Staging page

The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only. As a general rule, this includes the inferior arm(s) of a randomized study, unless said regimens continue to be recommended by trustworthy sources such as the NCCN Guidelines. Is there a regimen missing from this list? See the main breast cancer page for current regimens.

0 regimens on this page 0 variants on this page

Neoadjuvant therapy

CVAP

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

Regimen

Study	Evidence
Smith et al. 2002	Non-randomized portion of RCT
Thomas et al. 2004b	Non-randomized portion of RCT

Chemotherapy

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

Endocrine therapy

• Prednisolone (Millipred)

Subsequent treatment

• 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 PubMed
2. 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 PubMed

Adjuvant therapy, sequential protocols

FAC-MV

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

Protocol

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

• Fluorouracil (5-FU)
• Doxorubicin (Adriamycin)
• Cyclophosphamide (Cytoxan)

Chemotherapy, MV portion

• 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

• Folinic acid (Leucovorin) rescue

21- to 28-day cycle for 4 cycles

References

1. Assikis V, Buzdar A, Yang Y, Smith T, Theriault R, Booser D, Valero V, Walters R, Singletary E, Ames F, Hortobagyi G. A phase III trial of sequential adjuvant chemotherapy for operable breast carcinoma: final analysis with 10-year follow-up. Cancer. 2003 Jun 1;97(11):2716-23. link to original article contains dosing details in abstract PubMed

Adjuvant therapy

ACT

ACT: Adriamycin (Doxorubicin), Cyclophosphamide, Tamoxifen

Regimen variant #1, 40/500/20

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Shien et al. 2014 (JCOG9401)	1994-1999	Phase 3 (E-esc)	Tamoxifen	Seems to have superior RFS
Shien et al. 2014 (JCOG9404)	1994-1999	Phase 3 (E-de-esc)	TUFT	Did not meet primary endpoint of OS

Preceding treatment

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 6: 40 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 6: 500 mg/m² IV once on day 1

Endocrine therapy

• Tamoxifen (Nolvadex) 20 mg PO once per day

28-day cycle for 6 cycles, then continuous for a total of 2 years

Regimen variant #2, 60/600/20

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fisher et al. 1990 (NSABP B-16)	1985-1988	Phase 3 (E-esc)	1. PFT	Not reported
			2. Tamoxifen	Seems to have superior OS

Preceding treatment

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin) as follows:
  • Cycles 1 to 4: 60 mg/m² IV once on day 1
• Cyclophosphamide (Cytoxan) as follows:
  • Cycles 1 to 4: 600 mg/m² IV once on day 1

Endocrine therapy

• Tamoxifen (Nolvadex) 10 mg PO twice per day

21-day cycle for 4 cycles, then continuous for a total of 5 years

References

1. NSABP B-16: Fisher B, Redmond C, Legault-Poisson S, Dimitrov NV, Brown AM, Wickerham DL, Wolmark N, Margolese RG, Bowman D, Glass AG, Kardinal CG, Robidoux A, Jochimsen P, Cronin W, Deutsch M, Fisher ER, Myers DB, Hoehn JL. Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol. 1990 Jun;8(6):1005-18. 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. JCOG9401: Shien T, Iwata H, Aogi K, Fukutomi T, Inoue K, Kinoshita T, Takahashi M, Matsui A, Shibata T, Fukuda H. Tamoxifen versus tamoxifen plus doxorubicin and cyclophosphamide as adjuvant therapy for node-positive postmenopausal breast cancer: results of a Japan Clinical Oncology Group Study (JCOG9401). Int J Clin Oncol. 2014 Dec;19(6):982-8. Epub 2014 Jan 7. link to original article contains dosing details in manuscript PubMed
3. JCOG9404: Shien T, Iwata H, Fukutomi T, Inoue K, Aogi K, Kinoshita T, Ando J, Takashima S, Nakamura K, Shibata T, Fukuda H. Tamoxifen plus tegafur-uracil (TUFT) versus tamoxifen plus Adriamycin (doxorubicin) and cyclophosphamide (ACT) as adjuvant therapy to treat node-positive premenopausal breast cancer (PreMBC): results of Japan Clinical Oncology Group Study 9404. Cancer Chemother Pharmacol. 2014 Sep;74(3):603-9. Epub 2014 Jul 24. link to original article link to PMC article contains dosing details in manuscript PubMed

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-RT-esc)	CMF	Superior OS

Preceding treatment

• Surgery

Chemotherapy

• Doxorubicin (Adriamycin)
• Vincristine (Oncovin)
• Cyclophosphamide (Cytoxan)
• Fluorouracil (5-FU)

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 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-RT-esc)	CMF	Did not meet endpoints of DFS/OS

Preceding treatment

• Surgery

Chemotherapy

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

References

1. 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

• Folinic acid (Leucovorin) 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

Protocol

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

• Cyclophosphamide (Cytoxan)
• Epirubicin (Ellence)
• Fluorouracil (5-FU)

Chemotherapy, CMF portion

• Cyclophosphamide (Cytoxan)
• Methotrexate (MTX)
• Fluorouracil (5-FU)

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 PubMed

CFP

CFP: Cyclophosphamide, Fluorouracil, Prednisone

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ahmann et al. 1978	NR	Phase 3 (E-esc)	Melphalan	Seems to have superior OS
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)
• Fluorouracil (5-FU)

Endocrine therapy

• Prednisone (Sterapred)

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 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 PubMed

CFP & Oophorectomy

CFP & Oophorectomy: Cyclophosphamide, Fluorouracil, Prednisone & Bilateral Oophorectomy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ahmann et al. 1977	NR	Randomized (E-esc)	Oophorectomy	Seems to have superior PFS

Preceding treatment

• Surgery, 3 weeks prior

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) 30 mg PO once per day on days 1 to 7
• Bilateral oophorectomy

