Breast cancer, ER-positive - historical

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The purpose of this page is to provide references to regimens that are obsolete, outdated, or of historical interest only.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 ER+ breast cancer page for current regimens.

15 regimens on this page
21 variants on this page


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

Chemotherapy

Endocrine therapy

28-day cycle for 26 cycles (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

Chemotherapy

Endocrine therapy

21-day cycle for 87 cycles (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

Bilateral oophorectomy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ahmann et al. 1977 NR Randomized (C) CFP & Oophorectomy Seems to have inferior PFS
Taylor et al. 1998 (SWOG S8692) 1987-08-01 to 1995-07-15 Randomized (C) Goserelin Inconclusive whether equivalent FFS/OS (co-primary endpoints)
Love et al. 2016 (OSU-0476) 2004-2011 Phase 3 (C) Mid-luteal phase oophorectomy Did not meet primary endpoint of OS

Preceding treatment

Endocrine therapy

Subsequent treatment

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. SWOG S8692: Taylor CW, Green S, Dalton WS, Martino S, Rector D, Ingle JN, Robert NJ, Budd GT, Paradelo JC, Natale RB, Bearden JD, Mailliard JA, Osborne CK. Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an intergroup study. J Clin Oncol. 1998 Mar;16(3):994-9. link to original article PubMed
  3. 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

CFP & Bilateral oophorectomy

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

Regimen

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

Preceding treatment

Chemotherapy

Endocrine therapy

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

CMFT

CMFT: Cyclophosphamide, Methotrexate, Fluorouracil, Tamoxifen

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Pritchard et al. 1996 (NCIC-CTG MA.4) 1984-1990 Phase 3 (C) Tamoxifen Did not meet endpoint of OS

Preceding treatment

Chemotherapy

Endocrine therapy

21-day cycle for 35 cycles (2 years)

References

  1. NCIC-CTG MA.4: Pritchard KI, Paterson AH, Paul NA, Zee B, Fine S, Pater J; National Cancer Institute of Canada Clinical Trials Group. Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. J Clin Oncol. 1996 Oct;14(10):2731-7. link to original article contains dosing details in manuscript PubMed
    1. Update: Pritchard KI, Paterson AH, Fine S, Paul NA, Zee B, Shepherd LE, Abu-Zahra H, Ragaz J, Knowling M, Levine MN, Verma S, Perrault D, Walde PL, Bramwell VH, Poljicak M, Boyd N, Warr D, Norris BD, Bowman D, Armitage GR, Weizel H, Buckman RA; NCIC-CTG. Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 1997 Jun;15(6):2302-11. link to original article PubMed

PFT

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

Regimen variant #1, 2 years of tamoxifen

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

Preceding treatment

Chemotherapy

Endocrine therapy

42-day cycle for 17 cycles (2 years)


Regimen variant #2, 5 years of tamoxifen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
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

Chemotherapy

Endocrine therapy

42-day cycle for 43 cycles (5 years)

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 contains dosing details in manuscript 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 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

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

Endocrine therapy

28-day cycle for 13 cycles (12 months)

References

  1. LBCS III: Goldhirsch A; Ludwig Breast Cancer Study Group. Randomised trial of chemo-endocrine therapy, endocrine therapy, and mastectomy alone in postmenopausal patients with operable breast cancer and axillary node metastasis. Lancet. 1984 Jun 9;1(8389):1256-60. link to original article contains dosing details in manuscript PubMed
  2. LBCS IV: Goldhirsch A; Ludwig Breast Cancer Study Group. Randomised trial of chemo-endocrine therapy, endocrine therapy, and mastectomy alone in postmenopausal patients with operable breast cancer and axillary node metastasis. Lancet. 1984 Jun 9;1(8389):1256-60. link to original article contains dosing details in manuscript 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 (E-de-esc) 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 co-primary endpoints of DOR/TTF/OS
Gershanovich et al. 1998 (AR/BC3) NR Randomized (C) 1. Letrozole; 0.5 mg/day Did not meet primary endpoint of ORR
2. Letrozole; 2.5 mg/day Might have inferior ORR

Endocrine therapy

Supportive therapy

Continued indefinitely

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. contains dosing details in abstract 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
  9. AR/BC3: Gershanovich M, Chaudri HA, Campos D, Lurie H, Bonaventura A, Jeffrey M, Buzzi F, Bodrogi I, Ludwig H, Reichardt P, O'Higgins N, Romieu G, Friederich P, Lassus M; Letrozole International Trial Group. Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Ann Oncol. 1998 Jun;9(6):639-45. link to original article contains dosing details in manuscript PubMed

Bilateral oophorectomy

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ingle et al. 1986a 1978-1984 Phase 3 (C) Tamoxifen Did not meet endpoints
Buchanan et al. 1986 1979-1983 Phase 3 (C) Tamoxifen Might have inferior PFS
Crump et al. 1997 NR Randomized (C) Tamoxifen Did not meet pooled endpoint of ORR

Note: while Crump et al. 1997 is a meta-analysis, it is also the primary report for a randomized trial used to support registration of this drug.

