J Clin Oncol. 1986 Apr;4(4):459-71. link to original article PubMed
   2. Update: Fisher B, Brown A, Wolmark N, Redmond C, Wickerham DL, Wittliff J, Dimitrov N, Legault-Poisson S, Schipper H, Prager D. Prolonging tamoxifen therapy for primary breast cancer: findings from the National Surgical Adjuvant Breast and Bowel Project clinical trial. Ann Intern Med. 1987 May;106(5):649-54. link to original article PubMed
4. NSABP B-11: Fisher B, Redmond C, Wickerham DL, Bowman D, Schipper H, Wolmark N, Sass R, Fisher ER, Jochimsen P, Legault-Poisson S, Dimitrov N, Wolter J, Bornstein R, Elias EG, LiCalzi N, Paterson AHG, Sutherland CM. Doxorubicin-containing regimens for the treatment of stage II breast cancer: the National Surgical Adjuvant Breast and Bowel Project experience. J Clin Oncol. 1989 May;7(5):572-82. link to original article PubMed
5. NSABP B-10: Fisher B, Brown A, Wolmark N, Fisher ER, Redmond C, Wickerham DL, Margolese R, Dimitrov N, Pilch Y, Glass A, Sutherland C, Foster R. Evaluation of the worth of corynebacterium parvum in conjunction with chemotherapy as adjuvant treatment for primary breast cancer: eight-year results from the National Surgical Adjuvant Breast and Bowel Project B-10. Cancer. 1990 Jul 15;66(2):220-7. link to original article PubMed

Thiotepa monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fisher et al. 1968 (NSABP B-01)	1958-1961	Phase 3 (E-esc)	Placebo	Did not meet primary endpoint of RR

Note: Day 0 is the day of surgery.

Chemotherapy

• Thiotepa (Tepadina) 0.2 mg/kg IV once per day on days 0 to 2

3-day course

References

1. NSABP B-01: Fisher B, Ravdin RG, Ausman RK, Slack NH, Moore GE, Noer RJ. Surgical adjuvant chemotherapy in cancer of the breast: results of a decade of cooperative investigation. Ann Surg. 1968 Sep;168(3):337-56. link to original article link to PMC article contains dosing details in manuscript PubMed
   1. Update: Fisher B, Slack N, Katrych D, Wolmark N. Ten year follow-up results of patients with carcinoma of the breast in a co-operative clinical trial evaluating surgical adjuvant chemotherapy. Surg Gynecol Obstet. 1975 Apr;140(4):528-34. PubMed

TMF

TMF: Thiotepa, Methotrexate, Fluorouracil

Regimen

Study	Dates of enrollment	Evidence
Semiglazov et al. 1994	1985-1990	Non-randomized part of RCT

Preceding treatment

• TMF induction followed by RT versus RT followed by Mastectomy

Chemotherapy

• Thiotepa (Thioplex) 20 mg IM once per day on days 1, 3, 5, 7, 9, 11
• Methotrexate (MTX) 40 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- to 42-day cycle for 4 to 6 cycles

References

1. Semiglazov VF, Topuzov EE, Bavli JL, Moiseyenko VM, Ivanova OA, Seleznev IK, Orlov AA, Barash NY, Golubeva OM, Chepic OF. Primary (neoadjuvant) chemotherapy and radiotherapy compared with primary radiotherapy alone in stage IIb-IIIa breast cancer. Ann Oncol. 1994 Sep;5(7):591-5. link to original article contains dosing details in manuscript PubMed

Metastatic disease, all lines of therapy

CAMF

CAMF: Cyclophosphamide, Adriamycin (Doxorubicin), Methotrexate, Fluorouracil
AFCM: Adriamycin (Doxorubicin), Fluorouracil, Cyclophosphamide, Methotrexate

Regimen variant #1

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Bezwoda et al. 1979	1976-1977	Randomized (E-switch-ic)	CMFV	Did not meet primary endpoint of ORR

Chemotherapy

• Cyclophosphamide (Cytoxan) 400 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 40 mg/m² IV once on day 1
• Methotrexate (MTX) 35 mg/m² IV once on day 8
• Fluorouracil (5-FU) 350 mg/m² IV once on day 8

28-day cycles

Regimen variant #2

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tranum et al. 1978	NR	Randomized (E-esc)	1. AF 2. FAC	Did not meet primary endpoint of ORR

Chemotherapy

• Cyclophosphamide (Cytoxan) 300 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 4, 9 to 12, 17 to 20: 40 mg/m² IV once on day 1
• Methotrexate (MTX) 10 mg/m² IV once on day 1
• Fluorouracil (5-FU) 300 mg/m² IV once per day on days 1 & 8

21-day cycles

Regimen variant #3

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Lippman et al. 1984	1977-1982	Randomized (C)	CAMFTP	Did not meet endpoint of ORR

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Cyclophosphamide (Cytoxan) 750 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 30 mg/m² IV once on day 1 (up to a maximum cumulative dose of 525 mg/m²)
• Methotrexate (MTX) 40 mg/m² IV once on day 8
• Fluorouracil (5-FU) 500 mg/m² IV once on day 8, given 60 minutes after methotrexate