35-day cycles

References

1. Ahmann DL, O'Connell MJ, Hahn RG, Bisel HF, Lee RA, Edmonson JH. An evaluation of early or delayed adjuvant chemotherapy in premenopausal patients with advanced breast cancer undergoing oophorectomy. N Engl J Med. 1977 Aug 18;297(7):356-60. link to original article contains dosing details in manuscript PubMed

CMFL

CMFL: Cyclophosphamide, Methotrexate, Fluorouracil, Leucovorin (Folinic acid)

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Goldhirsch et al. 1989 (LCBS V)	1981-1985	Phase 3 (E-esc)	No further treatment	Seems to have superior DFS

Preceding treatment

• Mastectomy

Chemotherapy

• Cyclophosphamide (Cytoxan)
• Methotrexate (MTX)
• Fluorouracil (5-FU)
• Folinic acid (Leucovorin)

8-day course

References

1. LCBS V: Goldhirsch A, Gelber RD; Ludwig Breast Cancer Study Group. Prolonged disease-free survival after one course of perioperative adjuvant chemotherapy for node-negative breast cancer. N Engl J Med. 1989 Feb 23;320(8):491-6. link to original article PubMed

CMFP

CMFP: Cyclophosphamide, Methotrexate, Fluorouracil, Prednisone

Regimen

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 primary endpoints of TTR/OS
Goldhirsch et al. 1988 (IBCSG V)	1981-1985	Phase 3 (C)	CMFL x 1	Seems to have superior OS
Mansour et al. 1989 (INT-0011)	1981-1988	Phase 3 (E-esc)	No further treatment	Superior DFS

Preceding treatment

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

Chemotherapy

• Cyclophosphamide (Cytoxan)
• Methotrexate (MTX)
• Fluorouracil (5-FU)

Endocrine therapy

• Prednisone (Sterapred)

28-day cycle for 6 to 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 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 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 PubMed

CMFPT

CMFPT: Cyclophosphamide, Methotrexate, Fluorouracil, Prednisone, Tamoxifen

Regimen

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
Tormey et al. 1990 (ECOG E5177)	1978-1982	Phase 3 (E-esc)	1. CMF 2. CMFP	Did not meet primary endpoints of TTR/OS
Goldhirsch et al. 1988 (IBCSG V)	1981-1985	Phase 3 (C)	CMFL x 1	Seems to have superior OS
Falkson et al. 1990	1982-NR	Phase 3 (C)	CMFPT x 4	Did not meet primary endpoint of DFS

Preceding treatment

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

Chemotherapy

• Cyclophosphamide (Cytoxan)
• Methotrexate (MTX)
• Fluorouracil (5-FU)

Endocrine therapy

• Prednisone (Sterapred)
• Tamoxifen (Nolvadex)

28-day cycle for 6 to 12 cycles

References

1. LBCS III/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
2. 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 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 PubMed
4. 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 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)	CMF	Superior DFS
			CMF-MER	Not reported
Rivkin et al. 1993 (SWOG S7827ER-)	1979-1984	Phase 3 (C)	CMFVP x 2 y	Did not meet primary endpoints of DFS/OS
Rivkin et al. 1996 (SWOG S7821)	1979-1989	Randomized (C)	CMFVP & Oophorectomy	Did not meet primary endpoints of DFS/OS
Perloff et al. 1996 (CALGB 8082)	1980-1984	Non-randomized portion of RCT
Budd et al. 1995 (SWOG S8313)	1984-1990	Phase 3 (C)	FAC-M	Might have superior DFS

Preceding treatment

• Surgery

Chemotherapy

• Cyclophosphamide (Cytoxan)
• Methotrexate (MTX)
• Fluorouracil (5-FU)
• Vincristine (Oncovin)

Endocrine therapy

• Prednisone (Sterapred)

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 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: 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 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 FAC x 3

Chemotherapy

• Cyclophosphamide (Cytoxan) 900 mg/m² IV over 60 hours 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

Subsequent treatment

• 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 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 FEC x 1
• Dutch National Study: 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

Stem cells re-infused on day 0

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 (C)	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
Miles et al. 2011	1998-2003	Phase 3 (C)	STn-KLH vaccine	Did not meet primary endpoints of TTP/OS

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

Chemotherapy

• Cyclophosphamide (Cytoxan)

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
3. 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

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 x 4, then ddCMF x 3	Seems to have superior OS

No longer used, but of historical interest.

Preceding treatment

• Surgery

Chemotherapy

• Epirubicin (Ellence)
• Cyclophosphamide (Cytoxan)
• Thiotepa (Thioplex)

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 PubMed

FAC & BCG

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

Regimen

Study	Evidence
Buzdar et al. 1979	Non-randomized

Preceding treatment

• Surgery

Chemotherapy

• Fluorouracil (5-FU)
• Doxorubicin (Adriamycin)
• Cyclophosphamide (Cytoxan)

Immunotherapy

• Bacillus Calmette-Guérin (BCG)

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 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)
• Fluorouracil (5-FU)

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. 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 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. 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)

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 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

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fisher et al. 1975 (NSABP B-05)	1972-1975	Phase 3 (E-esc)	Placebo	Might have superior DFS1
Fisher et al. 1977 (NSABP B-07)	1975-1976	Phase 3 (C)	PF	Seems to have inferior RFS
Glucksberg et al. 1982 (SWOG S7436)	1975-1978	Randomized (C)	CMFVP	Inferior OS
Rubens et al. 1983	1975-1979	Phase 3 (E-esc)	Observation	Might have superior RFS

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

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 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 PubMed
3. 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 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
4. 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 PubMed

Oophorectomy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ahmann et al. 1977	NR	Randomized (C)	CFP & Oophorectomy	Seems to have inferior PFS
Love et al. 2016 (OSU-0476)	2004-2011	Phase 3 (C)	Mid-luteal phase oophorectomy	Did not meet primary endpoint of OS

