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. 2025 Mar 17:1–22. Online ahead of print. doi: 10.1159/000545264

Table 3.

Intervention and outcomes in the included studies

Study ID Prior therapies in the advanced setting Agent/dose Dose modifications Treatment duration/follow-up Outcomes
Buzdar et al. [25] (2002) None I1: 40 mg/day droloxifene + placebo tamoxifen NI Mean treatment duration ORR
I2: 20 mg/day tamoxifen + placebo droloxifene I1: 196 (8–920) days I1: 27.1%
I2: 218 (6–969) days I2: 31.7%
p = 0.14
Campos et al. [26] (2009) Chemotherapy and hormonal therapy I1: exemestane 25 mg/day I2: anastrozole 1 mg/day NI I1: 17 weeks ORR (95% CI)
I1: 10.9 (4.5–21.3) %
I2: 15.6 (7.8–26.9) %
Median TTP
I1: 3.7 (0.7–34.3) months
I2: 18.5 weeks I2: 4.2 (0.9–0.2) months
Median OS
I1: 30.5 (1.1–41.3)
I2: 33.3 (2.6–44.7)
Gershanovich [27] (1997) ≤14 days tamoxifen I1: 1 toremifene 60 mg tablet daily No dose modifications were allowed Minimum treatment duration was 2 months ORR
I1: 20.4%
I2: 28.7%
I3: 20.8%
Median TTP
I1: 4.9 (3.8–7.3) months
I2: 6.1 (4.5–8.0) months
I3: 5.0 (3.7–6.2) months
I2: 2 toremifene 60 mg tablets twice a day Median follow-up 20.5 months I3:I1-HR, 1.015 (0.79–1.31), p = 0.905
I3:I2-HR, 1.124 (0.87–1.46), p = 0.374
Median OS
I1: 25.4 (20.8–31.0) months
I3: tamoxifen 40 mg tablet daily I2: 23.8 (20.9–29.7) months
I3: 23.4 (18.4–34.2) months
I3:I1-HR, 0.96 (0.72–1.28), p = 0.802
I3:I2-HR, 1.02 (0.76–1.36), p = 0.854
Maung and O’Shaughnessy, [28] (2001) 1 prior chemotherapy I1: oral exemestane 25 mg/day – – ORR
I2: tamoxifen 20 mg/day I1: 40.9%
I2: 13.6%
Osborne [29] (2002) 1 prior endocrine therapy except for fulvestrant and AIs I1: fulvestrant 250 mg every 28 days + matching placebo – Median follow-up of 16.8 months Median TTP (95.14% CI)
I1: 5.4 months
I2: 3.4 months
HR, 0.92 (0.74–1.14)
p = 0.43
I2: oral anastrozole 1 mg once daily + matching placebo ORR (95.14% CI)
I1: 17.5%
I2: 17.5%
OR, 1.01 (0.59–1.73)
p = 0.96
Robertson [30] (2016) 1 prior chemotherapy I1: IM fulvestrant No fulvestrant dose reductions were permitted Median Rx duration Median PFS
I1: 16.6 (3.83–20.99) months
500 mg on days 0, 14, 28, and every 28 days I2: 13.8 (11.99–16.59) months
Thereafter + anastrozole placebo HR, 0.80 (0.64–1.00)
I2: oral anastrozole 1 mg I1: 14.7 (0.9–37.7) months ORR
I1: 46%
500 mg on days 0, 14, 28, and every 28 days I1: 14.7 (0.9–37.7) months I2: 45%
Thereafter + anastrozole placebo OR 1.07 (0.72–1.61), p = 0.7290
Pritchard et al. [31] (2010) Endocrine therapy I1: fulvestrant 250 mg (AD) – – Median TTP
I1: 3.1 months
I2: fulvestrant 250 mg (LD) I2: 6.1 months
I3: 6.0 months
I3: fulvestrant 250 mg (HD) ORR
I1: 8.5 (2.4–20.4) %
I2: 5.9 (1.2–16.2) %