21-day cycles

References

1. Tranum B, Hoogstraten B, Kennedy A, Vaughn CB, Samal B, Thigpen T, Rivkin S, Smith F, Palmer RL, Costanzi J, Tucker WG, Wilson H, Maloney TR; SWOG. Adriamycin in combination for the treatment of breast cancer: a Southwest Oncology Group study. Cancer. 1978 Jun;41(6):2078-83. link to original article contains dosing details in manuscript PubMed
2. Bezwoda WR, de Moor NG, Derman D, Lange M, Saner R, Dando R. Combination chemotherapy of metastatic breast cancer: a randomized trial comparing the use of adriamycin to that of Vinblastine. Cancer. 1979 Aug;44(2):392-7. link to original article contains dosing details in manuscript PubMed
3. Lippman ME, Cassidy J, Wesley M, Young RC. A randomized attempt to increase the efficacy of cytotoxic chemotherapy in metastatic breast cancer by hormonal synchronization. J Clin Oncol. 1984 Jan;2(1):28-36. link to original article contains dosing details in manuscript PubMed

CAFVP

CAFVP: Cyclophosphamide, Adriamycin (Doxorubicin), Fluorouracil, Vincristine, Prednisone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Muss et al. 1978	1975-05 to 1976-08	Phase 3 (E-switch-ic)	CMFVP	Might have superior OS
Aisner et al. 1987 (CALGB 7682)	1976-1980	Phase 3 (E-esc)	1. CAF	Not reported
			2. CMF	Superior ORR

Note: this was "Phase I" of treatment; see paper for details of continuation.

Chemotherapy

• Cyclophosphamide (Cytoxan) as follows:
  • Cycle 1: 2 mg/kg PO once per day on days 1 to 14, then 100 mg PO once per day on days 15 to 28
  • Cycles 2 to 8: 100 mg PO once per day on days 1 to 28
• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 7: 20 mg/m² IV once per day on days 1 & 15
  • Cycle 8: 20 mg/m² IV once on day 1
• Fluorouracil (5-FU) as follows:
  • Cycle 1: 12 mg/kg IV once per day on days 1 to 3, 15
  • Cycles 2 to 8: 12 mg/kg IV once per day on days 1 & 15
• Vincristine (Oncovin) as follows:
  • Cycles 1 & 2: 25 mcg/kg IV once per day on days 1 & 15
  • Cycles 3 to 8: 25 mcg/kg IV once on day 15

Endocrine therapy

• Prednisone (Sterapred) as follows:
  • Cycle 1: 0.75 mg/kg PO once per day on days 1 to 14, then 10 mg PO once per day on days 15 to 28
  • Cycles 2 to 8: 10 mg PO once per day on days 1 to 28

28-day cycle for 8 cycles

References

1. Muss HB, White DR, Richards F 2nd, Cooper MR, Stuart JJ, Jackson DV, Rhyne L, Spurr CL. Adriamycin versus methotrexate in five-drug combination chemotherapy for advanced breast cancer: a randomized trial. Cancer. 1978 Nov;42(5):2141-8. link to original article contains dosing details in manuscript PubMed
2. CALGB 7482: Tormey DC, Weinberg VE, Leone LA, Glidewell OJ, Perloff M, Kennedy BJ, Cortes E, Silver RT, Weiss RB, Aisner J, Holland JF. A comparison of intermittent vs continuous and of adriamycin vs methotrexate 5-drug chemotherapy for advanced breast cancer: A Cancer and Leukemia Group B study. Am J Clin Oncol. 1984 Jun;7(3):231-9. link to original article PubMed
3. CALGB 7682: Aisner J, Weinberg V, Perloff M, Weiss R, Perry M, Korzun A, Ginsberg S, Holland JF; CALGB. Chemotherapy versus chemoimmunotherapy (CAF v CAFVP v CMF each +/- MER) for metastatic carcinoma of the breast: a CALGB study. J Clin Oncol. 1987 Oct;5(10):1523-33. link to original article contains dosing details in abstract PubMed

CFP

CFP: Cyclophosphamide, Fluorouracil, Prednisone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Creagan et al. 1984	NR	Phase 3 (C)	CAP, then CFP	Did not meet primary endpoint of ORR
Rosner et al. 1987	1981-1985	Randomized (E-de-esc)	1. CA 2. CMFVP	Did not meet primary endpoint of OS
Marschke et al. 1989	1982-1987	Randomized (C)	CMFP	Might have inferior ORR

Chemotherapy

• Cyclophosphamide (Cytoxan) 150 mg/m² IV once per day on days 1 to 5
• Fluorouracil (5-FU) 300 mg/m² IV once per day on days 1 to 5

Endocrine therapy

• Prednisone (Sterapred) 40 mg PO once per day, tapered to 10 mg PO once per day (details of taper not provided)