Preceding treatment

• Surgery

Endocrine therapy

• Bilateral oophorectomy

Subsequent treatment

• OSU-0476: Tamoxifen

References

1. Ahmann DL, O'Connell MJ, Hahn RG, Bisel HF, Lee RA, Edmonson JH. An evaluation of early or delayed adjuvant chemotherapy in premenopausal patients with advanced breast cancer undergoing oophorectomy. N Engl J Med. 1977 Aug 18;297(7):356-60. link to original article PubMed
2. OSU-0476: Love RR, Hossain SM, Hussain MM, Mostafa MG, Laudico AV, Siguan SS, Adebamowo C, Sun JZ, Fei F, Shao ZM, Liu Y, Akram Hussain SM, Zhang B, Cheng L, Panigaro S, Walta F, Chuan JH, Mirasol-Lumague MR, Yip CH, Navarro NS Jr, Huang CS, Lu YS, Ferdousy T, Salim R, Akhter C, Nahar S, Uy G, Young GS, Hade EM, Jarjoura D. Luteal versus follicular phase surgical oophorectomy plus tamoxifen in premenopausal women with metastatic hormone receptor-positive breast cancer. Eur J Cancer. 2016 Jun;60:107-16. Epub 2016 Apr 20. link to original article link to PMC article PubMed NCT00293540

Paclitaxel monotherapy, q3wk

T: Taxol (Paclitaxel)
P: Paclitaxel
pT: pacliTaxel

Regimen variant #1, 175 mg/m² q3wk

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Henderson et al. 2003 (INT 0148/CALGB 9344)	1994-1999	Phase 3 (E-RT-esc)	Observation	Superior OS

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

• INT 0148/CALGB 9344: Surgery, then AC x 4 versus AC; high-dose x 4 versus AC; very-high-dose x 4

Chemotherapy

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

21-day cycle for 4 cycles

References

1. 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

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)
• Doxorubicin (Adriamycin)
• Fluorouracil (5-FU)

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 PubMed

PF

PF: Phenylalanine mustard (Melphalan) & Fluorouracil

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fisher et al. 1977 (NSABP B-07)	1975-1976	Phase 3 (E-esc)	P	Seems to have superior RFS
Fisher et al. 1980 (NSABP B-08)	1976-1977	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)
• Fluorouracil (5-FU)

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 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

PFT

PFT: Phenylalanine mustard (Melphalan), 5-Fluorouracil, Tamoxifen

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Fisher et al. 1981 (NSABP B-09)	1977-1980	Phase 3 (E-RT-esc)	PF	Superior RFS
Fisher et al. 1990 (NSABP B-16)	1985-1988	Phase 3 (E-esc)	1. ACT	Not reported
			2. Tamoxifen	Seems to have superior DDFS

Preceding treatment

• Surgery

Chemotherapy

• Melphalan (Alkeran)
• Fluorouracil (5-FU)

Endocrine therapy

• Tamoxifen (Nolvadex)

References

1. 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
2. NSABP B-16: Fisher B, Redmond C, Legault-Poisson S, Dimitrov NV, Brown AM, Wickerham DL, Wolmark N, Margolese RG, Bowman D, Glass AG, Kardinal CG, Robidoux A, Jochimsen P, Cronin W, Deutsch M, Fisher ER, Myers DB, Hoehn JL. Postoperative chemotherapy and tamoxifen compared with tamoxifen alone in the treatment of positive-node breast cancer patients aged 50 years and older with tumors responsive to tamoxifen: results from the National Surgical Adjuvant Breast and Bowel Project B-16. J Clin Oncol. 1990 Jun;8(6):1005-18. link to original article 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

PT

PT: Prednisone & Tamoxifen

Regimen

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

Preceding treatment

• Mastectomy

Endocrine therapy

• Prednisone (Sterapred)
• Tamoxifen (Nolvadex)

References

1. LBCS III/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

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

Chemotherapy

• Thiotepa (Tepadina)

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 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 portion of RCT

Preceding treatment

• TMF, then RT versus RT, then Mastectomy

Chemotherapy

• Thiotepa (Thioplex)
• Methotrexate (MTX)
• Fluorouracil (5-FU)

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 PubMed

Metastatic disease, all lines of therapy

Aminoglutethimide monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Smith et al. 1978	1977-1978	Non-randomized
Santen et al. 1981	NR	Randomized (E-switch-ic)	Bilateral adrenalectomy	Did not meet primary endpoint of ORR
Stuart-Harris et al. 1984	NR	Phase 2
Canney et al. 1988	NR	Phase 3 (E-switch-ic)	MPA	Did not meet primary endpoint of ORR
Lundgren et al. 1989	NR	Phase 3 (E-switch-ic)	Megestrol	Did not meet primary endpoint of ORR
Garcia-Giralt et al. 1992	NR	Phase 3 (E-switch-ic)	MPA	Seems to have superior TTP
Robustelli della Cuna et al. 1993	NR	Phase 3 (C)	Aminoglutethimide; higher-dose	Did not meet primary endpoint of ORR
Gale et al. 1994	1977-NR	Phase 3 (E-switch-ic)	1. Tamoxifen 2. Bilateral adrenalectomy	Did not meet primary endpoints of DOR/TTF/OS

Endocrine therapy

• Aminoglutethimide (Cytadren)

Supportive therapy

• Hydrocortisone (Cortef)