I3: 15.2 (6.3–28.9) %
Robertson et al. [32] (2012) None I1: IM fulvestrant 500 mg (500 mg/month plus 500 mg on day 14 of month 1) – Median follow-up for TTP I1: 18.8 months Median TTP
I1: 23.4 months
I2: anastrozole 1 mg/day orally I2: 12.9 months I2: 13.1 months
HR, 0.64 (0.46–0.90), p = 0.01
Bonneterre et al. [33] (2000) None I1: anastrozole 1 mg once daily + tamoxifen placebo None Median follow-up: 19 months ORR
I1: 32.9%
I2: 32.6%
I2: tamoxifen: 20 mg once daily + anastrozole placebo p = 0.787
Median TTP (95% CI)
I1: 8.2 months
I2: 8.3 months
HR, 0.99 (0.86-N/R)
p = 0.941
Thurlimann et al. [34] (2004) None Anastrozole: 1 mg once daily + tamoxifen placebo None Median follow-up Median TTP
Tamoxifen: 20 mg once daily + anastrozole placebo 66.3 (3.9–81.6) months I1: 11.3 (3.2–16.8) months
I2: 8.3 (4.6–16.6) months
Rose et al. [35] (2003) Endocrine and 1 prior chemotherapy I1: letrozole 2.5 mg – Median duration of treatment Median TTP
I1: 5.7 (5.1–6.0) months
I2: 5.7 (4.6–6.1) months
I1: 5.9 months p = 0.92
ORR (90% CI)
I1: 19.1 (15.7–22.9) %
I2: anastrozole 1 mg I2: 5.6 months I2: 12.3 (9.6–15.6) %
OR, 1.70, p = 0.013
Median OS
I1: 22.0 (19.6–24.6)
I2: 20.3 (18.0–23.1)
HR, 0.95, p = 0.624
Xu [36] (2011) Endocrine I1: IM fulvestrant 250 mg every 4 weeks with matching daily anastrozole placebo – Mean duration of treatment Median TTP
I1: 110 days
I2: 159 days
HR, 1.314 (0.948–1.822)
p = 0.101
I2: anastrozole 1 mg daily I2: 174.3 days ORR
I1: 10%
with matching placebo to fulvestrant monthly I2: 14%
OR, 0.631 (0.244–1.635)
p = 0.343
Bajetta [37] (1994) Endocrinee and chemotherapy I1: IM formestane 250 mg every 2 weeks – – Median TTP
I1: 8 (8–46) months
I2: 9 (2–35) months
Median OS
I1: 30 (1–46) months
I2: IM formestane 500 mg every 2 weeks I2: 22 (2–47) months
ORR
I1: 28%
I2: 46%
p = 0.026
Zilembo et al. [38] (1995) None I1: IM formestane 250 mg every 2 weeks – Median treatment duration ORR
I2: IM formestane 500 mg every 2 weeks I1: 7 months I1: 33 (14–53) %
I2: 9 months I2: 46 (28–64) %
Chia et al. [39] (2008) None I1: IM fulvestrant 500 mg loading dose on day 0, 250 mg on day 14 and 28 then 250 mg every 28 days + matching placebo None Median follow-up: 13 months ORR (95% CI)
I1: 7.4%
I2: 6.7%
I2: exemestane 25 mg once daily + matching placebo OR, 1.12 (0.578–2.186)
p = 0.736
Median TTP (95% CI)
I1: 3.7 months
I2: 3.7 months
HR, 0.96 (0.819–1.133) p = 0.65
Di Leo et al. [40] (2010) None I1: IM fulvestrant 500 mg on days 0, 14, and 28 then every 28 days (±3 days) thereafter None Median duration Median PFS (95% CI)
I1: 6.5 months
I2: 5.5 months
I2: IM fulvestrant 250 mg + one placebo injection on days 0 and 14 then every 28 days I1: 174 days (10–1,441) HR, 0.80 (0.68–0.94) p = 0.006