35-day cycles

References

1. Creagan ET, Green SJ, Ahmann DL, Ingle JN, Edmonson JH, Marschke RF Jr. A phase III clinical trial comparing the combination cyclophosphamide, adriamycin, cisplatin with cyclophosphamide, 5-fluorouracil, prednisone in patients with advanced breast cancer. J Clin Oncol. 1984 Nov;2(11):1260-5. link to original article PubMed
2. Rosner D, Nemoto T, Lane WW. A randomized study of intensive versus moderate chemotherapy programs in metastatic breast cancer. Cancer. 1987 Mar 1;59(5):874-83. link to original article contains dosing details in manuscript PubMed
3. Marschke RF Jr, Ingle JN, Schaid DJ, Krook JE, Mailliard JA, Cullinan SA, Pfeifle DM, Votava HJ, Ebbert LP, Windschitl HE. Randomized clinical trial of CFP versus CMFP in women with metastatic breast cancer. Cancer. 1989 May 15;63(10):1931-7. link to original article PubMed

Chlorambucil & Prednisolone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Freckman et al. 1964	1955-1963	Non-randomized
Løber et al. 1983	1978-1980	Phase 3 (C)	1. Prednimustine; continuous	Inferior TTP
			2. Prednimustine; intermittent	Might have inferior TTP

Note: Per Freckman et al. 1964, chlorambucil was continued until moderate leukopenia, and then adjusted further.

Chemotherapy

• Chlorambucil (Leukeran) 10 mg PO twice per day

Endocrine therapy

• Prednisolone (Millipred) 10 mg PO three times per day on days 1 to 14, then 10 mg PO twice per day on days 15 to 21, then 10 to 15 mg/day PO

Continued indefinitely (see note)

References

1. Freckman HA, Fry HL, Mendez FL, Maurer ER. Chlorambucil-prednisolone therapy for disseminated breast carcinoma. JAMA. 1964 Jul 6;189:23-6. link to original article contains dosing details in manuscript PubMed
2. Løber J, Mouridsen HT, Christiansen IE, Dombernowsky P, Mattsson W, Rørth M. A phase III trial comparing prednimustine (LEO 1031) to chlorambucil plus prednisolone in advanced breast cancer. Cancer. 1983 Nov 1;52(9):1570-6. link to original article PubMed

CMFP

CMFP: Cyclophosphamide, Methotrexate, Fluorouracil, Prednisone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Canellos et al. 1974	NR	Non-randomized
Segaloff et al. 1985	1971-1976	Phase 3 (C)	CMFVP	Did not meet primary endpoint of OS
Tormey et al. 1982 (ECOG E2173)	1973-1974	Randomized (E-esc)	1. AV 2. CMF	Seems to have superior OS
Cummings et al. 1985	1978-1979	Randomized (E-esc)	CAF	Did not meet primary endpoint of ORR
Marschke et al. 1989	1982-1987	Randomized (E-esc)	CFP	Might have superior ORR
Bishop et al. 1999	1993-NR	Phase 3 (C)	Paclitaxel	Seems to have inferior OS

Chemotherapy

• Cyclophosphamide (Cytoxan) 100 mg/m² PO once per day on days 1 to 14
• Methotrexate (MTX) 40 mg/mg² IV once per day on days 1 & 8
• Fluorouracil (5-FU) 600 mg/mg² IV once per day on days 1 & 8

Endocrine therapy

• Prednisone (Sterapred) 40 mg/m² PO once per day on days 1 to 14

28-day cycle for 6 cycles

References

1. Canellos GP, Devita VT, Gold GL, Chabner BA, Schein PS, Young RC. Cyclical combination chemotherapy for advanced breast carcinoma. Br Med J. 1974 Feb 9;1(5901):218-20. link to original article link to PMC article PubMed
2. ECOG E2173: Tormey DC, Gelman R, Band PR, Sears M, Rosenthal SN, DeWys W, Perlia C, Rice MA. Comparison of induction chemotherapies for metastatic breast cancer: an Eastern Cooperative Oncology Group Trial. Cancer. 1982 Oct 1;50(7):1235-44. link to original article PubMed
3. Segaloff A, Hankey BF, Carter AC, Escher GC, Ansfield FJ, Talley RW. An evaluation of the effect of vincristine added to cyclophosphamide, 5-fluorouracil, methotrexate, and prednisone in advanced breast cancer. Breast Cancer Res Treat. 1985;5(3):311-9. link to original article PubMed
4. Cummings FJ, Gelman R, Horton J. Comparison of CAF versus CMFP in metastatic breast cancer: analysis of prognostic factors. J Clin Oncol. 1985 Jul;3(7):932-40. link to original article PubMed
5. Marschke RF Jr, Ingle JN, Schaid DJ, Krook JE, Mailliard JA, Cullinan SA, Pfeifle DM, Votava HJ, Ebbert LP, Windschitl HE. Randomized clinical trial of CFP versus CMFP in women with metastatic breast cancer. Cancer. 1989 May 15;63(10):1931-7. link to original article PubMed
6. Bishop JF, Dewar J, Toner GC, Smith J, Tattersall MH, Olver IN, Ackland S, Kennedy I, Goldstein D, Gurney H, Walpole E, Levi J, Stephenson J, Canetta R. Initial paclitaxel improves outcome compared with CMFP combination chemotherapy as front-line therapy in untreated metastatic breast cancer. J Clin Oncol. 1999 Aug;17(8):2355-64. link to original article contains dosing details in abstract PubMed