References

1. Smith IE, Fitzharris BM, McKinna JA, Fahmy DR, Nash AG, Neville AM, Gazet JC, Ford HT, Powles TJ. Aminoglutethimide in treatment of metastatic breast carcinoma. Lancet. 1978 Sep 23;2(8091):646-9. link to original article PubMed
2. Santen RJ, Worgul TJ, Samojlik E, Interrante A, Boucher AE, Lipton A, Harvey HA, White DS, Smart E, Cox C, Wells SA. A randomized trial comparing surgical adrenalectomy with aminoglutethimide plus hydrocortisone in women with advanced breast cancer. N Engl J Med. 1981 Sep 3;305(10):545-51. link to original article PubMed
3. Stuart-Harris R, Dowsett M, Bozek T, McKinna JA, Gazet JC, Jeffcoate SL, Kurkure A, Carr L, Smith IE. Low-dose aminoglutethimide in treatment of advanced breast cancer. Lancet. 1984 Sep 15;2(8403):604-7. link to original article PubMed
4. Canney PA, Priestman TJ, Griffiths T, Latief TN, Mould JJ, Spooner D. Randomized trial comparing aminoglutethimide with high-dose medroxyprogesterone acetate in therapy for advanced breast carcinoma. J Natl Cancer Inst. 1988 Sep 21;80(14):1147-51. link to original article PubMed
5. Lundgren S, Gundersen S, Klepp R, Lønning PE, Lund E, Kvinnsland S. Megestrol acetate versus aminoglutethimide for metastatic breast cancer. Breast Cancer Res Treat. 1989 Nov;14(2):201-6. link to original article PubMed
6. Garcia-Giralt E, Ayme Y, Carton M, Daban A, Delozier T, Fargeot P, Fumoleau P, Gorins A, Guerin D, Guerin R, Maillart P, Mauriac L, May-Levin F, Metz R, Namer M, Olivier JP, Pommatau E, Pouillart P, Pujade-Lauraine E, Rouesse J, Serrou B, Vitse M, Zylberait D. Second and third line hormonotherapy in advanced post-menopausal breast cancer: a multicenter randomized trial comparing medroxyprogesterone acetate with aminoglutethimide in patients who have become resistant to tamoxifen. Breast Cancer Res Treat. 1992;24(2):139-45. link to original article PubMed
7. Robustelli della Cuna G, Pannuti F, Martoni A, Camaggi CM, Strocchi E, Da Prada GA, Tanneberger S; Italian Cooperative Group. Aminoglutethimide in advanced breast cancer: prospective, randomized comparison of two dose levels. Anticancer Res. 1993 Nov-Dec;13(6B):2367-71. PubMed
8. Gale KE, Andersen JW, Tormey DC, Mansour EG, Davis TE, Horton J, Wolter JM, Smith TJ, Cummings FJ; ECOG. Hormonal treatment for metastatic breast cancer: an Eastern Cooperative Oncology Group Phase III trial comparing aminoglutethimide to tamoxifen. Cancer. 1994 Jan 15;73(2):354-61. link to original article PubMed

CAMF

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

Regimen

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
Bezwoda et al. 1979	1976-1977	Randomized (E-switch-ic)	CMFV	Did not meet primary endpoint of ORR
Lippman et al. 1984	1977-1982	Randomized (C)	CAMFTP	Did not meet endpoint of ORR

Chemotherapy

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

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 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 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 PubMed

CAF & MPA

CAF & MPA: Cyclophosphamide, Adriamycin (Doxorubicin), Fluorouracil, MedroxyProgesterone Acetate

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Tominaga et al. 1994	NR	Phase 3 (E-esc)	CAF	Seems to have superior ORR

Chemotherapy

• Cyclophosphamide (Cytoxan)
• Doxorubicin (Adriamycin)
• Fluorouracil (5-FU)

Endocrine therapy

• Medroxyprogesterone (MPA)

References

1. Tominaga T, Abe O, Ohshima A, Hayasaka H, Uchino J, Abe R, Enomoto K, Izuo M, Watanabe H, Takatani O, Yoshida M, Sakai K, Koyama H, Hattori T, Senoo T, Monden Y, Nomura Y. Comparison of chemotherapy with or without medroxyprogesterone acetate for advanced or recurrent breast cancer. Eur J Cancer. 1994;30A(7):959-64. link to original article contains dosing details in abstract PubMed

CAFVP

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

Regimen

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

Chemotherapy

• Cyclophosphamide (Cytoxan)
• Doxorubicin (Adriamycin)
• Fluorouracil (5-FU)
• Vincristine (Oncovin)

Endocrine therapy

• Prednisone (Sterapred)

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 PubMed
2. 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

CAV

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

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Muss et al. 1982	1979-1981	Randomized (E-esc)	CMF	Seems to have superior ORR
Zekan et al. 1984	1981-1982	Phase 3 (C)	CF	Did not meet primary endpoints
Gundersen et al. 1986	1982-1983	Phase 3 (C)	Doxorubicin	Did not meet endpoint of ORR
Powles et al. 1991	1985-1989	Phase 3 (C)	3M	Did not meet primary endpoint of ORR
Green et al. 1996	NR	Phase 3 (C)	VNC	Might have superior ORR

Chemotherapy

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

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 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 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 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 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 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-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)
• Fluorouracil (5-FU)

Endocrine therapy

• Prednisone (Sterapred)

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 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

Chemotherapy

• Chlorambucil (Leukeran)

Endocrine therapy

• Prednisolone (Millipred)

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 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

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

Preceding treatment

• FEC x 4

Chemotherapy

• Cyclophosphamide (Cytoxan) 6000 mg/m²
• Thiotepa (Thioplex) 800 mg/m²

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 PubMed NCT00002870

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)
• Methotrexate (MTX)
• Fluorouracil (5-FU)

Endocrine therapy

• Prednisone (Sterapred)

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)
• Methotrexate (MTX)
• Fluorouracil (5-FU)
• Vincristine (Oncovin)

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 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	1974-1975	Phase 3 (C)	CAF	Might have inferior OS1
Muss et al. 1978	1975-1976	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)
• Methotrexate (MTX)
• Fluorouracil (5-FU)
• Vincristine (Oncovin)

Endocrine therapy

• Prednisone (Sterapred)

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 PubMed
5. 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
6. 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

DES monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Kennedy 1965	NR in abstract	Randomized (E-switch-ic)	Testosterone	Not available
Carter et al. 1977	NR	Phase 3 (E-switch-ic)	DES; other dosings	See paper
Kiang et al. 1981	1975-1982	Randomized (C)	Cyclophosphamide, 5-FU, DES	Seems to have inferior OS1
Ingle et al. 1981	1977-1980	Phase 3 (C)	Tamoxifen	Did not meet primary endpoint of ORR

¹Reported efficacy for Kiang et al. 1981 is based on the 1985 update.