ORR (95% CI)
I1: 9.1%
I1: 145 days (7–1,387) I2: 10.2%
OR, 0.94 (0.57–1.55)
p = 0.795
Di Leo et al. [41] (2014) None I1: IM fulvestrant 500 mg on days 0, 14, and 28 then every 28 days (±3 days) thereafter None Median duration Median OS (95% CI)
I1: 174 days (10–1,441) I1: 26.4 months
I2: IM fulvestrant 250 mg + one placebo injection on days 0 and 14 then every 28 days I1: 145 days (7–1,387) I2: 22.3 months
HR = 0.81 (0.69–0.96)
p = 0.02
Goss et al. [42] (2007) None I1: atamestane 5 100 mg tabs (3 before or after breakfast, 2 before or after dinner) daily + toremifene one 60 mg tab in the morning daily None – ORR (95% CI)
I1: 30 (26–35) %
I2: 36 (31–40) %
OR, 1.27 (0.95–1.69)
p = 0.10
I2: letrozole 2.5 mg tab in the morning + 5 placebo tabs daily (3 before or after breakfast, 2 before, or after dinner) OS (95% CI)
I1: 3.01 years
I2: 2.79 years
HR, 0.99 (0.92–1.06)
p = 0.70
Howell et al. [43] (2004) None I1: fulvestrant 250 mg once monthly (i.e., every 28±3 days) + placebo 20 mg daily None Median Rx. duration ORR
I1: 8.3 (0.9–26.5) months I1: 31.6%
I2: 9.3 (0.9–25.1) months I2: 33.9%
I2: tamoxifen 20 mg daily orally + placebo to match fulvestrant Median follow-up: 31.1 months Median OS (95% CI)
I1: 36.9 months
I2: 38.7 months
HR, 1.29 (1.01–1.64), p = 0.04
Krop et al. [44] (2020) (Cohort 1) None I1: enzalutamide 160 mg daily + exemestane 50 mg daily None I1: 40.9 weeks ORR (95% CI)
I: 31% (17–48)
Control group: 19% (9–34)
p = 0.2216
I2: exemestane 25 mg + placebo daily Control group: 25.7 weeks Median PFS (95% CI)
I: 11.8 months (7.3–15.9)
Control group: 5.8 months (3.5–10.9)
HR, 0.82 (0.5–1.26) p = 0.3631
Krop et al. [44] (2020) (Cohort 2) One endocrine therapy and one chemotherapy I1: enzalutamide 160 mg daily + exemestane 50 mg daily None Median Rx. duration ORR (95% CI)
I: 10% (3–23)
Control group: 5% (1–16)
p = 0.3968
I2: exemestane 25 mg + placebo daily I: 10.2 weeks Median PFS (95% CI)
I: 3.6 months (1.9–5.5)
I: 10.2 weeks Control group: 3.9 months (2.6–5.4)
HR, 1.02 (0.66–1.59) p = 0.9212
Lipton et al. [45] (2008) One chemotherapy and endocrine therapy I1: letrozole 2.5 mg once daily None Median duration of study ORR (95% CI)
I1: 30% (26–35)
I2: tamoxifen 20 mg once daily 18 months I2: 20% (17–24)
OR, 1.71 (1.26–2.31) p = 0.0006
Llombart-Cussac et al. [62] (2012) Single line of chemotherapy (4 weeks before randomization) I1: exemestane 25 mg daily orally None Median follow-up of 9.1 months (0.07–79.96) ORR (95% CI)
I1: 36.2% (18.5–45.9)
I2: 46% (32.2–59.8)
I2: anastrozole 1 mg daily orally Median OS (95% CI)
I1: 19.9 months (15.32–24.46)
I2: 48.3 months (18.3–78.3)
HR, 1.33 (0.78–2.25), p = 0.296