CMFV

CMFV: Cyclophosphamide, Methotrexate, Fluorouracil, Vinblastine
CVMF: Cyclophosphamide, Vinblastine, Methotrexate, Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Edelstyn et al. 1975	NR	Randomized (E-esc)	CMFV; 1-day	Superior ORR
Bezwoda et al. 1979	1976-1977	Randomized (C)	CAMF	Did not meet primary endpoint of ORR

Chemotherapy

• Cyclophosphamide (Cytoxan) 400 mg/m² IV once on day 1
• Methotrexate (MTX) 35 mg/m² IV once on day 8
• Fluorouracil (5-FU) 350 mg/m² IV once on day 8
• Vinblastine (Velban) 6 mg/m² IV once on day 1

28-day cycles

References

1. Edelstyn GA, Bates TD, Brinkley D, MacRae KD, Spittle MF, Wheeler T. Comparison of 5-day, 1-day, and 2-day cyclical combination chemotherapy in advanced breast cancer. Lancet. 1975 Aug 2;2(7927):209-11. link to original article PubMed
2. Bezwoda WR, de Moor NG, Derman D, Lange M, Saner R, Dando R. Combination chemotherapy of metastatic breast cancer: a randomized trial comparing the use of adriamycin to that of Vinblastine. Cancer. 1979 Aug;44(2):392-7. link to original article contains dosing details in manuscript PubMed

CMFVP

CMFVP: Cyclophosphamide, Methotrexate, Fluorouracil, Vincristine, Prednisone
COMFP: Cyclophosphamide, Oncovin (Vincristine), Methotrexate, Fluorouracil, Prednisone
CFPMV: Cyclophosphamide, Fluorouracil, Prednisone, Methotrexate, Vincristine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Segaloff et al. 1985	1971-1976	Phase 3 (E-esc)	CMFP	Did not meet primary endpoint of OS
Hoogstraten et al. 1976	1972-1974	Phase 3 (E-esc)	Doxorubicin	Seems to have superior ORR
Smalley et al. 1977	1974-04-01 to 1975-07-01	Phase 3 (C)	CAF	Might have inferior OS1
Muss et al. 1978	1975-05 to 1976-08	Phase 3 (C)	CAFVP	Might have inferior OS
Carmo-Pereira et al. 1980	NR	Phase 3 (E-esc)	5-FU	Superior OS
Rosner et al. 1987	1981-1985	Randomized (E-esc)	1. CA 2. CFP	Did not meet primary endpoint of OS

¹Reported efficacy for Smalley et al. 1977 is based on the 1983 update.

Chemotherapy

• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1, 2, 5, 6, 9, 10, 13, 14, 17, 18: 75 mg/m² PO once per day on days 1 to 7
• Methotrexate (MTX) 15 mg/m² IV once on day 1
• Fluorouracil (5-FU) 300 mg/m² IV once on day 1
• Vincristine (Oncovin) 0.65 mg/m² IV once on day 1

Endocrine therapy

• Prednisone (Sterapred) 20 mg/m² PO once per day with taper (details not provided)

7-day cycle for 20 cycles

References

1. Hoogstraten B, George SL, Samal B, Rivkin SE, Costanzi JJ, Bonnet JD, Thigpen T, Braine H; SWOG. Combination chemotherapy and adriamycin in patients with advanced breast cancer: a Southwest Oncology Group study. Cancer. 1976 Jul;38(1):13-20. link to original article PubMed
2. Smalley RV, Carpenter J, Bartolucci A, Vogel C, Krauss S; Southeastern Cancer Study Group. A comparison of cyclophosphamide, adriamycin, 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, prednisone (CMFVP) in patients with metastatic breast cancer: a Southeastern Cancer Study Group project. Cancer. 1977 Aug;40(2):625-32. link to original article contains dosing details in manuscript PubMed
   1. Update: Smalley RV, Lefante J, Bartolucci A, Carpenter J, Vogel C, Krauss S. A comparison of cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) and cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone (CMFVP) in patients with advanced breast cancer. Breast Cancer Res Treat. 1983;3(2):209-20. link to original article PubMed
3. Muss HB, White DR, Richards F 2nd, Cooper MR, Stuart JJ, Jackson DV, Rhyne L, Spurr CL. Adriamycin versus methotrexate in five-drug combination chemotherapy for advanced breast cancer: a randomized trial. Cancer. 1978 Nov;42(5):2141-8. link to original article PubMed
4. Carmo-Pereira J, Costa FO, Henriques E. Single-drug vs combination cytotoxic chemotherapy in advanced breast cancer: a randomized study. Eur J Cancer. 1980 Dec;16(12):1621-5. link to original article contains dosing details in manuscript PubMed
5. CALGB 7482: Tormey DC, Weinberg VE, Leone LA, Glidewell OJ, Perloff M, Kennedy BJ, Cortes E, Silver RT, Weiss RB, Aisner J, Holland JF. A comparison of intermittent vs continuous and of adriamycin vs methotrexate 5-drug chemotherapy for advanced breast cancer: A Cancer and Leukemia Group B study. Am J Clin Oncol. 1984 Jun;7(3):231-9. link to original article PubMed
6. Segaloff A, Hankey BF, Carter AC, Escher GC, Ansfield FJ, Talley RW. An evaluation of the effect of vincristine added to cyclophosphamide, 5-fluorouracil, methotrexate, and prednisone in advanced breast cancer. Breast Cancer Res Treat. 1985;5(3):311-9. link to original article PubMed
7. Rosner D, Nemoto T, Lane WW. A randomized study of intensive versus moderate chemotherapy programs in metastatic breast cancer. Cancer. 1987 Mar 1;59(5):874-83. link to original article PubMed