Endocrine therapy

• Diethylstilbestrol (DES)

References

1. Kennedy BJ. Diethylstilbestrol versus testosterone propionate therapy in advanced breast cancer. Surg Gynecol Obstet. 1965 Jun;120:1246-50. PubMed
2. Carter AC, Sedransk N, Kelley RM, Ansfield FJ, Ravdin RG, Talley RW, Potter NR; Cooperative Breast Cancer Group. Diethylstilbestrol: recommended dosages for different categories of breast cancer patients: report of the Cooperative Breast Cancer Group. JAMA. 1977 May 9;237(19):2079-8. link to original article PubMed
3. Ingle JN, Ahmann DL, Green SJ, Edmonson JH, Bisel HF, Kvols LK, Nichols WC, Creagan ET, Hahn RG, Rubin J, Frytak S. Randomized clinical trial of diethylstilbestrol versus tamoxifen in postmenopausal women with advanced breast cancer. N Engl J Med. 1981 Jan 1;304(1):16-21. link to original article PubMed
4. Kiang DT, Frenning DH, Gay J, Goldman AI, Kennedy BJ. Combination therapy of hormone and cytotoxic agents in advanced breast cancer. Cancer. 1981 Feb 1;47(3):452-6. link to original article PubMed
   1. Update: Kiang DT, Gay J, Goldman A, Kennedy BJ. A randomized trial of chemotherapy and hormonal therapy in advanced breast cancer. N Engl J Med. 1985 Nov 14;313(20):1241-6. link to original article PubMed

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.

Chemotherapy

• Cyclophosphamide (Cytoxan)
• Thiotepa (Thioplex)
• Carboplatin (Paraplatin)

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 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

Chemotherapy

• Cyclophosphamide (Cytoxan)

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 PubMed

Estradiol monotherapy

Regimen variant #1, 6 mg/day

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ellis et al. 2009	2004-2008	Randomized Phase 2 (E-de-esc)	Estradiol; 30 mg/day	Did not meet primary endpoint of CBR

Endocrine therapy

• Estradiol 6 mg PO once per day

Continued indefinitely

Regimen variant #2, 30 mg/day

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Ellis et al. 2009	2004-2008	Randomized Phase 2 (C)	Estradiol; 6 mg/day	Did not meet primary endpoint of CBR

Endocrine therapy

• Estradiol 30 mg PO once per day

Continued indefinitely

References

1. Ellis MJ, Gao F, Dehdashti F, Jeffe DB, Marcom PK, Carey LA, Dickler MN, Silverman P, Fleming GF, Kommareddy A, Jamalabadi-Majidi S, Crowder R, Siegel BA. Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study. JAMA. 2009 Aug 19;302(7):774-80. link to original article link to PMC article contains dosing details in abstract PubMed NCT00324259

Fluoxymesterone monotherapy

Regimen

Study	Evidence
Kennedy 1958	Non-randomized

Endocrine therapy

• Fluoxymesterone (Halotestin)

References

1. Kennedy BJ. Fluoxymesterone therapy in advanced breast cancer. N Engl J Med. 1958 Oct 2;259(14):673-5. link to original article PubMed

Formestane monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Coombes et al. 1984	NR	Pilot
Thürlimann et al. 1997 (SAKK 20/90)	1991-1995	Phase 3 (E-switch-ic)	Megestrol	Did not meet primary endpoint of TTF

Endocrine therapy

• Formestane (Lentaron)

References

1. Coombes RC, Goss P, Dowsett M, Gazet JC, Brodie A. 4-Hydroxyandrostenedione in treatment of postmenopausal patients with advanced breast cancer. Lancet. 1984 Dec 1;2(8414):1237-9. link to original article PubMed
2. SAKK 20/90: Thürlimann B, Castiglione M, Hsu-Schmitz SF, Cavalli F, Bonnefoi H, Fey MF, Morant R, Löhnert T, Goldhirsch A; Swiss Group for Clinical Cancer Research. Formestane versus megestrol acetate in postmenopausal breast cancer patients after failure of tamoxifen: a phase III prospective randomised cross over trial of second-line hormonal treatment (SAKK 20/90). Eur J Cancer. 1997 Jun;33(7):1017-24. link to original article PubMed

Medroxyprogesterone monotherapy

Regimen variant #1, 500 mg/day

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cuna et al. 1978	NR	Phase 3 (E-de-esc)	MPA; 1000 mg/day	Did not meet primary endpoint of ORR
Pannuti et al. 1979 (UICC 75-09)	NR	Randomized (C)	MPA; 1500 mg/day	Did not meet primary endpoint of ORR
Canney et al. 1988	NR	Phase 3 (C)	Aminoglutethimide	Did not meet primary endpoint of ORR
Byrne et al. 1997 (ANZ8613)	1987-1993	Phase 3 (C)	MPA & Tamoxifen	Did not meet primary endpoint of TTP

Note: Canney et al. 1988 does not have dosing information in the abstract.