Endocrine therapy

References

  1. Ingle JN, Krook JE, Green SJ, Kubista TP, Everson LK, Ahmann DL, Chang MN, Bisel HF, Windschitl HE, Twito DI, Pfeifle DM. Randomized trial of bilateral oophorectomy versus tamoxifen in premenopausal women with metastatic breast cancer. J Clin Oncol. 1986 Feb;4(2):178-85. link to original article contains dosing details in abstract PubMed
  2. Buchanan RB, Blamey RW, Durrant KR, Howell A, Paterson AG, Preece PE, Smith DC, Williams CJ, Wilson RG. A randomized comparison of tamoxifen with surgical oophorectomy in premenopausal patients with advanced breast cancer. J Clin Oncol. 1986 Sep;4(9):1326-30. link to original article contains dosing details in manuscript PubMed
  3. Crump M, Sawka CA, DeBoer G, Buchanan RB, Ingle JN, Forbes J, Meakin JW, Shelley W, Pritchard KI. An individual patient-based meta-analysis of tamoxifen versus ovarian ablation as first line endocrine therapy for premenopausal women with metastatic breast cancer. Breast Cancer Res Treat. 1997 Jul;44(3):201-10. 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

Endocrine therapy

28-day cycle for 3 cycles

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 manuscript 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

Continued indefinitely

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 contains dosing details in manuscript 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

Estradiol monotherapy

Regimen variant #1, 6 mg/day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ellis et al. 2009 (WU 04-0412) 2004-2008 Randomized Phase 2 (E-de-esc) Estradiol; 30 mg/day Did not meet primary endpoint of CBR

Endocrine therapy

Continued indefinitely


Regimen variant #2, 30 mg/day

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ellis et al. 2009 (WU 04-0412) 2004-2008 Randomized Phase 2 (C) Estradiol; 6 mg/day Did not meet primary endpoint of CBR

Endocrine therapy

Continued indefinitely

References

  1. WU 04-0412: 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 variant #1, 20 mg/day

Study Evidence
Kennedy 1958 Non-randomized

Endocrine therapy

Continued indefinitely


Regimen variant #2, 40 mg/day

Study Evidence
Kennedy 1958 Non-randomized

Endocrine therapy

Continued indefinitely

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 contains dosing details in manuscript PubMed

Fluoxymesterone & Tamoxifen

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Ingle et al. 1988 1981-1985 Phase 3 (E-esc) Tamoxifen Seems to have superior TTP1

1Reported efficacy is based on the 1991 update.

Endocrine therapy

Continued indefinitely

References

  1. Ingle JN, Twito DI, Schaid DJ, Cullinan SA, Krook JE, Mailliard JA, Marschke RF, Long HJ, Gerstner JG, Windschitl HE, Everson LK, Pfeifle DM. Randomized clinical trial of tamoxifen alone or combined with fluoxymesterone in postmenopausal women with metastatic breast cancer. J Clin Oncol. 1988 May;6(5):825-31. link to original article contains dosing details in abstract PubMed
    1. Update: Ingle JN, Twito DI, Schaid DJ, Cullinan SA, Krook JE, Mailliard JA, Tschetter LK, Long HJ, Gerstner JG, Windschitl HE, Levitt R, Pfeifle DM. Combination hormonal therapy with tamoxifen plus fluoxymesterone versus tamoxifen alone in postmenopausal women with metastatic breast cancer: an updated analysis. Cancer. 1991 Feb 15;67(4):886-91. 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

14-day cycles

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 contains dosing details in manuscript PubMed

Medroxyprogesterone acetate 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

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

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

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

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 1993-03 to 1994-09 Phase 3 (C) 1. Anastrozole; 1 mg/day Seems to have inferior OS1
2. Anastrozole; 10 mg/day Did not meet endpoint of OS
Dombernowsky et al. 1998 (AR/BC2) 1993-03 to 1994-09 Randomized (C) 1. Letrozole; 0.5 mg/day Not reported
2. Letrozole; 2.5 mg/day Seems to have inferior OS
Kaufmann et al. 2000 1995-1998 Phase 3 (C) Exemestane Did not meet primary endpoint of ORR

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

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

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

Supportive therapy

Continued indefinitely

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 contains dosing details in manuscript PubMed

Metastatic disease, subsequent lines of therapy

Fluoxymesterone & Tamoxifen

Regimen

Study Dates of enrollment Evidence Comparator Comparative Efficacy
Tormey et al. 1983 NR Randomized (E-esc) Tamoxifen Superior TTTF

Endocrine therapy

Continued indefinitely

References

  1. Tormey DC, Lippman ME, Edwards BK, Cassidy JG. Evaluation of tamoxifen doses with and without fluoxymesterone in advanced breast cancer. Ann Intern Med. 1983 Feb;98(2):139-44. link to original article contains dosing details in abstract PubMed
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