Cyclophosphamide monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Rubens et al. 1975	1970-1974	Phase 3 (C)	CMFV	Did not meet primary endpoint of ORR
Miles et al. 2011	1998-2003	Phase 3 (C)	STn-KLH vaccine	Did not meet co-primary endpoints of TTP/OS

Chemotherapy

• Cyclophosphamide (Cytoxan) by the following weight-based criteria:
  • Less than 48 kg: 200 mg PO once per day
  • 48 to 58 kg: 250 mg PO once per day
  • More than 58 kg: 300 mg PO once per day

Continued indefinitely

References

1. Rubens RD, Knight RK, Hayward JL. Chemotherapy of advanced breast cancer: a controlled randomized trial of cyclophosphamide versus a four-drug combination. Br J Cancer. 1975 Dec;32(6):730-6. link to original article link to PMC article contains dosing details in manuscript PubMed
2. Miles D, Roché H, Martin M, Perren TJ, Cameron DA, Glaspy J, Dodwell D, Parker J, Mayordomo J, Tres A, Murray JL, Ibrahim NK; Theratope® Study Group. Phase III multicenter clinical trial of the sialyl-TN (STn)-keyhole limpet hemocyanin (KLH) vaccine for metastatic breast cancer. Oncologist. 2011;16(8):1092-100. Epub 2011 May 14. link to original article link to PMC article PubMed

Fluorouracil monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Carmo-Pereira et al. 1980	NR	Phase 3 (C)	CMFVP	Inferior OS

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Fluorouracil (5-FU) as follows:
  • Cycle 1: 500 mg/m² IV once per day on days 1 to 5
  • Cycle 2 onwards: 500 mg/m² IV once on day 1

7-day cycles

References

1. Carmo-Pereira J, Costa FO, Henriques E. Single-drug vs combination cytotoxic chemotherapy in advanced breast cancer: a randomized study. Eur J Cancer. 1980 Dec;16(12):1621-5. link to original article contains dosing details in manuscript PubMed

Fluorouracil & Methotrexate (MF)

MF: Methotrexate & 5-Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Sjöström et al. 1999	1994-1997	Phase 3 (C)	Docetaxel	Inferior TTP

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Methotrexate (MTX) 200 mg/m² IV over 15 minutes once per day on days 1 & 8, given first
• Fluorouracil (5-FU) 600 mg/m² IV bolus once per day on days 1 & 8, given second, one hour after methotrexate

21-day cycles

References

1. Sjöström J, Blomqvist C, Mouridsen H, Pluzanska A, Ottosson-Lönn S, Bengtsson NO, Ostenstad B, Mjaaland I, Palm-Sjövall M, Wist E, Valvere V, Anderson H, Bergh J; Scandinavian Breast Group. Docetaxel compared with sequential methotrexate and 5-fluorouracil in patients with advanced breast cancer after anthracycline failure: a randomised phase III study with crossover on progression by the Scandinavian Breast Group. Eur J Cancer. 1999 Aug;35(8):1194-201. link to original article contains dosing details in manuscript PubMed

Melphalan monotherapy

P: Phenylalanine mustard (Melphalan)

Regimen variant #1, 25 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Jones et al. 1995a	1990-1992	Phase 3 (C)	Vinorelbine	Seems to have inferior OS

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Melphalan (Alkeran) 25 mg/m² IV once on day 1

28-day cycles

Regimen variant #2, 30 mg/m²

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Canellos et al. 1976	NR	Phase 3 (C)	CMF	Seems to have inferior OS

Note: To our knowledge, this regimen variant was not tested as an experimental arm in an RCT in this context, prior to becoming a standard comparator arm.