Mauriac et al. [46] (2009) None I1: IM fulvestrant 500 mg on day 0, 250 mg on days 14 and 28 then 250 mg every 28±3 days thereafter None – ORR (95% CI)
I1: 15.1%
I2: exemestane 25 mg once daily orally I2: 16%
OR, 1.28 (0.47–3.09) p = 0.33
Mehta et al. [47] (2019) None I: fulvestrant 500 mg on day 1, 250 mg on days 14 and 28 then 250 mg every 28 days thereafter + anastrozole standard dose None Median follow-up of 7 years Median OS (95% CI)
I: 49.8 months
Control group: 42 months
Control group: anastrozole: standard dose HR, 0.82 (0.69–0.98)
p = 0.03
Median PFS (95% CI)
I: 15 months
Control group: 13.5 months
HR, 0.81 (0.69–0.94) p = 0.007
Mourisden et al. [48] (2001) One chemotherapy and endocrine therapy I1: letrozole 2.5 mg once daily None Median duration of study ORR (95% CI)
I1: 30% (26–35)
I2: 20% (17–24)
I2: tamoxifen 20 mg once daily 18 months OR, 1.71 (1.26–2.31) p = 0.0006
Median TTP
I1: 9.4 months
I2: 6.0 months
HR, 0.70 (0.60–0.82) p = 0.0001
Nabholtz et al. [49] (2000) None I1: anastrozole 1 mg once daily None Median follow-up of 17.7 months ORR
I2: tamoxifen 20 mg once daily I1: 21.1%
I2: 17%
Robertson et al. [50] (2009) None I1: fulvestrant 500 mg on days 0, 14±3, 28±3 then every 28±3 days None I1: 9.2 months (1–20.5) ORR (95% CI)
I2: 6.1 months (0–19.8) I1: 36%
I2: anastrozole 1 mg once daily Median follow-up: 8 months and 5.9 months I2: 35.5%
OR, 1.02 (0.56–1.87) p = 0.947
Arpino et al. [51] (2003) None I1: idoxifene one 20 mg + one 40 mg tablet daily/first 21 days (loading dose) then one 40 mg tab daily None – ORR
I1: 13%
I2: 9%
p = 0.39
I2: tamoxifen one 20 mg + one placebo daily for first 21 days then one 20 mg daily throughout Median TTP
I1: 166 days (140–230)
I2: 140 days (110–185)
p = 0.32
Gershanovich et al. [52] (1998) None I1: letrozole 2.5 mg once a day None Median treatment duration of about 5 months ORR (95% CI)
I1: 19.5% (13.8–25.2)
I2: 16.7% (11.4–21.9)
I3: 12.4% (7.5–17.2)
Median TTP (95% CI)
I1: 3.4 months
I2: 3.3 months
I3: 3.2 months
I2: letrozole 0.5 mg once a day Median follow-up duration: 20 months RR, 0.76 (0.57–0.9) p = 0.008
Median OS (95% CI)
I1: 28 months
I3: aminoglutethimide 250 mg twice daily + corticosteroid support I2: 21 months
I3: 20 months
RR, 0.69 (0.56–0.92) p = 0.021
Ellis et al. [53] (2015) None I1: fulvestrant 500 mg on days 0, 14, and 28 then every 28 days subsequently None Follow-up of about 6 months Median OS (95% CI)
I1: 54.1 months
I2: anastrozole: 1 mg daily I2: 48.4 months
H, 0.70 (0.50–0.98) p = 0.04
Ingle et al. [54] (1997) Chemotherapy I1: letrozole 0.5 mg per day None Minimum follow-up of 6 months ORR (95% CI)
I2: letrozole 2.5 mg per day I1: 20% (11–34)
I2: 22% (13–36)
Mourisden [55] (2007) Chemotherapy I1: letrozole 2.5 mg once daily orally None Median follow-up was 32 months Median OS