Endocrine therapy

• Medroxyprogesterone (MPA) 500 mg PO once per day

Continued indefinitely

Regimen variant #2, 900 mg/day

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
van Veelen et al. 1986	1980-1984	Phase 3 (E-switch-ic)	Tamoxifen	Did not meet primary endpoint of ORR

Endocrine therapy

• Medroxyprogesterone (MPA) 300 mg PO three times per day

Continued indefinitely

Regimen variant #3, 1000 mg/day (high-dose)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Cavalli et al. 1984	1979-1982	Phase 3 (E-esc)	MPA; low-dose	Superior ORR
Garcia-Giralt et al. 1992	NR	Phase 3 (C)	Aminoglutethimide	Seems to have inferior TTP
Castiglione-Gertsch et al. 1993	1982-1985	Phase 3 (E-switch-ic)	Tamoxifen	Might have superior TTP
Muss et al. 1994	1985-1990	Phase 3 (E-switch-ic)	Tamoxifen	Might have superior OS

Endocrine therapy

• Medroxyprogesterone (MPA) 1000 mg PO or IM once per day or 500 mg PO twice per day

Continued indefinitely

Regimen variant #4, 1200 mg/day (high-dose)

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Izuo et al. 1985	1981-1983	Phase 3 (E-switch-ic)	Mepitiostane	Did not meet primary endpoint of ORR

Endocrine therapy

• Medroxyprogesterone (MPA) 400 mg PO three times per day

Continued indefinitely

References

1. Cuna GR, Calciati A, Strada MR, Bumma C, Campio L. High dose medroxyprogesterone acetate (MPA) treatment in metastatic carcinoma of the breast: a dose-response evaluation. Tumori. 1978 Apr 30;64(2):143-9. link to original article contains dosing details in abstract PubMed
2. UICC 75-09: Pannuti F, Martoni A, Di Marco AR, Piana E, Saccani F, Becchi G, Mattioli G, Barbanti F, Marra GA, Persiani W, Cacciari L, Spagnolo F, Palenzona D, Rocchetta G. Prospective, randomized clinical trial of two different high dosages of medroxyprogesterone acetate (MAP) in the treatment of metastatic breast cancer. Eur J Cancer. 1979 Apr;15(4):593-601. link to original article contains dosing details in abstract PubMed
3. Cavalli F, Goldhirsch A, Jungi F, Martz G, Mermillod B, Alberto P. Randomized trial of low- versus high-dose medroxyprogesterone acetate in the induction treatment of postmenopausal patients with advanced breast cancer. J Clin Oncol. 1984 May;2(5):414-9. link to original article PubMed
4. Izuo M, Yoshida M, Tominaga T, Abe O, Enomoto K, Nomura Y, Kubo K, Takatani O. A phase III trial of oral high-dose medroxyprogesterone acetate (MPA) versus mepitiostane in advanced postmenopausal breast cancer. Cancer. 1985 Dec 1;56(11):2576-9. link to original article PubMed
5. van Veelen H, Willemse PH, Tjabbes T, Schweitzer MJ, Sleijfer DT. Oral high-dose medroxyprogesterone acetate versus tamoxifen: a randomized crossover trial in postmenopausal patients with advanced breast cancer. Cancer. 1986 Jul 1;58(1):7-13. link to original article contains dosing details in abstract PubMed
6. Canney PA, Priestman TJ, Griffiths T, Latief TN, Mould JJ, Spooner D. Randomized trial comparing aminoglutethimide with high-dose medroxyprogesterone acetate in therapy for advanced breast carcinoma. J Natl Cancer Inst. 1988 Sep 21;80(14):1147-51. link to original article PubMed
7. Garcia-Giralt E, Ayme Y, Carton M, Daban A, Delozier T, Fargeot P, Fumoleau P, Gorins A, Guerin D, Guerin R, Maillart P, Mauriac L, May-Levin F, Metz R, Namer M, Olivier JP, Pommatau E, Pouillart P, Pujade-Lauraine E, Rouesse J, Serrou B, Vitse M, Zylberait D. Second and third line hormonotherapy in advanced post-menopausal breast cancer: a multicenter randomized trial comparing medroxyprogesterone acetate with aminoglutethimide in patients who have become resistant to tamoxifen. Breast Cancer Res Treat. 1992;24(2):139-45. link to original article PubMed
8. Castiglione-Gertsch M, Pampallona S, Varini M, Cavalli F, Brunner K, Senn HJ, Goldhirsch A, Metzger U. Primary endocrine therapy for advanced breast cancer: to start with tamoxifen or with medroxyprogesterone acetate?. Ann Oncol. 1993 Nov;4(9):735-40. link to original article PubMed
9. Muss HB, Case LD, Atkins JN, Bearden JD 3rd, Cooper MR, Cruz JM, Jackson DV Jr, O'Rourke MA, Pavy MD, Powell BL, Richards F, Spurr CL, Eagle K, White DR; Piedmont Oncology Association. Tamoxifen versus high-dose oral medroxyprogesterone acetate as initial endocrine therapy for patients with metastatic breast cancer: a Piedmont Oncology Association study. J Clin Oncol. 1994 Aug;12(8):1630-8. link to original article contains dosing details in abstract PubMed
10. ANZ8613: Byrne MJ, Gebski V, Forbes J, Tattersall MH, Simes RJ, Coates AS, Dewar J, Lunn M, Flower C, Gill PG, Stewart J; Australian-New Zealand Breast Cancer Trials Group. Medroxyprogesterone acetate addition or substitution for tamoxifen in advanced tamoxifen-resistant breast cancer: a phase III randomized trial. J Clin Oncol. 1997 Sep;15(9):3141-8. link to original article contains dosing details in abstract PubMed