Chemotherapy

• Melphalan (Alkeran) 6 mg/m² PO once per day on days 1 to 5

42-day cycles

References

1. Canellos GP, Pocock SJ, Taylor SG 3rd, Sears ME, Klaasen DJ, Band PR. Combination chemotherapy for metastatic breast carcinoma: prospective comparison of multiple drug therapy with L-phenylalanine mustard. Cancer. 1976 Nov;38(5):1882-6. link to original article PubMed
2. Jones S, Winer E, Vogel C, Laufman L, Hutchins L, O'Rourke M, Lembersky B, Budman D, Bigley J, Hohneker J. Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer. J Clin Oncol. 1995 Oct;13(10):2567-74. link to original article contains dosing details in abstract PubMed

Methotrexate & Thiotepa

Regimen

Study	Evidence
Greenspan et al. 1963	Non-randomized

Note: this is possibly the first published trial of combination chemotherapy in breast cancer. Treatment details are not available for online review.

Chemotherapy

• Methotrexate (MTX)
• Thiotepa (Tepadina)

References

1. Greenspan EM, Fieber M, Lesnick G, Edelman S. Response of advanced breast carcinoma to the combination of the antimetabolite, Methotrexate, and the alkylating agent, thio-TEPA. J Mt Sinai Hosp N Y. 1963 May-Jun;30:246-67. PubMed

Mitoxantrone monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Harris et al. 1990	NR	Non-randomized part of RCT
Cowan et al. 1991 (SWOG S8203)	1983-1986	Phase 3 (C)	1. Bisantrene 2. Doxorubicin	Seems to have inferior OS

Chemotherapy

• Mitoxantrone (Novantrone) 14 mg/m² IV once on day 1

21-day cycles

References

1. Harris AL, Cantwell BM, Carmichael J, Wilson R, Farndon J, Dawes P, Ghani S, Evans RG. Comparison of short-term and continuous chemotherapy (mitozantrone) for advanced breast cancer. Lancet. 1990 Jan 27;335(8683):186-90. link to original article PubMed
2. SWOG S8203: Cowan JD, Neidhart J, McClure S, Coltman CA Jr, Gumbart C, Martino S, Hutchins LF, Stephens RL, Vaughan CB, Osborne CK. Randomized trial of doxorubicin, bisantrene, and mitoxantrone in advanced breast cancer: a Southwest Oncology Group study. J Natl Cancer Inst. 1991 Aug 7;83(15):1077-84. link to original article contains dosing details in abstract PubMed

Thiotepa monotherapy

Regimen

Study	Evidence
Bateman 1955	Non-randomized

Chemotherapy

• Thiotepa (Thioplex)

References

1. Bateman JC. Chemotherapy of solid tumors with triethylene thiophosphoramide. N Engl J Med. 1955 May 26;252(21):879-87. link to original article PubMed

Metastatic disease, first-line therapy

CAV

CAV: Cyclophosphamide, Adriamycin (Doxorubicin), Vincristine
VAC: Vincristine, Adriamycin (Doxorubicin), Cyclophosphamide

Regimen variant #1, 1/40/600

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Muss et al. 1982	1979-1981	Randomized (E-esc)	CMF	Seems to have superior ORR

Chemotherapy

• Vincristine (Oncovin) 1 mg/m² IV once on day 1
• Doxorubicin (Adriamycin) 40 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 200 mg/m² PO once per day on days 3 to 5

21-day cycles

Regimen variant #2, 1.4/30/400

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Powles et al. 1991	1985-1989	Phase 3 (C)	3M	Did not meet primary endpoint of ORR

Chemotherapy

• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1
• Doxorubicin (Adriamycin) 30 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 400 mg/m² IV once on day 1

21-day cycles

Regimen variant #3, 1.4/50/600

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Green et al. 1996	NR	Phase 3 (C)	VNC	Might have superior ORR

Chemotherapy

• Vincristine (Oncovin) by the following age-based criteria:
  • 60 years old or younger: 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1
  • Older than 60 years old: 1.4 mg/m² (maximum dose of 1 mg) IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycles

Regimen variant #4, 1.5/50/500

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Zekan et al. 1984	1981-04 to 1982-10	Phase 3 (C)	CF	Did not meet co-primary endpoints

Chemotherapy

• Vincristine (Oncovin) 1.5 mg/m² (maximum dose of 2 mg) IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² (maximum dose of 100 mg) IV once on day 1
• Cyclophosphamide (Cytoxan) 500 mg/m² IV once on day 1

21-day cycle for up to 9 cycles

Subsequent treatment

• CF maintenance

Regimen variant #5, 2/50/600

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Gundersen et al. 1986	1982-06 to 1983-12	Phase 3 (C)	Doxorubicin	Did not meet endpoint of ORR

Chemotherapy

• Vincristine (Oncovin) 2 mg IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) 600 mg/m² IV once on day 1