I1: 34 months
I2: tamoxifen 20 mg once daily orally I2: 30 months
p = 0.53
Ohno et al. [56] (2010) Endocrine therapy I1: fulvestrant (approved dose): 250 mg days 0 and 28 then every 28 days thereafter + 2 placebo injections on day 14 None Median duration of treatment ORR (95% CI)
I1: 197 days I1: 11.1% (3.7–24.1)
I2: fulvestrant (loading dose): 500 mg at day 0, 250 mg at days 14 and 28 then every 28 days thereafter I2: 225 days I2: 17.6% (8.4–30.9)
I3: 213 days I3: 10.6% (3.5–23.1)
Followed up for at least 24 weeks Median TTP
I3: fulvestrant (high dose): 500 mg on days 0, 14, and 28 then every 28 days thereafter I1: 6.0 months
I2: 7.5 months
I3: 6.0 months
Paridaens et al. [57] (2008) Radiotherapy and chemotherapy I1: exemestane 25 mg once daily orally None I1: 11.5 months (10.18–13.54) ORR (95% CI)
I1: 46%
I2: 6.57 months (5.78–10.91) I2: 31%
OR, 1.85 (1.21–2.82) p = 0.005
Median follow-up Median PFS (95% CI)
I2: tamoxifen 20 mg once daily orally I1: 9.9 months (8.7–11.8)
29 months (20–53) I2: 5.8 months (5.3–8.1)
Median OS (95% CI)
I1: 37.2 months (29.2–45.5)
I2: 43.3 months (32.8–51.6)
Thurlimann et al. [58] (1996) None I1: tamoxifen 20 mg/day p.o. None Minimum of 2 months treatment duration ORR (95% CI)
I1: 27% (21–35)
I2: 20% (13–29)
I2: fadrozole 1 mg p.o twice a day Follow-up of 3 years OR, 0.56 (0.28–1.11) p = 0.26
Wang et al. [59] (2023) None I1: IM fulvestrant 500 mg on days 0, 14, and 28 then every 28 thereafter ±3 days None 156 weeks treatment duration Median PFS (95% CI)
I1: 8.5 months
I2: 5.6 months
I2: exemestane: 25 mg/day orally HR, 0.62 (0.42–0.91)
p = 0.0014
ORR (95% CI)
I1: 19.5% (10.63–28.33)
I2: 6% (0.3–11.64) p = 0.017
Yamamoto et al. [60] (2013) Non-steroidal AI I1: toremifene 120 mg daily None Median follow-up period ORR (95% CI)
I1: 11.6% (5.1–24.5)
I2: 2.2% (1.2–16.7)
p = 0.069
I1: 69 weeks (13–144) Median PFS (95% CI)
I1: 7.3 months
I2: exemestane 25 mg daily I1: 69 weeks (13–144) I2: 3.7 months
HR, 0.61 (0.38–0.99) p = 0.045
I1: 69 weeks (13–144) Median OS (95% CI)
I1: 32.3 months
I2: 21.9 months
HR, 0.60 (0.26–1.39) p = 0.22
Zhang et al. [61] (2016) Endocrine therapy I1: IM fulvestrant 500 mg (two 5 mL) on days 0, 14, and 28 then every 28 days thereafter None Treatment exposure Median PFS (95% CI)
I1: 8.0 months (5.5–10.9)
I1: 6.5 months I2: 4.0 months (2.9–5.7)
I2: IM fulvestrant 250 mg (one 5 mL + one placebo injection) on days 1 and 28 then every 28 days thereafter + 2 placebo injection on day 14 HR, 0.75 (0.54–1.03) p = 0.078
I2: 3.8 months ORR
I1: 14.4%
I2: 9.1%

I1, intervention 1; I2, intervention 2; OR, odds ratio; HR, hazard ratio; NI, no information; IM, intramuscular.