Megestrol monotherapy

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Muss et al. 1988	1981-1984	Phase 3 (E-switch-ic)	Tamoxifen	Did not meet primary endpoint of ORR
Lundgren et al. 1989	NR	Phase 3 (C)	Aminoglutethimide	Did not meet primary endpoint of ORR
Gill et al. 1993	1984-1989	Phase 3 (E-switch-ic)	1. Tamoxifen 2. Megestrol & Tamoxifen	Did not meet endpoint of ORR
Buzdar et al. 1996	NR	Phase 3 (C)	Anastrozole	Seems to have inferior OS1
Russell et al. 1997 (SWOG S8312)	1984-1990	Phase 3 (C)	Aminoglutethimide, Hydrocortisone, Megestrol	Did not meet primary endpoint of OS
Muss et al. 1990	1985-1988	Phase 3 (C)	Megestrol; higher-dose	Seems to have inferior OS
Stuart et al. 1996	1985-1988	Phase 3 (E-switch-ic)	Tamoxifen	Did not meet endpoint of OS
Abrams et al. 1999 (CALGB 8741)	1987-1991	Phase 3 (C)	Megestrol; higher-dose	Did not meet primary endpoint of ORR
Buzdar et al. 1996 (Protocol 03)	1989-1991	Phase 3 (C)	Fadrozole	Did not meet primary endpoint of ORR
Buzdar et al. 1996 (Protocol 06)	1989-1991	Phase 3 (C)	Fadrozole	Did not meet primary endpoint of ORR
Thürlimann et al. 1997 (SAKK 20/90)	1991-1995	Phase 3 (C)	Formestane	Did not meet primary endpoint of TTF
Goss et al. 1999	1991-1995	Phase 3 (C)	Vorozole	Did not meet primary endpoint of ORR
Jonat et al. 1996	1993-1994	Phase 3 (C)	Anastrozole	Seems to have inferior OS1
Dombernowsky et al. 1998 (AR/BC2)	1993-1994	Randomized (C)	Letrozole; 0.5 mg/day	Not reported
			Letrozole; 2.5 mg/day	Seems to have inferior OS
Kaufmann et al. 2000	1995-1998	Phase 3 (C)	Exemestane	Seems to have inferior OS
Buzdar et al. 2001	NR	Phase 3 (C)	1. Letrozole; 0.5 mg/day 2. Letrozole; 2.5 mg/day	Did not meet primary endpoint of ORR

¹Reported efficacy for Jonat et al. 1996 & Buzdar et al. 1996 is based on the 1998 pooled update.