21-day cycle for up to 10 cycles

Subsequent treatment

• CM maintenance

References

1. Muss HB, Richards F 2nd, Jackson DV, Cooper MR, White DR, Stuart JJ, Ramseur W, Christian RM, Wells HB, Pope E, Spurr CL; Piedmont Oncology Association. Vincristine, doxorubicin, and cyclophosphamide versus low-dose intravenous cyclophosphamide, methotrexate, and 5-fluorouracil in advanced breast cancer: a randomized trial of the Piedmont Oncology Association. Cancer. 1982 Dec 1;50(11):2269-74. link to original article contains dosing details in manuscript PubMed
2. Zekan PJ, Muss HB, Capizzi RL, Cooper MR, Harding RW, Hopkins JO, Jackson DV, Ramseur WL, Richards F 2nd, Spurr CL, Stuart JJ, White DR, Pope E, Case D, Wells HB; Piedmont Oncology Association. High-dose cyclophosphamide and 5-fluorouracil versus vincristine, doxorubicin, and cyclophosphamide in advanced carcinoma of the breast: a phase III study of the Piedmont Oncology Association (POA). Cancer. 1984 Dec 1;54(11):2338-43. link to original article contains dosing details in manuscript PubMed
3. 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 original article contains dosing details in manuscript PubMed
4. Powles TJ, Jones AL, Judson IR, Hardy JR, Ashley SE. A randomised trial comparing combination chemotherapy using mitomycin C, mitozantrone and methotrexate (3M) with vincristine, anthracycline and cyclophosphamide (VAC) in advanced breast cancer. Br J Cancer. 1991 Aug;64(2):406-10. link to original article link to PMC article contains dosing details in manuscript PubMed
5. Green JA, Slater AJ, Campbell IR, Kelly V. Advanced breast cancer: a randomized study of doxorubicin or mitoxantrone in combination with cyclophosphamide and vincristine. Breast Cancer Res Treat. 1996;39(2):155-63. link to original article contains dosing details in manuscript PubMed

Mitoxantrone & Vinorelbine (MV)

MV: Mitoxantrone & Vinorelbine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Namer et al. 2001	1993-04 to 1995-12	Phase 3 (E-de-esc)	1a. FAC 1b. FEC	Equivalent ORR

Chemotherapy

• Mitoxantrone (Novantrone) 12 mg/m² IV once on day 1
• Vinorelbine (Navelbine) 25 mg/m² IV once per day on days 1 & 8

21-day cycles

References

1. Namer M, Soler-Michel P, Turpin F, Chinet-Charrot P, de Gislain C, Pouillart P, Delozier T, Luporsi E, Etienne PL, Schraub S, Eymard JC, Serin D, Ganem G, Calais G, Maillart P, Colin P, Trillet-Lenoir V, Prevost G, Tigaud D, Clavère P, Marti P, Romieu G, Wendling JL. Results of a phase III prospective, randomised trial, comparing mitoxantrone and vinorelbine (MV) in combination with standard FAC/FEC in front-line therapy of metastatic breast cancer. Eur J Cancer. 2001 Jun;37(9):1132-40. link to original article contains dosing details in manuscript PubMed

STAMP-I

Regimen

Study	Dates of enrollment	Evidence
Peters et al. 1988	NR	Non-randomized

Chemotherapy

• Carmustine (BCNU) 600 mg/m² IV once on day -3
• Cisplatin (Platinol) 55 mg/m²/day IV continuous infusion over 72 hours, started on day -6 (total dose: 165 mg/m²)
• Cyclophosphamide (Cytoxan) 1875 mg/m² IV once per day on days -6 to -4

Supportive therapy

• Autologous stem cells re-infused on days -1, 0, +1

One course

References

1. Peters WP, Shpall EJ, Jones RB, Olsen GA, Bast RC, Gockerman JP, Moore JO. High-dose combination alkylating agents with bone marrow support as initial treatment for metastatic breast cancer. J Clin Oncol. 1988 Sep;6(9):1368-76. link to original article contains dosing details in manuscript PubMed

VAP

VAP: Vincristine, Adriamycin (Doxorubicin), Prednisolone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Leonard et al. 1987	NR	Phase 3 (C)	VMP	Superior ORR

Chemotherapy

• Vincristine (Oncovin) 1.4 mg/m² (maximum dose of 2 mg) IV once on day 1
• Doxorubicin (Adriamycin) 50 mg/m² IV once on day 1

Endocrine therapy

• Prednisolone (Millipred) 40 mg PO once per day on days 1 to 5

21-day cycles

References

1. Leonard RC, Cornbleet MA, Kaye SB, Soukop M, White G, Hutcheon AW, Robinson S, Kerr ME, Smyth JF. Mitoxantrone versus doxorubicin in combination chemotherapy for advanced carcinoma of the breast. J Clin Oncol. 1987 Jul;5(7):1056-63. link to original article contains dosing details in manuscript PubMed

Metastatic disease, consolidation after first-line therapy

CHUT, then auto HSCT

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Biron et al. 2007 (Pegase 03)	1995-2001	Phase 3 (E-esc)	No further treatment	Superior DFS (co-primary endpoint)

Preceding treatment

• Induction FEC x 4

Chemotherapy

• Cyclophosphamide (Cytoxan) 1500 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose: 6000 mg/m²)
• Thiotepa (Thioplex) 200 mg/m²/day IV continuous infusion over 96 hours, started on day 1 (total dose: 800 mg/m²)

Supportive therapy

• Filgrastim (Neupogen) 5 mcg/kg SC once per day, started on day 1
• Mesna (Mesnex) 1600 mg/m²/day IV continuous infusion over 120 hours, started on day 1, 1 hour before cyclophosphamide (total dose: 8000 mg/m²)
• Autologous stem cells re-infused on day 8

One course

References

1. Pegase 03: Biron P, Durand M, Roché H, Delozier T, Battista C, Fargeot P, Spaeth D, Bachelot T, Poiget E, Monnot F, Tanguy ML, Curé H. Pegase 03: a prospective randomized phase III trial of FEC with or without high-dose thiotepa, cyclophosphamide and autologous stem cell transplantation in first-line treatment of metastatic breast cancer. Bone Marrow Transplant. 2008 Mar;41(6):555-62. Epub 2007 Nov 26. link to original article contains dosing details in manuscript PubMed NCT00002870

CTCb, then auto HSCT

CTCb: Cyclophosphamide, Thiotepa, Carboplatin

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Stadtmauer et al. 2000	1990-1997	Phase 3 (E-esc)	CMF	Did not meet primary endpoint of OS

No longer used, but of historical interest.

Preceding treatment

• Stadtmauer et al. 2000, patients who had previously received less than 400 mg/m² cumulative lifetime doxorubicin dose: Induction FAC x 4 to 6 cycles
• Stadtmauer et al. 2000, patients who had previously received 400 mg/m² to 500 mg/m² cumulative lifetime doxorubicin dose: Induction CMF x 4 to 6 cycles or CMFP x 4 to 6 cycles

Chemotherapy

• Cyclophosphamide (Cytoxan) 1500 mg/m²/day IV continuous infusion over 96 hours, start on day -6 (total dose: 6000 mg/m²)
• Thiotepa (Thioplex) 125 mg/m²/day IV continuous infusion over 96 hours, start on day -6 (total dose: 500 mg/m²)
• Carboplatin (Paraplatin) 200 mg/m²/day IV continuous infusion over 96 hours, start on day -6 (total dose: 800 mg/m²)

Supportive therapy

• Autologous stem cells re-infused on day 0

One course

References

1. Stadtmauer EA, O'Neill A, Goldstein LJ, Crilley PA, Mangan KF, Ingle JN, Brodsky I, Martino S, Lazarus HM, Erban JK, Sickles C, Glick JH; Philadelphia Bone Marrow Transplant Group. Conventional-dose chemotherapy compared with high-dose chemotherapy plus autologous hematopoietic stem-cell transplantation for metastatic breast cancer. N Engl J Med. 2000 Apr 13;342(15):1069-76. link to original article contains dosing details in manuscript PubMed

STAMP-I

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Vredenburgh et al. 2006	1992-1997	Phase 3 (E-esc)	Observation	Superior EFS

Preceding treatment

• Induction Duke AFM x 2 to 4

Chemotherapy

• Carmustine (BCNU) 600 mg/m² IV once on day -3
• Cisplatin (Platinol) 55 mg/m²/day IV continuous infusion over 72 hours, started on day -6 (total dose: 165 mg/m²)
• Cyclophosphamide (Cytoxan) 1875 mg/m² IV once per day on days -6 to -4

Supportive therapy

• Autologous stem cells re-infused on days -1, 0, +1

One course

References

1. Vredenburgh JJ, Madan B, Coniglio D, Ross M, Broadwater G, Niedzwiecki D, Edwards J, Marks L, Vandemark R, McDonald C, Affronti ML, Peters WP. A randomized phase III comparative trial of immediate consolidation with high-dose chemotherapy and autologous peripheral blood progenitor cell support compared to observation with delayed consolidation in women with metastatic breast cancer and only bone metastases following intensive induction chemotherapy. Bone Marrow Transplant. 2006 Jun;37(11):1009-15. link to original article contains dosing details in manuscript PubMed

Metastatic disease, subsequent lines of therapy

Mitomycin & Vinblastine (MV)

MV: Mitomycin & Vinblastine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Nabholtz et al. 1999 (TAX 304)	NR	Phase 3 (C)	Docetaxel	Inferior OS

Chemotherapy

• Mitomycin (Mutamycin) 12 mg/m² IV once on day 1
• Vinblastine (Velban) 6 mg/m² IV once on day 1

21-day cycle for up to 10 cycles

References

1. TAX 304: Nabholtz JM, Senn HJ, Bezwoda WR, Melnychuk D, Deschênes L, Douma J, Vandenberg TA, Rapoport B, Rosso R, Trillet-Lenoir V, Drbal J, Molino A, Nortier JW, Richel DJ, Nagykalnai T, Siedlecki P, Wilking N, Genot JY, Hupperets PS, Pannuti F, Skarlos D, Tomiak EM, Murawsky M, Alakl M, Aapro M; 304 Study Group. Prospective randomized trial of docetaxel versus mitomycin plus vinblastine in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy. J Clin Oncol. 1999 May;17(5):1413-24. link to original article contains dosing details in abstract PubMed