Endocrine therapy

• Megestrol (Megace) 160 mg PO once per day or 40 mg PO four times per day

Continued indefinitely

References

1. Muss HB, Wells HB, Paschold EH, Black WR, Cooper MR, Capizzi RL, Christian R, Cruz JM, Jackson DV, Powell BL, Richards F, White DR, Zekan PJ, Spurr CL, Pope E, Case D, Morgan TM; Piedmont Oncology Association. Megestrol acetate versus tamoxifen in advanced breast cancer: 5-year analysis--a phase III trial of the Piedmont Oncology Association. J Clin Oncol. 1988 Jul;6(7):1098-106. link to original article PubMed
2. Lundgren S, Gundersen S, Klepp R, Lønning PE, Lund E, Kvinnsland S. Megestrol acetate versus aminoglutethimide for metastatic breast cancer. Breast Cancer Res Treat. 1989 Nov;14(2):201-6. link to original article PubMed
3. Muss HB, Case LD, Capizzi RL, Cooper MR, Cruz J, Jackson D, Richards F 2nd, Powell BL, Spurr CL, White D, Zekan P, Read S, Cates-Wilkie S, Bearden J, McCullough J, Callahan R, Karb K, Atkins J, Paschal B, Ramseur B, Lusk J, Stanley V; Piedmont Oncology Association. High- versus standard-dose megestrol acetate in women with advanced breast cancer: a phase III trial of the Piedmont Oncology Association. J Clin Oncol. 1990 Nov;8(11):1797-805. link to original article PubMed
4. Gill PG, Gebski V, Snyder R, Burns I, Levi J, Byrne M, Coates A. Randomized comparison of the effects of tamoxifen, megestrol acetate, or tamoxifen plus megestrol acetate on treatment response and survival in patients with metastatic breast cancer. Ann Oncol. 1993 Nov;4(9):741-4. link to original article contains dosing details in abstract PubMed
5. Jonat W, Howell A, Blomqvist C, Eiermann W, Winblad G, Tyrrell C, Mauriac L, Roche H, Lundgren S, Hellmund R, Azab M. A randomised trial comparing two doses of the new selective aromatase inhibitor anastrozole (Arimidex) with megestrol acetate in postmenopausal patients with advanced breast cancer. Eur J Cancer. 1996 Mar;32A(3):404-12. link to original article contains dosing details in abstract PubMed
   1. Pooled update: Buzdar A, Jonat W, Howell A, Jones SE, Blomqvist C, Vogel CL, Eiermann W, Wolter JM, Azab M, Webster A, Plourde PV; Arimidex Study Group. Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. J Clin Oncol. 1996 Jul;14(7):2000-11. link to original article PubMed
   2. Pooled update: Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP, Vogel CL, Eiermann W, Wolter JM, Steinberg M, Webster A, Lee D; Arimidex Study Group. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Cancer. 1998 Sep 15;83(6):1142-52. Erratum in: Cancer 1999 Feb 15;85(4):1010. link to original article PubMed
6. Protocol 03: Buzdar AU, Smith R, Vogel C, Bonomi P, Keller AM, Favis G, Mulagha M, Cooper J. Fadrozole HCL (CGS-16949A) versus megestrol acetate treatment of postmenopausal patients with metastatic breast carcinoma: results of two randomized double blind controlled multiinstitutional trials. Cancer. 1996 Jun 15;77(12):2503-13. link to original article PubMed
7. Protocol 06: Buzdar AU, Smith R, Vogel C, Bonomi P, Keller AM, Favis G, Mulagha M, Cooper J. Fadrozole HCL (CGS-16949A) versus megestrol acetate treatment of postmenopausal patients with metastatic breast carcinoma: results of two randomized double blind controlled multiinstitutional trials. Cancer. 1996 Jun 15;77(12):2503-13. link to original article PubMed
8. Buzdar A, Jonat W, Howell A, Jones SE, Blomqvist C, Vogel CL, Eiermann W, Wolter JM, Azab M, Webster A, Plourde PV; Arimidex Study Group. Anastrozole, a potent and selective aromatase inhibitor, versus megestrol acetate in postmenopausal women with advanced breast cancer: results of overview analysis of two phase III trials. J Clin Oncol. 1996 Jul;14(7):2000-11. link to original article PubMed
   1. Update: Buzdar AU, Jones SE, Vogel CL, Wolter J, Plourde P, Webster A; Arimidex Study Group. A phase III trial comparing anastrozole (1 and 10 milligrams), a potent and selective aromatase inhibitor, with megestrol acetate in postmenopausal women with advanced breast carcinoma. Cancer. 1997 Feb 15;79(4):730-9. link to original article contains dosing details in abstract PubMed
   2. Pooled update: Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP, Vogel CL, Eiermann W, Wolter JM, Steinberg M, Webster A, Lee D; Arimidex Study Group. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Cancer. 1998 Sep 15;83(6):1142-52. Erratum in: Cancer 1999 Feb 15;85(4):1010. link to original article PubMed
9. Stuart NS, Warwick J, Blackledge GR, Spooner D, Keen C, Taylor AR, Tyrell C, Webster DJ, Earl H. A randomised phase III cross-over study of tamoxifen versus megestrol acetate in advanced and recurrent breast cancer. Eur J Cancer. 1996 Oct;32A(11):1888-92. link to original article contains dosing details in manuscript PubMed
10. SAKK 20/90: Thürlimann B, Castiglione M, Hsu-Schmitz SF, Cavalli F, Bonnefoi H, Fey MF, Morant R, Löhnert T, Goldhirsch A; Swiss Group for Clinical Cancer Research. Formestane versus megestrol acetate in postmenopausal breast cancer patients after failure of tamoxifen: a phase III prospective randomised cross over trial of second-line hormonal treatment (SAKK 20/90). Eur J Cancer. 1997 Jun;33(7):1017-24. link to original article PubMed
11. SWOG S8312: Russell CA, Green SJ, O'Sullivan J, Hynes HE, Budd GT, Congdon JE, Martino S, Osborne CK. Megestrol acetate and aminoglutethimide/hydrocortisone in sequence or in combination as second-line endocrine therapy of estrogen receptor-positive metastatic breast cancer: a Southwest Oncology Group phase III trial. J Clin Oncol. 1997 Jul;15(7):2494-501. link to original article PubMed
12. AR/BC2: Dombernowsky P, Smith I, Falkson G, Leonard R, Panasci L, Bellmunt J, Bezwoda W, Gardin G, Gudgeon A, Morgan M, Fornasiero A, Hoffmann W, Michel J, Hatschek T, Tjabbes T, Chaudri HA, Hornberger U, Trunet PF. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol. 1998 Feb;16(2):453-61. link to original article contains dosing details in abstract PubMed
13. Goss PE, Winer EP, Tannock IF, Schwartz LH; North American Vorozole Study Group. Randomized phase III trial comparing the new potent and selective third-generation aromatase inhibitor vorozole with megestrol acetate in postmenopausal advanced breast cancer patients. J Clin Oncol. 1999 Jan;17(1):52-63. link to original article PubMed
14. CALGB 8741: Abrams J, Aisner J, Cirrincione C, Berry DA, Muss HB, Cooper MR, Henderson IC, Panasci L, Kirshner J, Ellerton J, Norton L. Dose-response trial of megestrol acetate in advanced breast cancer: Cancer and Leukemia Group B phase III study 8741. J Clin Oncol. 1999 Jan;17(1):64-73. link to original article contains dosing details in abstract PubMed
15. Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N, Dugardyn JL, Nasurdi C, Mennel RG, Cervek J, Fowst C, Polli A, di Salle E, Arkhipov A, Piscitelli G, Miller LL, Massimini G; Exemestane Study Group. Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. J Clin Oncol. 2000 Apr;18(7):1399-411. link to original article contains dosing details in abstract PubMed
16. Buzdar A, Douma J, Davidson N, Elledge R, Morgan M, Smith R, Porter L, Nabholtz J, Xiang X, Brady C. Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol. 2001 Jul 15;19(14):3357-66. link to original article contains dosing details in abstract PubMed

Melphalan monotherapy

P: Phenylalanine mustard (Melphalan)

Regimen

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

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

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.

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 portion 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

Mitoxantrone & Vinorelbine (MV)

MV: Mitoxantrone & Vinorelbine

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Namer et al. 2001	NR in abstract	Phase 3 (E-switch-ic)	1a. FAC 1b. FEC	Equivalent ORR

Chemotherapy

• Mitoxantrone (Novantrone)
• Vinorelbine (Navelbine)

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 PubMed

STAMP-I

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Peters et al. 1988	NR	Non-randomized
Vredenburgh et al. 2006	1992-1997	Phase 3 (E-esc)	Observation	Superior EFS

Preceding treatment

• 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

Stem cells re-infused on days -1, 0, +1

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 PubMed
2. 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 PubMed

TAD (Tamoxifen)

TAD: Tamoxifen, Aminoglutethimide, Danazol

Regimen

Study	Dates of enrollment	Evidence	Comparator	Comparative Efficacy
Powles et al. 1984	1979-1983	Phase 3 (E-esc)	Tamoxifen	Seems to have superior ORR

Note: this patient population was not selected by hormone receptor status.

Endocrine therapy

• Tamoxifen (Nolvadex)
• Aminoglutethimide (Cytadren)
• Danazol (Danocrine)

References

1. Powles TJ, Ashley S, Ford HT, Gazet JC, Nash AG, Neville AM, Coombes RC. Treatment of disseminated breast cancer with tamoxifen, aminoglutethimide, hydrocortisone, and danazol, used in combination or sequentially. Lancet. 1984 Jun 23;1(8391):1369-73. link to original article 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

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)
• Doxorubicin (Adriamycin)

Endocrine therapy

• Prednisolone (Millipred)

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 PubMed